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Sunil Shrestha,1 Asmita Priyadarshini Khatiwada,2 Binaya Sapkota,3 Simit Sapkota,4,5 Prabhat Poudel,6 Bhuvan KC,7,8 Siew Li Teoh,1 Ali Qais Blebil,1 Vibhu Paudyal9 1School of Pharmacy, Monash University Malaysia, Jalan Lagoon Selatan, Bandar Sunway, Selangor, 47500, Malaysia; 2Department of Health Outcomes Research and Policy, Harrison College of Pharmacy, Auburn University, Auburn, AL, USA; 3Department of Pharmaceutical Sciences, Nobel College, Kathmandu, Nepal; 4Department of Clinical Oncology, Civil Service Hospital, Minbhawan, Kathmandu, Bagmati Province, Nepal; 5Department of Clinical Oncology, Kathmandu Cancer Center, Tathali, Bagmati Province, Nepal; 6Nepal Medical College Hospital, Kathmandu, Province Bagmati, Nepal; 7College of Public Health, Medical & Veterinary Sciences, James Cook University, Townsville, QLD, Australia; 8Faculty of Pharmacy and Pharmaceutical Sciences Monash University Parkville Campus Parkville, Melbourne, VIC 3052, Australia; 9School of Pharmacy, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UKCorrespondence: Sunil Shrestha; Vibhu Paudyal, Tel +60 102874113, Email Sunil.shrestha@monash.edu; sunilcresta@gmail.com; v.paudyal@bham.ac.ukIntroduction: Opioid stewardship has been widely used to promote rational use, monitoring and discontinuation of opioid therapy; however, its definition and scope of practice remain unclear.Objective: To synthesize definitions of opioid stewardship proposed by clinical practice guidelines and professional societies, and to offer a proposal for a universally acceptable definition.Methods: Systematic literature searches were performed (earliest records to May 2022) in six databases (MEDLINE, EMBASE, APA PsycINFO, Scopus, and CENTRAL) and grey sources guidelines development bodies and professional societies through Google. The conventional but widely applied content analysis and word frequencies were used to analyze the definitions and scope of practice.Results: After removing duplicates, 449 articles were retrieved (439 databases and registers and 11 from other sources), 19 of which included a definition of “opioids stewardship”. A total of 12 themes was identified in the definitions, including 1) improvement or appropriateness of prescribing opioids use, 2) mitigation of risk from opioids, 3) monitoring opioid use, 4) evaluation of opioid use, 5) judicious opioid use, 6) appropriateness of opioid disposal, 7) identification and treatment of opioid use disorder, 8) reduction in mortality associated with opioid overdoses, 9) appropriate procurement practices, 10) appropriate storage, 11) promoting better communications between patients and prescribers including education provision and 12) patient-centered decision-making.Conclusion: Opioid stewardship is inconsistently defined across professional and research literature. While there is a greater focus on appropriateness and need for improvement of prescribing and monitoring of opioid use, the importance of communications between patients and prescribers, and patient involvement in both prescribing and deprescribing decision-making remains sparse. A comprehensive definition has been proposed as part of the work. There is a need to develop and validate the proposed definition and scope of practice to promote rationale for opioid prescribing, use and attainment of favourable outcomes through international consensus involving practitioners, researchers, and patients.Keywords: opioid, opioid stewardship, opioid stewardship definition, stewardship

Siew Li Teoh,1 Huey Yi Chong,1 Salina Abdul Aziz,2 Norliza Chemi,2 Abdul Razak Othman,2 Nurzuriana Md Zaki,2 Possatorn Vanichkulpitak,3 Nathorn Chaiyakunapruk1,4–6 1School of Pharmacy, Monash University Malaysia, Selangor, 2Department of Psychiatry and Mental Health, Hospital Kuala Lumpur, Kuala Lumpur, Malaysia; 3Faculty of Pharmacy, Silpakorn University, Nakhon Pathom, 4Center of Pharmaceutical Outcomes Research (CPOR), Department of Pharmacy Practice, Faculty of Pharmaceutical Sciences, Naresuan University, Phitsanulok, Thailand; 5School of Pharmacy, University of Wisconsin, Madison, WI, USA; 6Health and Well-being Cluster, Global Asia in the 21st Century (GA21) Platform, Monash University Malaysia, Selangor, MalaysiaIntroduction: Schizophrenia (SCZ) is a highly debilitating disease despite its low prevalence. The economic burden associated with SCZ is substantial and mainly attributed to productivity loss. To improve the understanding of economic burden of SCZ in the low- and middle-income country regions, we aimed to determine the economic burden of SCZ in Malaysia.Methods: A retrospective study was conducted using a prevalence-based approach from a societal perspective in Malaysia with a 1 year period from 2013. We used micro-costing technique with bottom-up method and included direct medical cost, direct non-medical cost, and indirect cost. The main data source was medical chart review which was conducted in Hospital Kuala Lumpur (HKL). The medical charts were identified electronically by matching the unique patient’s identification number registered under the National Mental Health Schizophrenia Registry and the list of patients in HKL in 2013. Other data sources were government documents, literatures, and local websites. To ensure robustness of result, probabilistic sensitivity analysis was conducted.Results: The total estimated number of treated SCZ cases in Malaysia in 2015 was 15,104 with the total economic burden of USD 100 million (M) which was equivalent to 0.04% of the national gross domestic product. On average, the mean cost per patient was USD 6,594. Of the total economic burden of SCZ, 72% was attributed to indirect cost, costing at USD 72M, followed by direct medical cost (26%), costing at USD 26M, and direct non-medical cost (2%), costing at USD 1.7M.Conclusion: This study highlights the magnitude of economic burden of SCZ and informs the policy-makers that there is an inadequate support for SCZ patients. More resources should be allocated to improve the condition of SCZ patients and to reduce the economic burden.Keywords: economic burden, schizophrenia, Malaysia, cost of illness, lower-income countries, middle-income countries, societal perspective

Lack of pharmacogenomics knowledge among healthcare professionals is the most significant cited barrier to implementing pharmacogenomics in clinical settings. Despite the growth in research initiatives and awareness of pharmacogenomics, healthcare professionals continue to report a lack of knowledge and confidence in practicing pharmacogenomics. This study aims to assess the current pharmacogenomics knowledge gaps and learning needs of healthcare professionals in Malaysia. A modified Delphi with a multidisciplinary expert panel was conducted, and a purposive sampling method was used with predefined selection criteria. Fourteen study sites in Malaysia were included. The cut-off value to approach consensus was predefined as a threshold of 60% or higher, and a quantitative descriptive statistical analysis was performed. The study demonstrated that all experts rated the suggested educational content components as essential/important to be included in the educational intervention. Additionally, experts highlighted the significant barriers and gaps to adopting and practicing pharmacogenomics. To conclude, this multisite Delphi study enabled the development of a tailored, effective, evidence-based, competency-based educational intervention in pharmacogenomics for healthcare professionals in Malaysia. To keep up with the rapid evolution of the pharmacogenomics field, healthcare professionals should be equipped with the necessary competencies required to practice pharmacogenomics for better health outcomes. Future research is needed to determine the feasibility of the proposed educational intervention., (© 2024 The Author(s). Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Purpose: This study aimed to examine the trajectory in health-related quality of life (HRQoL) during and after hospitalisation for worsening of heart failure (HF) in Malaysia., Methods: 200 patients with heart failure and reduced ejection fraction (HFrEF) admitted into two hospitals in Malaysia due to worsening of HF were surveyed using the EQ-5D-5 L questionnaire. The primary outcomes were utility values at admission, discharge and 1-month post-discharge (1MPD). Secondary outcomes included the visual analogue scores (VAS) and the proportion of patients reporting each EQ-5D-5 L dimension levels. Missing data were imputed using multiple imputation, and generalised linear mixed models were fitted., Results: At admission, the unadjusted mean utility values and VAS scores for HFrEF patients in Malaysia were as low as 0.150 ± 0.393 and 38.2 ± 20.8, respectively. After a median hospital stay of 4 days, there was a significant improvement in utility values and VAS scores by 0.510 (95% CI: 0.455-0.564) and 28.8 (95% CI: 25.5-32.1), respectively. The utility value and VAS score at 1-month post-discharge were not significantly different from discharge. The proportion of HFrEF patients reporting problems and severe problems in mobility, self-care, usual activities, and anxiety/depression, pain/discomfort reduced at varying degree from admission to discharge and 1MPD., Conclusion: HF is a progressive condition with substantial variation in HRQoL during the disease trajectory. During hospitalisation due to worsening of HF, HFrEF population has unfavourable HRQoL. Rapid and significant HRQoL improvement was observed at discharge, which sustained over one month. The study findings can inform future cost-effectiveness analyses and policies., (© 2024. The Author(s).)

