Factors Related to Treatment Non-Adherence Among Caregivers of Pediatric and Adolescent Growth Hormone Deficiency Patients in Japan.

Background: About one-third of caregivers of pediatric or adolescent growth hormone deficiency (pGHD) patients in Japan have reported poor treatment adherence. However, few studies have examined factors related to adherence for that group. Objective: The aim of this study is to consider factors related to poor adherence to daily treatment among caregivers of pGHD patients in Japan. Methods: A cross-sectional survey was conducted among caregivers of pGHD patients in Japan. Caregivers were asked about demographic and treatment characteristics, health literacy, treatment satisfaction, opinions about treatment, and treatment adherence. Health literacy was assessed using the 14-item health literacy scale (HLS-14). Adherence was assessed using the 8-item Morisky Medication Adherence Scale (MMAS-8). Statistical association with adherence was considered using Chi-square and Student's t-testing. An exploratory factor analysis (EFA) and K-means cluster analysis was conducted to consider the influence of treatment satisfaction and opinions concerning treatment on adherence. Results: Responses were collected from 112 caregivers. The caregiver's age being 30-39 years old, the primary caregiver being male, the primary caregiver being employed, and low functional health literacy for the caregiver were associated with poor adherence. Patients being pre-elementary school age was also associated with poor adherence. Low satisfaction with drug treatment and/or their device and communication with healthcare professionals (HCPs), and lack of agreement with the importance of treatment management (eg, keeping injection records, getting informed about the disease/therapy, reporting non-adherence, and sticking to an administration schedule), were also associated with poor adherence. Conclusion: Strategies to improve treatment adherence among caregivers of pGHD patients in Japan should consider the age, gender, and employment status of the caregiver - as well as their functional literacy. Improvement in satisfaction with the drug or device used, better communication with HCPs, and greater awareness of the importance of treatment management, may also lead to better adherence.

A quantitative cross-sectional study of the burden of caring for patients with Lennox-Gastaut syndrome, Dravet syndrome, and tuberous sclerosis complex-associated epilepsy in Japan.

INTRODUCTION: Lennox-Gastaut syndrome (LGS), Dravet syndrome (DS), and tuberous sclerosis complex (TSC)-associated epilepsy are rare conditions associated with severe childhood-onset epilepsy. Caregivers play a critical role in the patients' care and may experience significant psychosocial and socioeconomic burden. This cross-sectional study determined the burden of caring for patients with these rare epilepsy conditions in Japan. METHODS: A quantitative online survey was used to assess patients' and caregivers' characteristics and the caregivers' emotional state, among others. Several validated questionnaires were used: the Hospital Anxiety and Depression Scale (HADS; 0-21 score) assessed the caregivers' emotional wellbeing, the Pediatric Quality of Life Inventory Family Impact Module (PedsQL FIM; 0-100 score) assessed the health-related quality of life (HRQoL) of the caregivers and their families, and the Work Productivity and Activity Impairment General Health (WPAI:GH; 0-100 % score) questionnaire assessed work productivity. RESULTS: A total of 36 caregivers responded (median [interquartile range (IQR)] age 43.5 [39.5, 48.3] years; 33/36 [92 %] female; 13/36 [36 %] working part-time and 13/36 [36 %] not working). Participants cared for 7/36 (19 %), 19/36 (53 %), and 10/36 (28 %) patients with LGS, DS, and TSC, respectively (median [IQR] age, 11.0 [6.8, 16.3] years; age at first seizure, 0 [0, 0] years). Patients received a median (IQR) of 4 (3, 5) treatment drug types. Patients experienced median (IQR) 3.0 (0, 21.0) epileptic seizures in the previous week; 28/36 (78 %) had severe intellectual disabilities, and 34/36 (94 %) had developmental delays. Caregivers reported stress (17/36 [47 %]), sleep problems (13/36 [36 %]), and anxiety (12/36 [33 %]). They spent a median (IQR) of 50.0 (17.5, 70.0) hours caregiving in the previous week, with 3.0 (1.0, 11.0) hours of seizure-specific care. Caregivers reported that their lives would be easier with a median (IQR) of 1.5 (0, 5.0) hours fewer per week caring for patients during/following seizures. Median HADS scores were 9.5 ('suspected anxiety diagnosis') and 7.5 ('no depression') for caregivers, and PedsQL FIM Total median score was 60.1, indicating HRQoL impairment for the caregiver and their family. WPAI:GH scores for paid workers indicated important work impairment. Higher caregiving hours (≥ 21 h vs. < 21 h in the previous week) resulted in higher caregiver burden as indicated by the HADS Total score (p = 0.0062) and PedsQL FIM Total score (p = 0.0007). CONCLUSIONS: Caregivers of patients with LGS, DS, or TSC in Japan experience a significant time burden, reduced HRQoL, and high level of work/activity impairment. Caregivers provide round-the-clock care to patients and rely on family and specialized caring services to help manage the increased caregiving time, which tends to be associated with greater emotional burden and HRQoL impact.

