Detailed Safety Assessment Research Articles

Bacteriocin characterization of Enterococcus faecium isolates and evaluation of their in situ anti-Listerial activity in Beyaz cheese

Nowadays, as the interest in natural preservatives increases, research on bioprotective cultures that produce bacteriocins and studies on the use of these cultures in foods are also increasing day by day. Present study aimed to investigate bacteriocin characterization and safety of Enterococcus faecium H108, H206 isolates and their potential utilization in the reduction of Listeria monocytogenes ATCC7644 in Beyaz cheese. Enterocin producing E. faecium H108 and H206 strains were isolated from raw cow's milk and identified by 16S rRNA sequencing. Enterocin containing supernatants of E. faecium H108 and H206 were found to be stable to heat various chemicals used in food industry, wide pH range, lysozyme and catalase enzymes. On the other hand, activity of enterocins were inactivated by proteolytic enzymes. Maximum activity of E. faecium H108 was 6400 AU/mL, while that of H206 was 12800 AU/mL, and the activities remained stable for 24 h. Supernatant of both E. faecium H108 and H206 inhibited L. monocytogenes growth in vitro. E. faecium H108 and H206 did not show haemolytic and DN-ase activities and were susceptible to most of the antibiotics tested. The isolates were used in Beyaz cheese and were found to significantly, but not completely inhibit L. monocytogenes growth. The findings of this research suggest that E. faecium H108 and H206 isolates, after a detailed safety assessment, might be employed as bioprotective cultures in Beyaz cheese with starter culture or hurdle technologies.

Comprehensive Assessment of Drug Kinetics, Neurotoxicity, and Safety of Sirolimus-Eluting Intracranial Stents in Canine Basilar Artery.

Sirolimus-eluting stents (SESs) have shown promise in treating intracranial atherosclerosis but concerns about potential neurotoxicity due to prolonged drug release exist. The aim of this study was to comprehensively assess the safety of SES, with a focus on neurotoxicity. Stents (1.50 × 7 or 12 mm) were implanted into the basilar arteries of 154 Labrador Retrievers (weighing >25 kg and aged older than 1 year) divided into 4 groups: baer-metal stent, polymer-coated stent, standard-dose SES (sirolimus dose: 71 μg), and high-dose SES group (sirolimus dose: 284 μg). Pharmacokinetic analysis was conducted using liquid chromatography-mass spectrometry on blood and tissue samples, and analysis of brain tissue was performed with 5 different special stains and immunohistochemistry protocols to assess axonal degeneration, vacuolization, astrocyte proliferation, microglial activation, or widespread neurodegeneration. In the standard-dose SES group, the stent released 10.56% of the drug on day 1 and 95.41% on day 28 postimplantation. In the high-dose SES group, corresponding figures were 40.20% on day 1 and 98.08% on day 28. Systemic drug concentration consistently remained below 1.5 ng/mL throughout the study. Arterial tissue concentration reached its peak at day 28 days in the standard-dose group and at 7 days in the high-dose group. Importantly, the brain and related tissue concentrations remained below 0.4 µg/g in both standard-dose and high-dose SES groups, peaking on day 21 in the standard-dose group and day 1 in the high-dose group. The detailed 180-day safety assessment revealed no adverse effects on the brain, even at high sirolimus doses in the SES group. This study provides robust evidence supporting the long-term pharmacokinetic safety of SESs in the context of intracranial interventions for high-grade intracranial atherosclerosis. The results adequately alleviate concerns related to neurotoxicity and substantiate the feasibility of using these stents as a therapeutic choice in neurosurgery.

An Artificial Neural Network for the prediction of the structural and foundational attention class of bridges according to the Italian Guidelines

