Integrating electro-Fenton and microalgae for the sustainable management of real food processing wastewater.

The present study demonstrates, for the first time, the feasibility of a two-step process consisting of Electro-Fenton (EF) followed by microalgae to treat highly loaded real food processing wastewater along with resource recovery. In the first step, EF with a carbon felt cathode and Ti/RuO2-IrO2 anode was applied at different current densities (3.16 mA cm-2, 4.74 mA cm-2 and 6.32 mA cm-2) to decrease the amount of organic matter and turbidity and enhance biodegradability. In the second step, the EF effluents were submitted to microalgal treatment for 15 days using a mixed culture dominated by Scenedesmus sp., Chlorosarcinopsis sp., and Coelastrum sp. Results showed that current density impacted the amount of COD removed by EF, achieving the highest COD removal of 77.5% at 6.32 mA cm-2 with >95% and 74.3% of TSS and PO43- removal, respectively. With respect to microalgae, the highest COD removal of 85% was obtained by the culture in the EF effluent treated at 6.32 mA cm-2. Remarkably, not only 85% of the remaining organic matter was removed by microalgae, but also the totality of inorganic N and P compounds, as well as 65% of the Fe catalyst that was left after EF. The removal of inorganic species also demonstrates the high complementarity of both processes, since EF does not have the capacity to remove such compounds, while microalgae do not grow in the raw wastewater. Furthermore, a maximum of 0.8 g L-1 of biomass was produced after cultivation, with an accumulation of 32.2% of carbohydrates and 25.9% of lipids. The implementation of the two processes represents a promising sustainable approach for the management of industrial effluents, incorporating EF in a water and nutrient recycling system to produce biomass that could be valorized into clean fuels.

Probing the Critical Role of Interfaces for Superior Performance in PbS Quantum Dot/Graphene Nanohybrid Broadband Photodetectors.

Colloidal quantum dots/graphene (QD/Gr) nanohybrids have been studied intensively for photodetection in a broadband spectrum including ultraviolet, visible, near-infrared, and shortwave infrared (UV-vis-NIR-SWIR). Since the optoelectronic process in the QD/Gr nanohybrid relies on the photogenerated charge carrier transfer from QDs to graphene, understanding the role of the QD-QD and QD-Gr interfaces is imperative to the QD/Gr nanohybrid photodetection. Herein, a systematic study is carried out to probe the effect of these interfaces on the noise, photoresponse, and specific detectivity in the UV-vis-NIR-SWIR spectrum. Interestingly, the photoresponse has been found to be negligible without a 3-mercaptopropionic acid (MPA) ligand exchange, moderate with a single ligand exchange after all QD layers are deposited on graphene, and maximum if it is performed after each QD layer deposition up to five layers of total QD thickness of 260-280 nm. Furthermore, exposure of graphene to C-band UV (UVC) for a short period of 4-5 min before QD deposition leads to improved photoresponse via removal of polar molecules at the QD/Gr interface. With the combination of the MPA ligand exchange and UVC exposure, optimal optoelectronic properties can be obtained on the PbS QD/Gr nanohybrids with high specific detectivity up to 2.6 × 1011, 1.5 × 1011, 5 × 1010, and 1.9 × 109 Jones at 400, 550, 1000, and 1700 nm, respectively, making the nanohybrids promising for broadband photodetection.

A sustainable activated carbon fiber/TiO2 cathode for the photoelectro-Fenton treatment of pharmaceutical pollutant enalapril.

In this work, a TiO2-decorated electrode was fabricated by dip coating activated carbon fibers (ACF) with TiO2, which were then used as a cathode for the photoelectro-Fenton (PEF) treatment of the pharmaceutical enalapril, an angiotensin-converting enzyme inhibitor that has been detected in several waterways. The TiO2 coating was found to principally improve the electrocatalytic properties of ACF for H2O2 production via the 2-e- O2 reduction, in turn increasing enalapril degradation by PEF. The effect of the current density on the mineralization of enalapril was evaluated and the highest TOC removal yield (80.5% in 3 h) was obtained at 8.33 mA cm-2, in the presence of 0.5 mmol L-1 of Fe2+ catalyst. Under those conditions, enalapril was totally removed within the first 10 min of treatment with a rate constant k = 0.472 min-1. In contrast, uncoated ACF only achieved 60% of TOC removal in 3 h at 8.33 mA cm-2. A degradation pathway for enalapril mineralization is proposed, based on the degradation by-products identified during treatment. Overall, the results demonstrate the promises of TiO2 cathodes for PEF, a strategy that has often been overlooked in favor of photoelectrocatalysis (PEC) based on TiO2-modified photoanodes.

