bluuebunny/crossref_metadata_2025 huggingface dataset:
Phylogeny of teleost connexins reveals highly inconsistent intra- and interspecies use of nomenclature and misassemblies in recent teleost chromosome assemblies
Authors: Mikalsen Svein-Ole , Tausen Marni , í Kongsstovu Sunnvør
Published: March 2020

Background

Based on an initial collecting of database sequences from the gap junction protein gene family (also called connexin genes) in a few teleosts, the naming of these sequences appeared variable. The reasons could be (i) that the structure in this family is variable across teleosts, or (ii) unfortunate naming. Rather clear rules for the naming of genes in fish and mammals have been outlined by nomenclature committees, including the naming of orthologous and ohnologous genes. We therefore analyzed the connexin gene family in teleosts in more detail. We covered the range of divergence times in teleosts (eel, Atlantic herring, zebrafish, Atlantic cod, three-spined stickleback, Japanese pufferfish and spotted pufferfish; listed from early divergence to late divergence).

Results

The gene family pattern of connexin genes is similar across the analyzed teleosts. However, (i) several nomenclature systems are used, (ii) specific orthologous groups contain genes that are named differently in different species, (iii) several distinct genes have the same name in a species, and (iv) some genes have incorrect names. The latter includes a human connexin pseudogene, claimed asGJA4P, but which in reality isCx39.2P(a delta subfamily gene often calledGJD2like). We point out the ohnologous pairs of genes in teleosts, and we suggest a more consistent nomenclature following the outlined rules from the nomenclature committees. We further show that connexin sequences can indicate some errors in two high-quality chromosome assemblies that became available very recently.

Conclusions

Minimal consistency exists in the present practice of naming teleost connexin genes. A consistent and unified nomenclature would be an advantage for future automatic annotations and would make various types of subsequent genetic analyses easier. Additionally, roughly 5% of the connexin sequences point out misassemblies in the new high-quality chromosome assemblies from herring and cod.
Patient-level factors influencing hypertension control in adults in Accra, Ghana
Authors: Okai Darlene Esinam , Manu Adom , Amoah Emefa Modey , Laar Amos , Akamah Joseph , Torpey Kwasi
Published: March 2020

Background

Effective control of blood pressure is necessary to avert the risk of cardiovascular diseases from uncontrolled hypertension. Despite evidence on the benefits of hypertension control, rates of control in Ghana remain low. This study assessed the patient-level factors that influence hypertension control among adults in Accra, Ghana.

Methods

A total of 360 hypertensive patients from two hospitals in Accra, Ghana were enrolled in the study. Patient socio-demographic characteristics were tabulated and associations between patient characteristics and hypertension control were estimated using chi-square tests and logistic regression.

Results

Less than a quarter of the patients had a controlled blood pressure. The patient’s sex [AOR = 3.53 (95% CI:1.73–7.25], educational at junior high school [AOR = 3.52(95% CI 1.72–7.22)], senior and junior high school [AOR = 2.64 (95% CI 1.40–6.66_] and AOR = 3.06 (95% CI 1.03–6.67)] and presence of a comorbidity [AOR = 2.41 (95% CI 1.32; 4.42)] predicted BP control among patients. Dyslipidaemia [AOR = 0.31, [0.11–0.89)] an increased pill burden, and length of diagnosis of 2–5 years (AOR = 0.27 (0.1–0.73)] however, were associated with reduced BP control [AOR = 0.32(95% CI: 0.18–0.57)]. The majority of patients reported forgetfulness, side effects of medication and high pill burden as reasons for missing their medications.

Conclusion

Knowledge of hypertension among patients is low. Sex, formal education and the presence of comorbidity and more specifically dyslipidaemia influences blood pressure control. High pill burden and 2–5 years since diagnosis negatively affects the attainment of blood pressure control.
Uncontrolled hypertension in Ethiopia: a systematic review and meta-analysis of institution-based observational studies
Authors: Amare Firehiwot , Hagos Bisrat , Sisay Mekonnen , Molla Bereket
Published: March 2020

Background

Uncontrolled hypertension is one of the major risk factors of cardiovascular and cerebrovascular diseases. The prevalence of hypertension in Ethiopia is expected to reach up to 30%. The aim of this study was to determine the prevalence of uncontrolled hypertension among hypertensive patients on treatment in Ethiopia.

Methods

Electronic databases and search engines including EMBASE (Ovid), PubMed/Medline, and Google Scholar were searched for original records in the English language addressing hypertension control in Ethiopia from 2000 to 2018. Data were extracted using a format prepared in Microsoft Excel and exported to STATA 15.0 software for analyses. The study protocol is registered at PROSPERO with reference number ID: CRD42018116336.

Results

A total of 13 studies with 5226 hypertension patients were included for systematic review and meta-analysis. The pooled prevalence of uncontrolled hypertension in Ethiopia was 48% (95% confidence interval (CI): 36, 61%). The result of the sub-group analysis, based on the year of publications, revealed that the prevalence of uncontrolled BP was highest in 2016 (63%; CI: 60, 67%) and in 2015 (59%; CI: 53, 65%). Univariate meta-regression revealed that sampling distribution was not a source of heterogeneity for the pooled estimate as well as the sub group analysis.