Porphyromonas gingivalis is the major pathogenic bacteria found in the subgingival plaque of patients with periodontitis, which leads to neuroinflammation. The bacteria destroy periodontal tissue through virulence factors, which are retained in the bacteria's outer membrane vesicles (OMV). This study aimed to determine the real-time effect of an intraperitoneal injection of P. gingivalis OMV on the production and expression of inflammatory markers and histopathological changes in adult zebrafishes' central nervous systems (CNS). Following the LD50 (21 µg of OMV), the zebrafish were injected intraperitoneally with 18 µg of OMVs, and the control group were injected with normal saline at seven different time points. Brains of experimental zebrafish were dissected at desired time points for colorimetric assays, ELISA, and histology. This study discovered that nitric oxide and PGE2 were significantly increased at 45 min, while IL-1β and IL-6 were expressed at subsequent 12 h and 24 h time points, respectively. Histopathological changes such as blood coagulation, astrocytosis, edema, spongiosis, and necrosis were observed between the 6hour and 24 h time points. The two apoptotic enzymes, caspases 3 and 9, were not expressed at any point. In summary, the OMV-induced neuroinflammatory responses and histopathological changes in adult zebrafish were time-point dependent. This study will enrich our understanding of the mechanism of P. gingivalis OMVs in neuroinflammation in a zebrafish model, most especially the timing of the expression of inflammatory mediators in relation to observable changes in brain tissues.

Introduction: Pain is the most common complaint among cancer patients, significantly impairing their health-related quality of life (HRQOL). There is limited evidence on the characteristics of pain among cancer patients in Nepal with low-resource settings., Objectives: The primary objective of this study was to evaluate the clinical characteristics of pain, factors influencing pain intensity, and the association of pain severity with quality of life (QoL) among cancer patients. Secondary objectives included investigating perceived barriers to pain management and medication adherence among these patients., Methods: This multi-center, cross-sectional study enrolled adult patients (over 18 years old) with reported cancer diagnoses experiencing pain. Socio-demographic characteristics (e.g., age, gender, educational status), clinical characteristics (e.g. cancer diagnosis, staging), and pain characteristics (e.g., duration, type, location, medicines used for pain management, etc.) were recorded. Outcomes were assessed using the Numeric rating scale (NRS), Pain management Index, European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire, Barriers Questionnaire II, Medication Adherence Rating Scale, and Hospital Anxiety and Depression Scale., Results: Four hundred and eight patients participated in the study. The mean ± SD age was 54.87 ± 15.65, with 226 patients (55.4%) being female. The most common cancer diagnoses were cervical (17.6%), lung (11.8%), and colon/rectum (12.0%) cancers. The most common pain locations were the head and neck (27.0%); a majority (55.6%) reported pain duration of more than 3 months. Nociceptive pain was reported by 42.4% of patients; the mean ± SD of NRS was 4.31 ± 2.69, with 32.4% of patients experiencing moderate pain. Patients with mixed pain type (B = 1.458, p < 0.001) or pain in multiple sites (B = 1.175, p < 0.001), lower Karnofsky Performance Status (KPS) (B = -1.308, p < 0.001), and specific cancer diagnoses such as prostate (B = -2.045, p = 0.002), pancreatic (B = 1.852, p = 0.004), oesophageal (B = 1.674, p = 0.012), and ovarian cancer (B = 1.967, p = 0.047), experienced varying degrees of increased NRS score. The combined chemotherapy and radiotherapy treatment modality was associated with a lower NRS score (B = -0.583, p = 0.017). A significant inverse relationship was observed between pain severity and global health status/QoL (B = -37.36, p < 0.001. Key barriers to pain management included moderate perceptions of physiological effects, communication issues between doctors and patients, and concerns about the harmful effects of pain medicine. The prevalence of non-adherence to pain medications was 13.97%., Conclusion: In conclusion, this study highlights the multi-faceted nature of pain management and QoL for cancer patients in Nepal with low-resource settings. These findings underscore the multifactorial nature of pain perception in cancer patients, with mixed pain types, pain in multiple sites, lower KPS, and specific cancer diagnoses, all contributing significantly to pain severity. Additionally, pain severity was associated with declining QoL. These findings contribute valuable insights into the complex aspects of cancer pain and its broader implications for the well-being of patients, offering a foundation for targeted interventions and improved pain management strategies in the context of cancer care in low-resource settings., (© 2024. The Author(s).)

Parkinson's disease (PD) is a common motor neurodegenerative disease that still lacks effective therapeutic options. Previous studies have reported that lactoferrin exhibited neuroprotective effects in cellular and animal models of PD, typically induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) or 1-methyl-4-phenylpyridinium (MPP + ) synthetic toxin. However, the neuroprotective capacity of lactoferrin in the rotenone-induced cellular model of PD remains relatively less established. Unlike MPTP/MPP + , rotenone is a naturally occurring environmental toxin known to induce chronic toxicity and increase the risk of PD in humans. In this study, we constructed a cellular model of PD by differentiating SH-SY5Y neuroblastoma cells with retinoic acid into mature dopaminergic neurons with increased β-tubulin III and tyrosine hydroxylase expression, followed by 24 h of rotenone exposure. Using this cellular model of PD, we showed that lactoferrin (1-10 µg/ml) pre-treatment for 48 h decreased loss of cell viability, mitochondrial membrane potential impairment, reactive oxygen species generation and pro-apoptotic activities (pan-caspase activation and nuclear condensation) in cells exposed to rotenone (1 and 5 µM) using biochemical assays, Hoechst 33342 staining and immunocytochemical techniques. We further demonstrated that 48 h of lactoferrin (10 µg/ml) pre-treatment decreased Bax:Bcl2 ratio and p42/44 mitogen-activated protein kinase expression but increased pAkt expression in 5 µM rotenone-exposed cells. Our study demonstrates that lactoferrin neuroprotective capacity is present in the rotenone-induced cellular model of PD, further supporting lactoferrin as a potential PD therapeutic that warrants further studies., (© 2024. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Introduction: Deprescribing serves as a pivotal measure to mitigate the drug-related problem due to polypharmacy. This study aimed to map the factors influencing healthcare providers' deprescribing decision using the Behaviour Change Wheel framework and develop an innovative conceptual model to support deprescribing practice., Methods: A cross-sectional online survey targeting doctors and pharmacists was conducted to assess the influence of various factors on healthcare providers' comfort in recommending deprescribing. The conceptual model was formulated, based on the existing deprescribing framework and the Behaviour Change Wheel. The model's robustness was scrutinised through Partial Least Squares Structural Equation Modeling (PLS-SEM), and model-fitting indices were employed to obtain the best-fit model., Results: A total of 736 responses were analysed with the final best-fit model consisting of 24 items in 5 constructs ( R 2 : 0.163; SRMR: 0.064; rho&#95;c: 0.750-0.862; AVE: 0.509-0.627) and three independent factors. Based on the results, we proposed that deprescribing could be promoted through strategies aimed at enhancing healthcare providers internal capabilities such as knowledge levels, when patients' condition deteriorated and previous experiences with adverse events of drugs. Organisational support in providing such educational opportunities is important, with the empowerment of patient and healthcare providers through policy enhancements, guideline development, and effective communication., Conclusion: The deprescribing behaviours of healthcare professionals are influenced by an intricate interplay of patient, prescriber, and system factors. Enhancing deprescribing practices necessitates a comprehensive strategy that encompasses providers and patients' education, the development of structured deprescribing guidelines, the implementation of deprescribing support tools, and the enhancement of communication between healthcare providers., Competing Interests: No potential conflict of interest was reported by the author(s)., (© 2024 The Author(s). Published by Informa UK Limited, trading as Taylor & Francis Group.)

