Creation of a pandemic memory by tracing COVID-19 infections and immunity in Luxembourg (CON-VINCE).

BACKGROUND: During the COVID-19 pandemic swift implementation of research cohorts was key. While many studies focused exclusively on infected individuals, population based cohorts are essential for the follow-up of SARS-CoV-2 impact on public health. Here we present the CON-VINCE cohort, estimate the point and period prevalence of the SARS-CoV-2 infection, reflect on the spread within the Luxembourgish population, examine immune responses to SARS-CoV-2 infection and vaccination, and ascertain the impact of the pandemic on population psychological wellbeing at a nationwide level. METHODS: A representative sample of the adult Luxembourgish population was enrolled. The cohort was followed-up for twelve months. SARS-CoV-2 RT-qPCR and serology were conducted at each sampling visit. The surveys included detailed epidemiological, clinical, socio-economic, and psychological data. RESULTS: One thousand eight hundred sixty-five individuals were followed over seven visits (April 2020-June 2021) with the final weighted period prevalence of SARS-CoV-2 infection of 15%. The participants had similar risks of being infected regardless of their gender, age, employment status and education level. Vaccination increased the chances of IgG-S positivity in infected individuals. Depression, anxiety, loneliness and stress levels increased at a point of study when there were strict containment measures, returning to baseline afterwards. CONCLUSION: The data collected in CON-VINCE study allowed obtaining insights into the infection spread in Luxembourg, immunity build-up and the impact of the pandemic on psychological wellbeing of the population. Moreover, the study holds great translational potential, as samples stored at the biobank, together with self-reported questionnaire information, can be exploited in further research. TRIAL REGISTRATION: Trial registration number: NCT04379297, 10 April 2020.

A Phase 2, Randomized, Multicenter, Placebo-Controlled, Proof-of-Concept Trial of Oral Fexinidazole in Adults With Chronic Indeterminate Chagas Disease.

BACKGROUND: Chagas disease (CD) has significant global health impact, but safe, effective treatments remain elusive. The nitroimidazole fexinidazole is a potential treatment. METHODS: This double-blind, randomized, placebo-controlled, dose-finding, proof-of-concept study was conducted in Bolivia. Adults with serologically confirmed chronic indeterminate CD and positive PCR were randomly assigned to 1 of 6 fexinidazole regimens (1200 or 1800 mg/day for 2, 4, or 8 weeks) or placebo. Target recruitment was 20 patients/arm. The primary endpoint was sustained parasitological clearance by serial negative qPCR from end of treatment (EOT) until 6 months follow-up in the intention-to-treat (ITT) population. Follow-up was extended to 12 months. RESULTS: Enrollment was interrupted after 4/47 patients presented with transient asymptomatic grade 3 and 4 neutropenia. Treatment of ongoing patients was stopped in all patients administered >2 weeks. A total of 40 patients received treatment with fexinidazole from 3 days to 8 weeks. Delayed-onset neutropenia (n = 8) and increased liver enzymes (n = 8) were found in fexinidazole patients vs none in the placebo arm. In the ITT analysis, sustained parasitological clearance from EOT to 12 months follow-up varied between 66.7% (1200 mg-2 week) and 100.0% (1800 mg-2 week). Rapid, sustained clearance of parasitemia was observed in all treated patients with available data, but not in any patients in the placebo group, at 12 months (P = .0056). Further exploratory exposure-response analysis suggested low dosages of fexinidazole may be safe and effective. CONCLUSIONS: Further evaluation is needed to establish fexinidazole's minimum effective dosage and risk-benefit relationship. Results suggest potential for effective treatment regimens <10 days. CLINICAL TRIALS REGISTRATION: NCT02498782.

Machine learning for predicting neurodegenerative diseases in the general older population: a cohort study.

BACKGROUND: In the older general population, neurodegenerative diseases (NDs) are associated with increased disability, decreased physical and cognitive function. Detecting risk factors can help implement prevention measures. Using deep neural networks (DNNs), a machine-learning algorithm could be an alternative to Cox regression in tabular datasets with many predictive features. We aimed to compare the performance of different types of DNNs with regularized Cox proportional hazards models to predict NDs in the older general population. METHODS: We performed a longitudinal analysis with participants of the English Longitudinal Study of Ageing. We included men and women with no NDs at baseline, aged 60 years and older, assessed every 2 years from 2004 to 2005 (wave2) to 2016-2017 (wave 8). The features were a set of 91 epidemiological and clinical baseline variables. The outcome was new events of Parkinson's, Alzheimer or dementia. After applying multiple imputations, we trained three DNN algorithms: Feedforward, TabTransformer, and Dense Convolutional (Densenet). In addition, we trained two algorithms based on Cox models: Elastic Net regularization (CoxEn) and selected features (CoxSf). RESULTS: 5433 participants were included in wave 2. During follow-up, 12.7% participants developed NDs. Although the five models predicted NDs events, the discriminative ability was superior using TabTransformer (Uno's C-statistic (coefficient (95% confidence intervals)) 0.757 (0.702, 0.805). TabTransformer showed superior time-dependent balanced accuracy (0.834 (0.779, 0.889)) and specificity (0.855 (0.0.773, 0.909)) than the other models. With the CoxSf (hazard ratio (95% confidence intervals)), age (10.0 (6.9, 14.7)), poor hearing (1.3 (1.1, 1.5)) and weight loss 1.3 (1.1, 1.6)) were associated with a higher DNN risk. In contrast, executive function (0.3 (0.2, 0.6)), memory (0, 0, 0.1)), increased gait speed (0.2, (0.1, 0.4)), vigorous physical activity (0.7, 0.6, 0.9)) and higher BMI (0.4 (0.2, 0.8)) were associated with a lower DNN risk. CONCLUSION: TabTransformer is promising for prediction of NDs with heterogeneous tabular datasets with numerous features. Moreover, it can handle censored data. However, Cox models perform well and are easier to interpret than DNNs. Therefore, they are still a good choice for NDs.

