bluuebunny/crossref_metadata_2025 huggingface dataset:
SUMOylation protects FASN against proteasomal degradation in breast cancer cells treated with grape leaf extract
Authors: Floris Andrea , Mazarei Michael , Yang Xi , Robinson Aaron Elias , Zhou Jennifer , Barberis Antonio , D’hallewin Guy , Azara Emanuela , Spissu Ylenia , Iglesias-Ara Ainhoa , Orru Sandro , Tomasi Maria Lauda
Published: February 2020

Background: Existing therapeutic strategies for breast cancer are limited by tumor recurrence and drug-resistance. Several epidemiological studies indicate that antioxidant plant-derived compounds such as flavonoids reduce adverse outcomes and have been identified as a potential source of antineoplastic agent with less undesirable side effects. Activation of lipid metabolism is an early event in carcinogenesis and a central hallmark in breast cancer. In fact, inhibition of fatty-acid synthesis in breast cancer results in cytotoxicity that triggers apoptosis. Here, we describe the novel regulation of lipid metabolism in breast cancer cells whereby the protein stability and degradation of fatty-acid synthase (FASN), the key enzyme in de novo fatty-acid synthesis, is regulated by SUMOylation.Methods: The phenolic characterization were analyzed by Liquid Chromatography-Mass Spectrometry (LCMS). Profile protein contents was evaluated by Mass Spectrometry (LC-MS/MS). The experiments were performed using MCF7, SKBR-3 human carcinoma cell lines and MCF-12A breast epithelial cell line treated with Vermentino hydroalcoholic extract in dose and time course responses. Protein and mRNA levels were analyzed by western blotting/Co-immunoprecipitation (Co-IP) and RT-PCR, respectively. The number of viable cells and the cell-surviving has been detected by MTT and clonogenicity assays. Apoptotic induction was determined by Flow Cytometric assay using Annexin V-FITC and sorted by A FACSC analysis.Results: We first tested the potential antitumorigenic effects of Vitis vinifera L. cv. Vermentino leaf hydroalcoholic extract in MCF-7 and SKBR-3 breast cancer cell lines and found that this compound demonstrated cytotoxic effects. We went on to determine that FASN and UBC9, the sole E2 enzyme required for SUMOylation, were significantly reduced by treatment with the Vermentino extract. Moreover, we found that FASN was SUMOylated in human breast cancer tissues and cell lines. Finally, lack of SUMOylation caused by SUMO2 silencing reduced FASN protein stability.Conclusion: Altogether, these results suggest that SUMOylation protects FASN against proteasomal degradation and may exert oncogenic activity through alteration of lipid metabolism in breast cancer. Importantly, we found that these effects were significantly inhibited by treatment with Vermentino leaf extract, which supports the additional validation of the therapeutic value of this compound.
Impact of changes in the methodology of external price referencing on medicine prices: discrete-event simulation
Authors: Vogler Sabine , Schneider Peter , Lepuschütz Lena
Published: February 2020

Background: Several governments apply the policy of external price referencing (EPR), which considers the prices of a medicine in one or more other countries for the purpose of setting the price in the own country. Different methodological choices can be taken to design the EPR policy. The study aimed to analyse whether, or not, and how changes in the methodology of EPR can impact medicine prices.Methods: The real-life EPR methodology as of Q1/2015 was surveyed in all European Union Member States, Iceland, Norway and Switzerland through a questionnaire responded by national pricing authorities. Different scenarios were developed related to the parameters of the EPR methodology. Discrete-event simulations of fictitious prices in the 28 countries of the study that had EPR in place were run for a period of 10 years. The continuation of the real-life EPR methodology in the countries as surveyed in 2015, without any change, served as base case.Results: Consideration of discounts (an assumed 20% discount in five large economies and the mandatory discount in Germany, Greece and Ireland) and determining the reference price based on the lowest price in the country basket would result in higher price reductions (on average -47.2% and -34.2% compared to the base case). An adjustment of medicine price data of the reference countries by purchasing power parities would lead to higher prices in some more affluent countries (e.g. Switzerland, Norway) and lower prices in lower-income economies (Bulgaria, Romania, Hungary, Poland). Regular price revisions and changes in the basket of reference countries would also impact medicine prices, however to a lesser extent.Conclusions: EPR has some potential for cost-containment. Medicine prices could be decreased further if certain parameters of the EPR methodology were changed. If public payers aim to apply EPR to keep medicine prices at more affordable levels, they are encouraged to explore the cost-containment potential of this policy and to take appropriate methodological choices in the design of EPR.
Service Sector Growth in Iran: Knowledge-based Economy or Premature Deindustrialization?
Authors: Momeni Farshad , Fattahi Soheil , Najafi Seyed Mohammad Sajjad , Moghadam Shahabodin Fuladi
Published: February 2020

In recent decades, most of the national economies have experienced a similar trend of growth in service sector. In economic literature service sector growth can be rooted in two distinct phenomena: knowledge-based economy or premature deindustrialization. This paper seeks to investigate the nature of service sector growth based on its effect on total factor productivity (TFP) in Iran. In particular, Kalman filter approach is used to estimate this effect. Service sector valued added and share of employment are used as the two separate proxies for service sector size in order to improve robustness of the results. Empirical results show that service sector growth did not increase overall productivity over the period of 1975-2015. Consequently, service sector growth in Iran did not root in knowledge-based economy and the whole progress could be considered as premature deindustrialization.
The role of Mycobacterium tuberculosis complex strain on apoptosis and necroptosis state of macrophages derived from active pulmonary tuberculosis patients
Authors: Yanti Budi , Mulyadi Mulyadi , Amin Muhammad , Harapan Harapan , Mertaniasih Ni Made , Soetjipto Soetjipto
Published: February 2020

