bluuebunny/crossref_metadata_2025 huggingface dataset:
S-15 in combination of Akt inhibitor promotes the expansion of CD45RA−CCR7+ tumor infiltrating lymphocytes with high cytotoxic potential and downregulating PD-1+Tim-3+ cells as well as regulatory T cells
Authors: Xu Benling , Yuan Long , Chen Guangyu , Li Tiepeng , Zhou Jinxue , Zhang Chengjuan , Qin Peng , Muthana Musleh M. , Wang Shengdian , Du Xuexiang , Gao Quanli
Published: December 2019

Background

Autologous tumor-infiltrating lymphocytes (Tils) immunotherapy is a promising treatment in patients with advanced hepatocellular cancer. Although Tils treatment has shown great promise, their persistence and the efficacy after adoptive-transfer are insufficient and remain a challenge. Studies have demonstrated that IL-15 and Akt inhibitor can regulate T cell differentiation and memory. Here, we constructed S-15 (Super human IL-15), a fusion protein consisting of human IL-15, the sushi domain of the IL-15 receptor α chain and human IgG-Fc. Herein we compared the effects of S-15 with IL-2 or in combination with Akti on the expansion and activation of Tils.

Methods

Hepatocellular cancer tissues were obtained from 6 patients, Tils were expanded using IL-2, IL-2/S-15, IL-2/Akti or in combination IL-2/S-15/Akti. At day 10, anti-CD3 antibody was added to the culture media and expanded to day 25. The composition, exhaustion and T-cell differentiation markers (CD45RA/CCR7) were analyzed by flow cytometry.

Results

We found that IL-2/S-15/Akti expanded Tils and showed the highest percentage of central memory CD45RA−CCR7+ phenotype prior to anti-CD3 antibody activation and after anti-CD3 antibody activation. T cells cultured with IL-2/S-15/Akti exhibited a mixture of CD4+, CD8+, and CD3+CD4−CD8− T cells; S-15 in combination with Akt inhibitor downregulated the expression of PD-1+Tim-3+ on Tils and decreased the Tregs in Tils. Additionally, the Tils expanded in the presence of the Akt inhibitor and S-15 showed enhanced antitumor activity as indicated by the increase in IFN-γ producing tumor infiltrating CD8+ T cells and without comprising the Tils expansion.

Conclusion

Our study elucidates that IL-2/S-15/Akti expanded Tils and represent a viable source for the cellular therapy for patients with hepatocellular cancer.
Validation of Plasmodium falciparum dUTPase as the target of 5′-tritylated deoxyuridine analogues with anti-malarial activity
Authors: Pérez-Moreno Guiomar , Sánchez-Carrasco Paula , Ruiz-Pérez Luis Miguel , Johansson Nils Gunnar , Müller Sylke , Baragaña Beatriz , Hampton Shahienaz Emma , Gilbert Ian Hugh , Kaiser Marcel , Sarkar Sandipan , Pandurangan Thiyagamurthy , Kumar Vijeesh , González-Pacanowska Dolores
Published: December 2019

Background

Malaria remains as a major global problem, being one of the infectious diseases that engender highest mortality across the world. Due to the appearance of resistance and the lack of an effective vaccine, the search of novel anti-malarials is required. Deoxyuridine 5′-triphosphate nucleotido-hydrolase (dUTPase) is responsible for the hydrolysis of dUTP to dUMP within the parasite and has been proposed as an essential step in pyrimidine metabolism by providing dUMP for thymidylate biosynthesis. In this work, efforts to validate dUTPase as a drug target in Plasmodium falciparum are reported.

Methods

To investigate the role of PfdUTPase in cell survival different strategies to generate knockout mutants were used. For validation of PfdUTPase as the intracellular target of four inhibitors of the enzyme, mutants overexpressing PfdUTPase and HsdUTPase were created and the IC50 for each cell line with each compound was determined. The effect of these compounds on dUTP and dTTP levels from P. falciparum was measured using a DNA polymerase assay. Detailed localization studies by indirect immunofluorescence microscopy and live cell imaging were also performed using a cell line overexpressing a Pfdut-GFP fusion protein.

Results

Different attempts of disruption of the dut gene of P. falciparum were unsuccessful while a 3′ replacement construct could recombine correctly in the locus suggesting that the enzyme is essential. The four 5′-tritylated deoxyuridine analogues described are potent inhibitors of the P. falciparum dUTPase and exhibit antiplasmodial activity. Overexpression of the Plasmodium and human enzymes conferred resistance against selective compounds, providing chemical validation of the target and confirming that indeed dUTPase inhibition is involved in anti-malarial activity. In addition, incubation with these inhibitors was associated with a depletion of the dTTP pool corroborating the central role of dUTPase in dTTP synthesis. PfdUTPase is mainly localized in the cytosol.

Conclusion

These results strongly confirm the pivotal and essential role of dUTPase in pyrimidine biosynthesis of P. falciparum intraerythrocytic stages.
A new method for detecting the outer corneal contour in images from an ultra-fast Scheimpflug camera
Authors: Jędzierowska Magdalena , Koprowski Robert , Wilczyński Sławomir , Krysik Katarzyna
Published: December 2019

Background

The Corvis® ST tonometer is an innovative device which, by combining a classic non-contact tonometer with an ultra-fast Scheimpflug camera, provides a number of parameters allowing for the assessment of corneal biomechanics. The acquired biomechanical parameters improve medical diagnosis of selected eye diseases. One of the key elements in biomechanical measurements is the correct corneal contour detection, which is the basis for further calculations. The presented study deals with the problem of outer corneal edge detection based on a series of images from the afore-mentioned device. Corneal contour detection is the first and extremely important stage in the acquisition and analysis of corneal dynamic parameters.

