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Alzheimer's Disease (AD) is a growing global public health challenge. The development of new therapies is urgently needed, and a complex ecosystem of organizations has grown to facilitate AD drug discovery and development. Masterfully collating information on the drug development ecosystem, this book emphasizes the contributions of each aspect in the pipeline with a uniform approach to chapters, enabling readers to access relevant information quickly. Topics covered include drug discovery, non-clinical testing model, use of artificial intelligence, management of clinical trials, funding and financing models as well as biomarker and imaging development. The critical role of advocacy in both fundraising for drug development and the eventual implementation of treatment advances is presented. This is the definitive overview of how the ecosystem works in transferring an AD drug from its discovery in the laboratory through clinical trial testing to regulatory review and eventual marketing.
Non-Newtonian fluids are characterized by complex rheological behaviour that affects the hydrodynamic features, such as the flow rate–pressure drop relation. While flow rate–pressure drop measurements of such fluids are common in the literature, a comparison of experimental data with theory is rare, even for shear-thinning fluids at low Reynolds number, presumably due to the lack of analytical expressions for the flow rate–pressure drop relation covering the entire range of pressures and flow rates. Such a comparison, however, is of fundamental importance as it may provide insight into the adequacy of the constitutive model that was used and the values of the rheological parameters. In this work, we present a theoretical approach to calculating the flow rate–pressure drop relation of shear-thinning fluids in long, narrow channels that can be used for comparison with experimental measurements. We utilize the Carreau constitutive model and provide a semi-analytical expression for the flow rate–pressure drop relation. In particular, we derive three asymptotic solutions for small, intermediate and large values of the dimensionless pressures or flow rates, which agree with distinct limits previously known and allow us to approximate analytically the entire flow rate–pressure drop curve. We compare our semi-analytical and asymptotic results with the experimental measurements of Pipe et al. (Rheol. Acta, vol. 47, 2008, pp. 621–642) and find excellent agreement. Our results rationalize the change in the slope of the flow rate–pressure drop data, when reported in log–log coordinates, at high flow rates, which cannot be explained using a simple power-law model.
Background: Effective inpatient stewardship initiatives can improve antibiotic prescribing, but impact on outcomes like Clostridioides difficile infections (CDIs) is less apparent. However, the effect of inpatient stewardship efforts may extend to the postdischarge setting. We evaluated whether an intervention targeting inpatient fluoroquinolone (FQ) use in a large healthcare system reduced incidence of postdischarge CDI. Methods: In August 2019, 4 acute-care hospitals in a large healthcare system replaced standalone FQ orders with order sets containing decision support. Order sets redirected prescribers to syndrome order sets that prioritize alternative antibiotics. Monthly patient days (PDs) and antibiotic days of therapy (DOT) administered for FQs and NHSN-defined broad-spectrum hospital-onset (BS-HO) antibiotics were calculated using patient encounter data for the 23 months before and 13 months after the intervention (COVID-19 admissions in the previous 7 months). We evaluated hospital-onset CDI (HO-CDI) per 1,000 PD (defined as any positive test after hospital day 3) and 12-week postdischarge (PDC- CDI) per 100 discharges (any positive test within healthcare system <12 weeks after discharge). Interrupted time-series analysis using generalized estimating equation models with negative binomial link function was conducted; a sensitivity analysis with Medicare case-mix index (CMI) adjustment was also performed to control for differences after start of the COVID-19 pandemic. Results: Among 163,117 admissions, there were 683 HO-CDIs and 1,009 PDC-CDIs. Overall, FQ DOT per 1,000 PD decreased by 21% immediately after the intervention (level change; P < .05) and decreased at a consistent rate throughout the entire study period (−2% per month; P < .01) (Fig. 1). There was a nonsignificant 5% increase in BS-HO antibiotic use immediately after intervention and a continued increase in use after the intervention (0.3% per month; P = .37). HO-CDI rates were stable throughout the study period, with a nonsignificant level change decrease of 10% after the intervention. In contrast, there was a reversal in the trend in PDC-CDI rates from a 0.4% per month increase in the preintervention period to a 3% per month decrease in the postintervention period (P < .01). Sensitivity analysis with adjustment for facility-specific CMI produced similar results but with wider confidence intervals, as did an analysis with a distinct COVID-19 time point. Conclusion: Our systemwide intervention using order sets with decision support reduced inpatient FQ use by 21%. The intervention did not significantly reduce HO-CDI but significantly decreased the incidence of CDI within 12 weeks after discharge. Relying on outcome measures limited to inpatient setting may not reflect the full impact of inpatient stewardship efforts and incorporating postdischarge outcomes, such as CDI, should increasingly be considered.
In this narrative review we consider what is known about mental health conditions in the prison system in Bangladesh and describe the current provision of mental health services for prisoners with mental health needs. We contextualise this within the literature on mental health conditions in correctional settings in the wider sub-continental region and low- and middle-income countries (LMICs) more broadly. We augment findings from the literature with information from unstructured interviews with local experts, and offer recommendations for research, policy and practice.
In 829 hospital encounters for patients with COVID-19, 73.2% included orders for antibiotics; however, only 1.8% had respiratory cultures during the first 3 hospital days isolating bacteria. Case–control analysis of 30 patients and 96 controls found that each antibiotic day increased the risk of isolating multidrug-resistant gram-negative bacteria (MDR-GNB) in respiratory cultures by 6.5%.
