Selection Of Endpoints Research Articles

What Are Good Muscle Endpoints for Translational Studies?

What Are Good Muscle Endpoints for Translational Studies? Jörn Rittweger()1,2 1Institute of Aerospace Medicine, German Aerospace Center, Cologne, Germany 2Department of Pediatrics and Adolescent Medicine, University of Cologne, Cologne, Germany © The Author Abstract Muscles matter to our health because of their size, their involvement in energy metabolism and their relevance for locomotion. Adequate selection of good endpoints is crucial for successfully designing translational studies. At least eight different muscle functions matter to health, namely the mechanical functions of exerting force, velocity, power, elastic storage and braking power, the two metabolic functions of substrate uptake (e.g. carbohydrates, lipids and amino acids) and substrate provision (e.g. lactate and amino acids) and secretory functions. However, specific endpoint tests have been validated for muscle force and power only. Walking speed and grip strength demonstrate good predictive value for hard clinical endpoints, such as disability, loss of autonomy and death. Vertical jump power also has good ecological validity and construct validity, and it depicts excellent test-retest reliability, which is an important advantage with regard to the study of power. Assessment of muscle mass, e.g. by magnetic resonance imaging, dual energy X-ray absorptiometry or bioelectrical impedance, should be considered as an important secondary endpoint to enhance construct validity. Further secondary endpoints should be included wherever they are likely to enhance the plausibility of the study outcome and assessment of test-retest reliability at baseline is always recommended. Well-established methods exist for three relevant muscular endpoints, namely power, strength and muscle mass, and these endpoints lend themselves to utilization in clinical studies. However, such validated methods lack a number of additional muscle functions that are scientifically only emerging. This applies foremost to the metabolic function of muscles but also to its role in storage and dissipation of mechanical energy.

Immunoinformatics prediction of potential B-cell and T-cell epitopes as effective vaccine candidates for eliciting immunogenic responses against Epstein–Barr virus

BackgroundThe ongoing search for viable treatment options to curtail Epstein Barr Virus (EBV) pathogenicity has necessitated a paradigmatic shift towards the design of peptide-based vaccines. Potential B-cell and T-cell epitopes were predicted for nine antigenic EBV proteins that mediate epithelial cell-attachment and spread, capsid self-assembly, DNA replication and processivity. MethodsPredictive algorithms incorporated in the Immune Epitope Database (IEDB) resources were used to determine potential B-cell epitopes based on their physicochemical attributes. These were combined with a string-kernel method and an antigenicity predictive AlgPred tool to enhance accuracy in the end-point selection of highly potential antigenic EBV B-cell epitopes. NetCTL 1.2 algorithms enabled the prediction of probable T-cell epitopes which were structurally modeled and subjected to blind peptide-protein docking with HLA-A*02:01. All-atom molecular dynamics (MD) simulation and Molecular Mechanics Generalized-Born Surface Area methods were used to investigate interaction dynamics and affinities of predicted T-cell peptide-protein complexes. ResultsComputational predictions and sequence overlapping analysis yielded 18 linear (continuous) and discontinuous (conformational) subunit epitopes from the antigenic proteins with characteristic surface accessibility, flexibility and antigenicity, and predictive scores above the threshold value (1) set. A novel site was identified on HLA-A*02:01 with preferential affinity binding for modeled BMRF2, BXLF1 and BGLF4 T-cell epitopes. Interaction dynamics and energies were also computed in addition to crucial residues that mediated complex formation and stability. ConclusionThis study implemented an integrative meta-analytical approach to model highly probable B-cell and T-cell epitopes as potential peptide-vaccine candidates for the treatment of EBV-related diseases.

Gene therapy for ischaemic heart disease and heart failure.

