Medullary Thyroid Cancer: Molecular Drivers and Immune Cellular Milieu of the Tumour Microenvironment-Implications for Systemic Treatment.

In this review, we explore the underlying molecular biology of medullary thyroid carcinoma (MTC) and its interplay with the host immune system. MTC is consistently driven by a small number of specific pathogenic variants, beyond which few additional genetic events are required for tumorigenesis. This explains the exceedingly low tumour mutational burden seen in most MTC, in contrast to other cancers. However, because of the low tumour mutational burden (TMB), there is a correspondingly low level of tumour-associated neoantigens that are presented to the host immune system. This reduces tumour visibility and vigour of the anti-tumour immune response and suggests the efficacy of immunotherapy in MTC is likely to be poor, acknowledging this inference is largely based on the extrapolation of data from other tumour types. The dominance of specific RET (REarranged during Transfection) pathogenic variants in MTC tumorigenesis rationalizes the observed efficacy of the targeted RET-specific tyrosine kinase inhibitors (TKIs) in comparison to multi-kinase inhibitors (MKIs). Therapeutic durability of pathway inhibitors is an ongoing research focus. It may be limited by the selection pressure TKI treatment creates, promoting survival of resistant tumour cell clones that can escape pathway inhibition through binding-site mutations, activation of alternate pathways, and modulation of the cellular and cytokine milieu of the tumour microenvironment (TME).

Outcomes of thyroidectomy in symptomatic, euthyroid Hashimoto's patients: a case control study.

BACKGROUND: Hashimoto's thyroiditis (HT) is managed with thyroid hormone replacement to maintain a euthyroid state. A subset of patients have refractory symptoms, which improve with thyroidectomy (TT). There remains a reluctance to proceed with surgery due to perceptions of complications, and limited data availability regarding improvements in quality of life (QoL). This retrospective case control study aims to analyse the outcomes and QoL scores for symptomatic euthyroid HT patients who underwent TT. METHODS: Thirty euthyroid patients who underwent TT for the management of HT between 2017 and 2022 were identified. An age-matched control group of patients who underwent TT for symptomatic multinodular goitre (MNG) were randomly selected. Demographics, biochemistry, histology, outcomes, and pre- and post-operative SF-36 and ThyPRO-39 scores were compared between groups. RESULTS: There were no surgical complications in the HT group, whilst two MNG patients had complications. There was a similar rate of parathyroid auto-transplantation in both groups, more glands were transplanted in the HT group. There was a significant difference in pre- and post-operative QoL scores for both groups. Comparison revealed a significant improvement in hyperthyroid symptoms, social life and daily life scores in the HT group. There was a significant difference in pre- and post-operative anti-TPO, anti-TG and TSH levels in the HT group. CONCLUSION: Patients with symptomatic Hashimoto's thyroiditis, despite being euthyroid, may benefit from total thyroidectomy however this remains under-utilized. This study demonstrated that thyroidectomy was associated with an improvement in validated post-operative quality of life scores and was not associated with increased complication rates for appropriately selected patients.

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.

Patient reported outcomes in brachial plexus birth injury: results from the iPLUTO world-wide consensus survey.

PURPOSE: Brachial plexus birth injuries (BPBI) can have lifelong effects on the development and functional use of the upper extremity. Currently there is no agreement with regards to what patient-reported outcome (PRO) measures should be used. Therefore, the ability to compare the effects of treatment between individuals and institutions is challenging. This study aimed to achieve consensus among clinicians on the use of PRO measures within this patient group to allow for improved comparison of treatments and outcomes in the future. MATERIALS AND METHODS: Online, a 3 round Delphi survey was completed by 35 international multi-disciplinary specialist centers. RESULTS: All respondents (100%) agreed that PRO measures are useful for clinical evaluation and patient treatment. None of the outcome measures scored >75% agreement for ability to assess responsiveness and current state in children with BPBI as most outcome measures were judged as not specific for BPBI. Additionally, participant centers were asked their perspective on the best available PRO option for each of the 3 categories: functional use of the upper limb, quality of life and pain. This resulted in endorsement by the participant centers of the Brachial Plexus Outcome Measure - Self-Evaluation, the Pediatric Quality of Life Inventory, and Visual Analogue Scale/Brief Pain Inventory respectively. CONCLUSION: International specialists in BPBI agree that PRO measures are important to use both clinically and in research in children aged 5 years and above.

