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Despite the proven safety and clinical efficacy of the Measles vaccine, many countries are seeing new heights of vaccine hesitancy or refusal, and are experiencing a resurgence of measles infections as a consequence. With the use of novel machine learning tools, we investigated the prevailing negative sentiments related to Measles vaccination through an analysis of public Twitter posts over a 5-year period. We extracted original tweets using the search terms related to "measles" and "vaccine," and posted in English from January 1, 2017, to December 15, 2022. Of these, 155,363 tweets were identified to be negative sentiment tweets from unique individuals, through the use of Bidirectional Encoder Representations from Transformers (BERT) Named Entity Recognition and SieBERT, a pretrained sentiment in English analysis model. This was followed by topic modeling and qualitative thematic analysis performed inductively by the study investigators. A total of 11 topics were generated after applying BERTopic. To facilitate a global discussion of results, the topics were grouped into four different themes through iterative thematic analysis. These include (a) the rejection of "anti-vaxxers" or antivaccine sentiments, (b) misbeliefs and misinformation regarding Measles vaccination, (c) negative transference due to COVID-19 related policies, and (d) public reactions to contemporary Measles outbreaks. Theme 1 highlights that the current public discourse may further alienate those who are vaccine hesitant because of the disparaging language often used, while Themes 2 and 3 highlight the typology of misperceptions and misinformation underlying the negative sentiments related to Measles vaccination and the psychological tendency of disconfirmation bias. Nonetheless, the analysis was based solely on Twitter and only tweets in English were included; hence, the findings may not necessarily generalize to non-Western communities. It is important to further understand the thinking and feeling of those who are vaccine hesitant to address the issues at hand.

Objectives: The aim of these Clinical Practice Guidelines is to provide evidence-based recommendations to assist healthcare providers in the screening, diagnosis and management of patients with postmenopausal osteoporosis (OP)., Methods: A list of key clinical questions on the assessment, diagnosis and treatment of OP was formulated. A literature search using the PubMed, Medline, Cochrane Databases of Systematic Reviews, and OVID electronic databases identified all relevant articles on OP based on the key clinical questions, from 2014 onwards, to update from the 2015 edition. The articles were graded using the SIGN50 format. For each statement, studies with the highest level of evidence were used to frame the recommendation., Results: This article summarizes the diagnostic and treatment pathways for postmenopausal OP. Risk stratification of patients with OP encompasses clinical risk factors, bone mineral density measurements and FRAX risk estimates. Non-pharmacological measures including adequate calcium and vitamin D, regular exercise and falls prevention are recommended. Pharmacological measures depend on patients' fracture risk status. Very high-risk individuals are recommended for treatment with an anabolic agent, if available, followed by an anti-resorptive agent. Alternatively, parenteral anti-resorptive agents can be used. High-risk individuals should be treated with anti-resorptive agents. In low-risk individuals, menopausal hormone replacement or selective estrogen receptor modulators can be used, if indicated. Patients should be assessed regularly to monitor treatment response and treatment adjusted, as appropriate., Conclusions: The pathways for the management of postmenopausal OP in Malaysia have been updated. Incorporation of fracture risk stratification can guide appropriate treatment., Competing Interests: The authors declare no competing interests., (© 2023 The Korean Society of Osteoporosis. Publishing services by Elsevier B.V.)

Background: Risk stratification in paracetamol (acetaminophen) poisoning is crucial because hepatotoxicity is common and can be mitigated with treatment. However, current risk stratification tools have limitations., Aims: We evaluated the diagnostic performance of the paracetamol concentration × aminotransferase multiplication product, for predicting hepatotoxicity after paracetamol overdose., Methods: Medline, Cochrane Library and Embase were searched for eligible papers. We used random effects models to obtain pooled estimates of the likelihood ratios and diagnostic odds ratios, from which sensitivity and specificity were computed. We assessed two commonly used cut-off values of paracetamol × aminotransferase, 1500 mg/L × IU/L and 10,000 mg/L × IU/L. Using the confusion matrices of these two cut-offs, area under the summary receiver operator characteristic curve and optimal cut-off values in different clinical scenarios were established., Results: Six studies comprising 5036 participants were included. In 4051 patients, using the cut-off of 1500 mg/L × IU/L, a diagnostic odds ratio of 31.90 (95%CI: 9.52-106.90), sensitivity of 0.98 (95%CI: 0.94-1.00) and specificity of 0.66 (95%CI: 0.49-0.89) were obtained. In 3983 patients, using the cut-off of 10,000 mg/L × IU/L, a diagnostic odds ratio of 99.34 (95%CI: 12.26-804.87), sensitivity of 0.65 (95%CI: 0.51-0.82) and specificity of 0.97 (95%CI: 0.95-1.00) were obtained. For staggered ingestions, the 1500 mg/L × IU/L cut-off yielded a diagnostic odds ratio of 69.53 (95%CI: 4.03-1199.75), sensitivity of 1.00 (95%CI: 0.87-1.00) and specificity of 0.74 (95%CI: 0.43-1.00). Next, using the 10,000 mg/L × IU/L cut-off in this scenario yielded a diagnostic odds ratio of 254.58 (95%CI: 11.12-5827.60), sensitivity of 0.79 (95%CI: 0.59-1.00) and specificity of 0.98 (95%CI: 0.94-1.00). The overall summary receiver operator characteristic curve was 0.91 (95%CI: 0.75-0.97), and the optimal cut-off value was 3840 mg/L × IU/L. The summary receiver operator characteristic curve in patients with staggered ingestions was 0.96 (95%CI: 0.85-0.99). The summary receiver operator characteristic curve in patients with staggered ingestions and whose paracetamol concentration was below the detectable limit of 10 mg/L at presentation was 0.97 (95%CI: 0.94-0.99)., Conclusion: In this first meta-analysis, paracetamol × aminotransferase demonstrates its use in prognosticating hepatotoxicity in patients with paracetamol poisoning. It complements the Rumack-Matthew nomogram as it has shown promise in addressing two key limitations of the nomogram: it is usable after more than 24 h between overdose and acetylcysteine treatment, and it is applicable in staggered ingestions.

Aim: Neurostimulation techniques are effective treatments for major depressive disorders (MDD). However, the optimal sequence of electroconvulsive therapy (ECT) and transcranial magnetic stimulation (TMS) as part of antidepressant treatment algorithm is unclear. We examined the cost-effectiveness of ECT and TMS in MDD., Methods: A decision-analytic model was developed to determine total costs, quality-adjusted life-years (QALYs) and incremental cost-effectiveness ratios (ICERs) for 10 strategies. Each strategy comprised four treatment lines with ECT and TMS incorporated as second, third, or fourth line. A scenario analysis that explored the cost-effectiveness of maintenance approach by continuing ECT and TMS after acute treatment was performed., Results: In the base case, fourth-line TMS after three preceding trials of antidepressants was least costly at US$ 5523 yielding 1.424 QALYs. Compared with this strategy, fourth-line ECT and third-line TMS followed by ECT were cost-effective with ICERs of US$ 7601 per QALY gained and US$ 11 388 per QALY gained, respectively. In the scenario analysis where continuation treatments of ECT and TMS were provided, third-line TMS followed by ECT was cost-effective, with an ICER of US$ 17 198 per QALY gained. Effectiveness of ECT and cost of managing severe depression were influential parameters affecting the cost-effectiveness results., Conclusions: In acute treatment of MDD, fourth-line ECT was the most cost-effective strategy. In maintenance treatment, the strategy that incorporated third-line TMS and fourth-line ECT was cost-effective. The overall findings confirmed the value of neurostimulation therapies which should be offered early in the process of managing depression., (© 2020 John Wiley & Sons Australia, Ltd.)