Gene therapy has been expected to become a novel treatment method since the structure of DNA was discovered in 1953. The morbidity from cardiovascular diseases remains remarkable despite the improvement of percutaneous interventions and pharmacological treatment, underlining the need for novel therapeutics. Gene therapy-mediated therapeutic angiogenesis could help those who have not gained sufficient symptom relief with traditional treatment methods. Especially patients with severe coronary artery disease and heart failure could benefit from gene therapy. Some clinical trials have reported improved myocardial perfusion and symptom relief in CAD patients, but few trials have come up with disappointing negative results. Translating preclinical success into clinical applications has encountered difficulties in successful transduction, study design, endpoint selection, and patient selection and recruitment. However, promising new methods for transducing the cells, such as retrograde delivery and cardiac-specific AAV vectors, hold great promise for myocardial gene therapy. This review introduces gene therapy for ischaemic heart disease and heart failure and discusses the current status and future developments in this field.

Integrative immunoinformatics paradigm for predicting potential B-cell and T-cell epitopes as viable candidates for subunit vaccine design against COVID-19 virulence

BackgroundThe increase in global mortality rates from SARS-COV2 (COVID-19) infection has been alarming thereby necessitating the continual search for viable therapeutic interventions. Due to minimal microbial components, subunit (peptide-based) vaccines have demonstrated improved efficacies in stimulating immunogenic responses by host B- and T-cells. MethodsIntegrative immunoinformatics algorithms were used to determine linear and discontinuous B-cell epitopes from the S-glycoprotein sequence. End-point selection of the most potential B-cell epitope was based on highly essential physicochemical attributes. NetCTL-I and NetMHC-II algorithms were used to predict probable MHC-I and II T-cell epitopes for globally frequent HLA-A∗O2:01, HLA-B∗35:01, HLA-B∗51:01 and HLA-DRB1∗15:02 molecules. Highly probable T-cell epitopes were selected based on their high propensities for C-terminal cleavage, transport protein (TAP) processing and MHC-I/II binding. ResultsPreferential epitope binding sites were further identified on the HLA molecules using a blind peptide-docking method. Phylogenetic analysis revealed close relativity between SARS-CoV-2 and SARS-CoV S-protein. LALHRSYLTPGDSSSGWTAGAA242→263 was the most probable B-cell epitope with optimal physicochemical attributes. MHC-I antigenic presentation pathway was highly favourable for YLQPRTFLL269-277 (HLA-A∗02:01), LPPAYTNSF24-32 (HLA-B∗35:01) and IPTNFTISV714-721 (HLA-B∗51:01). Also, LTDEMIAQYTSALLA865-881 exhibited the highest binding affinity to HLA-DR B1∗15:01 with core interactions mediated by IAQYTSALL870-878. COVID-19 YLQPRTFLL269-277 was preferentially bound to a previously undefined site on HLA-A∗02:01 suggestive of a novel site for MHC-I-mediated T-cell stimulation. ConclusionThis study implemented combinatorial immunoinformatics methods to model B- and T-cell epitopes with high potentials to trigger immunogenic responses to the S protein of SARS-CoV-2.

Design of Clinical Trials Evaluating Sedation in Critically Ill Adults Undergoing Mechanical Ventilation: Recommendations From Sedation Consortium on Endpoints and Procedures for Treatment, Education, and Research (SCEPTER) Recommendation III.

Clinical trials evaluating the safety and effectiveness of sedative medication use in critically ill adults undergoing mechanical ventilation differ considerably in their methodological approach. This heterogeneity impedes the ability to compare results across studies. The Sedation Consortium on Endpoints and Procedures for Treatment, Education, and Research Recommendations convened a meeting of multidisciplinary experts to develop recommendations for key methodologic elements of sedation trials in the ICU to help guide academic and industry clinical investigators. A 2-day in-person meeting was held in Washington, DC, on March 28-29, 2019, followed by a three-round, online modified Delphi consensus process. Thirty-six participants from academia, industry, and the Food and Drug Administration with expertise in relevant content areas, including two former ICU patients attended the in-person meeting, and the majority completed an online follow-up survey and participated in the modified Delphi process. The final recommendations were iteratively refined based on the survey results, participants' reactions to those results, summaries written by panel moderators, and a review of the meeting transcripts made from audio recordings. Fifteen recommendations were developed for study design and conduct, subject enrollment, outcomes, and measurement instruments. Consensus recommendations included obtaining input from ICU survivors and/or their families, ensuring adequate training for personnel using validated instruments for assessments of sedation, pain, and delirium in the ICU environment, and the need for methodological standardization. These recommendations are intended to assist researchers in the design, conduct, selection of endpoints, and reporting of clinical trials involving sedative medications and/or sedation protocols for adult ICU patients who require mechanical ventilation. These recommendations should be viewed as a starting point to improve clinical trials and help reduce methodological heterogeneity in future clinical trials.

