Unveiling the emergence of SARS-CoV-2 JN.1 sub-variant: Insights from the first cases at Charles Nicolle Hospital, Tunisia.

The JN.1 sub-variant is a new variant of the SARS-CoV-2 Omicron strain, derived from the BA.2.86 sub-variant. It was first detected in late 2023 and has quickly spread to many countries, becoming the most prevalent variant in some regions. JN.1 exhibits a unique mutation (L455S) in the spike protein compared to the BA.2.86 lineage, which may affect its transmissibility and immune evasion capabilities. JN.1 has been designated as a "variant of interest" by the World Health Organization due to its rapidly increasing spread and is being closely monitored for its impact on the COVID-19 pandemic. This study describes the emergence of SARS-CoV-2 JN.1 sub-variant in Tunisia, and reports its mutation profiles.Nasopharyngeal samples collected over a four-month period (October 2023 to January 2024) were subjected to RNA extraction and real-time RT-PCR confirmation of SARS-CoV-2 infection. The whole-genome sequencing was performed by an iSeq 100 sequencer and COVIDSeq kit reagents (Illumina, USA).Mutation analysis, using the NextClade platform and GISAID database, revealed the presence of JN.1 in 15 out of 80 positive cases (18.75%) during the study period.The emergence of JN.1 highlights the ongoing evolution of SARS-CoV-2 and the need for continued surveillance and research to better understand the characteristics and impact of emerging variants.

Genomic surveillance of SARS-CoV-2 in North Africa: 4 years of GISAID data sharing.

Objectives: This study aimed to construct geographically, temporally, and epidemiologically representative data sets for SARS-CoV-2 in North Africa, focusing on Variants of Concern (VOCs), Variants of Interest (VOIs), and Variants Under Monitoring (VUMs). Methods: SARS-CoV-2 genomic sequences and metadata from the EpiCoV database via the Global Initiative on Sharing All Influenza Data platform were analyzed. Data analysis included cases, deaths, demographics, patient status, sequencing technologies, and variant analysis. Results: A comprehensive analysis of 10,783 viral genomic sequences from six North African countries revealed notable insights. SARS-CoV-2 sampling methods lack standardization, with a majority of countries lacking clear strategies. Over 59% of analyzed genomes lack essential clinical and demographic metadata, including patient age, sex, underlying health conditions, and clinical outcomes, which are essential for comprehensive genomic analysis and epidemiological studies, as submitted to the Global Initiative on Sharing All Influenza Data. Morocco reported the highest number of confirmed COVID-19 cases (1,272,490), whereas Tunisia leads in reported deaths (29,341), emphasizing regional variations in the pandemic's impact. The GRA clade emerged as predominant in North African countries. The lineage analysis showcased a diversity of 190 lineages in Egypt, 26 in Libya, 121 in Tunisia, 90 in Algeria, 146 in Morocco, and 10 in Mauritania. The temporal dynamics of SARS-CoV-2 variants revealed distinct waves driven by different variants. Conclusions: This study contributes valuable insights into the genomic landscape of SARS-CoV-2 in North Africa, highlighting the importance of genomic surveillance in understanding viral dynamics and informing public health strategies.

Drug-Drug Interaction between Tacrolimus and Fluconazole in a Kidney Transplant Recipient.

We report a case of tacrolimus and fluconazole drug-drug interaction in a 20-year-old female kidney transplant recipient with stable kidney function. The patient's tacrolimus blood concentrations were in the therapeutic range until fluconazole was administrated for Candida albicans infection, on day 58 posttransplant. Tacrolimus blood concentration increased by 125% (18.4 ng/mL) on day 79 and by 212% (25.4 ng/mL) on day 84 posttransplant. On day 92, tacrolimus trough blood concentration returned to the therapeutic range (5.6 ng/mL), with decrease of tacrolimus daily dose by 50% (to 4 mg). After fluconazole withdrawal, the patient was returned to the initial tacrolimus daily dose (8 mg) to maintain a tacrolimus trough blood concentration in the therapeutic range. Fluconazole coadministration with tacrolimus shows a significant clinical effect on tacrolimus trough blood concentration in kidney transplant patients. Maintaining a tacrolimus trough blood concentration in the therapeutic range is crucial for these patients; therefore, physicians should be aware of fluconazole prescriptions.

