IL-1 and IL-1ra are key regulators of the inflammatory response to RNA vaccines.

The use of lipid-formulated RNA vaccines for cancer or COVID-19 is associated with dose-limiting systemic inflammatory responses in humans that were not predicted from preclinical studies. Here, we show that the 'interleukin 1 (IL-1)-interleukin 1 receptor antagonist (IL-1ra)' axis regulates vaccine-mediated systemic inflammation in a host-specific manner. In human immune cells, RNA vaccines induce production of IL-1 cytokines, predominantly IL-1ß, which is dependent on both the RNA and lipid formulation. IL-1 in turn triggers the induction of the broad spectrum of pro-inflammatory cytokines (including IL-6). Unlike humans, murine leukocytes respond to RNA vaccines by upregulating anti-inflammatory IL-1ra relative to IL-1 (predominantly IL-1α), protecting mice from cytokine-mediated toxicities at >1,000-fold higher vaccine doses. Thus, the IL-1 pathway plays a key role in triggering RNA vaccine-associated innate signaling, an effect that was unexpectedly amplified by certain lipids used in vaccine formulations incorporating N1-methyl-pseudouridine-modified RNA to reduce activation of Toll-like receptor signaling.

Hereditary transthyretin amyloidosis presenting with prominent autonomic dysfunction.

A 56-year-old man reported 2 years of slowly progressive exertional fatigue, presyncope, paraesthesia, generalised weakness and nocturnal bowel frequency. He had an abnormal Valsalva ratio and significant postural hypotension. Serum N-terminal pro-B-type natriuretic peptide and troponin T were elevated. Transthoracic echocardiogram identified thickening of the biventricular walls, interatrial septum and atrioventricular valve leaflets. Global longitudinal strain was reduced with relative apical sparing, suspicious for cardiac amyloidosis. Technetium-99m and 3,3-diphosphono-1,2-propanodicarboxylic acid scintigraphy supported a diagnosis of transthyretin amyloidosis (ATTR). However, urinary Bence Jones protein (kappa) was identified despite a normal kappa/lambda light chain ratio and no serum paraprotein. Bone marrow and buccal biopsy provided histological confirmation of amyloid. The bone marrow had no evidence of plasma cell dyscrasia but positive TTR immunohistochemistry. The patient had a T60A genetic mutation for hereditary ATTR. Overlapping cardiac and autonomic symptoms prompt an amyloid workup, which then must distinguish AL amyloid from ATTR pathology.

Efficacy and Contextual (Placebo) Effects of CGRP Antibodies for Migraine: Systematic Review and Meta-analysis.

BACKGROUND: CGRP Antibodies are high-cost newly licensed migraine preventatives. OBJECTIVE: To calculate the overall reduction in monthly migraine days and the proportion contextual effect (PCE) using meta-analysis. The PCE is the ratio between the reduction in Monthly Migraine Days in the placebo group and the reduction in Monthly Migraine Days in the CGRP-Ab group after 3 months of treatment. METHODS: Meta-analysis of randomized double-blind placebo-controlled trials of anti-CGRP antibodies in people with episodic migraine (EM) or chronic migraine (CM) in persons aged 18 or over. Non-randomized trials and trials in persons under 18 years excluded. Search of National Clinical Trials Register 2000-2019, MEDLINE to September 2019, Hand search of major headache conference abstract books 2012-2019. Two investigators used standard proforma to reach consensus. Trial quality assessed using Cochrane Collaboration risk of bias tool. PRISMA guidelines followed. RESULTS: 21 completed trials with 13367 participants (8075 EM, 5292 CM). Compared to placebo, pooled reduction in MMD was 1.50 days in 15 EM trials (95%CI 1.16, 1.84; I2  = 69%, Phetereogeneity  < .001) and 2.24 days in 7 CM trials (95%CI 1.82, 2.65, I2  = 15%, Phetereogeneity  = .320). In EM trials, pooled PCE was 0.66 (95%CI 0.59,0.75; I2  = 64%, Phetereogeneity  = .001). In CM trials the PCE was .68 (95%CI 0.61, 0.75; I2  = 20%, Phetereogeneity  = .280). Industry funded every study, but risk of bias was low. CONCLUSIONS: CGRPAbs are effective but sixty-six percent of the benefit is from contextual effects, including placebo effect. Contextual effects merit further scrutiny as a means of improving migraine headache.

