bluuebunny/crossref_metadata_2025 huggingface dataset:
Current treatment algorithm for the management of patients with myelofibrosis, JAK inhibitors, and beyond
Authors: Harrison Claire N. , McLornan Donal P.
Published: April 2019

Myelofibrosis (MF) is a heterogeneous disorder characterized by splenomegaly, constitutional symptoms, ineffective hematopoiesis, and an inherent risk of leukemic transformation. The past decade has seen a massive shift in available therapeutic options for our patients and we are learning how and when to use novel agents, either alone or in combination, during the disease course. This has translated into improved management of splenomegaly, significant amelioration in disease-related symptom burden for many, and may lead to improved survival. But limitations in the therapeutic options remain. Moreover, enhanced delineation of the mutational landscape of MF has offered both increasingly complex prognostic algorithms and yielded further potential therapeutic avenues. In this review, we will focus on stratifying both standard and experimental therapeutic management in 2017 and 2018 and postulate on the emerging treatments that will likely become part of our increasingly complex treatment algorithm.
Secondary CNS relapse in diffuse large B-cell lymphoma: defining high-risk patients and optimization of prophylaxis strategies
Authors: Savage Kerry J.
Published: April 2019

Despite improvement in survival in diffuse large B-cell lymphoma (DLBCL) with the introduction of rituximab, central nervous system (CNS) relapse continues to represent a clinical challenge. A number of studies have evaluated clinical risk factors in an attempt to identify high-risk patients to direct CNS staging investigations and consider prophylaxis strategies. The CNS International Prognostic Index is a robust and reproducible risk model that can identity patients at high risk of CNS relapse, but its specificity remains limited. Studies are emerging of biomarkers that predict CNS relapse that can be integrated with clinical risk models to better identify high-risk patients for CNS-directed prophylaxis strategies. Because CNS parenchymal disease is the predominant compartment, prophylaxis should include deeply penetrant drugs such as high-dose methotrexate. However, this has been associated with toxicity and has limited use in older patients. Novel therapies are being tested in primary CNS lymphoma with encouraging results and may represent rational strategies to be further explored in the prophylaxis setting.
Treatment of inherited bone marrow failure syndromes beyond transplantation
Authors: Calado Rodrigo T. , Clé Diego V.
Published: April 2019

Despite significant progress in transplantation by the addition of alternative hematopoietic stem cell sources, many patients with inherited bone marrow failure syndromes are still not eligible for a transplant. In addition, the availability of sequencing panels has significantly improved diagnosis by identifying cryptic inherited cases. Androgens are the main nontransplant therapy for bone marrow failure in dyskeratosis congenita and Fanconi anemia, reaching responses in up to 80% of cases. Danazol and oxymetholone are more commonly used, but virilization and liver toxicity are major adverse events. Diamond-Blackfan anemia is commonly treated with corticosteroids, but most patients eventually become refractory to this treatment and toxicity is limiting. Growth factors still have a role in inherited cases, especially granulocyte colony-stimulating factor in congenital neutropenias. Novel therapies are warranted and thrombopoietin receptor agonists, leucine, quercetin, and novel gene therapy approaches may benefit inherited cases in the future.
The new tool “KIT” in advanced systemic mastocytosis
Authors: Shomali William , Gotlib Jason
Published: April 2019

Mastocytosis is a rare disease characterized by KIT-driven expansion and accumulation of neoplastic mast cells in various tissues. Although mediator symptoms related to mast cell activation can impose a symptom burden in cutaneous disease and across the spectrum of systemic mastocytosis subtypes, the presence of an associated hematologic neoplasm and/or organ damage denotes advanced disease and the potential for increased morbidity and mortality. In addition to the revised 2016 World Health Organization classification of mastocytosis, a new diagnostic and treatment toolkit, tethered to enhanced molecular characterization and monitoring, is poised to transform the management of patients with advanced systemic mastocytosis (advSM). Although the efficacy of midostaurin and novel selective KIT D816V inhibitors, such as avapritinib (BLU-285), have validated KIT as a therapeutic target, the clinical and biologic heterogeneity of advSM requires that we reimagine the blueprint for tackling these diseases and use tools that move beyond KIT-centric approaches.
Are CAR T cells better than antibody or HCT therapy in B-ALL?
Authors: Pulsipher Michael A.
Published: April 2019

Multicenter trials in children and young adults using second-generation CD19-targeted chimeric antigen receptor (CAR) T cells have shown dramatic levels of remission in patients with multiply relapsed/refractory disease (80% to ≥90%). Early results in adult trials have also shown significant responses, and strategies aimed at mitigating toxicities associated with the therapy have improved tolerability. Therefore, if available, CAR T-cell therapy deserves consideration for salvage of children and adults with B-lineage acute lymphoblastic leukemia (B-ALL) who are multiply relapsed, refractory, or relapsed after a previous allogeneic transplantation. For patients with a first relapse or who have persistent minimal residual disease (MRD) after initial or relapse therapy, treatment with blinatumomab or inotuzumab is reasonable to help patients achieve MRD− remission before definitive therapy with allogeneic hematopoietic cell transplantation (HCT). A number of studies in younger patients using 4-1BB–based CAR T-cell constructs lentivirally transduced into patient T cells and then optimally expanded have resulted in long-term persistence without further therapy. In 1 study using CD28-based CARs in adults, the benefit of HCT after CAR T-cell therapy was not clear, because a group of patients experienced long-term remissions without HCT. These data suggest that CAR T-cell therapy may be able to substitute for transplantation in many patients, avoiding the risks and long-term consequences of HCT. With this is mind, and with emerging data better defining ways of enhancing CAR T-cell persistence and avoiding relapse through antigen escape, CAR T cells will have a growing role in treatment of both pediatric and adult B-ALLs in the coming years.
Clinical consequences of clonal hematopoiesis of indeterminate potential
Authors: Steensma David P.
Published: April 2019