Conclusion

The prevalence of uncontrolled hypertension was high in Ethiopia. This alarming public health issue fuels the ever-increasing cardiovascular and cerebrovascular diseases. The ministry of health has to design a policy and implementation mechanisms to reduce uncontrolled hypertension prevalence and improve awareness on blood pressure control.
A comparison of the characteristics and treatment outcomes of migrant and Australian-born users of a national digital mental health service
Authors: Kayrouz Rony , Karin Eyal , Staples Lauren G. , Nielssen Olav , Dear Blake F. , Titov Nickolai
Published: March 2020

Background

To explore the characteristics and compare clinical outcomes of non-Australian born (migrant) and Australian-born users of an Australian national digital mental health service.

Methods

The characteristics and treatment outcomes of patients who completed online treatment at the MindSpot Clinic between January 2014 and December 2016 and reported a country of birth other than Australia were compared to Australian-born users. Data about the main language spoken at home were used to create distinct groups. Changes in symptoms of depression and anxiety were measured using the Patient Health Questionnaire-9 Item (PHQ-9), and Generalized Anxiety Disorder Scale – 7 Item (GAD-7), respectively.

Results

Of 52,020 people who started assessment at MindSpot between 1st January 2014 and 22nd December 2016, 45,082 reported a country of birth, of whom 78.6% (n = 35,240) were Australian-born, and 21.4% (n = 9842) were born overseas. Of 6782 people who completed the online treatment and reported country of birth and main language spoken at home, 1631 (24%) were migrants, 960 (59%) were from English-speaking countries, and 671 (41%) were from non-English speaking countries. Treatment-seeking migrant users reported higher rates of tertiary education than Australian-born users. The baseline symptom severity, and rates of symptom reduction and remission following online treatment were similar across groups.

Conclusions

Online treatment was associated with significant reductions in anxiety and depression in migrants of both English speaking and non-English speaking backgrounds, with outcomes similar to those obtained by Australian-born patients. DMHS have considerable potential to help reduce barriers to mental health care for migrants.
Biology of phosphatidylserine (PS): basic physiology and implications in immunology, infectious disease, and cancer
Authors: Calianese David C. , Birge Raymond B.
Published: March 2020

Phosphatidylserine (PS) is an anionic phospholipid found on the membranes of a variety of organelles throughout the cell, most notably the plasma membrane. Under homeostatic conditions, PS is typically restricted to the inner leaflet of the plasma membrane. However, during cellular activation and/or induction of cell death, PS is externalized on the outer surface via the activation of phospholipid scramblases. Externalized PS not only changes the biochemical and biophysical properties of the plasma membrane but also initiates a series of interactions between endogenous extracellular proteins as well as receptors on neighboring cells to stimulate engulfment (efferocytosis) that influence the surrounding immune milieu. In this thematic series published in Cell Communication and Signaling, we feature review articles that highlight recent work in the field of PS biology, including the biochemistry and physiological significance of PS externalization, therapeutic applications and efforts to target PS, as well as posit open questions that remain in the field.
Prevalence of depression and associated factors among epileptic patients at Ilu Ababore zone hospitals, South West Ethiopia, 2017: a cross‑sectional study
Authors: Engidaw Nigus Alemnew , Bacha Lemi , Kenea Adamu
Published: March 2020

Background

Depression is one of the most common and overwhelming mental disorder in patients with epilepsy. Despite its high prevalence, depression continues to be under-recognized and undertreated. This study aimed to assess the prevalence of depression and its associated factors among epileptic patients attending the outpatient department of Ilu Ababore zone hospitals, Southwest Ethiopia, 2017.

Methods

Institution-based cross-sectional study was carried out among 402 individual with epilepsy. The participants were selected using systematic random sampling technique. Depression was measured using Beck’s Depression Inventory II. Oslo 3 Social Support Scale was used to assess social support. Perceived Stress Scale was used to assess the stress level of epileptic patients. The data were entered into Epi Info version 7 and analyzed by the SPSS version 20 software. We computed bivariate and multivariate binary logistic regressions to assess factors associated with depression. Statistical significance was declared at p-value < 0.05.

Results

A total of 402 study participants were interviewed with a response rate of 96.2%. The prevalence of depression was found to be 48.1%. In the final multivariate analysis, educational status [unable to read and write (AOR = 4.01,95% CI = 3.82, 8.28), primary (AOR = 3.43, 95% CI = 3.12,9.29), secondary (AOR = 2.01, 95% CI = 1.89,7.24)], high perceived stress (AOR = 3.21, 95% CI = 2.70, 8.41), poor social support (AOR = 2.04, 95% CI = 1.42, 2.78), onset of illness < 6 year (AOR = 2.40, 95%CI = 2.10,7.91), seizure frequency of [1–11 per year (AOR = 2.34, 95% = 1.41, 4.36), ≥ 12/year (AOR = 3.49, 95% CI = 3.43, 6.40)], and polytherapy (AOR = 2.73, 95%CI = 2.52, 7.14) were independent predictors of depression among epileptic patients at p-value < 0.05.

Conclusion and recommendation

Overall, the prevalence of depression was found to be high. Having lower educational status, early onset of illness, poor social support, high perceived stress, high seizure frequency, and polytherapy were factors statistically associated with depression. Clinicians need to give emphasis to epileptic patients with high perceived stress, low educational status, and poor social support. An early depression-focused regular screening for epileptic patient should be carried out by trained health professionals. Linkage with mental health service providers also needs to be considered.
3D-printed titanium implant-coated polydopamine for repairing femoral condyle defects in rabbits
Authors: Zhong Weiyang , Li Jianxiao , Hu Chenbo , Quan Zhengxue , Jiang Dianming , Huang Guangbin , Wang Zhigang
Published: March 2020

Background

Large segmental bone defects are still one of the challenges for orthopaedic surgeons. Although 3D-printed porous titanium is a potential bone substitute material because of its porous structure simulating natural bone, the titanium surface has low bioactivity, integrates with bone tissue through the simple mechanical interlock. The study aims to investigate the capability and osteogenesis of 3D-printed porous titanium (3D PPT)-coated polydopamine (PDA) for repairing bone defects.

