bluuebunny/crossref_metadata_2025 huggingface dataset:
Social determinants of HIV infection, hotspot areas and subpopulation groups in Ethiopia: evidence from the National Demographic and Health Survey in 2011
Authors: Lakew Yihunie , Benedict Susan , Haile Demewoz
Published: November 2015

Objective

This study identifies social determinants of HIV infection, hotspot areas and subpopulation groups in Ethiopia.

Design

The study used data from the 2011 Ethiopian Demographic and Health Survey (EDHS). Sample blood tests from the finger pricks collected on filter paper cards were labelled with a barcode unique to each respondent. Spatial scan statistics and geographic information system tools were used to map hotspot areas of HIV prevalence. Bivariate and multivariable logistic regression models were used to identify social determinants of HIV infection.

Population

A total of 30 625 adults (16 515 women and 14 110 men) were included from 11 administrative states of Ethiopia.

Main outcome measures

Laboratory-confirmed HIV serostatus is the main outcome variable.

Results

HIV prevalence reached 10–21% in the central, eastern and western geographic clusters of Ethiopia. Multivariable analysis showed that individuals who were in the middle, richer and richest wealth quintiles had increased odds of having HIV over those in the poorest quintile. Adults who had primary, secondary and higher educational levels had higher odds of being HIV positive than non-educated individuals. The odds of having HIV were higher among adults who had multiple lifetime sexual partners than those with a single partner. An increasing odds of HIV infection were observed among adults in the age groups of 25–29, 30–34, 35–39 and 40–45 years compared with adults in the age group of 45–49 years. Merchants had higher odds of being HIV positive than those who were not employed. The odds of having HIV were higher among urban residents and females than among rural residents and males, respectively.

Conclusions

This study found statistically significant HIV concentrations in administrative zones of central, eastern and western Ethiopia. Geospatial monitoring and targeting of prevention strategies for specific population groups is recommended.
Cross-sectional study of depression and help-seeking in Uttarakhand, North India
Authors: Mathias Kaaren , Goicolea Isabel , Kermode Michelle , Singh Lawrence , Shidhaye Rahul , Sebastian Miguel San
Published: November 2015

Objectives

This study sought to use a population-based cross-sectional survey to describe depression prevalence, healthcare seeking and associations with socioeconomic determinants in a district in North India.

Setting

This study was conducted in Sahaspur and Raipur, administrative blocks of Dehradun district, Uttarakhand, in July 2014.

Participants

A population-based sample of 960 people over the age of 18 years was selected in 30 randomised clusters after being stratified by rural:urban census ratios.

Primary outcome measures

The survey used a validated screening tool, Patient Health Questionnaire, to identify people with depression, and collected information regarding socioeconomic variables and help-seeking behaviours. Depression prevalence and health seeking behaviours were calculated, and multivariable logistic regression was used to assess associations between risk factors and depression.

Results

Prevalence of depression was 6% (58/960), with a further 3.9% (37/960) describing a depressive episode of over 2 weeks in the past 12 months. Statistically significant adjusted OR for depression of more than 2 were found for people who were illiterate, classified as Scheduled Caste/Tribe or Other Backward Castes, living in temporary material housing and who had recently taken a loan. While over three quarters of people with depression (79%) had attended a private or government general medical practitioner in the past 3 months, none had received talking therapy (100% treatment gap) and two people (3.3%) had been prescribed antidepressants.

Conclusions

There are clear associations between social, educational and economic disadvantage and depression in this population. Strategies that address the social determinants of depression, such as education, social exclusion, financial protection and affordable housing for all are indicated. To address the large treatment gap in Uttarakhand, we must ensure access to primary and secondary mental health providers who can recognise and appropriately manage depression.
An embedded checklist in the Anesthesia Information Management System improves pre-anaesthetic induction setup: a randomised controlled trial in a simulation setting
Authors: Wetmore Douglas , Goldberg Andrew , Gandhi Nishant , Spivack John , McCormick Patrick , DeMaria Samuel
Published: November 2015

Background

Anaesthesiologists work in a high stress, high consequence environment in which missed steps in preparation may lead to medical errors and potential patient harm. The pre-anaesthetic induction period has been identified as a time in which medical errors can occur. The Anesthesia Patient Safety Foundation has developed a Pre-Anesthetic Induction Patient Safety (PIPS) checklist. We conducted this study to test the effectiveness of this checklist, when embedded in our institutional Anesthesia Information Management System (AIMS), on resident performance in a simulated environment.

Methods

Using a randomised, controlled, observer-blinded design, we compared performance of anaesthesiology residents in a simulated operating room under production pressure using a checklist in completing a thorough pre-anaesthetic induction evaluation and setup with that of residents with no checklist. The checklist was embedded in the simulated operating room's electronic medical record.

Results

Data for 38 anaesthesiology residents shows a statistically significant difference in performance in pre-anaesthetic setup and evaluation as scored by blinded raters (maximum score 22 points), with the checklist group performing better by 7.8 points (p<0.01). The effects of gender and year of residency on total score were not significant. Simulation duration (time to anaesthetic agent administration) was increased significantly by the use of the checklist.

