bluuebunny/crossref_metadata_2025 huggingface dataset:
Understanding and applying pharmacometric modelling and simulation in clinical practice and research
Authors: Standing Joseph F.
Published: August 2016

Understanding the dose–concentration–effect relationship is a fundamental component of clinical pharmacology. Interpreting data arising from observations of this relationship requires the use of mathematical models; i.e. pharmacokinetic (PK) models to describe the relationship between dose and concentration and pharmacodynamic (PD) models describing the relationship between concentration and effect. Drug development requires several iterations of pharmacometric model‐informed learning and confirming. This includes modelling to understand the dose–response in preclinical studies, deriving a safe dose for first‐in‐man, and the overall analysis of Phase I/II data to optimise the dose for safety and efficacy in Phase III pivotal trials. However, drug development is not the boundary at which PKPD understanding and application stops. PKPD concepts will be useful to anyone involved in the prescribing and administration of medicines for purposes such as determining off‐label dosing in special populations, individualising dosing based on a measured biomarker (personalised medicine) and in determining whether lack of efficacy or unexpected toxicity maybe solved by adjusting the dose rather than the drug. In clinical investigator‐led study design, PKPD can be used to ensure the optimal dose is used, and crucially to define the expected effect size, thereby ensuring power calculations are based on sound prior information. In the clinical setting the most likely people to hold sufficient expertise to advise on PKPD matters will be the pharmacists and clinical pharmacologists. This paper reviews fundamental PKPD principles and provides some real‐world examples of PKPD use in clinical practice and applied clinical research.
Risk prediction tool for grade re‐classification in men with favourable‐risk prostate cancer on active surveillance
Authors: Mamawala Mufaddal M. , Rao Karthik , Landis Patricia , Epstein Jonathan I. , Trock Bruce J. , Tosoian Jeffrey J. , Pienta Kenneth J. , Carter H. Ballentine
Published: August 2016

Objective

To create a nomogram for men on active surveillance (AS) for prediction of grade re‐classification (GR) above Gleason score 6 (Grade group >2) at surveillance biopsy.

Patients and Methods

From a cohort of men enrolled in an AS programme, a multivariable model was used to identify clinical and pathological parameters predictive of GR. Nomogram performance was assessed using receiver operating characteristic curves, calibration, and decision curve analysis.

Results

Of 1 374 men, 254 (18.50%) were re‐classified to Gleason ≥7 on surveillance prostate biopsy. Variables predictive of GR were earlier year of diagnosis [≤2004 vs ≥2005; odds ratio (OR) 2.16, P < 0.001], older age (OR 1.05, P < 0.001), higher prostate‐specific antigen density [OR 1.19 (per 0.1 unit increase), P = 0.04], bilateral disease (OR 2.86, P < 0.001), risk strata (low‐risk vs very‐low‐risk, OR 1.79, P < 0.001), and total number of biopsies without GR (OR 0.68, P < 0.001). On internal validation, a nomogram created using the multivariable model had an area under the curve of 0.757 (95% confidence interval 0.730–0.797) for predicting GR at the time of next surveillance biopsy.

Conclusion

The nomogram described is currently being used at each return visit to assess the need for a surveillance biopsy, and could increase retention in AS.
Cenozoic tectonic subsidence in the Qiongdongnan Basin, northern South China Sea
Authors: Zhao Zhongxian , Sun Zhen , Sun Longtao , Wang Zhenfeng , Sun Zhipeng
Published: August 2016

A number of major controversies exist in the South China Sea, including the timing and pattern of seafloor spreading, the anomalous alternating strike‐slip movement on the Red River Fault, the existence of anomalous post‐rift subsidence and how major submarine canyons have developed. The Qiongdongnan Basin is located in the intersection of the northern South China Sea margin and the strike‐slip Red River fault zone. Analysing the subsidence of the Qiongdongnan Basin is critical in understanding these controversies. The basin‐wide unloaded tectonic subsidence is computed through 1D backstripping constrained by the reconstruction of palaeo‐water depths and the interpretation of dense seismic profiles and wells. Results show that discrete subsidence sags began to form in the central depression during the middle and late Eocene (45–31.5 Ma). Subsequently in the Oligocene (31.5–23 Ma), more faults with intense activity formed, leading to rapid extension with high subsidence (40–90 m Myr−1). This extension is also inferred to be affected by the sinistral movement of the offshore Red River Fault as new subsidence sags progressively formed adjacent to this structure. Evidence from faults, subsidence, magmatic intrusions and strata erosion suggests that the breakup unconformity formed at ca. 23 Ma, coeval with the initial seafloor spreading in the southwestern subbasin of the South China Sea, demonstrating that the breakup unconformity in the Qiongdongnan Basin is younger than that observed in the Pearl River Mouth Basin (ca. 32–28 Ma) and Taiwan region (ca. 39–33 Ma), which implies that the seafloor spreading in the South China Sea began diachronously from east to west. The post‐rift subsidence was extremely slow during the early and middle Miocene (16 m Myr−1, 23–11.6 Ma), probably caused by the transient dynamic support induced by mantle convection during seafloor spreading. Subsequently, rapid post‐rift subsidence occurred during the late Miocene (144 m Myr−1, 11.6–5.5 Ma) possibly as the dynamic support disappeared. The post‐rift subsidence slowed again from the Pliocene to the Quaternary (24 m Myr−1, 5.5–0 Ma), but a subsidence centre formed in the west with the maximum subsidence of ca. 450 m, which coincided with a basin with the sediment thickness exceeding 5500 m and is inferred to be caused by sediment‐induced ductile crust flow. Anomalous post‐rift subsidence in the Qiongdongnan Basin increased from ca. 300 m in the northwest to ca. 1200 m in the southeast, and the post‐rift vertical movement of the basement was probably the most important factor to facilitate the development of the central submarine canyon.
Structure‐based discovery of novel US28 small molecule ligands with different modes of action
Authors: Lückmann Michael , Amarandi Roxana‐Maria , Papargyri Natalia , Jakobsen Mette H. , Christiansen Elisabeth , Jensen Lars J. , Pui Aurel , Schwartz Thue W. , Rosenkilde Mette M. , Frimurer Thomas M.
Published: August 2016

