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Abstract Background Clinical practice guidelines on limitation of life-sustaining treatments (LST) in the intensive care unit (ICU), in the form of withholding or withdrawal of LST, state that there is no ethical difference between the two. Such statements are not uniformly accepted worldwide, and there are few studies on LST limitation in Asia. This study aimed to evaluate the predictors and outcomes of withholding and withdrawal of LST in Singapore, focusing on the similarities and differences between the two approaches. Methods This was a multicentre observational study of patients admitted to 21 adult ICUs across 9 public hospitals in Singapore over an average of three months per year from 2014 to 2019. The primary outcome measures were withholding and withdrawal of LST (cardiopulmonary resuscitation, invasive mechanical ventilation, and vasopressors/inotropes). The secondary outcome measure was hospital mortality. Multivariable generalised mixed model analysis was used to identify independent predictors for withdrawal and withholding of LST and if LST limitation predicts hospital mortality. Results There were 8907 patients and 9723 admissions. Of the former, 80.8% had no limitation of LST, 13.0% had LST withheld, and 6.2% had LST withdrawn. Common independent predictors for withholding and withdrawal were increasing age, absence of chronic kidney dialysis, greater dependence in activities of daily living, cardiopulmonary resuscitation before ICU admission, higher Acute Physiology and Chronic Health Evaluation (APACHE) II score, and higher level of care in the first 24 h of ICU admission. Additional predictors for withholding included being of Chinese race, the religions of Hinduism and Islam, malignancy, and chronic liver failure. The additional predictor for withdrawal was lower hospital paying class (with greater government subsidy for hospital bills). Hospital mortality in patients without LST limitation, with LST withholding, and with LST withdrawal was 10.6%, 82.1%, and 91.8%, respectively (p

BackgroundTo date, studies investigating the association between pre-biologic biomarker levels and post-biologic outcomes have been limited to single biomarkers and assessment of biologic efficacy from structured clinical trials.AimTo elucidate the associations of pre-biologic individual biomarker levels or their combinations with pre-to-post biologic changes in asthma outcomes in real-life.MethodsThis was a registry-based, cohort study using data from 23 countries, which shared data with the International Severe Asthma Registry (May 2017-February 2023). The investigated biomarkers (highest pre-biologic levels) were immunoglobulin E (IgE), blood eosinophil count (BEC) and fractional exhaled nitric oxide (FeNO). Pre- to approximately 12-month post-biologic change for each of three asthma outcome domains (i.e. exacerbation rate, symptom control and lung function), and the association of this change with pre-biologic biomarkers was investigated for individual and combined biomarkers.ResultsOverall, 3751 patients initiated biologics and were included in the analysis. No association was found between pre-biologic BEC and pre-to-post biologic change in exacerbation rate for any biologic class. However, higher pre-biologic BEC and FeNO were both associated with greater post-biologic improvement in FEV1 for both anti-IgE and anti-IL5/5R, with a trend for anti-IL4Rα. Mean FEV1 improved by 27-178 mL post-anti-IgE as pre-biologic BEC increased (250 to 1000 cells/µL), and by 43-216 mL and 129-250 mL post-anti-IL5/5R and -anti-IL4Rα, respectively along the same BEC gradient. Corresponding improvements along a FeNO gradient (25-100 ppb) were 41-274 mL, 69-207 mL and 148-224 mL for anti-IgE, anti-IL5/5R, and anti-IL4Rα, respectively. Higher baseline BEC was also associated with lower probability of uncontrolled asthma (OR 0.392; p=0.001) post-biologic for anti-IL5/5R. Pre-biologic IgE was a poor predictor of subsequent pre-to-post-biologic change for all outcomes assessed for all biologics. The combination of BEC + FeNO marginally improved the prediction of post-biologic FEV1 increase (adjusted R2: 0.751), compared to BEC (adjusted R2: 0.747) or FeNO alone (adjusted R2: 0.743) (p=0.005 and

