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This book examines the role of war in shaping the African state, society, and economy. Richard J. Reid helps students understand different patterns of military organization through Africa's history; the evolution of weaponry, tactics, and strategy; and the increasing prevalence of warfare and militarism in African political and economic systems. He traces shifts in the culture and practice of war from the first millennium into the era of the external slave trades, and then into the nineteenth century, when a military revolution unfolded across much of Africa. The repercussions of that revolution, as well as the impact of colonial rule, continue to this day. The frequency of coups d'états and civil war in Africa's recent past is interpreted in terms of the continent's deeper past.

This book is the first major study in several decades to consider Uganda as a nation, from its precolonial roots to the present day. Here, Richard J. Reid examines the political, economic, and social history of Uganda, providing a unique and wide-ranging examination of its turbulent and dynamic past for all those studying Uganda's place in African history and African politics. Reid identifies and examines key points of rupture and transition in Uganda's history, emphasising dramatic political and social change in the precolonial era, especially during the nineteenth century, and he also examines the continuing repercussions of these developments in the colonial and postcolonial periods. By considering the ways in which historical culture and consciousness has been ever present - in political discourse, art and literature, and social relationships - Reid defines the true extent of Uganda's viable national history. -- publisher's website.

The optimal timing of anticoagulation for patients with acute ischaemic stroke with atrial fibrillation is uncertain. We investigated the efficacy and safety of early compared with delayed initiation of direct oral anticoagulants (DOACs) in patients with acute ischaemic stroke associated with atrial fibrillation. We performed a multicentre, open-label, blinded-endpoint, parallel-group, phase 4, randomised controlled trial at 100 UK hospitals. Adults with atrial fibrillation and a clinical diagnosis of acute ischaemic stroke and whose physician was uncertain of the optimal timing for DOAC initiation were eligible for inclusion in the study. We randomly assigned participants (1:1) to early (ie, ≤4 days from stroke symptom onset) or delayed (ie, 7–14 days) anticoagulation initiation with any DOAC, using an independent online randomisation service with random permuted blocks and varying block length, stratified by stroke severity at randomisation. Participants and treating clinicians were not masked to treatment assignment, but all outcomes were adjudicated by a masked independent external adjudication committee using all available clinical records, brain imaging reports, and source images. The primary outcome was a composite of recurrent ischaemic stroke, symptomatic intracranial haemorrhage, unclassifiable stroke, or systemic embolism incidence at 90 days in a modified intention-to-treat population. We used a gatekeeper approach by sequentially testing for a non-inferiority margin of 2 percentage points, followed by testing for superiority. OPTIMAS is registered with ISRCTN (ISRCTN17896007) and ClinicalTrials.gov (NCT03759938), and the trial is ongoing. Between July 5, 2019, and Jan 31, 2024, 3648 patients were randomly assigned to early or delayed DOAC initiation. 27 participants did not fulfil the eligibility criteria or withdrew consent to include their data, leaving 3621 patients (1814 in the early group and 1807 in the delayed group; 1981 men and 1640 women) in the modified intention-to-treat analysis. The primary outcome occurred in 59 (3·3%) of 1814 participants in the early DOAC initiation group compared with 59 (3·3%) of 1807 participants in the delayed DOAC initiation group (adjusted risk difference [RD] 0·000, 95% CI –0·011 to 0·012). The upper limit of the 95% CI for the adjusted RD was less than the non-inferiority margin of 2 percentage points (pnon-inferiority=0·0003). Superiority was not identified (psuperiority=0·96). Symptomatic intracranial haemorrhage occurred in 11 (0·6%) participants allocated to the early DOAC initiation group compared with 12 (0·7%) participants allocated to the delayed DOAC initiation group (adjusted RD 0·001, –0·004 to 0·006; p=0·78). Early DOAC initiation within 4 days after ischaemic stroke associated with atrial fibrillation was non-inferior to delayed initiation for the composite outcome of ischaemic stroke, intracranial haemorrhage, unclassifiable stroke, or systemic embolism at 90 days. Our findings do not support the current common and guideline-supported practice of delaying DOAC initiation after ischaemic stroke with atrial fibrillation. British Heart Foundation.

This text provides a panoramic global history of Africa in the age of imperialism.

Adult mammalian central nervous system axons have intrinsically poor regenerative capacity, so axonal injury has permanent consequences. One approach to enhancing regeneration is to increase the axonal supply of growth molecules and organelles. We achieved this by expressing the adaptor molecule Protrudin which is normally found at low levels in non-regenerative neurons. Elevated Protrudin expression enabled robust central nervous system regeneration both in vitro in primary cortical neurons and in vivo in the injured adult optic nerve. Protrudin overexpression facilitated the accumulation of endoplasmic reticulum, integrins and Rab11 endosomes in the distal axon, whilst removing Protrudin’s endoplasmic reticulum localization, kinesin-binding or phosphoinositide-binding properties abrogated the regenerative effects. These results demonstrate that Protrudin promotes regeneration by functioning as a scaffold to link axonal organelles, motors and membranes, establishing important roles for these cellular components in mediating regeneration in the adult central nervous system. Increasing the supply of growth machinery to axons is a potential strategy for promoting repair after injury. Here the authors demonstrate that the endoplasmic reticulum adaptor molecule Protrudin provides cellular components that support axonal regeneration in the adult CNS.