Clonally restricted hematopoiesis is a common aging-associated biological state that predisposes to subsequent development of a hematological malignancy or cardiovascular death. Clonal expansion driven by leukemia-associated somatic mutations, such as DNMT3A, ASXL1, or TET2, is best characterized, but oligoclonality can also emerge without recognized leukemia-driver mutations, perhaps as a result of stochastic neutral drift. Murine models provide compelling evidence that a major mechanism of increased cardiovascular mortality in the context of clonal hematopoiesis is accelerated atherogenesis driven by inflammasome-mediated endothelial injury, resulting from proinflammatory interactions between endothelium and macrophages derived from circulating clonal monocytes. Altered inflammation likely influences other biological processes as well. The rate of development of overt neoplasia in patients with clonal hematopoiesis of indeterminate potential (CHIP), as currently defined, is 0.5% to 1% per year. Contributing factors to clonal progression other than acquisition of secondary mutations in hematopoietic cells (ie, stronger leukemia drivers) are incompletely understood. Disordered endogenous immunity in the context of increased proliferative pressure, short telomeres leading to chromosomal instability, an unhealthy marrow microenvironment that favors expansion of clonal stem cells and acquisition of new mutations while failing to support healthy hematopoiesis, and aging-associated changes in hematopoietic stem cells, including altered DNA damage response, an altered transcriptional program, and consequences of epigenetic alterations, are all potential contributors to clonal progression. Clinical management of patients with CHIP includes monitoring for hematological changes and reduction of modifiable cardiovascular risk factors; eventually, it will also likely include anti-inflammatory therapies and targeted approaches to prune emergent dangerous clones.
The MDS genomics-prognosis symbiosis
Authors: Nazha Aziz
Published: April 2019

Myelodysplastic syndromes (MDS) are clonal disorders characterized by the accumulation of complex genomic abnormalities that define disease phenotype, prognosis, and the risk of transformation to acute myeloid leukemia. The clinical manifestations and overall outcomes of MDS are very heterogeneous with an overall survival that can be measured in years for some patients to a few months for others. Prognostic scoring systems are important staging tools that aid physicians in their treatment recommendations and decision-making and can help patients understand their disease trajectory and expectations. Several scoring systems have been developed in MDS with the International Prognostic Scoring System and its revised version, the most widely used systems in clinical practice and trial eligibility. These models and others use mainly clinical variables that are obtained from bone marrow biopsy and peripheral blood measurements. Adding molecular data to current models may improve its predictive power but the ultimate method to incorporate this information remains a work in progress. Novel methods to develop a personalized prediction model that provides outcomes that are specific for a patient are currently under way and may change how we think about risk stratification in MDS patients in the future.
The rheumatology/hematology interface: CAPS and MAS diagnosis and management
Authors: Gansner John M. , Berliner Nancy
Published: April 2019

Catastrophic antiphospholipid antibody syndrome (CAPS) and macrophage activation syndrome (MAS) are both life-threatening hematologic disorders that infrequently afflict patients with rheumatologic disease. CAPS is characterized by fulminant multiorgan damage related to small vessel thrombosis in the setting of persistent antiphospholipid antibodies. It can occur in patients with rheumatologic diseases such as systemic lupus erythematosus but can also affect patients who do not have rheumatologic disease. By contrast, the term MAS is applied when patients with rheumatologic disease develop hemophagocytic lymphohistiocytosis (HLH); therefore, patients with MAS have an underlying rheumatologic disease by definition. Similar to CAPS, HLH/MAS can have a fulminant presentation, but the pathogenesis and manifestations are different. In both CAPS and MAS, management generally includes but is not limited to immunosuppression with steroids. Fatalities are relatively common and morbidity is often significant. Early recognition of these disorders and initiation of timely treatment are important. More effective therapies for both syndromes are urgently needed.
Novel insights and therapeutic approaches in idiopathic multicentric Castleman disease
Authors: Fajgenbaum David C.
Published: April 2019

