bluuebunny/crossref_metadata_2025 huggingface dataset:
Outcome of adult congenital heart disease patients undergoing cardiac surgery: clinical experience of dr. Sardjito hospital
Authors: Kurniawaty Juni , Widyastuti Yunita
Published: December 2019

Background

Patients with congenital heart disease require surgery to correct the cardiac defect they had in order to prevent heart failure. Unfortunately, data regarding outcome of adult CHD in Indonesia is still limited. In contrast with developed countries, many congenital heart surgery patients in developing countries are adults. The purpose of this study was to investigate the outcomes of cardiac surgery procedures among adult congenital heart disease patients, and what factors that might influence the outcome of surgery.

Methods

A retrospective study was performed on adult congenital heart disease patients undergoing cardiac surgery at Dr. Sardjito Hospital between April 2018 and March 2019. Variables included in the study were demographic characteristics, laboratory test results, comorbidities, premedication, Cardiopulmonary Bypass (CPB) and ischemia duration were included in the analysis. Outcomes were in-hospital mortality, hospital length of stay, and ICU length of stay.

Results

A total of 25 congenital heart disease patients [19 Atrial Septeal Defect (ASD) patients, and 6 Ventricular Septal Defect (VSD) patients] underwent a cardiac surgery procedure at Dr. Sardjito Hospital during the study period. Mean age was 31 ± 14.92 years. The majority of patients had pulmonary hypertension. During the study period, none of the patients died during postoperative care in the hospital, mean hospital length of stay (LOS) was 8.35 ± 3.39 days and ICU LOS was 26.53 ± 11.33 h.

Conclusion

Surgery in adult patients with congenital heart disease may be successfully performed with low morbidity and mortality.
Visit-to-visit variability of glycemia and vascular complications: the Hoorn Diabetes Care System cohort
Authors: Slieker Roderick C. , van der Heijden Amber A. W. H. , Nijpels Giel , Elders Petra J. M. , ’t Hart Leen M. , Beulens Joline W. J.
Published: December 2019

Background

Glycemic variation has been suggested to be a risk factor for diabetes-related complications. Previous studies did not address confounding of diabetes duration, number of visits and length of follow-up. Here, we characterize glycemic variability over time and whether its relation to diabetes-related complications and mortality is independent from diabetes- and follow-up duration.

Materials and methods

Individuals with type 2 diabetes (n = 6770) from the Hoorn Diabetes Care System cohort were included in this study. The coefficient of variation (CV) was calculated over 5-year sliding intervals. People divided in quintiles based on their CV. Cox proportional hazard models were used to investigate the role of glycemic CV as risk factor in diabetes-related complications and mortality.

Results

The coefficient of variation of glucose (FG-CV) increased with time, in contrast to HbA1c (HbA1c-CV). People with a high FG-CV were those with an early age of diabetes onset (ΔQ5–Q1 = − 2.39 years), a higher BMI (ΔQ5–Q1 = + 0.92 kg/m2), an unfavorable lipid profile, i.e. lower levels of HDL-C (ΔQ5–Q1 = − 0.06 mmol/mol) and higher triglycerides (ΔQ5–Q1 =+ 1.20 mmol/mol). People with the highest FG-CV in the first 5-year interval showed an increased risk of insulin initiation, retinopathy, macrovascular complications and mortality independent of mean glycemia, classical risk factors and medication use. For HbA1c, the associations were weaker and less consistent.

Conclusions

Individuals with a higher FG-CV have an unfavorable metabolic profile and have an increased risk of developing micro- and macrovascular complications and mortality. The association of HbA1c-CV with metabolic outcomes and complications was less consistent in comparison to FG-CV.
Synthetic control devices for gene regulation in Penicillium chrysogenum
Authors: Mózsik László , Büttel Zsófia , Bovenberg Roel A. L. , Driessen Arnold J. M. , Nygård Yvonne
Published: December 2019

Background

Orthogonal, synthetic control devices were developed forPenicillium chrysogenum, a model filamentous fungus and industrially relevant cell factory. In the synthetic transcription factor, the QF DNA-binding domain of the transcription factor of the quinic acid gene cluster ofNeurospora crassais fused to the VP16 activation domain. This synthetic transcription factor controls the expression of genes under a synthetic promoter containing quinic acid upstream activating sequence (QUAS) elements, where it binds. A gene cluster may demand an expression tuned individually for each gene, which is a great advantage provided by this system.

