The increasing burden of asthma acute care in Singapore: an update on 15-year population-level evidence.

BACKGROUND: In Singapore, there is currently scarce population-based research informing the recent trends of asthma-related healthcare burdens. In this study, we investigated the past 25-year trends of asthma-related hospitalisations, emergency department (ED) visits and deaths in Singapore and projected the future burdens from 2023 to 2040. METHODS: We acquired annually-measured data from the Singapore Ministry of Health Clinical and National Disease Registry, containing 25-year asthma-related hospitalisation and death rates as well as 15-year ED visit rates. We conducted change-point analysis and generalised linear modelling to identify time intervals with stable trends and estimate asthma-related healthcare utilisation and mortality rates. To project future asthma-related burdens, we developed a probabilistic model which combined projections of future population size with the estimated rate outcomes from the last stable period. RESULTS: Our results show that the asthma hospitalisation rate in Singapore had remained at approximately 80 episodes per 100,000 from 2003 to 2019 and are likely to grow by 1.7% each year (95% CI: 0.7, 5.0%), leading to a total of 163,633 episodes from 2023 to 2040 which corresponds to an estimated $103,075,820 based on 2022 USD. Besides, Singapore's asthma-related ED visit rate was 390 per 100,000 in 2019 and is expected to decline by 3.4% each year (95% CI: - 5.8, 0.0%), leading to a total of 208,145 episodes from 2023 to 2040 which corresponds to USD$15,053,795. In contrast, the 2019 asthma-related mortality rate in Singapore was approximately 0.57 per 100,000 and is likely to stay stably low (change per year: -1.3, 95% CI: - 11.0, 4.3%). Between 2023 and 2040, Singapore's estimated total number of asthma-related deaths is 638 episodes. CONCLUSIONS: Currently, the burden of asthma acute care in Singapore is high; Singapore's asthma-related hospitalisation and ED visit rates are relatively higher than those of other developed economies, and its asthma admission rate is expected to increase significantly over time, possibly indicating excess resource use for asthma. The established national asthma programme in Singapore, together with recent efforts in reinforcing primary care at the national level, provides opportunities to reduce avoidable asthma admissions.

QRISK3 underestimates the risk of cardiovascular events in patients with COPD.

BACKGROUND: Patients with chronic obstructive pulmonary disease (COPD) are at increased risk of cardiovascular disease (CVD). The extent to which the excess CVD risk is captured by risk factors in QRISK, a widely used CVD risk scoring tool, is not well studied. METHODS: We created an incidence cohort of diagnosed COPD patients from the United Kingdom (UK) Clinical Practice Research Datalink GOLD database (January 1998-July 2018). The outcome was a composite of fatal or non-fatal CVD events. Sex-specific age-standardised incidence ratios (SIR) were compared with values for the UK primary-care population. The observed 10-year CVD risk was derived using the Kaplan-Meier estimator and was compared with predicted 10-year risk from the QRISK3 tool. RESULTS: 13 208 patients (mean age 64.9 years, 45% women) were included. CVD incidence was 3.53 events per 100 person-years. The SIR of CVD was 1.71 (95% CI 1.61 to 1.75) in women and 1.62 (95%CI 1.54-1.64) in men. SIR was particularly high among patients younger than 65 years (women=2.13 (95% CI 1.94 to 2.19); men=1.86 (95% CI 1.74 to 1.90)). On average, the observed 10-year risk was 52% higher than QRISK predicted score (33.5% vs 22.1%). The difference was higher in patients younger than 65 years (observed risk 82% higher than predicted). CONCLUSION: People living with COPD are at a significantly heightened risk of CVD over and beyond their predicted risk. This is particularly the case for younger people whose 10-year CVD risk can be >80% higher than predicted. Risk scoring tools must be validated and revised to provide accurate CVD predictions in patients with COPD.

Risk of all-cause mortality or hospitalization for pneumonia associated with inhaled ß2-agonists in patients with asthma, COPD or asthma-COPD overlap.

ß2-agonists provide necessary bronchodilatory action, are recommended by existing clinical practice guidelines and are widely prescribed for patients with these conditions. We examined the risk of all-cause mortality and hospitalization for pneumonia associated with long-or short-acting ß2-agonists (LABA or SABA) or ICS (inhaled corticosteroids)/LABA use. In a nested case-control of 185,407 patients, we found no association between ß2-agonist use and the risk of pneumonia in patients with asthma, COPD, or asthma-COPD overlap. In contrast, new SABA [HR 1.82 (95% CI 1.04-3.20)] or LABA [HR 2.77 (95% CI 1.22-6.31)] use was associated with an increased risk of all-cause mortality compared to ICS use in COPD patients.