Interaction Between Tacrolimus and Proton Pump Inhibitor in a Kidney Transplant Recipient.

We aimed to present a drug monitoring profile of tacrolimus and proton pump inhibitor coadministration in a 23-year-old male patient with a history of high blood pressure who underwent kidney transplant. The patient's serum trough levels of tacrolimus were in the therapeutic range until omeprazole 20 mg daily was prescribed. Tacrolimus trough serum level increased to 29.5 ng/mL under the same daily dose and to 13.9 ng/mL after tacrolimus daily dose was decreased to 6 mg/day. This increase in tacrolimus serum level was behind a renal function alteration. After withdrawal of omeprazole, tacrolimus trough serum level returned to the therapeutic range. Because interactions between tacrolimus and omeprazole could result in toxicities, careful monitoring of tacrolimus serum levels should be considered to adjust the dosage.

Prevalence of indeterminate tuberculosis interferon-gamma release assays in COVID-19 patients: Systematic review and meta-analysis.

Background and Aims: The reliability of interferon-gamma-release-assays (IGRAs) for tuberculosis (TB) testing in coronavirus disease 2019 (COVID-19) patients is unknown. This study aimed to systematically review the prevalence of indeterminate TB-IGRA following SARS-CoV-2 infection or vaccination and to review associated factors. Methods: This systematic literature review was guided according to the PRISMA guidelines by searching PubMed, Scopus, Web of Science, Clinicalkey, and Cochrane Library. Studies reporting results of TB-IGRA tests (QuantiFERON [QFT]-TB, T-SPOT.TB) in COVID-19 patients or vaccines were included. The random effects model was used to assess the prevalence of indeterminate IGRA results. Heterogeneity was evaluated using the Τ 2 and 95% predictive interval. Results: Of the 273 citations screened, 12 articles were included in the final analysis including a total of 2107 patients. The overall pooled effect size proportion of indeterminate QFT-TB results, estimated in eight studies using the QFT-TB Plus assay, was 0.26 (95% CI: 0.205-0.324, Τ 2 = 0.158). The mean true effect size was 0.26 (95% predictive interval: [0.110-0.500]). A subgroup analysis was not undertaken due to the small number of studies. Indeterminate QFT-TB rates were associated with COVID-19 severity, steroid treatment, inflammation-related parameters, neutrophilia, and lymphopenia. Conclusion: Indeterminate QFT-TB results in COVID-19 patients occur in almost one-quarter of tests performed. Further studies are needed to assess associated factors.

Therapeutic Drug Monitoring of Tacrolimus in Tunisian Renal Transplant Patients during the Tuberculosis Infection: A Retrospective, Observational, Single-centre Analysis.

Tuberculosis is a challenge in organ transplantation due to the interaction between Anti- Tuberculosis Treatment (ATT) and immunosuppressive drugs, such as Tacrolimus (TAC). This study aimed to assess this interaction and discuss the guidelines used in this specific case. METHODS: A retrospective, observational, single-center analysis was performed at the Department of Clinical Pharmacology (National Centre of Pharmacovigilance, Tunisia). We analyzed the database of patients who received TAC from 2009 until 2018. We included samples provided from renal transplant patients infected by Mycobacterium tuberculosis after transplantation. Trough blood levels (C0) were determined using an immunoassay analyzer. The Therapeutic Range (TR) of TAC was considered between 5 and 10 ng/mL. Pharmacokinetic parameters were compared between the period of co-administration of TAC/ATT (period A) and the period during which patients received only TAC (period B). RESULTS: Seven renal transplant patients treated by TAC were included. 41 samples were analyzed (16; period A, 25; period B). Only 6 % of C0 values were found within TR during period A, while this rate was 44% during period B. During period A, 88% of TAC C0 was under the lower limit of TR, indicating a high risk of transplant rejection. The mean C0 and C0/D were significantly lower during period A (3.11±1.53 ng/mL vs 7.11 ± 3.37 ng/mL; p = 0.001 and 33.06 ± 24.89 vs 83.14 ± 44.46; p = 0.0006, respectively), without difference in doses between periods. CONCLUSION: Considering the results of this study, clinicians are suggested to monitor TAC closely in this particular circumstance.

