OpenHands: An Open-Source Statistical Shape Model of the Finger Bones.

This paper presents statistical shape models of the four fingers of the hand, with an emphasis on anatomic analysis of the proximal and distal interphalangeal joints. A multi-body statistical shape modelling pipeline was implemented on an exemplar training dataset of computed tomography (CT) scans of 10 right hands (5F:5M, 27-37 years, free from disease or injury) imaged at 0.3 mm resolution, segmented, meshed and aligned. Model generated included pose neutralisation to remove joint angle variation during imaging. Repositioning was successful; no joint flexion variation was observed in the resulting model. The first principal component (PC) of morphological variation represented phalanx size in all fingers. Subsequent PCs showed variation in position along the palmar-dorsal axis, and bone breadth: length ratio. Finally, the models were interrogated to provide gross measures of bone lengths and joint spaces. These models have been published for open use to support wider community efforts in hand biomechanical analysis, providing bony anatomy descriptions whilst preserving the security of the underlying imaging data and privacy of the participants. The model describes a small, homogeneous population, and assumptions cannot be made about how it represents individuals outside the training dataset. However, it supplements anthropometric datasets with additional shape information, and may be useful for investigating factors such as joint morphology and design of hand-interfacing devices and products. The model has been shared as an open-source repository ( https://github.com/abel-research/OpenHands ), and we encourage the community to use and contribute to it.

Engaging multisector stakeholders to identify priorities for global health innovation, change and research: an engagement methodology and application to prosthetics service delivery in Cambodia.

PURPOSE: While innovation is known to catalyse solutions to global sustainable development challenges, lack of engagement from stakeholders during conceptualisation and development may influence the degree of success of implementation. METHODS AND MATERIALS: This paper presents a complete and novel engagement methodology, developed from value led business modelling approaches, for working with multi-sector stakeholders. The methodology can be used to determine barriers and facilitators to clinical practice innovations or translational research, within a country-specific context. The approach has then been applied in the Cambodian prosthetics and orthotics sector to provide a practice-based exemplar application of the framework. RESULTS: This approach seeks to ensure the suitability and sustainability of clinical practice and research programmes being implemented within a complex ecosystem. A theoretical basis, drawn from academic and business innovation sectors, has been consolidated and adapted for practical application to design, direct, and inform initiatives in low resource settings. CONCLUSIONS: The methods presented provide a way to both develop and articulate the mission, vision, and goals of any proposed change, and to effectively communicate these with stakeholders in a way that engages the personal and professional values that exist in their ecosystem. It provides a structured process through which meaningful conversations can happen, and a basis for relationship management with key stakeholders; intrinsic to enable a sustained legacy from research and development.

The engagement from stakeholders during conceptualisation and throughout development can determine the success, or not, of any implementation and scale of innovation.This paper presents a conceptual stakeholder-led engagement methodology, developed from value led business modelling approaches, for determining barriers and facilitators to translational global healthcare research in a country-specific context, in this case the Cambodian prosthetics and orthotics sector.Subsequent research and development work in this area needs to carefully manage and negotiate influencing factors identified through the application of the described methodology, to ensure initiatives (whether research or wider national development work) are sustainable and successful.

Inter-observer Variability of Clinical Activity Score: Assessments in Patients With Thyroid Eye Disease.

PURPOSE: Thyroid eye disease (TED) can be difficult to manage. The range of available treatments is expanding rapidly; however, cost is a concern and some patients do not respond. The Clinical Activity Score (CAS) was devised as a measure of disease activity and a potential predictor of response to anti-inflammatory treatment. Despite the widespread use of the CAS, inter-observer variability has not been investigated. The aim of the study was to determine the inter-observer variability of the CAS in patients with TED. DESIGN: Prospective reliability analysis. METHODS: Nine patients with a spectrum of clinical features of TED were assessed by 6 experienced observers on the same day. Agreement among the observers was analyzed using the Krippendorff alpha. RESULTS: The Krippendorff alpha for the total CAS was 0.532 (95% CI = 0.199-0.665), whereas alpha values for the individual components of the CAS varied between 0.171 (CI = 0.000-0.334) for lid redness and 0.671 (CI = 0.294-1.000) for spontaneous pain. Assuming that a CAS value ≥3 implies suitability of the patient for anti-inflammatory treatment, the calculated Krippendorff alpha for agreement among assessors on whether treatment should be given or not given was 0.332 (95% CI = 0.0011-0.5862). CONCLUSIONS: This study has shown unreliable inter-observer variability in total CAS and most individual CAS components, thus highlighting the need for improving the performance of the CAS or seeking other methods to assess activity.

