Updates in Small Interfering RNA for the Treatment of Dyslipidemias.

PURPOSE OF REVIEW: Atherosclerotic cardiovascular disease (ASCVD) is still the leading cause of death worldwide. Despite excellent pharmacological approaches, clinical registries consistently show that many people with dyslipidemia do not achieve optimal management, and many of them are treated with low-intensity lipid-lowering therapies. Beyond the well-known association between low-density lipoprotein cholesterol (LDL-C) and cardiovascular prevention, the atherogenicity of lipoprotein(a) and the impact of triglyceride (TG)-rich lipoproteins cannot be overlooked. Within this landscape, the use of RNA-based therapies can help the treatment of difficult to target lipid disorders. RECENT FINDINGS: The safety and efficacy of LDL-C lowering with the siRNA inclisiran has been documented in the open-label ORION-3 trial, with a follow-up of 4 years. While the outcome trial is pending, a pooled analysis of ORION-9, ORION-10, and ORION-11 has shown the potential of inclisiran to reduce composite major adverse cardiovascular events. Concerning lipoprotein(a), data of OCEAN(a)-DOSE trial with olpasiran show a dose-dependent drop in lipoprotein(a) levels with an optimal pharmacodynamic profile when administered every 12 weeks. Concerning TG lowering, although ARO-APOC3 and ARO-ANG3 are effective to lower apolipoprotein(apo)C-III and angiopoietin-like 3 (ANGPTL3) levels, these drugs are still in their infancy. In the era moving toward a personalized risk management, the use of siRNA represents a blossoming armamentarium to tackle dyslipidaemias for ASCVD risk reduction.

Maternal exposure to air pollutants, PCSK9 levels, fetal growth and gestational age - An Italian cohort.

OBJECTIVE: Exposure to airborne pollutants during pregnancy appears to be associated with uterine growth restriction and adverse neonatal outcome. Proprotein convertase subtilisin/kexin type (PCSK9), the key modulator of low-density lipoprotein (LDL) metabolism, increases following particulate matter (PM10) exposure. Because maternal cholesterol is required for fetal growth, PCSK9 levels could be used to evaluate the potential impact of airborne pollutants on fetal growth. DESIGN: A cohort of 134 healthy women during early pregnancy (11-12 weeks of gestational age) was studied. RESULTS: A significant association between circulating PCSK9 levels and three tested air pollutants (PM10, PM2.5, nitric oxide (NO2)) was found. Of importance, gestational age at birth was reduced by approximately 1 week for each 100 ng/mL rise in circulating PCSK9 levels, an effect that became more significant at the highest quartile of PM2.5 (with a 1.8 week advance in delivery date for every 100 ng/mL rise in circulating PCSK9; p for interaction = 0.026). This finding was supported by an elevation of the odds ratio for urgent cesarean delivery for each 100 ng/mL rise in PCSK9 (2.99, 95% CI, 1.22-6.57), similar trends being obtained for PM10 and NO2. CONCLUSIONS: The association between exposure to air pollutants during pregnancy and elevation in PCSK9 advances our understanding of the unforeseen influences of environmental exposure in terms of pregnancy associated disorders.

Depression and cardiovascular risk-association among Beck Depression Inventory, PCSK9 levels and insulin resistance.

BACKGROUND: Depression and cardiovascular disease (CVD) are among the most common causes of disability in high-income countries, depression being associated with a 30% increased risk of future CV events. Depression is twice as common in people with diabetes and is associated with a 60% rise in the incidence of type 2 diabetes, an independent CVD risk factor. Proprotein convertase subtilisin/kexin type 9 (PCSK9), a key regulator of low-density lipoprotein cholesterol, has been related to a large number of CV risk factors, including insulin resistance. Aim of this study was to investigate whether the presence of depression could affect PCSK9 levels in a population of obese subjects susceptible to depressive symptoms and how these changes may mediate a pre-diabetic risk. RESULTS: In 389 obese individuals, the Beck Depression Inventory (BDI-II) was significantly associated with PCSK9 levels. For every one-unit increment in BDI-II score, PCSK9 rose by 1.85 ng/mL. Depression was associated also with the HOMA-IR (homeostatic model assessment index of insulin resistance), 11% of this effect operating indirectly via PCSK9. CONCLUSIONS: This study indicates a possible mechanism linking depression and insulin resistance, a well-known CV risk factor, providing evidence for a significant role of PCSK9.

