Emerging Variants and Fading Immunity: Analyzing the Impact in Epidemic Modeling

Outbreaks like the recent COVID-19 pandemic underscore the importance of quick and informed responses to control and mitigate the epidemic. This thesis aims to develop a model that can provide deeper insights into how epidemics progress and behave. Accurate epidemic simulation can provide valuable insights into how an epidemic affects the population. This thesis considers both epidemic spread and epidemic severity, and integrates fading immunity into the epidemic model, creating a more realistic representation of real-life scenarios. This research also extends the model by considering diverse population structures in the contact network where different age groups have different levels of immunity strength. An evolutionary algorithm was used to generate and evolve personal contact networks. We analyzed the epidemic dynamics within these networks, focusing on how different proportions of young and old individuals impact the spread and severity of the epidemic. Results reveal that older populations with weaker immunity experience more severe infections, while younger populations with stronger immunity mitigate both spread and severity. The thesis also explores the impact on variant generation, showing that when using the epidemic spread fitness function there is a tendency to produce more variants than when using the epidemic severity fitness function, highlighting the virus's need to mutate in response to existing immunity. When the population is dominated by younger individuals, even though fewer variants are being generated, successful variants tend to exhibit a higher mutation distance to overcome the robust immunity present in the community

Formaldehyde content and quality characteristics of selected fish and seafood from wet markets

Formaldehyde was used by fishermen and fish vendors to preserve the freshness and quality of fish and seafood. The study was undertaken to determine the formaldehyde content and quality characteristics of fish and seafood from wet markets. Formaldehyde content was in the range of 0.38 to 15.75 μg g-1. Three types of biogenic amines (histamine, putrescine and cadaverine) were detected from all samples in which histamine content ranged from 0.25 to 1.97 μg g-1, putrescine from 0.33 to 9.09 μg g-1 and cadaverine from 0.34 to 5.81 μg g-1. Amino acids as biogenic amines precursor were also determined with lysine ranged from 12.75 to 28.80mg g-1, arginine from 8.17 to 27.83 mg g-1 and histidine from 1.93 to 10.14 mg g-1. As for the microbiological analyses, total plate counts for all fish types ranged from 5.68 to 7.13 log cfu g-1 and the proteolytic counts from 5.12 to 6.91 log cfu g-1. Samples were also analyzed for the presence of putrescine/ cadavarine/ histamine producing bacteria where the counts ranged from 3.50 to 6.52 log cfu g-1. The pH of all selected fish ranged from 6.25 to 7.28. There was no significant difference (p>0.05) among fish purchased from different wet markets. Hence this study suggested that fish and seafood from wet markets can be considered in good quality since the formaldehyde content and microbiological counts were still below the permissible limits

Evaluation of Impact of Prescribing Safety Assessment Workshop on Medical Doctors Using Kirkpatrick Model

Background Clinical pharmacology training is a prerequisite for all medical graduates. Prescription writing errors are not infrequent at primary health care level leading to threat to patient safety. Prescribers lacks uniform structured training and assessment which is one of the major factors for this situation across the country. In lots of institutions despite proper curriculum, learners lack interest because the subject importance is insignificant. Hence to bring more interest in pharmacology for prescribers there is a dire need for innovative and interesting methods of teaching and assessment, one of which is prescribing safety assessment (PSA). Objectives To assess if the PSA is superior method of training prescription writing than CPW To evaluate the workshop on prescription writing using guidelines of Kirkpatrick Model   Methods It was an experimental study. 44 medical doctors participated; a pre-test was taken 01 week before the workshop. Afterwards, they were randomized into 02 groups, group A went through PSA and group B followed conventional prescription writing (CPW) 01-day workshop. At the end, post-test was taken from both groups. The qualitative data was also collected from participants on feedback proforma consisting of few closed ended questions on Likert scale. Results The independent t-test was used to compare the data as it was in normal distribution. Posttest performance of PSA group significantly increased P ˂ 0.001 as compared to CPW. Reaction  to closed ended 13 questions on Likert scale showed high satisfaction from 4.32 to 4.84 on 5 points  Likert scale on workshop satisfaction. Conclusion PSA is an effective teaching and assessment strategy for learning clinical pharmacology. The study objectively proves its effectiveness in comparison to CPW and provides a guideline to implement this innovative and useful tool for teaching and assessment. Keywords Prescribing safety assessment, conventional prescription writing, Faculty development, Workshop, Impact, Kirkpatrick model

Efficacy of Chemotherapy for Locally Advanced and Metastatic Pancreatic Cancer: A real life experience and outcome from a tertiary referral centre.

