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.

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.

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.

Volumetric MRI is a promising outcome measure of muscle reinnervation.

The development of outcome measures that can track the recovery of reinnervated muscle would benefit the clinical investigation of new therapies which hope to enhance peripheral nerve repair. The primary objective of this study was to assess the validity of volumetric Magnetic Resonance Imaging (MRI) as an outcome measure of muscle reinnervation by testing its reproducibility, responsiveness and relationship with clinical indices of muscular function. Over a 3-year period 25 patients who underwent nerve transfer to reinnervate elbow flexor muscles were assessed using intramuscular electromyography (EMG) and MRI (median post-operative assessment time of 258 days, ranging from 86 days pre-operatively to 1698 days post- operatively). Muscle power (Medical Research Council (MRC) grade) and Stanmore Percentage of Normal Elbow Assessment (SPONEA) assessment was also recorded for all patients. Sub-analysis of peak volitional force (PVF), muscular fatigue and co-contraction was performed in those patients with MRC > 3. The responsiveness of each parameter was compared using Pearson or Spearman correlation. A Hierarchical Gaussian Process (HGP) was implemented to determine the ability of volumetric MRI measurements to predict the recovery of muscular function. Reinnervated muscle volume per unit Body Mass Index (BMI) demonstrated good responsiveness (R2 = 0.73, p < 0.001). Using the temporal and muscle volume per unit BMI data, a HGP model was able to predict MRC grade and SPONEA with a mean absolute error (MAE) of 0.73 and 1.7 respectively. Muscle volume per unit BMI demonstrated moderate to good positive correlations with patient reported impairments of reinnervated muscle; co- contraction (R2 = 0.63, p = 0.02) and muscle fatigue (R2 = 0.64, p = 0.04). In summary, volumetric MRI analysis of reinnervated muscle is highly reproducible, responsive to post-operative time and demonstrates correlation with clinical indices of muscle function. This encourages the view that volumetric MRI is a promising outcome measure for muscle reinnervation which will drive advancements in motor recovery therapy.

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.

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.

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.

Strategies for Peripheral Nerve Repair.

PURPOSE OF REVIEW: This review focuses on biomechanical and cellular considerations required for development of biomaterials and engineered tissues suitable for implantation following PNI, as well as translational requirements relating to outcome measurements for testing success in patients. RECENT FINDINGS: Therapies that incorporate multiple aspects of the regenerative environment are likely to be key to improving therapies for nerve regeneration. This represents a complex challenge when considering the diversity of biological, chemical and mechanical factors involved. In addition, clinical outcome measures following peripheral nerve repair which are sensitive and responsive to changes in the tissue microenvironment following neural injury and regeneration are required. SUMMARY: Effective new therapies for the treatment of PNI are likely to include engineered tissues and biomaterials able to evoke a tissue microenvironment that incorporates both biochemical and mechanical features supportive to regeneration. Translational development of these technologies towards clinical use in humans drives a concomitant need for improved clinical measures to quantify nerve regeneration.

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.

Characterising cellular and molecular features of human peripheral nerve degeneration.

Nerve regeneration is a key biological process in those recovering from neural trauma. From animal models it is known that the regenerative capacity of the peripheral nervous system (PNS) relies heavily on the remarkable ability of Schwann cells to undergo a phenotypic shift from a myelinating phenotype to one that is supportive of neural regeneration. In rodents, a great deal is known about the molecules that control this process, such as the transcription factors c-Jun and early growth response protein 2 (EGR2/KROX20), or mark the cells and cellular changes involved, including SOX10 and P75 neurotrophin receptor (p75NTR). However, ethical and practical challenges associated with studying human nerve injury have meant that little is known about human nerve regeneration.The present study addresses this issue, analysing 34 denervated and five healthy nerve samples from 27 patients retrieved during reconstructive nerve procedures. Using immunohistochemistry and Real-Time quantitative Polymerase Chain Reaction (RT-qPCR), the expression of SOX10, c-Jun, p75NTR and EGR2 was assessed in denervated samples and compared to healthy nerve. Nonparametric smoothing linear regression was implemented to better visualise trends in the expression of these markers across denervated samples.It was found, first, that two major genes associated with repair Schwann cells in rodents, c-Jun and p75NTR, are also up-regulated in acutely injured human nerves, while the myelin associated transcription factor EGR2 is down-regulated, observations that encourage the view that rodent models are relevant for learning about human nerve injury. Second, as in rodents, the expression of c-Jun and p75NTR declines during long-term denervation. In rodents, diminishing c-Jun and p75NTR levels mark the general deterioration of repair cells during chronic denervation, a process thought to be a major obstacle to effective nerve repair. The down-regulation of c-Jun and p75NTR reported here provides the first molecular evidence that also in humans, repair cells deteriorate during chronic denervation.

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.

Generating intrafusal skeletal muscle fibres in vitro: Current state of the art and future challenges.