Conclusion

Required use of a pre-induction checklist improves anaesthesiology resident performance in a simulated environment. The PIPS checklist as an integrated part of a departmental AIMS warrant further investigation as a quality measure.
Improving the acute care of COPD patients across Gloucestershire: a quality improvement project.
Authors: Miller Craig , Cushley Claire , Redler Kasey , Mitchell Claire , Aynsley Day Elizabeth , Mansfield Helen , Nye Abigail
Published: November 2015

Admissions for exacerbations of chronic obstructive pulmonary disease (COPD) present a significant proportion of patients in the acute medical take. The British Thoracic Society (BTS) provides guidelines for time specific interventions, that should be delivered to those with an acute exacerbation of COPD through the admission care bundle. These include correct diagnosis, correct assessment of oxygenation, early administration of treatment, recognition of respiratory failure, and specialist review. Gloucestershire Hospitals NHS Foundation Trust (GHNHSFT) chose improvement in acute COPD care to be a local Commissioning for Quality and Innovation (CQUIN) scheme, which enables commissioners to reward excellence by linking a proportion of English healthcare providers’ income to the achievement of local quality improvement goals. The effects of initiatives put in place by senior clinicians had waned, and further improvements were required to meet the CQUIN target.

The aim of the scheme was to improve compliance with the BTS guidelines and CQUIN scheme for patients admitted with an exacerbation of COPD.

Specific bundle paperwork to be used for all patients admitted to the Trust with an exacerbation of COPD was introduced to the Trust in June 2014, with training and education of medical staff at that time. This had improved compliance rates from 10% to 63% by September 2014. Compliance with each intervention was audited through the examination of notes of patients admitted with an exacerbation of COPD. Compliance rates had plateaued over the last three months, and so a focus group involving junior medical staff met in September 2014 to try to increase awareness further, in order to drive greater improvements in care, and meet the CQUIN requirements. Their strategies were implemented, and then compliance with the CQUIN requirements was reaudited as described above.

The December 2014 audit results showed a further improvement in overall COPD care, with 73% of patients receiving all elements of the COPD admission care bundle, versus 63% in September 2014. Appropriate blood gas analysis, nebuliser administration, and respiratory review also improved. Prescription of steroids and antibiotics remained static, with 96% of patients receiving these treatments within four hours in the emergency department (ED). The only criteria which showed a decline was appropriate oxygen prescription, which dipped from 97% to 87%.

After the effect of initial strategies plateaued, this quality improvement project facilitated a further increase in compliance with the CQUIN targets, both improving patient care, and safeguarding continued CQUIN funding. There is further work to be done to maintain and support further improvement in standards, and to encourage use of the COPD admission bundle paperwork for documentation purposes.
Method for identification ofCryptococcus neoformansandCryptococcus gattiiuseful in resource-limited settings
Authors: Ogundeji Adepemi O , Albertyn Jacobus , Pohl Carolina H , Sebolai Olihile M
Published: November 2015

Aims

The high HIV/AIDS burden in Sub-Saharan Africa has led to cryptococcosis becoming a public health concern. In this resource-limited setting, conventional identification methods are mainly used to diagnose cryptococcal infections. However, these methods are often inconsistent, and importantly, cannot discriminate between the aetiological agents,Cryptococcus neoformansandC. gattii. Therefore, there is a need for an alternative reliable method to identify these species.

Methods

We examined the usefulness of a PCR method, including a restriction digest, in identifying clinicalC. neoformansandC. gattiiisolates. In addition, matrix-assisted laser desorption ionisation time-of-flight mass spectrometry (MALDI-ToF MS) was performed for validation purposes.

Results

The intraspecific variation between tested strains allowed for their delineation into three traditional varieties ofC. neoformans, that is, varietal forms:neoformans,grubiiandgattii. Furthermore, we uncovered a restriction site (signature sequence: 5′-AATATT-3′) that is present only in the distinct speciesC. neoformans(varietal formsneoformansandgrubii), and is, importantly, absent in the distinct speciesC. gattii(C. neoformansvar.gattii). Thus, we were able to discriminate the distinct species by directly digesting the PCR amplicons using the endonucleaseSspI. It was also possible to delineate some tested isolates as eitherC. neoformansorC. gattiiusing our MALDI-ToF MS data.

Conclusions

The possibility of performing only a restriction digest makes the outlined method, similar to conventional techniques, economical and easy to optimise for routine use in resource-limited settings.
Primary cutaneous T-cell lymphomas: a review
Authors: Sidiropoulos Konstantinos G , Martinez-Escala M Estela , Yelamos Oriol , Guitart Joan , Sidiropoulos Michael
Published: November 2015

Primary cutaneous T-cell lymphomas (CTCLs) represent a number of extranodal lymphomas arising from a malignant population of lymphocytes in the skin, with the most common type being mycosis fungoides (MF) representing half of all primary CTCLs. Despite advances in immunohistochemistry and molecular methodology, significant diagnostic challenges remain due to phenotypic overlap of primary CTCLs with several inflammatory dermatoses, secondary lymphomas, among other conditions. Clinical features such as presentation and morphology, staging, histology, immunophenotype and molecular features must be considered in detail before a diagnosis is made in order to minimise false-positive, false-negative and indeterminate diagnoses. Herein, we review primary CTCLs, including epidemiological data, a brief summary of clinical presentations, immunophenotype, molecular signatures and differential diagnoses.
Challenges in the diagnosis of cutaneous adnexal tumours
Authors: Danialan Richard , Mutyambizi Kudakwashe , Aung Phyu P , Prieto Victor G , Ivan Doina
Published: November 2015