Introduction: To report response rate, progression-free survival and overall survival in patients with advanced pancreatic cancer treated with different available chemotherapeutic regimens over ten years. Materials and Methods: This is a retrospective observational study. All patients with locally advanced and metastatic pancreatic cancer at Shaukat Khanum Memorial Cancer Hospital and Research Centre, Lahore, Pakistan, from January 2008 to December 2017 were studied. Data were collected from the hospital information system. The characteristics and outcomes of all the patients were analyzed. Progression-free survival and overall survival were also estimated. Kaplan Meier curves and Log-rank test were applied, and SPSS version 20 was used for data analysis. Results: Eighty-seven (87) subjects with a median age of 56 years (range 21-76) were included. Sixty-two (71%) subjects were male. The most common tumor location was the head of the pancreas in 46(53%) of all the subjects. Sixty-three (72%) subjects had elevated CA-19.9 values. About 47(54%) subjects had locally advanced pancreatic cancer (LAPC), and 40(46%) subjects had metastatic pancreatic cancer (MPC). Chemotherapy regimens used were FOLFIRINOX in 23(26%), gemcitabine-based 66(65%) and capecitabine-based in 8 (9%) of the subjects.  One (1%) subject had a complete response (CR), 12(14%) had a partial response (PR), 10 (11%) had stable disease, and 59(68%) of the subjects had progressive disease (PD). The objective response rate (ORR) was 15%, and the disease control rate (DCR) was 26%. In MPC, the ORR was 10%, DCR was 18%, and tumor progression was seen in 72% of the patients, while in LAPC, the ORR was 19.1, DCR 34% and tumor progression was documented in 64% of the patients, respectively. The FOLFIRNOX chemotherapy regimen had better ORR, DCR and lesser number of progressions as compared to Gemcitabine and Capecitabine based chemotherapy regimens. The Median PFS of the whole group was 32-weeks, and the median OS was 54-weeks. The PFS was significantly higher for LAPC (39 weeks) as compared to the MPC group (25 weeks) (p=0.028). There was no statistically significant difference between the OS of these 2 groups (p=0.451). In addition, PFS was significantly higher with FOLFIRINOX chemotherapy as compared to the other chemotherapy regimens. Regarding OS, there was no statistically significant difference among all chemotherapy regimen groups (p=0.267). Conclusion: Based on our results, FOLFIRINOX remained the most effective chemotherapy regimen despite the dose modifications and toxicities in all groups, indicating that modified FOLFIRINOX could be considered as a first-line regimen in south East Asian population

Dolutegravir twice-daily dosing in children with HIV-associated tuberculosis: a pharmacokinetic and safety study within the open-label, multicentre, randomised, non-inferiority ODYSSEY trial

Background: Children with HIV-associated tuberculosis (TB) have few antiretroviral therapy (ART) options. We aimed to evaluate the safety and pharmacokinetics of dolutegravir twice-daily dosing in children receiving rifampicin for HIV-associated TB. Methods: We nested a two-period, fixed-order pharmacokinetic substudy within the open-label, multicentre, randomised, controlled, non-inferiority ODYSSEY trial at research centres in South Africa, Uganda, and Zimbabwe. Children (aged 4 weeks to <18 years) with HIV-associated TB who were receiving rifampicin and twice-daily dolutegravir were eligible for inclusion. We did a 12-h pharmacokinetic profile on rifampicin and twice-daily dolutegravir and a 24-h profile on once-daily dolutegravir. Geometric mean ratios for trough plasma concentration (Ctrough), area under the plasma concentration time curve from 0 h to 24 h after dosing (AUC0–24 h), and maximum plasma concentration (Cmax) were used to compare dolutegravir concentrations between substudy days. We assessed rifampicin Cmax on the first substudy day. All children within ODYSSEY with HIV-associated TB who received rifampicin and twice-daily dolutegravir were included in the safety analysis. We described adverse events reported from starting twice-daily dolutegravir to 30 days after returning to once-daily dolutegravir. This trial is registered with ClinicalTrials.gov (NCT02259127), EudraCT (2014–002632-14), and the ISRCTN registry (ISRCTN91737921). Findings: Between Sept 20, 2016, and June 28, 2021, 37 children with HIV-associated TB (median age 11·9 years [range 0·4–17·6], 19 [51%] were female and 18 [49%] were male, 36 [97%] in Africa and one [3%] in Thailand) received rifampicin with twice-daily dolutegravir and were included in the safety analysis. 20 (54%) of 37 children enrolled in the pharmacokinetic substudy, 14 of whom contributed at least one evaluable pharmacokinetic curve for dolutegravir, including 12 who had within-participant comparisons. Geometric mean ratios for rifampicin and twice-daily dolutegravir versus once-daily dolutegravir were 1·51 (90% CI 1·08–2·11) for Ctrough, 1·23 (0·99–1·53) for AUC0–24 h, and 0·94 (0·76–1·16) for Cmax. Individual dolutegravir Ctrough concentrations were higher than the 90% effective concentration (ie, 0·32 mg/L) in all children receiving rifampicin and twice-daily dolutegravir. Of 18 children with evaluable rifampicin concentrations, 15 (83%) had a Cmax of less than the optimal target concentration of 8 mg/L. Rifampicin geometric mean Cmax was 5·1 mg/L (coefficient of variation 71%). During a median follow-up of 31 weeks (IQR 30–40), 15 grade 3 or higher adverse events occurred among 11 (30%) of 37 children, ten serious adverse events occurred among eight (22%) children, including two deaths (one tuberculosis-related death, one death due to traumatic injury); no adverse events, including deaths, were considered related to dolutegravir. Interpretation: Twice-daily dolutegravir was shown to be safe and sufficient to overcome the rifampicin enzyme-inducing effect in children, and could provide a practical ART option for children with HIV-associated TB