Objective The role of Mycobacterium tuberculosis complex (MTBC) strain in tuberculosis (TB) infection in human is still questioned. The aim of this study was to determine whether MTBC strain is associated with apoptosis and necroptosis by measuring the expression of specific signaling pathways components (Fas-associated protein with death domain (FADD) and receptor interacting protein 3 (RIP3)), as well as the level of apoptosis.Results We recruited 24 TB patients infected with M. tuberculosis Beijing strain and six patients with M. bovis BCG strain. Data indicated that those who infected with M. tuberculosis were more frequent to have severe lung damage than M. bovis (odds ratio [OR]: 7.60; 95% confidence interval [CI]: 1.07-54.09). M. tuberculosis infection was also associated with lower expression of FADD and lower apoptosis level of macrophage cells compared to M. bovis . No significant different of RIP3 between strain groups. In conclusion, M. tuberculosis Beijing strain is associated with severe pulmonary damage, inhibits FADD expression and reduces apoptosis level in macrophages derived from TB. This suggests that MTBC strain potentially be used as determinant of progressivity of disease and tissue damage in TB cases.
The whole blood phagocytosis assay: a clinically relevant test of neutrophil function and dysfunction in community-acquired pneumonia
Authors: Reiné Jesús , Rylance Jamie , Ferreira Daniela M. , Pennington Shaun H. , Welters Ingeborg Dorothea , Parker Robert , Morton Ben
Published: February 2020

OBJETIVE: To refine and validate a neutrophil function assay with clinical relevance for patients with community-acquired pneumonia (CAP). Design: Two phase cross-sectional study to standardise and refine the assay in blood from healthy volunteers and test neutrophil phagocytic function in hospital patients with CAP. Participants: Phase one: Healthy adult volunteers (n=30). Phase two: Critical care patients with severe CAP (n=16), ward-level patients with moderate CAP (n=15) and respiratory outpatients (no acute disease, n=15).RESULTS: Our full standard operating procedure for the assay is provided. Patients with severe CAP had significantly decreased neutrophil function compared to moderate severity disease (median phagocytic index 2.8 vs. 18.0, p=0.014). Moderate severity pneumonia neutrophil function was significantly higher than control samples (median 18.0 vs. 1.6, p=0.015). There was no significant difference between critical care and control neutrophil function (median 2.8 vs. 1.6, p=0.752). Conclusions: Our whole blood neutrophil assay is simple, reproducible and clinically relevant. Changes in neutrophil function measured in this pneumonia cohort is in agreement with previous studies. The assay has potential to be used to identify individuals for clinical trials of immunomodulatory therapies, to risk-stratify patients with pneumonia, and to refine our understanding of ‘normal’ neutrophil function in infection.
Using three statistical methods to analyze the association between exposure to 13 compounds and obesity in children and adolescents: National Health and Nutrition Examination Survey 2005-2010
Authors: Wu Bangsheng , Jiang Yi , Jin Xiaoqing , He Li
Published: February 2020

Background: Various risk factors influence obesity differently, and too much environmental endocrine disruption may increase the occurrence of obesity. However, most of the previous studies have considered only a unitary exposure or a set of similar exposures instead of mixed exposures, which entail complicated interactions. We utilized three statistical models to evaluate the interactions between mixed chemicals to analyze the association between 13 different chemical exposures and obesity in children and adolescents. Methods: We fitted the generalized linear regression, weighted quantile sum (WQS) regression, and Bayesian kernel machine regression (BKMR) to analyze the association between the mixed exposures and obesity in the participants aged 6-19 in the National Health and Nutrition Examination Survey (NHANES) 2005–2010. Results: In the logistic regression model, 2,5-dichlorophenol (2,5-DCP) (P = 0.001), monoethyl phthalate (MEP) (P = 0.005), and mono-isobutyl phthalate (MiBP) (P = 0.023) were found to be positively associated with obesity, while methylparaben (MeP) (P = 0.011) was negatively associated with obesity. In the multivariable linear regression, MEP was the only chemical found to be associated with the body mass index (BMI) z-score (P = 0.003). In the WQS regression model, the WQS index had a significant association (P = 0.001) with the outcome in the obesity model, in which 2,5-DCP (weighted 0.35), 2,4,6-trichlorophenol (2,4,6-TCP) (weighted 0.16), MEP (weighted 0.14), and MiBP (weighted 0.12) all had relatively high weights. In the BKMR model, despite no statistically significant difference in the overall association between the chemical mixtures and the outcome (obesity or BMI z-score), there was nonetheless an increasing trend. 2,5-DCP, MEP, and MiBP were found to be positively associated with obesity, while fixing other chemicals at their median concentrations. Conclusion: Comparing the three statistical models, we found that 2,5-DCP, MEP, and MiBP may play an important role in the 13 exposures. Considering the advantages and disadvantages of the three statistical models, our study confirms the necessity to combine different statistical models on obesity when dealing with mixed exposures.
Effects of Hydrothermal Conditions on the Net Primary Productivity in the Source Region of Yangtze River, China
Authors: Yuan Zhe , Wang Yongqiang , Xu Jijun , Yin Jun , Chen Shu
Published: February 2020

