搜索结果：Annual review of pharmacology and toxicology

For more than three decades, the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) has provided a framework to quantify health loss due to diseases, injuries, and associated risk factors. This paper presents GBD 2023 findings on disease and injury burden and risk-attributable health loss, offering a global audit of the state of world health to inform public health priorities. This work captures the evolving landscape of health metrics across age groups, sexes, and locations, while reflecting on the remaining post-COVID-19 challenges to achieving our collective global health ambitions. The GBD 2023 combined analysis estimated years lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life-years (DALYs) for 375 diseases and injuries, and risk-attributable burden associated with 88 modifiable risk factors. Of the more than 310 000 total data sources used for all GBD 2023 (about 30% of which were new to this estimation round), more than 120 000 sources were used for estimation of disease and injury burden and 59 000 for risk factor estimation, and included vital registration systems, surveys, disease registries, and published scientific literature. Data were analysed using previously established modelling approaches, such as disease modelling meta-regression version 2.1 (DisMod-MR 2.1) and comparative risk assessment methods. Diseases and injuries were categorised into four levels on the basis of the established GBD cause hierarchy, as were risk factors using the GBD risk hierarchy. Estimates stratified by age, sex, location, and year from 1990 to 2023 were focused on disease-specific time trends over the 2010-23 period and presented as counts (to three significant figures) and age-standardised rates per 100 000 person-years (to one decimal place). For each measure, 95% uncertainty intervals [UIs] were calculated with the 2·5th and 97·5th percentile ordered values from a 250-draw distribution. Total numbers of global DALYs grew 6·1% (95% UI 4·0-8·1), from 2·64 billion (2·46-2·86) in 2010 to 2·80 billion (2·57-3·08) in 2023, but age-standardised DALY rates, which account for population growth and ageing, decreased by 12·6% (11·0-14·1), revealing large long-term health improvements. Non-communicable diseases (NCDs) contributed 1·45 billion (1·31-1·61) global DALYs in 2010, increasing to 1·80 billion (1·63-2·03) in 2023, alongside a concurrent 4·1% (1·9-6·3) reduction in age-standardised rates. Based on DALY counts, the leading level 3 NCDs in 2023 were ischaemic heart disease (193 million [176-209] DALYs), stroke (157 million [141-172]), and diabetes (90·2 million [75·2-107]), with the largest increases in age-standardised rates since 2010 occurring for anxiety disorders (62·8% [34·0-107·5]), depressive disorders (26·3% [11·6-42·9]), and diabetes (14·9% [7·5-25·6]). Remarkable health gains were made for communicable, maternal, neonatal, and nutritional (CMNN) diseases, with DALYs falling from 874 million (837-917) in 2010 to 681 million (642-736) in 2023, and a 25·8% (22·6-28·7) reduction in age-standardised DALY rates. During the COVID-19 pandemic, DALYs due to CMNN diseases rose but returned to pre-pandemic levels by 2023. From 2010 to 2023, decreases in age-standardised rates for CMNN diseases were led by rate decreases of 49·1% (32·7-61·0) for diarrhoeal diseases, 42·9% (38·0-48·0) for HIV/AIDS, and 42·2% (23·6-56·6) for tuberculosis. Neonatal disorders and lower respiratory infections remained the leading level 3 CMNN causes globally in 2023, although both showed notable rate decreases from 2010, declining by 16·5% (10·6-22·0) and 24·8% (7·4-36·7), respectively. Injury-related age-standardised DALY rates decreased by 15·6% (10·7-19·8) over the same period. Differences in burden due to NCDs, CMNN diseases, and injuries persisted across age, sex, time, and location. Based on our risk analysis, nearly 50% (1·27 billion [1·18-1·38]) of the roughly 2·80 billion total global DALYs in 2023 were attributable to the 88 risk factors analysed in GBD. Globally, the five level 3 risk factors contributing the highest proportion of risk-attributable DALYs were high systolic blood pressure (SBP), particulate matter pollution, high fasting plasma glucose (FPG), smoking, and low birthweight and short gestation-with high SBP accounting for 8·4% (6·9-10·0) of total DALYs. Of the three overarching level 1 GBD risk factor categories-behavioural, metabolic, and environmental and occupational-risk-attributable DALYs rose between 2010 and 2023 only for metabolic risks, increasing by 30·7% (24·8-37·3); however, age-standardised DALY rates attributable to metabolic risks decreased by 6·7% (2·0-11·0) over the same period. For all but three of the 25 leading level 3 risk factors, age-standardised rates dropped between 2010 and 2023-eg, declining by 54·4% (38·7-65·3) for