Coprevalence and associations of diabetes mellitus and hypertension among people living with HIV/AIDS in Cameroon.

BACKGROUND: The association between HIV infection and increased cardiometabolic risk, attributed to chronic inflammation in people living with HIV (PLWH) and/or antiretroviral therapy (ART) effects, has been inconsistent. In this study, we aimed to assess the associations of HIV-related factors with hypertension (HTN) and type-2 diabetes mellitus (T2DM), and the potential mediation effects of body mass index (BMI) in the associations between ART use and HTN or T2DM in PLWH in Cameroon. METHODS: A cross-sectional study was conducted with 14,119 adult PLWH from Cameroon enrolled in the International epidemiology Databases to Evaluate AIDS (IeDEA) between 2016 and 2021. HTN was defined as systolic/diastolic blood pressure ≥ 140/90 mmHg and/or current use of antihypertensive medication, while T2DM was defined as fasting blood sugar ≥ 126 mg/dL and/or use of antidiabetic medications. Univariable and multivariable multinomial logistic regression analyses examined the associations of factors with HTN alone, T2DM alone, and both (HTN + T2DM). Mediation analyses were conducted to assess the potential mediation roles of BMI, while controlling for age, sex, and smoking. RESULTS: Of the 14,119 participants, 9177 (65%) were women, with a median age of 42 (25th-75th percentiles: 35-51) years. Age > 50 years was associated with HTN alone, T2DM alone, and HTN + T2DM compared to the age group 19-29 years. Men had higher odds of having HTN + T2DM. Overweight and obesity were predictors of HTN alone compared to being underweight. WHO stages II and III HIV disease were inversely associated with HTN alone compared to stage I. The odds of diabetes alone were lower with ART use. BMI partially mediated the association between ART use and hypertension, with a proportion of mediation effect of 49.6% (all p < 0.02). However, BMI did not mediate the relationship between ART use and diabetes. CONCLUSIONS: Traditional cardiovascular risk factors were strongly associated with hypertension among PLWH, while HIV-related exposures had smaller associations. BMI partially mediated the association between ART use and hypertension. This study emphasizes the importance of screening, monitoring, and managing HTN and T2DM in older, male, and overweight/obese PLWH. Further research on the associations of HIV disease stage and ART use with HTN and T2DM is warranted.

Prevalence and associations of chronic kidney disease among antiretroviral therapy-naïve persons living with HIV in Lagos, Nigeria.

BACKGROUND: Chronic kidney disease (CKD) affects almost 10% of the global populace including people living with HIV (PLWH). PLWH acquire CKD from both traditional and HIV-specific CKD risk factors. This study aimed to determine the prevalence of CKD and associated factors among antiretroviral therapy (ART) naïve PLWH in Lagos, Nigeria.  METHODS: This is a secondary data analysis among adult (≥ 18 years) ART-naïve PLWH enrolled at a large ART clinic in Lagos over 6 years. CKD was defined as estimated glomerular filtration rates (eGFR) below 60ml/min/1.73m2 over 3 months. Three estimators [Body surface area corrected Cockcroft Gault (BSA-CG), Modification of Diet in Renal Disease (MDRD), Chronic kidney disease Epidemiology Collaboration (CKD-EPI)] were used to determine the burden of CKD with no race correction factor. Age- and sex-standardised prevalence rates were determined. Cohen Kappa and Spearman correlations were used to compare the estimators. Logistic regressions were applied to identify variables associated with prevalent CKD. RESULTS: Among 2 772 PLWH, the mean age was 38 years with males older than females (p < 0.001). The majority of participants were females (62.1%), married (54.8%), employed (85.7%), had underweight or normal body mass index (BMI) (62.2%), and were diagnosed with World Health Organization (WHO) clinical stages 1 and 2 (55.5%). The age- and sex-standardised prevalence of CKD ranged from 10.0 - 17.6% with the highest Spearman's correlation (0.928) observed with MDRD and CKD-EPI equations. Increasing age [AOR (95% CI), equation] was significantly associated with CKD across all equations [1.09 (1.06 - 1.13), BSA-CG; 1.07 (1.05 - 1.10), MDRD; 1.09 (1.06 -1.12), CKD-EPI]. Other variables associated with CKD [AOR (95% CI), equation] were anaemia [2.50 (1.34 - 4.68), BSA-CG; 1.73 (1.04 - 2.86), MDRD], BMI <25 kg/m2 [3.35 (1.55 - 7.26), BSA-CG; 2.02 (1.18 - 3.46), CKD-EPI], and CD4 counts ≤ 200 cells/µL [2.02 (1.06 - 3.87), BSA-CG]. CONCLUSION: There was a high prevalence of CKD among ART-naïve PLWH at enrollment, which highlights the need to evaluate this population for CKD. Aside increasing age and low CD4 counts, none of the traditional or HIV-specific risk factors were related to CKD diagnosis.