CD138 mediates selection of mature plasma cells by regulating their survival.

Antibody secreting cells (ASCs) are critical effector cells and long-lived sentinels for immune memory. ASCs are highly dependent on exogenous soluble factors such as interleukin-6 (IL-6) and APRIL, to prevent their cell death. We have found that the canonical surface marker of ASCs, CD138 (syndecan-1), which is upregulated during ASC maturation, is required in a cell-intrinsic manner to mount an effective long-term humoral immune response following immunization. Surface expression of CD138 increased heparan sulfate levels on ASCs, which are known to bind pro-survival cytokines, leading to increased survival in a cell-intrinsic manner in vivo. In IL-6 and APRIL-deficient hosts, ASCs underwent extensive apoptosis independently of CD138 expression. We propose a model in which CD138 expression on fully mature ASCs provides a selective survival advantage over less mature, newly minted ASCs, by enhancing pro-survival cytokine signaling.

Impact of a telephone-first consultation system in general practice.

PURPOSE OF THE STUDY: Increasing pressure on general practice prompts innovative change in service organisation. This study sought to evaluate the impact of introducing a telephone-first consultation system in a socioeconomically deprived population. STUDY DESIGN: An interrupted time series of preplanned outcomes for 2 years before and 1 year postintroduction of a telephone-first system was used to measure the volume and type of general practitioner (GP) consultations and the number of patients consulted per year. Emergency department (ED) and GP out-of-hours attendances, the number of outpatient referrals, and the number of requests for laboratory tests were measured as secondary outcomes. RESULTS: The telephone-first system was associated with a 20% increase in total GP consultations (telephone and face-to-face, effect estimate at 12 months, p=0.001). Face-to-face consultations decreased by 39% (p<0.001), while telephone consultations increased by 131% (p<0.001). The volume of individual patient requests for a GP consultation and the number of treatment room nurse consultations did not change. Secondary outcome measures showed no change in hospital outpatient referrals, number of requests for laboratory tests, and ED or GP out-of-hours attendances. CONCLUSIONS: A telephone-first system in a deprived urban general practice can decrease delays to GP-patient contacts. The number of patients seeking a medical intervention did not differ irrespective of the consultation system used. The telephone-first system did not affect GP out-of-hours, laboratory investigations or secondary care contacts.

Radiological Eye Deviation as a Predictor of Large Vessel Occlusion in Acute Ischaemic Stroke.

BACKGROUND: Detection of large vessel occlusion (LVO) is required for endovascular therapy in acute ischemic stroke (AIS) but CT angiography (CTA) is not always performed at primary stroke centers. Eye deviation on CT brain has been associated with improved stroke detection, but comparisons with angiographic status have been limited. This study sought to determine if radiological eye deviation was associated with LVO. METHODS: All AIS patients given intravenous thrombolysis who had acute CTA performed in 2 stroke units were reviewed over 2013-2015 for the presence of LVO. Eye deviation was determined by 2 clinicians blinded to LVO status. Logistic regression was performed to determine which factors predicated LVO. RESULTS: Total 195 AIS patients with acute CTA were identified; 124 (64%) had LVO. Median age was 72 (IQR 64-82) years, median National Institutes of Health Stroke Scale (NIHSS) was 12 (IQR 7-14). LVO patients had a higher NIHSS (15 versus 7, p < .01) and were more likely to have eye deviation on CT brain (71% versus 22.5%, p < .01). Logistic regression confirmed NIHSS score and eye deviation were associated with LVO, with odds ratios of 1.15 (per point) and 5.13 respectively. NIHSS less than equal to 11 gave greatest sensitivity (78.5%) and specificity (76.1%) for LVO with a positive predictive value of 84.7%. Eye deviation was similar with sensitivity 71%, specificity 77.5%, and 84.6%. CONCLUSIONS: Eye deviation on CT brain is strongly associated with LVO. Presence of eye deviation on CT should alert clinicians to probability of LVO and for formal angiographic testing if not already performed.

Infratentorial superficial siderosis: Classification, diagnostic criteria, and rational investigation pathway.

