The current state of understanding of oncology expanded access programs in Malaysia.

INTRODUCTION: An expanded access program (EAP) is a regulatory mechanism that provides access to an investigational drug, which is not approved for use, in treating life-threatening conditions when all the standard-ofcare treatments are exhausted. MATERIALS AND METHODS: An online, anonymous, voluntary survey was conducted to assess the level of knowledge and understanding about EAPs among Malaysian oncologists using SurveyMonkey® between April 2020 and June 2020. Oncologists who had enquired about EAP in the past, were invited at random to participate in the survey. Participants who did not provide consent or failed to complete the survey were excluded. RESULTS: A total of 15 oncologists participated in the survey, from both public (46.6%) and private (46.6%) practices. Most respondents (80%) had filed between 1 to 10 EAP applications in the past 12 months. For 73.3% respondents, resources or training were not provided for EAPs from institutions. Around 53% of the respondents reported that their knowledge of EAPs and application processes including country regulations is 'good'. The majority of respondents (73.3%) reported that the educational modules on an overview of EAPs, country regulations and the EAP application process will be beneficial. Most participants received information about the existing EAPs either by reaching out to a pharmaceutical sponsor or through another health care provider and some received information about the existing EAPs through their institutions or patients/caregivers. Most of the respondents recommended that pharmaceutical companies should have readily available information related to the availability and application of EAPs for all pipeline products on their websites. DISCUSSION: EAPs are crucial treatment access pathways to provide investigational drugs to patients who have exhausted their treatment options and are not eligible for participation in clinical trials. Malaysian oncologists have a fair understanding about the EAPs and the application processes. CONCLUSION: Additional training and awareness are needed for Malaysian oncologists to upscale the utilisation of EAPs.

An economic evaluation of the randomized controlled trial of topical corticosteroid and home-based narrowband ultraviolet B for active and limited vitiligo (the HI-Light Vitiligo Trial).

BACKGROUND: Economic evidence for vitiligo treatments is absent. OBJECTIVES: To determine the cost-effectiveness of (i) handheld narrowband ultraviolet B (NB-UVB) and (ii) a combination of topical corticosteroid (TCS) and NB-UVB compared with TCS alone for localized vitiligo. METHODS: Cost-effectiveness analysis alongside a pragmatic, three-arm, placebo-controlled randomized controlled trial with 9 months' treatment. In total 517 adults and children (aged ≥ 5 years) with active vitiligo affecting < 10% of skin were recruited from secondary care and the community and were randomized 1: 1: 1 to receive TCS, NB-UVB or both. Cost per successful treatment (measured on the Vitiligo Noticeability Scale) was estimated. Secondary cost-utility analyses measured quality-adjusted life-years using the EuroQol 5 Dimensions 5 Levels for those aged ≥ 11 years and the Child Health Utility 9D for those aged 5 to < 18 years. The trial was registered with number ISRCTN17160087 on 8 January 2015. RESULTS: The mean ± SD cost per participant was £775 ± 83·7 for NB-UVB, £813 ± 111.4 for combination treatment and £600 ± 96·2 for TCS. In analyses adjusted for age and target patch location, the incremental difference in cost for combination treatment compared with TCS was £211 (95% confidence interval 188-235), corresponding to a risk difference of 10·9% (number needed to treat = 9). The incremental cost was £1932 per successful treatment. The incremental difference in cost for NB-UVB compared with TCS was £173 (95% confidence interval 151-196), with a risk difference of 5·2% (number needed to treat = 19). The incremental cost was £3336 per successful treatment. CONCLUSIONS: Combination treatment, compared with TCS alone, has a lower incremental cost per additional successful treatment than NB-UVB only. Combination treatment would be considered cost-effective if decision makers are willing to pay £1932 per additional treatment success.

Household economic burden and outcomes of patients with schizophrenia after being unlocked and treated in rural China.

