Genetic and clinical predictors of rifapentine and isoniazid pharmacokinetics in paediatrics with tuberculosis infection.

OBJECTIVES: Twelve weekly doses of rifapentine and isoniazid (3HP regimen) are recommended for TB preventive therapy in children with TB infection. However, they present with variability in the pharmacokinetic profiles. The current study aimed to develop a pharmacokinetic model of rifapentine and isoniazid in 12 children with TB infection using NONMEM. METHODS: Ninety plasma and 41 urine samples were collected at Week 4 of treatment. Drug concentrations were measured using a validated HPLC-UV method. MassARRAY® SNP genotyping was used to investigate genetic factors, including P-glycoprotein (ABCB1), solute carrier organic anion transporter B1 (SLCO1B1), arylacetamide deacetylase (AADAC) and N-acetyl transferase (NAT2). Clinically relevant covariates were also analysed. RESULTS: A two-compartment model for isoniazid and a one-compartment model for rifapentine with transit compartment absorption and first-order elimination were the best models for describing plasma and urine data. The estimated (relative standard error, RSE) of isoniazid non-renal clearance was 3.52 L·h-1 (23.1%), 2.91 L·h-1 (19.6%), and 2.58 L·h-1 (20.0%) in NAT2 rapid, intermediate and slow acetylators. A significant proportion of the unchanged isoniazid was cleared renally (2.7 L·h-1; 8.0%), while the unchanged rifapentine was cleared primarily through non-renal routes (0.681 L·h-1; 3.6%). Participants with the ABCB1 mutant allele had lower bioavailability of rifapentine, while food prolonged the mean transit time of isoniazid. CONCLUSIONS: ABCB1 mutant allele carriers may require higher rifapentine doses; however, this must be confirmed in larger trials. Food did not affect overall exposure to isoniazid and only delayed absorption time.

Investigating the Association Between Type 2 Diabetes Mellitus and Pathological Responses Among Breast Cancer Patients Receiving Neoadjuvant Chemotherapy.

INTRODUCTION: The relationship between type 2 diabetes mellitus (T2DM) and pathological responses after neoadjuvant chemotherapy (NACT) is controversial. In this study, we aim to determine the association of pathological responses in breast cancer women with T2DM after receiving NACT. METHODS: Medical records of breast cancer women with T2DM who received NACT from January 2016 to January 2021 at the medical center in the Gujranwala Institute of Nuclear Medicine and Radiotherapy, Pakistan, were identified and retrieved retrospectively. Variables, including pathological responses, diabetes status, and other clinical data, were collected. Patients were grouped as diabetic and nondiabetic based on the doctor's diagnosis or the diabetic's medication history recorded upon the breast cancer diagnosis. Factors influencing the pathological complete response (pCR) were determined using multivariate logistic regression utilizing IBM SPSS Statistics (version 20). RESULTS: A total of 1372 patient files who received NACT and breast cancer surgery from January 2016 to January 2021 were selected. Out of 1372 breast cancer women receiving NACT, 345 (25.1%) had pre-existing diabetes, while 1027 (74.85%) were without pre-existing diabetes. The most common molecular subtypes of breast cancer were luminal A and B. Two hundred fifty-eight patients (18.8%) had a pCR after receiving NACT. The pCR in diabetic patients was 3.9%, and in nondiabetes, 14.9%. Most women had a pathological partial response (pPR) after the NACT 672 (48.9%). The pPR in diabetic patients was 11.0%, and in nondiabetic patients, it was 38.0%. In nondiabetics, the odds of achieving pPR increase more than pathological no response after the NACT with odd ratio: 1.71 (95% confidence interval: 1.24-2.37). The probability of pCR in patients with luminal B was 1.67 times higher than that in patients with triple-negative breast cancer with odd ratio: 1.67, 95% confidence interval (1.00-2.79), P = 0.05. CONCLUSIONS: The results of the study show that T2DM may have an adverse impact on pCR and pPR following NACT and surgery. Further investigation is needed to explore how changes in blood glucose levels over time impact pathological responses.