Placing the results of the SOLIDARITY trial with regards to remdesivir in perspective.

Remdesivir, a repurposed antiviral, was first accorded approval by the US Food Drug Administration (FDA) for the treatment of COVID-19 which necessitates hospitalization. However, the interim data of SOLIDARITY trial revealed no benefits with remdesivir for COVID-19 patients which led immediate debates in social media and the press about the utility of the drug. Both preclinical and clinical data demonstrated its efficacy in COVID-19. The recently concluded ACTT-1 trial showed its efficacy in reducing the duration of hospital stay which is of utmost importance for a country like India where reduction in bed occupancy can save lives of many and eases the financial burden of patient and government. Our benefit-risk analysis of ACTT-1 trial also favored the use of remdesivir over standard of care. The SOLIDARITY trial was fundamentally different from other clinical trials on remdesivir with respect to its design, adaptive nature, and selection of endpoints. Moreover, the success of antiviral therapy also depends on the timing of initiation and combination with other drugs. Hence we believe that drugs like Remdesivir are very important for countries like India where soft end points such as time to recovery and clinical improvement and early discharge become extremely significant during a pandemic.

Peanut oral immunotherapy in a pediatric allergy clinic: Patient factors associated with clinical outcomes

BackgroundAdditional information is needed to inform optimal patient selection, expected outcomes, and treatment end points for clinical peanut oral immunotherapy (OIT). ObjectiveTo provide insight into the optimal patient selection, expected outcomes, and treatment end points for clinical peanut oral immunotherapy by analyzing a real-world peanut OIT cohort. MethodsRecords were reviewed for 174 children undergoing peanut OIT at a pediatric allergy clinic. Patient age, peanut skin prick test results, and peanut-specific immunoglobulin E (sIgE) results, with inclusion of additional foods in OIT, were analyzed for correlations with OIT outcomes. ResultsTo date, 144 patients have achieved maintenance dosing, 50 of whom transitioned to ad lib twice-weekly peanut ingestion. A total of 30 discontinued OIT. In addition, 47 patients who underwent multifood OIT had no significant difference in reactions (FDR-adjusted P = .48) or time-to-reach maintenance (FDR-adjusted P = .48) compared with those on peanut OIT alone. Age at initiation inversely correlated with achievement of maintenance: 92% of patients 0.5 to less than 5 years, 81% of those 5 to less than 11 years, and 70% of those 11 to less than 18 years reached and continued maintenance (P = .01). Baseline peanut-sIgE level positively correlated with number of reactions during updosing (P < .001) and maintenance (P = .005), though it was not significantly different in patients achieving successful maintenance vs those who discontinued OIT (P = .09). Furthermore, 66% of patients experienced greater than or equal to 1 adverse reaction during OIT. Of those on ad lib peanut ingestion, 2 reported mild reactions after lapses in peanut consumption. ConclusionClinical peanut OIT has similar outcomes to research protocols. OIT can be successful in older children and those with high peanut-sIgE levels, though these factors affect outcomes. Clinical and laboratory criteria can guide successful transition to intermittent ad lib peanut consumption.

Time dependent impact of copper oxide nanomaterials on the expression of genes associated with oxidative stress, metal binding, inflammation and mucus secretion in single and co-culture intestinal in vitro models

