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Phase three trials of the monoclonal antibodies lecanemab and donanemab, which target brain amyloid, have reported statistically significant differences in clinical end-points in early Alzheimer's disease. These drugs are already in use in some countries and are going through the regulatory approval process for use in the UK. Concerns have been raised about the ability of healthcare systems, including those in the UK, to deliver these treatments, considering the resources required for their administration and monitoring.
Aims
To estimate the scale of real-world demand for monoclonal antibodies for Alzheimer's disease in the UK.
Method
We used anonymised patient record databases from two National Health Service trusts for the year 2019 to collect clinical, demographic, cognitive and neuroimaging data for these cohorts. Eligibility for treatment was assessed using the inclusion criteria from the clinical trials of donanemab and lecanemab, with consideration given to diagnosis, cognitive performance, cerebrovascular disease and willingness to receive treatment.
Results
We examined the records of 82 386 people referred to services covering around 2.2 million people. After applying the trial criteria, we estimate that a maximum of 906 people per year would start treatment with monoclonal antibodies in the two services, equating to 30 200 people if extrapolated nationally.
Conclusions
Monoclonal antibody treatments for Alzheimer's disease are likely to present a significant challenge for healthcare services to deliver in terms of the neuroimaging and treatment delivery. The data provided here allows health services to understand the potential demand and plan accordingly.
Humans operating in extreme environments often conduct their operations at the edges of the limits of human performance. Sometimes, they are required to push these limits to previously unattained levels. As a result, their margins for error in execution are much smaller than that found in the general public. These same small margins for error that impact execution may also impact risk, safety, health, and even survival. Thus, humans operating in extreme environments have a need for greater refinement in their preparation, training, fitness, and medical care. Precision medicine (PM) is uniquely suited to address the needs of those engaged in these extreme operations because of its depth of molecular analysis, derived precision countermeasures, and ability to match each individual (and his or her specific molecular phenotype) with any given operating context (environment). Herein, we present an overview of a systems approach to PM in extreme environments, which affords clinicians one method to contextualize the inputs, processes, and outputs that can form the basis of a formal practice. For the sake of brevity, this overview is focused on molecular dynamics, while providing only a brief introduction to the also important physiologic and behavioral phenotypes in PM. Moreover, rather than a full review, it highlights important concepts, while using only selected citations to illustrate those concepts. It further explores, by demonstration, the basic principles of using functionally characterized molecular networks to guide the practical application of PM in extreme environments. At its core, PM in extreme environments is about attention to incremental gains and losses in molecular network efficiency that can scale to produce notable changes in health and performance. The aim of this overview is to provide a conceptual overview of one approach to PM in extreme environments, coupled with a selected suite of practical considerations for molecular profiling and countermeasures.
To assess the proportion of inpatients who received guideline-concordant antibiotics for community-acquired bacterial pneumonia (CABP) in special populations of the All of Us database.
Background:
CABP contributes significantly to healthcare burden worldwide. The American Thoracic Society and Infectious Disease Society of America jointly published guidelines for the treatment of CABP. Guideline-concordant antibiotics for CABP are associated with better patient and cost outcomes.
Methods:
This was a retrospective cohort study of patients with pneumonia (n = 1608; SNOMED 233604007) from 10/1/2018 to 1/01/22 in the All of Us database. Cases were excluded for treatment setting other than inpatient, prior (within 90 days) pneumonia, receipt of intravenous antibiotics, respiratory isolation of methicillin-resistant Staphylococcus aureus (MRSA) or Pseudomonas aeruginosa, and/or other non-community-acquired types of pneumonia. Patients were grouped based on patient age, sex, race, and ethnicity. The proportion of patients on guideline-concordant therapy was compared within groups using chi-square statistics. Significant associations were assessed using multivariate logistic regression models.