Result

A total of 15,400 images from the Corvis® ST tonometer acquired from 110 patients undergoing routine ophthalmologic examinations were analysed. A method of outer corneal edge detection on the basis of a series of images from the Corvis® ST was proposed. The method was compared with known and commonly used edge detectors: Sobel, Roberts, and Canny operators, as well as others, known from the literature. The analysis was carried out in MATLAB® version 9.0.0.341360 (R2016a) with the Image Processing Toolbox (version 9.4) and the Neural Network Toolbox (version 9.0). The method presented in this paper provided the smallest values of the mean error (0.16%), stability (standard deviation 0.19%) and resistance to noise, characteristic for Corvis® ST tonometry tests, compared to the methods known from the literature. The errors were 5.78 ± 9.19%, 3.43 ± 6.21%, and 1.26 ± 3.11% for the Roberts, Sobel, and Canny methods, respectively.

Conclusions

The proposed new method for detecting the outer corneal contour increases the accuracy of intraocular pressure measurements. It can be used to analyse dynamic parameters of the cornea.
The respective parts of incidence and lethality in socioeconomic differences in cancer mortality. An analysis of the French network Cancer registries (FRANCIM) data
Authors:   the French Network of Cancer Registries (FRANCIM), Bryere Joséphine , Tron Laure , Menvielle Gwenn , Launoy Guy
Published: December 2019

Background

To determine relevant public health actions and to guide intervention priorities, it is of great importance to assess the relative contribution of incidence and lethality to social inequalities in cancer mortality.

Methods

The study population comprised 185,518 cases of cancer diagnosed between 2006 and 2009 recorded in the French registries. Survival was known for each patient (endpoint: 30/06/2013). Deprivation was assessed using the European Deprivation Index. We studied the influence of deprivation on mortality, incidence and lethality rates and quantified the respective proportions of incidence and lethality in social inequalities in mortality by calculating attributable deaths.

Results

For cancers with social inequalities both in incidence and lethality, excess mortality in deprived was mainly caused by social inequalities in incidence (e.g. men lung cancer: 87% of excess deaths in the deprived caused by inequalities in incidence). Proportions were more balanced for some cancer sites (e.g. cervical cancer: 56% incidence, 44% lethality). For cancer sites with a higher incidence in the least deprived (e.g. breast cancer), the excess-lethality in deprived leads entirely the higher mortality among the deprived.

Conclusions

Most of the excess mortality in deprived is due to the excess incidence of tobacco-dependent cancers and the excess lethality of screenable cancers.
Deletion of the Mir-106b~ 25 MicroRNA cluster attenuates atherosclerosis in Apolipoprotein E knockout mice
Authors: Semo Jonathan , Chernin Gil , Jonas Michael , Shimoni Sara , George Jacob
Published: December 2019

Background

MicroRNAs are short non-coding RNAs that regulate gene expression. The aim of this study was to gain an understanding of the possible role of the miR-106b~ 25 microRNA cluster in regulating atherosclerosis in mice.

Methods

MiR-106b~ 25 knockout mice were outcrossed into Apolipoprotein E (ApoE) knockout background to generate double knockout mice. At 36 weeks of age, lesion size was evaluated in the aortic sinus by oil-red-O staining.

Results

Lesion size was 2-fold smaller in double KO mice in comparison to ApoE KO mice. In addition, collagen staining showed a trend towards a stable plaque phenotype in the double KO mice. Lipid profiling of plasma samples of double KO and ApoE KO mice using FPLC revealed over 2-fold decrease in Very low density lipoprotein (VLDL) cholesterol content and a 50% decrease in low density lipoprotein (LDL) cholesterol content in double KO mice. By using target prediction software, we have identified several possible targets for the miR-106b~ 25 cluster including the VLDL and LDL receptors. We found that upon feeding miR-106b~ 25 KO mice with high fat diet, the expression of LDL and VLDL receptors was higher than in the wild-type mice, suggesting the miR-106b~ 25 cluster regulates atherosclerosis by influencing clearance of VLDL and LDL from the plasma.

Conclusions

We identified the miR-106b~ 25 cluster as a novel regulator of atherosclerosis in ApoE KO mice, presumably by regulating plasma cholesterol levels.
Dimerization of MORC2 through its C-terminal coiled-coil domain enhances chromatin dynamics and promotes DNA repair
Authors: Xie Hong-Yan , Zhang Tai-Mei , Hu Shu-Yuan , Shao Zhi-Ming , Li Da-Qiang
Published: December 2019

Decondesation of the highly compacted chromatin architecture is essential for efficient DNA repair, but how this is achieved remains largely unknown. Here, we report that microrchidia family CW-type zinc finger protein 2 (MORC2), a newly identified ATPase-dependent chromatin remodeling enzyme, is required for nucleosome destabilization after DNA damage through loosening the histone-DNA interaction. Depletion of MORC2 attenuates phosphorylated histone H2AX (γH2AX) focal formation, compromises the recruitment of DNA repair proteins, BRCA1, 53BP1, and Rad51, to sites of DNA damage, and consequently reduces cell survival following treatment with DNA-damaging chemotherapeutic drug camptothecin (CPT). Furthermore, we demonstrate that MORC2 can form a homodimer through its C-terminal coiled-coil (CC) domain, a process that is enhanced in response to CPT-induced DNA damage. Deletion of the C-terminal CC domain in MORC2 disrupts its homodimer formation and impairs its ability to destabilize histone-DNA interaction after DNA damage. Consistently, expression of dimerization-defective MORC2 mutant results in impaired the recruitment of DNA repair proteins to damaged chromatin and decreased cell survival after CPT treatment. Together, these findings uncover a new mechanism for MORC2 in modulating chromatin dynamics and DDR signaling through its c-terminal dimerization.
Two precision medicine predictive tools for six malignant solid tumors: from gene-based research to clinical application
Authors: Zhang Zhiqiao , He Tingshan , Huang Liwen , Ouyang Yanling , Li Jing , Huang Yiyan , Wang Peng , Ding Jianqiang
Published: December 2019

