Cost-effectiveness analysis of lemborexant for treating insomnia in Japan: a model-based projection, incorporating the risk of falls, motor vehicle collisions, and workplace accidents.

BACKGROUND: Lemborexant has demonstrated statistically significant improvements in sleep onset and sleep maintenance compared with placebo and zolpidem tartrate extended release, measured both objectively using polysomnography and subjectively using sleep diaries, in the phase 3 clinical trial SUNRISE 1. This study evaluated the cost-effectiveness of lemborexant compared with suvorexant, zolpidem immediate release (IR), and untreated insomnia. METHODS: A decision-tree model was developed for falls, motor vehicle collisions, and workplace accidents associated with insomnia and insomnia treatments from a Japanese healthcare perspective and with a 6-month time horizon. The model extracted subjective sleep onset latency treatment responses and disutility values for non-responders from SUNRISE 1. Cost-effectiveness was assessed using incremental cost per quality-adjusted life year (QALY) gained. One-way and probabilistic sensitivity analyses were conducted to evaluate the impact of parameter uncertainty on the results. RESULTS: In the base-case analysis, the mean estimated QALYs for lemborexant, suvorexant, zolpidem-IR, and untreated insomnia were 0.4220, 0.4204, 0.4113, and 0.4163, and expected medical costs were JPY 34 034, JPY 38 371, JPY 38 139, and JPY 15 383, respectively. Lemborexant saved JPY 4337 and JPY 4105 compared with suvorexant or zolpidem-IR, respectively, while conferring QALY benefits. The incremental cost-effectiveness ratio (ICER) of lemborexant compared with that of untreated insomnia was JPY 3 220 975 /QALY. Lemborexant was dominant over suvorexant and zolpidem-IR and was cost-effective when compared with untreated insomnia. Sensitivity analyses supported the results' robustness. CONCLUSIONS: In a Japanese clinical practice setting, lemborexant may represent a better investment for treating insomnia in the healthcare system in Japan.

Treatment patterns and medical costs after hepatectomy in real-world practice for patients with hepatocellular carcinoma in Japan.

AIM: To examine the treatment patterns and medical costs in real-world practice among patients who received hepatectomy for hepatocellular carcinoma (HCC) in Japan. METHODS: Data of patients who underwent hepatectomy as an initial therapy for primary HCC were extracted from a Japanese medical claims database from April 2008 to December 2019. The types of additional treatments for recurrent HCC and medical costs for up to 3 years from the first hepatectomy were analyzed. The average cumulative cost per patient starting on the date of the first hepatectomy was calculated using the Kaplan-Meier sample-average method. RESULTS: Data from 2 342 patients (median age, 71 years) were analyzed. Overall, 35.6% of patients received at least one HCC treatment within 3 years of the first hepatectomy. The total average cumulative 3-years medical cost was JPY 4 993 300 (95% confidence interval [CI]: 4 804 100 to 5 220 500). Surgical procedures were the most costly components in the first month after hepatectomy, whereas the costs of drugs, which mainly included antiviral and antineoplastic medications, increased thereafter. Patients with advanced stage HCC, hepatitis C, or a higher Charlson Comorbidity Index at hepatectomy, or those who required additional treatment, especially with antineoplastic drugs for recurrent HCC, incurred higher medical costs. CONCLUSIONS: Patients with HCC after hepatectomy experienced a large economic burden, which was more serious for those with advanced stage HCC, higher comorbidities, and hepatitis at baseline and for patients treated with antineoplastic drugs. A treatment selection that considers its medical cost burden would help to reduce some of these economic burdens.

Coding and prescription rates of osteoporosis are low among distal radius fracture patients in Japan.