HDL therapy today: from atherosclerosis, to stent compatibility to heart failure.

Epidemiologically, high-density lipoprotein (HDL) cholesterol levels have been inversely associated to cardiovascular (CV) events, although a Mendelian Randomisation Study had failed to establish a clear causal role. Numerous atheroprotective mechanisms have been attributed to HDL, the main being the ability to promote cholesterol efflux from arterial walls; anti-inflammatory effects related to HDL ligands such as S1P (sphingosine-1-phosphate), resolvins and others have been recently identified. Experimental studies and early clinical investigations have indicated the potential of HDL to slow progression or induce regression of atherosclerosis. More recently, the availability of different HDL formulations, with different phospholipid moieties, has allowed to test other indications for HDL therapy. Positive reports have come from studies on coronary stent biocompatibility, where the use of HDL from different sources reduced arterial cell proliferation and thrombogenicity. The observation that low HDL-C levels may be associated with an enhanced risk of heart failure (HF) has also suggested that HDL therapy may be applied to this condition. HDL infusions or apoA-I gene transfer were able to reverse heart abnormalities, reduce diastolic resistance and improve cardiac metabolism. HDL therapy may be effective not only in atherosclerosis, but also in other conditions, of relevant impact on human health.Key messagesHigh-density lipoproteins have as a major activity that of removing excess cholesterol from tissues (particularly arteries).Knowledge on the activity of high-density lipoproteins on health have however significantly widened.HDL-therapy may help to improve stent biocompatibility and to reduce peripheral arterial resistance in heart failure.

A new dawn for managing dyslipidemias: The era of rna-based therapies.

The high occurrence of atherosclerotic cardiovascular disease (ASCVD) events is still a major public health issue. Although a major determinant of ASCVD event reduction is the absolute change of low-density lipoprotein-cholesterol (LDL-C), considerable residual risk remains and new therapeutic options are required, in particular, to address triglyceride-rich lipoproteins and lipoprotein(a) [Lp(a)]. In the era of Genome Wide Association Studies and Mendelian Randomization analyses aimed at increasing the understanding of the pathophysiology of ASCVD, RNA-based therapies may offer more effective treatment options. The advantage of oligonucleotide-based treatments is that drug candidates are targeted at highly specific regions of RNA that code for proteins that in turn regulate lipid and lipoprotein metabolism. For LDL-C lowering, the use of inclisiran - a silencing RNA that inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9) synthesis - has the advantage that a single s.c. injection lowers LDL-C for up to 6 months. In familial hypercholesterolemia, the use of the antisense oligonucleotide (ASO) mipomersen, targeting apolipoprotein (apoB) to reduce LDL-C, has been a valuable therapeutic approach, despite unquestionable safety concerns. The availability of specific ASOs lowering Lp(a) levels will allow rigorous testing of the Lp(a) hypothesis; by dramatically reducing plasma triglyceride levels, Volanesorsen (APOC3) and angiopoietin-like 3 (ANGPTL3)-LRx will further clarify the causality of triglyceride-rich lipoproteins in ASCVD. The rapid progress to date heralds a new dawn in therapeutic lipidology, but outcome, safety and cost-effectiveness studies are required to establish the role of these new agents in clinical practice.

Comprehensive investigation of pesticides in Brazilian surface water by high resolution mass spectrometry screening and gas chromatography-mass spectrometry quantitative analysis.