Background: The ecosystems and natural environment of the Source Region of Yangtze River (SRYR) is highly susceptible to the climate change. Quantifying the response of vegetation Net Primary Productivity (NPP) to the changes of hydrothermal conditions is an important way to identify and predict global ecosystem dynamics. Methods: Using MODIS/Terra Yearly NPP data at 1km×1km spatial resolution, the spatial-temporal variation of NPP was analyzed at first. Then, correlations between NPP and hydrothermal conditions were evaluated with soil water content and accumulated temperature. Finally, a response model was built to analyze the sensitivity of the NPP to precipitation and temperature changes. Result: (1) NPP is generally lower in the western SRYR and increases gradually toward the east, with an average value of 85.2 gC/m 2 . The total NPP had increased by 1.42TgC per year from 2000 to 2014. The fastest change rate of NPP is presented in the Downstream region, followed by the middle stream region and Dam River Basin; (2) the NPP of one specific year has obvious relationship with the accumulated temperature of the same year and the soil water deficit of the previous year. The temperature is the dominant climate factor impacting vegetation growth in the SRYR; (3) It is shown an increase of NPP by 0.194 TgC (nearly 30%) with a 1-°C increase in annual mean temperature. While a 10% increase in annual precipitation corresponds to an increase in NPP by 0.517 TgC (nearly 5%). Conclusion: A warming, wetting and greening SRYR was detected in recent decade. The NPP in SRYR is more sensitive to changes in temperature than changes in precipitation.
Pyruvate anaplerosis is a mechanism of resistance to pharmacological glutaminase inhibition in Triple-receptor Negative Breast Cancer
Authors: Singleton Dean C , Dechaume Anne-Lise , Murray Pamela M , Katt William P , Baguley Bruce C , Leung Euphemia Y
Published: February 2020

Background Glutamine serves as an important nutrient with many cancer types displaying glutamine dependence. Following cellular uptake glutamine is converted to glutamate in a reaction catalysed by mitochondrial glutaminase. This glutamate has many uses, including acting as an anaplerotic substrate ( via alpha-ketoglutarate) to replenish TCA cycle intermediates. CB-839 is a potent, selective, orally bioavailable glutaminase inhibitor that has activity in Triple receptor-Negative Breast Cancer (TNBC) cell lines and evidence of efficacy in advanced TNBC patients. Methods A panel of eleven breast cancer cell lines was used to investigate the anti-proliferative effects of the glutaminase inhibitors CB-839 and BPTES in different types of culture medium, with or without additional pyruvate supplementation. The abundance of the TCA cycle intermediate fumarate was quantified as a measure if TCA cycle anaplerosis. Pyruvate secretion by TNBC cultures was then assessed with or without AZD3965, a monocarboxylate transporter 1 (MCT1) inhibitor. Finally, two dimensional (2D) monolayer and three dimensional (3D) spheroid assays were used to compare the effect of microenvironmental growth conditions on CB-839 activity. Results The anti-proliferative activity of CB-839 in a panel of breast cancer cell lines was similar to published reports, but with a major caveat; growth inhibition by CB-839 was strongly attenuated in culture medium containing pyruvate. This pyruvate-dependent attenuation was also observed with a related glutaminase inhibitor, BPTES. Studies demonstrated that exogenous pyruvate acted as an anaplerotic substrate preventing the decrease of fumarate in CB-839-treated conditions. Furthermore, endogenously produced pyruvate secreted by TNBC cell lines was able to act in a paracrine manner to significantly decrease the sensitivity of recipient cells to glutaminase inhibition. Suppression of pyruvate secretion using the MCT1 inhibitor AZD3965, antagonised this paracrine effect and increased CB-839 activity. Finally, CB-839 activity was significantly compromised in 3D compared with 2D TNBC culture models, suggesting that 3D microenvironmental features impair glutaminase inhibitor responsiveness. Conclusion This study highlights the potential influence that both circulating and tumour-derived pyruvate can have on glutaminase inhibitor efficacy. Furthermore, it highlights the benefits of 3D spheroid cultures to model the features of the tumour microenvironment and improve the in vitro investigation of cancer metabolism-targeted therapeutics.
Clonal architectures predict clinical outcome in gastric adenocarcinoma based genomic variation and tumor evolution and heterogeneity in gastric adenocarcinoma
Authors: Ren Chenxia , Wu Cuiling , Wang Niuniu , Lian Changhong , Yang Changqing
Published: February 2020