The diagnosis of cutaneous adnexal neoplasms, a heterogeneous group of entities, is often perceived by practising pathologists as challenging. A systematic approach to diagnosis is necessary for classification of these lesions, which establishes the tumour differentiation (follicular, sebaceous, sweat gland or apocrine) and evaluates histological features differentiating between benign and malignant entities. Consideration of clinical history is a necessary adjunct in evaluation of the adnexal neoplasm, as characteristic anatomical sites are described for many adnexal lesions. In some instances, immunohistochemical studies may also be employed to aid the diagnosis. The differential diagnosis between primary cutaneous adnexal neoplasms and cutaneous metastases from visceral tumours may also be difficult. Clinical, radiological, histological and immunohistochemical characteristics will be further discussed, considering that the correct diagnosis has a significant impact on the patient's management and prognosis.
A qualitative study to assess the potential of the human papillomavirus vaccination programme to encourage under-screened mothers to attend for cervical screening
Authors: Spencer Angela M , Brabin Loretta , Roberts Stephen A , Patnick Julietta , Elton Peter , Verma Arpana
Published: November 2015

Background

Coverage of the UK National Health Service Cervical Screening Programme is declining. Under-screened women whose daughters participate in the human papillomavirus (HPV) vaccination programme could be stimulated to attend. We investigated whether factors associated with the vaccination programme changed mothers’ intentions for future screening.

Methods

Questionnaires were sent to mothers of girls aged 12–13 years across two North West primary care trusts (n=2387) to assess the effect of the HPV vaccination programme on screening intentions. This identified mothers whose intentions had changed. Consent was sought to contact them for a semi-structured interview to discuss their screening intentions. Key themes were identified using framework analysis.

Results

97/606 women responding to the questionnaire had changed their views about cervical screening. 23 women were interviewed, 10 of whom expressed a positive change and 13 no change. Most had discussed the vaccine information, including cervical screening, with their daughters. Mothers who made a positive change decision recognised their daughters’ risk of cervical cancer, the need for future screening, and the importance of their own example. In this way daughters became ‘significant others’ in reinforcing their mothers’ cervical screening motivation.

Conclusions

A daughter's invitation for HPV vaccination instigates a reassessment of cervical screening intention in some under-screened mothers.
Flying beneath the clouds at the edge of the world: using a hexacopter to supplement abundance surveys of Steller sea lions (Eumetopias jubatus) in Alaska
Authors: Sweeney Kathryn L. , Helker Van T. , Perryman Wayne L. , LeRoi Donald J. , Fritz Lowell W. , Gelatt Tom S. , Angliss Robyn P.
Published: November 2015

Aerial imagery is the most effective method National Marine Fisheries Service (NMFS) uses to assess abundance of Steller sea lions (Eumetopias jubatus). These images are traditionally captured from occupied aircraft, but the long distances between airfields along the 1900 km Aleutian Island chain, inclement weather during the survey season, and dangerous winds at sites adjacent to cliffs severely limit flying opportunities. Because of the pressing need for current trend information for a population in persistent decline we turned to a small unoccupied aircraft system (UAS), an APH-22 hexacopter. Our primary objective was to supplement traditional aerial surveys during the annual abundance survey. The second objective was to test whether the resolution of images captured with the hexacopter was adequate for sighting permanently marked individuals. From June to July 2014, NMFS biologists based on a research vessel assessed sites from Attu Island to the Delarof Islands (n = 23), surveying sites from land (n = 12) and with the hexacopter (n = 11). Simultaneously, traditional aerial surveys were conducted east of the Delarof Islands (n = 172). This combined approach enabled us to conduct the most complete survey of adult, juvenile, and newborn Steller sea lions in the Aleutian Islands since the 1970s. Images collected also allowed for us to identify alpha-numeric permanent marks on individuals as small as juveniles. With this successful implementation of UAS, NMFS plans to use the hexacopter to supplement future surveys.
Dark atoms with nuclear shell: A status review
Authors: Cudell J. R. , Khlopov M.
Published: November 2015

Among dark atom scenarios, the simplest and most predictive one is that of O-helium (OHe) dark atoms, in which a leptonlike doubly charged particle O––is bound to a primordial helium nucleus, and is the main constituent of dark matter. The OHe cosmology has several successes: it leads to a warmer-than-cold-dark matter scenario for large-scale-structure formation, it can provide an explanation for the excess in positron annihilation line in the galactic bulge and it may explain the results of direct dark matter searches. This model liberates the physics of dark atoms from many unknown features of new physics, but it is still not free from astrophysical uncertainties. It also demands a deeper understanding of the details of known nuclear and atomic physics, which are still somewhat unclear in the case of nuclear interacting “atomic” shells. These potential problems of the OHe scenario are also discussed.
Special properties of differential inverse power series rings
Authors: Paykan K. , Moussavi A.
Published: November 2015

In this paper, we continue to study the differential inverse power series ring [Formula: see text], where [Formula: see text] is a ring equipped with a derivation [Formula: see text]. We characterize when [Formula: see text] is a local, semilocal, semiperfect, semiregular, left quasi-duo, (uniquely) clean, exchange, right stable range one, abelian, projective-free, [Formula: see text]-ring, respectively. Furthermore, we prove that [Formula: see text] is a domain satisfying the [Formula: see text] on principal left ideals if and only if so does [Formula: see text]. Also, for a piecewise prime ring (PWP) [Formula: see text] we determine a large class of the differential inverse power series ring [Formula: see text] which have a generalized triangular matrix representation for which the diagonal rings are prime. In particular, it is proved that, under suitable conditions, if [Formula: see text] has a (flat) projective socle, then so does [Formula: see text]. Our results extend and unify many existing results.
One-Pot Hydrothermal Synthesis of Sulfur-Doped SnO2 Nanoparticles and their Enhanced Photocatalytic Properties
Authors: Ma Lin , Xu Limei , Xu Xuyao , Zhou Xiaoping , Zhang Lingling
Published: November 2015

