Database of historic ports and coastal sailing routes in England and Wales

This data paper presents a reconstruction of historical ports and coastal routes in England and Wales during the age of the sailing ship, ending at the beginning of the twentieth century. The dataset was created by an amalgamation of twenty different sources,including geographical data, primary sources and secondary literature. Ports found in historical documents were listed by year of appearance and georeferenced. Ports that appear in multiple sour-ces were listed only once. Coastal routes between ports were drawn based on navigation charts and bathymetry data, distinguishing five categories with different characteristics. Visibility from the coast was deduced from elevation rasters and lighthouse locations. Subsequently both ports and coastal routes were checked using topo-logical rules to ensure the connectivity of the network. The data is provided in shapefile format with all the attributes and can be analysed using Geographical Information Systems (GIS) for different types of geographical and historical studies

Pneumococcal Induced T-activation with Resultant Thrombotic Microangiopathy

Thrombotic microangiopathies are disorders resulting from platelet thromboses forming in the microvasculature with resultant schistocyte forms. Hemolytic uremic syndrome (HUS) is a microangiopathic hemolytic anemia often complicated by acute renal failure in children. HUS is typically caused by bacterial infection, most commonly enterohemorrhagic Escherichia coli. Neuraminidase-producing organisms, such as Streptococcus pneumoniae have also been reported as potential etiologies. The pathogenesis in these cases involves cleavage of sialic acid residues from the surfaces of erythrocytes, platelets, and glomerular capillary endothelial cells, exposing the Thomsen-Friedenreich antigen, a process known as T-activation. We describe a 2-year-old girl who presented with pneumococcal pneumonia and sepsis ultimately resulting in a thrombotic microangiopathy with acute renal failure, most consistent with HUS. The patient’s direct antiglobulin test was positive. Polyagglutination was observed with human adult serum, but not with umbilical cord serum. Her red blood cells (RBCs) were reactive against peanut and soybean lectins, but not Salvia sclarea or Salvia horminum lectins. These findings are consistent with T-activation. Clinicians should be cognizant of the possibility of T-activation with resultant HUS in patients infected with neuraminidase-producing bacteria. Such patients may be difficult to identify using monoclonal typing antisera, as these typically do not have anti-T antibodies. Whether such patients are at risk for transfusion-associated hemolysis is debatable

Phylogenetic surveillance of viral genetic diversity and the evolving molecular epidemiology of human immunodeficiency virus type 1

With ongoing generation of viral genetic diversity and increasing levels of migration, the global human immunodeficiency virus type 1 (HIV-1) epidemic is becoming increasingly heterogeneous. In this study, we investigate the epidemiological characteristics of 5,675 HIV-1 pol gene sequences sampled from distinct infections in the United Kingdom. These sequences were phylogenetically analyzed in conjunction with 976 complete-genome and 3,201 pol gene reference sequences sampled globally and representing the broad range of HIV-1 genetic diversity, allowing us to estimate the probable geographic origins of the various strains present in the United Kingdom. A statistical analysis of phylogenetic clustering in this data set identified several independent transmission chains within the United Kingdom involving recently introduced strains and indicated that strains more commonly associated with infections acquired heterosexually in East Africa are spreading among men who have sex with men. Coalescent approaches were also used and indicated that the transmission chains that we identify originated in the late 1980s to early 1990s. Similar changes in the epidemiological structuring of HIV epidemics are likely to be taking in place in other industrialized nations with large immigrant populations. The framework implemented here takes advantage of the vast amount of routinely generated HIV-1 sequence data and can provide epidemiological insights not readily obtainable through standard surveillance methods

Perfectionism and performance in a new basketball training task: Does striving for perfection enhance or undermine performance?

Objectives: In the psychology of sport and exercise, the question of how perfectionism affects performance is highly debated. While some researchers have identified perfectionism as a hallmark quality of elite athletes, others see perfectionism as a maladaptive characteristic that undermines, rather than helps, athletic performance. Against this background, the purpose of the present study was to investigate how different aspects of perfectionism predict performance and performance increments. Method: A study was conducted with 122 undergraduate athletes to investigate how perfectionism during training affects performance and performance increments in a series of trials with a new basketball training task. Two aspects of perfectionism were examined: striving for perfection and negative reactions to imperfection. Design: The design was a correlational prospective design. Results: Results showed that striving for perfection during training predicted higher performance in the new task. In contrast, negative reactions to imperfection predicted lower performance when athletes attempted the task for the first time, once the positive influence of striving for perfection on task performance was partialled out. However, negative reactions to imperfection did not undermine performance in the consecutive trials. On the contrary, athletes with both high levels of striving for perfection and high levels of negative reactions to imperfection showed the greatest performance increments over the series of trials. Conclusion: The findings suggest that perfectionism is not necessarily a maladaptive characteristic that generally undermines sport performance. Instead, when learning a new training task, perfectionism may enhance performance and lead to performance increments over repeated trials

