Sudden Increases in Listeriosis Rates in England and Wales, 2001 and 2003

The monthly incidence of listeriosis infections in England and Wales had 2 sudden increases during April 2001 (41%) and March 2003 (48%). Although no causative association is demonstrated, these increases correspond to key dates relating to the onset and aftermath of the 2001 foot and mouth disease outbreak in the United Kingdom

Minocycline 200 mg or 400 mg versus placebo for mild Alzheimer's disease: the MADE Phase II, three-arm RCT

Background: Minocycline is an anti-inflammatory drug and protects against the toxic effects of β-amyloid in vitro and in animal models of Alzheimer’s disease. To the best of our knowledge, no randomised placebo-controlled clinical trials in patients with Alzheimer’s disease looking at the efficacy and tolerability of minocycline have been carried out. Objectives: The trial investigated whether or not minocycline was superior to placebo in slowing down the rate of decline in cognitive and functional ability over 2 years. The safety and tolerability of minocycline were also assessed. Design: A Phase II, three-arm, randomised, double-blind, multicentre trial with a semifactorial design. Participants continued on trial treatment for up to 24 months. Setting: Patients were identified from memory services, both within the 32 participating NHS trusts and within the network of memory services supported by the Dementias and Neurodegenerative Diseases Research Network (also known as DeNDRoN). Participants: Patients with standardised Mini Mental State Examination scores of > 23 points and with Alzheimer’s disease assessed by the National Institute on Aging–Alzheimer’s Association’s criteria were identified from memory services. Intervention: Patients with mild Alzheimer’s disease were randomly allocated 1 : 1 : 1 to receive one of three treatments: arm 1 – 400 mg per day of minocycline; arm 2 – 200 mg per day of minocycline; or arm 3 – placebo. Patients continued treatment for 24 months. Participants, investigators and outcome assessors were blind to treatment allocation. Main outcome measures: Primary outcome measures were decline in standardised Mini Mental State Examination and Bristol Activities of Daily Living Scale scores of combined minocycline treatment arms versus placebo, as analysed by intention-to-treat repeated measures regression. Results: Between 23 May 2014 and 14 April 2016, 554 participants were randomised. Of the 544 eligible participants, the mean age was 74.3 years and the average standardised Mini Mental State Examination score was 26.4 points. A total of 252 serious adverse events were reported, with the most common categories being neuropsychiatric and cardiocirculatory. Significantly fewer participants completed treatment with 400 mg of minocycline [29% (53/184)] than 200 mg [62% (112/181)] or placebo [64% (114/179)] (p < 0.0001), mainly because of gastrointestinal symptoms (p = 0.0008), dermatological side effects (p = 0.02) and dizziness (p = 0.01). Assessment rates were also lower in the 400-mg treatment arm: 68% (119 of 174 expected) for standardised Mini Mental State Examination scores at 24 months, compared with 82% (144/176) for the 200-mg treatment arm and 84% (140/167) for the placebo arm. Decline in standardised Mini Mental State Examination scores over the 24-month study period in the combined minocycline arms was similar to that in the placebo arm (4.1- vs. 4.3-point reduction; p = 0.9), as was the decline in the 400- and 200-mg treatment arms (3.3 vs. 4.7 points; p = 0.08). Likewise, worsening of Bristol Activities of Daily Living Scale scores over 24 months was similar in all trial arms (5.7, 6.6 and 6.2 points in the 400-mg treatment arm, 200-mg treatment arm and placebo arm, respectively; a p-value of 0.57 for minocycline vs. placebo and a p-value of 0.77 for 400 vs. 200 mg of minocycline). Results were similar in different patient subgroups and in sensitivity analyses adjusting for missing data. Limitations: Potential limitations of the study include that biomarkers were not used to confirm the diagnosis of Alzheimer’s disease, as these and apolipoprotein E (APOE) genotyping are not routinely available within the NHS. Compliance was also worse than expected and differential follow-up rates were observed, with fewer assessments obtained for the 400-mg treatment arm than for the 200-mg treatment and placebo arms. Conclusions: Minocycline does not delay the progress of cognitive or functional impairment in people with mild Alzheimer’s disease over a 2-year period. Minocycline at a dose of 400 mg is poorly tolerated in this population. Future work: The Minocycline in mild Alzheimer’s DiseasE (MADE) study provides a framework for a streamlined trial design that can be usefully applied to test other disease-modifying therapies

