bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cost-effectiveness analysis of atezolizumab in advanced triple-negative breast cancer
Authors: Phua Lee Cheng , Lee Soo Chin , Ng Kwong , Aziz Mohamed Ismail Abdul 
Published: February 2020

Abstract
Background The IMpassion130 trial demonstrated that adding atezolizumab to nanoparticle albumin-bound (nab)-paclitaxel improved the survival of patients with untreated, advanced, programmed death ligand 1 (PDL1)-positive triple-negative breast cancer (TNBC). In view of the high cost of immunotherapy, it is important to examine its value with respect to both benefits and costs. In this study, the cost-effectiveness of atezolizumab/nab-paclitaxel combination therapy relative to nab-paclitaxel monotherapy was evaluated for the first-line treatment of advanced, PDL1-positive TNBC, from a healthcare system perspective. Methods A three-state partitioned-survival model was developed to compare the clinical and economic outcomes of treatment with atezolizumab/nab-paclitaxel combination therapy with nab-paclitaxel monotherapy in patients with advanced TNBC. Clinical data were obtained from the IMpassion130 trial and extrapolated to 5 years. Health state utilities were retrieved from the literature, while direct costs were sourced from public healthcare institutions in Singapore. The primary outcomes of the model were life years (LYs), quality-adjusted LYs (QALYs), costs and incremental cost-effectiveness ratios (ICERs). One-way and probabilistic sensitivity analyses and scenario analyses were conducted to explore the impact of specific assumptions and uncertainties. Results Adding atezolizumab to nab-paclitaxel resulted in an additional 0.361 QALYs (0.636 LYs) at an ICER of S$324,550 per QALY gained. The ICER remained high at $67,092 per QALY even when atezolizumab was priced zero. One-way sensitivity analysis showed that the ICER was most sensitive to variations in the cost of atezolizumab and the time horizon. Scenario analyses confirmed that the combination therapy was unlikely to be cost-effective even under extremely favourable assumptions. Conclusions Given the exceedingly high ICER, adding atezolizumab to nab-paclitaxel was unlikely to represent a cost-effective use of healthcare resources for the treatment of advanced PDL1-positive TNBC. Our findings will be useful in informing funding policy decisions alongside other considerations such as comparative effectiveness, unmet need and budget impact.
How well does Malaysia achieve value for money in public sector purchasing of medicines? Evidence from medicines procurement prices from 2010 to 2014
Authors: Ham Nurhafiza Md , Perera Prasadini N , Rannan-Eliya Ravindra P 
Published: February 2020

Abstract
Background Malaysia’s public healthcare sector provides a greater volume of medicines at lower overall cost, indicating its importance in providing access to medicines for Malaysians. However, the Ministry of Health (MOH), as the main healthcare provider, has concerns about the continuous increase in the public sector medicines budget, and achieving efficiencies in medicines procurement is an important goal. The objectives of this study were to assess the overall trend in public sector pharmaceutical procurement efficiency from 2010 to 2014, and determine if the three different ways in which MOH procures medicines influences efficiency.Methods We matched medicines from the public sector procurement report by medicine formulation to medicines with a Management Sciences for Health (MSH) International Reference Price (IRP) for each year. Price ratios were calculated, and utilizing the information on quantity and expenditure for each product, summary measures of procurement efficiency were reported as quantity- and expenditure-weighted average price ratios (WAPRs) for each year. Utilizing MOH procurement data to obtain information on procurement type, a multiple regression analysis, controlling for a number of factors that can influence prices, assessed whether procured efficiency (relative to IRPs) differed by MOH procurement type.Results Malaysia’s public sector purchased medicines at two to three times the IRP throughout the study period. However, procurement prices were relatively stable in terms of WAPRs each year (2.2 and 3.2 in 2010 to 1.9 and 2.9 in 2014 for quantity and expenditure WAPRs, respectively). Procurement efficiency did not vary between the three different methods of MOH procurement. Procurement efficiency of both imported innovators and imported generics were significantly lower ( P <0.001 and P <0.01) than local generic products, and medicine source and category influenced the procurement efficiency of each MOH procurement mechanism.Conclusion The design of different medicines procurement mechanisms, along with the balance of interests that Malaysia has sought to achieve in its public procurement procedures, have not been able to achieve lower public sector medicines procurement prices (relative to IRP). Introducing pooled procurement options along with continuous monitoring of procurement efficiency and exploring ways to improve price competition among local and foreign suppliers is recommended.
Catastrophic costs of Tuberculosis care in a population with internal migrants in China
Authors: Jiang Qi , Lu Liping , Hong Jianjun , Jin Xiaoping , Gao Qian , Bang Heejung , DeRiemer Kathryn , Yang Chongguang 
Published: February 2020

