bluuebunny/crossref_metadata_2025 huggingface dataset:
Loss of amyloid precursor protein exacerbates early inflammation in Niemann-Pick disease type C
Authors: Shin Samuel D. , Shin Alexandra , Mayagoitia Karina , Siebold Lorraine , Rubini Marsilio , Wilson Christopher G. , Bellinger Denise L. , Soriano Salvador
Published: December 2019

Background

Niemann-Pick disease type C (NPC) is a progressive neurodegenerative condition that results in early fatality. NPC is inherited in an autosomal recessive pattern from mutations in NPC1 or NPC2 genes. The etiology of NPC is poorly defined. In that regard, neuroinflammation occurs early in the disease and we have recently unveiled an atypical pattern of interferon signaling in pre-symptomatic Npc1−/− mice, with microglial activation, anti-viral response, activation of antigen-presenting cells, and activation and chemotaxis of T lymphocytes as the key affected pathologic pathways. Furthermore, IP-10/CXCL10, a potent IFN-γ-responsive cytokine, was identified as the potential mediator of these early inflammatory abnormalities. Here, we asked whether this aberrant signaling may be exacerbated by the loss of amyloid precursor protein (APP) function, a loss known to shorten lifespan and accelerate neurodegeneration in Npc1−/− mice.

Methods

We carried out genome-wide comparative transcriptome analyses of pre-symptomatic Npc1+/+/App+/+, Npc1−/−/App+/+, Npc1+/+/App−/−, and Npc1−/−/App−/− mouse cerebella to identify biological pathways in the NPC brain further affected by the loss of APP. Gene Set Enrichment Analysis and Ingenuity Pathway Analysis were utilized for molecular mapping and functional upstream pathway analyses of highly differentially expressed genes. We simultaneously measured the expression of 32 inflammatory cytokines and chemokines in the cerebella from these mice, including those identified in our genome-wide analyses. Finally, we used immunohistochemistry to measure T cell infiltration in the cerebellum.

Results

Expression of IFN-γ- and IFN-α-responsive genes in pre-symptomatic Npc1−/−/App−/− cerebella is upregulated compared with Npc1−/−/App+/+ mice, compounding the dysregulation of microglial activation, anti-viral response, activation of antigen-presenting cells, and T-lymphocyte activation and chemotaxis pathways present in the NPC brain. Multiplex protein analysis further showed elevated expression of IP-10/CXCL10, a potent downstream effector of IFN-γ, as well as RANTES/CCL5, eotaxin/CCL11 and IL-10, prior to symptomatic onset in Npc1−/−/App−/− cerebella, compared with Npc1−/−/App+/+mice. In the terminal disease stage, loss of APP caused pleiotropic differential expression of the vast majority of cytokines evaluated. Finally, we present evidence of T cell infiltration in Npc1−/−/App−/− cerebella.

Conclusions

Loss of APP exacerbates the pathogenic neuroinflammation that occurs prior to symptomatic onset in the NPC brain. These findings shed new light on the function of APP as a cytoprotective modulator in the CNS, offering potential evidence-based therapies against NPC.
Family planning counseling and its associations with modern contraceptive use, initiation, and continuation in rural Uttar Pradesh, India
Authors: Dehingia Nabamallika , Dixit Anvita , Averbach Sarah , Choudhry Vikas , Dey Arnab , Chandurkar Dharmendra , Nanda Priya , Silverman Jay G. , Raj Anita
Published: December 2019

Background

We examine the association between the quality of family planning (FP) counseling received in past 24 months, and current modern contraceptive use, initiation, and continuation, among a sample of women in rural Uttar Pradesh, India.

Methods

This study included data from a longitudinal study with two rounds of representative household survey (2014 and 2016), with currently married women of age 15–49 years; the analysis excluded women who were already using a permanent method of contraceptive during the first round of survey and who reported discontinuation because they wanted to be pregnant (N = 1398). We measured quality of FP counseling using four items on whether women were informed of advantages and disadvantages of different methods, were told of method(s) that are appropriate for them, whether their questions were answered, and whether they perceived the counseling to be helpful. Positive responses to every item was categorized as higher quality counseling, vs lower quality counseling for positive response to less than four items. Outcome variables included modern contraceptive use during the second round of survey, and a variable categorizing women based on their contraceptive use behavior during the two rounds: continued-users, new-users, discontinued-users, and non-users.

Results

Around 22% had received any FP counseling; only 4% received higher-quality counseling. Those who received lower-quality FP counseling had 2.42x the odds of reporting current use of any modern contraceptive method (95% CI: 1.56–3.76), and those who received higher quality FP counseling at 4.14x the odds of reporting modern contraceptive use (95% CI: 1.72–9.99), as compared to women reporting no FP counseling. Women receiving higher-quality counseling also had higher likelihood of continued use (ARRR 5.93; 95% CI: 1.97–17.83), as well as new use or initiation (ARRR: 4.2; 95% CI: 1.44–12.35) of modern contraceptives. Receipt of lower-quality counseling also showed statistically significant associations with continued and new use of modern contraceptives, but the effect sizes were smaller than those for higher-quality counseling.