Cost-effectiveness analyses for mirtazapine and sertraline in dementia: randomised controlled trial

BACKGROUND Depression is a common and costly comorbidity in dementia. There are very few data on the cost-effectiveness of antidepressants for depression in dementia and their effects on carer outcomes. AIMS To evaluate the cost-effectiveness of sertraline and mirtazapine compared with placebo for depression in dementia. METHOD A pragmatic, multicentre, randomised placebo-controlled trial with a parallel cost-effectiveness analysis (trial registration: ISRCTN88882979 and EudraCT 2006-000105-38). The primary cost-effectiveness analysis compared differences in treatment costs for patients receiving sertraline, mirtazapine or placebo with differences in effectiveness measured by the primary outcome, total Cornell Scale for Depression in Dementia (CSDD) score, over two time periods: 0-13 weeks and 0-39 weeks. The secondary evaluation was a cost-utility analysis using quality-adjusted life years (QALYs) computed from the Euro-Qual (EQ-5D) and societal weights over those same periods. RESULTS There were 339 participants randomised and 326 with costs data (111 placebo, 107 sertraline, 108 mirtazapine). For the primary outcome, decrease in depression, mirtazapine and sertraline were not cost-effective compared with placebo. However, examining secondary outcomes, the time spent by unpaid carers caring for participants in the mirtazapine group was almost half that for patients receiving placebo (6.74 v. 12.27 hours per week) or sertraline (6.74 v. 12.32 hours per week). Informal care costs over 39 weeks were £1510 and £1522 less for the mirtazapine group compared with placebo and sertraline respectively. CONCLUSIONS In terms of reducing depression, mirtazapine and sertraline were not cost-effective for treating depression in dementia. However, mirtazapine does appear likely to have been cost-effective if costing includes the impact on unpaid carers and with quality of life included in the outcome. Unpaid (family) carer costs were lower with mirtazapine than sertraline or placebo. This may have been mediated via the putative ability of mirtazapine to ameliorate sleep disturbances and anxiety. Given the priority and the potential value of supporting family carers of people with dementia, further research is warranted to investigate the potential of mirtazapine to help with behavioural and psychological symptoms in dementia and in supporting carers

Inositol trisphosphate receptor-mediated Ca 2+ signalling stimulates mitochondrial function and gene expression in core myopathy patients

Core myopathies are a group of childhood muscle disorders caused by mutations of the ryanodine receptor (RyR1), the Ca2+ release channel of the sarcoplasmic reticulum. These mutations have previously been associated with elevated inositol trisphosphate receptor (IP3R) levels in skeletal muscle myotubes derived from patients. However, the functional relevance and the relationship of IP3R mediated Ca2+ signalling with the pathophysiology of the disease is unclear. It has also been suggested that mitochondrial dysfunction underlies the development of central and diffuse multi-mini-cores, devoid of mitochondrial activity, which is a key pathological consequence of RyR1 mutations. Here we used muscle biopsies of central core and multi-minicore disease patients with RyR1 mutations, as well as cellular and in vivo mouse models of the disease to characterize global cellular and mitochondrial Ca2+ signalling, mitochondrial function and gene expression associated with the disease. We show that RyR1 mutations that lead to the depletion of the channel are associated with increased IP3-mediated nuclear and mitochondrial Ca2+ signals and increased mitochondrial activity. Moreover, western blot and microarray analysis indicated enhanced mitochondrial biogenesis at the transcriptional and protein levels and was reflected in increased mitochondrial DNA content. The phenotype was recapitulated by RYR1 silencing in mouse cellular myotube models. Altogether, these data indicate that remodelling of skeletal muscle Ca2+ signalling following loss of functional RyR1 mediates bioenergetic adaptation

The mitochondrial calcium uniporter regulates breast cancer progression via HIF-1\u3b1

