Acetazolamide in Acute Decompensated Heart Failure with Volume Overload.

BACKGROUND: Whether acetazolamide, a carbonic anhydrase inhibitor that reduces proximal tubular sodium reabsorption, can improve the efficiency of loop diuretics, potentially leading to more and faster decongestion in patients with acute decompensated heart failure with volume overload, is unclear. METHODS: In this multicenter, parallel-group, double-blind, randomized, placebo-controlled trial, we assigned patients with acute decompensated heart failure, clinical signs of volume overload (i.e., edema, pleural effusion, or ascites), and an N-terminal pro-B-type natriuretic peptide level of more than 1000 pg per milliliter or a B-type natriuretic peptide level of more than 250 pg per milliliter to receive either intravenous acetazolamide (500 mg once daily) or placebo added to standardized intravenous loop diuretics (at a dose equivalent to twice the oral maintenance dose). Randomization was stratified according to the left ventricular ejection fraction (≤40% or >40%). The primary end point was successful decongestion, defined as the absence of signs of volume overload, within 3 days after randomization and without an indication for escalation of decongestive therapy. Secondary end points included a composite of death from any cause or rehospitalization for heart failure during 3 months of follow-up. Safety was also assessed. RESULTS: A total of 519 patients underwent randomization. Successful decongestion occurred in 108 of 256 patients (42.2%) in the acetazolamide group and in 79 of 259 (30.5%) in the placebo group (risk ratio, 1.46; 95% confidence interval [CI], 1.17 to 1.82; P<0.001). Death from any cause or rehospitalization for heart failure occurred in 76 of 256 patients (29.7%) in the acetazolamide group and in 72 of 259 patients (27.8%) in the placebo group (hazard ratio, 1.07; 95% CI, 0.78 to 1.48). Acetazolamide treatment was associated with higher cumulative urine output and natriuresis, findings consistent with better diuretic efficiency. The incidence of worsening kidney function, hypokalemia, hypotension, and adverse events was similar in the two groups. CONCLUSIONS: The addition of acetazolamide to loop diuretic therapy in patients with acute decompensated heart failure resulted in a greater incidence of successful decongestion. (Funded by the Belgian Health Care Knowledge Center; ADVOR ClinicalTrials.gov number, NCT03505788.).

Real-world validation of smartphone-based photoplethysmography for rate and rhythm monitoring in atrial fibrillation.

AIMS: Photoplethysmography- (PPG) based smartphone applications facilitate heart rate and rhythm monitoring in patients with paroxysmal and persistent atrial fibrillation (AF). Despite an endorsement from the European Heart Rhythm Association, validation studies in this setting are lacking. Therefore, we evaluated the accuracy of PPG-derived heart rate and rhythm classification in subjects with an established diagnosis of AF in unsupervised real-world conditions. METHODS AND RESULTS: Fifty consecutive patients were enrolled, 4 weeks before undergoing AF ablation. Patients used a handheld single-lead electrocardiography (ECG) device and a fingertip PPG smartphone application to record 3907 heart rhythm measurements twice daily during 8 weeks. The ECG was performed immediately before and after each PPG recording and was given a diagnosis by the majority of three blinded cardiologists. A consistent ECG diagnosis was exhibited along with PPG data of sufficient quality in 3407 measurements. A single measurement exhibited good quality more often with ECG (93.2%) compared to PPG (89.5%; P < 0.001). However, PPG signal quality improved to 96.6% with repeated measurements. Photoplethysmography-based detection of AF demonstrated excellent sensitivity [98.3%; confidence interval (CI): 96.7-99.9%], specificity (99.9%; CI: 99.8-100.0%), positive predictive value (99.6%; CI: 99.1-100.0%), and negative predictive value (99.6%; CI: 99.0-100.0%). Photoplethysmography underestimated the heart rate in AF with 6.6 b.p.m. (95% CI: 5.8 b.p.m. to 7.4 b.p.m.). Bland-Altman analysis revealed increased underestimation in high heart rates. The root mean square error was 11.8 b.p.m. CONCLUSION: Smartphone applications using PPG can be used to monitor patients with AF in unsupervised real-world conditions. The accuracy of AF detection algorithms in this setting is excellent, but PPG-derived heart rate may tend to underestimate higher heart rates.

The Feasibility of Semi-Continuous and Multi-Frequency Thoracic Bioimpedance Measurements by a Wearable Device during Fluid Changes in Hemodialysis Patients.