Scientific Review of the Proarrhythmic Risks of Oligonucleotide Therapeutics: Are Dedicated ICH S7B/E14 Studies Needed for Low-Risk Modalities?

Oligonucleotide therapeutics (ONTs) represent a new modality with unique pharmacological and chemical properties that modulate gene expression with a high degree of target specificity mediated by complementary Watson-Crick base pair hybridization. To date, the proarrhythmic assessment of ONTs has been influenced by International Conference on Harmonization (ICH) E14 and S7B guidance. To document current hERG/QTc evaluation practices, we reviewed US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) Approval Packages (source: PharmaPendium.com) and collated preclinical and clinical studies for 17 marketed ONTs. In addition, clinical QTc data from 12 investigational ONTs were obtained from the literature. Of the marketed ONTs, eight were tested in the hERG assay with no inhibitory effect identified at the top concentration (range: 34-3,000 µM) tested. Fourteen of the ONTs were evaluated in nonhuman primate cardiovascular studies with 11 of them in dedicated telemetry studies. No effect on QTc intervals were observed (at high exposure multiples) in all studies. Clinically, four ONTs were evaluated in TQT studies; an additional six ONTs were assessed by concentration-QTc interval analysis, and six by routine safety electrocardiogram monitoring. None of the clinical studies identified a QTc prolongation risk; the same was true for the 12 investigational ONTs. A search of the FDA Adverse Event Database indicated no association between approved ONTs and proarrhythmias. Overall, the collective weight of evidence from 29 ONTs demonstrate no clinical proarrhythmic risk based on data obtained from ICH S7B/E14 studies. Thus, new ONTs may benefit from reduced testing strategies because they have no proarrhythmic risk, a similar cardiac safety profile as monoclonal antibodies, proteins, and peptides.

Decreased need for RRT in liver transplant recipients after pretransplant treatment of hepatorenal syndrome-type 1 with terlipressin.

Hepatorenal syndrome-acute kidney injury (HRS-AKI), a serious complication of decompensated cirrhosis, has limited therapeutic options and significant morbidity and mortality. Terlipressin improves renal function in some patients with HRS-1, while liver transplantation (LT) is a curative treatment for advanced chronic liver disease. Renal failure post-LT requiring renal replacement therapy (RRT) is a major risk factor for graft and patient survival. A post hoc analysis with a 12-month follow-up of LT recipients from a placebo-controlled trial of terlipressin (CONFIRM; NCT02770716) was conducted to evaluate the need for RRT and overall survival. Patients with HRS-1 were treated with terlipressin plus albumin or placebo plus albumin for up to 14 days. RRT was defined as any type of procedure that replaced kidney function. Outcomes compared between groups included the incidence of HRS-1 reversal, the need for RRT (pretransplant and posttransplant), and overall survival. Of the 300 patients in CONFIRM (terlipressin n = 199; placebo, n = 101), 70 (23%) underwent LT alone (terlipressin, n = 43; placebo, n = 27) and 5 had simultaneous liver-kidney transplant (terlipressin, n = 3, placebo, n = 2). The rate of HRS reversal was significantly higher in the terlipressin group compared with the placebo group (37%, n = 16 vs. 15%, n = 4; p = 0.033). The pretransplant need for RRT was significantly lower among those who received terlipressin ( p = 0.007). The posttransplant need for RRT, at 12 months, was significantly lower among those patients who received terlipressin and were alive at Day 365, compared to placebo ( p = 0.009). Pretransplant treatment with terlipressin plus albumin in patients with HRS-1 decreased the need for RRT pretransplant and posttransplant.

Predictors of Respiratory Failure Development in a Multicenter Cohort of Inpatients With Cirrhosis.