The human cytomegalovirus‐encoded G protein‐coupled receptor US28 is a constitutively active receptor, which can recognize various chemokines. Despite the recent determination of its 2.9 Å crystal structure, potent and US28‐specific tool compounds are still scarce. Here, we used structural information from a refined US28:VUF2274 complex for virtual screening of >12 million commercially available small molecule compounds. Using a combined receptor‐ and ligand‐based approach, we tested 98 of the top 0.1% ranked compounds, revealing novel chemotypes as compared to the ~1.45 million known ligands in the ChEMBL database. Two compounds were confirmed as agonist and inverse agonist, respectively, in both IP accumulation and Ca2+ mobilization assays. The screening setup presented in this work is computationally inexpensive and therefore particularly useful in an academic setting as it enables simultaneous testing in binding as well as in different functional assays and/or species without actual chemical synthesis.
Endoscopic cyclophotocoagulation versus second glaucoma drainage device after prior aqueous tube shunt surgery
Authors: Murakami Yohko , Akil Handan , Chahal Jasdeep , Dustin Laurie , Tan James , Chopra Vikas , Francis Brian
Published: August 2016

Background

To evaluate the efficacy in controlling intraocular pressure (IOP) with endoscopic cyclophotocoagulation (ECP) versus implantation of a second glaucoma drainage device (GDD‐2) in the treatment of uncontrolled glaucoma with a prior aqueous tube shunt.

Design

A nonrandomized retrospective chart review.

Participants

Patients with refractory glaucoma following a failed initial tube shunt (Baerveldt Glaucoma Implant 350), who underwent ECP or GDD‐2 with Baerveldt Glaucoma Implant as a second surgery. Twenty‐five eyes underwent ECP, and 48 eyes received a GDD‐2.

Methods

ECP or second tube‐shunt surgery.

Main Outcome Measures

Reduction in IOP and antiglaucoma medications, and Kaplan–Meier survival with success defined as lOP ≥ 5 mmHg and ≤ 21 mmHg and ≥ 20% reduction from preoperative IOP. Secondary outcome measures were visual acuity and the presence of any postoperative complications.

Results

Both ECP and GDD‐2 significantly lowered IOP (Student's t test) and number of antiglaucoma medications (Wilcoxon paired signed rank test). There were no significant differences in postoperative IOP (Student's t test) or antiglaucoma medications (Mann Whitney test) between ECP and GDD‐2 at 6 and 12 months. There was also no difference in the Kaplan–Meier survival outcomes between the two groups.

Conclusion

Both ECP and GDD‐2 are both effective as second surgeries for refractory glaucoma that has failed a prior aqueous shunt.
Effects of logging on roadless space in intact forest landscapes of the Congo Basin
Authors: Kleinschroth Fritz , Healey John R. , Gourlet‐Fleury Sylvie , Mortier Frédéric , Stoica Radu S.
Published: August 2016

Forest degradation in the tropics is often associated with roads built for selective logging. The protection of intact forest landscapes (IFL) that are not accessible by roads is high on the biodiversity conservation agenda and a challenge for logging concessions certified by the Forest Stewardship Council (FSC). A frequently advocated conservation objective is to maximize the retention of roadless space, a concept that is based on distance to the nearest road from any point. We developed a novel use of the empty‐space function – a general statistical tool based on stochastic geometry and random sets theory – to calculate roadless space in a part of the Congo Basin where road networks have been expanding rapidly. We compared the temporal development of roadless space in certified and uncertified logging concessions inside and outside areas declared IFL in 2000. Inside IFLs, road‐network expansion led to a decrease in roadless space by more than half from 1999 to 2007. After 2007, loss leveled out in most areas to close to 0 due to an equilibrium between newly built roads and abandoned roads that became revegetated. However, concessions in IFL certified by FSC since around 2007 continuously lost roadless space and reached a level comparable to all other concessions. Only national parks remained mostly roadless. We recommend that forest‐management policies make the preservation of large connected forest areas a top priority by effectively monitoring – and limiting – the occupation of space by roads that are permanently accessible.
Incremental value of live/real time three‐dimensional transesophageal echocardiography over the two‐dimensional technique in the assessment of a tuberculoma involving the left atrium and appendage
Authors: Kemaloğlu Öz Tuğba , Elsayed Mahmoud , Nanda Navin C. , Kalenderoğlu Koray , Akyüz Şükrü , Atasoy Işıl , Ösken Altuğ , Onuk Tolga , Eren Mehmet
Published: August 2016

Intracardiac tuberculomas are extremely rare, and cardiac involvement in tuberculosis accounts for only 0.5% of extrapulmonary tuberculosis. We report for the first time incremental value of live/real time three‐dimensional transesophageal echocardiography over two‐dimensional transesophageal echocardiography in the assessment of a tuberculoma involving the left atrium and left atrial appendage.
Match and mismatch between opening area and resistance in mild and moderate rheumatic mitral stenosis
Authors: El‐Dosouky Ibtesam Ibrahim
Published: August 2016

Background

Mitral valve resistance (MVR) is a hemodynamic consequence of mitral stenosis (MS), but it has no clear threshold with a shortage of data to be reliable. We aimed to investigate match and mismatch between opening area and resistance especially in patients with moderate and mild MS.