Results

The control devices were characterized with respect to three of their main components: expression of the synthetic transcription factors, upstream activating sequences, and the affinity of the DNA binding domain of the transcription factor to the upstream activating domain. This resulted in synthetic expression devices, with an expression ranging from hardly detectable to a level similar to that of highest expressed native genes. The versatility of the control device was demonstrated by fluorescent reporters and its application was confirmed by synthetically controlling the production of penicillin.

Conclusions

The characterization of the control devices in microbioreactors, proved to give excellent indications for how the devices function in production strains and conditions. We anticipate that these well-characterized and robustly performing control devices can be widely applied for the production of secondary metabolites and other compounds in filamentous fungi.
Integration of a multi-step heterologous pathway in Saccharomyces cerevisiae for the production of abscisic acid
Authors: Otto Maximilian , Teixeira Paulo Gonçalves , Vizcaino Maria Isabel , David Florian , Siewers Verena
Published: December 2019

Background

The sesquiterpenoid abscisic acid (ABA) is mostly known for regulating developmental processes and abiotic stress responses in higher plants. Recent studies show that ABA also exhibits a variety of pharmacological activities. Affordable and sustainable production will be required to utilize the compound in agriculture and as a potential pharmaceutical.Saccharomyces cerevisiaeis an established workhorse for the biotechnological production of chemicals. In this study, we constructed and characterised an ABA-producingS. cerevisiaestrain using the ABA biosynthetic pathway fromBotrytis cinerea.

Results

Expression of theB. cinereagenesbcaba1,bcaba2,bcaba3andbcaba4was sufficient to establish ABA production in the heterologous host. We characterised the ABA-producing strain further by monitoring ABA production over time and, since the pathway contains two cytochrome P450 enzymes, by investigating the effects of overexpressing the nativeS. cerevisiaeor theB. cinereacytochrome P450 reductase. Both, overexpression of the native or heterologous cytochrome P450 reductase, led to increased ABA titres. We were able to show that ABA production was not affected by precursor or NADPH supply, which suggested that the heterologous enzymes were limiting the flux towards the product. TheB. cinereacytochrome P450 monooxygenases BcABA1 and BcABA2 were identified as pathway bottlenecks and balancing the expression levels of the pathway enzymes resulted in 4.1-fold increased ABA titres while reducing by-product formation.

Conclusion

This work represents the first step towards a heterologous ABA cell factory for the commercially relevant sesquiterpenoid.
RETRACTED ARTICLE: Correlations between chromobox homolog 8 and key factors of epithelial–mesenchymal transition in hepatocellular carcinoma
Authors: Zhu Xiaonian , Luo Wei , Bei Chunhua , Kong Juan , Zhang Shidong , Fu Yuanyuan , Li Di , Tan Shengkui
Published: December 2019

Background

Hepatocellular carcinoma (HCC) is one of the most common malignancies worldwide, especially in China, with high metastasis and poor prognosis. Recently, as the core component of the polycomb repressive complexes 1 (PRC1), chromobox protein homolog 8 (CBX8) is considered as an oncogene and prognostic marker in HCC.

Methods

A tissue microarray of 166 paired HCC and adjacent non-tumor samples were collected to identify the relationship between CBX8 and epithelial mesenchymal transition (EMT) associated proteins by Spearman correlation analysis. Knock-down of CBX8 in HCC cells was conducted to detect the biologic functions of CBX8 in HCC metastasis.

Results

We found out that CBX8 was over-expressed in HCC and its expression was closely related to the metastasis of HCC patients. In addition, knock-down of CBX8 was found to inhibit the invasion and migration ability of HCC cells. Moreover, there was a significant relationship between expression of CBX8 and EMT associated proteins both in HCC cells and tumor tissues.