Prevalence, Incidence, and Clinical Characteristics of Thyroid Eye Disease in Japan.

Background: Although thyroid eye disease (TED) can impact social and psychological well-being, the epidemiological evidence of TED is lacking in Japan. Methods: Nationwide claims databases provided by JMDC Inc. and Medical Data Vision Co., Ltd. and national population statistics are used. Three TED definitions ranging from a strict definition only including a TED diagnosis to a broad definition including a TED diagnosis and considering ocular symptoms are considered. The proportion of patients by severity and disease activity are estimated based on definitions that would allow identification of those patients within the claims data. Results: The incidence rate per 100 000 person-years ranged from 7.3 to 11.1 for the strict and broad TED definitions, respectively. For fiscal year 2020 (April 2020 to March 2021) the prevalence rate ranged between 24.65 (strict TED) and 37.58 (broad TED) per 100 000 persons. These correspond to 25 383 and 38 697 patients for the strict and broad TED definitions, respectively. Regardless of the definition used, a predominance of female patients was observed, and the highest burden of the disease was seen in the age group of 35 to 59. Mild and inactive forms of TED were predominant (about 85% and 74%, respectively). Conclusion: The incidence and prevalence of TED in Japan were 7.3 to 11.1 per 100 000 person-years and 24.65 to 37.58 per 100 000 persons, respectively. The robust results of this database study add valuable real-world evidence on the incidence and prevalence of TED in Japan.

Perception of Adherence to Daily Human Growth Hormone Treatments Among Pediatric and Adolescent Patients in Japan: A Cross-Sectional Survey of Physicians and Caregivers.

Background: Poor adherence to daily human growth hormone (hGH) treatment has been shown to be associated with poor clinical outcomes for growth hormone deficiency (GHD) patients. However, few studies have examined the perception of adherence to hGH treatment among both physicians and caregivers in Japan. Objective: The aim of this study is to examine the perception of adherence for daily hGH treatment among physicians and caregivers of pediatric and adolescent patients treated with GH in Japan. Moreover, we explore reasons for skipping treatment and the potential impact of a once-weekly treatment on adherence. Methods: A cross-sectional survey was conducted in Japan among physicians that prescribe daily hGH treatment and caregivers that have administered daily hGH treatment to children/adolescents for 3 months or longer. The Morisky Medication Adherence Scale (MMAS-8) was used to gauge perceived adherence for both physician and caregiver groups. Caregivers were also questioned regarding reasons for missing injections. Moreover, both groups were asked about the impact of a once-weekly treatment on adherence. Results: Responses were collected from 123 physicians and 112 caregivers. Physicians reported that 18.1% of patients have poor adherence based on the MMAS-8 instrument. In contrast, 32.1% of the caregivers reported poor adherence. "Simply forgetting", "Patient refused/resisted", and being "Busy with school activities, etc" were the most commonly selected reasons by caregivers for missing an injection. Physicians felt that a once-weekly injection could improve adherence for 64.5% of patients with poor adherence. Moreover, 56.9% of the caregivers that reported an experience of missed injections felt that a once-weekly injection would improve their adherence. Conclusion: Approaches to improve adherence to hGH treatment in Japan are continuously needed. While further research is needed to understand factors most likely to improve adherence, availability of a once-weekly treatment is expected to help improve adherence.