Methods

This study comprised 88 patients with moderate and mild rheumatic MS. Transthoracic echocardiographic study estimated the following: mitral valve area (MVA) by both planimetry (2D) and pressure half‐time (PHT), mitral valve score (MVS), mean transmitral pressure gradient (MPG), diastolic filling time (DFT), left ventricular out flow tract diameter (LVOTd) and velocity‐time integral (LVOTvti), and MVR = MPG/aortic flow ratio [(LVOTd) (LVOTvti)/DFT] in dynes·s/cm5. Patients were classified into two groups: group 1 (51 patients) with matched MVR and group 2 (37 patients) with mismatched higher MVR.

Results

In the matched group, moderate MS showed MVR <105 dynes·s/cm5 and <76dynes·s/cm5 with mild MS. Group 2 compared to group 1 had higher NYHA class (1.4±0.6 vs 1.2±0.4, P<.05) and higher MVS (8.1±1.8 vs 7±0.9, P<.05). MVR showed positive correlation with MVS (r=.5, P<.05), and logistic regression analysis showed that MVS is the only independent predictor of the MVR severity in the mismatched group (i.e., with higher MVR compared to the ROC analysis results) (B±SE=6.997±2.826, t=2.476, 95% CI 1.241±12.752 with an odds ratio=0.412, P<.05).

Conclusion

On investigating match and mismatch between opening area and resistance, the only independent predictor of mismatch is the mitral valve score.
Synchrony as an Adaptive Mechanism for Large‐Scale Human Social Bonding
Authors: Launay Jacques , Tarr Bronwyn , Dunbar Robin I. M.
Published: August 2016

Humans have developed a number of specific mechanisms that allow us to maintain much larger social networks than would be expected given our brain size. For our primate cousins, social bonding is primarily supported using grooming, and the bonding effect this produces is primarily mechanistically underpinned by the release of endorphins (although other neurohormones are also likely to be involved). Given large group sizes and time budgeting constraints, grooming is not viable as the primary social bonding mechanism in humans. Instead, during our evolutionary history, we developed other behaviours that helped us to feel connected to our social communities. Here, we propose that synchrony might act as direct means to encourage group cohesion by causing the release of neurohormones that influence social bonding. By acting on ancient neurochemical bonding mechanisms, synchrony can act as a primal and direct social bonding agent, and this might explain its recurrence throughout diverse human cultures and contexts (e.g. dance, prayer, marching, music‐making). Recent evidence supports the theory that endorphins are released during synchronised human activities, including sport, but particularly during musical interaction. Thus, synchrony‐based activities are likely to have developed due to the fact that they allow the release of these hormones in large‐scale human communities, providing an alternative to social bonding mechanisms such as grooming.
A meta‐analysis of fertilizer‐induced soil NO and combined NO+N2O emissions
Authors: Liu Shuwei , Lin Feng , Wu Shuang , Ji Cheng , Sun Yi , Jin Yaguo , Li Shuqing , Li Zhaofu , Zou Jianwen
Published: August 2016

Soils are among the important sources of atmospheric nitric oxide (NO) and nitrous oxide (N2O), acting as a critical role in atmospheric chemistry. Updated data derived from 114 peer‐reviewed publications with 520 field measurements were synthesized using meta‐analysis procedure to examine the N fertilizer‐induced soil NO and the combined NO+N2O emissions across global soils. Besides factors identified in earlier reviews, additional factors responsible for NO fluxes were fertilizer type, soil C/N ratio, crop residue incorporation, tillage, atmospheric carbon dioxide concentration, drought and biomass burning. When averaged across all measurements, soil NO‐N fluxes were estimated to be 4.06 kg ha−1 yr−1, with the greatest (9.75 kg ha−1 yr−1) in vegetable croplands and the lowest (0.11 kg ha−1 yr−1) in rice paddies. Soil NO emissions were more enhanced by synthetic N fertilizer (+38%), relative to organic (+20%) or mixed N (+18%) sources. Compared with synthetic N fertilizer alone, synthetic N fertilizer combined with nitrification inhibitors substantially reduced soil NO emissions by 81%. The global mean direct emission factors of N fertilizer for NO (EFNO) and combined NO+N2O (EFc) were estimated to be 1.16% and 2.58%, with 95% confidence intervals of 0.71–1.61% and 1.81–3.35%, respectively. Forests had the greatest EFNO (2.39%). Within the croplands, the EFNO (1.71%) and EFc (4.13%) were the greatest in vegetable cropping fields. Among different chemical N fertilizer varieties, ammonium nitrate had the greatest EFNO (2.93%) and EFc (5.97%). Some options such as organic instead of synthetic N fertilizer, decreasing N fertilizer input rate, nitrification inhibitor and low irrigation frequency could be adopted to mitigate soil NO emissions. More field measurements over multiyears are highly needed to minimize the estimate uncertainties and mitigate soil NO emissions, particularly in forests and vegetable croplands.
Multispectral imaging for highly accurate analysis of tumour‐infiltrating lymphocytes in primary melanoma
Authors: Vasaturo Angela , Di Blasio Stefania , Verweij Dagmar , Blokx Willeke A M , van Krieken J Han , de Vries I Jolanda M , Figdor Carl G
Published: August 2016

Aims

The quality and quantity of the infiltration of immune cells into tumour tissues have substantial impacts on patients’ clinical outcomes, and are associated with response to immunotherapy. Therefore, the precise analysis of tumour‐infiltrating lymphocytes (TILs) is becoming an important additional pathological biomarker. Analysis of TILs is usually performed semiquantitatively by pathologists on haematoxylin and eosin‐stained or immunostained tissue sections. However, automated quantification outperforms semiquantitative approaches, and is becoming the standard. Owing to the presence of melanin pigment, this approach is seriously hampered in melanoma, because the spectrum of melanin lies close to that of commonly used immunohistochemical stains. Aim of this study is to overcome the technical issues due to the presence of melanin for an automated and accurate quantification of TILs in melanoma.