Serial galactomannan (GM) monitoring can aid the diagnosis of invasive aspergillosis (IA) and optimise treatment decisions. However, widespread adoption of mould-active prophylaxis has reduced the incidence of IA and challenged its use. We evaluated the cost-effectiveness of prophylaxis-biomarker strategies. A Markov model simulating high-risk patients undergoing routine GM surveillance with mould-active versus non-mould-active prophylaxis was constructed. The incremental cost for each additional quality-adjusted life-year (QALY) gained over a lifetime horizon was calculated. In 40- and 60-year-old patients receiving mould-active prophylaxis coupled with routine GM surveillance, the total cost accrued was the lowest at SGD 11,227 (USD 8255) and SGD 9234 (USD 6790), respectively, along with higher QALYs gained (5.3272 and 1.1693). This strategy, being less costly and more effective, dominated mould-active prophylaxis with no GM monitoring or GM surveillance during non-mould-active prophylaxis. The prescription of empiric antifungal treatment was influential in the cost-effectiveness. When the GM test sensitivity was reduced from 80% to 30%, as might be anticipated with the use of mould-active prophylactic agents, the conclusion remained unchanged. The likelihood of GM surveillance with concurrent mould-active prophylaxis being cost-effective was 77%. Routine GM surveillance remained cost-effective during mould-active prophylaxis despite lower IA breakthroughs. Cost-saving from reduced empirical antifungal treatment was an important contributing factor.

Context: Coconut oil is rich in medium-chain fatty acids and has been claimed to have numerous health benefits., Objective: This review aimed to examine the evidence surrounding coconut oil consumption and its impact on cardiovascular health., Data Sources: A systematic literature search of the PubMed, Embase, the Cochrane Library, and CINAHL databases, up to May 2019, was performed., Data Extraction: Study characteristics including study design, population, intervention, comparator, outcome, and source of funding were summarized., Data Analysis: Meta-analyses included 12 studies to provide estimates of effects. Subgroup analyses were performed to account for any differences in the study-level characteristics. When compared with plant oils and animal oils, coconut oil was found to significantly increase high-density lipoprotein cholesterol (HDL-C) by 0.57 mg/dL (95%CI, 0.40-0.74 mg/dL; I2 = 6.7%) and 0.33 mg/dL (0.01-0.65 mg/dL; I2 = 0%), respectively. Coconut oil significantly raised low-density lipoprotein cholesterol (LDL-C) by 0.26 mg/dL (0.09-0.43 mg/dL; I2 = 59.7%) compared with plant oils and lowered LDL-C (-0.37 mg/dL; -0.69 to -0.05 mg/dL; I2 = 48.1%) compared with animal oils. No significant effects on triglyceride were observed. Better lipid profiles were demonstrated with the virgin form of coconut oil., Conclusion: Compared with animal oils, coconut oil demonstrated a better lipid profile n comparison with plant oils, coconut oil significantly increased HDL-C and LDL-C., (© The Author(s) 2019. Published by Oxford University Press on behalf of the International Life Sciences Institute. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: The study evaluated the cost-effectiveness of hydrotherapy versus land-based therapy in patients with musculoskeletal disorders (MSDs) in Singapore., Methods: A decision-analytic model was constructed to compare the cost-effectiveness of hydrotherapy to land-based therapy over 3 months from societal perspective. Target population comprised patients with low back pain (LBP), osteoarthritis (OA), rheumatoid arthritis (RA), total hip replacement (THR) and total knee replacement (TKR). Subgroup analyses were carried out to determine the cost-effectiveness of hydrotherapy in individual MSDs. Relative treatment effects were obtained through a systematic review of published data., Results: Compared to land-based therapy, hydrotherapy was associated with an incremental cost-effectiveness ratio (ICER) of SGD 27 471 per quality-adjusted life-year (QALY) gained, which was below the willingness-to-pay threshold of SGD 70 000 per QALY (one gross domestic product per capita in Singapore in 2015). For the respective MSDs, hydrotherapy were dominant (more effective and less costly) in THR and TKR, cost-effective for LBP and RA, and not cost-effective for OA. Treatment adherence and cost of hydrotherapy were key drivers to the ICER values., Conclusions: Hydrotherapy was a cost-effective rehabilitation compared to land-based therapy for a population with MSDs in Singapore. However, the benefit of hydrotherapy was not observed in patients with OA., (© The Author(s) 2018. Published by Oxford University Press on behalf of Faculty of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Aim: Compared with second-generation durable polymer drug-eluting stents (DP-DES), the cost-effectiveness of biodegradable polymer drug-eluting stents (BP-DES) remains unclear in the real-world setting. We assessed the cost-effectiveness of BP-DES in patients with coronary artery disease undergoing percutaneous coronary intervention (PCI)., Methods: We developed a decision-analytic model to compare the cost-effectiveness of BP-DES to DP-DES over 1 year and 5 years from healthcare payer perspective. Relative treatment effects during the first year post-PCI were obtained from a real-world population analysis while clinical event risks in the subsequent 4 years were derived from a meta-analysis of published studies., Results: At 1 year, based on the clinical data analysis of 497 propensity-score matched pairs of patients, BP-DES were associated with an incremental cost-effectiveness ratio (ICER) of USD20 503 per quality-adjusted life-year (QALY) gained. At 5 years, BP-DES yielded an ICER of USD4062 per QALY gained. At the willingness-to-pay threshold of USD50 400 (one gross domestic product per capita in Singapore in 2015), BP-DES were cost-effective. Sensitivity analysis showed that the cost of stents had a significant impact on the cost-effectiveness of BP-DES. Threshold analysis demonstrated that if the cost difference between BP-DES and DP-DES exceeded USD493, BP-DES would not be cost-effective in patients with 1 year of follow-up., Conclusions: Biodegradable polymer drug-eluting stents were cost-effective compared with DP-DES in patients with coronary artery disease at 1 year and 5 years after PCI. It is worth noting that the cost of stents had a significant impact on the findings., (© 2018 John Wiley & Sons Ltd.)

Febrile neutropenia (FN) is associated with substantial morbidity and necessitates empirical broad-spectrum antimicrobial treatment. In this prospective cohort study, a risk-guided management strategy for FN using empirical piperacillin/tazobactam (TZP) or a carbapenem was evaluated. The analysis involved 723 FN episodes in hospitalised adult patients, including those with severe sepsis or prior infection/colonisation with extended-spectrum β-lactamase (ESBL)-producing Enterobacteriaceae. Propensity score matching analysis was used to adjust for baseline differences between treatment groups and produced 267 matched pairs. The primary outcome was all-cause mortality. Secondary outcomes were the incidences of drug-resistant Gram-negative (including ESBL-producing) and Gram-positive bacterial isolates and of invasive pulmonary aspergillosis (IPA) and their associated mortality. There was no difference in mortality between empirical carbapenem and TZP [18/267 (6.7%) vs. 14/267 (5.2%); P = 0.466]. Higher incidences of drug-resistant Gram-negative isolates [77/267 (28.8%) vs. 26/267 (9.7%); P < 0.001], including ESBL-producing bacteria [57/267 (21.3%) vs. 16/267 (6.0%); P < 0.001], were observed in carbapenem-treated episodes where its use lowered mortality. Mortality rates for ESBL-positive infections were 5.3% (3/57) and 25.0% (4/16) (P = 0.037) and for drug-resistant Gram-negative infections were 6.5% (5/77) and 23.1% (6/26) (P = 0.018) in carbapenem- and TZP-treated episodes, respectively. More IPA was observed with carbapenem use [16/267 (6.0%) vs. 6/267 (2.2%); P = 0.029]. Antifungal prophylaxis reduced the risk of death (odds ratio = 0.39, 95% confidence interval 0.17-0.87; P = 0.017). Risk-guided carbapenem prescribing in FN correctly identified cases prone to drug-resistant Gram-negative infections and reduced the mortality in these episodes., (Copyright © 2018 Elsevier B.V. and International Society of Chemotherapy. All rights reserved.)