INTRODUCTION: This study aimed to clarify the coding and prescription rates for osteoporosis in distal radius fracture patients and to investigate the associated factors to help prevent subsequent osteoporotic fracture. MATERIALS AND METHODS: Between 2014-2015, among 294,374 eligible individuals (42% female) aged 50-75 years in a health insurance claims database, we identified 192 individuals (mean age: 59.8 years, 74% female), counted the coding of distal radius fracture (International Statistical Classification of Diseases and Related Health Problems, 10th revision (ICD-10) code: S525, S526), and determined if the patient had been assigned the code for osteoporosis and been prescribed osteoporosis medications. Logistic regression was performed to identify factors related to each rate. RESULTS: The osteoporosis coding rate and osteoporosis medication prescription rate were 17.2% (n = 33) and 10.9% (n = 21), respectively. Most codes were assigned ≤ 3 months after injury (88%) at the distal radius fracture treatment facilities (84.8%). Patients who were assigned the code for osteoporosis or treated with osteoporosis medications were older (p = 0.08, p = 0.02, respectively), female (p = 0.05, p = 0.06, respectively) and having comorbidity (p = 0.02, p = 0.07, respectively). After adjustment, being female and having comorbidity remained the independent factors for the assignment of the code for osteoporosis (OR: 3.30, 95%, CI: 1.08-10.07, OR: 2.77, 95% CI: 1.24-6.12, respectively). No factor remained significant for the osteoporosis prescription. Active vitamin D analogues were most frequently prescribed medication (67%) followed by bisphosphonates (48%). CONCLUSION: The overall coding and prescription rates for osteoporosis after distal radius fracture were low, which suggested that physician adherence to the osteoporosis guideline was low.

The Prevalence and Characteristics of Older Japanese Adults with Polypharmacy, Based on Regionally Representative Health Insurance Claims Data.

We aimed to clarify the prevalence of polypharmacy among elderly individuals in Japan. We used the data obtained from a large-scale population-based representative database of health insurance claims in a single prefecture in Japan. We examined all of the outpatient and pharmaceutical health insurance claims for National Health Insurance and those for Late-stage Elderly Health Insurance in Nagasaki Prefecture, Japan between April and June 2016. When two or more claim forms were issued for a patient in a single month, we combined the data and identified the number of prescribed drugs for each person. The definition of polypharmacy is a the prescription of six or more drugs per month. We investigated the prevalence of polypharmacy among the beneficiaries of the two insurance systems. Of the 605,406 beneficiaries of the 2 insurance systems, 121,033 (20.0%) patients with polypharmacy were identified. The prevalence of polypharmacy increased with age, especially among the beneficiaries aged > 85 years, with about half of the beneficiaries having polypharmacy status. About half of the people aged > 85 years in the database had polypharmacy status. When a drug is prescribed to an elderly individual, it is necessary to consider the possibility of polypharmacy-related problems.

The Prevalence of Duplicate Prescription of Oral Antibiotic Drugs in Outpatient Care among People Insured by Corporate Health Insurance Societies in Japan.

Inappropriate antimicrobial use is a global problem, especially because the use of antimicrobials in excess of appropriate doses is associated with increased antimicrobial resistance. Duplicate prescriptions are an issue contributing to inappropriate antimicrobial use. This study aimed to analyse antibiotic prescriptions during a specific month to examine the frequency of outpatients receiving duplicate antibiotic prescriptions and the associated determinants. Utilizing the Japan Medical Data Centre health insurance claim database, we retrospectively identified 527,110 insured individuals with at least one medicine prescription in October 2014. Data regarding age, gender, antibiotic drug usage, and health insurance status were extracted. Duplicate prescriptions entailed a patient receiving two or more prescriptions of systemic antibiotics from multiple facilities within one month. The risk factors for duplicate antibiotic prescriptions were evaluated using logistic regression analysis. Of the total sample, 131,709 individuals (25.0%) received antibiotics, and 24,529 of these individuals (18.6%) had duplicate prescriptions. Third-generation cephalosporins accounted for the largest proportion of prescriptions (37.4%). Duplicate prescriptions were significantly associated with sex, age, medical facilities, and health insurance status. These findings could help to identify patients at risk of duplicate antibiotic prescriptions, highlighting the need to promote proper antimicrobial use in both patients and medical professionals.

Safety and Efficacy of Lemborexant in Insomnia Patients: Results of a Postmarketing Observational Study of Dayvigo® Tablets.

