Assessment of the nlmixr R package for population pharmacokinetic modeling: A metformin case study.

AIM: nlmixr offers first-order conditional estimation (FOCE), FOCE with interaction (FOCEi) and stochastic approximation estimation-maximisation (SAEM) to fit nonlinear mixed-effect models (NLMEM). We modelled metformin's pharmacokinetic data using nlmixr and investigated SAEM and FOCEi's performance with respect to bias and precision of parameter estimates, and robustness to initial estimates. METHOD: Compartmental models were fitted. The final model was determined based on the objective function value and inspection of goodness-of-fit plots. The bias and precision of parameter estimates were compared between SAEM and FOCEi using stochastic simulations and estimations. For robustness, parameters were re-estimated as the initial estimates were perturbed 100 times and resultant changes evaluated. RESULTS: The absorption kinetics of metformin depend significantly on food status. Under the fasted state, the first-order absorption into the central compartment was preceded by zero-order infusion into the depot compartment, whereas for the fed state, the absorption into the depot was instantaneous followed by first-order absorption from depot into the central compartment. The means of relative mean estimation error (rMEE) ( ME E SAEM ME E FOCEi ) and rRMSE ( RMS E SAEM RMS E FOCEi ) were 0.48 and 0.35, respectively. All parameter estimates given by SAEM appeared to be narrowly distributed and were close to the true value used for simulation. In contrast, the distribution of estimates from FOCEi were skewed and more biased. When initial estimates were perturbed, FOCEi estimates were more biased and imprecise. DISCUSSION: nlmixr is reliable for NLMEM. SAEM was superior to FOCEi in terms of bias and precision, and more robust against initial estimate perturbations.

Glucocerebrosidase (GBA) gene variants in a multi-ethnic Asian cohort with Parkinson's disease: mutational spectrum and clinical features.

GBA variants are associated with increased risk and earlier onset of Parkinson's disease (PD), and more rapid disease progression especially with "severe" variants typified by p.L483P. GBA mutation screening studies from South-East Asia, with > 650 million inhabitants of diverse ancestries, are very limited. We investigated the spectrum of GBA variants, and associated clinico-demographic features, in a multi-ethnic PD cohort in Malaysia. Patients (n = 496) were recruited from seven centres, primarily of Chinese (45%), Malay (37%), and Indian (13%) ethnicities. All GBA coding exons were screened using a next-generation sequencing-based PD gene panel and verified with Sanger sequencing. We identified 14 heterozygous GBA alleles consisting of altogether 17 missense variants (8 classified as pathogenic or likely pathogenic for PD) in 25 (5.0%) patients, with a substantially higher yield among early (< 50 years) vs. late-onset patients across all three ethnicities (9.1-13.2% vs. 1.0-3.2%). The most common variant was p.L483P (including RecNciI, n = 11, 2.2%), detected in all three ethnicities. Three novel variants/recombinant alleles of uncertain significance were found; p.P71L, p.L411P, and p.L15S(;)S16G(;)I20V. The common European risk variants, p.E365K, p.T408M, and p.N409S, were not detected. A severe disease course was noted in the majority of GBA-variant carriers, across a range of detected variants. We report a potentially novel observation of spine posture abnormalities in GBA-variant carriers. This represents the largest study on GBA variation from South-East Asia, and highlights that these populations, especially those with EOPD, would be relevant for studies including clinical trials targeting GBA pathways.

Association study of MCCC1/LAMP3 and DGKQ variants with Parkinson's disease in patients of Malay ancestry.

