Serum neurofilament light chain measurements following nerve trauma.

BACKGROUND: Optimal functional recovery following peripheral nerve injuries (PNIs) is dependent upon early recognition and prompt referral to specialist centres for appropriate surgical intervention. Technologies which facilitate the early detection of PNI would allow faster referral rates and encourage improvements in patient outcomes. Serum Neurofilament light chain (NfL) measurements are cheaper to perform, easier to access and interpret than many conventional methods used for nerve injury diagnosis, such as electromyography and/or magnetic resonance imaging assessments, but changes in serum NfL levels following traumatic PNI have not been investigated. This pre-clinical study aimed to determine whether serum NfL levels can: (1) detect the presence of a nerve trauma and (2) delineate between different severities of nerve trauma. METHODS: A rat sciatic nerve crush and common peroneal nerve crush were implemented as controlled animal models of nerve injury. At 1-, 3-, 7- and 21-days post-injury, serum samples were retrieved for analysis using the SIMOA® NfL analyser kit. Nerve samples were also retrieved for histological analysis. Static sciatic index (SSI) was measured at regular time intervals following injury. RESULTS: Significant 45-fold and 20-fold increases in NfL serum levels were seen 1-day post-injury following sciatic and common peroneal nerve injury, respectively. This corresponded with an eightfold higher volume of axons injured in the sciatic compared to the common peroneal nerve (p < .001). SSI measurements post-injury revealed greater reduction in function in the sciatic crush group compared with the common peroneal crush group. CONCLUSIONS: NfL serum measurements represent a promising method for detecting traumatic PNI and stratifying their severity. Clinical translation of these findings could provide a powerful tool to improve the surgical management of nerve-injured patients.

Once Bitten: Mosquito-Borne Malariotherapy and the Emergence of Ecological Malariology Within and Beyond Imperial Britain.

This article explores the extent to which the emergence of networked conceptions of etiology and network-oriented approaches to the organization of medical practice were historically congruent. Focusing on interwar malariology, it contextualizes the development of ecological approaches to infection management and control in terms of mosquito-borne malariotherapeutic practice. In Britain, mosquito breeding programs directed toward the therapeutic infection of mental hospital patients prompted malariologists to modify and refine existing environmental approaches to malaria. Breeding mosquitoes, attending to patients, and maintaining sources of malarial blood modified malariologists' etiological presumptions, contributing to a wider breakdown of associations between race, place, and disease. Simultaneously, the emergence of an international network of malariotherapy-devoted institutions helped transform malariological practice. Examination of a collaboration between British and Romanian malariologists shows one way in which this network contributed to the transformation of malariology from a formal League of Nations-focused endeavor to one distributed along common lines of research and prevention.

Making and Unmaking a "Bactericidal" Organism: Sterile Surgical Maggots and Organic Antiseptics in Inter-War America.

This article charts the popularization of and eventual disengagement with an approach to wound infection control centered on the medical efficacy of living beings (maggots) in 1920s and 1930s America. Baltimore surgeon William Stevenson Baer successfully drew on his wartime experience to promote the use of sterile or "surgical" maggots in the treatment for deep-seated bone infection at this time. This article situates the practices he promoted in the context of President Herbert Hoover's contemporary establishment of the "associative state," thereby drawing out the relevance of the latter to medical governance. In so doing, it conveys an image of the development of early twentieth-century infection control that contrasts with narratives centered on medically productive aspects of biomedical industrialization and specialization. The incorporation of surgical maggot research and evaluation within the United States Department of Agriculture played a critical role in the subsequent abandonment of the use of maggots as medical aides. Hoover's orientation of this institution towards the support of large-scale private enterprise helped motivate efforts to synthetically replicate (and thereby displace) maggots' medical efficacy. Ultimately, maggot-based therapeutics proved incompatible with conditions created by the orientation of American governmental institutions towards corporate subsidy rather than the support of individuals.

Reducing the Risk and Impact of Brachial Plexus Injury Sustained From Prone Positioning-A Clinical Commentary.