Florence Elizabeth & Martha Baker Dunn Correspondence

Entries include correspondence from the Maine State Library to Florence and her deceased mother Martha, both of whom were published in the anthology Maine and Vermont Poets, a handwritten biography, and a handwritten letter of presentation

Interpretation of active-control randomised trials: the case for a new analytical perspective involving averted events

Active-control trials, where an experimental treatment is compared with an established treatment, are performed when the inclusion of a placebo control group is deemed to be unethical. For time-to-event outcomes, the primary estimand is usually the rate ratio, or the closely-related hazard ratio, comparing the experimental group with the control group. In this article we describe major problems in the interpretation of this estimand, using examples from COVID-19 vaccine and HIV pre-exposure prophylaxis trials. In particular, when the control treatment is highly effective, the rate ratio may indicate that the experimental treatment is clearly statistically inferior even when it is worthwhile from a public health perspective. We argue that it is crucially important to consider averted events as well as observed events in the interpretation of active-control trials. An alternative metric that incorporates this information, the averted events ratio, is proposed and exemplified. Its interpretation is simple and conceptually appealing, namely the proportion of events that would be averted by using the experimental treatment rather than the control treatment. The averted events ratio cannot be directly estimated from the active-control trial, and requires an additional assumption about either: (a) the incidence that would have been observed in a hypothetical placebo arm (the counterfactual incidence) or (b) the efficacy of the control treatment (relative to no treatment) that pertained in the active-control trial. Although estimation of these parameters is not straightforward, this must be attempted in order to draw rational inferences. To date, this method has been applied only within HIV prevention research, but has wider applicability to treatment trials and other disease areas

Perceptions of diagnosis and management of patients with acute respiratory distress syndrome: a survey of United Kingdom intensive care physicians

BackgroundAcute respiratory distress syndrome (ARDS) is a potentially devastating refractory hypoxemic illness with multi-organ involvement. Although several randomised controlled trials into ventilator and fluid management strategies have provided level 1 evidence to guide supportive therapy, there are few, established guidelines on how to manage patients with ARDS. In addition, and despite their continued use, pharmacotherapies for ARDS disease modulation have no proven benefit in improving mortality. Little is known however about the variability in diagnostic and treatment practices across the United Kingdom (UK). The aim of this survey, therefore, was to assess the use of diagnostic criteria and treatment strategies for ARDS in critical care units across the UK.MethodsThe survey questionnaire was developed and internally piloted at University Hospital Southampton NHS Foundation Trust. Following ethical approval from University of Southampton Ethics and Research Committee, a link to an online survey engine (Survey Monkey) was then placed on the Intensive Care Society (UK) website. Fellows of The Intensive Care Society were subsequently personally approached via e-mail to encourage participation. The survey was conducted over a period of 3 months.ResultsThe survey received 191 responses from 125 critical care units, accounting for 11% of all registered intensive care physicians at The Intensive Care Society. The majority of the responses were from physicians managing general intensive care units (82%) and 34% of respondents preferred the American European Consensus Criteria for ARDS. There was a perceived decline in both incidence and mortality in ARDS. Primary ventilation strategies were based on ARDSnet protocols, though frequent deviations from ARDSnet positive end expiratory pressure (PEEP) recommendations (51%) were described. The majority of respondents set permissive blood gas targets (hypoxia (92%), hypercapnia (58%) and pH (90%)). The routine use of pharmacological agents is rare. Neuromuscular blockers and corticosteroids are considered occasionally and on a case-by-case basis. Routine (58%) or late (64%) tracheostomy was preferred to early tracheostomy insertion. Few centres offered routine follow-up or dedicated rehabilitation programmes following hospital discharge.ConclusionsThere is substantial variation in the diagnostic and management strategies employed for patients with ARDS across the UK. National and/or international guidelines may help to improve standardisation in the management of ARDS