BACKGROUND: Genome-wide association studies (GWAS) have shown that variants in the 3-methylcrotonyl-CoA carboxylase (MCCC1)/lysosome-associated membrane protein 3 (LAMP3) loci (rs10513789, rs12637471, rs12493050) reduce the risk of Parkinson's disease (PD) in Caucasians, Chinese and Ashkenazi-Jews while the rs11248060 variant in the diacylglycerol kinase theta (DGKQ) gene increases the risk of PD in Caucasian and Han Chinese cohorts. However, their roles in Malays are unknown. Therefore, this study aims to investigate the association of these variants with the risk of PD in individuals of Malay ancestry. METHODS: A total of 1114 subjects comprising of 536 PD patients and 578 healthy controls of Malay ancestry were recruited and genotyped using Taqman® allelic discrimination assays. RESULTS: The G allele of rs10513789 (OR = 0.83, p = 0.001) and A allele of rs12637471 (OR = 0.79, p = 0.007) in the MCCC1/LAMP3 locus were associated with a protective effect against developing PD in the Malay population. A recessive model of penetrance showed a protective effect of the GG genotype for rs10513789 and the AA genotype for rs12637471. No association with PD was found with the other MCCC1/LAMP3 rs12493050 variant or with the DGKQ (rs11248060) variant. No significant associations were found between the four variants with the age at PD diagnosis. CONCLUSION: MCCC1/LAMP3 variants rs10513789 and rs12637471 protect against PD in the Malay population.

SLC17A3 rs9379800 and Ischemic Stroke Susceptibility at the Northern Region of Malaysia.

OBJECTIVES: The relationships of Paired Like Homeodomain 2 (PITX2), Ninjurin 2 (NINJ2), TWIST-Related Protein 1 (TWIST1), Ras Interacting Protein 1 (Rasip1), Solute Carrier Family 17 Member 3 (SLC17A3), Methylmalonyl Co-A Mutase (MUT) and Fer3 Like BHLH Transcription Factor (FERD3L) polymorphisms and gene expression with ischemic stroke have yet to be determined in Malaysia. Hence, this study aimed to explore the associations of single nucleotide polymorphisms (SNPs) and gene expression with ischemic stroke risk among population who resided at the Northern region of Malaysia. MATERIALS AND METHODS: Study subjects including 216 ischemic stroke patients and 203 healthy controls were recruited upon obtaining ethical clearance. SNP genotyping was performed using polymerase chain reaction-restriction fragment length polymorphism assays. Gene expression levels were quantified by real-time polymerase chain reaction assays. Statistical and genetic analyses were conducted with SPSS version 22.2, PLINK version 1.07 and multifactor dimensionality reduction software. RESULTS: Study subjects with G allele, CG or GG genotypes of SLC17A3 rs9379800 demonstrated increased risk of ischemic stroke with the odds ratios ranging from 1.76-fold to 3.14-fold (p<0.05). When stratified study subjects according to the ethnicity, SLC17A3 rs9379800 G allele and CG genotype contributed to 2.14- and 2.96-fold of ischemic stroke risk among Malay population significantly, in the multivariate analysis (p<0.05). However, no significant associations were observed for PITX2, NINJ2, TWIST1, Rasip1, and MUT polymorphisms with ischemic stroke risk in the multivariate analysis for the pooled cases and controls as well as when stratified them according to the ethnicity. Lower mRNA expression levels of Rasip1, SLC17A3, MUT and FERD3L were observed among cases (p<0.05). After FDR adjustment, the mRNA level of SLC17A3 remained significantly associated with ischemic stroke among Malay population (q=0.034). CONCLUSION: In conclusion, this study suggests that SLC17A3 rs9379800 polymorphism and its gene expression contribute to significant ischemic stroke risk among Malaysian population, particularly the Malay who resided at the Northern Region of the country. Our findings can provide useful information for the future diagnosis, management and treatment of ischemic stroke patients.

Stroke Patients' Characteristics and Clinical Outcomes: A Pre-Post COVID-19 Comparison Study.