Pharmacometric modeling of drug adverse effects: an application of mixture models in schizophrenia spectrum disorder patients treated with clozapine.

Clozapine has superior efficacy to other antipsychotics yet is underutilized due to its adverse effects, such as neutropenia, weight gain, and tachycardia. The current investigation aimed to introduce a pharmacometric approach to simultaneously model drug adverse effects, with examples from schizophrenia spectrum patients receiving clozapine. The adverse drug effects were represented as a function of time by incorporating a mixture model to describe individual susceptibility to the adverse effects. Applications of the proposed method were presented by analyzing retrospective data from patients' medical records in Psychiatric Clinic, Penang General Hospital. Tachycardia, weight gain, and absolute neutrophils count (ANC) decrease were best described by an offset, a piecewise linear, and a transient surge function, respectively. 42.9% of the patients had all the adverse effects, including weight gain (0.01 kg/m2 increase every week over a baseline of 24.7 kg/m2 until stabilizing at 279 weeks), ANC decrease (20% decrease from 4540 cells/µL week 12-20.8), and tachycardia (14% constant increase over a baseline of 87.9 bpm for a clozapine maintenance dose of 450 mg daily). 32.5% of the patients had only tachycardia, while the remaining 24.6% had none of the adverse effects. A new pharmacometric approach was proposed to describe adverse drug effects with examples of clozapine-induced weight gain, ANC drop, and tachycardia. The current approach described the longitudinal time changes of continuous data while assessing patient susceptibility. Furthermore, the model revealed the possible co-existence of ANC drop and weight gain; thus, neutrophil monitoring might predict future changes in body weight.

Population pharmacokinetics analyses of rifampicin in adult and children populations: A systematic review.

AIMS: Rifampicin has become an essential component as the first-line therapy for pulmonary tuberculosis (PTB). Several population pharmacokinetic (PK) studies on rifampicin in adult and child populations have been studied previously, therefore the aims of the systematic review were (i) to summarize the relevant published studies and significant covariates that influence the PK of rifampicin across different populations, and (ii) to identify any knowledge gap that requires additional research in the future. METHODS: A total of 121 relevant population PK articles were systematically identified using PubMed and Scopus from inception to October 2021. Review articles, in-vitro and physiological methods, animal studies and noncompartmental analysis were excluded. RESULTS: Nineteen studies, of which 16 involved adults, two involved children, and one involved both adults and children, were included in the review. The structural model of rifampicin can be described as one compartment with a transient compartment absorption model and first-order elimination in most of the studies. Pharmaceutical formulation, body weight, gender, pregnancy status, diabetes and nutritional supplementation were found to be the significant covariates that affect the PK parameters. External validation of the developed PK model was only conducted in two studies. CONCLUSIONS: The source of variability for PK parameters of rifampicin remains inconsistent and poorly understood even though there were many potential covariates investigated in the selected studies. Exploring other possible factors and implementing a strict sampling strategy by considering the induction effects might uncover precise and reliable information. Furthermore, external validation should be frequently conducted to produce better predictability of model performance.

Time-Dissociated Pharmacokinetic Pharmacodynamic Model of Cyclosporine Among Malaysian Renal Transplant Recipients.