Patient-reported outcome measures were judged as useful both in clinic and in research for brachial plexus birth injury (BPBI), according to a panel of specialized centers.Currently available outcome measures were judged as not specific for BPBI.The panel endorsed the following measures as best available: the Brachial Plexus Outcome Measure ­ Self-Evaluation scale for functional evaluation, the Pediatric Quality of Life Inventory for disease-related quality of life and the Faces Pain Scale - Revised/Visual Analogue Scale/Brief Pain Inventory for pain.

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.

Vegan versus meat-based cat food: Guardian-reported health outcomes in 1,369 cats, after controlling for feline demographic factors.

Increasing concerns about environmental sustainability, farmed animal welfare and competition for traditional protein sources, are driving considerable development of alternative pet foods. These include raw meat diets, in vitro meat products, and diets based on novel protein sources including terrestrial plants, insects, yeast, fungi and potentially seaweed. To study health outcomes in cats fed vegan diets compared to those fed meat, we surveyed 1,418 cat guardians, asking about one cat living with them, for at least one year. Among 1,380 respondents involved in cat diet decision-making, health and nutrition was the factor considered most important. 1,369 respondents provided information relating to a single cat fed a meat-based (1,242-91%) or vegan (127-9%) diet for at least a year. We examined seven general indicators of illness. After controlling for age, sex, neutering status and primary location via regression models, the following risk reductions were associated with a vegan diet for average cats: increased veterinary visits- 7.3% reduction, medication use- 14.9% reduction, progression onto therapeutic diet- 54.7% reduction, reported veterinary assessment of being unwell- 3.6% reduction, reported veterinary assessment of more severe illness- 7.6% reduction, guardian opinion of more severe illness- 22.8% reduction. Additionally, the number of health disorders per unwell cat decreased by 15.5%. No reductions were statistically significant. We also examined the prevalence of 22 specific health disorders, using reported veterinary assessments. Forty two percent of cats fed meat, and 37% of those fed vegan diets suffered from at least one disorder. Of these 22 disorders, 15 were most common in cats fed meat, and seven in cats fed vegan diets. Only one difference was statistically significant. Considering these results overall, cats fed vegan diets tended to be healthier than cats fed meat-based diets. This trend was clear and consistent. These results largely concur with previous, similar studies.

Correction: Vegan versus meat-based dog food: Guardian-reported indicators of health.

[This corrects the article DOI: 10.1371/journal.pone.0265662.].

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.

The heart of the matter: secretory pheochromocytoma presenting as recurrent biventricular heart failure (Takotsubo cardiomyopathy).

Takotsubo's syndrome (TS) is an acute, transient cardiomyopathy occurring secondary to physical or emotional stressors through catecholamine excess. Secretory pheochromocytomas have been previously implicated in cases of TS (PTS), however, often present atypically, are associated with reoccurrence, and have higher rates of complications. We describe the case of a 70-year-old female who presented central chest pain, hypotension and electrocardiogram changes on a background of a 6-month prior episode of resolved Takotsubo's with unknown cause. After progressing to cardiogenic shock with biventricular failure, computerized tomography coronary aortogram revealed an incidental adrenal mass, later proven to be a secretory pheochromocytoma on biochemistry and subsequent histology. PTS has been associated with recurrence and rarely presents as cardiogenic shock. This case highlights the complexity of TS presentations and complications and the diagnostic delays that may occur in PTS.

Vegan versus meat-based dog food: Guardian-reported indicators of health.

Alternative pet foods may offer benefits concerning environmental sustainability and the welfare of animals processed into pet foods. However, some worry these may compromise the welfare of pets. We asked 2,639 dog guardians about one dog living with them, for at least one year. Among 2,596 involved in pet diet decision-making, pet health was a key factor when choosing diets. 2,536 provided information relating to a single dog, fed a conventional meat (1,370 = 54%), raw meat (830 = 33%) or vegan (336 = 13%) diet for at least one year. We examined seven general indicators of ill health: unusual numbers of veterinary visits, medication use, progression onto a therapeutic diet after initial maintenance on a vegan or meat-based diet, guardian opinion and predicted veterinary opinion of health status, percentage of unwell dogs and number of health disorders per unwell dog. Dogs fed conventional diets appeared to fare worse than those fed either of the other two diets. Dogs fed raw meat appeared to fare marginally better than those fed vegan diets. However, there were statistically significant differences in average ages. Dogs fed raw meat were younger, which has been demonstrated to be associated with improved health outcomes. Additionally, non-health related factors may have improved apparent outcomes for dogs fed raw meat, for three of seven general health indicators. We also considered the prevalence of 22 specific health disorders, based on predicted veterinary assessments. Percentages of dogs in each dietary group considered to have suffered from health disorders were 49% (conventional meat), 43% (raw meat) and 36% (vegan). Significant evidence indicates that raw meat diets are often associated with dietary hazards, including nutritional deficiencies and imbalances, and pathogens. Accordingly, the pooled evidence to date indicates that the healthiest and least hazardous dietary choices for dogs, are nutritionally sound vegan diets.

