The pharmacogenetics of tacrolimus in renal transplant patients: association with tremors, new-onset diabetes and other clinical events.

Our study is the first study to investigate the effect of SNPs in CYP3A5, CYP3A4, ABCB1 and POR genes on the incidence of tremors, nephrotoxicity, and diabetes mellitus. A total of 223 renal transplant patients receiving tacrolimus and mycophenolate mofetil (MMF) were recruited. Both adults and children patients participated in the study. Genotyping was performed using PROFLEX-PCR followed by RFLP. MPA and tacrolimus plasma concentrations were measured by immunoassay. The AUC0-12h of MMF was estimated by a Bayesian method. We found a statistically significant association between the CYP3A5*3 and CYP3A4*1B genotypes and the tacrolimus exposure. We found a lower occurrence of nephrotoxicity (p = 0.03), tremor (p = 0.01), and new-onset diabetes (p = 0.002) associated with CYP3A5*1 allele. The CYP3A4*1B allele was significantly associated with a lower occurrence of new-onset diabetes (p = 0.026). The CYP3A5*1 allele was significantly associated with an increased risk of acute and chronic rejection (p = 0.03 and p < 0.001, respectively). Our results support the usefulness of tacrolimus pharmacokinetics in pre-kidney transplant assessments.

A Population Pharmacokinetic Model to Predict the Individual Starting Dose of Tacrolimus for Tunisian Adults after Renal Transplantation.

BACKGROUND: Tacrolimus is the most frequently used immunosuppressive drug for preventing renal rejection. However, its use is hampered by its narrow therapeutic index and large intra and interpatient variability in pharmacokinetics. The objective of this study was to externally validate a tacrolimus population pharmacokinetic model developed for the Dutch population and adjust the model for the Tunisian population for use in predicting the starting dose requirement after kidney transplantation. METHODS: Data on tacrolimus exposure were obtained from kidney transplant recipients (KTRs) during the first 3 months post-transplantation. External validation of the Dutch model and its adjustment for the Tunisian population was performed using nonlinear mixed-effects modeling. RESULTS: In total, 1901 whole-blood predose tacrolimus concentrations from 196 adult KTRs were analyzed. According to a visual predictive check, the Dutch model underestimated the starting dose for the Tunisian adult population. The effects of age, together with the CYP3A5*3 and CYP3A4*22 genotypes on tacrolimus clearance were significantly different in the Tunisian population than in the Dutch population. Based on a bodyweight-based dosing, only 21.9% of tacrolimus concentrations were within the target range, whereas this was estimated to be 54.0% with the newly developed model-based dosing. After adjustment, the model was successfully validated internally in a Tunisian population. CONCLUSIONS: A starting-dose population pharmacokinetic model of tacrolimus for Tunisian KTRs was developed based on a previously published Dutch model. Using this starting dose could potentially increase the percentage of patients achieving target tacrolimus concentrations after the initial starting dose.

Association between Human Leukocyte Antigen (HLA) DQB1*06 and HLA DQB1*03 and adverse outcomes in a group of critically ill patients with COVID-19 in Tunisia: a cross-sectional study.

Introduction: Human Leukocyte Antigen (HLA) system is a highly polymorphic genetic system associated with the prognosis of several infectious diseases. The aim of this study is to investigate the association of HLA polymorphism with the outcome of coronavirus disease 2019 (COVID-19) in Tunisian critically ill patients. Methods: this retrospective cross-sectional study included 42 consecutive patients hospitalized in intensive care unit (ICU) for COVID-19 in March 2021. Genotyping of HLA loci was performed by LABType™ sequence-specific oligonucleotide (SSO) typing kits (One lambda Inc, USA). Statistical analyses were performed using Statistical Package for Social Sciences (SPSS®) version 23.0. A p-value <0.05 was considered significant. Multivariable regression analysis was performed for the association between HLA polymorphism with adverse outcomes with adjustment for potential confounders such as age, sex, co-morbidities and blood type. Results: patients included in our study had a mean age of 64.5 ± 11.5 (34-83) years and were mainly men (64.3%; (n=27)). The most common cardiovascular risk factors were obesity (61.9%; (n=26)) and hypertension (26.2%; (n=11)). Thirty-two patients died (76.2%). Eleven patients (26.2%) required intubation during hospitalization. We found that HLA DQB1*06 allele was significantly associated with protection against mortality aOR: 0.066, 95% CI 0.005-0.821; p = 0.035. HLA DQB1*03 allele was significantly associated with protection against intubation aOR: 0.151, 95% CI 0.023-0.976; p = 0.047. Conclusion: it was found that there are 2 protective HLA alleles against COVID-19 severity and mortality in critically ill patients. This could allow focusing on people genetically predisposed to develop severe forms of COVID-19.

