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Background: Tui Na (Chinese massage) is a relatively simple, inexpensive, and non-invasive intervention, and has been used to treat stroke patients for many years in China. Tui Na acts on specific parts of the body which are called meridians and acupoints to achieve the role of treating diseases. Yet the underlying neural mechanism associated with Tui Na is not clear due to the lack of detection methods., Objective: Functional near-infrared spectroscopy (fNIRS) was used to explore the changes of sensorimotor cortical neural activity in patients with upper limb motor dysfunction of stroke and healthy control groups during Tui Na Hegu Point., Methods: Ten patients with unilateral upper limb motor dysfunction after stroke and eight healthy subjects received Tui Na. fNIRS was used to record the hemodynamic data in the sensorimotor cortex and the changes in blood flow were calculated based on oxygenated hemoglobin (Oxy-Hb), the task session involved repetitive Tui Na on Hegu acupoint, using a block design [six cycles: rest (20 seconds); Tui Na (20 seconds); rest (30 seconds)]. The changes in neural activity in sensorimotor cortex could be inferred according to the principle of neurovascular coupling, and the number of activated channels in the bilateral hemisphere was used to calculate the lateralization index., Result: 1. For hemodynamic response induced by Hegu acupoint Tui Na, a dominant increase in the contralesional primary sensorimotor cortex during Hegu point Tui Na of the less affected arm in stroke patients was observed, as well as that in healthy controls, while this contralateral pattern was absent during Hegu point Tui Na of the affected arm in stroke patients. 2. Concerning the lateralization index in stroke patients, a significant difference was observed between lateralization index values for the affected arm and the less affected arm (P < 0.05). Wilcoxon tests showed a significant difference between lateralization index values for the affected arm in stroke patients and lateralization index values for the dominant upper limb in healthy controls (P < 0.05), and no significant difference between lateralization index values for the less affected arm in stroke patients and that in healthy controls (P = 0.36)., Conclusion: The combination of Tui Na and fNIRS has the potential to reflect the functional status of sensorimotor neural circuits. The changes of neuroactivity in the sensorimotor cortex when Tui Na Hegu acupoint indicate that there is a certain correlation between acupoints in traditional Chinese medicine and neural circuits., (© 2023. BioMed Central Ltd., part of Springer Nature.)

Objectives: Thrombin generation assays and activated partial thromboplastin time (aPTT)-based clot waveform analysis (CWA), are some examples of global coagulation assays. Each modality evaluates different aspects of the clot forming process to globally define haemostasis with exclusive measurement parameters. Data on CWA are emerging, but its performance against other haemostatic assays is yet to be ascertained. This study evaluates the correlation between aPTT-based CWA and CAT parameters across a range of INR in warfarin-treated patients., Patients/methods: A prospective study consisting of patients on warfarin anticoagulation with varying INR levels. CWA and CAT were performed for the study subjects., Results: 54 samples were included covering an INR range from 1.33-6.89, with a mean of 4.31 +/- 1.13. For CAT parameters, endogenous thrombin potential (ETP) and peak thrombin were assessed. Both unadjusted and adjusted (adjusted for final plateau transmittance) aPTT-based CWA were evaluated for parameters min1 (maximum velocity), min2 (maximum acceleration) and max2 (maximum deceleration). Peak thrombin showed significant correlation with all CWA parameters (min1: r = 0.435, P <0.001; min2: r = 0.485, P <0.001; max2: r = 0.578, P <0.001; adjusted min1: r = 0.734, P <0.001, adjusted min2: r = 0.693, P <0.001; adjusted max2: r = 0.751, P <0.001). ETP correlated significantly with all CWA parameters except unadjusted min1 (min1: r = 0.235, P  = 0.087; min2: r = 0.326, P  = 0.016; max2: r = 0.437, P <0.001; adjusted min1: r = 0.610, P <0.001, adjusted min2: r = 0.563, P <0.001; adjusted max2: r = 0.642, P <0.001)., Conclusion: We demonstrated a modest correlation between CAT and CWA parameters. Adjusted CWA improved this correlation. These findings provide additional understanding of CWA and it's role in the evaluation of global haemostatic function.

Upper limb motor dysfunction after stroke is a serious threat to the living quality of patients and their families. Recovery of upper limb motor function after stroke largely relies on the activation and remodeling of neural circuits. rTMS (repetitive transcranial magnetic stimulation) has been proved to promote the reconstruction of neural synapses and neural circuits. However, there are still a large number of patients who cannot fully recover and leave behind varying degrees of dysfunction. Considering the systemic pathology after stroke, in addition to focal brain injury, stroke can also cause extensive dysfunction of peripheral organs. The rehabilitation strategy for stroke should combine the treatment of primary brain lesions with the intervention of secondary systemic damage. The aim of this trial is to verify the efficacy of rTMS synergize with Tui Na (Chinese Massage) on upper limb motor function after ischemic stroke, and to explore the mechanism of activation and remodeling of sensorimotor neural circuits with functional near-infrared spectroscopy. Ninety patients will be randomly assigned to either rTMS + Tui Na + conventional rehabilitation group (the experimental group) or rTMS + conventional rehabilitation group (the control group) in 1:1 ratio. Intervention is conducted five sessions a week, with a total of twenty sessions. The primary outcome is Fugl-Meyer Assessment, and the secondary outcomes include Muscle Strength, Modified Ashworth Assessment, Modified Barthel Index Assessment, motor evoked potentials and functional near-infrared spectroscopy. There are four time points for the evaluation, including baseline, 2 weeks and 4 weeks after the start of treatment, and 4 weeks after the end of treatment. This study is a randomized controlled trial. This study was approved by Institutional Ethics Committee of Shanghai Third Rehabilitation Hospital Affiliated to Shanghai University of Traditional Chinese Medicine (approval No. SH3RH-2021-EC-012) on December, 16th, 2021. The protocol was registered with Chinese Clinical Trial Registry (ChiCTR2200056266), on February 3th, 2022. Patient recruitment was initiated on February 10th, 2022, and the study will be continued until December 2023., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Chen, Zhu, Mao, Zheng, Huang, Liu, Chen, Cao and Xu.)