Background & Aims: The induction of effective CD8+ T cells is thought to play a critical role in the functional cure of chronic hepatitis B (CHB). Additionally, the use of checkpoint inhibitors is being evaluated to overcome T-cell dysfunction during CHB., Methods: A chimpanzee adenoviral vector (ChAdOx1-HBV) and a Modified vaccinia Ankara boost (MVA-HBV) encoding the inactivated polymerase, core, and S region from a consensus genotype C HBV were studied. Fifty-five patients with virally suppressed CHB and HBsAg <4,000 IU/ml were enrolled. Group 1 received MVA-HBV intramuscularly on Day 0 and 28, Group 2 received ChAdOx1-HBV on Day 0 and MVA-HBV on Day 28 (VTP-300), Group 3 received VTP-300 + low-dose nivolumab (LDN) on Day 28, and Group 4 received VTP-300 plus LDN with both injections., Results: VTP-300 alone and in combination with LDN was well tolerated with no treatment-related serious adverse events. Reductions of HBsAg were demonstrated in Group 2: 3 of 18 patients with starting HBsAg <50 IU/ml had durable log 10 declines of >0.7 log 10 at 2 months after the last dose. Group 3 (n = 18) had mean reductions in HBsAg of 0.76 log 10 and 0.80 log 10 (p <0.001) at 2 and 7 months after the last dose. Two patients developed persistent non-detectable HBsAg levels. CD4+ and CD8+ antigen-specific T-cell responses were generated and there was a correlation between IFN-γ ELISpot response and HBsAg decline in Group 2., Conclusions: VTP-300 induced CD4+ and CD8+ T cells and lowered HBsAg in a subset of patients with baseline values below 100 IU/ml. The addition of LDN resulted in significant reduction in surface antigen. VTP-300 is a promising immunotherapeutic that warrants further development alone or in combination therapies., Impact and Implications: The induction of potent, durable CD8+ T cells may be critical to achieving a functional cure in chronic HBV infection. A prime-boost immunotherapeutic consisting of an adenoviral-vector encoding hepatitis B antigens followed by a pox virus boost was shown to induce CD8+ T cells and to lower HBsAg, either alone or more impactfully when administered in conjunction with a checkpoint inhibitor, in patients with chronic hepatitis B. The use of immunotherapeutics in this setting warrants further evaluation., Clintrials: NCT047789., (Copyright © 2024 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Alzheimer's disease (AD) poses a major worldwide health challenge because of its profound impact on cognitive abilities and overall well-being. Despite extensive research and numerous clinical trials, therapeutic options remain limited. Our study aimed to investigate the potential of Kelulut honey (KH) as a novel therapeutic agent for addressing the multifactorial pathology of AD. We tried to evaluate the disease-attenuating and neuroprotective potential of KH in the intrahippocampally induced AD rat model by utilizing histochemistry and enzyme-linked immunosorbent assay (ELISA) studies. A total of 26 male Sprague Dawley rats weighing ~280-380 g were randomly divided into three groups: Control, AD-induced (Aβ), and AD-induced and treated with KH (Aβ+KH). The latter two groups underwent stereotaxic surgery, where 6.25 µg of amyloid β 1-42 peptides were injected intrahippocampally. One-week post-surgery, KH was administered to the treatment group at a dose of 1 g/kg body weight for a period of four weeks, after which the rats went through behavior tests. After completion of behavior analysis, the rats were sacrificed, and the brains were processed for histochemistry and ELISA studies. The open field test analysis demonstrated that KH improved the locomotion of Aβ+KH compared to Aβ ( p = 0.0013). In comparison, the Morris water maze did not show any nootropic effects on cognition with a paradoxical increase in time spent in the target quadrant by the Aβ group ( p = 0.029). Histochemical staining showed markedly increased Congo-red-stained amyloid plaques, which were significantly reduced in dentate gyrus of Aβ+KH compared to Aβ ( p < 0.05). Moreover, significantly higher apoptosis was seen in the Aβ group compared to Aβ+KH ( p < 0.01) and control groups ( p < 0.001). Furthermore, the ELISA studies deduced more phosphorylated tau in the diseased group compared to Aβ+KH ( p = 0.038) and controls ( p = 0.016). These findings suggest that KH consumption for twenty-eight days has the potential to attenuate the pathological burden of disease while exerting neuroprotective effects in rodent models of AD.

Despite extensive preclinical research over the years, a significant gap remains in our understanding of the specific effects of methamphetamine (METH) and amphetamine (AMPH) withdrawal. Understanding these differences could be pivotal to unveiling the unique pathophysiology underlying each stimulant. This may facilitate the development of targeted and effective treatment strategies tailored to the specific characteristics of each substance. Following PRISMA guidelines, this systematic review was conducted to examine alterations in spontaneous locomotor activity, specifically horizontal activity, in animals experiencing withdrawal from extended and repeated administration of AMPH or METH. Original articles were retrieved from four electronic databases, supplemented by a review of the references cited in the published papers. A total of thirty-one full-length articles (n = 31) were incorporated in the analysis. The results indicated that six studies documented a significant increase in horizontal activity among animals, seven studies reported decreased locomotion, and eighteen studies (8 AMPH; 10 METH) reported no significant alterations in the animals' locomotor activity. Studies reporting heightened locomotion mainly employed mice undergoing withdrawal from METH, studies reporting diminished locomotion predominantly involved rats undergoing withdrawal from AMPH, and studies reporting no significant changes in horizontal activity employed both rats and mice (12 rats; 6 mice). Drug characteristics, routes of administration, animal models, dosage regimens, duration, and assessment timing seem to influence the observed outcomes. Despite more than 50% of papers enlisted in this review indicate no significant changes in the locomotion during the stimulant withdrawal, the unique reactions of animals to withdrawal from METH and AMPH reported by some underscore the need for a more nuanced understanding of stimulant withdrawal., 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. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Kumar, Naina Mohamed, Mohamed, Ugusman, Muzaimi, Mohamed, Yahaya, Teoh, Kamaluddin, Abdul Hamid, Mehat and Shanmugam.)

