Combustion-Derived Pollutants Linked with Kidney Disease in Low-Lying Flood-Affected Areas in the Balkans.

Tens of thousands of people in southern Europe suffer from Balkan endemic nephropathy (BEN), and four times as many are at risk. Incidental ingestion of aristolochic acids (AAs), stemming from the ubiquitousAristolochia clematitis(birthwort) weed in the region, leads to DNA adduct-induced toxicity in kidney cells, the primary cause of BEN. Numerous cofactors, including toxic organics and metals, have been investigated, but all have shown small contributions to the overall BEN relative to non-BEN village distribution gradients. Here, we reveal that combustion-derived pollutants from wood and coal burning in Serbia also contaminate arable soil and test as plausible causative factors of BEN. Using a GC-MS screening method, biomass-burning-derived furfural and coal-burning-derived medium-chain alkanes were detected in soil samples from BEN endemic areas levels at up to 63-times and 14-times higher, respectively, than in nonendemic areas. Significantly higher amounts were also detected in colocated wheat grains. Coexposure studies with cultured kidney cells showed that these pollutants enhance DNA adduct formation by AA, - the cause of AA nephrotoxicity and carcinogenicity. With the coincidence of birthwort-derived AAs and the widespread practice of biomass and coal burning for household cooking and heating purposes and agricultural burning in rural low-lying flood-affected areas in the Balkans, these results implicate combustion-derived pollutants in promoting the development of BEN.

Aortic Valve Replacement Versus Conservative Treatment in Asymptomatic Severe Aortic Stenosis: The AVATAR Trial.

BACKGROUND: Surgical aortic valve replacement (SAVR) represents a class I indication in symptomatic patients with severe aortic stenosis (AS). However, indications for early SAVR in asymptomatic patients with severe AS and normal left ventricular function remain debated. METHODS: The AVATAR trial (Aortic Valve Replacement Versus Conservative Treatment in Asymptomatic Severe Aortic Stenosis) is an investigator-initiated international prospective randomized controlled trial that evaluated the safety and efficacy of early SAVR in the treatment of asymptomatic patients with severe AS, according to common criteria (valve area ≤1 cm2 with aortic jet velocity >4 m/s or a mean transaortic gradient ≥40 mm Hg), and with normal left ventricular function. Negative exercise testing was mandatory for inclusion. The primary hypothesis was that early SAVR would reduce the primary composite end point of all-cause death, acute myocardial infarction, stroke, or unplanned hospitalization for heart failure compared with a conservative strategy according to guidelines. The trial was designed as event-driven to reach a minimum of 35 prespecified events. The study was performed in 9 centers in 7 European countries. RESULTS: Between June 2015 and September 2020, 157 patients (mean age, 67 years; 57% men) were randomly allocated to early surgery (n=78) or conservative treatment (n=79). Follow-up was completed in May 2021. Overall median follow-up was 32 months: 28 months in the early surgery group and 35 months in the conservative treatment group. There was a total of 39 events, 13 in early surgery and 26 in the conservative treatment group. In the early surgery group, 72 patients (92.3%) underwent SAVR with operative mortality of 1.4%. In an intention-to-treat analysis, patients randomized to early surgery had a significantly lower incidence of primary composite end point than those in the conservative arm (hazard ratio, 0.46 [95% CI, 0.23-0.90]; P=0.02). There was no statistical difference in secondary end points, including all-cause mortality, first heart failure hospitalizations, major bleeding, or thromboembolic complications, but trends were consistent with the primary outcome. CONCLUSIONS: In asymptomatic patients with severe AS, early surgery reduced a primary composite of all-cause death, acute myocardial infarction, stroke, or unplanned hospitalization for heart failure compared with conservative treatment. This randomized trial provides preliminary support for early SAVR once AS becomes severe, regardless of symptoms. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02436655.

Fabrication of a Simple and Efficient HPLC Reduction Column for Online Conversion of Aristolochic Acids to Aristolactams Prior to Sensitive Fluorescence Detection.