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.

A qualitative investigation into the results of a discrete choice experiment and the impact of COVID-19 on patient preferences for virtual consultations.

OBJECTIVES: To conduct a qualitative investigation on a subset of participants from a previously completed Discrete Choice Experiment (DCE) to understand why factors identified from the DCE are important, how they influenced preference for virtual consultations (VC) and how COVID-19 has influenced preference for VC. METHODS: A quota sample was recruited from participants who participated in our DCE. We specifically targeted participants who were strongly in favour of face-to-face consultations (F2F - defined as choosing all or mostly F2F in the DCE) or strongly in favour of virtual consultations (VC - defined as choosing all or mostly VC consultations in the DCE) to elicit a range of views. Interviews were conducted via telephone or videoconference, audio recorded, transcribed verbatim and uploaded into NVIVO software. A directed content analysis of transcripts was undertaken in accordance with a coding framework based on the results of the DCE and the impact of COVID-19 on preference. RESULTS: Eight F2F and 5 VC participants were included. Shorter appointments were less 'worth' travelling in for than a longer appointment and rush hour travel had an effect on whether travelling was acceptable, particularly when patients experienced pain as a result of extended journeys. Socioeconomic factors such as cost of travel, paid time off work, access to equipment and support in its use was important. Physical examinations were preferable in the clinic whereas talking therapies were acceptable over VC. Several participants commented on how VC interferes with the patient-clinician relationship. VC during COVID-19 has provided patients with the opportunity to access their care virtually without the need for travel. For some, this was extremely positive. CONCLUSIONS: This study investigated the results of a previously completed DCE and the impact of COVID-19 on patient preferences for VC. Theoretically informative insights were gained to explain the results of the DCE. The use of VC during the COVID-19 pandemic provided opportunities to access care without the need for face-to-face social interactions. Many felt that VC would become more commonplace after the pandemic, whereas others were keen to return to F2F consultations as much as possible. This qualitative study provides additional context to the results of a previously completed DCE.

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.

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.

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.

The pathophysiology associated with primary (idiopathic) frozen shoulder: A systematic review.

BACKGROUND: Frozen shoulder is a common yet poorly understood musculoskeletal condition, which for many, is associated with substantial and protracted morbidity. Understanding the pathology associated with this condition may help to improve management. To date this has not been presented in a systematic fashion. As such, the aim of this review was to summarise the pathological changes associated with this primary frozen shoulder. DATABASES: Medline, Embase, CINAHL, AMED, BNI and the Cochrane Library, were searched from inception to 2nd May, 2014. To be included participants must not have undergone any prior intervention. Two reviewers independently conducted the; searches, screening, data extraction and assessment of Risk of Bias using the Cochrane Risk of Bias Assessment Tool for non-Randomised Studies of Interventions (ACROBAT-NRSI). Only English language publications reporting findings in humans were included. The findings were summarised in narrative format. RESULTS: Thirteen observational studies (involving 417 shoulders) were included in the review. Eight studies reported magnetic resonance imaging or arthrography findings and 5 recorded histological findings. When reported mean ages of the participants ranged from 40.0 to 59.8 years. Duration of symptoms ranged from 0 to 30 months. The majority of studies (n = 7) were assessed to be of moderate risk of bias, two studies at high risk and the remaining four were rated as low risk of bias. Study characteristics were poorly reported and there was widespread variety observed between studies in respect of data collection methods and inclusion criteria employed. Pathological changes in the anterior shoulder joint capsule and related structures were commonly reported. Imaging identified pathological changes occurring in the coracohumeral ligament, axillary fold and rotator interval. Obliteration of the subcoracoid fat triangle also appeared to be pathognomonic. Histological studies were inconclusive but suggested that immune, inflammatory and fibrotic changes where associated with primary frozen shoulder. CONCLUSIONS: This systematic review presents a summary of what is currently known about the tissue pathophysiology of primary frozen shoulder. Further studies that use standardised inclusion and exclusion criteria and investigate changes in naïve tissue at different stages of the condition are required.