The state of conservation, maintenance and monitoring of bridges has gained attention in the last decade over the world especially in Italy, where a large number of structures are present and, multiple cases of collapses of bridges have recently occurred. To address this problem and to provide a prioritization on bridges where detailed safety assessments are necessary, in 2020 the Italian Ministry of Transport and Infrastructure issues Guidelines, based on a multi-level and multi-risk approach. Six levels of assessment are foreseen: the first three must be applied to all bridges (Levels 0-2), while the last three (Levels 3-5) only for the bridges which are characterized by high risk deriving from the analyses of the previous levels. Focusing on the first three levels, Level 0 consists of a census of all the existing bridges, collecting registry data mainly deriving from the existing documentation. Level 1 consists of visual inspections, which are used to point out the conservation status of the bridge and the surrounding area. Level 2 provides for a risk-based classification starting from the data previously collected. Levels 0-2 must be applied indiscriminately to all bridges. Thus, to prioritize inspections, it could be helpful to have a tool capable to predict the state of conservation of bridge and to assess the associated risks, starting from data gathered with census. For this reason, this paper proposed an Artificial Neural Network (ANN) capable to assess the level of degradation and structural and foundational risk level of existing bridges, using a reduced set of information derived from Level 0 activities. This tool can be used to: I) rationally schedule the inspections, starting from structures that could have a higher probability to be heavily degraded, II) support managing and planning activities at territorial level, promptly furnishing information about the structural and foundational risk of the bridges.

Safety, immunogenicity and efficacy of Relcovax®, a dual receptor binding domain (RBD) and nucleocapsid (N) subunit protein vaccine candidate against SARS-CoV-2 virus

SARS-CoV-2, severe acute respiratory syndrome coronavirus-2, causes coronavirus disease- 2019 (COVID-19). Mostly, COVID-19 causes respiratory symptoms that can resemble those of a cold, the flu, or pneumonia. COVID-19 may harm more than just lungs and respiratory systems. It may also have an impact on other parts of the body and debilitating effects on humans, necessitating the development of vaccines at an unprecedented rate in order to protect humans from infections. In response to SARS-CoV-2 infection, mRNA, viral vector-based carrier and inactivated virus-based vaccines, as well as subunit vaccines, have recently been developed. We developed Relcovax®, a dual antigen (Receptor binding domain (RBD) and Nucleocapsid (N) proteins) subunit protein vaccine candidate. Preliminary mouse preclinical studies revealed that Relcovax® stimulates cell-mediated immunity and provides broader protection against two SARS-CoV-2 variants, including the delta strain. Before conducting human studies, detailed preclinical safety assessments are required, so Relcovax® was tested for safety, and immunogenicity in 28-day repeated dose toxicity studies in rats and rabbits. In the toxicity studies, there were no mortality or morbidity, abnormal clinical signs, abnormalities in a battery of neurobehavioral observations, abnormalities in detailed clinical and ophthalmological examinations, or changes in body weights or feed consumption. In any of the studies, no abnormal changes in organ weights, haematology, clinical chemistry, urinalysis parameters, or pathological findings were observed. Immunogenicity tests on rats and rabbits revealed 100 % seroconversion. Relcovax® was therefore found to be safe in animals, with a No Observed Adverse Effect Level (NOAEL) of 20 µg/protein in rats and rabbits. In efficacy studies, Relcovax® immunised hamsters demonstrated dose-dependent protection against SARS-CoV-2 infection, with a high dose (20 µg/protein) being the most protective, while in cynomolgus macaque monkey study, lowest dose 5 µg/protein had the highest efficacy. In conclusion, Relcovax® was found to be safe, immunogenic, and efficacious in in vivo studies.

Safety Assessment of Pressure Vessels Exceeding the Design Service Life of a Petrochemical Company's Rubber Plant

The rubber plant of a petrochemical company has been built for a long time, some pressure vessels have exceeded the design service life or 20 years. It belongs to the pressure vessel beyond the design service life. A large number of devices and pressure vessels have entered or are about to enter the extended service stage. The detailed safety assessment of all equipment in service beyond the time limit is costly, inefficient and not targeted. Therefore, in this paper, through the screening of time-dependent damage modes. Focus on safety assessment of equipment with time-dependent damage such as corrosion, fatigue and creep. According to the screening and evaluation results, the safety assessment results and inspection management suggestions of the pressure vessel of the whole set of equipment are given. It is hoped that it can provide a reference for enterprises to manage the safety of pressure vessels beyond the design service life.

