Robotic-assisted surgery for left-sided colon and rectal resections is associated with reduction in the postoperative surgical stress response and improved short-term outcomes: a cohort study.

INTRODUCTION: There is growing evidence that the use of robotic-assisted surgery (RAS) in colorectal cancer resections is associated with improved short-term outcomes when compared to laparoscopic surgery (LS) or open surgery (OS), possibly through a reduced systemic inflammatory response (SIR). Serum C-reactive protein (CRP) is a sensitive SIR biomarker and its utility in the early identification of post-operative complications has been validated in a variety of surgical procedures. There remains a paucity of studies characterising post-operative SIR in RAS. METHODS: Retrospective study of a prospectively collected database of consecutive patients undergoing OS, LS and RAS for left-sided and rectal cancer in a single high-volume unit. Patient and disease characteristics, post-operative CRP levels, and clinical outcomes were reviewed, and their relationships explored within binary logistic regression and propensity scores matched models. RESULTS: A total of 1031 patients were included (483 OS, 376 LS, and 172 RAS). RAS and LS were associated with lower CRP levels across the first 4 post-operative days (p < 0.001) as well as reduced complications and length of stay compared to OS in unadjusted analyses. In binary logistic regression models, RAS was independently associated with lower CRP levels at Day 3 post-operatively (OR 0.35, 95% CI 0.21-0.59, p < 0.001) and a reduction in the rate of all complications (OR 0.39, 95% CI 0.26-0.56, p < 0.001) and major complications (OR 0.5, 95% CI 0.26-0.95, p = 0.036). Within a propensity scores matched model comparing LS versus RAS specifically, RAS was associated with lower post-operative CRP levels in the first two post-operative days, a lower proportion of patients with a CRP ≥ 150 mg/L at Day 3 (20.9% versus 30.5%, p = 0.036) and a lower rate of all complications (34.7% versus 46.7%, p = 0.033). CONCLUSIONS: The present observational study shows that an RAS approach was associated with lower postoperative SIR, and a better postoperative complications profile.

The first reptilian allergen and major allergen for fish-allergic patients: Crocodile ß-parvalbumin.

BACKGROUND: Clinical cross-reactivity between bony fish, cartilaginous fish, frog, and chicken muscle has previously been demonstrated in fish-allergic patients. In indicative studies, two reports of anaphylaxis following the consumption of crocodile meat and IgE-cross-binding were linked to the major fish allergen parvalbumin (PV). This study investigates IgE-binding proteins in crocodile meat with a focus on PV and their clinical relevance. METHODS: Proteins were extracted from muscle tissue of crocodile, three bony fish, and two cartilaginous fish. A cohort of fish-allergic pediatric patients (n = 77) underwent allergen skin prick testing (SPT) to three fish preparations (n = 77) and crocodile (n = 12). IgE-binding proteins were identified and quantified by SDS-PAGE, mass spectrometric analyses, and immunoblotting using commercial and in-house antibodies, as well as individual and pooled patients' serum. PV isoforms were purified or recombinantly expressed before immunological analyses, including human mast cell degranulation assay. RESULTS: Of the tissues analyzed, PV was most abundant in heated crocodile preparation, triggering an SPT of ≥3 mm in 8 of 12 (67%) fish-allergic patients. Seventy percent (31 of 44) of fish PV-sensitized patients demonstrated IgE-binding to crocodile PV. Crocodile ß-PV was the major IgE-binding protein but 20-fold less abundant than α-PV. Cellular reactivity was demonstrated for ß-PV and epitopes predicted, explaining frequent IgE-cross-binding of ß-PVs. Both PV isoforms are now registered as the first reptile allergens with the WHO/IUIS (ß-PV as Cro p 1 and α-PV as Cro p 2). CONCLUSION: Fish-allergic individuals may be at risk of an allergy to crocodile and should seek specialist advice before consuming crocodilian meat.

MRGPRX2 activation in mast cells by neuromuscular blocking agents and other agonists: Modulation by sugammadex.