Guidelines to inform the generation of clinically relevant and realistic blast loading conditions for primary blast injury research.

'Primary' blast injuries (PBIs) are caused by direct blast wave interaction with the human body, particularly affecting air-containing organs. With continued experimental focus on PBI mechanisms, recently on blast traumatic brain injury, meaningful test outcomes rely on appropriate simulated conditions. Selected PBI predictive criteria (grouped into those affecting the auditory system, pulmonary injuries and brain trauma) are combined and plotted to provide rationale for generating clinically relevant loading conditions. Using blast engineering theory, explosion characteristics including blast wave parameters and fireball dimensions were calculated for a range of charge masses assuming hemispherical surface detonations and compared with PBI criteria. While many experimental loading conditions are achievable, this analysis demonstrated limits that should be observed to ensure loading is clinically relevant, realistic and practical. For PBI outcomes sensitive only to blast overpressure, blast scaled distance was demonstrated to be a useful parameter for guiding experimental design as it permits flexibility for different experimental set-ups. This analysis revealed that blast waves should correspond to blast scaled distances of 1.75

Allocation of funding into blast injury-related research and blast traumatic brain injury between 2000 and 2019: analysis of global investments from public and philanthropic funders.

INTRODUCTION: There is little systematic tracking or detailed analysis of investments in research and development for blast injury to support decision-making around research future funding. METHODS: This study examined global investments into blast injury-related research from public and philanthropic funders across 2000-2019. Research databases were searched using keywords, and open data were extracted from funder websites. Data collected included study title, abstract, award amount, funder and year. Individual awards were categorised to compare amounts invested into different blast injuries, the scientific approaches taken and analysis of research investment into blast traumatic brain injury (TBI). RESULTS: A total of 806 awards were identified into blast injury-related research globally, equating to US$902.1 million (m, £565.9m GBP). There was a general increase in year-on-year investment between 2003 and 2009 followed by a consistent decline in annual funding since 2010. Pre-clinical research received $671.3 m (74.4%) of investment. Brain-related injury research received $427.7 m (47.4%), orthopaedic injury $138.6 m (15.4%), eye injury $63.7 m (7.0%) and ear injury $60.5m (6.7%). Blast TBI research received a total investment of $384.3 m, representing 42.6% of all blast injury-related research. The U.S. Department of Defense funded $719.3 m (80%). CONCLUSIONS: Investment data suggest that blast TBI research has received greater funding than other blast injury health areas. The funding pattern observed can be seen as reactive, driven by the response to the War on Terror, the rising profile of blast TBI and congressionally mandated research.

Developing a control framework for self-adjusting prosthetic sockets incorporating tissue injury risk estimation and generalized predictive control.

To perform activities of daily living (ADL), people with lower limb amputation depend on the prosthetic socket for stability and proprioceptive feedback. Poorly fitting sockets can cause discomfort, pain, limb tissue injuries, limited device usage, and potential rejection. Semi-passively controlled adjustable socket technologies exist, but these depend upon the user's perception to determine safe interfacial pressure levels. This paper presents a framework for automatic control of an adjustable transtibial prosthetic socket that enables active adaptation of residuum-socket interfacial loading through localized actuators, based on soft tissue injury risk estimation. Using finite element analysis, local interfacial pressure vs. compressive tissue strain relationships were estimated for three discrete anatomical actuator locations, for tissue injury risk assessment within a control structure. Generalized Predictive Control of multiple actuators was implemented to maintain interfacial pressure within estimated safe and functional limits. Controller simulation predicted satisfactory dynamic performance in several scenarios. Actuation rates of 0.06-1.51 kPa/s with 0.67% maximum overshoot, and 0.75-1.58 kPa/s were estimated for continuous walking, and for a demonstrative loading sequence of ADL, respectively. The developed platform could be useful for extending recent efforts in adjustable lower limb prosthetic socket design, particularly for individuals with residuum sensory impairment.