Methods and results

Here, we successfully applied a novel multispectral imaging (MSI) technique to enumerate T cells in human primary melanomas. This microscopy technique combines imaging with spectroscopy to obtain both quantitative expression data and the tissue distributions of different cellular markers. We demonstrate that MSI allows complete and accurate analysis of TILs, successfully avoiding the blurring of images by melanin pigments, in whole tissue slide primary melanoma lesions, which could otherwise not be accurately detected by conventional digital image methodologies.

Conclusions

Our study highlights the potential of MSI for accurate assessment of immune cell infiltrates, including those in notoriously difficult tissues, such as pigmented melanomas. Quantification of tumour infiltration by different immune cell types is crucial in the search for new biomarkers to predict patient responses to immunotherapies. Our findings show that this innovative microscopy technique is an important extension of the armamentarium of pathologists.
Mechanical Properties and Reliability of Li2O‐Stabilized β″‐Alumina Ceramics: Effect of Synthesizing Method
Authors: Ahmadi Moghadam Hajar , Paydar Mohammad Hossein
Published: August 2016

Li2O‐stabilized β″‐alumina powder has been synthesized by the solid‐state and double‐zeta processes. It was shown that by the double‐zeta process, the β″‐alumina fraction of sintered samples was 10% higher, showing around 99% of β″‐alumina fraction. Using β″‐alumina powder produced by the double‐zeta process, the sintered density improved, microstructure was more uniform and leads to improvement in hardness, strength and Weibull modulus due to more uniform microstructure and absence of abnormal grain growth. The higher fracture toughness of the solid‐state‐processed samples could be due to crack deflection mechanism.
Functional exhaustion of CD4+ T cells induced by co‐stimulatory signals from myeloid leukaemia cells
Authors: Ozkazanc Didem , Yoyen‐Ermis Digdem , Tavukcuoglu Ece , Buyukasik Yahya , Esendagli Gunes
Published: August 2016

To cope with immune responses, tumour cells implement elaborate strategies such as adaptive resistance and induction of T‐cell exhaustion. T‐cell exhaustion has been identified as a state of hyporesponsiveness that arises under continuous antigenic stimulus. Nevertheless, contribution of co‐stimulatory molecules to T‐cell exhaustion in cancer remains to be better defined. This study explores the role of myeloid leukaemia‐derived co‐stimulatory signals on CD4+ T helper (Th) cell exhaustion, which may limit anti‐tumour immunity. Here, CD86 and inducible T‐cell co‐stimulator ligand (ICOS‐LG) co‐stimulatory molecules that are found on myeloid leukaemia cells supported Th cell activation and proliferation. However, under continuous stimulation, T cells co‐cultured with leukaemia cells, but not with peripheral blood monocytes, became functionally exhausted. These in vitro‐generated exhausted Th cells were defined by up‐regulation of programmed cell death 1 (PD‐1), cytotoxic T‐lymphocyte antigen 4 (CTLA‐4), lymphocyte activation gene 3 (LAG3) and T‐cell immunoglobulin and mucin domain‐containing protein 3 (TIM‐3) inhibitory receptors. They were reluctant to proliferate upon re‐stimulation and produced reduced amounts of interleukin‐2 (IL‐2), tumour necrosis factor‐α (TNF‐α) and interferon‐γ (IFN‐γ). Nonetheless, IL‐2 supplementation restored the proliferation capacity of the exhausted Th cells. When the co‐stimulation supplied by the myeloid leukaemia cells were blocked, the amount of exhausted Th cells was significantly decreased. Moreover, in the bone marrow aspirates from patients with acute myeloid leukaemia (AML) or myelodysplastic syndrome (MDS), a subpopulation of Th cells expressing PD‐1, TIM‐3 and/or LAG3 was identified together with CD86+ and/or ICOS‐LG+ myeloid blasts. Collectively, co‐stimulatory signals derived from myeloid leukaemia cells possess the capacity to facilitate functional exhaustion in Th cells.
Functional interleukin‐33 receptors are expressed in early progenitor stages of allergy‐related granulocytes
Authors: Tsuzuki Hirofumi , Arinobu Yojiro , Miyawaki Kohta , Takaki Ayako , Ota Shun‐ichiro , Ota Yuri , Mitoma Hiroki , Akahoshi Mitsuteru , Mori Yasuo , Iwasaki Hiromi , Niiro Hiroaki , Tsukamoto Hiroshi , Akashi Koichi
Published: August 2016