Conclusions

Findings suggest the value of FP counseling. With a patient-centered approach to counseling, continued use of modern contraceptives can be supported among married women of reproductive age. Unfortunately, FP counseling, particularly higher-quality FP counseling remains rare.
Comparative pathologic analysis of mediastinal B-cell lymphomas: selective expression of p63 but no GATA3 optimally differentiates primary mediastinal large B-cell lymphoma from classic Hodgkin lymphoma
Authors: Kim Hyun-Jung , Kim Hee Kyung , Park Gyeongsin , Min Soo Kee , Cha Hee Jeong , Lee Hyekyung , Choi Suk Jin , Na Hee Young , Choe Ji-Young , Kim Ji Eun
Published: December 2019

Background

Interpretation of mediastinal biopsy is often challenging even for experienced pathologists especially when a hematolymphoid neoplasm is suspected. Primary mediastinal large B-cell lymphoma (PMLBCL) and classic Hodgkin lymphoma (CHL) represent two major types of mature B-cell lymphomas of the mediastinum. Although PMLBCL and mediastinal CHL share many clinicopathologic characteristics, their treatment strategies and responses are remarkably different. We therefore aimed to find distinctive histologic or protein markers to better differentiate these two lesions.

Methods

Search for primary mediastinal B-cell lymphomas found 52 consecutive cases from 3 university hospitals of Korea during 2005 to 2012. Among them, 32 cases that were available for additional immunohistochemistry (IHC) assessment were enrolled in this study. These cases consisted of the following: CHL (N = 13), PMLBCL (N = 16), and B-cell lymphoma unclassifiable, with features intermediate between diffuse large B-cell lymphoma and CHL (gray zone lymphoma, N = 3). Along with the clinicopathologic findings, the expression of p63, GATA3 and cyclin E was investigated by IHC in the three categorized lesions mentioned above.

Results

Most clinical features overlapped between PMLBCL and CHL except for the increased disease progression and mortality found in PMLBCL. In the pathologic review, the presence of epithelioid granuloma favored a diagnosis of CHL, whereas reticulated or alveolar patterns of fibrosis were characteristic of PMLBCL. For protein markers, p63 was predominantly positive in PMLBCL (15/16) compared with CHL (2/13), which indicates that p63 is a marker of the highest diagnostic accuracy when calculated by the area under the ROC curve. GATA3 was expressed in the majority of CHL cases (10/13) compared with PMLBCL (0/16), while the expression of cyclin E was only rarely present in a minor population of PMLBCL.

Conclusions

P63 expression in tumor cells, even focal expression, and no GATA3 is the most helpful feature in distinguishing PMLBCL from mediastinal CHL.
Changes in traditional ecological knowledge of forage plants in immigrant villages of Ningxia, China
Authors: Ma Ying , Luo Binsheng , Zhu Qiang , Ma Dongxing , Wen Qi , Feng Jinchao , Xue Dayuan
Published: December 2019

Background

Ecological migration serves as an important measure for poverty eradication as well as for the protection, inheritance, and utilization of traditional ecological knowledge. This study investigated and cataloged the traditional forage plant resources and recorded the associated traditional knowledge of immigrant villages in Hongsibu District of Ningxia, China. The diversity of traditional forage plant resources and the changes in associated traditional ecological knowledge were compared among ecological immigrant villages from different emigration areas, with a hope of providing a reference for forage development, the conservation of wild forage plant resources, and the development of regional animal husbandry.

Methods

From March 2018 to May 2019, a field investigation was conducted in six villages in Ningxia. Through the snowball technique, a total of 315 immigrants were interviewed using various methods, including semistructured interviews and key person interviews, which included opportunities for free listing. The changes in the utilization of traditional forage plants were compared between the ecological migrants and the original inhabitants, and the causes underlying the changes were analyzed. In addition, the major forage plant species in the research area were investigated and evaluated.

Results

(1) The six investigated villages reported 224 traditional forage plant species that belong to 42 families and 150 genera. Compared with their original living areas, the number of traditional forage plant species used in the immigrant villages decreased with the increase in the relocation distance. (2) The utilization of traditional forage plants varied among the immigrants who moved to Hongsibu District from forest areas, loess hilly areas, and semiarid desertified areas. The smaller the difference was in ecological environment between the immigration and emigration areas, the more the traditional forage plant knowledge had been retained. (3) The diversity and associated knowledge of traditional forage plants retained by ecological migrants are closely correlated to gender, age, education level, and occupation.

Conclusion

This study revealed that the diversity of traditional forage plants and associated knowledge retained after migration vary among ecological immigrants from different areas; generally, the immigrants that relocated from a closer place retained more ecological knowledge. In the immigrant villages with significantly different natural resources and a long distance from the migrants’ original locations, the diversity of traditional forage plants decreased, and the traditional knowledge about forage plants showed signs of being forgotten and abandoned by the younger generation. Therefore, measures are urgently needed to document and protect the forage plant resources and preserve the traditional knowledge of ecological immigrants.
Opioid use disorder in Germany: healthcare costs of patients in opioid maintenance treatment
Authors: Reimer Jens , Vogelmann Tobias , Trümper Daniel , Scherbaum Norbert
Published: December 2019

Background

Opioid Use Disorder (OUD) is a substance use disorder with a chronic course associated with comorbid mental and somatic disorders, a high burden of psychosocial problems and opioid maintenance treatment (OMT) as a standard treatment. In the US, OUD imposes a significant economic burden on society, with annual societal costs estimated at over 55 billion dollars. Surprisingly, in Europe and especially in Germany, there is currently no detailed information on the healthcare costs of patients with OUD. The goal of the present research is to gather cost information about OUD patients in OMT with a focus on maintenance medication and relapses.

