Strategies for Medical Device Development: User and Stakeholder Perceptions.

Medical device development involves user safety, and it is governed by specific regulations. The failure of medical device developers to consider the influence of users, the environment, and related organizations on product development during the design and development process can result in added risks to the use of medical technologies. Although many studies have examined the medical device development process, there has been no systematic and comprehensive assessment of the key factors affecting medical device development. This research synthesized the value of medical device industry stakeholders' experiences through a literature review and interviews with industry experts. Then, it establishes an FIA-NRM model to identify the key factors affecting medical device development and suggests appropriate pathways for improvement. Results indicate that the development of medical devices should begin with stabilizing organizational characteristics, followed by strengthening technical capability and use environment, and finally, consideration should be given to the user action of medical devices. The results provide medical device developers with optimal development pathways and resource allocation recommendations to support developers in developing medical device development strategies as well as ensuring the safety and effectiveness of the products for end users.

Clinical benefit of second-generation long-acting injectable antipsychotics in preventing re-hospitalization in patients with schizophrenia: A real-world study in Japan.

BACKGROUND: Real-world evidence on the benefits of long-acting injectable (LAI) antipsychotics (AP) in patients with schizophrenia is limited, especially in the employed population in Japan. This study evaluates the effectiveness of LAI AP in preventing re-hospitalization in patients with schizophrenia, including the employed population. METHODS: This retrospective, observational, population-based study used the Japan Medical Data Center (JMDC) health insurance claims database to identify patients having schizophrenia before or on the day of the first LAI AP prescription (index date), and receiving LAI AP between April 1, 2012 and December 31, 2019. The number of all-cause, psychiatric-, and schizophrenia-related hospitalizations at baseline (365 days before index date) and during the 1-year follow-up period were evaluated. RESULTS: Of the 1692 patients who received LAI AP during the study period, 146 were included (employed: 55 [37.7 %]; dependent: 91 [62.3 %]). The mean age was 37 years; 50.7 % (n = 74) were females. During baseline period, 61 (41.8 %) patients were not hospitalized. During the follow-up period, 67 (45.9 %) patients underwent hospitalization ≤ 7 days; all-cause: 100 (68.7 %); psychiatry-related: 104 (76.2 %); schizophrenia-related: 114 (78.1 %). A higher proportion of patients were hospitalization-free during the follow-up in the employed vs. dependent population: all cause: 69.1 % vs. 61.5 %; psychiatric-related 76.4 % vs. 67.0 %, schizophrenia-related: 87.3 % vs. 71.4 %. CONCLUSION: This study demonstrated the effectiveness of LAI AP in preventing hospitalization in Japan. During the follow-up period, patients with schizophrenia receiving LAI AP, including the employed population, had a significant decrease in hospitalization length and re-hospitalization rate compared to baseline.

Impact of sensor data pre-processing strategies and selection of machine learning algorithm on the prediction of metritis events in dairy cattle.

