Intensive care doctors and nurses personal preferences for intensive Care, as compared to the general population: a discrete choice experiment

Background To test the hypothesis that Intensive Care Unit (ICU) doctors and nurses differ in their personal preferences for treatment from the general population, and whether doctors and nurses make different choices when thinking about themselves, as compared to when they are treating a patient. Methods Cross sectional, observational study conducted in 13 ICUs in Australia in 2017 using a discrete choice experiment survey. Respondents completed a series of choice sets, based on hypothetical situations which varied in the severity or likelihood of: death, cognitive impairment, need for prolonged treatment, need for assistance with care or requiring residential care. Results A total of 980 ICU staff (233 doctors and 747 nurses) participated in the study. ICU staff place the highest value on avoiding ending up in a dependent state. The ICU staff were more likely to choose to discontinue therapy when the prognosis was worse, compared with the general population. There was consensus between ICU staff personal views and the treatment pathway likely to be followed in 69% of the choices considered by nurses and 70% of those faced by doctors. In 27% (1614/5945 responses) of the nurses and 23% of the doctors (435/1870 responses), they felt that aggressive treatment would be continued for the hypothetical patient but they would not want that for themselves. Conclusion The likelihood of returning to independence (or not requiring care assistance) was reported as the most important factor for ICU staff (and the general population) in deciding whether to receive ongoing treatments. Goals of care discussions should focus on this, over likelihood of survival

Inherently safer technology gaps analysis study.

Approved for public release; further dissemination unlimited

Reducing the Risk of Cognitive Decline and Dementia: WHO Recommendations

With population ageing worldwide, dementia poses one of the greatest global challenges for health and social care in the 21st century. In 2019, around 55 million people were affected by dementia, with the majority living in low- and middle-income countries. Dementia leads to increased costs for governments, communities, families and individuals. Dementia is overwhelming for the family and caregivers of the person with dementia, who are the cornerstone of care and support systems throughout the world. To assist countries in addressing the global burden of dementia, the World Health Organisation (WHO) developed the Global Action Plan on the Public Health Response to Dementia 2017–2025. It proposes actions to be taken by governments, civil society, and other global and regional partners across seven action areas, one of which is dementia risk reduction. This paper is based on WHO Guidelines on risk reduction of cognitive decline and dementia and presents recommendations on evidence-based, multisectoral interventions for reducing dementia risks, considerations for their implementation and policy actions. These global evidence-informed recommendations were developed by WHO, following a rigorous guideline development methodology and involved a panel of academicians and clinicians with multidisciplinary expertise and representing geographical diversity. The recommendations are considered under three broad headings: lifestyle and behaviour interventions, interventions for physical health conditions and specific interventions. By supporting health and social care professionals, particularly by improving their capacity to provide gender and culturally appropriate interventions to the general population, the risk of developing dementia can be potentially reduced, or its progression delayed

Sequestration and Tissue Accumulation of Human Malaria Parasites: Can We Learn Anything from Rodent Models of Malaria?

The sequestration of Plasmodium falciparum–infected red blood cells (irbcs) in the microvasculature of organs is associated with severe disease; correspondingly, the molecular basis of irbc adherence is an active area of study. In contrast to P. falciparum, much less is known about sequestration in other Plasmodium parasites, including those species that are used as models to study severe malaria. Here, we review the cytoadherence properties of irbcs of the rodent parasite Plasmodium berghei ANKA, where schizonts demonstrate a clear sequestration phenotype. Real-time in vivo imaging of transgenic P. berghei parasites in rodents has revealed a CD36-dependent sequestration in lungs and adipose tissue. In the absence of direct orthologs of the P. falciparum proteins that mediate binding to human CD36, the P. berghei proteins and/or mechanisms of rodent CD36 binding are as yet unknown. In addition to CD36-dependent schizont sequestration, irbcs accumulate during severe disease in different tissues, including the brain. The role of sequestration is discussed in the context of disease as are the general (dis)similarities of P. berghei and P. falciparum sequestration

Green Space and cognitive ageing: a retrospective life course analysis in the Lothian Birth Cohort 1936

