NIHR Wellcome Trust Southampton Clinical Research Facility

Cirrhosis is a major cause of morbidity and mortality; however, there are no approved therapies except orthotopic liver transplantation. Preclinical studies showed that bone-marrow-derived macrophage injections reduce inflammation, resolve fibrosis and stimulate liver regeneration. In a multicenter, open-label, parallel-group, phase 2 randomized controlled trial (ISRCTN10368050) in n = 51 adult patients with compensated cirrhosis and Model for End-Stage Liver Disease (MELD) score ≥10 and ≤17, we evaluated the efficacy of autologous monocyte-derived macrophage therapy (n = 27) compared to standard medical care (n = 24). The primary endpoint was the difference in baseline to day 90 change in MELD score (ΔMELD) between treatment and control groups (ΔΔMELD). Secondary endpoints included adverse clinical outcomes, non-invasive fibrosis biomarkers and health-related quality of life (HRQoL) at 90 d, 180 d and 360 d. The ΔΔMELD between day 0 and day 90 in the treatment group compared to controls was −0.87 (95% confidence interval: −1.79, 0.0; P = 0.06); therefore, the primary endpoint was not met. During 360-d follow-up, five of 24 participants in the control group developed a total of 10 severe adverse events, four of which were liver related, and three deaths (two liver related), whereas no liver-related severe adverse events or deaths occurred in the treatment group. Although no differences were observed in biomarkers or HRQoL, exploratory analysis showed anti-inflammatory serum cytokine profiles after macrophage infusion. This study reinforces the safety and potential efficacy of macrophage therapy in cirrhosis, supporting further investigation.

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Abstract Blood group antigens are the archetypal example of human genetic variation. Here, we characterised the functional metabolic consequences in individuals homozygous for a 17bp deletion in SMIM1 (rs566629828; minor allele frequency 0.0147) and thus lacking the protein defining the Vel blood group. Our analysis, in separate cohorts of SMIM1-/- individuals (UK Biobank, NHS Blood and Transplant, Danish Blood Donor Study, Copenhagen Hospital Biobank) and a mouse model, identified an increase in body weight accompanied by a range of metabolic differences, including dyslipidemia, changes in the leptin-adiponectin ratio, increased liver enzymes and lower total thyroid hormone levels. These changes in the metabolic state were at least in part due to a reduction in resting energy expenditure, as assessed during an in-depth clinical assessment of SMIM1-/- individuals. Additionally, electronic health records suggest that individuals lacking this 78-amino-acid type II transmembrane protein may be more prone to cerebral bleeds and thrombotic stroke.

To study the phenotype and laterality of cranial autonomic symptoms (CAS) in a cohort of migraineurs, and to understand any associations with headache laterality and frequency.

Damage to small nociceptive fibres may contribute to painful diabetic neuropathy. We aimed to compare large and small nerve fibre measurements together with skin biopsy and corneal confocal microscopy in patients with type 1 diabetes and painful or painless diabetic neuropathy. We have assessed the McGill pain questionnaire, neuropathy disability score, vibration perception threshold, warm and cold sensation thresholds, electrophysiology, corneal confocal microscopy and skin biopsy in participants with type 1 diabetes and painful (n=41) or painless (n=50) diabetic neuropathy and control subjects (n=50). The duration of diabetes, body mass index, glycated haemoglobin (HbA1c), blood pressure and lipid profile did not differ between subjects with painful and painless neuropathy. Neuropathy disability score and vibration perception threshold were higher and sural nerve conduction velocity was lower, but sural nerve amplitude, peroneal nerve amplitude and conduction velocity and cold and warm sensation thresholds did not differ between patients with painful compared to painless diabetic neuropathy. However, intraepidermal nerve fibre density, corneal nerve fibre density, corneal nerve branch density and corneal nerve fibre length were significantly lower in subjects with painful compared to painless diabetic neuropathy. There is evidence of more severe neuropathy, particularly small fibre damage in the skin and cornea, of patients with painful compared to painless diabetic neuropathy.