Effect of Pre-Meal Metformin With or Without an Acute Exercise Bout on Postprandial Lipemic and Glycemic Responses in Metabolic Syndrome Patients: A Randomized, Open Label, Crossover Study.

INTRODUCTION: Both exercise and pre-meal metformin could lower postprandial glucose and lipid profiles. AIMS: To explore whether pre-meal metformin administration is superior to metformin administration with the meal in reducing postprandial lipid and glucose metabolism, and whether its combination with exercise confer superior benefits in metabolic syndrome patients. MATERIALS AND METHODS: In a randomized crossover design, 15 metabolic syndrome patients were assigned to 6 sequences including 3 experimental conditions: metformin administration with a test meal (met-meal), metformin administration 30 min prior to a test meal (pre-meal-met) with or without an exercise bout designed to expend 700 Kcal at 60% VO2 peak performed the evening just before pre-meal-met condition. Only 13 participants (3 males, 10 females; age: 46 ± 9.86, HbA1c: 6.23 ± 0.36) were included in the final analysis. RESULTS: Postprandial triglyceridemia was unaffected by any condition (all P > .05). However, both pre-meal-met (-7.1%, P = .009) and pre-meal-metx (-8.2%, P = .013) significantly reduced total cholesterol AUC with no significant differences between the two latter condition (P = .616). Similarly, LDL-cholesterol levels were significantly lower during both pre-meal-met (-10.1%, P = .013) and pre-meal-metx (-10.7%, P = .021) compared to met-meal with no difference between latter conditions (P = .822). Plasma glucose AUC was significantly reduced by pre-meal-metx compared to both pre-meal-met (-7.5%, P = .045) and met-meal (-8%, P = .03). Insulin AUC was significantly lower during pre-meal-metx compared to met-meal (-36.4%, P = .044). CONCLUSIONS: Metformin administration 30 minutes prior to meal seems to exert favorable effects on postprandial TC and LDL-Cholesterol levels compared to its administration with meal. Addition of one exercise bout only improved postprandial glycemia and insulinemia. TRIAL REGISTRY: Pan African clinical trial registry, Identifier PACTR202203690920424.

DPYD and TYMS polymorphisms as predictors of 5 fluorouracil toxicity in colorectal cancer patients.

Colorectal cancer (CRC) is the third most common cancer and the fourth leading cause of cancer death. 5-Fluorouracil (5-FU) is an essential component of systemic chemotherapy for CRC. Our objective was to determine the genotypic frequency of polymorphisms affecting dihydropyrimidine dehydrogenase (DPYD) and thymidylate synthetase (TYMS) genes and to correlate the genetic profile with the toxicity due to 5-FU, also considering nongenetic factors. This is a prospective study that involved 66 patients. We extracted DNA by salting out methods. We carried out the genotyping of the different polymorphisms by simple PCR for the TYMS 5'UTR and by PCR-RFLP for DPYD: 1905 + 1 G > A, 85 T > C, 496 A > G, 1679 T > G, c.483 + 18G > A and the TYMS: 5'UTR VNTR, 5'UTR G > C and 3'UTR. The study of the association of DPYD and TYMS polymorphisms with the various signs of toxicity under 5-FU revealed that the polymorphisms 496 A > G were significantly associated with hepatotoxicity: OR = 3.85 (p = 0.04). In addition, 85 T > C was significantly associated with mucositis and neurotoxicity: OR = 4.35 (p = 0.03), OR = 3.79 (p = 0.02). For TYMS, the only significant association we observed for 5'UTR with vomiting: OR = 3.34 (p = 0.04). The incidence of adverse reactions related to 5-FU appears to be influenced in patients with CRC by the identified DPYD and TYMS gene polymorphisms in the Tunisian population.

Variability in response to vitamin D supplementation according to vitamin D metabolism related gene polymorphisms in healthy adults.