BACKGROUND: Neuromuscular-blocking agents (NMBAs) can cause both IgE-dependent and IgE-independent anaphylactic reactions, with activation of the mast cell receptor MRGPRX2 being important to the latter. Sugammadex, a reversal agent for certain aminosteroid NMBAs, has been proposed as an antidote for these anaphylactic events with conflicting outcomes. OBJECTIVE: We further characterize the involvement of MRGPRX2 in NMBA-induced mast cell activation and determine how this is influenced by sugammadex. We then apply these in vitro results to infer the possible utility of sugammadex in the acute management of non-IgE-dependent anaphylaxis. METHODS: The LAD2 human mast cell line and a MRGPRX2 knock-down derivative were used to validate the involvement of MRGPRX2 and to test the effect of sugammadex on mast cell activation by NMBAs and other MRGPRX2 agonists. RESULTS: All MRGPRX2 agonists tested were shown to induce MRGPRX2-dependent LAD2 mast cell calcium mobilization and cytokine release and all, apart from rocuronium, induced degranulation. Co-treatment of mast cells with sugammadex and some MRGPRX2 agonists significantly reduced cell activation, but if sugammadex was administered a few minutes following stimulation, degranulation was not attenuated. However, addition of sugammadex up to 180 min following LAD2 MRGPRX2 stimulation, significantly reduced CCL2 mRNA and protein induction. CONCLUSIONS AND CLINICAL RELEVANCE: We show that sugammadex, known to reverse muscle blockade by certain NMBAs, is also able to reduce MRGPRX2 activation by NMBAs and other, but not all, MRGPRX2 agonists. As sugammadex was ineffective in attenuating mast cell degranulation when added rapidly post MRGPRX2 activation, this suggests against the agent having efficacy in controlling acute symptoms of anaphylaxis to NMBAs caused by MRGPRX2 activation. Interestingly, however, sugammadex did impair MRGPRX2-induced CCL2 release, suggesting that it may have some benefit in perhaps dampening less well-defined adverse effects of MRGPRX2-dependent anaphylaxis associated with the more slowly elaborated mast cell mediators.

Cancer and motor neuron disease-causal or coincidental? Two contrasting cases.

INTRODUCTION: Motor neuron disease (MND) can occur in patients with cancer, but there is minimal evidence that this is more than by chance. We contrast two cases of motor neuronopathies occurring in the context of systemic malignancy and argue that in one case the cause was most likely paraneoplastic, while in the other it was not. CASE 1: A 61-year-old woman developed progressive walking difficulties over 9 months with weakness and stiffness in her legs. EMG showed fibrillations and positive sharp waves in multiple lower limb muscles bilaterally, with neurogenic units and a reduced recruitment pattern. An invasive ductal carcinoma of the breast was identified and she continued to deteriorate neurologically with worsening mobility, upper limb spasticity and fasciculations. She died approximately 26 months after symptom onset. CASE 2: A 57-year-old woman developed weight loss and weakness of her right arm without any sensory symptoms. At presentation, she had wasting and fasciculations in her right upper limb muscles, with normal reflexes, normal left upper limb and lower limb examination. Over the following week, she developed left upper limb weakness and fasciculations, brisk knee reflexes, and flexor plantar responses. Her EMG showed upper and lower limb denervation. She was found to have anti-Hu and anti-CV2 antibodies present in serum. A PET-CT showed active uptake in lymph nodes in the right hilum. Biopsy confirmed a small cell lung cancer. She had chemoradiation therapy and the tumour went into remission. She has remained well on follow-up 24 months later, regaining weight and strength after her chemotherapy. She continues to be monitored for cancer recurrence, but thus far appears to be in remission. CONCLUSION: In cases with rapidly progressive MND, particularly of upper limb onset, consideration should be given to testing anti-neuronal antibodies and searching for an occult tumour.

Identification of an Immortalized Human Airway Epithelial Cell Line with Dyskinetic Cilia.

