Perspectives on the comparative benefits of body-powered and myoelectric upper limb prostheses.

BACKGROUND: Patient access to body-powered and myoelectric upper limb prostheses in the United States is often restricted by a healthcare system that prioritizes prosthesis prescription based on cost and perceived value. Although this system operates on an underlying assumption that design differences between these prostheses leads to relative advantages and disadvantages of each device, there is limited empirical evidence to support this view. MAIN TEXT: This commentary article will review a series of studies conducted by our research team with the goal of differentiating how prosthesis design might impact user performance on a variety of interrelated domains. Our central hypothesis is that the design and actuation method of body-powered and myoelectric prostheses might affect users' ability to access sensory feedback and account for device properties when planning movements. Accordingly, other domains that depend on these abilities may also be affected. While our work demonstrated some differences in availability of sensory feedback based on prosthesis design, this did not result in consistent differences in prosthesis embodiment, movement accuracy, movement quality, and overall kinematic patterns. CONCLUSION: Collectively, our findings suggest that performance may not necessarily depend on prosthesis design, allowing users to be successful with either device type depending on the circumstances. Prescription practices should rely more on individual needs and preferences than cost or prosthesis design. However, we acknowledge that there remains a dearth of evidence to inform decision-making and that an expanded research focus in this area will be beneficial.

Material Flow Analysis and Occupational Exposure Assessment in Additive Manufacturing End-of-Life Material Management.

Additive manufacturing (AM) offers a variety of material manufacturing techniques for a wide range of applications across many industries. Most efforts at process optimization and exposure assessment for AM are centered around the manufacturing process. However, identifying the material allocation and potentially harmful exposures in end-of-life (EoL) management is equally crucial to mitigating environmental releases and occupational health impacts within the AM supply chain. This research tracks the allocation and potential releases of AM EoL materials within the US through a material flow analysis. Of the generated AM EoL materials, 58% are incinerated, 33% are landfilled, and 9% are recycled by weight. The generated data set was then used to examine the theoretical occupational hazards during AM EoL material management practices through generic exposure scenario assessment, highlighting the importance of ventilation and personal protective equipment at all stages of AM material management. This research identifies pollution sources, offering policymakers and stakeholders insights to shape pollution prevention and worker safety strategies within the US AM EoL management pathways.

Electrical Stimulation of Regenerative Peripheral Nerve Interfaces (RPNIs) Induces Referred Sensations in People With Upper Limb Loss.

Individuals with upper limb loss lack sensation of the missing hand, which can negatively impact their daily function. Several groups have attempted to restore this sensation through electrical stimulation of residual nerves. The purpose of this study was to explore the utility of regenerative peripheral nerve interfaces (RPNIs) in eliciting referred sensation. In four participants with upper limb loss, we characterized the quality and location of sensation elicited through electrical stimulation of RPNIs over time. We also measured functional stimulation ranges (sensory perception and discomfort thresholds), sensitivity to changes in stimulation amplitude, and ability to differentiate objects of different stiffness and sizes. Over a period of up to 54 months, stimulation of RPNIs elicited sensations that were consistent in quality (e.g. tingling, kinesthesia) and were perceived in the missing hand and forearm. The location of elicited sensation was partially-stable to stable in 13 of 14 RPNIs. For 5 of 7 RPNIs tested, participants demonstrated a sensitivity to changes in stimulation amplitude, with an average just noticeable difference of 45 nC. In a case study, one participant was provided RPNI stimulation proportional to prosthetic grip force. She identified four objects of different sizes and stiffness with 56% accuracy with stimulation alone and 100% accuracy when stimulation was combined with visual feedback of hand position. Collectively, these experiments suggest that RPNIs have the potential to be used in future bi-directional prosthetic systems.

Review of generic scenario environmental release and occupational exposure models used in chemical risk assessment.