Methods

Fifteen 6-month New Zealand white rabbits were implanted with PDA-3D PPT to repair 6 mm × 10 mm defects on the femoral condyle compared with the group of 3D PPT and comparing with the blank group. After 6 weeks and 12 weeks, micro-CT and histological examination were performed to observe bone growth.

Results

All the PDA-3D PPT group, the 3D PPT group and the blank group recovered in good condition. The images showed that the boundaries between the implant area and the surrounding area were obscure in the three groups. The results of micro-CT demonstrated that at 6 weeks and 12 weeks, the bone volume (BV) values of PDA-3D PPT implants group were significantly higher than those of the 3D PPT implants group and blank group (P < 0.05), the BV/tissue volume (TV) and the trabecular number (Tb.N) of PDA-3D PPT implants were significantly higher than those of the 3D PPT group and blank group (P < 0.05). The results of un-decalcified bone slicing showed that ore new bone appeared to form around the PDA-3D PPT than that of 3D PPT and blank group. The bone-implant contact (BIC) of PDA-3D PPT was better (P < 0.05) than that of 3D PPT group.

Conclusion

PDA-3D PPT could improve the bioactivity and promote the growth and healing of bone tissue and can be a promising repairing material.
Mangled finger salvage using cross-finger revascularization
Authors: Chen Song , Wen Gen , Cheng Liang , Chai Yimin
Published: March 2020

Background

Mangled finger with impaired arteria digitalis communis remains to be a challenge for replantation surgery due to the limited amount of tissue to work with.

Methods

Out of 554 hands with total finger amputations treated by replantation of finger/fingers from July 2012 to June 2018, there were 7 cases of damaged arteria digitalis communis, all of which were replanted by anastomosing distal adjacent radial/ulnar digital artery to distal end of ulnar/radial digital artery of amputation finger, and 2 veins were anastomosed for each finger. A skin pedicle was made by suturing both dorsal and palmar skin of adjacent fingers, and detachment was performed 4 weeks postoperatively.

Results

The survival rate was 100%. Mean total active motion was 191.4° (ranging from 170 to 220°). Mean 2-point discrimination was 8 mm static (ranging from 6 to 11 mm), and mean grip strength was 35.3 kg (range, 29 to 40 kg).

Conclusions

Based on our experience, cross-finger revascularization is an effective and safe alternative for mangled finger salvage when arteria digitalis communis is damaged, and good functional prognosis can be expected.
Pullback attraction in $H_{0}^{1}$ for semilinear heat equation in expanding domains
Authors: Xiao Yanping , Bai Yuqin , Zhang Huanhuan
Published: March 2020

In this article, we consider the pullback attraction in $H_{0}^{1}$H01 of pullback attractor for semilinear heat equation with domains expanding in time. Firstly, we establish higher-order integrability of difference about variational solutions; then, we prove the continuity of variational solution in $H_{0}^{1}(O_{t})$H01(Ot). As application of continuity, we obtain the pullback $\mathscr{D}_{\lambda _{1}}$Dλ1 attraction in $H_{0}^{1}$H01-norm.
Growth of solutions to two systems of q-difference differential equations
Authors: Tu Hongqiang , Yuan Wenjun
Published: March 2020

This paper is devoted to studying the growth of entire or meromorphic solutions to two systems ofq-difference differential equations. The estimates on the growth order of meromorphic solutions are obtained, which are extensions of previous results due to Xu et al . Examples are given to illustrate the existence of solutions of such systems.
Analysis of economic convergence of Islamic justice in selected Islamic countries
Authors: Alizadeh Emamzadeh Mohammad Reza
Published: March 2020

Justice is the most important principle in Islam and measures the extent to which decisions in Islamic countries comply with Islamic doctrine. Economic justice is a sub-domain of justice and is further subdivided to distributive justice. Distributive justice implies that improvement in economic well-being of an individual occurs to the detriment of another’s. The present study investigates economic convergence of Islamic justice in selected Islamic countries (Albania, Bangladesh, Azerbaijan, Egypt, Guinea, Iran, Iraq, Jordan, Kazakhstan, Kosovo, Kyrgyzstan, Malaysia, Maldives, Niger, Pakistan, Senegal, Tajikistan, Turkey, Yemen And Tunisia) during 1995–2015 using beta-type convergence and generalized method of moment. It is argued that growth rate of income distribution in communities that suffer from bad income distribution system will move in the long run towards fair distribution. Results of absolute beta convergence indicate convergence of Gini coefficient at rate of 0.31. The Gini coefficient is significant at 1%. Moreover, results of conditional beta convergence reveal convergence of Gini coefficient. Inflation rate and GDP positively affect this convergence.
Analyzing the genomic and transcriptomic architecture of milk traits in Murciano-Granadina goats
Authors: Guan Dailu , Landi Vincenzo , Luigi-Sierra María Gracia , Delgado Juan Vicente , Such Xavier , Castelló Anna , Cabrera Betlem , Mármol-Sánchez Emilio , Fernández-Alvarez Javier , de la Torre Casañas José Luis Ruiz , Martínez Amparo , Jordana Jordi , Amills Marcel
Published: March 2020

Background

In this study, we aimed to investigate the molecular basis of lactation as well as to identify the genetic factors that influence milk yield and composition in goats. To achieve these two goals, we have analyzed how the mRNA profile of the mammary gland changes in seven Murciano-Granadina goats at each of three different time points, i.e. 78 d (T1, early lactation), 216 d (T2, late lactation) and 285 d (T3, dry period) after parturition. Moreover, we have performed a genome-wide association study (GWAS) for seven dairy traits recorded in the 1st lactation of 822 Murciano-Granadina goats.