Systematic Literature Review of the Use of Productivity Losses/Gains in Cost-Effectiveness Analyses of Immune-Mediated Disorders.

INTRODUCTION: In light of the lack of an agreed international standard for how to conduct cost-effectiveness analyses (CEAs), including cost-utility analyses (CUAs) from a societal perspective, there is uncertainty regarding to what extent the inclusion of productivity losses/gains in economic evaluations can affect cost-effectiveness results and subsequently decisions on whether to recommend new health technologies. To investigate this, we conducted a systematic review of CEAs and CUAs of drug-based therapies for a set of chronic immune-mediated disorders to understand how cost elements and calculation methods related to productivity losses/gains are used, examine the impact on the incremental cost-effectiveness ratio (ICER) of including productivity costs, and explore factors that affect the inclusion of productivity loss. METHODS: Databases (MEDLINE® In-process, MEDLINE, Embase and Cochrane Library) were searched from January 2010 to October 2020 by two independent reviewers for all CEAs and CUAs in adults with any of the following conditions: ankylosing spondylitis, chronic idiopathic urticaria, Crohn's disease, fibromyalgia, juvenile idiopathic arthritis, psoriasis, rheumatoid arthritis, systemic lupus erythematosus and ulcerative colitis. Relevant study data were extracted and evidence was synthesized for both qualitative and quantitative analysis. Productivity cost elements including absenteeism, presenteeism, unemployment/early retirement, premature mortality and informal care were extracted, along with the method used to determine them. A multivariate analysis was performed to identify factors associated with the inclusion of productivity loss. RESULTS: Our searches identified 5016 records, culminating in 198 unique studies from 234 publications following screening. Most of the studies investigated rheumatoid arthritis (37.0%) or psoriasis (32.0%). The majority were CUAs, with some including both a CEA and a CUA (73.0%). Most studies used a payer perspective only (28.5%) or a societal perspective only (21.0%). Of the 49 studies incorporating productivity losses/gains, 42 reported the type of cost element used; all of these used patient absenteeism, either alone or in addition with other elements. Only 16 studies reported the method used to value productivity changes, of which eight used a human capital approach, four used a friction cost approach and four used both approaches. Twenty-eight of the 49 studies (57.1%) reported inclusion of productivity losses/gains as contributing to more favourable cost-effectiveness outcomes and ICERs, while 12 (24.5%) reported no substantial impact. On the basis of a multivariate analysis, rheumatoid arthritis as the target disease had a statistically significant association with the inclusion of productivity loss compared with psoriasis and inflammatory bowel disease. CONCLUSIONS: The results of our review suggest that incorporating productivity cost elements may positively affect cost-effectiveness outcomes in evaluations of therapeutics for immune-mediated disorders. Our work highlights the continued need for clarity when reporting how CEAs and CUAs in this disease area are conducted, in order to better inform healthcare decision-making.

A Systematic Literature Review of Economic Evaluations and Cost Studies of the Treatment of Psoriasis, Atopic Dermatitis, and Chronic Urticaria.

INTRODUCTION: Psoriasis (PSO), atopic dermatitis (AD), and chronic urticaria (CU) are common manifestations of immunological skin and subcutaneous conditions and have been shown to have a substantial impact on the quality of life of patients. The cost of treating those conditions can also be high, as the use of biologic treatments has become more common for moderate to severe patients. In this review, we examine characteristics of economic evaluations and cost studies conducted for the three conditions. METHODS: A literature search was conducted using PubMed, Embase, and the Cochrane Library from January 1, 2016 to October 26, 2020 to identify economic evaluations where the cost of one or more drug treatment was evaluated and cost studies covering any intervention type. Each database was searched using keyword and MeSH terms related to treatment costs (e.g., health care cost, drug cost, etc.) and each condition (e.g., PSO, AD, eczema, CU, etc.). RESULTS: A total of 123 studies were reviewed, including 104 studies (85%) of PSO (including psoriasis, plaque psoriasis, psoriatic arthritis, and psoriasis vulgaris), 14 studies (11%) of AD, and 5 studies (4%) of CU. Seventy-two studies (59%) reviewed reported the inclusion of biologic treatments, 10 studies (8%) did not include biologic treatments, and 41 studies (33%) did not report whether or not a biologic treatment was included. While nearly all studies (98%) included direct costs, only 22 studies (18%) included indirect costs. CONCLUSIONS: Economic evaluations for AD and CU may be needed in order to better understand the value of new treatments. Moreover, a clearer delineation for biologic treatments and indirect costs (i.e., productivity losses and gains) may be required.