No effects of transcranial direct current stimulation on visual evoked potential and peak gamma frequency.

Evidence suggests that the visual evoked potential (VEP) and gamma oscillations elicited by visual stimuli reflect the balance of excitatory and inhibitory (E-I) cortical processes. As tDCS has been shown to modulate E-I balance, the current study investigated whether amplitudes of VEP components (N1 and P2) and peak gamma frequency are modulated by transcranial direct current stimulation (tDCS). Healthy adults underwent two electroencephalography (EEG) recordings while viewing stimuli designed to elicit a robust visual response. Between the two recordings, participants were randomly assigned to three tDCS conditions (anodal-, cathodal-, and sham-tDCS) or received no-tDCS. tDCS electrodes were placed over the occipital cortex (Oz) and the left cheek with an intensity of 2 mA for 10 min. Data of 39 participants were analysed for VEP amplitudes and peak gamma frequency using mixed-model ANOVAs. The results showed no main effects of tDCS in any metric. Possible explanations for the absence of tDCS effects are discussed.

Changes in Tissue Composition and Load Response After Transtibial Amputation Indicate Biomechanical Adaptation.

Despite the potential for biomechanical conditioning with prosthetic use, the soft tissues of residual limbs following lower-limb amputation are vulnerable to damage. Imaging studies revealing morphological changes in these soft tissues have not distinguished between superficial and intramuscular adipose distribution, despite the recognition that intramuscular fat levels indicate reduced tolerance to mechanical loading. Furthermore, it is unclear how these changes may alter tissue tone and stiffness, which are key features in prosthetic socket design. This study was designed to compare the morphology and biomechanical response of limb tissues to mechanical loading in individuals with and without transtibial amputation, using magnetic resonance imaging in combination with tissue structural stiffness. The results revealed higher adipose infiltrating muscle in residual limbs than in intact limbs (residual: median 2.5% (range 0.2-8.9%); contralateral: 1.7% (0.1-5.1%); control: 0.9% (0.4-1.3%)), indicating muscle atrophy and adaptation post-amputation. The intramuscular adipose content correlated negatively with daily socket use, although there was no association with time post-amputation. Residual limbs were significantly stiffer than intact limbs at the patellar tendon site, which plays a key role in load transfer across the limb-prosthesis interface. The tissue changes following amputation have relevance in the clinical understanding of prosthetic socket design variables and soft tissue damage risk in this vulnerable group.

Defining blast loading 'zones of relevance' for primary blast injury research: A consensus of injury criteria for idealised explosive scenarios.

Blast injuries remain a serious threat to defence and civilian populations around the world. 'Primary' blast injuries (PBIs) are caused by direct blast wave interaction with the human body, particularly affecting air-containing organs. Work to define blast loading conditions for injury research has received relatively little attention, though with a continued experimental focus on PBIs and idealised explosion assumptions, meaningful test outcomes and subsequent clinical applications, rely on appropriate simulated conditions. This paper critically evaluates and combines existing PBI criteria (grouped into those affecting the auditory system, pulmonary injuries and brain trauma) as a function of idealised blast wave parameters. For clinical blast injury researchers, analysis of the multi-injury criteria indicates zones of appropriate loading conditions for human-scale test items and demonstrates the importance of simulating blast conditions that are both realistic and relevant to the injury type. For certain explosive scenarios, spatial interpretation of the 'zones of relevance' could support emergency response and hazard preparedness by informing triage, patient management and resource allocation, thus leading to improved health outcomes. This work will prove useful to clinical blast injury researchers, blast protection engineers and clinical practitioners involved in the triage, diagnosis, and treatment of PBIs.

Investigating the effects of tDCS on Visual Orientation Discrimination Task Performance: 'The possible influence of placebo'.