Association between Inhaled ß2-agonists Initiation and Risk of Major Adverse Cardiovascular Events: A Population-based Nested Case-Control Study.

Purpose: Despite ample evidence underpinning the efficacy of ß2-agonists in asthma and chronic obstructive pulmonary disease (COPD), the occurrence of ß1- and ß2-adrenoceptors in the heart suggests that ß2-agonists may have deleterious cardiac effects. We investigated the association between new users of long-or short-acting ß2-agonists (LABA or SABA) or ICS (inhaled corticosteroids)/LABA and major adverse cardiovascular events (MACE). Methods: A nested case-control analysis was conducted using the UK Clinical Practice Research Datalink of patients with asthma, COPD or asthma-COPD overlap with initial treatment of LABA, SABA, ICS/LABA, ICS, long-or short-acting muscarinic antagonist (LAMA or SAMA) between 01 January 1998 and 31 July 2018. The primary outcome was MACE, defined as the first occurrence of stroke, heart failure, myocardial infarction, arrhythmia, or cardiovascular death. Each case was matched with up to 10 controls on age, sex, date of cohort-entry, and duration of follow-up. The risk of MACE associated with ß2-agonists was estimated using conditional logistic regression after controlling for potential confounders. Results: The cohort included 180,567 new users of ß2-agonists, ICS, SAMA, or LAMA. Among asthmatics, ß2-agonists were not associated with the risk of MACE (SABA vs ICS: HR 1.29 [0.96-1.73]; ICS/LABA vs ICS, HR 0.75 [0.33-1.73]). In contrast, among COPD patients, LABA (HR, 2.38 [1.04-5.47]), SABA (HR, 2.02 [1.13-3.59]) and ICS/LABA (HR, 2.08 [1.04-4.16]) users had an increased risk of MACE compared with SAMA users. Among patients with asthma-COPD overlap, SABA (HR, 2.57 [1.26-5.24]) was associated with an increased risk of MACE compared with ICS. Conclusion: In conclusion, initiation of LABA, SABA, or ICS/LABA in COPD or SABA in asthma-COPD overlap is associated with increased risk of MACE. No associations were observed among patients with asthma.

Comparative safety and effectiveness of inhaled bronchodilators and corticosteroids for treating asthma-COPD overlap: a systematic review and meta-analysis.

OBJECTIVE: To determine the safety and effectiveness of current pharmacotherapies consisting of long-acting beta2-agonist (LABA) and/or inhaled corticosteroids (ICS) in patients with asthma-COPD overlap. DATA SOURCES: A systematic search was conducted using the PubMed, EMBASE, and Web of Science databases up to June 2018. STUDY SELECTIONS: Only studies comparing the safety and effectiveness of LABA and/or ICS in patients with asthma-COPD overlap were included. A meta-analysis was performed to calculate risk ratio (RR) and 95% confidence interval (CI) using Inverse Variance Random-effects model. RESULTS: From a total of 3382 articles retrieved, three randomized controlled trials (RCTs), six cohort studies (CS), one nested case control study fulfilled the inclusion criteria for three independent meta-analyses representing 181,603 participants. Three CS results show LABA was associated with decreased risk of myocardial infarction (combined RR: 0.80, 95% CI 0.74-0.87) versus non-LABA use; ICS/LABA was associated with a lower risk of death or hospitalization (combined RR: 0.82, 95% CI 0.75-0.90) compared to no use. Results from RCTs, no clear difference in lung function decline in FEV1 was found (combined mean difference: 0.08, 95% CI 0.15-0.32) in patients receiving ICS and/or LABA compared to placebo. However, due to lack of data, exacerbations, fractures and nontuberculous mycobacterial pulmonary disease outcomes were not meta-analyzed. CONCLUSIONS: Among patients with asthma-COPD overlap, LABA is associated with decreased risk of myocardial infarction; and the combination therapy of ICS/LABA appears to reduce the risk of death or hospitalization. More studies of quality data and larger number of patients are needed. REGISTRATION: PROSPERO (CRD42018090863).