BACKGROUND AND OBJECTIVE: A prospective, postmarketing observational study was conducted to evaluate the safety and efficacy of lemborexant (LEM) tablets in daily clinical practice in Japan. No other studies of a similar size have been conducted since the marketing approval of LEM, making this the first report of its kind. METHODS: Insomnia patients (n = 550) administered LEM (5-10 mg daily) for the first time were enrolled. Adverse events were collected for target events (somnolence, parasomnia, narcolepsy and associated conditions, suicidal ideation and suicidal behavior). Overall improvement of insomnia symptoms was assessed by the investigator based on the patient's complaint. Subjective sleep onset latency (sSOL) and subjective total sleep time (sTST) were investigated as sleep parameters. RESULTS: A case report form was obtained from 539 patients. The incidence of adverse drug reactions (ADRs) was 7.65% for somnolence, 1.76% for nightmares, 0.59% for abnormal dreams, and 0.20% for sleep paralysis. No serious ADRs or ADRs related to suicidal ideation or suicidal behavior were observed. The efficacy rate at the final evaluation was 80.83%. Decreased sSOL and increased sTST were observed as assessed starting from Week 8 of treatment. CONCLUSION: Based on the results of this study, the safety result was consistent with the safety profile described in the current package insert. Efficacy results also indicated that LEM is clinically useful.

Classification of Hippocampal Ripples: Convolutional Neural Network Learns Episode-Specific Changes.

The hippocampus is known to play an important role in memory by processing spatiotemporal information of episodic experiences. By recording synchronized multiple-unit firing events (ripple firings with 300 Hz-10 kHz) of hippocampal CA1 neurons in freely moving rats, we previously found an episode-dependent diversity in the waveform of ripple firings. In the present study, we hypothesized that changes in the diversity would depend on the type of episode experienced. If this hypothesis holds, we can identify the ripple waveforms associated with each episode. Thus, we first attempted to classify the ripple firings measured from rats into five categories: those experiencing any of the four episodes and those before experiencing any of the four episodes. In this paper, we construct a convolutional neural network (CNN) to classify the current stocks of ripple firings into these five categories and demonstrate that the CNN can successfully classify the ripple firings. We subsequently indicate partial ripple waveforms that the CNN focuses on for classification by applying gradient-weighted class activation mapping (Grad-CAM) to the CNN. The method of t-distributed stochastic neighbor embedding (t-SNE) maps ripple waveforms into a two-dimensional feature space. Analyzing the distribution of partial waveforms extracted by Grad-CAM in a t-SNE feature space suggests that the partial waveforms may be representative of each category.

[Functional Movement Disorders That Do Not Improve after Explaining the Diagnosis: Do Not Treat the Disease, Treat the Patient].

The most important factor in the treatment of functional movement disorders is the initial discussion between the doctor and the patient, wherein the doctor must inform the patient regarding their diagnosis and obtain their consent. To obtain consent, explanations must be tailored to the patient's knowledge. To do so, it is important to know the patient. In this process, psychological factors may be speculated. The rationale for the diagnosis, including test results, should be presented to the patient. Although the choice of future treatment should be left to the patient, the doctor must assure the patient of their continued support until they recover.

Dual-Arm Visuo-Haptic Optical Tweezers for Bimanual Cooperative Micromanipulation of Nonspherical Objects.

Cooperative manipulation through dual-arm robots is widely implemented to perform precise and dexterous tasks to ensure automation; however, the implementation of cooperative micromanipulation through dual-arm optical tweezers is relatively rare in biomedical laboratories. To enable the bimanual and dexterous cooperative handling of a nonspherical object in microscopic workspaces, we present a dual-arm visuo-haptic optical tweezer system with two trapped microspheres, which are commercially available end-effectors, to realize indirect micromanipulation. By combining the precise correction technique of distortions in scanning optical tweezers and computer vision techniques, our dual-arm system allows a user to perceive the real contact forces during the cooperative manipulation of an object. The system enhances the dexterity of bimanual micromanipulation by employing the real-time representation of the forces and their directions. As a proof of concept, we demonstrate the cooperative indirect micromanipulation of single nonspherical objects, specifically, a glass fragment and a large diatom. Moreover, the precise correction method of the scanning optical tweezers is described. The unique capabilities offered by the proposed dual-arm visuo-haptic system can facilitate research on biomedical materials and single-cells under an optical microscope.