The potential for ingestion of copper oxide nanomaterials (CuO NMs) is increasing due to their increased exploitation. Investigation of changes in gene expression allows toxicity to be detected at an early stage of NM exposure and can enable investigation of the mechanism of toxicity. Here, undifferentiated Caco-2 cells, differentiated Caco-2 cells, Caco-2/HT29-MTX (mucus secreting) and Caco-2/Raji B (M cell model) co-cultures were exposed to CuO NMs and copper sulphate (CuSO4) in order to determine their impacts. Cellular responses were measured in terms of production of reactive oxygen species (ROS), the gene expression of an antioxidant (haem oxygenase 1 (HMOX1)), the pro-inflammatory cytokine (interleukin 8 (IL8)), the metal binding (metallothionein 1A and 2A (MT1A and MT2A)) and the mucus secreting (mucin 2 (MUC2)), as well as HMOX-1 protein level. While CuSO4 induced ROS production in cells, no such effect was observed for CuO NMs. However, these particles did induce an increase in the level of HMOX-1 protein and upregulation of HMOX1, MT2A, IL8 and MUC2 genes in all cell models. In conclusion, the expression of HMOX1, IL8 and MT2A were responsive to CuO NMs at 4 to 12 h post exposure when investigating the toxicity of NMs using intestinal in vitro models. These findings can inform the selection of endpoints, timepoints and models when investigating NM toxicity to the intestine in vitro in the future.

A better understanding on efficacy data of phase III trials for COVID-19 vaccines

<p indent="0mm">The clinical trial of vaccine efficacy is designed to compare the difference of incidence rate of disease or infections between vaccine group and placebo group, and to calculate the vaccine protection rate. Up to now, 22 COVID-19 vaccine candidates were under evaluation in phase III clinical trials, with the first two mRNA vaccines Moderna, and Pfizer/BioNTech announced efficacy of 94.1% and 95.0% for symptomatic COVID-19. However, several doubts concerning these results were raised, particularly by Peter Doshi, who speculated that a real efficacy of Pfizer/BioNTech’s mRNA vaccine could be as low as 29%. The debates around the efficacy of the COVID-19 vaccines became hot than ever in China, which might lead to increased vaccine skepticism, vaccination hesitation and undermine public confidence. Therefore, we need to have a better understanding on the efficacy data and interpret the results correctly. The selection of appropriate clinical endpoints with specific definition is critical. Hierarchical endpoints are often used in vaccine clinical trials to comprehensively evaluate the protective efficacy. Definition of hierarchical endpoints on basis of WHO clinical progression scale for COVID-19 could help to evaluate vaccine efficacy against COVID-19 with different severity, and compare the data from different trials. In general, vaccine efficacy is expected to be higher for the clinical endpoints with higher severity. In addition, both sensitivity and specificity of the disease surveillance system could have impacts on the vaccine efficacy. Specificity is more important than sensitivity, especially in the case of low incidence rate of the endpoint, which has a great impact on the protective efficacy of the vaccine, and often leads to the underestimation of vaccine efficacy. We compared phase III efficacy trial protocols of COVID-19 vaccine candidates sponsored by Moderna, Pfizer/BioNTech, AstraZeneca/University of Oxford and Johnson &amp; Johnson, according to these impact factors mentioned above. Comparing with Moderna, AstraZeneca/University of Oxford and Johnson &amp; Johnson’s trials to adopt a sensitive definition of suspected COVID-19 cases, Pfizer/BioNTech’s surveillance for diseases was mostly based on a passive surveillance involving self-report and self-sampling for case screening, which could compromise the sensitivity of the surveillance system capturing suspected COVID-19 cases. In addition, diagnostic testing to confirm the causative pathogen is important. However, the sensitivity of quantitative RT-PCR, the current goldstandard assay for diagnosis of SARS-CoV-2, is imperfect and influenced by viral load, sample type, and timing. Thus, collecting more than one specimen from suspected cases at more than one time points during the disease course, could results in a better sensitivity as well as specificity. Importantly, the serologic tests of antibody targeting at the N protein of SARS-CoV-2 could be used to identify whether it is naturally infected by SARS-CoV-2. At last, sharing and opening of trial protocols and the disclosure of trial data will contribute to better and more scientific evaluation of the efficacy of COVID-19 vaccine candidates. Extending the period of case surveillance and accumulating data on the protective efficacy of COVID-19 vaccines can contribute to understand the true protective efficacy of the vaccine.