Results

The expression profiles of the mammary gland in the early (T1) and late (T2) lactation were quite similar (42 differentially expressed genes), while strong transcriptomic differences (more than one thousand differentially expressed genes) were observed between the lactating (T1/T2) and non-lactating (T3) mammary glands. A large number of differentially expressed genes were involved in pathways related with the biosynthesis of amino acids, cholesterol, triglycerides and steroids as well as with glycerophospholipid metabolism, adipocytokine signaling, lipid binding, regulation of ion transmembrane transport, calcium ion binding, metalloendopeptidase activity and complement and coagulation cascades. With regard to the second goal of the study, the performance of the GWAS allowed us to detect 24 quantitative trait loci (QTLs), including three genome-wide significant associations: QTL1 (chromosome 2, 130.72-131.01 Mb) for lactose percentage, QTL6 (chromosome 6, 78.90-93.48 Mb) for protein percentage and QTL17 (chromosome 17, 11.20 Mb) for both protein and dry matter percentages. Interestingly, QTL6 shows positional coincidence with the casein genes, which encode 80% of milk proteins.

Conclusions

The abrogation of lactation involves dramatic changes in the expression of genes participating in a broad array of physiological processes such as protein, lipid and carbohydrate metabolism, calcium homeostasis, cell death and tissue remodeling, as well as immunity. We also conclude that genetic variation at the casein genes has a major impact on the milk protein content of Murciano-Granadina goats.
Metabolomic profiling of metoprolol hypertension treatment reveals altered gut microbiota-derived urinary metabolites
Authors: Brocker Chad N. , Velenosi Thomas , Flaten Hania K. , McWilliams Glenn , McDaniel Kyle , Shelton Shelby K. , Saben Jessica , Krausz Kristopher W. , Gonzalez Frank J. , Monte Andrew A.
Published: March 2020

Introduction

Metoprolol succinate is a long-acting beta-blocker prescribed for the management of hypertension (HTN) and other cardiovascular diseases. Metabolomics, the study of end-stage metabolites of upstream biologic processes, yield insight into mechanisms of drug effectiveness and safety. Our aim was to determine metabolomic profiles associated with metoprolol effectiveness for the treatment of hypertension.

Methods

We performed a prospective pragmatic trial (NCT02293096) that enrolled patients between 30 and 80 years with uncontrolled HTN. Patients were started on metoprolol succinate at a dose based upon systolic blood pressure (SBP). Urine and blood pressure measurements were collected weekly. Individuals with a 10% decline in SBP or heart rate (HR) were considered responsive. Genotype for the CYP2D6 enzyme, the primary metabolic pathway for metoprolol, was evaluated for each subject. Unbiased metabolomic analyses were performed on urine samples using UPLC-QTOF mass spectrometry.

Results

Urinary metoprolol metabolite ratios are indicative of patient CYP2D6 genotypes. Patients taking metoprolol had significantly higher urinary levels of many gut microbiota-dependent metabolites including hydroxyhippuric acid, hippuric acid, and methyluric acid. Urinary metoprolol metabolite profiles of normal metabolizer (NM) patients more closely correlate to ultra-rapid metabolizer (UM) patients than NM patients. Metabolites did not predict either 10% SBP or HR decline.

Conclusion

In summary, urinary metabolites predict CYP2D6 genotype in hypertensive patients taking metoprolol. Metoprolol succinate therapy affects the microbiome-derived metabolites.
A comprehensive evaluation of ensemble learning for stock-market prediction
Authors: Nti Isaac Kofi , Adekoya Adebayo Felix , Weyori Benjamin Asubam
Published: March 2020

Stock-market prediction using machine-learning technique aims at developing effective and efficient models that can provide a better and higher rate of prediction accuracy. Numerous ensemble regressors and classifiers have been applied in stock market predictions, using different combination techniques. However, three precarious issues come in mind when constructing ensemble classifiers and regressors. The first concerns with the choice of base regressor or classifier technique adopted. The second concerns the combination techniques used to assemble multiple regressors or classifiers and the third concerns with the quantum of regressors or classifiers to be ensembled. Subsequently, the number of relevant studies scrutinising these previously mentioned concerns are limited. In this study, we performed an extensive comparative analysis of ensemble techniques such as boosting, bagging, blending and super learners (stacking). Using Decision Trees (DT), Support Vector Machine (SVM) and Neural Network (NN), we constructed twenty-five (25) different ensembled regressors and classifiers. We compared their execution times, accuracy, and error metrics over stock-data from Ghana Stock Exchange (GSE), Johannesburg Stock Exchange (JSE), Bombay Stock Exchange (BSE-SENSEX) and New York Stock Exchange (NYSE), from January 2012 to December 2018. The study outcome shows that stacking and blending ensemble techniques offer higher prediction accuracies (90–100%) and (85.7–100%) respectively, compared with that of bagging (53–97.78%) and boosting (52.7–96.32%). Furthermore, the root means square error (RMSE) recorded by stacking (0.0001–0.001) and blending (0.002–0.01) shows a better fit of ensemble classifiers and regressors based on these two techniques in market analyses compared with bagging (0.01–0.11) and boosting (0.01–0.443). Finally, the results undoubtedly suggest that an innovative study in the domain of stock market direction prediction ought to include ensemble techniques in their sets of algorithms.
Changes in extremely heavy and light snow-cover winters due to global warming over high mountainous areas in central Japan
Authors: Kawase Hiroaki , Yamazaki Takeshi , Sugimoto Shiori , Sasai Takahiro , Ito Rui , Hamada Takashi , Kuribayashi Masatoshi , Fujita Mikiko , Murata Akihiko , Nosaka Masaya , Sasaki Hidetaka
Published: March 2020