AIMS: Patients with severe mental disorders in low-resource settings have limited access to services, resulting in overwhelming caregiving burden for families. In extreme cases, this has led to the long-term restraining of patients in their homes. China underwent a nationwide initiative to unlock patients and provide continued treatment. This study aims to quantify household economic burden in families after unlocking and treatment, and to identify factors associated with increased burden due to schizophrenia. METHODS: A total of 264 subjects were enrolled from three geographically diverse provinces in 2012. Subjects were patients with schizophrenia who were previously put under restraints and had participated in the 'unlocking and treatment' intervention. The primary outcome was the current household economic burden, obtained from past year financial information collected through on-site interview. Patient disease characteristics, treatment, outcomes and family caregiving burden were collected as well. Univariate and multivariate linear regression were used to construct risk factor models for indirect economic burden. RESULTS: After participating in the intervention, 85% of patients continued to receive mental health services, 70% used medication as prescribed and 80% were never relocked. Family members reported significantly decreased caregiving burden after receiving the intervention. Mean direct and indirect household economic burdens were CNY963 (US$31.7) and CNY11 724 (US$1670) per year, respectively, while family total income was on average CNY12 108 (US$1913) per year. Greater disease severity and poorer patient psychosocial function at time of study were found to be independent factors related to increased indirect burden. CONCLUSIONS: The 'unlocking and treatment' intervention has improved the lives of patients and families. Indirect burden due to disease is still a major economic issue that needs to be addressed, potentially through improving treatment and patient functioning. Our findings contribute to the unravelling and eventual elimination of chronic restraining of mentally ill patients in low-resource settings.

Paediatric palliative care improves patient outcomes and reduces healthcare costs: evaluation of a home-based program.

BACKGROUND: Around the world, different models of paediatric palliative care have responded to the unique needs of children with life shortening conditions. However, research confirming their utility and impact is still lacking. This study compared patient-related outcomes and healthcare expenditures between those who received home-based paediatric palliative care and standard care. The quality of life and caregiver burden for patients receiving home-based paediatric palliative care were also tracked over the first year of enrolment to evaluate the service's longitudinal impact. METHOD: A structured impact and cost evaluation of Singapore-based HCA Hospice Care's Star PALS (Paediatric Advance Life Support) programme was conducted over a three-year period, employing both retrospective and prospective designs with two patient groups. RESULTS: Compared to the control group (n = 67), patients receiving home-based paediatric palliative care (n = 71) spent more time at home than in hospital in the last year of life by 52 days (OR = 52.30, 95% CI: 25.44-79.17) with at least two fewer hospital admissions (OR = 2.46, 95% CI: 0.43-4.48); and were five times more likely to have an advance care plan formulated (OR = 5.51, 95% CI: 1.55-19.67). Medical costs incurred by this group were also considerably lower (by up to 87%). Moreover, both patients' quality of life (in terms of pain and emotion), and caregiver burden showed improvement within the first year of enrolment into the programme. DISCUSSION: Our findings suggest that home-based paediatric palliative care brings improved resource utilization and cost-savings for both patients and healthcare providers. More importantly, the lives of patients and their caregivers have improved, with terminally ill children and their caregivers being able to spend more quality time at home at the final stretch of the disease. CONCLUSIONS: The benefits of a community paediatric palliative care programme have been validated. Study findings can become key drivers when engaging service commissioners or even policy makers in appropriate settings.

Vascular risk assessment in older adults without a history of cardiovascular disease.

