Specific Endpoints Research Articles

Systematic review and network meta-analysis: efficacy of licensed drugs for abdominal bloating in irritable bowel syndrome with constipation.

Although bloating is a highly prevalent and troublesome symptom in irritable bowel syndrome with constipation (IBS-C), treatment is empirical with no specific guidelines for its management. To conduct a pairwise and network meta-analysis, using a frequentist approach, of Food and Drug Administration-licensed drugs for IBS-C comparing their efficacy for abdominal bloating as a specific endpoint. We searched the medical literature through December 2020 to identify randomised controlled trials (RCTs) in IBS-C, with abdominal bloating reported as a dichotomous assessment. Efficacy of each drug was reported as a pooled relative risk (RR) with 95% confidence intervals (CIs) to summarise effect of each comparison tested. Treatments were ranked according to their P-score. We identified 13 eligible RCTs, containing 10 091 patients. Linaclotide 290µg o.d., lubiprostone 8µg b.d., tenapanor 50mg b.d. and tegaserod 6mg b.d. were all superior to placebo for abdominal bloating in patients with IBS-C, in both pairwise and the network meta-analyses. Linaclotide demonstrated the greatest improvement in abdominal bloating in both pairwise and network meta-analysis (RR of failure to achieve an improvement in abdominal bloating=0.78; 95% CI 0.74-0.83, number needed to treat=7, P-score 0.97). Indirect comparison revealed no significant differences between individual drugs. We found all licensed drugs for IBS-C to be superior to placebo for abdominal bloating. Linaclotide appeared to be the most efficacious at relieving abdominal bloating. Further research is needed to assess long-term efficacy of these agents and to better understand the precise mechanism of improving bloating.

Turmeric and its bioactive constituents trigger cell signaling mechanisms that protect against diabetes and cardiovascular diseases.

Turmeric, the rhizome of Curcuma longa plant belonging to the ginger family Zingiberaceae, has a history in Ayurvedic and traditional Chinese medicine for treatment of chronic diseases, including metabolic and cardiovascular diseases (CVD). This parallels a prevalence of age- and lifestyle-related diseases, especially CVD and type 2 diabetes (T2D), and associated mortality which has occurred in recent decades. While the chemical composition of turmeric is complex, curcuminoids and essential oils are known as two major groups that display bioactive properties. Curcumin, the most predominant curcuminoid, can modulate several cell signaling pathways involved in the etiology and pathogenesis of CVD, T2D, and related morbidities. Lesser bioactivities have been reported from other curcuminoids and essential oils. This review examines the chemical compositions of turmeric, and related bioactive constituents. A focus was placed on the cellular and molecular mechanisms that underlie the protective effects of turmeric and turmeric-derived compounds against diabetes and CVD, compiled from the findings obtained with cell-based and animal models. Evidence from clinical trials is also presented to identify potential preventative and therapeutic efficacies. Clinical studies with longer intervention durations and specific endpoints for assessing health outcomes are warranted in order to fully evaluate the long-term protective efficacy of turmeric.

Microdosimetry calculations and estimation of the relative biological effectiveness of the low-energy electrons released during Gd neutron capture reaction

In this study, we try to estimate the relative biological effectiveness (RBE) of low-energy electrons released during the gadolinium neutron capture reaction (157GdNCR) using microdosimetric methods. It is assumed that the 157Gd is uniformly distributed throughout the cells and can be bound to DNAs. The microdosimetric parameters of Gd electrons along with those of carbon ions and protons were calculated using the Geant4-DNA and ROOT software.It was found that for a DNA target, the yD-ratio of carbon ions relative to reference radiation is proportional to the relevant RBE, independent of the radiation quality. Comparing the microdosimetric parameters of Gd electrons with those of carbon ions obtained in a 10-nm target, we evaluated the RBE of Gd electrons. In the case where 157Gd distributed inside of the DNA target, the RBE values of Gd electrons were obtained 2.36 and 2.21 using the modified microdosimetric kinetic model and biological weighting function with specific cell type and end-points, respectively. Although the amount of specific energy of Gd electrons in the DNA target is strongly dependent on the 157Gd distribution relative to the target, the RBE variations to the 157Gd distribution are low. The mean energy deposited of Gd electrons in the DNA target during one 157GdNCR with a value of 220.41 eV (equivalent to 207.73 kGy) is large enough for the induction of double-strand break of DNA.This microdosimetric estimation of the RBE of Gd electrons can be useful for assessing the biological dose of Gd electrons in neutron capture therapy. For other Gd compounds or Auger-electron emitters with heterogeneous distributions inside the cells, by comparing with the results obtained in this study, one can evaluate the RBE of their Auger electrons.