Background and Objectives: The Coronavirus disease 2019 (COVID-19) pandemic caused significant disruption to established medical care systems globally. Thus, this study was aimed to compare the admission and outcome variables such as number of patient and its severity, acute recanalisation therapy given pre-post COVID-19 at a primary stroke centre located in Malaysia. Methods: This cross-sectional hospital-based study included adult ischaemic stroke patients. Variables of the study included the number of ischaemic stroke patients, the proportions of recanalisation therapies, stroke severity during admission based on the National Institutes of Health Stroke Scale, functional outcome at discharge based on the modified Rankin Scale, and relevant workflow metrics. We compared the outcome between two six-month periods, namely the pre-COVID-19 period (March 2019 to September 2019) and the COVID-19 period (March 2020 to September 2020). Results: There were 131 and 156 patients, respectively, from the pre-COVID-19 period and the COVID-19 period. The median door-to-scan time and the median door-to-reperfusion time were both significantly shorter in the COVID-19 period (24.5 min versus 12.0 min, p = 0.047) and (93.5 min versus 60.0 min, p = 0.015), respectively. There were also significantly more patients who received intravenous thrombolysis (7.6% versus 17.3%, p = 0.015) and mechanical thrombectomy (0.8% versus 6.4%, p = 0.013) in the COVID-19 period, respectively. Conclusions: The COVID-19 pandemic may not have caused disruptions of acute stroke care in our primary stroke centre. Our data indicated that the number of ischaemic stroke events remained stable, with a significant increase of recanalisation therapies and better in-hospital workflow metrics during the COVID-19 pandemic period. However, we would like to highlight that the burden of COVID-19 cases in the study area was very low. Therefore, the study may not have captured the true burden (and relevant delays in stroke patient management) during the COVID-19 pandemic. The effect of the pandemic crisis is ongoing and both pre-hospital and in-hospital care systems must continue to provide optimal, highly time-dependent stroke care services.

Predictors of Recurrent Ischemic Stroke in Obese Patients With Type 2 Diabetes Mellitus: A Population-based Study.

BACKGROUND: Diabetes and obesity are established risk factors for stroke. The current study aimed to assess risk factors of ischemic stroke recurrence in diabetic patients based on their body mass index (BMI). METHODS: A total of 4005 diabetic patients who had a history of ischemic stroke were identified in a retrospective cross-sectional dataset from the Malaysian National Neurology Registry. Patients were classified based on BMI, and multivariable regression analysis was used to evaluate the association between risk factors and recurrent ischemic stroke. RESULTS: Among obese patients, those with ischemic heart disease (aOR, 1.873; 95% CI, 1.131-3.103), received formal education (aOR, 2.236; 95% CI, 1.306-3.830), and received anti-diabetic medication (aOR, 1.788; 95% CI, 1.180-2.708) had a higher stroke recurrence risk, while receiving angiotensin receptors blockers (aOR, 0.261; 95% CI, 0.126-0.543) lowered the odds of recurrence. Overweight patients with hypertension (aOR, 1.011; 95% CI, 1.002-1.019) for over 10 years (aOR, 3.385; 95% CI, 1.088-10.532) and diabetes prior to the first stroke (aOR, 1.823; 95% CI, 1.020-3.259) as well as those received formal education (aOR, 2.403; 95% CI, 1.126-5.129) had higher odds of stroke recurrence, while receiving angiotensin-converting enzyme inhibitors (aOR, 0.244; 95% CI, 0.111-0.538) lowered the recurrence risk. Normal weight East Malaysians (aOR, 0.351; 95% CI, 0.164-0.750) receiving beta-blockers (aOR, 0.410; 95% CI, 0.174-0.966) had lower odds of stroke recurrence. CONCLUSIONS: Ischemic heart disease, hypertension, receiving anti-hypertensive agents, and educational level were independent predictors of recurrent stroke in obese patients. Managing the modifiable risk factors can decrease the odds of stroke recurrence.

Clinicians' Perceived Understanding of Biostatistical Results in the Medical Literature: A Cross-Sectional Study.

Background and objectives: The continuum of evidence-based medicine (EBM) depends solely on clinicians' commitment to keep current with the latest clinical information. Exploration on clinicians' understanding of biostatistical results in the medical literature is sparse to date. This study aimed to evaluate clinicians' perceived understanding of biostatistical results in the medical literature and the factors influencing them. Materials and Methods: A cross-sectional study was conducted among 201 clinicians at the Seberang Jaya Hospital, a cluster-lead research hospital in Northern Malaysia. A self-administered questionnaire that consisted of items on sociodemographics, validated items on clinicians' confidence level in interpreting statistical concepts, perceived understanding of biostatistics, and familiarity with different statistical methods were used. Descriptive, univariate, and multivariate analyses were conducted. Results: Perceived understanding of biostatistical results among clinicians in our sample was nearly 75%. In the final regression model, perceived understanding was significantly higher among clinicians who were able to interpret p-values with complete confidence (AOR = 3.0, 95% CI 1.1-8.1), clinicians who regularly encounter measures of central tendencies (AOR = 2.3, 95% CI 1.1-5.2), and clinicians who regularly encounter inferential statistics (AOR = 2.2, 95% CI 1.1-4.5) while appraising the medical literature. Conclusions: High perceived understanding was significantly associated with clinicians' confidence in interpreting statistical concepts and familiarity with different statistical methods. Our findings form a platform to understand clinicians' ability to appraise rigorous biostatistical results in the medical literature for the retrieval of evidence-based data to be used in routine clinical practice.

