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Background: Primary care providers help older adults with medication use problems in Malaysia and globally. They help older adults with medication management, appropriate use, and administration; however, their perspectives and challenges regarding medication use problems in older adults have not been adequately explored. Methods: The study used a qualitative methodology comprising 30 in-depth interviews among general practitioners and pharmacists in Penang, Malaysia, in public and private primary care settings. Participants were recruited based on purposive sampling. Interviews were transcribed verbatim, and data were coded based on the principles of thematic analysis in NVivo. Objective: This study aims to understand primary care providers' perspectives and challenges regarding medication use problems experienced by older adults. Results: Six themes emerged from the study. Theme one highlighted the pharmaceutical care needs of older adults with sensory impairments and accessibility issues. The second and third themes explored medicines management support and potentially inappropriate medication use. Theme four supported collaborative practice, prescribing, and deprescribing among primary health care providers. Theme five discussed health service delivery aligned to older adults' health care needs. The final theme emphasised social and welfare support. Conclusion: This study identified various challenges professional primary care providers face in providing aligned healthcare services for older adults and proposed recommendations for further strengthening healthcare quality. Inputs from the primary healthcare system frontier are essential to reduce the challenges and uplift the quality of ageing populations' healthcare in Malaysia. 2023 Elsevier B.V. Scopus

The physiological mechanisms underlying variation in aggression in fish remain poorly understood. One possibly confounding variable is the lack of standardization in the type of stimuli used to elicit aggression. The presentation of controlled stimuli in videos, a.k.a. video playback, can provide better control of the fight components. However, this technique has produced conflicting results in animal behavior studies and needs to be carefully validated. For this, a similar response to the video and an equivalent live stimulus needs to be demonstrated. Further, different physiological responses may be triggered by live and video stimuli, and it is important to demonstrate that video images elicit appropriate physiological reactions. Here, the behavioral and endocrine responses of male Siamese fighting fish Betta splendens to a matched-for-size conspecific fighting behind a one-way mirror, presented live or through video playback, were compared. The video playback and live stimulus elicited a strong and similar aggressive response by the focal fish, with a fight structure that started with stereotypical threat displays and progressed to overt attacks. Postfight plasma levels of the androgen 11-ketotestosterone were elevated as compared to controls, regardless of the type of stimuli. Cortisol also increased in response to the video images, as previously described for live fights in this species. These results show that the interactive component of a fight and its resolution are not needed to trigger an endocrine response to aggression in this species. The study also demonstrates for the first time in a fish a robust endocrine response to video stimuli and supports the use of this technique for researching aggressive behavior in B. splendens.

The mechanisms of action of hormones regulating aggression in fish remain poorly understood. One possibly confounding variable is the lack of standardization in the type of stimuli used to elicit aggression. The presentation of controlled stimuli in videos, a.k.a. video playback, can provide better control of the fight components. However, this technique has produced conflicting results in animal behaviour studies and needs to be carefully validated. Here, the response of male Betta splendens to a matched for size conspecific fighting behind a one-way mirror presented live or through video playback was compared. Despite their non-interactive nature, both stimuli elicited a strong aggressive response by focal fish, which started with stereotypical threat displays and progressed to overt attacks. Overall, the frequency and duration of aggressive behaviours and swimming activity were similar towards live and video stimuli. Post-fight plasma levels of the androgen 11-ketotestosterone were elevated as compared to controls, regardless of the type of stimuli. Cortisol also increased in response to the video images, as previously described for interactive live fights in this species. The study shows for the first time in a fish a robust endocrine response to video stimuli and supports the use of this technique for researching aggressive behaviour in B. splendens.

The Malaysian Elders Longitudinal Research (MELoR) study found 1 in 4 residents aged 65 years and over living in the Klang Valley of Malaysia fall at least once a year in their survey conducted between 2013 and 2015. Recent figures obtained from the First Older Persons’ National Health and Morbidity Survey conducted in 2018 revealed that 15% of Malaysians aged 60 years and over fall at least once a year. In a 10-year follow-up study involving 200 individuals who presented to the emergency department over a six-month period in 2002, 22% were no longer alive at one year, and 80% had died at 10 years. Older age, indoor falls, subsequent hospital admission and functional impairment predicted death at one year. Cross-sectional data from MELoR revealed ethnic differences in fall prevalence, with the ethnic Indians more likely to report falls in the past 12 months compared to the ethnic Malays. Independent risk factors for falls identified from MELoR were urinary incontinence, reduced grip strength, hearing impairment, comorbidities and reducing walking speed. The ethnic differences in falls in our population remain unexplained. Lifestyle and cultural practices may well be the underlying rationale, but genetic influences cannot currently be ruled out. The results of a randomized controlled trial on multifactorial interventions, the Malaysian Falls Assessment and Intervention Trial (MyFAIT), was published last year. Mo differences in falls outcomes with an individualized multifactorial intervention were observed, despite improvements in physical performance and psychological status in the intervention group compared to the control group. The research group has now secured two-year funding to evaluate post-fall behavior in our setting in the Life After Falls (LiAF) study. In addition, dissemination and upskilling efforts are underway through training workshops, formation of the Malaysian Falls Network (MyFalls) and collaborations with the private sector to increase awareness on falls and increase fall prevention efforts throughout the country.