Conclusions

Our results indicate that CBX8 promotes metastasis of HCC by inducing EMT process.
Extended spectrum β-lactamase producing uropathogenic Escherichia coli and the correlation of biofilm with antibiotics resistance in Nepal
Authors: Shrestha Raju , Khanal Santosh , Poudel Pramod , Khadayat Karan , Ghaju Sajani , Bhandari Anita , Lekhak Sunil , Pant Narayan Dutt , Sharma Manisha , Marasini Bishnu P.
Published: December 2019

Background

Urinary tract infection (UTI) is one of the frequently diagnosed infectious diseases which is caused mainly by Escherichia coli. E. coli confers resistance against the two major classes of antibiotics due to the production of extended spectrum β-lactamase enzymes (ESBL), biofilm, etc. Biofilm produced by uropathogenic E. coli (UPEC) protects from host immune system and prevent entry of antimicrobial compounds. The main objective of this cross-sectional study was to determine the correlation of biofilm production and antibiotic resistance as well as to characterize the pgaA and pgaC genes responsible for biofilm formation among uropathogenic ESBL producing E. coli.

Methods

A total of 1977 mid-stream urine samples were examined and cultured for bacterial strain identification. ESBL was detected by combined disc method following CLSI whereas biofilm formation was analyzed by semi-quantitative method. Furthermore, the pgaA and pgaC genes responsible for biofilm formation in UPEC were detected by multiplex PCR. All the statistical analyses were done via IBM SPSS Statistics 21 where Pearson’s correlation test were used to determine correlation (−1 ≥ r ≤ 1).

Results

E. coli was the predominant causative agent, which accounted 159 (59.3%) of the Gram-negative bacteria, where 81 (50.9%) E. coli strains were found to be ESBL producers. In addition, 86 (54.1%) E. coli strains were found to be biofilm producers. Both the pgaA and pgaC genes were detected in 45 (93.7%) the UPEC isolates, which were both biofilm and ESBL producers. Moreover, there was a positive correlation between biofilm and ESBL production.

Conclusion

The analyses presented weak positive correlation between biofilm and ESBL production in which biofilm producing UPEC harbors both pgaA and pgaC genes responsible for biofilm formation.
Chemotherapeutic drugs stimulate the release and recycling of extracellular vesicles to assist cancer cells in developing an urgent chemoresistance
Authors: Wang Xiaokun , Qiao Dongjuan , Chen Likun , Xu Meng , Chen Shupeng , Huang Liyan , Wang Fang , Chen Zhen , Cai Jiye , Fu Liwu
Published: December 2019

Background

Chemotherapy is a widely used treatment for cancer. However, the development of acquired multidrug resistance (MDR) is a serious issue. Emerging evidence has shown that the extracellular vesicles (EVs) mediate MDR, but the underlying mechanism remains unclear, especially the effects of chemotherapeutic agents on this process.

Methods

Extracellular vesicles isolation was performed by differential centrifugation. The recipient cells that acquired ATP-binding cassette sub-family B member 1 (ABCB1) proteins were sorted out from co-cultures according to a stringent multi-parameter gating strategy by fluorescence-activated cell sorting (FACS). The transfer rate of ABCB1 was measured by flow cytometry. The xenograft tumor models in mice were established to evaluate the transfer of ABCB1 in vivo. Gene expression was detected by real-time PCR and Western blotting.

Results

Herein, we show that a transient exposure to chemotherapeutic agents can strikingly increase Rab8B-mediated release of extracellular vesicles (EVs) containing ABCB1 from drug-resistant cells, and accelerate these EVs to circulate back onto plasma membrane of sensitive tumor cells via the down-regulation of Rab5. Therefore, intercellular ABCB1 transfer is significantly enhanced; sensitive recipient cells acquire a rapid but unsustainable resistance to evade the cytotoxicity of chemotherapeutic agents. More fascinatingly, in the xenograft tumor models, chemotherapeutical drugs also locally or distantly increase the transfer of ABCB1 molecules. Furthermore, some Non-small-cell lung carcinoma (NSCLC) patients who are undergoing primary chemotherapy have a rapid increase of ABCB1 protein in their monocytes, and this is obviously associated with poor chemotherapeutic efficacy.