Repeated single-point measurements of thoracic bioimpedance at a single (low) frequency are strongly related to fluid changes during hemodialysis. Extension to semi-continuous measurements may provide longitudinal details in the time pattern of the bioimpedance signal, and multi-frequency measurements may add in-depth information on the distribution between intra- and extracellular fluid. This study aimed to investigate the feasibility of semi-continuous multi-frequency thoracic bioimpedance measurements by a wearable device in hemodialysis patients. Therefore, thoracic bioimpedance was recorded semi-continuously (i.e., every ten minutes) at nine frequencies (8-160 kHz) in 68 patients during two consecutive hemodialysis sessions, complemented by a single-point measurement at home in-between both sessions. On average, the resistance signals increased during both hemodialysis sessions and decreased during the interdialytic interval. The increase during dialysis was larger at 8 kHz (∆ 32.6 Ω during session 1 and ∆ 10 Ω during session 2), compared to 160 kHz (∆ 29.5 Ω during session 1 and ∆ 5.1 Ω during session 2). Whereas the resistance at 8 kHz showed a linear time pattern, the evolution of the resistance at 160 kHz was significantly different (p < 0.0001). Measuring bioimpedance semi-continuously and with a multi-frequency current is a major step forward in the understanding of fluid dynamics in hemodialysis patients. This study paves the road towards remote fluid monitoring.

Secondary infection in COVID-19 critically ill patients: a retrospective single-center evaluation.

BACKGROUND: Patients infected with severe acute respiratory syndrome coronavirus (SARS-CoV-2) can develop severe illness necessitating intensive care admission. Critically ill patients are susceptible for the development of secondary bacterial infections. Due to a combination of virus- and drug-induced immunosuppression, critically ill patients with corona virus disease 2019 (COVID-19) may even have a higher risk of developing a secondary infection. These secondary infections can aggravate the severity of illness and increase the risk of death. Further research on secondary infections in COVID-19 patients is essential. Therefore, the objective of this study was to investigate the incidence and associated risk factors of secondary bacterial infections and to identify the most common groups of pathogens in critically ill COVID-19 patients. METHODS: This mono-center, retrospective observational cohort study was performed at the intensive care unit (ICU) of the Jessa Hospital, Hasselt, Belgium. All adult COVID-19 patients admitted to the ICU from 13th March 2020 until 17th October 2020, were eligible for inclusion in the study. Data from the resulting 116 patients were prospectively entered into a customized database. The resulting database was retrospectively reviewed to investigate three types of secondary bacterial infections (secondary pneumonia, bloodstream infections of unknown origin, catheter-related sepsis). RESULTS: Of 94 included patients, 68% acquired at least one of the studied secondary bacterial infections during their ICU stay. Almost two thirds of patients (65.96%, n = 62) acquired a secondary pneumonia, whereas 29.79% (n = 28) acquired a bacteremia of unknown origin and a smaller proportion of patients (14.89%, n = 14) acquired a catheter-related sepsis. Male gender (P = 0.05), diabetes mellitus (P = 0.03) and the cumulative dose of corticosteroids (P = 0.004) were associated with increased risk of secondary bacterial infection. The most common pathogens detected in the cultures of patients with secondary pneumonia were Gram-negative bacilli. Bacteremia of unknown origin and catheter-related sepsis were mostly caused by Gram-positive cocci. CONCLUSION: This study confirms that the incidence of secondary bacterial infections is very high in critically ill COVID-19 patients. These patients are at highest risk of developing secondary pneumonia. Male gender, a history of diabetes mellitus and the administration of corticosteroids were associated with increased risk of secondary bacterial infection.

The effect of intravenous ferric carboxymaltose on cardiac reverse remodelling following cardiac resynchronization therapy-the IRON-CRT trial.

AIMS: Iron deficiency is common in heart failure with reduced ejection fraction (HFrEF) and negatively affects cardiac function and structure. The study the effect of ferric carboxymaltose (FCM) on cardiac reverse remodelling and contractile status in HFrEF. METHODS AND RESULTS: Symptomatic HFrEF patients with iron deficiency and a persistently reduced left ventricular ejection fraction (LVEF <45%) at least 6 months after cardiac resynchronization therapy (CRT) implant were prospectively randomized to FCM or standard of care (SOC) in a double-blind manner. The primary endpoint was the change in LVEF from baseline to 3-month follow-up assessed by three-dimensional echocardiography. Secondary endpoints included the change in left ventricular end-systolic (LVESV) and end-diastolic volume (LVEDV) from baseline to 3-month follow-up. Cardiac performance was evaluated by the force-frequency relationship as assessed by the slope change of the cardiac contractility index (CCI = systolic blood pressure/LVESV index) at 70, 90, and 110 beats of biventricular pacing. A total of 75 patients were randomized to FCM (n = 37) or SOC (n = 38). At baseline, both treatment groups were well matched including baseline LVEF (34 ± 7 vs. 33 ± 8, P = 0.411). After 3 months, the change in LVEF was significantly higher in the FMC group [+4.22%, 95% confidence interval (CI) +3.05%; +5.38%] than in the SOC group (-0.23%, 95% CI -1.44%; +0.97%; P < 0.001). Similarly, LVESV (-9.72 mL, 95% CI -13.5 mL; -5.93 mL vs. -1.83 mL, 95% CI -5.7 mL; 2.1 mL; P = 0.001), but not LVEDV (P = 0.748), improved in the FCM vs. the SOC group. At baseline, both treatment groups demonstrated a negative force-frequency relationship, as defined by a decrease in CCI at higher heart rates (negative slope). FCM resulted in an improvement in the CCI slope during incremental biventricular pacing, with a positive force-frequency relationship at 3 months. Functional status and exercise capacity, as measured by the Kansas City Cardiomyopathy Questionnaire and peak oxygen consumption, were improved by FCM. CONCLUSIONS: Treatment with FCM in HFrEF patients with iron deficiency and persistently reduced LVEF after CRT results in an improvement of cardiac function measured by LVEF, LVESV, and cardiac force-frequency relationship.