With all the sensor data currently generated at high frequency in dairy farms, there is potential for earlier diagnosis of postpartum diseases compared with traditional monitoring methodologies. Our objectives were 1) to compare the impact of sensor data pre-processing on classifier performance by using multiple time windows before a given metritis event, while considering other cow-level factors and farm-scheduled activities; 2) to compare the performance of random forest (RF), k-nearest neighbors (k-NN), and support vector machine (SVM) classifiers at different decision thresholds using different number of past observations (time-lags) for the detection of behavioral patterns associated with changes in metritis scores; and 3) to compare classifier performance between each one of the five behaviors registered every hour by an ear-tag 3-axis accelerometer (CowManager, Agis Autimatisering, Harmelen, Netherlands). A total of 239 metritis events were created by comparing metritis scores between two consecutive clinical evaluations from cows that were retrospectively selected from a dataset containing sensor data and health information during the first 21 days postpartum from June 2014 to May 2017. Hourly sensor data classified by the accelerometer as either ruminating, eating, not active (including both standing or lying), and two different levels of activity (active and high activity) behaviors corresponding to the 3 days before each metritis event were aggregated every 24-, 12-, 6-, and 3-hour time windows. Multiple time-lags were also used to determine the optimal number of past observations needed for optimal classification. Similarly, different decision thresholds were compared in terms of model performance. Depending on the classifier, algorithm hyperparameters were optimized using grid search (RF, k-NN, SVM) and random search (RF). All behaviors changed throughout the study period and showed distinct daily patterns. From the three algorithms, RF had the highest F1 score followed by k-NN and SVM. Furthermore, sensor data aggregated every 6- or 12-h time windows had the best model performance at multiple time-lags. We concluded that the data from the first 3 days post-partum should be discarded when studying metritis, and either one of the five behaviors measured with CowManager could be used when predicting metritis when sensor data were aggregated every 6- or 12-hour time windows, and using time-lags corresponding to 2-3 days before a given event, depending on the time window used. This study shows how to maximize sensor data in their potential for disease prediction, enhancing the performance of algorithms used in machine learning.

Weighting the relative importance of behaviors affecting gait score.

This research communication evaluates experts' opinions on the importance and weights of six gait aspects. In 2016, a Qualtrics (Qualtrics LLC., Provo, Utah) survey was distributed to lameness experts. Six gait aspects - general symmetry, tracking, spine curvature, head bobbing, speed and abduction as well as adduction were included. Respondents were asked to rank the gait aspects from 1 (most important) to 6 (least important), and to indicate which weight each gait aspect should receive when assessing lameness. For each gait aspect, frequency (percentage %) was used to describe the distribution of rank, and medians as well as 25th and 75th percentiles were used to summarize assigned weights. Thirty-nine percent of respondents ranked general symmetry first, followed by 32% for tracking, and 19% ranked spine curvature third. Head bobbing ranked fourth with 10% whereas, speed, abduction and adduction were not ranked. The median, 25th and 75th percentiles weight for each gait aspect were: general symmetry (25, 15, and 30), tracking (20, 10, and 30), spine curvature (20, 10, and 21), head bobbing (15, 10, and 20), speed (10, 5, and 20), and abduction and adduction (10, 5, and 10). General symmetry and tracking were deemed the most important gait aspects. A composite gait score can be calculated based on weighted importance of different gait aspects to indicate possible lameness.

Systemic Lupus Erythematosus: Targeted Literature Review of the Epidemiology, Current Treatment, and Disease Burden in the Asia Pacific Region.

OBJECTIVE: To understand the epidemiology, current treatment, and disease burden of systemic lupus erythematosus (SLE) in the Asia Pacific (APAC) region. METHODS: A targeted literature review of published evidence on SLE in the APAC region was conducted, using the Medline database (2008-2018), conference proceedings, and other supplementary sources. RESULTS: The current review identified 70 studies conducted in China (n = 15), Japan (n = 13), Taiwan (n = 12), Korea (n = 9), Australia (n = 7), Hong Kong (n = 6), Singapore (n = 4), and multiple places within the APAC region (n = 4). Incidence rates (per 100,000 persons per year) ranged from 0.9-8.4, while prevalence rates ranged from 3.7-127 (per 100,000 persons); however, recent data were limited. Asian patients with SLE were reported to have higher disease severity, disease activity (higher SLE disease activity index scores), and organ damage accrual, along with increased morbidity, mortality, and susceptibility to renal involvement compared with other ethnicities in the APAC region. The risk of developing SLE is higher in the Asian population. Routinely used SLE therapies included belimumab, hydroxychloroquine, cyclophosphamide, tacrolimus, azathioprine, mycophenolate mofetil, and glucocorticoids; however, prescribing patterns varied across the region. Increased disease activity was associated with high economic burden and poor quality of life for SLE patients in the APAC region. CONCLUSION: SLE remains a disease with a significant unmet medical need for an innovative therapy that is well-tolerated and effective for patients in the APAC region. Further evidence is required to better characterize the disease and fully capture the burden and impact of SLE in the APAC region. This review has highlighted where there is a paucity of data from patients across the APAC region.