Primary ciliary dyskinesia is an inherited, currently incurable condition. In the respiratory system, primary ciliary dyskinesia causes impaired functioning of the mucociliary escalator, leading to nasal congestion, cough, and recurrent otitis media, and commonly progresses to cause more serious and permanent damage, including hearing deficits, chronic sinusitis, and bronchiectasis. New treatment options for the condition are thus necessary. In characterizing an immortalized human bronchial epithelial cell line (BCi-NS1.1) grown at an air-liquid interface to permit differentiation, we have identified that these cells have dyskinetic motile cilia. The cells had a normal male karyotype, and phenotypic markers of epithelial cell differentiation emerged, as previously shown. Ciliary beat frequency (CBF) as assessed by high-speed videomicroscopy was lower than normal (4.4 Hz). Although changes in CBF induced by known modulators were as expected, the cilia displayed a dyskinetic, circular beat pattern characteristic of central microtubular agenesis with outer doublet transposition. This ultrastructural defect was confirmed by electron microscopy. We propose that the BCi-NS1.1 cell line is a useful model system for examination of modulators of CBF and more specifically could be used to screen for novel drugs with the ability to enhance CBF and perhaps repair a dyskinetic ciliary beat pattern.

Sacral neuromodulation for faecal incontinence - 10 years' experience at a Scottish tertiary centre.

INTRODUCTION: Sacral nerve stimulation (SNS) is increasingly popular in the management of faecal incontinence. This paper reports the first 10-year experience of SNS in the management of faecal incontinence at a tertiary referral centre. Data was collected in a prospectively maintained database. RESULTS: In total 130 patients were referred. The majority were women (94%) under 75-year-old (98%). Seven patients were found to have full-thickness rectal prolapse at the initial work-up and proceeded to rectopexy. Eighty-three patients underwent temporary SNS testing with 73.5% positive outcome, of which 52 patients had permanent implant insertion. There were four failures of SNS (7%) following implantation despite successful temporary testing, seven infection, one lead migration and three post-operative pain/numbness. One patient subsequently developed colorectal cancer requiring SNS removal. A higher frequency of episodes of incontinence was associated with positive SNS outcome (p = 0.007). There was no significant association between age, sex, type of faecal incontinence, previous anorectal/pelvic surgery, colonoscopic or USS findings and the likelihood of successful SNS. Of the 52 patients with SNS implants, 27 patients were seen only once for follow-up; the remaining 25 patients were seen more than once - five of these were part of our initial cases of routine 6- and 12-monthly follow-up, 6 patients were seen for adjustment of voltages, whereas the remaining 14 patients were seen for complications of the implants. If the initial five patients were excluded, only 38% of patients would have been seen more frequently on an as-required basis. CONCLUSION: SNS is a safe and effective option in the management of faecal incontinence. Of the initial work-up, endoscopy and examination-under-anaesthesia (EUA) or proctogram are essential and more likely to influence the likelihood of suitability of SNS testing. A patient-led drop-in approach to follow-up is feasible to allow patients to be seen on an as-required basis.

Analysis of lesion localisation at colonoscopy: outcomes from a multi-centre U.K. study.

BACKGROUND: Colonoscopy is currently the gold standard for detection of colorectal lesions, but may be limited in anatomically localising lesions. This audit aimed to determine the accuracy of colonoscopy lesion localisation, any subsequent changes in surgical management and any potentially influencing factors. METHODS: Patients undergoing colonoscopy prior to elective curative surgery for colorectal lesion/s were included from 8 registered U.K. sites (2012-2014). Three sets of data were recorded: patient factors (age, sex, BMI, screener vs. symptomatic, previous abdominal surgery); colonoscopy factors (caecal intubation, scope guide used, colonoscopist accreditation) and imaging modality. Lesion localisation was standardised with intra-operative location taken as the gold standard. Changes to surgical management were recorded. RESULTS: 364 cases were included; majority of lesions were colonic, solitary, malignant and in symptomatic referrals. 82% patients had their lesion/s correctly located at colonoscopy. Pre-operative CT visualised lesion/s in only 73% of cases with a reduction in screening patients (64 vs. 77%; p = 0.008). 5.2% incorrectly located cases at colonoscopy underwent altered surgical management, including conversion to open. Univariate analysis found colonoscopy accreditation, scope guide use, incomplete colonoscopy and previous abdominal surgery significantly influenced lesion localisation. On multi-variate analysis, caecal intubation and scope guide use remained significant (HR 0.35, 0.20-0.60 95% CI and 0.47; 0.25-0.88, respectively). CONCLUSION: Lesion localisation at colonoscopy is incorrect in 18% of cases leading to potentially significant surgical management alterations. As part of accreditation, colonoscopists need lesion localisation training and awareness of when inaccuracies can occur.