Triple-negative breast cancer (TNBC) represents the most aggressive breast tumor subtype. However, the molecular determinants responsible for the metastatic TNBC phenotype are only partially understood. We here show that expression of the mitochondrial calcium uniporter (MCU), the selective channel responsible for mitochondrial Ca(2+) uptake, correlates with tumor size and lymph node infiltration, suggesting that mitochondrial Ca(2+) uptake might be instrumental for tumor growth and metastatic formation. Accordingly, MCU downregulation hampered cell motility and invasiveness and reduced tumor growth, lymph node infiltration, and lung metastasis in TNBC xenografts. In MCU-silenced cells, production of mitochondrial reactive oxygen species (mROS) is blunted and expression of the hypoxia-inducible factor-1α (HIF-1α) is reduced, suggesting a signaling role for mROS and HIF-1α, downstream of mitochondrial Ca(2+) Finally, in breast cancer mRNA samples, a positive correlation of MCU expression with HIF-1α signaling route is present. Our results indicate that MCU plays a central role in TNBC growth and metastasis formation and suggest that mitochondrial Ca(2+) uptake is a potential novel therapeutic target for clinical intervention

Cost-effectiveness of donepezil and memantine in moderate to severe Alzheimer's disease (the DOMINO-AD trial).

OBJECTIVE: Most investigations of pharmacotherapy for treating Alzheimer's disease focus on patients with mild-to-moderate symptoms, with little evidence to guide clinical decisions when symptoms become severe. We examined whether continuing donepezil, or commencing memantine, is cost-effective for community-dwelling, moderate-to-severe Alzheimer's disease patients. METHODS: Cost-effectiveness analysis was based on a 52-week, multicentre, double-blind, placebo-controlled, factorial clinical trial. A total of 295 community-dwelling patients with moderate/severe Alzheimer's disease, already treated with donepezil, were randomised to: (i) continue donepezil; (ii) discontinue donepezil; (iii) discontinue donepezil and start memantine; or (iv) continue donepezil and start memantine. RESULTS: Continuing donepezil for 52 weeks was more cost-effective than discontinuation, considering cognition, activities of daily living and health-related quality of life. Starting memantine was more cost-effective than donepezil discontinuation. Donepezil-memantine combined is not more cost-effective than donepezil alone. CONCLUSIONS: Robust evidence is now available to inform clinical decisions and commissioning strategies so as to improve patients' lives whilst making efficient use of available resources. Clinical guidelines for treating moderate/severe Alzheimer's disease, such as those issued by NICE in England and Wales, should be revisited. © 2016 The Authors. International Journal of Geriatric Psychiatry published by John Wiley & Sons Ltd

Oncolytic reovirus as a combined antiviral and anti-tumour agent for the treatment of liver cancer

Objective: Oncolytic viruses (OVs) represent promising, proinflammatory cancer treatments. Here, we explored whether OV-induced innate immune responses could simultaneously inhibit HCV while suppressing hepatocellular carcinoma (HCC). Furthermore, we extended this exemplar to other models of virus-associated cancer. Design and results: Clinical grade oncolytic orthoreovirus (Reo) elicited innate immune activation within primary human liver tissue in the absence of cytotoxicity and independently of viral genome replication. As well as achieving therapy in preclinical models of HCC through the activation of innate degranulating immune cells, Reo-induced cytokine responses efficiently suppressed HCV replication both in vitro and in vivo. Furthermore, Reo-induced innate responses were also effective against models of HBV-associated HCC, as well as an alternative endogenous model of Epstein–Barr virus-associated lymphoma. Interestingly, Reo appeared superior to the majority of OVs in its ability to elicit innate inflammatory responses from primary liver tissue. Conclusions: We propose that Reo and other select proinflammatory OV may be used in the treatment of multiple cancers associated with oncogenic virus infections, simultaneously reducing both virus-associated oncogenic drive and tumour burden. In the case of HCV-associated HCC (HCV-HCC), Reo should be considered as an alternative agent to supplement and support current HCV-HCC therapies, particularly in those countries where access to new HCV antiviral treatments may be limited

A pragmatic, multicentre, double-blind, placebo-controlled randomised trial to assess the safety, clinical and cost-effectiveness of mirtazapine and carbamazepine in people with Alzheimer’s disease and agitated behaviours: the HTA-SYMBAD trial