Subregional 6-[18F]fluoro-ʟ-m-tyrosine uptake in the striatum in Parkinson's disease.

BACKGROUND: In idiopathic Parkinson's disease (PD) the clinical features are heterogeneous and include different predominant symptoms. The aim of the present study was to determine the relationship between subregional aromatic l-amino acid decarboxylase (AADC) activity in the striatum and the cardinal motor symptoms of PD using high-resolution positron emission tomography (PET) with an AADC tracer, 6-[18F]fluoro-ʟ-m-tyrosine (FMT). METHODS: We assessed 101 patients with PD and 19 healthy volunteers. PD was diagnosed based on the UK Brain Bank criteria by two experts on movement disorders. Motor symptoms were measured with the Unified Parkinson's Disease Rating Scale (UPDRS). FMT uptake in the subregions of the striatum was analyzed using semi-automated software for region-of-interest demarcation on co-registered magnetic resonance images. RESULTS: In all PD patients, FMT uptake was decreased in the posterior putamen regardless of predominant motor symptoms and disease duration. Smaller uptake values were found in the putamen contralateral to the side with more affected limbs. The severity of bradykinesia, rigidity, and axial symptoms was correlated with the decrease of FMT uptake in the putamen, particularly in the anterior part. No significant correlation was observed between tremors and FMT uptake. CONCLUSIONS: Decrease of FMT uptake in the posterior putamen appears to be most sensitive in mild PD and uptake in the anterior putamen may reflect the severity of main motor symptoms, except for tremor.

How can the national burden of Parkinson's disease comorbidity and mortality be estimated for the Japanese population?

BACKGROUND: Good medical care results in long survival for patients with Parkinson's disease (PD). However, little is known about the burden of PD comorbidity and mortality in Japan. This is the first study to examine comorbid diseases of PD decedents and extrapolate PD death rates from multiple-cause coding mortality data for the total population of Japan. METHODS: Data for 4589 certified deaths due to PD as the underlying cause of death (ICD-10 code: G20) were obtained from the 2008 Japanese vital statistics. Of those, comorbidities listed in the death certificates of 477 randomly selected decedents were analyzed. All diseases or conditions mentioned on death certificates were counted and ranked in descending order of frequency. The death rates (per 100,000 population) from PD were calculated using Japanese National Vital Statistics. The estimated rate of deaths with PD was extrapolated using US death data from a multiple-cause coding system, as no such system is available in Japan, with adjustment for the difference in disease structure between countries. RESULTS: Average age at death was 80.9 years. The top 5 comorbid diseases ranked as contributory causes of death were cerebrovascular diseases (4.0%), dementia (3.8%), diabetes mellitus (3.6%), malignant neoplasm (2.5%), and heart diseases (2.3%). Overall, the death rates from and with PD were 3.6 and 5.8, respectively. CONCLUSIONS: Analysis restricted to data from the underlying-cause coding system underestimated the national burden of PD comorbidity and mortality. Use of death certificates and multiple-cause mortality data complement the existing system.

A phase I study of aromatic L-amino acid decarboxylase gene therapy for Parkinson's disease.

Gene transfer of dopamine-synthesizing enzymes into the striatal neurons has led to behavioral recovery in animal models of Parkinson's disease (PD). We evaluated the safety, tolerability, and potential efficacy of adeno-associated virus (AAV) vector-mediated gene delivery of aromatic L-amino acid decarboxylase (AADC) into the putamen of PD patients. Six PD patients were evaluated at baseline and at 6 months, using multiple measures, including the Unified Parkinson's Disease Rating Scale (UPDRS), motor state diaries, and positron emission tomography (PET) with 6-[(18)F]fluoro-L-m-tyrosine (FMT), a tracer for AADC. The short-duration response to levodopa was measured in three patients. The procedure was well tolerated. Six months after surgery, motor functions in the OFF-medication state improved an average of 46% based on the UPDRS scores, without apparent changes in the short-duration response to levodopa. PET revealed a 56% increase in FMT activity, which persisted up to 96 weeks. Our findings provide class IV evidence regarding the safety and efficacy of AADC gene therapy and warrant further evaluation in a randomized, controlled, phase 2 setting.