Evaluation of the potential immunogenicity of recombinant human bone morphogenetic proteins

Introduction. Bone morphogenetic proteins (BMPs) are a subgroup of the transforming growth factor-β (TGF-β) superfamily where they play an important role in bone formation and repair. Recombinant human bone morphogenetic proteins (rhBMPs) are currently being clinically evaluated for their effectiveness in enhancing bone tissue regeneration processes after injuries and diseases of the musculoskeletal system. Clinical trials were accompanied by detailed safety assessments using both in vitro and in vivo assays. Concerns were initially raised about the immunogenicity of some therapeutic proteins due to their non-human origin. However, proteins derived from human serum or tissues and products derived from recombinant DNA, such as rhBMPs, identical or nearly identical to native human proteins, have also been shown to be immunogenic. The purpose. of this study is to review the potential immunogenicity of rhBMPs and compare the results of preclinical and clinical studies available to date between rhBMP-2 and rhBMP-7. Materials and methods. Using PubMed, Embase, the Cochrane Database, and Google Scholar, we conducted a comprehensive search for original papers, literature reviews, case reports, and meta-analyses demonstrating possible immune responses to rhBMPs. Results. This study analyzes possible reactions from the immune system when using rhBMPs in both clinical and preclinical studies. Antibody production has been found to be one of the side effects of rhBMPs. However, reported cases of immunogenicity of rhBMPs vary greatly due to the lack of standardization of methods. Conclusion. No immunologically related adverse events were observed in various clinical trials, and antibody formation never adversely affected new bone formation and clinical outcomes.

Advanced Thermal-Hydraulic experiments and instrumentation for heavy liquid metal reactors

Heavy-liquid metals (HLMs), such as lead and lead–bismuth eutectic (LBE), are proposed as primary coolants in accelerator driven systems and next-generation fast reactors. In Europe, the reference systems using HLMs are MYRRHA (LBE) and ALFRED (lead). Extensive R&D programs have been established for supporting their detailed design and safety assessment, including thermal–hydraulic experiments at representative operating conditions in an HLM environment. These experiments aim both at a design verification and at the validation of numerical models, which allow an extrapolation of the results. Advanced instrumentation, capable of sustaining high temperatures and corrosion, is necessary for accurate measurements, often in compact geometries.This article presents an overview of recent experiences and ongoing activities on pool-type and loop-type HLM experiments. Pool tests include the measurement of forced- and natural-circulation flow patterns in several scenarios representative of nominal and decay heat removal conditions. Loop tests are focused on the evaluation of specific components, like mockups of the fuel assembly, control rod and heat exchangers. They involve the measurement of global variables, such as flow rate and pressure difference, and local quantities like temperature, velocity and vibrations. In addition to traditional techniques, other instrumentation based on optical fibers, ultrasonic and electromagnetic methods are discussed.

Dryopteris juxtapostia Root and Shoot: Determination of Phytochemicals; Antioxidant, Anti-Inflammatory, and Hepatoprotective Effects; and Toxicity Assessment.

An estimated 450 species of Dryopteris in the Dryoperidaceae family grow in Japan, North and South Korea, China, Pakistan, and Kashmir. This genus has been reported to have biological capabilities; however, research has been conducted on Dryopteris juxtapostia. Therefore, with the present study, we aimed to exploring the biological potential of D. juxtapostia root and shoot extracts. We extracted dichloromethane and methanol separately from the roots and shoots of D. juxtapostia. Antioxidant activity was determined using DPPH, FRAP, and H2O2 assays, and anti-inflammatory activities were evaluated using both in vitro (antiurease activity) and in vivo (carrageenan- and formaldehyde-induced paw edema) studies. Toxicity was evaluated by adopting a brine shrimp lethality assay followed by determination of cytotoxic activity using an MTT assay. Hepatoprotective effects of active crude extracts were examined in rats. Activity-bearing compounds were tentatively identified using LC-ESI-MS/MS analysis. Results suggested that D. juxtapostia root dichloromethane extract exhibited better antioxidant (DPPH, IC50 of 42.0 µg/mL; FRAP, 46.2 mmol/g; H2O2, 71% inhibition), anti-inflammatory (urease inhibition, 56.7% at 50 µg/mL; carrageenan-induced edema inhibition, 61.7% at 200 µg/mL; formaldehyde-induced edema inhibition, 67.3% at 200 µg/mL), brine shrimp % mortality (100% at 1000 µg/mL), and cytotoxic (HeLa cancer, IC50 of 17.1 µg/mL; prostate cancer (PC3), IC50 of 45.2 µg/mL) effects than D. juxtapostia root methanol extract. D. juxtapostia shoot dichloromethane and methanol extracts exhibited non-influential activity in all biological assays and were not selected for hepatoprotective study. D. juxtapostia root methanol extract showed improvement in hepatic cell structure and low cellular infiltration but, in contrast the dichloromethane extract, did not show any significant improvement in hepatocyte morphology, cellular infiltration, or necrosis of hepatocytes in comparison to the positive control, i.e., paracetamol. LC-ESI-MS/MS analysis showed the presence of albaspidin PP, 3-methylbutyryl-phloroglucinol, flavaspidic acid AB and BB, filixic acid ABA and ABB, tris-desaspidin BBB, tris-paraaspidin BBB, tetra-flavaspidic BBBB, tetra-albaspidin BBBB, and kaempferol-3-O-glucoside in the dichloromethane extract, whereas kaempferol, catechin, epicatechin, quinic acid, liquitrigenin, and quercetin 7-O-galactoside in were detected in the methanol extract, along with all the compounds detected in the dichloromethane extract. Hence, D. juxtapostia is safe, alongside other species of this genus, although detailed safety assessment of each isolated compound is obligatory during drug discovery.