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.

Central Nervous System–Specific Outcomes of Phase 3 Randomized Clinical Trials in Patients With Advanced Breast Cancer, Lung Cancer, and Melanoma

This cohort study determines the proportion of phase 3 clinical trials for patients with metastatic breast cancer, lung cancer, and melanoma that included patients with brain metastases and/or evaluated central nervous system–specific end points.

Towards sea cucumbers as a new model in embryo-larval bioassays: Holothuria tubulosa as test species for the assessment of marine pollution

Sea cucumbers are widely distributed deposit-feeders that represent an important component of benthic communities worldwide. These echinoderms were recently proposed as candidates in embryo bioassays to provide a new tool in the toxicity assessment of pollutants in marine water and sediments. The aim of this study is to evaluate the usefulness of a new species, Holothuria tubulosa (Gmelin, 1788), as a model organism for sensitive embryo bioassays, defining the acceptability of controls, minimum sample size, embryo density and salinity range. Cadmium (Cd), copper (Cu), lead (Pb), mercury (Hg), sodium dodecyl sulphate (SDS) and 4-n-nonylphenol (NP) were used as reference toxicants to assess specific embryotoxicity endpoints. Sea cucumber sensitivity to marine sediment elutriates were finally assessed by comparing their responsiveness in tandem with that of routinely employed sea urchin embryos. The results showed an acceptability threshold of 10% (abnormal embryos), a minimum sample size of 200 embryos, an embryo density of 200 embryos/mL and an optimal salinity range of 36–37‰. The sensitivity to the environmental pollutants and matrices tested revealed values (expressed as EC50) comparable with those of embryos belonging to other marine invertebrates commonly used in bioassays, indicating that this species has a good level of responsiveness. A specific integrative toxicity index (ITI) was applied, combining the frequency of developmental anomalies and weighting their severity. ITI data demonstrated good discrimination of sample toxicity, with a dose-dependent increase of teratogenic effects for all the tested substances, indicating H. tubulosa as a promising species for future assessments of marine pollution.

Pesticides and Soil Invertebrates: A Hazard Assessment

Agricultural pesticide use and its associated environmental harms is widespread throughout much of the world. Efforts to mitigate this harm have largely been focused on reducing pesticide contamination of the water and air, as runoff and pesticide drift are the most significant sources of offsite pesticide movement. Yet pesticide contamination of the soil can also result in environmental harm. Pesticides are often applied directly to soil as drenches and granules and increasingly in the form of seed coatings, making it important to understand how pesticides impact soil ecosystems. Soils contain an abundance of biologically diverse organisms that perform many important functions such as nutrient cycling, soil structure maintenance, carbon transformation, and the regulation of pests and diseases. Many terrestrial invertebrates have declined in recent decades. Habitat loss and agrichemical pollution due to agricultural intensification have been identified as major driving factors. Here, we review nearly 400 studies on the effects of pesticides on non-target invertebrates that have egg, larval, or immature development in the soil. This review encompasses 275 unique species, taxa or combined taxa of soil organisms and 284 different pesticide active ingredients or unique mixtures of active ingredients. We identified and extracted relevant data in relation to the following endpoints: mortality, abundance, biomass, behavior, reproduction, biochemical biomarkers, growth, richness and diversity, and structural changes. This resulted in an analysis of over 2,800 separate “tested parameters,” measured as a change in a specific endpoint following exposure of a specific organism to a specific pesticide. We found that 70.5% of tested parameters showed negative effects, whereas 1.4% and 28.1% of tested parameters showed positive or no significant effects from pesticide exposure, respectively. In addition, we discuss general effect trends among pesticide classes, taxa, and endpoints, as well as data gaps. Our review indicates that pesticides of all types pose a clear hazard to soil invertebrates. Negative effects are evident in both lab and field studies, across all studied pesticide classes, and in a wide variety of soil organisms and endpoints. The prevalence of negative effects in our results underscores the need for soil organisms to be represented in any risk analysis of a pesticide that has the potential to contaminate soil, and for any significant risk to be mitigated in a way that will specifically reduce harm to soil organisms and to the many important ecosystem services they provide.