Castleman disease (CD) describes a heterogeneous group of hematologic disorders that share characteristic lymph node histopathology. Patients of all ages present with either a solitary enlarged lymph node (unicentric CD) or multicentric lymphadenopathy (MCD) with systemic inflammation, cytopenias, and life-threatening multiple organ dysfunction resulting from a cytokine storm often driven by interleukin 6 (IL-6). Uncontrolled human herpesvirus-8 (HHV-8) infection causes approximately 50% of MCD cases, whereas the etiology is unknown in the remaining HHV-8-negative/idiopathic MCD cases (iMCD). The limited understanding of etiology, cell types, and signaling pathways involved in iMCD has slowed development of treatments and contributed to historically poor patient outcomes. Here, recent progress for diagnosing iMCD, characterizing etio-pathogenesis, and advancing treatments are reviewed. Several clinicopathological analyses provided the evidence base for the first-ever diagnostic criteria and revealed distinct clinical subtypes: thrombocytopenia, anasarca, fever, reticulin fibrosis/renal dysfunction, organomegaly (iMCD-TAFRO) or iMCD-not otherwise specified (iMCD-NOS), which are both observed all over the world. In 2014, the anti-IL-6 therapy siltuximab became the first iMCD treatment approved by the US Food and Drug Administration, on the basis of a 34% durable response rate; consensus guidelines recommend it as front-line therapy. Recent cytokine and proteomic profiling has revealed normal IL-6 levels in many patients with iMCD and potential alternative driver cytokines. Candidate novel genomic alterations, dysregulated cell types, and signaling pathways have also been identified as candidate therapeutic targets. RNA sequencing for viral transcripts did not reveal novel viruses, HHV-8, or other viruses pathologically associated with iMCD. Despite progress, iMCD remains poorly understood. Further efforts to elucidate etiology, pathogenesis, and treatment approaches, particularly for siltuximab-refractory patients, are needed.
Anticoagulating patients with high-risk acquired thrombophilias
Authors: Skeith Leslie
Published: April 2019

Antiphospholipid syndrome (APS), heparin-induced thrombocytopenia, and paroxysmal nocturnal hemoglobinuria are 3 acquired thrombophilias that carry a high risk of venous and arterial thromboembolism. Management of these conditions has largely included anticoagulation with a vitamin K antagonist after an initial period of a parenteral anticoagulant, for as long as the thrombotic risk is still present. The available evidence for the use of direct oral anticoagulants (DOACs) is limited and primarily consists of case series and cohort studies, which are summarized in this chapter. Randomized trials evaluating DOACs in patients with APS are reviewed. Further research is needed prior to widely adopting DOACs for use in these high-risk acquired thrombophilias; however, there may be selected low-risk subgroups where DOAC use is possible after careful consideration and patient discussion.
Approach to the treatment of the older, unfit patient with myeloma from diagnosis to relapse: perspectives of a US hematologist and a geriatric hematologist
Authors: Wildes Tanya M. , Anderson Kenneth C.
Published: April 2019

Mrs. A. is a 73-year-old woman who has developed increasing fatigue and lower back pain over the past year. The pain limits her exercise tolerance such that she can now walk only 1 block. She is a retired schoolteacher who does volunteer efforts in her community but has limited her activities due to fatigue. Karnofsky performance status is 70%. She has a history of chronic hypertension treated with a diuretic, adult-onset diabetes mellitus treated with metformin, and hypothyroidism treated with levothyroxine. Initial evaluation reveals anemia, renal dysfunction, an elevated total protein, and an L2 compression fracture on lumbosacral radiographs. Results of initial and subsequent evaluation are shown below, and she is referred to a hematologist for further evaluation, which revealed the following: calcium 9.0 mg/dL, creatinine 3.2 mg/dL with estimated creatinine clearance using the Modification of Diet in Renal Disease equation of 15 mL/min, hemoglobin 9.6 g/dL, total protein 11 g/dL, albumin 3.2 g/dL, immunoglobulin A (IgA) λ M protein 6.8 g/dL, total IgA 7.2 g/dL, IgG 0.4g/dL, IgM 0.03 g/dL, free κ <0.01 mg/L, free λ 1000 mg/L, serum free light chain ratio <0.01, β-2–microglobulin 4.2, viscosity 3.0, lactate dehydrogenase 200 U/L, urine protein electrophoresis: 125 mg/dL with 30% M protein, and urine immunofixation: λ light chain. Skeletal bone survey showed lytic lesions in femurs and humeri and diffusely in ribs bilaterally as well as compression fractures at T4, T6, and L2. Bone marrow biopsy revealed λ-restricted plasma cells comprising 50% of the bone marrow core. Fluorescence in situ hybridization testing on marrow showed that del 17p was present in 80% of the plasma cells. Mrs. A. is informed of the diagnosis of multiple myeloma and the need for therapy. She requests consultation with 2 of the leading world experts. However, she wants to be treated near her home and does not want treatment on a clinical trial.
Adipocyte alterations in endometriosis: reduced numbers of stem cells and microRNA induced alterations in adipocyte metabolic gene expression
Authors: Zolbin Masoumeh Majidi , Mamillapalli Ramanaiah , Nematian Sepide E. , Goetz Teddy G. , Taylor Hugh S.
Published: April 2019

Background

Endometriosis is an estrogen dependent, inflammatory disorder occurring in 5–10% of reproductive-aged women. Women with endometriosis have a lower body mass index (BMI) and decreased body fat compared to those without the disease, yet few studies have focused on the metabolic abnormalities in adipose tissue in women with endometriosis. Previously, we identified microRNAs that are differentially expressed in endometriosis and altered in the serum of women with the disease. Here we explore the effect of endometriosis on fat tissue and identified a role for endometriosis-related microRNAs in fat metabolism and a reduction in adipocyte stem cell number.