Background: Gastric cancer is a highly heterogeneous disease. Due to the lack of effective molecular markers and personalized treatment, the prognosis of patients with gastric cancer is still rather poor. This paper attempts to explore the genomic instability and intratumoral heterogeneity of gastric cancer through bioinformatics analysis. Methods: According to the RNA-Seq data, copy number variation data and clinical follow-up information data of TCGA, brunet algorithm in NMF was used to identify SNV signature. ABSOLUTE algorithm was used to screen and identify CNV signature. The relationship between clonal state and survival of genes was analyzed with Kaplan-Meier method. The Spearman method was used to evaluate the correlation between clonal/sub-clonal events and TMB and neoantigen. Results: Mutation analysis of SNV mutation and CNA data in the TCGA gastric cancer dataset divided mutation of TCGA gastric cancer samples into three signatures with significant differences. Furthermore, the clonal/sub-clonal events of SCNA and SNV were analyzed to identify the clonal/sub-clonal status of mutations in STAD samples. It was further found that the number of mutations in TP53, TTN and MUC16 genes was the highest (> 20%) among the samples. The number of CNV (Gain) in MIEN1, GRB7 and PNMT genes was the highest (> 10%) among the samples. A series of early gastric cancer genes, such as TP53, USH2A and GLI3 as well as advanced genes such as CTNNB1, LRP1B and ERBB4 were further identified. Ultimately, the clonal/sub-clonal status of 5 early genes, 12 intermediate genes and 8 advanced genes was significantly correlated with the overall survival rate of patients. In addition, there was a significant correlation between clonal/sub-clonal events and TMB/Neoantigens. Conclusion: In this paper, the relationship between intratumoral heterogeneity and genomic instability was evaluated based on developmental data of gastric cancer cloning system. A series of molecular features determined by screening can be used as a marker of potential gastric cancer heterogeneity, which is of great significance to the personalized treatment of gastric cancer.
The lack of selection criteria for surgery in patients with non-colorectal non-neuroendocrine liver metastases
Authors: Bohlok Ali , Lucidi Valerio , Bouazza Fikri , Daher Ali , Germanova Desislava , Laethem Jean luc Van , Hendlisz Alain , donckier Vincent
Published: February 2020

Background The benefit of surgery in patients with non-colorectal non-neuroendocrine liver metastases (NCRNNELM) remains controversial. At the population level, several statistical prognostic factors and scores have been proposed but inconsistently verified. At the patient level, no selection criteria have been demonstrated to guide individual therapeutic decision making. We aimed to evaluate potential individual selection criteria to predict the benefit of surgery in patients undergoing treatment for NCRNNELM. Methods Data for 114 patients undergoing surgery for NCRNNELM were reviewed. In this population, we identified an early relapse group (ER), defined as patients with unresectable recurrence <1 year postoperatively who did not benefit from surgery (N=28), and a long-term survival group (LTS), defined as patients who were recurrence-free ≥5-years postoperatively and benefited from surgery (N=20). Clinicopathologic parameters, the Association Française de Chirurgie ( AFC) score, and a modified 4-point Clinical Risk Score (mCRS) (excluding CEA level) were analyzed and compared between LTS and ER groups. Results The majority of patients were female and a majority had an ASA score ≤2 at the time of liver surgery. Median age was 55 years. Almost half of the patients (46%) presented with a single liver metastasis. Intermediate- and low-risk AFC scores represented 40% and 60% of the population, respectively. Five- and ten-year overall survival (OS) and disease-free survival (DFS) rates were 56% and 27%, and 30% and 12%, respectively. Negative prognostic factors were size of liver metastases >50 mm and delay between primary and NCRNNELM <24 months for OS and DFS, respectively. AFC score was not prognostic while high-risk mCRS (score 3-4) was predictive for poorer OS. The clinicopathologic parameters were similar in the ER and LTS groups, except the presence of N+ primary tumor and the size of liver metastases were significantly higher in the ER group. Conclusion In patients with resectable NCRNNELM , no predictive factors or scores were found to accurately preoperatively differentiate individual cases in whom surgery would be futile from those in whom surgery could be associated with a significant oncological benefit.
How to determine the shape of nuclear molecules with polarized gamma-rays
Authors: Fortunato Lorenzo
Published: February 2020

A method has been recently proposed to establish the geometry of the
alpha-cluster arrangement in ^{12}12C
making use of polarized gamma-rays. The ratio of intensities of
scattered radiation at 90 degrees along and perpendicular to the initial
direction of the electric field vector, called depolarization ratio, is
a key quantity that allows to underpin the nature of totally symmetric
modes of vibrations. This allows to connect with the underlying
point-group structure and therefore to the geometric shape of the
nuclear molecule. This method is reviewed for
^{12}12C
and extended to other configurations, such as three unequal clusters and
four identical clusters (e.g. ^{16}16O).
The extended methylene blue reduction test and milk quality
Authors: Pérez-Lomas Mayra , Cuaran-Guerrero Milton J. , Yépez-Vásquez Lucía , Pineda-Flores Holger , Núñez-Pérez Jimmy , Espin-Valladares Rosario , Recalde-Posso Edmundo , Trujillo-Toledo Luis E. , Pais-Chanfrau José M.
Published: February 2020

Introduction. This study aimed to evaluate the quality of milk produced by six cattlemen’s associations in small, isolated farming communities of Carchi, Ecuador. It involved a herd of 814 cows and lasted eight consecutive months. Another aim was to propose a suitable methodology for milk quality evaluation.

Study objects and methods. All milk samples were analyzed for total solids, protein, fat, acidity, density, total bacterial count (TBC) and somatic cell count (SCC). Each sample was subjected to an extended qualitative methylene blue reduction test (MBRTe) for which 10 mL of milk, with 0.5 mL of methylene blue, was incubated at 37°C for 24 h.