Central nervous system infratentorial superficial siderosis (iSS) is increasingly detected by blood-sensitive magnetic resonance imaging (MRI) sequences. Despite this, there are no standardized diagnostic criteria, and the clinical-radiological spectrum, causes, and optimum investigation strategy are not established. We reviewed clinical and radiological details of patients with iSS assessed at a specialist neurological center during 2004-2016 using predefined standardized radiological criteria. All imaging findings were rated blinded to clinical details. We identified 65 patients with iSS, whom we classified into 2 groups: type 1 (classical) and type 2 (secondary) iSS. Type 1 (classical) iSS included 48 patients without any potentially causal radiologically confirmed single spontaneous or traumatic intracranial hemorrhage, of whom 39 (83%) had hearing loss, ataxia, or myelopathy; type 2 (secondary) iSS included 17 patients with a potentially causal radiologically confirmed spontaneous or traumatic intracranial hemorrhage, of whom none had hearing loss, ataxia, or myelopathy. Of the patients with type 1 (classical) iSS, 40 (83%) had a potentially causal cranial or spinal dural abnormality, 5 (11%) had an alternative cause, and 3 (6%) had no cause identified. Intra-arterial digital subtraction angiography did not identify any underlying causal lesions for type 1 iSS. Type 1 (classical) iSS, defined using simple radiological criteria, is associated with a characteristic neurological syndrome. Rational investigation, including spinal MRI, nearly always reveals a potential cause, most often a dural abnormality. Catheter angiography appears to be unhelpful, suggesting that classical iSS is not associated with macrovascular arterial pathology. Recognition of type 1 (classical) iSS should allow timely diagnosis and early consideration of treatment. Ann Neurol 2017;81:333-343.

Hypoactive-hypoalert behaviour and thalamic hypometabolism due to intracranial hypotension.

A 47-year-old man presented with a 9-year history of a hypoalert hypoactive behaviour syndrome, caused by the deep brain swelling variant of spontaneous intracranial hypotension. Along with apathy with retained cognition, he had stable ataxia, impaired upgaze and episodes of central apnoea. MRI brain showed a sagging brainstem, pointed ventricles and reduced angle between the vein of Galen and the straight sinus, but no meningeal enhancement or subdural collections. A dopamine transporter scan showed preganglionic dopamine receptor deficiency; a fluorodeoxy glucose positron emission tomography scan showed bilateral hypothalamic hypometabolism. This variant of spontaneous intracranial hypotension may alter deep brain functioning within the basal ganglia and thalamus, causing the hypoactive-hypoalert behaviour phenotype.

Primary care perceptions of neurology and neurology services.

BACKGROUND: Neurophobia (fear of neural sciences) and evaluation of independent sector contracts in neurology have seldom been examined among general practitioners (GPs). METHODS: A questionnaire determined GPs' perceptions of neurology compared with other medical specialties. GP experiences of neurology services with independent sector companies and the local National Health Service (NHS) were compared. Areas of potential improvement in NHS neurology services were recorded from thematic analyses. RESULTS: Among 76 GPs neurology was perceived to be as interesting as other medical specialties. GPs reported less knowledge, more difficulty and less confidence in neurology compared with other medical specialties. There was a preference for a local NHS neurology service (p<0.001), which was easier to contact (p<0.001) and provided better follow-up. GPs reported that local neurology services provided better patient satisfaction. CONCLUSIONS: GPs prefer local NHS neurology services to independent sector contracts. GPs' evaluations should inform commissioning of neurology services. Combating neurophobia should be an integral part of responsive commissioning.

Stroke Laterality Bias in the Management of Acute Ischemic Stroke.

BACKGROUND: Little is known of the impact of stroke laterality on the management process and outcome of patients with acute ischemic stroke (AIS). METHODS: Consecutive patients admitted to a general hospital over 1 year with supratentorial AIS were eligible for inclusion in the study. Baseline characteristics and risk factors, delays in hospital admission, imaging, intrahospital transfer to an acute stoke unit, stroke severity and classification, length of hospital admission, as well as 10-year mortality were measured and compared among right and left hemisphere AIS patients. RESULTS: There were 141 patients (77 men, 64 women; median age 73 [interquartile range 63-79] years), There were 71 patients with left hemisphere AIS and 70 with right hemisphere AIS. Delays to hospital admission from stroke onset to neuroimaging were similar among right and left hemisphere AIS patients. Delay in transfer to an acute stroke unit (ASU) following hospital admission was on average 14 hours more for right hemisphere compared to left hemisphere AIS patients (P = .01). Laterality was not associated with any difference in 10-year survival. CONCLUSIONS: Patients with mild and nondominant AIS merit particular attention to minimize their intrahospital transfer time to an ASU.