Interleukin‐33 (IL‐33) induces T helper type 2 (Th2) cytokine production and eosinophilia independently of acquired immunity, leading to innate immunity‐mediated allergic inflammation. Allergy‐related innate myeloid cells such as eosinophils, basophils and mast cells express the IL‐33 receptor (IL‐33R), but it is still unknown how IL‐33 regulates allergic inflammation involving these cells and their progenitors. Here, we revealed that the functional IL‐33R was expressed on eosinophil progenitors (EoPs), basophil progenitors (BaPs) and mast cell progenitors (MCPs). In the presence of IL‐33, these progenitors did not expand, but produced a high amount of Th2 and pro‐inflammatory cytokines such as IL‐9, IL‐13, IL‐1β and IL‐6. The amount of cytokines produced by these progenitors was greater than that by mature cells. In vivo, IL‐33 stimulated the expansion of EoPs, but it was dependent upon the elevated serum IL‐5 that is presumably derived from type 2 innate lymphoid cells that express functional IL‐33R. These data collectively suggest that EoPs, BaPs and MCPs are not only the sources of allergy‐related granulocytes, but can also be sources of allergy‐related cytokines in IL‐33‐induced inflammation. Because such progenitors can differentiate into mature granulocytes at the site of inflammation, they are potential therapeutic targets in IL‐33‐related allergic diseases.
The Impact of 9/11 on the Self-Employment Outcomes of Arab and Muslim Immigrants
Authors: Wang Chunbei
Published: August 2016

This paper examines the effects of 9/11 on the self-employment outcomes of Arab and Muslim immigrants. Using CPS Data 2000–2005 and a difference-in-differences approach, I analyze the changes in their self-employment entry/exit decisions and earnings after 9/11 using native whites as the main comparison group. I find that the Arab and Muslim immigrants are less likely to enter self-employment after 9/11, especially into industries that require higher levels of capital investment. However, there is no evidence that 9/11 has negative impacts on their exit decisions or earnings. The paper further documents a shift of Arab and Muslim immigrants’ businesses toward industries such as construction, finance/real estate/insurance services, and professional services after 9/11, areas in which they have performed well.
Catalytic Effect of CeO2‐Stabilized ZrO2 Ceramics with Strong Shock‐Heated Mono‐ and Di‐Atomic Gases
Authors: Vishakantaiah Jayaram , Reddy Kalidevapura Polareddy Jagannatha
Published: August 2016

The reducibility of synthesized ceria‐stabilized zirconia (CSZ) with strong shock‐heated test gases is investigated. Free piston‐driven shock tube operating at hypersonic speed at Mach number of 6–8 has been used to heat the ultrahigh pure test gases like Ar to ~12800 K, N2 to ~7960 K, and O2 to ~5500 K at a medium reflected shock pressure (5.0–7.4 MPa) for a short duration of 1–2 ms test time. Under this extreme thermodynamic condition, test gases undergo real gas effects. The structural and spectroscopic investigations of CSZ (Ce2Zr2O8) after interaction with shock‐heated argon gas show pyrochlore structure of Ce2Zr2O7−δ which is observed to be black in color. In presence of shock‐heated N2 gas, CSZ remains in fluorite structure by changing its color to pale green as nitrogen atoms fill oxygen vacancies. After O2 interaction with the shock wave, CSZ remains pale yellow but the X‐ray diffraction pattern shows the presence of monoclinic ZrO2 due to phase separation. During reduction process, Ce4+ has been reduced to Ce3+ which is an unusual effect. In this study, the catalytic and surface recombination effects of CSZ due to shock‐induced compression in millisecond timescale are presented.
Reactive Hydrothermal Liquid‐Phase Densification (rHLPD) of Ceramics – A Study of the BaTiO3[TiO2] Composite System
Authors: Vakifahmetoglu Cekdar , Anger Jean Francois , Atakan Vahit , Quinn Sean , Gupta Surojit , Li Qinghua , Tang Ling , Riman Richard E.
Published: August 2016

A densification process called reactive hydrothermal liquid‐phase densification (rHLPD), based on principles of hydrothermal reaction, infiltration, reactive crystallization, and liquid‐phase sintering, is presented. rHLPD can be used to form monolithic ceramic components at low temperatures. The densification of barium titanate–titania composite monoliths was studied to demonstrate proof of concept for this densification model. Permeable, green titania (anatase) compacts were infiltrated with aqueous barium hydroxide solutions and reacted under hydrothermal conditions in the temperature range 90°C–240°C. The effects of reaction time and temperature on the conversion of titania (anatase) into barium titanate were studied. Utilizing a 72 h reaction at 240°C between l.0 M Ba(OH)2, an anatase (TiO2) powder compact, and a corresponding Ba/Ti ratio of 1.5, it was possible to crystallize a composite 95 wt% (88 mol%) BaTiO3 and 5 wt% (12 mol%) TiO2. The composite had a relative density of ~90% with a compressive strength of 172 ± 21 MPa and a flexural strength of 49 ± 4 MPa.
The function and evolution of male and female genitalia in Phyllophaga Harris scarab beetles (Coleoptera: Scarabaeidae)
Authors: Richmond M. P. , Park J. , Henry C. S.
Published: August 2016

Genitalia diversity in insects continues to fuel investigation of the function and evolution of these dynamic structures. Whereas most studies have focused on variation in male genitalia, an increasing number of studies on female genitalia have uncovered comparable diversity among females, but often at a much finer morphological scale. In this study, we analysed the function and evolution of male and female genitalia in Phyllophaga scarab beetles, a group in which both sexes exhibit genitalic diversity. To document the interaction between male and female structures during mating, we dissected flash‐frozen mating pairs from three Phyllophaga species and investigated fine‐scale morphology using SEM. We then reconstructed ancestral character states using a species tree inferred from mitochondrial and nuclear loci to elucidate and compare the evolutionary history of male and female genitalia. Our dissections revealed an interlocking mechanism of the female pubic process and male parameres that appears to improve the mechanical fit of the copulatory position. The comparative analyses, however, did not support coevolution of male and female structures and showed more erratic evolution of the female genitalia relative to males. By studying a group that exhibits obvious female genitalic diversity, we were able to demonstrate the relevance of female reproductive morphology in studies of male genital diversity.
The Prevalence of Canine Oral Protozoa and Their Association with Periodontal Disease
Authors: Patel Niran , Colyer Alison , Harris Steve , Holcombe Lucy , Andrew Peter
Published: August 2016