Considerations of Statistical Errors in a Study Protocol for Clinical Trials

Statistics are essential for clinical trials, and it is very important to have an accurate understanding of the purpose of the study and to apply the appropriate statistical design or methodology. Prior to conducting a clinical trial, the research protocol requires approval from the IRB (Institutional Review Board) or regulatory agency approval, and contains a variety of contents. The research protocol conducts clinical trials according to GCP (Good Clinical Practice) and describe clinical design and statistical methodologies for demonstrate the efficacy and safety of new drug or new medical devices using the obtained data in clinical trials. At this time, statistical design is applied for the protocol based on the primary study objective. The primary study objective is to influence the selection of primary endpoint to evaluate this, the sample size, the technique of minimizing the bias, the statistical analysis and method of testing the statistical hypothesis. However, statistical errors and contradictions are easy to find in the study protocol and the same errors are repeated many times, so in this paper we aim to avoid these errors in clinical studies and apply them correctly in clinical trials, intended to be helpful in derives scientific design, validity, and reliable results.

Incident Fluence Analysis for 755-nm Picosecond Laser Treatment of Pigmented Skin Lesions Based on Threshold Fluences for Melanosome Disruption.

Background and ObjectivesIn this study, the threshold fluences for disrupting the melanosomes for pigmented skin lesion treatment were determined using a 755‐nm picosecond laser for clinical use. Based on the melanosome disruption thresholds, incident fluences corresponding to the target lesion depths were evaluated in silico for different laser spot sizes.Study Design/Materials and MethodsMelanosome samples were isolated from porcine eyes as alternative samples for human cutaneous melanosomes. The isolated melanosomes were exposed to 755‐nm picosecond laser pulses to measure the mean particle sizes by dynamic light scattering and confirm their disruption by scanning electron microscopy. The threshold fluences were statistically determined from the relationships between the irradiated fluences and the mean particle sizes. Incident fluences of picosecond laser pulses for the disruption of melanosomes located at different depths in skin tissue were calculated through a light transport simulation using the obtained thresholds.ResultsThe threshold fluences of 550‐ and 750‐picosecond laser pulses were determined to be 2.19 and 2.49 J/cm2, respectively. The numerical simulation indicated that appropriate incident fluences of picosecond laser pulses differ depending on the depth distribution of the melanosomes in the skin tissue, and large spot sizes are desirable for disrupting the melanosomes more deeply located within the skin tissue.ConclusionThe threshold fluences of picosecond laser pulses for melanosome disruption were determined. The incident fluence analysis based on the thresholds for melanosome disruption provides valuable information for the selection of irradiation endpoints for picosecond laser treatment of pigmented skin lesions. Lasers Surg. Med. © 2021 The Authors. Lasers in Surgery and Medicine published by Wiley Periodicals LLC

Non-Animal Strategies for Toxicity Assessment of Nanoscale Materials: Role of Adverse Outcome Pathways in the Selection of Endpoints.

Faster, cheaper, sensitive, and mechanisms-based animal alternatives are needed to address the safety assessment needs of the growing number of nanomaterials (NM) and their sophisticated property variants. Specifically, strategies that help identify and prioritize alternative schemes involving individual test models, toxicity endpoints, and assays for the assessment of adverse outcomes, as well as strategies that enable validation and refinement of these schemes for the regulatory acceptance are needed. In this review, two strategies 1) the current nanotoxicology literature review and 2) the adverse outcome pathways (AOPs) framework, a systematic process that allows the assembly of available mechanistic information concerning a toxicological response in a simple modular format, are presented. The review highlights 1) the most frequently assessed and reported ad hoc in vivo and in vitro toxicity measurements in the literature, 2) various AOPs of relevance to inhalation toxicity of NM that are presently under development, and 3) their applicability in identifying key events of toxicity for targeted in vitro assay development. Finally, using an existing AOP for lung fibrosis, the specific combinations of cell types, exposure and test systems, and assays that are experimentally supported and thus, can be used for assessing NM-induced lung fibrosis, are proposed.

