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Visual working memory and action: functional links and bi-directional influences
No full textWorking memory bridges perception to action over extended delays, enabling flexible goal-directed behaviour. To date, studies of visual working memory – concerned with detailed visual representations such as shape and colour – have considered visual memory predominantly in the context of visual task demands, such as visual identification and search. Another key purpose of visual working memory is to directly inform and guide upcoming actions. Taking this as a starting point, I review emerging evidence for the pervasive bi-directional links between visual working memory and (planned) action, and discuss these links from the perspective of their common goal of enabling flexible and precise behaviour
“The Legality of Prisoner of War Labour in England, 1648–1655”
No full textPrisoners of war formed a legally distinct category amongst the many thousands of people forcibly employed in England and the English American colonies in the mid-seventeenth century, but they have yet to be studied as such. Focusing on 1648 to 1655, this article explains how a succession of English governments sent their war captives into servitude with private masters despite the prohibition of hard labour for Christian prisoners in the customary laws of war. They instead operated under the logic
of the English poor law, in which the indigent could meaningfully consent to serve a master even while under duress. The case of Scottish and Dutch prisoners of war in the Bedford Level fen drainage project shows how the Council of State and the drainage company board members conceptualized common prisoners as willing workmen. Prisoners, ambassadors, and a variety of English observers instead thought that war captives should not have to work for their subsistence or their captors’ profit. Nevertheless, common prisoners continued to labour under the aegis of free contracts into the eighteenth century
The mechanics of human brain organoids
No full textOrganoids are prototypes of human organs derived from cultured human stem cells. They provide a reliable and accurate experimental model to study the physical mechanisms underlying the early developmental stages of human organs and, in particular, the early morphogenesis of the cortex. Here we propose a mathematical model to elucidate the role played by two mechanisms which have been experimentally proven to be crucial in shaping human brain organoids: the contraction of the inner core of the organoid and the microstructural remodeling of its outer cortex. Our results show that both mechanisms are crucial for the final shape of the organoid and that perturbing those mechanisms can lead to pathological morphologies which are reminiscent of those associated with lissencephaly (smooth brain)
Efficacy, patient-reported outcomes, and safety of the anti-granulocyte macrophage colony-stimulating factor antibody otilimab (GSK3196165) in patients with rheumatoid arthritis: a randomised, phase 2b, dose-ranging study
No full textBackground
The human monoclonal antibody otilimab inhibits granulocyte-macrophage colony-stimulating factor (GM-CSF), a key driver in immune-mediated inflammatory conditions. We aimed to evaluate the efficacy, safety, and key patient-reported outcomes related to pain in patients with active rheumatoid arthritis receiving otilimab.
Methods
This phase 2b, dose-ranging, multicentre, placebo-controlled study was done at 64 sites across 14 countries. Patients aged 18 years or older with rheumatoid arthritis who were receiving stable methotrexate were randomly assigned (1:1:1:1:1:1) to subcutaneous placebo or otilimab 22·5 mg, 45 mg, 90 mg, 135 mg, or 180 mg, plus methotrexate, once weekly for 5 weeks, then every other week until week 50. The randomisation schedule was generated by the sponsor, and patients were assigned to treatment by interactive response technology. Randomisation was blocked (block size of six) but was not stratified. Investigators, patients, and the sponsor were blinded to treatment. An unblinded administrator prepared and administered the study drug. The primary endpoint was the proportion of patients who achieved disease activity score for 28 joints with C-reactive protein (DAS28-CRP) 3·2 (week 24) escaped to otilimab 180 mg. Patients who escaped were treated as non-responders in their original assigned group. Safety endpoints were incidence of adverse events and serious adverse events, infections, and pulmonary events. Efficacy and safety outcomes were assessed in the intention-to-treat population. This study is registered with ClinicalTrials.gov, NCT02504671.
