The effect of prescription drug insurance on the incidence of potentially inappropriate prescribing: evidence from Medicare Part D

The Medicare Part D program has been documented to increase the affordability and accessibility of drugs and improve the quality of prescription drug use; however, less is known about the equity impact of the Part D program on potentially inappropriate prescribing—specifically, incidences of polypharmacy and potentially inappropriate medication (PIM) use based on different racial/ethnic groups. Using a difference in the regression discontinuity design, we found that among Whites, Part D was associated with increases in polypharmacy and “broadly defined” PIM use, while the use of “always avoid” PIM remained unchanged. Conversely, Blacks and Hispanics reported no changes in such drug utilization patterns

Glycogen synthase kinase 3 beta suppresses polyglutamine aggregation by inhibiting Vaccinia-related kinase 2 activity

Huntington's disease (HD) is a neurodegenerative disorder caused by an abnormal expansion of polyglutamine repeats in the N-terminal of huntingtin. The amount of aggregate-prone protein is controlled by various mechanisms, including molecular chaperones. Vaccinia-related kinase 2 (VRK2) is known to negatively regulate chaperonin TRiC, and VRK2-facilitated degradation of TRiC increases polyQ protein aggregation, which is involved in HD. We found that VRK2 activity was negatively controlled by glycogen synthase kinase 3 beta (GSK3 beta). GSK3 beta directly bound to VRK2 and inhibited the catalytic activity of VRK2 in a kinase activity-independent manner. Furthermore, GSK3 beta increased the stability of TRiC and decreased the formation of HttQ103-GFP aggregates by inhibiting VRK2. These results indicate that GSK3 beta signaling may be a regulatory mechanism of HD progression and suggest targets for further therapeutic trials for HD.1131Ysciescopu

Stress-induced nuclear translocation of CDK5 suppresses neuronal death by downregulating ERK activation via VRK3 phosphorylation

Although extracellular signal-related kinase 1/2 (ERK 1/2) activity is generally associated with cell survival, prolonged ERK activation induced by oxidative stress also mediates neuronal cell death. Here we report that oxidative stress-induced cyclin-dependent kinase 5 (CDK5) activation stimulates neuroprotective signaling via phosphorylation of vaccinia-related kinase 3 (VRK3) at Ser 108. The binding of vaccinia H1-related (VHR) phosphatase to phosphorylated VRK3 increased its affinity for phospho-ERK and subsequently downregulated ERK activation. Overexpression of VRK3 protected human neuroblastoma SH-SY5Y cells against hydrogen peroxide (H2O2)-induced apoptosis. However the CDK5 was unable to phosphorylate mutant VRK3, and thus the mutant forms of VRK3 could not attenuate apoptotic process. Suppression of CDK5 activity results in increase of ERK activation and elevation of proapoptotic protein Bak expression in mouse cortical neurons. Results from VRK3-deficient neurons were further confirmed the role of VRK3 phosphorylation in H2O2-evoked ERK regulation. Importantly, we showed an association between phospho-VRK3 levels and the progression of human Alzheimer’s disease (AD) and Parkinson’s disease (PD). Together our work reveals endogenous protective mechanism against oxidative stress-induced neuronal cell death and suggest VRK3 as a potential therapeutic target in neurodegenerative diseases.1186Ysciescopu

Vaccinia-Related Kinase 2 Mediates Accumulation of Polyglutamine Aggregates via Negative Regulation of the Chaperonin TRiC