Under the Toxic Substances Control Act (TSCA), the United States Environmental Protection Agency (USEPA) is required to determine whether a new chemical substance poses an unreasonable risk to human health or the environment before the chemical is manufactured in or imported into the United States. This manuscript provides a review of the process used to evaluate the risk associated with a chemical based on the scenarios and models used in the evaluation. Specifically, the Generic Scenarios and Emission Scenario Documents developed by the USEPA were reviewed, along with background documentation prepared by USEPA to identify the core elements of the environmental release and occupational exposure scenarios used to assess the risk of the chemical being evaluated. Additionally, this contribution provides an overview of methods used to model occupational exposures and environmental releases as part of the chemical evaluation process used in other jurisdictions, along with work being performed to improve these models. Finally, the alternative methods to evaluate occupational exposures and environmental releases that may be used as part of the decision-making process regarding a chemical are identified. The contribution provides a path forward for reducing the time required and improving the chemical evaluation of the unreasonable risk determination regarding the manufacture or import of a chemical.

Phagocytosis increases an oxidative metabolic and immune suppressive signature in tumor macrophages.

Phagocytosis is a key macrophage function, but how phagocytosis shapes tumor-associated macrophage (TAM) phenotypes and heterogeneity in solid tumors remains unclear. Here, we utilized both syngeneic and novel autochthonous lung tumor models in which neoplastic cells express the fluorophore tdTomato (tdTom) to identify TAMs that have phagocytosed neoplastic cells in vivo. Phagocytic tdTompos TAMs upregulated antigen presentation and anti-inflammatory proteins, but downregulated classic proinflammatory effectors compared to tdTomneg TAMs. Single-cell transcriptomic profiling identified TAM subset-specific and common gene expression changes associated with phagocytosis. We uncover a phagocytic signature that is predominated by oxidative phosphorylation (OXPHOS), ribosomal, and metabolic genes, and this signature correlates with worse clinical outcome in human lung cancer. Expression of OXPHOS proteins, mitochondrial content, and functional utilization of OXPHOS were increased in tdTompos TAMs. tdTompos tumor dendritic cells also display similar metabolic changes. Our identification of phagocytic TAMs as a distinct myeloid cell state links phagocytosis of neoplastic cells in vivo with OXPHOS and tumor-promoting phenotypes.

Application of read-across methods as a framework for the estimation of emissions from chemical processes.

The read-across method is a popular data gap filling technique with developed application for multiple purposes, including regulatory. Within the US Environmental Protection Agency's (US EPA) New Chemicals Program under Toxic Substances Control Act (TSCA), read-across has been widely used, as well as within technical guidance published by the Organization for Economic Co-operation and Development, the European Chemicals Agency, and the European Center for Ecotoxicology and Toxicology of Chemicals for filling chemical toxicity data gaps. Under the TSCA New Chemicals Review Program, US EPA is tasked with reviewing proposed new chemical applications prior to commencing commercial manufacturing within or importing into the United States. The primary goal of this review is to identify any unreasonable human health and environmental risks, arising from environmental releases/emissions during manufacturing and the resulting exposure from these environmental releases. The authors propose the application of read-across techniques for the development and use of a framework for estimating the emissions arising during the chemical manufacturing process. This methodology is to utilize available emissions data from a structurally similar analogue chemical or a group of structurally similar chemicals in a chemical family taking into consideration their physicochemical properties under specified chemical process unit operations and conditions. This framework is also designed to apply existing knowledge of read-across principles previously utilized in toxicity estimation for an analogue or category of chemicals and introduced and extended with a concurrent case study.

Use of regenerative peripheral nerve interfaces and intramuscular electrodes to improve prosthetic grasp selection: a case study.