Introduction: Pain is a significant healthcare challenge, impacting millions worldwide. Pharmacists have increasingly taken on expanded roles in managing pain, particularly in primary and ambulatory care contexts. This umbrella review aims to systematically evaluate evidence from published systematic reviews that explore the impact of pharmacist-delivered interventions on clinical, humanistic, and economic outcomes related to pain., Methods: A systematic search was conducted across six electronic databases, including Ovid Embase, MEDLINE, CINAHL, Scopus, CENTRAL, APA PsycINFO, and DARE, from inception until June 2023. Prior to inclusion, two independent reviewers assessed study titles and abstracts. Following inclusion, an assessment of the methodological quality of the included studies was conducted. AMSTAR 2 was used to evaluate the methodological quality of the included SRs., Results: From 2055 retrieved titles, 11 systematic reviews were included, with 5 out of 11 being meta-analyses. These SRs encompassed diverse pharmacist-led interventions such as education, medication reviews, and multi-component strategies targeting various facets of pain management. These findings showed favorable clinical outcomes, including reduced pain intensity, improved medication management, enhanced overall physical and mental well-being, and reduced hospitalization durations. Significant pain intensity reductions were found due to pharmacists' interventions, with standardized mean differences (SMDs) ranging from -0.76 to -0.22 across different studies and subgroups. Physical functioning improvements were observed, with SMDs ranging from -0.38 to 1.03. Positive humanistic outcomes were also reported, such as increased healthcare provider confidence, patient satisfaction, and quality of life (QoL). QoL improvements were reported, with SMDs ranging from 0.29 to 1.03. Three systematic reviews examined pharmacist interventions' impact on pain-related economic outcomes, highlighting varying cost implications and the need for robust research methodologies to capture costs and benefits., Conclusion: This umbrella review highlights the effectiveness of pharmacist-delivered interventions in improving clinical, humanistic, and economic outcomes related to pain management. Existing evidence emphasises on the need to integrate pharamacists into multi-disciplinary pain management teams. Further research is needed to investigate innovative care models, such as pharmacist-independent prescribing initiatives within collaborative pain management clinics., Competing Interests: Declaration of competing interest The authors declare that during the registration of this umbrella review in PROSPERO, it was indicated that the findings from the included studies would be reported following the guidelines of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020. However, once the review commenced, it was determined that the Preferred Reporting Items for Overviews of Reviews (PRIOR) would be more suitable for guiding umbrella reviews. This change in reporting guidelines may have influenced the review process and interpretation of the results. Additionally, some findings of this umbrella review were presented at the First Conference of the ISPOR Student Network Asia-Pacific Region on February 16–17, 2024. Apart from these, the authors have no competing interest to declare., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Objectives: A meta-analytic review was performed to critically synthesize the evidence of oil pulling on improving the parameters of gingival health, plaque control and bacteria counts against chlorhexidine and other mouthwash or oral hygiene practices., Methods: Databases including Medline, Embase and bibliographies were searched from inception to 1 April 2023. Randomized controlled trials (RCTs) with 7 days or longer duration of oil pulling with edible oils in comparison to chlorhexidine or other mouthwashes or oral hygiene practice concerning the parameters of plaque index scores (PI), gingival index scores (GI), modified gingival index scores (MGI) and bacteria counts were included. Cochrane's Risk of Bias (ROB) tool and the Grading of Recommendations Assessment, Development and Evaluation (GRADE) framework were employed to determine the quality of evidence. Two authors independently conducted study selection and data extraction. Meta-analyses of the effect of oil pulling on the parameters were conducted using an inverse-variance random-effects model., Results: Twenty-five trials involving 1184 participants were included. Twenty-one trials comparing oil pulling (n = 535) to chlorhexidine (n = 286) and non-chlorhexidine intervention (n = 205) were pooled for meta-analysis. More than half of the trials (n = 17) involved participants with no reported oral health issues. The duration of intervention ranged from 7 to 45 days, with half of the trials using sesame oil. When compared to non-chlorhexidine mouthwash interventions, oil pulling clinically and significantly improved MGI scores (Standardized mean difference, SMD = -1.14; 95% confidence interval [CI]: -1.31, -0.97). Chlorhexidine was more effective in reducing the PI scores compared to oil pulling, with an SMD of 0.33 (95% CI: 0.17, 0.49). The overall quality of the body of evidence was very low., Conclusions: There was a probable benefit of oil pulling in improving gingival health. Chlorhexidine remained superior in reducing the amount of plaque, compared to oil pulling. However, there was very low certainty in the evidence albeit the clinically beneficial effect of oil pulling intervention., (© 2023 The Authors. International Journal of Dental Hygiene published by John Wiley & Sons Ltd.)

Traumatic brain injury (TBI) is a major global health issue that affects millions of people every year. It is caused by any form of external force, resulting in temporary or permanent impairments in the brain. The pathophysiological process following TBI usually involves excitotoxicity, mitochondrial dysfunction, oxidative stress, inflammation, ischemia, and apoptotic cell death. It is challenging to find treatment for TBI due to its heterogeneous nature, and no therapeutic interventions have been approved thus far. Neurotrophins may represent an alternative approach for TBI treatment because they influence various functional activities in the brain. The present review highlights recent studies on neurotrophins shown to possess neuroprotective roles in TBI. Neurotrophins, specifically brain-derived neurotrophic factor (BDNF) and nerve growth factor (NGF) have demonstrated reduced neuronal death, alleviated neuroinflammatory responses and improved neurological functions following TBI via their immunomodulatory, anti-inflammatory and antioxidant properties. Further studies are required to ensure the efficacy and safety of neurotrophins to be used as TBI treatment in clinical settings., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Aim: This study aimed to examine the validity of EQ-5D-5L among HFrEF patients in Malaysia, and to explore the measurement equivalence of three main language versions., Methods: We surveyed HFrEF patients from two hospitals in Malaysia, using Malay, English or Chinese versions of EQ-5D-5L. EQ-5D-5L dimensional scores were converted to utility scores using the Malaysian value set. A confirmatory factor analysis longitudinal model was constructed. The utility and visual analog scale (VAS) scores were evaluated for validity (convergent, known-group, responsiveness), and measurement equivalence of the three language versions., Results: 200 HFrEF patients (mean age = 61 years), predominantly male (74%) of Malay ethnicity (55%), completed the admission and discharge EQ-5D-5L questionnaire in Malay (49%), English (26%) or Chinese (25%) languages. 173 patients (86.5%) were followed up at 1-month post-discharge (1MPD). The standardized factor loadings and average variance extracted were ≥ 0.5 while composite reliability was ≥ 0.7, suggesting convergent validity. Patients with older age and higher New York Heart Association (NYHA) class reported significantly lower utility and VAS scores. The change in utility and VAS scores between admission and discharge was large, while the change between discharge and 1MPD was minimal. The minimal clinically important difference for utility and VAS scores was ±0.19 and ±11.01, respectively. Malay and English questionnaire were equivalent while the equivalence of Malay and Chinese questionnaire was inconclusive., Limitation: This study only sampled HFrEF patients from two teaching hospitals, thus limiting the generalizability of results to the entire heart failure population., Conclusion: EQ-5D-5L is a valid questionnaire to measure health-related quality of life and estimate utility values among HFrEF patients in Malaysia. The Malay and English versions of EQ-5D-5L appear equivalent for clinical and economic assessments.

Background & Objectives: Despite much clinical and laboratory research that has been performed to explore the mechanisms of Parkinson's disease (PD), its pathogenesis remains elusive to date. Therefore, this study aimed to identify possible regulators of neurodegeneration by performing microarray analysis of the zebrafish PD model's brain following rotenone exposure., Methods: A total of 36 adult zebrafish were divided into two groups: control (n = 17) and rotenonetreated (n = 19). Fish were treated with rotenone water (5 μg/L water) for 28 days and subjected to locomotor behavior analysis. Total RNA was extracted from the brain tissue after rotenone treatment. The cDNA synthesized was subjected to microarray analysis and subsequently validated by qPCR., Results: Administration of rotenone has significantly reduced locomotor activity in zebrafish (p < 0.05), dysregulated dopamine-related gene expression ( dat, th1 , and th2, p < 0.001), and reduced dopamine level in the brain (p < 0.001). In the rotenone-treated group, genes involved in cytotoxic T lymphocytes ( gzm3, cd8a, p < 0.001) and T cell receptor signaling ( themis, lck, p < 0.001) were upregulated significantly. Additionally, gene expression involved in microgliosis regulation ( tyrobp, p < 0.001), cellular response to IL-1 ( ccl34b4, il2rb, p < 0.05), and regulation of apoptotic process ( dedd1, p < 0.001) were also upregulated significantly., Conclusion: The mechanisms of T cell receptor signaling, microgliosis regulation, cellular response to IL-1, and apoptotic signaling pathways have potentially contributed to PD development in rotenonetreated zebrafish., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Cervical cancer is a prevalent and often devastating disease affecting women worldwide. Traditional treatment modalities such as surgery, chemotherapy, and radiation therapy have significantly improved survival rates, but they are often accompanied by side effects and challenges that can impact a patient's quality of life. In recent years, the integration of essential oils into the management of cervical cancer has gained attention. This review provides an in-depth exploration of the role of various essential oils in cervical cancer, offering insights into their potential benefits and the existing body of research. The review also delves into future directions and challenges in this emerging field, emphasizing promising research areas and advanced delivery systems. The encapsulation of essential oils with solid lipid nanoparticles, nanoemulsification of essential oils, or the combination of essential oils with conventional treatments showed promising results by increasing the anticancer properties of essential oils. As the use of essential oils in cervical cancer treatment or management evolves, this review aims to provide a comprehensive perspective, balancing the potential of these natural remedies with the challenges and considerations that need to be addressed.

