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'In the Shadow of Slavery' explores the wealth of plant life brought to the Americas by slaves and slave ships as provisions, medicines, cordage and bedding, and afterwards cultivated in garden plots. These included coffee, watermelon and okra, as well as the constituents of many well-known products.

In the 24-month MS-STAT phase 2 trial, we showed that high-dose simvastatin significantly reduced the annualised rate of whole brain atrophy in patients with secondary progressive multiple sclerosis (SPMS). We now describe the results of the MS-STAT cognitive substudy, in which we investigated the treatment effect on cognitive, neuropsychiatric, and health-related quality-of-life (HRQoL) outcome measures. We did a secondary analysis of MS-STAT, a 24-month, double-blind, controlled trial of patients with SPMS done at three neuroscience centres in the UK between Jan 28, 2008, and Nov 4, 2011. Patients were randomly assigned (1:1) to either 80 mg simvastatin (n=70) or placebo (n=70). The cognitive assessments done were the National Adult Reading Test, Wechsler Abbreviated Scale of Intelligence, Graded Naming Test, Birt Memory and Information Processing Battery (BMIPB), Visual Object and Space Perception battery (cube analysis), Frontal Assessment Battery (FAB), and Paced Auditory Serial Addition Test. Neuropsychiatric status was assessed using the Hamilton Depression Rating Scale and the Neuropsychiatric Inventory Questionnaire. HRQoL was assessed using the self-reported 36-Item Short Form Survey (SF-36) version 2. Assessments were done at study entry, 12 months, and 24 months. Patients, treating physicians, and outcome assessors were masked to treatment allocation. Analyses were by intention to treat. MS-STAT is registered with ClinicalTrials.gov, number NCT00647348. Baseline assessment revealed impairments in 60 (45%) of 133 patients on the test of frontal lobe function (FAB), and in between 13 (10%) and 43 (33%) of 130 patients in tests of non-verbal and verbal memory (BMIPB). Over the entire trial, we noted significant worsening on tests of verbal memory (T score decline of 5·7 points, 95% CI 3·6–7·8; p<0·0001) and non-verbal memory (decline of 6·8 points, 4·8–8·7; p<0·0001). At 24 months, the FAB score was 1·2 points higher in the simvastatin-treated group than in the placebo group (95% CI 0·2–2·3). The simvastatin group also had a 2·5 points better mean physical component score of the SF-36 (95% CI 0·3–4·8; p=0·028). A treatment effect was not noted for any other outcomes. To our knowledge, this SPMS cohort is the largest studied to date with comprehensive longitudinal cognitive, neuropsychiatric, and HRQoL assessments. We found evidence of a positive effect of simvastatin on frontal lobe function and a physical quality-of-life measure. Although we found no effect of simvastatin on the other outcome measures, these potential effects warrant confirmation and underline the importance of fully assessing cognition and quality of life in progressive multiple sclerosis treatment trials. The Moulton Foundation, the Berkeley Foundation, the Multiple Sclerosis Trials Collaboration, the Rosetrees Trust, a personal contribution from A W Pidgley CBE, and the National Institute for Health Research University College London Hospitals Biomedical Research Centre and University College London.

\"The language of special responsibilities is ubiquitous in world politics, with policymakers and commentators alike speaking and acting as though particular states have, or ought to have, unique obligations in managing global problems. Surprisingly, scholars are yet to provide any in-depth analysis of this fascinating aspect of world politics. This path-breaking study examines the nature of special responsibilities, the complex politics that surround them and how they condition international social power. The argument is illustrated with detailed case-studies of nuclear proliferation, climate change and global finance. All three problems have been addressed by an allocation of special responsibilities, but while this has structured politics in these areas, it has also been the subject of ongoing contestation. With a focus on the United States, this book argues that power must be understood as a social phenomenon and that American power varies significantly across security, economic and environmental domains\"-- Provided by publisher.