Healthcare decision-makers are constantly challenged by growing healthcare needs in tandem with rising healthcare costs. Disinvesting in technologies and practices that are "low in value" is one strategy to re-allocate limited resources to the most effective, safe and cost-effective technologies. We put forward a health technology reassessment framework and examined the opportunities and challenges on technology disinvestment in Singapore and deliberated on possible solutions. We coordinated and supported a disinvestment programme in 2 hospitals, 1 specialist centre and 9 primary care institutions in the public healthcare sector. The key processes were identifying, prioritising and assessing low-value health technologies and practices, disseminating and implementing disinvestment recommendations, and post-implementation evaluation. Through case studies, we explored the barriers and enablers to the success of the programme. One of the barriers to disinvestment included difficulty in demonstrating a lack of benefit of in-use technologies from published studies. Differing viewpoint and priority might preclude a healthcare leader's support in such initiatives and that posed an unsurmountable hurdle. On the other hand, engaging the stakeholder throughout the evidence review process and striking a balance between rigour and timeliness of review were likely to assure success. Lastly, monitoring the impact on resources and patient outcomes can be diverse and methods need to be developed. Understanding barriers and enablers in health technology disinvestment can translate into improved opportunities for eliminating and minimising resource wastage.

Background: Compared to electroconvulsive therapy (ECT), the cost-effectiveness of repetitive transcranial magnetic stimulation (rTMS) in the management of treatment-resistant depression (TRD) remains unclear., Objective/hypothesis: This study evaluated the cost-effectiveness of rTMS vs. ECT for TRD from Singapore societal perspective., Methods: We constructed a Markov model to project the cost and benefit of rTMS compared with ECT over one year in patients with TRD. The relative treatment effects between rTMS and ECT were obtained from meta-analyses of published trials. The effectiveness and quality of life data for patients using ECT, resource use for TRD and their associated costs were derived from the national tertiary mental institution in Singapore., Results: At one year, rTMS was cost-effective relative to ECT. The incremental cost-effectiveness ratio (ICER) associated with ECT was Singapore dollars (SGD) 311,024 per quality-adjusted life-year (QALY) gained. This exceeded the willingness-to-pay threshold of SGD 70,000 per QALY gained. A similar trend was observed for ICER per remission achieved (i.e., SGD 143,811 per remission achieved with ECT). In the subgroup analysis, rTMS was found to be less costly and more effective than ECT in nonpsychotic depressive patients. In the scenario analysis, ECT employed as an ambulatory service yielded a much smaller ICER (i.e., SGD 78,819 per QALY gained) compared to the standard inpatient setting., Conclusions: rTMS was a cost-effective treatment compared to ECT in TRD over one year. The cost-effectiveness of rTMS was attenuated when ECT was used in the outpatient setting., (© 2017 International Neuromodulation Society.)

Most mainstream automatic speech recognition (ASR) systems consider all feature frames equally important. However, acoustic landmark theory is based on a contradictory idea that some frames are more important than others. Acoustic landmark theory exploits quantal nonlinearities in the articulatory-acoustic and acoustic-perceptual relations to define landmark times at which the speech spectrum abruptly changes or reaches an extremum; frames overlapping landmarks have been demonstrated to be sufficient for speech perception. In this work, experiments are conducted on the TIMIT corpus, with both Gaussian mixture model (GMM) and deep neural network (DNN)-based ASR systems, and it is found that frames containing landmarks are more informative for ASR than others. It is discovered that altering the level of emphasis on landmarks by re-weighting acoustic likelihood tends to reduce the phone error rate (PER). Furthermore, by leveraging the landmark as a heuristic, one of the hybrid DNN frame dropping strategies maintained a PER within 0.44% of optimal when scoring less than half (45.8% to be precise) of the frames. This hybrid strategy outperforms other non-heuristic-based methods and demonstrate the potential of landmarks for reducing computation.

Aims: The safety and efficacy of BP-DES compared to second-generation DP-DES remain unclear in the real-world setting. We compared the clinical outcomes of biodegradable polymer drug-eluting stents (BP-DES) with second-generation durable polymer drug-eluting stents (DP-DES) in an all-comer percutaneous coronary intervention (PCI) registry., Methods/results: The study included a cohort of 1065 patients treated with either BP-DES or DP-DES from January 2009 through October 2015. Propensity score matching was performed to account for potential confounders and produced 497 matched pairs of patients. The primary endpoint was target lesion failure (TLF) at one-year follow-up. The rates of TLF were comparable between BP-DES and DP-DES (8.7% vs 9.1%, P = .823) at 1 year. The rates of stent thrombosis at 30 days (0.4% vs 0.4%, P = 1.00) and 1 year (0.8% vs 0.8%, P = 1.00) did not differ between BP-DES and DP-DES. There were no significant differences in other clinical outcomes including target vessel failure (8.9% vs 9.5%, P = .741), in-stent restenosis (1.8% vs 1.0%, P = .282), and cardiac death (6.4% vs 7.4%, P = .533) at 1 year. Multivariate cox regression analysis showed that the risk of TLF at one-year did not differ significantly between BP-DES and DP-DES (hazard ratio 0.94, P = .763)., Conclusions: Efficacy and safety of BP-DES were not better than DP-DES at one-year follow-up., (© 2018 John Wiley & Sons Ltd.)

Osteoarthritis prevalence is expected to increase markedly in the Asia-Pacific region due to rapid population aging. Identifying effective and safe therapeutic options to manage osteoarthritic pain is viewed as a priority. The Asia-Pacific Experts on Topical Analgesics Advisory Board developed consensus statements for use of topical NSAIDs in musculoskeletal pain. Evidence supporting these statements in osteoarthritic pain was reviewed. Best available evidence indicates that topical NSAIDs have a moderate effect on relief of osteoarthritic pain, comparable to that of oral NSAIDs but with a better risk-to-benefit ratio. International clinical practice guidelines recommend topical NSAIDs on par with or ahead of oral NSAIDs for pain management in patients with knee and hand osteoarthritis, and as the first-line choice in persons aged ≥75 years.

Objective: Following an osteoporotic fracture, pharmacological treatment is recommended to increase bone mineral density and prevent future fractures. However, the rate of starting treatment after an osteoporotic hip fracture remains low. The objective of this study was to survey the treatment rate following a low-trauma hip fracture at a tertiary private hospital in Malaysia over a period of 5 years., Methods: The computerised hospital discharge records were searched using the terms "hip," "femur," "femoral," "trochanteric," "fracture," or "total hip replacement" for all patients over the age of 50, admitted between 2010 and 2014. The medical charts were obtained and manually searched for demographic data and treatment information. Hip operations done for non-low-trauma-related fracture and arthritis were excluded., Results: Three hundred seventy patients over the age of 50 years were admitted with a hip fracture, of which 258 (69.7%) were low trauma, presumed osteoporotic, hip fractures. The median age was 79.0 years (interquartile range [IQR], 12.0). Following a hip fracture, 36.8% (95 of 258) of the patients received treatment, but out of these, 24.2% (23 of 95) were on calcium/vitamin D only. The median duration of treatment was 1 month (IQR, 2.5). In 2010, 56.7% of the patients received treatment, significantly more than subsequent years 2011-2014, where approximately only 30% received treatment., Conclusions: Following a low-trauma hip fracture, approximately 72% of patients were not started on active antiosteoporosis therapy. Of those who were, the median duration of treatment was 1 month. This represents a missed opportunity for the prevention of future fractures.