Periodontal disease is one of the most important health concerns for companion animals. Research into canine forms of periodontitis has focused on the identification and characterization of the bacterial communities present. However, other microorganisms are known to inhabit the oral cavity and could also influence the disease process. A novel, broad spectrum 18S PCR was developed and used, in conjunction with next‐generation sequencing analyses to target the identification of protists. Trichomonas sp. and Entamoeba sp. were identified from 92 samples of canine plaque. The overall prevalence of trichomonads was 56.52% (52/92) and entamoebae was 4.34% (4/92). Next‐generation sequencing of pooled healthy, gingivitis, early‐stage periodontitis, and severe periodontitis samples revealed the proportion of trichomonad sequences to be 3.51% (health), 2.84% (gingivitis), 6.07% (early periodontitis), and 35.04% (severe periodontitis), respectively, and entamoebae to be 0.01% (health), 0.01% (gingivitis), 0.80% (early‐stage periodontitis), and 7.91% (severe periodontitis) respectively. Both genera of protists were statistically associated with plaque from dogs with periodontal disease. These findings provide the first conclusive evidence for the presence of oral protozoa in dog plaque and suggest a possible role for protozoa in the periodontal disease process.
Free and open‐source automated 3‐D microscope
Authors: WIJNEN BAS , PETERSEN EMILY E. , HUNT EMILY J. , PEARCE JOSHUA M.
Published: August 2016

Open‐source technology not only has facilitated the expansion of the greater research community, but by lowering costs it has encouraged innovation and customizable design. The field of automated microscopy has continued to be a challenge in accessibility due the expense and inflexible, noninterchangeable stages. This paper presents a low‐cost, open‐source microscope 3‐D stage. A RepRap 3‐D printer was converted to an optical microscope equipped with a customized, 3‐D printed holder for a USB microscope. Precision measurements were determined to have an average error of 10 μm at the maximum speed and 27 μm at the minimum recorded speed. Accuracy tests yielded an error of 0.15%. The machine is a true 3‐D stage and thus able to operate with USB microscopes or conventional desktop microscopes. It is larger than all commercial alternatives, and is thus capable of high‐depth images over unprecedented areas and complex geometries. The repeatability is below 2‐D microscope stages, but testing shows that it is adequate for the majority of scientific applications. The open‐source microscope stage costs less than 3–9% of the closest proprietary commercial stages. This extreme affordability vastly improves accessibility for 3‐D microscopy throughout the world.
Scanning electron microscopy image representativeness: morphological data on nanoparticles
Authors: ODZIOMEK KATARZYNA , USHIZIMA DANIELA , OBERBEK PRZEMYSLAW , KURZYDŁOWSKI KRZYSZTOF JAN , PUZYN TOMASZ , HARANCZYK MACIEJ
Published: August 2016

A sample of a nanomaterial contains a distribution of nanoparticles of various shapes and/or sizes. A scanning electron microscopy image of such a sample often captures only a fragment of the morphological variety present in the sample. In order to quantitatively analyse the sample using scanning electron microscope digital images, and, in particular, to derive numerical representations of the sample morphology, image content has to be assessed. In this work, we present a framework for extracting morphological information contained in scanning electron microscopy images using computer vision algorithms, and for converting them into numerical particle descriptors. We explore the concept of image representativeness and provide a set of protocols for selecting optimal scanning electron microscopy images as well as determining the smallest representative image set for each of the morphological features. We demonstrate the practical aspects of our methodology by investigating tricalcium phosphate, Ca3(PO4)2, and calcium hydroxyphosphate, Ca5(PO4)3(OH), both naturally occurring minerals with a wide range of biomedical applications.
Fine structure characterization of martensite/austenite constituent in low‐carbon low‐alloy steel by transmission electron forward scatter diffraction
Authors: LI C.W. , HAN L.Z. , LUO X.M. , LIU Q.D. , GU J.F.
Published: August 2016

Transmission electron forward scatter diffraction and other characterization techniques were used to investigate the fine structure and the variant relationship of the martensite/austenite (M/A) constituent of the granular bainite in low‐carbon low‐alloy steel. The results demonstrated that the M/A constituents were distributed in clusters throughout the bainitic ferrite. Lath martensite was the main component of the M/A constituent, where the relationship between the martensite variants was consistent with the Nishiyama–Wassermann orientation relationship and only three variants were found in the M/A constituent, suggesting that the variants had formed in the M/A constituent according to a specific mechanism. Furthermore, the Σ3 boundaries in the M/A constituent were much longer than their counterparts in the bainitic ferrite region. The results indicate that transmission electron forward scatter diffraction is an effective method of crystallographic analysis for nanolaths in M/A constituents.
Chronic consumption of Annona muricata juice triggers and aggravates cerebral tau phosphorylation in wild‐type and MAPT transgenic mice
Authors: Rottscholl Robert , Haegele Marlen , Jainsch Britta , Xu Hong , Respondek Gesine , Höllerhage Matthias , Rösler Thomas W. , Bony Emilie , Le Ven Jessica , Guérineau Vincent , Schmitz‐Afonso Isabelle , Champy Pierre , Oertel Wolfgang H. , Yamada Elizabeth S. , Höglinger Günter U.
Published: August 2016