Methods

Primary adipocyte cells cultured from 20 patients with and without endometriosis were transfected with mimics and inhibitors of microRNAs 342-3p or Let 7b-5p to model the status of these microRNAs in endometriosis. RNA was extracted for gene expression analysis by qRT-PCR. PCNA expression was used as a marker of adipocyte proliferation. Endometriosis was induced experimentally in 9-week old female C57BL/6 mice and after 10 months fat tissue was harvested from both the subcutaneous (inguinal) and visceral (mesenteric) tissue. Adipose-derived mesenchymal stem cells in fat tissue were characterized in both endometriosis and non-endometriosis mice by FACS analysis.

Results

Gene expression analysis showed that endometriosis altered the expression of Cebpa, Cebpb, Ppar-γ, leptin, adiponectin, IL-6, and HSL, which are involved in driving brown adipocyte differentiation, appetite, insulin sensitivity and fat metabolism. Each gene was regulated by an alteration in microRNA expression known to occur in endometriosis. Analysis of the stem cell content of adipose tissue in a mouse model of endometriosis demonstrated a reduced number of adipocyte stem cells.

Conclusions

We demonstrate that microRNAs Let-7b and miR-342-3p affected metabolic gene expression significantly in adipocytes of women with endometriosis. Similarly, there is a reduction in the adipose stem cell population in a mouse model of endometriosis. Taken together these data suggest that endometriosis alters BMI in part through an effect on adipocytes and fat metabolism.
Treat and extend regimen with aflibercept for chronic central retinal vein occlusions: 2 year results of the NEWTON study
Authors: Khurana Rahul N. , Chang Louis K. , Bansal Alok S. , Palmer James D. , Wu Chengqing , Wieland Mark R.
Published: April 2019

Background

To determine whether aflibercept (Eylea; Regeneron Pharmaceuticals, Inc., Tarrytown, NY) could continue to extend the macular edema free interval in patients on a treat and extend (TAE) with non-ischemic central retinal vein occlusions (CRVOs) previously treated with ranibizumab (Lucentis; Genentech, Inc., South San Francisco, CA) or bevacizumab (Avastin; Genentech, Inc., South San Francisco, CA) in the second year.

Methods

Twenty patients with macular edema secondary to non-ischemic CRVOs previously treated with ranibizumab or bevacizumab were prospectively treated with intravitreal aflibercept injection (IAI) using a TAE dosing regimen. Injection frequencies were extended 2 weeks if there were no signs of disease activity on OCT or change in visual acuity. In the second year of the study, patients who have recurrences of macular edema could be re-challenged with a longer treatment interval under the following criterion: absence of any macular edema on three consecutive visits with the same treatment interval.

Results

Twenty patients had an average duration of a CRVO for 22 months (range 7–90) and averaged an anti-VEGF treatment every 42 days (range 28–60 days). The macular edema free interval increased from 38 to 75 days when switched to aflibercept (p = 0.000003) at month 24. There was an average increase of 37 days (median 34 days; range 0–91 days) in the macular edema free interval with aflibercept. At the month 24 visit, 50% (8/16) went > 12 weeks with a macular edema free interval between IAI. There was an improvement in vision (+ 8 ETDRS letters, p = 0.006) and decreased retinal thickness (158 µm, p = 0.00003) with aflibercept treatment at month 24.

Conclusions

The 2-year results of the NEWTON study demonstrated the sustained benefits of a TAE dosing regimen with aflibercept in patients with chronic CRVOs. The visual acuity gains and anatomic improvements observed at year one were maintained through month 24 with less visits and treatments. This may help minimize the treatment burden in patients with recurrent macular edema secondary to non-ischemic CRVO.

Trial Registration ClinicalTrials.gov, NCT01870427, Registered June 6, 2013, https://clinicaltrials.gov/ct2/show/NCT01870427?cond=NEWTON&rank=1.

Presented at the RETICON 2017: The Retina Congress with Live Surgery, Chennai, India-April 2017.
Seismic fault attribute estimation using a local fault model
Authors: Lou Yihuai , Zhang Bo , Wang Ruiqi , Lin Tengfei , Cao Danping
Published: April 2019