Methods

We analysed health claims data of four million persons covered by statutory health insurance in Germany, applying a cost-of-illness approach and aimed at examining the direct costs of OMT patients in Germany. Patients with an ICD-10 code F11.2 and at least one claim of an OMT medication were stratified into the treatment groups buprenorphine, methadone or levomethadone, based on the first prescription in each of the follow-up years. Costs were stratified for years with and without relapses. Group comparisons were performed with ANOVA.

Results

We analysed 3165 patient years, the total annual sickness funds costs were on average 7470 € per year and patient. Comparing costs of levomethadone (8400 €, SD: 11,080 €), methadone (7090 €, SD: 10,900 €) and buprenorphine (6670 €, SD: 7430 €) revealed significant lower costs of buprenorphine compared to levomethadone (p < 0.0001). In years with relapses, costs were higher than in years without relapses (8178 € vs 7409 €; SD: 11,622, resp. 10,378 €). In years with relapses, hospital costs were the major cost driver.

Conclusions

The present study shows the costs of OUD patients in OMT for the first time with a German dataset. Healthcare costs for patients with an OUD in OMT are associated with more than two times the cost of an average German patients. Preventing relapses might have significant impact on costs. Patients in different OMT were dissimilar which may have affected the cost differences.
New hemostatic device for grade IV–V liver injury in porcine model: a proof of concept
Authors: Segura-Sampedro Juan José , Pineño-Flores Cristina , Craus-Miguel Andrea , Morales-Soriano Rafael , González-Argente Francesc Xavier
Published: December 2019

Background

The liver is the most injured organ following abdominal trauma. Uncontrolled bleeding remains the main cause of early liver injury-related death, with a mortality rate of 50–54% in the first 24 h after admission and with 80% of operative deaths. Packing and reoperation account for the increased survival in severe liver trauma, and they are recommended for severe liver injuries (grades IV–V).

Perihepatic packing can lead to several potential complications. An excessive packing can cause complications due to abdominal compartment syndrome, while a soft packing may be ineffective, and thus, bleeding can continue inadvertently with the consequent hypovolemic shock and potentially death.

Methods

We designed a new vacuum-based device to perform perihepatic packing without the negative side-effects of the classic technique. We conducted a prospective pilot feasibility study in a porcine model. We compared the traditional perihepatic packing (PHP) (n = 2) with the new VacBagPack device (VBP) (n = 2).

Results

Both pigs survived with the new device and showed an equivalent outcome to the one that survived in the traditional technique group. Blood tests were similar too. This suggests that VBP could be at least as effective as traditional PHP.

Conclusions

We establish a first step towards the development of a new packing device. A new study with a bigger sample size still in pigs will be conducted. Also, an industrial model of the device is currently in production.
Primary total hip arthroplasty using an uncemented Wagner SL stem in elderly patients with Dorr type C femoral bone
Authors: Zhen Ping , Liu Jun , Li Xusheng , Lu Hao , Zhou Shenghu
Published: December 2019

Background

The purpose of this study was to review retrospectively the primary total hip arthroplasties operated upon with the cementless Wagner Self-Locking stem in patients with type C femoral bone.

Methods

Twenty-eight total hip arthroplasties were performed in 25 patients aged ≥ 60 years using a cementless Wagner Self-Locking femoral component between 2006 and 2011. According to Dorr’s criteria, all 28 femora were classified as type C bone. All patients were treated with THA using a cementless Wagner cone prosthesis. Clinical and radiologic evaluations were performed on all patients.

Results

Mean follow-up period was 125 ± 10.5 months (range 96 to 156 months). Average Harris hip score pre-operatively was 46 ± 9 (range 39 to 62) and at the last follow-up was 90 ± 9 (range 83 to 98). The stem to canal fill is calculated as percentages on the operative side at three distinct levels: just below the lesser trochanter, at midstem, and 1 cm above the tip of the component on anteroposterior radiograph. The mean proximal stem-to-canal fill percentages were 97% ± 2.1%, 95% ± 3.5%, and 88% ± 2.6%, respectively (anteroposterior view) and 92% ± 2.2%, 86% ± 1.9%, and 83% ± 2.5%, respectively (lateral view). Radiographic evaluation demonstrated good osteointegration of the implants in the follow-up.

Conclusions

Based on the long-straight cylindrical tapered stem design, the cementless Wagner SL stem can achieve reliable stability by close apposition of the stem and wide stovepipe femoral canal from metaphysis to diaphysis in type C bone.
Design and evaluation of nano-hydroxyapatite/poly(vinyl alcohol) hydrogels coated with poly(lactic-co-glycolic acid)/nano-hydroxyapatite/poly(vinyl alcohol) scaffolds for cartilage repair
Authors: Su Weiping , Hu Yihe , Zeng Min , Li Mingqing , Lin Shaoru , Zhou Yangying , Xie Jie
Published: December 2019

Background

Poly(vinyl alcohol) (PVA) hydrogels have been widely used in synthetic cartilage materials. However, limitations of PVA hydrogels such as poor biomechanics and limited cell ingrowth remain challenges in this field.