To investigate future changes in snow cover and snowfall over mountainous areas in central Japan, we conducted regional climate projections using a high-resolution non-hydrostatic regional climate model (NHRCM) with 5 km and 1 km grid spacings. Boundary conditions are derived from the database for Policy Decision making for Future climate change (d4PDF) 20 km regional climate projections (d4PDF20). The d4PDF20 assumes two future climates when global mean surface air temperatures are approximately 2 K and 4 K warmer than in the preindustrial period. Experiments with 5 km grid spacing are conducted by NHRCM for 372 years in d4PDF20 in each climate. Experiments with 1 km grid spacing are performed focusing on 5 years with heavy, median, and light snow cover of mountainous areas in each climate. In the years with heavy snow cover in 2 K and 4 K warming climates, snowfall is enhanced from late December to February at more than 2000 m above sea level (mASL) in the northern parts of Japan’s Northern Alps, resulting in heavy snow cover comparable to that in the present climate. Heavy daily snowfall remarkably increases due to global warming in the years with heavy snow cover. At low elevations below 500 mASL, snowfall decreases in all ranges of snowfall intensity in the 4 K warming climate, while the frequency of heavy daily snowfall increases in the 2 K warming climate. Precipitation is enhanced around the Japan-Sea Polar-airmass Convergence Zone and the mountainous area facing the Sea of Japan, resulting in strengthened heavy snowfall at high elevations where the winter mean temperature is approximately − 10 °C in the present climate. On the other hand, remarkable reductions in snow cover and snowfall are projected in years with light snow cover. Our results indicate that global warming causes heavy and light mid-winter snowfalls at high elevations of Japan’s Northern Alps that are more extreme than those in the present climate.

Graphical abstract
Epidemiological differences in levels of depressive signs among nocturnal symptoms of insomnia; results from the HUNT study
Authors: Bragantini Daniela , Sivertsen Børge , Gehrman Philip , Lydersen Stian , Güzey Ismail Cüneyt
Published: March 2020

Background

Insomnia is a sleep disorder characterized by multiple nocturnal symptoms (sleep onset, maintenance and terminal insomnia). However, these symptoms are assumed to have the same weight in the diagnosis and consequences of insomnia. In particular, little is known regarding whether these nocturnal symptoms are equally related to depression. In this study, we compared level of depressive signs among individuals reporting different patterns of nocturnal symptoms of insomnia.

Methods

We used data from the large population-based HUNT3 study. The final sample included 7933 individuals (4317 cases, 3616 controls). Signs of depression were measured using the depression subscale of the Hospital Anxiety and Depression Scale (HADS-D), while the three nocturnal symptoms of insomnia were assessed using a Likert-like scale (“Never”, “Sometimes”, “Several times a week”). Individuals reporting to experience at least one symptom of insomnia “Several times a week” were grouped according to their pattern of reported symptoms and their HADS-D levels compared.

Results

Participants reporting sleep onset insomnia combined with terminal insomnia had the highest depression score (M = 5.4, SD = 3.4), but reporting maintenance insomnia in addition does not increase the HADS-D scores any further (M = 5.2, SD = 3.6). Accordingly, sleep maintenance insomnia alone had the lowest score (M = 3.4, SD = 2.9).

Conclusions

We found several differences among patterns of symptoms of insomnia but not all of them are clinically relevant. Further studies in clinical samples may help reveal relevant differences among patterns of symptoms, which may aid in refining interventions for concomitant depression and insomnia.
Statistical significance: p value, 0.05 threshold, and applications to radiomics—reasons for a conservative approach
Authors: Di Leo Giovanni , Sardanelli Francesco
Published: March 2020

Here, we summarise the unresolved debate about p value and its dichotomisation. We present the statement of the American Statistical Association against the misuse of statistical significance as well as the proposals to abandon the use of p value and to reduce the significance threshold from 0.05 to 0.005. We highlight reasons for a conservative approach, as clinical research needs dichotomic answers to guide decision-making, in particular in the case of diagnostic imaging and interventional radiology. With a reduced p value threshold, the cost of research could increase while spontaneous research could be reduced. Secondary evidence from systematic reviews/meta-analyses, data sharing, and cost-effective analyses are better ways to mitigate the false discovery rate and lack of reproducibility associated with the use of the 0.05 threshold. Importantly, when reporting p values, authors should always provide the actual value, not only statements of “p < 0.05” or “p ≥ 0.05”, because p values give a measure of the degree of data compatibility with the null hypothesis. Notably, radiomics and big data, fuelled by the application of artificial intelligence, involve hundreds/thousands of tested features similarly to other “omics” such as genomics, where a reduction in the significance threshold, based on well-known corrections for multiple testing, has been already adopted.
Amplitude variation with offset inversion using acoustic-elastic local solver
Authors: Jaimes-Osorio Ligia Elena , Malcolm Alison , Gholami Ali
Published: March 2020