Effects of biologic and target synthetic disease-modifying anti-rheumatic drugs on sarcopenia in spondyloarthritis and rheumatoid arthritis: a systematic review and meta-analysis.

Sarcopenia is a syndrome defined by generalized and progressive loss of skeletal muscle mass, strength, and function. Besides affecting elderly population, it is actually common among inflammatory rheumatic diseases (IRD) patients. We performed a systematic literature review with a meta-analysis to investigate the influence of biologic and target synthetic disease-modifying anti-rheumatic drugs (bDMARDs/tsDMARDs) on sarcopenia in IRD. A systematic search has been performed on Pubmed, Scopus, and Web of science. Studies characteristics were collected. Assessment tools were body composition (total lean mass (TLM) and percentage, appendicular skeletal mass (ASM), fat-free mass and index (FFM and FFMI), skeletal mass index (SMI) and segmental lean mass (SLM)), and muscle strength and physical performance tests. Treatment effect defined the difference in change from baseline to the end of follow-up treatment was divided by the pooled SD of the difference. Twenty-two studies on 778 patients receiving bDMARDs/tsDMARDs and 157 controls were reviewed. They investigated rheumatoid arthritis (RA) (N = 14), spondyloarthritis (SpA) (N = 6), psoriatic arthritis (N = 1), and both RA and SpA (N = 1). tsDMARDs were used in one study with no effect on sarcopenia. Ten studies demonstrated that bDMARDs increased significantly muscle measures in 347 patients (44.6%) with a significant increase in TLM (6/15 studies; 57.4%), FFMI (4/6 studies; 59.9%), ASM (2/5 studies; 17.6%), SMI (2/5 studies; 18.1%), and SLM (2/2 studies; 3.6%). bDMARDs showed also a positive effect on handgrip strength in 1/3 of studies (45.2%) and on physical performance in 1/2 of studies (61%). In 1/5 of comparative studies, IRD patients on bDMARDs showed significantly higher increase of TLM in comparison to controls naïve bDMARDs. Regarding diagnosis, positive effect of bDMARDs was seen in 67.4% in SpA versus 49.3% in RA, with a significant increase of TLM, ASM and FFMI in 59.4%, 100%, and 65.2% in SpA versus 54.9%, 24.1%, and 54.8% in RA, respectively. Meta-analysis assessed the effect of bDMARD on TLM in 10 studies. There was no statistically significant difference [SMD - 0.10 (95% Confidence Interval - 0.26 - 0.06; tau2 = 0). Heterogeneity across studies was null, and the 95% confidence interval (index of precision) was equal to the 95% predictive interval. The first systematic literature review showed that bDMARDs have a significant improve effect in nearly half of RA and SpA patients on muscle mass and muscle strength, assessed separately. However, the meta-analysis concluded that bDMARDs have no significant effect on TLM.

Phylogenetic and amino acid signature analysis of the SARS-CoV-2s lineages circulating in Tunisia.

Since the beginning of the Coronavirus disease-2019 pandemic, there has been a growing interest in exploring SARS-CoV-2 genetic variation to understand the origin and spread of the pandemic, improve diagnostic methods and develop the appropriate vaccines. The objective of this study was to identify the SARS-CoV-2s lineages circulating in Tunisia and to explore their amino acid signature in order to follow their genome dynamics. Whole genome sequencing and genetic analyses of fifty-eight SARS-CoV-2 samples collected during one-year between March 2020 and March 2021 from the National Influenza Center were performed using three sampling strategies.. Multiple lineage introductions were noted during the initial phase of the pandemic, including B.4, B.1.1, B.1.428.2, B.1.540 and B.1.1.189. Subsequently, lineages B1.160 (24.2%) and B1.177 (22.4%) were dominant throughout the year. The Alpha variant (B.1.1.7 lineage) was identified in February 2021 and firstly observed in the center of our country. In addition, A clear diversity of lineages was observed in the North of the country. A total of 335 mutations including 10 deletions were found. The SARS-CoV-2 proteins ORF1ab, Spike, ORF3a, and Nucleocapsid were observed as mutation hotspots with a mutation frequency exceeding 20%. The 2 most frequent mutations, D614G in S protein and P314L in Nsp12 appeared simultaneously and are often associated with increased viral infectivity. Interestingly, deletions in coding regions causing consequent deletions of amino acids and frame shifts were identified in NSP3, NSP6, S, E, ORF7a, ORF8 and N proteins. These findings contribute to define the COVID-19 outbreak in Tunisia. Despite the country's limited resources, surveillance of SARS-CoV-2 genomic variation should be continued to control the occurrence of new variants.