Methods

This work aimed to design novel nano-hydroxyapatite (nano-HA)/poly(vinyl alcohol) (PVA) hydrogels coated with a poly(lactic-co-glycolic acid) (PLGA)/nano-HA/PVA scaffold to counter the limitations of PVA hydrogels. The core, comprising nano-HA/PVA hydrogel, had the primary role of bearing the mechanical load. The peripheral structure, composed of PLGA/nano-HA/PVA, was designed to favor interaction with surrounding cartilage.

Results

The double-layer HA/PVA hydrogel coated with PLGA/HA/PVA scaffold was successfully prepared using a two-step molding method, and the mechanical properties and biocompatibility were characterized. The mechanical properties of the novel PLGA/HA/PVA scaffold modified HA/PVA hydrogel were similar to those of native cartilage and showed greater sensitivity to compressive stress than to tensile stress. Rabbit chondrocytes were seeded in the composites to assess the biocompatibility and practicability in vitro. The results showed that the peripheral component comprising 30 wt% PLGA/5 wt% HA/15 wt% PVA was most conducive to rabbit chondrocyte adhesion and proliferation.

Conclusions

The study indicated that the double-layer HA/PVA hydrogel coated with PLGA/HA/PVA scaffold has the potential for cartilage repair.
Correlation analysis between the pulmonary function test and the radiological parameters of the main right thoracic curve in adolescent idiopathic scoliosis
Authors: Wang Yonggang , Yang Fengguang , Wang Dongmin , Zhao Haiyan , Ma Zhanjun , Ma Peifen , Hu Xuchang , Wang Shixiong , Kang Xuewen , Gao Bingren
Published: December 2019

Background

Scoliosis causes thoracic deformities, and it is necessary to assess these changes in pulmonary function test (PFT). To determine how measurements of spinal and thoracic cage deformities are related to pulmonary function.

Methods

Seventy-two patients with main right thoracic curvature in adolescent idiopathic scoliosis (AIS) underwent a PFT and a radiological parameter evaluation of spinal and thoracic cage deformities. Simple and multiple linear regressions were also used to note whether a combination of variables might better predict PFT values. Means were compared using the two-sample t test or one-way ANOVA with Tukey’s multiple comparison methods.

Results

Forced vital capacity (FVC)% predicted had significantly negative correlations with main thoracic curve Cobb (MT-Cobb) (R2 = 0.648, p < 0.001), main thoracic curve-rib hump (MT-RH) (R2 = 0.522, p < 0.001), main thoracic curve apical vertebral body-to-rib ratio (MT-AVB-R) (R2 = 0.536, p < 0.001), and main thoracic curve apical vertebra translation (MT-AVT) (R2 = 0.383, p < 0.001). Multiple regression analysis was performed with FVC% predicted as the dependent variable and MT-Cobb, MT-RH, MT-AVB-R, and MT-AVT as the independent variables. MT-Cobb, MT-RH, MT-AVB-R, and MT-AVT were factors with a significant effect on FVC% predicted (p < 0.001). For 45 patients who had preoperative FVC impairment (FVC% predicted < 80%), their MT-Cobb averaged 76.71°. Twenty-seven patients with normal preoperative FVC (FVC% predicted ≥ 80%) had a smaller mean MT-Cobb of 52.03° (p < 0.001). In other radiological parameters, the impaired FVC group had a MT-AVT of 54.29 mm compared to 38.06 mm for the normal FVC group (p < 0.001). MT-AVB-R averaged 2.92 for the impaired FVC group and 1.78 for the normal FVC group (p < 0.001). MT-RH averaged 28.79 mm for the impaired group and 16.62 mm for the normal group (p < 0.001). Further stratification of preoperative PFT results is divided into three groups. The three groups also showed significant differences in MT-Cobb, MT-RH, MT-AVB-R, and MT-AVT (p < 0.001).

Conclusion

Severe scoliosis leads to an increased degree of thoracic deformity, which increases the risk of lung damage in AIS. Moreover, a more accurate assessment of pulmonary function is achieved through radiological parameters and PFTs.
How can forest management increase biomass accumulation and CO2 sequestration? A case study on beech forests in Hesse, Germany
Authors: Krug Joachim H. A.
Published: December 2019

Background

While the capability of forests to sequester carbon dioxide (CO2) is acknowledged as an important component in fighting climate change, a closer look reveals the difficulties in determining the actual contribution by forest management when indirect and natural impacts are to be factored out. The goal of this study is to determine the direct human-induced impacts on forest growth by cumulative biomass growth and resulting structural changes, exemplified for a dominating forest species Fagus sylvatica L. in central Europe. In 1988, forest reserves with directly adjacent forest management areas (under business as usual management) were established in the federal state of Hesse, Germany. Thereof, 212 ha of forest reserve and 224 ha of management area were selected for this study. Biomass changes were recorded for a time span of 19 to 24 years by methods used in the National Inventory Report (NIR) and structural changes by standard approaches, as well as by a growth-dominance model.

Results

The results indicate a higher rate of cumulative biomass production in the investigated management areas and age classes. The cumulative biomass growth reveals a superior periodic biomass accumulation of about 16%. For beech alone, it is noted to be about 19% higher in management areas than in forest reserves. When harvests are not included, forest reserves provide about 40% more biomass than management areas. The analysis of growth-dominance structures indicates that forest management led to a situation where trees of all sizes contributed to biomass increment more proportionally; a related increase in productivity may be explained by potentially improved resource-use efficiency.