Burden of HIV and treatment outcomes among TB patients in rural Kenya: a 9-year longitudinal study.

BACKGROUND: Although tuberculosis (TB) patients coinfected with HIV are at risk of poor treatment outcomes, there is paucity of data on changing trends of TB/HIV co-infection and their treatment outcomes. This study aims to estimate the burden of TB/HIV co-infection over time, describe the treatment available to TB/HIV patients and estimate the effect of TB/HIV co-infection on TB treatment outcomes. METHODS: This was a retrospective data analyses from TB surveillance in two counties in Kenya (Nyeri and Kilifi): 2012‒2020. All TB patients aged ≥ 18 years were included. The main exposure was HIV status categorised as infected, negative or unknown status. World Health Organization TB treatment outcomes were explored; cured, treatment complete, failed treatment, defaulted/lost-to-follow-up, died and transferred out. Time at risk was from date of starting TB treatment to six months later/date of the event and Cox proportion with shared frailties models were used to estimate effects of TB/HIV co-infection on TB treatment outcomes. RESULTS: The study includes 27,285 patients, median (IQR) 37 (29‒49) years old and 64% male. 23,986 (88%) were new TB cases and 91% were started on 2RHZE/4RH anti-TB regimen. Overall, 7879 (29%, 95% 28‒30%) were HIV infected. The proportion of HIV infected patient was 32% in 2012 and declined to 24% in 2020 (trend P-value = 0.01). Uptake of ARTs (95%) and cotrimoxazole prophylaxis (99%) was high. Overall, 84% patients completed six months TB treatment, 2084 (7.6%) died, 4.3% LTFU, 0.9% treatment failure and 2.8% transferred out. HIV status was associated with lower odds of completing TB treatment: infected Vs negative (aOR 0.56 (95%CI 0.52‒0.61) and unknown vs negative (aOR 0.57 (95%CI 0.44‒0.73). Both HIV infected and unknown status were associated with higher hazard of death: (aHR 2.40 (95%CI 2.18‒2.63) and 1.93 (95%CI 1.44‒2.56)) respectively and defaulting treatment/LTFU: aHR 1.16 (95%CI 1.01‒1.32) and 1.55 (95%CI 1.02‒2.35)) respectively. HIV status had no effect on hazard of transferring out and treatment failure. CONCLUSION: The overall burden of TB/HIV coinfection was within previous pooled estimate. Our findings support the need for systematic HIV testing as those with unknown status had similar TB treatment outcomes as the HIV infected.

A systematic review of the quality of conduct and reporting of survival analyses of tuberculosis outcomes in Africa.

BACKGROUND: Survival analyses methods (SAMs) are central to analysing time-to-event outcomes. Appropriate application and reporting of such methods are important to ensure correct interpretation of the data. In this study, we systematically review the application and reporting of SAMs in studies of tuberculosis (TB) patients in Africa. It is the first review to assess the application and reporting of SAMs in this context. METHODS: Systematic review of studies involving TB patients from Africa published between January 2010 and April 2020 in English language. Studies were eligible if they reported use of SAMs. Application and reporting of SAMs were evaluated based on seven author-defined criteria. RESULTS: Seventy-six studies were included with patient numbers ranging from 56 to 182,890. Forty-three (57%) studies involved a statistician/epidemiologist. The number of published papers per year applying SAMs increased from two in 2010 to 18 in 2019 (P = 0.004). Sample size estimation was not reported by 67 (88%) studies. A total of 22 (29%) studies did not report summary follow-up time. The survival function was commonly presented using Kaplan-Meier survival curves (n = 51, (67%) studies) and group comparisons were performed using log-rank tests (n = 44, (58%) studies). Sixty seven (91%), 3 (4.1%) and 4 (5.4%) studies reported Cox proportional hazard, competing risk and parametric survival regression models, respectively. A total of 37 (49%) studies had hierarchical clustering, of which 28 (76%) did not adjust for the clustering in the analysis. Reporting was adequate among 4.0, 1.3 and 6.6% studies for sample size estimation, plotting of survival curves and test of survival regression underlying assumptions, respectively. Forty-five (59%), 52 (68%) and 73 (96%) studies adequately reported comparison of survival curves, follow-up time and measures of effect, respectively. CONCLUSION: The quality of reporting survival analyses remains inadequate despite its increasing application. Because similar reporting deficiencies may be common in other diseases in low- and middle-income countries, reporting guidelines, additional training, and more capacity building are needed along with more vigilance by reviewers and journal editors.