Social determinants of health and diabetes self-care management in South Africa.

OBJECTIVE: Diabetes is an incapacitating condition affecting millions of people in South Africa. Maintaining optimal glycaemic control is crucial in preventing diabetes complications, highlighting the importance of diabetes self-care. This study examined how Social Determinants of Health (SDoH) are associated with self-care management practices in individuals with diabetes in South Africa using the framework developed by the Healthy People 2020 initiative. METHODS: This study utilised cross-sectional Project Mind baseline data collected in 2017. Self-care management was coded on a scale from '0' (never) to '7' (daily adherence). For analysis, this scale was dichotomised into two categories: low self-care (scores 0-5) and high self-care (scores 6-7). Furthermore, adherence with these daily self-care activities was categorised into three levels: no adherence, partial adherence (inconsistent or partial adherence to activities), and full adherence (consistent adherence to all self-care activities). RESULTS: The analytical sample (n = 539) was predominantly female (76%), with a mean age of 54 years, urban residents (60%), unemployed (70%), and attained secondary education (11.3%). In determining the attainment of a higher scale of self-care, age (AOR = 1.02, CI=[0.99,1.05]) and secondary education (AOR = 1.13, CI=[1.02, 2.03]) were associated with an increase in the scale of self-care. Conversely, urban residency (AOR = 0.50, CI=[0.29,0.88]) and being obese (AOR = 0.43, CI=[0.19,1.00]) were associated with a lower scale of self-care. Although not statistically robust, food insecurity decreased while being a woman and having a stable house showed an increased association. Travelling longer distances to access healthcare was positively associated with no adherence, and urban residency has a negative association with full adherence relative to partial adherence. CONCLUSIONS: The associations between SDoH and diabetes self-care management within a South African context highlight the need for a more holistic understanding and approach to interventions. Future endeavours should examine these determinants more broadly and formulate integrative strategies to ameliorate diabetes self-care.

Targeted proteomics identifies potential biomarkers of dysglycaemia, beta cell function and insulin sensitivity in Black African men and women.

AIMS/HYPOTHESIS: Using a targeted proteomics approach, we aimed to identify and validate circulating proteins associated with impaired glucose metabolism (IGM) and type 2 diabetes in a Black South African cohort. In addition, we assessed sex-specific associations between the validated proteins and pathophysiological pathways of type 2 diabetes. METHODS: This cross-sectional study included Black South African men (n=380) and women (n=375) who were part of the Middle-Aged Soweto Cohort (MASC). Dual-energy x-ray absorptiometry was used to determine fat mass and visceral adipose tissue, and fasting venous blood samples were collected for analysis of glucose, insulin and C-peptide and for targeted proteomics, measuring a total of 184 pre-selected protein biomarkers. An OGTT was performed on participants without diabetes, and peripheral insulin sensitivity (Matsuda index), HOMA-IR, basal insulin clearance, insulin secretion (C-peptide index) and beta cell function (disposition index) were estimated. Participants were classified as having normal glucose tolerance (NGT; n=546), IGM (n=116) or type 2 diabetes (n=93). Proteins associated with dysglycaemia (IGM or type 2 diabetes) in the MASC were validated in the Swedish EpiHealth cohort (NGT, n=1706; impaired fasting glucose, n=550; type 2 diabetes, n=210). RESULTS: We identified 73 proteins associated with dysglycaemia in the MASC, of which 34 were validated in the EpiHealth cohort. Among these validated proteins, 11 were associated with various measures of insulin dynamics, with the largest number of proteins being associated with HOMA-IR. In sex-specific analyses, IGF-binding protein 2 (IGFBP2) was associated with lower HOMA-IR in women (coefficient -0.35; 95% CI -0.44, -0.25) and men (coefficient -0.09; 95% CI -0.15, -0.03). Metalloproteinase inhibitor 4 (TIMP4) was associated with higher insulin secretion (coefficient 0.05; 95% CI 0.001, 0.11; p for interaction=0.025) and beta cell function (coefficient 0.06; 95% CI 0.02, 0.09; p for interaction=0.013) in women only. In contrast, a stronger positive association between IGFBP2 and insulin sensitivity determined using an OGTT (coefficient 0.38; 95% CI 0.27, 0.49) was observed in men (p for interaction=0.004). A posteriori analysis showed that the associations between TIMP4 and insulin dynamics were not mediated by adiposity. In contrast, most of the associations between IGFBP2 and insulin dynamics, except for insulin secretion, were mediated by either fat mass index or visceral adipose tissue in men and women. Fat mass index was the strongest mediator between IGFBP2 and insulin sensitivity (total effect mediated 40.7%; 95% CI 37.0, 43.6) and IGFBP2 and HOMA-IR (total effect mediated 39.1%; 95% CI 31.1, 43.5) in men. CONCLUSIONS/INTERPRETATION: We validated 34 proteins that were associated with type 2 diabetes, of which 11 were associated with measures of type 2 diabetes pathophysiology such as peripheral insulin sensitivity and beta cell function. This study highlights biomarkers that are similar between cohorts of different ancestry, with different lifestyles and sociodemographic profiles. The African-specific biomarkers identified require validation in African cohorts to identify risk markers and increase our understanding of the pathophysiology of type 2 diabetes in African populations.