Risk Stratification Towards Precision Medicine in Heart Failure - Current Progress and Future Perspectives.

Clinical risk stratification is a key strategy used to identify low- and high-risk subjects to optimize the management, ranging from pharmacological treatment to palliative care, of patients with heart failure (HF). Using statistical modeling techniques, many HF risk prediction models that combine predictors to assess the risk of specific endpoints, including death or worsening HF, have been developed. However, most risk prediction models have not been well-integrated into the clinical setting because of their inadequacy and diverse predictive performance. To improve the performance of such models, several factors, including optimal sampling and biomarkers, need to be considered when deriving the models; however, given the large heterogeneity of HF, the currently advocated one-size-fits-all approach is not appropriate for every patient. Recent advances in techniques to analyze biological "omics" information could allow for the development of a personalized medicine platform, and there is growing awareness that an integrated approach based on the concept of system biology may be an excessively naïve view of the multiple contributors and complexity of an individual's HF phenotype. This review article describes the progress in risk stratification strategies and perspectives of emerging precision medicine in the field of HF management.

Valve Academic Research Consortium 3: updated endpoint definitions for aortic valve clinical research.

The Valve Academic Research Consortium (VARC), founded in 2010, was intended to (i) identify appropriate clinical endpoints and (ii) standardize definitions of these endpoints for transcatheter and surgical aortic valve clinical trials. Rapid evolution of the field, including the emergence of new complications, expanding clinical indications, and novel therapy strategies have mandated further refinement and expansion of these definitions to ensure clinical relevance. This document provides an update of the most appropriate clinical endpoint definitions to be used in the conduct of transcatheter and surgical aortic valve clinical research. Several years after the publication of the VARC-2 manuscript, an in-person meeting was held involving over 50 independent clinical experts representing several professional societies, academic research organizations, the US Food and Drug Administration (FDA), and industry representatives to (i) evaluate utilization of VARC endpoint definitions in clinical research, (ii) discuss the scope of this focused update, and (iii) review and revise specific clinical endpoint definitions. A writing committee of independent experts was convened and subsequently met to further address outstanding issues. There were ongoing discussions with FDA and many experts to develop a new classification schema for bioprosthetic valve dysfunction and failure. Overall, this multi-disciplinary process has resulted in important recommendations for data reporting, clinical research methods, and updated endpoint definitions. New definitions or modifications of existing definitions are being proposed for repeat hospitalizations, access site-related complications, bleeding events, conduction disturbances, cardiac structural complications, and bioprosthetic valve dysfunction and failure (including valve leaflet thickening and thrombosis). A more granular 5-class grading scheme for paravalvular regurgitation (PVR) is being proposed to help refine the assessment of PVR. Finally, more specific recommendations on quality-of-life assessments have been included, which have been targeted to specific clinical study designs. Acknowledging the dynamic and evolving nature of less-invasive aortic valve therapies, further refinements of clinical research processes are required. The adoption of these updated and newly proposed VARC-3 endpoints and definitions will ensure homogenous event reporting, accurate adjudication, and appropriate comparisons of clinical research studies involving devices and new therapeutic strategies.

Multiple internal controls enhance reliability for PCR and real time PCR detection of Rathayibacter toxicus

Rathayibacter toxicus is a toxigenic bacterial plant pathogen indigenous to Australia and South Africa. A threat to livestock industries globally, the bacterium was designated a U.S. Select Agent. Biosecurity and phytosanitary concerns arise due to the international trade of seed and hay that harbor the bacterium. Accurate diagnostic protocols to support phytosanitary decisions, delineate areas of freedom, and to support research are required to address those concerns. Whole genomes of three genetic populations of R. toxicus were sequenced (Illumina MiSeq platforms), assembled and genomic regions unique to each population identified. Highly sensitive and specific TaqMan qPCR and multiplex endpoint PCR assays were developed for the detection and identification of R. toxicus to the population level of discrimination. Specificity was confirmed with appropriate inclusivity and exclusivity panels; no cross reactivity was observed. The endpoint multiplex PCR and TaqMan qPCR assays detected 10 fg and 1 fg of genomic DNA, respectively. To enhance reliability and increase confidence in results, three types of internal controls with no or one extra primer were developed and incorporated into each assay to detect both plant and artificial internal controls. Assays were validated by blind ring tests with multiple operators in three international laboratories.