In this work, a comprehensive investigation on the occurrence of pesticides in the Paraná 3 hydrographic basin of Paraná State, Brazil, was made by application of wide-scope screening based on ultra-high performance liquid chromatography (LC) and gas chromatography (GC) both coupled to quadrupole time-of-flight mass spectrometry (QTOF MS). The use of two complementary techniques, such as GC-QTOF MS and LC-QTOF MS, allowed screening a large number of compounds with different polarity and volatility. This screening approach was applied to 17 samples, enabling the detection of fifty-two pesticides and six metabolites. In a second step, an specific research was made on the herbicide atrazine, one of the most frequent compounds in samples, and its major transformation products (TPs), which were quantitatively analyzed by dispersive liquid-liquid microextraction (DLLME) followed by GC-MS measurement. Twenty-one agricultural streams from the Paraná 3 hydrographic basin were sampled twice in 2017, each time along six successive weeks. Additional samples were also collected after rain events exceeding 10 mm. In total, 407 samples were quantitatively analyzed by DLLME/GC-MS. Atrazine concentrations did not exceed the maximum permitted concentration of 2 µg L-1 according to Brazilian legislation, and only one surface water sample, collected after precipitation events, was slightly above this value (2.89 µg L-1). The maximum concentrations for the TPs desethylatrazine and deisopropylatrazine were 0.80 and 1.22 µg L-1, respectively. Based on the quantification results, a map was produced showing the occurrence of atrazine and its TPs in the area under study. This is the first time that the presence of agrochemicals is evaluated in the Paraná 3 hydrographic basin.

Changes in circulating pro-protein convertase subtilisin/kexin type 9 levels - experimental and clinical approaches with lipid-lowering agents.

Regulation of pro-protein convertase subtilisin/kexin type 9 (PCSK9) by drugs has led to the development of a still small number of agents with powerful activity on low-density lipoprotein cholesterol levels, associated with a significant reduction of cardiovascular events in patients in secondary prevention. The Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk (FOURIER) and Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab (ODYSSEY OUTCOMES) studies, with the two available PCSK9 antagonists, i.e. evolocumab and alirocumab, both reported a 15% reduction in major adverse cardiovascular events. Regulation of PCSK9 expression is dependent upon a number of factors, partly genetic and partly associated to a complex transcriptional system, mainly controlled by sterol regulatory element binding proteins. PCSK9 is further regulated by concomitant drug treatments, particularly by statins, enhancing PCSK9 secretion but decreasing its stimulatory phosphorylated form (S688). These complex transcriptional mechanisms lead to variable circulating levels making clinical measurements of plasma PCSK9 for cardiovascular risk assessment a debated matter. Determination of total PCSK9 levels may provide a diagnostic tool for explaining an apparent resistance to PCSK9 inhibitors, thus indicating the need for other approaches. Newer agents targeting PCSK9 are in clinical development with a major interest in those with a longer duration of action, e.g. RNA silencing, allowing optimal patient compliance. Interest has been expanded to areas not only limited to low-density lipoprotein cholesterol reduction but also investigating other non-lipid pathways raising cardiovascular risk, in particular inflammation associated to raised high-sensitivity C-reactive protein levels, not significantly affected by the present PCSK9 antagonists.

ETC-1002 (Bempedoic acid) for the management of hyperlipidemia: from preclinical studies to phase 3 trials.

INTRODUCTION: Tolerability problems in treating hypercholesterolemic patients undergoing statin treatment are of growing concern to physicians and patients, thus underlining the need for an agent with a similar mechanism but minimal side effects. A drug with a somewhat similar mechanism to statins but free of muscular side effects is ETC-1002 (bempedoic acid). It inhibits cholesterol biosynthesis at a step preceding HMG-CoA reductase, i.e. ATP citrate lyase (ACLY). A prodrug, ETC-1002 is converted to the active agent only in liver, not in skeletal muscle, and this may prevent any myotoxic activity. Area covered: The mechanism of ETC-1002 activity is described in detail, considering that ACLY inhibition markedly attenuated atherosclerosis in animal models. Clinical studies are also reported. Expert opinion: Present day LDL-C lowering treatments lead to significant reductions of cardiovascular (CV) events but, at times, the need to interrupt statin treatment appears to be dangerous due to a rapid rise in CV risk. The excellent tolerability of ETC-1002 makes it a useful alternative, either alone or as an adjunct to ezetimibe, for patients with statin intolerance needing to achieve significant CV risk reduction. ETC-1002 is also associated with a marked fall in high-sensitivity C-reactive protein.