Results:
A total of 1608 cases were included, and 45% of these patients received guideline-concordant antibiotics. Non-Hispanic White (NHW) patients vs. Black patients were associated with a 36% higher likelihood for receiving guideline-concordant antibiotics (adjusted OR, 1.36; 95% CI 1.02–1.81), whereas NHW vs. Hispanic patients were associated with a 34% lower likelihood for receiving guideline-concordant antibiotics (aOR 0.66; 0.48–0.91).
Conclusion:
Black patients with CABP in the All of Us database were less likely to receive guideline-concordant antibiotics, and Hispanic patients were more likely to receive guideline-concordant antibiotics, than NHW patients.
High performance health financing requires funding levels that are adequate, sustainable and resilient to meet country health goals, pooling that is sufficient to spread the financial risks of ill-health across the population, and spending that is both efficient and equitable to assure the desired levels of health service coverage, quality, and financial protection for all people. This chapter describes the various components of health financing and how they interact to determine how rapidly countries can approach the goal of Universal Health Coverage.
Cognitive Bias Modification for paranoia (CBM-pa) is a novel, theory-driven psychological intervention targeting the biased interpretation of emotional ambiguity associated with paranoia. Study objectives were (i) test the intervention's feasibility, (ii) provide effect size estimates, (iii) assess dose–response and (iv) select primary outcomes for future trials.
Methods
In a double-blind randomised controlled trial, sixty-three outpatients with clinically significant paranoia were randomised to either CBM-pa or an active control (text reading) between April 2016 and September 2017. Patients received one 40 min session per week for 6 weeks. Assessments were given at baseline, after each interim session, post-treatment, and at 1- and 3-months post-treatment.
Results
A total of 122 patients were screened and 63 were randomised. The recruitment rate was 51.2%, with few dropouts (four out of 63) and follow-up rates were 90.5% (1-month) and 93.7% (3-months). Each session took 30–40 min to complete. There was no statistical evidence of harmful effects of the intervention. Preliminary data were consistent with efficacy of CBM-pa over text-reading control: patients randomised to the intervention, compared to control patients, reported reduced interpretation bias (d = −0.48 to −0.76), improved symptoms of paranoia (d = −0.19 to −0.38), and lower depressed and anxious mood (d = −0.03 to −0.29). The intervention effect was evident after the third session.
Conclusions
CBM-pa is feasible for patients with paranoia. A fully powered randomised control trial is warranted.
It is well known that John Stuart Mill (JSM) repeatedly acknowledges Harriet Taylor Mill's (HTM) substantial contribution to On Liberty. After her death, however, he decides to publish the book under his name only. Are we justified in continuing this practice, initiated by JSM, of refusing unequivocal co-authorship status to HTM? Drawing on stylometric analyses, we make a preliminary case that JSM did not write On Liberty all by himself and that HTM had a hand in formulating it. Drawing on plausible standards for authorship ascription, we further point out that authorship status requires, in addition to a substantial contribution, the approval by all contributors. We discuss potential reasons to assume that HTM did not approve the published version of On Liberty and would have objected to including her name on the title page.
We present an overview of the SkyMapper optical follow-up programme for gravitational-wave event triggers from the LIGO/Virgo observatories, which aims at identifying early GW170817-like kilonovae out to
$\sim200\,\mathrm{Mpc}$
distance. We describe our robotic facility for rapid transient follow-up, which can target most of the sky at
$\delta<+10\deg $
to a depth of
$i_\mathrm{AB}\approx 20\,\mathrm{mag}$
. We have implemented a new software pipeline to receive LIGO/Virgo alerts, schedule observations and examine the incoming real-time data stream for transient candidates. We adopt a real-bogus classifier using ensemble-based machine learning techniques, attaining high completeness (
$\sim98\%$
) and purity (
$\sim91\%$
) over our whole magnitude range. Applying further filtering to remove common image artefacts and known sources of transients, such as asteroids and variable stars, reduces the number of candidates by a factor of more than 10. We demonstrate the system performance with data obtained for GW190425, a binary neutron star merger detected during the LIGO/Virgo O3 observing campaign. In time for the LIGO/Virgo O4 run, we will have deeper reference images allowing transient detection to
$i_\mathrm{AB}\approx 21\,\mathrm{mag}$
.