Aristolochic acids (AAs) are nephrotoxic and carcinogenic nitrophenanthrene carboxylic acids produced naturally by plants from the Aristolochia and Asarum genera, which have been used extensively as herbal medicines. In addition to consuming AA-containing herbal medicinal products, there is emerging evidence that humans are also exposed to AA through the environment. In 2022, the World Health Organization (WHO) called for global action to remove AA exposure sources and to implement preventative measures against the development of AA-associated cancers. Herein, we report the development of a simple and efficient iron powder-packed reduction column that allows online post-column conversion of the nonfluorescing AA to its corresponding strongly fluorescing aristolactam (AL), facilitating the sensitive and selective detection of AA in herbal medicinal products, food grain, arable soil, or groundwater samples by high-performance liquid chromatography with fluorescence detection. Moreover, AL, a group of naturally occurring derivatives of AA that have demonstrated toxicity to cultured bacteria, human cells, and rats, is monitored and quantified simultaneously with AA in one single run without sacrificing sensitivity. In comparison with existing analytical methods for AA measurement, the newly developed method is not only inexpensive and less laborious, but it also offers improved sensitivity. We believe this novel method will find wide application in identifying the presence of AA in food, herbal medicines, and environmental samples, thus assisting in the identification and removal of AA exposure sources.

Effects of Diet on Aristolochic Acid-DNA Adduct Formation: Implications for Balkan Endemic Nephropathy Etiology.

Prolonged exposure to aristolochic acids (AAs) through AA-containing herbal medicine or AA-contaminated food is associated with the development of aristolochic acid nephropathy (AAN) and Balkan endemic nephropathy (BEN), both public health risks to which the World Health Organization is calling for global action to remove exposure sources. The AA exposure-induced DNA damage is believed to be related to both the nephrotoxicity and carcinogenicity of AA observed in patients suffering from BEN. While the chemical toxicology of AA is well-studied, we investigated in this study the understated effect of different nutrients, food additives, or health supplements on DNA adduct formation by aristolochic acid I (AA-I). By culturing human embryonic kidney cells in an AAI-containing medium enriched with different nutrients, results showed that cells cultured in fatty acid-, acetic acid-, and amino acid-enriched media produced ALI-dA adducts at significantly higher frequencies than that cultured in the normal medium. ALI-dA adduct formation was most sensitive to amino acids, indicating that amino acid- or protein-rich diets might lead to a higher risk of mutation and even cancer. On the other hand, cells cultured in media supplemented with sodium bicarbonate, GSH, and NAC reduced ALI-dA adduct formation rates, which sheds light on their potential use as risk-mitigating strategies for people at risk of AA exposure. It is anticipated that the results of this study will help to better understand the effect of dietary habits on cancer and BEN development.

Occupational radiation exposure of electrophysiology staff with reproductive potential and during pregnancy: an EHRA survey.

AIMS: Electrophysiology (EP) is a growing field in cardiology, with an increasing involvement of young people. Nevertheless, concerns about radiation exposure and its impact on reproduction and pregnancy may discourage the choice of an EP career. The study is aimed at investigating the level of awareness and main sources of concern about the effects of radiation on reproductive potential and pregnancy, exploring the safety measures adopted in different EP labs, and verifying the adherence to the current guidelines. METHODS AND RESULTS: An online survey was conducted using the European Heart Rhythm Association (EHRA) infrastructure from April to June 2022. A total of 252 EP personnel (42% women) participated, from 50 countries and different professional roles. Most participants expressed concerns regarding the effects of radiation on reproductive capacity (67.1%) and offspring diseases (68.2%). Only 37.9% of participants were aware of the EHRA 2017 consensus document about occupational radiation exposure. Most participants (80.9%) considered that occupational radiation during pregnancy is not safe. EP female staff were not allowed to work in the EP lab during pregnancy in 48.1% of cases. Zero-fluoroscopy was the preferred choice to continue working in the EP lab during pregnancy. CONCLUSION: EP staff, including both men and women, have concerns about the effects of radiation on reproductive capacity. Despite the recommendations issued by international bodies, implementation of the policies regarding pregnancy and occupational radiation exposure is heterogeneous. Zero-fluoroscopy is the preferred approach to ensure safety during pregnancy in the EP lab.