Lifestyle interventions to reduce sedentary behaviour in clinical populations: A systematic review and meta-analysis of different strategies and effects on cardiometabolic health.

Cardiometabolic comorbidities are highly prevalent in clinical populations, and have been associated (partly) with their sedentary lifestyle. Although lifestyle interventions targeting sedentary behaviour (SB) have been studied extensively in the general population, the effect of such strategies in clinical populations is not yet clear. Therefore, this systematic review and meta-analysis evaluated the effect of different lifestyle interventions on SB and cardiometabolic health in clinical populations. Randomised controlled trials were collected from five bibliographic databases (PubMed, Embase, Web of Science, The Cochrane Central Register of Controlled Trials, and Scopus). Studies were eligible for inclusion if they evaluated a lifestyle intervention to reduce objectively measured SB, in comparison with a control intervention among persons with a clinical condition. Data were pooled using a random-effects meta-analysis. In total, 7094 studies were identified. Eighteen studies met the inclusion criteria and were categorised in five population groups: overweight/obesity, type 2 diabetes mellitus, cardiovascular, neurological/cognitive and musculoskeletal diseases. Participants reduced their SB by 64 min/day (95%CI: [-91, -38] min/day; p < 0.001), with larger within-group differences of multicomponent behavioural interventions including motivational counselling, self-monitoring, social facilitation and technologies (-89 min/day; 95%CI: [-132, -46] min/day; p < 0.001). Blood glycated haemoglobin concentration (-0.17%; 95% CI: [-0.30, -0.04]%; p = 0.01), fat percentage (-0.66%; 95% CI: [-1.26, -0.06]%, p = 0.03) and waist circumference (-1.52 cm; 95%CI: [-2.84, -0.21] cm; p = 0.02) were significantly reduced in the intervention groups compared to control groups. Behavioural lifestyle interventions reduce SB among clinical populations and improve cardiometabolic risk markers such as waist circumference, fat percentage, and glycaemic control. Sedentary behaviour, Cardiometabolic health, Clinical populations.

Determinants of exposure levels of bisphenols in flemish adolescents.

The broadly used industrial chemical bisphenol A (BPA), applied in numerous consumer products, has been under scrutiny in the past 20 years due to its widespread detection in humans and the environment and potential detrimental effects on human health. Following implemented restrictions and phase-out initiatives, BPA is replaced by alternative bisphenols, which have not received the same amount of research attention. As a part of the fourth cycle of the Flemish Environment and Health Study (FLEHS IV, 2016-2020), we monitored the internal exposure to six bisphenols in urine samples of 423 adolescents (14-15 years old) from Flanders, Belgium. All measured bisphenols were detected in the study population, with BPA and its alternatives bisphenol F (BPF) and bisphenol S (BPS) showing detection frequencies > 50%. The reference values show that exposure to these compounds is extensive. However, the urinary BPA level decreased significantly in Flemish adolescents compared to a previous cycle of the FLEHS (2008-2009). This suggests that the replacement of BPA with its analogues is ongoing. Concentrations of bisphenols measured in the Flemish adolescents were generally in the same order of magnitude compared to recent studies worldwide. Multiple regression models were used to identify determinants of exposure based on information on demographic and lifestyle characteristics of participants, acquired through questionnaires. Some significant determinants could be identified: sex, season, smoking behavior, educational level of the parents, recent consumption of certain foods and use of certain products were found to be significantly associated with levels of bisphenols. Preliminary risk assessment showed that none of the estimated daily intakes (EDIs) of BPA exceeded the tolerable daily intake, even in a high exposure scenario. For alternative bisphenols, no health-based guidance values are available, but in line with the measured urinary levels, their EDIs were lower than that of BPA. This study is, to the best of our knowledge, the first to determine internal exposure levels of other bisphenols than BPA in a European adolescent population.

