The Impact of LRRK2 G2019S on Parkinson’s Disease: Clinical Phenotype and Treatment in Tunisian Patients

Objective@#LRRK2-G2019S is the most frequent mutation in North African Parkinson’s disease (PD) patients. Data on its impact on disease progression and treatment response remain elusive. Therefore, we investigated the clinical features, treatments, and complications of PD in Tunisian patients according to their LRRK2-G2019S profile. @*Methods@#This longitudinal retrospective study was performed in the Department of Neurology, Razi University Hospital. We included clinically diagnosed PD patients according to the Movement Disorders Society criteria and reviewed their medical records for clinical, treatment, and neuropsychological assessments. All patients were screened for the LRRK2-G2019S mutation using Sanger sequencing. The correlation between LRRK2-G2019S and clinical PD features was evaluated. @*Results@#We included 393 PD patients, 41.5% of whom had LRRK2-G2019S mutations. Patients with mutations were younger (p = 0.017), and female PD patients had a greater mutation frequency (p = 0.008). Mutation carriers exhibited distinct clinical features, with a greater frequency of postural instability gait difficulty forms (adjusted-p < 0.001). During disease progression, carriers showed a faster annual progression in the Unified Parkinson’s Disease Rating Scale Section III scores (adjusted-p = 0.009), and significantly higher levodopa equivalent dose values in later stages (1060.81 vs. 877.83 for 6-8 years). Motor complications, such as dyskinesia (adjusted-p < 0.001) and motor fluctuations (31.9% vs. 25.7%, adjusted-p < 0.001), were more prevalent in carriers, particularly in the later stages. LRRK2-G2019S carriers also exhibited a lower prevalence of non-motor symptoms, including episodic memory (adjusted-p < 0.001), attention (adjusted-p < 0.001), and dysexecutive disorders (adjusted-p = 0.038), as well as neuropsychiatric symptoms and dysautonomic signs. @*Conclusion@#The present study demonstrated that the variability of the clinical profile among Tunisian PD patients was explained by the incomplete penetrance of LRRK2-G2019S, which increased with age. Further studies using biomarker and disease progression data are necessary to improve PD management.

[Development and validation of a new HPLC method for determination of lamotrigine and clinical application]

Background: Lamotrigine is an effective anticonvulsant drug used in the treatment of epilepsy. It has a narrow therapeutic range, a large inter and intra-individual pharmacokinetic variability and some concentration-dependent side effects

Aim: The aim of this study was to develop and validate a new method for lamotrigine quantitation in plasma using HPLC with UV/visible detection

Methods: A rapid HPLC-UV method was developed for the determination of lamotrigine in plasma. All solvents used were HPLC grade

Results:After liquid-liquid extraction, chromatographic separation was achieved using an RP 18 [250 mm] column. The mobile phase was composed of acetonitrile and 0.1 M potassium dihyrogenophosphate [25/75] [v/v]. Barbital sodium was used as internal standard. This technique was linear over the 2 micro g/mL to 50 micro g/mL range [r= 0.99]. Detection and quantification limits were 0.07 micro g/mL and 0.21 micro g/mL, respectively. Within-day coefficient of variation [13.37 to 16%] and day-to-day coefficients of variation [15.68 to 16.63%] at three different concentrations. Under these conditions, each analysis required no longer than 10 min. We finally evaluated the plasma concentrations of lamotrigine in Tunisian patients treated with this drug

Conclusion: The results found are similar to those previously described and the developed method is repeatable and reproducible. It can be used for clinical applications

[Pharmacokinetik population of methotrexate in Tunisian population with acute lymphoblastic leukemia]

Background: The use of high dose of MTX in the treatment of the leukemia is actually better controlled by renal preparation, control of plasma concentrations and administration of folinic acid. However, High dose MTX has been proven to cause substantial toxicity and have high intra-and inter-patient variability. Population pharmacokinetic analysis is a useful tool for identification of sources of pharmacokinetic variability during anticancer drug development and can aid the design of alternative dosing regimens to enhance their efficacy and safety

Aim: The aim of our study is to developed and validate a population pharmacokinetics model of our population. We hereby describe the clinical covariates [age, sex and clearance of the creatinine] that influence MTX pharmacokinetic for predicting optimal dose to reduce MTX toxicity

Method: It is a prospective study achieved between January 2005 to January 2012 in the Service of Clinical Pharmacology. Including 273 patients treated for acute lymphocytic leukaemia 2582 plasma concentration was achieved. The data have been analyzed with Nonmem[copyright sign] software [non linear regression to mixed effect]

Results:The age of our patients varied from 2 to 23 years with an average of 13 years. The patients received high dose MTX therapy [1 to 8 g/m2] in 24 hours infusion every 15 days. Three compartiment models describe the pharmacokinetic of MTX. The most important covariables affecting the model were clearance of the creatinine, age and weight. We obtained a good correlation between the predicted and the observed concentrations

Conclusion: The development of population pharmacokinetics model of MTX allows us to propose a therapeutic diagram adapted to every patient according to its morphological and pharmacological features while taking in consideration the therapeutic objective

A year of genomic surveillance reveals how the SARS-CoV-2 pandemic unfolded in Africa

The progression of the SARS-CoV-2 pandemic in Africa has so far been heterogeneous and the full impact is not yet well understood. Here, we describe the genomic epidemiology using a dataset of 8746 genomes from 33 African countries and two overseas territories. We show that the epidemics in most countries were initiated by importations, predominantly from Europe, which diminished following the early introduction of international travel restrictions. As the pandemic progressed, ongoing transmission in many countries and increasing mobility led to the emergence and spread within the continent of many variants of concern and interest, such as B.1.351, B.1.525, A.23.1 and C.1.1. Although distorted by low sampling numbers and blind-spots, the findings highlight that Africa must not be left behind in the global pandemic response, otherwise it could become a breeding ground for new variants.

The evolving SARS-CoV-2 epidemic in Africa: Insights from rapidly expanding genomic surveillance.

Investment in Africa over the past year with regards to SARS-CoV-2 genotyping has led to a massive increase in the number of sequences, exceeding 100,000 genomes generated to track the pandemic on the continent. Our results show an increase in the number of African countries able to sequence within their own borders, coupled with a decrease in sequencing turnaround time. Findings from this genomic surveillance underscores the heterogeneous nature of the pandemic but we observe repeated dissemination of SARS-CoV-2 variants within the continent. Sustained investment for genomic surveillance in Africa is needed as the virus continues to evolve, particularly in the low vaccination landscape. These investments are very crucial for preparedness and response for future pathogen outbreaks. One-Sentence SummaryExpanding Africa SARS-CoV-2 sequencing capacity in a fast evolving pandemic.