Comparing real-life carbamazepine exposure between innovator and generic formulation.

BACKGROUND: Carbamazepine is an anticonvulsant largely used in the treatment of epilepsy. The use of generic antiepileptic drugs (AEDs) is controversial because of the eventual possibility to loss seizures control. The aim of our study was to compare the concentration over dose ratio of two products containing carbamazepine, the innovator (Tégrétol®-NOVARTIS) and the generic (Taver®-MEDOCHEMIE). METHODS: It is a retrospective study (2009-2016) including 32 patients treated with carbamazepine. Patients were treated initially by innovator then switched to generic or vice versa. All patients have at least one level of carbamazepine plasma concentration (C0) with the innovator or the generic formulation. Monitoring of carabamazepine was made using immunoassay method (ARCHITECT-ABOTT®). RESULTS: The mean age of our patients was 28.4 years and ranged from 2 to 55 years. The sex ratio M/F was 1.46. The mean ratio C0/dose for the innovator group was 0.723 (min/max: 0.017/1.73), and the mean ratio C0/dose for the generic group was also 0.607 (min/max: 0.064/1.68). There was no statistically significant difference between both groups (P=0.16). CONCLUSION: Our results confirm the difference between the innovator and the generic formulation of carbamazepine. So, switching from innovator to generic seems to be safe and exposure to carbamazepine remains the same.

Antiphospholipid antibodies in the obstetric antiphospholipid syndrome: Detection and antibodies profile at the Maternity and Neonatal Medicine Center of Monastir, Tunisia.

PURPOSE: This study aimed to implement lupus anticoagulant (LAC) detection techniques according to the International Society on Thrombosis and Hemostasis (ISTH) recommendations, in the Biological Laboratory of the Maternity and Neonatal Medicine Center (Monastir, Tunisia) and to evaluate the profile and the prevalence of antiphospholipid antibodies (aPL) in the obstetric antiphospholipid syndrome (OAPS). METHODS: We collected two groups: a "case group" (53 women who presented one or more obstetrical criteria of APS) and a "control group." LAC was detected following the four steps recommended by ISTH 2009. Anticardiolipin (aCL) and antibeta-2-glycoprotein I (aß2GPI) antibodies testing were performed by enzyme-linked immunosorbent assay (ELISA). RESULTS: aPL were found in five patients: three patients with isolated LAC, one patient with isolated IgG aCL, and one patient with triple positivity (LAC, aCL IgM, aß2GPI IgM). Concerning LAC, 13 (24.52%) of 53 patients had a screening step with at least one positive test. The mixing step was positive in four patients and then confirmed in the confirmatory test. Thus, the prevalence of LAC in our study group is 7.54%. Surprisingly, among these positive patients, one patient had an associated combined factor V (FV) and factor VIII (FVIII) deficiency. CONCLUSION: There is no single test and no algorithm that can detect all types of LAC. It seems that the recent 2020 ISTH algorithm allows a better detection of low activity LAC than the 2009 algorithm. In our study, the most frequently identified antiphospholipid antibodies were LAC more than aCL and aß2GPI.

Is there a ceiling lamotrigine serum level in epileptic children in remission?