Gender Differences in Inhaled Pharmacotherapy Utilization in Patients with Obstructive Airway Diseases (OADs): A Population-Based Study.

Purpose: Gender differences in the incidence, susceptibility and severity of many obstructive airway diseases (OADs) have been well recognized. However, gender differences in the inhaled pharmacotherapy profile are not well characterized. Methods: We conducted a retrospective cohort study to investigate gender differences in new-users of inhaled corticosteroids (ICS), short-or long-acting beta2-agonist (SABA or LABA), ICS/LABA, short-or long-acting muscarinic antagonist (SAMA or LAMA) among patients with asthma, COPD or asthma-COPD overlap (ACO). We used Clinical Practice Research Datalink to identify OAD patients, 18 years and older, who were new-users (1-year washout period) from 01-January-1998 to 31-July-2018. Multivariable logistic regression was used to examine gender differences in each of the inhaled pharmacotherapies after controlling for potential confounders. Results: A total of 242,079 new-users (asthma: 84.93%; COPD: 10.19%; ACO: 4.88%) of inhaled pharmacotherapies were identified. The multivariable analyses showed that males with COPD were more likely to be a new user of a LABA (odds ratio [OR] 1.29; 95% confidence interval [CI], 1.12-1.49), LAMA (OR 1.21; 95% CI 1.10-1.33), SAMA (OR 1.11; 95% CI 1.01-1.21) and less likely to be a new user of a SABA (OR 0.84; 95% CI, 0.80-0.89) compared to females. Similar patterns were also observed for patients with ACO; males were more likely to be prescribed with LABA (OR 1.26; 95% CI 1.03-1.55), LAMA (OR 1.28; 95% CI 1.11-1.48), SAMA (OR 1.28; 95% CI 1.11-1.48), and less likely to be a new user of a SABA (OR 0.89; 95% CI, 0.82-0.96). Also, males with asthma were more likely to be a new-user of ICS/LABA (OR 1.15; 95% CI, 1.08-1.23) and less likely to start an ICS (OR 0.97; 95% CI, 0.95-0.99) in comparison with females. Conclusion: Our study showed significant gender differences in new-users of inhaled pharmacotherapies among OAD patients. Adjusting for proxies of disease severity, calendar year, smoking and socioeconomic status did not change the association by gender.

Validated methods to identify patients with asthma-COPD overlap in healthcare databases: a systematic review protocol.

INTRODUCTION: Asthma-chronic obstructive pulmonary disease (COPD) overlap (ACO) is characterised by patients presenting symptoms of both asthma and COPD. Many efforts have been made to validate different methods of identifying asthma-COPD overlap cases based on symptoms, spirometry and medical history in epidemiological studies using healthcare databases. There are various coding algorithm strategies that can be used and selection depends on targeted validation. The primary objectives of this systematic review are to identify validated methods (or algorithms) that identify patients with ACO from healthcare databases and summarise the reported validity measures of these methods. METHODS: MEDLINE, EMBASE databases and the Web of Science will be systematically searched by using appropriate search strategies that are able to identify studies containing validated codes and algorithms for the diagnosis of ACO in healthcare databases published, in English, before October 2018. For each selected study, we require the presence of at least one test measure (eg, sensitivity, specificity etc). We will also include studies, in which the validated algorithm is compared with an external reference standard such as questionnaires completed by patients or physicians, medical charts review, manual review or an independent second database. For all selected studies, a uniform table will be created to summarise the following vital information: name of author, publication year, country, data source, population, clinical outcome, algorithms, reference standard method of validation and characteristics of the test measure used to determine validity. PROSPERO REGISTRATION NUMBER: CRD42018087472.

DoE based Olanzapine loaded poly-caprolactone nanoparticles decreases extrapyramidal effects in rodent model.