Background

The current study aimed to construct competing endogenous RNA (ceRNA) regulation network and develop two precision medicine predictive tools for colorectal cancer (CRC).

Methods

Differentially expressed (DE) analyses were performed between CRC tissues and normal tissues. A ceRNA regulation network was constructed based on DElncRNAs, DEmiRNAs, and DEmRNAs.

Results

Fifteen mRNAs (ENDOU, MFN2, FASLG, SHOC2, VEGFA, ZFPM2, HOXC6, KLK10, DDIT4, LPGAT1, BEX4, DENND5B, PHF20L1, HSP90B1, and PSPC1) were identified as prognostic biomarkers for CRC by multivariate Cox regression. Then a Fifteen-mRNA signature was developed to predict overall survival for CRC patients. Concordance indexes were 0.817, 0.838, and 0.825 for 1-, 2- and 3-year overall survival. Patients with high risk scores have worse OS compared with patients with low risk scores.

Conclusion

The current study provided deeper understanding of prognosis-related ceRNA regulatory network for CRC. Two precision medicine predictive tools named Smart Cancer Survival Predictive System and Gene Survival Analysis Screen System were constructed for CRC. These two precision medicine predictive tools can provide valuable precious individual mortality risk prediction before surgery and improve the individualized treatment decision-making.
Transient receptor potential melastatin 2 channels are overexpressed in myalgic encephalomyelitis/chronic fatigue syndrome patients
Authors: Balinas Cassandra , Cabanas Helene , Staines Donald , Marshall-Gradisnik Sonya
Published: December 2019

Background

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is hallmarked by a significant reduction in natural killer (NK) cell cytotoxicity, a mechanism tightly regulated by calcium (Ca2+). Interestingly, interleukin-2 (IL-2) increases NK cell cytotoxicity. Transient receptor potential melastatin 2 (TRPM2) ion channels are fundamental for Ca2+signalling in NK cells. This pilot investigation aimed to characterise TRPM2 and CD38 surface expression in vitro on NK cells in ME/CFS patients. This investigation furthermore examined the pharmaceutical effect of 8-bromoadenosine phosphoribose (8-Br-ADPR) andN6-Benzoyladenosine-3′,5′-cyclic monophosphate (N6-Bnz-cAMP) on TRPM2 and CD38 surface expression and NK cell cytotoxicity between ME/CFS and healthy control (HC) participants.

Methods

Ten ME/CFS patients (43.45 ± 12.36) and 10 HCs (43 ± 12.27) were age and sex-matched. Isolated NK cells were labelled with fluorescent antibodies to determine baseline and drug-treated TRPM2 and CD38 surface expression on NK cell subsets. Following IL-2 stimulation, NK cell cytotoxicity was measured following 8-Br-ADPR andN6-Bnz-cAMP drug treatments by flow cytometry.

Results

Baseline TRPM2 and CD38 surface expression was significantly higher on NK cell subsets in ME/CFS patients compared with HCs. Post IL-2 stimulation, TRPM2 and CD38 surface expression solely decreased on the CD56DimCD16+subset. 8-Br-ADPR treatment significantly reduced TRPM2 surface expression on the CD56BrightCD16Dim/−subset within the ME/CFS group. Baseline cell cytotoxicity was significantly reduced in ME/CFS patients, however no changes were observed post drug treatment in either group.

Conclusion

Overexpression of TRPM2 on NK cells may function as a compensatory mechanism to alert a dysregulation in Ca2+homeostasis to enhance NK cell function in ME/CFS, such as NK cell cytotoxicity. As no improvement in NK cell cytotoxicity was observed within the ME/CFS group, an impairment in the TRPM2 ion channel may be present in ME/CFS patients, resulting in alterations in [Ca2+]imobilisation and influx, which is fundamental in driving NK cell cytotoxicity. Differential expression of TRPM2 between NK cell subtypes may provide evidence for their role in the pathomechanism involving NK cell cytotoxicity activity in ME/CFS.
The prognostic role of circulating CD8+ T cell proliferation in patients with untreated extensive stage small cell lung cancer
Authors: An Ning , Wang Haoyi , Jia Wenxiao , Jing Wang , Liu Chao , Zhu Hui , Yu Jinming
Published: December 2019

Background

Immunosuppression caused by tumorigenesis may promote tumor progress and invasion. Here, we investigated whether the characteristics of circulating T lymphocyte subtypes in patients with extensive small cell lung cancer (ED-SCLC) can be used as an alternative marker of tumor progression.

Methods

This study included 36 newly diagnosed ED-SCLC patients before treatment and the patients were followed up. 22 age and sex-matched healthy volunteers were selected as control. The percentages and proliferation potential of T lymphocyte subpopulations from peripheral blood were measured.