The MS4A family: counting past 1, 2 and 3.

The MS4A (membrane-spanning 4-domain family, subfamily A) family of proteins contains some well-known members including MS4A1 (CD20), MS4A2 (FcɛRIß) and MS4A3 (HTm4). These three MS4A family members are expressed on the cell surface of specific leukocyte subsets and have been well characterized as having key roles in regulating cell activation, growth and development. However, beyond MS4A1-3 there are a large number of related molecules (18 to date in humans) where our understanding of their biological roles is at a relatively nascent stage. This review examines the larger MS4A family focusing on their structure, expression, regulation and characterized and/or emerging biological roles. Our own work on one family member MS4A8B, and its possible role in epithelial cell regulation, is also highlighted.

The impact of open versus laparoscopic resection for colon cancer on C-reactive protein concentrations as a predictor of postoperative infective complications.

BACKGROUND: There is increasing evidence that C-reactive protein is a useful negative predictor of infective complications and anastomotic leak following surgery for colorectal cancer. In particular, C-reactive protein concentrations on postoperative days 3 and 4 have been proposed to be of clinical utility since they aid safe and early discharge of selected patients following colorectal surgery. However, it is not clear whether such thresholds are also applicable in laparoscopic surgery. The aim of the present study was to compare the value of daily C-reactive protein concentrations in the prediction of postoperative infective complications in patients undergoing open versus laparoscopic resection for colon cancer. METHODS: Patients with histologically proven colon cancer who were considered to have undergone potentially curative resection in one of two university teaching hospitals in Glasgow were included in the study (n = 344). Patient characteristics were collected in a prospective surgical database. All resections were elective cases and were performed using either open (n = 191) or laparoscopic surgery (n = 153). Daily blood samples to measure C-reactive protein concentrations perioperatively were taken routinely. Patients were assessed for postoperative infective and non-infective complications. RESULTS: The majority of patients were aged 65 years or older (75%), male (52%), had left-sided tumors (54%), node negative disease (77%), and did not undergo neoadjuvant treatment (94%). Patients undergoing open and laparoscopic resection were similar in terms of age, sex, tumor site, TNM stage, comorbidity, and infective complications. In contrast, preoperative and postoperative days 1-3 C-reactive protein concentrations were lower following laparoscopic compared with open resection in the whole cohort (n = 344; all p < 0.001) and in those who did not develop infective complications (n = 251; all p < 0.001). The median length of hospital stay was shorter in the laparoscopic resection (p < 0.001). During follow-up, 127 (37%) patients developed a postoperative complication, 93 (73%) of which were infective complications. In those who developed an infective complication, there was no significant difference in the C-reactive protein concentrations between open and laparoscopic resections on postoperative days 1-4. C-reactive protein thresholds predictive of infective complications were the same on postoperative days 3 (180 mg/l) and 4 (140 mg/l) following both open and laparoscopic resection for colon cancer. CONCLUSIONS: The results of the present study show that although the magnitude of the systemic inflammatory response, as evidenced by C-reactive protein, following surgery was greater in open compared with laparoscopic resection, the threshold concentrations of C-reactive protein for the development of postoperative infective complications were remarkably similar on days 3 and 4.

Scottish Intercollegiate Guidelines Network Guidance on Dementia: The Investigation of Suspected Dementia (SIGN 168) with Focus on Biomarkers-Executive Summary.