The purpose of present investigation was to nano-encapsulate atypical antipsychotic such as Olanzapine in polymeric nanoparticles in order to explore the possibility of minimizing drug associated extrapyramidal adverse effects. The polymeric nanoparticulate systems were prepared using FDA approved polymer, polycaprolactone, by simple technique of nanoprecipitation using factorial design by DoE approach. The significant factors selected for the optimization during formulation development process were polymer content and surfactant concentration at three different levels (32 factorial design). The effect of selected significant factors were studied in depth on significant responses such as particle size and encapsulation efficiency. The optimized formulation was further surface modified with surfactant (polysorbate 80) so as to enhance the brain targeting efficiency of developed nanoparticles via endocytosis pathway. Furthermore, catalepsy was induced in rodent model and the designed formulations were investigated in comparison with pure drug solution for efficiency in decreasing extrapyramidal adverse effects. The results of in vitro characterization studies demonstrated a narrow size distributed nanoparticles (73.28 ±â€¯2.14 nm) with high stability indicating zetapotential (-32.46 ±â€¯1.15 mV) and high encapsulation efficiency (78.77 ±â€¯2.83%). In vitro release studies resulted in an extended release of atypical antipsychotic for 60 h from drug-loaded optimized nanoparticulate formulations. The catalepsy studies in rodent model demonstrated a significant decrease in extra pyramidal adverse effects as compared to the pure atypical antipsychotic. Thus, the designed antipsychotic loaded polymeric nanoparticulate system may be highly promising for the tremendous improvement of antipsychotic therapy with reduced adverse effects.

In Situ Alloying of Thermally Conductive Polymer Composites by Combining Liquid and Solid Metal Microadditives.

Room-temperature liquid metals (LMs) are attractive candidates for thermal interface materials (TIMs) because of their moderately high thermal conductivity and liquid nature, which allow them to conform well to mating surfaces with little thermal resistance. However, gallium-based LMs may be of concern due to the gallium-driven degradation of many metal microelectronic components. We present a three-component composite with LM, copper (Cu) microparticles, and a polymer matrix, as a cheaper, noncorrosive solution. The solid copper particles alloy with the gallium in the LM, in situ and at room temperature, immobilizing the LM and eliminating any corrosion issues of nearby components. Investigation of the structure-property-process relationship of the three-component composites reveals that the method and degree of additive blending dramatically alter the resulting thermal transport properties. In particular, microdispersion of any combination of the LM and Cu additives results in a large number of interfaces and a thermal conductivity below 2 W m-1 K-1. In contrast, a shorter blending procedure of premixed LM and Cu particle colloid into the polymer matrix yields a composite with polydispersed filler and effective intrinsic thermal conductivities of up to 17 W m-1 K-1 (effective thermal conductivity of up to 10 W m-1 K-1). The LM-Cu colloid alloying into CuGa2 provides a limited, but practical, time frame to cast the uncured composite into the desired shape, space, or void before the composite stiffens and cures with permanent characteristics.

Design and in vivo evaluation of solid lipid nanoparticulate systems of Olanzapine for acute phase schizophrenia treatment: Investigations on antipsychotic potential and adverse effects.

The present paper discusses the design, characterization and in vivo evaluation of glyceryl monostearate nanoparticles of Olanzapine, an atypical antipsychotic drug for acute schizophrenia treatment, during which hospitalization is mandatory and adverse effects are at its peak. The solid lipid nanoparticulate system was obtained by emulsification-ultra sonication technique wherein three factors such as solid lipid content, concentration of surfactant and drug: solid lipid ratio were selected at three different levels in order to study their influence on significant characteristic responses such as particle size, encapsulation efficiency and drug content. A Box Behnken design with 17 runs involving whole factors at three levels was employed for the study. The optimized formulation was further coated with Polysorbate 80 in order to enhance its brain targeting potential through endocytosis transport process via blood brain barrier. The designed formulations were pre-clinically tested successfully in Wistar rat model for in vivo antipsychotic efficacy (apomorphine induced psychosis) and adverse effects (weight gain study for 28days). The results obtained indicated that solid lipid nanoparticles had very narrow size distribution (151.29±3.36nm) with very high encapsulation efficiency (74.51±1.75%). Morphological studies by SEM have shown that solid lipid nanoparticles were spherical in shape with smooth surface. Olanzapine-loaded nanoparticles prepared from solid lipid, extended the release of drug for 48h, as found by the in vitro release studies. The formulations also exhibited high redispersibility after freeze-drying and stability study results demonstrated good stability, with no significant change for a period of 6months. In vivo evaluation and adverse effects studies of Olanzapine-loaded nanoparticulate systems in animal model have demonstrated an improved therapeutic efficacy than pure Olanzapine. The antipsychotic effect of drug loaded nanoparticulate systems was maintained for 48h as compared to 8h antipsychotic action of pure Olanzapine solution. The weight gain studies for 28days demonstrated a significant inhibition in weight gain for Olanzapine-loaded nanoparticulate systems as compared to the pure Olanzapine. The present research findings indicate that OLN-loaded nanoparticulate systems may be highly promising for effective delivery of Olanzapine with better efficacy and minimum adverse effects.