Conclusions

Chemotherapeutic agents stimulate the secretion and recycling of ABCB1-enriched EVs through the dysregulation of Rab8B and Rab5, leading to a significant increase of ABCB1 intercellular transfer, thus assisting sensitive cancer cells to develop an urgent resistant phenotype. Our findings provide a new molecular mechanism of how chemotherapeutic drugs assist sensitive cancer cells in acquiring an urgent resistance.
Novel nanomedicine with a chemical-exchange saturation transfer effect for breast cancer treatment in vivo
Authors: Jia Yanlong , Wang Chaochao , Zheng Jiehua , Lin Guisen , Ni Dalong , Shen Zhiwei , Huang Baoxuan , Li Yan , Guan Jitian , Hong Weida , Chen Yuanfeng , Wu Renhua
Published: December 2019

Background

Nanomedicine is a promising new approach to cancer treatment that avoids the disadvantages of traditional chemotherapy and improves therapeutic indices. However, the lack of a real-time visualization imaging technology to monitor drug distribution greatly limits its clinical application. Image-tracked drug delivery is of great clinical interest; it is useful for identifying those patients for whom the therapy is more likely to be beneficial. This paper discusses a novel nanomedicine that displays features of nanoparticles and facilitates functional magnetic resonance imaging but is challenging to prepare.

Results

To achieve this goal, we synthesized an acylamino-containing amphiphilic block copolymer (polyethylene glycol-polyacrylamide-polyacetonitrile, PEG-b-P(AM-co-AN)) by reversible addition-fragmentation chain transfer (RAFT) polymerization. The PEG-b-P(AM-co-AN) has chemical exchange saturation transfer (CEST) effects, which enable the use of CEST imaging for monitoring nanocarrier accumulation and providing molecular information of pathological tissues. Based on PEG-b-P(AM-co-AN), a new nanomedicine PEG-PAM-PAN@DOX was constructed by nano-precipitation. The self-assembling nature of PEG-PAM-PAN@DOX made the synthesis effective, straightforward, and biocompatible. In vitro studies demonstrate decreased cytotoxicity of PEG-PAM-PAN@DOX compared to free doxorubicin (half-maximal inhibitory concentration (IC50), mean ~ 0.62 μg/mL vs. ~ 5 μg/mL), and the nanomedicine more efficiently entered the cytoplasm and nucleus of cancer cells to kill them. Further, in vivo animal experiments showed that the nanomedicine developed was not only effective against breast cancer, but also displayed an excellent sensitive CEST effect for monitoring drug accumulation (at about 0.5 ppm) in tumor areas. The CEST signal of post-injection 2 h was significantly higher than that of pre-injection (2.17 ± 0.88% vs. 0. 09 ± 0.75%,p < 0.01).

Conclusions

The nanomedicine with CEST imaging reflects the characterization of tumors and therapeutic functions has great potential medical applications.
HIV/HCV co-infection and associated risk factors among injecting drug users in Dar es Salaam, Tanzania: potential for HCV elimination
Authors: Leyna Germana Henry , Makyao Neema , Mwijage Alexander , Ramadhan Angela , Likindikoki Samuel , Mizinduko Mucho , Leshabari Melkizedeck Thomas , Moen Kåre , Mmbaga Elia John
Published: December 2019

Background

Chronic HCV infection causes substantial morbidity and mortality and, in co-infection with HIV, may result in immunological and virological failure following antiretroviral treatment. Estimates of HCV infection, co-infection with HIV and associated risk practices among PWID are scarce in Africa. This study therefore aimed at estimating the prevalence of HCV and associated risk factors among PWID in the largest metropolitan city in Tanzania to inform WHO elimination recommendations.

Methods

An integrated bio-behavioral survey using respondent-driven sampling was used to recruit PWID residing in Dar es Salaam, Tanzania. Following face-to-face interviews, blood samples were collected for HIV and HCV testing. Weighted modified Poisson regression modeling with robust standard errors was used in the analysis.

Results

A total of 611 PWID with a median age of 34 years (IQR, 29–38) were recruited through 4 to 8 waves. The majority of participants (94.3%) were males, and the median age at first injection was 24 years (IQR, 19–30). Only 6.55% (40/611) of participants reported to have been enrolled in opioid treatment programs. The weighted HCV antibody prevalence was 16.2% (95%CI, 13.0–20.1). The corresponding prevalence of HIV infection was 8.7% (95%CI, 6.4–11.8). Of the 51 PWID who were infected with HIV, 22 (43.1%) were HCV seropositive. Lack of access to clean needles (adjusted prevalence ratio (APR), 1.76; 95%CI, 1.44; 12.74), sharing a needle the past month (APR, 1.72; 95%CI, 1.02; 3.00), not cleaning the needle the last time shared (APR, 2.29; 95%CI, 1.00; 6.37), and having unprotected not using a transactional sex (APR, 1.87; 95%CI, 1.00; 3.61) were associated with increased risk of HCV infection. On the other hand, not being on opioid substitution therapy was associated with 60% lower likelihood of infection.

