bluuebunny/crossref_metadata_2025_split huggingface dataset:
Differential discounting in the economic evaluation of healthcare programs
Authors: John Jürgen , Koerber Florian , Schad Mareike 
Published: December 2019

Abstract
Background
The question of appropriate discount rates in health economic evaluations has been a point of continuous scientific debate. Today, it is widely accepted that, under certain conditions regarding the social objective of the healthcare decision maker and the fixity of the budget for healthcare, a lower discount rate for health gains than for costs is justified if the consumption value of health is increasing over time. To date, however, there is neither empirical evidence nor a strong theoretical a priori supporting this assumption. Given this lack of evidence, we offer an additional approach to check the appropriateness of differential discounting.

Methods
Our approach is based on a two-goods extension of Ramsey’s optimal growth model which allows accounting for changing relative values of goods explicitly. Assuming a constant elasticity of substitution (CES) utility function, the growth rate of the consumption value of health depends on three variables: the growth rate of consumption, the growth rate of health, and the income elasticity of the willingness to pay for health. Based on a review of the empirical literature on the monetary value of health, we apply the approach to obtain an empirical value of the growth rate of the consumption value of health in Germany.

Results
The empirical literature suggests that the income elasticity of the willingness to pay for health is probably not larger but rather smaller than 1 and probably not smaller but rather larger than 0.2. Combining this finding with reasonable values of the annual growth rates in consumption (1.5–1.6%) and health (0.1%) suggests, for Germany, an annual growth rate of the consumption value of health between 0.3 and 1.5%.

Conclusion
In the light of a two-goods extension of Ramsey’s optimal growth model, the available empirical evidence makes the case for a growing consumption value of health. Therefore, the current German practice of applying the same discount rate to costs and health gains introduces a systematic bias against healthcare technologies with upfront costs and long-term health effects. Differential discounting with a lower rate for health effects appears to be a more appropriate discounting model.
A paradoxical situation in regressivity or progressivity of out of pocket payment for health care: which one is a matter of the health policy maker’s decision to intervention?
Authors: Bayati Mohsen , Mehrolhassani Mohammad Hossein , Yazdi-Feyzabadi Vahid 
Published: December 2019

Abstract
Background
Equity in health financing as one main aspect of health equity plays an essential role on the path toward universal health coverage. Out of pocket payment (OOP), a source with high share to total health expenditure, is an inequitable mechanism for health financing.

Main body
The OOP has been considered regressive (Kakwani index with a negative value) in nature. However, in some studies especially in developing countries, it is reported to be progressive (Kakwani index with a positive value). The main questions are: Is the progressive OOP equitable? What causes this contradiction? What can we do for the proper interpretation? And what are policy implications of this issue? In this commentary we briefly elaborate on these issues. We present several reasons for progressivity of OOP, and several methodological and policy issues for addressing it.

Conclusions
Even if the OOP is progressive and the share of poor people is low, this may financially limit their access to health services, increase their risk of incurring catastrophic health expenditure (CHE), and even pushing them more into poverty. In order to provide a comprehensive picture of equity in health financing, other financial protection indicators such as the redistributive effect, re-rating, exposure to CHE, and impoverishment due to health expenditure should also be estimated and reviewed.
Ubiquitin-specific protease 22 is critical to in vivo angiogenesis, growth and metastasis of non-small cell lung cancer
Authors: Zhang Keqiang , Yang Lu , Wang Jinhui , Sun Ting , Guo Yuming , Nelson Rebecca , Tong Tommy R. , Pangeni Rajendra , Salgia Ravi , Raz Dan J. 
Published: December 2019

Abstract
Background
Loss of monoubiquitination of histone H2B (H2Bub1) was found to be associated with poor differentiation, cancer stemness, and enhanced malignancy of non-small cell lung cancer (NSCLC). Herein, we investigated the biological significance and therapeutic implications of ubiquitin-specific protease 22 (USP22), an H2Bub1 deubiquitinase, in non-small cell lung cancer (NSCLC).

Methods
USP22 expression and its clinical relevance were assessed in NSCLC patients. The effects of USP22 knockout on sensitivity to cisplatin and irradiation, and growth, metastasis of NSCLC xenografts, and survival of cancer-bearing mice were investigated. The underlying mechanisms of targeting USP22 were explored.