Findings
Between July 23, 2015, and Dec 29, 2017, 222 patients were randomly assigned (37 to each group). 86 (49%) of 175 escaped to otilimab 180 mg at week 12 and 57 (69%) of 83 at week 24. At week 24, the proportion of patients with DAS28-CRP <2·6 was two (5%) of 37 in the otilimab 22·5 mg group, six (16%) of 37 in the 45 mg group, seven (19%) of 37 in the 90 mg group, five (14%) of 37 in the 135 mg group, five (14%) of 37 in the 180 mg, and one (3%) of 37 in the placebo group. The largest difference was achieved with otilimab 90 mg (16·2%; odds ratio [OR] 8·39, 95% CI 0·98–72·14; p=0·053). Adverse events were reported pre-escape in 19–24 (51–65%) patients and post escape in 10–17 (40–61%) patients across otilimab dose groups and in 18 (49%) of 37 and 22 (67%) of 33 in the placebo group. The most common adverse event was nasopharyngitis: 3–9 (8–24%) in otilimab groups and one (3%) in the placebo group pre-escape and 1–3 (4–10%) in otilimab groups and seven (21%) in the placebo group post escape. Pre-escape serious adverse events were foot fracture (otilimab 45 mg); arthralgia, myocardial infarction, dizziness (otilimab 90 mg); oesophageal spasm, acute pyelonephritis (otilimab 22·5 mg), and uterine leiomyoma (otilimab 135 mg). Post-escape serious adverse events were ankle fracture (placebo) and rheumatoid arthritis (otilimab 135 mg). There were no deaths or pulmonary events of clinical concern, and rates of serious infection were low.
Interpretation
Otilimab plus methotrexate was well tolerated and, despite not achieving the primary endpoint of DAS28-CRP remission, there were improvements compared with placebo in disease activity scores. Of note, patients reported significant improvement in pain and physical function, supporting further clinical development of otilimab in rheumatoid arthritis
On moral obligations and our chances of fulfilling them
No full textMany actions we perform affect the chances of fulfilling our moral obligations. The moral status of such actions is important and deeply neglected. In this paper, I begin rectifying this neglect by asking: under what conditions, if any, is it morally wrong to perform an action that will lower the chance of one fulfilling a moral obligation? In §1, I introduce this question and motivate concern with its answer. I argue, in §2, that certain actions an agent has good reason to believe will drastically lower their chances of fulfilling a moral obligation in the future, relative to at least one alternative action available, are pro tanto morally wrong. This answer, I argue, captures our intuitions in a range of cases, avoids the problems that other views considered here face, and can be plausibly defended against some independent objections. I conclude in §3 by noting some consequences for normative and practical ethics of the moral wrongness of at least some actions that lower the chances of fulfilling our moral obligations, and by raising a series of important questions regarding these actions for future consideration
The effect of acute citalopram on self-referential emotional processing and social cognition in healthy volunteers
No full textBackground
Depression is characterised by negative views of the self. Antidepressant treatment may remediate negative self-schema through increasing processing of positive information about the self. Changes in affective processing during social interactions may increase expression of prosocial behaviours, improving interpersonal communications.
Aims
To examine whether acute administration of citalopram is associated with an increase in positive affective learning biases about the self and prosocial behaviour.
Method
Healthy volunteers (n = 41) were randomised to either an acute 20 mg dose of citalopram or matched placebo in a between-subjects double-blind design. Participants completed computer-based cognitive tasks designed to measure referential affective processing, social cognition and expression of prosocial behaviours.
Results
Participants administered citalopram made more cooperative choices than those administered placebo in a prisoner's dilemma task (β = 20%, 95% CI: 2%, 37%). Exploratory analyses indicated that participants administered citalopram showed a positive bias when learning social evaluations about a friend (β = 4.06, 95% CI: 0.88, 7.24), but not about the self or a stranger. Similarly, exploratory analyses found evidence of increased recall of positive words and reduced recall of negative words about others (β = 2.41, 95% CI: 0.89, 3.93), but not the self, in the citalopram group.
Conclusions
Participants administered citalopram showed greater prosocial behaviours, increased positive recall and increased positive learning of social evaluations towards others. The increase in positive affective bias and prosocial behaviours towards others may, at least partially, be a mechanism of antidepressant effect. However, we found no evidence that citalopram influenced self-referential processing
New frontiers in atom probe tomography: a review of research enabled by cryo and/or vacuum transfer systems
No full textThere has been a recent surge in the use of cryo and/or vacuum specimen preparation and transfer systems to broaden the scope of research enabled by the microscopy technique of atom probe tomography. This is driven by the fact that, as for many microscopes, the application of atom probes to air- and temperature-sensitive materials or wet biological specimens has previously been limited by transfer through air at room temperature. Here we provide an overview of areas of research that benefit from these new transfer and analysis protocols, as well as a review of current advances in transfer devices, environmental cells, and glove boxes for controlled specimen manipulation. This includes the study of catalysis and corrosion, biological samples, liquid-solid interfaces, natural aging, and the distribution of hydrogen in materials
Independent risk factors for simvastatin-related myopathy and relevance to different types of muscle symptom
No full textAims:
Statins are widely used to prevent cardiovascular events, but little is known about the impact of different risk factors for statin-related myopathy or their relevance to reports of other types of muscle symptom.