Lipid lowering drugs and inflammatory changes: an impact on cardiovascular outcomes?

Inflammatory changes are responsible for maintenance of the atherosclerotic process and may underlie some of the most feared vascular complications. Among the multiple mechanisms of inflammation, the arterial deposition of lipids and particularly of cholesterol crystals is the one responsible for the activation of inflammasome NLRP3, followed by the rise of circulating markers, mainly C-reactive protein (CRP). Elevation of lipoproteins, LDL but also VLDL and remnants, associates with increased inflammatory changes and coronary risk. Lipid lowering medications can reduce cholesterolemia and CRP: patients with elevations of both are at greatest cardiovascular (CV) risk and receive maximum benefit from therapy. Evaluation of the major drug series indicates that statins exert the largest LDL and CRP reduction, accompanied by reduced CV events. Other drugs, mainly active on the triglyceride/HDL axis, for example, PPAR agonists, may improve CRP and the lipid pattern, especially in patients with metabolic syndrome. PCSK9 antagonists, the newest most potent medications, do not induce significant changes in inflammatory markers, but patients with the highest baseline CRP levels show the best CV risk reduction. Parallel evaluation of lipids and inflammatory changes clearly indicates a significant link, both guiding to patients at highest risk, and to the best pharmacological approach. Key messages Lipid lowering agents with "pleiotropic" effects provide a more effective approach to CV prevention In CANTOS study, patients achieving on-treatment hsCRP concentrations ≤2 mg/L had a higher benefit in terms of reduction in major CV events The anti-inflammatory activity of PCSK9 antagonists appears to be of a minimal extent.

Near-field spectroscopy and tuning of sub-surface modes in plasmonic terahertz resonators.

Highly confined modes in THz plasmonic resonators comprising two metallic elements can enhance light-matter interaction for efficient THz optoelectronic devices. We demonstrate that sub-surface modes in such double-metal resonators can be revealed with an aperture-type near-field probe and THz time-domain spectroscopy despite strong mode confinement in the dielectric spacer. The sub-surface modes couple a fraction of their energy to the resonator surface via surface waves, which we detected with the near-field probe. We investigated two resonator geometries: a λ/2 double-metal patch antenna with a 2 µm thick dielectric spacer, and a three-dimensional meta-atom resonator. THz time-domain spectroscopy analysis of the fields at the resonator surface displays spectral signatures of sub-surface modes. Investigations of strong light-matter coupling in resonators with sub-surface modes therefore can be assisted by the aperture-type THz near-field probes. Furthermore, near-field interaction of the probe with the resonator enables tuning of the resonance frequency for the spacer mode in the antenna geometry from 1.6 to 1.9 THz (~15%).

Time resolved Fabry-Perot measurements of cavity temperature in pulsed QCLs.

Temperature rise during operation is a central concern of semiconductor lasers and especially difficult to measure during a pulsed operation. We present a technique for in situ time-resolved temperature measurement of quantum cascade lasers operating in a pulsed mode at ~9.25 µm emission wavelength. Using a step-scan approach with 5 ns resolution, we measure the temporal evolution of the spectral density, observing longitudinal Fabry-Perot modes that correspond to different transverse modes. Considering the multiple thin layers that make up the active layer and the associated Kapitza resistance, thermal properties of QCLs are significantly different than bulk-like laser diodes where this approach was successfully used. Compounded by the lattice expansion and refractive index changes due to time-dependent temperature rise, Fabry-Perot modes were observed and analyzed from the time-resolved emission spectra of quantum cascade lasers to deduce the cavity temperature. Temperature rise of a QCL in a pulsed mode operation between -160 °C to -80 °C was measured as a function of time. Using the temporal temperature variations, a thermal model was constructed that led to the extraction of cavity thermal conductivity in agreement with previous results. Critical in maximizing pulsed output power, the effect of the duty cycle on the evolution of laser heating was studied in situ, leading to a heat map to guide the operation of pulsed lasers.