Modeling and Simulation Strategy to Support the Development of ARS-1 (Intranasal Epinephrine) for Adult and Pediatric Subjects with Systemic Allergies

ARS-1 (Neffy)(IN epinephrine) has been shown to exhibit be equivalent pharmacokinetic exposure (AUC0-t) compared withrespect to IM injection with dosed with a needle and syringe (RLD), but with more rapid absorption. The mean hemodynamic response with ARS-1 was significantly greater and more consistent than with IM injection. based on pharmacokinetic considerations and similar exposure patterns. PK/PD differences that may be associated with the route of administration, receptor engagement or equilibration that may be contributing factors. Various modeling and simulation techniques provide a means to a) explore possible factors that may contribute to PK/PD differences between ARS-1 and the RLD, b) evaluate the clinical relevance of the differences observed to date though a clinical trial simulation, and c) examine the extrapolation suitability of the adult clinical experience for pediatric subjects. Both physiologically based pharmacokinetic (PBPK) and pop-PK/PD-informed clinical trial simulation (CTS) models are under development. The PBPK model will address both the likelihood that epinephrine reaches its intended site of action in adequate quantities to elicit the desired therapeutic effect and also the ability to account for size, ontogeny and maturation effects that define the pediatric population across various age strata [Barrett, 2012]. Standard inputs to build the PBPK model include physiochemical properties of epinephrine (MW, solubility, permeability, etc.), P450 metabolism data and any data in animal models describing biodistribution and PK/PD. Additional data from which the model (once developed) may be further tuned, optimized and validated includes any human (adult or pediatric) PK/PD data as well. Clinical trial simulation (CTS) leverages prior knowledge (PK and PK/PD including safety indices) about various treatments (experimental and reference) with consideration for study design constructs (e.g., sampling scheme, dose, strata and sample size) to explore the probability of success based on this prior knowledge, various design scenarios and critical assumptions [Läer, 2009]. Both PBPK and CTS model development is underway with the goal of informing endpoint selection, dose recommendations and study designs for upcoming pediatric and adult trials. All models are developed on validated systems with coding representations and solutions to be shared with regulatory authorities. Having complementary but distinct models provides a framework to facilitate robust decision making. Key decisions regarding the development of ARS-1 for adult and pediatric subjects with systemic allergies will be informed by quantitative methods using the current best knowledge regarding the drug actions and therapeutic window. This model-based framework is intended to evolve as knowledge about the drug product grows and will be a future resource for regulatory decision making and ultimately clinical performance in the intended patients receiving treatment with ARS-1.

How to integrate evidence from patient preference studies into health technology assessment: a critical review and recommendations.

Health technology assessment (HTA) agencies vary in their use of quantitative patient preference data (PP) and the extent to which they have formalized this use in their guidelines. Based on the authors' knowledge of the literature, we identified six different PP "use cases" that integrate PP into HTA in five different ways: through endpoint selection, clinical benefit rating, predicting uptake, input into economic evaluation, and a means to weight all HTA criteria. Five types of insight are distinguished across the use cases: understanding what matters to patients, predicting patient choices, estimating the utility generated by treatment benefits, estimating the willingness to pay for treatment benefits, and informing distributional considerations. Summarizing the literature on these use cases, we recommend circumstances in which PP can add value to HTA and the further research and guidance that is required to support the integration of PP in HTA. Where HTA places more emphasis on clinical outcomes, novel endpoints are available; or where there are already many treatment options, PP can add value by helping decision makers to understand what matters to patients. Where uptake is uncertain, PP can be used to estimate uptake probability. Where indication-specific utility functions are required or where existing utility measures fail to capture the value of treatments, PP can be used to generate or supplement existing utility estimates. Where patients are paying out of pocket, PP can be used to estimate willingness to pay.

PMS43 Efficacy And Safety Of Pharmaceutical Treatments For Systemic Lupus Erythematosus (SLE): A Systematic Literature Review (SLR) Of Randomized Controlled Trials (RCTs)