Results and discussion. As a result, we obtained the following types of clots: MBRTe-I (homogeneous solid/liquid clot), MBRTe-II (lumpy clot), MBRTe-III (gaseous clot) and MBRTe-IV (lumpy + gaseous clot). The study showed significant differences in the quality of milk between different associations, suggesting that some of them did not comply with good practices of milking, handling and storage of fresh milk. The quality of milk was classified as good in one association, as regular in another association, and as low in four associations. The MBRTe classified 37% of the samples as MBRTe-I, 18% as MBRTe-II, 14% as MBRTe-III and 12% as MBRTe-IV. Of the MBRTe-I samples, 95% showed the TBC and SCC values of first quality milk. The MBRTe-II had the TBC values of first quality milk, but exceeded the SCC, while the MBRTe-III had good SCC values, but exceeded the TBC. Finally, the MBRTe-IV samples exceeded the permissible levels of both TBC and SCC.

Conclusion. It was proved that the MBRTe can help milk producers evaluate the quality of milk and alert them to the possible presence of mastitis in the herd. The MBRTe is a reliable and cheap method that is quick and easy to perform.
Biological value of semi-smoked sausages with cedar oil cake
Authors: Gurinovich Galina , Patrakova Irina , Seregin Sergey , Gargaeva Alesya , Alekseevnina Oksana , Myshalova Olga , Patshina Marina
Published: February 2020

Introduction. Development of novel meat products with better quality and biological value remains one of priority objectives of modern food industry. New meat products correspond with the principles of healthy diet due to their improved fatty acid profile and lower sodium content. The present research featured semi-smoked sausages with 15% of cedar oilcake and a low-sodium curing mix. The cedar nut oilcake is as a source of highly unsaturated fatty acids and high-grade protein. In addition to the physiological effect, the low-sodium curing mix increases the resistance of the combined fat phase to deterioration during storage.

Study objects and methods. Sausages of control and experimental formulations were made in laboratory conditions. The control formulation included raw second-grade beef, semi-fat pork (30% of fat), and traditional curing ingredients, i.e. sodium chloride and nitrite curing mix. In the experimental formulation, 15% of the semi-fat pork was replaced by cedar oil cake, and 30% of sodium chloride – by magnesium chloride. The samples were tested for fatty and amino acid composition, biological value of the lipid and protein phase, chemical composition, as well as physical, chemical, and sensory properties. Other research data included water activity, as well as acid, peroxide, and thiobarbituric value during storage at a temperature of 4 ± 2°C for 15 days.

Results and discussion. The study of fatty acid composition showed significant differences in the ratio of saturated (SFA), monounsaturated (MUFA), and polyunsaturated fatty acids (PUFA, P ˂ 0.05) in the samples. When 15% of pork was replaced by cedar oilcake, the amount of SFA decreased by 19.8%, while the content of MUFA and PUFA increased by 10.2% and 24.9%, respectively. These changes improved the indices of atherogenicity and thrombogenicity. The quality of the protein component also improved, as the utility coefficient of amino acids increased from 0.83 to 0.87, and the coefficient of comparable redundancy decreased from 7.2 g/100 g of protein to 5.35 g/100 g of protein. The sausages with cedar oil cake and low sodium chloride content received a high consumer evaluation. The hydrolysis of the lipid fraction was the same in both samples. The process of lipid oxidation was inhibited, which can partially be explained by a lower water activity.

Conclusion. The biological value, consumer quality, and storage stability of semi-smoked sausages could be improved by replacing fat-containing meat raw materials with cedar oil cake and reducing sodium chloride content. The new product demonstrated a better nutrition quality and can be recommended for mass production.
The Effect of PDE5 Inhibitors on the Male Reproductive Tract
Authors: Sofikitis Nikolaos , Kaltsas Aris , Dimitriadis Fotios , Rassweiler Jens , Grivas Nikolaos , Zachariou Athanasios , Kaponis Apostolos , Tsounapi Panagiota , Paterakis Napoleon , Karagiannis Andreas , Skouros Sotirios , Giannakis Ioannis , Champilomatis Ioannis , Paschopoulos Minas , Daphnis Diamantis , Giakoumakis Ioannis , R.Gabales Melinda , M. Chua Jo Ben , Lantin III Pedro L. , Mamoulakis Charalampos , Takenaka Atsushi
Published: February 2020

The therapeutic range of cyclic nucleotide phosphodiesterase 5 inhibitors (PDE5) inhibitors is getting
wider in the last years. This review study focuses on the potential employment of PDE5 inhibitors as an adjunct
tool for the therapeutic management of male infertility. The literature tends to suggest a beneficial effect of PDE5
inhibitors on Leydig and Sertoli cells secretory function. It also appears that PDE5 inhibitors play a role in the
regulation of the contractility of the testicular tunica albuginea and the epididymis. Moreover, scientific data
suggest that PDE5 inhibitors enhance the prostatic secretory function leading to an improvement in sperm motility.
Other studies additionally demonstrate the role of PDE5 inhibitors in the regulation of the sperm capacitation
process. Placebo-controlled, randomized, blind studies are necessary to unambiguously incorporate PDE5 inhibitors
as an adjunct tool for the pharmaceutical treatment of semen disorders and male infertility.
Peptide Receptor Radionuclide Therapy: Looking Back, Looking Forward
Authors: Feijtel Danny , de Jong Marion , Nonnekens Julie
Published: February 2020