Relationship of oxidative stress to visceral adiposity in youth and role played by vitamin D.

BACKGROUND: Visceral adipose tissue (VAT) accumulation is a major cardiometabolic risk factor, associated with increased inflammation. Oxidative stress (OS) is also associated with inflammation and cardiometabolic issues, yet mainly through general obesity. Both OS and obesity were linked to vitamin D deficiency. OBJECTIVES: To investigate whether OS increase is associated with VAT accumulation in youth, and whether in the presence of VAT accumulation, a higher vitamin D status is associated with lower OS. METHODS: One hundred and fifty-eight youth with overweight/obesity, 7 to 17 years old, were recruited (Pediatric Clinic, Luxembourg). We assessed visceral and subcutaneous abdominal adipose tissues by magnetic resonance imaging, OS by DNA/RNA oxidative damage with ELISA and vitamin D by high-performance liquid chromatography. RESULTS: VAT was the body fat compartment the most strongly associated with OS (RPearson : 0.298; P < 10-4 ). The general linear (GLM) models assessing the relationship between OS, VAT and vitamin D concentrations showed that "Log10 OS = (0.003 × VAT) + 3.911 (R2adjusted : 0.083; P-value < 10-4 )"; "Log10 OS = (0.003 × VAT) - (0.156 × log10 vitamin D) + 4.110 (R2adjusted : 0.101; P-value < 10-4 )". After back-transformation of the log-values into normal values, the GLM showed that, for a person with an average value of VAT (40.7 cm2 ), a 10 cm2 increase in VAT would increase OS by approx. 771.833 pg/mL, after age, gender, Tanner stage and physical activity adjustment. An approximate increase of 9 ng/mL of vitamin D would counterbalance this negative effect of increased VAT. CONCLUSION: Dietary strategies improving vitamin D status should be investigated to tackle VAT and OS increase.

Designing noninferiority tuberculosis treatment trials: Identifying practical advantages for drug regimens with acceptable effectiveness.

In this Collection Review for the Novel Treatments for Tuberculosis Collection, Piero Olliaro and Michael Vaillant discuss the considerations when choosing a non-inferiority margin that is meaningful from statistical, ethical, clinical, and health standpoint.

Single dose moxidectin versus ivermectin for Onchocerca volvulus infection in Ghana, Liberia, and the Democratic Republic of the Congo: a randomised, controlled, double-blind phase 3 trial.

BACKGROUND: The morbidity and socioeconomic effects of onchocerciasis, a parasitic disease that is primarily endemic in sub-Saharan Africa, have motivated large morbidity and transmission control programmes. Annual community-directed ivermectin treatment has substantially reduced prevalence. Elimination requires intensified efforts, including more efficacious treatments. We compared parasitological efficacy and safety of moxidectin and ivermectin. METHODS: This double-blind, parallel group, superiority trial was done in four sites in Ghana, Liberia, and the Democratic Republic of the Congo. We enrolled participants (aged ≥12 years) with at least 10 Onchocerca volvulus microfilariae per mg skin who were not co-infected with Loa loa or lymphatic filariasis microfilaraemic. Participants were randomly allocated, stratified by sex and level of infection, to receive a single oral dose of 8 mg moxidectin or 150 µg/kg ivermectin as overencapsulated oral tablets. The primary efficacy outcome was skin microfilariae density 12 months post treatment. We used a mixed-effects model to test the hypothesis that the primary efficacy outcome in the moxidectin group was 50% or less than that in the ivermectin group. The primary efficacy analysis population were all participants who received the study drug and completed 12-month follow-up (modified intention to treat). This study is registered with ClinicalTrials.gov, number NCT00790998. FINDINGS: Between April 22, 2009, and Jan 23, 2011, we enrolled and allocated 998 participants to moxidectin and 501 participants to ivermectin. 978 received moxidectin and 494 ivermectin, of which 947 and 480 were included in primary efficacy outcome analyses. At 12 months, skin microfilarial density (microfilariae per mg of skin) was lower in the moxidectin group (adjusted geometric mean 0·6 [95% CI 0·3-1·0]) than in the ivermectin group (4·5 [3·5-5·9]; difference 3·9 [3·2-4·9], p<0·0001; treatment difference 86%). Mazzotti (ie, efficacy-related) reactions occurred in 967 (99%) of 978 moxidectin-treated participants and in 478 (97%) of 494 ivermectin-treated participants, including ocular reactions (moxidectin 113 [12%] participants and ivermectin 47 [10%] participants), laboratory reactions (788 [81%] and 415 [84%]), and clinical reactions (944 [97%] and 446 [90%]). No serious adverse events were considered to be related to treatment. INTERPRETATION: Skin microfilarial loads (ie, parasite transmission reservoir) are lower after moxidectin treatment than after ivermectin treatment. Moxidectin would therefore be expected to reduce parasite transmission between treatment rounds more than ivermectin could, thus accelerating progress towards elimination. FUNDING: UNICEF/UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases.