The chondroitin sulfate moiety mediates thrombomodulin-enhanced adhesion and migration of vascular smooth muscle cells.

BACKGROUND: Thrombomodulin (TM), a transmembrane glycoprotein highly expressed in endothelial cells (ECs), is a potent anticoagulant maintaining circulation homeostasis. Under inflammatory states, TM expression is drastically reduced in ECs while vascular smooth muscle cells (VSMCs) show a robust expression of TM. The functional role of TM in VSMCs remains elusive. METHODS: We examined the role of TM in VSMCs activities in human aortic VSMCs stimulated with platelet-derived growth factor-BB (PDGF-BB). Using rat embryonic aorta-derived A7r5 VSMCs which do not express TM, the role of the chondroitin sulfate (CS) moiety of TM in VSMCs was delineated with cells expressing wild-type TM and the CS-devoid TM mutant. RESULTS: Expression of TM enhanced cell migration and adhesion/spreading onto type I collagen, but had no effect on cell proliferation. Knocking down TM with short hairpin RNA reduced PDGF-stimulated adhesion and migration of human aortic VSMCs. In A7r5 cells, TM-mediated cell adhesion was eradicated by pretreatment with chondroitinase ABC which degrades CS moiety. Furthermore, the TM mutant (TMS490, 492A) devoid of CS moiety failed to increase cell adhesion, spreading or migration. Wild-type TM, but not TMS490, 492A, increased focal adhesion kinase (FAK) activation during cell adhesion, and TM-enhanced cell migration was abolished by a function-blocking anti-integrin ß1 antibody. CONCLUSION: Chondroitin sulfate modification is required for TM-mediated activation of ß1-integrin and FAK, thereby enhancing adhesion and migration activity of VSMCs.

Reactive oxygen species derived from NADPH oxidase 1 and mitochondria mediate angiotensin II-induced smooth muscle cell senescence.

Cellular senescence has emerged as an important player in both physiology and pathology. Excessive reactive oxygen species (ROS) is known to mediate cellular senescence. NADPH oxidases are major sources for ROS production in the vascular wall; the roles of different NADPH oxidase isoforms in cellular senescence remain unclear, however. We investigated the roles of two NADPH oxidase isoforms in mitochondrial dysfunction during angiotensin II (Ang II)-induced cellular senescence of human aortic vascular smooth muscle cells (VSMCs). Ang II (10(-7)M) stimulated ROS generation, exhibiting early increases between 30 and 60min and sustained increases between 24h and 72h, and induced VSMCs senescence after 48h or 72h treatment as assessed with senescence-associated ß-galactosidase activity and the expression of two cell cycle inhibitors, p21 and p16. ROS scavengers and membrane-permeable catalase (catalase-PEG) reduced Ang II-stimulated cellular senescence. Furthermore, small interfering RNA (siRNA) of NADPH oxidase catalytic subunit Nox1, but not that of another isoform Nox4, inhibited Ang II-induced cellular senescence. Nox1 siRNA inhibited both early and sustained ROS increases induced by Ang II. In addition, a mitochondrial-specific antioxidant, mitoQ10, effectively inhibited Ang II-induced ROS increases and cellular senescence. Ang II decreased ATP synthesis and induced mitochondrial membrane depolarization, which were attenuated by pre-treating cells with Nox1 siRNA, mitoQ10 or catalase-PEG. The effect of Ang II on the mitochondrial regulator peroxisome-proliferator-activated receptor gamma coactivator-1α (PGC-1α) and its downstream genes was examined. Ang II stimulated S570 phosphorylation of PGC-1α with concomitant decreases in catalase and uncoupling protein-2 (UCP-2) levels between 12h and 72h, which were inhibited by Nox1 siRNA. Knockdown of both catalase and UCP-2 mimicked Ang II-induced VSMC senescence. These results suggested that Ang II-stimulated Nox1 activation mediates mitochondrial dysfunction, probably by decreasing PGC-1α activity and increasing mitochondrial oxidative stress, and leads to cellular senescence of VSMCs.