OBJECTIVE: The aim of this study was to determine the influence of polymorphisms in some key gene actors of the vitamin D (vitD) metabolic pathway on supplementation efficacy. METHODS: In total, 245 healthy participants were recruited from occupational medicine service in Sahloul University Hospital with vitD deficiency [25(OH)D ≤ 30 ng/ml]. After giving an informed consent, all participants were asked to complete a generalized questionnaire and to follow a detailed personalized supplementation protocol. Genetic study was performed by PCR-RFLP for 15 single nucleotide polymorphisms (SNPs) belonging to DBP, CYP2R1, CYP27B14, CYP24A1 and VDR genes. Statistical study was carried out with SPSS23.0. RESULTS: Among the studied SNPs, non-response was significantly associated with variant alleles of rs4588 (OR* = 11.51; p < 0.001), rs10766197 (OR* = 6.92; p = 0.008) and rs12794714 (OR* = 5.09; p = 0.004). These three SNPs contributed in 18.8% in response variability with rs4588 being the most influential (10.3%). There was a significant linear negative correlation between baseline 25(OH)D and post supplementation 25(OH)D concentration (r = -0.437; p < 0.001) as well as a linear negative association between the increase in 25(OH)D concentration and GRS (GRS: genetic risk score = the sum of risk alleles) (r = -0.149; p = 0.033). CONCLUSIONS: DBP-rs4588, CYP2R1-rs10766197 and rs12794714 variants are associated with variations in serum 25(OH)D concentrations and efficacy of response to vitD supplementation in Tunisian adults. Taking into account these variations can help to better adapt vitD intake to ensure a higher response to supplementation.

Primary hyperoxaluria type 1: Clinical, genetic, and evolutionary characteristics in Tunisian children.

INTRODUCTION: There are three types of primary hyperoxaluria, with type 1 considered the most severe. AIM: To analyze the clinical, genetic, and evolutionary characteristics of type 1 primary hyperoxaluria with pediatric onset. METHODS: This was a retrospective, descriptive study that included Tunisian children under the age of 18 at the time of diagnosis over a period of 25 years (January 1, 1996, to December 31, 2022). RESULTS: Thirty-five patients were included, with a mean age of 4.1 years. The most common presenting circumstances of the disease were nephrolithiasis and end-stage renal failure. The average serum creatinine level was 225.42 µmol/l. Five mutations were identified, with the p.Ile244Thr mutation being the most prevalent. Nephrocalcinosis, surgical intervention, and a creatinine level ≥57 µmol/l were predictive of progression to end-stage renal failure. The infantile form was predictive of mortality. CONCLUSIONS: Screening for the disease would improve the prognosis of this condition.

Epidemiology of metabolic syndrome in Tunisia. HSHS 5 study.

OBJECTIVE: To measure the prevalence of metabolic syndrome and its components in the HSHS cohort (Hammam Sousse, Tunisia), in 2009, and to identify its determining factors. METHODS: This was a descriptive epidemiological study of the "community based" type having focused on a random sample of people aged 20 and over. The metabolic syndrome was defined according to the criteria of the "International Diabetes Federation" (IDF 2005) and those of the "National Cholesterol Education Program-Adult Treatment Panel III" (NCEP-ATP III, 2001). RESULTS: The study involved 1441 people including 960 women (66.6%). The age- and sex-adjusted prevalences of increased waist circumference, blood pressure, blood sugar and triglycerides, and decreased HDL-cholesterol were respectively 63.2%, 95%CI[62.5-63.8]; 47.7%, 95%CI[47.4-48.6]; 25.7%, 95%CI[25.1-26.2]; 11.9%, 95%CI[11.4-12.3] and 65,6%, 95%CI[65.0-66.2], according to IDF thresholds and 37.4%, 95%CI[36.3-37.6]; 45.7%, 95%CI[45.4-46.6]; 13.8%, 95%CI[13.4-14.2]; 8.4%, 95%CI[8.0-8.7] and 61.9%, 95%CI[61.2-62.5], according to those of the NCEP-ATP III. The prevalence of metabolic syndrome adjusted for age and sex was 36.5% 95%CI[33.0%-38.9%] according to the IDF definition and 23.0% 95%CI[20.4%-25.6%] according to that of NCEP-ATP III. The multivariate study by logistic regression made it possible to retain three significant independent determining factors of the metabolic syndrome: age ≥40 years, low level of physical activity and family history of diabetes mellitus with respectively adjusted ORs of 3.77 95%CI[2.70-5.27], 1.39 95%CI[1.01-1.89], 1.62 95%CI[1.21-2.15], according to IDF and 5.87 95%CI[3.88 -8.88], 1.47 95%CI[1.07-2.01] and 1.45 95%CI[1.07-1.96], according to NCEP-ATP III . CONCLUSION: With this high prevalence rate of the metabolic syndrome, the establishment of an action plan would be essential. This plan should be based on the combination of the promotion of physical activity and screening for the components of the metabolic syndrome, particularly in subjects aged 40 or over, with a family history of diabetes mellitus.