Relationship between weight status and anti-malarial drug efficacy and safety in children in Mali.

BACKGROUND: Anti-malarial treatments effectiveness remains a critical challenge for control programmes. However, when drug efficacy is established, the dose is calculated based on a predefined weight according to the patient age. Based on the hypothesis that the standard assumption of weight according to the age when administering the drug could lead to a therapeutic failure potentially due to under-dosing (in the case of overweight) or over-dosing (in case of underweight). In this study, the relationship between weight status and malaria drug efficacy in clearing current Plasmodium falciparum infection and preventing reinfection after treatment was investigated. METHODS: Data were drown from a clinical trial conducted previously to investigate malaria drug efficacy in 749 children from Mali (2002-2004). Participants were treated either with artesunate + amodiaquine (AS + AQ, n1 = 250), artesunate + sulfadoxine-pyrimethamine (AS + SP, n2 = 248) or artesunate (AS, n3 = 251) and followed for 28 days after treatment. The World Health Organization (WHO) z-score was used to define weight status. A Chi square test was used to compare outcomes according to drugs, weight status and the dynamic of ALAT, ASAT, creatinine and haemoglobin level. Logistic regression models were developed to determine the effect of baseline parameters (weight status, aspartate transaminase, alanine aminotransferase, creatinine and haemoglobin level) on drug efficacy as per WHO criteria. RESULTS: Without molecular correction, in AS + AQ arm, the rate of adequate clinical and parasitological response (ACPR) was higher in the group of underweight children 94.74% compared to children with normal and overweight (91.24% and 80.43% respectively, p = 0.03). After PCR correction, treatment efficacy was similar in the three groups of patients and was above 98% (p = 0.4). Overweight was observed to have no impact on recrudescence. However, it was associated with an increased risk of new infections in the (AS + AQ) arm (OR = 0.21, 95% CI [0.06; 0.86], p = 0.03). CONCLUSIONS: The findings suggest that weight deficiency has no deleterious effect on anti-malarial drug efficacy. An increase in the rate of reinfection in overweight children treated by AS + AQ should be further explored in larger studies.

Blood pharmacokinetic of 17 common pesticides in mixture following a single oral exposure in rats: implications for human biomonitoring and exposure assessment.

Human biomonitoring provides information about chemicals measured in biological matrices, but their interpretation remains uncertain because of pharmacokinetic (PK) interactions. This study examined the PKs in blood from Long-Evans rats after a single oral dose of 0.4 mg/kg bw of each pesticide via a mixture of the 17 pesticides most frequently measured in humans. These pesticides are ß-endosulfan; ß-hexachlorocyclohexane [ß-HCH]; γ-hexachlorocyclohexane [γ-HCH]; carbofuran; chlorpyrifos; cyhalothrin; cypermethrin; diazinon; dieldrin; diflufenican; fipronil; oxadiazon; pentachlorophenol [PCP]; permethrin; 1,1-dichloro-2,2bis(4-chlorophenyl)ethylene [p,p'-DDE]; 1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane [p,p'-DDT]; and trifluralin. We collected blood at 10 min to 48-h timepoints in addition to one sample before gavage (for a control). We used GS-MS/MS to measure the pesticide (parents and major metabolites) concentrations in plasma, determined the PK parameters from 20 sampling timepoints, and analyzed the food, litter, and cardboard in the rats' environment for pesticides. We detected many parents and metabolites pesticides in plasma control (e.g., diethyl phosphate [DEP]; PCP; 3-phenoxybenzoic acid [3-PBA]; 3,5,6-trichloro-2-pyridinol [TCPy], suggesting pre-exposure contamination. The PK values post-exposure showed that the AUC0-∞ and Cmax were highest for TCPy and PCP; ß-endosulfan, permethrin, and trifluralin presented the lowest values. Terminal T1/2 and MRT for γ-HCH and ß-HCH ranged from 74.5 h to 117.1 h; carbofuran phenol presented the shortest values with 4.3 h and 4.8 h. These results present the first PK values obtained through a realistic pattern applied to a mixture of 17 pesticides to assess exposure. This study also highlights the issues of background exposure and the need to work with a relevant mixture found in human matrices.

Comparative analysis of the association between 35 frailty scores and cardiovascular events, cancer, and total mortality in an elderly general population in England: An observational study.