Conclusions

The results allow a conclusion on management-induced structural changes and their impact on carbon sequestration for Fagus sylvatica L., the dominating forest species in central Germany. This affirms a potential superiority of managed forests to forests where the management was abandoned in terms of biomass accumulation and reveal the impact and effect of the respective interventions. Especially the analysis of growth-dominance structures indicates that forest management resulted in more balanced dominance structures, and these in higher individual biomass increment. Forest management obviously led to a situation where trees of all sizes contributed to biomass increment more proportionally.
Oral health-related quality of life in Loeys-Dietz syndrome, a rare connective tissue disorder: an observational cohort study
Authors: Nguyen Quynh C. , Duverger Olivier , Mishra Rashmi , Mitnik Gabriela Lopez , Jani Priyam , Frischmeyer-Guerrerio Pamela A. , Lee Janice S.
Published: December 2019

Background

Loeys-Dietz syndrome (LDS) is a rare connective tissue disorder whose oral manifestations and dental phenotypes have not been well-characterized. The aim of this study was to explore the influence of oral manifestations on oral health-related quality of life (OHRQoL) in LDS patients.

Material and methods

LDS subjects were assessed by the craniofacial team at the National Institutes of Health Clinical Center Dental Clinic between June 2015 and January 2018. Oral Health Impact Profile (OHIP-14) questionnaire, oral health self-care behavior questionnaire and a comprehensive dental examination were completed for each subject. OHRQoL was assessed using the OHIP-14 questionnaire with higher scores corresponding to worse OHRQoL. Regression models were used to determine the relationship between each oral manifestation and the OHIP-14 scores using a level of significance of p ≤ 0.05.

Results

A total of 33 LDS subjects (51.5% female) aged 3–57 years (19.6 ± 15.1 years) were included in the study. The OHIP-14 scores (n = 33) were significantly higher in LDS subjects (6.30 [SD 6.37]) when compared to unaffected family member subjects (1.50 [SD 2.28], p < 0.01), and higher than the previously reported scores of the general U.S. population (2.81 [SD 0.12]). Regarding oral health self-care behavior (n = 32), the majority of LDS subjects reported receiving regular dental care (81%) and maintaining good-to-excellent daily oral hygiene (75%). Using a crude regression model, worse OHRQoL was found to be associated with dental hypersensitivity (β = 5.24; p < 0.05), temporomandibular joints (TMJ) abnormalities (β = 5.92; p < 0.01), self-reported poor-to-fair oral health status (β = 6.77; p < 0.01), and cumulation of four or more oral manifestations (β = 7.23; p < 0.001). Finally, using a parsimonious model, self-reported poor-to-fair oral health status (β = 5.87; p < 0.01) and TMJ abnormalities (β = 4.95; p < 0.01) remained significant.

Conclusions

The dental hypersensitivity, TMJ abnormalities, self-reported poor-to-fair oral health status and cumulation of four-or-more oral manifestations had significant influence on worse OHRQoL. Specific dental treatment guidelines are necessary to ensure optimal quality of life in patients diagnosed with LDS.
Researching violence against women and girls in South Sudan: ethical and safety considerations and strategies
Authors: Contreras-Urbina Manuel , Blackwell Alexandra , Murphy Maureen , Ellsberg Mary
Published: December 2019

Background

Globally, it is estimated that at least one out of every three women experiences violence by an intimate partner and/or non-partner throughout their lifetime. Women and girls are at even higher risk of violence in conflict and humanitarian crises. Although effort has expanded to build rigorous evidence and research on violence against women and girls (VAWG) among conflict-affected populations, methodological and ethical challenges remain. Basic ethical research practices are more challenging in conflict-affected populations and therefore require supplementary protections. While it is important to follow international ethical guidelines, in practice it is sometimes difficult depending on the setting. The aim of this paper is to present the main ethical challenges that occur when conducting research on VAWG in conflict and humanitarian settings, as well as potential strategies to address these challenges, based on a recent study carried out in South Sudan in 2016.

Case presentation

This paper provides an analysis utilizing the World Health Organization guidelines on doing research on VAWG and in conflict and humanitarian settings. The paper analyses four main components: the first component is a risk-benefit assessment, which includes identifying the research gap and evaluating feasibility with local stakeholders. The second component is a methodological and conceptual approach, which involves both local stakeholders and external experts in order to develop flexible methods that can be used in a volatile conflict setting. The third component is safety considerations, which emphasizes the importance of collaborating with a partner with strong local networks. The last component is analysis and research uptake. This component describes the importance of developing different research products, and disseminating them in a way to ensure they would be relevant and minimize any risks to the participants.