Background Agitation is common and impacts negatively on people with dementia and carers. Non-drug patient-centred care is first-line treatment, but we need other treatment when this fails. Current evidence is sparse on safer and effective alternatives to antipsychotics. Objectives To assess clinical and cost-effectiveness and safety of mirtazapine and carbamazepine in treating agitation in dementia. Design Pragmatic, phase III, multicentre, double-blind, superiority, randomised, placebo-controlled trial of the clinical effectiveness of mirtazapine over 12 weeks (carbamazepine arm discontinued). Setting Twenty-six UK secondary care centres. Participants Eligibility: probable or possible Alzheimer’s disease, agitation unresponsive to non-drug treatment, Cohen-Mansfield Agitation Inventory score ≥ 45. Interventions Mirtazapine (target 45 mg), carbamazepine (target 300 mg) and placebo. Outcome measures Primary: Cohen-Mansfield Agitation Inventory score 12 weeks post randomisation. Main economic outcome evaluation: incremental cost per six-point difference in Cohen-Mansfield Agitation Inventory score at 12 weeks, from health and social care system perspective. Data from participants and informants at baseline, 6 and 12 weeks. Long-term follow-up Cohen-Mansfield Agitation Inventory data collected by telephone from informants at 6 and 12 months. Randomisation and blinding Participants allocated 1 : 1 : 1 ratio (to discontinuation of the carbamazepine arm, 1 : 1 thereafter) to receive placebo or carbamazepine or mirtazapine, with treatment as usual. Random allocation was block stratified by centre and residence type with random block lengths of three or six (after discontinuation of carbamazepine, two or four). Double-blind, with drug and placebo identically encapsulated. Referring clinicians, participants, trial management team and research workers who did assessments were masked to group allocation. Results Two hundred and forty-four participants recruited and randomised (102 mirtazapine, 102 placebo, 40 carbamazepine). The carbamazepine arm was discontinued due to slow overall recruitment; carbamazepine/placebo analyses are therefore statistically underpowered and not detailed in the abstract. Mean difference placebo-mirtazapine (−1.74, 95% confidence interval −7.17 to 3.69; p = 0.53). Harms: The number of controls with adverse events (65/102, 64%) was similar to the mirtazapine group (67/102, 66%). However, there were more deaths in the mirtazapine group (n = 7) by week 16 than in the control group (n = 1). Post hoc analysis suggests this was of marginal statistical significance (p = 0.065); this difference did not persist at 6- and 12-month assessments. At 12 weeks, the costs of unpaid care by the dyadic carer were significantly higher in the mirtazapine than placebo group [difference: £1120 (95% confidence interval £56 to £2184)]. In the cost-effectiveness analyses, mean raw and adjusted outcome scores and costs of the complete cases samples showed no differences between groups. Limitations Our study has four important potential limitations: (1) we dropped the proposed carbamazepine group; (2) the trial was not powered to investigate a mortality difference between the groups; (3) recruitment beyond February 2020, was constrained by the COVID-19 pandemic; and (4) generalisability is limited by recruitment of participants from old-age psychiatry services and care homes. Conclusions The data suggest mirtazapine is not clinically or cost-effective (compared to placebo) for agitation in dementia. There is little reason to recommend mirtazapine for people with dementia with agitation. Future work Effective and cost-effective management strategies for agitation in dementia are needed where non-pharmacological approaches are unsuccessful. Study registration This trial is registered as ISRCTN17411897/NCT03031184. Funding This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 27, No. 23. See the NIHR Journals Library website for further project information. Plain language summary It is common for people with Alzheimer’s disease to experience agitation, for example feeling restless or unsettled. If left untreated, agitation can lead to poorer quality of life and increased hospitalisation and strain for family carers. Often these symptoms are treated with medications that are usually used to manage psychosis (antipsychotic drugs), but such medication has limited effectiveness and can cause serious adverse effects to patients, including risk of increased death. Two medications that are already commonly prescribed for other health issues, mirtazapine (an antidepressant) and carbamazepine (a drug used to treat epilepsy), had been identified as a possible alternative way of treating agitation in Alzheimer’s disease that might not have the harms associated with antipsychotic medication. In this study, we compared the effects of giving mirtazapine or carbamazepine with a dummy drug (placebo) in people with Alzheimer’s disease who were experiencing agitation. The results of the study showed that neither medication was any more effective than the placebo in reducing agitation over 12 weeks in terms of improving symptoms, or in economic terms. Mirtazapine may