unsafe sanitation, 50·5% (33·3-63·1) for unsafe water source, and 45·2% (25·6-72·0) for no access to handwashing facility, and by 44·9% (37·3-53·5) for child growth failure. The three leading level 3 risk factors for which age-standardised attributable DALY rates rose were high BMI (10·5% [0·1 to 20·9]), drug use (8·4% [2·6 to 15·3]), and high FPG (6·2% [-2·7 to 15·6]; non-significant). Our findings underscore the complex and dynamic nature of global health challenges. Since 2010, there have been large decreases in burden due to CMNN diseases and many environmental and behavioural risk factors, juxtaposed with sizeable increases in DALYs attributable to metabolic risk factors and NCDs in growing and ageing populations. This long-observed consequence of the global epidemiological transition was only temporarily interrupted by the COVID-19 pandemic. The substantially decreasing CMNN disease burden, despite the 2008 global financial crisis and pandemic-related disruptions, is one of the greatest collective public health successes known. However, these achievements are at risk of being reversed due to major cuts to development assistance for health globally, the effects of which will hit low-income countries with high burden the hardest. Without sustained investment in evidence-based interventions and policies, progress could stall or reverse, leading to widespread human costs and geopolitical instability. Moreover, the rising NCD burden necessitates intensified efforts to mitigate exposure to leading risk factors-eg, air pollution, smoking, and metabolic risks, such as high SBP, BMI, and FPG-including policies that promote food security, healthier diets, physical activity, and equitable and expanded access to potential treatments, such as GLP-1 receptor agonists. Decisive, coordinated action is needed to address long-standing yet growing health challenges, including depressive and anxiety disorders. Yet this can be only part of the solution. Our response to the NCD syndemic-the complex interaction of multiple health risks, social determinants, and systemic challenges-will define the future landscape of global health. To ensure human wellbeing, economic stability, and social equity, global action to sustain and advance health gains must prioritise reducing disparities by addressing socioeconomic and demographic determinants, ensuring equitable health-care access, tackling malnutrition, strengthening health systems, and improving vaccination coverage. We live in times of great opportunity. Gates Foundation and Bloomberg Philanthropies.

Timely and comprehensive analyses of causes of death stratified by age, sex, and location are essential for shaping effective health policies aimed at reducing global mortality. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2023 provides cause-specific mortality estimates measured in counts, rates, and years of life lost (YLLs). GBD 2023 aimed to enhance our understanding of the relationship between age and cause of death by quantifying the probability of dying before age 70 years (70q0) and the mean age at death by cause and sex. This study enables comparisons of the impact of causes of death over time, offering a deeper understanding of how these causes affect global populations. GBD 2023 produced estimates for 292 causes of death disaggregated by age-sex-location-year in 204 countries and territories and 660 subnational locations for each year from 1990 until 2023. We used a modelling tool developed for GBD, the Cause of Death Ensemble model (CODEm), to estimate cause-specific death rates for most causes. We computed YLLs as the product of the number of deaths for each cause-age-sex-location-year and the standard life expectancy at each age. Probability of death was calculated as the chance of dying from a given cause in a specific age period, for a specific population. Mean age at death was calculated by first assigning the midpoint age of each age group for every death, followed by computing the mean of all midpoint ages across all deaths attributed to a given cause. We used GBD death estimates to calculate the observed mean age at death and to model the expected mean age across causes, sexes, years, and locations. The expected mean age reflects the expected mean age at death for individuals within a population, based on global mortality rates and the population's age structure. Comparatively, the observed mean age represents the actual mean age at death, influenced by all factors unique to a location-specific population, including its age structure. As part of the modelling process, uncertainty intervals (UIs) were generated using the 2·5th and 97·5th percentiles from a 250-draw distribution for each metric. Findings are reported as counts and age-standardised rates. Methodological improvements for cause-of-death estimates in GBD 2023 include a correction