In the pathogenesis of tauopathies, genetic and environmental factors have been identified. While familial clustering led to the identification of mutations in MAPT encoding the microtubule‐associated protein tau, the high incidence of a sporadic tauopathy endemic in Guadeloupe was linked to the plant‐derived mitochondrial complex I inhibitor annonacin. The interaction of both factors was studied in the present work in a realistic paradigm over a period of 12 months. Mice over‐expressing either human wild‐type tau or R406W mutant tau as well as non‐transgenic mice received either regular drinking water or commercially available tropical fruit juice made of soursop (Annona muricata L.) as dietary source of neurotoxins. HPLC‐MS analysis of this juice identified several Annonaceous acetogenins, mainly annonacin (16.2 mg/L), and 41 isoquinoline alkaloids (18.0 mg/L, mainly asimilobine and reticuline). After 12 month of juice consumption, several brain regions showed an increased number of neurons with phosphorylated tau in the somatodendritic compartment of R406W mice and, to a much lesser extent, of non‐transgenic mice and mice over‐expressing human wild‐type tau. Moreover, juice drinking was associated with a reduction in synaptophysin immunoreactivity, as well as an increase in 3‐nitrotyrosine (3NT) reactivity in all three genotypes. The increase in 3NT suggests that Annona muricata juice promotes the generation of reactive nitrogen species. This study provides first experimental evidence that long‐lasting oral ingestion of a widely consumed environmental factor can induce somatodendritic accumulation of hyperphosphorylated tau in mice expressing rodent or human wild‐type tau, and can accelerate tau pathology in R406W‐MAPT transgenic mice.

image
An isolated involvement in mental health care – experiences of parents of young adults
Authors: Andershed Birgitta , Ewertzon Mats , Johansson Anita
Published: August 2016

Aims and objectives

To explore parents’ involvement in the informal and professional care of their young adult child with mental illness. A further aim was to examine concepts in the caring theory of ‘Involvement in the light–Involvement in the dark’ in the context of mental health care.

Background

Mental illness has increased among young people in high‐income countries, and suicide is now the leading cause of death for this group. Because of their disease, these young people may have difficulty in carrying out daily, taken‐for‐granted, tasks. Consequently, they often become dependent on their parents, and their parents shoulder a considerable responsibility.

Design

A secondary descriptive design with a deductive content analysis was used.

Methods

Ten parents who have a son or daughter with long‐term mental illness (aged 18–25 years) were interviewed. The deductive analysis was based on the caring theory of ‘Involvement in the light–Involvement in the dark’.

Results

The results are described using the following concepts in the theory: ‘Knowing’, ‘Doing’, ‘Being’ and ‘Attitude of the health professionals’. The result are to a great extent consistent with the ‘Involvement in the dark’ metaphor, which describes an isolated involvement in which the parents were not informed, seen or acknowledged by the health professionals. Continuous support by professionals with a positive attitude was described as being of decisive importance for meaningful involvement. The theory's transferability is strengthened to the mental health care context.

Conclusions

Parents have a considerable need for knowledge that can enable them to choose how they should act (be) and what they should do, in order to help and support their child.

Relevance to clinical practice

Since the patient, the family members and the professionals are mutually dependent, it is important to make use of each other’s knowledge in a partnership to achieve a common caring strategy.
Relationship between insulin‐like growth factor 1, leptin and ghrelin levels and catch‐up growth in small for gestational age infants of 27–31 weeks during neonatal intensive care unit admission
Authors: Ohkawa Natsuki , Shoji Hiromichi , Ikeda Naho , Suganuma Hiroki , Shimizu Toshiaki
Published: August 2016

Aim

Poor post‐natal growth is related to later morbidity and poor cognitive development in preterm infants. We investigated the relationship between plasma insulin‐like growth factor 1 (IGF‐1), leptin, active ghrelin levels and post‐natal growth in preterm infants small for gestational age (SGA).

Methods

Plasma IGF‐1, leptin and active ghrelin levels were measured at birth and at 2, 4, 6 and 8 weeks after birth in 42 very low birthweight (VLBW) infants (born between 27 and 31 weeks of gestation), including 14 SGA infants with extrauterine growth restriction (EUGR), 6 SGA infants without EUGR and 22 appropriate‐for‐gestational‐age infants.

Results

At birth, IGF‐1 levels in SGA infants without EUGR did not differ significantly from those in SGA infants with EUGR. However, IGF‐1 levels in SGA infants without EUGR were as high as those observed in appropriate‐for‐gestational‐age infants and were significantly different from those in SGA infants with EUGR at 4 and 8 weeks of age. Leptin and ghrelin levels did not differ significantly among the three groups at any time point.

Conclusion

IGF‐1 is related to catch‐up growth in SGA VLBW infants during neonatal intensive care unit admission; however, this does not appear to be the case for leptin and ghrelin. IGF‐1 level monitoring may be useful for predicting EUGR in preterm VLBW infants.
The Encroachment Speed of Potentially Disruptive Innovations with Indirect Network Externalities: The Case of E‐Readers
Authors: Parry Mark E. , Kawakami Tomoko
Published: August 2016