Sulfur-doped SnO2 nanoparticles with ultrafine sizes have been successfully prepared by a one-pot hydrothermal method. The obtained samples are characterized by X-ray diffraction (XRD), energy dispersive X-ray spectroscopy (EDX), X-ray photoelectron spectroscopy (XPS), high resolution transmission electron microscopy (HRTEM), thermogravimetric (TG), analyzer UV-Vis spectroscopy, photoluminescence (PL) and electrochemical impedance spectroscopy (EIS). The experimental results indicate that the doping level of sulfur element as well as the bandgaps of SnO2 can be controlled to a certain extent by varying the amount of L-cysteine (L-cys). When evaluated as photocatalysts in the degradation of rhodamine B (RhB) and reduction of Cr(VI) under visible light region, the resultant sulfur-doped SnO2 nanoparticles demonstrate obviously enhanced photocatalytic activities due to the markedly improved visible light response and effective separation of the photo-generated electron–hole pairs.
Effects of pulse width and repetition rate of pulsed laser on kinetics and production of singlet oxygen luminescence
Authors: Chen Defu , Wang Ying , Li Buhong , Lin Huiyun , Lin Xuechun , Gu Ying
Published: November 2015

Pulsed and continuous-wave (CW) lasers have been widely used as the light sources for photodynamic therapy (PDT) treatment. Singlet oxygen (1O2) is known to be a major cytotoxic agent in type-II PDT and can be directly detected by its near-infrared luminescence at 1270[Formula: see text]nm. As compared to CW laser excitation, the effects of pulse width and repetition rate of pulsed laser on the kinetics and production of 1O2 luminescence were quantitatively studied during photosensitization of Rose Bengal. Significant difference in kinetics of 1O2 luminescence was found under the excitation with various pulse widths of nanosecond, microsecond and CW irradiation with power of 20[Formula: see text]mW. The peak intensity and duration of 1O2 production varied with the pulse widths for pulsed laser excitation, while the 1O2 was generated continuously and its production reached a steady state with CW excitation. However, no significant difference ([Formula: see text]) in integral 1O2 production was observed. The results suggest that the PDT efficacy using pulsed laser may be identical to the CW laser with the same wavelength and the same average fluence rate below a threshold in solution.
Comparing clay mineral diagenesis in interbedded sandstones and mudstones, Vienna Basin, Austria
Authors: Gier Susanne , Worden Richard H. , Krois Peter
Published: November 2015

There is no consensus about the rate and style of clay mineral diagenesis in progressively buried sandstones v. interbedded mudstones. The diagenetic evolution of interbedded Miocene sandstones and mudstones from the Vienna Basin (Austria) has therefore been compared using core-based studies, petrography, X-ray diffraction and X-ray fluorescence. There was a common provenance for the coarse- and fine-grained sediments, and the primary depositional environment of the host sediment had no direct effect on illitization. The sandstones are mostly lithic arkoses dominated by framework grains of quartz, altered feldspars and carbonate rock fragments. Sandstone porosity has been reduced by quartz overgrowths and calcite cement; their pore-filling authigenic clay minerals consist of mixed-layer illite–smectite, illite, kaolinite and chlorite. In sandstones, smectite illitization progresses with depth; at 2150 m there is a transition from randomly interstratified to regular interstratified illite–smectite. The overall mineralogy of mudstones is surprisingly similar to the sandstones. However, for a given depth, feldspars are more altered to kaolinite, and smectite illitization is more advanced in sandstones than in mudstones. The higher permeability of sandstones allowed faster movement of material and pore fluid necessary for illitization and feldspar alteration than in mudstones. The significance of this work is that it has shown that open-system diagenesis is important for some clay mineral diagenetic reactions in sandstones, while closed-system diagenesis seems to operate for clay mineral diagenesis in mudstones.
NoDB
Authors: Alagiannis Ioannis , Borovica-Gajic Renata , Branco Miguel , Idreos Stratos , Ailamaki Anastasia
Published: November 2015

As data collections become larger and larger, users are faced with increasing bottlenecks in their data analysis. More data means more time to prepare and to load the data into the database before executing the desired queries. Many applications already avoid using database systems, for example, scientific data analysis and social networks, due to the complexity and the increased
data-to-query
time, that is, the time between getting the data and retrieving its first useful results. For many applications data collections keep growing fast, even on a daily basis, and this
data deluge
will only increase in the future, where it is expected to have much more data than what we can move or store, let alone analyze.

We here present the design and roadmap of a new paradigm in database systems, called NoDB, which
do not require data loading while still maintaining the whole feature set of a modern database system.
In particular, we show how to make raw data files a first-class citizen, fully integrated with the query engine. Through our design and lessons learned by implementing the NoDB philosophy over a modern Database Management Systems (DBMS), we discuss the fundamental limitations as well as the strong opportunities that such a research path brings. We identify performance bottlenecks specific for in situ processing, namely the repeated parsing and tokenizing overhead and the expensive data type conversion. To address these problems, we introduce an adaptive indexing mechanism that maintains positional information to provide efficient access to raw data files, together with a flexible caching structure. We conclude that NoDB systems are feasible to design and implement over modern DBMS, bringing an unprecedented positive effect in usability and performance.
Myocardial Po2does not limit aerobic metabolism in the postischemic heart
Authors: Chung Youngran
Published: November 2015