Epidemiology of obesity in Tunisia: HSHS4 study (Hammam Sousse Sahloul Heart Study).

INTRODUCTION: The HSHS study is a community-based survey focused on cardiovascular risk factors. AIM: The objectives of this specific analysis were to determine the prevalence of obesity and overweight in the general population of Hammam Sousse (Tunisia) and to identify their predisposing factors. METHODS: HSHS was conducted with a random sample of households, composed by the EPI (Expanded Program on Immunization) technique. All people aged 20 and over, met on the day of the survey, at their homes, were included. Obesity, overweight and weight overload were defined with reference to Body Mass Index (BMI): Obesity (BMI≥30 kg/m²), Overweight (25≤BMI (25≤BMI <30 kg/m²), weight overload (BMI≥25 kg/m²). Physical activity was evaluated according to the level of energy equivalents (Metabolic Equivalent Task) or MET, this level was considered low below 600 MET min/week. The calculated prevalences were accompanied by their 95%CI (Confidence Intervals). The multivariate study was conducted by logistic regression, measuring the adjusted Odds Ratio (ORa) Results: The study population was composed of 481 men and 960 women, (sex-ratio=0.50). The age ranged from 20 to 96 years with an average of 49.6±16444 years in men and 46.6±16.2 in women (p <0.05). After adjusting for age and sex, the prevalence rates of overweight, obesity, and weight overload were respectively 36.18%, 95%CI [35.38%-36.62%], 28.11%; 95%CI [27.42%-28.58%] and 64.28%; 95%CI [63.38%-64.62%]. Obesity was determined, in addition to female sex, age 40 or over and low level of education, by low level of physical activity (ORa=1.56; 95%CI [1.21-2.03], p<10-2). CONCLUSION: In adults, the prevalence of obesity and overweight were high and determined by insufficient physical activity. The results of this study, which can be extrapolated to other Tunisian cities, should motivate the general population to establish a heart health promotion plan, in partnership with civil society.

[Epidemiology of smoking in the male population in Tunisia. HSHS Study 6].

OBJECTIVES: To determine the prevalence of smoking in the male population of Hammam Sousse (Tunisia), to describe its modalities and to analyse its determining factors. METHODS: This was a "community-based" study, carried out on a random sample of households, including a population of males aged 20 or over. The data were collected, at home, using a specific support consisting of a lifestyle questionnaire, a physical examination, and a biological assessment, oriented towards cardiovascular risk factors. Smoking behaviour covered both forms of cigarettes and Narghile. "Current smokers" included all men declaring that they smoked at the time of the survey, including "regular smokers", who smoked daily at the time of the survey, and "occasional smokers", less than once a day. The group of "non-smokers" at the time of the survey was the sum of "ex-smokers" and those "who had never smoked". The prevalences were calculated after their weighting according to age and the adjusted odds ratios were measured following a multivariate study by logistic regression. RESULTS: The study population was composed of 481 men with an average age of 49.6±16.35 years and a median of 49 years. Mean body mass index and systolic blood pressure were 26.9 kg/m2 ±4.20 and 151.9 mmHg±24.36, respectively. After adjusting for age, the proportions of current users, former users and subjects who had never used tobacco (all forms combined) were respectively 50.4% (95% CI [49.49-51.3]), 17.4% (95% CI [16.71-18.08]) and 30.9% (95% CI [30.06-31.73]). Daily cigarette consumption was characterized by an average onset at age 20.1±6.91 years, an average duration of 27.0±15.22 years and an average amount of 17.6±9.8 cigarettes smoked per day. After adjusting for age, level of education, and socioeconomic level, smoking behaviour was attributed to a single independent risk factor: the presence of a smoker in the family, with an adjusted OR of 45.17 (p (p<10-3) for regular cigarette smokers, and 29.66 for regular tobacco users of all forms. CONCLUSION: Smoking would be a real endemic in Tunisia, threatening the cardiovascular health of the country. The national health system is called upon to strengthen its action plan for the prevention and control of smoking, in all living environments: family, school, work, health centre, etc.