INTRODUCTION: Seizure control, in patients with epilepsy, is proportionally associated with health-related quality of life. Antiepileptic therapy leads to seizure remission in most cases. However, some patients are resistant to treatment despite achieving high doses which can be explained by interindividual variability of antiepileptic drugs' metabolism. A ceiling exposure, in epilepsy, helps to adapt the therapeutic strategy in a faster way and to prevent unnecessary exposure to adverse drug reactions. Due to the increasing use of new generations of antiepileptic drugs, we aimed to explore the distribution of lamotrigine (LMT) trough serum levels in epileptic children, stratified between remission and ongoing seizures, in order to determine whether there is a ceiling effect associated with remission. METHODS: We conducted a retrospective study (2012-2021) including children, with generalized epilepsy (2-18 years), addressed for a therapeutic drug monitoring of LMT trough serum levels. Patients in remission, should have as lasting three times the longest pre-treatment seizure-free interval and more than one year. RESULTS: The population of 114 children with generalized epilepsy was divided in to groups: epileptic children in remission (36) and epileptic children with ongoing seizures (78). There was no significant difference in age and sex in the two groups. Median LMT daily dose and trough serum levels were significantly higher in group 2. The highest LMT serum trough level was 11µg/mL in group 1 and 23.1µg/mL in group 2. Valproate was associated in 29%. There was no significant difference of the distribution of valproate in the two groups (P=0.08). CONCLUSIONS: Children in remission had a LMT trough serum levels under 11µg/mL and a daily dose of 3.36mg/kg/day or less. These results suggest that this LMT serum level and daily dose might be associated with a ceiling effect in epileptic children.

The COVID-19 Pandemic and the Need for an Integrated and Equitable Approach: An International Expert Consensus Paper.

BACKGROUND: One year after the declaration of the coronavirus disease 2019 (COVID-19) pandemic by the World Health Organization (WHO) and despite the implementation of mandatory physical barriers and social distancing, humanity remains challenged by a long-lasting and devastating public health crisis. MANAGEMENT: Non-pharmacological interventions (NPIs) are efficient mitigation strategies. The success of these NPIs is dependent on the approval and commitment of the population. The launch of a mass vaccination program in many countries in late December 2020 with mRNA vaccines, adenovirus-based vaccines, and inactivated virus vaccines has generated hope for the end of the pandemic. CURRENT ISSUES: The continuous appearance of new pathogenic viral strains and the ability of vaccines to prevent infection and transmission raise important concerns as we try to achieve community immunity against severe acute respiratory syndrome coronavirus type 2 (SARS-CoV-2) and its variants. The need of a second and even third generation of vaccines has already been acknowledged by the WHO and governments. PERSPECTIVES: There is a critical and urgent need for a balanced and integrated strategy for the management of the COVID-19 outbreaks organized on three axes: (1) Prevention of the SARS-CoV-2 infection, (2) Detection and early diagnosis of patients at risk of disease worsening, and (3) Anticipation of medical care (PDA). CONCLUSION: The "PDA strategy" integrated into state policy for the support and expansion of health systems and introduction of digital organizations (i.e., telemedicine, e-Health, artificial intelligence, and machine-learning technology) is of major importance for the preservation of citizens' health and life world-wide.

Drug interaction between carbamazepine and other antiepileptic drugs in Tunisian epileptic patients.

INTRODUCTION: Carbamazepine could be used on monotherapy or associated to other antiepileptic drugs (AED). In these cases, drug interactions should be taken into account. AIM: To assess the influence of the coadministration of CBZ with other AED on the trough plasmatic concentration (C0) of CBZ in epileptic adults. METHODS: We performed a retrospective study over a period of 9 years in the Department of Clinical Pharmacology in the Tunisian National Centre "Chalbi Belkahia" of Pharmacovigilance. Our study included samples from adult patients receiving CBZ alone or associated to other AED for epilepsy. Trough plasma CBZ plasma concentrations were measured by an immunological method. Included samples were divided in four groups: i/ group 1 (G1) receiving CBZ as monotherapy, ii/ group 2 (G2) treated by CBZ with an enzyme inducer (phenobarbital or phenytoin), iii/ group 3 (G3) taking CBZ associated to an enzyme inhibitor (valproic acid (VPA)), iv/ group 4 (G4), treated by CBZ associated to enzyme inducer (phenobarbital or phenytoin) and enzyme inhibitor (valproic acid) at the same time. RESULTS: There were no significant differences between different groups in age, weight and sex ratio. However statistical analysis showed a significant decrease in C0/D CBZ ratio between G1 and G2 and between G1 and G4 (p<0.001). However, the difference was not significant between G1 and G3 (p=1.2044). CONCLUSION: It is important to check and to prevent the consequences of the interaction between CBZ and other AED in order to avoid inefficiency and toxicity.