Peptide receptor radionuclide therapy (PRRT) is a highly effective anti-cancer treatment
modality for patients with non-resectable, metastasized neuroendocrine tumors (NETs). During PRRT,
specific receptors that are overexpressed on the cancer cells are targeted with a peptide labeled with a
DNA-damaging radionuclide. Even though PRRT is a powerful treatment for metastasized NET patients,
the majority still cannot be cured at this stage of the disease. Hence, many investigators focus on
improving the therapeutic efficacy of this therapy. Improving PRRT can, for example, be achieved by
using other radionuclides with different physical properties, by combining PRRT with radiosensitizing
agents or by radiolabeling peptides with different characteristics. However, due to lack of extensive
knowledge of radiobiological responses of cancer cells to PRRT, biological parameters that influence
absorbed dose or that might even elicit insensitivity to therapy remain elusive and the context in which
these improvements will be successful warrants further investigation. In this review, we will discuss the
development of PRRT, its clinical merits in current treatment and future perspectives. We will highlight
different radionuclides and their benefits and pitfalls, as well as different peptide-conjugates that hold
these radionuclides. We will zoom in on the latest developments regarding combinatorial treatments
and how investigators from different disciplines such as dosimetry and radiobiology are now joining
forces to improve PRRT for NETs.
Curative Effects of Dhatryadi ghrita Bioactive Extracts on Ethanol Withdrawal Syndrome in Wistar Rats
Authors: Pal Rashmi S. , Mishra Amrita
Published: February 2020

Background:

Alcohol withdrawal syndrome leads to irritability, aggressiveness, body
posture and motor abnormalities, sensory hyper reactivity and changes in various enzyme levels.
Dhatryadi ghrita penetrates the blood-brain barrier to decrease the cravings for alcohol in this syndrome.

Objective:

To evaluate the effect of alcoholic extract of Dhatryadi ghrita on alcohol withdrawal
syndrome in Wistar rats.

Material & Methods:

A liquid diet with 7.2%, v/v ethanol was administered to the Wistar rats for
21 days. Control group animals received saline and normal diet. After alcohol withdrawal, rats
were examined at 6th and 24th hour for anxiety and hyper locomotor activity as major withdrawal
signs. Anxiety due to ethanol withdrawal was tested with the help of elevated plus maze, light and
dark models. The hyper locomotor activity was assessed using Actophotometer. The hepatic enzymes
level was determined with the help of the Bio-chemical Analyzer. ghrita extracts (100,
200,300 mg/kg, oral) were administered to different groups and diazepam as standard (2 mg/kg,
i.p) was administered to the treatment group animals 30 minutes before alcohol withdrawal estimation.
Drug treatment was administered 30 minutes before the second observation at the 24th hour.

Results:

Findings from the present study revealed that Ghrita extract treatment at doses 100, 200
and 300 mg/kg, oral in ethanol-dependent rats had a significant protective effect on signs and symptoms
of ethanol withdrawal in alcohol-dependent rats.

Conclusion:

Dhatryadi extract acts effectively for the treatment of alcohol abstinence syndrome.
The extract treatment has beneficial effects on ethanol withdrawal depressive-like behavior in rats.
AKTUALISASI NILAI-NILAI OLAHRAGA SEBAGAI UPAYA MEMBANGUN KARAKTER BANGSA
Authors: Sukarmin Yustinus
Published: February 2020

Abstract: Actualization of Sports Values as an Attempt to Build Nation Character. Honesty, caring, politeness, loyalty, discipline, and responsibility are some good values that should be the foundations the nation’s life. At present, however, they are rarely found in daily life. Deceit, carelessness, rudeness, hypocrisy, and negligence are more dominant in the country. In sports, some good values, such as devotion, fairness, discipline, cooperation, and hard work can be actualized as an attempt to rebuild the nation character. They must be actualized in various aspects of life through leaders’ exemplary deeds in the family, school, society, and country.
Patient-Reported Outcome Measures in Cystic Fibrosis: Protocol for a Systematic Review
Authors: Ratnayake Irushi , Ahern Susannah , Ruseckaite Rasa
Published: February 2020

Background

Patients with cystic fibrosis (CF) can struggle with burdensome symptoms and treatment regimens that negatively affect every aspect of their life. As physiological parameters can fail to capture these complications, the assessment of health-related quality of life (HRQOL) has gained prominence. HRQOL can be measured using standardized patient questionnaires called patient-reported outcome measures (PROMs). The Australian Cystic Fibrosis Data Registry (ACFDR) collects clinical data on adult and pediatric patients with CF. The incorporation of PROMs into the ACFDR would enable monitoring of HRQOL trends, benchmarking of HRQOL outcomes, and support of HRQOL research in CF.

Objective

Prior to incorporation of a PROM in the ACFDR, this systematic review was planned to evaluate whether any suitable PROMs are currently being used for CF.