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with systemic involvement causing widespread inflammation and tissue damage in affected organs. Limited success of available treatments requires novel therapies to address the high unmet need. This research aimed to identify efficacy and safety endpoints from RCTs assessing treatments for SLE. A SLR was conducted according to standard guidelines, including RCTs assessing treatments of SLE published in PubMed, Embase, and Cochrane (1999–2019). Outcomes of interest included any efficacy and safety endpoints. Of 14,083 initial hits, 54 publications were included. Among these, 46 reported efficacy outcomes, 42 described safety outcomes. Belimumab and anifrolumab were analyzed in 8 and 3 studies, respectively. Nine other investigational agents were tested in 2 respective studies. Mean patient age ranged 18.5–55.3 years; 93.1% were female. Mean disease duration from first diagnosis to RCT enrollment was 8.0 years. The most frequently reported efficacy endpoints were SLE responder index (SRI-4) (18/54), change in corticosteroid use (18/54), change in British Isles Lupus Assessment Group (BILAG) index (14/54), occurrence of flares (12/54) and BILAG-based Combined Lupus Assessment (BICLA) (10/54). The average difference in SRI-4 and BICLA between active interventions against placebo was 15% and 11% at Week 24 and 9% and 14% at Week 52, respectively. The rates of serious adverse events ranged 0%–40% across treatment arms. Death occurred in 15 RCTs (0.3%–11% for active treatments, ≤2% for placebo). This research revealed a high heterogeneity of study designs, population baseline characteristics and endpoint selection across RCTs in SLE. Efficacy levels of SLE treatments vary depending on the endpoint used, with overall high placebo rates observed. The revealed methodological challenges need to be addressed for indirect treatment comparisons to be able to inform formal value assessments of therapies aiming to improve the currently limited treatment success in SLE.

Detecting the effects of chronic metal exposure on benthic systems: Importance of biomarker and endpoint selection

Understanding metal toxicity to benthic systems is still an ecotoxicological priority and, although numerous biomarkers exist, a multi-biomarker and endpoint approach with sediment as the delivery matrix combined with life-history relevant exposure timescales is missing. Here we assess potential toxicity by measuring a suite of biomarkers and endpoints after exposing the ecologically important polychaete Alitta(Nereis)virens to sediment spiked with environmentally relevant concentrations of copper and zinc (and in combination) for 3, 6 and 9 months. We compared biomarker and endpoint sensitivity providing a guide to select the appropriate endpoints for the chosen time frame (exposure period) and concentration (relevant to Sediment Quality Guidelines) needed to identify effects for benthic polychaetes such as A. virens. Target bioavailable sediment and subsequent porewater concentrations reflect the global contamination range, whilst tissue concentrations, although elevated, were comparable with other polychaetes. Survival reduced as concentrations increased, but growth was not significantly different between treatments. Metabolic changes were restricted to significant reductions in protein after 9 months exposure across all copper concentrations, and reductions in lipid at high copper concentrations (3 months). Significant changes in feeding behaviour and increases in metallothionein-like protein concentration were limited to the medium and high copper and zinc concentrations, respectively, both after 6 months exposure. Despite data highlighting A. virens′ metal tolerance, DNA damage and protein concentrations are the most sensitive biomarkers. Copper and zinc cause biomarker responses at concentrations routinely found in coastal sediments that are characterised as low contamination, suggesting a reappraisal of the current input sources (especially copper) is required.

Is micropollutant-loaded powdered activated carbon from a wastewater treatment plant toxic to the bivalve Corbicula sp.?

BackgroundIn order to reduce emissions of micropollutants (MPs) via effluents of wastewater treatment plants (WWTPs), additional treatment steps are suggested and already deployed in selected WWTPs. Next to advanced oxidation processes, the application of powdered activated carbon (PAC) is considered a promising and suitable option as MP removal rates of 80% and more can be achieved. However, this method might also hold a drawback as a complete retention of PAC applied within the WWTP cannot always be guaranteed. Hence, small amounts of MP-loaded PAC can enter receiving waters with potentially negative consequences for aquatic organisms. The present study investigated possible effects of MP-loaded PAC from a WWTP as compared to unloaded, native PAC on the bivalve Corbicula sp. in a 10-week exposure experiment. The PAC types were administered in concentrations of 1, 10 and 100 mg/L in a semi-static sediment–water system.ResultsMolecular biomarker responses for xenobiotic metabolism (i.e., glutathione-S-transferase (GST)) and oxidative stress (i.e., catalase (CAT) activity and lipid peroxidation) were analyzed and in none of the treatments, significant differences to the control could be detected, except for the CAT activity in the 1 mg/L PACWWTP treatment. Moreover, the filtration rate of individual bivalves was measured after 5 and 10 weeks of exposure and compared to the initial filtration rate with the result that the presence of PAC did not affect the filtration rate of Corbicula sp. In summary, despite the selection of sensitive endpoints and a comparatively long exposure period, no significant effects were detected for unloaded and MP-loaded PAC even at the highest test concentration, which is far away from environmental relevance.ConclusionsThese results give an auspicious perspective for the application of PAC in WWTPs. Even when small PAC leakages from WWTPs occur, adverse effects for aquatic organisms appear to be neglectable based on our findings.