BACKGROUND: Cyclosporine is an essential component of many immunosuppressive regimens. However, its pharmacokinetic and pharmacodynamic (PKPD) modeling has not been widely investigated. This study aims to develop a time-dissociated PKPD model of cyclosporine in renal transplant patients. METHODS: Medical records of renal transplant patients at Penang General Hospital were retrospectively analyzed. A time-dissociated PKPD model with covariate effects was developed using NONMEM to evaluate renal graft function response, quantified as estimated glomerular filtration rate (eGFR), toward the cyclosporine cumulative exposure (area under the concentration-time curve). The final model was integrated into a tool to predict the potential outcome. Individual eGFR predictions were evaluated based on the clinical response recorded as acute rejection/nephrotoxicity events. RESULTS: A total of 1256 eGFR readings with 2473 drug concentrations were obtained from 107 renal transplant patients receiving cyclosporine. An Emax drug effect with a linear drug toxicity model best described the data. The baseline renal graft level (E0), maximum effect (Emax), area under the concentration-time curve achieving 50% of the maximum effect, and nephrotoxicity slope were estimated as 12.9 mL·min-1·1.73 m-2, 50.7 mL·min-1·1.73 m-2, 1740 ng·h·mL-1, and 0.00033, respectively. The hemoglobin level was identified as a significant covariate affecting the E0. The model discerned acute rejection from nephrotoxicity in 19/24 cases. CONCLUSIONS: A time-dissociated PKPD model successfully described a large number of observations and was used to develop an online tool to predict renal graft response. This may help discern early rejection from nephrotoxicity, especially for patients unwilling to undergo a biopsy or those waiting for biopsy results.

Health-related quality of life and its association with sociodemographic, economic, health status and lifestyles among HIV-positive patients in northern Malaysia.

Sociodemographic status and medical problems were widely reported as the major factors in people living with HIV (PLHIV) with lower health-related quality of life (HRQoL). However, lifestyles and cultural changes are rarely studied. A multicentred cross-sectional study was conducted among 137 virally suppressed PLHIV on antiretroviral therapy (ART) in northern Malaysia by face-to-face interviews and World Health Organization Quality of Life (WHOQOL)-BREF questionnaire. It was to explore their health and socioeconomic status, lifestyles, and associations with different HRQoL domains. The result of multiple linear regression showed that smoking was a predominant risk factor of lower physical (beta coefficient (ß): -5.82, 95% confidence interval (CI): -9.97 to -1.66; p = 0.006), social (ß: -8.76, 95% CI: -15.12 to -2.40; p = 0.007), and environmental domain scores (ß: -10.25, 95% CI: -15.21 to -5.30; p < 0.001). Poor physical health also associated with unemployment (p < 0.001) and adverse drug reaction (p = 0.015). Ethnicity was a significant factor of psychological (p = 0.007) and environment domain score (p = 0.009). HRQoL of PLHIV is strongly associated with their lifestyles and societal class. Mandatory lifestyle screening, behavioural interventions and re-employment assistance should be implemented on all PLHIV.

The association between cigarette smoking and efavirenz plasma concentration using the population pharmacokinetic approach.

AIMS: Efavirenz is still widely used as the preferred first-line antiretroviral agent in middle- and low-income countries, including Malaysia. The efavirenz population pharmacokinetic profile among HIV-positive smokers is still unknown. We aimed to assess the association of smoking with efavirenz and the differences in HIV clinical outcomes. METHODS: A total of 154 stable HIV-positive patients on efavirenz in northern Malaysia were recruited with a sparse sampling for this multicentre prospective cohort study. The association between smoking and efavirenz pharmacokinetic parameters was determined using the nonlinear mixed-effect model. A mixture model of clearance was adopted to describe the metaboliser status because genetic data are unavailable. The effect of smoking on HIV clinical markers (CD4, CD4/CD8 ratio and viral blips) for at least 2 years after the antiretroviral initiation was also investigated. RESULTS: Our data were best fitted with a 1-compartment mixture model with first-order absorption without lag time. Smoking significantly associated with higher clearance (ß = 1.39; 95% confidence interval: 1.07 to 1.91), while weight affected both clearance and volume. From the mixture model, 20% of patients were in the slow clearance group, which mimic the genotype distribution of slow metaboliser. An efavirenz dose reduction is not recommended for smokers ≥60 kg with normal metabolism rate. Smoking significantly associated with slower normalisation of CD4 and CD4/CD8 ratio. CONCLUSIONS: HIV-positive smokers presented with significantly higher efavirenz clearance and unfavourable clinical outcomes. Close monitoring of adherence and clinical response among smokers is warranted.