Preeclampsia (PE) is a pregnancy complication characterized by severe hypertension and multiple organ damage. Gut microbiota has been linked to PE by previous amplicon sequencing studies. To resolve the PE gut microbiota in a higher taxonomy resolution, we performed shotgun metagenomic sequencing on the fecal samples from 40 early-onset PE and 37 healthy pregnant women. We recovered 1,750 metagenome-assembled genomes (representing 406 species) from the metagenomic dataset and profiled their abundances. We found that PE gut microbiota had enriched in some species belonging to Blautia , Pauljensenia , Ruminococcus , and Collinsella and microbial functions such as the bacitracin/lantibiotics transport system, maltooligosaccharide transport system, multidrug efflux pump, and rhamnose transport system. Conversely, the gut microbiome of healthy pregnant women was enriched in species of Bacteroides and Phocaeicola and microbial functions including the porphyrin and chlorophyll metabolism, pyridoxal-P biosynthesis, riboflavin metabolism, and folate biosynthesis pathway. PE diagnostic potential of gut microbial biomarkers was developed using both species and function profile data. These results will help to explore the relationships between gut bacteria and PE and provide new insights into PE early warning., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lv, Li, Wen, Wang, Li, He, Lv, Xiao, Duan, Chen, Yi, Yan and Yin.)

Recovering and distinguishing different ionospheric layers and signals usually requires slow and complicated procedures. In this work, we construct and train five convolutional neural network (CNN) models: DeepLab, fully convolutional DenseNet24 (FC-DenseNet24), deep watershed transform (DWT), Mask R-CNN, and spatial attention-UNet (SA-UNet) for the recovery of ionograms. The performance of the models is evaluated by intersection over union (IoU). We collect and manually label 6131 ionograms, which are acquired from a low-latitude ionosonde in Taiwan. These ionograms are contaminated by strong quasi-static noise, with an average signal-to-noise ratio (SNR) equal to 1.4. Applying the five models to these noisy ionograms, we show that the models can recover useful signals with IoU > 0.6. The highest accuracy is achieved by SA-UNet. For signals with less than 15% of samples in the data set, they can be recovered by Mask R-CNN to some degree (IoU > 0.2). In addition to the number of samples, we identify and examine the effects of three factors: (1) SNR, (2) shape of signal, (3) overlapping of signals on the recovery accuracy of different models. Our results indicate that FC-DenseNet24, DWT, Mask R-CNN and SA-UNet are capable of identifying signals from very noisy ionograms (SNR < 1.4), overlapping signals can be well identified by DWT, Mask R-CNN and SA-UNet, and that more elongated signals are better identified by all models.

The technique of active ionospheric sounding by ionosondes requires sophisticated methods for the recovery of experimental data on ionograms. In this work, we applied an advanced algorithm of deep learning for the identification and classification of signals from different ionospheric layers. We collected a dataset of 6131 manually labeled ionograms acquired from low-latitude ionosondes in Taiwan. In the ionograms, we distinguished 11 different classes of the signals according to their ionospheric layers. We developed an artificial neural network, FC-DenseNet24, based on the FC-DenseNet convolutional neural network. We also developed a double-filtering algorithm to reduce incorrectly classified signals. That made it possible to successfully recover the sporadic E layer and the F2 layer from highly noise-contaminated ionograms whose mean signal-to-noise ratio was low, SNR = 1.43. The Intersection over Union (IoU) of the recovery of these two signal classes was greater than 0.6, which was higher than the previous models reported. We also identified three factors that can lower the recovery accuracy: (1) smaller statistics of samples; (2) mixing and overlapping of different signals; (3) the compact shape of signals.