INTRODUCTION: Prone positioning is deployed as a critical treatment for improving oxygenation in patients with Acute Respiratory Distress Syndrome. This regimen is currently highly prevalent in the COVID-19 pandemic. The pandemic has brought about increased concern about how best to safely avoid brachial plexus injuries when caring for unconscious proned patients. METHODS: A review of the published literature on brachial plexus injuries secondary to proning ventilated patients was performed. This was combined with a review of available international critical care guidelines in order to produce a succinct set of guidelines to aid critical care departments in reducing brachial plexus injuries during these challenging times. DISCUSSION: There is no one manner in which prone positioning an unconscious patient can be made universally safe. This paper provides 6 key steps to reducing the incidence of brachial plexus injuries while proning and suggests a safe and sensible management and referral pathway for the conscious patient in which a brachial plexus injury is identified. CONCLUSION: There is in truth no completely safe position for every patient and certainly there will be anomalies in anatomy that will predispose certain individuals to nerve injury. Thus the injury rate cannot be reduced to zero but an understanding of the principles of protection will inform those undertaking positioning.

Is peer assessment an effective learning tool in an internationally and educationally heterogeneous cohort of students?

Background: Peer assessment is a well-established tool in peer-assisted learning, however there is little work in its use across a multidisciplinary cohort. Twenty-two students of a variety of undergraduate backgrounds from different nationalities attended a 3-week university summer school on the topic of peripheral nerve injuries. Methods: Peer assessment of an oral presentation made up an aspect of the formative assessment of the course. Students were surveyed using a Likert score on their impression of peer assessment as a learning and assessment tool. Results: Fourteen (64%) students agreed that the peer assessment process improved the learning process and 5 (23%) strongly agreed. Thirteen (59%) students agreed and nine (41%) strongly agreed that it improved the engagement with their peers' presentation. Seventeen (77%) students either agreed or strongly agreed that it was appropriate to use as a method of formative assessment. Discussion: Students agreed that peer assessment improved learning and engagement and is an appropriate assessment tool. Whereas peer assessment has been proven to be an effective method for assessment and reflective learning within a homogenous group, this study demonstrates that this remains true in a heterogeneous cohort of international undergraduates where expertise, underlying knowledge base, and learning approaches may vary.

Being well together? Promoting health and well-being through more than human collaboration and companionship.

Being well together, an inaugural Research Forum, will critically examine the myriad ways humans have formed partnerships with non-human species to improve health across time and place. Across the humanities and social sciences, a growing body of scholarship has begun to rethink the prominence of the 'human' in our accounts of the world by exploring the category less as an individualised essence and more as a temporal process of becoming. From this perspective, being human becomes a process of 'becoming with', performed through interactions with non-human others. This paper introduces a diverse collection of studies, originally presented at a workshop held at the University of Manchester in 2018, which explored how emergent approaches within animal studies might productively and playfully engage with the medical humanities. In each case, human health and well-being is shown to rest on the cultivation of relationships with other species. Being well is rethought and remapped as a more than human process of being well together. Collectively, this research forum invites reflection on what the medical humanities might look like from a more than human perspective.

Low frequency oscillating gradient spin-echo sequences improve sensitivity to axon diameter: An experimental study in viable nerve tissue.

Mapping axon diameters within the central and peripheral nervous system could play an important role in our understanding of nerve pathways, and help diagnose and monitor an array of neurological disorders. Numerous diffusion MRI methods have been proposed for imaging axon diameters, most of which use conventional single diffusion encoding (SDE) spin echo sequences. However, a growing number of studies show that oscillating gradient spin echo (OGSE) sequences can provide additional advantages over conventional SDE sequences. Recent theoretical results suggest that this is especially the case in realistic scenarios, such as when fibres have unknown or dispersed orientation. In the present study, we adopt the ActiveAx approach to experimentally investigate the extent of these advantages by comparing the performances of SDE and trapezoidal OGSE in viable nerve tissue. We optimise SDE and OGSE ActiveAx protocols for a rat peripheral nerve tissue and test their performance using Monte Carlo simulations and a 800 mT/m gradient strength pre-clinical imaging experiment. The imaging experiment uses excised sciatic nerve from a rat's leg placed in a MRI compatible viable isolated tissue (VIT) maintenance chamber, which keeps the tissue in a viable physiological state that preserves the structural complexity of the nerve and enables lengthy scan times. We compare model estimates to histology, which we perform on the nerve post scanning. Optimisation produces a three-shell SDE and OGSE ActiveAx protocol, with the OGSE protocol consisting of one SDE sequence and two low-frequency oscillating gradient waveform sequences. Both simulation and imaging results show that the OGSE ActiveAx estimates of the axon diameter index have a higher accuracy and a higher precision compared to those from SDE. Histology estimates of the axon diameter index in our nerve tissue samples are 4-5.8 µm and these are excellently matched with the OGSE estimates 4.2-6.5 µm, while SDE overestimates at 5.2-8 µm for the same sample. We found OGSE estimates to be more precise with on average a 0.5 µm standard deviation compared to the SDE estimates which have a 2 µm standard deviation. When testing the robustness of the estimates when the number of the diffusion gradient directions reduces, we found that both OGSE and SDE estimates are affected, however OGSE is more robust to these changes than the SDE. Overall, these results suggest, quantitatively and in in vivo conditions, that low-frequency OGSE sequences may provide improved accuracy of axon diameter mapping compared to standard SDE sequences.