Falls are major issues affecting the older population with potentially serious complications, including fractures, head injury, institutionalization, fear of falling and depression. While risk factors for falls have been established across Western Europe and North America, geographical differences in falls risk have not been well researched. We aim to examine the clinical and physical risk factors for falls in a middle-income South East Asian country. Cross-sectional data from the Malaysian Elders Longitudinal Research (MELoR) study involving 1,362 community dwelling individuals aged 55 years and above was utilized. Information on sociodemographic and medical history was obtained by computer-assisted questionnaires completed during home visits and hospital-based detailed health checks. Univariate and multivariate analyses compared non-fallers and fallers in the previous 12 months. Urinary incontinence, hearing impairment, depression, arthritis and cognitive impairment were risk factors for falls in the past 12 months after adjustment for age in our study population. Awareness about the risk factors in a population helps the design of fall prevention strategies that target specific or multiple risk factors.

A rapid demographic transition to aging populations is imminent over the next decade, especially in Southeast Asian countries. An aging population presents a host of medical challenges, such as multimorbidity; chronic illnesses; and geriatric syndromes, such as frailty, falls, dementia, and incontinence. In order to tackle such issues efficiently, there is an urgent need to train future doctors in geriatric medicine. Aged care is a specialty in medicine that was not traditionally part of the undergraduate medical curriculum. With the changing demographic, aged care content needs to be integrated into the existing curriculum for undergraduate medical students. In this paper, we present an introductory novice level geriatric module that was developed for first-year medical undergraduate students in Monash University, Malaysia. The module consisted of collaborative active learning sessions on healthy aging, interaction with older adults from the community, and a simulated experiential activity. Feedback was collected from students on module completion. The immediate impact of the module was positive from the student responses. The findings from this study will be useful to inform the development and implementation of future educational interventions for aged care, as well as to support the establishment of a vertically integrated aged care curriculum, in order to prepare future doctors to provide healthcare for the ageing Asian population.

The role of hormones as modulators of aggressive behavior in fish remains poorly understood. Androgens and corticosteroids, in particular, have been associated with aggressive behavior in fish but it is still not clear if animals adjust the secretion of these hormones to regulate behavior during ongoing fights, in response to fight outcomes in order to adjust aggressive behavior in subsequent fights, or both. With its stereotyped displays and high aggression levels, the Siamese fighting fish Betta splendens is an excellent model to investigate this question. Here, we compared the behavioral and endocrine response of male B. splendens to fights where there is no winner or loser by presenting them with a size-matched live interacting conspecific behind a transparent partition or with a mirror image. The aggressive response started with threat displays that were overall similar in frequency and duration towards both types of stimuli. Fights transitioned to overt attacks and interacting with a live conspecific elicited a higher frequency of attempted bites and head hits, as compared with the mirror image. There was a pronounced increase in plasma androgens (11-ketotestosterone and testosterone) and corticosteroids (cortisol) levels in response to the aggression challenge, independent of stimulus type. Post-fight intra-group levels of these hormones did not correlate with measures of physical activity or aggressive behavior. A linear discriminant analysis including all behavioral and endocrine data was a poor classifier of fish from the conspecific and mirror trials, showing that overall the behavioral and endocrine response to mirror images and conspecifics was similar. The results show that fight resolution is not necessary to induce an evident increase in peripheral levels of androgens and corticosteroids in B. splendens. However, the function of these hormones during present and future aggressive contests remains to be clarified.