Epidemiology of dyslipidemia in Tunisia, HSHS 3 study (Hammam Sousse Sahloul Heart Study).

INTRODUCTION: Dyslipidemia is a major cause of morbidity and mortality worldwide because it increases the risk of cardiovascular diseases. AIM: To determine the prevalence of dyslipidemia and its components in the general population of Hammam Sousse (Tunisia) and to identify its risk factors. METHODS: This was an analysis of the HSHS database (Hammam Sousse Sahloul Heart Study), a «community-based¼ cross-sectional study on cardiovascular risk factors including dyslipidemia, with a random sample in two-stages, proportional-probability clusters. All subjects above 20 years underwent a lifestyle interview, clinical examination with anthropometric measurements, and blood sampling. Dyslipidemia was defined by: total cholesterol ≥5.2 mmol/l, hyper LDL (Low Density Lipoprotein) cholesterolemia ≥4.1 mmol/l, hypo HDL (High Density Lipoprotein) cholesterolemia <1.03 mmol/l for men and <1.29 mmol/l for women and hyper-triglyceridaemia: ≥2.26 mmol/l. Multivariate logistic regression analysis was conducted to determine factors independently associated with dyslipidemia. RESULTS: The study population was composed of 481 males (M) and 960 females (F), with a sex ratio of 0.5. Mean cholesterol was higher in women (5 mmol/l±1.01) than in men (4.8 mmol/l±0.92). Only 24.9% of men and 29.1% of women had normal HDL cholesterol levels. Women had higher levels of hypercholesterolemia and LDL cholesterolemia than men (p<10-6). Multivariate analysis showed that dyslipidemia was independently and statistically significantly associated with age ≥40 years (p<10-3), physical inactivity (p<10-3) and obesity (p=0.025). CONCLUSION: As a result of the epidemiological situation of dyslipidemia, the promotion of an active lifestyle seems essential. In addition, nutritional education improves the lipid profile by promoting weight loss and balancing lipid consumption.

Novel sensitive immunosensor for the selective detection of Engrailed 2 urinary prostate cancer biomarker.

Engrailed 2 (EN2) is a homeodomain-containing transcription factor expressed in prostate cancer (PCa) cell lines and is secreted into the urines. It is nowadays considered as a promising non-invasive biomarker for PCa early diagnosis. Herein, we report the design of an electrochemical immunosensor for EN2 detection. The biosensor fabrication involved a covalent immobilization of anti-EN2 antibodies onto a poly para amino benzoic acid (PABA) film electropolymerized on a gold electrode. Square wave voltammetry was investigated for EN2 detection in a phosphate buffer solution in a concentration range of 10-5 ng/mL to 1 µg/mL. The limit of detection of the designed sensor was equal to 10-5 ng/mL and the sensitivity was of order of (29 ± 2) µL/ng. The dissociation constant Kd of the "complex" EN2/anti-EN2, estimated from a Hill model, was of order of (0.9 ± 0.2) fM. Experimental results revealed that the immunosensor enabled selective detection of EN2 in a mixture of three proteins which can be found in men' urine: human serum albumin (HSA), prostate-specific antigen (PSA) and immunoglobulin G (IgG). Tests in artificial urine, with an ionic strength of 0.18 M, have been done and results were found comparable to those obtained in PBS (0.16 M). These encouraging results show a potentially promising future for the development of an electrochemical biosensor for robust and accurate urinary biomarkers detection.

Epidemiology of diabetes mellitus in Tunisia. HSHS 2 study (Hammam Sousse Sahloul Heart Study).