Here we investigate brain functional connectivity in patients with visual snow syndrome (VSS). Our main objective was to understand more about the underlying pathophysiology of this neurological syndrome. Twenty‐four patients with VSS and an equal number of gender and age‐matched healthy volunteers attended MRI sessions in which whole‐brain maps of functional connectivity were acquired under two conditions: at rest while watching a blank screen and during a visual paradigm consisting of a visual‐snow like stimulus. Eight unilateral seed regions were selected a priori based on previous observations and hypotheses; four seeds were placed in key anatomical areas of the visual pathways and the remaining were derived from a pre‐existing functional analysis. The between‐group analysis showed that patients with VSS had hyper and hypoconnectivity between key visual areas and the rest of the brain, both in the resting state and during a visual stimulation, compared with controls. We found altered connectivity internally within the visual network; between the thalamus/basal ganglia and the lingual gyrus; between the visual motion network and both the default mode and attentional networks. Further, patients with VSS presented decreased connectivity during external sensory input within the salience network, and between V5 and precuneus. Our results suggest that VSS is characterised by a widespread disturbance in the functional connectivity of several brain systems. This dysfunction involves the pre‐cortical and cortical visual pathways, the visual motion network, the attentional networks and finally the salience network; further, it represents evidence of ongoing alterations both at rest and during visual stimulus processing.

Emerging evidence suggests that activation of the complement system is critical in the pathogenesis of the novel coronavirus, SARS-CoV-2, the causative agent of COVID-19-related lung injury. Inhibition of the terminal complement pathway by targeting complement protein 5 (C5) may be an effective therapeutic intervention in CoV-mediated disease.1 Paroxysmal nocturnal haemoglobinuria (PNH) is a rare, acquired haematopoietic stem cell (HSC) disease characterised by intravascular haemolysis, increased thromboembolic risk and bone marrow failure.2 The lack of GPI-linked complement regulators, especially CD55 and CD59, makes PNH erythrocytes exquisitely sensitive to complement activation, which can occur continuously, spontaneously and acutely and lead to devastating complications as a result of uncontrolled intravascular haemolysis. Precipitation of haemolysis, both in untreated patients and in those on anti-complement therapy,3 can be induced by any complement-activating events such as infection, trauma, surgery and pregnancy. Although viral infections have been shown to induce haemolysis by activating complement, there has been no published report of COVID-19 in the context of PNH during the ongoing pandemic, and neither has the added benefit of therapeutic complement inhibition, especially with monoclonal antibodies targeting C5 including eculizumab and ravulizumab, been examined. Here we report the clinical course, degree of intravascular haemolysis and outcomes of COVID-19 in four patients with PNH, two well-established on terminal complement inhibitor and two treatment-naïve PNH patients. Our index patient (patient 1, Table I) presented in mid-March 2020 with symptoms of fever (39·1°C), myalgia, dry cough and anosmia. She had a long-standing history of PNH and her disease activity, symptoms and haemolysis were well controlled on a long-acting C5 inhibitor, ravulizumab,4 and prior to this with a first generation monoclonal antibody, eculizumab.3 She was not hypoxic. SARS-CoV2 infection was confirmed by reverse transcriptase-polymerase chain reaction (RT-PCR) assay. She did not have elevated inflammatory markers and her chest radiology was normal. Interestingly, her haemolytic markers were not significantly elevated, and terminal complement was adequately inhibited, as measured by an undetectable CH50/AH50. Yes Ravulizumab 3300 mg × 8 weekly 6 years Yes Eculizumab 1500 mg × 2 weekly 11 years Subsequently, we identified three additional PNH patients with concurrent presentation with clinical symptoms of COVID-19 and RT-PCR-confirmed COVID-19 (Table I). Two patients naïve to complement inhibitor treatment (patients 3 and 4), both with moderate/large PNH clones accompanied by a degree of haemolysis, required hospitalisation for COVID-19 pneumonia and also showed active signs of inflammation [high C-reactive protein (CRP)] and worsening haemolysis [high lactate dehydrogenase (LDH) compared to baseline], due to uncontrolled complement activation. The clinical course of these two individuals, not on anti-complement therapy but on primary prophylaxis with warfarin, was protracted and needed prolonged hospitalisation, readmission and supplemental oxygen therapy. Patient 2, on a high dose of eculizumab, had a similar presentation to the index patient and was found to be anaemic requiring blood transfusion, but with a clear chest radiograph, normal CRP and normal LDH. It is clear that complement plays a key role and is an integral component of the innate immune response to pathogens and its dysregulation or activation, either due to acquired deficiency of complement regulatory proteins (i.e. PNH) or due to viral infection (i.e. SARS-CoV-2), and can lead to significant tissue damage and importantly thrombosis due to endothelial damage.5 Our patients illustrate the presence of both conditions (PNH and COVID-19) concurrently and the differential response seen in patients already on effective complement inhibition compared to patients not on C5 inhibition. The beneficial effect of complement inhibition in not only controlling the intravascular haemolysis due to PNH, but also dampening the hyperinflammatory lung damage during COVID-19 has been illustrated with our small series. The adverse effect in patients not on C5 inhibitors may be circumstantial, as other known COVID-19 risk factors of mortality and morbidity,6 like older age, comorbidity, high body mass index (BMI) and male gender could have contributed to the worse outcome. SARS-CoV-2 infection,7 like other virus infections such as influenza virus and respiratory syncytial virus, is likely to induce massive complement activation in this ‘vulnerable’ group and can lead to severe life-threatening complications and hospitalisation. Emerging evidence suggests that the activation of the complement system, even in the absence of PNH, is key in the pathogenesis of COVID-19-related lung injury8 and therefore C5 inhibition may be an effective therapeutic strategy in CoV-mediated disease. Trials (SOLID-C19, CORIMUNO19-ECU and ALXN1210-COV-305), are ongoing to test the efficacy of terminal complement inhibition in dampening the progression of complications and improve outcomes in patients with COVID-19·9