Results

CD4+ CD25+ Foxp3+ regulatory T cells (Tregs) were elevated in ED-SCLC patients compared with healthy controls (p = 0.0083). In contrast, the percentages of CD3+ and CD3+CD4+ T cells were significantly lower in SCLC patients (p < 0.001; p = 0.0014). The proliferation (%divided) of CD8+ T cells of SCLC patients was suppressed compared with healthy controls (p = 0.0058), but not of CD4+ T cells (p = 0.1611). Multivariate analyses showed that the %divided of CD8+ T cells is an independent predictor for PFS (HR: 4.342, 95% CI 1.324–14.245; p = 0.015). The percentages of peripheral Tregs and the degree of chemotherapy or radiotherapy induced lymphopenia negatively correlated with the proliferation of CD8+ T cells (p = 0.0225, r = − 0.379; p = 0.0003, r = − 0.464).

Conclusion

The present study indicates that SCLC patients have impaired immunity in peripheral blood, and the proliferation potential of circulating CD8+ T cells is a significant predicator for PFS.
Cumulative fluid accumulation is associated with the development of acute kidney injury and non-recovery of renal function: a retrospective analysis
Authors: Zhang Jing , Crichton Siobhan , Dixon Alison , Seylanova Nina , Peng Zhiyong Y. , Ostermann Marlies
Published: December 2019

Background

Acute kidney injury (AKI) is common in patients in the intensive care unit (ICU) and may be present on admission or develop during ICU stay. Our objectives were (a) to identify factors independently associated with the development of new AKI during early stay in the ICU and (b) to determine the risk factors for non-recovery of AKI.

Methods

We retrospectively analysed prospectively collected data of patients admitted to a multi-disciplinary ICU in a single tertiary care centre in the UK between January 2014 and December 2016. We identified all patients without AKI or end-stage renal failure on admission to the ICU and compared the outcome and characteristics of patients who developed AKI according to KDIGO criteria after 24 h in the ICU with those who did not develop AKI in the first 7 days in the ICU. Multivariable logistic regression was applied to identify factors associated with the development of new AKI during the 24–72-h period after admission. Among the patients with new AKI, we identified those with full, partial or no renal recovery and assessed factors associated with non-recovery.

Results

Among 2525 patients without AKI on admission, the incidence of early ICU-acquired AKI was 33.2% (AKI I 41.2%, AKI II 35%, AKI III 23.4%). Body mass index, Sequential Organ Failure Assessment score on admission, chronic kidney disease (CKD) and cumulative fluid balance (FB) were independently associated with the new development of AKI. By day 7, 69% had fully recovered renal function, 8% had partial recovery and 23% had no renal recovery. Hospital mortality was significantly higher in those without renal recovery. Mechanical ventilation, diuretic use, AKI stage III, CKD, net FB on first day of AKI and cumulative FB 48 h later were independently associated with non-recovery with cumulative fluid balance having a U-shape association.

Conclusions

Early development of AKI in the ICU is common and mortality is highest in patients who do not recover renal function. Extreme negative and positive FB were strong risk factors for AKI non-recovery.
Maintained high sustained serum malondialdehyde levels after severe brain trauma injury in non-survivor patients
Authors: Lorente Leonardo , Martín María M. , Abreu-González Pedro , Ramos Luis , Cáceres Juan J. , Argueso Mónica , Solé-Violán Jordi , Jiménez Alejandro , García-Marín Victor
Published: December 2019

Objective

Higher blood malondialdehyde (biomarker of lipid peroxidation) levels in the first hours of traumatic brain injury (TBI) have been found in patients with a worst prognosis. The objective of this study was to determine whether serum malondialdehyde levels during the first week of severe TBI could be used as mortality biomarkers. This was a multicenter, prospective and observational study performed in six Spanish Intensive Care Units. We included patients with severe TBI (defined as Glasgow Coma Scale < 9), and with Injury Severity Score in non-cranial aspects < 9. We determined serum malondialdehyde concentrations at days 1, 4 and 8 of TBI. We stablished 30-day mortality as the end-point study.

Results

We found that serum malondialdehyde concentrations at days 1 (p < 0.001), 4 (p < 0.001), and 8 (p < 0.001) of TBI were higher in non-survivor (n = 34) than in survivor (n = 90) patients. We found an area under curve of serum malondialdehyde concentrations at days 1, 4, and 8 of TBI to predict 30-day mortality of 77% (p < 0.001), 87% (p < 0.001) and 84% (p < 0.001) respectively. Thus, the new and most relevant findings of our study were serum malondialdehyde levels during the first week of TBI could be used as mortality biomarkers.
Reporting quality of Cochrane systematic reviews with Chinese herbal medicines
Authors: Zhang Xuan , Aixinjueluo Qi-Ying , Li Si-Yao , Song Lisa-L , Lau Chung-Tai , Tan Ran , Bian Zhao-Xiang
Published: December 2019

Background

Chinese herbal medicines (CHMs) are the major interventions of traditional Chinese medicine (TCM), which are typically administered as either single herbs or formulas. The Cochrane systematic reviews (SRs) of CHMs are essential references for evaluating the efficacy and safety of CHMs interventions; they are expected to be accurate and reliable. This study aimed to assess the reporting quality of these SRs, particularly whether necessary information related to CHM was adequately reported.

Methods

The Cochrane Database was systematically searched for all SRs of CHM that were published up to 31 December 2017. The primary analysis was to assess their reporting quality based on 27-item of the Preferred Reporting Items for Systematic reviews and Meta-Analyses (PRISMA) and 9-item of CHM-related information designed according to TCM theory. Descriptive statistics were additionally used to analyze their baseline characteristics.