Long-term residential exposure to air pollution is associated with hair cortisol concentration and differential leucocyte count in Flemish adolescent boys.

BACKGROUND: Exposure to air pollution and traffic noise are associated with adverse health outcomes in adolescents. Chronic endocrine stress and systemic inflammation have been hypothesized to underlie the adverse health effects. Simultaneous assessment of inflammation and chronic endocrine stress in epidemiological studies is lacking. The aim of the study was to investigate biomarkers of chronic endocrine stress and inflammation in relation to long-term residential exposure to air pollution and traffic noise in adolescents. METHODS: In Flemish adolescents (14-15 years), we determined hair cortisol concentration (HCC) as a chronic stress biomarker in 3-cm scalp-near hair sections (n = 395), and leucocyte and leucocyte subtype counts (neutrophils, monocytes, lymphocytes) as inflammatory biomarkers in peripheral blood (n = 385). Daily particulate matter (PM2.5, PM10), nitrogen dioxide (NO2) and black carbon (BC) concentrations were modelled at the residential address and averaged over 3-month and 1-year periods prior to sampling. Residential traffic noise level was estimated and classified in 5 dB intervals. Sex-specific associations between residential exposures and effect biomarkers were studied using linear regression models, adjusted for a priori selected covariates. RESULTS: In boys, HCC increased with a factor 1.30 (95% CI: 1.10, 1.54) for an increase in 1-year mean NO2 from the 25th to 75th percentile (p75/p25), after adjustment for age, BMI, personal and neighborhood socioeconomic status. The corresponding estimate for PM10 was 1.24 (95% CI: 1.02, 1.51). Total leucocyte count in boys, adjusted for the aforementioned covariates and recent health complaints, was positively associated with PM2.5, PM10, NO2 and BC. In particular, the neutrophil count increased with a factor 1.11 (95% CI: 1.03, 1.19) for a (p75/p25)-factor increase in 1-year mean BC, corresponding estimates for PM2.5, PM10 and NO2 were 1.10 (95% CI: 1.01, 1.19), 1.10 (95% CI: 1.01, 1.20) and 1.08 (95% CI: 1.00, 1.16). Lymphocyte count increased with a factor 1.05 (95% CI: 1.01, 1.10) for a (p75/p25)-factor increase in 1-year mean NO2. Similar results were observed for 3-month mean exposures. Results were robust to adjustment for recent air pollution exposure. In girls, air pollutants were not associated with HCC or differential leucocyte count. Residential traffic noise level was not associated with HCC or leucocyte counts in boys nor girls. CONCLUSIONS: Long-term residential exposure to air pollutants was positively associated with chronic endocrine stress and inflammation in adolescent boys, not in girls. This study may contribute to a better understanding of the early pathophysiological changes that may underlie adverse health effects of air pollution exposure in adolescents.

Citrate dose for continuous hemofiltration: effect on calcium and magnesium balance, parathormone and vitamin D status, a randomized controlled trial.

BACKGROUND: Regional citrate anticoagulation may cause a negative calcium balance, systemic hypocalcemia and parathormone (PTH) activation but randomzed studies are not available. Aim was to determine the effect of citrate dose on calcium (Ca) and magnesium (Mg) balance, PTH and Vitamin D. METHODS: Single center prospective randomized study. Patients, requiring continuous venovenous hemofiltration (CVVH) with citrate, randomized to low dose citrate (2.5 mmol/L) vs. high dose (4.5 mmol/L) for 24 h, targeting post-filter ionized calcium (pfiCa) of 0.325-0.4 mmol/L vs. 0.2-0.275 mmol/L, using the Prismaflex® algorithm with 100% postfilter calcium replacement. Extra physician-ordered Ca and Mg supplementation was performed aiming at systemic iCa > 1.0 mmol/L. Arterial blood, effluent and post-filter aliquots were taken for balance calculations (area under the curve), intact (i), oxidized (ox) and non-oxidized (nox) PTH, 25-hydroxy-Vitamin D (25D) and 1,25-dihydroxy-Vitamin D (1,25D). RESULTS: 35 patients were analyzed, 17 to high, 18 to low citrate. Mean 24-h Ca balance was - 9.72 mmol/d (standard error 1.70) in the high vs - 1.18 mmol/d (se 1.70)) (p = 0.002) in the low citrate group and 24-h Mg-balance was - 25.99 (se 2.10) mmol/d vs. -17.63 (se 2.10) mmol/d (p = 0.008) respectively. Physician-ordered Ca supplementation, higher in the high citrate group, resulted in a positive Ca-balance in both groups. iPTH, oxPTH or noxPTH were not different between groups. Over 24 h, median PTH decreased from 222 (25th-75th percentile 140-384) to 162 (111-265) pg/ml (p = 0.002); oxPTH from 192 (124-353) to 154 pg/ml (87-231), p = 0.002. NoxPTH did not change significantly. Mean 25 D (standard deviation), decreased from 36.5 (11.8) to 33.3 (11.2) nmol/l (p = 0.003), 1,25D rose from 40.9 pg/ml (30.7) to 43.2 (30.7) pg/ml (p = 0.046), without differences between groups. CONCLUSIONS: A higher citrate dose caused a more negative CVVH Ca balance than a lower dose, due to a higher effluent Calcium loss. Physician-ordered Ca supplementation, targeting a systemic iCa > 1.0 mmol/L, higher in the high citrate group, resulted in a positive Ca-balance in both groups. iPTH and oxPTH declined, suggesting decreased oxidative stress, while noxPTH did not change. 25D decreased while 1,25-D rose. Mg balance was negative in both groups, more so in the high citrate group. TRIAL REGISTRATION: ClinicalTrials.gov : NCT02194569. Registered 18 July 2014.