To understand the changes in functional connectivity between brain areas of potential importance in migraine during different phases of the attack. Migraine is a symptomatically heterogeneous disorder. Understanding the possible changes in brain function and, therefore, neurobiology during different phases of the migraine attack is important in developing disease biomarkers and advancing therapeutics. Randomized, double-blind, placebo-controlled, multi-visit experimental study. Subjects aged 18-50years with migraine with and without aura (≤22 headache days per month) were recruited from across the UK using advertising, from both population and hospital clinic samples (n=53). Consented subjects were randomized to a 0.5µg/kg/min nitroglycerin infusion or to placebo over 20minutes across different study visits, during the period February 2015-July 2017.* All subjects were exposed to a nitroglycerin infusion at least on 1 occasion at screening.** For those subjects who consented to participate in imaging visits (n=25), structural T1, T2 and FLAIR sequences and resting state blood oxygen level dependant contrast (rsBOLD) time series, using a multiecho EPI sequence, were conducted over 30-40minutes at baseline and rsBOLD during premonitory symptoms and migraine headache on a 3T General Electric MR750 MRI scanner. For the placebo visit, the imaging was conducted at the same times following infusion in the absence of symptoms. Montreal Neurological Institute (MNI) coordinates were used to characterize identified brain areas of connectivity change. Using repeated measures ANOVA models with time (visit number) and trigger substance (nitroglycerin/placebo) as factors, significant positive functional coupling was found between the thalami bilaterally and the right precuneus and cuneus regions during the nitroglycerin-triggered premonitory phase (T=3.23, peak connectivity change at [-6, -68, 40] for left thalamus, P=0.012 and [-4, -68, 40] for right thalamus, P=0.019). The nitroglycerin-triggered premonitory phase was associated with a change in the direction of connectivity from positive to negative between the pons and the limbic lobe (T=3.47, peak connectivity change at [2, 8, 50], P<0.001). The headache phase of the nitroglycerin-triggered migraine attack was associated with ongoing negative functional coupling between the pons and the cingulate and frontal cortices, and positive functional coupling between the pons and the cerebellar tonsils and medulla (T=3.47, peak connectivity change at [-8, -52, -58], P=0.007). Understanding the functional reorganization between subcortical and cortical brain areas in different phases of the migraine attack provides novel insights into the abnormal sensory processing and integration during migraine, as well as functional correlation with clinical symptoms displayed during each phase. [*Correction added on July 22, 2020 after first online publication: This sentence was revised from, "Consented subjects had a 0.5 μg/kg/min nitroglycerin infusion…".] [**Correction added on July 22, 2020 after first online publication: This sentence was revised from, "… at least on 1 occasion at screening."].