BACKGROUND: Frail elderly people experience elevated mortality. However, no consensus exists on the definition of frailty, and many frailty scores have been developed. The main aim of this study was to compare the association between 35 frailty scores and incident cardiovascular disease (CVD), incident cancer, and all-cause mortality. Also, we aimed to assess whether frailty scores added predictive value to basic and adjusted models for these outcomes. METHODS AND FINDINGS: Through a structured literature search, we identified 35 frailty scores that could be calculated at wave 2 of the English Longitudinal Study of Ageing (ELSA), an observational cohort study. We analysed data from 5,294 participants, 44.9% men, aged 60 years and over. We studied the association between each of the scores and the incidence of CVD, cancer, and all-cause mortality during a 7-year follow-up using Cox proportional hazard models at progressive levels of adjustment. We also examined the added predictive performance of each score on top of basic models using Harrell's C statistic. Using age of the participant as a timescale, in sex-adjusted models, hazard ratios (HRs) (95% confidence intervals) for all-cause mortality ranged from 2.4 (95% CI: 1.7-3.3) to 26.2 (95% CI: 15.4-44.5). In further adjusted models including smoking status and alcohol consumption, HR ranged from 2.3 (95% CI: 1.6-3.1) to 20.2 (95% CI: 11.8-34.5). In fully adjusted models including lifestyle and comorbidity, HR ranged from 0.9 (95% CI: 0.5-1.7) to 8.4 (95% CI: 4.9-14.4). HRs for CVD and cancer incidence in sex-adjusted models ranged from 1.2 (95% CI: 0.5-3.2) to 16.5 (95% CI: 7.8-35.0) and from 0.7 (95% CI: 0.4-1.2) to 2.4 (95% CI: 1.0-5.7), respectively. In sex- and age-adjusted models, all frailty scores showed significant added predictive performance for all-cause mortality, increasing the C statistic by up to 3%. None of the scores significantly improved basic prediction models for CVD or cancer. A source of bias could be the differences in mortality follow-up time compared to CVD/cancer, because the existence of informative censoring cannot be excluded. CONCLUSION: There is high variability in the strength of the association between frailty scores and 7-year all-cause mortality, incident CVD, and cancer. With regard to all-cause mortality, some scores give a modest improvement to the predictive ability. Our results show that certain scores clearly outperform others with regard to three important health outcomes in later life. Finally, we think that despite their limitations, the use of frailty scores to identify the elderly population at risk is still a useful measure, and the choice of a frailty score should balance feasibility with performance.

Agreement Between 35 Published Frailty Scores in the General Population.

In elderly populations, frailty is associated with higher mortality risk. Although many frailty scores (FS) have been proposed, no single score is considered the gold standard. We aimed to evaluate the agreement between a wide range of FS in the English Longitudinal Study of Ageing (ELSA). Through a literature search, we identified 35 FS that could be calculated in ELSA wave 2 (2004-2005). We examined agreement between each frailty score and the mean of 35 FS, using a modified Bland-Altman model and Cohen's kappa (κ). Missing data were imputed. Data from 5,377 participants (ages ≥60 years) were analyzed (44.7% men, 55.3% women). FS showed widely differing degrees of agreement with the mean of all scores and between each pair of scores. Frailty classification also showed a very wide range of agreement (Cohen's κ = 0.10-0.83). Agreement was highest among "accumulation of deficits"-type FS, while accuracy was highest for multidimensional FS. There is marked heterogeneity in the degree to which various FS estimate frailty and in the identification of particular individuals as frail. Different FS are based on different concepts of frailty, and most pairs cannot be assumed to be interchangeable. Research results based on different FS cannot be compared or pooled.

Cardiometabolic risk: leg fat is protective during childhood.

BACKGROUND: Childhood obesity is associated with early cardiometabolic risk (CMR), increased risk of adulthood obesity, and worse health outcomes. Leg fat mass (LFM) is protective beyond total fat mass (TFM) in adults. However, the limited evidence in children remains controversial. OBJECTIVE: We investigated the relationship between LFM and CMR factors in youth. SUBJECTS: A total of 203 overweight/obese children, 7-17-yr-old, followed in the Pediatric Clinic, Luxembourg. METHODS: TFM and LFM by dual energy x-ray absorptiometry and a detailed set of CMR markers were analyzed. RESULTS: After TFM, age, sex, body mass index (BMI) Z-score, sexual maturity status, and physical activity adjustments, negative significant partial correlations were shown between LFM and homeostasis model assessment of insulin resistance (HOMA) (variance explained: 6.05% by LFM*; 7.18% by TFM**), fasting insulin (variance explained: 5.71% by LFM*; 6.97% by TFM**), triglycerides (variance explained: 3.96% by LFM*; 2.76% by TFM*), systolic blood pressure (variance explained: 2.68% by LFM*; 4.33% by TFM*), C-reactive protein (variance explained: 2.31% by LFM*; 4.28% by TFM*), and resistin (variance explained: 2.16% by LFM*; 3.57% by TFM*). Significant positive partial correlations were observed between LFM and high-density lipoprotein (HDL) cholesterol (variance explained: 4.16% by LFM*) and adiponectin (variance explained: 3.09% by LFM*) (*p-value < 0.05 and **p-value < 0.001). In order to adjust for multiple testing, Benjamini-Hochberg method was applied and the adjusted significance level was determined for each analysis. LFM remained significant in the aforementioned models predicting HOMA, fasting insulin, triglycerides, and HDL cholesterol (Benjamini and Hochberg corrected p-value < 0.01). CONCLUSIONS: LFM is protective against CMR in children, at least in terms of insulin resistance and adverse blood lipid profiles.