Presentation of coefficient of variation for bioequivalence sample-size calculation
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The current study aimed to further contribute information on intrasubject coefficient of variation (CV) from 43 bioequivalence studies conducted by our center. Consistent with Yuen et al. (2001), current work also attempted to evaluate the effect of different parameters (AUC0-t, AUC0-∞, and Cmax) used in the estimation of the study power. Furthermore, we have estimated the number of subjects required for each study by looking at the values of intrasubject CV of AUC0-∞ and have also taken into consideration the minimum sample-size requirement set by the US FDA. A total of 37 immediate-release and 6 extended-release formulations from 28 different active pharmaceutical ingredients (APIs) were evaluated. Out of the total number of studies conducted, 10 studies did not achieve satisfactory statistical power on two or more parameters; 4 studies consistently scored poorly across all three parameters. In general, intrasubject CV values calculated from Cmax were more variable compared to either AUC0-t and AUC0-∞. 20 out of 43 studies did not achieve more than 80% power when the value was calculated from Cmax value, compared to only 11 (AUC0-∞) and 8 (AUC0-t) studies. This finding is consistent with Steinijans et al. (1995) [2] and Yuen et al. (2001) [3]. In conclusion, the CV values obtained from AUC0-t and AUC0-∞ were similar, while those derived from Cmax were consistently more variable. Hence, CV derived from AUC instead of Cmax should be used in sample-size calculation to achieve a sufficient, yet practical, test power.
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Acute Stroke Registry Malaysia, 2010-2014: Results from the National Neurology Registry.

BACKGROUND: Stroke remains a major health burden worldwide. The incidence and prevalence rates of stroke are decreasing in developed countries, an opposite trend is taking place in the Asia Pacific, where an increasing number of patients are being diagnosed with acute stroke. The results of the present study on acute stroke in multi-ethnic Malaysia will significantly contribute to the global stroke epidemiological data. We aimed to present epidemiological data of stroke including incidence and prevalence rates as well as associated risk factors from a prospective nationwide hospital-based registry from 2010 to 2014. METHODS: Patients diagnosed with stroke upon admission at the hospital were prospectively enrolled into the registry from January 1, 2010, to December 31, 2014. Descriptive analyses were performed. RESULTS: A total of 7668 patients were available for analysis. On average, patients were aged 62.7 years (standard deviation of 12.5). Ischemic stroke accounts for 79.4% of the cohort with a slightly higher proportion of male patients (55%). Ischemic stroke incidence is estimated to increase annually by 29.5% and hemorrhagic stroke by 18.7%. Hypertension is a major risk factor for both ischemic and hemorrhagic strokes regardless of stroke event with an excess of 8.4% hypertensive female compare to male patients (P ≤ .001). Majority of patients with ischemic and hemorrhagic strokes experienced mild and moderate stroke with 11.7% and 21.1%, respectively, documented as severe (P ≤ .001). CONCLUSIONS: The incidence and prevalence of stroke in Malaysia increased dramatically in the 5-year study period. Therefore, implementation of risk factor control strategies is important to prevent further increase of stroke burden in the country.

Prevalence of Stroke-Associated Pneumonia and Its Predictors Among Hyperglycaemia Patients During Acute Ischemic Stroke.