A capital Scot: microscopes and museums in Robert E. Grant's zoology (1815-1840).

Early nineteenth-century zoology in Britain has been characterized as determined by the ideological concerns of its proponents. Taking the zoologist Robert E. Grant as an exemplary figure in this regard, this article offers a differently nuanced account of the conditions under which natural-philosophical knowledge concerning animal life was established in post-Napoleonic Britain. Whilst acknowledging the ideological import of concepts such as force and law, it points to an additional set of concerns amongst natural philosophers - that of appropriate tool use in investigation. Grant's studies in his native Edinburgh relied heavily on the use of microscopes. On his arrival in London, however, he entered a culture in which a different set of objects - museum specimens - held greater persuasive power. This article relates changes in Grant's ideas and practices to the uneven emphases on microscopic and museological evidence amongst European, Scottish and English natural philosophers at this time. In so doing, it identifies the reliance of London-based natural philosophers on museology as constituting a limiting effect on the kinds of claim that Grant sought to make regarding the nature of life.

Mechanisms underlying clinical efficacy of Angiotensin II type 2 receptor (AT2R) antagonist EMA401 in neuropathic pain: clinical tissue and in vitro studies.

BACKGROUND: The clinical efficacy of the Angiotensin II (AngII) receptor AT2R antagonist EMA401, a novel peripherally-restricted analgesic, was reported recently in post-herpetic neuralgia. While previous studies have shown that AT2R is expressed by nociceptors in human DRG (hDRG), and that EMA401 inhibits capsaicin responses in cultured hDRG neurons, the expression and levels of its endogenous ligands AngII and AngIII in clinical neuropathic pain tissues, and their signalling pathways, require investigation. We have immunostained AngII, AT2R and the capsaicin receptor TRPV1 in control post-mortem and avulsion injured hDRG, control and injured human nerves, and in cultured hDRG neurons. AngII, AngIII, and Ang-(1-7) levels were quantified by ELISA. The in vitro effects of AngII, AT2R agonist C21, and Nerve growth factor (NGF) were measured on neurite lengths; AngII, NGF and EMA401 effects on expression of p38 and p42/44 MAPK were measured using quantitative immunofluorescence, and on capsaicin responses using calcium imaging. RESULTS: AngII immunostaining was observed in approximately 75% of small/medium diameter neurons in control (n = 5) and avulsion injured (n = 8) hDRG, but not large neurons i.e. similar to TRPV1. AngII was co-localised with AT2R and TRPV1 in hDRG and in vitro. AngII staining by image analysis showed no significant difference between control (n = 12) and injured (n = 13) human nerves. AngII levels by ELISA were also similar in control human nerves (4.09 ± 0.36 pmol/g, n = 31), injured nerves (3.99 ± 0.79 pmol/g, n = 7), and painful neuromas (3.43 ± 0.73 pmol/g, n = 12); AngIII and Ang-(1-7) levels were undetectable (<0.03 and 0.05 pmol/g respectively). Neurite lengths were significantly increased in the presence of NGF, AngII and C21 in cultured DRG neurons. AngII and, as expected, NGF significantly increased signal intensity of p38 and p42/44 MAPK, which was reversed by EMA401. AngII mediated sensitization of capsaicin responses was not observed in the presence of MAP kinase inhibitor PD98059, and the kinase inhibitor staurosporine. CONCLUSION: The major AT2R ligand in human peripheral nerves is AngII, and its levels are maintained in injured nerves. EMA401 may act on paracrine/autocrine mechanisms at peripheral nerve terminals, or intracrine mechanisms, to reduce neuropathic pain signalling in AngII/NGF/TRPV1-convergent pathways.