Modern cardiovascular risk prediction tools, which have their genesis in the Framingham Heart Study, have allowed more accurate risk stratification and targeting of treatments worldwide over the last seven decades. Better cardiovascular risk factor control during this time has led to a reduction in cardiovascular mortality and, at least in part, to improved life expectancy. As a result, western societies as a whole have seen a steady increase in the proportion of older persons in their populations. Unfortunately, several studies have shown that the same tools which have contributed to this increase cannot be reliably extrapolated for use in older generations. Recent work has allowed recalibration of existing models for use in older populations but these modified tools still require external validation before they can be confidently applied in clinical practice. Another complication is emerging evidence that aggressive risk factor modification in older adults, particularly more frail individuals, may actually be harmful. This review looks at currently available cardiovascular risk prediction models and the specific challenges faced with their use in older adults, followed by analysis of recent attempts at recalibration for this cohort. We discuss the issue of frailty, looking at our evolving understanding of its constituent features and various tools for its assessment. We also review work to date on the impact of frailty on cardiovascular risk modification and outline its potentially central role in determining the most sensible approach in older patients. We summarise the most promising novel markers of cardiovascular risk which may be of use in improving risk prediction in older adults in the future. These include markers of vascular compliance (such as aortic pulse wave velocity and pulse wave analysis), of endothelial function (such as flow mediated dilation, carotid intima-media thickness and coronary artery calcium scores), and also biochemical and circulating cellular markers.

Stratifying healthcare costs using the Diabetes Complication Severity Index.

OBJECTIVE: We aim to determine whether healthcare costs for patients diagnosed with Type 2 Diabetes Mellitus (T2DM) are associated with the severity of diabetes complications as measured by the Diabetes Complication Severity Index (DCSI). METHODS: Retrospective cohort analysis was performed on a 2007 primary care cohort of T2DM patients. The DCSI is a 13-point scale, which comprises 7 categories of complications and their severity levels. Healthcare cost data from 2008 and 2009 were used as primary outcome. Inpatient and outpatient costs incurred for services consumed by patients within the provider network were included. Generalized linear model with log-link and gamma distribution was used to predict healthcare costs. RESULTS: Of the 59,767 T2DM patients, 2977 (5.0%) deaths occurred and 1336 (2.2%) were lost to follow up. Healthcare cost was strongly associated with increase in DCSI score. Compared to patients without complications, those with more complications (higher DCSI score) had an increased risk of higher healthcare costs. Risk ratio (RR) increased from 1.25 (95%CI: 1.19-1.32) for DCSI=1 to 1.61 (1.51-1.72) for DCSI=2; 2.10 (1.91-2.31) for DCSI=3; 2.52 (2.21-2.87) for DCSI=4 and 3.62 (3.09-4.25) for DCSI≥5. As a continuous score, a one-point increase in the DCSI was associated with a cost increase of 27% (95%CI: 1.25-1.29). CONCLUSION: The DCSI score is a useful tool for predicting direct healthcare costs. The DCSI can be used to triage high-risk patients for more focused secondary prevention interventions at primary care level, in a bid to lower overall healthcare costs.

A century of medical students' activities (Medical College Union/Medical Society).

The Medical College Union (MCU) was formed in 1922 to encourage and promote comradeship and public spirit amongst the students of King Edward VII College of Medicine. The Medical College Union Society was founded and held its first meeting on 31 July 1936. However, the Annual Report for 1940-42 made no reference to the Society at all and it was hence considered to cease to exist as an official body. The Medical Society (Medsoc), headed by Mr Goon Sek Mun, was formed in 1949 and it organised various activities and events for the faculty. Some of these are still being held annually today, with the addition of several others and phasing out of some. These were organised by the individual subgroups in the Medical society, like the Social, Welfare, Sports and Publications committees. The Medsoc also acts as the students' voice in conveying their opinions to the administration and the Dean. With the expected advent of a new medical school in Singapore--a postgraduate one in the Outram Campus, the medical student community in Singapore will only get larger. There should be a role for Medsoc to foster closer ties between the student communities.

Selective laser sintering of biocompatible polymers for applications in tissue engineering.