Results

A total of 109 Cochrane SRs of CHM were identified from 1999 to 2017. For 27-item of PRISMA, 26 had the reporting compliances higher than 50%, of which 11 were fully reporting (100%). However, for CHM-related information, 65 (59.6%) SRs did not report the specific name of the CHM in the title, 42 (38.5%) lacked TCM-related rationales in the introduction, 62 (56.9%) did not include CHM-related characteristics in the additional analyses, and 77 (70.6%) did not analyze CHM results in terms of TCM-related theories in the discussion. Of 97 SRs that included clinical trials, 38 (39.2%) did not provide the details of composition and dosage of CHMs, 85 (87.6%) did not report the CHM sources, 13 (13.4%) did not provide the dosage form, 95 (97.9%) lacked CHM quality control information, and 57 (58.8%) did not describe details of the controls. For 62 (72.9%) of 85 SRs that included meta-analysis, it was impossible to assess whether meta-analysis had been properly conducted due to inadequate reporting of CHM interventions.

Conclusion

Although the Cochrane SRs of CHM showed reporting compliance with PRISMA checklist, their reporting quality needs improvement, especially about full reporting of CHM interventions and of TCM-related rationales. Reporting guideline of “PRISMA extension for CHM interventions” should be developed thus to improve their quality.
Overnight oximetry in children undergoing adenotonsillectomy: A single center experience
Authors: Liu C. Carrie , Chaput Kathleen H. , Kirk Valerie , Yunker Warren
Published: December 2019

Background

Obstructive sleep apnea (OSA) is the most common indication for adenotonsillectomy in children. Home-based sleep oximetry continues to be used in the diagnosis of pediatric OSA despite a lack of correlation with lab-based polysomnography. This study investigates whether factors influence surgeons in selecting patients for home-based sleep oximetry, how the study findings are used in patient management, and whether abnormal oximetry findings are associated with post-operative complications.

Methods

A retrospective review was performed on children with suspected OSA who had undergone a tonsillectomy and/or an adenoidectomy over a three-year period. Demographic features, comorbidities, pre-operative oximetry results, and post-operative complications were recorded. Data analysis consisting primarily of logistic regression was performed using Stata 12.0 (College Station, Texas).

Results

Data was collected from 389 children. Two hundred and seventy-one children underwent pre-operative oximetry (69.7%). There was no significant association between age or the presence of comorbidities and the likelihood of undergoing pre-operative sleep oximetry. The post-operative complication rate was 0.8%. There was no significant association between abnormal sleep oximetry parameters and post-operative complications. Children with one or more abnormal sleep oximetry parameters were more likely to be observed in hospital for at least one night (OR 2.4, p < 0.0001).

Conclusions

Our study suggests that surgeons are using home-based sleep oximetry findings to inform the post-operative care of children with suspected OSA, as those with abnormal home-based sleep oximetry findings were more likely to be observed in hospital. These hospital admissions may be unnecessary given the poor correlation of home-based oximetry and PSG as well as the low rate of serious post-operative complications.
Estimating the elastic properties of mica and clay minerals
Authors: Vernik Lev , Anantharamu Venkatesh
Published: December 2019

The orientation distribution of the platelets of the phyllosilicate minerals, including mica clays, significantly affects the elastic velocities and anisotropy of shales. Despite a substantial number of publications on shale elasticity in general and, more specifically, on the elastic properties of clay minerals (phyllosilicates) and clay mineral aggregates with varying degree of the platelet preferred orientation, our understanding of these properties is still rather limited. Elastic properties of mudrocks, influenced by the presence of variously oriented phyllosilicates, such as muscovite, illite, and illite/smectite platelets, can be well-constrained if not accurately estimated by a combination of microstructural observations and semiempirical rock-physics models for conventional shale. The orientation distribution data from published literature are used to relate the maximum platelet pole orientation density to the double median orientation angle [Formula: see text] with respect to the bedding plane, both of which relate to the platelet alignment strength. The [Formula: see text] angle is an equally intuitive orientation distribution parameter, which we rely upon in a heuristic approach to model bedding-normal anisotropic elastic moduli and P- and S-wave velocities of zero-porosity clay (matrix) aggregates as a function of the median orientation angle of clay platelets composing these aggregates. It is demonstrated that zero-porosity illite-dominated aggregates with perfect platelet alignment ([Formula: see text]) should have the platelet-normal elastic moduli of [Formula: see text], [Formula: see text], and a [Formula: see text] ratio of approximately [Formula: see text]. The platelet-normal moduli and mineral density of muscovite are significantly greater than those of illite, whereas the respective moduli of the smectite-dominated clay composite are smaller (and the velocity ratio is greater) than those estimated for illite-dominated clays. Finally, it is also shown that the platelet-normal velocity ratio gradually decreases in the smectite, illite, and muscovite series.
2D anisotropic multicomponent Gaussian-beam migration under complex surface conditions
Authors: Han Jianguang , Lü Qingtian , Gu Bingluo , Yan Jiayong , Zhang Hao
Published: December 2019