Misfolding of proteins containing abnormal expansions of polyglutamine (polyQ) repeats is associated with cytotoxicity in several neurodegenerative disorders, including Huntington's disease. Recently, the eukaryotic chaperonin TRiC hetero-oligomeric complex has been shown to play an important role in protecting cells against the accumulation of misfolded polyQ protein aggregates. It is essential to elucidate how TRiC function is regulated to better understand the pathological mechanism of polyQ aggregation. Here, we propose that vaccinia-related kinase 2 (VRK2) is a critical enzyme that negatively regulates TRiC. In mammalian cells, overexpression of wild-type VRK2 decreased endogenous TRiC protein levels by promoting TRiC ubiquitination, but a VRK2 kinase-dead mutant did not. Interestingly, VRK2-mediated downregulation of TRiC increased aggregate formation of a polyQ-expanded huntingtin fragment. This effect was ameliorated by rescue of TRiC protein levels. Notably, small interference RNA-mediated knockdown of VRK2 enhanced TRiC protein stability and decreased polyQ aggregation. The VRK2-mediated reduction of TRiC protein levels was subsequent to the recruitment of COP1 E3 ligase. Among the members of the COP1 E3 ligase complex, VRK2 interacted with RBX1 and increased E3 ligase activity on TRiC in vitro. Taken together, these results demonstrate that VRK2 is crucial to regulate the ubiquitination-proteosomal degradation of TRiC, which controls folding of polyglutamine proteins involved in Huntington's disease.open118Ysciescopu

Disparities in the utilisation of preventive health services by the employment status: an analysis of 2007-2012 South Korean national survey

Objectives This study aims to investigate the differences in the utilisation of preventive health services among standard, nonstandard workers, the self-employed, and unpaid family workers. Methods We used the 4th and 5th Korea National Health and Nutrition Examination Survey, a nationwide survey conducted from the year 2007 to 2012. Economically active workers between the ages of 25 and 64 were grouped into standard, nonstandard, the self-employed, and the unpaid family workers (N = 16,964). Outcome variables are the uptake of preventive health services including influenza vaccination, regular medical check-up, and four types of cancer screenings. We used multivariate logistic models. Results Overall, non-standard workers, the self-employed, and unpaid family workers were less likely to use the preventive health care compared to the standard workers. In particular, the selfemployed were less likely to use all the six services compared to the standard workers and showed the lowest level of uptakes among the four working groups. Moreover, the service uptake of the non-standard workers was lower than that of standard workers in all services; except the colon cancer screening. On the other hand, unpaid family workers showed mixed results. While the uptake of influenza vaccination and regular health screening were lower, participation to the cancer screening was not lower compared to that of standard workers. Conclusion There were gaps in the utilisation of preventive services among workers depending on their employment types. Access to preventive health care services of nonstandard workers, the self-employed, and unpaid family workers should be prioritised

The effect of social and financial incentives in the provision and organisation of healthcare in the Republic of Korea