On-site testing and case management to improve hepatitis C care in drug users: a prospective, longitudinal, multicenter study in the DAA era.

BACKGROUND: Screening and treatment of hepatitis C virus (HCV) infection in people who use drugs (PWUD) remains insufficient. Reducing the burden of HCV infection in PWUD requires interventions focusing on the different steps of the HCV care cascade. METHODS: We performed a prospective, multicenter study, evaluating the impact of an HCV care model on the HCV care cascade among PWUD attending an addiction care center in Belgium between 2015 and 2018. Interventions within the care model consisted of pre-test counseling, on-site HCV screening and case management services. A multiple logistic regression model was performed to identify the independent factors influencing the outcomes. RESULTS: During the study period, 441 PWUD were registered at the addiction care center, 90% (395/441) were contacted, 88% (349/395) were screened for HCV infection. PWUD were more likely to be screened if they had ever injected drugs (p < .001; AOR 6.411 95% CI 3.464-11.864). In 45% (157/349), the HCV antibody (Ab) test was positive, and in 27% (94/349) HCV RNA was positive. Within the Belgian reimbursement criteria (fibrosis stage ≥ F2), 44% (41/94) were treated. Specialist evaluation at the hospital was lower for PWUD receiving decentralized opioid agonist therapy (p = .005; AOR 0.430 95% CI 0.005-0.380), PWUD with unstable housing in the past 6 months before inclusion (p = .015; AOR 0.035 95% CI 0.002-0.517) or if they were recently incarcerated (p = .001; AOR 0.010 95% CI 0.001-0.164). CONCLUSIONS: This HCV care model demonstrated high screening, linkage to care, and treatment initiation among PWUD in Belgium. Using the cascade of care to guide interventions is easy and necessary to monitor results. This population needs guidance, not only for screening and treatment initiation but also for the long-term follow-up since one in six had cirrhosis and could develop hepatocellular carcinoma. Further interventions are necessary to increase linkage to care and treatment initiation. Universal access to direct-acting antiviral therapy from 2019 will contribute to achieving HCV elimination in the PWUD population. TRIAL REGISTRATION: Clinical trial registration details: www.clinicaltrials.gov ( NCT03106194 ).

Gestational hypertensive disorders show unique patterns of circulatory deterioration with ongoing pregnancy.

A combined assessment of heart, arteries, veins, and body fluid content throughout pregnancy has not yet been reported. We hypothesized that a gradual aggravation of circulatory dysfunction exists from the latent to the clinical phase of gestational hypertensive disease (GHD), and that pathways are unique for preeclampsia with early onset < 34 wk (EPE) and late onset ≥ 34 wk (LPE), and gestational hypertension (GH). Women with singleton pregnancy and no known diseases were invited for a prospective, observational study and had standardized sphygmomanometric blood pressure measurement, bioimpedance body water spectrum analysis, impedance cardiography for cardiac and arterial assessment, and combined Doppler-ECG of hepatic and renal interlobar veins and uterine arteries. Outcome was categorized as uncomplicated (UP, n = 1,700), EPE ( n = 87), LPE ( n = 218), or GH ( n = 188). A linear mixed model for repeated measurements, corrected for age, parity, and body mass index, was employed in SAS 9.4 to analyze trimestral changes within and between groups. From the first to the third trimester, body water increased in all groups, and an increasing number of abnormal parameters relative to UP occurred in all GHD. First-trimester blood pressure and peripheral resistance were higher in GHD than UP, together with increased uterine flow resistance and extracellular water in EPE, and with lower heart rate and aorta flow velocity in LPE. An overall gestational rise of body water volumes coexists with a gradual worsening of cardiovascular dysfunction in GHD, of which pathophysiological pathways are unique for EPE, LPE, and GH, respectively.