Conclusions

The study in South Sudan provided an excellent opportunity to put into practice the international ethical guidelines to carry out research on VAWG in conflict and humanitarian settings. The study enabled the research team to reflect on the guidelines and develop strategies to cope with new methodological and ethical challenges that arose in this complex setting, adapting the guidelines, as necessary. It demonstrated the necessity of developing a strong yet adaptable methodology with multiple alternative plans to solve any safety or ethical issues that occur throughout the entirety of the study. It also revealed the importance of collaborating with an implementing partner and gathering input from both local and international stakeholders on research design, analysis and uptake. Most importantly, the study in South Sudan emphasized that this type of complex research requires significant planning, in addition to substantial financial and human resources. Donor buy-in and flexibility is therefore essential.
Endothelial-mesenchymal transition harnesses HSP90α-secreting M2-macrophages to exacerbate pancreatic ductal adenocarcinoma
Authors: Fan Chi-Shuan , Chen Li-Li , Hsu Tsu-An , Chen Chia-Chi , Chua Kee Voon , Li Chung-Pin , Huang Tze-Sing
Published: December 2019

Background

Endothelial-to-mesenchymal transition (EndoMT) can provide a source of cancer-associated fibroblasts which contribute to desmoplasia of many malignancies including pancreatic ductal adenocarcinoma (PDAC). We investigated the clinical relevance of EndoMT in PDAC, and explored its underlying mechanism and therapeutic implication.

Methods

Expression levels of 29 long non-coding RNAs were analyzed from the cells undergoing EndoMT, and an EndoMT index was proposed to survey its clinical associations in the PDAC patients of The Cancer Genome Atlas database. The observed clinical correlation was further confirmed by a mouse model inoculated with EndoMT cells-involved PDAC cell grafts. In vitro co-culture with EndoMT cells or treatment with the conditioned medium were performed to explore the underlying mechanism. Because secreted HSP90α was involved, anti-HSP90α antibody was evaluated for its inhibitory efficacy against the EndoMT-involved PDAC tumor.

Results

A combination of low expressions of LOC340340, LOC101927256, and MNX1-AS1 was used as an EndoMT index. The clinical PDAC tissues with positive EndoMT index were significantly correlated with T4-staging and showed positive for M2-macrophage index. Our mouse model and in vitro cell-culture experiments revealed that HSP90α secreted by EndoMT cells could induce macrophage M2-polarization and more HSP90α secretion to promote PDAC tumor growth. Furthermore, anti-HSP90α antibody showed a potent therapeutic efficacy against the EndoMT and M2-macrophages-involved PDAC tumor growth.

Conclusions

EndoMT cells can secrete HSP90α to harness HSP90α-overproducing M2-type macrophages to promote PDAC tumor growth, and such effect can be targeted and abolished by anti-HSP90α antibody.
Benchmarking transposable element annotation methods for creation of a streamlined, comprehensive pipeline
Authors: Ou Shujun , Su Weija , Liao Yi , Chougule Kapeel , Agda Jireh R. A. , Hellinga Adam J. , Lugo Carlos Santiago Blanco , Elliott Tyler A. , Ware Doreen , Peterson Thomas , Jiang Ning , Hirsch Candice N. , Hufford Matthew B.
Published: December 2019

Background

Sequencing technology and assembly algorithms have matured to the point that high-quality de novo assembly is possible for large, repetitive genomes. Current assemblies traverse transposable elements (TEs) and provide an opportunity for comprehensive annotation of TEs. Numerous methods exist for annotation of each class of TEs, but their relative performances have not been systematically compared. Moreover, a comprehensive pipeline is needed to produce a non-redundant library of TEs for species lacking this resource to generate whole-genome TE annotations.

Results

We benchmark existing programs based on a carefully curated library of rice TEs. We evaluate the performance of methods annotating long terminal repeat (LTR) retrotransposons, terminal inverted repeat (TIR) transposons, short TIR transposons known as miniature inverted transposable elements (MITEs), and Helitrons. Performance metrics include sensitivity, specificity, accuracy, precision, FDR, and F1. Using the most robust programs, we create a comprehensive pipeline called Extensive de-novo TE Annotator (EDTA) that produces a filtered non-redundant TE library for annotation of structurally intact and fragmented elements. EDTA also deconvolutes nested TE insertions frequently found in highly repetitive genomic regions. Using other model species with curated TE libraries (maize and Drosophila), EDTA is shown to be robust across both plant and animal species.

Conclusions

The benchmarking results and pipeline developed here will greatly facilitate TE annotation in eukaryotic genomes. These annotations will promote a much more in-depth understanding of the diversity and evolution of TEs at both intra- and inter-species levels. EDTA is open-source and freely available: https://github.com/oushujun/EDTA.
A novel framework for horizontal and vertical data integration in cancer studies with application to survival time prediction models
Authors: Mihaylov Iliyan , Kańduła Maciej , Krachunov Milko , Vassilev Dimitar
Published: December 2019

Background

Recently high-throughput technologies have been massively used alongside clinical tests to study various types of cancer. Data generated in such large-scale studies are heterogeneous, of different types and formats. With lack of effective integration strategies novel models are necessary for efficient and operative data integration, where both clinical and molecular information can be effectively joined for storage, access and ease of use. Such models, combined with machine learning methods for accurate prediction of survival time in cancer studies, can yield novel insights into disease development and lead to precise personalized therapies.

Results

We developed an approach for intelligent data integration of two cancer datasets (breast cancer and neuroblastoma) − provided in the CAMDA 2018 ‘Cancer Data Integration Challenge’, and compared models for prediction of survival time. We developed a novel semantic network-based data integration framework that utilizes NoSQL databases, where we combined clinical and expression profile data, using both raw data records and external knowledge sources. Utilizing the integrated data we introduced Tumor Integrated Clinical Feature (TICF) − a new feature for accurate prediction of patient survival time. Finally, we applied and validated several machine learning models for survival time prediction.