Population pharmacokinetic modelling to characterize the effect of chronic kidney disease on tenofovir exposure after tenofovir alafenamide administration.

BACKGROUND: Tenofovir alafenamide is gradually replacing tenofovir disoproxil fumarate, both prodrugs of tenofovir, in HIV prevention and treatment. There is thus an interest in describing tenofovir pharmacokinetics (PK) and its variability in people living with HIV (PLWH) under tenofovir alafenamide in a real-life setting. OBJECTIVES: To characterize the usual range of tenofovir exposure in PLWH receiving tenofovir alafenamide, while assessing the impact of chronic kidney disease (CKD). METHODS: We conducted a population PK analysis (NONMEM®) on 877 tenofovir and 100 tenofovir alafenamide concentrations measured in 569 PLWH. Model-based simulations allowed prediction of tenofovir trough concentrations (Cmin) in patients having various levels of renal function. RESULTS: Tenofovir PK was best described using a one-compartment model with linear absorption and elimination. Creatinine clearance (CLCR, estimated according to Cockcroft and Gault), age, ethnicity and potent P-glycoprotein inhibitors were statistically significantly associated with tenofovir clearance. However, only CLCR appeared clinically relevant. Model-based simulations revealed 294% and 515% increases of median tenofovir Cmin in patients with CLCR of 15-29 mL/min (CKD stage 3), and less than 15 mL/min (stage 4), respectively, compared with normal renal function (CLCR = 90-149 mL/min). Conversely, patients with augmented renal function (CLCR > 149 mL/min) had a 36% decrease of median tenofovir Cmin. CONCLUSIONS: Kidney function markedly affects circulating tenofovir exposure after tenofovir alafenamide administration in PLWH. However, considering its rapid uptake into target cells, we suggest only a cautious increase of tenofovir alafenamide dosage intervals to 2 or 3 days only in case of moderate or severe CKD, respectively.

Dosing strategies of imipenem in neonates based on pharmacometric modelling and simulation.

OBJECTIVES: Imipenem is a broad-spectrum antibacterial agent used in critically ill neonates after failure of first-line treatments. Few studies have described imipenem disposition in this population. The objectives of our study were: (i) to characterize imipenem population pharmacokinetics (PK) in a cohort of neonates; and (ii) to conduct model-based simulations to evaluate the performance of six different dosing regimens aiming at optimizing PK target attainment. METHODS: A total of 173 plasma samples from 82 neonates were collected over 15 years at the Lausanne University Hospital, Switzerland. The majority of study subjects were preterm neonates with a median gestational age (GA) of 27 weeks (range: 24-41), a postnatal age (PNA) of 21 days (2-153) and a body weight (BW) of 1.16 kg (0.5-4.1). PK data were analysed using non-linear mixed-effect modelling (NONMEM). RESULTS: A one-compartment model best characterized imipenem disposition. Population PK parameters estimates of CL and volume of distribution were 0.21 L/h and 0.73 L, with an interpatient variability (CV%) of 20.1% on CL in a representative neonate (GA 27 weeks, PNA 21 days, BW 1.16 kg, serum creatinine, SCr 46.6 µmol/L). GA and PNA exhibited the greatest impact on PK parameters, followed by SCr. These covariates explained 36% and 15% of interindividual variability in CL, respectively.Simulated regimens using a dose of 20-25 mg/kg every 6-12 h according to postnatal age led to the highest PTA (T>MIC over 100% of time). CONCLUSIONS: Dosing adjustment according to BW, GA and PNA optimizes imipenem exposure in neonates.

Waist circumference thresholds predicting incident dysglycaemia and type 2 diabetes in Black African men and women.