Obesity in pregnancy causes a volume overload in third trimester.

BACKGROUND: Obesity is a major risk factor for cardiovascular diseases. In this study, we aimed to investigate the maternal circulatory differences during pregnancy between obese and normal weight women. MATERIALS AND METHODS: The functioning of the maternal circulation (arteries, veins, heart and body fluid) was assessed by ECG-Doppler ultrasound, impedance cardiography (ICG) and bio-impedance during pregnancy in obese women (BMI ≥30 kg/m2 ) and normal weight, nonobese women (BMI 20-25 kg/m2 ). In this observational study, 232 assessments were performed in the obese group, whereas 919 assessments were performed in the nonobese group. RESULTS: Relative to nonobese women, the overall cardiovascular function in obese women during first and second trimester is consistent with a high volume/low-resistance circulation. In third trimester, cardiac output of obese women decreases from 9.2 (8.2-10.7) L/min to 8.5 (7.6-9.6) L/min (P = .037) whereas this is not true in the nonobese women (from 7.8 (7-8.5) L/min to 7.8 (6.8-8.9) L/min, P = .536). Simultaneously, the persistently lower peripheral vascular resistance in obese vs nonobese women disappears (880 (761-1060) dyn.sec/cm5 vs 928 (780-1067). CONCLUSIONS: The circulatory gestational adaptations between nonobese and obese women were generally similar. The findings in the third trimester suggest that a pregnancy in obese women start as a state of high volume/low resistance, gradually shifting to a volume overload with decrease of cardiac output and disappearance of low vascular resistance. This evolution makes obese women vulnerable for gestational hypertensive diseases.

Development of a biophysical screening model for gestational hypertensive diseases.

BACKGROUND: To investigate the possibility of using maternal biophysical parameters only in screening for the different types of gestational hypertensive diseases. METHODS: A total of 969 pregnant women were randomly screened in first and second trimester, of which 8 developed Early-onset Preeclampsia, 29 Late-onset Preeclampsia, 35 Gestational Hypertension and 897 women had a normal outcome. An observational maternal hemodynamics assessment was done via standardized electrocardiogram-Doppler ultrasonography, Impedance Cardiography and bio-impedance, acquiring functional information on heart, arteries, veins and body fluid. Preliminary prediction models were developed to test the screening potential for early preeclampsia, late preeclampsia and gestational hypertension using a Partial Least Square Discriminant Analysis. RESULTS: A combined model using maternal characteristics with cardiovascular parameters in first and second trimester offers high screening performance with Area Under the Curve of 99,9% for Early-onset Preeclampsia, 95,3% for Late-onset Preeclampsia and 94% for Gestational Hypertension. CONCLUSIONS: Using biophysical parameters as fundament for a new prediction model, without the need of biochemical parameters, seems feasible. However, validation in a large prospective study will reveal its true potential.

Exposure to Environmental Pollutants and Their Association with Biomarkers of Aging: A Multipollutant Approach.

Mitochondrial DNA (mtDNA) content and telomere length are putative aging biomarkers and are sensitive to environmental stressors, including pollutants. Our objective was to identify, from a set of environmental exposures, which exposure is associated with leukocyte mtDNA content and telomere length in adults. This study includes 175 adults from 50 to 65 years old from the cross-sectional Flemish Environment and Health study, of whom leukocyte telomere length and mtDNA content were determined using qPCR. The levels of exposure of seven metals, 11 organohalogens, and four perfluorinated compounds (PFHxS, PFNA, PFOA, PFOS) were measured. We performed sparse partial least-squares regression analyses followed by ordinary least-squares regression to assess the multipollutant associations. While accounting for possible confounders and coexposures, we identified that urinary cadmium (6.52%, 95% confidence interval, 1.06, 12.28), serum hexachlorobenzene (2.89%, 018, 5.68), and perfluorooctanesulfonic acid (11.38%, 5.97, 17.08) exposure were positively associated ( p < 0.05) with mtDNA content, while urinary copper (-9.88%, -14.82, -4.66) and serum perfluorohexanesulfonic acid (-4.75%, -8.79, -0.54) exposure were inversely associated with mtDNA content. Urinary antimony (2.69%, 0.45, 4.99) and mercury (1.91%, 0.42, 3.43) exposure were positively associated with leukocyte telomere length, while urinary copper (-3.52%, -6.60, -0.34) and serum perfluorooctanesulfonic acid (-3.64%, -6.60, -0.60) showed an inverse association. Our findings support the hypothesis that environmental pollutants interact with molecular hallmarks of aging.

Intelligence gain and social cost savings attributable to environmental lead exposure reduction strategies since the year 2000 in Flanders, Belgium.