Conclusion

We developed a framework for semantic integration of clinical and omics data that can borrow information across multiple cancer studies. By linking data with external domain knowledge sources our approach facilitates enrichment of the studied data by discovery of internal relations. The proposed and validated machine learning models for survival time prediction yielded accurate results.

Reviewers

This article was reviewed by Eran Elhaik, Wenzhong Xiao and Carlos Loucera.
Tamoxifen in Duchenne muscular dystrophy (TAMDMD): study protocol for a multicenter, randomized, placebo-controlled, double-blind phase 3 trial
Authors: Nagy Sara , Hafner Patricia , Schmidt Simone , Rubino-Nacht Daniela , Schädelin Sabine , Bieri Oliver , Fischer Dirk
Published: December 2019

Background

Duchenne muscular dystrophy (DMD) is an inherited neuromuscular disorder of childhood with a devastating disease course. Several targeted gene therapies and molecular approaches have been or are currently being tested in clinical trials; however, a causative therapy is still not available and best supportive care is limited to oral glucocorticoids with numerous long-term side effects. Tamoxifen is a selective estrogen receptor regulator, and shows antioxidant actions and regulatory roles in the calcium homeostasis besides its antitumor activity. In a mouse model of DMD, oral tamoxifen significantly improved muscle strength and reduced muscle fatigue. This multicenter, randomized, double-blind, placebo-controlled phase III trial aims to demonstrate safety and efficacy of tamoxifen over placebo in pediatric patients with DMD. After completion of the double-blind phase, an open-label extension of the study will be offered to all participants.

Methods/design

At least 71 ambulant and up to 20 nonambulant patients with DMD are planned to be enrolled at multiple European sites. Patients will be randomly assigned to receive either tamoxifen 20 mg or placebo daily over 48 weeks. In the open-label extension phase, all patients will be offered tamoxifen for a further 48 weeks. The primary endpoint of the double-blind phase is defined as the change of the D1 domain of the motor function measure in ambulant patients or a change of the D2 domain in nonambulant patients under tamoxifen compared to placebo. Secondary outcome measures include change in timed function tests, quantitative muscle testing, and quantitative magnetic resonance imaging of thigh muscles. Laboratory analyses including biomarkers of tamoxifen metabolism and muscle dystrophy will also be assessed.

Discussion

The aim of the study is to investigate whether tamoxifen can reduce disease progression in ambulant and nonambulant patients with DMD over 48 weeks. Motor function measures comprise the primary endpoint, whereas further clinical and radiological assessments and laboratory biomarkers are performed to provide more data on safety and efficacy. An adjacent open-label extension phase is planned to test if earlier initiation of the treatment with tamoxifen (verum arm of double-blind phase) compared to a delayed start can reduce disease progression more efficiently.

Trial registration

ClinicalTrials.gov, NCT03354039. Registered on 27 November 2017.
Promoting mental health and wellbeing in schools: examining Mindfulness, Relaxation and Strategies for Safety and Wellbeing in English primary and secondary schools: study protocol for a multi-school, cluster randomised controlled trial (INSPIRE)
Authors: Hayes Daniel , Moore Anna , Stapley Emily , Humphrey Neil , Mansfield Rosie , Santos Joao , Ashworth Emma , Patalay Praveetha , Bonin Eva-Maria , Moltrecht Bettina , Boehnke Jan R. , Deighton Jessica
Published: December 2019

Background

There are increasing rates of internalising difficulties, particularly anxiety and depression, being reported in children and young people in England. School-based, universal prevention programmes are thought to be one way of helping tackle such difficulties. This protocol describes a four-arm cluster randomised controlled trial, investigating the effectiveness of three different interventions when compared to usual provision, in English primary and secondary pupils. The primary outcome for Mindfulness and Relaxation interventions is a measure of internalising difficulties, while Strategies for Safety and Wellbeing will be examined in relation to intended help-seeking. In addition to the effectiveness analysis, a process and implementation evaluation and a cost-effectiveness evaluation will be undertaken.

Methods and analysis

Overall, 160 primary schools and 64 secondary schools will be recruited across England. This corresponds to 17,600 participants. Measures will be collected online at baseline, 3–6 months later, and 9–12 months after the commencement of the intervention. An economic evaluation will assess the cost-effectiveness of the interventions. Moreover, a process and implementation evaluation (including a qualitative research component) will explore several aspects of implementation (fidelity, quality, dosage, reach, participant responsiveness, adaptations), social validity (acceptability, appropriateness and feasibility), and their moderating effects on the outcomes of interest, and perceived impact.

Discussion

This trial aims to address important questions about whether schools’ practices around the promotion of mental wellbeing and the prevention of mental health problems can: (1) be formalised into feasible and effective models of school-based support and (2) whether these practices and their effects can be sustained over time. Given the focus of these interventions on mirroring popular practice in schools and on prioritising approaches that present low-burden, high-acceptability to schools, if proved effective, and cost-effective, the findings will indicate models that are not only empirically tested but also offer high potential for widespread use and, therefore, potentially widespread benefits beyond the life of the trial.