Elastic-wave migration in anisotropic media is a vital challenge, particularly for areas with irregular topography. Gaussian-beam migration (GBM) is an accurate and flexible depth migration technique, which is adaptable for imaging complex surface areas. It retains the dynamic features of the wavefield and overcomes the multivalued traveltimes and caustic problems of Kirchhoff migration. We have extended the GBM method to work for 2D anisotropic multicomponent migration under complex surface conditions. We use Gaussian beams to calculate the wavefield from irregular topography, and we use two schemes to derive the down-continued recorded wavefields. One is based on the local slant stack as in classic GBM, in which the PP- and PS-wave seismic records within the local region are directly decomposed into local plane-wave components from irregular topography. The other scheme does not perform the local slant stack. The Green’s function is calculated with a Gaussian beam summation emitted from the receiver point at the irregular surface. Using the crosscorrelation imaging condition and combining with the 2D anisotropic ray-tracing algorithm, we develop two 2D anisotropic multicomponent Gaussian-beam prestack depth migration (GB-PSDM) methods, i.e., using the slant stack and nonslant stack, for irregular topography. Numerical tests demonstrate that our anisotropic multicomponent GB-PSDM can accurately image subsurface structures under complex topography conditions.
Closing the gap between training needs and training provision in addiction medicine
Authors: Arya Sidharth , Delic Mirjana , Ruiz Blanca Iciar Indave , Klimas Jan , Papanti Duccio , Stepanov Anton , Cock Victoria , Krupchanka Dzmitry
Published: December 2019

Substance use disorders pose a significant global social and economic burden. Although effective interventions exist, treatment coverage remains limited. The lack of an adequately trained workforce is one of the prominent reasons. Recent initiatives have been taken worldwide to improve training, but further efforts are required to build curricula that are internationally applicable. We believe that the training needs of professionals in the area have not yet been explored in sufficient detail. We propose that a peer-led survey to assess those needs, using a standardised structured tool, would help to overcome this deficiency. The findings from such a survey could be used to develop a core set of competencies which is sufficiently flexible in its implementation to address the specific needs of the wide range of professionals working in addiction medicine worldwide.
Valproate and Retinoic Acid in Combination With Decitabine in Elderly Nonfit Patients With Acute Myeloid Leukemia: Results of a Multicenter, Randomized, 2 × 2, Phase II Trial
Authors: Lübbert Michael , Grishina Olga , Schmoor Claudia , Schlenk Richard F. , Jost Edgar , Crysandt Martina , Heuser Michael , Thol Felicitas , Salih Helmut R. , Schittenhelm Marcus M. , Germing Ulrich , Kuendgen Andrea , Götze Katharina S. , Lindemann Hans-Walter , Müller-Tidow Carsten , Heil Gerhard , Scholl Sebastian , Bug Gesine , Schwaenen Carsten , Giagounidis Aristoteles , Neubauer Andreas , Krauter Jürgen , Brugger Wolfram , De Wit Maike , Wäsch Ralph , Becker Heiko , May Annette M. , Duyster Justus , Döhner Konstanze , Ganser Arnold , Hackanson Björn , Döhner Hartmut ,   on behalf of the DECIDER Study Team
Published: December 2019

PURPOSE

DNA-hypomethylating agents are studied in combination with other epigenetic drugs, such as histone deacetylase inhibitors or differentiation inducers (eg, retinoids), in myeloid neoplasias. A randomized, phase II trial with a 2 × 2 factorial design was conducted to investigate the effects of the histone deacetylase inhibitor valproate and all- trans retinoic acid (ATRA) in treatment-naive elderly patients with acute myeloid leukemia (AML).

PATIENTS AND METHODS

Two hundred patients (median age, 76 years; range, 61-92 years) ineligible for induction chemotherapy received decitabine (20 mg/m2 intravenously, days 1 to 5) alone (n = 47) or in combination with valproate (n = 57), ATRA (n = 46), or valproate + ATRA (n = 50). The primary endpoint was objective response, defined as complete and partial remission, tested at a one-sided significance level of α = .10. Key secondary endpoints were overall survival, event-free survival, and progression-free survival and safety.

RESULTS

The addition of ATRA resulted in a higher remission rate (21.9% with ATRA v 13.5% without ATRA; odds ratio, 1.80; 95% CI, 0.86 to 3.79; one-sided P = .06). For valproate, no effect was observed (17.8% with valproate v 17.2% without valproate; odds ratio, 1.06; 95% CI, 0.51 to 2.21; one-sided P = .44). Median overall survival was 8.2 months with ATRA v 5.1 months without ATRA (hazard ratio, 0.65; 95% CI, 0.48 to 0.89; two-sided P = .006). Improved survival was observed across risk groups, including patients with adverse cytogenetics, and was associated with longer response duration. With valproate, no survival difference was observed. Toxicities were predominantly hematologic, without relevant differences between the 4 arms.

CONCLUSION

The addition of ATRA to decitabine resulted in a higher remission rate and a clinically meaningful survival extension in these patients with difficult-to-treat disease, without added toxicity.
Biomarkers and Noncalcified Coronary Artery Plaque Progression in Older Men Treated With Testosterone
Authors: Shaikh Kashif , Ellenberg Susan S , Nakanishi Rine , Snyder Peter J , Lee Juhwan , Wenger Nanette K , Lewis Cora E , Swerdloff Ronald S , Preston Peter , Hamal Sajad , Stephens-Sheilds Alisa , Bhasin Shalender , Cherukuri Lavanya , Cauley Jane A , Crandall Jill P , Cunningham Glenn R , Ensrud Kristine E , Matsumoto Alvin M , Molich Mark E , Alla Venkata M , Birudaraju Divya , Nezarat Negin , Rai Kelash , Almeida Shone , Roy Sion K , Sheikh Mohammad , Trad George , Budoff Mathew J
Published: December 2019

Objective

Recent results from the Cardiovascular Trial of the Testosterone Trials showed that testosterone treatment of older men with low testosterone was associated with greater progression of noncalcified plaque (NCP). We evaluated the effect of anthropometric measures and cardiovascular biomarkers on plaque progression in individuals in the Testosterone Trial.