Conventional amplitude variation with offset (AVO) inversion analysis uses the Zoeppritz equations, which are based on a plane-wave approximation. However, because real seismic data are created by point sources, wave reflections are better modeled by spherical waves than by plane waves. Indeed, spherical reflection coefficients deviate from planar reflection coefficients near the critical and postcritical angles, which implies that the Zoeppritz equations are not applicable for angles close to critical reflection in AVO analysis. Elastic finite-difference simulations provide a solution to the limitations of the Zoeppritz approximation because they can handle near- and postcritical reflections. We have used a coupled acoustic-elastic local solver that approximates the wavefield with high accuracy within a locally perturbed elastic subdomain of the acoustic full domain. Using this acoustic-elastic local solver, the local wavefield generation and inversion are much faster than performing a full-domain elastic inversion. We use this technique to model wavefields and to demonstrate that the amplitude from within the local domain can be used as a constraint in the inversion to recover elastic material properties. Then, we focus on understanding how much the amplitude and phase contribute to the reconstruction accuracy of the elastic material parameters ([Formula: see text], [Formula: see text], and [Formula: see text]). Our results suggest that the combination of amplitude and phase in the inversion helps with the convergence. Finally, we analyze elastic parameter trade-offs in AVO inversion, from which we find that to recover accurate P-wave velocities we should invert for [Formula: see text] and [Formula: see text] simultaneously with fixed density.
A lateral well in the Shublik Formation, Alaska North Slope, with implications for unconventional resource potential
Authors: Hosford Scheirer Allegra , Bird Kenneth J.
Published: March 2020

Analyses of a horizontal well drilled in the Shublik Formation within the southern part of the Prudhoe Bay field provide the first glimpse of the unit’s potential as an unconventional resource. Drilled in 1996, the 1450 ft (442 m) long well, PBU X-19B L1, targeted the 17 ft (5 m) thick Shublik Zone B. More than 70% of the lateral well path sampled that target, a feat of precise geosteering years before the unconventional revolution. The well operator’s drilling plan focused on the middle subzone of Zone B. The well history ascribes the focus on the middle subzone to its high silt content, open fractures, and significant hydrocarbon shows. Contrary to the drilling narrative, cuttings from 41 intervals indicate that siltstone monotonically decreases in Shublik Zone B, on average, from 50% to 40% to 30% in the three subzones from top to base. The limestone concentration inversely varies with the siltstone concentration through Zone B, steadily increasing from top to base (40%, 50%, and 60%). Hydrocarbon shows in the upper and middle subzones of Zone B range from good to fair, whereas the shows in the lower Zone B are weaker. Unfortunately, scant geochemical analyses of oil produced from the Shublik flow test combined with engineering difficulties prevent a definitive conclusion as to the source of the oil — the fractured Shublik Formation or the underlying Ivishak Sandstone. However, on the basis of favorable lithology, hydrocarbon shows, and fracture density, the upper and middle subzones of Zone B should be targeted as a potential unconventional accumulation if and when a well is drilled in the pod of active source rock downdip.
GDC-0449 in patients with advanced chondrosarcomas: A French Sarcoma Group (FSG)/French and U.S. National Cancer Institutes phase II collaborative study.
Authors: Italiano Antoine , Le Cesne Axel , Cassier Philippe A , Ray-Coquard Isabelle , Domont Julien , Piperno-Neumann Sophie , Duffaud Florence , Penel Nicolas , Takebe Naoko , Blay Jean-Yves , Bui Nguyen Binh
Published: March 2020

10005

Background: Chondrosarcomas (CS) exhibit a strong activation of hedgehog (Hh) signaling which plays a crucial role in cartilage tumorigenesis. Preclinical data show that hedgehog blockade reduces strongly chondrosarcoma cell proliferation and tumour size. GDC-0449 is a small-molecule antagonist of the Hh pathway. Methods: This is a multicentric single-arm phase 2 clinical trial based on two-stage Simon’s design which assesses safety and efficacy of GDC-0449 in patients (pts) with advanced CS. All pts had to have documented progressive disease (PD) as per RECIST 1.1 before study entry. Pts receive GDC-0449 150mg (oral route), daily until PD or unacceptable toxicity. The primary endpoint is the 6-month non-PD rate according to RECIST. Based on the following hypotheses: 20% 6-month non-PD rate (H0), 40% acceptable 6-month non-PD rate (H1), 10% type I error rate, 90% power, a total of 37 assessable pts are necessary (17 for the first stage + 20 for the second stage). Following the inclusion of the first 17 pts, if ≥ four pts are progression-free at 6 months, the accrual will continue. In order to account for not assessable pts (+/- 10%), 41 pts will be recruited. Accrual started in February 2011 in six centers of the FSG. Results: As of January 24 2012, 40 pts (28 males, 12 females) have been included in the study. Median age is 59 years (30-86). The most frequent histological subtype is conventional CS (n=32). Twenty eight pts (70%) had grade 1 or 2 adverse events (AE) possibly related to the drug whereas 3 pts (7.5%) had grade 3 or 4 AE. The planned interim statistical analysis performed after central histological and radiological review showed that four patients out of the first 17 evaluable patients had stable disease indicating that GDC-0449 had reached the primary endpoint to justify continuing accrual after the 1st step of the study. 15 pts are still on treatment. Molecular analyses are available for 21 pts. No mutation of SMO was detected. qRT-PCR experiments and PTCH sequencing are ongoing. Conclusions: GDC-0449 is well tolerated and shows some activity in a subset of pts with advanced CS. Final clinical and molecular data will be presented at the meeting.
Phase III, placebo-controlled trial (SUCCEED) evaluating ridaforolimus as maintenance therapy in advanced sarcoma patients following clinical benefit from prior standard cytotoxic chemotherapy: Long-term (≥ 24 months) overall survival results.
Authors: Blay Jean-Yves , Chawla Sant P. , Ray-Coquard Isabelle , Cesne Axel Le , Staddon Arthur P. , Milhem Mohammed M. , Penel Nicolas , Riedel Richard F. , Bui Nguyen Binh , Cranmer Lee D. , Reichardt Peter , Bompas Emmanuelle , Alcindor Thierry , Rushing Daniel A. , Song Yang , Ebbinghaus Scot , Haluska Frank G. , Dodion Pierre F. , Demetri George D.
Published: March 2020