BACKGROUND: Hyperglycaemia (HG) during an acute ischemic stroke (AIS) is not only associated with unfavourable functional outcomes but also associated with stroke-associated pneumonia (SAP). This study aimed to determine the prevalence of SAP among Malaysian patients with AIS and the predictors of SAP among patients with HG during AIS. METHODS: This is a retrospective cross-sectional study that included patients with AIS admitted to Hospital Sultanah Nur Zahirah, Malaysia from 2017 to 2020. SAP was defined as infection with pneumonia during the first seven days after IS. HG was defined as a blood glucose level > 7.8 mmol/L within 72 h after admission. Patients with SAP were divided into two groups according to HG status. Multivariate logistic regression analysis was performed using SPSS software, version 22 (IBM Corp., Armonk, NY) to identify SAP predictors among patients with HG. Kaplan-Meier log-rank test was used to compare the survival rate from unfavourable functional outcomes between hyperglycaemic patients with and without SAP. RESULTS: Among 412 patients with AIS, 69 (16.74%) had SAP. The prevalence of SAP among patients with HG and normoglycemia during AIS was 20.98%, and 10.65%, respectively. Age above 60 years, leucocytosis, and National Institute of Health Stroke Scale (NIHSS) > 14 on admission were independent predictors of SAP with aOR of 2.08 (95% CI;1.01-4.30), 2.83 (95% CI; 1.41-5.67), and 3.67 (95% CI; 1.53-8.80), respectively. No significant difference in unfavourable functional outcomes survival was found among patients with and without SAP (p = 0.653). CONCLUSION: This study demonstrated the prevalence of SAP was higher among patients with HG compared to normoglycemia during AIS. The patient being old, leucocytosis and severe stroke upon admission predict the occurrence of SAP among patients with HG during AIS.

Stroke incidence in the South West District of the Penang Island, Malaysia: PEARLs: Penang Acute Stroke Research Longitudinal Study.

OBJECTIVES: This community based incidence study aims to report the stroke incidence in the south-west region of the Penang Island. METHODS: All strokes occurring in the population of residents in the southwest region of the Penang Island, Malaysia during a period of 12 months, from April 2010 to March 2011 were screened and assessed. Standard definitions for stroke were used. All stroke cases were ascertained using multiple overlapping sources. Incidence rate was based on first ever in a lifetime stroke cases. All recurrent strokes were excluded from the incidence count. RESULTS: The overall stroke incidence rate in the study region during the study period was 67 per 100,000 after age adjustment to 2010 Malaysian population. CONCLUSION: This study provides the first stroke incidence data in Malaysia and is vital for effective health system planning.

Predictive model of recurrent ischemic stroke: model development from real-world data.

Background: There are established correlations between risk factors and ischemic stroke (IS) recurrence; however, does the hazard of recurrent IS change over time? What is the predicted baseline hazard of recurrent IS if there is no influence of variable predictors? This study aimed to quantify the hazard of recurrent IS when the variable predictors were set to zero and quantify the secondary prevention influence on the hazard of recurrent ischemic stroke. Methods: In the population cohort involved in this study, data were extracted from 7,697 patients with a history of first IS attack registered with the National Neurology Registry of Malaysia from 2009 to 2016. A time-to-recurrent IS model was developed using NONMEM version 7.5. Three baseline hazard models were fitted into the data. The best model was selected using maximum likelihood estimation, clinical plausibility, and visual predictive checks. Results: Within the maximum 7.37 years of follow-up, 333 (4.32%) patients had at least one incident of recurrent IS. The data were well described by the Gompertz hazard model. Within the first 6 months after the index IS, the hazard of recurrent IS was predicted to be 0.238, and 6 months after the index attack, it reduced to 0.001. The presence of typical risk factors such as hyperlipidemia [HR, 2.22 (95%CI: 1.81-2.72)], hypertension [HR, 2.03 (95%CI: 1.52-2.71)], and ischemic heart disease [HR, 2.10 (95%CI: 1.64-2.69)] accelerated the hazard of recurrent IS, but receiving antiplatelets (APLTs) upon stroke decreased this hazard [HR, 0.59 (95%CI: 0.79-0.44)]. Conclusion: The hazard of recurrent IS magnitude differs during different time intervals based on the concomitant risk factors and secondary prevention.

A Parametric Time-to-Event Modelling of Recurrent Ischemic Stroke After Index Stroke Among Patients With and Without Diabetes Mellitus: Implementation of Temporal Validation of the Model.