News and failures from recent treatment trials in systemic sclerosis.

There have been many recent trials in systemic sclerosis (SSc) that have explored treatment for skin or lung. Some have been encouraging, but there has also been disappointment reflecting potential limitations of treatment effect of study design. These trials are discussed and reviewed. Studies conducted in SSc are described and discussed with a focus on endpoint selection and trial design as well as potential mechanism of action and treatment effect. Studies have included very encouraging trials of interleukin 6 blockade, immunosuppression, and broad-spectrum tyrosine kinase inhibition. Other trials including recent studies of peroxisome proliferator-activated receptor agonists and specific intracellular signaling inhibitors such as imatinib or anti-transforming growth factor beta blocking strategies have been more disappointing. Trial design is improving, and overall, there are now almost positive trials using agents with great promise, and studies are also providing important biological insight into SSc. It is hoped that ongoing studies will further progress the field and move it toward better treatments for SSc that still represent a major unmet medical need.

Clinical Endpoints for Evaluating Efficacy in COVID-19 Vaccine Trials.

Several vaccine candidates to protect against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or coronavirus disease 2019 (COVID-19) have entered or will soon enter large-scale, phase 3, placebo-controlled randomized clinical trials. To facilitate harmonized evaluation and comparison of the efficacy of these vaccines, a general set of clinical endpoints is proposed, along with considerations to guide the selection of the primary endpoints on the basis of clinical and statistical reasoning. The plausibility that vaccine protection against symptomatic COVID-19 could be accompanied by a shift toward more SARS-CoV-2 infections that are asymptomatic is highlighted, as well as the potential implications of such a shift.

The 'SELection End points in Communities of bacTeria' (SELECT) Method: A Novel Experimental Assay to Facilitate Risk Assessment of Selection for Antimicrobial Resistance in the Environment.

Background:Antimicrobial resistance (AMR) is one of the most significant health threats to society. A growing body of research demonstrates selection for AMR likely occurs at environmental concentrations of antibiotics. However, no standardized experimental approaches for determining selective concentrations of antimicrobials currently exist, preventing appropriate environmental and human health risk assessment of AMR.Objectives:We aimed to design a rapid, simple, and cost-effective novel experimental assay to determine selective effect concentrations of antibiotics and to generate the largest experimental data set of selective effect concentrations of antibiotics to date.Methods:Previously published methods and data were used to validate the assay, which determines the effect concentration based on reduction of bacterial community (wastewater) growth. Risk quotients for test antibiotics were generated to quantify risk.Results:The assay (SELection End points in Communities of bacTeria, or the SELECT method) was used to rapidly determine selective effect concentrations of antibiotics. These were in good agreement with quantitative polymerase chain reaction effect concentrations determined within the same experimental system. The SELECT method predicted no effect concentrations were minimally affected by changes in the assay temperature, growth media, or microbial community used as the inoculum. The predicted no effect concentrations for antibiotics tested ranged from for ciprofloxacin to for erythromycin.Discussion:The lack of evidence demonstrating environmental selection for AMR, and of associated human health risks, is a primary reason for the lack of action in the mitigation of release of antibiotics into the aquatic environment. We present a novel method that can reliably and rapidly fill this data gap to enable regulation and subsequent mitigation (where required) to lower the risk of selection for, and human exposure to, AMR in aquatic environments. In particular, ciprofloxacin and, to a lesser extent, azithromycin, cefotaxime, and trimethoprim all pose a significant risk for selection of AMR in the environment. https://doi.org/10.1289/EHP6635