BACKGROUND: Recent lead (Pb) exposure reduction strategies enabled to lower children's blood lead levels (B-Pb) worldwide. This study reports the estimated intelligence gain and social cost savings attributable to recent exposure reduction based on reported B-Pb levels observed in adolescents sampled within the framework of the Flemish Environment and Health Studies (FLEHS, Belgium), i.e. in 2003-2004 (FLEHSI), in 2008-2009 (FLEHSII), and in 2013-2014 (FLEHSIII). METHODS: Intelligence Quotient (IQ) loss per 100,000 individuals - attributable to B-Pb above 20 µg/L - was estimated based on widely accepted dose response functions between children's B-Pb and IQ (- 1.88 IQ points for a duplication in B-Pb from 20 µg/L onwards; 95% Confidence Interval (CI): - 1.16;-2.59) and B-Pb exposure distribution parameters of FLEHS studies. The results were translated to the Flemish population of 15-year-olds. Given a 3-year time gap between subsequent sampling periods, the exposure distribution of each study was assumed 3 years prior to the study as well. Economic impact was estimated based on expected decrease in lifetime earnings (€ 19,464 per decreasing IQ point in 2018). RESULTS: The percentage of the adolescent population exceeding a B-Pb of 20 µg/L decreased from 57% (FLEHSI) to 23% (FLEHSII), and even further to 2.5% (FLEHSIII). The estimated IQ loss per 100,000 individuals was 94,280 (95% CI: 58,427-130,138) in FLEHSI, 14,993 (95% CI: 9289-20,695) in FLEHSII, and 976 (95% CI: 604-1347) in FLEHSIII. This translates into a total loss of 378,962 (95%CI: 234,840-523,091) IQ points within the Flemish population of 15-year-olds between 2000 and 2014. Assuming that current exposure levels do not reincrease, the expected IQ loss during the subsequent period of 15 years is estimated to be maximally 10,275 (95%CI: 6363-14,182) points. CONCLUSIONS: 7176 (95%CI: 4447-9905) million € of social cost savings were achieved by Pb reduction strategies in Flanders over 15 years. If current exposure levels further reduce to B-Pb below 20 µg/L for the whole population, social cost savings may increase up to 7376 (95%CI: 4571-10,181) million €. Given the relatively low lead contamination in Flanders, the global impact of ongoing reduction strategies is expected to be tremendous.

Effect of play-based family-centered psychomotor/psychosocial stimulation on the development of severely acutely malnourished children under six in a low-income setting: a randomized controlled trial.

BACKGROUND: The World Health Organization (WHO) recommends incorporating psychosocial stimulation into the management of severe acute malnutrition (SAM). However, there is little evidence about the effectiveness of these interventions for SAM children, particularly when serious food shortages and lack of a balanced diet prevail. The objective of this study was to examine whether family-based psychomotor/psychosocial stimulation in a low-income setting improves the development, linear growth, and nutritional outcomes in children with SAM. METHOD: Children with SAM (N = 339) admitted for treatment to the Jimma University Specialized Hospital, Ethiopia, were randomized to a control (n = 170) or intervention (n = 169) group. Both groups received routine medical care and nutritional treatment at the hospital. The intervention group additionally received play-based psychomotor/psychosocial stimulation during their hospital stay, and at home for 6 months after being discharged from hospital. The fine motor (FM) and gross motor (GM) functions, language (LA) and personal-social (PS) skills of the children were assessed using adapted Denver II, the social-emotional (SE) behavior was assessed using adapted Ages and Stages Questionnaires: Social-Emotional, and the linear growth and nutritional status were determined through anthropometric assessments. All outcomes were assessed before the intervention, upon discharge from hospital, and 6 months after discharge (as end-line). The overtime changes of these outcomes measured in both groups were compared using Generalized Estimating Equations. RESULTS: The intervention group improved significantly on GM during hospital follow-up by 0.88 points (p < 0.001, effect size = 0.26 SD), and on FM functions during the home follow-up by 1.09 points (p = 0.001, effect size = 0.22 SD). Both young and older children benefited similarly from the treatment. The intervention did not contribute significantly to linear growth and nutritional outcomes. CONCLUSION: Psychomotor/psychosocial stimulation of SAM children enhances improvement in gross motor functions when combined with standard nutrient-rich diets, but it can enhance the fine motor functions even when such standard dietary care is not available. TRIAL REGISTRATION: The trial was retrospectively registered on 30 January 2017 at the US National Institute of Health (ClinicalTrials.gov) # NCT03036176 .

Random effects models for estimation of the probability and time to progression of a continuous biomarker.