The relationship between cost and the recommendation, refusal, and discontinuation of treatment for chronic myeloid leukemia and multiple myeloma in Japan: a cross-sectional exploratory survey.

AIMS: This study aimed to ascertain the number of patients with chronic myelogenous leukemia (CML) and transplant-ineligible patients with multiple myeloma (MM) not recommended by their physicians for optimal drug treatment or who refuse, discontinue, reduce, or skip treatment owing to cost in Japan. METHODS: A cross-sectional survey was conducted among hematologists, hematologic oncologists, and oncologists in Japan treating ≥1 patient with CML or ≥5 transplant-ineligible patients with MM per year. RESULTS: A total of 212 physicians participated: 105 treating patients with CML and 107 treating transplant-ineligible patients with MM. While treatment cost did not lead to non-optimal treatment most patients, physicians reported that they recommended non-optimal treatment to 6.53% of their patients with CML and 1.41% of their transplant-ineligible patients with MM, that 1.51 and 0.35% of their patients, respectively, refused treatment and that 1.97 and 0.71% discontinued treatment owing to treatment cost. However, no significant differences in the effect of treatment cost on recommendation, discontinuation, refusal, or reduction of treatment were observed. Non-recommendation of optimal treatment owing to treatment cost was most common for third-line CML and fourth-line transplant-ineligible MM treatment. Discontinuation due to treatment cost was most common in third-line treatment for both. CONCLUSION: Our results show that non-optimal treatment due to treatment cost occurs among some physicians in Japan for patients with CML and transplant-ineligible patients with MM, but it may be limited to a small percentage of patients. Further research is needed to identify the drivers of treatment decisions for physicians and patients, including those involving treatment cost.

Phosphatase PHLPP2 regulates the cellular response to metabolic stress through AMPK.

PHLPP2 is a member of the PHLPP family of phosphatases, known to suppress cell growth by inhibiting proliferation or promoting apoptosis. Oncogenic kinases Akt, S6K, and PKC, and pro-apoptotic kinase Mst1, have been recognized as functional targets of the PHLPP family. However, we observed that, in T-leukemia cells subjected to metabolic stress from glucose limitation, PHLPP2 specifically targets the energy-sensing AMP-activated protein kinase, pAMPK, rather than Akt or S6K. PHLPP2 dephosphorylates pAMPK in several other human cancer cells as well. PHLPP2 and pAMPK interact with each other, and the pleckstrin homology (PH) domain on PHLPP2 is required for their interaction, for dephosphorylating and inactivating AMPK, and for the apoptotic response of the leukemia cells to glucose limitation. Silencing PHLPP2 protein expression prolongs the survival of leukemia cells subjected to severe glucose limitation by promoting a switch to AMPK-mediated fatty acid oxidation for energy generation. Thus, this study reveals a novel role for PHLPP2 in suppressing a survival response mediated through AMPK signaling. Given the multiple ways in which PHLPP phosphatases act to oppose survival signaling in cancers and the pivotal role played by AMPK in redox homeostasis via glucose and fatty acid metabolism, the revelation that AMPK is a target of PHLPP2 could lead to better therapeutics directed both at cancer and at metabolic diseases.

Hepatic lysosomal acid lipase overexpression worsens hepatic inflammation in mice fed a Western diet.