Idiopathic Intracranial Hypertension in the Northwest of Northern Ireland: Epidemiology and Clinical Management.

BACKGROUND: There is limited literature on the epidemiology of idiopathic intracranial hypertension (IIH). The diagnosis and management of IIH require a multidisciplinary approach. We sought to study the incidence as well as prevalence of IIH and to evaluate the current management of IIH in the northwest of Northern Ireland. METHODS: Medical records of patients diagnosed with IIH between 2007 and 2014 in a general hospital in Northern Ireland were reviewed. Clinical and outcome data were retrieved. RESULTS: There were 45 patients with IIH, 44 women: 1 man. The mean age at presentation was 29.4 (SD 9.8) years and mean body mass index (BMI) 39.8 (SD 9.5) kg/ m(2). All patients had neuroimaging, 44 (98%) had CT/MR venogram and 41 (91%) had visual perimetry. The crude incidence of IIH was 2.36 per 100,000 (95% CI 1.65-3.37). For women, the incidence was 4.65 per 100,000/year (95% CI 3.25-6.66). The prevalence was 14.3 per 100,000 overall (95% CI 9.72-20.9) but 28.1 per 100,000 in women (95% CI 19.2-41.2). Visual field defects were identified in 25 of 41 (61%); 4 patients (9%) required shunting procedures. At follow-up, the mean BMI decreased by 1.6 kg/m(2) (p = 0.024). CONCLUSIONS: The incidence of IIH in the northwest of Northern Ireland is among the highest ever reported and probably reflects the known increase in obesity.

Clinical and diagnostic findings in patients with elevated cerebrospinal bilirubin.

INTRODUCTION: Cerebrospinal fluid (CSF) spectroscopy can identify subarachnoid haemorrhage (SAH) when CT is negative in patients presenting with acute severe headache. The primary objective of this study was to evaluate the clinical use and usefulness of CSF spectrophotometry. Secondary objectives were to identify other causes of elevated CSF bilirubin, to analyse headache descriptions and to compare clinical features in patients with an elevated CSF bilirubin among those with and without an intracranial vascular cause of SAH (avSAH). METHODS: Consecutive patients admitted to two hospitals in Enniskillen and Londonderry between 1 January 2004 and 30 September 2014 with CSF spectroscopy bilirubin results were identified from a clinical chemistry laboratory dataset. Patients with elevated CSF bilirubin were studied. Clinical demographics, delays to investigation and final diagnoses were recorded. Patients with avSAH were compared with patients without avSAH. RESULTS: Among 1813 patients with CSF spectrophotometry results, requests increased more than threefold during the study (p<0.001). Fifty-six patients had elevated CSF bilirubin. Ten (17.9%) had avSAH, of which 8 (14.3%) had aneurysmal SAH. Non-vascular causes of elevated CSF bilirubin included meningitis, spontaneous intracranial hypotension and carcinomatous meningitis. Headache descriptions varied. Time from headache onset to admission, CT scan and lumbar puncture did not differ significantly for patients with avSAH and non-avSAH. CSF red cell counts were higher among patients with avSAH than patients with non-avSAH (p=0.005). CONCLUSIONS: CSF bilirubin measurement has an important role in identifying avSAH in CT-negative patients presenting with a thunderclap headache. Better clinical selection of patients is required as CSF spectrophotometry, although sensitive, is not specific for SAH.

An unusual cause of hemifacial spasm.

Hemifacial spasm is not an infrequent presentation and a vascular loop is commonly implicated. Cerebellopontine angle (CPA) lesions are uncommon but can be excluded with appropriate imaging. There have been only around 150 case reports of CPA lipoma; hemifacial spasm has been associated only in eight cases. We present an additional case and discuss the literature and management.

A quality improvement programme with a specialist nurse in a neurovascular clinic.