Faults in the subsurface can be an avenue of, or a barrier to, hydrocarbon flow and pressure communication. Manual interpretation of discontinuities on 3D seismic amplitude volume is the most common way to define faults within a reservoir. Unfortunately, 3D seismic fault interpretation can be a time-consuming and tedious task. Seismic attributes such as coherence help define faults, but suffer from “staircase” artifacts and nonfault-related stratigraphic discontinuities. We assume that each sample of the seismic data is located at a potential fault plane. The hypothesized fault divides the seismic data centered at the analysis sample into two subwindows. We then compute the coherence for the two subwindows and full analysis window. We repeat the process by rotating the hypothesized fault plane along a set of user-defined discrete fault dip and azimuth. We obtain almost the same coherence values for the subwindows and the full window if the analysis point is not located at a fault plane. The “best” fault plane results in maximum coherence for the subwindows and minimum coherence for the full window if the analysis point is located at a fault plane. To improve the continuity of the fault attributes, we finally smooth the fault probability attribute along the estimated fault plane. We illustrate the effectiveness of our workflow by applying it to a synthetic and two real seismic data. The results indicate that our workflow successfully produces a continuous fault attribute without staircase artifacts and stratigraphic discontinuities.
Progression Risk Stratification of Asymptomatic Waldenström Macroglobulinemia
Authors: Bustoros Mark , Sklavenitis-Pistofidis Romanos , Kapoor Prashant , Liu Chia-Jen , Kastritis Efstathios , Zanwar Saurabh , Fell Geoffrey , Abeykoon Jithma P. , Hornburg Kalvis , Neuse Carl Jannes , Marinac Catherine R. , Liu David , Soiffer Jenny , Gavriatopoulou Maria , Boehner Cody , Cappuccio Joseph M. , Dumke Henry , Reyes Kaitlen , Soiffer Robert J. , Kyle Robert A. , Treon Steven P. , Castillo Jorge J. , Dimopoulos Meletios A. , Ansell Stephen M. , Trippa Lorenzo , Ghobrial Irene M.
Published: April 2019

BACKGROUND

Waldenström macroglobulinemia (WM) is preceded by asymptomatic WM (AWM), for which the risk of progression to overt disease is not well defined.

METHODS

We studied 439 patients with AWM, who were diagnosed and observed at Dana-Farber Cancer Institute between 1992 and 2014.

RESULTS

During the 23-year study period, with a median follow-up of 7.8 years, 317 patients progressed to symptomatic WM (72%). Immunoglobulin M 4,500 mg/dL or greater, bone marrow lymphoplasmacytic infiltration 70% or greater, β2-microglobulin 4.0 mg/dL or greater, and albumin 3.5 g/dL or less were all identified as independent predictors of disease progression. To assess progression risk in patients with AWM, we trained and cross-validated a proportional hazards model using bone marrow infiltration, immunoglobulin M, albumin, and beta-2 microglobulin values as continuous measures. The model divided the cohort into three distinct risk groups: a high-risk group with a median time to progression (TTP) of 1.8 years, an intermediate-risk group with a median TTP of 4.8 years, and a low-risk group with a median TTP of 9.3 years. We validated this model in two external cohorts, demonstrating robustness and generalizability. For clinical applicability, we made the model available as a Web page application ( www.awmrisk.com ). By combining two cohorts, we were powered to identify wild type MYD88 as an independent predictor of progression (hazard ratio, 2.7).

CONCLUSION

This classification system is positioned to inform patient monitoring and care and, for the first time to our knowledge, to identify patients with high-risk AWM who may need closer follow-up or benefit from early intervention.
Cyclo-oxygenase-2 expression is associated with mean standardised uptake value on 18F-Fluorodeoxyglucose positron emission tomography in oesophageal adenocarcinoma
Authors: Foley Kieran G , Christian Adam , Peaker James , Marshall Christopher , Spezi Emiliano , Kynaston Howard , Roberts Ashley
Published: April 2019

Objectives:

This pilot study investigated the association of four PET image features and cyclo-oxygenase-2 (COX-2) expression in patients with oesophageal adenocarcinoma. The prognostic significance of these biomarkers was also assessed.

Methods:

50 consecutive patients [median age = 68 (range 47 – 84), males = 45) with oesophageal adenocarcinoma had PET/CT staging between January 2011 and July 2015. The maximum and mean standardised uptake values (SUVmax and SUVmean), metabolic tumour volume (MTV) and tumour lesion glycolysis (TLG) were calculated from the primary tumour. Their association with COX-2 status was assessed using Mann-Whitney U tests. Kaplan-Meier and Cox regression analysis tested their prognostic significance. A p-value < 0.05 was considered statistically significant.

Results:

32 tumours (64.0%) were COX-2 positive. There was a significant association between SUVmean and COX-2 status (p = 0.019). TLG (hazard ratio (HR) 1.001, 95 % confidence intervals (CI) 1.000 – 1.002, p = 0.018) was significantly associated with overall survival on multivariable analysis.

Conclusions:

This study investigated the association between PET image features and COX-2 expression in oesophageal adenocarcinoma. The preliminary results signal that a combination of TLG (calculated as product of MTV and SUVmean) and COX-2 status may be a strong and clinically important prognostic biomarker. Our research group are planning a prospective, multi-centre study to validate these findings.

Advances in knowledge:

Mean standardised uptake value (SUVmean) on PET imaging is associated with COX-2 expression in oesophageal adenocarcinoma.
MSF: Modulated Sub-graph Finder
Authors: Farman Mariam R. , Hofacker Ivo L. , Amman Fabian
Published: April 2019

High throughput techniques such as RNA-seq or microarray analysis have proven to be invaluable for the characterizing of global transcriptional gene activity changes due to external stimuli or diseases. Differential gene expression analysis (DGEA) is the first step in the course of data interpretation, typically producing lists of dozens to thousands of differentially expressed genes. To further guide the interpretation of these lists, different pathway analysis approaches have been developed. These tools typically rely on the classification of genes into sets of genes, such as pathways, based on the interactions between the genes and their function in a common biological process. Regardless of technical differences, these methods do not properly account for cross talk between different pathways and most of the methods rely on binary separation into differentially expressed gene and unaffected genes based on an arbitrarily set p-value cut-off.