lead to additional carer costs as compared to placebo. The study findings are stronger for mirtazapine than carbamazepine because the carbamazepine arm was stopped when it had recruited less than half the numbers needed. That was done because the study was not recruiting quickly enough to support both the mirtazapine and the carbamazepine arms. The findings from this study show that mirtazapine should not be recommended to treat agitation in Alzheimer’s disease. More work is needed to formulate effective ways and to test new drug and non-drug treatments for agitation in dementia. Scientific summary Background Agitation is common in people with dementia and impacts negatively on the quality of life of both people with dementia and carers. Non-drug patient-centred care is the first-line treatment, but there is a need for other treatment when this fails. Current evidence is sparse on safer and effective alternatives to antipsychotics. We assessed efficacy and safety of mirtazapine (an antidepressant) and carbamazepine (an anticonvulsant) prescribed for agitation in dementia. Aim To assess the safety, clinical and cost-effectiveness of mirtazapine and carbamazepine in the treatment of agitation in dementia. Primary objectives To determine if mirtazapine is more clinically effective in reducing agitated behaviours in dementia than placebo, measured by Cohen-Mansfield Agitation Inventory (CMAI) score 12 weeks post randomisation. To determine if carbamazepine is more clinically effective in reducing agitated behaviours in dementia than placebo measured by CMAI score 12 weeks post randomisation. Methods Design Pragmatic, phase III, multicentre, double-blind, superiority, randomised, placebo-controlled trial of the clinical effectiveness of mirtazapine and carbamazepine over 12 weeks. Intervention (1) Mirtazapine, (2) carbamazepine and (3) placebo. Target dose: 45 mg of mirtazapine or 300 mg of carbamazepine. Inclusion and exclusion criteria Patients were eligible if the following criteria were met: a clinical diagnosis of probable or possible Alzheimer’s disease a diagnosis of co-existing agitated behaviours evidence that the agitated behaviours have not responded to management an assessment of CMAI (Long Form) score of 45 or greater written informed consent to enter and be randomised into the trial availability of a suitable informant. Exclusion criteria included: current treatment with antidepressants [including Monoamine Oxidase Inhibitors (MAOIs)], anticonvulsants or antipsychotics contraindications to the administration of mirtazapine or carbamazepine patients with second-degree atrioventricular block patients with a history of bone marrow depression or history of hepatic porphyrias cases too critical for randomisation (i.e. where there is a suicide risk or where the patient presents a risk of harm to others) female subjects under the age of 55 years of childbearing potential. Setting Participants were drawn from existing patients and new patient referrals to old age psychiatric services, memory clinics, specific Participant Identification Centres, primary care centres and those in care homes in 26 UK sites. Consent Capacity to consent was assessed before proceeding with the consent process and included consideration of the provision of assent by the patient and consent on their behalf by their legal representative. If the patient had capacity to consent, the carer consented to the provision of information on data for measures on the patient (e.g. CMAI) and also on themselves in terms of impact. Randomisation and blinding Participants were allocated in a 1 : 1 : 1 ratio (up to the discontinuation of the carbamazepine arm and 1 : 1 thereafter) to receive placebo or carbamazepine or mirtazapine, together with treatment as usual. Random allocation was block stratified by centre and type of residence (care home vs. own household) with random block lengths of three or six up to the discontinuation of the carbamazepine arm and thereafter of two or four. The trial was double-blind, with drug and placebo identically encapsulated. Referring clinicians, participants, the trial management team and the research workers who did baseline and follow-up assessments were masked to group allocation. Outcomes Primary outcome CMAI score (Long Form) at 12 weeks. Secondary outcomes Costs derived from Client Service Receipt Inventory, and quality-adjusted life-years from cost data alongside supplemented information from Dementia-Specific Quality of Life and EuroQol-5 Dimensions, five-level version interviews 12 weeks post randomisation. CMAI score and cost at 6 weeks post randomisation. Patient and carer quality of life, and carer outcomes at 6 and 12 weeks post randomisation. Adverse events from week 0 to week 16 and adherence at 6 and 12 weeks post randomisation. CMAI score, adverse events and adherence at 6 and 12 weeks, conditional on evidence of effectiveness of Investigational Medicinal Product over placebo. Longer-term follow-up: CMAI score, institutionalisation, death and clinical management at 26 and 52 weeks post randomisation. Sample size and statistical analysis An initial calculated sample size of 400 (randomised 1 : 1 : 1) provided 90% power using