Abstract Background Protection Motivation Theory could be another potential and good framework that addresses essential elements in a behavioural change leading to positive fall protective behaviours. The positive behavioural change could reduce the risk of falls and improve the quality of life of the older community. The study aims to evaluate the reliability and validity of the culturally adapted Protection Motivation Theory scale for older adults' fall protection motivation or protective behaviours to reduce fall risk. Methods A cross-sectional study was conducted to establish a psychometric instrument validation. A total of 389 participants aged 55 years and above were included. The study was conducted in Sarawak, Malaysia, from November 2021 to January 2022 in two phases, translation of the PMT Scale, cross-cultural adaptation, face validation and pre-testing of the PMT Scale. The participants were selected using multistage random sampling in a primary healthcare clinic. Data entry and statistical analysis were performed using IBM SPSS version 26 for exploratory factor analysis and SmartPLS version 3.3.7 for confirmatory factor analysis using partial least square structural equation modelling. Results The Kaiser–Meyer–Olkin value was 0.760, Bartlett's sphericity test was significant and the total variance explained was 61%. It identified 31 items within eight dimensions of the Protection Motivation Theory scale. The Higher Order Constructs' measurement model indicates that the convergent and discriminant validity were established (Cronbach's alpha and composite reliability: ≥ 0.740; average variance extracted: 0.619 to 0.935 and Henseler's Heterotrait-Monotrait criterion for all constructs' discriminant validity:

Tumour-associated angiogenesis play key roles in tumour growth and cancer metastasis. Consequently, several anti-angiogenic drugs such as sunitinib and axitinib have been approved for use as anti-cancer therapies. However, the majority of these drugs target the vascular endothelial growth factor A (VEGFA)/VEGF receptor 2 (VEGFR2) pathway and have shown mixed outcome, largely due to development of resistances and increased tumour aggressiveness. In this study, we used the zebrafish model to screen for novel anti-angiogenic molecules from a library of compounds derived from natural products. From this, we identified canthin-6-one, an indole alkaloid, which inhibited zebrafish intersegmental vessel (ISV) and sub-intestinal vessel development. Further characterisation revealed that treatment of canthin-6-one reduced ISV endothelial cell number and inhibited proliferation of human umbilical vein endothelial cells (HUVECs), suggesting that canthin-6-one inhibits endothelial cell proliferation. Of note, canthin-6-one did not inhibit VEGFA-induced phosphorylation of VEGFR2 in HUVECs and downstream phosphorylation of extracellular signal-regulated kinase (Erk) in leading ISV endothelial cells in zebrafish, suggesting that canthin-6-one inhibits angiogenesis independent of the VEGFA/VEGFR2 pathway. Importantly, we found that canthin-6-one impairs tumour-associated angiogenesis in a zebrafish B16F10 melanoma cell xenograft model and synergises with VEGFR inhibitor sunitinib malate to inhibit developmental angiogenesis. In summary, we showed that canthin-6-one exhibits anti-angiogenic properties in both developmental and pathological contexts in zebrafish, independent of the VEGFA/VEGFR2 pathway and demonstrate that canthin-6-one may hold value for further development as a novel anti-angiogenic drug.

Approximately 25% to 40% of patients with chronic obstructive pulmonary disease (COPD) have the eosinophilic endotype. It is important to identify this group accurately because they are more symptomatic and are at increased risk for exacerbations and accelerated decline in forced expiratory volume in the 1st second. Importantly, this endotype is a marker of treat ment responsiveness to inhaled corticosteroid (ICS), resulting in decreased mortality risk. In this review, we highlight differences in the biology of eosinophils in COPD compared to asthma and the different definitions of the COPD eosinophilic endotype based on sputum and blood eosinophil count (BEC) with the corresponding limitations. Although BEC is useful as a biomarker for eosinophilic COPD endotype, optimal BEC cut-offs can be combined with clinical characteristics to improve its sensitivity and specificity. A targeted approach comprising airway eosinophilia and appropriate clinical and physiological features may improve identification of subgroups of patients who would benefit from biologic therapy or early use of ICS for disease modification.