Expanding health insurance has significantly improved the population's health. However, the modalities and strategies for expanding healthcare provision have taken on a distinctive form in Asian countries, particularly in East Asia, which is sometimes referred to as the developmental welfare state model (Kwon, 2009a). Rather than being based on a social right, welfare expansion was a means of supporting economic policies and rewarding those who contributed to national development. These social policies were strongly driven by government elites, including the president (Kwon, 1995). Rather than providing all social services directly, the government constructed long-term plans and contracted out the provision of services to the private sector. Among East Asian countries, South Korea exemplifies this characteristic in healthcare provision, with a very different organisation of the health system from that of Western countries. It can be roughly summarised as the rapid introduction of social health insurance and its integration into national health insurance, led by the national elite, the establishment of private capital-driven healthcare institutions, and state control of reimbursement costs to prevent healthcare costs from exploding. While these features have the advantage of ensuring that most people have health insurance in a short period, the government's price control and the profit-seeking of healthcare institutions—many of which are based on private capital—have created an incentive structure that maximises the volume of healthcare and maximises the price per unit of care under the fee-for-service system. As a result, a range of adverse health outcomes gradually emerged in the 1990s and 2000s, including high antibiotic prescribing rates and caesarean sections. Governments implemented interventions to address the negative consequences of the distorted incentive structure. However, these solutions were often patchwork or indiscriminate adoption of foreign policy practices rather than addressing the underlying health system failures. Various attempts were made to change provider behaviour, mainly through the use of financial and social incentives. While there has been some evaluation of these attempts, there is still a lack of comprehensive assessment of their effectiveness and side effects. This thesis examines how social and financial incentives result from policy interventions that aim to improve healthcare efficiency and quality by examining three different interventions where we can establish exogenous variation in some social or financial incentives influencing providers' health behaviours. The thesis aims to evaluate the direct spillover of social and financial incentives in Korean health policies for better policy design and to provide policy implications. Unintended Effects of antibiotic prescription rate disclosure The first paper examines the effect of social incentives on healthcare provision in Korea, specifically in the intended and unintended consequences of the antibiotic prescription rate disclosure in 2006. As mentioned earlier, providers in Korea were placed in a situation where they had to generate income based on the volume of services. While reimbursement costs for consultations were low, a structure was formed in a way that providers could supplement part of their income by prescribing medication and directly dispensing medication at hospitals or clinics. In such a situation, even for mild common colds, the prescription of antibiotics or injections increased rapidly, and the prescription rate for antibiotics in acute respiratory infections exceeded 50%. Such high antibiotic prescription rates are a typical waste of the healthcare system and a factor that causes long-term antimicrobial resistance, resulting in significant economic and medical costs (O'Neill, 2016). With the separation of prescribing and dispensing in 2000, doctors only issued prescriptions, and patients obtained medication from pharmacies. However, the high antibiotic prescription rate persisted for over 20 years and showed no signs of decreasing. At the urging of civil society, the government hastily introduced a public reporting policy. The policy of disclosing information in 2006 is regarded as having successfully reduced the antibiotic prescription rate in the country. However, as highlighted in this paper, the swift implementation of policies resulted in a coding shift, a significant unintended consequence that undermined the policy objectives. Specifically, this coding shift was particularly pronounced in medical staff with high rates of antibiotic prescription in the past and in departments that encountered acute respiratory diseases subject to information disclosure. Furthermore, we document that the prescription rate for broad-spectrum antibiotics did not decrease as the policy focused solely on the overall prescription rate. It demonstrates that medical staff face varying social pressures, namely social incentives, the influence of which depends on the degree of deviation from the norm shared within the professional society. Not all medical staff chose the ideal approach of reducing prescription rates, with some opting for socially undesirable methods. In this chapter, we draw on the theory of motivation change and explore ways to mitigate these side effects. Incentives to prevent unnecessary caesarean sections. The second paper discusses how to correct the distorted incentive structure with financial and social incentives to enhance quality in obstetric care, namely, reducing the share of unnecessary c-sections. In the late 1970s, when compulsory health insurance was introduced, midwives performed more deliveries than doctors. Not surprisingly, there was a significant difference in the cost between the midwives who performed natural deliveries and doctors who performed c-sections, and this continued to be the case even as the number of c-sections performed by doctors increased rapidly in the 1980s and 1990s. Even after health insurance was introduced, small clinics and hospitals performed c-sections in medically unindicated cases due to the high reimbursement cost for c-sections. The effect of insurance coverage on c-section uptake was stark: the c-section rate, which was only about 8% in the 1980s, reached over 45% in the early 2000s. In this chapter, we demonstrate that the introduction of both supply and demand side incentives by increasing the reimbursement cost for doctors who perform normal (vaginal) deliveries by 50% and exempting out-of-pocket payments for mothers who choose normal deliveries lead to a reduction in the c-section rate for first-time mothers decreased by about 3.6 pp. The paper also examines the effect of subsequent public reporting on c-section rates that was expanded several times. This effect was more substantial in areas with higher c-section rates before the policy. We propose two mechanisms. First, higher reimbursement fees for regular deliveries resulted in an increase in the number of doctors in small clinics. This increase in medical professionals increased the availability of normal deliveries, which typically require more time compared to caesarean sections. In addition, the expansion of public reporting, which came about a year and a half after the reimbursement cost increase, reduced c-sections in the short term, but the effect was short-lived. This observation illustrates the adverse effects of a significant difference in payer costs between two elective procedures and low compensation for a time-consuming procedure. At the same time, it shows that governments and insurers can dramatically reduce unnecessary c-sections by adjusting payment levels. It also reveals that the effect of repeated public reporting is not significant and that while increasing public reporting may have a positive short-term effect, it is only a temporary shock to providers. In turn, it highlights the importance of careful reimbursement design in incentive design. Do social and financial incentives increase the quality of stroke care? Finally, the last paper turns to emergency healthcare and looks at the combination of social and financial incentives at the organisational level. Here, the distorted incentive structure encompassed little incentive to provide the best possible medical care for severe emergency conditions resulting from a stroke or myocardial infarction in hospital-level medical institutions. Small and medium-sized hospitals have proliferated due to the lack of consistent government hospital policies and support. In small hospitals, the number of severe emergency cases is also small; therefore, they cannot afford to have specialists available for 24-hour care. In such situations, ambulances transfer emergency patients to nearby hospitals with no medical staff with particular specialities or hospitals with insufficient resources. Patients are transferred to larger hospitals, often missing the optimal golden hour. This paper examines the impact of public reporting on mortality rates for stroke patients following the government's September 2007 announcement of a financial incentive program in July 2011. The results indicate that neither intervention impacted short-term mortality, with borderline evidence that public reporting reduced 365-d mortality rates by around 2pp. We also found evidence that the incentive program reduced the 365-d mortality rate by about 3.1 pp, mainly due to a reduction in the mortality rate for patients with ischemic stroke. As a secondary outcome, both policies were found to reduce the length of stay by about 1-2 days, with the incentive program significantly reducing the length of stay for haemorrhagic stroke, which has a longer average length of stay, thus reducing the total cost of care. Finally, we checked for spillover effects, whereby these changes increase outpatient visits or readmissions after discharge but found no evidence. Overall, we find that healthcare providers not only maximise their economic incentives and patient benefits in their payoff function but also consider broader social incentives. However, as the effect of the social incentive is strong, we document evidence of a high likelihood of side (spillover) effects, and it has been confirmed that some medical providers can engage in various behaviours that undermine policy objectives. In addition, the effects of these social incentives may decrease over time, suggesting that various efforts are needed to align providers' incentives with those pursued in the policy design instead of utilising the tactic of shaming healthcare providers. Second, we show that the side effects resulting from distorted incentive structures can be addressed through incentive corrections, which can significantly contribute to achieving efficiency and quality goals. Thirdly, this paper demonstrates that social and economic incentives have powerful effects even at the organisational level and that support for fixed costs in a hospital environment where market failures occur can achieve hospital service efficiency and promote efficiency through economy of scope