Scope Polymethoxylated flavonoids are present in citrus fruit in a range of chemical structures and abundance. These compounds have potential for anticarcinogenesis, antitumor, and cardiovascular protective activity, but the effect on angiogenesis has not been well studied. Methods and results Human umbilical vein endothelial cells (HUVECs) in vitro and zebrafish (Danio rerio) in vivo models were used to screen and identify the antiangiogenesis activity of seven polymethoxylated flavonoids; namely, hesperetin, naringin, neohesperidin, nobiletin, scutellarein, scutellarein tetramethylether, and sinensetin. Five, excluding naringin and neohesperidin, showed different degrees of potency of antiangiogenesis activity. Sinensetin, which had the most potent antiangiogenesis activity and the lowest toxicity, inhibited angiogenesis by inducing cell cycle arrest in the G0/G1 phase in HUVEC culture and downregulating the mRNA expressions of angiogenesis genes flt1, kdrl, and hras in zebrafish. Conclusion The in vivo structure–activity relationship (SAR) analysis indicated that a flavonoid with a methoxylated group at the C3′ position offers a stronger antiangiogenesis activity, whereas the absence of a methoxylated group at the C8 position offers lower lethal toxicity in addition to enhancing the antiangiogenesis activity. This study provides new insight into how modification of the chemical structure of polymethoxylated flavonoids affects this newly identified antiangiogenesis activity.

Aim of the study Indirubin is an active ingredient of the traditional Chinese medicine, Dang Gui Long Hui Wan, commonly used for the treatment of chronic myelocytic leukemia (CML) and other inflammatory conditions. These anti-leukemic and anti-inflammatory activities may be mediated by anti-angiogenic action. To investigate the anti-angiogenic activity of indirubin, we tested its inhibitory effect on blood vessel formation in zebrafish embryos and on endothelial cell proliferation in culture. Materials and methods The anti-angiogenic activity of indirubin was tested using transgenic zebrafish embryos with fluorescent vasculature and human umbilical vein endothelial cells (HUVECs). Apoptosis was analyzed with a terminal deoxynucleotidyl transferase mediated dUTP nick end labeling (TUNEL) assay. Results Indirubin dose-dependently inhibited intersegmental vessel formation in zebrafish embryos. It also inhibited HUVEC proliferation by the induction of cellular apoptosis and cell-cycle arrest at the G0/G1 phase. Conclusions The anti-angiogenic activity of indirubin may partly contribute to its anti-leukemic and anti-psoriatic properties and may be valuable for the treatment of diseases with excessive angiogenesis. The zebrafish model of angiogenesis was further validated in this study.

ObjectivesFalls represent major health issues within the older population. In low/middle-income Asian countries, falls in older adults remain an area which has yet to be studied in detail. Using data from the Malaysian Elders Longitudinal Research (MELoR), we have estimated the prevalence of falls among older persons in an urban population, and performed ethnic comparisons in the prevalence of falls.DesignCross-sectional analysis was carried out using the first wave data from MELoR which is a longitudinal study.SettingUrban community dwellers in a middle-income South East Asian country.Participants1565 participants aged ≥55 years were selected by simple random sampling from the electoral rolls of three parliamentary constituencies.Outcome measuresConsenting participants from the MELoR study were asked the question ‘Have you fallen down in the past 12 months?’ during their computer-assisted home-based interviews. Logistic regression analyses were conducted to compare the prevalence of falls among various ethnic groups.ResultsThe overall estimated prevalence of falls for individuals aged 55 years and over adjusted to the population of Kuala Lumpur was 18.9%. The estimated prevalence of falls for the three ethnic populations of Malays, Chinese and Indian aged 55 years and over was 16.2%, 19.4% and 23.8%, respectively. Following adjustment for ethnic discrepancies in age, gender, marital status and education attainment, the Indian ethnicity remained an independent predictor of falls in our population (relative risk=1.45, 95% CI 1.08 to 1.85).ConclusionThe prevalence of falls in this study is comparable to other previous Asian studies, but appears lower than Western studies. The predisposition of the Indian ethnic group to falls has not been previously reported. Further studies may be needed to elucidate the causes for the ethnic differences in fall prevalence.

The Ewings Sarcoma Oncoprotein (EWS) interacts with several components of the mammalian transcriptional and pre-mRNA splicing machinery and is also found in the cytoplasm and even on the cell surface. The apparently diverse cellular functions of EWS are, however, not well characterized. EWS harbours a potent N-terminal transcriptional activation domain (the EAD) that is revealed in the context of oncogenic EWS-fusion proteins (EFPs) and a C-terminal RNA-binding domain (RBD) that recruits pre-mRNA splicing factors and may couple transcription and splicing. In contrast to EFPs, the presumed transcriptional role of normal EWS remains enigmatic. Here, we report that multiple RGG-boxes within the RBD are necessary and sufficient for cis-repression of the EAD and that RGG-boxes can also repress in-trans, within dimeric partners. Lys can functionally substitute for Arg, indicating that the basic nature of the Arg side chain is the critical determinant of RGG-box-mediated repression. In addition to the EAD, RGG-boxes can repress a broad range of activation domains (including those of VP16, E1a and CREB), but repression can be alleviated by the simultaneous presence of more than one activation domain. We therefore propose that a key function of RGG boxes within native EWS is to restrict promiscuous activation by the EAD while still allowing EWS to enter functional transcription complexes and participate in other transactions involving pre-mRNAs.