Background and Aims: CT-P13 is the first biosimilar monoclonal antibody to infliximab, and was recently approved in the European Union, Japan, Korea, and USA for all six indications of infliximab. However, studies directly assessing the biologic activity of CT-P13 versus inflximab in the context of inflammatory bowel disease [IBD] are still scanty. In the present study, we aimed to compare the biological activities of CT-P13 and infliximab with specific focus on intestinal cells so as to gain insight into the potential biosimilarity of these two agents for treatment of IBD., Methods: CT-P13 and infliximab were investigated and compared by in vitro experiments for their neutralisation ability of soluble tumour necrosis factor alpha [sTNFα] and membrane-bound tumour necrosis factor alpha [mTNFα], suppression of cytokine release by reverse signalling, induction of regulatory macrophages and wound healing, and antibody-dependent cell cytotoxicity [ADCC]., Results: CT-P13 showed similar biological activities to infliximab as gauged by neutralisation of soluble TNFα, as well as blockade of apoptosis and suppression of pro-inflammatory cytokines in intestinal Caco-2 cells. Infliximab and CT-P13 equally induced apoptosis and outside-to-inside signals through transmembrane TNFα [tmTNFα]. Moreover, regulatory macrophage induction and ensuing wound healing were similarly exerted by CT-P13 and infliximab. However, neither CT-P13 nor infliximab exerted any significant ADCC of ex vivo-stimulated peripheral blood monocytes or lamina propria mononuclear cells from IBD patients., Conclusions: These findings indicate that CT-P13 and infliximab exert highly similar biological activities in intestinal cells, and further support a mechanistic comparability of these two drugs in the treatment of IBD., (Copyright © 2016 European Crohn’s and Colitis Organisation (ECCO). Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com)

Objectives: To evaluate the characteristics of a novel human cell line, F2N78, including growth performance, physicochemical properties, and biological activity via direct comparison with CHO cells., Results: The culture performance and physicochemical properties of antibodies produced from F2N78 and CHO cells were compared. For charge variants, antibodies produced from F2N78 cells contained a greater acidic charge variants than CHO cells. Regarding main glycoforms, degree of galactosylation was 52% in CT-A produced from F2N78 cells compared to CHO cells (37%). For sialic acid forms, α-2,6-linked sialic acid and N-acetylneuraminic acid (NANA) residues were observed in antibodies produced from F2N78 cells. In contrast, only α-2,3 linked sialic acid forms were detected in antibodies produced from CHO cells, and NANA and N-glycolylneuraminic acid were detected. Hybrid structure and bisecting structure were only observed in F2N78 cells., Conclusions: F2N78 cells stably produced antibodies with human specific N-glycan. The novel expression system based on human cells may facilitate the development of an alternative host cell for production of recombinant proteins.

Background: Novel oral anticoagulants (NOACs) expand the treatment options for patients with atrial fibrillation (AF). Their benefits need to be weighed against the risk-benefit ratio in real-world elderly patients, prompting this cost-effectiveness study of NOACs (apixaban, dabigatran, edoxaban and rivaroxaban), warfarin and aspirin for stroke prevention in AF., Methods: Applying effectiveness estimates from a network meta-analysis involving over 800,000 patients from randomised controlled trials and observation studies, our Markov model projected cost and health outcomes for a cohort of 65-year-old AF patients over a life-time. We performed subgroup analysis stratified by age (65-74 and ≥75years), with further analysis limited to observational studies involving dabigatran and rivaroxaban., Results: Compared to warfarin, NOACs (except dabigatran 110) were associated with incremental cost-effectiveness ratios ranging from USD 24,476 to USD 41,448 that were within cost-effectiveness threshold of USD 49,700 (one gross domestic product per capita in Singapore in 2015). Aspirin regimens were dominated. In elderly aged ≥75years, cost effectiveness of NOACs (except apixaban) decreased, owing to worsened performance in safety profile. Analysis limited to observational studies revealed that dabigatran 150 and rivaroxaban were not cost-effective, reflecting increased bleeding risks in non-controlled settings. Threshold analyses revealed that apixaban was no longer cost-effective at two to three times higher bleeding risk., Conclusions: Whilst NOACs are cost-effective in the younger elderly compared to warfarin, their benefits appear to be offset by worsened risk profile in older elderly, especially in non-controlled settings. Decisions on appropriate AF treatment should balance treatment-related benefits, risks, and patient preference., (Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.)

Background and Aim: The high cost of chronic hepatitis C (HCV) direct-acting antivirals (DAAs) poses significant financial challenges for health payers, especially in Asia. A personalized treatment strategy based on individualized probability of virological response using oral DAAs as second-line therapy would seem practical but has not been studied., Methods: We performed a Markov model to project health outcomes and costs for patients with genotype 1 HCV through 10 treatment strategies over a lifetime period. The implication of retreatment was also incorporated to reflect real-life situation., Results: Using boceprevir and peginterferon/ribavirin (BOC/PR, the least costly treatment) as a base case, the all-oral therapies such as ombitasvir/paritaprevir/ritonavir-dasabuvir are cost-effective with an incremental cost-effective ratio of $US50 828. However, the all-oral DAAs would no longer be cost-effective compared with conventional therapies if retreatment were taken into account. A road map strategy using rapid virological response to guide use of BOC/PR and sofosbuvir/PR had the most favorable incremental cost-effective ratio ($US27 782) relative to BOC/PR. Nevertheless, the trade-off with the cost-effectiveness of the road map strategy is an increased number of liver-related deaths compared with all-oral DAAs (52 vs 10-20 per 10 000 patients) by incorporating retreatment., Conclusions: The 12-week all-oral DAAs were cost-effective options using conventional drug-to-drug comparison. However, they cease to be cost-effective when treatment strategies incorporating DAA retreatment for interferon failures are incorporated. HCV management can be optimized by adopting individualized treatment algorithm providing a practical solution to health payers to make oral DAAs accessible to those who need them most., (© 2016 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background: In the management of Asian patients with acute coronary syndrome (ACS), the comparative cost-effectiveness of ticagrelor and prasugrel, referenced to generic clopidogrel, is unknown., Objective: To assess the cost-effectiveness of ticagrelor and prasugrel as compared with generic clopidogrel in patients with ACS in Singapore., Methods: A Markov model simulating a typical cohort of 62-year-old patients with ACS was constructed from a patient's perspective over a lifetime horizon. Treatment effects and adverse events, including nonfatal myocardial infarction, major bleeding related to non-coronary artery bypass grafting, dyspnea, or death, were estimated from pivotal trials comparing clopidogrel with ticagrelor and prasugrel, respectively. Costs were estimated from a tertiary hospital with more than 1500 admissions for ACS per year., Results: The incremental cost-effectiveness ratio (ICER) per life-year gained for ticagrelor was about three times more favorable than for prasugrel (Singapore dollar [SGD] 13,276 vs. SGD 38,809). The ICER per quality-adjusted life-year (QALY) for prasugrel and ticagrelor, however, was comparable at SGD 18,921 and SGD 18,647, respectively. Deterministic sensitivity analysis revealed that the ICER per QALY gained for prasugrel and ticagrelor was most sensitive to the hazard ratio of all-cause mortality and utility for dyspnea, respectively. Probabilistic sensitivity analysis demonstrated that compared with clopidogrel, the probabilities of prasugrel and ticagrelor being cost-effective are 87.1% and 88.3% based on the willingness-to-pay value of SGD 65,000 (one time the gross domestic product per capita in Singapore)., Conclusions: Ticagrelor is more cost-effective than prasugrel in reducing all-cause mortality in patients with ACS. The cost-effectiveness of ticagrelor and prasugrel become similar, however, when accounting for the impact of dyspnea on QALY., (Copyright © 2016 International Society for Pharmacoeconomics and Outcomes Research (ISPOR). Published by Elsevier Inc. All rights reserved.)