HnRNP Q suppresses polyglutamine aggregation by reducing Vaccinia-related kinase 2 mRNA stability

Huntington’s disease (HD) is a progressive neurodegenerative disorder caused by a CAG trinucleotide repeat expansion in the huntingtin (HTT) gene, which encodes a polyglutamine tract in the HTT protein. Misfolding of proteins containing abnormal expansions of polyglutamine (polyQ) repeats is associated with cytotoxicity in HD. We have previously shown that vaccinia-related kinase 2 (VRK2) downregulates chaperonin TRiC protein levels through the ubiquitin-proteasome system by recruiting the E3 ligase COP1 and by destabilizing USP25 which is deubiquiting enzyme. Here we found that basal level of VRK2 in neuronal cells is regulated by post-transcriptional regulation. HnRNP Q specifically binds to 3’UTR of VRK2 mRNA in neuronal cells and reduces its stability. We report a dramatic increase polyglutamine aggregation by reducing hnRNP Q level. Thus, our results demonstrate that decreased brain hnRNP Q contributes to HD neurological phenotype and open new novel prognostic marker of HD.1

Multi-channel plastic-scintillator-based detection system for monitoring tritium in air

To overcome the limitations of the ionization chamber-based tritium monitor, a design for a multichannel plastic scintillator-based detection chamber for monitoring tritium in air is proposed. The performance of the chamber was characterized by Monte Carlo-based calculations with various design parameters such as thickness of the plastic scintillator (t) and number of channels (n). We considered the volume and detection efficiency of the chamber to evaluate the performance of the detector. The expected counting rate curve was in good agreement with the expected simplified physical model. The minimum detectable activity (MDA) was shown at t = 0.5 mm and n = 48 and estimated to be 29.9 kBq/m3. Compared with the experimentally estimated MDA, the relative difference was approximately 24%. However, this difference is understandable considering the different lower level of discrimination and light loss during transportation assumed in the model. The proposed tritium detection chamber is expected to be useful for environmental monitoring at some level as well as for monitoring of tritium leaks from fusion or CANada Deuterium Uranium (CANDU)-type reactors