Abstract
Background Although a free diagnosis and baseline treatment package was offered for tuberculosis (TB), hidden costs incurred by patients and their households could worsen their socio-economic and health status, particularly for migrants. We estimated the prevalence of catastrophic cost of TB patients and its associated factors in an urban population with internal migrants in China. Methods A cross-sectional survey was conducted to enroll culture-confirmed pulmonary TB patients in Songjiang district, Shanghai, between December 1, 2014, and December 31, 2015. Consenting participants completed a questionnaire, which collected direct and indirect costs before and after the diagnosis of TB. The catastrophic cost was defined as the annual expenses of TB care that exceeds 20% of total household income. We used logistic regression to identify factors associated with catastrophic costs. Results Overall, 248 drug-susceptible TB patients were enrolled, with 70% (174 of 248) of them being internal migrants. Migrant patients were significantly younger compared to resident patients. The total costs were 25,824 ($3,689) and 13,816 ($1,974) Chinese Yuan (RMB) for resident and internal migrant patients, respectively. The direct medical cost comprised about 70% of the total costs among both migrant and resident patients. Overall, 55% (132 of 248) of patients experienced high expenses ( > 10% of total household income), and 22% (55 of 248) experienced defined catastrophic costs. However, the reimbursement for TB care only reduced the prevalence of catastrophic costs to 20% (49 of 248). More than half of the internal migrants had no available health insurance (52%, 90 of 174). Hospitalizations, no available insurance, and older age contributed significantly to the occurrence of catastrophic costs. Conclusions. The catastrophic cost of TB service cannot be overlooked, despite the free policy. Migrants have difficulties benefiting from health insurance in urban cities. Interventions, including expanded medical financial assistance, are needed to secure universal TB care.
Parkinson´s related protein DJ-1 is involved in aberrant cell cycle re-entry through Cdk5
Authors: López-Grueso Mª José , Padilla Carmen Alicia , Bárcena José Antonio , Requejo-Aguilar Raquel 
Published: February 2020

Abstract
DJ-1 is a multifunctional protein involved in Parkinson disease (PD) that can act as antioxidant, molecular chaperone, protease, glyoxalase and transcriptional regulator. However, the exact mechanism by which DJ-1 dysfunction contributes to development of Parkinson´s disease remains elusive. Here, using a comparative proteomic analysis between normal cortical neurons and neurons lacking DJ-1, we show that this protein is involved in cell cycle checkpoints disruption as a consequence of increased amount of p-Tau and a-synuclein proteins, altered signalling pathways, as the phosphoinositide-3-kinase/protein kinase B (PI3K/AKT) and mitogen-activated protein kinase (MAPK), and deregulation of cyclin-dependent kinase 5 (Cdk5). Cdk5 is normally involved in dendritic growth, axon formation and the establishment of synapses, but can also contribute to cell cycle progression, as in our case, in pathological conditions. In addition, we observed a decrease in proteasomal activity, probably due to Tau phosphorylation that can also lead to activation of mitogenic signalling pathways. Taken together, our findings indicate, for the first time, that aborted cell cycle re-entry could be at the onset of DJ-1 associated PD. Thereby, new approaches targeting cell cycle re-entry can be envisaged to improve current therapeutic strategies.
High-resolution imaging of autophagosome formation by LC3 and ATG12 in cells using scanning electron-assisted dielectric microscopy
Authors: Okada Tomoko , Ogura Toshihiko 
Published: February 2020