Nonalcoholic fatty liver disease (NAFLD) is characterized by the accumulation of lipid droplets in hepatocytes. NAFLD development and progression is associated with an increase in hepatic cholesterol levels and decreased autophagy and lipophagy flux. Previous studies have shown that the expression of lysosomal acid lipase (LAL), encoded by the gene LIPA, which can hydrolyze both triglyceride and cholesteryl esters, is inversely correlated with the severity of NAFLD. In addition, ablation of LAL activity results in profound NAFLD. Based on this, we predicted that overexpressing LIPA in the livers of mice fed a Western diet would prevent the development of NAFLD. As expected, mice fed the Western diet exhibited numerous markers of NAFLD, including hepatomegaly, lipid accumulation, and inflammation. Unexpectedly, LAL overexpression did not attenuate steatosis and had only minor effects on neutral lipid composition. However, LAL overexpression exacerbated inflammatory gene expression and infiltration of immune cells in mice fed the Western diet. LAL overexpression also resulted in abnormal phagosome accumulation and lysosomal lipid accumulation depending upon the dietary treatment. Overall, we found that hepatic overexpression of LAL drove immune cell infiltration and inflammation and did not attenuate the development of NAFLD, suggesting that targeting LAL expression may not be a viable route to treat NAFLD in humans.

Productivity loss/gain in cost-effectiveness analyses for vaccines: a systematic review.

Introduction: The kinds of costs included in cost-effectiveness analyses (CEAs) for vaccines, such as direct medical costs and indirect costs, may affect their outcomes. While some guidelines recommend inclusion of costs associated with productivity losses/gains, very little guidance is provided about the productivity elements to include and their calculation approach.Areas covered: We conducted a systematic review of CEAs for vaccines and vaccine programs published between 1 January 2010 and 19 November 2019 that included productivity costs using Medline, Embase, and the Cochrane Library. The kind of productivity elements included their calculation approach, and the impact of their inclusion on cost-effectiveness are summarized. Among 88 studies identified, productivity elements included were reported for 71 studies (81%) with absenteeism being the most commonly included element. Only 24 studies (27%) reported the approach used to calculate productivity costs (human capital vs. friction approach). Most studies (81%) reported a more favorable cost-effectiveness with the inclusion of productivity losses/gains.Expert opinion: Inclusion of productivity losses/gains for CEAs for vaccines has resulted in more favorable cost-effectiveness based on the studies reviewed. However, clearer guidance on the productivity elements to include by disease area and more transparency on the calculation method used may be needed.

Lipophagy-derived fatty acids undergo extracellular efflux via lysosomal exocytosis.

The autophagic degradation of lipid droplets (LDs), termed lipophagy, is a major mechanism that contributes to lipid turnover in numerous cell types. While numerous factors, including nutrient deprivation or overexpression of PNPLA2/ATGL (patatin-like phospholipase domain containing 2) drive lipophagy, the trafficking of fatty acids (FAs) produced from this pathway is largely unknown. Herein, we show that PNPLA2 and nutrient deprivation promoted the extracellular efflux of FAs. Inhibition of autophagy or lysosomal lipid degradation attenuated FA efflux highlighting a critical role for lipophagy in this process. Rather than direct transport of FAs across the lysosomal membrane, lipophagy-derived FA efflux requires lysosomal fusion to the plasma membrane. The lysosomal Ca2+ channel protein MCOLN1/TRPML1 (mucolipin 1) regulates lysosomal-plasma membrane fusion and its overexpression increased, while inhibition blocked FA efflux. In addition, inhibition of autophagy/lipophagy or MCOLN1, or sequestration of extracellular FAs with BSA attenuated the oxidation and re-esterification of lipophagy-derived FAs. Overall, these studies show that the well-established pathway of lysosomal fusion to the plasma membrane is the primary route for the disposal of FAs derived from lipophagy. Moreover, the efflux of FAs and their reuptake or subsequent extracellular trafficking to adjacent cells may play an important role in cell-to-cell lipid exchange and signaling.Abbreviations: ACTB: beta actin; ADRA1A: adrenergic receptor alpha, 1a; ALB: albumin; ATG5: autophagy related 5; ATG7: autophagy related 7; BafA1: bafilomycin A1; BECN1: beclin 1; BHBA: beta-hydroxybutyrate; BSA: bovine serum albumin; CDH1: e-cadherin; CQ: chloroquine; CTSB: cathepsin B; DGAT: diacylglycerol O-acyltransferase; FA: fatty acid; HFD: high-fat diet; LAMP1: lysosomal-associated membrane protein 1; LD: lipid droplet; LIPA/LAL: lysosomal acid lipase A; LLME: Leu-Leu methyl ester hydrobromide; MAP1LC3B/LC3: microtubule associated protein 1 light chain 3 beta; MCOLN1/TRPML1: mucolipin 1; MEF: mouse embryo fibroblast; PBS: phosphate-buffered saline; PIK3C3/VPS34: phosphatidylinositol 3-kinase catalytic subunit type 3; PLIN: perilipin; PNPLA2/ATGL patatin-like phospholipase domain containing 2; RUBCN (rubicon autophagy regulator); SM: sphingomyelin; TAG: triacylglycerol; TMEM192: transmembrane protein 192; VLDL: very low density lipoprotein.