Impact of the Severity of Alzheimer's Disease on the Quality of Life, Activities of Daily Living, and Caregiving Costs for Institutionalized Patients on Anti-Alzheimer Medications in Japan.

BACKGROUND: Alzheimer's disease (AD) increases societal costs and decreases the activities of daily living (ADL) and quality of life (QoL) of the affected individuals. OBJECTIVE: We assess the impact of AD severity on ADL, QoL, and caregiving costs in Japanese facilities for the elderly. METHODS: Patients with AD in facilities for the elderly were included (47 facilities, N = 3,461). The QoL, ADL, and disease severity of patients were assessed using Barthel Index (BI), EuroQoL-5D-5L (EQ-5D-5L), and Mini-Mental State Examination (MMSE), respectively. Annual caregiving costs were estimated using patients' claims data. The patients were subcategorized into the following three groups according to the MMSE score: mild (21≤MMSE≤30), moderate (11≤MMSE≤20), and severe (0≤MMSE≤10). Changes among the three groups were evaluated using the Jonckheere-Terpstra test. RESULTS: Four hundred and one participants were on anti-AD medicines, of whom 287 (age: 86.1±6.4 years, 76.7% women) in the mild (n = 53, 84.0±6.9 years, 71.7%), moderate (n = 118, 86.6±5.9 years, 76.3%), and severe (n = 116, 86.6±6.5 years, 79.3%) groups completed the study questionnaires. The mean BI and EQ-5D-5L scores for each group were 83.6, 65.1, and 32.8 and 0.801, 0.662, and 0.436, respectively. The mean annual caregiving costs were 2.111, 2.470, and 2.809 million JPY, respectively. As AD worsened, the BI and EQ-5D-5L scores decreased and annual caregiving costs increased significantly. CONCLUSION: AD severity has an impact on QoL, ADL, and caregiving costs.

Postural Abnormality in Parkinson's Disease: A Large Comparative Study With General Population.

BACKGROUND: Postural abnormalities in Parkinson's disease (PD) patients and unimpaired elderly are not well differentiated. Factors related to postural abnormality associated with PD are controversial. OBJECTIVE: We assessed differences in postural change between PD patients and unimpaired elderly and elucidated factors related to abnormal posture in PD patients. METHODS: We measured the dropped head angle (DHA), anterior flexion angle (AFA), and lateral flexion angle (LFA) of the thoracolumbar spine of an unprecedented 1,117 PD patients and 2,732 general population participants (GPPs) using digital photographs. Two statistical analyses were used for elucidating factors related to these angles. RESULTS: In GPPs, age was correlated with DHA, AFA, and LFA. DHAs, AFAs, and LFAs of PD patients and age-matched GPPs were 21.70° ± 14.40° and 13.13° ± 10.79°, 5.98° ± 12.67,°and - 3.82° ± 4.04°, and 0.86° ± 4.25° and 1.33° ± 2.16°, respectively. In PD patients, factors related to DHA were age, male sex, and H & Y stage during ON time. Factors related to AFA were age, duration of disease, H & Y stage during ON and OFF times, pain, vertebral disease, and bending to the right. A factor related to LFA was AFA. CONCLUSIONS: DHA and AFA of GGPs correlated with age and were larger in PD patients than those with in GPPs. Some PD patients showed angles far beyond the normal distribution. Thus, factors associated with disease aggravation affected postural abnormality in PD patients.

GCH1 mutations in dopa-responsive dystonia and Parkinson's disease.