Objective.Advanced myoelectric hands enable users to select from multiple functional grasps. Current methods for controlling these hands are unintuitive and require frequent recalibration. This case study assessed the performance of tasks involving grasp selection, object interaction, and dynamic postural changes using intramuscular electrodes with regenerative peripheral nerve interfaces (RPNIs) and residual muscles.Approach.One female with unilateral transradial amputation participated in a series of experiments to compare the performance of grasp selection controllers with RPNIs and intramuscular control signals with controllers using surface electrodes. These experiments included a virtual grasp-matching task with and without a concurrent cognitive task and physical tasks with a prosthesis including standardized functional assessments and a functional assessment where the individual made a cup of coffee ('Coffee Task') that required grasp transitions.Main results.In the virtual environment, the participant was able to select between four functional grasps with higher accuracy using the RPNI controller (92.5%) compared to surface controllers (81.9%). With the concurrent cognitive task, performance of the virtual task was more consistent with RPNI controllers (reduced accuracy by 1.1%) compared to with surface controllers (4.8%). When RPNI signals were excluded from the controller with intramuscular electromyography (i.e. residual muscles only), grasp selection accuracy decreased by up to 24%. The participant completed the Coffee Task with 11.7% longer completion time with the surface controller than with the RPNI controller. She also completed the Coffee Task with 11 fewer transition errors out of a maximum of 25 total errors when using the RPNI controller compared to surface controller.Significance.The use of RPNI signals in concert with residual muscles and intramuscular electrodes can improve grasp selection accuracy in both virtual and physical environments. This approach yielded consistent performance without recalibration needs while reducing cognitive load associated with pattern recognition for myoelectric control (clinical trial registration number NCT03260400).

Temporal and spatial goal-directed reaching in upper limb prosthesis users.

Understanding the fundamental characteristics of prosthetic movement control is imperative in improving prosthesis design and training. This study quantified how using an upper limb prosthesis affected performance during goal-directed reaching tasks. Nine prosthesis users with unilateral transradial limb absence and nine healthy controls completed a series of goal-directed reaching movements with different goals: one spatial and three temporal with different goal frequencies. We quantified end-point accuracy, smoothness, and peak speed for the spatial task and temporal accuracy, horizontal distance, and speed for the temporal task. For the temporal task, we also used a goal-equivalent manifold (GEM) approach to decompose variability in movement distance and speed into those perpendicular and tangential to the GEM. Detrended fluctuation analysis (DFA) quantified the temporal persistence of each time series. For the spatial task, movements made with prostheses were less smooth, had larger end-point errors, and had slower peak speed compared to those with control limbs (p < 0.041). For the temporal task, movements made with prostheses and intact limbs of prosthesis users and control limbs were similar in distance and speed and had similar timing errors (p > 0.138). Timing errors, distance, speed, and GEM deviations were corrected similarly between prosthetic limbs and control limbs (p > 0.091). The mean and variability of distance, speed, and perpendicular deviations decreased with increased goal frequency (p < 0.001). Our results suggest that prosthesis users have a sufficient internal model to successfully complete ballistic movements but are unable to accurately complete movements requiring substantial feedback.

Characterizing sensory thresholds and intensity sensitivity of Regenerative Peripheral Nerve Interfaces: A Case Study.

Current prosthetic limbs offer little to no sensory feedback. Developments in peripheral nerve interfaces provide opportunities to restore some level of tactile feedback that is referred to the prosthetic limb. One such method is a Regenerative Peripheral Nerve Interface (RPNI), composed of a muscle graft wrapped around a free nerve ending. Here, we characterize perception and discomfort thresholds, as well as sensitivity to stimulation through two-alternative forced choice discrimination tasks. One person with transradial amputation who had one RPNI constructed from the median nerve and two constructed from the ulnar nerve participated. Average perception thresholds across all RPNIs were between 950 and 1120 nC with variance of less than 350 nC over a 36-month period. Discomfort thresholds were from 3880 nC to 9770 nC across all RPNIs. The just noticeable difference for the Median RPNI was 520 nC, larger than either the Ulnar-1 or Ulnar-2 RPNIs (210 nC, 470 nC, respectively). We also calculated Weber fractions to compare sensitivity between different RPNIs and relate our results to previous studies. Weber fractions for each of the Median, Ulnar-1, and Ulnar-2 RPNIs were 0.134, 0.088, 0.087, respectively. This work is the first to quantify the functional stimulation range and sensitivity of RPNIs in a human participant. Future work will focus on characterizing RPNI sensation in additional individuals to determine if these findings are generalizable to the amputee population.