AIMS AND OBJECTIVES: To measure the impact of a quality improvement programme with a stroke specialist nurse and increased capacity at neurovascular clinics. BACKGROUND: Transient ischaemic attack and minor stroke are medical emergencies prompting urgent assessment and treatment. Delays in specialist assessment and management are frequent and may increase stroke risk. DESIGN: Pre- and post evaluation of intervention. METHODS: All patients referred to a neurovascular clinic were recorded during two phases: 2006-2008 and 2010-2012. For the 2010-2012 period, a stroke specialist nurse contacted all patients with appointment details, provided driving advice and asked for an eyewitness to attend the clinic. Diagnosis, delay in specialist assessment, prevalence of transient ischaemic attack/minor stroke as confirmed at the clinic and compliance with UK driving regulations were measured and compared before and after this intervention. RESULTS: A total of 1327 patients were assessed in the two study phases. Referrals to the neurovascular service increased without a decrease in the prevalence of transient ischaemic attack/minor stroke. Delays from clinical event to assessment were decreased for referrals from 36·5-13 days, and adherence to the UK driving restrictions improved for confirmed transient ischaemic attack/minor stroke patients from 61-94%. Fewer patients failed to attend a neurovascular appointment arranged by the stroke specialist nurse than those who failed a general neurology appointment arranged by partial booking. CONCLUSIONS: This quality improvement programme reduced delays for all referred patients, improved compliance with driving regulations and demonstrated efficient use of neurovascular clinic spaces. Increasing local capacity may unmask more transient ischaemic attack/minor stroke patients. RELEVANCE TO CLINICAL PRACTICE: A stroke nurse can help improve the efficiency of a neurovascular clinic and improve patient safety with driving advice.

Two different presentations, one diagnosis.

Acute confusion and hyponatraemia are common presentations in acute medicine. We report two cases of anti-voltage gated potassium channel (VGKC) antibody-related limbic encephalitis highlighting the variable presentation of this condition. Both patients were thoroughly investigated with MRI scan of brain, lumbar puncture, EEG as well as infective and autoimmune screens for encephalitis. Anti-VGKC antibodies were positive for both patients and prompt treatment with immunotherapy yielded good recovery. Patients presenting with confusion and seizures who have no demonstrable infectious or metabolic cause should have investigation for an autoimmune cause expedited. In addition, psychiatric presentations with atypical features such as drowsiness should prompt similar investigations. The outcome of anti-VGKCrelated limbic encephalitis is improved with early treatment employing steroids or immunotherapy.

Bariatric surgery tourism in the COVID-19 era.

Background: Since the start of the Covid-19 pandemic primary and secondary health care services in Northern Ireland have observed an increase in the number of patients who have had bariatric surgery outside of the UK. This study sought to estimate the frequency of bariatric surgery tourism and to audit indications, blood monitoring and medical complications. Methods: All primary care centres within the Western Health Social Care Trust (WHSCT) were invited to document the number of patients undergoing bariatric surgery between January 1, 2017 and December 31, 2022. For one primary care centre, patients who underwent bariatric surgery were assessed against the National Institute of Health and Clinical Excellence (NICE) guideline indications for bariatric surgery. In addition, the blood monitoring of these patients was audited against the British Obesity and Metabolic Surgery Society (BOMSS) guidelines for up to two years following surgery. Medical contacts for surgical complications of bariatric surgery were recorded. Results: Thirty-five of 47 (74.5%) GP surgeries replied to the survey, representing 239,961 patients among 325,126 registrations (73.8%). In the six year study period 463 patients had reported having bariatric surgery to their GP. Women were more likely to have had bariatric surgery than men (85.1% versus 14.9%). There was a marked increase in the number of patients undergoing bariatric surgery with each year of the study (p<0.0001 chi square for trend). Twenty-one of 47 patients (44.7%) evaluated in one primary care centre fulfilled NICE criteria for bariatric surgery. The level of three-month monitoring ranged from 23% (for vitamin D) to 89% (electrolytes), but decreased at two years to 9% (vitamin D) and 64% (electrolytes and liver function tests). Surgical complication prevalence from wound infections was 19% (9 of 44). Antidepressant medications were prescribed for 23 of 47 patients (48.9%). Conclusions: The WHSCT has experienced a growing population of patients availing of bariatric surgery outside of the National Health Service. In view of this and the projected increase in obesity prevalence, a specialist obesity management service is urgently required in Northern Ireland.