Conclusions

The HCV antibody prevalence among PWID is lower than global estimates indicating potential for elimination. Improving access to safe injecting paraphernalia, promoting safer injecting practices is the focus of prevention programing. Screening for HIV/HCV co-infection should be intensified in HIV care, opioid substitution programs, and other point of care for PWID. Use of direct-acting antiretroviral treatment would accelerate the achievement of hepatitis infection elimination goal by 2030.
Doctor retention and distribution in post-apartheid South Africa: tracking medical graduates (2007–2011) from one university
Authors: George Ann , Blaauw Duane , Thompson Jarred , Green-Thompson Lionel
Published: December 2019

Background

Doctor emigration from low- and middle-income countries represents a financial loss and threatens the equitable delivery of healthcare. In response to government imperatives to produce more health professionals to meet the country’s needs, South African medical schools increased their student intake and changed their selection criteria, but little is known about the impact of these changes. This paper reports on the retention and distribution of doctors who graduated from the University of the Witwatersrand, South Africa (SA), between 2007 and 2011.

Methods

Data on 988 graduates were accessed from university databases. A cross-sectional descriptive email survey was used to gather information about graduates’ demographics, work histories, and current work settings. Frequency and proportion counts and multiple logistic regressions of predictors of working in a rural area were conducted. Open-ended data were analysed using content analysis.

Results

The survey response rate was 51.8%. Foreign nationals were excluded from the analysis because of restrictions on them working in SA. Of 497 South African respondents, 60% had completed their vocational training in underserved areas. At the time of the study, 89% (444) worked as doctors in SA, 6.8% (34) practised medicine outside the country, and 3.8% (19) no longer practised medicine. Eighty percent of the 444 doctors still in SA worked in the public sector. Only 33 respondents (6.6%) worked in rural areas, of which 20 (60.6%) were Black. Almost half (47.7%) of the 497 doctors still in SA were in specialist training appointments.

Conclusions

Most of the graduates were still in the country, with an overwhelmingly urban and public sector bias to their distribution. Most doctors in the public sector were still in specialist training at the time of the study and may move to the private sector or leave the country. Black graduates, who were preferentially selected in this graduate cohort, constituted the majority of the doctors practising in rural areas. The study confirms the importance of selecting students with rural backgrounds to provide doctors for underserved areas. The study provides a baseline for future tracking studies to inform the training of doctors for underserved areas.
Developing evidence briefs for policy: a qualitative case study comparing the process of using a guidance-contextualization workbook in Peru and Uganda
Authors: Alvarez Elizabeth , Lavis John N. , Brouwers Melissa , Carmona Clavijo Gloria , Sewankambo Nelson , Solari Lely , Schwartz Lisa
Published: December 2019

Background

Translating research evidence from global guidance into policy can help strengthen health systems. A workbook was developed to support the contextualization of the WHO’s ‘Optimizing health worker roles to improve maternal and newborn health’ (OptimizeMNH) guidance. This study evaluated the use of the workbook for the development of evidence briefs in two countries — Peru and Uganda. Findings surrounding contextual factors, steps in the process and evaluation of the workbook are presented.

Methods

A qualitative embedded case study was used. The case was the process of using the workbook to support the contextualization of global health systems guidance, with local evidence, to develop evidence briefs. Criterion sampling was used to select the countries, participants for interviews and documents included in the study. A template-organizing style and constant comparison were used for data analysis.

Results

A total of 19 participant-observation sessions and 8 interviews were conducted, and 50 documents were reviewed. Contextual factors, including the cadres, or groups, of health workers available in each country, the way the problem and its causes were framed, potential policy options to address the problem, and implementation considerations for these policy options, varied substantially between Peru and Uganda. However, many similarities were found in the process of using the workbook. Overall, the workbook was viewed positively and participants in both countries would use it again for other topics.