The Anthropocene Epoch offers both unprecedented challenges and opportunities for humanity. Which of those prevails will depend on decisions made at all levels, from global to individual, over coming years. There have been many warnings of the risks arising from our current myopic development pathways but the prospect of serious, and even catastrophic, effects may not motivate action on the scale and pace required; indeed it can result in feelings of impotence and resignation.
The industrial revolution, the rise of nation states, and the emergence of market societies represented a turning point in the history of human civilization – a Great Transformation, as memorably characterized by economic historian Karl Polanyi (1). Indeed, there are echoes of Polanyi’s phrase in the Great Acceleration, the vast upscaling of the human enterprise that has brought us up against planetary boundaries (2). We can assert, without hyperbole, that another civilizational transformation is now needed – a transformation in how energy and materials are used, in how humans co-exist with the natural world, and in the accompanying social and economic underpinnings of modern societies (3, 4).
The story has to begin during the long (in human but not geological terms) period of the last nearly 12,000 years forming the Holocene Epoch, when humanity emerged from hunter-gatherer to agrarian communities and later into growing urban settlements founded on trade, and increasingly manufacturing. The Holocene was notable for its relative climatic stability, which allowed civilization as we know it to emerge. It was interrupted only by little ice ages – significant on human scale but minimally so on a geological scale. Much can be learned from the impacts of relatively modest fluctuations in climate on human society over this period (3). These lessons help us assess the likely effects of rapid climate and other changes on health and development in the future (see Chapter 2).
The Sustainable Development Goals (SDGs) were adopted in 2015 by all UN member states and represent an ambitious, far-reaching programme of action. If implemented, they would set nations on a course that significantly enhances the prospects for sustaining human progress with a lower level of environmental impacts than today’s development pathway. The SDGs are the latest manifestation of a process than can be traced at least as far back as the Earth Summit in Rio de Janeiro in 1992. There, over 170 countries adopted Agenda 21, a comprehensive action plan to catalyse a global partnership for sustainable development aimed at improving human lives and protecting the environment. The Earth Summit was a significant milestone; it established the fundamental principle that the attainment of healthy and productive lives in harmony with nature should be at the heart of the sustainable development agenda. It led to a number of crucial international conventions including the UN Framework Convention on Climate Change and the UN Convention on Biological Diversity. Nevertheless, subsequent progress was disappointing in several respects. The creation of a fair and just trading system which would foster the development of least developed countries proceeded slowly, with many wealthy nations maintaining subsidies favouring their own interests. Growth in development assistance proceeded at a slower rate than agreed and inequities between and within nations were pervasive, offsetting many of the potential benefits of economic growth. Environmental degradation continued apace, as we have seen, and the opportunity to capitalize on the momentum of the Earth Summit largely dissipated (1).
Providing equitable access to nutritious and affordable food for a growing world population in the face of multiple environmental changes is one of the greatest challenges facing humanity. Despite steep increases in agricultural yields beginning in the mid-twentieth century, the global food system is failing to provide nutritious food for much of the world’s population. The food system also imposes a heavy burden on Earth systems; it is a major driver of land use change, biodiversity loss, freshwater depletion, air and water pollution and climate change, as outlined in Chapters 1–3. Current food systems are also grossly inefficient, with, for example, overuse of nitrogen and phosphorus in some regions and underuse in others, together with high levels of food loss and waste, such that about 30% of food produced is never eaten (1). This chapter focuses on potential strategies to improve nutrition and health while reducing the environmental footprint of food systems, with the aim of staying within planetary boundaries.
Many of the dramatic changes across the planet during the Anthropocene Epoch cannot be reversed within our lifespans, so it becomes imperative to adapt to change as far as possible. According to the IPCC, adaptation is ‘the process of adjustment to actual or expected climate and its effects. In human systems, adaptation seeks to moderate or avoid harm or exploit beneficial opportunities. In some natural systems, human intervention may facilitate adjustment to expected climate and its effects’ (1, p. SPM 5). While this definition refers only to climate, the context in which adaptation has been most thoroughly considered, the concept of adaptation is applicable to the full range of planetary changes. As implied by the IPCC definition, an adaptation action might be taken proactively, to reduce harm in advance of an impact, or reactively, in response to a perceived or real health risk.
Environmental change will pose numerous challenges to health systems, as described in earlier chapters. They will need to become more resilient to shocks, including extreme events, and be able to detect and respond to changing patterns of disease (see Chapter 5). This chapter describes four major ways in which health professionals can catalyse rapid decarbonization of the economy and support moves to live within planetary boundaries while protecting health: reducing the burden of preventable ill-health; reducing the environmental impact of health care; contributing to slowing population growth; and providing broader societal leadership.
The Anthropocene Epoch confronts humanity with unprecedented challenges. Meeting these challenges demands fundamentally different modes of thought, institutions, technologies, policies, values, and governance systems than those that propelled the Great Acceleration. Humanity is at a crossroads. With environmental stressors intensifying, and with the world population growing, we need integrated solutions across sectors to address today’s challenges and to reduce future risks to a minimum. The scale of change required is dramatic.