COVID-19 and Cancer: Special Considerations for Patients Receiving Immunotherapy and Immunosuppressive Cancer Therapies.

Patients with cancer generally have a higher risk of adverse outcomes from COVID-19, with higher age, male sex, poor performance status, cancer type, and uncontrolled malignant disease as the main risk factors. However, the influence of specific cancer therapies varies and raises concerns during the pandemic. In patients undergoing cancer immunotherapy or other immunosuppressive cancer treatments, we summarize the evidence on outcomes from COVID-19; address the safety, immunogenicity, and efficacy of COVID-19 vaccination; and review COVID-19 antiviral therapeutics for the patient with cancer. Despite higher mortality for patients with cancer, treatment with immune checkpoint inhibitors does not seem to increase mortality risk based on observational evidence. Inhibitory therapies directed toward B-cell lineages, including monoclonal antibodies against CD20 and CAR T-cell therapies, are associated with poor outcomes in COVID-19; however, the data are sparse. Regarding vaccination in patients receiving immune checkpoint inhibitors, clinical efficacy comparable to that in the general population can be expected. In patients undergoing B-cell-depleting therapy, immunogenicity and clinical efficacy are curtailed, but vaccination is not futile, which is thought to be due to the cellular response. Vaccine reactogenicity and toxicity in all groups of patients with cancer are comparable to that of the general population. Preexposure prophylaxis with monoclonal antibodies directed against the viral spike may provide passive immunity for those not likely to mount an adequate vaccine response. If infected, prompt treatment with monoclonal antibodies or oral small molecule antivirals is beneficial, though with oral antiviral therapies, care must be taken to avoid drug interactions in patients with cancer.

The Prolonged Diagnostic Pathway of Young Adults (Aged 25-39) with Cancer in the United Kingdom: Results from the Young Adult Cancer Patient Journey Study.

PURPOSE: Teenagers and young adults (TYAs; aged 13-24) experience prolonged intervals to cancer diagnosis. Insight into diagnostic intervals in young adults (YAs; aged 25-39) and subgroups at risk for long intervals is lacking. We investigated the diagnostic pathway of YA cancer patients, examined patient and tumor characteristics associated with its length, and compared the patient interval length of our sample with a TYA cohort. METHODS: In this cross-sectional survey YAs diagnosed with cancer in the UK in the past five years completed a questionnaire describing their patient (time from first symptom to first doctor consultation) and healthcare interval (from first consultation until consultation with a cancer specialist), sociodemographic, and clinical characteristics. Associations between characteristics and interval length were examined and compared with previously published data in TYAs. RESULTS: Among 341 YAs the patient interval lasted ≥2 weeks, ≥1 month, and ≥3 months in 60%, 42%, and 21%, respectively, compared to 48%, 27%, and 12% in the TYA group. The healthcare interval lasted ≥2 weeks, ≥1 month, and ≥3 months in 62%, 40%, and 17% of YA patients, respectively. YAs with melanoma or cervical cancer were most likely to experience long intervals, whereas YAs with breast cancer and leukemia were most likely to experience short intervals. CONCLUSIONS: Most YAs were not seen by a cancer specialist within 2 weeks of GP consultation. Interval lengths in YAs were associated with cancer diagnosis. Patient intervals were longer among YAs than among TYAs. Our study highlights long diagnostic pathways among YAs and calls for more awareness among healthcare professionals about malignancies in this age group.

Getting a Grip on the Impact of Incidental Feedback From Body-Powered and Myoelectric Prostheses.