Objectives: This study aims to quantify the preferences of patients with advanced cancer for quality of life (QoL) outcomes versus survival extension in Malaysia. The secondary aim of this study is to explore the change in preferences over time., Methods: A discrete choice experiment was developed to include 7 attributes valued in cancer management: physical, psychological and social functioning, pain control, survival, place of death, and cost. Patients were recruited via convenience sampling from 2 Malaysian public hospitals. The survey questionnaire was administered to patients within 6 months of their cancer diagnosis with a follow-up 3 months later. Conditional logit regression was used to estimate the preference weight, relative attribute importance, and willingness to pay., Results: One hundred valid responses were collected at baseline and 45 at follow-up. Respondents placed higher values on QoL improvements from severe to moderate or mild levels and to achieve home death over survival extension from 6 to 18 months. However, additional improvements (from moderate to mild) in some of the QoL outcomes were not valued as highly as life extension from 12 to 18 months, showing that it was vital for patients to avoid being in "severe" health dysfunction. Improving physical dysfunction from severe to mild yielded 3 times as much value as additional 1-year survival. After 3 months, the respondents' preferences changed significantly, with increased relative attribute importance of physical functioning, pain control, and cost., Conclusions: As QoL outcomes are valued more than survival, palliative care should be introduced as early as possible to alleviate suffering related to advanced cancer., Competing Interests: Author Disclosures Links to the individual disclosure forms provided by the authors are available here., (Copyright © 2023 International Society for Pharmacoeconomics and Outcomes Research, Inc. Published by Elsevier Inc. All rights reserved.)

Introduction: Parkinson's disease (PD) is the second most common neurodegenerative disease caused by selective degeneration of dopaminergic neurons in the substantia nigra. Metallothionein has been shown to act as a neuroprotectant in various brain injury. Thus, this study aims to identify the effects of full-length human metallothionein 2 peptide (hMT2) in paraquat-induced brain injury in the zebrafish., Methodology: A total of 80 adult zebrafish were divided into 4 groups namely control, paraquat-treated, pre-hMT2-treated, and post-hMT2-treated groups. Fish were treated with paraquat intraperitoneally every 3 days for 15 days. hMT2 were injected intracranially on day 0 (pre-treated group) and day 16 (post-treated group). Fish were sacrificed on day 22 and the brains were collected for qPCR, ELISA and immunohistochemistry analysis., Results: qPCR analysis showed that paraquat treatment down-regulated the expression of genes related to dopamine activity and biosynthesis ( dat and th1 ) and neuroprotective agent ( bdnf ). Paraquat treatment also up-regulated the expression of the mt2 , smtb and proinflammatory genes ( il-1α , il-1β , tnf-α and cox-2 ). hMT2 treatment was able to reverse the effects of paraquat. Lipid peroxidation decreased in the paraquat and pre-hMT2-treated groups. However, lipid peroxidation increased in the post-hMT2-treated group. Paraquat treatment also led to a reduction of dopaminergic neurons while their numbers showed an increase following hMT2 treatment., Conclusion: Paraquat has been identified as one of the pesticides that can cause the death of dopaminergic neurons and affect dopamine biosynthesis. Treatment with exogenous hMT2 could reverse the effects of paraquat in the zebrafish brain.

Introduction: Neurotrophin-3 (NT3) is a neuroprotective growth factor that induces the development, maintenance and survival of neurons. This study aims to localize NT3-expressing cells in the adult zebrafish brain and examine the role of NT3 in a zebrafish Parkinson's disease (PD) model. Methods: Cellular localization of NT3 in adult zebrafish brains was conducted using in situ hybridization. Subsequently, adult zebrafish were injected intraperitoneally with 100 μg/g of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and treated with 400 ng/g body weight of recombinant NT3 (rNT3) via intracranial injection 24 h following MPTP injection. The fish were assessed for neurobehavioral, gene expression, immunohistology, and protein analysis on days 3, 5 and 10 post-MPTP injection. Results: Our findings showed that NT3 was extensively expressed throughout the adult zebrafish brain in neurons. Administration of rNT3 has significantly improved locomotor activity, with upregulation of th1 , dat , ntf3 and bdnf gene expressions compared to MPTP-induced zebrafish. Dopaminergic neurons were also significantly increased in the zebrafish brain following rNT3 treatment. ELISA analysis reported raised GST and decreased caspase-3 levels on day 3 of assessment. The trophic changes of rNT3, however, decline as the assessment day progresses. Conclusion: This study is the first to examine the role of NT3 in the adult zebrafish PD model. NT3 has remarkable trophic effects in the zebrafish PD model. However, further study is needed to examine the dosage requirements and long-term effects of NT3 in PD., 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 © 2023 Omar, Kumar and Teoh.)

Alzheimer's disease (AD) is characterized by the pathologic deposition of amyloid and neurofibrillary tangles in the brain, leading to neuronal damage and defective synapses. These changes manifest as abnormalities in cognition and behavior. The functional deficits are also attributed to abnormalities in multiple neurotransmitter systems contributing to neuronal dysfunction. One such important system is the dopaminergic system. It plays a crucial role in modulating movement, cognition, and behavior while connecting various brain areas and influencing other neurotransmitter systems, making it relevant in neurodegenerative disorders like AD and Parkinson's disease (PD). Considering its significance, the dopaminergic system has emerged as a promising target for alleviating movement and cognitive deficits in PD and AD, respectively. Extensive research has been conducted on dopaminergic neurons, receptors, and dopamine levels as critical factors in cognition and memory in AD. However, the exact nature of movement abnormalities and other features of extrapyramidal symptoms are not fully understood yet in AD. Recently, a previously overlooked element of the dopaminergic system, the dopamine transporter, has shown significant promise as a more effective target for enhancing cognition while addressing dopaminergic system dysfunction in AD., 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. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Shaikh, Ahmad, Teoh, Kumar and Yahaya.)