Abstract
Background Autophagy is an intracellular self-eating system that plays a central role in cellular recycling. The formation of functional autophagosomes depends on several autophagy- related proteins, including LC3 and Atg12. To analyse an autophagy system, it is essential to precisely examine the cellular functions of cells in liquid condition. For this purpose, we have developed a novel scanning electron-assisted dielectric microscope (SE-ADM) for nanoscale observations of intact cells in aqueous conditions. Results Here, we first show that our SE-ADM system observes LC3- and Atg12-containing autophagosomes in cells labelled with antibody-binding gold nano-colloids in medium. We observe that during autophagosome formation, Atg12 localises along the actin mesh structure, whereas LC3 forms arcuate or circular alignments. Our system also detects the different distribution properties of LC3 and Atg12. Atg12 is broadly distributed, whereas LC3 is localised over a smaller range. These differences in spatial-distribution manifest as differently sized spots on fluorescence optical microscopy. Conclusion The direct SE-ADM observations of living cells incubated with nanoparticles in a medium may be useful for analysing various cell functions.
Surgical outcomes and survival for T4 gastric cancer extending to the transverse colon
Authors: Wang Gang-Cheng , Gao Chong-Qing , Wang You-cai , Lv Hui-Fang , Chen Bei-Bei , Nie Cai-Yun , Chen Xiao-Bing , Liu Yingjun 
Published: February 2020

Abstract
Purpose Extended multi-organ resection for locally advanced (T4) gastric cancer remains controversial. Herein we aimed to evaluate the surgical outcomes and survival of patients with T4 gastric cancer extending to the transverse colon. Materials and Methods Between 2011 and 2015, forty patients had undergone curative resection for T4 gastric cancer extending to the transverse colon. Patient characteristics, related complications, long-term survival, and prognostic factors for T4 gastric cancer were analyzed. Results ost-operative morbidity occurred in 5 (12.5%) patients. The 1-, 3-, and 5-year overall survival rates were 75.0%, 49.2%, and 36.9%, respectively. Univariate analysis revealed that tumor size ( P =0.049), advanced T stage ( P =0.013), and lymph node metastasis ( P =0.006) are poor prognostic factors of overall survival. Based on multivariate analysis, advanced T stage and lymph node metastasis were identified as independent prognosis factors. Conclusions Patients with T4 gastric cancer extending to the transverse colon might benefit from curative resection with acceptable morbidity and mortality.
A nomogram to predict skip metastasis in papillary thyroid cancer
Authors: Ouyang Qianhui , Wang Wenlong 
Published: February 2020

Abstract
Background Skip metastases are defined as lateral lymph node metastasis (LNM) without the involvement of central LNM in papillary thyroid cancer (PTC), and it is difficult to predict in clinical practice. Our study aimed to investigate the risk factors of skip metastasis and establish a nomogram for predicting the probability of skip metastasis in PTC patients. Patients and Methods A total of 378 consecutive PTC patients with clinically suspected LNM who underwent modified radical neck dissection (MRND) from March 2018 to July 2019 were enrolled in our hospital, Univariate and multivariate analyses were used to examine risk factors of skip metastasis, and a nomogram prediction model was established and internal validated. Results The incidence of skip metastasis was 11.9% (45/378). Primary tumor size ≦1cm(OR=2.703, 95%CI,1342-5.464; P =0.005 ), Age(OR=1.051, 95%CI, 1.017-1.805, P =0.005), Primary tumor location in the upper portion(OR=6.799, 95%CI, 2.710-17.060, P < 0.001)were found to be independent risk factors for skip metastasis in PTC patients. A nomogram based upon these predictors performed well. With an area under the curve (AUC) of 0.806 (95%CI,0.736-0.876) and the P value of the Hosmer-Lemeshow goodness of fit test was 0.66, Decision curve analysis revealed that nomogram was clinically useful. Conclusion Based on the risk factors of skip metastasis and established a high-performance nomogram, which can provide an individual risk assessment and guide treatment decisions for patients.
Evaluating 10 years of state-funded GP training in GP offices in Switzerland
Authors: Baumann Kim , Lindemann Fanny , Diallo Beatrice , Rozsnyai Zsofia , Streit Sven 
Published: February 2020