Digoxin therapeutic drug monitoring: age influence and adverse events.

INTRODUCTION: Digoxin is a cardiac glycoside, used to control rapid ventricular rates in atrial fibrillation and to reduce the hospitalizations due to heart failure. Digoxin has a narrow therapeutic range. So, in the treatment of older patients (≥ 65 years), it is important to set the optimal dose of digoxin to prevent toxicity and therapeutic drug monitoring of digoxin trough plasmatic concentration (C0) may be useful. AIM: To assess measured C0, to evaluate age influence on digoxin pharmacokinetic parameters and to report adverse events in patients administered digoxin. METHODS: It consisted in a retrospective study. We included all the patients addressed to the department of clinical pharmacology for digoxin C0 measurement by an automated fluorescence polarization immunoassay. Therapeutic ranges of digoxin C0 were: 1 to 2.5 ng.mL-1 in children, 0.8 to 2 ng.mL-1 in adults and 0.5 to 0.9 ng.mL-1 in older adults (≥ 65 years) in atrial fibrillation and heart failure. RESULTS: We collected 183 samples from 132 patients. Sex ratio M/W was 0.47. Mean age was 60 years and 57% of patients were older adults. Mean dose of digoxin was 0.3 mg.day-1. In older adults, 45% were administered daily doses over 0.125 mg.day-1. Mean digoxin C0 was 1.6 ng.mL-1. There was more supra-therapeutic C0 in older adults than younger ones (p<0.0001).There was no correlation between C0 and daily dose of digoxin. Adverse events, mainly cardiac and digestive, were reported in 47 patients (36%), among this population 47% were older adults. CONCLUSION: TDM is useful to prevent toxicity, mainly in older adults where diagnosis may be difficult to establish.

Development and validation method for estimation paclitaxel in plasma.

BACKGROUND: Paclitaxel (PTX) is an anticancer drug used in the treatment of many cancer , alone or in combination with other anti-tumors. It has a narrow therapeutic range, a large inter and intra-individual pharmacokinetic variability and haematological toxicity. The most effective pharmacokinetic parameter seems to be the time during which the plasma concentration is over 0.05 µmol/L. AIM: To develop and validate a new method for PTX quantitation in plasma using HPLC with UV/visible detection. METHODS: A rapid HPLC-UV method was developed for the determination of PTX level 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 (49/51) (v/v). Clonazepam was used as internal standard. This technique was linear over the range 50 ng/mL to 1500 ng/mL (r= 0.998). The evaluation of precision showed that our method is repeatable with a within-day coefficient of variation (CV) ranging from 6.94 to 18.78 % and reproducible for three studied concentrations low, medium and high with day-to-day CV of 14.92, 10.46 and 11.8% respectively. Under these conditions, each analysis required no longer than 12.81 min. CONCLUSION: We have developed and validate a new assay for PTX monitoring using HPLC with UV detection which is sensible, specific, reliable and easy to carry out in clinical use for its therapeutic drug monitoring.

Early interaction between tacrolimus and rifampin.

Drug interactions are unavoidable and need to be proactively identified and managed, in particular, the inductive effect of rifampin on tacrolimus whose potency and duration data are limited. We report the case of a renal transplant patient who was prescribed tacrolimus with preserved tough blood levels (C0) of 7.9 +/- 2 ng/mL. He presented ganglionic tuberculosis and started rifampin. One day later, C0 was 2.6 ng/mL with 5 mg/day. The serum creatinin was normal. Nine days later, C0 was 1.6 ng/mL with 7 mg/day. In this case-report, the tacrolimus-rifampin interaction occurred just one day after rifampin introduction necessitating early C0 monitoring.