for the misclassification of deaths due to COVID-19, updates to the method used to estimate COVID-19, and updates to the CODEm modelling framework. This analysis used 55 761 data sources, including vital registration and verbal autopsy data as well as data from surveys, censuses, surveillance systems, and cancer registries, among others. For GBD 2023, there were 312 new country-years of vital registration cause-of-death data, 3 country-years of surveillance data, 51 country-years of verbal autopsy data, and 144 country-years of other data types that were added to those used in previous GBD rounds. The initial years of the COVID-19 pandemic caused shifts in long-standing rankings of the leading causes of global deaths: it ranked as the number one age-standardised cause of death at Level 3 of the GBD cause classification hierarchy in 2021. By 2023, COVID-19 dropped to the 20th place among the leading global causes, returning the rankings of the leading two causes to those typical across the time series (ie, ischaemic heart disease and stroke). While ischaemic heart disease and stroke persist as leading causes of death, there has been progress in reducing their age-standardised mortality rates globally. Four other leading causes have also shown large declines in global age-standardised mortality rates across the study period: diarrhoeal diseases, tuberculosis, stomach cancer, and measles. Other causes of death showed disparate patterns between sexes, notably for deaths from conflict and terrorism in some locations. A large reduction in age-standardised rates of YLLs occurred for neonatal disorders. Despite this, neonatal disorders remained the leading cause of global YLLs over the period studied, except in 2021, when COVID-19 was temporarily the leading cause. Compared to 1990, there has been a considerable reduction in total YLLs in many vaccine-preventable diseases, most notably diphtheria, pertussis, tetanus, and measles. In addition, this study quantified the mean age at death for all-cause mortality and cause-specific mortality and found noticeable variation by sex and location. The global all-cause mean age at death increased from 46·8 years (95% UI 46·6-47·0) in 1990 to 63·4 years (63·1-63·7) in 2023. For males, mean age increased from 45·4 years (45·1-45·7) to 61·2 years (60·7-61·6), and for females it increased from 48·5 years (48·1-48·8) to 65·9 years (65·5-66·3), from 1990 to 2023. The highest all-cause mean age at death in 2023 was found in the high-income super-region, where the mean age for females reached 80·9 years (80·9-81·0) and for males 74·8 years (74·8-74·9). By comparison, the lowest all-cause mean age at death occurred in sub-Saharan Africa, where it was 38·0 years (37·5-38·4) for females and 35·6 years (35·2-35·9) for males in 2023. Lastly, our study found that all-cause 70q0 decreased across each GBD super-region and region from 2000 to 2023, although with large variability between them. For females, we found that 70q0 notably increased from drug use disorders and conflict and terrorism. Leading causes that increased 70q0 for males also included drug use disorders, as well as diabetes. In sub-Saharan Africa, there was an increase in 70q0 for many non-communicable diseases (NCDs). Additionally, the mean age at death from NCDs was lower than the expected mean age at death for this super-region. By comparison, there was an increase in 70q0 for drug use disorders in the high-income super-region, which also had an observed mean age at death lower than the expected value. We examined global mortality patterns over the past three decades, highlighting-with enhanced estimation methods-the impacts of major events such as the COVID-19 pandemic, in addition to broader trends such as increasing NCDs in low-income regions that reflect ongoing shifts in the global epidemiological transition. This study also delves into premature mortality patterns, exploring the interplay between age and causes of death and deepening our understanding of where targeted resources could be applied to further reduce preventable sources of mortality. We provide essential insights into global and regional health disparities, identifying locations in need of targeted interventions to address both communicable and non-communicable diseases. There is an ever-present need for strengthened health-care systems that are resilient to future pandemics and the shifting burden of disease, particularly among ageing populations in regions with high mortality rates. Robust estimates of causes of death are increasingly essential to inform health priorities and guide efforts toward achieving global health equity. The need for global collaboration to reduce preventable mortality is more important than ever, as shifting burdens of disease are affecting all nations, albeit at different paces and scales. Gates Foundation.