Background: Previous studies have shown that BD patients exhibited impairment when performing a verbal fluency task (VFT) and abnormal prefrontal cortex activation during this task. However, no study has specifically examined whether patients with type II BD demonstrate difficulty in performing VFT and impairments in relevant neural correlates or whether these are related to psychotic symptoms, the present study aimed to examine these issues., Methods: Forty-nine patients with type II BD (21 patients with psychotic symptoms [BDIIp] and 28 patients without psychotic symptoms [BDIIn]) and 45 matched healthy controls (HCs) participated the study and completed the VFTs, while their brain activity was recorded with near-infrared spectroscopy (NIRS)., Results: Both BDIIp and BDIIn patients showed poorer performance on VFTs than HCs. In addition, BDII patients showed lower brain activation than HCs in bilateral dorsolateral prefrontal cortex and right frontal pole, these results were mainly driven by BDIIn patients. Moreover, subjective psychotic symptoms were positively significantly correlated with left dorsolateral prefrontal cortex activation in BDII patients., Conclusions: Type II BD patients showed significant impairment when performing VFTs and reduced activation in the prefrontal cortex, and subjective psychotic symptoms were associated with brain activation in left dorsolateral prefrontal cortex in BDII patients., (Copyright © 2021. Published by Elsevier B.V.)

Background: Imbalances in gut microbiota composition are linked to hypertension, host metabolic abnormalities, systemic inflammation, and other conditions. In the present study, we examined the changes of gut microbiota in women with early-onset preeclampsia (PE) and in normotensive, uncomplicated pregnant women during late pregnancy and at 1 and 6 weeks postpartum. Methods: Gut microbiota profiles of women with PE and healthy pregnant women in the third trimester and at 1 and 6 weeks postpartum were assessed by 16S rRNA gene amplicon sequencing. Plasma levels of interleukin-6 (IL-6), intestinal fatty acid-binding protein (I-FABP), zonulin, and lipopolysaccharide (LPS) were measured in the third trimesters. Results: At the genus level, 8 bacterial genera were significantly enriched in the antepartum samples of PE patients compared to healthy controls, of which Blautia, Ruminococcus2, Bilophila , and Fusobacterium represented the major variances in PE microbiomes. Conversely, 5 genera, including Faecalibacterium, Gemmiger, Akkermansia, Dialister , and Methanobrevibacter , were significantly depleted in antepartum PE samples. Maternal blood pressure and liver enzyme levels were positively correlated to the PE-enriched genera such as Anaerococcus, Ruminococcus2, Oribacterium , and Bilophila , while the fetal features (e.g., Apgar score and newborn birth weight) were positively correlated with PE-depleted genera and negatively correlated with PE-enriched genera. Moreover, maternal blood IL-6 level was positively associated with gut Bilophila and Oribacterium , whereas LPS level was negatively associated with Akkermansia . In terms of postpartum women, both the gut microbial composition and the PE-associated microbial alterations were highly consistent with those of the antepartum women. Conclusion: PE diagnosed in the third trimester of pregnancy is associated with a disrupted gut microbiota composition compared with uncomplicated pregnant women, which are associated with maternal clinical features (blood pressure level and liver dysfunction) and newborn birth weight. Moreover, these antepartum alterations in gut microbiota persisted 6 weeks postpartum.

Competing Interests: Competing interests: None declared.

Background and Purpose: High fidelity human patient simulation (HPS) has been incorporated in various United States doctor of pharmacy programs with favorable learning experiences, knowledge retention, and problem-solving skills reported. In Singapore, HPS is a novel learning technique as it has not been utilized in the Bachelor of Science (Pharmacy) curriculum or for continuing professional education (CPE). It is necessary to evaluate acceptance of HPS compared to asynchronous online learning (AOL)., Educational Activity and Setting: Nineteen participants from two institutions completed the study in Singapore. This was an experimental study design with participants randomized into groups A and B. Group A completed AOL followed by HPS, whereas group B completed them in reverse order. Acceptance of teaching modalities was evaluated with a Likert scale survey and analyzed with Fisher's exact test. Educational content was congestive heart failure and was evaluated externally for equivalency., Findings: All participants enjoyed the HPS activity compared to 13 (68.4%; p = 0.02) for AOL. Eighteen (94.7%) and 15 (78.9%; p = 0.34) participants felt that HPS activity and AOL improved their critical and decision-making skills respectively. Sixteen (84.2%) and 17 (89.5%) agreed that AOL and HPS activity improved their confidence (p = 1.00)., Discussion: Participants enjoyed HPS activity significantly more than AOL. HPS activity could be used to achieve improved critical and decision-making skills of learners as there was a trend of more learners perceiving improvement compare to AOL., Summary: High fidelity HPS learning was well received by participants in Singapore and can be implemented in CPE., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Hyperkalaemic periodic paralysis is a rare skeletal muscle disorder which is characterised by episodic muscle paralysis associated with hyperkalaemia. Although it is an autosomal-dominant disease, cases of de novo mutations have been reported. We report the case of a 30-year-old woman, gravida 5 para 3+1, who was planned for an elective repeated caesarean section at 38 weeks and 3 days of pregnancy. She developed recurrent episodes of hyperkalaemic periodic paralysis after receiving corticosteroids. Intravenous calcium gluconate was administered to normalise potassium levels (from 6.3 mmol/L to 4.1 mmol/L). Extra anaesthetic precautions were taken during the caesarean delivery. Postoperatively, she was well and discharged from the ward. She encountered similar symptoms in her third pregnancy, and there was no family history of muscle weakness which suggested a de novo mutation. Pregnancy seemed to result in vulnerability to hyperkalaemic attacks as she was never symptomatic outside pregnancy., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Ltd (unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Strategies to prevent mortality from obstetric venous thromboembolism begin with identification, risk stratification and subsequently, implementation of prophylactic measures. We sought to identify the burden of pharmacologic thromboprophylaxis in postpartum women, including the main clinical indications and its uptake in a multireligious population, with Islam as the official religion. A total of 2514 deliveries between 1st January to 31st December 2016, across three centres in Malaysia were reviewed retrospectively from hospital-based registries. 770 (30.62%) patients fulfilled the criteria for thromboprophylaxis based on the revised 2015 criteria proposed by the Royal College of Obstetricians and Gynaecologists. A combination of age, parity, BMI, caesarean section and preterm births were the main indications. One out of the five patients who delivered vaginally required thromboprophylaxis. In our setting with a sizable Muslim population, low molecular weight heparin was the thromboprophylaxis of choice in more than two-third of the patients. The information obtained from this study allows better local resource planning. Impact statement What is already known on this subject: Risk factors for venous thromboembolism in pregnancy and puerperium are largely drawn from registries due to the rarity of the index event. Up to 7% of women require antenatal thromboprophylaxis based on the criteria proposed by the Royal College of Obstetrician and Gynaecologists in 2009. What do the results of this study add: Using the RCOG guideline revised in 2015, a significant proportion of women delivering vaginally would require postnatal thromboprophylaxis based on age, parity and BMI. When either age or parity, both with relatively low odds ratio for thrombosis were omitted, a substantial proportion of women would not achieve the threshold for prophylaxis. Despite a sizable Muslim population in the country, the uptake of low molecular weight heparin was relatively high. What are the implications of these findings for clinical practice and/or future research: Cost-benefit studies should consider the adjusted odds ratio of individual indications on a VTE event. While uptake and acceptability is high, prospective studies on medication adherence is equally pertinent.