Background: The field of pharmacogenomics is rapidly advancing, but its adoption and implementation remain slow and lacking. Lack of pharmacogenomics knowledge among healthcare professionals is the most frequently cited barrier to adopting and implementing pharmacogenomics in clinical settings., Objectives: This study aimed to critically evaluate and determine the effectiveness of educational interventions in improving pharmacogenomics knowledge and practice., Methods: Four electronic databases were searched: MEDLINE, EMBASE, CENTRAL, and PsycINFO. Studies on pharmacogenomics educational interventions for health care professionals and students with pre- and post-intervention assessments and results were included. No restrictions were placed on time, language, or educational contexts. The educational outcomes measured include both objective and subjective outcomes. The pharmacogenomics competency domains used to judge educational interventions are based on the competency domains listed by the American Association of Colleges of Pharmacies (AACP). The National Heart, Lung, and Blood Institute of the National Institutes of Health was used for the quality assessment of pre-post studies with no control group and the controlled intervention studies. No meta-analysis was conducted; the data were synthesized qualitatively. The systematic review was reported in accordance with the PRISMA statement., Results: Fifty studies were included in this review. All included studies integrated the AACP pharmacogenomics competency domains into their educational interventions. Most of the studies had educational interventions that integrated clinical cases (n = 44; 88%). Knowledge was the most frequently evaluated outcome (n = 34; 68%) and demonstrated significant improvement after the educational intervention that integrated AACP pharmacogenomics competency domains and employed active learning with clinical case inclusion., Conclusion: This review provided evidence of the effectiveness of educational interventions in improving pharmacogenomics knowledge and practice. Incorporating pharmacogenomics competency domains into education and training, with patient cases for healthcare professionals and students, dramatically improved their pharmacogenomics knowledge, attitudes, and confidence in practice., Competing Interests: Declaration of competing interest No potential conflict of interest was reported by the author(s)., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Polypharmacy and potentially inappropriate medications (PIM) are common among older adults. To guide appropriate prescribing, healthcare professionals often rely on explicit criteria to identify and deprescribe inappropriate medications, or to start medications due to prescribing omission. However, most explicit PIM criteria were developed with inadequate guidance from quality metrics or integrating real-world data, which are rich and valuable data source., Aim: To develop a list of medications to facilitate appropriate prescribing among older adults., Methods: A preliminary list of PIM and potential prescribing omission (PPO) were generated from systematic review, supplemented with local pharmacovigilance data of adverse reaction incidents among older people. Twenty-one experts from nine specialties participated in two Delphi to determine the list of PIM and PPO in February and March 2023. Items that did not reach consensus after the second Delphi round were adjudicated by six geriatricians., Results: The preliminary list included 406 potential candidates, categorised into three sections: PIM independent of diseases, disease dependent PIM and omitted drugs that could be restarted. At the end of Delphi, 92 items were decided as PIM, including medication classes, such as antacids, laxatives, antithrombotics, antihypertensives, hormones, analgesics, antipsychotics, antidepressants, and antihistamines. Forty-two disease-specific PIM criteria were included, covering circulatory system, nervous system, gastrointestinal system, genitourinary system, and respiratory system. Consensus to start potentially omitted treatment was achieved in 35 statements across nine domains., Conclusions: The newly developed PIM criteria can serve as a useful tool to guide clinicians and pharmacists in identifying PIMs and PPOs during medication review and facilitating informed decision-making for appropriate prescribing., (© 2023. Dr. Zaheer-Ud-Din Babar and Auckland UniServices Ltd.)

Background: Polypharmacy and the use of potentially inappropriate medications (PIMs) are prevalent among older patients admitted to hospitals, posing a heightened risk of adverse drug events. This trial aims to evaluate the effectiveness of a pharmacist-led deprescribing intervention in reducing medications, PIM and improving clinical outcomes, using the locally developed Malaysian Potentially Inappropriate Prescribing Screening tool in Older Adults (MALPIP)., Methods: This is an 18-month cluster-randomized, open-label, parallel-arm controlled trial conducted at 14 public hospitals in the Perak state of Malaysia. Patients aged 60 and above, who have at least one medication and one comorbidity are eligible. A stratified-cluster randomization design is employed, with 7 hospitals assigned to the control arm and 7 hospitals assigned to the intervention arm. The MALPIP screening tool will be used in the intervention group to review the medications. If PIM is detected, the pharmacists will discuss with doctors and decide whether to stop or reduce the dose. The primary outcomes of this trial are the total number of medications and number of PIM. The secondary outcomes include fall, emergency department visits, readmissions, quality of life and mortality. Outcomes will be measured during enrolment, discharge, 6, 12, and 18 months., Discussion: This REVMED trial aims to test the hypothesis that a pharmacist-led deprescribing intervention initiated in the hospital will reduce the total number of medications and PIM 18 months after hospital discharge, reducing fall, emergency department visits, readmissions, mortality and lead to improvement in quality of life. Trial findings will quantify the clinical outcomes associated with reducing medications and PIM for hospitalized older adults with polypharmacy., Trial Registration Number: This trial was prospectively registered at clinicaltrials.gov (NCT05875623) on the 25th of May 2023. NCT05875623 Clinicaltrials.gov URL: NCT05875623 registered on 25th July 2023., (© 2023. Dr. Zaheer-Ud-Din Babar and Auckland UniServices Ltd.)

Objectives: Decision-analytic models (DAMs) with varying structures and assumptions have been applied in economic evaluations (EEs) to assist decision making for heart failure with reduced ejection fraction (HFrEF) therapeutics. This systematic review aimed to summarize and critically appraise the EEs of guideline-directed medical therapies (GDMTs) for HFrEF., Methods: A systematic search of English articles and gray literature, published from January 2010, was performed on databases including MEDLINE, Embase, Scopus, NHSEED, health technology assessment, Cochrane Library, etc. The included studies were EEs with DAMs that compared the costs and outcomes of angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, angiotensin-receptor neprilysin inhibitors, beta-blockers, mineralocorticoid-receptor agonists, and sodium-glucose cotransporter-2 inhibitors. The study quality was evaluated using the Bias in Economic Evaluation (ECOBIAS) 2015 checklist and Consolidated Health Economic Evaluation Reporting Standards (CHEERS) 2022 checklists., Results: A total of 59 EEs were included. Markov model, with a lifetime horizon and a monthly cycle length, was most commonly used in evaluating GDMTs for HFrEF. Most EEs conducted in the high-income countries demonstrated that novel GDMTs for HFrEF were cost-effective compared with the standard of care, with the standardized median incremental cost-effectiveness ratio (ICER) of $21 361/quality-adjusted life-year. The key factors influencing ICERs and study conclusions included model structures, input parameters, clinical heterogeneity, and country-specific willingness-to-pay threshold., Conclusions: Novel GDMTs were cost-effective compared with the standard of care. Given the heterogeneity of the DAMs and ICERs, alongside variations in willingness-to-pay thresholds across countries, there is a need to conduct country-specific EEs, particularly in low- and middle-income countries, using model structures that are coherent with the local decision context., (Copyright © 2023. Published by Elsevier Inc.)

Introduction: Parkinson's disease (PD) is the second most common neurodegenerative disease that severely affects the quality of life of patients and their family members. Exposure to 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has been shown to reflect behavioral, molecular, and proteomic features of PD. This study aimed to assess the protocol for inducing PD following MPTP injection in adult zebrafish., Methods: Fish were injected with 100 μg/g of MPTP intraperitoneally once or twice and then assessed on days 1 to 30 post-injection., Results: Between one-time and two-time injections, there was no significant difference in most locomotor parameters, expressions of tyrosine hydroxylase-2 ( th2 ) and dopamine transporter ( dat ) genes, and dopaminergic neurons (tyrosine hydroxylase positive, TH+ cells) counts. However, caspase-3 levels significantly differed between one- and two-time injections on the day 1 assessment., Discussion: Over a 30-day period, the parameters showed significant differences in swimming speed, total distance traveled, tyrosine hydroxylase-1 ( th1 ) and dat gene expressions, caspase-3 and glutathione protein levels, and TH+ cell counts. Days 3 and 5 showed the most changes compared to the control. In conclusion, a one-time injection of MPTP with delayed assessment on days 3 to 5 is a good PD model for animal studies., 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 © 2023 Omar, Kumar and Teoh.)