Neuropsychiatric manifestations and sleep disturbances with dolutegravir-based antiretroviral therapy versus standard of care in children and adolescents: a secondary analysis of the ODYSSEY trial

BACKGROUND: Cohort studies in adults with HIV showed that dolutegravir was associated with neuropsychiatric adverse events and sleep problems, yet data are scarce in children and adolescents. We aimed to evaluate neuropsychiatric manifestations in children and adolescents treated with dolutegravir-based treatment versus alternative antiretroviral therapy. METHODS: This is a secondary analysis of ODYSSEY, an open-label, multicentre, randomised, non-inferiority trial, in which adolescents and children initiating first-line or second-line antiretroviral therapy were randomly assigned 1:1 to dolutegravir-based treatment or standard-of-care treatment. We assessed neuropsychiatric adverse events (reported by clinicians) and responses to the mood and sleep questionnaires (reported by the participant or their carer) in both groups. We compared the proportions of patients with neuropsychiatric adverse events (neurological, psychiatric, and total), time to first neuropsychiatric adverse event, and participant-reported responses to questionnaires capturing issues with mood, suicidal thoughts, and sleep problems. FINDINGS: Between Sept 20, 2016, and June 22, 2018, 707 participants were enrolled, of whom 345 (49%) were female and 362 (51%) were male, and 623 (88%) were Black-African. Of 707 participants, 350 (50%) were randomly assigned to dolutegravir-based antiretroviral therapy and 357 (50%) to non-dolutegravir-based standard-of-care. 311 (44%) of 707 participants started first-line antiretroviral therapy (ODYSSEY-A; 145 [92%] of 157 participants had efavirenz-based therapy in the standard-of-care group), and 396 (56%) of 707 started second-line therapy (ODYSSEY-B; 195 [98%] of 200 had protease inhibitor-based therapy in the standard-of-care group). During follow-up (median 142 weeks, IQR 124–159), 23 participants had 31 neuropsychiatric adverse events (15 in the dolutegravir group and eight in the standard-of-care group; difference in proportion of participants with ≥1 event p=0·13). 11 participants had one or more neurological events (six and five; p=0·74) and 14 participants had one or more psychiatric events (ten and four; p=0·097). Among 14 participants with psychiatric events, eight participants in the dolutegravir group and four in standard-of-care group had suicidal ideation or behaviour. More participants in the dolutegravir group than the standard-of-care group reported symptoms of self-harm (eight vs one; p=0·025), life not worth living (17 vs five; p=0·0091), or suicidal thoughts (13 vs none; p=0·0006) at one or more follow-up visits. Most reports were transient. There were no differences by treatment group in low mood or feeling sad, problems concentrating, feeling worried or feeling angry or aggressive, sleep problems, or sleep quality. INTERPRETATION: The numbers of neuropsychiatric adverse events and reported neuropsychiatric symptoms were low. However, numerically more participants had psychiatric events and reported suicidality ideation in the dolutegravir group than the standard-of-care group. These differences should be interpreted with caution in an open-label trial. Clinicians and policy makers should consider including suicidality screening of children or adolescents receiving dolutegravir