COSPAR Sample Safety Assessment Framework (SSAF).

The Committee on Space Research (COSPAR) Sample Safety Assessment Framework (SSAF) has been developed by a COSPAR appointed Working Group. The objective of the sample safety assessment would be to evaluate whether samples returned from Mars could be harmful for Earth's systems (e.g., environment, biosphere, geochemical cycles). During the Working Group's deliberations, it became clear that a comprehensive assessment to predict the effects of introducing life in new environments or ecologies is difficult and practically impossible, even for terrestrial life and certainly more so for unknown extraterrestrial life. To manage expectations, the scope of the SSAF was adjusted to evaluate only whether the presence of martian life can be excluded in samples returned from Mars. If the presence of martian life cannot be excluded, a Hold & Critical Review must be established to evaluate the risk management measures and decide on the next steps. The SSAF starts from a positive hypothesis (there is martian life in the samples), which is complementary to the null-hypothesis (there is no martian life in the samples) typically used for science. Testing the positive hypothesis includes four elements: (1) Bayesian statistics, (2) subsampling strategy, (3) test sequence, and (4) decision criteria. The test sequence capability covers self-replicating and non-self-replicating biology and biologically active molecules. Most of the investigations associated with the SSAF would need to be carried out within biological containment. The SSAF is described in sufficient detail to support planning activities for a Sample Receiving Facility (SRF) and for preparing science announcements, while at the same time acknowledging that further work is required before a detailed Sample Safety Assessment Protocol (SSAP) can be developed. The three major open issues to be addressed to optimize and implement the SSAF are (1) setting a value for the level of assurance to effectively exclude the presence of martian life in the samples, (2) carrying out an analogue test program, and (3) acquiring relevant contamination knowledge from all Mars Sample Return (MSR) flight and ground elements. Although the SSAF was developed specifically for assessing samples from Mars in the context of the currently planned NASA-ESA MSR Campaign, this framework and the basic safety approach are applicable to any other Mars sample return mission concept, with minor adjustments in the execution part related to the specific nature of the samples to be returned. The SSAF is also considered a sound basis for other COSPAR Planetary Protection Category V, restricted Earth return missions beyond Mars. It is anticipated that the SSAF will be subject to future review by the various MSR stakeholders.

Spatial modelling for population replacement of mosquito vectors at continental scale.

Malaria is one of the deadliest vector-borne diseases in the world. Researchers are developing new genetic and conventional vector control strategies to attempt to limit its burden. Novel control strategies require detailed safety assessment to ensure responsible and successful deployments. Anopheles gambiae sensu stricto (s.s.) and Anopheles coluzzii, two closely related subspecies within the species complex Anopheles gambiae sensu lato (s.l.), are among the dominant malaria vectors in sub-Saharan Africa. These two subspecies readily hybridise and compete in the wild and are also known to have distinct niches, each with spatially and temporally varying carrying capacities driven by precipitation and land use factors. We model the spread and persistence of a population-modifying gene drive system in these subspecies across sub-Saharan Africa by simulating introductions of genetically modified mosquitoes across the African mainland and its offshore islands. We explore transmission of the gene drive between the two subspecies that arise from different hybridisation mechanisms, the effects of both local dispersal and potential wind-aided migration to the spread, and the development of resistance to the gene drive. Given the best current available knowledge on the subspecies' life histories, we find that an introduced gene drive system with typical characteristics can plausibly spread from even distant offshore islands to the African mainland with the aid of wind-driven migration, with resistance beginning to take over within a decade. Our model accounts for regional to continental scale mechanisms, and demonstrates a range of realistic dynamics including the effect of prevailing wind on spread and spatio-temporally varying carrying capacities for subspecies. As a result, it is well-placed to answer future questions relating to mosquito gene drives as important life history parameters become better understood.