Sensory feedback from body-powered and myoelectric prostheses are limited, but in different ways. Currently, there are no empirical studies on how incidental feedback differs between body-powered and myoelectric prostheses, or how these differences impact grasping. Thus, the purpose of this study was to quantify differences in grasping performance between body-powered and myoelectric prosthesis users when presented with different forms of feedback. Nine adults with upper limb loss and nine without (acting as controls) completed two tasks in a virtual environment. In the first task, participants used visual, vibration, or force feedback to assist in matching target grasp apertures. In the second task, participants used either visual or force feedback to identify the stiffness of a virtual object. Participants using either prosthesis type improved their accuracy and reduced their variability compared to the no feedback condition when provided with any form of feedback (p < 0.001). However, participants using body-powered prostheses were significantly more accurate and less variable at matching grasp apertures than those using myoelectric prostheses across all feedback conditions. When identifying stiffness, body-powered prosthesis users were more accurate using force feedback (64% compared to myoelectric users' 39%) while myoelectric users were more accurate using visual feedback (65% compared to body-powered users' 53%). This study supports previous findings that body-powered prosthesis users receive limited force and proprioceptive feedback, while myoelectric prosthesis users receive almost no force or proprioceptive feedback from their device. This work can inform future supplemental feedback that enhances rather than reproduces existing incidental feedback.

The helminth glycoprotein omega-1 improves metabolic homeostasis in obese mice through type 2 immunity-independent inhibition of food intake.

Type 2 immunity plays an essential role in the maintenance of metabolic homeostasis and its disruption during obesity promotes meta-inflammation and insulin resistance. Infection with the helminth parasite Schistosoma mansoni and treatment with its soluble egg antigens (SEA) induce a type 2 immune response in metabolic organs and improve insulin sensitivity and glucose tolerance in obese mice, yet, a causal relationship remains unproven. Here, we investigated the effects and underlying mechanisms of the T2 ribonuclease omega-1 (ω1), one of the major S mansoni immunomodulatory glycoproteins, on metabolic homeostasis. We show that treatment of obese mice with plant-produced recombinant ω1, harboring similar glycan motifs as present on the native molecule, decreased body fat mass, and improved systemic insulin sensitivity and glucose tolerance in a time- and dose-dependent manner. This effect was associated with an increase in white adipose tissue (WAT) type 2 T helper cells, eosinophils, and alternatively activated macrophages, without affecting type 2 innate lymphoid cells. In contrast to SEA, the metabolic effects of ω1 were still observed in obese STAT6-deficient mice with impaired type 2 immunity, indicating that its metabolic effects are independent of the type 2 immune response. Instead, we found that ω1 inhibited food intake, without affecting locomotor activity, WAT thermogenic capacity or whole-body energy expenditure, an effect also occurring in leptin receptor-deficient obese and hyperphagic db/db mice. Altogether, we demonstrate that while the helminth glycoprotein ω1 can induce type 2 immunity, it improves whole-body metabolic homeostasis in obese mice by inhibiting food intake via a STAT6-independent mechanism.

Supporting contaminated sites management with Multiple Criteria Decision Analysis: Demonstration of a regulation-consistent approach.

This study proposes a set of key decision-making features of the contaminated site remediation process to assist in selecting the most appropriate decision support method(s). Using a case study consistent with the requirements of the U.S. regulation for contaminated sites management, this article shows that suitable Multiple Criteria Decision Analysis methods can be selected based on a dynamic and evolving problem structuring. The selected methods belong to the family of PROMETHEE methods and can provide ranking recommendations of the considered alternatives using variable structures of the criteria, evaluation of the alternatives and exploitation of the preference model. It was found that in order to support a quick and up-to-date application of powerful decision support techniques in the process of remediation of contaminated sites, decision analysts and stakeholders should interact and co-develop the process. This research also displays how such interactions can guarantee a transparent and traceable decision recommendation so that stakeholders can better understand why some alternatives perform comprehensively better than others when a multitude of inputs is used in the decision-making process.