Use of Productivity Loss/Gain in Cost-Effectiveness Analyses for Drugs: A Systematic Review.

BACKGROUND: Inclusion of productivity losses and gains in cost-effectiveness analyses for drugs is recommended by pharmacoeconomic guidelines in some countries and is considered optional in others. Often guidelines recommend analysis based on the payer perspective, but suggest that a supplemental analysis based on the societal perspective may be submitted that includes productivity losses/gains. However, there is no universally recognized framework for the approach to including productivity losses and gains in pharmacoeconomic analyses. OBJECTIVES: This study aimed to systematically review literature on cost-effectiveness analyses of drug interventions that included costs associated with productivity losses/gains and to summarize the types cost elements included and cost calculation methods employed. Moreover, this study examines variations in the calculation of productivity losses/gains by target disease type, geographic region, income group, period of analysis, and analysis time horizon-as well as the impact of their inclusion on the study outcomes. METHODS: A search of three databases was performed, including MEDLINE, Embase, and the Cochrane Library, to identify cost-effectiveness and cost-utility analyses that included indirect costs such as productivity losses/gains. Publications from January 2010 to October 2019 were examined and selected for inclusion by two independent reviewers. In addition to the citation details, data on the country of analysis, country income group, target disease area, study sponsorship, type of analysis, study design, time horizon, analysis perspective, productivity loss/gain elements included, the approach used to estimate productivity losses/gains, and the impact of their inclusion on the study outcome-namely the incremental cost effectiveness ratio-were extracted and summarized. RESULTS: The search strategy identified 5038 unique studies, and 208 were included in the final analysis. Among the studies reviewed, 165 (79%) were conducted in high-income countries and 160 (77%) were conducted for North American and European/Central Asian countries. The productivity loss/gain elements included in the analysis were reported for 169 studies (81%). Absenteeism only was included for 98 studies (47%), and absenteeism plus presenteeism was included for 29 studies (14%). Absenteeism plus some other element such as costs associated with unemployment and/or early retirement was included for 32 studies (15%) examined. Only one out of four of the studies reviewed included information on the approach used to estimate productivity losses/gains, which was predominantly the human capital approach. One-hundred forty-four studies (69%) reported the impact of including productivity losses/gains on the ICER, with 110 studies (53%) reporting that their inclusion contributed to more favorable cost-effectiveness. CONCLUSIONS: Although inclusion of productivity losses/gains was shown to have a favorable impact on evaluations for many studies, their impact and method of calculation was often not reported or was unclear. Further examination and discussion is needed to consider the optimal framework for considering productivity losses/gains in cost-effectiveness analyses, including the appropriate cost elements to include (e.g., patient absenteeism, caregiver absenteeism, presenteeism, unemployment, etc.) and how those costs should be estimated.

Systematic literature review of clinical outcomes in adults with metastatic or advanced synovial sarcoma.