INTRODUCTION: Hospitalized patients with cirrhosis can develop respiratory failure (RF), which is associated with a poor prognosis, but predisposing factors are unclear. METHODS: We prospectively enrolled a multicenter North American cirrhosis inpatient cohort and collected admission and in-hospital data (grading per European Association for the Study of Liver-Chronic Liver Failure scoring system, acute kidney injury [AKI], infections [admission/nosocomial], and albumin use) in an era when terlipressin was not available in North America. Multivariable regression to predict RF was performed using only admission day and in-hospital events occurring before RF. RESULTS: A total of 511 patients from 14 sites (median age 57 years, admission model for end-stage liver disease [MELD]-Na 23) were enrolled: RF developed in 15%; AKI occurred in 24%; and 11% developed nosocomial infections (NI). At admission, patients who developed RF had higher MELD-Na, gastrointestinal (GI) bleeding/AKI-related admission, and prior infections/ascites. During hospitalization, RF developers had higher NI (especially respiratory), albumin use, and other organ failures. RF was higher in patients receiving albumin (83% vs 59%, P < 0.0001) with increasing doses (269.5 ± 210.5 vs 208.6 ± 186.1 g, P = 0.01) regardless of indication. Admission for AKI, GI bleeding, and high MELD-Na predicted RF. Using all variables, NI (odds ratio [OR] = 4.02, P = 0.0004), GI bleeding (OR = 3.1, P = 0.002), albumin use (OR = 2.93, P = 0.01), AKI (OR = 3.26, P = 0.008), and circulatory failure (OR = 3.73, P = 0.002) were associated with RF risk. DISCUSSION: In a multicenter inpatient cirrhosis study of patients not exposed to terlipressin, 15% of patients developed RF. RF risk was highest in those admitted with AKI, those who had GI bleeding on admission, and those who developed NI and other organ failures or received albumin during their hospital course. Careful volume monitoring and preventing nosocomial respiratory infections and renal or circulatory failures could reduce this risk.

Not Your Typical Hyperammonemia: Non-hepatic Severe Hyperammonemia in an Adult.

Hyperammonemia in adults is most often due to cirrhosis. Ammonia is metabolized through the urea cycle. With liver disease, this pathway is altered, and urea is unable to be formed, creating a buildup of ammonia with numerous side effects, including encephalopathy. A less common presentation is hyperammonemia in the absence of liver disease. We present a rare case of non-cirrhotic hyperammonemia due to a splenogonadal shunt.

Hybrid TiO2/Carbon quantum dots heterojunction photoanodes for solar photoelectrocatalytic wastewater treatment.

The modification of titanium dioxide (TiO2) is a strategy to maximize the utilization of sunlight. Carbon quantum dots (CQDs) are carbon nanomaterials with outstanding optical and electronic properties that are suitable for that purpose. In this work, three types of hybrid TiO2/CQD photoelectrodes were synthesized following different methods: 1) deposition of a CQD layer on top of TiO2 (labelled as TiO2-CQD); 2) deposition of a TiO2 layer on top of CQDs (labelled as CQD-TiO2) and; 3) deposition of a mixed CQD + TiO2 layer (labelled as CQD + TiO2). The photoelectrodes were investigated for the photoelectrocatalytic degradation of phenol as model pollutant under simulated solar light and TiO2-CQD showed the highest apparent reaction rate constant of kapp = 0.0117 min-1 with 40% of TOC removal in 6 h of treatment. CQDs were found to enhance photon absorption in the visible region of the electromagnetic spectrum and in turn phenol degradation by promoting the separation of photogenerated charge carriers through electron transfer via the Ti-O-C bonds formed at the TiO2-CQD interface. Finally, the performance of the TiO2-CQD photoanode was evaluated for the treatment of real wastewater from the membrane fabrication sector, confirming its photoelectrocatalytic efficiency under solar radiation with 93% of TOC removal in 8 h of treatment and kapp = 0.0058 min-1.

Hepatorenal Syndrome-Acute Kidney Injury in Liver Transplantation.

Hepatorenal syndrome (HRS) is a serious complication of cirrhosis. HRS nomenclature has recently changed to HRS-AKI (acute kidney injury). HRS is a complex response to chronic vasodilatory changes brought about by portal hypertension and exacerbated by inflammatory responses that portends poor prognosis to patients with cirrhosis. This syndrome is commonly seen in the setting of infections, particularly spontaneous bacterial peritonitis. Because of the frequency of renal injury in the patient with cirrhosis, HRS-AKI has to be considered high in the differential diagnosis of AKI. Discontinuation of potential triggering agents and elimination of pre-renal AKI, intrinsic renal disease, and structural uropathy as causes of injury are imperative on presentation. Volume expansion with albumin and vasoconstrictive drugs to counteract the underlying splanchnic vasodilation constitutes the most effective medical modality to manage this process. Although the most effective therapy is generally considered to be liver transplantation (LT), the logistic barriers of offering this life-saving therapy on time to all needing it is a major limitation. Terlipressin has been shown to reverse HRS-AKI in a significant proportion of those treated and consequently can lead to increased LT patient survival and freedom from renal replacement therapy. We will review the impact of HRS on the management of patients awaiting LT, present strategies to prevent this significant complication, and discuss major implications of recent therapeutic advances in the setting of LT.