Abstract
Background Switzerland lacks future general practitioners (GPs). Residents who wished to specialize as general practitioners were formerly trained solely in hospital settings. To better prepare and also attract more young doctors to become GPs, the canton of Bern has implemented a partly state-funded vocational training program in GP practices. Our study examines the efficacy of this 10-year program, identifies factors that positively influence residents in their decision to become a GP and the distribution of new GPs in the canton of Bern, who had taken part in the traineeship. Methods This cross-sectional survey among all residents, who participated in a traineeship in general practice from 2008 to 2017 in the canton of Bern asked if residents had taken a subsequent career choice as a GP and if so in which region. Residents scored the importance of their traineeship and their mentor’s influence on becoming a GP. By using zip codes of work area of respondents already working as GPs and matching it with population census data, we could obtain the distribution of GPs on a per capita basis. Results Out of 165 residents who participated in a traineeship, 151 (92%) completed our survey. 81% had chosen a career as a GP or were on track to become a GP. Almost half of the participants became GPs in the offices of their mentors. Our respondents emphasized the importance of their mentors influence as well as the training program in their decision-making to become a GP. Most mentioned benefits of being a GP were broad field of medical care (37%) and a fulfilling doctor-patient relationship (34%). We could show an increase in GP practices in the canton of Bern, not only in urban but also accordingly in rural areas. Conclusions Most residents continued subsequent careers as general practitioners after having completed a GP traineeship, with almost half of them in the region of their training. A vocational training program helped motivating young doctors to become GPs and underserved regions of the canton of Bern to gain new GPs.
Recent Trends and Variations in General Practitioners’ Involvement in Accident Care in Switzerland: an Analysis of Claims Data
Authors: Höglinger Marc , Knöfler Fabio , Stosch Rita Schaumann-von , Scholz Stefan M. , Eichler Klaus 
Published: February 2020

Abstract
BACKGROUND As in other countries, there is concern and some fragmentary evidence that GPs’ central role in the Swiss healthcare system might be changing or even be in decline. Our study gives a systematic account of GPs’ involvement in accident care from 2008 to 2016 and identifies changes in GPs’ involvement in this typical field of primary care: how frequently GPs were involved along the care pathway, to what extent they figured as initial care provider, and what their role in the care pathway was. METHODS Using a claims dataset from the largest Swiss accident insurer with two million accident cases, we constructed individual care pathways, i.e., when and from which providers patients received care. We calculated probabilities for the involvement of various care provider groups, for initial care provision, and for the role of GPs in patients’ care pathways, adjusted for injury and patient characteristics using multinomial regression. RESULTS In 2014, GPs were involved in 70% of all accident cases requiring outpatient care but no inpatient stay, and provided initial care in 56%. While involvement stayed at about the same level for accidents occurring from 2008 to 2014, the share of accidents where GPs provided initial care decreased by 4 percentage points. The share of cases where GPs acted as sole care provider decreased by 7 percentage points down to 44%. At the same time, accident cases involving care from an ED at any point in time increased from 38% to 46% and the share receiving initial care from an ED from 30 to 35 percentage points – apparently substituting for the declining involvement of GPs in initial care. GPs’ involvement in accident care is higher in rural compared to urban regions, among elderly compared to younger patients, and among Swiss compared to non-Swiss citizens. CONCLUSIONS GPs play a key role in accident care with considerable variation depending on region and patient profile. From 2008 to 2014, there is a remarkable decline in GPs’ provision of initial care after an accident. This is a strong indication that the GPs’ role in the Swiss healthcare system is changing.
ZNF213 facilitates ER alpha signaling in breast cancer cells
Authors: Zhuang Ting , Yang Huijie , Zhao Wuchen , Li Xin , Niu Zhiguo , Huang Qingsong 
Published: February 2020