This study modelled the cost-effectiveness of 11 oral antipsychotics for relapse prevention among patients with remitted schizophrenia in Singapore. A network meta-analysis determined the relative efficacy and tolerability of 11 oral antipsychotics (amisulpride, aripiprazole, chlorpromazine, haloperidol, olanzapine, paliperidone, quetiapine, risperidone, sulpiride, trifluoperazine and ziprasidone). The clinical estimates were applied in a Markov model to estimate lifetime costs and quality-adjusted life-years gained. Quality-of-life data were obtained from published literature. Resource utilization and cost data were retrieved from local hospital databases. The annual direct cost of healthcare services for a patient experiencing a relapse episode was three-fold that of a patient not in relapse of schizophrenia. The most favourable pharmacological treatment for relapse prevention was olanzapine with an annual probability of relapse of 0.24 (0.13-0.38) with placebo as a reference of 0.75 (0.73-0.78). Olanzapine emerged as the dominant treatment with the highest quality-adjusted life-years gained and lowest lifetime costs. Ziprasidone, aripiprazole and paliperidone incurred higher lifetime costs compared with no treatment. Probability and cost of relapse were key drivers of cost-effectiveness in sensitivity analyses. The data can help prescribers in choosing appropriate treatment and payers in allocating resources for the clinical management of this serious psychiatric disorder.

Background: For treatment of patients diagnosed with schizophrenia, comparative long-term effectiveness of antipsychotic drugs to reduce relapses when minimising adverse effects is of clinical interest, hence prompting this review., Aims: To evaluate the comparative long-term effectiveness of antipsychotic drugs., Method: We systematically searched electronic databases for reports of randomised controlled trials (RCTs) of antipsychotic monotherapy aimed at reducing relapse risks in schizophrenia. We conducted network meta-analysis of 18 antipsychotics and placebo., Results: Studies of 10 177 patients in 56 reports were included; treatment duration averaged 48 weeks (range 4-156). Olanzapine was significantly more effective than chlorpromazine (odds ratio (OR) 0.35, 95% CI 0.14-0.88) or haloperidol (OR=0.50, 95% CI 0.30-0.82); and fluphenazine decanoate was more effective than chlorpromazine (OR=0.31, 95% CI 0.11-0.88) in relapse reduction. Fluphenazine decanoate, haloperidol, haloperidol decanoate and trifluoperazine produced more extrapyramidal adverse effects than olanzapine or quetiapine; and olanzapine was associated with more weight gain than other agents., Conclusions: Except for apparent superiority of olanzapine and fluphenazine decanoate over chlorpromazine, most agents showed intermediate efficacy for relapse prevention and differences among them were minor. Typical antipsychotics yielded adverse neurological effects, and olanzapine was associated with weight gain. The findings may contribute to evidence-based treatment selection for patients with chronic psychotic disorders., Declaration of Interest: R.J.B. received grants from the Bruce J. Anderson Foundation and the McLean Private Donors Psychopharmacology Research Fund., Copyright and Usage: © The Royal College of Psychiatrists 2016. This is an open access article distributed under the terms of the Creative Commons Non-Commercial, No Derivatives (CC BY-NC-ND) licence.

Objectives: Effective formulary management in healthcare institutions safeguards rational drug use and optimizes health outcomes. We implemented a formulary management program integrating the principles of health technology assessment (HTA) to improve the safe, appropriate, and cost-effective use of medicine in Singapore., Methods: A 3-year formulary management program was initiated in 2011 in five public healthcare institutions. This program was managed by a project team comprising HTA researchers. The project team worked with institutional pharmacy and therapeutics (P&T) committees to: (i) develop tools for formulary drug review and decision making; (ii) enhance the HTA knowledge and skills of formulary pharmacists and members of P&T committees; (iii) devise a prioritization framework to overcome resource constraints and time pressure; and (iv) conceptualize and implement a framework to review existing formulary., Results: Tools that facilitate drug request submission, drug review, and decision making were developed for formulary drug inclusion. A systematic framework to review existing formulary was also developed and tested in selected institutions. A competency development plan was rolled out over 2 years to enhance formulary pharmacists' proficiency in systematic literature search and review, meta-analysis, and pharmacoeconomic evaluation. The plan comprised training workshops and on-the-job knowledge transfer between the project team and institutional formulary pharmacists through collaborating on selected drug reviews. A resource guide that consolidated the tools and templates was published to encourage the adoption of best practices in formulary management., Conclusions: Based on the concepts of HTA, we implemented an evidence-based approach to optimize formulary management.

Introduction: Novel oral anticoagulants (NOACs) expanded the options for stroke prevention in atrial fibrillation (AF). Earlier studies comparing their relative effectiveness and safety typically do not incorporate age-related differences or postmarketing studies. This study aimed to summarize and compare clinical and safety outcomes of oral antithrombotics for stroke prevention in AF in younger (65-74 years) and older (≥75 years) elderly., Methods: We searched PubMed, Embase, and The Cochrane Library from inception through May 1, 2015, for randomized and nonrandomized studies comparing NOACs, warfarin, and aspirin in elderly with AF. Stroke and systemic embolism (SSE) and major bleeding (MB) are the main outcomes. We also studied secondary outcomes of ischemic stroke, all-cause mortality, intracranial bleeding, and gastrointestinal bleeding., Results: Of 5255 publications identified, 25 randomized controlled trials and 24 nonrandomized studies of 897,748 patients were included. NOACs reduced the risk of SSE compared with warfarin (rate ratios [RRs] range from 0.78-0.82). Relative to SSE, NOACs demonstrated a smaller benefit for ischemic stroke (dabigatran 110 mg, RR 1.08; edoxaban, 1.00; apixaban, 0.99). On the contrary, aspirin was associated with a significantly higher risk of SSE, ischemic stroke, and mortality than warfarin or NOACs (RR > 1), particularly in older elderly. Regarding safety, medium-dose aspirin (100-300 mg daily) and aspirin/clopidogrel combination showed an increased risk of MB compared with warfarin (RR 1.17 and 1.15, respectively), as per dabigatran 150 mg and rivaroxaban in older elderly (RR 1.17 and 1.12, respectively). Among the NOACs, dabigatran 150 mg conferred greater gastrointestinal bleeding risk compared with warfarin (RR 1.51), whereas rivaroxaban (RR 0.73) demonstrated less benefit of reduced intracranial bleeding than other NOACs (RRs range 0.39-0.46)., Conclusions: Lower rates of SSE and intracranial bleeding were observed with the NOACs compared with warfarin. Dabigatran 150 mg and rivaroxaban were associated with higher rates of MB in older elderly., (Copyright © 2015 AMDA – The Society for Post-Acute and Long-Term Care Medicine. Published by Elsevier Inc. All rights reserved.)