Objectives Compared with the first stroke, neurological impairment caused by stroke recurrence is more serious, more difficult to treat, and has a higher mortality rate, especially among ischemic stroke (IS) patients with diabetes mellitus (DM). Although there are established correlations between factors and IS recurrence, there were some issues regarding the naive hazard of IS recurrence with no risk factor influence, and how does the baseline hazard differ among patients with DM and non-DM? To answer all these questions, two time-to-event (TTE) models of recurrent IS after the index IS were developed among IS patients with DM and non-DM. Method A total of 7697 patients with an index IS attack were extracted from the Malaysian Registry of Neurology and stratified according to DM status. Several parametric survival models were evaluated using nonlinear mixed-effect modeling software (NONMEM 7.5). The final model was determined according to the lowest objective function value, graphical evaluation, numerical diagnostics, and clinical plausibility. Additionally, the final model was validated internally and temporally using Kaplan-Meier visual predictive checks (KM-VPCs). Results One hundred ninety-five (5.82%) of 3493 DM patients and 138 (3.28%) of 4204 non-DM patients developed a recurrent IS with a maximum follow-up of 7.37 years. Gompertz's model best fitted the data. With no influence on risk factors, the index IS attack was predicted to contribute to the hazard of recurrent IS by 0.356 and 0.253 within the first six months after the index IS among patients with and without DM, respectively. Even after six months of index IS, the recurrent IS baseline hazard was not equal to zero among both groups (0.0023, 0.0018). Moreover, after incorporating the time and risk factors, the recurrent hazards increased exponentially during the first three years after the index IS followed by an exponential reduction afterward. The recurrent IS predictors among DM patients were ischemic heart disease (IHD) and hyperlipidemia (HPLD). IHD and HPLD increased the hazard of recurrent IS by 2.40 and 1.88 times, respectively, compared to those without IHD and HPLD before index IS (HR, 2.40 (1.79-3.20)), and (HR, 1.88 (1.44-2.45)) respectively. Conclusion The baseline hazard was the highest during the first six months after the index IS. Moreover, receiving medications for secondary prevention failed to demonstrate a significant association with reducing IS recurrence among IS patients with DM, suggesting a need for more intensive patient screening and new strategies for secondary prevention among IS patients with DM.

Genetic study of early-onset Parkinson's disease in the Malaysian population.

BACKGROUND: About 5-10% of Parkinson's disease (PD) cases are early onset (EOPD), with several genes implicated, including GBA1, PRKN, PINK1, and SNCA. The spectrum and frequency of mutations vary across populations and globally diverse studies are crucial to comprehensively understand the genetic architecture of PD. The ancestral diversity of Southeast Asians offers opportunities to uncover a rich PD genetics landscape, and identify common regional mutations and new pathogenic variants. OBJECTIVES: This study aimed to investigate the genetic architecture of EOPD in a multi-ethnic Malaysian cohort. METHODS: 161 index patients with PD onset ≤50 years were recruited from multiple centers across Malaysia. A two-step approach to genetic testing was used, combining a next-generation sequencing-based PD gene panel and multiplex ligation-dependent probe amplification (MLPA). RESULTS: Thirty-five patients (21.7%) carried pathogenic or likely pathogenic variants involving (in decreasing order of frequency): GBA1, PRKN, PINK1, DJ-1, LRRK2, and ATP13A2. Pathogenic/likely pathogenic variants in GBA1 were identified in thirteen patients (8.1%), and were also commonly found in PRKN and PINK1 (11/161 = 6.8% and 6/161 = 3.7%, respectively). The overall detection rate was even higher in those with familial history (48.5%) or age of diagnosis ≤40 years (34.8%). PRKN exon 7 deletion and the PINK1 p.Leu347Pro variant appear to be common among Malay patients. Many novel variants were found across the PD-related genes. CONCLUSIONS: This study provides novel insights into the genetic architecture of EOPD in Southeast Asians, expands the genetic spectrum in PD-related genes, and highlights the importance of diversifying PD genetic research to include under-represented populations.

Spatial Dynamics and Multiscale Regression Modelling of Population Level Indicators for COVID-19 Spread in Malaysia.