Clinical and genetic aspects of hereditary spastic paraplegia in patients from Turkey.

OBJECTIVES: Hereditary spastic paraplegias (HSPs) are a heterogenous group of rare neurodegenerative disorders that present with lower limb spasticity. It is known as complicated HSP if spasticity is accompanied by additional features such as cognitive impairment, cerebellar syndrome, thin corpus callosum, or neuropathy. Most HSP families show autosomal dominant (AD) inheritance. On the other hand, autosomal recessive (AR) cases are also common because of the high frequency of consanguineous marriages in our country. This study aimed to investigate the clinical and genetic aetiology in a group of HSP patients. PATIENTS AND METHODS: We studied 21 patients from 17 families. Six of them presented with recessive inheritance. All index patients were screened for ATL1 and SPAST gene mutations to determine the prevalence of the most frequent types of HSP in our cohort. Whole exome sequencing was performed for an AD-HSP family, in combination with homozygosity mapping for five selected AR-HSP families. RESULTS: Two novel causative variants were identified in PLP1 and SPG11 genes, respectively. Distribution of HSP mutations in our AD patients was found to be similar to European populations. CONCLUSION: Our genetic studies confirmed that clinical analysis can be misleading when defining HSP subtypes. Genetic testing is an important tool for diagnosis and genetic counselling. However, in the majority of AR HSP cases, a genetic diagnosis is not possible.

Emergency Etoposide-Cisplatin (Em-EP) for patients with germ cell tumours (GCT) and trophoblastic neoplasia (TN).

BACKGROUND: Etoposide (E) at 100 mg/m2 combined with Cisplatin (P) at 20 mg/m2 represents an induction 2-day regimen embedded in our clinical practice for patients with advanced GCT or TN at high risk of early death. We evaluated 24/7 Em-EP administration to a combined GCT-TN cohort at our Emergency Cancer Treatment Centre (ECTC) to determine its efficacy within the acute setting. METHODS: Patients who received Em-EP during a five-year interval were identified from electronic databases at Imperial College Healthcare NHS Trust. Data collected included demographics, treatment details and clinical outcome. RESULTS: Em-EP was administered in the emergency setting to 104 patients, predominantly young adults (median age 35, range 17-71). Half the cases were GCT (n = 52): 22 male (6 seminomas, 13 non-seminomas); 30 female (2 dysgerminomas, 28 non-dysgerminomas). The other 50% were treated for TN (n = 52): 45 gestational (GTN) and 7 non-gestational. Most patients received Em-EP for a new cancer diagnosis (n = 100, 96%), within 24 h (n = 93, 89%) and out-of-hours (n = 74, 70%). Indications for Em-EP included symptomatic disease (n = 66, 63%), high-burden disease, (n = 51, 49%) and organ failure requiring Intensive Care Unit support (n = 9, 9%). Neutropenic sepsis was observed in 5%. Four-week overall survival after Em-EP administration was 98%. CONCLUSIONS: Despite the potentially fatal complications encountered in the acute setting, early mortality with Em-EP is low at our ECTC. Specialist units that treat unwell patients with advanced GCT or TN should consider making Em-EP available 24/7 for emergency administration. Its efficacy within a prospective cohort and in other platinum-sensitive malignancies requires evaluation.

Purpose-Driven Reconciliation of Approaches to Estimate Chemical Releases.

A framework is presented to address the toolbox of chemical release estimation methods available for manufacturing processes. Although scientists and engineers often strive for increased accuracy, the development of fit-for-purpose release estimates can speed results that could otherwise delay decisions important to protecting human health and the environment. A number of release estimation approaches are presented, with the newest using decision trees for regression and prediction. Each method is evaluated in a case study for cumene production to study the reconciliation of data quality concerns and requirements for time, resources, training, and knowledge. The evaluation of these decision support criteria and the lessons learned are used to develop a purpose-driven framework for estimating chemical releases.