The non-invasive neuromodulation technique tDCS offers the promise of a low cost tool for both research and clinical applications in psychology, psychiatry and neuroscience. However, findings regarding its efficacy are often equivocal. A key issue is that the clinical and cognitive applications studied are often complex and thus effects of tDCS are difficult to predict given its known effects on the basic underlying neurophysiology, namely alterations in cortical inhibition-excitation balance. As such, it may be beneficial to assess the effects of tDCS in tasks whose performance has a clear link to cortical inhibition-excitation balance such as the visual orientation discrimination task (ODT). In prior studies in our laboratory no practise effects were found during 2 consecutive runs of the ODT, thus in the current investigation, to examine the effects of tDCS, subjects received 10 minutes of 2mA occipital tDCS (sham, anode, cathode) between a first and second run of ODT. Surprisingly, subjects' performance significantly improved in the second run of ODT compared to the first one regardless of the tDCS stimulation type they received (anodal, cathodal, or sham-tDCS). Possible causes for such an improvement could have been due to either a generic 'placebo' effect of tDCS (as all subjects received some form of tDCS) or an increased delay period between the two runs of ODT of the current study compared to our previous work (10 minutes duration required to administer tDCS as opposed to ~2 minutes in previous studies as a 'break'). As such, we tested these two possibilities with a subsequent experiment in which subjects received 2 minutes or 10 minutes delay between the 2 runs (with no tDCS) or 10 minutes of sham-tDCS. Only sham-tDCS resulted in improved performance thus these data add to a growing literature suggesting that tDCS has powerful placebo effect that may occur even in the absence of active cortical modulation.

Quantifying Soft Tissue Artefacts and Imaging Variability in Motion Capture of the Fingers.

This study assessed the accuracy of marker-based kinematic analysis of the fingers, considering soft tissue artefacts (STA) and marker imaging uncertainty. We collected CT images of the hand from healthy volunteers with fingers in full extension, mid- and full-flexion, including motion capture markers. Bones and markers were segmented and meshed. The bone meshes for each volunteer's scans were aligned using the proximal phalanx to study the proximal interphalangeal joint (PIP), and using the middle phalanx to study the distal interphalangeal joint (DIP). The angle changes between positions were extracted. The HAWK protocol was used to calculate PIP and DIP joint flexion angles in each position based on the marker centroids. Finally the marker locations were 'corrected' relative to the underlying bones, and the flexion angles recalculated. Static and dynamic marker imaging uncertainty was evaluated using a wand. A strong positive correlation was observed between marker- and CT-based joint angle changes with 0.980 and 0.892 regression slopes for PIP and DIP, respectively, and Root Mean Squared Errors below 4°. Notably for the PIP joint, correlation was worsened by STA correction. The 95% imaging uncertainty interval was < ± 1° for joints, and < ± 0.25 mm for segment lengths. In summary, the HAWK marker set's accuracy was characterised for finger joint flexion angle changes in a small group of healthy individuals and static poses, and was found to benefit from skin movements during flexion.

Establishing a measurement array to assess tissue tolerance during loading representative of prosthetic use.

BACKGROUND: In the early stages of rehabilitation after primary amputation, residual limb soft tissues have not been mechanically conditioned to support load and are vulnerable to damage from prosthetic use. There is limited quantitative knowledge of skin and soft tissue response to prosthetic loading. METHODS: An in-vivo protocol was developed to establish suitable measures to assess tissue tolerance during loading representative of early prosthesis use. Ten participants without amputation one participant with trans-tibial amputation were recruited, and pressure applied to their calf in increments from 20 to 60 mmHg. Measurements were recorded at relevant skin sites including interface pressures, transcutaneous oxygen (TCPO2) and carbon dioxide (TCPCO2) tensions and inflammatory biomarkers. FINDINGS: At the maximum cuff pressure, mean interface pressures were between 66 and 74 mmHg, associated with decreased TCPO2 values. On the release of pressure, the ischaemic response was reversed. Significant upregulation (p < 0.05) in inflammatory biomarker IL-1α and its antagonist IL-1RA were observed at all sites immediately following loading. INTERPRETATION: The protocol was successful in applying representative prosthetic loads to lower limb tissues and monitoring the physiological response, both in terms of tissue ischemia and skin inflammation. Results indicated that the measurement approaches were sensitive to changes in interface conditions, offering a promising approach to monitor tissue status for people with amputation.

Predictive prosthetic socket design: part 1-population-based evaluation of transtibial prosthetic sockets by FEA-driven surrogate modelling.