As technology advances, mobile devices have gradually turned into wearable devices. Furthermore, virtual reality (VR), augmented reality (AR), and mixed reality (MR) are being increasingly applied in medical fields such as medical education and training, surgical simulation, neurological rehabilitation, psychotherapy, and telemedicine. Research results demonstrate the ability of VR, AR, and MR to ameliorate the inconveniences that are often associated with traditional medical care, reduce incidents of medical malpractice caused by unskilled operations, and reduce the cost of medical education and training. What is more, the application of these technologies has enhanced the effectiveness of medical education and training, raised the level of diagnosis and treatment, improved the doctor-patient relationship, and boosted the efficiency of medical execution. The present study introduces VR, AR, and MR applications in medical practice and education with the aim of helping health professionals better understand the applications and use these technologies to improve the quality of medical care.

Background: There are no commercially available nasal irrigation solutions containing corticosteroids. Instead, such preparations are extemporaneously prepared by adding existing corticosteroid formulations to nasal irrigation solutions. The stability of the corticosteroid betamethasone 17-valerate (B17V), in nasal irrigation solutions of different compositions and pH and stored under different temperatures, was studied to determine the optimal choice of solution and storage conditions., Methods: Triplicate extemporaneous preparations made with B17V were prepared by adding a predetermined volume of B17V lotion to each nasal irrigation solution: normal saline (NS), sodium bicarbonate (NaHCO 3 ) powder dissolved in tap water, and a commercially available powder mixture (FLO Sinus Care Powder), dissolved in tap water or pre-boiled tap water. Preparations were stored at 30°C and 4°C. Sampling was carried out at 0, 1, 2, 6, and 24 hours. The concentrations of B17V and its degradation compound, betamethasone 21-valerate (B21V), were determined by high-performance liquid chromatography., Results: Preparations stored at 30°C contained a lower amount of B17V and higher amount of B21V than those stored at 4°C. B17V stability in nasal irrigation solutions decreased in the following order: NS, FLO in fresh tap water, FLO in pre-boiled tap water, and NaHCO 3 . The degradation rate of B17V increased with higher storage temperature and higher pH., Conclusion: B17V is most stable when added to NS and least stable in NaHCO 3 solution. FLO solution prepared with either cooled boiled water or tap water is an alternative if administered immediately. Storage at 4°C can better preserve stability of B17V, over a period of 24 hours., (© 2017 ARS-AAOA, LLC.)

Purpose The purpose of this paper is to assess the safety and efficiency of, and acceptance by, patients for an express refill service (ERS). Design/methodology/approach A pilot uncontrolled, cross-sectional, single-centred study was conducted at the outpatient pharmacy of a tertiary acute care hospital. Under ERS, prescriptions were dispensed without clinical review and counselling for patients refilling prescription medications. Efficiency was assessed by comparing processing times of ERS prescriptions with regular prescriptions. Safety was assessed by independent review of prescriptions by two pharmacists. Patient acceptance was assessed by a survey. Findings ERS reduced processing time of prescriptions by more than 30 per cent compared to the regular fill process. ERS was generally safe for patients, with drug-related problems identified in only one prescription which may have warranted closer monitoring. It was accepted by patients who opted for the service, as 91.4 per cent agreed or strongly agreed that they were satisfied with the service. Research limitations/implications The study was conducted on a small convenience sample of patients in a single centre, with no control group. Practical implications Results showed that ERS was efficient, safe and well-accepted for select patients refilling their prescriptions. This leads to shorter waiting times and greater patient satisfaction. Originality/value This is the first published study that has explored the feasibility of an express prescription refill service. Despite some limitations, this study showed that omitting prospective clinical review and patient counselling for a defined population segment is safe, and can reduce processing time and improve patient satisfaction.