To overcome this limitation, we developed a novel approach to identify concertedly modulated sub-graphs in the global cell signaling network, based on the DGEA results of all genes tested. To this end, expression patterns of genes are integrated according to the topology of their interactions and allow potentially to read the flow of information and identify the effectors. The described software, named Modulated Sub-graph Finder (MSF) is freely available at https://github.com/Modulated-Subgraph-Finder/MSF.
Preliminary assessment of adaptive evolution of mitochondrial protein coding genes in darters (Percidae: Etheostomatinae)
Authors: Kral Leos G. , Watson Sara
Published: April 2019

Background: Mitochondrial DNA of vertebrates contains genes for 13 proteins involved in oxidative phosphorylation. Some of these genes have been shown to undergo adaptive evolution in a variety of species. This study examines all mitochondrial protein coding genes in 11 darter species to determine if any of these genes show evidence of positive selection.

Methods: The mitogenome from four darter was sequenced and annotated. Mitogenome sequences for another seven species were obtained from GenBank. Alignments of each of the protein coding genes were subject to codon-based identification of positive selection by Selecton, MEME and FEL.

Results: Evidence of positive selection was obtained for six of the genes by at least one of the methods. CYTB was identified as having evolved under positive selection by all three methods at the same codon location.

Conclusions: Given the evidence for positive selection of mitochondrial protein coding genes in darters, a more extensive analysis of mitochondrial gene evolution in all the extant darter species is warranted.
Patient treatment pathways of multidrug-resistant tuberculosis cases in coastal South India: Road to a drug resistant tuberculosis center
Authors: Rathi Priya , Shringarpure Kalpita , Unnikrishnan Bhaskaran , Pandey Abhinav , Nair Abhirami
Published: April 2019

Background: Delays in initiating multidrug-resistant tuberculosis (MDR TB) treatment adds risk to individual patients and the community due to disease progression, and on-going transmission.  The Government of India offers free TB diagnosis and treatment, however many presumptive MDR TB patients wander within the Indian healthcare system and delay accessing the programme. To better improve access to care, it is imperative to understand the treatment pathways taken by MDR TB patients. We aimed to describe the diagnostic and treatment pathway taken by presumptive MDR TB patients registered in the Programmatic Management Drug-resistant TB Program (PMDT).

Methods: We conducted a cross-sectional study of all patients registered during August 2016 – April 2017 at one PMDT center of a district in Karnataka, India. A semi-standardized questionnaire collected the number, type (private vs public sector), and dates of healthcare facilities (HCFs) visits prior to the initiation of MDR TB treatment.  Delays were the number of days, expressed in medians and interquartile range (IQR), from the date of onset of illness until the date of initiation of MDR TB treatment.

Results: We found that patients preferred private HCFs; however, due to lack of treatment and unaffordability they shifted to public HCFs. Median delay to register under the program was more in private HCFs (180days) in comparison with public HCFs (120 days). We also found that the diagnosis of MDR among presumptive MDR cases (detection rates) were much higher (80%) in public HCFs.

Conclusion: Awareness regarding the availability of free standard diagnosis and appropriate treatment under the TB program should be increased in the general population and private practitioners. The government should involve private HCFs to provide standard diagnostics and treatment to the patients seeking a private facility.
Determinants of knowledge, attitude and practice in patients with both type 2 diabetes and chronic kidney disease in Fiji
Authors: Zibran Mohammed Alvis , Mohammadnezhad Masoud
Published: April 2019

Background:In Fiji, Type 2 diabetes mellitus (T2DM) and Chronic kidney disease (CKD) are amongst the top four causes of premature mortality, disability and death. This study aims to identify the determinants of knowledge, attitude and practice (KAP) in T2DM patients with CKD in Fiji in 2018.

Methods:A cross-sectional study was conducted at Sigatoka Sub-divisional Hospital (SSH) in Fiji in July-August, 2018 using a self-structured questionnaire to test KAP of 225 patients. The inclusion criteria were confirmed T2DM patients (Fijian citizens) with CKD, aged 30 years or above and attending Special Out-Patient's Department (SOPD) at SSH. Independent t-test and ANOVA was used to test differences between demographic variable and practice score while non-parametric tests were used for knowledge and attitude. Spearman correlation and multiple linear regressions were also done. All the tests were set at 5% level of significance.

Results: From 249 questionnaires distributed, 225 responded thus response rate was 95%. The mean KAP level was high: knowledge, 23.3/30 (SD±3.25); attitude, 23.1/30 (SD±2.73) and practice, 7.1/10 (SD±2.04). A high level of knowledge was seen in those with university-level education (p<0.001), unemployed (p=0.05) and high average monthly income (p=0.03). Those aged 61-70 years had a 0.53-point lower attitude score (p=0.05) than other age categories, while those >70 years had a 1.78-point lower attitude score (p=0.01) than other age categories. Fijians of Indian descent (FID) had lower attitude (p=0.002) and higher practice (p=0.001) scores.