Background: Explicit potentially inappropriate medications (PIM) criteria are commonly used to identify and deprescribe potentially inappropriate prescriptions among older patients. Most of these criteria were developed specifically for the Western population, which might not be applicable in an Asian setting. The current study summarizes the methods and drug lists to identify PIM in older Asian people., Methods: A systematic review of published and unpublished studies were carried out. Included studies described the development of explicit criteria for PIM use in older adults and provided a list of medications that should be considered inappropriate. PubMed, Medline, EMBASE, Cochrane CENTRAL, CINAHL, PsycINFO, and Scopus searches were conducted. The PIMs were analyzed according to the general conditions, disease-specific conditions, and drug-drug interaction classes. The qualities of the included studies were assessed using a nine-point evaluation tool. The kappa agreement index was used to evaluate the level of agreement between the identified explicit PIM tools., Results: The search yielded 1206 articles, and 15 studies were included in our analysis. Thirteen criteria were identified in East Asia and two in South Asia. Twelve out of the 15 criteria were developed using the Delphi method. We identified 283 PIMs independent of medical conditions and 465 disease-specific PIMs. Antipsychotics were included in most of the criteria (14/15), followed by tricyclic antidepressants (TCAs) (13/15), antihistamines (13/15), sulfonylureas (12/15), benzodiazepines (11/15), and nonsteroidal anti-inflammatory drug (NSAIDs) (11/15). Only one study fulfilled all the quality components. There was a low kappa agreement (k = 0.230) between the included studies., Conclusion: This review included 15 explicit PIM criteria, which most listed antipsychotics, antidepressants, and antihistamines as potentially inappropriate. Healthcare professionals should exercise more caution when dealing with these medications among older patients. These results may help healthcare professionals in Asian nations to create regional standards for the discontinuation of potentially harmful drugs for elderly patients., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: Due to the high burden of cancer-related suffering, it is paramount to understand the gaps in cancer care that lead to suffering. Advanced cancer patients have unmet needs and challenges that differ from those with early-stage cancer due to the rapid disease progression. By exploring advanced cancer patients' lived experiences and needs from the physical, psychological, social, and spiritual aspects, this study aims to identify gaps in the Malaysian health system and propose contextualised measures to improve cancer care., Methods: Semi-structured, in-depth interviews were conducted to explore advanced cancer patients' lived experiences and needs from the physical, psychological, social, and spiritual aspects. The interviews were then transcribed and coded. Themes were developed from the codes using iterative thematic approach., Results: The lived experiences and needs of nineteen patients converged into four major themes: disruption to daily lives, psychosocial and spiritual support system, information needs, and financial needs. This study described predominantly how cancer impacted patients' lives and livelihood, how patients coped with their psychological conditions after diagnosis, the need for effective communication and trust in a multicultural society, and how finance affected access to and experience of cancer care., Conclusion: Advanced cancer patients had different needs beyond receiving medical treatments. A concerted effort is required from clinicians, allied health professionals, social workers, support groups, and family members to understand and fulfil these needs., (© 2023. The Author(s).)

Alzheimer's disease (AD), a leading cause of dementia, has been a global concern. AD is associated with the involvement of the central nervous system that causes the characteristic impaired memory, cognitive deficits, and behavioral abnormalities. These abnormalities caused by AD is known to be attributed by extracellular aggregates of amyloid beta plaques and intracellular neurofibrillary tangles. Additionally, genetic factors such as abnormality in the expression of APOE, APP, BACE1, PSEN-1, and PSEN-2 play a role in the disease. As the current treatment aims to treat the symptoms and to slow the disease progression, there has been a continuous search for new nutraceutical agent or medicine to help prevent and cure AD pathology. In this quest, honey has emerged as a powerful nootropic agent. Numerous studies have demonstrated that the high flavonoids and phenolic acids content in honey exerts its antioxidant, anti-inflammatory, and neuroprotective properties. This review summarizes the effect of main flavonoid compounds found in honey on the physiological functioning of the central nervous system, and the effect of honey intake on memory and cognition in various animal model. This review provides a new insight on the potential of honey to prevent AD pathology, as well as to ameliorate the damage in the developed AD.

Introduction: Evidence-based services to support cancer patients with pain via clinical pharmacy services are currently lacking. Therefore, there is a need to undertake a randomized controlled trial (RCT) to explore the effectiveness of clinical pharmacists (CPs)' input into the multidisciplinary team (MDT) in providing better therapeutic outcomes for cancer pain management., Objectives: The main aim of this pilot RCT is to determine the feasibility and preliminary efficacy of integrating CPs into the MDT for cancer pain management on the clinical outcomes of cancer patients experiencing pain., Methods: This study protocol outlines two-armed multicenter pilot RCT. Cancer patients suffering from pain will be randomly allocated to receive either clinical pharmacy services, i.e., PharmaCAP trial intervention from the CP, or the usual standard care (i.e., control group). Patients will be recruited consecutively from two hospitals in Kathmandu valley, Nepal. The outcomes will be assessed at baseline (pre-intervention) and 4 weeks post-intervention. The primary feasibility outcomes will include eligibility rate, recruitment rate, willingness to participate, acceptability of screening procedures and random allocation, possible contamination between the groups, intervention fidelity and compliance, treatment satisfaction, and patient understanding of the provided interventions. Subsequently, the primary clinical outcome, i.e., pain intensity of cancer patients, will be assessed. The secondary clinical outcomes will include health-related quality of life (HRQoL), anxiety, depression, adverse drug reactions, and patient medication compliance following the integration of CP into the healthcare team., Discussion: The feasibility and potential for integrating CP involvement in MDT to improve clinical outcomes of cancer patients with pain will be evaluated through the PharmaCAP trial., Trial Registration: ClinicalTrials.gov NCT05021393. Registered on 25th August 2022., (© 2023. The Author(s).)

Intervertebral disc (IVD) degeneration is a major contributing factor for discogenic low back pain (LBP), causing a significant global disability. The IVD consists of an inner core proteoglycan-rich nucleus pulposus (NP) and outer lamellae collagen-rich annulus fibrosus (AF) and is confined by a cartilage end plate (CEP), providing structural support and shock absorption against mechanical loads. Changes to degenerative cascades in the IVD cause dysfunction and instability in the lumbar spine. Various treatments include pharmacological, rehabilitation or surgical interventions that aim to relieve pain; however, these modalities do not halt the pathologic events of disc degeneration or promote tissue regeneration. Loss of stem and progenitor markers, imbalance of the extracellular matrix (ECM), increase of inflammation, sensory hyperinnervation and vascularization, and associated signaling pathways have been identified as the onset and progression of disc degeneration. To better understand the pain originating from IVD, our review focuses on the anatomy of IVD and the pathophysiology of disc degeneration that contribute to the development of discogenic pain. We highlight the key mechanisms and associated signaling pathways underlying disc degeneration causing discogenic back pain, current clinical treatments, clinical perspective and directions of future therapies. Our review comprehensively provides a better understanding of healthy IVD and degenerative events of the IVD associated with discogenic pain, which helps to model painful disc degeneration as a therapeutic platform and to identify signaling pathways as therapeutic targets for the future treatment of discogenic pain.

There is mounting evidence that metabolic syndrome (MetS) contributes to the development of neurodegenerative disorders such as Alzheimer’s disease. Honey, which has been used for generations, is high in antioxidants and has been demonstrated to benefit the brain and mental health by reducing oxidative stress and boosting cognitive outcomes. Honey from the stingless bees of Heterotrigona itama has been found to have higher phenolic content compared to other types of honeys. The aim of this study is to investigate the effects of stingless bee honey (SBH) supplementation and to compare it with a pure form of antioxidant, caffeic acid (CA), on MetS parameters and inflammatory markers in the brains of MetS-induced rats. A total of 32 male Wistar rats were divided equally into groups of control, high-carbohydrate high-fructose (HCHF) diet (MetS), HCHF + SBH supplemented (1 g/kg) (SBH), and HCHF + CA supplemented (10 mg/kg) (CA) groups. The total duration for SBH and CA supplementation was eight weeks. The HCHF diet was found to promote hypertension, hyperglycemia, and hypertriglyceridemia, and to increase brain TNF-α levels. Supplementation with SBH and CA significantly reversed (p < 0.05) the hyperglycemic and hypertensive effects of the HCHF diet. Although both supplemented groups showed no significant changes to serum HDL or TG, SBH significantly reduced (p < 0.05) brain TNF-α levels and increased (p < 0.05) brain BDNF levels. Immunohistochemistry investigations of neurogenesis (EdU) and apoptosis (TUNEL) on the cornu Ammonis 1 (CA1) and dentate gyrus (DG) areas of the hippocampus showed no changes with SBH and CA supplementation compared to the control. These findings suggest that SBH and CA have the potential to mitigate HCHF-induced MetS effects and possess neuroprotective abilities.