Adding anthropometric measures of regional adiposity to BMI improves prediction of cardiometabolic, inflammatory and adipokines profiles in youths: a cross-sectional study.

BACKGROUND: Paediatric research analysing the relationship between the easy-to-use anthropometric measures for adiposity and cardiometabolic risk factors remains highly controversial in youth. Several studies suggest that only body mass index (BMI), a measure of relative weight, constitutes an accurate predictor, whereas others highlight the potential role of waist-to-hip ratio (WHR), waist circumference (Waist C), and waist-to-height ratio (WHtR). In this study, we examined the effectiveness of adding anthropometric measures of body fat distribution (Waist C Z Score, WHR Z Score and/or WHtR) to BMI Z Score to predict cardiometabolic risk factors in overweight and obese youth. We also examined the consistency of these associations with the "total fat mass + trunk/legs fat mass" and/or the "total fat mass + trunk fat mass" combinations, as assessed by dual energy X-ray absorptiometry (DXA), the gold standard measurement of body composition. METHODS: Anthropometric and DXA measurements of total and regional adiposity, as well as a comprehensive assessment of cardiometabolic, inflammatory and adipokines profiles were performed in 203 overweight and obese 7-17 year-old youths from the Paediatrics Clinic, Centre Hospitalier de Luxembourg. RESULTS: Adding only one anthropometric surrogate of regional fat to BMI Z Score improved the prediction of insulin resistance (WHR Z Score, R(2): 45.9%. Waist C Z Score, R(2): 45.5%), HDL-cholesterol (WHR Z Score, R(2): 9.6%. Waist C Z Score, R(2): 10.8%. WHtR, R(2): 6.5%), triglycerides (WHR Z Score, R(2): 11.7%. Waist C Z Score, R(2): 12.2%), adiponectin (WHR Z Score, R(2): 14.3%. Waist C Z Score, R(2): 17.7%), CRP (WHR Z Score, R(2): 18.2%. WHtR, R(2): 23.3%), systolic (WHtR, R(2): 22.4%), diastolic blood pressure (WHtR, R(2): 20%) and fibrinogen (WHtR, R(2): 21.8%). Moreover, WHR Z Score, Waist C Z Score and/or WHtR showed an independent significant contribution according to these models. These results were in line with the DXA findings. CONCLUSIONS: Adding anthropometric measures of regional adiposity to BMI Z Score improves the prediction of cardiometabolic, inflammatory and adipokines profiles in youth.

Fixed dose artesunate amodiaquine - a phase IIb, randomized comparative trial with non-fixed artesunate amodiaquine.

BACKGROUND: Pharmacokinetic (PK) and pharmacodynamic (PD) data are limited for artesunate (AS) and amodiaquine (AQ) in uncomplicated Plasmodium falciparum. METHODS: From 2007-8, 54 P. falciparum-infected, Kenyan adults were assigned randomly fixed dose (FD) ASAQ (n = 26) or non-fixed (NF) ASAQ (n = 28). Total doses were 600 mg AS (both arms) + 1,620 mg (FD) or 1,836 mg (NF)AQ. Follow-up extended over 28 days. PK data were collected for AS, dihydroartemisinin (DHA), AS + DHA combined as DHA equivalents (DHAeq), AQ, desethylamodiaquine (DAQ),and their relationships assessed against the PD collected data consisting of parasitological efficacy, adverse events (AEs), and the Bazett's corrected QTinterval (QTcB). RESULTS: Mean AUC 0-72 of dihydroartemisinin equivalents (DHAeq) when administered as a fixed dose (FD) compared to NF dose were similar: 24.2 ±4.6 vs 26.4±6.9 µmol*h/L (p = 0.68) Parasite clearance rates were also similar after 24 hrs: 17/25 (68%) vs 18/28(64.3%) (p = 0.86),as well as at 48 hrs: 25/8 (100%)vs 26 (92.9%)/28 (p = 0.49). Mean FD vs NF DAQ AUC0-28 were 27.6±3.19 vs 32.7±5.53 mg*h/L (p = 0.0005). Two PCR-proven new infections occurred on Day (D) 28 for estimated, in vivo, DAQ minimum inhibitory concentrations of 15.2 and 27.5 ng/mL. Combining the FD and NF arms, the mean QTcB at D2+4 hrs increased significantly (p = 0.0059) vs baseline: 420 vs410 ms (∆ = 9.02 (95% confidence interval 2.72-15.31 ms), explained by falling heart rates, increasing DAQ concentrations and female sex in a general linear mixed effects model. Ten of 108 (9.26%) AEs (5/arm) reported by 37/54 (68.5%) patients were possibly or probably drug related. Severe, asymptomatic neutropaenia developed in 2/47 (4.25%) patients on D28: 574/µL (vsD0: 5,075/µL), and 777/µL (vsD0: 3,778/µL). CONCLUSIONS: Tolerability of both formulations was good. For QTcB, a parameter for ECG modifications, increases were modest and due to rising DAQ concentrations and falling heart rates as malaria resolved. Rapid parasite clearance rates and no resistant infections suggest effective pharmacokinetics of both formulations.