The ability to use biological substitutes to repair or replace damaged tissues lead to the development of Tissue Engineering (TE), a field that is growing in scope and importance within biomedical engineering. Anchorage dependent cell types often rely on the use of temporary three-dimensional scaffolds to guide cell proliferation. Computer-controlled fabrication techniques such as Rapid Prototyping (RP) processes have been recognised to have an edge over conventional manual-based scaffold fabrication techniques due to their ability to create structures with complex macro- and micro-architectures. Despite the immense capabilities of RP fabrication for scaffold production, commercial available RP modelling materials are not biocompatible and are not suitable for direct use in the fabrication of scaffolds. Work is carried out with several biocompatible polymers such as Polyetheretherketone (PEEK), Poly(vinyl alcohol) (PVA), Polycaprolactone (PCL) and Poly(L-lactic acid) (PLLA) and a bioceramic namely, Hydroxyapatite (HA). The parameters of the selective laser sintering (SLS) process are optimised to cater to the processing of these materials. SLS-fabricated scaffold specimens are examined using a Scanning Electron Microscope (SEM). Results observed from the micrographs indicate the viability of them being used for building TE scaffolds and ascertain the capabilities of the SLS process for creating highly porous scaffolds for Tissue Engineering applications.

Overview on SARS in Asia and the world.

Severe Acute Respiratory Syndrome (SARS) is the first major novel infectious disease to hit the international community in the 21st century. It originated in southern China in November 2002, reached Hong Kong in February 2003 and spread rapidly thereafter to 29 countries/regions on five continents. At the end of the epidemic, the global cumulative total was 8098 with 774 deaths. Seven Asian countries/regions were among the top ten on the list. Mainland China and Hong Kong, SAR, accounted for 87% of all cases and 84% of all deaths. Severe acute respiratory syndrome is caused by a novel coronavirus. It has alarmed the world with its infectivity and significant morbidity and mortality, its lack of a rapid, reliable diagnostic test and lack of effective specific treatment and vaccination. The adverse impact on travel and business around the world, particularly in Asia, has been enormous. Some lessons learnt from this epidemic included: (1) any outbreak of infectious disease can rapidly spread around the world by air travel; (2) early reporting of the outbreak to neighbouring countries/regions and the World Health Organization is essential to prevent international spread; and (3) infection control, tracing and quarantine of contacts are essential to control the epidemic. Many questions remain unanswered, including the origin and pathogenesis of the novel coronavirus, the natural history and the best specific treatment of the disease. The SARS-CoV has probably jumped from an animal host to humans. There is an urgent need to evaluate the human-animal habitat in southern China and to remove animal reservoirs if found.

Design and analytic considerations in determining the cost-effectiveness of early intervention in asthma from a multinational clinical trial.

Demand for economic and outcomes data in support of drug formulary listing in private and government-sponsored health programs has led to fundamental changes in drug development. In part as a response to these pressures, the pharmaceutical industry has begun to include economic and quality-of-life endpoints in clinical trials with the hope of providing information to answer health policy questions on the economic value of its products. Here, the design and health economic techniques that will be used to analyze the START (inhaled Steroid Treatment As Regular Therapy in early asthma) study-a multinational (31 countries), randomized, placebo-controlled trial of 7240 patients with mild asthma over 3 years-will be presented. START compares the effect of once-daily administration of an inhaled glucocorticosteroid (Pulmicort Turbuhaler to conventional therapy in the management of newly diagnosed asthma, for which the use of this therapy is currently not the standard. The START study will examine both clinical effectiveness (measured as symptom-free days) and asthma-related costs for both treatment arms, aggregated for all patients across all countries. We believe that presenting the analytical plan prior to disseminating the results is an important way of increasing the credibility of economic evaluations. However, using clinical trials for collecting economic data poses several challenges, and the methods for conducting such evaluations are being developed. This paper will present and discuss several methodological options and the current state of the art for conducting economic evaluations alongside multinational clinical trials.

Hospitalised low-risk community-acquired pneumonia: outcome and potential for cost-savings.