Enterobacter cloacae septicemia in a triple-cannula extracorporeal membrane oxygenation circulatory support treated with Seraph-100 Microbind affinity blood filter.

Bloodstream infections (BSI) are frequently encountered during extracorporeal membrane oxygenation (ECMO) support. Once septicemia is observed, treatment should be rapid, adequate, and multifaceted, particularly in advanced ECMO configurations. We report on a case of a 60-year-old male patient with acute-on-chronic heart failure due to ischemic cardiomyopathy. The treatment was complicated by cardiogenic shock requiring veno-arterial ECMO support, and, due to persistent pulmonary congestion, an upgrade with an additional left-atrial drainage cannula. After seven days of ECMO support, septicemia with shock ensued. Ex iuvantibus antibiotic treatment was started promptly. We wanted to minimize the likelihood of bacterial biofilm build-up requiring an exchange of the ECMO circuit and cannula, which was expected to be challenging. Therefore, we added a Seraph-100 Microbind affinity blood filter (providing blood purification with the potential for rapid bacterial clearance) to the ECMO circuit. Initial blood cultures tested positive for Enterobacter cloacae. Following a course of Seraph-100 treatment, bacteremia, septicemia, and shock resolved. There was no need for a circuit or cannula exchange. The additional eleven days of ECMO support were uneventful. The patient was successfully bridged to long-term mechanical circulatory support. We believe that the synergistic effect of early implementation of both broad-spectrum antibiotic treatment and blood purification with the potential for rapid bacterial clearance (such as the one provided with the Seraph-100 Microbind affinity blood filter) is crucial in BSI in patients receiving advanced ECMO.

Initial rhythm control with cryoballoon ablation vs drug therapy: Impact on quality of life and symptoms.

BACKGROUND: Cryoballoon ablation (CBA) as a first-line rhythm control strategy is superior to antiarrhythmic drugs (AADs) for preventing atrial fibrillation (AF) recurrence; the impact of first-line CBA on quality of life (QoL) and symptoms has not been well characterized. METHODS: Patients aged 18 to 75 with symptomatic paroxysmal AF naïve to rhythm control therapy were randomized (1:1) to CBA (Arctic Front Advance, Medtronic) or AAD (Class I or III). Symptoms and QoL were assessed at baseline, 1, 3, 6, 9, and 12 months using the EHRA classification and Atrial Fibrillation Effect on QualiTy-of-Life (AFEQT) and SF-36v2 questionnaires. Symptomatic palpitations were evaluated via patient diary. RESULTS: Overall, 107 patients were randomized to CBA and 111 to AAD; crossovers occurred in 9%. Larger improvements in the AFEQT summary, subscale and treatment satisfaction scores were observed at 12 months with CBA vs AAD (all P <0.05). At 12 months, the mean adjusted difference in the AFEQT summary score was 9.9 points higher in the CBA group (95% CI: 5.5 -14.2, P <0.001). Clinically important improvements in the SF-36 physical and mental component scores were observed at 12 months in both groups, with no significant between group differences at this timepoint. In the CBA vs AAD group, larger improvements in EHRA class were observed at 6, 9 and 12 months (P <0.05) and the incidence rate of symptomatic palpitations was lower (4.6 vs 15.2 days/year post-blanking; IRR: 0.30, P <0.001). CONCLUSIONS: In patients with symptomatic AF, first-line CBA was superior to AAD for improving AF-specific QoL and symptoms. TRIAL REGISTRATION: ClinicalTrials.gov number: NCT01803438.

Current perspectives on wearable rhythm recordings for clinical decision-making: the wEHRAbles 2 survey.