Background Oral anticoagulation with warfarin is the cornerstone therapy in atrial fibrillation (AF) for stroke prevention. Multi-disciplinary anticoagulation management services have been shown to be cost-effective in the United States, Hong Kong and Thailand, but the findings are not readily generalizable to Singapore's healthcare system. Objective This study aimed to evaluate the cost-effectiveness of pharmacist-managed anticoagulation clinic (ACC) compared with usual care (UC) for the management of older adults with AF receiving oral anticoagulation with warfarin. Setting Pharmacist-managed ACC in an academic medical centre. Method A Markov model with 3-month cycle length and 30-year time horizon compared costs and quality-adjusted life-years (QALYs) of ACC and UC from the patient's and healthcare provider's perspectives. Four pathways based on time in therapeutic range (TTR) were: ACC TTR < 70 %, ACC TTR ≥ 70 %, UC TTR < 70 % and UC TTR ≥ 70 %. A hypothetical cohort of 70-year-old Singaporean AF patients receiving warfarin was utilised. Local data from national disease registries, patient surveys and hospital databases were used. When local data was not available, published studies on Asian populations were utilized when available. One-way sensitivity analyses and probabilistic sensitivity analyses were performed to account for uncertainties. Costs and QALYs were discounted annually by 3 %. Main outcome measure Costs and QALYs of ACC and UC. Results Pharmacist-managed ACC was found to dominate UC in all comparisons. It improved effectiveness by 0.19 and 0.13 QALYs at TTR < 70 % and TTR ≥ 70 % respectively compared with UC. From the patient's perspective, ACC reduced costs by SG$1222.67 (€1110.24) for TTR < 70 % and SG$1008.16 (€915.46) for TTR ≥ 70 %. Similar trends were observed from the healthcare provider's perspective, with ACC reducing costs by SG$1444.79 (€1311.94) for TTR < 70 % and SG$1269.17 (€1152.46) for TTR ≥ 70 % compared with UC. The results were robust to variations of the parameters over their plausible ranges in one-way sensitivity analyses. Probabilistic sensitivity analyses demonstrated that ACC was cost-effective more than 79 % of the time from both perspectives at a willingness-to-pay threshold of SG$69,050 (€62,701) per QALY. Conclusion Pharmacist-managed ACC is more effective and less costly compared with UC regardless of the quality of anticoagulation therapy. The findings support the current body of evidence demonstrating the cost-effectiveness of ACC.

Introduction: Elderly patients intrinsically have higher bleeding risks, deterring clinicians from prescribing them oral anticoagulants. Setting a narrow international normalized ratio (INR) target range might potentially mitigate some of these risks. This study sought to compare the outcomes of elderly patients who were assigned to either a narrow INR target range or the conventional INR target range in a real-world environment., Methods: This was a retrospective cohort study with the primary and secondary outcomes being the mean percentage time above INR 3.0 and the mean percentage time below INR 2.0 and the incidents of bleeding and thromboembolism associated with oral anticoagulant therapy, respectively. Patients and health care workers managing them had no prior knowledge of this study., Results: Data of 150 patients with a narrow INR target range (2.0-2.5) and 164 patients with a conventional INR target range (2.0-3.0) were collected and analyzed. The narrow INR group had significantly higher underlying risks of bleeding than the conventional INR group. Patients in the narrow INR group had a significantly lower percentage time above INR 3.0 but no significant difference in the percentage time below INR 2.0. Adjusted incidence rate ratio (IRR) for bleeding events was significantly lower for the narrow INR group, while the adjusted IRR for thromboembolic events between both groups was similar., Conclusion: Patients assigned to a narrow INR target range in real-world practice spent a significantly lower amount of time below an INR of 3.0 compared to conventional INR target range with lower incidents of bleeding complications and no increase in subtherapeutic INRs., (© The Author(s) 2015.)

Introduction: This study aimed to compare medication adherence and treatment persistence of patients on warfarin versus rivaroxaban in Singapore. A secondary objective was to identify significant covariates influencing adherence., Materials and Methods: A retrospective cohort study was conducted where data from September 2009 to October 2014 was retrieved from the hospital electronic databases. Prescription records of rivaroxaban patients with 3 months or more of continuous prescription were extracted and compared against those of patients on warfarin. Primary outcome of adherence was determined based on the medication possession ratio (MPR), while treatment persistence was determined by outpatient clinic appointment gaps., Results: A total of 94 rivaroxaban and 137 warfarin users were analysed by complete case analysis. The MPR of warfarin patients was lower than rivaroxaban patients by 10% (95% CI, 6.4% to 13.6%; P <0.0001). Also, there were more warfarin patients who had gaps in treatment persistence compared to those prescribed rivaroxaban (8.0% vs 1.1%; P = 0.03). Significant factors affecting medication adherence were age and duration of anticoagulant use. For every 10-year increase in age, MPR increased by 1.7% (95% CI, 0.7% to 2.8%). Similarly, for every year increase in duration of use, MPR increased by 1.8% (95% CI, 0.6% to 3.0%). Race, gender, concomitant medication and type of residence were not found to be significant covariates in the multivariable analysis., Conclusion: Patients on rivaroxaban are likely to be more adherent to their prescribed oral anticoagulant with increasing age and duration of treatment influencing adherence.