Validation and clinical interpretation of the St George's respiratory questionnaire for COPD (SGRQ-C) after adaptation to Malaysian language and culture, in patients with COPD.

BACKGROUND: Cultural differences affect the administration and results of health status questionnaires. "Cross cultural adaptation" ensures retention of psychometric properties such as validity and reliability at an item and/or scale level. OBJECTIVE: To develop a Malaysian version of St George's respiratory COPD specific questionnaire (SGRQ-CM), to evaluate the full spectrum of psychometric properties (reliability, validity and responsiveness), to test the factor structure and to assess minimum clinically important difference for the SGRQ-CM, to be used in population of Malaysia. METHODOLOGY: SGRQ-C was translated to Bahasa Malaysia using a standard protocol. 240 COPD patients were included in the study. All patients were followed-up for six months. Construct validity, internal consistency, item convergent validity, test-retest ability, responsiveness, factor analysis and MCID of the Malaysian version of SGRQ-C to be used in population of Malaysia were evaluated. RESULTS: The Cronbach alpha coefficient and intraclass correlation coefficients (ICC) for SGRQ-CM were reported as 0.87, and 0.88 respectively. Correlation of SGRQ-CM with CAT, EQ-5D-5 L, mMRC dyspnea scales and FEV1%predicted were reported as 0.86, - 0.82, 0.72 and - 0.42 respectively. Correlation coefficient between the subscales and other clinical and health status measures ranged from r = - 0.35 to r = - 0.87. The MCID was reported as 5.07 (- 2.54-12.67). CONCLUSION: The Malaysian version of SGRQ-C has a good psychometric property comparable to those of the original version and has a strong evidence of validity, reliability and responsiveness towards disease severity in Malaysian COPD patients. It can be recommended as a reliable quality of life measure for future research.

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.

Aspergillus and progression of lung disease in children with cystic fibrosis.

BACKGROUND: The impact of Aspergillus on lung disease in young children with cystic fibrosis is uncertain. AIMS: To determine if positive respiratory cultures of Aspergillus species are associated with: (1) increased structural lung injury at age 5 years; (2) accelerated lung function decline between ages 5 years and 14 years and (3) to identify explanatory variables. METHODS: A cross-sectional analysis of association between Aspergillus positive bronchoalveolar lavage (BAL) cultures and chest high-resolution CT (HRCT) scan findings at age 5 years in subjects from the Australasian Cystic Fibrosis Bronchoalveolar Lavage (ACFBAL) study was performed. A non-linear mixed-effects disease progression model was developed using FEV1% predicted measurements at age 5 years from the ACFBAL study and at ages 6-14 years for these subjects from the Australian Cystic Fibrosis Data Registry. RESULTS: Positive Aspergillus BAL cultures at age 5 years were significantly associated with increased HRCT scores for air trapping (OR 5.53, 95% CI 2.35 to 10.82). However, positive Aspergillus cultures were not associated with either FEV1% predicted at age 5 years or FEV1% predicted by age following adjustment for body mass index z-score and hospitalisation secondary to pulmonary exacerbations. Lung function demonstrated a non-linear decline in this population. CONCLUSION: In children with cystic fibrosis, positive Aspergillus BAL cultures at age 5 years were associated contemporaneously with air trapping but not bronchiectasis. However, no association was observed between positive Aspergillus BAL cultures on FEV1% predicted at age 5 years or with lung function decline between ages 5 years and 14 years.

Pseudomonas aeruginosa eradication therapy and risk of acquiring Aspergillus in young children with cystic fibrosis.