10010

Background: The mammalian target of rapamycin (mTOR) regulates cell growth and proliferation and is abnormally activated in many sarcomas. Ridaforolimus, an oral mTOR inhibitor, demonstrated clinical activity in previous nonrandomized trials in advanced sarcomas following failure of prior chemotherapy. Methods: An international, multicenter, placebo-controlled, phase 3 trial was conducted to evaluate maintenance therapy with ridaforolimus in patients with metastatic soft-tissue or bone sarcomas who achieved disease control from prior chemotherapy. Patients were randomized (1:1) to receive oral ridaforolimus (40 mg) or placebo once daily for 5 days each week. The primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival (OS) and safety and tolerability. For OS, patients were to be followed at 3-month intervals for at least 24 months and up to 60 months after randomization. Results: 702 of 711 randomized patients received treatment. At the time of the data cutoff for OS (386 deaths), patients in the study population had been followed for at least 15 months. Median OS was 93.3 weeks with ridaforolimus vs 83.4 weeks with placebo (hazard ratio [HR]=0.88; 95% confidence interval [CI]: 0.72, 1.08; P=0.23). Ridaforolimus significantly improved PFS vs placebo (HR=0.72; 95% CI: 0.61, 0.85; P=0.0001; median PFS: 17.7 weeks vs 14.6 weeks); PFS improved across all prespecified baseline characteristics. As expected from the class of mTOR inhibitors, the most common adverse events with ridaforolimus were stomatitis, thrombocytopenia, noninfectious pneumonitis, hypertriglyceridemia, hyperglycemia, infections, and rash. Conclusions: Oral ridaforolimus was generally well-tolerated and significantly improved PFS in metastatic sarcoma patients with benefit from prior chemotherapy, offering an effective treatment alternative to surveillance alone. Results of a long-term OS analysis (prespecified to occur at 67% mortality, 24 months minimum follow-up) in the intent-to-treat population will be available in early 2012.
18f-FDG-PET imaging as an early survival predictor in patients with high-grade soft tissue sarcomas undergoing neoadjuvant therapy.
Authors: Herrmann Ken , Benz Matthias R. , Czernin Johannes , Auerbach Martin , Tap William D. , Dry Sarah M , Schuster Tibor , Eckardt Jeff J. , Phelps Michael E. , Eilber Frederick C.
Published: March 2020

10012

Background: Neoadjuvant therapy is associated with considerable toxicity and limited survival benefits in patients with soft tissue sarcoma (STS). We prospectively evaluated whether 18F-FDG PET/CT (PET) imaging after the initial cycle and after end of neoadjuvant therapy could predict overall survival in these patients. Methods: 76 patients (primary STS: n=57; metastatic disease: n=19) with high grade STS were included in this study. PET was performed prior to (n=76), after one cycle (n=52) and after the end of neoadjuvant therapy (n=74). Overall survival was correlated with changes of SUVpeak, RECIST, histopathological response and other parameters predictive of STS survival. Results: One-, two- and five- year survival rates were 95±3.0%, 86±4.6% and 68±6.6% for primary STS. Corresponding one- and two- year survival rates for recurrent/metastatic STS were 77±10.0% and 47±12.1%. Optimal cut-off for early decreases in SUV peak were significant predictors of survival in log-rank test (p=0.027 and p=0.043). However, late decreases in SUV peak were only predictive in primary STS (SUV peak decrease 57%; p=0.035) but not in recurrent/metastatic STS (SUV peak decrease 52%; p=0.057). In primary STS, 7/15 early PET non-responders but only 4/24 early PET responders died during follow up (p=0.068). Conclusions: 18F-FDG-PET seems feasible to predict survival after the initial cycle of neoadjuvant chemotherapy in both patients with primary STS and recurrent/metastatic STS and can potentially serve as an intermediate endpoint biomarker in clinical research and patient care.
Growth modulation index (GMI) as a metric of clinical benefit assessment among advanced soft tissue sarcoma (ASTS) patients receiving trabectedin as salvage therapy.
Authors: Penel Nicolas , Demetri George D. , Blay Jean-Yves , Cousin Sophie , Maki Robert G. , Chawla Sant P. , Judson Ian Robert , von Mehren Margaret , Schoffski Patrick , Verweij Jaap , Casali Paolo Giovanni , Rodenhuis Sjoerd , Gomez Javier , Nieto Antonio , Zintl Patrik , Pontes Valero Maria Jose , Cassar Alexia , Le Cesne Axel
Published: March 2020