New IRSL ages of eolianites close to Muñique (Lanzarote) demonstrate the influence of millennial scale climatic variability on the sedimentary dynamics on the Canary Islands during the last glacial cycle. The repetitive succession of interstadial and stadial climatic conditions formed multiple sequences of eolian deposits, each in general comprising three depositional types. DepoType 1 and DepoType 2 consist mainly of marine biogenic carbonate detritus with small amounts of dust from the Sahara representing interstadial conditions. DepoType 2 compared to DepoType 1 is characterized by larger amounts of land snails and calcified brood cells. A DepoType 3 rich in dust from African subtropical/tropical Latisols terminates a sequence. IRSL dating on DepoType 3 type deposits clearly shows that these were deposited during Heinrich Events under stadial conditions. The stadial cooling of the North Atlantic Ocean caused a southern shift of climate zones that culminated during Heinrich Events when the arctic climate reaches its most southerly extent. As a consequence, atmospheric changes led to massive dust supply from the then-dry Sahel. The increase in dust and precipitation from the dry DepoTypes 1 to the more humid DepoTypes 3 originates from a modified atmospheric dynamic during a millennial cycle.
Over the past century and a half, Americans have contested the meaning of civil rights. The term first emerged as a distinctive, salient, and meaningful category of American political discourse at the end of the Civil War during a national debate over the rights due to America’s four million newly emancipated black men, women, and children. It became a focal point for a generation of struggle over the meaning of freedom, the boundaries of racial equality, and the responsibilities of the federal government. As a category of law, it helped open the door to some of the most ambitious constitutional and legal transformations in American history, even as it served to contain the scope of those changes.
This book revolves around a deceptively simple question: What do we mean when we say that something is an issue of civil rights? Americans use the term all the time. We have government agencies dedicated to protecting civil rights. We know the heroic struggle for racial equality of the 1960s as the civil rights movement. We’re now supposedly in a post-civil rights era – even as we’re constantly on the watch for new civil rights movements. We identify certain people as civil rights icons. We declare public officials good or bad on civil rights. All of this assumes “civil rights” includes certain things and not others. But look up the term in a dictionary or legal reference work and you’ll find a mix of abstractions and stilted legalisms, none of which captures the depth and complexity of meaning that is conveyed with its invocation and none of which hints at historic and ongoing struggles over its contents.
“What are civil rights?” James F. Wilson asked his colleagues in the United States House of Representatives on March 1, 1866. Less than a year since the end of the Civil War, with Congress consumed with the task of reconstructing a nation torn apart, the Iowa Republican stood on the floor of the House to defend what was referred to as the “Civil Rights” bill. The proposed law – its full title was “An Act to protect all Persons in the United States in their Civil Rights, and furnish the Means of their vindication” – would provide federal protection of certain basic rights for the millions of recently emancipated black Americans.
Ward Connerly considers himself a dedicated proponent of civil rights. A black man born in Jim Crow Louisiana, Connerly has sought to carry on what he sees as the vital work of the civil rights movement. As a student at California State in the early 1960s, he testified before the state legislature in support of a law that would ban housing discrimination. After a successful business career, he was appointed to the University of California Board of Regents, and he then rose to national prominence in the 1990s for his efforts to get California voters to approve the Civil Rights Initiative, an amendment to the state constitution that was modeled on the language of the Civil Right Act of 1964.
John Marshall Harlan deserves a prominent place in any history of civil rights in the United States. In the closing years of the nineteenth century, when eight justices of the United States Supreme Court saw no constitutional violation in a Louisiana law requiring racial segregation in railcars, Justice Harlan stood alone in declaring the equal protection clause of the Fourteenth Amendment a barrier to the malicious spread of Jim Crow. The words of his dissenting opinion in Plessy v. Ferguson (1896) have echoed through the years. “Our Constitution is color-blind, and neither knows nor tolerates classes among citizens,” he wrote. “In respect of civil rights, all citizens are equal before the law.