Fine et al. from USA have identified a sub-group of patients with community-acquired pneumonia (CAP) with a low risk of mortality and suggested that it may be cost-effective to manage them as outpatients. The aims of this study were: to evaluate the outcome of low risk CAP patients that were hospitalised in our local setting, and to gauge the number of such patients in order to estimate the potential cost-savings by treating them as outpatients, as well as the safety of such an approach. All patients with CAP admitted to our hospital from 1 April 1997 to 1 March 1998 were enrolled into this prospective cohort study. Low-risk patients were identified, and their hospital outcome compared with other patients. Hospitalisation charges were obtained from the Finance Department. There were 226 patients with CAP. The average age was 64 years with a range of 12 to 96 years. The median hospital stay was 6 days. Mortality was 13.7%. 16.8% required admission to the ICU; none of these were low-risk patients. There were 47 (21%) low-risk patients, and there was no mortality in this group. They had significantly shorter hospital stay (6.4 days versus 10 days) and lower hospitalisation charges ($2,160 versus $5,770) compared to other CAP patients. Only one low-risk patient had a positive blood culture. In conclusion, nearly one-fifth of our CAP admissions consisted of low-risk patients that experienced no mortality, and required a significantly shorter hospitalisation. The management of such patients who are young (< or = 50 years), with no serious co-morbidities in an outpatient setting may be a cost-effective strategy, and this group of patients consumed 9% of the total hospitalisation charges for CAP.

Some state space models of HIV pathogenesis under treatment by anti-viral drugs in HIV-infected individuals.

In this paper we have extended the model of HIV pathogenesis under treatment by anti-viral drugs given by Perelson et al. [A.S. Perelson et al., Science 271 (1999) 1582] to a stochastic model. By using this stochastic model as the stochastic system model, we have developed a state space model for the HIV pathogenesis under treatment by anti-viral drugs. In this state space model, the observation model is a statistical model based on the observed numbers of RNA virus copies over different times. For this model we have developed procedures for estimating and predicting the numbers of infectious free HIV and non-infectious free HIV as well as the numbers of different types of T cells through extended Kalman filter method. As an illustration, we have applied the method of this paper to the data of patient Nos. 104, 105 and 107 given by Perelson et al. [A.S. Perelson et al., Science 271 (1999) 1582] under treatment by Ritonavir. For these individuals, it is shown that within two weeks since treatment, most of the free HIV are non-infectious, indicating the usefulness of the treatment. Furthermore, the Kalman filter method revealed a much stronger effect of the treatment within the first 10 to 20 h than that predicted by the deterministic model.

An improved, inexpensive method for the large-scale purification of human nerve growth factor.

Human nerve growth factor (hNGF) was purified to near homogeneity on a large scale from human term placenta with an improved and inexpensive method. The purification procedure included tissue homogenization, ultrafiltration and single CM-cellulose column chromatography. The purified hNGF was a 14.4-kDa protein with an isoelectric point of approximately 9.3. The specific activity of the purified hNGF was approximately 38000 units/mg, and the activity was completely inhibited by the monoclonal antibody against recombinant hNGF (rhNGF). Western-blot analysis showed that the purified hNGF could interact with the monoclonal antibody against rhNGF.

A state space model for the HIV epidemic in homosexual populations and some applications.

In this paper we have developed a state space model for the HIV epidemic in homosexual populations which have been divided into subpopulations according to sexual activity levels. In this model, the stochastic dynamic system model is the stochastic model of the HIV epidemic in terms of the chain multinomial model whereas the observation model is a statistical model based on the observed AIDS incidences. This model is applied to the San Francisco homosexual population for estimating the numbers of susceptible people, infective people and AIDS cases and for estimating the probabilities of HIV transmission from infective people to susceptible people given sexual contacts. The results show that the estimated numbers of AIDS incidence trace closely the observed numbers indicating the usefulness of the model. It is observed that the estimated numbers of latent people show multimodal curves and that HIV infection takes place during the primary stage and very late stage. The results have further shown that there are significant differences between the observed AIDS incidences and the estimates by the embedded deterministic model. These results indicate that using the embedded deterministic model to estimate the HIV-infected people and to predict future AIDS cases can be very misleading in some cases.

Stochastic modeling of the dynamics of CD4+ T-cell infection by HIV and some Monte Carlo studies.