Novel wearable devices for heart rhythm analysis using either photoplethysmography (PPG) or electrocardiogram (ECG) are in daily clinical practice. This survey aimed to assess impact of these technologies on physicians' clinical decision-making and to define, how data from these devices should be presented and integrated into clinical practice. The online survey included 22 questions, focusing on the diagnosis of atrial fibrillation (AF) based on wearable rhythm device recordings, suitable indications for wearable rhythm devices, data presentation and processing, reimbursement, and future perspectives. A total of 539 respondents {median age 38 [interquartile range (IQR) 34-46] years, 29% female} from 51 countries world-wide completed the survey. Whilst most respondents would diagnose AF (83%), fewer would initiate oral anticoagulation therapy based on a single-lead ECG tracing. Significantly fewer still (27%) would make the diagnosis based on PPG-based tracing. Wearable ECG technology is acceptable for the majority of respondents for screening, diagnostics, monitoring, and follow-up of arrhythmia patients, while respondents were more reluctant to use PPG technology for these indications. Most respondents (74%) would advocate systematic screening for AF using wearable rhythm devices, starting at patients' median age of 60 (IQR 50-65) years. Thirty-six percent of respondents stated that there is no reimbursement for diagnostics involving wearable rhythm devices in their countries. Most respondents (56.4%) believe that costs of wearable rhythm devices should be shared between patients and insurances. Wearable single- or multiple-lead ECG technology is accepted for multiple indications in current clinical practice and triggers AF diagnosis and treatment. The unmet needs that call for action are reimbursement plans and integration of wearable rhythm device data into patient's files and hospital information systems.

Cryoballoon ablation vs. antiarrhythmic drugs: first-line therapy for patients with paroxysmal atrial fibrillation.

AIMS: Treatment guidelines for patients with atrial fibrillation (AF) suggest that patients should be managed with an antiarrhythmic drug (AAD) before undergoing catheter ablation (CA). This study evaluated whether pulmonary vein isolation employing cryoballoon CA is superior to AAD therapy for the prevention of atrial arrhythmia (AA) recurrence in rhythm control naive patients with paroxysmal AF (PAF). METHODS AND RESULTS: A total of 218 treatment naive patients with symptomatic PAF were randomized (1 : 1) to cryoballoon CA (Arctic Front Advance, Medtronic) or AAD (Class I or III) and followed for 12 months. The primary endpoint was ≥1 episode of recurrent AA (AF, atrial flutter, or atrial tachycardia) >30 s after a prespecified 90-day blanking period. Secondary endpoints included the rate of serious adverse events (SAEs) and recurrence of symptomatic palpitations (evaluated via patient diaries). Freedom from AA was achieved in 82.2% of subjects in the cryoballoon arm and 67.6% of subjects in the AAD arm (HR = 0.48, P = 0.01). There were no group differences in the time-to-first (HR = 0.76, P = 0.28) or overall incidence [incidence rate ratio (IRR)=0.79, P = 0.28] of SAEs. The incidence rate of symptomatic palpitations was lower in the cryoballoon (7.61 days/year) compared with the AAD arm (18.96 days/year; IRR = 0.40, P < 0.001). CONCLUSIONS: Cryoballoon CA was superior to AAD therapy, significantly reducing AA recurrence in treatment naive patients with PAF. Additionally, cryoballoon CA was associated with lower symptom recurrence and a similar rate of SAEs compared with AAD therapy.

Analysis of Polycyclic Aromatic Hydrocarbons and Phthalate Esters in Soil and Food Grains from the Balkan Peninsula: Implication on DNA Adduct Formation by Aristolochic Acid I and Balkan Endemic Nephropathy.