Results
Overexpression of USP22 was observed in 49.0% (99/202) of NSCLC tissues; higher USP22 immunostaining was found to be associated with enhanced angiogenesis and recurrence of NSCLC. Notably, USP22 knockout dramatically suppressed in vitro proliferation, colony formation; and angiogenesis, growth, metastasis of A549 and H1299 in mouse xenograft model, and significantly prolonged survival of metastatic cancer-bearing mice. Furthermore, USP22 knockout significantly impaired non-homologous DNA damage repair capacity, enhanced cisplatin and irradiation-induced apoptosis in these cells. In terms of underlying mechanisms, RNA sequencing and gene ontology enrichment analysis demonstrated that USP22 knockout significantly suppressed angiogenesis, proliferation, EMT, RAS, c-Myc pathways, concurrently enhanced oxidative phosphorylation and tight junction pathways in A549 and H1299 NSCLC cells. Immunoblot analysis confirmed that USP22 knockout upregulated E-cadherin, p16; reduced ALDH1A3, Cyclin E1, c-Myc, and attenuated activation of AKT and ERK pathways in these cells.

Conclusions
Our findings suggest USP22 plays critical roles in the malignancy and progression of NSCLC and provide rationales for targeting USP22, which induces broad anti-cancer activities, as a novel therapeutic strategy for NSCLC patient.
N-methyl-D-aspartate (NMDA) receptor expression and function is required for early chondrogenesis
Authors: Matta Csaba , Juhász Tamás , Fodor János , Hajdú Tibor , Katona Éva , Szűcs-Somogyi Csilla , Takács Roland , Vágó Judit , Oláh Tamás , Bartók Ádám , Varga Zoltan , Panyi Gyorgy , Csernoch László , Zákány Róza 
Published: December 2019

Abstract
Background
In vitro chondrogenesis depends on the concerted action of numerous signalling pathways, many of which are sensitive to the changes of intracellular Ca2+ concentration. N-methyl-D-aspartate (NMDA) glutamate receptor is a cation channel with high permeability for Ca2+. Whilst there is now accumulating evidence for the expression and function of NMDA receptors in non-neural tissues including mature cartilage and bone, the contribution of glutamate signalling to the regulation of chondrogenesis is yet to be elucidated.

Methods
We studied the role of glutamatergic signalling during the course of in vitro chondrogenesis in high density chondrifying cell cultures using single cell fluorescent calcium imaging, patch clamp, transient gene silencing, and western blotting.

Results
Here we show that key components of the glutamatergic signalling pathways are functional during in vitro chondrogenesis in a primary chicken chondrogenic model system. We also present the full glutamate receptor subunit mRNA and protein expression profile of these cultures. This is the first study to report that NMDA-mediated signalling may act as a key factor in embryonic limb bud-derived chondrogenic cultures as it evokes intracellular Ca2+ transients, which are abolished by the GluN2B subunit-specific inhibitor ifenprodil. The function of NMDARs is essential for chondrogenesis as their functional knock-down using either ifenprodil or GRIN1 siRNA temporarily blocks the differentiation of chondroprogenitor cells. Cartilage formation was fully restored with the re-expression of the GluN1 protein.

Conclusions
We propose a key role for NMDARs during the transition of chondroprogenitor cells to cartilage matrix-producing chondroblasts.
Early fatigue in cancer patients receiving PD-1/PD-L1 checkpoint inhibitors: an insight from clinical practice
Authors: Cortellini Alessio , Vitale Maria G. , De Galitiis Federica , Di Pietro Francesca R. , Berardi Rossana , Torniai Mariangela , De Tursi Michele , Grassadonia Antonino , Di Marino Pietro , Santini Daniele , Zeppola Tea , Anesi Cecilia , Gelibter Alain , Occhipinti Mario Alberto , Botticelli Andrea , Marchetti Paolo , Rastelli Francesca , Pergolesi Federica , Tudini Marianna , Silva Rosa Rita , Mallardo Domenico , Vanella Vito , Ficorella Corrado , Porzio Giampiero , Ascierto Paolo A. 
Published: December 2019

Abstract
Background
Fatigue was reported as the most common any-grade adverse event (18.3%), and the most common grade 3 or higher immune-related adverse event (irAE) (0.89%) in patients receiving PD-1/PD-L1 checkpoint inhibitors in clinical trial.