Conclusions

Organizations that produce global guidance, such as WHO, need to consider institutionalizing the application of the workbook into their guidance development processes to help users at the national/subnational level create actionable and context-relevant policies. Feedback mechanisms also need to be established so that the evidence briefs and health policies arising from global guidance are tracked and the findings coming out of such guideline contextualization processes can be taken into consideration during future guidance development and research priority-setting.
The impact of National Health Insurance upon accessibility of health services and financial protection from catastrophic health expenditure: a case study of Savannakhet province, the Lao People’s Democratic Republic
Authors: Bodhisane Somdeth , Pongpanich Sathirakorn
Published: December 2019

Introduction

Many schemes have been implemented by the government of the Lao People’s Democratic Republic to provide equity in health service utilisation. Initially, health service utilisations were fully supported by the government and were subsequently followed by the Revolving Drug Fund. In the 2000s, four health financing schemes, namely the Social Security Organization, the State Authority for Social Security, the Health Equity Fund and Community-Based Health Insurance (CBHI), were introduced with various target groups. However, as these voluntary schemes have suffered from a very low enrolment rate, the government decided to pilot the National Health Insurance (NHI) scheme, which offers a flat, co-payment system for health service utilisation. This study aims to assess the effectiveness of the NHI in terms of its accessibility and in providing financial protection from catastrophic health expenditure.

Methods

The data collection process was implemented in hospitals of two districts of Savannakhet province. A structured questionnaire was used to retrieve all required information from 342 households; the information comprised of the socioeconomics of the household, accessibility to health services and financial payment for both outpatient and inpatient department services. Binary logistic regression models were used to discover the impact of NHI in terms of accessibility and financial protection. The impact of NHI was then compared with the outcomes of the preceding, voluntary CBHI scheme, which had been the subject of earlier studies.

Results

Under the NHI, it was found that married respondents, large households and the level of income significantly increased the probability of accessibility to health service utilisation. Most importantly, NHI significantly improved accessibility for the poorest income quantile. In terms of financial protection, households with an existing chronic condition had a significantly higher chance of suffering financial catastrophe when compared to households with healthy members. As probability of catastrophic expenditure was not affected by income level, it was indicated that NHI is able to provide equity in financial protection.

Conclusion

The models found that the NHI significantly enhances accessibility for poor income households, improving health service distribution and accessibility for the various income levels when compared to the CBHI coverage. Additionally, it was also found that NHI had enhanced financial protection since its introduction. However, the NHI policy requires a dramatically high level of government subsidy; therefore, there its long-term sustainability remains to be determined.
Palliative Care Evidence Review Service (PaCERS): a knowledge transfer partnership
Authors: Mann Mala , Woodward Amanda , Nelson Annmarie , Byrne Anthony
Published: December 2019

The importance of linking evidence into practice and policy is recognised as a key pillar of a prudent approach to healthcare; it is of importance to healthcare professionals and decision-makers across the world in every speciality. However, rapid access to evidence to support service redesign, or to change practice at pace, is challenging. This is particularly so in smaller specialties such as Palliative Care, where pressured multidisciplinary clinicians lack time and skill sets to locate and appraise the literature relevant to a particular area. Therefore, we have initiated the Palliative Care Evidence Review Service (PaCERS), a knowledge transfer partnership through which we have developed a clear methodology to conduct evidence reviews to support professionals and other decision-makers working in palliative care.

PaCERS methodology utilises modified systematic review methods as there is no agreed definition or an accepted methodology for conducting rapid reviews. This paper describes the stages involved based on our iterative recent experiences and engagement with stakeholders, who are the potential beneficiaries of the research. Uniquely, we emphasise the process and opportunities of engagement with the clinical workforce and policy-makers throughout the review, from developing and refining the review question at the start through to the importance of demonstrating impact. We are faced with the challenge of the trade-off between the timely transfer of evidence against the risk of impacting on rigour. To address this issue, we try to ensure transparency throughout the review process. Our methodology aligns with key principles of knowledge synthesis in defining a process that is transparent, robust and improving the efficiency and timeliness of the review.

Our reviews are clinically or policy driven and, although we use modified systematic review methods, one of the key differences between published review processes and our review process is in our relationship with the requester. This streamlining approach to synthesising evidence in a timely manner helps to inform decisions faced by clinicians and decision-makers in healthcare settings, supporting, at pace, knowledge transfer and mobilisation.
Differential discounting in the economic evaluation of healthcare programs
Authors: John Jürgen , Koerber Florian , Schad Mareike
Published: December 2019

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

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

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

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

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

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

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

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.