Strokes can have a catastrophic impact on patients' health-related quality of life (HRQoL). In addition to warfarin, two novel oral anticoagulants, i.e., dabigatran and rivaroxaban, have been approved to prevent strokes. This study aimed to use direct measures to elicit patient-reported utilities (i.e., preferences) for anticoagulant-related outcomes. A cross-sectional survey was administered to 100 patients taking warfarin in an anticoagulation clinic. Utilities for six long-term and four short-term anticoagulant-related health states were elicited by the visual analogue scale (VAS) and standard gamble (SG) methods. Health states with the highest SG-derived mean utility values were "well on rivaroxaban" (mean ± SD = 0.90 ± 0.15), "well on warfarin" (0.86 ± 0.17), and "well on dabigatran" (0.83 ± 0.18). Approximately half of the patients considered major ischemic stroke (-1.57 ± 6.77) and intracranial hemorrhage (-1.99 ± 6.98) to be worse than death. The percentages of patients who considered a particular health state worse than death ranged from 0 to 55 % among various health states assessed. The VAS had similar findings. Good logical consistency was observed in both VAS- and SG-derived utility values. Ischemic stroke and intracranial hemorrhage had a significant impact on patients' HRQoL. Greater variation in patients' preferences was observed for more severely impaired health states, indicating the need for individualized medical decision-making. In this study, both long-term and short-term health states were included in the utility assessment. The findings of this study can be used in cost-utility analysis of future anticoagulation therapies.

Purpose: This study aimed to evaluate the cost-effectiveness of dabigatran and rivaroxaban compared with warfarin for the prevention of stroke in patients with atrial fibrillation (AF) in Singapore., Methods: A Markov model was constructed to compare the lifetime costs, quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratios (ICERs) of dabigatran 110 and 150 mg, rivaroxaban 20 mg and adjusted-dose warfarin from the perspective of the Singapore healthcare system, using clinical data from published studies, utilities from a patient-reported survey and costs from hospital databases. The target population was a hypothetical cohort of 65-year-old AF patients with no contraindications to anticoagulation., Results: In the base-case analysis, the QALYs were 8.75 with warfarin, 8.73 with dabigatran 110 mg, 8.82 with dabigatran 150 mg, and 9.33 with rivaroxaban. The costs were Singapore dollar (SG$) 34,648 for warfarin, SG$54,919 for dabigatran 110 mg, SG$50,484 for dabigatran 150 mg and SG$51,975 for rivaroxaban. The ICER of rivaroxaban versus warfarin was SG$29,697 (US$26,727) per QALY. Rivaroxaban and warfarin had extended dominance over the high-dose dabigatran. The low-dose dabigatran was dominated by warfarin. Deterministic sensitivity analyses showed that the ICER of rivaroxaban versus warfarin was sensitive to cost of rivaroxaban and utilities for rivaroxaban and warfarin. Probability sensitivity analysis demonstrated that the probability of rivaroxaban being the optimal choice was 97.8% and 99.5% at a willingness-to-pay threshold of SG$65,000 (US$58,500) and SG$130,000 (US$117,000) per QALY, respectively., Conclusion: Rivaroxaban may be a cost-effective alternative to warfarin for the prevention of stroke in patients with AF in Singapore.

Introduction: A better understanding of patients' knowledge, satisfaction and concerns can identify deficits and help develop targeted patient education. This study aimed to examine patients' knowledge, satisfaction and concerns regarding warfarin therapy and assess their association with warfarin adherence and international normalized ratio (INR) control., Materials and Methods: A cross-sectional survey was conducted in a convenience sample of patients taking warfarin in an anticoagulation clinic. The questionnaire consisted of questions on patients' knowledge, satisfaction and concerns regarding warfarin treatment. Patients' warfarin refill records and time within the therapeutic INR range were retrieved from hospital databases., Results: One hundred and eighty-three patients participated in the survey. Patients had inadequate knowledge of warfarin-diet and warfarin-drug interactions. Over 40% of the respondents were not satisfied with the waiting time to see a pharmacist. The most common concerns of taking warfarin were worries about warfarin-drug interactions (36.1%), forgetting to take warfarin (26.2%) and worries about side effects (25.7%). Higher satisfaction was associated with better knowledge (r=0.24, p=0.001) and fewer concerns (rs=-0.23, p=0.002). Better knowledge and higher satisfaction were associated with higher warfarin adherence (rs=0.21 and 0.16; p=0.01 and 0.046, respectively). Better knowledge, higher satisfaction, fewer concerns, and better warfarin adherence were associated with good INR control (p=0.003, 0.02, 0.03 and 0.003, respectively)., Conclusions: This study highlighted patients' concerns and deficits in knowledge regarding warfarin treatment, and also demonstrated their association with warfarin adherence and INR control., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