Simulation and Fast vulnerability analysis of a Chinese masonry pagoda

Abstract As an important historical relic of human being, masonry pagoda is the great significance in the eastern and western architectural cultures. Most of the existing masonry pagodas in China which have been seriously damaged urgently need detailed structural safety assessment, repair and reinforcement. The paper choose a Chinese masonry pagoda as a case, conducted a series simulation analysis with Abauqs. Through numerical simulation, the seismic performance of the pagoda can be evaluated, which can not only predict the hidden danger and weak link in its structure, but also provide useful reference for the reinforcement and repair of the pagoda. It also adopts a very convenient 3D CAD method to quickly assess the seismic vulnerability of existing masonry pagoda according the reference.

Detailed safety assessment for the VVER-1000 fuel assembly

Detailed safety assessment for the VVER-1000 fuel assembly

Detailed safety assessment for the VVER-1000 fuel assembly

Detailed safety assessment for the VVER-1000 fuel assembly

Structural integrity assessment of Calandria of 540 MWe PHWR for in-vessel corium retention

The safety demonstration of nuclear power plant, even for very low probability severe accident scenarios, has been an important requirement. A postulated severe accident is one of the beyond design basis plant states which can have significant consequences resulting from the nuclear fuel degradation. Such accident scenarios call for detailed safety assessment and provision of design features and guidelines for the operating personnel to manage the accident. In the present work, structural integrity assessment of Calandria assembly of a typical 540 MWe Indian Pressurized Heavy Water Reactor has been carried out to assess the duration of in-Calandria retention of core debris/corium for a postulated severe core damage accident scenario. The premise of the study, methodology and analysis tools used to assess structural integrity and failure timeline are discussed. Sequentially coupled thermo-mechanical analysis has been carried out for the thermal and mechanical loads arising out of the postulated accident and structural response of Calandria assembly is evaluated. The Calandria undergoes significant creep/plasticity deformation after loss of cooling through Calandria vault water. Plastic instability, excessive inelastic strains and creep-stress rupture criteria are considered to assess the structural failure of Calandria assembly. It is observed that the Calandria is able to maintain the structural integrity for reasonable duration of more than two days without any management action. Thus, the robustness of the PHWR design is demonstrated. Realistic assessment of timeline of in-Calandria corium/debris retention under such severe core damage accident loading are vital for assessing the severe accident management guidelines.

Transverse cracking in embankment dams resulting from cross-valley differential settlements

This article investigates transverse cracking in embankment dams resulting from cross-valley differential settlements during and post-construction, in which concentrated leak erosion may initiate. Based on case studies and numerical analyses, it is shown that valley profiles with a step in the upper part of the abutment and subject to large post-construction settlements within the embankment, or within compressible soil in the foundation, are most likely to be subject to cracking. Estimated localised strains at the crest > 1%, and in particular >2%, are likely to be indicative of conditions conducive to transverse cracking. Smaller strains but greater than about 0.25% may also result in cracking but they are likely to be narrower and shallower. The article also gives general guidance on the likely width and depth of cracking. The information presented is only suitable for preliminary dam safety assessments. For detailed dam safety assessments and risk assessments where decisions are to be made on whether risks are tolerable, or upgrades required, site-specific cross-valley numerical analyses should be carried out. These detailed analyses should model the cross-valley profile accurately, material parameters more rigorously than has been done in the parametric studies reported in this article.

Nanomedicines - Tiny particles and big challenges

After decades of research, nanotechnology has been used in a broad array of biomedical products including medical devices, drug products, drug substances, and pharmaceutical-grade excipients. But like many great achievements in science, there is a fine balance between the risks and opportunities of this new technology. Some materials and surface structures in the nanosize range can exert unexpected toxicities and merit a more detailed safety assessment. Regulatory agencies such as the United States Food and Drug Administration or the European Medicines Agency have started dealing with the potential risks posed by nanomaterials. Considering that a thorough characterization is one of the key aspects of controlling such risks this review presents the regulatory background of nanosafety assessment and provides some practical advice on how to characterize nanomaterials and drug formulations. Further, the challenges of how to maintain and monitor pharmaceutical quality through a highly complex production processes will be discussed.