Blockade of B7-H1 (programmed death ligand 1) enhances humoral immunity by positively regulating the generation of T follicular helper cells.

T follicular helper (T(FH)) cells are critical initiators in the development of T cell-dependent humoral immunity and the generation of protective immunity. We demonstrate that T(FH) cell accumulation and Ab production are negatively regulated by B7-H1 (programmed death ligand 1) in response to both helminth infection and active immunization. Following immunization of B7-H1(-/-) mice with keyhole limpet hemocyanin or helminth Ags, there is a profound increase in induction of T(FH) cells as a result of increased cell cycling and decreased apoptosis relative to wild-type mice. The increase in T(FH) cells in the absence of B7-H1 was associated with significant elevations in Ag-specific Ig response. Cotransfer experiments in vivo demonstrated that B7-H1 expression on B cells was required for negatively regulating T(FH) cell expansion and production of Ag-specific Ig. Treatment of immunized wild-type mice with anti-B7-H1 or anti-programmed death 1 mAbs, but not anti-B7-DC, led to a significant expansion of the T(FH) cell population and an enhanced Ag-specific Ig response. Our results demonstrate that the coinhibitory B7-H1/programmed death 1 pathway can limit the expansion of T(FH) cells and constrain Ag-specific Ig responses. This finding has direct implications for investigations examining the feasibility of therapeutically manipulating this pathway and reveals new insights into the regulation of the humoral immune response.

Serum Neurofilaments in Motor Neuron Disease and Their Utility in Differentiating ALS, PMA and PLS.

Neurofilament levels are elevated in many neurodegenerative diseases and have shown promise as diagnostic and prognostic biomarkers in Amyotrophic Lateral Sclerosis (ALS), the most common form of Motor Neuron Disease (MND). This study assesses serum neurofilament light (NFL) and neurofilament heavy (NFH) chain concentrations in patients with ALS, other variants of motor neuron disease such as Progressive Muscular Atrophy (PMA) and Primary Lateral Sclerosis (PLS), and a range of other neurological diseases. It aims to evaluate the use of NFL and NFH to differentiate these conditions and for the prognosis of MND disease progression. NFL and NFH levels were quantified using electrochemiluminescence immunoassays (ECLIA). Both were elevated in 47 patients with MND compared to 34 patients with other neurological diseases and 33 healthy controls. NFL was able to differentiate patients with MND from the other groups with a Receiver Operating Characteristic (ROC) curve area under the curve (AUC) of 0.90 (p < 0.001). NFL correlated with the rate of disease progression in MND (rho 0.758, p < 0.001) and with the ALS Functional Rating Scale (rho -0.335, p = 0.021). NFL levels were higher in patients with ALS compared to both PMA (p = 0.032) and PLS (p = 0.012) and were able to distinguish ALS from both PMA and PLS with a ROC curve AUC of 0.767 (p = 0.005). These findings support the use of serum NFL to help diagnose and differentiate types of MND, in addition to providing prognostic information to patients and their families.

Germinal center expansion but not plasmablast differentiation is proportional to peptide-MHCII density via CD40-CD40L signaling strength.

T follicular helper (TFH) cells promote expansion of germinal center (GC) B cells and plasma cell differentiation. Whether cognate peptide-MHCII (pMHCII) density instructs selection and cell fate decisions in a quantitative manner remains unclear. Using αDEC205-OVA to differentially deliver OVA peptides to GC B cells on the basis of DEC205 allelic copy number, we find DEC205+/+ B cells take up 2-fold more antigen than DEC205+/- cells, leading to proportional TFH cell help and B cell expansion. To validate these results, we establish a caged OVA peptide, which is readily detected by OVA-specific TFH cells after photo-uncaging. In situ uncaging of peptides leads to multiple serial B-T contacts and cell activation. Differential CD40 signaling, is both necessary and sufficient to mediate 2-fold differences in B cell expansion. While plasmablast numbers are increased, pMHCII density does not directly control the output or quality of plasma cells. Thus, we distinguish the roles TFH cells play in expansion versus differentiation.