Conclusion:Patients with both T2DM and CKD at SSH have high levels of KAP. The determinants of KAP have been shown and thus, this study identified high-risk groups for low KAP, which can become the focus of future public health intervention.
Analysis of correlation-based biomolecular networks from different omics data by fitting stochastic block models
Authors: Baum Katharina , Rajapakse Jagath C. , Azuaje Francisco
Published: April 2019

Background:Biological entities such as genes, promoters, mRNA, metabolites or proteins do not act alone, but in concert in their network context. Modules, i.e., groups of nodes with similar topological properties in these networks characterize important biological functions of the underlying biomolecular system. Edges in such molecular networks represent regulatory and physical interactions, and comparing them between conditions provides valuable information on differential molecular mechanisms. However, biological data is inherently noisy and network reduction techniques can propagate errors particularly to the level of edges. We aim to improve the analysis of networks of biological molecules by deriving modules together with edge relevance estimations that are based on global network characteristics. 

Methods: We propose to fit the networks to stochastic block models (SBM), a method that has not yet been investigated for the analysis of biomolecular networks. This procedure both delivers modules of the networks and enables the derivation of edge confidence scores. We apply it to correlation-based networks of breast cancer data originating from high-throughput measurements of diverse molecular layers such as transcriptomics, proteomics, and metabolomics. The networks were reduced by thresholding for correlation significance or by requirements on scale-freeness. 

Results and discussion:We find that the networks are best represented by the hierarchical version of the SBM, and many of the predicted blocks have a biological meaning according to functional annotation. The edge confidence scores are overall in concordance with the biological evidence given by the measurements. As they are based on global network connectivity characteristics and potential hierarchies within the biomolecular networks are taken into account, they could be used as additional, integrated features in network-based data comparisons. Their tight relationship to edge existence probabilities can be exploited to predict missing or spurious edges in order to improve the network representation of the underlying biological system.
Houses of Culture as Places of/in Memory
Authors: Chovancová Petra
Published: April 2019

This paper introduces key concepts of a preliminary project concerning houses of culture in former Czechoslovakia. Houses of culture used to be perceived as one of the signs, as well as a platform of establishing power during the communist era. The project will concentrate on various aspects of planning, building and managing houses of culture. In our research project we apply the “history from below” approach while viewing these Houses as a kind of “les Lieux de Mémoire” (places of memory). The chosen approach will require one to find historical witnesses and conduct a series of interviews with them in order to find out how houses of culture shaped their life during the communist era and, on the other hand, how people shaped the cultural life of these institutions.
Ethics and Humanism in the Machine Era
Authors: Grassi Edmondo
Published: April 2019

In a society based on technology, the human being loses their centrality and triggers the fourth revolution by means of scientific advancement and digital progress: that of the rupture of anthropocentrism, of industry 4.0 and of the infosphere. The scientific and academic debate must focus its attention, among various elements, on the formulation of new ethical principles that can guide a person in their interaction, interconnection and, in some cases, “fusion” with the “machine” and its accompanying values. The advent of artificial intelligences is producing changes in the management of common liberties, of private and public life, of the individual and of the community, which increasingly seek in the “artificialisation” of the self and in their relationship with machines, places, subjects, reflections of interaction with each other and with the other self. The sophistication of technology and, therefore, of reality indicate the need to rethink the relationship between the tangibility of the natural and its mechaniseddigitalised representations. What will be the ethics of the future? What are the values to support in the new revolution that sees the person flanked by the machine? What are, at present, the global choices on these issues?
The Pursuit of Freedom in Private Life as Reflected in Contemporary Russian Comics
Authors: Saduov Ruslan
Published: April 2019

This article reviews how My Sex, the Russian autobiographical graphic novel by Alyona Kamyshevskaya, reflects public-private relationships in the USSR and contemporary Russia. In particular, the focus is on how the Soviet state tabooed sexuality, leaving its people unaware of basic physiological information and causing them to make harmful uninformed decisions. My Sex is seen as an example of the consequences of public intrusion into the private sphere regarding aspects that should stay untouched.
The Circumstances of Art in the Public Space
Authors: Rudyjová Michaela
Published: April 2019

The public space and the art within it have taken different forms and functions in history, namely changing from being an agora, to present-day so-called hybrid forms. The resulting state of forms and functions of art in the public space depends on several determinants, including freedom and restrictions concerning the public space. While under totalitarian regimes priorities and restrictions prevail, after the fall of totalitarian regimes almost unlimited freedom comes into being. Consequently, questions arise regarding who makes decisions on the forms of art placed in the public space, and on what grounds such decisions are made. In our article, in taking the example of one city we are looking for the answers to questions whether and how it is possible to map the art in the public urban space, as well as who, and on what grounds, makes decisions regarding expressions of art in the public space. Methodologically, we have based our research on the identification and analysis of relevant documents of cultural policy related to a given place and on interviews with a chosen relevant expert who is involved in the public space.
Optimal Prescriptive Trees
Authors: Bertsimas Dimitris , Dunn Jack , Mundru Nishanth
Published: April 2019