As COVID-19 dispersion occurs at different levels of gradients across geographies, the application of spatiotemporal science via computational methods can provide valuable insights to direct available resources and targeted interventions for transmission control. This ecological-correlation study evaluates the spatial dispersion of COVID-19 and its temporal relationships with crucial demographic and socioeconomic determinants in Malaysia, utilizing secondary data sources from public domains. By aggregating 51,476 real-time active COVID-19 case-data between 22 January 2021 and 4 February 2021 to district-level administrative units, the incidence, global and local Moran indexes were calculated. Spatial autoregressive models (SAR) complemented with geographical weighted regression (GWR) analyses were executed to determine potential demographic and socioeconomic indicators for COVID-19 spread in Malaysia. Highest active case counts were based in the Central, Southern and parts of East Malaysia regions of Malaysia. Countrywide global Moran index was 0.431 (p = 0.001), indicated a positive spatial autocorrelation of high standards within districts. The local Moran index identified spatial clusters of the main high-high patterns in the Central and Southern regions, and the main low-low clusters in the East Coast and East Malaysia regions. The GWR model, the best fit model, affirmed that COVID-19 spread in Malaysia was likely to be caused by population density (ß coefficient weights = 0.269), followed by average household income per capita (ß coefficient weights = 0.254) and GINI coefficient (ß coefficient weights = 0.207). The current study concluded that the spread of COVID-19 was concentrated mostly in the Central and Southern regions of Malaysia. Population's average household income per capita, GINI coefficient and population density were important indicators likely to cause the spread amongst communities.

Knowledge of acute stroke management and the predictors among Malaysian healthcare professionals.

Background: Despite rapid advances in acute ischaemic stroke (AIS) management, many healthcare professionals (HCPs) might not be aware of the latest recommended management of AIS patients. Therefore, we aimed to determine the level and factors associated with AIS management knowledge among Malaysian HCPs. Methods: This cross-sectional online questionnaire study was conducted nationwide among 627 HCPs in Malaysia using the Acute Stroke Management Questionnaire (ASMaQ). Multiple logistic regression was used to predict the relationship between the independent variables (age, gender, years of service, profession, work setting, work sector, seeing stroke patients in daily practice, and working with specialists) and the outcome variable (good vs poor knowledge). Results: Approximately 76% (95% CI [73-79%]) of HCPs had good overall knowledge of stroke. The highest proportion of HCPs with good knowledge was noted for General Stroke Knowledge (GSK) [88.5% (95% CI [86-91%])], followed by Advanced Stroke Management (ASM) [61.2% (95% CI [57-65%])] and Hyperacute Stroke Management (HSM) [58.1% (95% CI [54-62%])]. The odds of having poor knowledge of stroke were significantly higher among non-doctor HCPs [adjusted OR = 3.46 (95% CI [1.49-8.03]), P = 0.004]; among those not seeing stroke patients in daily practice [adjusted OR = 2.67 (95% CI [1.73-4.10]), P < 0.001]; and among those working without specialists [adjusted OR = 2.41 (95% CI [1.38-4.18]), P = 0.002]. Conclusions: Stroke education should be prioritised for HCPs with limited experience and guidance. All HCPs need to be up-to-date on the latest AIS management and be able to make a prompt referral to an appropriate facility. Therefore, more stroke patients will benefit from advanced stroke care.

Positive global environmental impacts of the COVID-19 pandemic lockdown: a review.

Global environmental change is mainly due to human behaviours and is a major threat to sustainability. Despite all the health and economic consequences, the impact of the COVID-19 pandemic lockdown on environmental health warrants the scientific community's attention. Thus, this article examined and narratively reviewed the impact of several drastic measures taken on the macro environment and holistic planetary health. We note that the amount of pollution in the air, water, soil, and noise showed a significant decline during the pandemic. Global air quality improved due to lower anthropogenic emissions of air pollutants and atmospheric particles. Water ecosystems also demonstrated signs of recuperation in many countries. Less commercial fishing internationally resulted in the restoration of some aquatic life. Additionally, significant reduction of solid and water waste led to less soil pollution. Some places experienced cleaner beaches and ocean water while wildlife sightings in urban areas across the world occurred more often. Lastly, the COVID-19 pandemic lockdown also led to a worldwide decline in noise pollution. However, the beneficial environmental effects will not be permanent as the world gradually returns to its pre-pandemic status quo. Therefore, behavioural changes such as adopting a lifestyle that reduces carbon footprint are needed to make a positive impact on the environment. In addition, world leaders should consider the national policy changes necessary to ensure continuity of as many of the positive environmental impacts from the COVID-19 pandemic lockdown as possible. Those changes would also serve to lessen the likelihood of another zoonotic calamity.