AIMS: To determine the waist circumference (WC) thresholds for the prediction of incident dysglycaemia and type 2 diabetes (T2D) in Black South African (SA) men and women and to compare these to the advocated International Diabetes Federation (IDF) Europid thresholds. MATERIALS AND METHODS: In this prospective study, Black SA men (n = 502) and women (n = 527) from the Middle-aged Sowetan Cohort study who had normal or impaired fasting glucose at baseline (2011-2015) were followed up until 2017 to 2018. Baseline measurements included anthropometry, blood pressure and fasting glucose, HDL cholesterol and triglyceride concentrations. At follow-up, glucose tolerance was assessed using an oral glucose tolerance test. The Youden index was used to determine the optimal threshold of WC to predict incident dysglycaemia and T2D. RESULTS: In men, the optimal WC threshold was 96.8 cm for both dysglycaemia and T2D (sensitivity: 56% and 70%; specificity: 74% and 70%, respectively), and had higher specificity (P < 0.001) than the IDF threshold of 94 cm. In women, the optimal WC threshold for incident dysglycaemia was 91.8 cm (sensitivity 86%, specificity 37%) and for T2D it was 95.8 cm (sensitivity 85%, specificity 45%), which had lower sensitivity, but higher specificity to predict incident dysglycaemia and T2D than the IDF threshold of 80 cm (sensitivity: 97% and 100%; specificity: 12% and 11%, respectively)). CONCLUSIONS: We show for the first time using prospective cohort data from Africa that the IDF Europid WC thresholds are not appropriate for an African population, and show that African-specific WC thresholds perform better than the IDF Europid thresholds to predict incident dysglycaemia and T2D.

Valproate in status epilepticus: Correlation between loading dose, serum levels, and clinical response.

BACKGROUND AND PURPOSE: Intravenous valproate (VPA) is an established treatment of status epilepticus (SE), but optimal loading dose was not fully assessed. We aimed at analyzing the correlation between VPA loading dose and subsequent plasma levels with clinical response in SE. METHODS: This was a retrospective study in one referral center of all consecutive VPA-naïve SE episodes treated with VPA between January 2013 and June 2019, in which total VPA trough plasma levels after intravenous loading dose were available. Response to VPA, defined as last antiseizure medication introduced before SE resolution (without the need for additional treatment), was correlated with VPA loading dose and trough level. Correlations were adjusted for other SE characteristics. RESULTS: Among 128 SE episodes, 53 (41%) responded to VPA. Median VPA loading dose was 25.2 mg/kg (range, 7-58 mg/kg). Loading doses and total plasma levels were not associated with the probability of response or mortality. Correcting for other possible confounders (number of previously tried treatment, demographics, SE severity) did not alter these findings. Only 3.8% of SE episodes that responded to VPA received >30 mg/kg. CONCLUSIONS: A high loading dose (>30 mg/kg) is not associated with a greater response rate in patients with SE. Therefore, it seems to bring little benefit. If confirmed in further studies, a dosage of 25-30 mg/kg appears adequate in SE.

Treatment-emergent adverse events and antiseizure medication actual drug load.

OBJECTIVE: The correlation between treatment-emergent adverse events (TEAE) and antiseizure medication (ASM) drug load is a controversial topic. Previous studies used daily defined dosage (DDD) to measure drug load. We aim to assess if ASM adjusted to body weight and plasma levels were associated with TEAE. METHODS: We analyzed clinical visits of a trial on therapeutic drug monitoring in outpatients with epilepsy. TEAE, treatment, and its changes, as well as ASM plasma levels, were recorded at each visit. Each medication level was stratified according to its position in relation to its proposed reference range (below, in the lower half, upper half, or above). RESULTS: We analyzed 424 visits (151 participants). Treatment-emergent adverse events were reported in 84 (20%) visits. There was no significant difference when comparing visits with TEAE with those without TEAE in terms of ASM drug load (calculated with DDD), corrected for body weight, their changes since the last visit, as well as summed plasma levels compared to reference ranges. SIGNIFICANCE: Actual drug load seems not to represent a major determinant of TEAE recorded during routine visits, even when accounting thoroughly for the patient's exposure to the treatment. The use of structured questionnaires and neuropsychometric tests may assess more accurately the potential consequences of drug loads.

Iodine deficiency in pregnancy along a concentration gradient is associated with increased severity of preeclampsia in rural Eastern Cape, South Africa.