Secondary progressive multiple sclerosis, for which no satisfactory treatment presently exists, accounts for most of the disability in patients with multiple sclerosis. Simvastatin, which is widely used for treatment of vascular disease, with its excellent safety profile, has immunomodulatory and neuroprotective properties that could make it an appealing candidate drug for patients with secondary progressive multiple sclerosis. We undertook a double-blind, controlled trial between Jan 28, 2008, and Nov 4, 2011, at three neuroscience centres in the UK. Patients aged 18–65 years with secondary progressive multiple sclerosis were randomly assigned (1:1), by a centralised web-based service with a block size of eight, to receive either 80 mg of simvastatin or placebo. Patients, treating physicians, and outcome assessors were masked to treatment allocation. The primary outcome was the annualised rate of whole-brain atrophy measured from serial volumetric MRI. Analyses were by intention to treat and per protocol. This trial is registered with ClinicalTrials.gov, number NCT00647348. 140 participants were randomly assigned to receive either simvastatin (n=70) or placebo (n=70). The mean annualised atrophy rate was significantly lower in patients in the simvastatin group (0·288% per year [SD 0·521]) than in those in the placebo group (0·584% per year [0·498]). The adjusted difference in atrophy rate between groups was −0·254% per year (95% CI −0·422 to −0·087; p=0·003); a 43% reduction in annualised rate. Simvastatin was well tolerated, with no differences between the placebo and simvastatin groups in proportions of participants who had serious adverse events (14 [20%] vs nine [13%]). High-dose simvastatin reduced the annualised rate of whole-brain atrophy compared with placebo, and was well tolerated and safe. These results support the advancement of this treatment to phase 3 testing. The Moulton Foundation [charity number 1109891], Berkeley Foundation [268369], the Multiple Sclerosis Trials Collaboration [1113598], the Rosetrees Trust [298582] and a personal contribution from A Pidgley, UK National Institute of Health Research (NIHR) University College London Hospitals/UCL Biomedical Research Centres funding scheme.

Ageing is one of the most important risk factors for the development of several neurodegenerative diseases including progressive multiple sclerosis (MS). Cellular senescence (CS) is a key biological process underlying ageing. Several stressors associated with ageing and MS pathology such as oxidative stress, mitochondrial dysfunction, cytokines and replicative exhaustion are known triggers of CS. Senescent cells exhibit stereotypical metabolic and functional changes, which include cell-cycle arrest and acquiring a pro-inflammatory phenotype secreting cytokines, growth factors, metalloproteinases and reactive oxygen species. They accumulate with ageing and can convert neighboring cells to senescence in a paracrine manner. In MS, accelerated cellular senescence may drive disease progression by promoting chronic non-remitting inflammation, loss or altered immune, glial and neuronal function, failure of remyelination, impaired blood-brain barrier integrity and ultimately neurodegeneration. Here we discuss the evidence linking cellular senescence to the pathogenesis of MS and the putative role of senolytic and senomorphic agents as neuroprotective therapies in tackling disease progression.

The growth of disseminated tumor metastases is a major cause of mortality in patients with cancer, and bone is a common site for metastasis. This Review summarizes the cellular and molecular components of the metastatic cascade and highlights potential new directions for future therapeutic strategies to target bone metastasis. The skeleton is one of the most common sites for metastatic cancer, and tumors arising from the breast or prostate possess an increased propensity to spread to this site. The growth of disseminated tumor cells in the skeleton requires tumor cells to inhabit the bone marrow, from which they stimulate local bone cell activity. Crosstalk between tumor cells and resident bone and bone marrow cells disrupts normal bone homeostasis, which leads to tumor growth in bone. The metastatic tumor cells have the ability to elicit responses that stimulate bone resorption, bone formation or both. The net result of these activities is profound skeletal destruction that can have dire consequences for patients. The molecular mechanisms that underlie these painful and often incurable consequences of tumor metastasis to bone are beginning to be recognized, and they represent promising new molecular targets for therapy. Key Points Bone is a common site of metastasis for many tumors, such as breast, lung and prostate cancer A continuum of bone metastasis exists that extends from primarily osteolytic lesions with limited osteoblast activity to bone metastases that are predominantly osteoblastic, with limited osteoclast activity The complex interactions between circulating tumor cells, circulating host cells, platelets and cell-derived factors are critical for tumor establishment at metastatic sites Tumor activation of bone resorption is complex and involves both receptor activator of nuclear factor κB ligand (RANKL)-dependent and RANKL-independent mechanisms Targeting bone resorption with bisphosphonates reduces osteolytic bone resorption and improves disease-free survival All steps in the metastatic process and the interaction with host cells are valid therapeutic targets for the treatment of bone metastasis and tumor progression