In order to improve warfarin adherence, we must first know the rate of non-adherence and the reasons for it. Assessment of warfarin adherence is important in improving patients' warfarin-taking behavior and International Normalized Ratio (INR) control. This study aimed to compare three medication adherence measures in patients taking warfarin: the 8-item Morisky Medication Adherence Scale (MMAS), the 100-point Visual Analogue Scale (VAS) and medication refill adherence (MRA). A cross-sectional observational study was conducted in a convenience sample of 174 patients taking warfarin at an anticoagulation clinic. A survey questionnaire that included the MMAS, VAS, and demographic and warfarin-related clinical questions was administered to patients in English or Chinese depending on their preferences. The MRA and INR values were retrieved from hospital electronic databases. Most participants were adherent to warfarin as indicated by the three measures. A weak association was found between the MMAS and the other two adherence measures. The MMAS and MRA were associated with the percentage of INRs within range in the past 2 weeks. Moreover, the MRA was weakly associated with time within the therapeutic INR range in the past 3 months and 2 weeks. The findings provide insights into the differences among three medication adherence measures and may assist healthcare providers to select the most suitable measure for the assessment of warfarin adherence.

There is no patient-reported medication adherence measure that has been validated in Singapore. This study aimed to validate the 8-item Morisky Medication Adherence Scale (MMAS) in patients taking warfarin in Singapore. A cross-sectional survey was conducted in a convenience sample of 151 patients taking warfarin at an anticoagulation clinic in 2011. Respondents completed the MMAS in English or Chinese depending on their preference. The MMAS had a Cronbach's alpha of 0.56 and good criterion-related validity as the scale scores were associated with warfarin refill rates (p = 0.04). Respondents with higher MMAS scores were found to have a higher percentage of International Normalised Ratios (INRs) within the therapeutic range (p = 0.01), higher adherence to diet recommendations (p = 0.02), and less perceived difficulty in taking all medications (p < 0.001); they were also more likely to take warfarin at the same time every day (p < 0.001). Confirmatory factor analysis showed that the eight items loaded onto one factor (RMSEA = 0.03). The sensitivity, specificity, positive predictive value and negative predictive value of the MMAS for identifying patients with poor INR control were 73.0%, 35.6%, 49.5% and 60.5%, respectively, using the time in the therapeutic INR range as the gold standard. This study shows that the 8-item MMAS has good validity and moderate reliability in patients taking warfarin. Future research is needed to investigate the scale's psychometric properties in other patient populations and clinical settings.

Aim: The concept of a pharmacist/advanced practice nurse (APN)-led Rheumatology Monitoring Clinic (RMC) is a novel service in Singapore; we therefore conducted a questionnaire survey of patient experience., Methods: Patients attending the RMC were provided with a set of questionnaires. As a substudy, a separate questionnaire was given to the rheumatologists and therapists conducting the RMC., Results: Of the 105 patients surveyed, a total of 97 (92.4%) patients were satisfied/strongly satisfied with the overall service, and none were dissatisfied; 96% felt that the pharmacists/APNs provided clear, detailed information about their disease and medication, while 92% of patients were confident they knew what side-effects were possible. Ninety-two percent and 93% of patients were more likely to adhere to treatment, and were willing to come back for follow-up at the RMC, respectively. There was no difference in patient satisfaction in the average Likert summed scores, between the pharmacists and APNs. Age, gender, ethnicity and underlying disease did not exert any influence on the responses. All the rheumatologists surveyed were satisfied with the patients' management and the professionalism of the therapists. They opined that the RMC freed up time for them to see more complex cases. All the pharmacists/APNs concurred that the referrals were appropriately selected., Conclusions: We established the acceptability of a non-physician-led clinic in our local setting and highlighted the usefulness of having a routine clinic for monitoring medication toxicity and patient education. The RMC received positive feedback from patients, rheumatologists and allied health therapists, with a high degree of satisfaction among the respondents., (© 2012 The Authors International Journal of Rheumatic Diseases © 2012 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd.)

Temporary interruption of anticoagulation therapy is usually recommended for anticoagulated patients undergoing invasive procedures to minimize their bleeding risks. We validated the current consensus recommendation on warfarin interruption which were based on Western population studies to determine if they could safely be applied to Asians. The international normalized ratios (INR) in twenty warfarinised patients with a stable INR of 2-3 were prospectively measured at days 0, 3 and 5 after stopping warfarin for procedures or at completion of treatment. The median INR at days 0, 3 and 5 were 2.30 (95% CI 2.16-2.43), 1.32 (95% CI 1.22-1.57) and 1.06 (95% CI 1.05-1.13) respectively (P < 0.001 for trend). All patients were below therapeutic INRs by day 3 with 14 patients (70%, 95% CI 49.92-90.08) achieving INR readings below 1.5. By day 5, all INRs were below 1.5 and only 2 patients (10%, 95% CI -3.15 to 23.15) had INRs above 1.2. There were no significant peri-procedure bleeding or thrombotic events in the 1 month following interruption of warfarin. Our results suggest that the current international recommendation of stopping warfarin for 5 days prior to procedure can safely be applied to Asians without compromising risk of bleeding or thrombosis.