BACKGROUND: Preeclampsia is a leading cause of maternal mortality and morbidity in South Africa. Iodine deficiency in pregnancy, which is amenable to correction through iodine supplementation, has been reported to increase the risk of preeclampsia. However, the association of iodine nutrition status with preeclampsia in South Africa has not been studied. METHODS: We enrolled 51 randomly selected normotensive pregnant controls at term together with 51 consecutively selected cases of preeclampsia and 51 cases of severe preeclampsia/eclampsia, all in the third trimester, from Mthatha Regional and Nelson Mandela Academic Hospital in the Eastern Cape Province. Urinary iodine concentration (UIC), serum thyroid-stimulating hormone (TSH), triiodothyronine (FT3), thyroxine (FT4) and thyroglobulin (Tg) levels were compared between cases and controls. RESULTS: The respective chronological and gestational ages at enrolment for normotensive, preeclampsia and severe preeclampsia/eclampsia participants were: age 23, 24 and 19 years (p = 0.001), and gestational age 38, 34, and 35 weeks (p < 0.001). The median gravidity was 1 for all three groups. The median UIC, FT4, FT3 revealed a decreasing and Tg a rising trend with the severity of preeclampsia (p < 0.05). TSH had a non-significant rising trend (p > 0.05). The respective median values for normotensive, preeclampsia and severe preeclampsia/eclampsia participants were UIC 217.1, 127.7, and 98.8 µg/L; FT4 14.2, 13.7, and 12. pmol/L; FT3 4.8, 4.4, and 4.0 pmol//L; Tg 19.4, 21.4, and 32. Nine microgram per liter; TSH 2.3, 2.3, and 2.5 mIU/L. UIC < 100 µg/L, Tg > 16 µg/L and FT4 < 11.3 pmol/L were independent predictors of preeclampsia/eclampsia syndrome. CONCLUSION: Women with severe preeclampsia/eclampsia had significantly low UIC and high Tg, suggesting protracted inadequate iodine intake. Inadequate iodine intake during pregnancy severe enough to cause elevated Tg and FT4 deficiency was associated with an increased risk of severe preeclampsia/eclampsia.

An innovative approach in monitoring oral cholera vaccination campaign: integration of a between-round survey.

BACKGROUND: Monitoring and Evaluation (M&E) is essential in ensuring population's access to immunization. Surveys are part of this M&E approach but its timing limits the use of its results to improve the coverage of the evaluated campaign. An oral cholera vaccination campaign was organized in a health district of the Far North region of Cameroon and involved an innovative M&E approach. The aim of this project was to assess the feasibility and effect of using recommendations of a community-based immunization and communication coverage survey conducted after the first round of an OCV campaign on the coverage of the second-round of the campaign. METHODS: Two community-based surveys were included in the M&E plan and conducted at the end of each of the campaign rounds. Data were collected by trained and closely supervised surveyors and reported using smartphones. Key results of the first-round survey were disseminated to campaign implementing team prior to the second round. The two rounds of the pre-emptive campaign were organized by the Cameroon Ministry of Public Health and partners with a two-week interval in the Mogode Health District of the Far North region of Cameroon in May and June 2017. RESULTS: Of 120 targeted clusters, 119 (99.1%) and 117 (97.5%) were reached for the first and second rounds respectively. Among the Mogode population eligible for vaccination, the immunization coverage based on evidence (card or finger mark) were estimated at 81.0% in the first round and increased to 88.8% in the second round (X2=69.0 and p <0.00). For the second round, we estimated 80.1% and 4.3% of persons who were administered 2 doses and 1 dose of OCV with evidence respectively, and 3.8% of persons who have not been vaccinated. The distribution of campaign communication coverage per health area was shared with the campaign coordination team for better planning of the second round campaign activities. CONCLUSIONS: It is feasible to plan and implement coverage survey after first round OCV campaign and use its results for the better planning of the second round. For the present study, this is associated to the improvement of OCV coverage in the second-round vaccination. If this is persistent in other contexts, it may apply to improve coverage of any health campaign that is organized in more than one round.

[Metabolism and therapeutic monitoring of azathioprine in gastroenterology and hepatology]. / Métabolisme et suivi thérapeutique de l'azathioprine en gastroentérologie et hépatologie.

Azathioprine keeps an important place in the treatment of inflammatory bowel disease and autoimmune hepatitis. This molecule has a narrow therapeutic margin, associated with a risk of toxicity, particularly hematological and hepatic. Its complex metabolism is subject to genetic polymorphisms that are reflected in the inter-individual variability observed in the response to treatment and its tolerance profile. Hence, its use requires a good knowledge of this molecule. Treatment is initiated after a preliminary workup, followed by a progressive titration of the dosage while closely monitoring possible toxicities. Monitoring of blood levels of metabolites (including active ones) helps guide personalized dose adjustment.

L'azathioprine garde actuellement une place importante dans le traitement des maladies inflammatoires chroniques de l'intestin et de l'hépatite autoimmune. Il s'agit d'une molécule à marge thérapeutique étroite, associée à un risque de toxicité, notamment hématologique et hépatique. Son métabolisme complexe est influencé par des polymorphismes génétiques qui sont reflétés dans la variabilité interindividuelle observée dans la réponse au traitement et le profil de tolérance. Son utilisation nécessite donc une bonne connaissance de cette molécule. L'instauration du traitement se fait après un bilan préalable, puis une titration progressive des posologies, tout en surveillant étroitement les éventuelles toxicités. Le monitoring des concentrations sanguines des métabolites (notamment actifs) permet de guider l'adaptation personnalisée des posologies.