Advice on lifestyle changes (diet, red wine and physical activity) does not affect internal carotid and middle cerebral artery blood flow velocity in patients with carotid arteriosclerosis in a randomized controlled trial.

BACKGROUND: A Mediterranean diet, with and without small daily amounts of red wine, and physical activity reduce the risk of cerebrovascular disease and improve cognition. An increase in cerebral blood flow may be the underlying mechanism. Under normal conditions, cerebral blood flow velocity changes in the internal carotid arteries and in large basal cerebral arteries correlate closely with cerebral blood flow changes, as the diameter of these vessels hardly changes and only the smaller vessels downstream change their diameter. METHODS: A prospective randomized controlled trial was performed in 108 patients with carotid atherosclerosis (mean age 64 years, 67% men, 66% on statin therapy). Half of them were advised to follow a polyphenol-rich modified Mediterranean diet including 1-2 tomatoes, 3-5 walnuts and a bar of dark chocolate (25 g) a day and to perform moderate physical exercise for 30 min/day (lifestyle changes). Within these two groups, half of the patients were randomized either to avoid any alcohol or to drink 100 ml of red wine (women) or 200 ml of red wine (men) daily. Bilateral middle cerebral and internal carotid blood flow velocity (peak systolic, peak end-diastolic and mean) was measured at baseline and after 4 and 20 weeks using colour-coded duplex ultrasound. Insonation depth and insonation angle were used to identically place the sample volume during follow-up investigations. A general linear model with Tukey-Kramer adjustment for multiple comparisons was used to assess the primary end points. For the analysis we used the mean values of the right and left artery. RESULTS: Neither lifestyle changes nor red wine had an effect on peak systolic, peak end-diastolic or mean cerebral blood flow velocity. CONCLUSIONS: Advice on lifestyle changes, including a modified polyphenol-rich Mediterranean diet, a glass of red wine daily and physical exercise, did not affect middle cerebral and internal carotid blood flow velocity in our patient group with carotid atherosclerosis. An increase in cerebral blood flow is thus unlikely to be the cause of the reduced risk of cerebrovascular disease and improved cognitive functioning described in the literature. One possible explanation for the fact that blood flow velocity was not affected by red wine, diet and physical activity advice is that two thirds of our patients were already on statin therapy. Statins increase cerebral blood flow and vasomotor reactivity via nitric oxide.

Diagnostic tests for human Schistosoma mansoni and Schistosoma haematobium infection: a systematic review and meta-analysis.

BACKGROUND: Accurate diagnosis is pivotal for implementing strategies for surveillance, control, and elimination of schistosomiasis. Despite their low sensitivity in low-endemicity areas, microscopy-based urine filtration and the Kato-Katz technique are considered as reference diagnostic tests for Schistosoma haematobium and Schistosoma mansoni infections, respectively. We aimed to collate all available evidence on the accuracy of other proposed diagnostic techniques. METHODS: In this systematic review and meta-analysis, we searched PubMed, Embase, the Cochrane Library, and LILACS for studies published from database inception to Dec 31, 2022, investigating the sensitivity and specificity of diagnostic tests for S haematobium and S mansoni infections against Kato-Katz thick smears or urine microscopy (reference tests) involving adults (aged ≥18 years), school-aged children (aged 7 to 18 years), or preschool-aged children (aged 1 month to 7 years). We extracted raw data on true positives, true negatives, false positives, and false negatives for the diagnostic tests and data on the number of participants, study authors, publication year, journal, study design, participants' age and sex, prevalence of Schistosoma infection, and treatment status. To account for imperfect reference tests, we used a hierarchical Bayesian latent class meta-analysis to model test accuracy. FINDINGS: Overall, we included 121 studies, assessing 28 different diagnostic techniques. Most studies (103 [85%] of 121) were done in Africa, 14 (12%) in South America, one (1%) in Asia, and one (1%) in an unknown country. Compared with the reference test, Kato-Katz thick smears, circulating cathodic antigen urine cassette assay version 1 (CCA1, 36 test comparisons) had excellent sensitivity (95% [95% credible interval 88-99]) and reasonable specificity (74% [63-83]) for S mansoni. ELISA-based tests had a performance comparable to circulating cathodic antigen, but there were few available test comparisons. For S haematobium, proteinuria (42 test comparisons, sensitivity 73% [62-82]; specificity 94% [89-98]) and haematuria (75 test comparisons, sensitivity 85% [80-90]; specificity 96% [92-99]) reagent strips showed high specificity, with haematuria reagent strips having better sensitivity. Despite limited data, nucleic acid amplification tests (NAATs; eg, PCR or loop-mediated isothermal amplification [LAMP]) showed promising results with sensitivity estimates above 90%. We found an unclear risk of bias of about 70% in the use of the reference or index tests and of 50% in patient selection. All analyses showed substantial heterogeneity (I2>80%). INTERPRETATION: Although NAATs and immunological diagnostics show promise, the limited information available precludes drawing definitive conclusions. Additional research on diagnostic accuracy and cost-effectiveness is needed before the replacement of conventional tests can be considered. FUNDING: WHO and Luxembourg Institute of Health.