BACKGROUND: National epidemiological studies on diabetes mellitus are rare, ancient and often carried out schools or clinics settings. OBJECTIVES: To determine the prevalence of diabetes mellitus and identify its risk factors in the adult population of the city of Hammam Sousse (Tunisia) during the year 2009. METHODS: This study is a part of analysis of the HSHS database (Hammam Sousse Sahloul Heart Study), a «community-based¼ cross-sectional study on cardiovascular risk factors including diabetes mellitus, with a two-stage proportional probability cluster random sample. All subjects aged 20 years and more underwent a lifestyle interview, clinical examination with anthropometric measurements, and blood sampling. The diagnosis of diabetes mellitus was defined by a fasting blood glucose level ≥7 mmol/l. Overweight was defined by a Body Mass Index (BMI) ≥ 25 kg/m². A multivariate logistic regression analysis was conducted to determine independent risk factors associated with diabetes mellitus. RESULTS: The population was composed of 481 males (M) and 960 females (F), a sex ratio of 0.5 with mean ages respectively of 49.6±16.35 years and 46.6±16.18 years. The prevalence of diabetes mellitus adjusted by age and sex was 12.1% (95%CI[11.7-12.5]); M: 12.7% (95%CI[12.1-13.3]), F: 11.5% (95%CI[10.9-12.1]). The prevalence rate of patients newly detected with diabetes mellitus was 1.9% (95%CI[1.7-2.1]): M: 1.8% (95%CI[1.6-2.0]), F: 2.1% (95%CI[1.8-2.4]). The multivariate study revealed five independent factors significantly associated with diabetes mellitus. In addition to non-modifiable factors (male gender, age ≥40 years old, low schooling level and family history of diabetes), diabetes mellitus was 2 (95%CI[1.3-3.2]) times more prevalent in overweight cases. CONCLUSION: In deep trouble of this epidemiological situation of diabetes mellitus, it is urgent to launch a universal intervention strategy based on the promotion of a healthy lifestyle motivating regular physical activity and a low-calorie diet.

Epidemiology of arterial hypertension in Tunisia: Hammam Sousse Sahloul Heart Study (HSHS).

INTRODUCTION: Tunisia is experiencing a double burden of morbidity, characterized by the explosion of cardiovascular diseases and their risk factors including arterial Hypertension. The objective of this study, based on the HSHS cohort (Hammam Sousse Sahloul Heart Study), was to determine the prevalence of hypertension in the general population and to identify its predisposing factors. METHODS: HSHS is a cardiovascular health promotion initiative in the city of Hammam Sousse (Tunisia). The study was conducted via a random sample of households, using the WHO PEV technique, made up of 33 clusters, of 33 households each. All people aged 20 and over, included, benefited from a questionnaire, a physical examination and a biological assessment. The Systolic Blood Pressure (SBP) and the Diastolic Blood Pressure (DBP) were measured from the average of the last two measurements, by an OMRON type tensiometer, of suitable width. These prevalences were adjusted according to sex and age group, by their weighting coefficients in the general population, and they were accompanied by their 95% CIs. Binary logistic regression was conducted to identify independent factors associated with hypertension. RESULTS: The study population was composed of 481 men (33.4%) and 960 women (66.6%), with an average age of 49.6±16.35 years in males (M) and 46.6±16.18 in females (F). In addition to the family history of hypertension, the sufficient weekly consumption of vegetables and fruits was low (M: 32.4%, F: 24.9%). The adjusted rate of hypertension in the adult study population was 32.5%, 95%CI[31.9-33.1] (M: 36.4%, 95%CI[35, 5-37.3]; F: 28.4%; 95% CI[27.6-29.2]), reaching in the age group of 60 years and above: M: 74.6% (95%CI[66.9-82.3], F: 82.7% (95%CI[73.8-83.6]) Multivariate analysis identified five independent factors significantly associated with hypertension: male sex (ORa=1.55 [1.18-2.03]), age over 40 years (ORa=6.54[4.70-9.11]), low level of schooling (ORa=1.80 [1.36-2.38]), low physical activity (ORa=1.42[1.07-1.88]) and high socio-economic level (ORa=1 .84 [1.30-2.63]). CONCLUSION: The HSHS study confirmed the high prevalence of hypertension, and the extent of its low detection and control. Hence the need for a universal approach to health promotion, oriented towards the general population, piloted by its local organizations, based on the adoption of a healthy lifestyle, and centered on physical activity.

The pharmacogenetics of mycophenolate mofetil in Tunisian renal transplant patients.