Here, (-)-Tetrahydroalstonine (THA) was isolated from Alstonia scholaris and investigated for its neuroprotective effect towards oxygen–glucose deprivation/re-oxygenation (OGD/R)-induced neuronal damage. In this study, primary cortical neurons were pre-treated with THA and then subjected to OGD/R induction. The cell viability was tested by the MTT assay, and the states of the autophagy–lysosomal pathway and Akt/mTOR pathway were monitored by Western blot analysis. The findings suggested that THA administration increased the cell viability of OGD/R-induced cortical neurons. Autophagic activity and lysosomal dysfunction were found at the early stage of OGD/R, which were significantly ameliorated by THA treatment. Meanwhile, the protective effect of THA was significantly reversed by the lysosome inhibitor. Additionally, THA significantly activated the Akt/mTOR pathway, which was suppressed after OGD/R induction. In summary, THA exhibited promising protective effects against OGD/R-induced neuronal injury by autophagy regulation through the Akt/mTOR pathway.

There is growing evidence that tumour heterogeneity has an imperative role in cancer development, evolution and resistance to therapy. Continuing advancements in biomedical research enable tumour heterogeneity to be observed and studied more critically. As one of the most heterogeneous human cancers, melanoma displays a high level of biological complexity during disease progression. However, much is still unknown regarding melanoma tumour heterogeneity, as well as the role it plays in disease progression and treatment response. This review aims to provide a concise summary of the importance of tumour heterogeneity in melanoma.

Abstract Background A major outbreak of the Zika virus (ZIKV) has been reported in Brazil in 2015. Since then, it spread further to other countries in the Americas and resulted in declaration of the Public Health Emergency of International Concern (PHEIC) by World Health Organization. In 2016, Singapore reported its first minor ZIKV epidemic. Malaysia shares similar ecological environment as Brazil and Singapore which may also favor ZIKV transmission. However, no ZIKV outbreak has been reported in Malaysia to date. This study aimed to discuss all confirmed ZIKV cases captured under Malaysia ZIKV surveillance system after declaration of the PHEIC; and explore why Malaysia did not suffer a similar ZIKV outbreak as the other two countries. Methods This was an observational study reviewing all confirmed ZIKV cases detected in Malaysia through the ZIKV clinical surveillance and Flavivirus laboratory surveillance between June 2015 and December 2017. All basic demographic characteristics, co-morbidities, clinical, laboratory and outcome data of the confirmed ZIKV cases were collected from the source documents. Results Only eight out of 4043 cases tested positive for ZIKV infection during that period. The median age of infected patients was 48.6 years and majority was Chinese. Two of the subjects were pregnant. The median interval between the onset of disease and the first detection of ZIKV Ribonucleic Acid (RNA) in body fluid was 3 days. Six cases had ZIKV RNA detected in both serum and urine samples. Phylogenetic analysis suggests that isolates from the 7 cases of ZIKV infection came from two clusters, both of which were local circulating strains. Conclusion Despite similar ecological background characteristics, Malaysia was not as affected by the recent ZIKV outbreak compared to Brazil and Singapore. This could be related to pre-existing immunity against ZIKV in this population, which developed after the first introduction of the ZIKV in Malaysia decades ago. A serosurvey to determine the seroprevalence of ZIKV in Malaysia was carried out in 2017. The differences in circulating ZIKV strains could be another reason as to why Malaysia seemed to be protected from an outbreak.

Lymphangiogenesis, the formation of new lymphatic vessels from pre-existing vasculature, plays critical roles in disease, including in cancer metastasis and chronic inflammation. Preclinical and recent clinical studies have now demonstrated therapeutic utility for several anti-lymphangiogenic agents, but optimal agents and efficacy in different settings remain to be determined. We tested the anti-lymphangiogenic property of 3,4-Difluorobenzocurcumin (CDF), which has previously been implicated as an anti-cancer agent, using zebrafish embryos and cultured vascular endothelial cells. We used transgenic zebrafish labelling the lymphatic system and found that CDF potently inhibits lymphangiogenesis during embryonic development. We also found that the parent compound, Curcumin, does not inhibit lymphangiogenesis. CDF blocked lymphatic and venous sprouting, and lymphatic migration in the head and trunk of the embryo. Mechanistically, CDF impaired VEGFC-VEGFR3-ERK signalling in vitro and in vivo. In an in vivo pathological model of Vegfc-overexpression, treatment with CDF rescued endothelial cell hyperplasia. CDF did not inhibit the kinase activity of VEGFR3 yet displayed more prolonged activity in vivo than previously reported kinase inhibitors. These findings warrant further assessment of CDF and its mode of action as a candidate for use in metastasis and diseases of aberrant lymphangiogenesis.