Background: Synovial sarcoma (SS) is a rare, aggressive soft tissue sarcoma with a poor prognosis after metastasis. The objective of this study was to conduct a systematic review of the clinical evidence for therapeutic options for adults with metastatic or advanced SS. Materials & methods: Relevant databases were searched with predefined keywords. Results: Thirty-nine publications reported clinical data for systemic treatment and other interventions. Data on survival outcomes varied but were generally poor (progression-free survival: 1.0-7.7 months; overall survival: 6.7-29.2 months) for adults with metastatic and advanced SS. A high frequency of neutropenia with systemic treatment and low quality of life post-progression were reported. Conclusion: Reported evidence suggests poor outcomes in adults with metastatic and advanced SS and the need for the development of new treatment modalities.

Structural basis for transcriptional start site control of HIV-1 RNA fate.

Heterogeneous transcriptional start site usage by HIV-1 produces 5'-capped RNAs beginning with one, two, or three 5'-guanosines (Cap1G, Cap2G, or Cap3G, respectively) that are either selected for packaging as genomes (Cap1G) or retained in cells as translatable messenger RNAs (mRNAs) (Cap2G and Cap3G). To understand how 5'-guanosine number influences fate, we probed the structures of capped HIV-1 leader RNAs by deuterium-edited nuclear magnetic resonance. The Cap1G transcript adopts a dimeric multihairpin structure that sequesters the cap, inhibits interactions with eukaryotic translation initiation factor 4E, and resists decapping. The Cap2G and Cap3G transcripts adopt an alternate structure with an elongated central helix, exposed splice donor residues, and an accessible cap. Extensive remodeling, achieved at the energetic cost of a G-C base pair, explains how a single 5'-guanosine modifies the function of a ~9-kilobase HIV-1 transcript.

Hepatic PLIN5 signals via SIRT1 to promote autophagy and prevent inflammation during fasting.

Lipid droplets (LDs) are energy-storage organelles that are coated with hundreds of proteins, including members of the perilipin (PLIN) family. PLIN5 is highly expressed in oxidative tissues, including the liver, and is thought to play a key role in uncoupling LD accumulation from lipotoxicity; however, the mechanisms behind this action are incompletely defined. We investigated the role of hepatic PLIN5 in inflammation and lipotoxicity in a murine model under both fasting and refeeding conditions and in hepatocyte cultures. PLIN5 ablation with antisense oligonucleotides triggered a pro-inflammatory response in livers from mice only under fasting conditions. Similarly, PLIN5 mitigated lipopolysaccharide- or palmitic acid-induced inflammatory responses in hepatocytes. During fasting, PLIN5 was also required for the induction of autophagy, which contributed to its anti-inflammatory effects. The ability of PLIN5 to promote autophagy and prevent inflammation were dependent upon signaling through sirtuin 1 (SIRT1), which is known to be activated in response to nuclear PLIN5 under fasting conditions. Taken together, these data show that PLIN5 signals via SIRT1 to promote autophagy and prevent FA-induced inflammation as a means to maintain hepatocyte homeostasis during periods of fasting and FA mobilization.

The Antiviral and Cancer Genomic DNA Deaminase APOBEC3H Is Regulated by an RNA-Mediated Dimerization Mechanism.

Human APOBEC3H and homologous single-stranded DNA cytosine deaminases are unique to mammals. These DNA-editing enzymes function in innate immunity by restricting the replication of viruses and transposons. APOBEC3H also contributes to cancer mutagenesis. Here, we address the fundamental nature of RNA in regulating human APOBEC3H activities. APOBEC3H co-purifies with RNA as an inactive protein, and RNase A treatment enables strong DNA deaminase activity. RNA-binding-defective mutants demonstrate clear separation of function by becoming DNA hypermutators. Biochemical and crystallographic data demonstrate a mechanism in which double-stranded RNA mediates enzyme dimerization. Additionally, APOBEC3H separation-of-function mutants show that RNA binding is required for cytoplasmic localization, packaging into HIV-1 particles, and antiviral activity. Overall, these results support a model in which structured RNA negatively regulates the potentially harmful DNA deamination activity of APOBEC3H while, at the same time, positively regulating its antiviral activity.

Cost-utility analysis of sofosbuvir for the treatment of genotype 2 chronic hepatitis C in Japan.