Trial registration

ISRCTN16386254. Registered on 30 August 2018.
Chemotherapy in conjunction with traditional Chinese medicine for survival of patients with early female breast cancer: protocol for a non-randomized, single center prospective cohort study
Authors: Liu Chien-Ting , Chen Yen-Hao , Huang Yu-Chuen , Chen Shih-Yu , Tsai Ming-Yen
Published: December 2019

Background

Chemotherapy after surgery for breast cancer plays a fundamental role in reducing the risk of distant and local recurrence. An increasing number of patients seek traditional Chinese medicine (TCM) during adjuvant chemotherapy to relieve symptom discomfort and side effects as well as to strengthen the body’s defenses. However, evidence on how concurrent TCM treatment affects prognosis is scarce. This trial aims to evaluate the association between TCM treatment and disease-free survival outcomes for patients with early breast cancer who are undergoing adjuvant chemotherapy.

Methods/design

This is a non-randomized, single center, prospective cohort study begun in November 2018 in Kaohsiung, Taiwan. A sample of 310 participants diagnosed with early breast cancer was recruited from the Breast Cancer Research Team and will be followed up every 3 to 6 months until October 2023. Detailed information of the participants, including general information, history of cancer, quality of life, side effects and safety of treatment, TCM body constitution, and meridian energy analysis, was collected face to face at baseline.

Discussion

This is the first prospective observational cohort study on TCM in patients with early breast cancer who are receiving adjuvant chemotherapy to evaluate the prognosis. Through this trial, we hope to assess the feasibility of a larger-scale clinical trial in the future and formulate an integrated TCM care program.

Trial registration

ClinicalTrials.gov, NCT03797248. Registered on 5 January 2019.
FIREVAT: finding reliable variants without artifacts in human cancer samples using etiologically relevant mutational signatures
Authors: Kim Hyunbin , Lee Andy Jinseok , Lee Jongkeun , Chun Hyonho , Ju Young Seok , Hong Dongwan
Published: December 2019

Background

Accurate identification of real somatic variants is a primary part of cancer genome studies and precision oncology. However, artifacts introduced in various steps of sequencing obfuscate confidence in variant calling. Current computational approaches to variant filtering involve intensive interrogation of Binary Alignment Map (BAM) files and require massive computing power, data storage, and manual labor. Recently, mutational signatures associated with sequencing artifacts have been extracted by the Pan-cancer Analysis of Whole Genomes (PCAWG) study. These spectrums can be used to evaluate refinement quality of a given set of somatic mutations.

Results

Here we introduce a novel variant refinement software, FIREVAT (FInding REliable Variants without ArTifacts), which uses known spectrums of sequencing artifacts extracted from one of the largest publicly available catalogs of human tumor samples. FIREVAT performs a quick and efficient variant refinement that accurately removes artifacts and greatly improves the precision and specificity of somatic calls. We validated FIREVAT refinement performance using orthogonal sequencing datasets totaling 384 tumor samples with respect to ground truth. Our novel method achieved the highest level of performance compared to existing filtering approaches. Application of FIREVAT on additional 308 The Cancer Genome Atlas (TCGA) samples demonstrated that FIREVAT refinement leads to identification of more biologically and clinically relevant mutational signatures as well as enrichment of sequence contexts associated with experimental errors. FIREVAT only requires a Variant Call Format file (VCF) and generates a comprehensive report of the variant refinement processes and outcomes for the user.

Conclusions

In summary, FIREVAT facilitates a novel refinement strategy using mutational signatures to distinguish artifactual point mutations called in human cancer samples. We anticipate that FIREVAT results will further contribute to precision oncology efforts that rely on accurate identification of variants, especially in the context of analyzing mutational signatures that bear prognostic and therapeutic significance. FIREVAT is freely available at https://github.com/cgab-ncc/FIREVAT
Improved RA classification among early arthritis patients with the concordant presence of three RA autoantibodies: analysis in two early arthritis clinics
Authors: Regueiro Cristina , Rodríguez-Martínez Lorena , Nuño Laura , Ortiz Ana M. , Villalba Alejandro , Pascual-Salcedo Dora , Martínez-Feito Ana , González-Alvaro Isidoro , Balsa Alejandro , Gonzalez Antonio
Published: December 2019

Background

The patients with RA benefit from early identification soon after the first clinical symptoms appear. The 2010 ACR/EULAR classification criteria were developed to fulfill this need and their application has been demonstrated to be effective. However, there is still room for improvement. Therefore, we aimed to evaluate the potential of the concordant presence of RF, anti-CCP and anti-carbamylated protein antibodies to improve current RA classification among early arthritis (EA) patients.

Methods

Data from the first visit of 1057 patients in two EA prospective cohorts were used. The serological scores from the 2010 ACR/EULAR criteria and the concordant presence of the three RA autoantibodies were assessed relative to a gold standard consisting of the RA classification with the 1987 ACR criteria at the 2 years of follow-up.

Results

The concordant presence of three antibodies showed predictive characteristics allowing for direct classification as RA (positive predictive value = 96.1% and OR = 80.9). They were significantly better than the corresponding to the high antibody titers defined as in the 2010 classification criteria (PPV = 88.8%, OR = 26.1). In addition, the concordant presence of two antibodies was also very informative (PPV = 82.3%, OR = 15.1). These results allowed devising a scoring system based only on antibody concordance that displayed similar overall performance as the serological scoring system of the 2010 criteria. However, the best classification was obtained combining the concordance and 2010 serological systems, a combination with a significant contribution from each of the two systems.

Discussion

The concordant presence of RA autoantibodies showed an independent contribution to the classification of EA patients that permitted increased discrimination and precision.