BACKGROUND: While Aspergillus detection rates in adults, adolescents and older children with cystic fibrosis (CF) have increased, the risk of acquiring this fungal pathogen in young children is unknown. AIM: To determine the risk and explanatory factors of acquiring Aspergillus in children with CF by age 5 years. METHODS: Cross-sectional analysis of clinical, bronchoalveolar lavage and treatment data from the Australasian Cystic Fibrosis Bronchoalveolar Lavage study was used to identify predictive factors for detecting Aspergillus at age 5 years. A parametric repeated time-to-event model quantitatively described the risk and factors associated with acquiring Aspergillus and Pseudomonas aeruginosa from birth until age 5 years. RESULTS: Cross-sectional analysis found that the number of P. aeruginosa eradication courses increased the odds of detecting Aspergillus at age 5 years (OR 1.61, 95% CI 1.23 to 2.12). The median (IQR) age for the first P. aeruginosa positive culture was 2.38 (1.32-3.79) years and 3.69 (1.68-4.74) years for the first Aspergillus positive culture. The risk of P. aeruginosa and Aspergillus events changes with time after the first year of study entry. It also decreases for P. aeruginosa after completing P. aeruginosa eradication (HR 0.15, 95% CI 0.00 to 0.79), but increases for Aspergillus events (HR 2.75, 95% CI 1.45 to 5.41). The risk of acquiring both types of events increases after having had a previous event. CONCLUSION: In young children with CF, completing P. aeruginosa eradication therapy and previous Aspergillus events are associated with increased risk of acquiring Aspergillus.

A systematic review of studies examining the rate of lung function decline in patients with cystic fibrosis.

A systematic review was performed (i) to describe the reported overall rate of progression of CF lung disease quantified as FEV1%predicted decline with age, (ii) to summarise identified influencing risk factors and (iii) to review methods used to analyse CF lung disease progression data. A search of publications providing FEV1%predicted values over age was conducted in PUBMED and EMBASE. Baseline and rate of FEV1%predicted decline were summarised overall and by identified risk factors. Thirty-nine studies were included and reported variable linear rates of lung function decline in patients with CF. The overall weighted mean FEV1%predicted over age was graphically summarised and showed a nonlinear, time-variant decline of lung function. Compared to their peers, Pseudomonas aeruginosa infection and pancreatic insufficiency were most commonly associated with lower baseline and more rapid FEV1%predicted declines respectively. Considering nonlinear models and drop-out in lung disease progression, analysis is lacking and more studies are warranted.

Semi-physiological Pharmacokinetic Model of Clozapine and Norclozapine in Healthy, Non-smoking Volunteers: The Impact of Race and Genetics.

BACKGROUND AND OBJECTIVES: Clozapine is the medication of choice for treatment-resistant schizophrenia. However, it has a complex metabolism and unexplained interindividual variability. The current work aims to develop a pharmacokinetic model of clozapine and norclozapine in non-smokers and assess the impact of demographic and genetic predictors. METHODS: Healthy volunteers were recruited in a population pharmacokinetic study. Blood samples were collected at 30 min and 1, 2, 3, 5 and 8 h following a single flat dose of clozapine (12.5 mg). The clozapine and norclozapine concentrations were measured via high-performance liquid chromatography-ultraviolet method. A semi-physiological pharmacokinetic model of clozapine and norclozapine was developed using nonlinear mixed-effects modeling. Clinical and genetic predictors were evaluated, including CYP1A2 (rs762551) and ABCB1 (rs2032582), using restriction fragment length polymorphism. RESULTS: A total of 270 samples were collected from 33 participants. The data were best described using a two-compartment model for clozapine and a two-compartment model for norclozapine with first-order absorption and elimination and pre-systemic metabolism. The estimated (relative standard error) clearance of clozapine and norclozapine were 27 L h-1 (31.5 %) and 19.6 L h-1 (30%), respectively. Clozapine clearance was lower in sub-Saharan Africans (n = 4) and higher in Caucasians (n = 9) than Asians (n = 20). Participants with CYP1A2 (rs762551) (n = 18) and ABCB1 (rs2032582) (n = 12) mutant alleles had lower clozapine clearance in the univariate analysis. CONCLUSIONS: This is the first study to develop a semi-physiological pharmacokinetic model of clozapine and norclozapine accounting for the pre-systemic metabolism. Asians required lower doses of clozapine as compared with Caucasians, while clozapine pharmacokinetics in sub-Saharan Africans should be further investigated in larger trials.