Abstract
Background Breast cancer is the most common women malignancy worldwide, while estrogen receptor alpha positive type accounts for two third of all breast cancers. Although ER alpha positive breast cancer could be effectively controlled by endocrine therapy, more than half of the cases could develop endocrine resistance, making it an important clinical issue in breast cancer treatment. Thus, decoding the detailed mechanism, which controls ER alpha signaling activation and ER alpha protein stability, is of great importance for the improvement of breast cancer therapy. Methods ZNF213 and ER alpha protein expression level were measured by western blot, while ER alpha target genes were determined by QPCR. WST-1 assay was used to measure cell proliferation. RNA sequence was performed by Ingenuity pathway analysis. The ER alpha signaling activities were measured with luciferase assay, QPCR and western blotting. Protein stability assay and ubiquitin assay were used to determine ER alpha protein degradation and ubiquitination. The immuno-precipation was utilized to determine ER alpha and ZNF213 interaction. The ubiquitin-based immuno-precipitation assay was sued to detect specific ubiquitination manner on ER alpha. The prognostic data of ZNF213 was derived from public available database. Results Here, we identified ZNF213 as a novel zinc finger protein, which modulates ER alpha protein. ZNF213 expression correlates with poor outcome in endocrine treated patients. ZNF213 depletion inhibits ER alpha signaling and proliferation in breast cancer cells. Further mechanistic studies show that ZNF213 is located in cytosol and nuclear, which modulates ER alpha stability via inhibiting ER alpha K48-linked ubiquitination. Conclusions Our study reveals an interesting post-translational mechanism between ER alpha and ZNF213 in breast cancer. Targeting ZNF213 could be an appealing strategy for ER alpha positive breast cancer.
Magnetic targeting enhances the cutaneous wound healing effects of human mesenchymal stem cell-derived iron oxide exosomes
Authors: Li Xiuying , Wang Ying , Li Binxi , Li Jing , Wei Zhenhong , Lv Huiying , Wu Liya , Zhang Hao , Yang Bai , Xu Xiaohua , Jiang Jinlan 
Published: February 2020

Abstract
Human mesenchymal stem cell (MSC)-derived exosomes (Exos) are a promising therapeutic agent for cell-free regenerative medicine. However, their poor organ-targeting ability and therapeutic efficacy have been found to critically limit their clinical applications. In the present study, we fabricated iron oxide nanoparticle (NP)-labeled exosomes (Exo+NPs) from NP-treated MSCs and evaluated their therapeutic efficacy in a clinically relevant model of skin injury. We found that the Exos could be readily internalized by human umbilical vein endothelial cells (HUVECs), and significantly promoted their proliferation, migration, and angiogenesis both in vitro and in vivo . Moreover, the protein expression of proliferative markers (Cyclin D1 and Cyclin A2), growth factors (VEGFA), and migration chemokines (CXCL12) was significantly upregulated after Exo treatment. Unlike the Exos prepared from untreated MSCs, the Exo+NPs contained NPs that acted as a magnet-guided navigation tool. The in vivo systemic injection of Exo+NPs with magnetic guidance significantly increased the number of Exo+NPs that accumulated at the injury site. Furthermore, these accumulated Exo+NPs significantly enhanced endothelial cell proliferation, migration, and angiogenic tubule formation in vivo ; moreover, they reduced scar formation, and increased CK19, PCNA, and collagen expression in vivo . Collectively, these findings confirm the development of therapeutic efficacy-potentiated extracellular nanovesicles and demonstrate their feasibility in cutaneous wound repair.