Associations between attainment of incentivised primary care indicators and emergency hospital admissions among type 2 diabetes patients: a population-based historical cohort study.

England has invested considerably in diabetes care over recent years through programmes such as the Quality and Outcomes Framework and National Diabetes Audit. However, associations between specific programme indicators and key clinical endpoints, such as emergency hospital admissions, remain unclear. We aimed to examine whether attainment of Quality and Outcomes Framework and National Diabetes Audit primary care diabetes indicators is associated with diabetes-related, cardiovascular, and all-cause emergency hospital admissions. Historical cohort study. A total of 330 English primary care practices, 2010-2017, using UK Clinical Practice Research Datalink. A total of 84,441 adults with type 2 diabetes. The primary outcome was emergency hospital admission for any cause. Secondary outcomes were (1) diabetes-related and (2) cardiovascular-related emergency admission. There were 130,709 all-cause emergency admissions, 115,425 diabetes-related admissions and 105,191 cardiovascular admissions, corresponding to unplanned admission rates of 402, 355 and 323 per 1000 patient-years, respectively. All-cause hospital admission rates were lower among those who met HbA1c and cholesterol indicators (incidence rate ratio = 0.91; 95% CI 0.89-0.92; p < 0.001 and 0.87; 95% CI 0.86-0.89; p < 0.001), respectively), with similar findings for diabetes and cardiovascular admissions. Patients who achieved the Quality and Outcomes Framework blood pressure target had lower cardiovascular admission rates (incidence rate ratio = 0.98; 95% CI 0.96-0.99; p = 0.001). Strong associations were found between completing 7-9 (vs. either 4-6 or 0-3) National Diabetes Audit processes and lower rates of all admission outcomes (p-values < 0.001), and meeting all nine National Diabetes Audit processes had significant associations with reductions in all types of emergency admissions by 22% to 26%. Meeting the HbA1c or cholesterol Quality and Outcomes Framework indicators, or completing 7-9 National Diabetes Audit processes, was also associated with longer time-to-unplanned all-cause, diabetes and cardiovascular admissions. Attaining Quality and Outcomes Framework-defined diabetes intermediate outcome thresholds, and comprehensive completion of care processes, may translate into considerable reductions in emergency hospital admissions. Out-of-hospital diabetes care optimisation is needed to improve implementation of core interventions and reduce unplanned admissions.