Invasive fungal infections (IFIs) are associated with high mortality rates and large economic burdens. Triazole prophylaxis is used for at-risk patients with hematological malignancies or stem cell transplants. We evaluated both the efficacy and the cost-effectiveness of triazole prophylaxis. A network meta-analysis (NMA) of randomized controlled trials (RCTs) evaluating fluconazole, itraconazole capsule and solution, posaconazole, and voriconazole was conducted. The outcomes of interest included the incidences of IFIs and deaths. This was coupled with a cost-effectiveness analysis from patient perspective over a lifetime horizon. Probabilities of transitions between health states were derived from the NMA. Resource use and costs were obtained from the Singapore health care institution. Data on 5,505 participants in 21 RCTs were included. Other than itraconazole capsule, all triazole antifungals were effective in reducing IFIs. Posaconazole was better than fluconazole (odds ratio [OR], 0.35 [95% confidence interval [CI], 0.16 to 0.73]) and itraconazole capsule (OR, 0.25 [95% CI, 0.06 to 0.97]), but not voriconazole (OR, 1.31 [95% CI, 0.43 to 4.01]), in preventing IFIs. Posaconazole significantly reduced all-cause deaths, compared to placebo, fluconazole, and itraconazole solution (OR, 0.49 to 0.54 [95% CI, 0.28 to 0.88]). The incremental cost-effectiveness ratio for itraconazole solution was lower than that for posaconazole (Singapore dollars [SGD] 12,546 versus SGD 26,817 per IFI avoided and SGD 5,844 versus SGD 12,423 per LY saved) for transplant patients. For leukemia patients, itraconazole solution was the dominant strategy. Voriconazole was dominated by posaconazole. All triazole antifungals except itraconazole capsule were effective in preventing IFIs. Posaconazole was more efficacious in reducing IFIs and all-cause deaths than were fluconazole and itraconazole. Both itraconazole solution and posaconazole were cost-effective in the Singapore health care setting., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)

Background: Statins have been shown to be beneficial in primary and secondary prevention settings; however, their role in the elderly remains a clinical conundrum, given that age-related factors could alter the risk-benefit ratio of statin treatment. This study aimed to critically evaluate the efficacy and safety of statins for primary prevention of cardiovascular disease (CVD) in the elderly., Methods: We systematically reviewed randomized controlled trials comparing any statins with placebo or usual care for primary prevention of CVD in subjects aged ≥65 years. Relative risks (RRs) using a random effects model were calculated and sensitivity analyses were performed to assess the robustness of findings., Results: Eight studies (n = 25,952) were included in the meta-analysis. Statins significantly reduced the risks of composite major adverse cardiovascular events (RR 0.82, 95% CI 0.74-0.92), nonfatal myocardial infarction [MI] (0.75, 0.59-0.94) and total MI (0.74, 0.61-0.90). Treatment effects of statins were statistically insignificant in fatal MI (0.43, 0.09-2.01), stroke (fatal: 0.76, 0.24-2.45; nonfatal: 0.76, 0.53-1.11; total: 0.85, 0.68-1.06) and all-cause mortality (0.96, 0.88-1.04). Significant differences were not observed in myalgia (0.88, 0.69-1.13), elevation of hepatic transaminases (0.98, 0.71-1.34), new-onset diabetes (1.07, 0.77-1.48), serious adverse events (1.00, 0.97-1.04) and discontinuation due to adverse events (1.10, 0.85-1.42). The occurrence of myopathy, rhabdomyolysis and cognitive impairment was largely unreported in the included trials., Conclusions: From a risk-benefit perspective, there is a role of statins for the primary prevention of major adverse cardiovascular events in elderly patients. Further studies are needed to ascertain the benefits of statins on fatal MI, stroke and all-cause mortality.

What Is Known and Objective: Proton pump inhibitors (PPIs) are one of the most widely used classes of drugs. However, the quantum clinical benefit of newer and more expensive PPIs over the older generation PPIs remains uncertain. This meta-analysis sought to assess the clinical and safety profiles of esomeprazole versus omeprazole at pharmacologically equivalent doses in healing gastroesophageal reflux disease (GERD), peptic ulcer disease and eradicating Helicobacter pylori (H. pylori) infection., Methods: PubMed and the Cochrane Library were searched for randomized controlled trials comparing esomeprazole with omeprazole at all doses up to February 2015. Trials were assessed by two reviewers for eligibility according to predefined study inclusion criteria. Meta-analysis was conducted using a random effects model, and heterogeneity in the estimated effects was investigated using meta-regression. Sensitivity analysis was performed to test the robustness of the findings., Results and Discussion: Fifteen trials were included and none of which compared esomeprazole with omeprazole in peptic ulcer disease. The included studies had not evaluated esomeprazole 20 mg versus omeprazole 40 mg. In GERD, esomeprazole 40 mg (relative risk (RR) = 1·07; 95% confidence interval (CI) 1·02 to 1·12) and 20 mg (RR=1·04; 95% CI 1·01 to 1·08) significantly improved esophagitis healing when compared with omeprazole 20 mg at week 8. The corresponding numbers needed to treat were 17 and 30, respectively. No significant difference was observed between esomeprazole 20 mg and omeprazole 20 mg at week 4. In H. pylori eradication, there was no difference in the treatment effects between esomeprazole 20 mg and omeprazole 20 mg (RR = 1·01;95% CI 0·96 to 1·05). Their safety profiles were comparable., What Is New and Conclusion: Esomeprazole demonstrated better esophagitis healing rate in patients with GERD than omeprazole at week 8. However, this clinical advantage diminished when both drugs were given at the same doses at week 4. Superiority of esomeprazole was not observed in the H. pylori eradication rates., (© 2015 John Wiley & Sons Ltd.)

Background: Major depressive disorder (MDD) impacts health, quality of life and workplace productivity. Antidepressant treatment is the primary therapeutic intervention. This study assessed the efficacy and tolerability of new generation antidepressants and their cost-effectiveness in the Singapore healthcare system., Methods: We conducted a systematic search for head-to-head randomised controlled trials on ten antidepressants (agomelatine, duloxetine, escitalopram, fluvoxamine, fluoxetine, mirtazapine, paroxetine, sertraline, trazodone and venlafaxine) employed as monotherapy in acute MDD management. We performed a network meta-analysis to compare their relative efficacy. The outcome measures for efficacy were response and remission rate, and mean change in Hamilton Depression Rating Scale (HDRS) score; and for tolerability, study withdrawal rates due to adverse events. To evaluate their relative cost effectiveness, a decision tree simulating a cohort of MDD patients using antidepressant as monotherapy was constructed from a societal perspective over 6 months. We used effectiveness data from our network meta-analysis and local data on resource use for depression in Singapore. The incremental cost expected for each additional quality-adjusted life-year (QALY) gained was calculated and presented as the incremental cost-effectiveness ratio (ICER)., Results: We identified 76 relevant articles for the network meta-analysis. Of the ten agents included in the analysis, mirtazapine and agomelatine were most efficacious in achieving response and remission, respectively. Mirtazapine and duloxetine resulted in the greatest magnitude of change in the HDRS score. Agomelatine, escitalopram and sertraline were the best tolerated of the drugs analysed, while duloxetine was the least well tolerated drug. Using a composite outcome of efficacy (response and remission rates) and tolerability, agomelatine, escitalopram and mirtazapine were the favoured treatments. In the cost-effectiveness analysis, apart from agomelatine, all the treatments were dominated by mirtazapine. Against mirtazapine, agomelatine was not cost effective given that its ICER exceeded the threshold value., Conclusion: Agomelatine, escitalopram and mirtazapine had favourable balance between efficacy and tolerability. In addition, mirtazapine was a cost-effective option in the Singapore healthcare system.