Intrafusal fibres are a specialised cell population in skeletal muscle, found within the muscle spindle. These fibres have a mechano-sensory capacity, forming part of the monosynaptic stretch-reflex arc, a key component responsible for proprioceptive function. Impairment of proprioception and associated dysfunction of the muscle spindle is linked with many neuromuscular diseases. Research to-date has largely been undertaken in vivo or using ex vivo preparations. These studies have provided a foundation for our understanding of muscle spindle physiology, however, the cellular and molecular mechanisms which underpin physiological changes are yet to be fully elucidated. Therefrom, the use of in vitro models has been proposed, whereby intrafusal fibres can be generated de novo. Although there has been progress, it is predominantly a developing and evolving area of research. This narrative review presents the current state of art in this area and proposes the direction of future work, with the aim of providing novel pre-clinical and clinical applications.

Evaluation of functional outcomes after brachial plexus injury.

Major nerve injuries such as those of the brachial plexus present a significant challenge for both rehabilitation and evaluation of outcome. With these often complex and multi-faceted injuries, correct selection of outcome measures is important. Healthy nerve function in humans heightens our interactions with the world, creating quality and enjoyment through our experiences of movement and touch. Therefore, assessments should be holistic and representative of all of these features. This article considers the assessment and evaluation of all of the features of nerve injury: sensorimotor, sensation (including that of pain), function and the psychosocial aspects. Current practice is described and combined with clinical experience and research findings to provide suggestions and recommendations for the selection of the most appropriate tools for use with this patient group.

Development of a "Surgical Shadowing Scheme" to improve undergraduate experiences of surgery.

PURPOSE: To establish a sustainable model for a "Surgical Shadowing Scheme" (SSS) and assess how this affects undergraduate attitudes to surgical careers. PATIENTS AND METHODS: Surgeons at university teaching hospitals associated with UCL Medical School and UCL Partners, United Kingdom, were approached for their willingness to participate in the scheme. Medical students were then invited to apply for the scheme, where students were individually matched to operating theater sessions with surgeons in their specialty of choice. Feedback was subsequently obtained, evaluating experiences of the placement and the effect this had on future career aspirations. RESULTS: After running for four consecutive years, approximately 220 students have participated in the scheme across a range of surgical units and specialties. A total of 91.5% of the students were pre-clinical (years 1-3), whilst the remainder were clinical (years 4-6). Fifty-four percent were female and 46% male. Eighty-three percent of the students did not have any previous experience of the specialty that they shadowed, and 67% agreed that participating in the scheme had either "increased" or "strongly increased" their desire to pursue a surgical career. Ninety-four percent said they would "recommend" or "strongly recommend" the SSS to a peer. Over a third of students reported scrubbing-up during their placements and 35% of these directly assisted the lead surgeon. Traditionally male-dominated surgical sub-specialties recruited a high proportion of female students. CONCLUSION: This is the first published example of an established "Surgical Shadowing Scheme" for medical undergraduates. Our SSS has been highly valued by students and indicates that even a single high-quality surgical exposure is sufficient to increase the desire of undergraduates to pursue a surgical career. We hope that this SSS will act as a blueprint for other centers to develop their own shadowing schemes, in turn helping to ensure that surgery continues to inspire and attract the very best candidates for the future.

The Effects of Surgical Antiseptics and Time Delays on RNA Isolated From Human and Rodent Peripheral Nerves.

Peripheral Nerve Injury (PNI) is common following blunt or penetrating trauma with an estimated prevalence of 2% among the trauma population. The resulting economic and societal impacts are significant. Nerve regeneration is a key biological process in those recovering from neural trauma. Real Time-quantitative Polymerase Chain Reaction (RT-qPCR) and RNA sequencing (RNA seq) are investigative methods that are often deployed by researchers to characterize the cellular and molecular mechanisms that underpin this process. However, the ethical and practical challenges associated with studying human nerve injury have meant that studies of nerve injury have largely been limited to rodent models of renervation. In some circumstances it is possible to liberate human nerve tissue for study, for example during reconstructive nerve repair. This complex surgical environment affords numerous challenges for optimizing the yield of RNA in sufficient quantity and quality for downstream RT-qPCR and/or RNA seq applications. This study characterized the effect of: (1) Time delays between surgical liberation and cryopreservation and (2) contact with antiseptic surgical reagents, on the quantity and quality of RNA isolated from human and rodent nerve samples. It was found that time delays of greater than 3 min between surgical liberation and cryopreservation of human nerve samples significantly decreased RNA concentrations to be sub-optimal for downstream RT-qPCR/RNA seq applications (<5 ng/µl). Minimizing the exposure of human nerve samples to antiseptic surgical reagents significantly increased yield of RNA isolated from samples. The detrimental effect of antiseptic reagents on RNA yield was further confirmed in a rodent model where RNA yield was 8.3-fold lower compared to non-exposed samples. In summary, this study has shown that changes to the surgical tissue collection protocol can have significant effects on the yield of RNA isolated from nerve samples. This will enable the optimisation of protocols in future studies, facilitating characterisation of the cellular and molecular mechanisms that underpin the regenerative capacity of the human peripheral nervous system.