Cultivation of carbohydrate-rich microalgae with great settling properties using cooling tower wastewater.

Wastewater treatment and simultaneous production of value-added products with microalgae represent a sustainable alternative. Industrial wastewater, characterized by high C/N molar ratios, can naturally improve the carbohydrate content in microalgae without the need for any external source of carbon while degrading the organic matter, macro-nutrients, and micro-nutrients. This study aimed to understand the treatment, reuse, and valorization mechanisms of real cooling tower wastewater (CWW) from a cement-processing industry mixed with domestic wastewater (DW) to produce microalgal biomass with potential for synthesis of biofuels or other value-added products. For this purpose, three photobioreactors with different hydraulic retention times (HRT) were inoculated simultaneously using the CWW-DW mixture. Macro- and micro-nutrient consumption and accumulation, organic matter removal, algae growth, and carbohydrate content were monitored for 55 days. High COD (> 80%) and macronutrient removals (> 80% of N and P) were achieved in all the photoreactors, with heavy metals below the limits established by local standards. The best results showed maximum algal growth of 1.02 g SSV L-1 and 54% carbohydrate accumulation with a C/N ratio of 31.24 mol mol-1. Additionally, the harvested biomass presented a high Ca and Si content, ranging from 11 to 26% and 2 to 4%, respectively. Remarkably, big flocs were produced during microalgae growth, which enhanced natural settling for easy biomass harvesting. Overall, this process represents a sustainable alternative for CWW treatment and valorization, as well as a green tool for generating carbohydrate-rich biomass with the potential to produce biofuels and fertilizers.

Assessment of sarcomere shortening and calcium transient in primary human and dog ventricular myocytes.

Understanding translation from preclinical observations to clinical findings is important for evaluating the efficacy and safety of novel compounds. Of relevance to cardiac safety is profiling drug effects on cardiomyocyte (CM) sarcomere shortening and intracellular Ca2+ dynamics. Although CM from different animal species have been used to assess such effects, primary human CM isolated from human organ donor heart represent an ideal non-animal alternative approach. We performed a study to evaluate primary human CM and have them compared to freshly isolated dog cardiomyocytes for their basic function and responses to positive inotropes with well-known mechanisms. Our data showed that simultaneous assessment of sarcomere shortening and Ca2+-transient can be performed with both myocytes using the IonOptix system. Amplitude of sarcomere shortening and Ca2+-transient (CaT) were significantly higher in dog compared to human CM in the basic condition (absence of treatment), while longer duration of sarcomere shortening and CaT were observed in human cells. We observed that human and dog CMs have similar pharmacological responses to five inotropes with different mechanisms, including dobutamine and isoproterenol (ß-adrenergic stimulation), milrinone (PDE3 inhibition), pimobendan and levosimendan (increase of Ca2+sensitization as well as PDE3 inhibition). In conclusion, our study suggests that myocytes obtained from both human donor hearts and dog hearts can be used to simultaneously assess drug-induced effects on sarcomere shortening and CaT using the IonOptix platform.

Best practice considerations for nonclinical in vivo cardiovascular telemetry studies in non-rodent species: Delivering high quality QTc data to support ICH E14/S7B Q&As.

The ICH E14/S7B Questions and Answers (Q&As) guideline introduces the concept of a "double negative" nonclinical scenario (negative hERG assay and negative in vivo QTc study) to demonstrate that a drug does not produce a clinically relevant QT prolongation (i.e., no QT liability). This nonclinical "double negative" data package, along with negative Phase 1 clinical QTc data, may be sufficient to substitute for a clinical Thorough QT (TQT) study in some specific cases. While standalone GLP in vivo cardiovascular studies in non-rodent species are standard practice during nonclinical drug development for small molecule programs, a variety of approaches to the design, conduct, analysis and interpretation are utilized across pharmaceutical companies and contract research organizations (CROs) that may, in some cases, negatively impact the stringent sensitivity needed to fulfill the new Q&As. Subject matter experts from both Pharma and CROs have collaborated to recommend best practices for more robust nonclinical cardiovascular telemetry studies in non-rodent species, with input from clinical and regulatory experts. The aim was to increase consistency and harmonization across the industry and to ensure delivery of high quality nonclinical QTc data to meet the proposed sensitivities defined within the revised ICH E14/S7B Q&As guideline (Q&As 5.1 and 6.1). The detailed best practice recommendations presented here cover the design and execution of the safety pharmacology cardiovascular study, including optimal methods for acquiring, analyzing, reporting, and interpreting the resulting QTc and pharmacokinetic data to allow for direct comparison to clinical exposures and assessment of safety margin for QTc prolongation.