Dynamics of a broad-band quantum cascade laser: from chaos to coherent dynamics and mode-locking.

The dynamics of a multimode quantum cascade laser, are studied in a model based on effective semiconductor Maxwell-Bloch equations, encompassing key features for the radiation-medium interaction such as an asymmetric frequency dependent gain and refractive index as well as the phase-amplitude coupling provided by the linewidth enhancement factor. By considering its role and that of the free spectral range, we find the conditions in which the traveling wave emitted by the laser at the threshold can be destabilized by adjacent modes, thus leading the laser emission towards chaotic or regular multimode dynamics. In the latter case our simulations show that the field oscillations are associated to self-confined structures which travel along the laser cavity, bridging mode-locking and solitary wave propagation. In addition, we show how a RF modulation of the bias current leads to active mode-locking yielding high-contrast, picosecond pulses. Our results compare well with recent experiments on broad-band THz-QCLs and may help in the understanding of the conditions for the generation of ultrashort pulses and comb operation in mid-IR and THz spectral regions.

Appropriateness of statin prescription in the elderly.

Statins, the most widely used drugs in the Western world, have become a pivotal component in the primary and secondary prevention of vascular diseases. Although benefits have been well documented in younger-than-75-year-old individuals, the value of statins in people aged >75years and over is controversial. The CTT meta-analysis calculated an absolute risk reduction of 0.6%/year per 38.7mg/dl reduction in LDL-C levels in patients aged >75years, that would translate into a number needed to treat of 167. However, the absolute effect of a 38.7mg/dl cholesterol lowering on the rate of annual ischemic heart disease mortality is 10-fold larger in older vs younger patients. In order to advise physician prescription, three major Guidelines have been published over the last few years, i.e. the AHA/ACC and the NLA in the US, and the ESC/EAS in Europe. Moreover, statin prescription in the elderly should also consider the cardiovascular outcomes of elderly patients reported in classical statin preventive trials which give important clues on adherence and persistence of use, as well as on drug safety. The present review discusses benefits of intensive vs moderate statin therapy, justifications for the use of aggressive lipid management in the very old and the use of statins in frail elderlies. The final decision on the therapeutic strategy with statins in elderlies at higher risk to develop cardiovascular events should be always based on a careful analysis of the patient's general health and on the presence of metabolic abnormalities or drug interactions potentially leading to risk.

Lipid-lowering therapy of everolimus-related severe hypertriglyceridaemia in a pancreatic neuroendocrine tumour (pNET).

WHAT IS KNOWN AND OBJECTIVE: Hypertriglyceridaemia (HTG) is a potentially serious side effect of everolimus therapy. We here report a case of severe HTG in an everolimus-treated patient and provide recommendations for its management. CASE SUMMARY: The patient was a 70-year-old woman, being treated with everolimus for a pancreatic neuroendocrine tumour (pNET). She developed severe HTG to a maximum of 969 mg/dL after 22 months of therapy. Treatment with fenofibrate rapidly normalized triglyceride (TG) levels. WHAT IS NEW AND CONCLUSION: Severe HTG may occur in everolimus-treated patients. Prescription of the appropriate therapy can allow patients to continue this medication.

Mode stabilization in quantum cascade lasers via an intra-cavity cascaded nonlinearity.