Global, Regional, and National Burden of Calcific Aortic Valve and Degenerative Mitral Valve Diseases, 1990-2017.

BACKGROUND: Nonrheumatic valvular diseases are common; however, no studies have estimated their global or national burden. As part of the Global Burden of Disease Study 2017, mortality, prevalence, and disability-adjusted life-years (DALYs) for calcific aortic valve disease (CAVD), degenerative mitral valve disease, and other nonrheumatic valvular diseases were estimated for 195 countries and territories from 1990 to 2017. METHODS: Vital registration data, epidemiologic survey data, and administrative hospital data were used to estimate disease burden using the Global Burden of Disease Study modeling framework, which ensures comparability across locations. Geospatial statistical methods were used to estimate disease for all countries, because data on nonrheumatic valvular diseases are extremely limited for some regions of the world, such as Sub-Saharan Africa and South Asia. Results accounted for estimated level of disease severity as well as the estimated availability of valve repair or replacement procedures. DALYs and other measures of health-related burden were generated for both sexes and each 5-year age group, location, and year from 1990 to 2017. RESULTS: Globally, CAVD and degenerative mitral valve disease caused 102 700 (95% uncertainty interval [UI], 82 700-107 900) and 35 700 (95% UI, 30 500-42 500) deaths, and 12.6 million (95% UI, 11.4 million-13.8 million) and 18.1 million (95% UI, 17.6 million-18.6 million) prevalent cases existed in 2017, respectively. A total of 2.5 million (95% UI, 2.3 million-2.8 million) DALYs were estimated as caused by nonrheumatic valvular diseases globally, representing 0.10% (95% UI, 0.09%-0.11%) of total lost health from all diseases in 2017. The number of DALYs increased for CAVD and degenerative mitral valve disease between 1990 and 2017 by 101% (95% UI, 79%-117%) and 35% (95% UI, 23%-47%), respectively. There is significant geographic variation in the prevalence, mortality rate, and overall burden of these diseases, with highest age-standardized DALY rates of CAVD estimated for high-income countries. CONCLUSIONS: These global and national estimates demonstrate that CAVD and degenerative mitral valve disease are important causes of disease burden among older adults. Efforts to clarify modifiable risk factors and improve access to valve interventions are necessary if progress is to be made toward reducing, and eventually eliminating, the burden of these highly treatable diseases.

The case for early identification and intervention of chronic kidney disease: conclusions from a Kidney Disease: Improving Global Outcomes (KDIGO) Controversies Conference.

Chronic kidney disease (CKD) causes substantial global morbidity and increases cardiovascular and all-cause mortality. Unlike other chronic diseases with established strategies for screening, there has been no consensus on whether health systems and governments should prioritize early identification and intervention for CKD. Guidelines on evaluating and managing early CKD are available but have not been universally adopted in the absence of incentives or quality measures for prioritizing CKD care. The burden of CKD falls disproportionately upon persons with lower socioeconomic status, who have a higher prevalence of CKD, limited access to treatment, and poorer outcomes. Therefore, identifying and treating CKD at the earliest stages is an equity imperative. In 2019, Kidney Disease: Improving Global Outcomes (KDIGO) held a controversies conference entitled "Early Identification and Intervention in CKD." Participants identified strategies for screening, risk stratification, and treatment for early CKD and the key health system and economic factors for implementing these processes. A consensus emerged that CKD screening coupled with risk stratification and treatment should be implemented immediately for high-risk persons and that this should ideally occur in primary or community care settings with tailoring to the local context.

Atrial thrombus detection on transoesophageal echocardiography in patients with atrial fibrillation undergoing cardioversion or catheter ablation: A pooled analysis of rates and predictors.