Telomere attrition is an established ageing biomarker and shorter peripheral blood leukocyte telomere length has been associated with increased risks of respiratory diseases. However, whether telomere length in disease-relevant sputum immune cells of chronic respiratory disease patients is shortened and which pathways are dysfunctional are not clear. Here we measured telomere length from sputum samples of bronchiectasis and asthmatic subjects and determined that telomere length in sputum of bronchiectasis subjects was significantly shorter (Beta = - 1.167, P.sub.Adj = 2.75 x 10.sup.-4). We further performed global gene expression analysis and identified genes involved in processes such as NLRP3 inflammasome activation and regulation of adaptive immune cells when bronchiectasis sputum telomere length was shortened. Our study provides insights on dysfunctions related to shortened telomere length in sputum immune cells of bronchiectasis patients., Author(s): Hui Fang Lim [sup.1] [sup.2], Nadia Suray Tan [sup.2], Roghayeh Dehghan [sup.3] [sup.4], Meixin Shen [sup.5], Mei Fong Liew [sup.1] [sup.2], Stella Wei Lee Bee [sup.6], Yee Yen Sia [...]

1 Department of Infectious Diseases, Tan Tock Seng Hospital, 2 National Centre for Infectious Diseases, 3 Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore, 4 Division of Infectious Diseases, University Medicine Cluster, National University Hospital, 5 Department of Infectious Diseases, Singapore General Hospital, 6 Department of Infectious Diseases, Changi General Hospital, 7 Infectious Diseases Care Pte Ltd, Mount Elizabeth Medical Centre, 8 The Novena Medical Specialists, Mount Elizabeth Novena Specialist Centre, 9 Department of Care and Counselling, Tan Tock Seng Hospital, 10Department of Pharmacy, Tan Tock Seng Hospital, 11Department of Pharmacy, Singapore General Hospital, 12Department of Pharmacy, National University Hospital, Singapore [ABSTRACT FROM AUTHOR]

The article presents a case study of a 53-year-old Chinese man with hypertension developed exertional dyspnea after receiving the COVID-19 vaccine. It reports the symptoms worsened, leading to chest discomfort, abnormal electrocardiogram (ECG) findings, and cardiomegaly. It mentions initial pneumonia treatment, condition worsened, leading to pericardiocentesis. It highlights the symptoms improved after the procedure, and was discharged after monitoring.

Vascular development of the central nervous system and blood-brain barrier (BBB) induction are closely linked processes. The role of factors that promote endothelial sprouting and vascular leak, such as vascular endothelial growth factor A, are well described, but the factors that suppress angiogenic sprouting and their impact on the BBB are poorly understood. Here, we show that integrin αVβ8 activates angiosuppressive TGFβ gradients in the brain, which inhibit endothelial cell sprouting. Loss of αVβ8 in the brain or downstream TGFβ1-TGFBR2-ALK5-Smad3 signaling in endothelial cells increases vascular sprouting, branching and proliferation, leading to vascular dysplasia and hemorrhage. Importantly, BBB function in Itgb8 mutants is intact during early stages of vascular dysgenesis before hemorrhage. By contrast, Pdgfb(ret/ret) mice, which exhibit severe BBB disruption and vascular leak due to pericyte deficiency, have comparatively normal vascular morphogenesis and do not exhibit brain hemorrhage. Our data therefore suggest that abnormal vascular sprouting and patterning, not BBB dysfunction, underlie developmental cerebral hemorrhage.