This is an executive summary of the recent guidance produced by the Scottish Intercollegiate Guidelines Network (SIGN) dementia guideline group with regards to the investigation of suspected dementia. This is a sub-section of the broader SIGN 168 guideline released in November 2023. The guideline group included clinicians with expertise in Old Age Psychiatry, Neurology, Radiology, and Nuclear Medicine supported by colleagues from the SIGN and Healthcare Improvement Scotland teams. There was representation from carers and support organizations with experience of dementia, to ensure the recommendations were appropriate from the perspective of the people being assessed for possible dementia and their carers. As the 2018 National Institute for Health and Clinical Excellence (NICE) dementia review included a review of the evidenced investigation of dementia, the SIGN guideline development group decided to focus on a review on the up-to-date evidence regarding the role of imaging and fluid biomarkers in the diagnosis of dementia. To give context to the consideration of more advanced diagnostic biomarker investigations, the guideline and this summary include the NICE guidance on the use of standard investigations as well as more specialist investigations. The evidence review supports consideration of the use of structural imaging, nuclear medicine imaging, and established Alzheimer's cerebrospinal fluid biomarkers (amyloid and tau) in the diagnosis of dementia. Although routine use of amyloid positron emission tomography imaging was not recommended, its potential use, under specialist direction, in patients with atypical or young-onset presentations of suspected Alzheimer's dementia was included as a clinical good practice point.

Plasminogen-stimulated inflammatory cytokine production by airway smooth muscle cells is regulated by annexin A2.

Plasminogen has a role in airway inflammation. Airway smooth muscle (ASM) cells cleave plasminogen into plasmin, a protease with proinflammatory activity. In this study, the effect of plasminogen on cytokine production by human ASM cells was investigated in vitro. Levels of IL-6 and IL-8 in the medium of ASM cells were increased by incubation with plasminogen (5-50 µg/ml) for 24 hours (P < 0.05; n = 6-9), corresponding to changes in the levels of cytokine mRNA at 4 hours. The effects of plasminogen were attenuated by α2-antiplasmin (1 µg/ml), a plasmin inhibitor (P < 0.05; n = 6-12). Exogenous plasmin (5-15 mU/ml) also stimulated cytokine production (P < 0.05; n = 6-8) in a manner sensitive to serine-protease inhibition by aprotinin (10 KIU/ml). Plasminogen-stimulated cytokine production was increased in cells pretreated with basic fibroblast growth factor (300 pM) in a manner associated with increases in urokinase plasminogen activator expression and plasmin formation. The knockdown of annexin A2, a component of the putative plasminogen receptor comprised of annexin A2 and S100A10, attenuated plasminogen conversion into plasmin and plasmin-stimulated cytokine production by ASM cells. Moreover, a role for annexin A2 in airway inflammation was demonstrated in annexin A2-/- mice in which antigen-induced increases in inflammatory cell number and IL-6 levels in the bronchoalveolar lavage fluid were reduced (P < 0.01; n = 10-14). In conclusion, plasminogen stimulates ASM cytokine production in a manner regulated by annexin A2. Our study shows for the first time that targeting annexin A2-mediated signaling may provide a novel therapeutic approach to the treatment of airway inflammation in diseases such as chronic asthma.

Impact of day 2 C-reactive protein on day 3 and 4 thresholds associated with infective complications following curative surgery for colorectal cancer.