International evidence suggests that green space has beneficial effects on general and mental health but little is known about how lifetime exposure to green space influences cognitive ageing. Employing a novel longitudinal life course approach, we examined the association between lifetime availability of public parks and cognitive ageing. Lifetime residential information was gathered from the participants of the Lothian Birth Cohort 1936 using a "life-grid" questionnaire at age 78 years. Parks information from 1949, 1969 and 2009 was used to determine a percentage of parks within a 1500 m buffer zone surrounding residence for childhood, adulthood, and later adulthood periods. Linear regressions were undertaken to test for association with age-standardised, residualised change in cognitive function (Moray House Test score) from age 11 to 70 years, and from age 70 to 76 (n = 281). The most appropriate model was selected using the results of a partial F-test, and then stratified by demographic, genetic and socioeconomic factors. The local provision of park space in childhood and adulthood were both important in explaining the change in cognitive function in later life. The association between childhood and adulthood park availability and change in the Moray House Test Score from age 70 to 76 was strongest for women, those without an APOE e4 allele (a genetic risk factor), and those in the lowest socioeconomic groups. Greater neighbourhood provision of public parks from childhood through to adulthood may help to slow down the rate of cognitive decline in later life, recognising that such environmental associations are always sensitive to individual characteristics

Blocking and its response to climate change

Purpose of review: Atmospheric blocking events represent some of the most high-impact weather patterns in the mid-latitudes, yet they have often been a cause for concern in future climate projections. There has been low confidence in predicted future changes in blocking, despite relatively good agreement between climate models on a decline in blocking. This is due to the lack of a comprehensive theory of blocking and a pervasive underestimation of blocking occurrence by models. This paper reviews the state of knowledge regarding blocking under climate change, with the aim of providing an overview for those working in related fields. Recent Findings: Several avenues have been identified by which blocking can be improved in numerical models, though a fully reliable simulation remains elusive (at least, beyond a few days lead time). Models are therefore starting to provide some useful information on how blocking and its impacts may change in the future, although deeper understanding of the processes at play will be needed to increase confidence in model projections. There are still major uncertainties regarding the processes most important to the onset, maintenance and decay of blocking and advances in our understanding of atmospheric dynamics, for example in the role of diabatic processes, continue to inform the modelling and prediction efforts. Summary: The term ‘blocking’ covers a diverse array of synoptic patterns, and hence a bewildering range of indices has been developed to identify events. Results are hence not considered fully trustworthy until they have been found using several different methods. Examples of such robust results are the underestimation of blocking by models, and an overall decline in future occurrence, albeit with a complex regional and seasonal variation. In contrast, hemispheric trends in blocking over the recent historical period are not supported by different methods, and natural variability will likely dominate regional variations over the next few decades

Human malarial disease: a consequence of inflammatory cytokine release

Malaria causes an acute systemic human disease that bears many similarities, both clinically and mechanistically, to those caused by bacteria, rickettsia, and viruses. Over the past few decades, a literature has emerged that argues for most of the pathology seen in all of these infectious diseases being explained by activation of the inflammatory system, with the balance between the pro and anti-inflammatory cytokines being tipped towards the onset of systemic inflammation. Although not often expressed in energy terms, there is, when reduced to biochemical essentials, wide agreement that infection with falciparum malaria is often fatal because mitochondria are unable to generate enough ATP to maintain normal cellular function. Most, however, would contend that this largely occurs because sequestered parasitized red cells prevent sufficient oxygen getting to where it is needed. This review considers the evidence that an equally or more important way ATP deficency arises in malaria, as well as these other infectious diseases, is an inability of mitochondria, through the effects of inflammatory cytokines on their function, to utilise available oxygen. This activity of these cytokines, plus their capacity to control the pathways through which oxygen supply to mitochondria are restricted (particularly through directing sequestration and driving anaemia), combine to make falciparum malaria primarily an inflammatory cytokine-driven disease