Balkan endemic nephropathy (BEN) is a chronic tubulointerstitial nephropathy affecting residents of rural farming areas in many Balkan countries. Although it is generally believed that BEN is an environmental disease caused by multiple geochemical factors with much attention on aristolochic acids (AAs), its etiology remains controversial. In this study, we tested the hypothesis that environmental contamination and subsequent food contamination by polycyclic aromatic hydrocarbons (PAHs) and phthalate esters are AA toxicity factors and important to BEN development. We identified significantly higher concentrations of phenanthrene, anthracene, diethyl phthalate (DEP), dibutyl phthalate (DBP), and benzyl butyl phthalate (BBP) in both maize and wheat grain samples collected from endemic villages than from nonendemic villages. Other PAHs and phthalate esters were also detected at higher concentrations in the soil samples from endemic villages. Subsequent genotoxicity testing of cultured human kidney cells showed an alarming phenomenon that phenanthrene, DEP, BBP, and DBP can interact synergistically with AAs to form elevated levels of AA-DNA adducts, which are associated with both the nephrotoxicity and carcinogenicity of AAs, further increasing their disease risks. This study provides direct evidence that prolonged coexposure to these environmental contaminants via dietary intake may lead to greater toxicity and accelerated development of BEN.

Symptom management strategies: Rhythm vs rate control in patients with atrial fibrillation in the Balkan region: Data from the BALKAN-AF survey.

BACKGROUND: Symptom-focused management is one of the cornerstones of optimal atrial fibrillation (AF) therapy. OBJECTIVES: To evaluate the use of rhythm control and rate control strategy. Second, to identify predictors of the use of amiodarone in patients with rhythm control and of the use of rhythm control strategy in patients with paroxysmal AF in the Balkans. METHODS: Prospective enrolment of consecutive patients from seven Balkan countries to the BALKAN-AF survey was performed. RESULTS: Of 2712 enrolled patients, 2522 (93.0%) with complete data were included: 1622 (64.3%) patients were assigned to rate control strategy and 900 (35.7%) to rhythm control. Patients with rhythm control were younger, more often hospitalised for AF and with less comorbidities (all P < .05) than those with rate control. Symptom score [European Heart Rhythm Association (EHRA)] was not an independent predictor of a rhythm control strategy [odds ratio (OR) 0.99, 95% confidence interval (CI) 0.90-1.10, P = .945]. The most commonly chosen antiarrhythmic agents were amiodarone (49.7%), followed by propafenone (24.3%). CONCLUSION: More than one-third of patients in the BALKAN-AF survey received a rhythm control strategy, and these patients tended to be younger with less comorbidities than those managed with rate control. EHRA symptom score is not significantly associated with rhythm control strategy. The most commonly used antiarrhythmic agents were amiodarone, followed by propafenone.

Clinical effectiveness of primary prevention implantable cardioverter-defibrillators: results of the EU-CERT-ICD controlled multicentre cohort study.

AIMS: The EUropean Comparative Effectiveness Research to Assess the Use of Primary ProphylacTic Implantable Cardioverter-Defibrillators (EU-CERT-ICD), a prospective investigator-initiated, controlled cohort study, was conducted in 44 centres and 15 European countries. It aimed to assess current clinical effectiveness of primary prevention ICD therapy. METHODS AND RESULTS: We recruited 2327 patients with ischaemic cardiomyopathy (ICM) or dilated cardiomyopathy (DCM) and guideline indications for prophylactic ICD implantation. Primary endpoint was all-cause mortality. Clinical characteristics, medications, resting, and 12-lead Holter electrocardiograms (ECGs) were documented at enrolment baseline. Baseline and follow-up (FU) data from 2247 patients were analysable, 1516 patients before first ICD implantation (ICD group) and 731 patients without ICD serving as controls. Multivariable models and propensity scoring for adjustment were used to compare the two groups for mortality. During mean FU of 2.4 ± 1.1 years, 342 deaths occurred (6.3%/years annualized mortality, 5.6%/years in the ICD group vs. 9.2%/years in controls), favouring ICD treatment [unadjusted hazard ratio (HR) 0.682, 95% confidence interval (CI) 0.537-0.865, P = 0.0016]. Multivariable mortality predictors included age, left ventricular ejection fraction (LVEF), New York Heart Association class

Aristolochic acid I: an investigation into the role of food crops contamination, as a potential natural exposure pathway.