Aim: The effects of variants in IMPDH, UGT1A9, UGT1A8, UGT2B7 and SLCO1B1 genes on the efficacy and safety of mycophenolate mofetil (MMF) in the Tunisian population were investigated. Materials & methods: A total of 245 kidney transplant patients being treated with MMF were recruited and cotreated with cyclosporine or tacrolimus. Genotyping was performed using the polymerase chain reaction-restriction fragment length polymorphism method. MMF, cyclosporine and tacrolimus trough levels were measured by immunoassay. The AUC (AUC0-12hMPA) was estimated by a Bayesian method. Results: In the tacrolimus-treated group, anemia and diarrhea were associated with the UGT1A9-98C and UGT1A9-275T alleles, respectively (p < 0.05). In the cyclosporine-treated group, leukopenia was associated with the SLCO1B1-521T allele (p < 0.05). Both groups had an increased risk of rejection (p < 0.05) associated with the variant alleles of IMPDH2-3757T>C, UGT1A9-2152C>T and UGT1A9-275C>A and the common allele of SLCO1B1-388A>G. However, no significant association was found between the studied genotypes and AUC0-12hMPA or cotreatment levels. Conclusion: The results constitute preliminary evidence for the inclusion of the pharmacogenetics of MMF in kidney pretransplantation evaluations.

Epidemiology of elderly dependency in Tunisia. HSHS study 7.

AIM: Measure the functional autonomy of elderly people and identify its components and determinants in the HSHS (Hammam-Sousse Sahloul Heart Study) population (phase 2009, Tunisia). METHODS: This study was concerned with the quality of life of elderly people aged 65 years or more, living at home from the HSHS cohort divided into two groups: young-old (65-74 years old) and old-old (≥75 years old). The autonomy was assessed using the "Activities of Daily Living" (ADL) scale ranging from 0 to 6, the "Instrumental Activities of Daily Living" (IADL) scale ranging from 0 to 8 and, the combined scale ranging from zero to 14, iso-weighted at one point per activity. Autonomy in daily activities was retained for an ADL score=6, and an IADL score (F=8; H=5). Subjects with an overall score (sum of ADL and IADL) of 10-14 points were considered globally autonomous. RESULTS: The population study was predominantly female (sex-ratio=0,6) with an important proportion of old-old (M=43%, F=37%). Autonomy rates were by ADL (M=57.4%, F=36.1%, p < 10-2), IADL (M=16%, F=23.9%), and by combined score (M=60.6%, F=69%, p=NS). The typology of dependency was dominated by transferring (M=35%, F=61%) and bathing (M=14%, F=19%) for ADL activities, and shopping (M=36%, F=49%) and the use of means of transport (M=22%, F=43%) for IADL activities. After adjustment, autonomy in daily activities was attributed to two independent factors: male sex (ORa=3.98, CI95% [1.328-11.971]) and age group 65-75 (ORa=4.04, CI95% [2.039- 8.025]). Autonomy in instrumental activities was associated with age group (ORa=31.5, CI95% [4.087-233.514]). Finally, overall autonomy (current and instrumental) was associated independently after logistic regression, with four independent factors, two of which were not modifiable: being female (ORa=3.1, CI95% [1.2-8.1]) and 65 to 75 years (ORa=6.2, CI95% [3.1-12.3]) and two modifiable factors: no recent hospitalization (ORa=3.8, CI95% [1.4-10.4]) and a sufficient level of physical activity (ORa=2.6, CI95% [1.3-5.3]). CONCLUSION: The physical dependency rate of the elderly is very high in Tunisia. The promotion of physical activity, the extension of similar studies and the development of could improve the support of these people.

Sedentary behavior, exercise and COVID-19: immune and metabolic implications in obesity and its comorbidities.

Many reports showed a dramatic decrease in the levels of physical activity during the current pandemic of SARS-CoV-2. This has substantial immune and metabolic implications, especially in those at risk or with metabolic diseases including individuals with obesity and Type 2 diabetes. In this study we discussed the route from physical inactivity to immune and metabolic aberrancies; focusing on how insulin resistance could represent an adaptive mechanism to the low physical activity levels and on how such an adaptive mechanism could shift to a pathognomonic feature of metabolic diseases, creating a vicious circle of immune and metabolic aberrancies. We provide a theoretical framework to the severe immunopathology of COVID-19 in patients with metabolic diseases. We finally discuss the idea of exercise as a potential adjuvant against COVID-19 and emphasize how even interrupting prolonged periods of sitting with short time breaks of very light activity could be a feasible strategy to limit the deleterious effects of the outbreak.