Summary: Warfarin-induced bleeding complications and high inter-patient variability are major hindrances to oral anticoagulant therapy. The present study identifies the influence of VKORC1 diplotypes, CYP2C9 and CYP2C19 variants on warfarin disposition and dose requirements in Chinese patients (n=107). The study subjects were genotyped for VKORC1, CYP2C9 and CYP2C19 polymorphic variants. Weekly warfarin dose requirements and S-warfarin clearance were stratified by VKORC1, CYP2C9 and CYP2C19 pharmacogenetics. The major VKORC1 diplotypes were H1-H1 (62%), H1-H7 (18%) and H1-H(*)(b) (10%). Warfarin dose requirements were significantly lower in patients with VKORC1 H1-H1 and H1-H(*)(a) diplotypes compared to patients harboring the H1-H7 and H1-H(*)(b) diplotypes (P<0.05). Hepatic tissues with H1-H1 diplotype had significantly lower expression of VKORC1 mRNA compared with liver tissues carrying the H1-H7 and H1-H(*)(b) diplotypes (P=0.006). The percent variability explained by VKORC1 diplotype status was 59.1% while the CYP2C9 genotype status accounted for 6.9% variability in warfarin dose requirements. Patient age and weight were significant covariates accounting for 29% and 8.6% of warfarin dose variability, respectively. The present study shows that VKORC1 diplotype status, CYP2C9 genotype, age and weight are significant covariates, accounting for 73.4% of interindividual variability in warfarin dose requirements among Chinese patients. Translation of these findings into clinical guidelines for warfarin dosing may be required to assess its impact on the safety and efficacy of warfarin.

Point-of-care (POC) coagulometers are increasingly used by patients for self-monitoring of oral vitamin K antagonists therapy. We studied the feasibility of introducing POC international normalised ratio (INR) testing in place of standard laboratory assays in a hospital-based anticoagulation clinic with 250 active patients. The CoaguChek XS system was first validated in 253 INR samples and found to have a correlation of r = 0.945 with standard assays. Variations increased with INR readings above 3.5 and this was chosen as the cutoff for acceptance of POC INR results. POC testing was done for 1,332 clinic visits during the subsequent 6-month study. Rate of rejections of INR over 3.5 was 4.3% (95% CI 3.3-5.5%). POC testing reduced clinic visit duration by 35 min (p < 0.001, 95% CI 25-45) without cost increments to patients or the laboratory. Among 232 respondents surveyed, 87.5% (95% CI 82.5-91.5%) preferred POC INR monitoring. Rates of thrombosis and major bleeding complications were 1.2% (95% CI 0.2-3.5%) and 0.4% (95% CI 0.01-2.2%), respectively. In conclusion, provided mechanisms are in place to address increased variations of INR at higher ranges, POC testing can be successfully implemented in busy hospital-based anticoagulation clinics.

What Is Already Known About This Subject: Recent studies on pharmacogenetics of warfarin have implicated apolipoprotein E (APOE) polymorphisms to influence the vitamin K dependent coagulation cascade and hence the efficacy of warfarin. Studies among Caucasian and African Americans showed a significant but conflicting role of apolipoprotein E (APOE) isoforms in warfarin pharmacogenetics. The contribution of APOE isoforms in influencing variations in warfarin requirements in Asian subjects remains to be investigated., What This Study Adds: This is the first report of a population study in Asians exploring the role of isoforms encoded by three APOE alleles (epsilon 2, epsilon 3, epsilon 4) in influencing warfarin dose requirements. The present study showed that the APOE epsilon 3/epsilon 3 isoform is the predominant genotype in the Asian population. The study also showed that APOE isoforms may not be important in affecting warfarin pharmacodynamics in Asian patients. It also suggested that the impact of different APOE isoforms depended on the frequency of APOE genotypes in the population, in particular the epsilon 4 allele containing genotypes., Aims: To investigate the influence of APOE genotypes and VKORC1 haplotypes on warfarin dose requirements in Asian patients., Methods: A total of 174 Asian patients (Chinese, n = 96; Malays, n = 50; Indians, n = 28) who had stable daily warfarin doses for at least 1 month were recruited. Following genomic DNA extraction from venous blood, pharmacogenetic analysis of APOE and VKORC1 genes was done by DNA sequencing., Results: The majority of the Asian patients (78%) harboured the APOE epsilon 3/epsilon 3 genotype. Different APOE genotypes were found not to have any significant influence on mean daily warfarin dose requirements. Warfarin dose requirements in the pooled Asian patients homozygous for the VKORC1 H1 haplotype were significantly lower compared with patients homozygous for the H7 haplotype (H1-H1 vs. H7-H7: 2.79 +/- 1.06 mg day(-1)vs. 5.45 +/- 2.3 mg day(-1), P < 0.001)., Conclusions: The present study suggests that APOE variants have minimal impact on warfarin dose requirements in Asian patients, probably due to the low frequency of epsilon 4 allele containing genotypes.

A new cytotoxic lobane diterpene, ineleganene (1), was isolated from the Formosan soft coral Sinularia inelegans. The structure of compound 1 was determined by 1D and 2D spectral analysis.