Aristolochic acid I (AAI) is a potent nephrotoxic and carcinogenic compound produced by plants of the Aristolochiaceae family and thoroughly investigated as a main culprit in the etiology of Balkan endemic nephropathy (BEN). So far, the AAI exposure was demonstrated to occur through the consumption of Aristolochia clematitis plants as traditional remedies, and through the contamination of the surrounding environment in endemic areas: soil, food and water contamination. Our study investigated for the first time the level of AAI contamination in 141 soil and vegetable samples from two cultivated gardens in non-endemic areas, A. clematitis being present in only one of the gardens. We developed and validated a simple and sensitive ultra-high-performance liquid chromatography-ion trap mass spectrometry method for qualitative and quantitative AAI analysis. The results confirmed the presence of AAI at nanogram levels in soil and vegetable samples collected from the non-endemic garden, where A. clematitis grows. These findings provide additional evidence that the presence of A. clematitis can cause food crops and soil contamination and unveil the pathway through which AAI could move from A. clematitis to other plant species via a common matrix: the soil. Another issue regarding the presence of AAI, in a non-endemic BEN area from Romania, could underlie a more widespread environmental exposure to AAI and explain certain BEN-like cases in areas where BEN has not been initially described.

Cryoballoon catheter ablation versus antiarrhythmic drugs as a first-line therapy for patients with paroxysmal atrial fibrillation: Rationale and design of the international Cryo-FIRST study.

BACKGROUND: Radiofrequency current (RFC) catheter ablation for patients with paroxysmal atrial fibrillation (AF) has been shown to be safe and effective in first-line therapy. Recent data demonstrates that RFC ablation provides better clinical outcomes compared to antiarrhythmic drug (AAD) in the treatment of early AF disease. Furthermore, studies comparing RFC and cryoballoon have established comparable efficacy and safety of pulmonary vein isolation (PVI) for patients with symptomatic paroxysmal AF. OBJECTIVES: The Cryo-FIRST trial was designed to compare AAD treatment against cryoballoon PVI as a first-line therapy in treatment naïve patients with AF. Efficacy and safety will be compared between the two cohorts and amongst subgroups. METHODS: The primary hypothesis is that cryoablation is superior to AAD therapy. To test this hypothesis, patients will be randomized in a 1:1 design. Using a 90-day blanking period, primary efficacy endpoint failure is defined as (at least) one episode of atrial arrhythmia with a duration >30 sec (documented by 7-day Holter or 12-lead ECG). Secondary endpoints (Quality-of-Life, rehospitalization, arrhythmia recurrence rate, healthcare utilization, and left atrial function) and adverse events will also be evaluated. Study enrollment will include 218 patients in up to 16 centers. CONCLUSIONS: This study will be a multi-national randomized controlled trial comparing cryoablation against AAD as a first-line treatment in patients with paroxysmal AF. The results may help guide the selection of patients for early AF disease therapy via cryoballoon ablation.

Stroke prevention in elderly patients with non-valvular atrial fibrillation in the BALKAN-AF survey.

BACKGROUND: Atrial fibrillation (AF) is common amongst the elderly, but this group tends to be suboptimally treated. Limited data are available on the stroke prevention strategies in the elderly, especially in the Balkan region. AIM: We investigated the use of oral anticoagulant therapy (OAC) amongst elderly AF patients in clinical practice in the Balkan region. METHOD: A 12-week prospective snapshot survey (2014-2015) of consecutive non-valvular AF patients was conducted in Albania, Bosnia and Herzegovina, Bulgaria, Croatia, Montenegro, Romania and Serbia. Data were collected via an electronic case report form. RESULTS: Of 2671 patients, 418 (15.6%) were ≥80 years old. Overall, OAC was used in 1965 patients (73.6%). Compared with younger patients, the elderly (age ≥ 80) had a higher mean CHA2 DS2 -VASc score (3.22 ± 1.71 vs 4.89 ± 1.35, P < .001) and more often a HAS-BLED score of ≥3 (n = 198 [47.0%] vs n = 625 [27.3%], P < .001), but were less likely to receive OAC (n = 269 [64.4%] vs n = 1696 [75.3%], odds ratio [OR] 0.91; 95%CI 0.86-0.97, P = .003). There was no significant association between OAC use and mean CHA2 DS2 -VASc (OR 0.86; 95%CI 0.75-1.00, P = .053) or HAS-BLED score (OR 1.21; 95%CI 0.81-1.81, P = .349) in the elderly. CONCLUSION: In the BALKAN-AF Survey, elderly AF patients were less likely to receive the guideline-adherent treatment despite their less favourable risk profile. Since OAC nonuse among the elderly was not associated with increased HAS-BLED score, factors other than patients' risk profile could influence the implementation of guideline-adherent treatment for thromboprophylaxis in the elderly AF patients.