Guided P2Y12 inhibitor therapy after percutaneous coronary intervention

Antiplatelet treatment regimens for patients after percutaneous coronary intervention (PCI) have undergone major changes and substantial improvements. Extensions or a shortening of treatment as well as the use of various scores have been assessed in numerous trials to maximise anti-ischaemic efficacy and minimise bleeding. 1 Collet JP Thiele H Barbato E et al. 2020 ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. Eur Heart J. 2020; (published online Aug 29.)https://doi.org/10.1093/eurheartj/ehaa575 Crossref PubMed Scopus (122) Google Scholar , 2 Knuuti J Wijns W Saraste A et al. 2019 ESC guidelines for the diagnosis and management of chronic coronary syndromes. Eur Heart J. 2020; 41: 407-477 Crossref PubMed Scopus (1634) Google Scholar The key limitation of these strategies is the inherent time delay in the implementation of any therapy adjustments. At the same time, several clinical trials have investigated tailored and guided antiplatelet treatment. 3 Sibbing D Aradi D Alexopoulos D et al. Updated expert consensus statement on platelet function and genetic testing for guiding P2Y12 receptor inhibitor treatment in percutaneous coronary intervention. JACC Cardiovasc Interv. 2019; 12: 1521-1537 Crossref PubMed Scopus (180) Google Scholar Unfortunately, the pioneering trials of tailored treatment did not meet their primary endpoints or show improvement in patients' outcomes. 4 Price MJ Berger PB Teirstein PS et al. Standard- vs high-dose clopidogrel based on platelet function testing after percutaneous coronary intervention: the GRAVITAS randomized trial. JAMA. 2011; 305: 1097-1105 Crossref PubMed Scopus (1130) Google Scholar , 5 Trenk D Stone GW Gawaz M et al. A randomized trial of prasugrel versus clopidogrel in patients with high platelet reactivity on clopidogrel after elective percutaneous coronary intervention with implantation of drug-eluting stents: results of the TRIGGER-PCI (Testing Platelet Reactivity in Patients Undergoing Elective Stent Placement on Clopidogrel to Guide Alternative Therapy with Prasugrel) Study. J Am Coll Cardiol. 2012; 59: 2159-2164 Crossref PubMed Scopus (521) Google Scholar Various explanations have been attributed to these disappointing results, including insufficient intensification of treatment in patients with low response to clopidogrel by limited use of potent P2Y12 inhibitors and preferential inclusion of low-risk patients. 3 Sibbing D Aradi D Alexopoulos D et al. Updated expert consensus statement on platelet function and genetic testing for guiding P2Y12 receptor inhibitor treatment in percutaneous coronary intervention. JACC Cardiovasc Interv. 2019; 12: 1521-1537 Crossref PubMed Scopus (180) Google Scholar To address these issues, a series of recent trials included patients at higher risk and investigated the use of platelet function testing (phenotyping) 6 Sibbing D Aradi D Jacobshagen C et al. Guided de-escalation of antiplatelet treatment in patients with acute coronary syndrome undergoing percutaneous coronary intervention (TROPICAL-ACS): a randomised, open-label, multicentre trial. Lancet. 2017; 390: 1747-1757 Summary Full Text Full Text PDF PubMed Scopus (295) Google Scholar or genetic testing (genotyping) 7 Claassens DMF Vos GJA Bergmeijer TO et al. A genotype-guided strategy for oral P2Y12 inhibitors in primary PCI. N Engl J Med. 2019; 381: 1621-1631 Crossref PubMed Scopus (212) Google Scholar , 8 Pereira NL Farkouh ME So D et al. Effect of genotype-guided oral P2Y12 inhibitor selection vs conventional clopidogrel therapy on ischemic outcomes after percutaneous coronary intervention: the TAILOR-PCI randomized clinical trial. JAMA. 2020; 324: 761-771 Crossref PubMed Scopus (93) Google Scholar as a strategy by including study groups with a clear distinction of testing versus no testing. Notably, these trials did not provide unequivocal results and were partly limited in sample size and sometimes underpowered to compare specific ischaemic and bleeding endpoints. Guided versus standard antiplatelet therapy in patients undergoing percutaneous coronary intervention: a systematic review and meta-analysisGuided selection of antiplatelet therapy improved both composite and individual efficacy outcomes with a favourable safety profile, driven by a reduction in minor bleeding, supporting the use of platelet function or genetic testing to optimise the choice of agent in patients undergoing PCI. Full-Text PDF

The clinical black, white, and gray lessons.

This review examines recent contradictory large, well-controlled randomized control trials assessing the effects of omega-3 fatty acids and colchicine on cardiovascular (CV) outcomes. The Reduction of Cardiovascular Events with Icosapent Ethyl-Intervention Trial (REDUCE-IT) and Statin Residual Risk Reduction with Epanova in high Cardiovascular Risk patients with Hypertriglyceridemia (STRENGTH) trial assessed the CV outcomes using high-dose omega-3 fatty acids in statin-treated patients with moderate hypertriglyceridemia and high-risk for CV disease with differing results. Similarly, Colchicine Cardiovascular Outcomes trial, (COLCOT) second Low Dose Colchicine (LoDoCo2), and Colchicine in patients with Acute Coronary Syndrome (COPS) assessed the CV outcomes using low-dose colchicine in patients with coronary artery disease with inconsistent results. These contradictory findings among studies assessing similar questions with the same drug or a drug within the same class challenge the scientific validity and clinical applicability of the derived conclusions. A comprehensive review revealed many differences between the trials, which could have contributed to observed divergent results. Consistent findings across multiple trials help strengthen the evidence for specific endpoints or sub-populations, and these findings must be included in guidelines. Large prospective cohort studies with diligent study protocols are warranted in the future to resolve unanswered dilemmas.