Purpose: This study aimed to evaluate the cost-effectiveness of statins for primary prevention of stroke and myocardial infarction (MI) in the elderly in Singapore., Methods: A Markov model was developed to investigate the lifetime costs, quality-adjusted life years (QALYs) and incremental cost-effectiveness ratios (ICERs) of statin treatment in those aged 65 years and older without a history of stroke or MI from the perspective of Singapore's healthcare system, using elderly-specific clinical data and local costs from hospital databases. A lifetime horizon was used and all costs and health outcomes were discounted at 3% annually., Results: In the base-case analysis, statin treatment prevented an additional four strokes and eight MIs among 1,000 "healthy" elderly individuals compared with no treatment. Statin treatment resulted in a QALY gain of 0.26 and additional costs of SGD 11,314 per person, yielding an ICER of SGD 43,925 (USD 33,495) per QALY gained. The results were sensitive to statin effectiveness, particularly statins' effect on all-cause mortality, and cost of statin medication. Probabilistic sensitivity analysis demonstrated that the probability of statin treatment being cost-effective was 72% at a willingness-to-pay threshold of SGD 65,000 (USD 49,546) per QALY gained. Shortening the time horizon from lifetime to 10 years (simulating limited life expectancy) considerably increased the ICER to SGD 291,313 (USD 167,171) per QALY. Female gender and younger age were also associated with higher ICERs owing to a lower baseline risk of cardiovascular disease (CVD) and higher costs to manage events in these subgroups., Conclusions: Statin treatment for the primary prevention of CVD in the elderly was cost-effective. However, treatment warrants re-evaluation when the prognosis of the individual is considered less than ten years; other goals may take precedence over CVD prevention.

Objective: To systematically review the efficacy and tolerability of 4 prostaglandin analogues (PGAs) as first-line monotherapies for intraocular pressure (IOP) lowering in adult patients with primary open-angle glaucoma or ocular hypertension., Data Sources: A literature search was performed in PubMed (1965-June 2013) and the Cochrane Library (1980-June 2013) using the search terms ocular hypertension, open-angle glaucoma, prostaglandin analogues, bimatoprost, latanoprost, tafluprost, and travoprost. Additional studies were searched from the reference lists of identified publications., Study Selection and Data Extraction: In all, 32 randomized controlled trials comparing between PGAs (bimatoprost 0.03%, latanoprost 0.005%, tafluprost 0.0015%, and travoprost 0.004%) or PGA with timolol were selected., Data Synthesis: A network meta-analysis was conducted. Using timolol as reference, the relative risks (RRs) of achieving treatment success, defined as the proportion of patients achieving at least 30% IOP reduction, with 95% CIs, were as follows: bimatoprost, 1.59 (1.28-1.98); latanoprost, 1.32 (1.00-1.74); travoprost, 1.33 (1.03-1.72); and tafluprost, 1.10 (0.85-1.42). The mean IOP reductions after 1 month were 1.98 (1.50-2.47), 1.01 (0.55-1.46), 1.08 (0.59-1.57), and 0.46 (-0.41 to 1.33) mm Hg, respectively, and the results were sustained at 3 months. Bimatoprost was associated with the highest risk of developing hyperemia, whereas latanoprost had the lowest risk, with RRs (95% CI) of 4.66 (3.49-6.23) and 2.30 (1.76-3.00), respectively., Conclusions: Bimatoprost achieved the highest efficacy in terms of IOP reduction, whereas latanoprost had the most favorable tolerability profile. This review serves to guide selection of the optimal PGA agent for individual patient care in clinical practice., (© The Author(s) 2014.)

Background: High-alert medications can cause significant patient harm when used in error. A multicenter, multidisciplinary, high-alert medication collaborative was established in Singapore in 2009 to identify and maintain a current list of high-alert medications and to create systematic approaches for preventing and reducing the risk of medication errors and adverse drug events (ADEs) for high-alert medications., Methods: The collaborative was led by a core multidisciplinary team consisting of pharmacists, nurses, and physicians, as well as clinical services and quality personnel, from six primary and acute care institutions. Multidisciplinary work groups were formed to drive the improvement efforts using the Plan-Do-Study-Act (PDSA) cycles. Tracking of improvement work was conducted with an adaptation of the Institute for Healthcare Improvement Trigger Tool method., Results: A localized high-alert medication list was developed through local ADE reports, literature review, an online survey of health care professionals, and expert opinion. Some 130 interventions were proposed to prevent, detect, and mitigate harm from the use of high-alert medications for 10 drug classes/drugs. A significant number of these interventions were tested and revised during the PDSA cycles before implementation throughout the institution and subsequent spread to other institutions. Outcome audits identified areas for improvement. The interventions, which were subsequently incorporated into the change packages, led to a 50% and 67% decline in the ADE rates for radiocontrast agents and heparin, respectively., Conclusion: The collaborative has provided a sound framework for ongoing development and refinement of high-alert medication change packages and for sharing of ADE data and best practices across the participating institutions.

Seeds of two selected clones of Artemisia annua L., TC1 and TC2, were germinated in a greenhouse. Four-week-old seedlings from both clones were grown in the Thù Đúc province of Ho Chi Minh City on 2(nd) January 2009 and Đà Lat on 20(th) January 2009. During this study period in Thù Đúc province, which is situated 4-5 m above sea level, was experiencing a tropical, dry season with temperatures ranging from 26.2°C-32.8°C. Đà Lat, situated at 1500-2000 m above sea level, was having temperate, dry season with lower temperatures, ranging from 10.5°C-18.0°C. The high temperatures and low elevation in Thù Đúc Province led to slow vegetative growth for all of the plants from the two different clones and the artemisinin contents were significantly reduced. The temperate environment of Đà Lat supported robustly growing plants, with plant heights and branch lengths 4-5 times taller and longer that those planted at Thù Đúc Province. The artemisinin contents of A. annua planted at Đà Lat were 3-4 times greater than those cultivated at Thù Đúc Province. Hence, this study indicated that the variations observed in plant growth and artemisinin contents were due to temperature effects because the two selected clones were genetically homogenous. The cold weather of Đà Lat was suitable for planting of A. annua as opposed to the tropical weather of Thù Đúc Province.

The development of a two phase hollow fiber liquid-phase microextraction technique, followed by gas-chromatography-flame ionization detection (GC-FID) for the profiling of the fatty acids (FAs) (lauric, myristic, palmitic, stearic, palmitoleic, oleic, linoleic, linolenic and arachidic) in vegetable oils is described. Heptadecanoic acid methyl ester was used as the internal standard. The FAs were transesterified to their corresponding methyl esters prior to the extraction. Extraction parameters such as type of extracting solvent, temperature, extraction time, stirring speed and salt addition were studied and optimized. Recommended conditions were extraction solvent, n-tridecane; extraction time, 35 min; extraction temperature, ambient; without addition of salt. Enrichment factors varying from 37 to 115 were achieved. Calibration curves for the nine FAs were well correlated (r(2)>0.994) within the range of 10-5000 μg L(-1). The limit of detection (signal:noise, 3) was 4.73-13.21 ng L(-1). The method was successfully applied to the profiling of the FAs in palm oils (crude, olein, kernel, and carotino cooking oil) and other vegetable oils (soybean, olive, coconut, rice bran and pumpkin). The encouraging enrichments achieved offer an interesting option for the profiling of the minor and major FAs in palm and other vegetable oils., (Copyright © 2010 Elsevier B.V. All rights reserved.)