Motivated by personalized decision making, given observational data [Formula: see text] involving features [Formula: see text], assigned treatments or prescriptions [Formula: see text], and outcomes [Formula: see text], we propose a tree-based algorithm called optimal prescriptive tree (OPT) that uses either constant or linear models in the leaves of the tree to predict the counterfactuals and assign optimal treatments to new samples. We propose an objective function that balances optimality and accuracy. OPTs are interpretable and highly scalable, accommodate multiple treatments, and provide high-quality prescriptions. We report results involving synthetic and real data that show that OPTs either outperform or are comparable with several state-of-the-art methods. Given their combination of interpretability, scalability, generalizability, and performance, OPTs are an attractive alternative for personalized decision making in a variety of areas, such as online advertising and personalized medicine.
Taking a dip
Authors: White Hilary
Published: April 2019

Hilary White kicks off a new series linking cooking to maths skills. Her recipes for healthy, tasty dips give children the opportunity to have fun following a sequence of steps to get to an end result.
Tea with a tiger
Authors: Harries Judith
Published: April 2019

Use the books of Judith Kerr as a springboard for focusing on people and communities, families and animals, and inspire children to create their own stories based on her popular characters.
Between the teeth
Authors: Rawstrone Annette
Published: April 2019

Some fortunate babies acquire teeth without any discomfort or pain and parents suddenly spot them, but others may notice that their child's gum is sore and red. Annette Rawstrone advises.
Join the dance
Authors: Hewson Claire
Published: April 2019

Moving to music delivers the feel good factor and when children make up their own dances they have fun working as a team, listening to each other's ideas and remembering sequences of moves.
Up and down
Authors: Hewson Claire
Published: April 2019

Support children to develop an enthusiasm for cleaning their teeth and acquiring the skills they need to do so effectively. Use picture books to extend their knowledge of keeping their teeth healthy.
Digging for letters
Authors: Harries Judith
Published: April 2019

In the final part of this series on sand play, Judith Harries focuses on sand as a fantastic resource for exploring letters of the alphabet, using magnetic letters, pebbles, vehicles and cardboard tubes.
Life course trajectories of family care
Authors: Keating Norah , Eales Jacquie , Funk Laura , Fast Janet , Min Joohong
Published: April 2019

More than 30 years ago, Elder theorised multiple life-course trajectories in domains such as family and work, punctuated by transitions that create the structure and rhythm of individual lives. We argue that in the context of population ageing, family care should be added as a life-course domain. We conceptualise life courses of family care with core elements of ‘care as doing’ and ‘care as being in relationship’, creating hypothetical family care trajectories to illustrate the diversity of life-course patterns of care. The framework provides a basis for considering influences of care on cumulative advantage/disadvantage for family carers.
The wrong Malevich: Art, revolution and the public sphere
Authors: Hutchinson Mark
Published: April 2019

This article argues that there is a radical division between Malevich’s pre-revolutionary and post-revolutionary thought and work. Underlying this division is a distinction between modernism as practices of negation within art and the avantgarde as the negation of the practice of art. Whilst Black Square and White on White have an established place in both art-history and contemporary theory, as the epitome of a certain type and moment of modernist art, what Malevich did after the revolution is poorly represented and poorly understood. After the revolution Malevich stopped painting, started teaching, wrote theory and started working collectively; this was an attempt at the radical transformation of art in conjunction with the radical transformation of society. Thus there is an exemplary distinction to be made between Malevich’s pre-revolutionary modernism and his post-revolutionary avant-gardism.
The critical invariant: Avant-garde and change
Authors: Altintzoglou Euripides
Published: April 2019

‘Change’ is the locus of the avant-garde’s revolutionary character. Historical claims and contemporary theorizations of the avant-garde enforce methodological distinctions between radical and conforming attitudes that fluctuate according to existing political agendas. This process of instrumentalization renders the avantgarde susceptible to the conformity of institutionalization. More importantly it prescribes the avant-garde with a subservient role that controls its operational means and deflates its capacity to produce politics. What is to be done, if the avant-garde achieves its goal for socio-political change? Are we to abandon the spirit of critical reflection and surrender to the conditions of the next system? How can there be an avant-garde after capitalism if its ends are solely confined in the substitution of one system with another? This article traces out this problem, assessing what kind of emancipatory potential we might expect, or hope for, from a post-capitalist avant-garde, by advancing a critical examination of recent theories of political subjectivity, the dialectics of change and the reconciliation of the institution.
The lure of diglossia: A conversation with Grant Kester
Authors: Garrido Castellano Carlos
Published: April 2019

This interview with Grant Kester touches on the main issues surrounding socially engaged art. Kester, one of the leading voices in the configuration of a specific critical approach to collaborative, socially led artistic processes, depicts in this conversation a broad panorama of practices spanning from the 1980s to the present moment, a time when mainstream art institutions have begun embracing social practice. Attentive to that process, Kester reconstructs some pivotal experiments oriented to the consecution of social change through artistic means. He also aims to frame the global purchase of socially engaged art, paying attention to how this expansion affects the critical approaches to specific artistic projects, and disclosing how socially engaged art projects can still hold an emancipative potential.