Characteristics of Autism Spectrum Disorder in Cornelia de Lange Syndrome

Background: The prevalence of Autism Spectrum Disorder (ASD) symptomatology is comparatively high in Cornelia de Lange Syndrome (CdLS). However, the profile and developmental trajectories of these ASD characteristics are potentially different to those observed in individuals with idiopathic ASD. In this study we examine the ASD profile in CdLS in comparison to a matched group of individuals with ASD.\ud \ud Method: The Autism Diagnostic Observation Schedule (ADOS) was administered to 20 individuals with CdLS (mean age = 11.34; range = 6yrs to 13yrs) and 20 individuals with idiopathic ASD (mean age = 10.42; range = 8yrs to 11yrs). Participants were matched according to adaptive behaviour skills and receptive language.\ud \ud Results: Sixty-five per cent (N= 13) of individuals with CdLS met the cut off score for autism on the total ADOS score. Further analysis at domain and item level indicated that individuals with CdLS showed significantly less repetitive behaviour, (specifically sensory interests); more eye contact, more gestures and less stereotyped speech than the ASD group. The CdLS group also showed higher levels of anxiety.\ud \ud Conclusions: The comparison between CdLS and idiopathic ASD indicates subtle group differences in the profile of ASD symptomatology that are not accounted for by degree of intellectual disability or receptive language skills. These differences may not be evident when relying solely upon clinical and domain level scores, but may be distinguishing features of the ASD presentations in the two disorders. The findings have implications for the conceptualisation and assessment of ASD in individuals with genetic syndromes

Monitoring the response of canine hyperadrenocorticism to trilostane treatment by assessment of acute phase protein concentrations

<b>Background</b>: Acute phase proteins (APPS) include haptoglobin (Hp), C-reactive protein (CRP) and serum amyloid A (SAA). Increased Hp concentrations may be induced by endogenous or exogenous glucocorticoids in dogs. <b>Objectives</b>: To assess whether control of hyperadrenocorticism (HAC) affects the concentrations of Hp, CRP, SAA, alkaline phosphatase (ALKP) and cholesterol, to determine whether these analytes can be used to assess control of HAC following trilostane treatment, and whether a combination of these tests offers a valid method of assessing disease control. <b>Methods</b>: Hp, CRP, SAA, ALKP and cholesterol were assessed in 11 dogs with spontaneous HAC before and after treatment with trilostane. Adequate control of HAC was defined as post-ACTH cortisol less than 150 nmol/l. <b>Results</b>: Significant reductions in Hp, ALKP, cholesterol and SAA (P<0·05) but not of CRP were found after control of HAC. Only Hp, cholesterol and ALKP were moderately informative (Se & Sp>0·7) of disease control when compared to adrenocorticotropin or corticotropin (ACTH) stimulation test. SAA and CRP were unhelpful (Se & Sp<0·7). The analysis of the combination of the analytes did not improve the correlation with ACTH stimulation test. <b>Clinical Relevance</b>: Relying on these analytes does not provide additional information over ACTH stimulation test results when assessing control of HAC treated with trilostane

AKT-mTORC1 reactivation is the dominant resistance driver for PI3Kβ/AKT inhibitors in PTEN-null breast cancer and can be overcome by combining with Mcl-1 inhibitors

Cancer therapeutic resistance; Target identificationResistencia terapéutica contra el cáncer; Identificación de objetivosResistència terapèutica contra el càncer; Identificació d'objectiusThe PI3K pathway is commonly activated in breast cancer, with PI3K-AKT pathway inhibitors used clinically. However, mechanisms that limit or enhance the therapeutic effects of PI3K-AKT inhibitors are poorly understood at a genome-wide level. Parallel CRISPR screens in 3 PTEN-null breast cancer cell lines identified genes mediating resistance to capivasertib (AKT inhibitor) and AZD8186 (PI3Kβ inhibitor). The dominant mechanism causing resistance is reactivated PI3K-AKT-mTOR signalling, but not other canonical signalling pathways. Deletion of TSC1/2 conferred resistance to PI3Kβi and AKTi through mTORC1. However, deletion of PIK3R2 and INPPL1 drove specific PI3Kβi resistance through AKT. Conversely deletion of PIK3CA, ERBB2, ERBB3 increased PI3Kβi sensitivity while modulation of RRAGC, LAMTOR1, LAMTOR4 increased AKTi sensitivity. Significantly, we found that Mcl-1 loss enhanced response through rapid apoptosis induction with AKTi and PI3Kβi in both sensitive and drug resistant TSC1/2 null cells. The combination effect was BAK but not BAX dependent. The Mcl-1i + PI3Kβ/AKTi combination was effective across a panel of breast cancer cell lines with PIK3CA and PTEN mutations, and delivered increased anti-tumor benefit in vivo. This study demonstrates that different resistance drivers to PI3Kβi and AKTi converge to reactivate PI3K-AKT or mTOR signalling and combined inhibition of Mcl-1 and PI3K-AKT has potential as a treatment strategy for PI3Kβi/AKTi sensitive and resistant breast tumours.This work was funded by the Wellcome Trust (WT206194) to KY and MJG and by AstraZeneca to KY, BRD, STB and JTL