As knowledge about genetic causes of disease improves, periodic reanalysis of clinical exome sequence could yield new genetic information. This study showed that a reanalysis of data initially analyzed about 6 years ago almost doubled the diagnostic yield and that a semiautomated approach to sequence analysis had a diagnostic sensitivity of 92.9%.

The recent emergence of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the underlying cause of Coronavirus Disease 2019 (COVID-19), has led to a worldwide pandemic causing substantial morbidity, mortality, and economic devastation. In response, many laboratories have redirected attention to SARS-CoV-2, meaning there is an urgent need for tools that can be used in laboratories unaccustomed to working with coronaviruses. Here we report a range of tools for SARS-CoV-2 research. First, we describe a facile single plasmid SARS-CoV-2 reverse genetics system that is simple to genetically manipulate and can be used to rescue infectious virus through transient transfection (without in vitro transcription or additional expression plasmids). The rescue system is accompanied by our panel of SARS-CoV-2 antibodies (against nearly every viral protein), SARS-CoV-2 clinical isolates, and SARS-CoV-2 permissive cell lines, which are all openly available to the scientific community. Using these tools, we demonstrate here that the controversial ORF10 protein is expressed in infected cells. Furthermore, we show that the promising repurposed antiviral activity of apilimod is dependent on TMPRSS2 expression. Altogether, our SARS-CoV-2 toolkit, which can be directly accessed via our website at https://mrcppu-covid.bio/ , constitutes a resource with considerable potential to advance COVID-19 vaccine design, drug testing, and discovery science.

Identifying genes and variants contributing to rare disease phenotypes and Mendelian conditions informs biology and medicine, yet potential phenotypic consequences for variation of >75% of the ~20,000 annotated genes in the human genome are lacking. Technical advances to assess rare variation genome-wide, particularly exome sequencing (ES), enabled establishment in the United States of the National Institutes of Health (NIH)-supported Centers for Mendelian Genomics (CMGs) and have facilitated collaborative studies resulting in novel “disease gene” discoveries. Pedigree-based genomic studies and rare variant analyses in families with suspected Mendelian conditions have led to the elucidation of hundreds of novel disease genes and highlighted the impact of de novo mutational events, somatic variation underlying nononcologic traits, incompletely penetrant alleles, phenotypes with high locus heterogeneity, and multilocus pathogenic variation. Herein, we highlight CMG collaborative discoveries that have contributed to understanding both rare and common diseases and discuss opportunities for future discovery in single-locus Mendelian disorder genomics. Phenotypic annotation of all human genes; development of bioinformatic tools and analytic methods; exploration of non-Mendelian modes of inheritance including reduced penetrance, multilocus variation, and oligogenic inheritance; construction of allelic series at a locus; enhanced data sharing worldwide; and integration with clinical genomics are explored. Realizing the full contribution of rare disease research to functional annotation of the human genome, and further illuminating human biology and health, will lay the foundation for the Precision Medicine Initiative.

BackgroundThe e-cigarette market has rapidly evolved, with a shift towards higher nicotine concentration and salt-based products, such as JUUL; however, the implications for youth vaping remain unclear.MethodsRepeat cross-sectional online surveys were conducted in 2017, 2018 and 2019, with national samples of youth aged 16–19 years recruited from commercial panels in Canada (n=12 018), England (n=11 362) and the USA (n=12 110). Regression models examined differences between countries and over time in the types of e-cigarette products used (design and nicotine content), reasons for using brands and differences in patterns of use, sociodemographics and dependence symptoms by brand/nicotine content.ResultsIn 2019, the use of pod- or cartridge-style e-cigarettes was greater in Canada and the USA than England, with Smok and JUUL the leading brands in all countries. In 2019, youth vapers in England were less likely to report using e-cigarettes with ≥2% nicotine (12.8%) compared with Canada (40.5%; adjusted OR (AOR)=4.96; 95% CI 3.51 to 7.01) and the USA (37.0%; AOR=3.99, 95% CI 2.79 to 5.71) and less likely to report using nicotine salt-based products (12.3%) compared with Canada (27.1%; AOR=2.77, 95% CI 1.93 to 3.99) and the USA (21.9%; AOR=2.00, 95% CI 1.36 to 2.95). In 2019, self-reported use of products with higher nicotine concentration was associated with significantly greater frequency of vaping, urges to vape and perceived vaping addiction (p<0.05 for all).ConclusionsThe use of high-nicotine salt-based products is associated with greater symptoms of dependence, including JUUL and other higher-nicotine brands. Greater use of high-nicotine salt-based products may account for recent increases in the frequency of vaping among youth in Canada and the USA.