Reperfused hypertrophic hearts are prone to develop reflow abnormalities, which are likely to impair O2return to the myocardium. Yet, reflow deficit may not be the only factor determining postischemic oxygenation in the hypertrophic heart. Altered O2demand may also contribute to hypoxia. In addition, the extent to which myocardial Po2dictates energy and functional recovery in the reperfused heart remains uncertain. In the present study, moderately hypertrophied hearts from spontaneously hypertensive rats were subjected to ischemia-reperfusion, and the recovery time courses of pH and high-energy phosphates were followed by31P NMR.1H NMR measurement of intracellular myoglobin assessed tissue O2levels. The present study found that the exacerbation of hypoxia in the postischemic spontaneously hypertensive rat heart arises mostly from impaired microvascular supply of O2. However, postischemic myocardial Po2, at least when it exceeds ∼18% of the preischemic level, does not limit mitochondrial respiration and high-energy phosphate resynthesis. It only passively reflects changes in the O2supply-demand balance.
Muscle heat: a window into the thermodynamics of a molecular machine
Authors: Loiselle Denis Scott , Johnston Callum Michael , Han June-Chiew , Nielsen Poul Michael Fønss , Taberner Andrew James
Published: November 2015

The contraction of muscle is characterized by the development of force and movement (mechanics) together with the generation of heat (metabolism). Heat represents that component of the enthalpy of ATP hydrolysis that is not captured by the microscopic machinery of the cell for the performance of work. It arises from two conceptually and temporally distinct sources: initial metabolism and recovery metabolism. Initial metabolism comprises the hydrolysis of ATP and its rapid regeneration by hydrolysis of phosphocreatine (PCr) in the processes underlying excitation-contraction coupling and subsequent cross-bridge cycling and sliding of the contractile filaments. Recovery metabolism describes those process, both aerobic (mitochondrial) and anaerobic (cytoplasmic), that produce ATP, thereby allowing the regeneration of PCr from its hydrolysis products. An equivalent partitioning of muscle heat production is often invoked by muscle physiologists. In this formulation, total enthalpy expenditure is separated into external mechanical work ( W) and heat ( Q). Heat is again partitioned into three conceptually distinct components: basal, activation, and force dependent. In the following mini-review, we trace the development of these ideas in parallel with the development of measurement techniques for separating the various thermal components.
Organ perfusion during voluntary pulmonary hyperinflation; a magnetic resonance imaging study
Authors: Kyhl Kasper , Drvis Ivan , Barak Otto , Mijacika Tanja , Engstrøm Thomas , Secher Niels H. , Dujic Zeljko , Buca Ante , Madsen Per Lav
Published: November 2015

Pulmonary hyperinflation is used by competitive breath-hold divers and is accomplished by glossopharyngeal insufflation (GPI), which is known to compress the heart and pulmonary vessels, increasing sympathetic activity and lowering cardiac output (CO) without known consequence for organ perfusion. Myocardial, pulmonary, skeletal muscle, kidney, and liver perfusion were evaluated by magnetic resonance imaging in 10 elite breath-hold divers at rest and during moderate GPI. Cardiac chamber volumes, stroke volume, and thus CO were determined from cardiac short-axis cine images. Organ volumes were assessed from gradient echo sequences, and organ perfusion was evaluated from first-pass images after gadolinium injection. During GPI, lung volume increased by 5.2 ± 1.5 liters (mean ± SD; P < 0.001), while spleen and liver volume decreased by 46 ± 39 and 210 ± 160 ml, respectively ( P < 0.05), and inferior caval vein diameter by 4 ± 3 mm ( P < 0.05). Heart rate tended to increase (67 ± 10 to 86 ± 20 beats/min; P = 0.052) as right and left ventricular volumes were reduced ( P < 0.05). Stroke volume (107 ± 21 to 53 ± 15 ml) and CO (7.2 ± 1.6 to 4.2 ± 0.8 l/min) decreased as assessed after 1 min of GPI ( P < 0.01). Left ventricular myocardial perfusion maximum upslope and its perfusion index decreased by 1.52 ± 0.15 s−1 ( P < 0.001) and 0.02 ± 0.01 s−1 ( P < 0.05), respectively, without transmural differences. Pulmonary tissue, spleen, kidney, and pectoral-muscle perfusion also decreased ( P < 0.05), and yet liver perfusion was maintained. Thus, during pulmonary hyperinflation by GPI, CO and organ perfusion, including the myocardium, as well as perfusion of skeletal muscles, are reduced, and yet perfusion of the liver is maintained. Liver perfusion seems to be prioritized when CO decreases during GPI.
Raf/ERK drives the proliferative and invasive phenotype of BMPR2-silenced pulmonary artery endothelial cells
Authors: Awad Keytam S. , Elinoff Jason M. , Wang Shuibang , Gairhe Salina , Ferreyra Gabriela A. , Cai Rongman , Sun Junfeng , Solomon Michael A. , Danner Robert L.
Published: November 2015