Primary Hypothyroidism in Childhood Cancer Survivors Treated With Radiation Therapy: A PENTEC Comprehensive Review

From the Pediatric Normal Tissue Effects in the Clinic (PENTEC) initiative, a systematic review and meta-analysis of publications reporting on radiation dose-volume effects for risk of primary hypothyroidism after radiation therapy for pediatric malignancies was performed. All studies included childhood cancer survivors, diagnosed at age <21 years, whose radiation therapy fields exposed the thyroid gland and who were followed for primary hypothyroidism. Children who received pituitary-hypothalamic or total-body irradiation were excluded. PubMed and the Cochrane Library were searched for studies published from 1970 to 2017. Data on age at treatment, patient sex, radiation dose to neck or thyroid gland, specific endpoints for hypothyroidism that were used in the studies, and reported risks of hypothyroidism were collected. Radiation dose-volume effects were modeled using logistic dose response. Relative excess risk of hypothyroidism as a function of age at treatment and sex was assessed by meta-analysis of reported relative risks (RR) and odds ratios. Fifteen publications (of 1709 identified) were included for systematic review. Eight studies reported data amenable for dose-response analysis. At mean thyroid doses of 10, 20, and 30 Gy, predicted rates of uncompensated (clinical) hypothyroidism were 4%, 7%, and 13%, respectively. Predicted rates of compensated (subclinical) hypothyroidism were 12%, 25%, and 44% after thyroid doses of 10, 20, and 30 Gy, respectively. Female sex (RR = 1.7, P < .0001) and age >15 years at radiation therapy (RR = 1.3, P = .005) were associated with higher risks of hypothyroidism. After a mean thyroid dose of 20 Gy, predicted risks of hypothyroidism were 13% for males <14 years of age, increasing to 29% for females >15 years of age. A radiation dose response for risk of hypothyroidism is evident; a threshold radiation dose associated with no risk is not observed. Thyroid dose exposure should be minimized when feasible. Data on hypothyroidism after radiation therapy should be better reported to facilitate pooled analyses.

Epigenetic changes by per- and polyfluoroalkyl substances (PFAS).

Increasing studies are examining per- and polyfluoroalkyl substances (PFAS) induced toxicity and resulting health outcomes, including epigenetic modifications (e.g., DNA methylation, histone modification, microRNA expression). We critically reviewed current evidence from human epidemiological, invitro, and animal studies, including mammalian and aquatic model organisms. Epidemiological studies identified the associations between perfluorooctane sulfonate (PFOS) or perfluorooctanoic acid (PFOA) exposure and epigenetic changes in both adult populations and birth cohorts. For invitro studies, various cell types including neuroblasts, preadipocytes, and hepatocytes have been employed to understand epigenetic effects of PFAS. In studies with animal models, effects of early life exposure to PFAS have been examined using rodent models, and aquatic models (e.g., zebrafish) have been more frequently used in recent years. Several studies highlighted oxidative stress as a key mediator between epigenetic modification and health effects. Collectively, previous research clearly suggest involvement of epigenetic mechanisms in PFAS induced toxicity, though these efforts have primarily focused on specific PFASs (i.e. mainly PFOS and PFOA) or endpoints (i.e. cancer). Additional studies are necessary to define specific linkages among epigenetic mechanisms and related biomarkers or phenotypical changes. In addition, future research is also needed for understudied PFAS and complex mixtures. Studies of epigenetic effects elicited by individual PFAS and mixtures are needed within an adverse outcome pathways framework, which will advance an understanding of PFAS risks to public health and the environment, and support efforts to design less hazardous chemicals.