3-Hydroxy-3-methylglutaryl-coenzyme A synthase (HMGS) is an enzyme in mevalonate biosynthesis. In plants, investigations have focused on HMG CoA reductase (HMGR) and less is known of the preceding enzyme, HMGS. To understand the regulation of HMGS, we have isolated a Brassica juncea cDNA encoding HMGS, BjHMGS1, for use as a hybridization probe in Northern blot analyses. BjHMGS is expressed in all plant organs and shows developmental regulation in flower, seed and seedling, with highest expression in early development. In seedlings, expression is highest in young hypocotyls and is induced during the greening of etiolated cotyledons. BjHMGS is down-regulated by abscisic acid, osmotic stress and dehydration, the effects of which arrested seedling growth. Thus BjHMGS expression shows correlation with rapid cell division and growth, like HMGR. This is not unexpected, as mevalonate is the precursor to many essential isoprenoid compounds, including sterols for membrane biogenesis. Wounding, methyl jasmonate or salicylic acid induce BjHMGS expression, suggesting that, like HMGR, HMGS is involved in defence. As in animals, coordinated regulation of HMGS with HMGR occurred in B. juncea upon germination and in response to salicylic acid. HMGS assays confirmed that Escherichia coli-expressed recombinant BjHMGS1 shows HMGS activity that is inhibited by F244, a specific inhibitor of HMGS. Southern blot analysis revealed gene families encoding HMGS in Brassica species and a summation of homologous genes in the fusion amphidiploid genome of B. juncea, a bi-parental species derived from diploids B. nigra and B. campestris.

Traditional Chinese medicinal herbs are a rich source of compounds with reported anti-inflammatory and anti-carcinogenic effects. Growing evidence shows the codependence of chronic inflammation and angiogenesis, and the potential benefits of targeting angiogenesis in the treatment of chronic inflammation and targeting inflammation in the treatment of diseases with impaired angiogenesis. We hypothesized that the anti-inflammatory activity of the natural compounds may owe at least some of its efficacy to their anti-angiogenic activity and hence we investigated the anti-angiogenic activity of these compounds in vivo in zebrafish embryos and in vitro in human umbilical vein endothelial cells (HUVECs). Nobiletin, a polymethoxylated flavonoid from citrus fruits, showed anti-angiogenic activity in both assays. Nobiletin inhibited the formation of intersegmental vessels (ISVs) in live transgenic zebrafish embryos expressing green fluorescent protein (GFP) in the vasculature. Cell cycle analysis of dissociated zebrafish embryo cells showed that nobiletin induced G0/G1 phase accumulation in a dose-dependent manner in GFP-positive endothelial cells. Nobiletin also dose-dependently induced VEGF-A mRNA expression. In HUVECs, nobiletin inhibited endothelial cell proliferation and, to a greater extent, tube formation in a dose-dependent manner. As in the in vivo study, nobiletin induced G0/G1 cell cycle arrest in HUVECs. However, this arrest was not accompanied by an increase in apoptosis, indicating a cytostatic effect of nobiletin. This study, for the first time, identifies nobiletin as having potent anti-angiogenic activity and suggests that nobiletin has a great potential for future research and development as a cytostatic anti-proliferative agent.

Resveratrol (RSV) has been shown to have anti-inflammatory activity and to have a protective role against atherosclerosis. Here it is shown, for the first time, that its derivative trans-3,5,4'-trimethoxystilbene (TMS) may be a more potent anti-inflammatory agent than resveratrol. A comparative analysis of the inhibitory activities of related stilbenes, resveratrol, TMS and polydatin (PD), on monocyte adhesion to TNF-α-activated endothelial cells showed TMS to be the most effective, with PD being the least effective. RSV and its analogues inhibited, albeit differentially, the protein and mRNA expression levels of inducible cell adhesion molecules, ICAM-1 and VCAM-1, in cultured endothelial cells. The mechanism of the inhibitory effects of these stilbenes on endothelial cell-monocyte cell adhesion can be attributed mainly to inhibition of NF-κB pathway activation. The results demonstrate that all three investigated stilbene compounds, especially TMS, exhibit a potent inhibitory effect on inflammation-induced cell-cell adhesion, expression of adhesion molecules and activation of the NF-κB pathway.