OBJECTIVE: Across Japan, around 2 million people are infected with hepatitis C virus (HCV) with long-term complications such as cirrhosis, hepatocellular carcinoma (HCC) and liver transplant (LT). Current treatment options have several limitations due to side effects, interferon intolerability and ineligibility, long treatment durations and low sustained virological responses (SVR) rates, especially for the most severe patients. Sofosbuvir (SOF) is the first nucleotide analog NS5B polymerase inhibitor with pan-genotypic activity. SOF, administered in combination with ribavirin (RBV) with or without pegylated interferon (PEGIFN) resulted in high SVR rates across genotype (GT) 1-6 patients. It is also the first available regimen for patients that are unsuitable for interferon. This analysis assessed the cost-utility ratio of sofosbuvir in GT2 patients in Japan. RESEARCH DESIGN AND METHODS: A Markov model followed a cohort of 10,000 GT2 patients until patients reached 100 years of age. Approximately 20% of patients initiated treatment at the cirrhotic stage. Comparators were based on the current recommendations in Japan, including PEGIFN with ribavirin (RBV), telaprevir (TVR) in combination with PEGIFN + RBV and no treatment. Costs and outcomes were discounted at 2%. RESULTS: Sofosbuvir was cost-effective across all the studied indications, especially in patients unsuitable for interferon, with incremental cost-effectiveness ratios (ICERs) lower than JPY 5,000,000. Compared to the other treatments included in the analysis, SOF + RBV resulted in improved clinical outcomes. Results were robust to sensitivity analyses. CONCLUSION: SOF combined with RBV was shown to be cost-effective in GT2 patients in Japan. Compared to PEGIFN + RBV, TVR + PEGIFN + RBV and no treatment SOF offers a more efficacious, shorter and better tolerated treatment option and extends treatment to reach HCV-infected patients who are ineligible for interferon-based regimens. Although adverse events were not included in the analyses, this would not make any changes to our conclusion.

Cost-utility analysis of ledipasvir/sofosbuvir for the treatment of genotype 1 chronic hepatitis C in Japan.

OBJECTIVE: Hepatitis C is the result of a ribonucleic acid (RNA) virus (hepatitis C virus; HCV). The Japan Society of Hepatology (JSH) estimated that 1.5-2 million people in Japan carry HCV. Six major HCV genotypes (GT) and a large number of subtypes have been described in the literature. In Japan, around 70% to 80% of people are infected with HCV genotype 1b. The progress of the disease primarily affects the liver and may lead to liver cirrhosis, hepatocellular carcinoma (HCC) and death. Sofosbuvir (SOF) is a nucleotide analogue NS5B inhibitor and ledipasvir (LDV) is an inhibitor of the HCV NS5A protein. They are combined in a single tablet regimen for the treatment of GT1 patients and resulted in sustained virological response (SVR) above 94% in large phase III trials. This analysis assesses the cost-utility of LDV/SOF in GT1 patients in Japan. RESEARCH DESIGN AND METHODS: A cohort of 10,000 patients was followed through a Markov model until they reached 100 years of age. GT1 treatment-naïve and experienced, non-cirrhotic and cirrhotic patients were studied separately. LDV/SOF was compared to several treatment regimens containing pegylated interferon (PEGIFN), telaprevir (TVR), simeprevir (SMV), daclatasvir (DCV), asunaprevir (ASV) and ribavirin (RBV). Discount rates of 2% were applied to costs and outcomes according to the Japanese guidelines. RESULTS: LDV/SOF was cost-effective against most comparators with incremental cost-effectiveness ratios (ICERs) below JPY 5,000,000. By applying a societal perspective, LDV/SOF was the dominant treatment strategy in all cases. Moreover, LDV/SOF reduced the number of cases of advanced liver disease. These results were robust to sensitivity analyses. CONCLUSIONS: LDV/SOF was cost-effective compared to most of the currently recommended treatments. Furthermore, LDV/SOF extends treatments to HCV-infected patients who are ineligible for interferon and RBV-based regimens. LDV/SOF thus has the potential to help reduce the burden of HCV in Japan.