A time-to-event modelling of sputum conversion within two months after antituberculosis initiation among drug-susceptible smear positive pulmonary tuberculosis patients: Implementation of internal and external validation.

Delayed sputum conversion has been associated with a higher risk of treatment failure or relapse among drug susceptible smear-positive pulmonary tuberculosis patients. Several contributing factors have been identified in many studies, but the results varied across regions and countries. Therefore, the current study aimed to develop a predictive model that explained the factors affecting time to sputum conversion within two months after initiating antituberculosis agents among Malaysian with drug-susceptible smear-positive pulmonary tuberculosis patients. Retrospective data of pulmonary tuberculosis patients followed up at a tertiary hospital in the Northern region of Malaysia from 2013 until 2018 were collected and analysed. Nonlinear mixed-effect modelling software (NONMEM 7.3.0) was used to develop parametric survival models. The final model was further validated using Kaplan-Meier-visual predictive check (KM-VPC) approach, kernel-based hazard rate estimation method and sampling-importance resampling (SIR) method. A total of 224 patients were included in the study, with 34.4 % (77/224) of the patients remained positive at the end of 2 months of the intensive phase. Gompertz hazard function best described the data. The hazard of sputum conversion decreased by 39 % and 33 % for moderate and advanced lesions as compared to minimal baseline of chest X-ray severity, respectively (adjusted hazard ratio (aHR), 0.61; 95 % confidence intervals (95 % CI), (0.44-0.84) and 0.67, 95 % CI (0.53-0.84)). Meanwhile, the hazard also decreased by 59 % (aHR, 0.41; 95 % CI, (0.23-0.73)) and 48 % (aHR, 0.52; 95 % CI, (0.35-0.79)) between active and former drug abusers as compared to non-drug abuser, respectively. The successful development of the internally and externally validated final model allows a better estimation of the time to sputum conversion and provides a better understanding of the relationship with its predictors.

The Impact of an Educational Intervention on Enhancing Clinical Knowledge of Physicians and Pharmacists Regarding Statins and Monitoring Parameters: The Experience of a Tertiary Teaching Hospital.

Introduction: Understanding the latest guideline recommendations is crucial for healthcare professionals to apply statin therapy effectively. Thus, the purpose of this study was to evaluate the efficacy of an educational intervention in enhancing the awareness and understanding of physicians and pharmacists concerning risk assessment of Atherosclerotic cardiovascular disease (ASCVD) and the role of statin therapy. Methods: This pre- and post-intervention study was conducted in Sana'a, Yemen's capital city, at the University of Science and Technology Hospital. The study was done between 11/2021-12/2021, and two separate educational sessions were held. The McNemar's test and Wilcoxon signed-rank test were employed as necessary. Results: Participants' awareness of the Framingham CVD risk calculator improved significantly from 40.4% pre-intervention to 78.7% post-intervention. Similarly, understanding of the parameters used in the 10-year ASCVD Risk calculator rose from 46.8% pre-intervention to 76.6% post-intervention. The ability to identify high, moderate, and low-intensity statin therapy, for instance, increased from 34% to 63.8% post-intervention. Regarding statins' contraindications, safety, and efficacy monitoring parameters, pre-intervention knowledge was unsatisfactory, and the educational intervention improved it significantly (p <0.05). For physicians, the median ASCVD risk assessment knowledge score was significantly improved from 4 (IQR = 3-5) pre-intervention to 7 (6.25-8) immediately post-intervention, while the statin therapy clinical knowledge median score significantly improved from 3 (1.25-6.5) to 9 (7.25-14.75) post-education intervention, p-values were 0.002 and 0.003; respectively. For pharmacists, a similar significant improvement (p <0.05) in the overall knowledge scores for both ASCVD risk assessment and statin therapy was noted. Conclusion: The educational intervention improved participants' knowledge of statin therapy and ASCVD risk assessment. Therefore, further education lectures and training programs through continuing medical education on the up-to-date guidelines' recommendations should be regularly implemented to raise awareness and improve the clinical knowledge and appropriateness of statins use in clinical settings. .