Self-assessed outcomes following double fascicular nerve transfer for elbow flexion.

Background: Double fascicular nerve transfer (DFT) is often performed to re-animate the elbow flexors. Studies of motor recovery following this surgery have exclusively reported on the objective outcome of muscle power. Questionnaire studies allow researchers and clinicians to learn from patients and better direct care towards their needs. To date, no research has focused on self-assessed recovery following DFT for elbow flexion. Methods: This observational cross-sectional study aimed to give an account of patient-assessed outcomes following DFT. The bespoke questionnaire included: (a) self-reported strength and (b) the Stanmore percentage of normal elbow assessment. Results: Sixty-two patients participated in the study. Participants were grouped according to time post-surgery. Statistical analysis confirmed that data were comparable between groups (p=0.10). Self-assessed strength: Median scores were 0.5 kg <2 years post-surgery, 3 kg at 2 to 5 years, 2 kg at 5 to 8 years and 1.3 kg in the >8 years group. Stanmore Percentage of Normal Elbow Assessment: Mean scores (%) were 35 (SD ± 25) <2 years, 56 (SD ± 31) at 2 to 5 years, 44 (SD ± 25) at 5 to 8 years and 46 (SD ± 29) >8 years groups. Conclusions: This is the first study of self-assessed recovery following DFT. Scores peaked around 4 years post-operation. Future research should focus on the long-term self-reported outcome of nerve transfer surgery.

Adult traumatic brachial plexus injuries: advances and current updates.

Nerve grafting, tendon transfer and joint fusion are routinely used to improve the upper limb function in patients with brachial plexus palsies. Newer techniques have been developed that provide additional options for reconstruction. Nerve transfer is a tool for restoring upper limb function in total root avulsions where nerve grafting is not possible. In partial brachial plexus injuries, nerve transfers can greatly improve shoulder, elbow, wrist and hand function. Intraoperative electrical stimulation can be used to diagnose precisely which nerve is injured and to choose which nerve fascicles should be transferred. Finally, measuring the postoperative outcome can improve the evaluation of our techniques. The aim of this article was to present the current techniques used to treat patients with brachial plexus injury.

An assessment of co-contraction in reinnervated muscle.

Aim: To investigate co-contraction in reinnervated elbow flexor muscles following a nerve transfer. Materials & methods: 12 brachial plexus injury patients who received a nerve transfer to reanimate elbow flexion were included in this study. Surface electromyography (EMG) recordings were used to quantify co-contraction during sustained and repeated isometric contractions of reinnervated and contralateral uninjured elbow flexor muscles. Reuslts: For the first time, this study reveals reinnervated muscles demonstrated a trend toward higher co-contraction ratios when compared with uninjured muscle and this is correlated with an earlier onset of muscle fatigability. Conclusion: Measurements of co-contraction should be considered within muscular function assessments to help drive improvements in motor recovery therapies.

Radiolucent cerclage for humerus fractures: beware of radial nerve injury-a case report.

A 73-year-old woman was referred to a National Centre for Peripheral Nerve Injury with a post-operative left radial nerve degenerative lesion following open reduction and internal fixation of a proximal third humerus fracture using radiolucent Arthrex FiberTape® Cerclage as an adjunct to plating to improve stability. Intra-operative photographs illustrate compression of the radial nerve under the cerclage construct. Use of radiolucent cerclage for humerus fractures is increasing with modern systems capable of withstanding an ultimate load of 4300 N. We highlight the risk of debilitating neurological injury when not deployed safely and describe anatomical high-risk zones for injury. We emphasize the impact of delay in diagnosis and treatment.

Classification of congenital anomalies of the hand and upper limb: development and assessment of a new system.