Non-caloric sweeteners: specific characteristics and safety assessment.

Non-caloric sweeteners are food additives that can be added to food and beverages, in substitution of sugar, thus allowing to decrease energy content and free sugars intake. However, many health care professionals have questioned the safety of these additives for human consumption. Therefore, it is crucial that health care professionals become familiar with the characteristics of each non-caloric sweetener (chemical structure, absorption profile, metabolism, and route of excretion) and with the findings of the detailed safety assessments done prior to their approval, so that they can be a reliable source of scientific information for their patients.The purpose of this article is to provide a better understanding of the safety assessment process of non-caloric sweeteners prior to their approval, which includes determining the non-observed adverse effect level and the acceptable daily intake.

Safety assessment of existing retaining structures

AbstractOver the last years, an increase of damages and defects of geotechnical structures has been observed during detailed safety assessments. This is mostly related to the rising age of these structures and the related decrease of the bearing capacity. The handling and dealing with these existing structures will be a challenging task for future civil engineers. This article should give an insight into damages and defects of retaining structures, which are quite difficult to detect and evaluate in terms of safety and risk. The first part of the article gives a short overview on the state of the art when it comes to the safety assessment of existing retaining structures and introduces a new, currently being edited, ÖGG guideline for this field of civil engineering. The second part deals with corrosion‐induced damages on cantilever walls and shows first results of the research project SIBS (safety assessment of existing retaining structures).

Potential for recycling of slightly radioactive metals arising from decommissioning within nuclear sector in Slovakia

The decommissioning of nuclear installations represents a complex process resulting in the generation of large amounts of waste materials containing various concentrations of radionuclides. Selection of an appropriate strategy of management of the mentioned materials strongly influences the effectiveness of decommissioning process keeping in mind safety, financial and other relevant aspects. In line with international incentives for optimization of radioactive material management, concepts of recycling and reuse of materials are widely discussed and applications of these concepts are analysed. Recycling of some portion of these materials within nuclear sector (e.g. scrap metals or concrete rubble) seems to be highly desirable from economical point of view and may lead to conserve some disposal capacity. However, detailed safety assessment along with cost/benefit calculations and feasibility study should be developed in order to prove the safety, practicality and cost effectiveness of possible recycling scenarios.Paper discussed the potential for recycling of slightly radioactive metals arising from decommissioning of NPPs within nuclear sector in Slovakia. Various available recycling scenarios are introduced and method for overall assessment of various recycling scenarios is outlined including the preliminary assessment of safety and financial aspects.

Safety Predictors in Performance of Activities of Daily Living in Patients with Parkinson’s Disease

Background: Safety is recognized as an important factor in personal independence. The aim of this study was to determine the association of factors, such as fatigue, duration of disease, age, dominant involved body side, gender, and severity of disease with safety performance and to identify safety predictors among effective factors for activities of daily living (ADL) among patients with Parkinson’s disease (PD). Methods: Sixty patients with PD participated in this study. Fatigue was assessed using the 16-item Parkinson fatigue scale (PFS-16), while performance safety was examined with the performance assessment of self-care skills (PASS). Linear multiple regression analysis was performed between PASS safety parameter as the dependent variable and independent variables with significant correlations with performance safety, using SPSS version 18. Results: A significant relationship was observed between ADL safety and fatigue (r = 0.557; P < 0.001), disease severity (r = 0.558; P ≤ -0.001), and age (r = -0.636; P < 0.001). Performance safety in physical and cognitive instrumental ADL showed the most significant correlation with fatigue severity. The stepwise multiple linear regression model revealed that age (F(1, 58), 39.32; P < 0.001) with an R2 of 0.64 could predict safety in ADL performance. Conclusions: Age, fatigue severity, and disease are predictors of performance safety in ADL among patients with PD. For implementing more effective interventions on safe ADL performance, rehabilitation teams should conduct more detailed safety assessments with a special focus on the effects of fatigue, aging, and disease severity on the performance of each activity.