Methods

This systematic review will be conducted in compliance with the PRISMA-P (Preferred Reporting Items for Systematic Reviews and Meta-Analyses Protocols) guidelines. MEDLINE, EMBASE, Scopus, CINAHL (Cumulative Index of Nursing and Allied Health Literature), PsycINFO, and Cochrane Library databases were searched for articles published between January 2009 and February 2019 on the use of PROMs to measure HRQOL in adult and pediatric patients with CF. Study designs such as observational studies, reviews and validation studies were included. Studies describing randomized controlled trials, dissertations, books, guideline statements, and abstracts were excluded. The COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) risk of bias checklist was used to assess the methodological quality of included studies. A descriptive synthesis of the results will be undertaken in line with the outcomes of this study.

Results

As of July 2019, the search has been conducted and 4530 records were screened. After two phases of screening, 97 studies were included in the final review and subjected to data extraction. Reviewers are currently in the process of critical appraisal.

Conclusions

This review will identify any PROM(s) that may be used to measure HRQOL in the ACFDR.

Trial Registration

PROSPERO International Prospective Register of Systematic Reviews CRD42019126931; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=126931
Use of Smart Technology for the Early Diagnosis of Complications After Cardiac Surgery: The Box 2.0 Study Protocol
Authors: Biersteker Tom E , Boogers Mark J , de Lind van Wijngaarden Robert AF , Groenwold Rolf HH , Trines Serge A , van Alem Anouk P , Kirchhof Charles JHJ , van Hof Nicolette , Klautz Robert JM , Schalij Martin J , Treskes Roderick W
Published: February 2020

Background

Atrial fibrillation (AF), sternal wound infection, and cardiac decompensation are complications that can occur after cardiac surgery. Early detection of these complications is clinically relevant, as early treatment is associated with better clinical outcomes. Remote monitoring with the use of a smartphone (mobile health [mHealth]) might improve the early detection of complications after cardiac surgery.

Objective

The primary aim of this study is to compare the detection rate of AF diagnosed with an mHealth solution to the detection rate of AF diagnosed with standard care. Secondary objectives include detection of sternal wound infection and cardiac decompensation, as well as assessment of quality of life, patient satisfaction, and cost-effectiveness.

Methods

The Box 2.0 is a study with a prospective intervention group and a historical control group for comparison. Patients undergoing cardiac surgery at Leiden University Medical Center are eligible for enrollment. In this study, 365 historical patients will be used as controls and 365 other participants will be asked to receive either The Box 2.0 intervention consisting of seven home measurement devices along with a video consultation 2 weeks after discharge or standard cardiac care for 3 months. Patient information will be analyzed according to the intention-to-treat principle. The Box 2.0 devices include a blood pressure monitor, thermometer, weight scale, step count watch, single-lead electrocardiogram (ECG) device, 12-lead ECG device, and pulse oximeter.

Results

The study started in November 2018. The primary outcome of this study is the detection rate of AF in both groups. Quality of life is measured with the five-level EuroQol five-dimension (EQ-5D-5L) questionnaire. Cost-effectiveness is calculated from a society perspective using prices from Dutch costing guidelines and quality of life data from the study. In the historical cohort, 93.9% (336/358) completed the EQ-5D-5L and patient satisfaction questionnaires 3 months after cardiac surgery.

Conclusions

The rationale and design of a study to investigate mHealth devices in postoperative cardiac surgery patients are presented. The first results are expected in September 2020.

Trial Registration

ClinicalTrials.gov NCT03690492; http://clinicaltrials.gov/show/NCT03690492

International Registered Report Identifier (IRRID)

DERR1-10.2196/16326
Opportunities and Recommendations for Improving Medication Safety: Understanding the Medication Management System in Primary Care Through an Abstraction Hierarchy (Preprint)
Authors: Baumgartner Andrew , Kunkes Taylor , Clark Collin M , Brady Laura A , Monte Scott V , Singh Ranjit , Wahler Jr Robert G , Chen Huei-Yen Winnie
Published: February 2020

BACKGROUND

Despite making great strides in improving the treatment of diseases, the minimization of unintended harm by medication therapy continues to be a major hurdle facing the health care system. Medication error and prescription of potentially inappropriate medications (PIMs) represent a prevalent source of harm to patients and are associated with increased rates of adverse events, hospitalizations, and increased health care costs. Attempts to improve medication management systems in primary care have had mixed results. Implementation of new interventions is difficult because of complex contextual factors within the health care system. Abstraction hierarchy (AH), the first step in cognitive work analysis (CWA), is used by human factors practitioners to describe complex sociotechnical systems. Although initially intended for the nuclear power domain and interface design, AH has been used successfully to aid the redesign of numerous health care systems such as the design of decision support tools, mobile patient monitoring apps, and a telephone triage system.

OBJECTIVE

This paper aims to refine our understanding of the primary care office in relation to a patient’s medication through the development of an AH. Emphasis was placed on the elements related to medication safety to provide guidance for the design of a safer medication management system in primary care.

METHODS

The AH development was guided by the methodology used by seminal CWA literature. It was initially developed by 2 authors and later fine-tuned by an expert panel of clinicians, social scientists, and a human factors engineer. It was subsequently refined until an agreement was reached. A means-ends analysis was performed and described for the nodes of interest. The model represents the primary care office space through functional purposes, values and priorities, function-related purposes, object-related processes, and physical objects.

RESULTS

This model depicts the medication management system at various levels of abstraction. The resulting components must be balanced and coordinated to provide medical treatment with limited health care resources. Understanding the physical and informational constraints on activities that occur in a primary care office depicted in the AH defines areas in which medication safety can be improved.