Introduction: We appraised the roles and responsibilities assigned to community pharmacists internationally and in Singapore., Materials and Methods: A systematic search of international peer-reviewed literature was undertaken using Medline. Grey literature was identified through generic search engines. The search period was from 1 January 1991 to 30 July 2009. The search criteria were English language manuscripts and search terms "community pharmacist", "community pharmacy", "disease management" and "roles" as a major heading. Boolean operators were used to combine the search terms. Identified abstracts were independently reviewed and the findings were presented as a narrative summary., Results: Overall, we reviewed 115 articles on an abstract level and retrieved 45 of those as full text articles for background information review and inclusion into the evidence report. Of the articles included in the review, 32% were from United Kingdom (UK). Literature highlights the multi-faceted role of the community pharmacist in disease management. Community pharmacists were involved in the management of asthma, arthritis, cardiovascular diseases, diabetes, depression, hypertension, osteoporosis and palliative care either alone or in the disease management team. Evidence of effectiveness for community pharmacy/ community pharmacist interventions exists for lipid, diabetes, and hypertension management and for preventive services such as weight management, osteoporosis prevention and fl u immunisation services. Majority of the community pharmacists in Singapore play the traditional role of dispensing. Attempts by the private community pharmacies to provide some professional services were not successful due to lack of funding. Factors found to impede the growth of community pharmacists are insufficient integration of community pharmacist input into healthcare pathways, poor relationship among pharmacists and physicians, lack of access to patient information, time constraints and inadequate compensation., Conclusion: Evidence from observational studies points out the wide range of roles played by the community pharmacist and provides insights into their integration into chronic disease management programmes and health promotion.

A comparative study of oxidative decomposition behavior of a wide range of vegetable oils and its correlation to iodine value (IV) using thermogravimetric analysis (TGA) was described. The oxidative decomposition of saturated fatty acids shows weight loss before 385 degrees C while oxidative decomposition of unsaturated fatty acids shows lower rate of weight loss (dWt/dt) compared to saturated fatty acids due to the oxidation process ('up taking ' of oxygen) involving breaking down of double bond to form primary and secondary oxidation products, which leads to some weight gain in the sample before being decomposed. The relative differences in the dWt/dt (%/min) of the both fatty acids give different decomposition steps in TGA thermogram, enabling IV to be determined through the percentage weight loss of saturated fatty acids per 100% of total sample weight (excluding weight loss from moisture and volatile compounds). Therefore, TGA method can be used as an alternative method for IV determination with no sample pre-dilution and solvent consumption. Using the TGA methods, good correlation (r = 0.9889) with standard AOCS method was achieved.

A flow injection analysis (FIA) procedure for the determination of anisidine value (AV) in palm olein using a triiodide detector is described. Undiluted oil sample and chloramine-T reagent were added to a reaction chamber, and reaction was accelerated by applying a short vortex action (typically for 30 s). After allowing the emulsified oil phase to be separated from the aqueous phase (bottom layer), an aliquot of the aqueous phase (containing unreacted chloramine-T) was aspirated into a carrier stream that contained I(-) where the chloramine-T oxidized the I- to form I3(-) which was finally detected by a flow-through triiodide potentiometric detector. Variables that affect the FIA signals such as size of the reaction chamber, oil and reagent flow rates, chloramine-T concentration, vortex time, time for phase separation, carrier stream pH and injected volume were studied. The optimized FIA procedure is linear over 1.0-23.0 AV. The method exhibits good repeatabililty (R.S.D. of +/-3.16% (n = 4) for the determination of 5.0 AV) and a sampling rate of 40 samples per hour was achieved. Good correlation (r2 = 0.996 (n = 4)) between the proposed method and the manual American Oil Chemists' Society procedure was found when applied to the determination of twenty different types of palm olein samples.

Vectors derived from adeno-associated virus type 2 (AAV2) are promising gene delivery vehicles, but it is still challenging to get the large number of recombinant adeno-associated virus (rAAV) particles required for large animal and clinical studies. Current transfection technology requires adherent cultures of HEK 293 cells that can only be expanded by preparing multiple culture plates. A single large-scale suspension culture could replace these multiple culture preparations, but there is currently no effective co-transfection scheme for generating rAAV from cells in suspension culture. Here, we weaned HEK 293 cells to suspension culture using hydrogel-coated six-well culture plates and established an efficient transfection strategy suitable for these cells. Then the cultures were gradually scaled up. We used linear polyethylenimine (PEI) to mediate transfection and obtained high transfection efficiencies ranging from 54% to 99%, thereby allowing efficient generation of rAAV vectors. Up to 10(13) rAAV particles and, more importantly, up to 10(11) infectious particles were generated from a 2-L bioreactor culture. The suspension-transfection strategy of this study facilitates the homogeneous preparation of rAAV at a large scale, and holds further potential as the basis for establishing a manufacturing process in a larger bioreactor., (2006 Wiley Periodicals, Inc.)

The MGpUK-5 cell line, transformed with a single-chain urokinase-type plasminogen activator (scu-PA) minigene, generated mRNA transcripts and scu-PA titers corresponding to 65% or 86% of the amount generated before serum-free adaptation, despite significant loss of scu-PA gene copies during adaptation to serum-free culture. To further augment scu-PA production, a culture strategy employing sodium butyrate was explored. In 60-mL spinner flask cultures, sodium butyrate in the concentration range 1-10 mM allowed scu-PA production 2- to 3-fold higher than that in the negative control culture. Its productivity-enhancing activity was dependent on cell density in a range of 1-5 x 10(6) cells/mL, generating 72,200 +/- 8,100 IU/mL (480 +/- 50 mg/L) in 60-mL spinner flask cultures. To confirm this result, cells were grown to 4.4 x 10(6) cells/mL and treated with 5 mM sodium butyrate in a 2.5-L perfusion culture. The scu-PA titer increased more than 2-fold, and specific production rate of scu-PA increased 3-fold by this treatment. Overall, this perfusion culture gave rise to 1.7 x 10(8) IU scu-PA (1.1 g), comparable to total scu-PA production in a batch butyrate-treated culture performed at a 25-L bioreactor scale (1.3-3.5 g). Our results suggest that sodium butyrate treatment on high-density culture enables scu-PA production in gram quantities.

Beta-carotene-15,15'-dioxygenase is an enzyme responsible for providing vertebrates with vitamin A by catalyzing oxidative cleavage of beta-carotene at its central double bond to two molecules of retinal in intestinal cells. However, little data have been reported regarding regulation of the enzyme activity. We have evaluated the effects of antioxidants and dietary flavonoids on the beta-carotene dioxygenase activity in vitro using a pig intestinal homogenate as the enzyme source. 2,6-Di-tert-butyl-4-methylphenol (BHT), a synthetic antioxidant, strongly inhibited the activity at the level of 10(-6) M (a mixed-type inhibition), whereas butylated hydroxyanisole, nor-dihydroguaiaretic acid, n-propyl gallate, and curcumin were moderately inhibitory. Flavonoids such as luteolin, quercetin, rhamnetin, and phloretin remarkably inhibited the dioxygenase activity noncompetitively, whereas flavanones, isoflavones, catechins, and anthocyanidins were less inhibitory. The structure-activity relationship indicated that catechol structure of ring B and a planar flavone structure were essential for inhibition. The enzyme inhibition was also indicated in the cultured Caco-2 cells by the significantly reduced conversion of beta-carotene to retinol when incubated with BHT and rhamnetin at 2 microM and 5 microM, respectively. The results suggest that some dietary antioxidants derived from food sources modulate conversion of beta-carotene to vitamin A in intestinal cells.

The ability of xanthophylls (canthaxanthin, zeaxanthin, and astaxanthin) as chain-breaking antioxidants was investigated in peroxyl radical-mediated peroxidation of phosphatidylcholine (PC) liposomes under atmospheric conditions using lipid-soluble and water-soluble radical generators. These xanthophylls retarded the chain propagation reaction of phosphatidylcholine hydroperoxides (PC-OOH) formation, although their activities to trap chain-carrying peroxyl radical were much less than that of alpha-tocopherol. In chick plasma studies, it was observed that endogenious xanthophylls participated in the antioxidant defenses against the attack of aqueous peroxyl radical. It was concluded that xanthophylls possess the ability to act as chain-breaking antioxidants in the peroxidation of membraneous phospholipids. Dietary xanthophylls may, therefore, be helpful in resisting membraneous phospholipids against oxidative damage in vivo.