OBJECTIVE: To summarize data on the rates and predictors of left atrial thrombus/left atrial appendage thrombus (LAT/LAAT) detection by transoesophageal echocardiography (TEE) before electrical cardioversion (ECV) or catheter ablation (CA) for atrial fibrillation (AF). METHODS: EMBASE, MEDLINE, and Web of Science Core Collection were searched to identify all studies providing relevant data and published by October 7, 2020. A random-effects meta-analysis method was used to pool effect size estimates. RESULTS: A total of 85 studies were included, reporting data from 56 660 patients with AF. In patients undergoing CA and ECV, the pooled prevalence of LAT/LAAT was 1.8% and 7.5% in those not on oral anticoagulation (OAC), 1.8% and 5.5% in those taking OAC, and 1.3% and 4.9% in case of adequate OAC, respectively. According to the type of OAC, the prevalence was 2.0% and 7.6% for vitamin K antagonist, 1.3% and 3.5% for direct oral anticoagulant. Predictors of LAT/LAAT detection were nonparoxysmal AF (odds ratio [OR]: 3.6, 95% confidence interval: 2.4-5.2), hypertension (OR: 2.9, 1.2-7.0), previous stroke (OR: 3.0, 1.6-5.63), heart failure (OR: 4.3, 2.7-6.8), and CHADS2 score ≥2 (OR: 3.3, 1.9-5.8) for patients undergoing CA; and heart failure (OR: 2.8, 1.3-6.2) and the CHA2 DS2 -VASc score (OR: 2.55, 1.5-4.5) for those undergoing ECV. CONCLUSION: The prevalence of LAT/LAAT in AF patients undergoing ECV or CA varies widely, mainly due to differences in patient risk profiles and OAC types. Further research should determine whether the predictors of LAT/LAAT detection identified by this study could be used to select patients who require preprocedural TEE.

Therapeutic Drug Monitoring of Newer Antiepileptic Drugs: A Randomized Trial for Dosage Adjustment.

OBJECTIVE: Therapeutic drug monitoring (TDM) of antiepileptic drugs (AEDs) is widely established for older generation AEDs, whereas there is limited evidence about newer AEDs. Our aim is to assess the benefit of TDM of newer generation AEDs in epilepsy. METHODS: We performed a randomized, controlled trial comparing systematic with rescue TDM of lamotrigine, levetiracetam, oxcarbazepine, topiramate, brivaracetam, zonisamide, or pregabalin. Participants were adults with epilepsy, in whom treatment with newer generation AEDs was initiated or needed adjustment. In the systematic TDM arm, AED plasma levels were available at each appointment, whereas in the rescue TDM arm, levels were known only if a study endpoint was reached (inefficacy or adverse events). The primary outcome was the proportion of participants followed 1 year without reaching one of the predefined endpoints. RESULTS: A total of 151 participants were enrolled; global retention in the study was similar in both arms (56% overall, 58% in the systematic, and 53% in the rescue TDM arm, p = 0.6, Cox regression). There was no difference in terms of outcome regarding treatment efficacy or tolerability. Partial adherence of clinicians to TDM (adjusting or not AED dosage based on blood levels) did not explain this lack of benefit. INTERPRETATION: This study provides class A evidence that systematic drug level monitoring of newer generation AEDs does not bring tangible benefits in the management of patients with epilepsy. Poor correlation between clinical effects and drug levels likely accounts for this finding. However, TDM is useful in several situations, such as pregnancy, as well as when there are compliance issues. ANN NEUROL 2020;87:22-29.

The association of red meat intake with inflammation and circulating intermediate biomarkers of type 2 diabetes is mediated by central adiposity.

We explored the role of lipid accumulation products and visceral adiposity on the association between red meat consumption (RMC) and markers of insulin resistance (IR) and inflammation in USA adults. Data on RMC and health outcome measurements were extracted from the 2005-2010 US National Health and Nutrition Examination Surveys. Overall 16 621 participants were included in the analysis (mean age = 47·1 years, 48·3 % men). ANCOVA and 'conceptus causal mediation' models were applied while accounting for survey design. In adjusted models, a lower RMC was significantly associated with a cardio-protective profile of IR and inflammation. BMI had significant mediation effects on the association between RMC and C-reactive protein (CRP), apo B, fasting blood glucose (FBG), insulin, homoeostatic model assessment of IR and ß-cell function, glycated Hb (HbA1c), TAG:HDL ratio and TAG glucose (TyG) index (all Ps < 0·05). Both waist circumference and anthropometrically predicted visceral adipose tissue mediated the association between RMC and CRP, FBG, HbA1c, TAG:HDL ratio and TyG index (all Ps < 0·05). Our findings suggest that adiposity, particularly the accumulation of abdominal fat, accounts for a significant proportion of the associations between red meat consumption, IR and inflammation.

Seizure freedom and plasma levels of newer generation antiseizure medications.