It has been proposed that finite element analysis can complement clinical decision making for the appropriate design and manufacture of prosthetic sockets for amputees. However, clinical translation has not been achieved, in part due to lengthy solver times and the complexity involved in model development. In this study, a parametric model was created, informed by variation in (i) population-driven residuum shape morphology, (ii) soft tissue compliance and (iii) prosthetic socket design. A Kriging surrogate model was fitted to the response of the analyses across the design space enabling prediction for new residual limb morphologies and socket designs. It was predicted that morphological variability and prosthetic socket design had a substantial effect on socket-limb interfacial pressure and shear conditions as well as sub-dermal soft tissue strains. These relationships were investigated with a higher resolution of anatomical, surgical and design variability than previously reported, with a reduction in computational expense of six orders of magnitude. This enabled real-time predictions (1.6 ms) with error vs the analytical solutions of < 4 kPa in pressure at residuum tip, and < 3% in soft tissue strain. As such, this framework represents a substantial step towards implementation of finite element analysis in the prosthetics clinic.

Predictive prosthetic socket design: part 2-generating person-specific candidate designs using multi-objective genetic algorithms.

In post-amputation rehabilitation, a common goal is to return to ambulation using a prosthetic limb, suspended by a customised socket. Prosthetic socket design aims to optimise load transfer between the residual limb and mechanical limb, by customisation to the user. This is a time-consuming process, and with the increase in people requiring these prosthetics, it is vital that these personalised devices can be produced rapidly while maintaining excellent fit, to maximise function and comfort. Prosthetic sockets are designed by capturing the residual limb's shape and applying a series of geometrical modifications, called rectifications. Expert knowledge is required to achieve a comfortable fit in this iterative process. A variety of rectifications can be made, grouped into established strategies [e.g. in transtibial sockets: patellar tendon bearing (PTB) and total surface bearing (TSB)], creating a complex design space. To date, adoption of advanced engineering solutions to support fitting has been limited. One method is numerical optimisation, which allows the designer a number of likely candidate solutions to start the design process. Numerical optimisation is commonly used in many industries but not prevalent in the design of prosthetic sockets. This paper therefore presents candidate shape optimisation methods which might benefit the prosthetist and the limb user, by blending the state of the art from prosthetic mechanical design, surrogate modelling and evolutionary computation. The result of the analysis is a series of prosthetic socket designs that preferentially load and unload the pressure tolerant and intolerant regions of the residual limb. This spectrum is bounded by the general forms of the PTB and TSB designs, with a series of variations in between that represent a compromise between these accepted approaches. This results in a difference in pressure of up to 31 kPa over the fibula head and 14 kPa over the residuum tip. The presented methods would allow a trained prosthetist to rapidly assess these likely candidates and then to make final detailed modifications and fine-tuning. Importantly, insights gained about the design should be seen as a compliment, not a replacement, for the prosthetist's skill and experience. We propose instead that this method might reduce the time spent on the early stages of socket design and allow prosthetists to focus on the most skilled and creative tasks of fine-tuning the design, in face-to-face consultation with their client.

Heavy metal pollution and co-selection for antibiotic resistance: A microbial palaeontology approach.

Frequent and persistent heavy metal pollution has profound effects on the composition and activity of microbial communities. Heavy metals select for metal resistance but can also co-select for resistance to antibiotics, which is a global health concern. We here document metal concentration, metal resistance and antibiotic resistance along a sediment archive from a pond in the North West of the United Kingdom covering over a century of anthropogenic pollution. We specifically focus on zinc, as it is a ubiquitous and toxic metal contaminant known to co-select for antibiotic resistance, to assess the impact of temporal variation in heavy metal pollution on microbial community diversity and to quantify the selection effects of differential heavy metal exposure on antibiotic resistance. Zinc concentration and bioavailability was found to vary over the core, likely reflecting increased industrialisation around the middle of the 20th century. Zinc concentration had a significant effect on bacterial community composition, as revealed by a positive correlation between the level of zinc tolerance in culturable bacteria and zinc concentration. The proportion of zinc resistant isolates was also positively correlated with resistance to three clinically relevant antibiotics (oxacillin, cefotaxime and trimethoprim). The abundance of the class 1 integron-integrase gene, intI1, marker for anthropogenic pollutants correlated with the prevalence of zinc- and cefotaxime resistance but not with oxacillin and trimethoprim resistance. Our microbial palaeontology approach reveals that metal-contaminated sediments from depths that pre-date the use of antibiotics were enriched in antibiotic resistant bacteria, demonstrating the pervasive effects of metal-antibiotic co-selection in the environment.