A proliferative endothelial cell phenotype, inflammation, and pulmonary vascular remodeling are prominent features of pulmonary arterial hypertension (PAH). Bone morphogenetic protein type II receptor (BMPR2) loss-of-function is the most common cause of heritable PAH and has been closely linked to the formation of pathological plexiform lesions. Although some BMPR2 mutations leave ligand-dependent responses intact, the disruption of ligand-independent, noncanonical functions are universal among PAH-associated BMPR2 genotypes, but incompletely understood. This study examined the noncanonical signaling consequences of BMPR2 silencing in human pulmonary artery endothelial cells to identify potential therapeutic targets. BMPR2 siRNA silencing resulted in a proliferative, promigratory pulmonary artery endothelial cell phenotype and disruption of cytoskeletal architecture. Expression profiling closely reflected these phenotypic changes. Gene set enrichment and promoter analyses, as well as the differential expression of pathway components identified Ras/Raf/ERK signaling as an important consequence of BMPR2 silencing. Raf family members and ERK1/2 were constitutively activated after BMPR2 knockdown. Two Raf inhibitors, sorafenib and AZ628, and low-dose nintedanib, a triple receptor tyrosine kinase inhibitor upstream from Ras, reversed the abnormal proliferation and hypermotility of BMPR2 deficiency. Inhibition of dysregulated Ras/Raf/ERK signaling may be useful in reversing vascular remodeling in PAH.
Pulmonary instillation of MWCNT increases lung permeability, decreases gp130 expression in the lungs, and initiates cardiovascular IL-6 transsignaling
Authors: Thompson Leslie C. , Holland Nathan A. , Snyder Ryan J. , Luo Bin , Becak Daniel P. , Odom Jillian T. , Harrison Benjamin S. , Brown Jared M. , Gowdy Kymberly M. , Wingard Christopher J.
Published: November 2015

Pulmonary instillation of multiwalled carbon nanotubes (MWCNT) has the potential to promote cardiovascular derangements, but the mechanisms responsible are currently unclear. We hypothesized that exposure to MWCNT would result in increased epithelial barrier permeability by 24 h postexposure and initiate a signaling process involving IL-6/gp130 transsignaling in peripheral vascular tissue. To test this hypothesis we assessed the impact of 1 and 10 μg/cm2MWCNT on transepithelial electrical resistance (TEER) and expression of barrier proteins and cell activation in vitro using normal human bronchial epithelial primary cells. Parallel studies using male Sprague-Dawley rats instilled with 100 μg MWCNT measured bronchoalveolar lavage (BAL) differential cell counts, BAL fluid total protein, and lung water-to-tissue weight ratios 24 h postexposure and quantified serum concentrations of IL-6, soluble IL-6r, and soluble gp130. Aortic sections were examined immunohistochemically for gp130 expression, and gp130 mRNA/protein expression was evaluated in rat lung, heart, and aortic tissue homogenates. Our in vitro findings indicate that 10 μg/cm2MWCNT decreased the development of TEER and zonula occludens-1 expression relative to the vehicle. In rats MWCNT instillation increased BAL protein, lung water, and induced pulmonary eosinophilia. Serum concentrations of soluble gp130 decreased, aortic endothelial expression of gp130 increased, and expression of gp130 in the lung was downregulated in the MWCNT-exposed group. We propose that pulmonary exposure to MWCNT can manifest as a reduced epithelial barrier and activator of vascular gp130-associated transsignaling that may promote susceptibility to cardiovascular derangements.
Detection of Dendritic Spines Using Wavelet-Based Conditional Symmetric Analysis and Regularized Morphological Shared-Weight Neural Networks
Authors: Wang Shuihua , Chen Mengmeng , Li Yang , Zhang Yudong , Han Liangxiu , Wu Jane , Du Sidan
Published: November 2015

Identification and detection of dendritic spines in neuron images are of high interest in diagnosis and treatment of neurological and psychiatric disorders (e.g., Alzheimer’s disease, Parkinson’s diseases, and autism). In this paper, we have proposed a novel automatic approach using wavelet-based conditional symmetric analysis and regularized morphological shared-weight neural networks (RMSNN) for dendritic spine identification involving the following steps: backbone extraction, localization of dendritic spines, and classification. First, a new algorithm based on wavelet transform and conditional symmetric analysis has been developed to extract backbone and locate the dendrite boundary. Then, the RMSNN has been proposed to classify the spines into three predefined categories (mushroom, thin, and stubby). We have compared our proposed approach against the existing methods. The experimental result demonstrates that the proposed approach can accurately locate the dendrite and accurately classify the spines into three categories with the accuracy of 99.1% for “mushroom” spines, 97.6% for “stubby” spines, and 98.6% for “thin” spines.
Multivisceral Resection with Performing a Double Roux-en-Y Reconstruction for Advanced Gastric Cancer
Authors: Rifatbegovic Zijah , Mehmedovic Zlatan , Mehmedovic Majda , Hasanovic Jasmin , Mestric Amra
Published: November 2015

Background. The role of multivisceral resection, in the setting of locally advanced gastric cancer, is still debated. Previous studies have reported a higher risk for perioperative morbidity and mortality, with limited objective benefit in terms of survival.Patient.A male patient, 55 years old, was admitted to the clinic of surgery for surgical treatment of bleeding gastric ulceration. Preoperative diagnostic evaluation was performed, and patient had undergone a surgical treatment which revealed a large mass in head of the pancreas, infiltrating the hepatoduodenal ligament and transverse mesocolon. Total gastrectomy, duodenopancreatectomy, and right hemicolectomy were performed. The digestive tube continuity was reestablished by deriving the double Roux limbs.Conclusion. The aim of this case presentation is to demonstrate a method of digestive tube reconstruction by performing the double Roux-en-Y reconstruction in advanced gastric cancer when the multivisceral resection is performed.
Fatigue Modeling via Mammalian Auditory System for Prediction of Noise Induced Hearing Loss
Authors: Sun Pengfei , Qin Jun , Campbell Kathleen
Published: November 2015