We present self-stabilization of the inter-mode separation of a quantum cascade laser (QCL) emitting at 9 µm via cascaded second order nonlinearity. This effect has been observed in lasers that have the optical cavity embedded into a microwave strip-line. The intermodal beat note spectra narrow with increasing laser output power, up to less than 100 kHz. A flat frequency response to direct modulation up to 14 GHz is reported for these microstrip QCLs. The laser inter-mode spacing can be locked to an external RF signal and tuned by more than 1 MHz from the free-running spacing. A parallel study on the same laser material in a non-microstrip line waveguide shows superior performances of the microstrip QCL in terms of the intermodal spectral locking and stability. Finally by analyzing our results with the theory of the injection locking of coupled oscillators, we deduce that the microwave power injected in the microstrip QCL is 2 orders of magnitude higher than in the reference laser.

Individual analysis of patients with HoFH participating in a phase 3 trial with lomitapide: The Italian cohort.

BACKGROUND AND AIMS: The efficacy and safety of lomitapide as adjunct treatment for adults with homozygous familial hypercholesterolaemia (HoFH) have been confirmed in a phase 3 trial. Given the small number of patients (N = 29), and variations in patient characteristics, examining individual cases provides additional details regarding patient management with lomitapide. Here, we examine the details of the Italian patient cohort in the phase 3 trial. METHODS AND RESULTS: The methodology of the multinational, single-arm, open-label, 78-week, dose-escalation, phase 3 trial has been previously reported. The current report details the Italian cohort of six patients (three males, three females) based on individual patient data, individual patient histories and narratives, and by mean data ± SD. Lomitapide was administered according to the dose-escalation protocol. At Week 78, concentrations of low-density lipoprotein-cholesterol were decreased by a mean of 42.6 ± 21.8% compared with baseline. Lomitapide was similarly well tolerated in the Italian cohort as in the entire study population. The most common adverse events were gastrointestinal symptoms. One patient showed an increase in liver transaminases >5× upper limit of normal that resolved after lomitapide treatment was reduced and maintained at a lower dose. CONCLUSION: The efficacy, safety and tolerability of lomitapide demonstrated in the Italian subgroup of patients are consistent with findings in the entire study population, and illustrate the broad applicability of lomitapide therapy across genotypes and clinical phenotypes. These data also provide an insight into the management of lomitapide use in a cohort of patients within a clinical trial protocol. Clinicaltrials.gov Identifier: NCT00730236.

Superradiant Emission from a Collective Excitation in a Semiconductor.

We report an anomalous wide broadening of the emission spectra of an electronic excitation confined in a two-dimensional potential. We attribute these results to an extremely fast radiative decay rate associated with superradiant emission from the ensemble of confined electrons. Lifetimes extracted from the spectra are below 100 fs and, thus, 6 orders of magnitude faster than for single particle transitions at similar wavelength. Moreover, the spontaneous emission rate increases with the electronic density, as expected for superradiant emission. The data, all taken at 300 K, are in excellent agreement with our theoretical model, which takes into account dipole-dipole Coulomb interaction between electronic excitations. Our experimental results demonstrate that the interaction with infrared light, which is usually considered a weak perturbation, can be a very efficient relaxation mechanism for collective electronic excitations in solids.

Optical sideband generation up to room temperature with mid-infrared quantum cascade lasers.

Mid-infrared (MIR) sideband generation on a near infrared (NIR) optical carrier is demonstrated within a quantum cascade laser (QCL). By employing an externally injected NIR beam, E(NIR), that is resonant with the interband transitions of the quantum wells in the QCL, the nonlinear susceptibility is enhanced, leading to both frequency mixing and sideband generation. A GaAs-based MIR QCL (E(QCL) = 135 meV) with an aluminum-reinforced waveguide was utilized to overlap the NIR and MIR modes with the optical nonlinearity of the active region. The resulting difference sideband (E(NIR) - E(QCL)) shows a resonant behavior as a function of NIR pump wavelength and a maximum second order nonlinear susceptibility, χ((2)), of ~1 nm/V was obtained. Further, the sideband intensity showed little dependence with the operating temperature of the QCL, allowing sideband generation to be realized at room temperature.