OBJECTIVES: Contrary to older antiseizure medications (ASM), correlation between plasma levels and seizure freedom is not well defined for newer generation ASM. We assessed correlations between efficacy and newer generation ASM plasma levels in patients with epilepsy. MATERIALS AND METHODS: Plasma medication levels were measured over two years in consecutive patients taking lamotrigine, levetiracetam, oxcarbazepine, topiramate, zonisamide, lacosamide, perampanel or pregabalin. Seizure freedom was defined as three times the longest inter-seizure pre-treatment interval, or at least one year. Each medication level was stratified according to its position in relation to its proposed reference range (below or in lower half vs upper half or above). RESULTS: 168 patients on stable therapy were included. ASM plasma levels of seizure-free patients were lower than those with ongoing seizures; 45/48 (93.7%) were in the lower half or below the reference ranges, compared to 86/106 (81.1%; p = .004). Lamotrigine plasma levels were significantly lower in seizure-free patients (median 2.4 mg/L range 0.4-6.5 mg/L, none above 6.5 mg/L) compared with those with ongoing seizures (5 mg/L, 0.5-14.2 mg/L; p < .0001). Levetiracetam showed similar results (7.2 mg/L, 1.6-15.1 mg/L; none above 15.1 mg/L in seizure-free patients vs 16.4 mg/L, 0.6-47.7 mg/L; p = .005). Demographics, epilepsy type and polytherapy did not influence the results. CONCLUSIONS: Efficacy of newer generation ASMs seems to be reached at the lower part or at times even below the reference ranges in drug responsive patients; this could inform regarding titrations of these treatments.

Risk models to predict late-onset seizures after stroke: A systematic review.

BACKGROUND AND PURPOSE: We performed a systematic review to evaluate available risk models to predict late seizure onset among stroke survivors. METHODS: We searched major databases (PubMed, SCOPUS, and Cochrane Library) from inception to October 2020 for articles on the development and/or validation of risk models to predict late seizures after a stroke. The impact of models to predict late-onset seizures was also assessed. We included seven articles in the final analysis. For each of these studies, we evaluated the study design and scope of predictors analyzed to derive each model. We assessed the performance of the models during internal and external validation in terms of discrimination and calibration. RESULTS: Three studies focused on ischemic stroke alone, with c-statistic values ranging from 0.73 to 0.77. The SeLECT model from Switzerland was externally validated in Italian, German, and Austrian cohorts where c-statistics ranged from 0.69 to 0.81. This model along with the PSEiCARe model, were internally validated and calibration performance was provided for both models. The CAVS and CAVE models reported on the risk of late-onset seizures in patients with hemorrhagic stroke. The CAVS model derivation cohort was racially diverse. The CAVS model's c-statistic was 0.76, while the CAVE model had a c-statistic of 0.81. Calibration and internal validation were not performed for either study. The CAVS model, created from a Finnish population, was externally validated in American and French cohorts, with c-statistics of 0.73 and 0.69, respectively. Finally, the two studies focusing on both types of stroke came from the PoSERS and INPOSE models. Neither model provided c-statistics, calibration metrics, internal or external validation information. We found no evidence of the presence of impact studies to assess the effect of adopting late-onset seizure risk models after stroke on clinical outcomes. CONCLUSION: The SeLECT model was the only model developed in line with proposed guidelines for appropriate model development. The model, which was externally validated in a very similar and homogeneous population, may need to be tested in a more racially/ethnic diverse and younger population; testing the SeLECT model, accounting for overall brain health is likely to improve the identification of high-risk patients for late post stroke seizures.

Prevalence and determinants of chronic kidney disease in urban adults' populations of northern Cameroon.

BACKGROUND: Chronic kidney disease (CKD) is a major health problem with growing prevalence in sub-Saharan Africa. AIM: Assess the prevalence and determinants of CKD in Garoua and Figuil cities of the North region of Cameroon. METHODS: A cross-sectional survey was conducted from January to June 2018 in the two cities, using a multi-level cluster sampling. All adults with low estimated glomerular filtration rate (eGFR) (< 60 ml/min/1.73 m2) by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation and/or albuminuria (≥ 30 mg/g) were reviewed three months later. Logistic regression models (accounting for the sampling strategy) were used to investigate the predictors of the outcomes. RESULTS: A total of 433 participants were included, with a mean age (95%CI) of 45.0 (43.4-46.6) years, 212 (48.7%) men, 294 (67.9%) from Garoua and 218 (45.6%) with no formal education. Risk factors for chronic nephropathy were highly prevalent including longstanding use of street medications (52.8%), herbal medicines (50.2%) and non-steroidal anti-inflammatory drugs (50%), alcohol consumption (34.4%), hypertension (33.9%), overweight/obesity (33.6%), hyperuricemia (16.8%), smoking (11.3%) and hyperglycemia (6.5%). The prevalence of CKD was 11.7% overall, 10.7% in Garoua and 13% in Figuil participants. Equivalents figures for CKD G3-5 and albuminuria were 2.8%, 2.0% and 4.5%; and 9.1%, 9.3% and 8.5%, respectively. History of diabetes, increase systolic blood pressure, hyperglycemia and hyperuricemia were predictors of CKD. CONCLUSION: The prevalence of CKD is as high in these northern cities as previously reported in southern cities of Cameroon, driven mostly by known modifiable risk factors of chronic nephropathy.