Determination of Aristolochic Acids in Vegetables: Nephrotoxic and Carcinogenic Environmental Pollutants Contaminating a Broad Swath of the Food Supply and Driving Incidence of Balkan Endemic Nephropathy.

Balkan endemic nephropathy (BEN) is a slowly progressive interstitial fibrotic disease affecting numerous people living along the Danube River in the Balkan Peninsula, of which aristolochic acids (AAs) produced naturally in Aristolochia plants are key etiological agents. However, the exposure biology of the disease remains poorly understood. Initially, the high incidence of BEN in the Balkan Peninsula was thought to occur through ingestion of bread prepared from flour made with wheat grains comingled with the seeds of Aristolochia clematitis L., an AA-containing weed that grows abundantly in the wheat fields of the affected areas. In this study, by a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method, we show for the first time that vegetables, in particular root vegetables of endemic areas, are extensively contaminated with AAs taken up through root absorption from the AA-tainted soil. Furthermore, we found a pH dependence of the n-octanol/water partition coefficient (Kow) of AAs, which resulted in a dramatically higher hydrophobicity-driven plant uptake efficiency of AAs into food crops in endemic areas, characterized by higher acidity levels, compared to non-endemic areas. We believe the results of this study have significantly unraveled the mystery surrounding the uneven distribution of BEN incidence.

Liquid chromatography-tandem mass spectrometry analysis of aristolochic acids in soil samples collected from Serbia: Link to Balkan endemic nephropathy.

RATIONALE: Over the past six decades, residents of farming villages in multiple countries of the Balkan peninsula have been suffering from a unique type of chronic renal disease, Balkan endemic nephropathy (BEN). It was speculated that environmental pollution by aristolochic acids (AAs) produced naturally by Aristolochia clematitis L., a weed that grows in the area, was causing the disease. However, the human exposure pathway to this class of phytotoxin remains obscure. Knowledge of the sink and stability of AAs in the environment would assist in the formulation of policy reducing exposure risk. METHODS: Using our newly developed liquid chromatography/tandem mass spectrometry method of high sensitivity and selectivity, we analysed over 130 soil samples collected from cultivation fields in southern Serbia for the presence of AAs. The environmental stability of AAs was also investigated by incubating soil samples spiked with AAs at various temperatures. RESULTS: The analysis detected AA-I in over two-fifths of the tested samples at sub-µg/kg to µg/kg levels, with higher concentrations observed in more acidic farmland soil. Furthermore, analysis of soil samples incubated at various temperatures revealed half-lives of over 2 months, indicating that AAs are relatively resistant to degradation. CONCLUSIONS: Cultivation soil in southern Serbia is being extensively contaminated with AAs released from the decomposition of A. clematitis weeds. Since AAs are resistant to degradation, it is possible that AAs could have been taken up by root absorption and transported to the edible part of food crops. Prolonged exposure to AA-contaminated food grown from polluted soil could be one of the main aetiological mechanisms of BEN observed in the area.

Occurrence and Environmental Stability of Aristolochic Acids in Groundwater Collected from Serbia: Links to Human Exposure and Balkan Endemic Nephropathy.