Evaluation of a human in vitro skin test for predicting drug hypersensitivity reactions.

The occurrence of drug hypersensitivity reactions (DHRs) following administration of low molecular weight (LMW) drugs is an important health concern. However, in vivo animal models which could be used as tools for the prediction of DHRs are lacking. As a result, research has focused on development of in vitro tools for predicting DHRs. In this study a novel human in vitro pre-clinical skin explant test was used to predict T cell-mediated hypersensitivity responses induced by LMW drugs. Responses in the skin explant test for 12 LMW drugs associated with T cell-mediated hypersensitivity in the clinic (abacavir, amoxicillin, carbamazepine, diclofenac, lamotrigine, lapatinib, lumiracoxib, nevirapine, ofloxacin, phenytoin, propranolol, sulfamethoxazole) were compared with responses for 5 drugs with few/no reports of T cell-mediated hypersensitivity reactions (acetaminophen, cimetidine, flecainide, metformin, verapamil). Changes in skin histology following in vitro exposure to the drugs as well as T cell proliferation and interferon gamma (IFNγ) production were studied. The results of the skin explant assays showed a good positive correlation (r = 0.77, p < .001) between the test outcome (prediction of positive or negative) and the clinical classification of the tested drugs. The T cell proliferation assay showed a correlation of r = 0.60 (p < .01) and the IFNγ assay r = 0.51 (p < .04). The data suggest that the skin explant model could be a useful tool to predict the potential of LMW drugs to induce DHRs.

Biomarkers in chronic graft-versus-host disease: quo vadis?

Biomarkers are increasingly used for diagnosis and treatment of transplant-related complications including the first biomarker-driven interventional trials of acute graft-versus-host disease (GvHD). In contrast, the development of biomarkers of chronic GvHD (cGvHD) has lagged behind due to a broader variety of manifestations, overlap with acute GvHD, a greater variation in time to onset and maximum severity, and lack of sufficient patient numbers within prospective trials. An international workshop organized by a North-American and European consortium was held in Marseille in March 2017 with the goal to discuss strategies for future biomarker development to guide cGvHD therapy. As a result of this meeting, two areas were prioritized: the development of prognostic biomarkers for subsequent onset of moderate/severe cGvHD, and in parallel, the development of qualified clinical-grade assays for biomarker quantification. The most promising prognostic serum biomarkers are CXCL9, ST2, matrix metalloproteinase-3, osteopontin, CXCL10, CXCL11, and CD163. Urine-proteomics and cellular subsets (CD4+ T-cell subsets, NK cell subsets, and CD19+CD21low B cells) represent additional potential prognostic biomarkers of cGvHD. A joint effort is required to verify the results of numerous exploratory trials before any of the potential candidates is ready for validation and subsequent clinical application.

A research note on the benefit of patient and public involvement in research: The experience of prostate cancer patients regarding information in radiotherapy.

AIM: To explore the inclusion of patient and public involvement (PPI) in a qualitative study on the experiences of men with prostate cancer regarding information in radiotherapy. METHOD: The application of PPI to one doctoral research study is explored with respect to two perspectives: firstly, involvement of a patient reference group who informed the research design and materials, and secondly, the involvement of a public involvement in research group (PIRg) in advising the researcher during the design process. DISCUSSION: PPI is recognised as an important component of contemporary health research. PPI is becoming a common and essential requirement for high quality research projects and yet literature exploring or reporting the involvement and influence of PPI is sparse. Consideration is given to the national PPI landscape that has shaped public involvement in health research. CONCLUSION: The contribution of PPI to this study appears to have been beneficial to the development and evaluation of the study design, the self-worth of the reference group participants and demonstrates that the value of PPI in health research should not be underestimated.