Seizure remission rates remain low in a resource-limited country, a multicentre comparison study in Malaysia.

Seizure remission rates of 60% with antiseizure medications were reported in developed countries, but might be lower in resource-limited countries. The challenges in epilepsy care in resource-limited regions were highlighted 10 years ago, and still remain an ongoing issue. This study aimed to determine the seizure freedom rates in level-2 epilepsy care centres (centres with general neurologists) compared to level-3/4 centres (centres with epileptologists providing epilepsy surgery evaluation) in Malaysia. This is a retrospective study of 1,347 adult epilepsy patients from two level-2 (n = 290) and two level-3/4 epilepsy care centres (n = 1,057). The seizure remission rates were significantly lower in level-2 centres (42.5%) compared to the level 3/4 centres (61.9%, p < 0.05). Level-2 centres had significantly more patients with undetermined seizure types compared to level-3/4 centres (6.6% vs 3.1%, p < 0.05). Level-3/4 centres had significantly more patients with epilepsy of structural and genetic origins, whereas more patients in level-2 centres had unknown aetiology (46.2% vs. 34.0% in level-3/4, p < 0.05). Level-2 centres had a lower neurologist-to-patient ratio (1:97 vs. 1:50 in level-3/4 centres, p < 0.05). Level-2 centres also had fewer patients, who underwent investigations such as EEG (74.1% vs. 89.6%) and brain MRI (54.1% vs. 72.4%, p < 0.05) in comparison with level-3/4 centres. Our study emphasized the existing challenges in epilepsy care in a resource-limited country to achieve the ideal 60% seizure remission rate.

Spinal cord infarction in a young patient with methamphetamine abuse.

We report a case of a 20-year-old man who was diagnosed with spontaneous spinal cord infarction after abusing methamphetamine for a year. He presented with sudden onset of bilateral upper and lower limb weakness. His MRI spine showed a long segment of high signal intensity seen predominantly in the anterior spinal cord from medulla to mid thoracic level as well as a pencil-like hyperintensity seen postcontrast suggestive of spinal cord ischaemia or infarct. Thus, he was empirically treated for presumed anterior spinal cord infarction. He then developed autonomic dysfunction and went into respiratory distress, which required invasive mechanical ventilation support. Subsequently, he developed cardiac arrythmia with supraventricular tachycardiac followed by asystole and succumbed to illness on day 9 despite maximal resuscitative efforts. This case report illustrates a rare spinal cord infarction caused by methamphetamine intoxication and the importance of identifying and treating it early.

Influence of Population Density for COVID-19 Spread in Malaysia: An Ecological Study.

The rapid transmission of highly contagious infectious diseases within communities can yield potential hotspots or clusters across geographies. For COVID-19, the impact of population density on transmission models demonstrates mixed findings. This study aims to determine the correlations between population density, clusters, and COVID-19 incidence across districts and regions in Malaysia. This countrywide ecological study was conducted between 22 January 2021 and 4 February 2021 involving 51,476 active COVID-19 cases during Malaysia's third wave of the pandemic, prior to the reimplementation of lockdowns. Population data from multiple sources was aggregated and spatial analytics were performed to visualize distributional choropleths of COVID-19 cases in relation to population density. Hierarchical cluster analysis was used to synthesize dendrograms to demarcate potential clusters against population density. Region-wise correlations and simple linear regression models were deduced to observe the strength of the correlations and the propagation effects of COVID-19 infections relative to population density. Distributional heats in choropleths and cluster analysis showed that districts with a high number of inhabitants and a high population density had a greater number of cases in proportion to the population in that area. The Central region had the strongest correlation between COVID-19 cases and population density (r = 0.912; 95% CI 0.911, 0.913; p < 0.001). The propagation effect and the spread of disease was greater in urbanized districts or cities. Population density is an important factor for the spread of COVID-19 in Malaysia.