Cardiovascular disease-specific mortality in 270,618 patients with non-small cell lung cancer

BackgroundThis study aimed to investigate the trend of cardiovascular disease (CVD)-specific mortality in patients with non-small cell lung cancer (NSCLC) and identify prognostic factors for CVD-specific death in stage NSCLC patients. MethodsIn this study, 270,618 NSCLC patients were collected from the Surveillance, Epidemiology, and End Results database. CVD- and NSCLC-specific cumulative mortality and proportion of death were calculated and graphically displayed to describe the probability of specific endpoints. Prognostic factors for CVD-specific mortality were evaluated by cause-specific hazard ratios (HR) with 95% confidence intervals (CI) using the competing risk model with non-cardiovascular death as competing risks. ResultsAmong all competing causes of death, lung cancer resulted in the highest cumulative mortality, followed by CVDs and other causes. In the proportion of cause-specific death, heart diseases accounted for approximately 5.3% of the total death, only secondary to primary cancer. In all three stages, higher age, squamous cell carcinoma, and no-or-unknown chemotherapy and/or radiotherapy were associated with a higher risk of CVD-specific death, while surgery treatment seemed to be a protective factor. Female gender was statistically related to CVD-specific death in stage I and III patients with HRs of 0.84 (0.78–0.91) and 0.84 (0.77–0.93), respectively. Interestingly, right-sided laterality was correlated with lower CVD-specific mortality with HR of 0.82 (0.74–0.90) in stage III. ConclusionsThis study illustrated the historical trend of CVD-specific death in NSCLC patients and assesses potential prognostic risk factors, highlighting the involvement of cardio-oncology teams in cancer treatment to provide optimal comprehensive care and long-term surveillance for cancer patients.

Effect-Based Trigger Values for Mixtures of Chemicals in Surface Water Detected with In Vitro Bioassays.

Effect-based trigger (EBT) values for in vitro bioassays are important for surface water quality monitoring because they define the threshold between acceptable and poor water quality. They have been derived for highly specific bioassays, such as hormone-receptor activation in reporter gene bioassays, by reading across from existing chemical guideline values. This read-across method is not easily applicable to bioassays indicative of adaptive stress responses, which are triggered by many different chemicals, and activation of nuclear receptors for xenobiotic metabolism, to which many chemicals bind with rather low specificity. We propose an alternative approach to define the EBT from the distribution of specificity ratios of all active chemicals. The specificity ratio is the ratio between the predicted baseline toxicity of a chemical in a given bioassay and its measured specific endpoint. Unlike many previous read-across methods to derive EBTs, the proposed method accounts for mixture effects and includes all chemicals, not only high-potency chemicals. The EBTs were derived from a cytotoxicity EBT that was defined as equivalent to 1% of cytotoxicity in a native surface water sample. The cytotoxicity EBT was scaled by the median of the log-normal distribution of specificity ratios to derive the EBT for effects specific for each bioassay. We illustrate the new approach using the example of the AREc32 assay, indicative of the oxidative stress response, and 2 nuclear receptor assays targeting the peroxisome proliferator-activated receptor gamma and the arylhydrocarbon receptor. The EBTs were less conservative than previously proposed but were able to differentiate untreated and insufficiently treated wastewater from wastewater treatment plant effluent with secondary or tertiary treatment and surface water. Environ Toxicol Chem 2021;40:487-499. © 2020 The Authors. Environmental Toxicology and Chemistry published by Wiley Periodicals LLC on behalf of SETAC.

Regressional analysis of the patella parameters of male cadaveric knees found among South East Nigerians: A useful guide to patella replacement during total knee replacement

Background: Total knee replacement (TKR) is a viable option for the management of osteoarthritis, and it has proven to be both effective and successful. Optimization of the patellofemoral joint kinematics is important for surgeons who choose to resurface the patella during TKR. The whole idea is to get the final patellar bone-prosthesis composite thickness to match the original patellar thickness before the surgery. Aim: To correlate patella height (PH) and patella width (PW) with patella thickness (PT) as well as build a regression model through which the dimensions can predict the thickness among the native knees of the South East Nigerians. Materials and Methods: This is a correlational, nonexperimental, and observational study conducted on 60 knees from 30 male cadavers taken from the anatomy laboratory of the University of Nigeria, Enugu Campus. The PH, PW, and PT were measured by using specific endpoints and the observed data were subjected to statistical correlation analysis. Results: PH and PT were strongly positively correlated, r(59) = 0.797, P < 0.001. Results of the multiple linear regression indicated that there was a collective significant effect between the PH, PW, and PT (F(2, 57) = 51.486, P < 0.001, R2 = 0.644). The individual predictors were examined further and indicated that PH (t = 4.931, P < 0.001) was a significant predictor whereas PW (t = 1.153, P = 0.254) was not a significant predictor in the model. The patella’s predicted thickness is equal to 1.734+0.328 (PH in cm) +0. PT increased 0.328 cm for each centimeter of height. The PH was the only significant predictor of PT. Conclusion: This study was able to establish a correlation between the PH, PW, and PT, and it was able to demonstrate PH and PW as predictors of PT among the population of South East Nigeria.