Improving the in Vivo QTc assay: The value of implementing best practices to support an integrated nonclinical-clinical QTc risk assessment and TQT substitute.

Recent updates and modifications to the clinical ICH E14 and nonclinical ICH S7B guidelines, which both relate to the evaluation of drug-induced delayed repolarization risk, provide an opportunity for nonclinical in vivo electrocardiographic (ECG) data to directly influence clinical strategies, interpretation, regulatory decision-making and product labeling. This opportunity can be leveraged with more robust nonclinical in vivo QTc datasets based upon consensus standardized protocols and experimental best practices that reduce variability and optimize QTc signal detection, i.e., demonstrate assay sensitivity. The immediate opportunity for such nonclinical studies is when adequate clinical exposures (e.g., supratherapeutic) cannot be safely achieved, or other factors limit the robustness of the clinical QTc evaluation, e.g., the ICH E14 Q5.1 and Q6.1 scenarios. This position paper discusses the regulatory historical evolution and processes leading to this opportunity and details the expectations of future nonclinical in vivo QTc studies of new drug candidates. The conduct of in vivo QTc assays that are consistently designed, executed and analyzed will lead to confident interpretation, and increase their value for clinical QTc risk assessment. Lastly, this paper provides the rationale and basis for our companion article which describes technical details on in vivo QTc best practices and recommendations to achieve the goals of the new ICH E14/S7B Q&As, see Rossman et al., 2023 (this journal).

Critical Review on the Mechanisms of Fe2+ Regeneration in the Electro-Fenton Process: Fundamentals and Boosting Strategies.

This review presents an exhaustive overview on the mechanisms of Fe3+ cathodic reduction within the context of the electro-Fenton (EF) process. Different strategies developed to improve the reduction rate are discussed, dividing them into two categories that regard the mechanistic feature that is promoted: electron transfer control and mass transport control. Boosting the Fe3+ conversion to Fe2+ via electron transfer control includes: (i) the formation of a series of active sites in both carbon- and metal-based materials and (ii) the use of other emerging strategies such as single-atom catalysis or confinement effects. Concerning the enhancement of Fe2+ regeneration by mass transport control, the main routes involve the application of magnetic fields, pulse electrolysis, interfacial Joule heating effects, and photoirradiation. Finally, challenges are singled out, and future prospects are described. This review aims to clarify the Fe3+/Fe2+ cycling process in the EF process, eventually providing essential ideas for smart design of highly effective systems for wastewater treatment and valorization at an industrial scale.

Early treatment with terlipressin in patients with hepatorenal syndrome yields improved clinical outcomes in North American studies.

Hepatorenal syndrome type 1 (HRS-1) is a serious complication of advanced cirrhosis and a potentially reversible form of acute kidney injury that is associated with rapidly deteriorating kidney function. Liver transplantation remains the only curative treatment for decompensated cirrhosis. However, terlipressin, a vasopressin analog, successfully reverses HRS-1, and may improve patient survival while awaiting liver transplantation. Patients with higher baseline serum creatinine have a reduced response to treatment with terlipressin. These post hoc analyses examined pooled data from 352 patients with HRS-1 treated with terlipressin in 3 North American-centric, Phase III, placebo-controlled clinical studies (i.e. OT-0401, REVERSE, and CONFIRM)-across 3 serum creatinine subgroups (i.e. <3, ≥3-<5, and ≥5 mg/dL)-to further delineate their correlation with HRS reversal, renal replacement therapy-free survival, and overall survival. Serum creatinine was significantly associated with HRS reversal in univariate and multivariate logistic regression analyses (P<0.001). The incidence of HRS reversal inversely correlated with serum creatinine subgroup (<3 mg/dL, 49.2%; ≥3-<5 mg/dL, 28.0%; ≥5 mg/dL, 9.1%). At Day 30 follow-up, renal replacement therapy-free survival was significantly higher for patients with HRS-1 in the lower serum creatinine subgroups than in the higher subgroup (<5 vs. >5 mg/dL; p=0.01). Terlipressin-treated patients with HRS-1, with a lower baseline serum creatinine level, had a higher overall survival (p<0.001) and higher transplant-free survival at Day 90 (p=0.04). Patients with HRS-1 and lower serum creatinine levels who were treated with terlipressin had higher HRS reversal and survival outcomes, highlighting the significant need to identify and treat patients with HRS-1 early when they often have lower serum creatinine levels, and likely a greater response to terlipressin.