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

SummaryBackground Azithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatoryactions. We aimed to evaluate the safety and efficacy of azithromycin in patients admitted to hospital with COVID-19.Methods In this randomised, controlled, open-label, adaptive platform trial (Randomised Evaluation of COVID-19Therapy [RECOVERY]), several possible treatments were compared with usual care in patients admitted to hospitalwith COVID-19 in the UK. The trial is underway at 176 hospitals in the UK. Eligible and consenting patients wererandomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once perday by mouth or intravenously for 10 days or until discharge (or allocation to one of the other RECOVERY treatmentgroups). Patients were assigned via web-based simple (unstratified) randomisation with allocation concealment andwere twice as likely to be randomly assigned to usual care than to any of the active treatment groups. Participants andlocal study staff were not masked to the allocated treatment, but all others involved in the trial were masked to theoutcome data during the trial. The primary outcome was 28-day all-cause mortality, assessed in the intention-to-treatpopulation. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936.Findings Between April 7 and Nov 27, 2020, of 16 442 patients enrolled in the RECOVERY trial, 9433 (57%) wereeligible and 7763 were included in the assessment of azithromycin. The mean age of these study participants was65·3 years (SD 15·7) and approximately a third were women (2944 [38%] of 7763). 2582 patients were randomlyallocated to receive azithromycin and 5181 patients were randomly allocated to usual care alone. Overall,561 (22%) patients allocated to azithromycin and 1162 (22%) patients allocated to usual care died within 28 days(rate ratio 0·97, 95% CI 0·87–1·07; p=0·50). No significant difference was seen in duration of hospital stay (median10 days [IQR 5 to >28] vs 11 days [5 to >28]) or the proportion of patients discharged from hospital alive within 28 days(rate ratio 1·04, 95% CI 0·98–1·10; p=0·19). Among those not on invasive mechanical ventilation at baseline, nosignificant difference was seen in the proportion meeting the composite endpoint of invasive mechanical ventilationor death (risk ratio 0·95, 95% CI 0·87–1·03; p=0·24).Interpretation In patients admitted to hospital with COVID-19, azithromycin did not improve survival or otherprespecified clinical outcomes. Azithromycin use in patients admitted to hospital with COVID-19 should be restrictedto patients in whom there is a clear antimicrobial indication

Updating the evidence on the association between serum cholesterol and risk of late-life dementia: Review and meta-analysis

Background: Cohort studies have reported that midlife high total serum cholesterol (TC) is associated with increased risk of Alzheimer's disease (AD) in late-life but findings have been based on few studies and previous reviews have been limited by a lack of compatible data. Objective: We synthesized all high quality data from cohort studies reporting on the association between total serum cholesterol measured and late-life cognitive outcomes including Alzheimer's disease (AD), vascular dementia (VaD), any dementia, mild cognitive impairment (MCI), and cognitive decline. Methods: The literature was searched up to October 2016 using a registered protocol. Thirty-four articles meeting study criteria were identified. Seventeen studies published from 1996 to 2014, including 23,338 participants were included in meta-analyses. Results: Relative risk of developing AD for adults with high TC in midlife was 2.14 (95% CI 1.33-3.44) compared with normal cholesterol. Individual studies that could not be pooled also reported high TC in midlife increased the risk of MCI and cognitive decline in late-life. High TC in late-life was not associated with MCI, AD, VaD, any dementia, or cognitive decline. Late-life measured HDL cholesterol and triglycerides were not associated with increased risk of VaD, and HDL was not associated with risk of MCI, AD, or any dementia. There were insufficient data to examine other cholesterol sub-fractions, sex differences, or APOE interactions. Conclusions: Significant gaps in the literature regarding TC and late-life dementia remain. Evidence suggests that high midlife TC increases risk of late-life AD, and may correlate with the onset of AD pathology

Proportion of dementia in Australia explained by common modifiable risk factors

Background: At present, dementia has no known cure. Interventions to delay onset and reduce prevalence of the disease are therefore focused on risk factor reduction. Previous population attributable risk estimates for western countries may have been underestimated as a result of the relatively low rates of midlife obesity and the lower weighting given to that variable in statistical models. Methods: Levin’s Attributable Risk which assumes independence of risk factors was used to calculate the proportion of dementia attributable to seven modifiable risk factors (midlife obesity, physical inactivity, smoking, low educational attainment, diabetes mellitus, midlife hypertension and depression) in Australia. Using a recently published modified formula and survey data from the Australia Diabetes, Obesity and Lifestyle Study, a more realistic population attributable risk estimate which accounts for non-independence of risk factors was calculated. Finally, the effect of a 5-20% reduction in each risk factor per decade on future dementia prevalence was computed. Results: Taking into consideration that risk factors do not operate independently, a more conservative estimate of 48.4% of dementia cases (117,294 of 242,500 cases) was found to be attributable to the seven modifiable lifestyle factors under study. We calculated that if each risk factor was to be reduced by 5%, 10%, 15% and 20% per decade, dementia prevalence would be reduced by between 1.6 and 7.2% in 2020, 3.3-14.9% in 2030, 4.9-22.8% in 2040 and 6.6-30.7% in 2050. Conclusion: Our largely theory-based findings suggest a strong case for greater investment in risk factor reduction programmes that target modifiable lifestyle factors, particularly increased engagement in physical activity. However, further data on risk factor treatment and dementia risk reduction from population-based studies are needed to investigate whether our estimates of potential dementia prevention are indeed realistic