Noise induced hearing loss (NIHL) remains as a severe health problem worldwide. Existing noise metrics and modeling for evaluation of NIHL are limited on prediction of gradually developing NIHL (GDHL) caused by high-level occupational noise. In this study, we proposed two auditory fatigue based models, including equal velocity level (EVL) and complex velocity level (CVL), which combine the high-cycle fatigue theory with the mammalian auditory model, to predict GDHL. The mammalian auditory model is introduced by combining the transfer function of the external-middle ear and the triple-path nonlinear (TRNL) filter to obtain velocities of basilar membrane (BM) in cochlea. The high-cycle fatigue theory is based on the assumption that GDHL can be considered as a process of long-cycle mechanical fatigue failure of organ of Corti. Furthermore, a series of chinchilla experimental data are used to validate the effectiveness of the proposed fatigue models. The regression analysis results show that both proposed fatigue models have high corrections with four hearing loss indices. It indicates that the proposed models can accurately predict hearing loss in chinchilla. Results suggest that the CVL model is more accurate compared to the EVL model on prediction of the auditory risk of exposure to hazardous occupational noise.
Relationship of Genetic Polymorphisms of the Chemokine, CCL5, and Its Receptor, CCR5, with Coronary Artery Disease in Taiwan
Authors: Ting Ke-Hsin , Ueng Kwo-Chang , Chiang Whei-Ling , Chou Ying-Erh , Yang Shun-Fa , Wang Po-Hui
Published: November 2015

The chemokine receptor CCR5 polymorphism, which confers resistance to HIV infection, has been associated with reduced risk of cardiovascular disease. However, the association of the chemokine, CCL5, and its receptor, CCR5, polymorphism and coronary artery disease (CAD) in the Taiwanese has not been studied. In this study, 483 subjects who received elective coronary angiography were recruited from Chung Shan Medical University Hospital. CCL5-403 and CCR5-59029 were determined by polymerase chain reaction-restriction fragment length polymorphism. We found that CCL5-403 with TT genotype frequencies was significantly associated with the risk of CAD group (odds ratio = 3.063 andp=0.012). Moreover, the frequencies of CCR5-59029 with GG or GA genotype were higher than AA genotype in acute coronary syndrome individuals (odds ratio = 1.853, CI = 1.176–2.921,p=0.008). In conclusion, we found that CCL5-403 polymorphism may increase genetic susceptibility of CAD. CCL5-403 or CCR5-59029 single nucleotide polymorphism may include genotype score and it may predict cardiovascular event.
Elucidation and Pharmacological Targeting of Novel Molecular Drivers of Follicular Lymphoma Progression
Authors: Bisikirska Brygida , Bansal Mukesh , Shen Yao , Teruya-Feldstein Julie , Chaganti Raju , Califano Andrea
Published: November 2015

Follicular lymphoma, the most common indolent subtype of non-Hodgkin lymphoma, is associated with a relatively long overall survival rate ranging from 6 to 10 years from the time of diagnosis. However, in 20% to 60% of follicular lymphoma patients, transformation to aggressive diffuse large B-cell lymphoma (DLBCL) reduces median survival to only 1.2 years. The specific functional and genetic determinants of follicular lymphoma transformation remain elusive, and genomic alterations underlying disease advancement have only been identified for a subset of cases. Therefore, to identify candidate drivers of follicular lymphoma transformation, we performed systematic analysis of a B-cell–specific regulatory model exhibiting follicular lymphoma transformation signatures using the Master Regulator Inference algorithm (MARINa). This analysis revealed FOXM1, TFDP1, ATF5, HMGA1, and NFYB to be candidate master regulators (MR) contributing to disease progression. Accordingly, validation was achieved through synthetic lethality assays in which RNAi-mediated silencing of MRs individually or in combination reduced the viability of (14;18)-positive DLBCL (t-DLBCL) cells. Furthermore, specific combinations of small-molecule compounds targeting synergistic MR pairs induced loss of viability in t-DLBCL cells. Collectively, our findings indicate that MR analysis is a valuable method for identifying bona fide contributors to follicular lymphoma transformation and may therefore guide the selection of compounds to be used in combinatorial treatment strategies. Cancer Res; 76(3); 664–74. ©2015 AACR.
Balancing Efficacy and Safety of an Anti-DLL4 Antibody through Pharmacokinetic Modulation
Authors: Couch Jessica A. , Zhang Gu , Beyer Joseph C. , de Zafra Christina L. Zuch , Gupta Priyanka , Kamath Amrita V. , Lewin-Koh Nicholas , Tarrant Jacqueline , Allamneni Krishna P. , Cain Gary , Yee Sharon , Ross Sarajane , Cook Ryan , Tsai Siao Ping , Ruppel Jane , Ridgway John Brady , Paluch Maciej , Hass Philip E. , Franklin Jayme , Yan Minhong
Published: November 2015

Purpose: Although agents targeting Delta-like ligand 4 (DLL4) have shown great promise for angiogenesis-based cancer therapy, findings in recent studies have raised serious safety concerns. To further evaluate the potential for therapeutic targeting of the DLL4 pathway, we pursued a novel strategy to reduce toxicities related to DLL4 inhibition by modulating the pharmacokinetic (PK) properties of an anti-DLL4 antibody.

Experimental Design: The F(ab′)2 fragment of anti-DLL4 antibody (anti-DLL4 F(ab′)2) was generated and assessed in efficacy and toxicity studies.