Methods
The aim of this retrospective multicenter study was to evaluate the correlations between “early ir-fatigue”, “delayed ir-fatigue”, and clinical outcomes in cancer patients receiving PD-1/PD-L1 inhibitors in clinical practice.

Results
517 patients were evaluated. After the 12-weeks landmark selection, 386 (74.7%) patients were eligible for the clinical outcomes analysis. 40.4% were NSCLC, 42.2% were melanoma, 15.3% renal cell carcinoma and 2.1% other malignancies. 76 patients (19.7%) experienced early ir-fatigue (within 1 month from treatment commencement), while 150 patients (38.9%) experienced delayed ir-fatigue. Early ir-fatigue was significantly related to shortened PFS (HR = 2.29 [95% CI 1.62–3.22], p < 0.0001) and OS (HR = 2.32 [95% CI 1.59–3.38], p < 0.0001) at the multivariate analysis. On the other hand, we found a significant association between the occurrence of early ir-fatigue, ECOG-PS ≥ 2 (p < 0.0001), and disease burden (p = 0.0003). Delayed ir-fatigue was not significantly related to PFS nor OS.

Conclusions
Early ir-fatigue seems to be negative prognostic parameter, but to proper weight its role we must to consider the predominant role of performance status, which was related to early ir-fatigue in the study population.
Gdf11 gene transfer prevents high fat diet-induced obesity and improves metabolic homeostasis in obese and STZ-induced diabetic mice
Authors: Lu Bingxin , Zhong Jianing , Pan Jianfei , Yuan Xiaopeng , Ren Mingzhi , Jiang Liping , Yang Yuqing , Zhang Guisheng , Liu Dexi , Zhang Chunbo 
Published: December 2019

Abstract
Background
The growth differentiation factor 11 (GDF11) was shown to reverse age-related hypertrophy on cardiomyocytes and considered as anti-aging rejuvenation factor. The role of GDF11 in regulating metabolic homeostasis is unclear. In this study, we investigated the functions of GDF11 in regulating metabolic homeostasis and energy balance.

Methods
Using a hydrodynamic injection approach, plasmids carrying a mouse Gdf11 gene were delivered into mice and generated the sustained Gdf11 expression in the liver and its protein level in the blood. High fat diet (HFD)-induced obesity was employed to examine the impacts of Gdf11 gene transfer on HFD-induced adiposity, hyperglycemia, insulin resistance, and hepatic lipid accumulation. The impacts of GDF11 on metabolic homeostasis of obese and diabetic mice were examined using HFD-induced obese and STZ-induced diabetic models.

Results
Gdf11 gene transfer alleviates HFD-induced obesity, hyperglycemia, insulin resistance, and fatty liver development. In obese and STZ-induced diabetic mice, Gdf11 gene transfer restores glucose metabolism and improves insulin resistance. Mechanism study reveals that Gdf11 gene transfer increases the energy expenditure of mice, upregulates the expression of genes responsible for thermoregulation in brown adipose tissue, downregulates the expression of inflammatory genes in white adipose tissue and those involved in hepatic lipid and glucose metabolism. Overexpression of GDF11 also activates TGF-β/Smad2, PI3K/AKT/FoxO1, and AMPK signaling pathways in white adipose tissue.

Conclusions
These results demonstrate that GDF11 plays an important role in regulating metabolic homeostasis and energy balance and could be a target for pharmacological intervention to treat metabolic disease.
Correlation of PMN elastase and PMN elastase-to-neutrophil ratio with disease activity in patients with myositis
Authors: Wu Siyu , Peng Wanchan , Zhang Yunli , Guo Jingjing , Fu Jinfang , Wang Wei 
Published: December 2019

Abstract
Background
Polymorphonuclear (PMN) elastase plays an important role in a variety of inflammatory disorders. Our aim was to analyse PMN elastase in idiopathic inflammatory myopathies (IIMs) and its association with disease activity.