CONCLUSIONS

Numerous means-ends relationships were identified and analyzed. These can be further evaluated depending on the specific needs of the user. Recommendations for optimizing a medication management system in a primary care facility were made. Individual practices can use AH for clinical redesign to improve prescribing and deprescribing practices.
A Systematic Framework for Analyzing Observation Data in Patient-Centered Registries: Case Study for Patients With Depression (Preprint)
Authors: Zolnoori Maryam , Williams Mark D , Leasure William B , Angstman Kurt B , Ngufor Che
Published: February 2020

BACKGROUND

Patient-centered registries are essential in population-based clinical care for patient identification and monitoring of outcomes. Although registry data may be used in real time for patient care, the same data may further be used for secondary analysis to assess disease burden, evaluation of disease management and health care services, and research. The design of a registry has major implications for the ability to effectively use these clinical data in research.

OBJECTIVE

This study aims to develop a systematic framework to address the data and methodological issues involved in analyzing data in clinically designed patient-centered registries.

METHODS

The systematic framework was composed of 3 major components: visualizing the multifaceted and heterogeneous patient-centered registries using a data flow diagram, assessing and managing data quality issues, and identifying patient cohorts for addressing specific research questions.

RESULTS

Using a clinical registry designed as a part of a collaborative care program for adults with depression at Mayo Clinic, we were able to demonstrate the impact of the proposed framework on data integrity. By following the data cleaning and refining procedures of the framework, we were able to generate high-quality data that were available for research questions about the coordination and management of depression in a primary care setting. We describe the steps involved in converting clinically collected data into a viable research data set using registry cohorts of depressed adults to assess the impact on high-cost service use.

CONCLUSIONS

The systematic framework discussed in this study sheds light on the existing inconsistency and data quality issues in patient-centered registries. This study provided a step-by-step procedure for addressing these challenges and for generating high-quality data for both quality improvement and research that may enhance care and outcomes for patients.

INTERNATIONAL REGISTERED REPORT

DERR1-10.2196/18366
The U.S. Toothpaste Market: A Competitive Profile
Authors: Datta Y.
Published: February 2020

This paper follows the path of seven studies (see below). However, it is different in one important respect: it also offers a benefit segmentation profile of the U.S. Toothpaste Market.Porter associates high market share with cost leadership strategy which is based on the idea of competing on a price that is lower than that of the competition. However, customer-perceived quality—not low cost—should be the foundation of competitive strategy, because it is far more vital to long-term competitive position and profitability than any other factor. So, a superior alternative is to offer better quality vs. the competition.In most consumer markets a business seeking market share leadership should try to serve the middle class by competing in the mid-price segment; and offering quality better than that of the competition: at a price somewhat higher, to signify an image of quality, and to ensure that the strategy is both profitable and sustainable in the long run. Quality, however, is a complex concept that consumers generally find difficult to understand. So, they often use relative price, and a brand’s reputation as a symbol of quality.In 2008 retail sales in the U.S. were $1.27 Billion for the Toothpaste Market. The market leader Crest had a market share of 34.7%, closely followed by Colgate with a share of 33.5%. We focused on the most popular pack-size—5.8-6.5oz—which had a 45.3% share. Employing Hierarchical Cluster Analysis, we tested two hypotheses: (1) That a market leader is likely to compete in the mid-price segment, and (2) That the unit price of the market leader is likely to be somewhat higher than that of the nearest competition. Employing U.S. retail sales data for 2008 and 2007, we found that, for both 2008 and 2007, the market leader in the U.S. Toothpaste market—Crest—was a member of the mid-price segment. Furthermore, the unit price of Crest was somewhat higher than that of Colgate, the runner-up, which was also a member of the mid-price segment.Thus, the results fully supported both Hypothesis I and II—for 2008 and 2007.We also found strong support for the idea, that relative price is a strategic variable, as we have hypothesized.We discovered five benefit segments. The most fundamental result of this analysis is that it revealed an avalanche of various brands of toothpaste that not only whitened teeth, but were also helpful in preventing tooth decay, as before.Finally, we discovered four strategic groups in the industry.
Jidor Sentulan: Kajian Rekonstruksi dan Budaya
Authors: Pramono Koko Hari
Published: February 2020

Jidor Sentulan merupakan kesenian tradisional asli Jombang yang keberadaannya terancam di era modernisasi saat ini. Penelitian ini bertujuan melakukan rekonstruksi kesejarahan dan kandungan nilai budaya yang terdapat dalam pertunjukan Jidor Sentulan. Penelitian dilakukan di desa Bongkot, Kecamatan Peterongan, Kabupaten Jombang. Jenis penelitian yang digunakan adalah deskriptif kualitatif. Sumber data penelitian adalah pertunjukan dan informan. Hasil penelitian menunjukkan bahwa kesenian ini muncul pada kisaran 1830-1840 di bawa oleh seorang prajurit Pangeran Diponegoro. Pertunjukan ini berbentuk drama yang mementaskan sebuah lakon dalam pertunjukannya. Cerita yang dipentaskan dalam pertunjukan memiliki nilai budaya, yaitu mengenai hakikat hidup manusia, hakikat karya manusia, dan hakikat hubungan antarmanusia.