Aristolochic acids (AAs) have been known as potent nephrotoxins since the use of AA-containing herbal medicines was linked with a series of sporadic renal fibrotic nephropathy cases, and yet an estimated 100 million people worldwide are still at risk today because of continued use of similar medicines. However, a similar nephropathic condition is endemic in the rural Balkan regions (e.g., Serbian farming villages) and AAs were again found to be the causative agents. In the case of this Balkan endemic nephropathy, AAs were found to have originated from a widespread local weed Aristolochia clematitis L. In this study, we tested the hypothesis that AAs released from decomposition of A. clematitis were also being leached into groundwater, thus polluting the drinking water of local residents. We initiated the study by developing a dispersive solid-phase extraction-based sample preparation method for water samples suspected of AA contamination. The validated method was then coupled with a liquid chromatography-tandem mass spectrometric method to measure AAs in groundwater samples collected from Serbia. Our study revealed for the first time that groundwater in Serbia is extensively contaminated with AA-I, at ng/L levels. Results also showed that AAs are long-lived water contaminants, with no observable concentration changes over a 2-month period of sample storage.

MANAGEMENT OF PATIENTS WITH CARDIAC IMPLANTABLE ELECTRONIC DEVICES UNDERGOING MAGNETIC RESONANCE IMAGING - PROPOSAL FOR UNIFIED HOSPITAL PROTOCOL: CROATIAN WORKING GROUP ON ARRHYTHMIAS AND CARDIAC PACING.

For many years, magnetic resonance imaging (MRI) was contraindicated in patients with cardiac implantable electronic devices (CIED). Today, there is a growing amount of evidence that MRI can be performed safely in the majority of patients with CIEDs. Firstly, there are devices considered MRI conditional by manufacturers that are available on the market and secondly, there is clear evidence that even patients with MRI non-conditional devices can also undergo MRI safely. Protocols have been developed and recommendations from different cardiac and radiologic societies have been published in recent years. However, the majority of physicians are still reluctant to refer these patients to MRI. Therefore, this document is published as a joint statement of the Croatian Working Group on Arrhythmias and Cardiac Pacing and Department of Radiology, Sestre milosrdnice University Hospital Centre to guide and ease the management of patients with CIED undergoing MRI. Also, we propose a unified protocol and checklist that could be used in Croatian hospitals.

Present criteria for prophylactic ICD implantation: Insights from the EU-CERT-ICD (Comparative Effectiveness Research to Assess the Use of Primary ProphylacTic Implantable Cardioverter Defibrillators in EUrope) project.

BACKGROUND: The clinical effectiveness of primary prevention implantable cardioverter defibrillator (ICD) therapy is under debate. It is urgently needed to better identify patients who benefit from prophylactic ICD therapy. The EUropean Comparative Effectiveness Research to Assess the Use of Primary ProphylacTic Implantable Cardioverter Defibrillators (EU-CERT-ICD) completed in 2019 will assess this issue. SUMMARY: The EU-CERT-ICD is a prospective investigator-initiated non-randomized, controlled, multicenter observational cohort study done in 44 centers across 15 European countries. A total of 2327 patients with heart failure due to ischemic heart disease or dilated cardiomyopathy indicated for primary prophylactic ICD implantation were recruited between 2014 and 2018 (>1500 patients at first ICD implantation, >750 patients non-randomized non-ICD control group). The primary endpoint was all-cause mortality, and first appropriate shock was co-primary endpoint. At baseline, all patients underwent 12­lead ECG and Holter-ECG analysis using multiple advanced methods for risk stratification as well as documentation of clinical characteristics and laboratory values. The EU-CERT-ICD data will provide much needed information on the survival benefit of preventive ICD therapy and expand on previous prospective risk stratification studies which showed very good applicability of clinical parameters and advanced risk stratifiers in order to define patient subgroups with above or below average ICD benefit. CONCLUSION: The EU-CERT-ICD study will provide new and current data about effectiveness of primary prophylactic ICD implantation. The study also aims for improved risk stratification and patient selection using clinical risk markers in general, and advanced ECG risk markers in particular.