Antibiotic Overprescribing among Neonates and Children Hospitalized with COVID-19 in Pakistan and the Implications.

There are concerns with excessive antibiotic prescribing among patients admitted to hospital with COVID-19, increasing antimicrobial resistance (AMR). Most studies have been conducted in adults with limited data on neonates and children, including in Pakistan. A retrospective study was conducted among four referral/tertiary care hospitals, including the clinical manifestations, laboratory findings, the prevalence of bacterial co-infections or secondary bacterial infections and antibiotics prescribed among neonates and children hospitalized due to COVID-19. Among 1237 neonates and children, 511 were admitted to the COVID-19 wards and 433 were finally included in the study. The majority of admitted children were COVID-19-positive (85.9%) with severe COVID-19 (38.2%), and 37.4% were admitted to the ICU. The prevalence of bacterial co-infections or secondary bacterial infections was 3.7%; however, 85.5% were prescribed antibiotics during their hospital stay (average 1.70 ± 0.98 antibiotics per patient). Further, 54.3% were prescribed two antibiotics via the parenteral route (75.5%) for ≤5 days (57.5), with most being 'Watch' antibiotics (80.4%). Increased antibiotic prescribing was reported among patients requiring mechanical ventilation and high WBCs, CRP, D-dimer and ferritin levels (p < 0.001). Increased COVID-19 severity, length of stay and hospital setting were significantly associated with antibiotic prescribing (p < 0.001). Excessive antibiotic prescribing among hospitalized neonates and children, despite very low bacterial co-infections or secondary bacterial infections, requires urgent attention to reduce AMR.

Determinants of Inadequate Empiric Antimicrobial Therapy in ICU Sepsis Patients in Al-Madinah Al-Munawwarah, Saudi Arabia: A Comparison of Artificial Neural Network and Regression Analysis.

In the management of sepsis, providing adequate empiric antimicrobial therapy is one of the most important pillars of sepsis management. Therefore, it is important to evaluate the adequacy of empiric antimicrobial therapy (EAMT) in sepsis patients admitted to intensive care units (ICU) and to identify the determinants of inadequate EAMT. The aim of this study was to evaluate the adequacy of empiric antimicrobial therapy in patients admitted to the ICU with sepsis or septic shock, and the determinants of inadequate EAMT. The data of patients admitted to the ICU units due to sepsis or septic shock in two tertiary healthcare facilities in Al-Madinah Al-Munawwarah were retrospectively reviewed. The current study used logistic regression analysis and artificial neural network (ANN) analysis to identify determinants of inadequate empiric antimicrobial therapy, and evaluated the performance of these two approaches in predicting the inadequacy of EAMT. The findings of this study showed that fifty-three per cent of patients received inadequate EAMT. Determinants for inadequate EAMT were APACHE II score, multidrug-resistance organism (MDRO) infections, surgical history (lower limb amputation), and comorbidity (coronary artery disease). ANN performed as well as or better than logistic regression in predicating inadequate EAMT, as the receiver operating characteristic area under the curve (ROC-AUC) of the ANN model was higher when compared with the logistic regression model (LRM): 0.895 vs. 0.854. In addition, the ANN model performed better than LRM in predicting inadequate EAMT in terms of classification accuracy. In addition, ANN analysis revealed that the most important determinants of EAMT adequacy were the APACHE II score and MDRO. In conclusion, more than half of the patients received inadequate EAMT. Determinants of inadequate EAMT were APACHE II score, MDRO infections, comorbidity, and surgical history. This provides valuable inputs to improve the prescription of empiric antimicrobials in Saudi Arabia going forward. In addition, our study demonstrated the potential utility of applying artificial neural network analysis in the prediction of outcomes in healthcare research.