Assessment of the impact of pregnancy and malaria infection on the variation of neutrophil levels in women from San, Mali.

BACKGROUND: In patients with severe neutropenia, infections can rapidly become serious and life-threatening. It is essential to understand whether pregnancy induces changes in neutrophil levels thereby posing an increased threat to the health of gravidae. METHODOLOGY: This cross-sectional study was conducted in San Health District (Mali) and involved pregnant women infected or not by malaria parasites and non-pregnant healthy volunteers. Subjects were categorized as having neutropenia, normal neutrophil levels, and neutrophilia regarding their neutrophil levels. A logistic regression analysis was performed to determine factors associated with neutrophil level variation in pregnant women. RESULTS: Whether or not the pregnant women were infected with malaria, 98 of the 202 cases (48.5%) showed neutrophilia. Surprisingly, 67 of the 71 cases of neutropenia (94.4%) observed in this study concerned healthy people who were not pregnant. The mean percentage of neutrophil levels was significantly (p < 0.001) lower (49.9%) in the first trimester compared to the second trimester of pregnancy (62.0%). A logistic regression model showed that compared to early pregnancy, the second (OR = 12.9, 95% CI 2.2-248.1, p = 0.018) and the third trimesters (OR = 13.7, 95% CI 2.3-257.5, p = 0.016) were strongly associated with the increase of neutrophil levels. CONCLUSIONS: Pregnancy can induce the production of mature neutrophils that are continually released into circulation. Neutrophil levels were lower during the first trimester of the pregnancy compared to the second and third trimesters, but not affected by the presence or absence of malaria infection.

Low diagnostic performance of thick blood smears of 50 µl in comparison with direct examination of 10 µl blood and the leukoconcentration technique of 5ml blood among loiasis-suspected patients with low microfilaremia in Gabon, Central Africa, using the STARD-BLCM guidelines.

BACKGROUND: The aim of this study was to determine performance indicators of thick blood smears of 50 µl (TBS-50), following the Standards for the Reporting of Diagnostic Accuracy Studies-Bayesian Latent Class Model (STARD-BLCM) guidelines. TBS-50 was compared with two common parasitological techniques-direct examination of 10 µl blood and a leukoconcentration of 5 ml-for the diagnosis of microfilaremic loiasis. METHODS: The study population was recruited among patients of the Department of Parasitology-Mycology-Tropical Medicine over a period of 1 year. Age, sex, symptoms, and eosinophilia variables were recorded from laboratory registers and medical files. Direct examination of 10 µl of blood, TBS-50, and the leukoconcentration technique with 5 ml of blood were performed for each patient. The classical formula and BLCM were used to determine the diagnostic accuracy of the three techniques as well as the prevalence of microfilaremic loiasis. Three models were built within the framework of BLCM-the BLCM model I and alternative models II and III-for sensitivity analysis. RESULTS: In total, 191 patients consented to be included. The direct blood examination and TBS-50 yielded comparable qualitative and quantitative results. Hence, they are reported together. The prevalence of Loa loa microfilaremia was 9.4% (95% CI 5.7-14.5; n = 18/191) with direct blood examination/TBS-50 and 12.6% [8.2-18.1] (n = 24/191) for leukoconcentration. Comparing TBS-50 with the leukoconcentration method using the classical formula, the sensitivity was 75.0% [53.3-90.2], specificity was 100.0% [97.8-100.0], the positive predictive value was 100.0% [81.5-100.0], and the negative predictive value was 96.5% [92.6-98.7]. The prevalence of microfilaremic loiasis was estimated at 9.7% [6.2-13.7] using BLCM model I. The outputs of BLCM model I showed sensitivity of 78.9% [65.3-90.3], specificity of 100.0% [99.3-100.0], a positive predictive value of 99.1% [87.2-100.0], and a negative predictive value of 93.0% [87.3-97.7] for direct blood examination/TBS-50. CONCLUSIONS: TBS-50 demonstrates low sensitivity relative to two other techniques. In one in five cases, the result will be falsely declared negative using these methods. However, this method can be deployed with limited funds.