The lipid-lowering effects of lomitapide are unaffected by adjunctive apheresis in patients with homozygous familial hypercholesterolaemia - a post-hoc analysis of a Phase 3, single-arm, open-label trial.

OBJECTIVE: Lomitapide (a microsomal triglyceride transfer protein inhibitor) is an adjunctive treatment for homozygous familial hypercholesterolaemia (HoFH), a rare genetic condition characterised by elevated low-density lipoprotein-cholesterol (LDL-C), and premature, severe, accelerated atherosclerosis. Standard of care for HoFH includes lipid-lowering drugs and lipoprotein apheresis. We conducted a post-hoc analysis using data from a Phase 3 study to assess whether concomitant apheresis affected the lipid-lowering efficacy of lomitapide. METHODS: Existing lipid-lowering therapy, including apheresis, was to remain stable from Week -6 to Week 26. Lomitapide dose was escalated on the basis of individual safety/tolerability from 5 mg to 60 mg a day (maximum). The primary endpoint was mean percent change in LDL-C from baseline to Week 26 (efficacy phase), after which patients remained on lomitapide through Week 78 for safety assessment and further evaluation of efficacy. During this latter period, apheresis could be adjusted. We analysed the impact of apheresis on LDL-C reductions in patients receiving lomitapide. RESULTS: Of the 29 patients that entered the efficacy phase, 18 (62%) were receiving apheresis at baseline. Twenty-three patients (13 receiving apheresis) completed the Week 26 evaluation. Of the six patients who discontinued in the first 26 weeks, five were receiving apheresis. There were no significant differences in percent change from baseline of LDL-C at Week 26 in patients treated (-48%) and not treated (-55%) with apheresis (p = 0.545). Changes in Lp(a) levels were modest and not different between groups (p = 0.436). CONCLUSION: The LDL-C lowering efficacy of lomitapide is unaffected by lipoprotein apheresis.

Fate of thiabendazole through the treatment of a simulated agro-food industrial effluent by combined MBR/Fenton processes at µg/L scale.

This study has been carried out to assess the performance of a combined system consisting of a membrane bioreactor (MBR) followed by an advanced oxidation process (Fenton/Photo-Fenton) for removing the fungicide thiabendazole (TBZ) in a simulated agro-food industrial wastewater. Previous studies have shown the presence of TBZ in the effluent of an agro-food industry treated by activated sludge in a sequencing batch reactor (SBR), thus reinforcing the need for alternative treatments for removal. In this study, a simulated agro-food industry effluent was enriched with 100 µg L(-1) TBZ and treated by combined MBR/Fenton and MBR/solar photo-Fenton systems. Samples were directly injected into a highly sensitive liquid chromatography-triple quadrupole-linear ion trap-mass spectrometer (LC-QqLiT-MS/MS) analytical system to monitor the degradation of TBZ even at low concentration levels (ng L(-1)). Results showed that the biological treatment applied was not effective in TBZ degradation, which remained almost unaltered; although most dissolved organic matter was biodegraded effectively. Fenton and solar photo-Fenton, were assayed as tertiary treatments. The experiments were run without any pH adjustment by using an iron dosage strategy in the presence of excess hydrogen peroxide. Both treatments resulted in a total degradation of TBZ, obtaining more than 99% removal in both cases. To assure the total elimination of contaminants in the treated waters, transformation products (TPs) of TBZ generated during Fenton degradation experiments were identified and monitored by liquid chromatography-quadrupole time-of-flight mass spectrometry (LC-QTOF-MS/MS). Up to four TPs could be identified. Two of them corresponded to mono-hydroxylated derivatives, typically generated under hydroxyl radicals driven processes. The other two corresponded with the hydrolysis of the TBZ molecule to yield benzoimidazole and thiazole-4-carboxamidine. All of them were also degraded during the treatment.