Guanosine triphosphate cyclohydrolase I (GCH1) mutations are associated with increased risk for dopa-responsive dystonia (DRD) and Parkinson's disease (PD). Herein, we investigated the frequency of GCH1 mutations and clinical symptoms in patients with clinically diagnosed PD and DRD. We used the Sanger method to screen entire exons in 268 patients with PD and 26 patients with DRD, with the examinations of brain magnetic resonance imaging scans, striatal dopamine transporter scans, and [123I] metaiodobenzylguanidine (MIBG) myocardiac scintigraphy scans. We identified 15 patients with heterozygous GCH1 mutations from seven probands and five sporadic cases. The prevalence of GCH1 mutations in probands was different between PD [1.9% (5/268)] and DRD [26.9% (7/26)] (p value < 0.0001). The onset age tends to be different between PD and DRD patients: 35.4 ± 25.3 and 16.5 ± 13.6, respectively (average ± SD; p = 0.08). Most of the patients were women (14/15). Dystonia was common symptom, and dysautonomia and cognitive decline were uncommon in our PD and DRD. All patients presented mild parkinsonism or dystonia with excellent response to levodopa. Seven of seven DRD and three of five PD presented normal heart-to-mediastinum ratio on MIBG myocardial scintigraphy. Five of six DRD and three of four PD demonstrated normal densities of dopamine transporter. Our findings elucidated the clinical characteristics of PD and DRD patients due to GCH1 mutations. PD patients with GCH1 mutations also had different symptoms from those seen in typical PD. The patients with GCH1 mutations had heterogeneous clinical symptoms.

Persistent Expression of Dopamine-Synthesizing Enzymes 15 Years After Gene Transfer in a Primate Model of Parkinson's Disease.

Restoring dopamine production in the putamen through gene therapy is a straightforward strategy for ameliorating motor symptoms for Parkinson's disease (PD). In a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) toxicity-based primate model of PD, we previously showed the safety and efficacy of adeno-associated viral (AAV) vector-mediated gene delivery to the putamen of three dopamine-synthesizing enzymes (tyrosine hydroxylase [TH], aromatic l-amino acid decarboxylase [AADC], and guanosine triphosphate cyclohydrolase I [GCH]) up to 10 months postprocedure. Although three of four monkeys in this study have previously undergone postmortem analysis, one monkey was kept alive for 15 years after gene therapy to evaluate long-term effects. Here, we report that this monkey showed behavioral recovery in the right-side limb that remained unchanged for 15 years, at which time euthanasia was carried out owing to onset of senility. Immunohistochemistry of the postmortem brain from this monkey revealed persistent expression of TH, AADC, and GCH genes in the lesioned putamen. Transduced neurons were broadly distributed, with the estimated transduction region occupying 91% of the left postcommissural putamen. No signs of cytotoxicity or Lewy body pathology were observed in the AAV vector-injected putamen. This study provides evidence of long-term safety and efficacy of the triple-transduction method as a gene therapy for PD.

Dropped head in Parkinson's disease.

"A propensity to bend the trunk forward" and "the chin is now almost immovably bent down upon the sternum" were described by James Parkinson in patients with Parkinson's disease (PD). The term "dropped head" was first reported in "Gerlier disease" in Switzerland and 'kubisagari' in Japan and since then also reported in myositis, myopathy, myasthenia gravis, amyotrophic lateral sclerosis, neuropathy, and hypothyroidism. Disproportionate antecollis occurs in about half cases of multiple system atrophy (MSA) and is considered dystonic in nature. Dropped head is considered rare in PD, both in advanced and early stages of PD. However, it is known to progress subacutely over a period of several days. In my experience, dropped head is relatively common in PD. The mechanism of dropped head in PD is either dystonia of flexor neck muscles or weakness of extensor neck muscles. The response of dropped head to various anti-parkinsonian medications is rather inconsistent. Levodopa is reported to induce amelioration in some patients while dopamine agonists can cause deterioration. Muscle afferent block with lidocaine and ethanol is reported to be effective, while the effect of botulinum toxin injection into the affected muscles is limited. The effect of stereotaxic neurosurgery on dropped head is controversial. Early diagnosis and prompt treatment is necessary to prevent muscle damage associated with longterm overstretch of extensor neck muscles.