The authors examine factors that affect the encroachment speed of disruptive innovations with indirect network externalities. The authors focus on the 2010 introduction of a new generation of e‐readers in Japan and explore the reasons why, relative to comparable e‐readers in the United States, the Japanese e‐readers were introduced later and adoption rates have been lower. Existing research suggests several possible explanations for these cross‐country differences, including the attitudes and behaviors of the firms that compose the paper book value network in Japan, environmental variables such as legal and regulatory constraints, and cultural differences between Japan and the United States. To assess the importance of these explanations, the authors interviewed 20 key figures in the United States and Japan and reviewed a variety of published information sources. Findings indicate that the slower encroachment speed of e‐readers in Japan reflects a kind of myopia among publishing industry insiders arising from three sources: (1) organizational factors, (2) technology factors, and (3) environmental factors. Important elements within these categories include the interpretation of the market performance of earlier generations of e‐readers, the interdependence of partners within the value network for e‐books, the presence of competing technology formats that create uncertainty among consumers regarding the availability of e‐books for a specific platform, and the existence of regulations and institutionalized activities that constrain the supply of e‐books and retail pricing flexibility. Findings have important implications for future studies of encroachment speed, the management of disruptive technologies, and strategic responses to potentially disruptive innovations launched by fringe competitors and new entrants.
Curative therapies are superior to standard of care (transarterial chemoembolization) for intermediate stage hepatocellular carcinoma
Authors: Pecorelli Anna , Lenzi Barbara , Gramenzi Annagiulia , Garuti Francesca , Farinati Fabio , Giannini Edoardo G. , Ciccarese Francesca , Piscaglia Fabio , Rapaccini Gian Lodovico , Di Marco Maria , Caturelli Eugenio , Zoli Marco , Borzio Franco , Sacco Rodolfo , Cabibbo Giuseppe , Felder Martina , Morisco Filomena , Gasbarrini Antonio , Baroni Gianluca Svegliati , Foschi Francesco G. , Biasini Elisabetta , Masotto Alberto , Virdone Roberto , Bernardi Mauro , Trevisani Franco ,   the Italian LiverCancer (ITA.LI.CA) group
Published: August 2016

Background & Aims

The Barcelona Clinic Liver Cancer intermediate stage (BCLC‐B) of hepatocellular carcinoma (HCC) includes extremely heterogeneous patients in terms of tumour burden and liver function. Transarterial‐chemoembolization (TACE) is the first‐line treatment for these patients although it may be risky/useless for someone, while others could undergo curative treatments. This study assesses the treatment type performed in a large cohort of BCLC‐B patients and its outcome.

Methods

Retrospective analysis of 485 consecutive BCLC‐B patients from the ITA.LI.CA database diagnosed with naïve HCC after 1999. Patients were stratified by treatment.

Results

29 patients (6%) were lost to follow‐up before receiving treatment. Treatment distribution was: TACE (233, 51.1%), curative treatments (145 patients, 31.8%), sorafenib (18, 3.9%), other (39, 8.5%), best supportive care (BSC) (21, 4.6%). Median survival (95% CI) was 45 months (37.4–52.7) for curative treatments, 30 (24.7–35.3) for TACE, 14 (10.5–17.5) for sorafenib, 14 (5.2–22.7) for other treatments and 10 (6.0–14.2) for BSC (P<.0001). Independent prognosticators were gender and treatment. Curative treatments reduced mortality (HR 0.197, 95%CI: 0.098–0.395) more than TACE (HR 0.408, 95%CI: 0.211–0.789) (P<.0001) as compared with BSC. Propensity score matching confirmed the superiority of curative therapies over TACE.

Conclusions

In everyday practice TACE represents the first‐line therapy in an half of patients with naïve BCLC‐B HCC since treatment choice is driven not only by liver function and nodule characteristics, but also by contraindications to procedures, comorbidities, age and patient opinion. The treatment type is an independent prognostic factor in BCLC‐B patients and curative options offer the best outcome.
Shear‐wave elastography of the liver and spleen identifies clinically significant portal hypertension: A prospective multicentre study
Authors: Jansen Christian , Bogs Christopher , Verlinden Wim , Thiele Maja , Möller Philipp , Görtzen Jan , Lehmann Jennifer , Vanwolleghem Thomas , Vonghia Luisa , Praktiknjo Michael , Chang Johannes , Krag Aleksander , Strassburg Christian P. , Francque Sven , Trebicka Jonel
Published: August 2016

Background & Aims

Clinically significant portal hypertension (CSPH) is associated with severe complications and decompensation of cirrhosis. Liver stiffness measured either by transient elastography (TE) or Shear‐wave elastography (SWE) and spleen stiffness by TE might be helpful in the diagnosis of CSPH. We recently showed the algorithm to rule‐out CSPH using sequential liver‐ (L‐SWE) and spleen‐Shear‐wave elastography (S‐SWE). This study investigated the diagnostic value of S‐SWE for diagnosis of CSPH.

Methods

One hundred and fifty‐eight cirrhotic patients with pressure gradient measurements were included into this prospective multicentre study. L‐SWE was measured in 155 patients, S‐SWE in 112 patients, and both in 109 patients.

Results

Liver‐shear‐wave elastography and S‐SWE correlated with clinical events and decompensation. SWE of liver and spleen revealed strong correlations with the pressure gradient and to differentiate between patients with and without CSPH. The best cut‐off values were 24.6 kPa:L‐SWE and 26.3 kPa:S‐SWE. L‐SWE ≤16.0 kPa and S‐SWE ≤21.7 kPa were able to rule‐out CSPH. Cut‐off values of L‐SWE >29.5 kPa and S‐SWE >35.6 kPa were able to rule‐in CSPH (specificity >92%). Patients with a L‐SWE >38.0 kPa had likely CSPH. In patients with L‐SWE ≤38.0 kPa, a S‐SWE >27.9 kPa ruled in CSPH. This algorithm has a sensitivity of 89.2% and a specificity of 91.4% to rule‐in CSPH. Patients not fulfilling these criteria may undergo HVPG measurement.

Conclusions

Liver and spleen SWE correlate with portal pressure and can both be used as a non‐invasive method to investigate CSPH. Even though external validation is still missing, these algorithms to rule‐out and rule‐in CSPH using sequential SWE of liver and spleen might change the clinical practice.