Learning and memory are essential to organism survival and are conserved across various species, especially vertebrates. Cognitive studies involving learning and memory require using appropriate model organisms to translate relevant findings to humans. Zebrafish are becoming increasingly popular as one of the animal models for neurodegenerative diseases due to their low maintenance cost, prolific nature and amenability to genetic manipulation. More importantly, zebrafish exhibit a repertoire of neurobehaviors comparable to humans. In this review, we discuss the forms of learning and memory abilities in zebrafish and the tests used to evaluate the neurobehaviors in this species. In addition, the pharmacological studies that used zebrafish as models to screen for the effects of neuroprotective and neurotoxic compounds on cognitive performance will be summarized here. Lastly, we discuss the challenges and perspectives in establishing zebrafish as a robust model for cognitive research involving learning and memory. Zebrafish are becoming an indispensable model in learning and memory research for screening neuroprotective agents against cognitive impairment.

Background: Understanding patient preferences in cancer management is essential for shared decision-making. Patient or societal willingness-to-pay (WTP) for desired outcomes in cancer management represents their preferences and values of these outcomes., Objective: The aim of this systematic review is to critically evaluate how current literature has addressed WTP in relation to cancer treatment and achievement of outcomes., Methods: Seven databases were searched from inception until 2 March 2021 to include studies with primary data of WTP values for cancer treatments or achievement of outcomes that were elicited using stated preference methods., Results: Fifty-four studies were included in this review. All studies were published after year 2000 and more than 90% of the studies were conducted in high-income countries. Sample size of the studies ranged from 35 to 2040, with patient being the most studied population. There was a near even distribution between studies using contingent valuation and discrete choice experiment. Based on the included studies, the highest WTP values were for a quality-adjusted life year (QALY) ($11,498-$589,822), followed by 1-year survival ($3-$198,576), quality of life (QoL) improvement ($5531-$139,499), and pain reduction ($79-$94,662). Current empirical evidence suggested that improvement in QoL and pain reduction had comparable weights to survival in cancer management., Conclusion: This systematic review provides a summary on stated preference studies that elicited patient preferences via WTP and summarised their respective values. Respondents in this review had comparable WTP for 1-year survival and QoL, suggesting that improvement in QoL should be emphasised together with survival in cancer management., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

This review aimed to critically evaluate the impact of pharmacist involvement in managing pain in cancer patients. Databases (including MEDLINE, Embase and CENTRAL) were searched with a broad search strategy for studies involving pharmacists and cancer pain management until February 10, 2021. The quality of studies and evidence were assessed using standardized tools and GRADE, respectively. A random-effects model was used for meta-analysis. Sixty-four studies were included. Common interventions delivered by the pharmacists were medication review, patient education, adverse drug reactions (ADRs) detection and management, pharmacological recommendations (in dosing and pharmacotherapy choice), and pain assessment. A pooled analysis of 3 randomized control trials showed a significant reduction in pain intensity with a standardized mean difference (SMD) of 0.35 [95% confidence intervals (CI): -0.55, -0.16]. Pooled analyses from nonrandomized studies of interventions also showed significant results in reduction of ADRs with an odds ratio of 0.69 (95% CI: 0.61, 0.79) and improvement in quality of life with SMD of 0.80 (95% CI: 0.29, 1.32). Thus, pharmacists significantly improve the clinical outcomes of cancer patients related to pain. This indicates the involvement of pharmacists directly or in collaboration with healthcare professionals in the oncology team is highly beneficial for the patients. PERSPECTIVES: This systematic review presents a comprehensive evaluation of pharmacist involvement in cancer pain management. This shows the importance of direct involvement of the pharmacist or as an important member of the multidisciplinary oncology team., (Copyright © 2022 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)

Globally, millions of people suffer from various substance use disorders (SUD), including mono-and polydrug use of opioids and methamphetamine. Brain regions such as the cingulate cortex, infralimbic cortex, dorsal striatum, nucleus accumbens, basolateral and central amygdala have been shown to play important roles in addiction-related behavioral changes. Clinical and pre-clinical studies have characterized these brain regions and their corresponding neurochemical changes in numerous phases of drug dependence such as acute drug use, intoxication, craving, withdrawal, and relapse. At present, many studies have reported the individual effects of opioids and methamphetamine. However, little is known about their combined effects. Co-use of these drugs produces effects greater than either drug alone, where one decreases the side effects of the other, and the combination produces a prolonged intoxication period or a more desirable intoxication effect. An increasing number of studies have associated polydrug abuse with poorer treatment outcomes, drug-related deaths, and more severe psychopathologies. To date, the pharmacological treatment efficacy for polydrug abuse is vague, and still at the experimental stage. This present review discusses the human and animal behavioral, neuroanatomical, and neurochemical changes underlying both morphine and methamphetamine dependence separately, as well as its combination. This narrative review also delineates the recent advances in the pharmacotherapy of mono- and poly drug-use of opioids and methamphetamine at clinical and preclinical stages., 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 Hazani, Naina Mohamed, Muzaimi, Mohamed, Yahaya, Teoh, Pakri Mohamed, Mohamad Isa, Abdulrahman, Ramadah, Kamaluddin and Kumar.)

Neurotrophin is a growth factor that regulates the development and repair of the nervous system. From all factors, two pioneer groups, the nerve growth factor (NGF) and brain derived neurotrophic factor (BDNF), have been widely explored for their role in disease pathogenesis and potential use as therapeutic agents. Nonetheless, neurotrophin-3 (NT3) and neurotrophin-4 (NT4) also have promising potential, albeit less popular than their counterparts. This review focuses on the latter two factors and their roles in the pathogenesis of brain disorders and potential therapies. An extensive literature search of NT3 and NT4 with their receptors, the TrkB and TrkC on the nervous system were extracted and analyzed. We found that NT3 and NT4 are not only involved in the pathogenesis of some neurodegenerative diseases, but also have promising therapeutic potential on injury- and vascular-related nervous system disease, neuropsychiatry, neurodegeneration and peripheral nerve diseases. In conclusion, the role of NT3 and NT4 should be further emphasized, and more studies could be explored on the potential use of these neurotrophins in the human study., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background: Listening to music is often used as a self-help intervention to improve sleep quality, but its efficacy among individuals without sleep disorder remains unclear., Methods: A search was performed on five databases to identify for studies that examined the use of music-based intervention to improve sleep quality among individuals without sleep disorder. Random-effects meta-analysis was performed, and the certainty of evidence was evaluated using GRADE (Grading of Recommendations Assessment, Development and Evaluation)., Results: Twenty-two articles which recruited 1,514 participants were included for review. Meta-analysis of six studies including 424 participants did not find an improvement in sleep quality among recipients of music-based intervention compared to those with standard care (mean difference: -0.80; 95% CI: -2.15 to 0.54, low-quality evidence). Subgroup analysis showed a clear improvement in sleep quality when interventions were administered for at least 3 weeks (-2.09; -3.84 to -0.34, n = 3). No difference in terms of sleep onset latency (standardized mean difference (SMD) -0.32; 95% CI -0.88 to 0.25, n = 4, very-low quality evidence) and sleep efficiency (SMD: -0.59; 95% CI -3.15 to 1.97, n = 2, very-low quality evidence) were observed. The effect of music-based intervention on anxiety, depression and quality of life were mixed with suggestions of possible benefits., Conclusion: Music-based intervention in addition to standard care appears to be a promising strategy to improve sleep quality when delivered for 3 week or longer. However, effects are inconsistent across studies and larger randomized controlled studies reporting long-term outcomes are needed before it can be recommended for routine use., Prospero Registration: CRD42018081193.