Methods

The Cardiovascular part of the trial included 170 men aged 65 years or older with low testosterone. Participants received testosterone gel or placebo gel for 12 months. The primary outcome was change in NCP volume from baseline to 12 months, as determined by coronary computed tomography angiography (CCTA). We assayed several markers of cardiovascular risk and analyzed each marker individually in a model as predictive variables and change in NCP as the dependent variable.

Results

Of 170 enrollees, 138 (73 testosterone, 65 placebo) completed the study and were available for the primary analysis. Of 10 markers evaluated, none showed a significant association with the change in NCP volume, but a significant interaction between treatment assignment and waist-hip ratio (WHR) (P = 0.0014) indicated that this variable impacted the testosterone effect on NCP volume. The statistical model indicated that for every 0.1 change in the WHR, the testosterone-induced 12-month change in NCP volume increased by 26.96 mm3 (95% confidence interval, 7.72-46.20).

Conclusion

Among older men with low testosterone treated for 1 year, greater WHR was associated with greater NCP progression, as measured by CCTA. Other biomarkers and anthropometric measures did not show statistically significant association with plaque progression.
Immune-Mediated Myopathies
Authors: Goyal Namita A.
Published: December 2019

PURPOSE OF REVIEW

This article summarizes the clinical features, diagnostic evaluation, and management of the common immune-mediated myopathies: dermatomyositis, antisynthetase syndrome, immune-mediated necrotizing myopathy, and overlap myositis.

RECENT FINDINGS

The identification of myositis-specific autoantibodies has improved the characterization of the subtypes of myositis and associated clinical phenotypes, as the severity of muscle involvement, extramuscular manifestations, and risk of malignancy may vary among the subtypes of autoimmune myopathies.

The understanding and diagnostic accuracy of the subtypes of autoimmune myopathies have been enhanced with careful attention to the key clinical features, the emergence of myositis-specific autoantibodies, the characterization of histopathologic hallmark features, and the aid of muscle imaging. Several immunotherapeutic options now exist that can be selected to target a specific subtype, often with a favorable prognosis, especially when treatment starts early in the disease course.
Sporadic Inclusion Body Myositis and Other Rimmed Vacuolar Myopathies
Authors: Weihl Conrad C.
Published: December 2019

PURPOSE OF REVIEW

This article reviews the clinical, laboratory, and histopathologic features of sporadic inclusion body myositis (IBM) and explores its pathogenic overlap with inherited myopathies that have IBM-like pathology.

RECENT FINDINGS

Sporadic IBM is the most common acquired muscle disease in patients older than 50 years of age and is becoming more prevalent because of the increasing age of the population, the emerging development of more inclusive diagnostic criteria, and the advent of a diagnostic autoantibody. No effective therapy is known, and the pathogenic mechanism remains unclear. Some pathogenic insight can be gleaned from other myopathies with pathologic similarities or hereditary inclusion body myopathies. Although clinically distinct from sporadic IBM, preclinical models of hereditary inclusion body myopathy have offered an opportunity to move some therapies toward clinical development.

Patients with sporadic IBM experience significant morbidity, and the disease is associated with a large unmet medical need. As therapies are developed, improved diagnosis will be essential. Early diagnosis relies on awareness, clinical history, physical examination, laboratory features, and appropriate muscle biopsy processing. Future research is needed to understand the natural history, identify genetic risk factors, and validate biomarkers to track disease progression. These steps are essential as we move toward therapeutic interventions.
Myasthenia Gravis and Congenital Myasthenic Syndromes
Authors: Ciafaloni Emma
Published: December 2019

PURPOSE OF REVIEW

Myasthenia gravis (MG) is an autoimmune neuromuscular disease that causes fluctuating weakness in ocular, bulbar, and limb muscles and can, in 15% of cases, cause myasthenic crisis, a neurologic emergency characterized by respiratory failure. Although infrequent, MG needs to be promptly recognized and treated because the potential for improvement and remission is very high. The diagnosis of MG can be challenging and delayed because of the fluctuating nature of muscle weakness and the overlap of signs and symptoms with other neuromuscular diseases.

This article reviews the importance of prompt recognition of the typical signs and symptoms, best tests to confirm the diagnosis, currently available acute and chronic treatment modalities, the role of thymectomy, and the natural history of the disease. Special consideration related to the diagnosis and management in women during pregnancy and in children will also be reviewed. This article also includes an overview of congenital myasthenic syndromes.

RECENT FINDINGS

Recent significant efforts in standardizing and improving the care of patients with MG have occurred, as well as new momentum in developing new drugs for patients with MG who do not adequately respond to currently available treatments. The number of clinical trials and drugs in development for MG is steadily increasing. Eculizumab has been recently approved by the US Food and Drug Administration (FDA) for adult patients with generalized MG who are acetylcholine receptor–antibody positive, based on the REGAIN (Safety and Efficacy of Eculizumab in Refractory Generalized Myasthenia Gravis) study, a phase 3, randomized, double-blind, placebo-controlled, multicenter trial. An international, multicenter, randomized trial comparing thymectomy plus prednisone with prednisone alone has demonstrated that thymectomy improves clinical outcome in patients with nonthymomatous MG. Clinical care guidelines have been published, and the recommendations for clinical research standards and the Myasthenia Gravis Foundation of America MGFA clinical classification published in 2000 have become widely accepted by the clinical and research community of MG experts.