Yoga-Based Lifestyle Intervention as a Potential Adjuvant in Addressing Anxiety, Fear, Depression, and Perceived Health in Mild-to-Moderate COVID-19 Patients. A Pilot Study

Introduction: Coronavirus infection (COVID-19) has led to a serious public health crisis that has affected both physical and mental health. As we are racing toward a solution for containing the virus, there is a profound need to address the mental health impact of COVID-19 such as anxiety, stress, and depression. The present study evaluates the impact of yoga on mental health issues arising in COVID-19 pandemic. Materials and Methods: Patients who are diagnosed as COVID-19 by polymerase chain reaction and graded as mild-to-moderate COVID-19 as per the ICMR criteria were enrolled for adjuvant yoga and naturopathy-based lifestyle modification, which includes postures, breath regulation, meditation, and eucalyptus essential oil inhalation for 14 days. SpO2 (saturated oxygen) and anxiety, stress, depression, fear, and health were assessed through the depression, anxiety, and stress scale (DASS) at baseline (day 1 of admission) and 7th day, as well as visual analog scale (VAS) at baseline and 7th and 14th day. Results: Statistically significant changes reduction were observed in DASS-21 scores and VAS scores (P &lt; 0.05) but not on SpO2. Slight increase in mean anxiety, depth of fear, sleep disturbance, and health status was observed in VAS between 7th and 14th day, which was statistically nonsignificant. Discussion: Supervised yoga sessions are reported to be of significant impact in alleviating the mental health issues in COVID-19 compared to nonsupervised sessions. Our results suggest the inclusion of yoga therapy into COVID-19 care as an adjuvant considering its impact on mental health. However, future randomized control trials are warranted with more specific end points to ensure enhanced acceptance of yoga in scientific community.

184. Pharmacist role in antimicrobial stewardship research: a 30-year experience

BackgroundAntimicrobial stewardship program (ASP) guidance from the Centers for Disease Control and Prevention recommends co-leadership of both an infectious-diseases (ID) physician and ID-trained pharmacist. Pharmacists play a key role in the therapeutic management, administration, and implementation of ASP interventions. The purpose of this study, conducted on behalf of the Society of Infectious Diseases Pharmacists, was to describe the involvement of pharmacists in publications of ASP interventional research.MethodsA PubMed search was conducted to identify publications in the United States and Canada from 1990–2019 including “antimicrobial (or antibiotic) stewardship” or “antimicrobial (or antibiotic) intervention.” Articles were screened for active interventions with comparator arms. A random subset of 100 pharmacist-authored manuscripts were selected using a time-based clustering strategy to review specific study designs, populations, interventions, and endpoints.ResultsOf 1,426 publications, 340 met inclusion. Two-thirds (228/340) of all interventional antimicrobial stewardship studies included a pharmacist author. Pharmacists were lead authors in 59% (135/228) of studies that included a pharmacist. Among the randomized subset of pharmacist-authored manuscripts (n=100), the average impact factor of journals with pharmacists as the first author was 3.52, compared to 5.25 as middle authors. Most studies were inpatient focused (89%), included adults (81%), and conducted in a single-site setting (84%). Pediatrics, immunocompromised, post-acute care, and ambulatory populations comprised less than 10% of the publications. The most common interventions described were audit and feedback (55%), guideline implementation (49%), and education (40%). Endpoints included drug utilization (66%), clinical outcomes (57%), safety events (46%), cost (40%), and appropriateness of therapy (35%).Figure 1. ConclusionPharmacists have an integral role in publication and dissemination of ASP research. Opportunities exist in multi-site collaboration as well as research in ambulatory, pediatric, and immunocompromised groups. Future research endpoints should be practical, generalizable, and patient-centered.Disclosures Kelly E. Pillinger, PharmD, BCIDP, Pharmacy Times (Other Financial or Material Support, Speaker) Haley Appaneal, PharmD, Shionogi (Grant/Research Support)