ROS-mediated downregulation of MYPT1 in smooth muscle cells: a potential mechanism for the aberrant contractility in atherosclerosis.

Reactive oxygen species (ROS) mediates the aberrant contractility in hypertension. Abnormal contractility occurs in atherosclerotic vessels but changes in proteins that regulate contractility remain poorly understood. Myosin phosphatase (MP) activity, which regulates smooth muscle relaxation, is regulated by the phosphorylation of its regulatory subunit, MP targeting subunit 1 (MYPT1). In the present study, we examined the roles of ROS in MP subunit expression both in cultured human aortic smooth muscle cells (HASMCs) and during atherosclerosis progression in apolipoprotein E-knockout (apoE-KO) mice. Furthermore, the effect of decreased MYPT1 on actin cytoskeleton and cell migration activity was assessed in HASMCs. Short hairpin RNA-mediated knockdown of MYPT1 increased stress fibers and attenuated platelet-derived growth factor-induced cell migration in HASMCs. Superoxide anion-inducing agent LY83583 downregulated MYPT1 mRNA and protein levels, but did not affect the phosphorylation of MYPT1 and catalytic subunit of MP, PP1δ. The LY83583-induced decrease in MYPT1 was abolished by co-treating with superoxide dismutase or by inhibiting NADPH oxidase with diphenyleneiodonium. Treatment of peroxynitrite, but not hydrogen peroxide (H2O2), downregulated MYPT1 protein expression and induced MYPT1 phosphorylation without affecting mRNA levels. Co-treatment with a proteasome inhibitor, MG-132, eliminated peroxynitrite-induced MYPT1 downregulation. In apoE-KO mice, MYPT1 protein, but not mRNA, levels were markedly decreased in 16-week- and 24-week-old mice. Oral estrogen treatment, which was previously shown to decrease aortic ROS levels, upregulated aortic MYPT1 expression. Moreover, reduction in MYPT1 expression correlated with increased aortic sensitivity toward vasoconstrictors. These results suggested that during atherosclerosis progression oxidative stress mediates the downregulation of MYPT1, which may inhibit smooth muscle cell migration and contribute to the aberrant contractility.

Costs of cervical cancer and precancerous lesions treatment in a publicly financed health care system.

PURPOSE: Although cervical cancer is the most frequent cancer for women in Taiwan, no examination of its treatment costs has yet been undertaken. This study aimed to investigate the costs of cervical cancer and precancerous lesion treatment in Taiwan. METHODS: A total of 7,398 cases of cervical intraepithelial neoplasia (CIN) lesions were identified from the Taiwan Cervical Cancer Screening Registration System in 2003. A further 1,469 cases of invasive cervical cancer (ICC) were also identified from a survey on cervical cancer staging information conducted by the Taiwan Cancer Registration Task Force. Resource usage covering the first 6 months after CIN diagnosis and the 5 years after ICC diagnosis were extracted from the National Health Insurance claims database. The duration of each visit and the transportation costs were collected by means of personal interviews with CIN/ICC patients. The mean and standard deviation of the treatment and indirect costs were estimated. RESULTS: The average total costs for CIN patients were NT$4,201 for CIN1, NT$8,623 for CIN2 and NT$14,406 for CIN3, with the indirect costs accounting for 25-33% of the total. The total costs for ICC patients were NT$210,230 for Stage 1, NT$392,387 for Stage 2, NT$433,969 for Stage 3 and NT$464,701 for Stage 4, with the indirect costs accounting for about 14-17% of the total. CONCLUSIONS: CIN and ICC treatment resulted in considerable costs to the healthcare system in Taiwan. Indirect costs associated with such treatment were also substantial and cannot be ignored.