The Oberg, Manske, and Tonkin (OMT) classification of congenital hand and upper limb anomalies was proposed in 2010 as a replacement for the Swanson International Federation of Societies for Surgery of the Hand classification system, which has been the accepted system of classification for the international surgical community since 1976. The OMT system separates malformations from deformations and dysplasias. Malformations are subdivided according to the axis of formation and differentiation that is primarily affected and whether the anomalies involve the whole limb or the hand plate. This review outlines the development of classification systems and explores the difficulty of incorporating our current knowledge of limb embryogenesis at a molecular level into current systems. An assessment of the efficacy of the OMT classification demonstrates acceptable inter- and intraobserver reliability. A prospective review of 101 patients confirms that all diagnoses could be classified within the OMT system. Consensus expert opinion allowed classification of those conditions for which there is not a clear understanding of the mechanism of dysmorphology. A refined and expanded OMT classification is presented.

Return to work following brachial plexus injury: A cross-sectional study.

Background: Qualitative studies following Brachial Plexus Injury (BPI) suggest that return to employment has a major influence on life satisfaction and psychological well-being. However, few studies have focused on return to work following BPI. The physical strain and intensity of an occupation may influence the ability of an individual to return to employment. This study aimed to provide information about the impact of workload intensity on employment status following BPI. Methods: This is an observational, retrospective study of 74 participants who responded to a postal questionnaire, sharing information regarding their employment status pre- and post-BPI. The reported occupations were assessed for workload intensity and assigned a Reichsausschuss für Arbeitszeitermittlung (REFA) classification by two assessors. Results: Forty-one out of 74 participants (57%) had to change their employment following their BPI. Changes in occupation were more likely if the pre-injury REFA score was 3 or 4 (n = 22). In the Complete plexus injury group (n = 8), 100% changed occupation. In the Partial plexus injury group (n = 66) 50% changed occupation. Hand dominance had no significant influence on change of employment (p = 0.37). Conclusion: This study is the first to focus on the impact of BPI on employment status and workload intensity. Just over half the participants did not maintain the same employment following their BPI and one in five became unemployed. Future research should review the factors that contribute to the inability to return to work. This may direct enhancements in rehabilitation provision and enable healthcare services to focus on facilitating individuals back to the workplace.

Newcastle approach to the elbow, a cadaveric study.

AIM: The aim of the current study was to assess the amount of the distal humerus articular surface exposed through the Newcastle approach, a posterior triceps preserving exposure of the elbow joint. METHOD: Twenty-four cadaveric elbows (12 pairs) were randomized to receive one of the four posterior surgical approaches: triceps reflecting, triceps splitting, olecranon osteotomy and Newcastle approach. The ratio of the articular surface exposed for each elbow was calculated and compared. RESULTS: The highest ratio observed was for Newcastle approach (0.75 ± 0.12) followed by olecranon osteotomy (0.51 ± 0.1), triceps reflecting (0.37 ± 0.08) and triceps splitting (0.35 ± 0.07). The differences between Newcastle approach and other approaches were statistically significant (p = 0.003 vs. osteotomy and <0.0001 vs. triceps reflecting and splitting). CONCLUSION: The Newcastle approach sufficiently exposes the distal humerus for arthroplasty or fracture fixation purposes. Its use is supported by the current study.

How to assess the recovery of muscular function following nerve injury: A view from surgeons and patients.

Patient experience of motor recovery from denervation paralysis is complex and textured. The Medical Research Council (MRC) system of grading muscle peak volitional force is widely used as a single measure of assessment. However, it is becoming clear that current motor function assessments are not reflecting the patient lived experience of muscle reinnervation. Therefore, this study aimed to engage international expert nerve surgeons in a classical Delphi process to achieve a consensus of opinion on the ideal clinical assessment of motor function. This was compared with patient-reported impairments of reinnervated muscle. Invitations to engage in the Delphi process were extended to expert peripheral nerve surgeons across two international specialist meetings. For comparison, patients who attended a "Nerve Injury Community Day" were invited to complete a questionnaire on patient-reported impairments of reinnervated muscle. Questions were designed on the basis of a literature review and the clinical experiences of a specialist nerve injury unit. A combination of direct yes/no, multiple choice, open-ended and Likert questions were employed throughout the questionnaires. Eighteen surgeons engaged with the Delphi process; 18 and 11 responded to the first and second rounds respectively. Thirty-one patients responded to the questionnaire. It was found that clinicians were strongly biased towards efferent assessments of muscular function, while patients strongly favoured muscular fatigue, co-contraction and pain when monitoring their own recovery. The findings suggest that current clinical assessments of muscular function are inadequate and should embody measurements of afferent muscular function to better reflect the lived experience of muscle reinnervation.