two-sided 5% significance tests to detect a drug versus placebo mean difference in CMAI score at 12 weeks of 6 points. This equated to an effect size of d = 0.4 (assuming a common standard deviation of 15) or a clinically significant 30% decrease in CMAI from placebo to active drug. With a realistic 15% attrition, a sample of 471 (157 per arm) was aimed for. Mid-trial, with the discontinuation of the carbamazepine arm, the sample size calculation was revisited with emerging data and it was adjusted so that the aim (excluding those randomised to carbamazepine) was for an overall sample of 222 (randomised 1 : 1) to provide 80% power using two-sided 5% significance tests to detect a mirtazapine versus placebo mean difference in CMAI score at 12 weeks of six points, assuming attrition of no more than 10%. Analyses were based on intention-to-treat (all participants were analysed according to the group to which they were randomised, irrespective of the treatment or dose received). The primary outcome (CMAI at 12 weeks) was analysed using a general linear regression model including baseline CMAI score as a covariate. General linear regression models were created for secondary outcomes. Economic evaluation The primary outcome for the economic evaluation was the incremental cost per six-point difference in CMAI score at 12 weeks, from a health and social care system perspective. Patient and public involvement Ensuring the involvement of people living with dementia and their family carers was integral to the Study of Mirtazapine for Agitated Behaviours in Dementia (SYMBAD) trial from the application for funding and trial design stage through to its conduct, analysis and communication. SN was a co-applicant and led on public/carer involvement in the trial throughout, and she was supported by a Lived Experience Advisory Panel (LEAP) group hosted by Sussex Partnership Foundation Trust (SPFT) co-ordinated by JF and the NIHR DeNDRoN (Dementias and Neurodegenerative Diseases Research Network) group. Protocol change Due to slower than expected recruitment the carbamazepine arm was discontinued in August 2018 when 40 people had been randomised to it. This summary therefore focusses on the mirtazapine versus placebo comparisons. Results Between January 2017 and February 2020, 204 participants were recruited and randomised to either the mirtazapine (n = 102) or placebo arm (n = 102). Mean CMAI scores at 12 weeks were not significantly different between participants allocated to receive mirtazapine and placebo [adjusted mean difference −1.74, 95% confidence interval (CI) −7.17 to 3.69; p = 0.53, direction of change in favour of mirtazapine but not statistically significant]. The number of controls with adverse events [65/102 (64%)] was similar to that in the mirtazapine group [67/102 (66%)]. There were more deaths in the mirtazapine group (n = 7) by week 16 than in the control group (n = 1), with post hoc analysis suggesting this was of marginal statistical significance (p = 0.065), but this difference did not persist at 6- and 12-month follow-ups. The cost-effectiveness analyses similarly showed no evidence of benefit of mirtazapine over placebo, and no difference in costs between groups at 12 weeks. The carbamazepine arm closed in August 2018 when there had been 40 randomisations to that group, we therefore do not have statistical power for comparisons with placebo. However, exploratory analyses using the same modelling as for mirtazapine versus placebo showed there was also little evidence of any benefits compared to placebo (adjusted mean difference 2.46, 95% CI −5.01 to 9.93; p = 0.52), with similar levels of adverse events reported [27/40 (68%)]. Conclusions This is a trial with negative findings but important clinical implications. The data suggest that mirtazapine is not clinically effective or cost-effective (compared to placebo) for clinically significant agitation in dementia. Our findings suggest that there is little reason to recommend the use of mirtazapine for people with dementia who experience agitation. Effective and cost-effective management strategies for agitation in dementia are needed, particularly where non-pharmacological approaches have been unsuccessful, and for people with dementia and their carers living in community settings. Trial registration This trial is registered as ISRCTN17411897 and ClinicalTrials.gov as NCT03031184. Funding This project was funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment, Vol. 27, No. 23. See the NIHR Journals Library website for further project information

Dreams and nightmares of liberal international law: capitalist accumulation, natural rights and state hegemony

This article develops a line of theorising the relationship between peace, war and commerce and does so via conceptualising global juridical relations as a site of contestation over questions of economic and social justice. By sketching aspects of a historical interaction between capitalist accumulation, natural rights and state hegemony, the article offers a critical account of the limits of liberal international law, and attempts to recover some ground for thinking about the emancipatory potential of international law more generally