Biomarkers play a key role in the monitoring of disease progression. The time taken for an individual to reach a biomarker exceeding or lower than a meaningful threshold is often of interest. Due to the inherent variability of biomarkers, persistence criteria are sometimes included in the definitions of progression, such that only two consecutive measurements above or below the relevant threshold signal that "true" progression has occurred. In previous work, a novel approach was developed, which allowed estimation of the time to threshold using the parameters from a linear mixed model where the residual variance was assumed to be pure measurement error. In this paper, we extend this methodology so that serial correlation can be accommodated. Assuming that the Markov property holds and applying the chain rule of probabilities, we found that the probability of progression at each timepoint can be expressed simply as the product of conditional probabilities. The methodology is applied to a cohort of HIV positive individuals, where the time to reach a CD4 count threshold is estimated. The second application we present is based on a study on abdominal aortic aneurysms, where the time taken for an individual to reach a diameter exceeding 55 mm is studied. We observed that erroneously ignoring the residual correlation when it is strong may result in substantial overestimation of the time to threshold. The estimated probability of the biomarker reaching a threshold of interest, expected time to threshold, and confidence intervals are presented for selected patients in both applications.

Low Volume Circulation in Normotensive Women Pregnant with Neonates Small for Gestational Age.

BACKGROUND: Pregnancies complicated with small for gestational age (SGA) neonates are reported with maternal circulatory maladaptations. OBJECTIVES: We aimed to understand the pathophysiology of the maternal circulation in normotensive SGA pregnancies and to point out the trimestral differences from those with appropriate-to-large (non-SGA [NGA]) neonates. METHODS: An observational study was conducted in 3 trimestral cohorts of normotensive pregnancies, categorized after birth according to neonatal birth weight percentile (BW%) as SGA (BW% ≤10, n = 158) or NGA (BW% > 10, n = 1,038). Standardized electrocardiogram-Doppler ultrasound, impedance cardiography, and bio-impedance were used to assess the maternal heart, arteries, veins, and fluid. RESULTS: Diastolic blood pressure and mean arterial pressure were not significantly different, unless in the third trimester. In SGA compared to NGA pregnancies, total peripheral resistance (TPR) was higher and total arterial compliance, cardiac output (CO), and total body water (TBW) were lower throughout pregnancy. Venous return-enhancing functions were activated. In NGA but not SGA pregnancies, a positive correlation was found between BW% and CO + TBW and a negative correlation between BW% and TPR. CONCLUSIONS: SGA pregnancies are characterized by lower maternal body fluid volume and CO, while normal blood pressures are maintained via increased TPR already from the first trimester onwards. Pregnancy-induced hemodynamic changes are superimposed on these characteristics.

Cord blood leptin and insulin levels in association with mitochondrial DNA content.

BACKGROUND: The developmental origins of health and disease theory states that a disturbance in the early life environment can contribute to disease risk in later life. Leptin and insulin are anorectic hormones involved in energy homeostasis and are crucial for foetal growth. Disturbances in the levels of these hormones contribute to obesity and diabetes. In adults, altered mitochondrial function is an important hallmark of metabolic disorders, including obesity and diabetes. However, the mitochondrial effects of early life metabolic variation are unexplored. We investigated whether there is an association between metabolic hormones and mitochondrial DNA (mtDNA) content in early life. METHODS: The study included 236 newborns from the FLEHS III birth cohort, Flanders (Belgium). Relative mtDNA content of cord blood leukocytes was determined using quantitative PCR. Cord blood levels of leptin and insulin were determined using immunoassays. We studied the association between these metabolic hormones and mtDNA content using multiple linear regression models, while accounting for covariates and potential confounders. RESULTS: Leptin and insulin levels were positively associated with cord blood mtDNA content. mtDNA content was respectively 4.49% (95% CI 1.15-7.93; p = 0.008) and 1.60% (95% CI 0.31-2.91; p = 0.02) higher for a interquartile range increase of respectively cord blood leptin and insulin levels. In a sensitivity analysis, we observed that insulin and leptin were independently associated to mtDNA content and that insulin was stronger associated to mtDNA content in boys than in girls. CONCLUSION: Neonatal metabolic hormones were associated with cord blood mtDNA content, which suggests that in early life the variation of mtDNA content might accommodate or reflect changes in the metabolic status.

Cluster analysis for repeated data with dropout: Sensitivity analysis using a distal event.

Degeneration of the aortic wall becomes life-threatening when the risk of rupture increases. Cluster analysis on repeated measures of the diameter of the artery revealed two subgroups of patients included in a surveillance program. These results were obtained under the assumption of missingness at random. In this article, we study the vulnerability of the cluster analysis results - the estimated trajectories and the posterior membership probabilities - by applying different missing-data models for non-ignorable dropout, as proposed by Muthen et al. (2011) to the growth of the diameter of the artery.