Angiogenesis plays an important role in the development of neoplastic diseases such as cancer. Resveratrol and its derivatives exert antiangiogenic effects, but the mechanisms of their actions remain unclear. The aim of this study was to evaluate the antiangiogenic activity of resveratrol and its derivative trans-3,5,4'-trimethoxystilbene in vitro using human umbilical vein endothelial cells (HUVECs) and in vivo using transgenic zebrafish, and to clarify their mechanisms of action in zebrafish by gene expression analysis of the vascular endothelial growth factor (VEGF) receptor (VEGFR2/KDR) and cell-cycle analysis. trans-3,5,4'-Trimethoxystilbene showed significantly more potent antiangiogenic activity than that of resveratrol in both assays. In zebrafish, trans-3,5,4'-trimethoxystilbene caused intersegmental vessel regression and downregulated VEGFR2 mRNA expression. Trans-3,5,4'-trimethoxystilbene also induced G2/M cell-cycle arrest, most specifically in endothelial cells of zebrafish embryos. We propose that the antiangiogenic and vascular-targeting activities of trans-3,5,4'-trimethoxystilbene result from the downregulation of VEGFR2 expression and cell-cycle arrest at G2/M phase.

Flavonoids isolated from Herba Epimedii such as icaritin, icariin and epimedin C have been suggested as potential bone anabolic compounds. However, the "specific localized effects" of these flavonoids in bone, in vivo, and the metabolism of these flavonoids in zebrafish larvae have never been demonstrated. In this study, we used multiple methods including in vivo imaging, drug metabolites profiling, transcriptomic and proteomic approaches to determine the mechanisms involved in the distribution and metabolism of the flavonoids in zebrafish larvae by measuring the fluorescence emission, in vivo, of icaritin and its glycoside derivatives. The fluorescence emission mechanism of icaritin in vitro was identified by spectrophotometric analysis, and the fluorescent property of icaritin was used as a probe to visualize the metabolism and distribution of icaritin and its glycoside derivatives in zebrafish larvae. Phase I and phase II metabolism of icaritin and its derivatives were identified in zebrafish by mass spectrometry. The combined transcriptomics and proteomics demonstrate a high degree of conservation of phase I and phase II drug metabolic enzymes between zebrafish larvae and mammals. Icaritin and its glycoside derivatives were demonstrated using combined approaches of in vivo imaging, drug metabolites identification, and transcriptomic and proteomic profiling to illustrate phase I and phase II metabolism of the flavonoids and their distribution in bone of zebrafish larvae. This study provides a new methodological model for use of the zebrafish larvae to examine drug metabolism.

This review and meta-analysis aimed to determine the clinical and humanistic outcomes of community pharmacy-based interventions on medication-related problems of older adults at the primary care level. We identified randomized controlled trials (RCTs) examining the impact of various community pharmacy-based interventions from five electronic databases (namely, MEDLINE (Ovid), EMBASE (Ovid), CINAHL, APA PSYInfo, and Scopus) from January 2010 to December 2020. Consequently, we assessed these interventions’ clinical and humanistic outcomes on older adults and compared them with non-intervention. We included 13 RCTs in the current review and completed a meta-analysis with six of them. The included studies had a total of 6173 older adults. Quantitative analysis showed that patient education was significantly associated with an increase in the discontinuation of sedative–hypnotics use (risk ratio 1.28; 95% CI (1.20, 1.36) I2 = 0%, p < 0.00001). Moreover, the qualitative analysis showed that medication reviews and education with follow-ups could improve various clinical outcomes, including reducing adverse drug events, reducing uncontrolled health outcomes, and improving appropriate medication use among the elderly population. However, medication review could not significantly reduce the number of older adults who fall (risk ratio 1.25; 95% CI (0.78, 1.99) I2 = 0%, p = 0.36) and require hospitalization (risk ratio 0.72; 95% CI (0.47, 1.12) I2 = 45%, p = 0.15). This study showed that community pharmacy-based interventions could help discontinue inappropriate prescription medications among older adults and could improve several clinical and humanistic outcomes. However, more effective community pharmacy-based interventions should be implemented, and more research is needed to provide further evidence for clinical and humanistic outcomes of such interventions on older adults.