MG is a highly treatable disease with many effective treatment modalities available and with a natural history that continues to improve thanks to better diagnostic tests and effective drugs. The diagnosis and management of patients affected by MG can be highly rewarding for any neurologist as most patients are able to live normal lives if treated appropriately. Nevertheless, future research is needed to address unresolved clinical issues, such as when and how to discontinue immunosuppressive medications in patients in remission, the role and timing of thymectomy in children, and better treatment options for refractory patients.
Facioscapulohumeral Muscular Dystrophies
Authors: Wagner Kathryn R.
Published: December 2019

PURPOSE OF REVIEW

Facioscapulohumeral muscular dystrophy (FSHD) is a common muscular dystrophy affecting both pediatric and adult patients. This article reviews the phenotype and pathophysiology of the disease as well as the recent efforts in clinical outcome measures and clinical trials.

RECENT FINDINGS

As the name implies, FSHD involves weakness of facial muscles, muscles that fix the scapula, and muscles overlying the humerus (biceps and triceps). The distinctive phenotype of FSHD occurs secondary to two different genetic mechanisms. FSHD type 1 (FSHD1) is due to a deletion on chromosome 4q, leading to hypomethylation and derepression of DUX4. FSHD type 2 (FSHD2) is due to mutations in SMCHD1 with resulting hypomethylation of the same subtelomeric region of chromosome 4q and derepression of DUX4. Understanding the central role of DUX4 has opened up the possibility of disease-modifying treatments. In preparation for clinical trials of novel agents, researchers are in the process of validating a number of clinical trial outcome measures including MRI, the 6-minute walk test, the FSHD Composite Outcome Measure, reachable workspace, electrical impedance myography, and the FSHD Health Index.

The treatment of FSHD is currently supportive only. While past clinical trials in FSHD have been largely disappointing, novel agents in development, including antisense oligonucleotides, gene therapy, and small molecules, hold promise for future meaningful therapies.
Self-reported disability in rural Malawi: prevalence, incidence, and relationship to chronic conditions
Authors: Prynn Josephine E. , Dube Albert , Mwaiyeghele Elenaus , Mwiba Oddie , Geis Steffen , Koole Olivier , Nyirenda Moffat , Kuper Hannah , Crampin Amelia C.
Published: December 2019

Background: Disability is a complex concept involving physical impairment, activity limitation, and participation restriction. The Washington Group developed a set of questions on six functional domains (seeing, hearing, walking, remembering, self-care, and communicating) to allow collection of comparable data on disability. We aimed to improve understanding of prevalence and correlates of disability in the low-income setting of Malawi.

Methods: This study is nested in the Karonga Health and Demographic Surveillance Site in Malawi; the Washington Group questions were added to the annual survey in 2014. We used cross-sectional data from the 2014 survey to estimate the current prevalence of disability and examine associations of disability with certain chronic conditions. We then reviewed the consistency of responses to the questions over time using data from the 2015 survey.

Results: Of 10,863 participants, 9.6% (95% CI 9.0-10.1%) reported disability in at least one domain. Prevalence was higher among women and increased with age. Obesity and diabetes were associated with disability, but hypertension and HIV were not. Participants reporting “no difficulty” or “can’t do at all” for any domain were likely to report the same status one year later, whereas there was considerable movement between people describing “some difficulty” and “a lot of difficulty”.

Conclusions: Disability prevalence is high and likely to increase over time. Further research into the situation of this population is crucial to ensure inclusive policies are created and sustainable development goals are met.
Development of accounting of the population of the Russian Empire (XVIII-XIX centuries)
Authors: Борщик Наталья , Borschik Natal'ya , Пархоменко Артем , Parhomenko Artem
Published: December 2019

The monograph covers a wide range of issues related to the study of the mechanism of state registration of subjects of the Russian Empire. The causes of the transition to the poll tax form residents of the country in the early eighteenth century, traced the evolution of the census office, its complication and improvement. The audits were supplemented by numerous population surveys conducted at the initiative of individual ministries and departments, regional authorities, local governments, were associated with the beginning of registration of natural population movement by the Russian Orthodox Church, etc. The role of demographic information in the formation of the main directions of the internal policy of the state is shown.
It is addressed to all readers interested in the demographic history of our country.
Socio-economic history of France
Authors: Худокормов Александр , KHudokormov Alyeksandr
Published: December 2019

The textbook gives a General idea of the socio-economic history of France from antiquity to the present day, examines the main features of the economy and society of the country, a comparative analysis with the features of socio-economic development of Russia, shows the direction of transformation in France, which are relevant for the Russian reality.
Meets the requirements of the Federal state educational standards of higher education of the last generation.
For students of higher educational institutions studying in the direction of training "Economics".
Motivation and stimulation of labor activity
Authors: Минева Оксана , Mineva Oksana , Арутюнян Светлана , Arutyunyan Svetlana , Гаджиева Елена , Gadzhieva Elena , Крюкова Екатерина , Kryukova Ekaterina , Кочеткова Наталья , Kochetkova Natal'ya , Мордасова Татьяна , Mordasova Tatyana , Храмова Татьяна , Khramova Tatyana
Published: December 2019

The textbook outlines the main theoretical developments and practical recommendations of the world's leading companies, allowing to build an effective system of motivation and stimulation of labor activity.
For the first time within the same discipline such topics as loyalty, engagement and satisfaction as the basis of building an effective system of motivation and stimulation of labour activity. The Appendix contains descriptions of problem situations and cases.
Meets the requirements of the Federal state educational standards of higher education of the last generation.
For students studying in the direction of training 38.03.03 "personnel Management", graduate students and teachers of higher educational institutions of economic specialties, specialists in the field of personnel management.