Investigations on pharmacokinetics and biodistribution of polymeric and solid lipid nanoparticulate systems of atypical antipsychotic drug: effect of material used and surface modification.

The present study focuses on the effect of material used for the preparation of nanoparticulate (NP) systems and surface modification on the pharmacokinetics and biodistribution of atypical antipsychotic, olanzapine (OLN). NP carriers of OLN were prepared from two different materials such as polymer (polycaprolactone) and solid lipid (Glyceryl monostearate). These systems were further surface modified with surfactant, Polysorbate 80 and studied for pharmacokinetics-biodistribution in Wistar rats using in-house developed bioanalytical methods. The pharmacokinetics and biodistribution studies resulted in a modified and varied distribution of NP systems with higher area under curve (AUC) values along with prolonged residence time of OLN in the rat blood circulation. The distribution of OLN to the brain was significantly enhanced with surfactant surface-modified NP systems, followed by nonsurface-modified NP formulations as compared with pure OLN solution. Biodistribution study demonstrated a low uptake of obtained NP systems by kidney and heart, thereby decreasing the nephrotoxicity and adverse cardiovascular effects. By coating the NP with surfactant, uptake of macrophage was found to be reduced. Thus, our studies confirmed that the biodistribution OLN could be modified effectively by incorporating in NP drug delivery systems prepared from different materials and surface modifications. A judicious selection of materials used for the preparation of delivery carriers and surface modifications would help to design a most efficient drug delivery system with better therapeutic efficacy.

Studying electrons on curved surfaces by trapping and manipulating multielectron bubbles in liquid helium.

Investigations of two-dimensional electron systems (2DES) have been achieved with two model experimental systems, covering two distinct, non-overlapping regimes of the 2DES phase diagram, namely the quantum liquid phase in semiconducting heterostructures and the classical phases observed in electrons confined above the surface of liquid helium. Multielectron bubbles in liquid helium offer an exciting possibility to bridge this gap in the phase diagram, as well as to study the properties of electrons on curved flexible surfaces. However, this approach has been limited because all experimental studies have so far been transient in nature. Here we demonstrate that it is possible to trap and manipulate multielectron bubbles in a conventional Paul trap for several hundreds of milliseconds, enabling reliable measurements of their physical properties and thereby gaining valuable insight to various aspects of curved 2DES that were previously unexplored.

Physicochemical and biological aspects of macrophage-mediated drug targeting in anti-microbial therapy.

Macrophages are important drug targets as they mediate a wide variety of infectious diseases. Visceral leishmaniasis (VL), schistosomiasis, brucellosis, and salmonellosis are some of the well-known infectious diseases in which macrophages play a prominent pathophysiological role. For instance, VL parasites exclusively house in the macrophages of liver and spleen. They are resistant to lysosomal degradation by unknown mechanisms, they survive and thrive safely within macrophages, they multiply, and they ultimately affect visceral organs, leading to severe pathological and sometimes even fatal conditions. The majority of routinely used drugs administered in free form distribute all over the body via systemic circulation, leading to relatively low therapeutic activity and a certain degree of toxicity. Unlike for nonmicrobial diseases, targeting parasites procuring resistance and ineffective therapeutic outcome can be obviously speculated in case of infectious disease. The preferential uptake by macrophages, intended to improve the balance between efficacy and toxicity, can be achieved by the use of nanomedicines, i.e. submicron-sized macromolecular or particulate drug delivery systems. This insight has stimulated researchers to use nanomedicines--which tend to be recognized by macrophages as 'foreign' and consequently are taken up by the intended target cells much more effectively than their free drug counterparts--to improve the treatment of infectious diseases. The literature reports extensively on such approaches; however, there are several constraints that limit the application of nanomedicine in macrophage-mediated drug targeting. Here, we briefly describe the strategies that are used to achieve effective drug targeting to macrophages, using VL as a model disease, and we also put forth an understanding of the most important limiting factors. Various physicochemical and biological factors used by researchers as reported in the literature are addressed, and the most important mechanisms and modes by which macrophage-specific drug targeting can be achieved are summarized. Based on the evidence obtained to date, it can be concluded that targeting macrophages is a valuable and validated strategy for improving the treatment of infectious diseases.