IntroductionAn algorithmically identified Multiple Sclerosis (MS) population in Wales using a diagnostic method based on McDonald criteria alone had less severe disease compared to those with multiple encounters. We investigated the nature of the encounters.MethodMS subjects were identified using two algorithms, ‘Manitoba10’ based on multiple healthcare encounters and based on McDonald criteria minus the Manitoba10 population ‘Not Manitoba10’. Top 10 primary admissions, number of chest infections (ICD10 J00-J06, J09-J18, J20-J22) and UTIs (ICD10 N390) were compared to the general population.Results1,845,360/4,616,124 subjects in the general population had a UTI or chest infection, versus (4,166/5,438) Manitoba10 and (2,346/4,153) Not Manitoba10. Mean UTI and chest infection admissions were significantly higher in Manitoba10 versus the general population (UTI 1.45,p<0.001, Chest 0.79,p<0.001); in Not Manitoba10 only UTI was significant (UTI 0.45,p<0.001, Chest 0.48,p=0.464). Manitoba10 cohort had significantly higher UTI/Chest infection admissions compared to Not Manitoba10 (p<0.001). Of the top 10 primary causes of hospital admission, Manitoba10 features more events related to increasing disability (Holiday relief care, sepsis, pneumonitis), whereas the general population has more frequent admissions for cancer related events and UTIs.DiscussionMS subjects with multiple encounters have more frequent hospital admissions for UTIs and chest infections potentially contributing to more severe disease.

BackgroundThe UK MS Register (UKMSR) developed an electronic version the Symbol Digit Modalities Test (SDMT) called the Cognitive Reaction (CoRe) test that has been validated within clinics on tablet computers. We developed a new version of the CoRe application (V2) for use on personal devices but also incorporates a range of symbols.AimTo establish the responsiveness to different symbol sets using the CoRe app.MethodsCoRe was adapted for use on Apple devices. Symbols sets were added, including: classic, emoji and pictographs. We recruited MS Register participants, with a link made available to the Apple testflight application.Results191 pwMS downloaded CoRe V2, 185 were linked to UKMSR data: 116 Relapsing, 61 Progressive, 8 unspecified pwMS. 131 used an iPhone and 60 a tablet. 644 tests were completed, with a mean per pwMS 3.05±2.5 (mean±SD). 264 completed the ‘classic’ symbols: answered 42.2±12.8, correct 41.5±13.6; 220 completed ‘emojis’, answered 54.6±16.07, correct 53.8±16.5; 160 completed ‘pictographs’, answered 44.6±14.2, correct 43.6±14.5. Linear regression with correct score as the dependent variable found that Emoji scores were increased by 12.5 [10, 15] and scores were decreased -0.5 per year [-0.6, -0.4].ConclusionPwMS performed better at a younger age and when using the emoji symbols compared to the classic and pictograph symbols. The basis of this difference requires further investigation.

IntroductionThe TYSABRI Observational Program (TOP) is an ongoing observational study of natalizumab treatment in relapsing-remitting multiple sclerosis (RRMS) patients. Country-specific data on relapse and disability outcomes, alongside global data, can provide information on natalizumab’s effectiveness in local practice.MethodsAnnualised relapse rate (ARR) was analysed in TOP UK (n=134) and global (N=6321) cohorts using data from July 2007 to November 2022. Cumulative probabilities of 24-week confirmed disability worsening (CDW) and improvement (CDI) were analysed in each cohort.ResultsARR decreased in UK patients from 2.21 in the year before initiation to 0.15 on natalizumab (P<0.0001), consistent with a global decrease from 2.00 to 0.18 (P<0.0001). ARR in subgroups based on number of prior disease modifying therapies and baseline Expanded Disability Status Scale scores will be presented. At 10 years follow-up, cumulative probability of CDI was 46.3% and 35.2% in the UK and global cohorts, respectively; cumulative probability of CDW was 60.3% and 40.7%.ConclusionsThe reduction in ARR on natalizumab was similar in the TOP UK and global cohorts, with the cumulative probability of CDI and CDW higher in the UK cohort. These findings support the real-world effectiveness of natalizumab.Support: Funded by Biogen. Disclosures: Included on the poster.

The resident macrophages of the central nervous system, microglia, are becoming increasingly implicated as active participants in neuropathology and ageing. Their diverse and changeable morphology is tightly linked with functions they perform, enabling assessment of their activity through image analysis. To better understand the contributions of microglia in health, senescence, and disease, it is necessary to measure morphology with both speed and reliability. A machine learning approach was developed to facilitate automatic classification of images of retinal microglial cells as one of five morphotypes, using a support vector machine (SVM). The area under the receiver operating characteristic curve for this SVM was between 0.99 and 1, indicating strong performance. The densities of the different microglial morphologies were automatically assessed (using the SVM) within wholemount retinal images. Retinas used in the study were sourced from 28 healthy C57/BL6 mice split over three age points (2, 6, and 28-months). The prevalence of ‘activated’ microglial morphology was significantly higher at 6- and 28-months compared to 2-months (p < .05 and p < .01 respectively), and ‘rod’ significantly higher at 6-months than 28-months ( p  < 0.01). The results of the present study propose a robust cell classification SVM, and further evidence of the dynamic role microglia play in ageing.