The shifting demographics of birth-related brachial plexus injury: The impact of socio-economic status and ethnic groups.

INTRODUCTION: Many of the risk factors for birth-related brachial plexus injury (BRBPI), such as maternal gestational diabetes and macrosomia, are known to vary between demographic groups. Socio-economic differences are known to influence access to healthcare, including elective caesarean section rates and access to consultant obstetricians, which could impact the rates of BRBPI. This study aims to explore whether BRBPI is affected by demographic factors. METHOD: This retrospective study compares cohorts of BRBPI patients referred to the Royal National Orthopaedic Hospital in 2004, 2014 and 2017. N = 67 in 2004, N = 61 in 2014 and N = 71 in 2017. RESULTS: The risk of BRBPI for Black patients was 6 times higher than for White patients, and 2.7 times higher for Asian patients as compared to White patients (p < 0.001). There was an unequal distribution of BRBPI occurring in patients from lower socio-economic groups based on the index of multiple deprivation, with the highest level seen in those from the second lowest quintile. Neither of these risk factors have changed within the three years that they were examined. CONCLUSION: In this sample, the risk of BRBPI varies with ethnic groups; patients from non-White backgrounds are at a higher risk overall and are disproportionately represented in the BRBPI cohort as compared to White groups. Similarly, there seems to be a trend towards greater risk for those from lower socio-economic groups. These changes are consistent each year, suggesting that these inconsistencies are yet to be addressed. Further studies are warranted to explore why these demographic factors are significantly affecting health outcomes.

Neuregulin 1 Drives Morphological and Phenotypical Changes in C2C12 Myotubes: Towards De Novo Formation of Intrafusal Fibres In Vitro.

Muscle spindles are sensory organs that detect and mediate both static and dynamic muscle stretch and monitor muscle position, through a specialised cell population, termed intrafusal fibres. It is these fibres that provide a key contribution to proprioception and muscle spindle dysfunction is associated with multiple neuromuscular diseases, aging and nerve injuries. To date, there are few publications focussed on de novo generation and characterisation of intrafusal muscle fibres in vitro. To this end, current models of skeletal muscle focus on extrafusal fibres and lack an appreciation for the afferent functions of the muscle spindle. The goal of this study was to produce and define intrafusal bag and chain myotubes from differentiated C2C12 myoblasts, utilising the addition of the developmentally associated protein, Neuregulin 1 (Nrg-1). Intrafusal bag myotubes have a fusiform shape and were assigned using statistical morphological parameters. The model was further validated using immunofluorescent microscopy and western blot analysis, directed against an extensive list of putative intrafusal specific markers, as identified in vivo. The addition of Nrg-1 treatment resulted in a 5-fold increase in intrafusal bag myotubes (as assessed by morphology) and increased protein and gene expression of the intrafusal specific transcription factor, Egr3. Surprisingly, Nrg-1 treated myotubes had significantly reduced gene and protein expression of many intrafusal specific markers and showed no specificity towards intrafusal bag morphology. Another novel finding highlights a proliferative effect for Nrg-1 during the serum starvation-initiated differentiation phase, leading to increased nuclei counts, paired with less myotube area per myonuclei. Therefore, despite no clear collective evidence for specific intrafusal development, Nrg-1 treated myotubes share two inherent characteristics of intrafusal fibres, which contain increased satellite cell numbers and smaller myonuclear domains compared with their extrafusal neighbours. This research represents a minimalistic, monocellular C2C12 model for progression towards de novo intrafusal skeletal muscle generation, with the most extensive characterisation to date. Integration of intrafusal myotubes, characteristic of native, in vivo intrafusal skeletal muscle into future biomimetic tissue engineered models could provide platforms for developmental or disease state studies, pre-clinical screening, or clinical applications.