Saliva diagnostic utility in patients with type 2 diabetes: Future standard method.

BACKGROUND: The purpose of the present study was to assess saliva reliability in diagnosis and monitoring type 2 diabetes instead of blood. METHODS: Blood and unstimulated whole saliva were collected from 300 type 2 diabetic subjects and 300 healthy controls in fasting. Then, the salivary flow rate was calculated. All parameters including glucose, urea, amylase, total protein, albumin, C-reactive protein (CRP), immunoglobulin A (IgA), potassium, calcium and chloride were assessed in the supernatant, using an autoanalyzer. Oral exam was conducted by a single examiner on full mouth excluding third molars. Statistical analysis was performed by the SPSS 20.0 version. RESULTS: Saliva screening showed that glucose, urea, amylase, total protein, potassium, calcium and chloride were significantly higher in patients compared to controls (p < 0.05). Whereas, the IgA level and salivary flow rate were significantly reduced in patients (p < 0.05). No significant difference was found in albumin and CRP levels (p > 0.05). There was a significant positive correlation between salivary and plasma glucose levels (r = 0.887, and r = 0.900, p < 0.001), as well as, salivary and blood urea (r = 0.586, and r = 0.688, p < 0.001) in patients and controls, respectively. CONCLUSIONS: From this study, saliva could be suggested as a useful diagnostic tool for type 2 diabetes.

Investigation of carbonic anhydrase 6 gene polymorphism rs2274327 in relation to the oral health status and salivary composition in type 2 diabetic patients.

OBJECTIVE: The aim of the present study was to investigate the oral manifestations and salivary composition in type 2 diabetics with periodontitis and to evaluate their association with CA6 gene polymorphism rs2274327. METHODS: Oral examination was performed by a single periodontist for 300 type 2 diabetics. Whole unstimulated saliva and blood were collected. The salivary pH, buffer capacity and flow rate were later measured. Immunoglobulin A and electrolytes were assessed using an autoanalyzer. CA6 gene polymorphism rs2274327 was screened by PCR-RFLP assay. The statistical analysis was performed using the SPSS 20.0 version. RESULTS: The salivary pH, buffer capacity and flow rate were significantly lower in the patients carrying TT genotype compared to CC and CT genotype carriers (p < .05). Furthermore, the DMFT index, OHI-s, PI, PPD and CAL were significantly higher in the subjects with TT genotype (p < .05). Carrying at least one T allele seemed to increase the risk of dental caries (OR = 2.59, p < .001), xerostomia (OR = 2.11, p=.003) and taste impairment (OR = 1.97, p < .05). CONCLUSION: CA6 gene polymorphism rs2274327 seemed to increase the risk of developing, dental caries, periodontitis, xerostomia and taste impairment in type 2 diabetics.

Computational approach and electrochemical measurements for protein detection with MIP-based sensor.

Rapid and accurate detection of proteins in biological fluids is increasingly required in the biomedical environment. Actually, it is performed with conventional techniques, which are generally run by robotized platforms at centralized laboratories. In this work, molecular dynamics calculations and an experimental procedure were conducted to set up electrochemical sensors based on polypyrrol (PPy) molecular imprinted polymers (MIP) for proteins detection. Here, prostate-specific antigen (PSA) was selected as a template model. Computational calculations indicate that for any PPy conformation and any amino-acid location in the protein, PSA molecules remain strongly inserted in the PPy polymer without biological alterations. One from possible orientations, appeared to be most probable as it presents the lowest absorption energy (-363 kcal mol-1) and largest contact area (4034.1 Å2). The device was then elaborated by in situ electropolymerization of PPy films. MIP's thickness and extraction duration were optimized by chronoamperometry. Square wave voltammetry technique was investigated for PSA detection in standard solution in the concentration range of 3x10 -8 ng.ml-1- 300 ng ml-1. According to the Hill equation, the equilibrium dissociation constant Kdbetween PSA and its imprint was estimated at Kd = (1.02 ±â€¯0.54) × 10-14 M, confirming the strong binding between the designed MIP and the protein as predicted by the computational study. PSA concentration values directly measured in 35 human serum samples were found closely correlated to those measured by the ELISA technique. The promising fast and low-cost sensor might be used successfully for proteins detection at low concentrations with high selectivity and reproducibility.