Methods
PMN elastase levels were measured using enzyme-linked immunosorbent assay in serum samples obtained from 74 patients with myositis (58 with dermatomyositis [DM] and 16 with polymyositis [PM]) and 22 healthy controls. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the discriminant capacity of PMN elastase level and PMN elastase-to-neutrophil ratio (ENR) in patients with active and remission myositis. The association of serum PMN elastase level and ENR with disease variables was evaluated in patients with IIMs. The disease specificity of PMN elastase level and ENR was further examined in 60 patients with other systemic autoimmune diseases.

Results
PMN elastase level and ENR were significantly higher in patients with active IIMs, DM, and PM than in patients with remission. ROC curve analysis revealed that PMN elastase level and ENR both outperformed creatine kinase (CK), the currently used laboratory marker, and strongly discriminated patients with active disease and those with remission of IIMs, DM, and PM (area under the ROC curve [AUC] 0.9, 0.9, and 0.88 for PMN elastase; AUC 0.96, 0.96, and 1.0 for ENR; AUC 0.72, 0.70, and 0.80 for CK, respectively). PMN elastase level and ENR were positively correlated with myositis disease activity assessment, CK, lactate dehydrogenase, aspartate aminotransferase, alanine aminotransferase, C-reactive protein, and erythrocyte sedimentation rate. PMN elastase level and ENR were higher in the anti-PM-Scl positive myositis group than those in the anti-PM-Scl negative myositis group. Nevertheless, PMN elastase was not a specific disease marker for IIMs when compared with other autoimmune diseases.

Conclusions
PMN elastase, particularly ENR, were significantly correlated with disease activity and could serve as useful biochemical markers for evaluating the disease activity of patients with IIMs. Thus, they are potentially helpful in monitoring disease progression and guiding treatment.
Stress-induced microglial activation occurs through β-adrenergic receptor: noradrenaline as a key neurotransmitter in microglial activation
Authors: Sugama Shuei , Takenouchi Takato , Hashimoto Makoto , Ohata Hisayuki , Takenaka Yasuhiro , Kakinuma Yoshihiko 
Published: December 2019

Abstract
Background
The involvement of microglia in neuroinflammatory responses has been extensively demonstrated. Recent animal studies have shown that exposure to either acute or chronic stress induces robust microglial activation in the brain. In the present study, we investigated the underlying mechanism of brain microglial activation by acute stress.

Methods
We first looked at the spatial distribution of the noradrenaline (NA)-synthesizing enzyme, DBH (dopamine β-hydroxylase), in comparison with NA receptors—β1, β2, and β3 adrenergic receptors (β1-AR, β2-AR, and β3-AR)—after which we examined the effects of the β-blocker propranolol and α-blockers prazosin and yohimbine on stress-induced microglial activation. Finally, we compared stress-induced microglial activation between wild-type (WT) mice and double-knockout (DKO) mice lacking β1-AR and β2-AR.

Results
The results demonstrated that (1) microglial activation occurred in most studied brain regions, including the hippocampus (HC), thalamus (TM), and hypothalamus (HT); (2) within these three brain regions, the NA-synthesizing enzyme DBH was densely stained in the neuronal fibers; (3) β1-AR and β2-AR, but not β3-AR, are detected in the whole brain, and β1-AR and β2-AR are co-localized with microglial cells, as observed by laser scanning microscopy; (4) β-blocker treatment inhibited microglial activation in terms of morphology and count through the whole brain; α-blockers did not show such effect; (5) unlike WT mice, DKO mice exhibited substantial inhibition of stress-induced microglial activation in the brain.

Conclusions
We demonstrate that neurons/microglia may interact with NA via β1-AR and β2-AR.
Loss of amyloid precursor protein exacerbates early inflammation in Niemann-Pick disease type C
Authors: Shin Samuel D. , Shin Alexandra , Mayagoitia Karina , Siebold Lorraine , Rubini Marsilio , Wilson Christopher G. , Bellinger Denise L. , Soriano Salvador 
Published: December 2019

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

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

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

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

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

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

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

Conclusions
Findings suggest the value of FP counseling. With a patient-centered approach to counseling, continued use of modern contraceptives can be supported among married women of reproductive age. Unfortunately, FP counseling, particularly higher-quality FP counseling remains rare.