Results: Anti-DLL4 F(ab′)2 enables greater control over the extent and duration of DLL4 inhibition, such that intermittent dosing of anti-DLL4 F(ab′)2 can maintain significant antitumor activity while markedly mitigating known toxicities associated with continuous pathway inhibition.

Conclusions: PK modulation has potentially broad implications for development of antibody-based therapeutics. Our safety studies with anti-DLL4 F(ab′)2 also provide new evidence reinforcing the notion that the DLL4 pathway is extremely sensitive to pharmacologic perturbation, further underscoring the importance of exercising caution to safely harness this potent pathway in humans. Clin Cancer Res; 22(6); 1469–79. ©2015 AACR.
AGS16F Is a Novel Antibody Drug Conjugate Directed against ENPP3 for the Treatment of Renal Cell Carcinoma
Authors: Doñate Fernando , Raitano Arthur , Morrison Kendall , An Zili , Capo Linnette , Aviña Hector , Karki Sher , Morrison Karen , Yang Peng , Ou Jimmy , Moriya Ryuichi , Shostak Yuriy , Malik Faisal , Nadell Rossana , Liu Wendy , Satpayev Daulet , Atkinson John , Joseph Ingrid B.J. , Pereira Daniel S. , Challita-Eid Pia M. , Stover David R.
Published: November 2015

Purpose: New cancer-specific antigens are required for the design of novel antibody–drug conjugates (ADC) that deliver tumor-specific and highly potent cytotoxic therapy.

Experimental Design: Suppression subtractive hybridization identified ectonucleotide pyrophosphatase/phosphodiesterase 3 (ENPP3 or CD203c) as a potential human cancer-specific antigen. Antibodies targeting the extracellular domain of human ENPP3 were produced and selected for specific binding to ENPP3. Expression of ENPP3 in normal and cancer tissue specimens was evaluated by immunohistochemistry (IHC). ADCs comprising anti-ENPP3 Ab conjugated with maleimidocaproyl monomethyl auristatin F via a noncleavable linker (mcMMAF) were selected for therapeutic potential using binding and internalization assays, cytotoxicity assays, and tumor growth inhibition in mouse xenograft models. Pharmacodynamic markers were evaluated by IHC in tissues and ELISA in blood.

Results: ENPP3 was highly expressed in clear cell renal cell carcinoma: 92.3% of samples were positive and 83.9% showed high expression. By contrast, expression was negligible in normal tissues examined, with the exception of the kidney. High expression was less frequent in papillary renal cell carcinoma and hepatocellular carcinoma samples. AGS16F, an anti-ENPP3 antibody–mcMMAF conjugate, inhibited tumor growth in three different renal cell carcinoma (RCC) xenograft models. AGS16F localized to tumors, formed the active metabolite Cys-mcMMAF, induced cell-cycle arrest and apoptosis, and increased blood levels of caspase-cleaved cytokeratin-18, a marker of epithelial cell death.

Conclusions: AGS16F is a promising new therapeutic option for patients with RCC and is currently being evaluated in a phase I clinical trial. Clin Cancer Res; 22(8); 1989–99. ©2015 AACR.
Taselisib (GDC-0032), a Potent β-Sparing Small Molecule Inhibitor of PI3K, Radiosensitizes Head and Neck Squamous Carcinomas Containing ActivatingPIK3CAAlterations
Authors: Zumsteg Zachary S. , Morse Natasha , Krigsfeld Gabriel , Gupta Gaorav , Higginson Daniel S. , Lee Nancy Y. , Morris Luc , Ganly Ian , Shiao Stephan L. , Powell Simon N. , Chung Christine H. , Scaltriti Maurizio , Baselga José
Published: November 2015

Purpose: Activating PIK3CA genomic alterations are frequent in head and neck squamous cell carcinoma (HNSCC), and there is an association between phosphoinositide 3-kinase (PI3K) signaling and radioresistance. Hence, we investigated the therapeutic efficacy of inhibiting PI3K with GDC-0032, a PI3K inhibitor with potent activity against p110α, in combination with radiation in HNSCC.

Experimental Design: The efficacy of GDC-0032 was assessed in vitro in 26 HNSCC cell lines with crystal violet proliferation assays, and changes in PI3K signaling were measured by Western blot analysis. Cytotoxicity and radiosensitization were assessed with Annexin V staining via flow cytometry and clonogenic survival assays, respectively. DNA damage repair was assessed with immunofluorescence for γH2AX foci, and cell cycle analysis was performed with flow cytometry. In vivo efficacy of GDC-0032 and radiation was assessed in xenografts implanted into nude mice.

Results: GDC-0032 inhibited potently PI3K signaling and displayed greater antiproliferative activity in HNSCC cell lines with PIK3CA mutations or amplification, whereas cell lines with PTEN alterations were relatively resistant to its effects. Pretreatment with GDC-0032 radiosensitized PIK3CA-mutant HNSCC cells, enhanced radiation-induced apoptosis, impaired DNA damage repair, and prolonged G2–M arrest following irradiation. Furthermore, combined GDC-0032 and radiation was more effective than either treatment alone in vivo in subcutaneous xenograft models.

Conclusions: GDC-0032 has increased potency in HNSCC cell lines harboring PIK3CA-activating aberrations. Further, combined GDC-0032 and radiotherapy was more efficacious than either treatment alone in PIK3CA-altered HNSCC in vitro and in vivo. This strategy warrants further clinical investigation. Clin Cancer Res; 22(8); 2009–19. ©2015 AACR.