10013

Background: Von Hoff has proposed GMI >1.33 in cancer clinical trials as a sign of drug activity. GMI is the ratio between time to progression (TTP) with the nth line (TTPn) of therapy divided by the TTPn-1 with the n-1th line of therapy. With this endpoint, each patient is his/her own control. Methods: We have carried out a retrospective analysis of 279 pretreated ASTS patients treated in four consecutive phase II trials with trabectedin 1.5 mg/m², given as a 24-hour infusion every 3 weeks. Results: The study population consisted of 170 women and 109 men with a median age of 52. The two most common histologies were leiomyosarcoma (145 patients, 52%) and liposarcoma (59, 21%). 142 (51%) patients received one prior line and 137 (49%) ≥2 lines. The median TTPn was 2.8 months (range: 0.2-26.8), whereas the median TTPn-1 was 4.0 months (range: 0.3-79.5). The Spearman correlation coefficient between TTPn-1 and TTPn was 0.07 (p=0.23). The median GMI was 0.6 (range: 0.0-14.4). 177 patients (63%) had a GMI <1, 21 (8%) a GMI = 1-1.33 and 81 (29%) a GMI >1.33. The median overall survival (OS) strongly correlated with GMI groups: OS was 9.1, 13.9 and 23.8 months, respectively (p=0.0005, log-rank test). There were also a strong correlations between response rate and GMI (p<0.0001, Fisher exact test), and between GMI and progression-free survival (<0.0001, log-rank test). The logistic regression analysis retained only performance status (PS) [OR=1.76 if PS=0; p<0.04] associated with GMI>1.33. Sarcoma grade (p=0.21), histological subtype (p=0.16), and number of prior chemotherapy lines (p=0.95) were not associated with GMI>1.33. Conclusions: Overall,≈30% of patients experienced GMI>1.33 regardless of histological subtype or grade, and number of prior lines of chemotherapy. Patients with PS=0 benefit more from trabectedin. GMI>1.33 is associated with longer OS (median ≈24 months). GMI is better defined than previously described parameter such as "Tumor Growth Rate" (Lopez-Martin, Abstract 3293, ASCO 2003). GMI as an indicator of drug activity merits further exploration in this setting.
Establishment of a chordoma xenograft and in vivo testing of compounds identified by high-throughput screening.
Authors: Trucco Matteo Maria , Wilky Breelyn A. , Awad Ola , Shah Preeti , Gul Naheed , Xia Menghang , Huang Ruili , Loeb David Mark
Published: March 2020

10025

Background: Chordoma is a rare primary bone malignancy that arises in the skull base, spine and sacrum and originates from remnants of the notochord. Therapy primarily consists of surgical resection and radiation. These tumors are typically resistant to conventional chemotherapy, and to date there are no FDA-approved agents for chordoma. The lack of in vivo models of chordoma has impeded the development of new therapies for this tumor. Methods: Primary tumor from a classic sacral chordoma was obtained, immediately processed into a single cell suspension and injected in to the parasacral area of a NOD/SCID/IL-2R gamma-null mouse, and tumor grew after 3 months. The NIH Chemical Genomics Center performed high-throughput screening of 2,816 compounds. Two established chordoma cell lines, U-CH1 and UCH2B, were treated and cell viability measured by CellTiter-Glo assay. Cells were incubated for 48 hours with drug concentrations ranging from 0.5nM to 46uM. The screen yielded several compounds that showed activity and two were tested in the xenograft. Results: We have established a xenograft model of dedifferentiated chordoma. High-throughput screening of compounds identified compounds that show activity against chordoma cell lines. In vivo testing of two identified compounds showed a dramatic reduction of tumor growth. Conclusions: We have established a xenograft model of dedifferentiated chordoma. High-throughput screening of compounds identified compounds that show activity against chordoma cell lines. In vivo testing of two identified compounds showed a dramatic reduction of tumor growth.
Pharmacokinetic analyses of vorinostat in patients with metastatic soft tissue sarcoma.
Authors: Schmitt Thomas , Andres Bianca , Liu Lu , Leisen Margarete , Ho Anthony D , Burhenne Juergen , Mikus Gerd , Egerer Gerlinde
Published: March 2020

10041^

Background: New treatment options for patients with metastatic soft tissue sarcoma (STS) are urgently needed. Preclinical studies suggest activity of vorinostat (V), a histone desacetylase (HDAC) inhibitor, in STS. Methods: We initiated a multicenter, open-label, non-randomized phase II trial (SAHA-I, NCT00918489) to investigate efficacy and safety of V in patients with metastatic STS failing 1°-line anthracycline-based CTX. Patients were treated with V 400 mg po QD for 28 days followed by a therapy-free period of 7 days. Blood samples for pharmacokinetic (PK) analyses were collected on day 7 of treatment cycle 1. Samples were acquired before and 30, 60, 90, 120, 240, 360, and 480 minutes after oral administration of V. Plasma- and intracellular concentration of V in peripheral blood mononuclear cells (PBMCs) was determined by mass spectrometry. Statistical differences were assessed by Wilcoxon matched-pairs signed rank test. This trial is ongoing. Results: Data on PK was available for n=8 subjects (male=4, female=4, median age=62 years). In plasma samples, mean Cmax (maximum concentration), tmax (time to reach max. concentration), AUC (area under the plasma-concentration time curve), t1/2 (elimination half-life) and Cl/F (apparent total clearance) were 350 ng/mL, 101 min, 71.1 min*µg/mL, 103 min and 5903 mL/min. The corresponding parameters in PBMCs were 558 ng/mL, 97.5 min, 208.4 min*µg/mL, 286 min and 2475 mL/min, respectively.The AUC plasma/PBMC ratio was 2.93, indicating accumulation of V in PBMCs. Differences in AUC (p=.008) and t1/2 (p=.01) reached statistical significance. Conclusions: Interestingly, significantly higher concentrations of V were achieved in PBMCs andelimination half-life was prolonged compared to plasma. These results suggest potent intracellular activity of V.