In this paper, we develop a stochastic model for the interaction between CD4+ T cells and the human immunodeficiency virus (HIV) virus by taking into account the basic biological mechanism as described in [1-4]. We studied this stochastic model through extensive Monte Carlo simulations. Our results show that, in some cases, there is a positive probability that the virus will be eliminated by the process. We have also shown that, at the earlier stage of the infection, the probability distributions of the CD4+ T cells and free HIV are skewed; however, these distributions will eventually converge to the Gaussian distributions after several years. A real-data example is given to illustrate the application of our model.

Helicobacter pylori eradication--comparison of three drug regimens and symptomatic assessment in duodenitis and antral gastritis.

Helicobacter pylori (Hp) eradication in peptic ulcer disease is associated with a greatly reduced recurrence rate. The optimal drug regimen for HP eradication remains uncertain. It is also unclear if eradication of Hp in duodenitis and antral gastritis improves symptoms. The aims of this study were to compare the efficacy of three drug regimens in the eradication of Hp and to assess if Hp eradication improved symptoms in patients with duodenitis and antral gastritis. Patients (n = 79) found to have duodenal ulcer, duodenitis and/or antral gastritis with a positive urease test (CLO) at endoscopy were allocated to one of the three regimens: A. omeprazole 20 mg b.d. and clarithromycin 500 mg t.d.s. for two weeks (n = 27), B. De-Nol 240 mg b.d. for four weeks, metronidazole 400 mg t.d.s. and amoxicillin 500 mg t.d.s. for one week (n = 26), and C. omeprazole 20 mg b.d. and amoxicillin 500 mg t.d.s. for two weeks (n = 26). In conclusion, traditional 'triple' therapy with bismuth and two antibiotics achieved the highest Hp eradication rate and was best tolerated. Recolonisation with Hp was uncommon after eradication. Dyspeptic symptoms improved with Hp eradication in duodenitis and antral gastritis.

Monte Carlo results for the 3-poly test for animal carcinogenicity experiments.

By using a two stage model of carcinogenesis, we generated Monte Carlo studies to assess the efficiency and robustness of the 3-poly test for animal carcinogenicity experiments. The Monte Carlo results indicate that the 3-poly test is quite powerful for detecting the carcinogenic effects of complete carcinogens, moderate promoters, and initiators with moderate or large effect, but, in some cases, it is less powerful for weak initiators or weak promoters. As expected, the 3-poly test is insensitive to the toxicity of many agents.

Characterization of HIV incubation distributions and some comparative studies.

In this paper we use a general stochastic model to characterize the HIV incubation distributions. We generate some Monte Carlo data under different conditions and compare the fitting of HIV incubation distributions by some well known parametric models and some non-parametric methods. The parametric models include most of those that have appeared in the literature. The non-parametric methods include the Kaplan--Meier method, the EMS method, the spline approximation and the Bacchetti method. The comparison criteria are the chi-square statistic, the residual sum of squares, the AIC and the BIC. We show that the non-parametric methods, especially the EMS method, provide excellent fits in almost all cases; for the parametric models, the generalized log-logistic distributions with three and with four parameters fit better than other parametric models.

Characterization of HIV infection and seroconversion by a stochastic model of the HIV epidemic.

In this paper we use a stochastic model for the HIV epidemic in homosexual populations to characterize the HIV infection and seroconversion. Using computer generated data, we compare the fitting of infection distributions and of seroconversion distributions by different parametric models as well as by nonparametric methods. The nonparametric methods include the Kaplan-Meier method, EMS method, Bacchetti's method, and the spline approximation. The parametric models include most of the models which have been used in the literature. The comparison criteria are the chi-square statistic, the AIC (Akaike Information Criterion) and the residual sums of squares. The numerical results suggest that for the proportional mixing pattern, the EMS method, the spline method, Bacchetti's method, and the generalized log-logistic distributions with three and with four parameters provide better fitting for the infection and the seroconversion distributions in most cases. For the restricted mixing patterns, the EMS method, the spline method, Bacchetti's method, and some mixtures of distributions provide close fitting to the infection and the seroconversion distributions.