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.

Patterns of dyslipidemia and its associated factors among prediabetic subjects. A cross-sectional study at a primary care clinic.

Introduction: Diabetes is closely linked to cardiovascular diseases, with diabetic dyslipidaemia serving as an established marker of the acceleration of complications, contributing to an increased cardiovascular risk among patients. Timely detection and early characterization of lipid abnormalities can help clinicians in implementing effective preventive measures. This study aimed to determine the patterns and associated factors of dyslipidaemia among Malaysian subjects with borderline diabetes. Methods: A retrospective study was conducted among subjects with borderline diabetes aged ≥18 years who visited a primary healthcare centre at Universiti Sains Malaysia from January 2017 to December 2018. Sociodemographic, clinical and laboratory data were obtained from electronic medical records. Data were analysed using SPSS version 25. Results: A total of 250 participants with borderline diabetes were included in the analysis. Of them, 93.6% (n=234) had lipid abnormalities. Isolated dyslipidaemia characterised by a high low-density lipoprotein cholesterol (LDL-C) level (38.8%, n=97) was the most common pattern found, followed by combined dyslipidaemia of high LDL-C and triglyceride (TG) levels (22.8%, n=57). The male sex was found to be significantly associated with hypertriglyceridemia (adjusted odds ratio [AOR] = 1.86, 95% confidence interval [CI] =1.09-3.1)(P=0.02). Diastolic blood pressure ≥90mmHg was significantly associated with a low HDL-C level (A0R=2.09, 95% CI=1.0-4.1) (P=0.03). Conclusion: The majority of subjects with borderline diabetes have lipid abnormalities. Specifically, isolated dyslipidaemia characterised by a high LDL-C level is alarmingly prevalent. Further large-scale robust studies are needed to confirm the present findings.

Perceptions and Knowledge of Public Towards Emerging Human Monkeypox in Yemen: A Cross-Sectional Study.

Background: The spread of monkeypox (mpox) worldwide poses a severe threat to human life. This virus leads to a disease with symptoms similar to smallpox in humans. To combat this threat, improving public knowledge and perception toward mpox is vital for public health preventive measures. Methods: A cross-sectional survey was carried out in Yemen from December 2022 to March 2023 to investigate public perception and knowledge of mpox. Individuals were approached through social media platforms using a convenient sampling approach. Linear regression was used to determine the association between participants' knowledge (dependent variable) and explanatory variables. Results: A total of 853 individuals consented to take part in the study. A significant proportion of respondents had a low knowledge level (N=572, 67.06%). Most participants knew about the nature of the diseases (75%, n=641), transmission mode (78.1%, n=668), hand sanitizer preventive measures, and skin- related symptoms. However, only 20.8% (n= 178) knew that diarrhea is not a symptom, and 25.4% (n= 217) knew antibiotics are unnecessary for mpox management. A proportion of 57.7% (n=492) of the participants feared human mpox, and 47.7% (n= 407) thought it was a conspiracy. Most participants had a good perception of local and international health authorities controlling the disease. Age, education level, having a health-related certificate, and receiving a 2-dose vaccination for COVID-19 had statistically significant associations with mpox knowledge level (P < 0.05). Social media platforms were the most often used information source about mpox (78.3%, n= 668), followed by articles (41.1%, n=351). Conclusion: The study reveals a low public knowledge about mpox in Yemen, emphasizing the need for targeted educational campaigns, especially via social media, to strengthen public health measures and disease control. Addressing Knowledge gaps and correcting misconceptions is crucial for improving preparedness and response to the disease.