BACKGROUND: The postoperative systemic inflammatory response, as evidenced by C-reactive protein (CRP) on days 3 and 4, has been reported to be associated with the development of infective complications following surgery for colorectal cancer. However, patients in enhanced recovery after surgery require earlier assessment at day 2, the peak CRP response to surgery. The aim of the present study was to assess the impact of day 2 CRP on the CRP concentrations on days 3 and 4. METHODS: Patients with colorectal cancer undergoing elective resection were recorded in a prospective database (n = 357). CRP was measured preoperatively and on days 1-4 postoperatively. Correlations between day 2 CRP and day 3 and day 4 CRP concentrations were examined. RESULTS: The majority of patients were ≥ 65 (72 %), male (53 %), underwent right or left hemicolectomy (63 %), and had node-negative disease (61 %). Day 2 CRP was not significantly associated with age, sex, operation type, or tumor stage. Day 2 CRP was directly associated with day 3 (r (2) = 0.601, p < 0.001) and day 4 (r (2) = 0.270, p < 0.001) CRP. The median day 2 CRP that corresponded with the previously described thresholds for predicting infective complications was ~190 mg/L, and for predicting an anastomotic leak 200 mg/L. CONCLUSIONS: A day 2 CRP concentration >190 mg/L was associated with day 3 and 4 CRP concentrations above established CRP thresholds for the development of infective complications.

Valproate pregnancy prevention scheme: what are the barriers to enrolling patients and how do we meet them?

Background: The UK Medicines Health products Regulation Agency instructs that valproate prescriptions should be restricted in women of childbearing age to those consenting to the Pregnancy Prevention Programme (PPP). We assessed the compliance and barriers to the valproate PPP. Methods: We retrospectively audited NHS Grampian's compliance with PPP guidelines among women of childbearing potential prescribed valproate between October 2017 and March 2018. Additionally, we prospectively reviewed new valproate prescriptions from February 2019 to March 2022 and compared this with our retrospective data to assess the effectiveness of our identification process using descriptive statistics. Results: We identified 351 women retrospectively and 80 women prospectively. Epilepsy, migraine and psychiatry were the main indications. There was a decline in valproate use over the years, particularly for epilepsy. Initially, only 132 (37.6%) met the PPP requirement, and eventually, 81 (23%) stopped the medication. Despite efforts, 38 (10.8%) had contact with secondary care but still did not meet PPP and 100 (28.5%) had no documentation or referral to secondary care. Patients not meeting PPP lacked capacity, most commonly with severe learning difficulties. Women treated for psychiatric purposes were less likely to meet PPP than other indications. Conclusions: A significant proportion of women continue valproate treatment without meeting the PPP requirement. This is linked to their indication for prescription and their comorbidities. Collaborative input from relevant specialities and primary care is required to fully achieve PPP if a national valproate database is to be established.

National audit of pathways in epileptic seizure referrals (NAPIER): A national, multicentre audit of first seizure clinics throughout the UK and Ireland.

BACKGROUND: Current guidelines set clinical standards for the management of suspected first seizures and epilepsy. We aimed to assess if these standards are being met across first seizure clinics nationally, to describe variations in care and identify opportunities for service delivery improvement. METHODS: Multicentre audit assessing the care of adults (≥16 years) referred to first seizure clinics from 31st December 2019 going backwards (30 consecutive patients per centre). Patients with pre-existing diagnosis of epilepsy were excluded. Anonymised referral, clinic, and follow-up data are reported with descriptive statistics. RESULTS: Data provided for 727 patients from 25 hospitals in the UK and Ireland (median age 41 years [IQR 26-59], 52% males). Median time to review was 48 days (IQR 26-86), with 13.8% (IQR 3.3%-24.0%) of patients assessed within 2 weeks. Seizure recurrence was seen in 12.7% (IQR 6.6%-17.4%) of patients awaiting first appointment. Documentation for witness accounts and driving advice was evident in 85.0% (IQR 74.0%-100%) and 79.7% (IQR 71.2%-96.4%) of first seizure/epilepsy patients, respectively. At first appointment, discussion of sudden unexpected death in epilepsy was documented in 30.1% (IQR 0%-42.5%) of patients diagnosed with epilepsy. In epilepsy patients, median time to MRI neuroimaging was 37 days [IQR 22-56] and EEG was 30 days [IQR 19-47]. 30.4% ([IQR 0%-59.5%]) of epilepsy patients were referred to epilepsy nurse specialists. CONCLUSIONS: There is variability nationally in the documented care of patients referred to first seizure clinics. Many patients are facing delays to assessment with epilepsy specialists with likely subsequent impact on further management.