Methods and Results:
An observational analysis was undertaken of 171 clinically adjudicated cases of myopathy (defined as unexplained muscle pain or weakness with creatine kinase >10× upper limit of normal) and, separately, of 15 208 cases of other muscle symptoms among 58 390 individuals with vascular disease treated with simvastatin for a mean of 3.4 years. Cox proportional hazards models were used to identify independent predictors of myopathy. The rate of myopathy was low: 9 per 10 000 person-years of simvastatin therapy. Independent risk factors for myopathy included: simvastatin dose, ethnicity, sex, age, body mass index, medically treated diabetes, concomitant use of niacin-laropiprant, verapamil, beta-blockers, diltiazem and diuretics. In combination, these risk factors predicted more than a 30-fold risk difference between the top and bottom thirds of a myopathy risk score (hazard ratio : 34.35, 95% CI: 12.73–92.69, P across thirds = 9·1 × 10−48). However, despite the strong association with myopathy, this score was not associated with the other reported muscle symptoms (P across thirds = 0.93). Likewise, although SLCO1B1 genotype was associated with myopathy, it was not associated with other muscle symptoms.
Conclusions:
The absolute risk of simvastatin-related myopathy is low, but individuals at higher risk can be identified to help guide patient management. The lack of association of the myopathy risk score with other muscle symptoms reinforces randomized placebo-controlled evidence that statins do not cause the vast majority of reported muscle symptoms
Health systems readiness and quality of inpatient malaria case-management in Kano State, Nigeria
No full textBackground
Nigeria was among the first African countries to adopt and implement change of treatment policy for severe malaria from quinine to artesunate. Seven years after the policy change health systems readiness and quality of inpatient malaria case-management practices were evaluated in Kano State of Nigeria.
Methods
A cross-sectional survey was undertaken in May 2019 at all public hospitals. Data collection comprised hospital assessments, interviews with inpatient health workers and data extraction from medical files for all suspected malaria patients admitted to the paediatric and medical wards in April 2019. Descriptive analyses included 22 hospitals, 154 health workers and 1,807 suspected malaria admissions analysed from malaria test and treat case-management perspective.
Results
73% of hospitals provided malaria microscopy, 27% had rapid diagnostic tests and 23% were unable to perform any parasitological malaria diagnosis. Artemisinin-based combination therapy (ACT) was available at 96% of hospitals, artemether vials at 68% while injectable quinine and artesunate were equally stocked at 59% of hospitals. 32%, 21% and 15% of health workers had been exposed to relevant trainings, guidelines and supervision respectively. 47% of suspected malaria patients were tested while repeat testing was rare (7%). 60% of confirmed severe malaria patients were prescribed artesunate. Only 4% of admitted non-severe test positive cases were treated with ACT, while 76% of test negative patients were prescribed an anti-malarial. Artemether was the most common anti-malarial treatment for non-severe test positive (55%), test negative (43%) and patients not tested for malaria (45%). In all categories of the patients, except for confirmed severe cases, artemether was more commonly prescribed for adults compared to children. 44% of artesunate-treated patients were prescribed ACT follow-on treatment. Overall compliance with test and treat policy for malaria was 13%.
Conclusions
Translation of new treatment policy for severe malaria into inpatient practice is compromised by lack of malaria diagnostics, stock-outs of artesunate and suboptimal health workers’ practices. Establishment of the effective supply chain and on-going supportive interventions for health workers accompanied with regular monitoring of the systems readiness and clinical practices are urgently needed
z-STED Imaging and Spectroscopy to Investigate Nanoscale Membrane Structure and Dynamics: supporting dataset
No full textThis dataset was used to generate the figures in the paper:
Barbotin A, Urbančič I, Galiani S, Eggeling C, Booth M, Sezgin E, z-STED imaging and spectroscopy to investigate nanoscale
membrane structure and dynamics, Biophysical Journal (2020), doi: https://doi.org/10.1016/j.bpj.2020.04.006.
It contains the raw data as well as the data analysis code in Python (when applicable). The compressed archive contains subfolders and instructions included in the relevant folders STED microscopy data of lipids in model systems and living cells