Comprehensive, comparable, and timely estimates of demographic metrics-including life expectancy and age-specific mortality-are essential for evaluating, understanding, and addressing trends in population health. The COVID-19 pandemic highlighted the importance of timely and all-cause mortality estimates for being able to respond to changing trends in health outcomes, showing a strong need for demographic analysis tools that can produce all-cause mortality estimates more rapidly with more readily available all-age vital registration (VR) data. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) is an ongoing research effort that quantifies human health by estimating a range of epidemiological quantities of interest across time, age, sex, location, cause, and risk. This study-part of the latest GBD release, GBD 2023-aims to provide new and updated estimates of all-cause mortality and life expectancy for 1950 to 2023 using a novel statistical model that accounts for complex correlation structures in demographic data across age and time. We used 24 025 data sources from VR, sample registration, surveys, censuses, and other sources to estimate all-cause mortality for males, females, and all sexes combined across 25 age groups in 204 countries and territories as well as 660 subnational units in 20 countries and territories, for the years 1950-2023. For the first time, we used complete birth history data for ages 5-14 years, age-specific sibling history data for ages 15-49 years, and age-specific mortality data from Health and Demographic Surveillance Systems. We developed a single statistical model that incorporates both parametric and non-parametric methods, referred to as OneMod, to produce estimates of all-cause mortality for each age-sex-location group. OneMod includes two main steps: a detailed regression analysis with a generalised linear modelling tool that accounts for age-specific covariate effects such as the Socio-demographic Index (SDI) and a population attributable fraction (PAF) for all risk factors combined; and a non-parametric analysis of residuals using a multivariate kernel regression model that smooths across age and time to adaptably follow trends in the data without overfitting. We calibrated asymptotic uncertainty estimates using Pearson residuals to produce 95% uncertainty intervals (UIs) and corresponding 1000 draws. Life expectancy was calculated from age-specific mortality rates with standard demographic methods. For each measure, 95% UIs were calculated with the 25th and 975th ordered values from a 1000-draw posterior distribution. In 2023, 60·1 million (95% UI 59·0-61·1) deaths occurred globally, of which 4·67 million (4·59-4·75) were in children younger than 5 years. Due to considerable population growth and ageing since 1950, the number of annual deaths globally increased by 35·2% (32·2-38·4) over the 1950-2023 study period, during which the global age-standardised all-cause mortality rate declined by 66·6% (65·8-67·3). Trends in age-specific mortality rates between 2011 and 2023 varied by age group and location, with the largest decline in under-5 mortality occurring in east Asia (67·7% decrease); the largest increases in mortality for those aged 5-14 years, 25-29 years, and 30-39 years occurring in high-income North America (11·5%, 31·7%, and 49·9%, respectively); and the largest increases in mortality for those aged 15-19 years and 20-24 years occurring in Eastern Europe (53·9% and 40·1%, respectively). We also identified higher than previously estimated mortality rates in sub-Saharan Africa for all sexes combined aged 5-14 years (87·3% higher in GBD 2023 than GBD 2021 on average across countries and territories over the 1950-2021 period) and for females aged 15-29 years (61·2% higher), as well as lower than previously estimated mortality rates in sub-Saharan Africa for all sexes combined aged 50 years and older (13·2% lower), reflecting advances in our modelling approach. Global life expectancy followed three distinct trends over the study period. First, between 1950 and 2019, there were considerable improvements, from 51·2 (50·6-51·7) years for females and 47·9 (47·4-48·4) years for males in 1950 to 76·3 (76·2-76·4) years for females and 71·4 (71·3-71·5) years for males in 2019. Second, this period was followed by a decrease in life expectancy during the COVID-19 pandemic, to 74·7 (74·6-74·8) years for females and 69·3 (69·2-69·4) years for males in 2021. Finally, the world experienced a period of post-pandemic recovery in 2022 and 2023, wherein life expectancy generally returned to pre-pandemic (2019) levels in 2023 (76·3 [76·0-76·6] years for females and 71·5 [71·2-71·8] years for males). 194 (95·1%) of 204 countries and territories experienced at least partial post-pandemic recovery in age-standardised mortality rates by 2023, with 61·8% (126 of 204) recovering to or falling below pre-pandemic levels. There were several mortality trajectories during and following the pandemic across countries and territories. Long-term mortality trends also varied considerably between age groups and locations, demonstrating the diverse landscape of health outcomes globally. This analysis identified several key differences in mortality trends from previous estimates, including higher rates of adolescent mortality, higher rates of young adult mortality in females, and lower rates of mortality in older age groups in much of sub-Saharan Africa. The findings also highlight stark differences across countries and territories in the timing and scale of changes in all-cause mortality trends during and following the COVID-19 pandemic (2020-23). Our estimates of evolving trends in mortality and life expectancy across locations, ages, sexes, and SDI levels in recent years as well as over the entire 1950-2023 study period provide crucial information for governments, policy makers, and the public to ensure that health-care systems, economies, and societies are prepared to address the world's health needs, particularly in populations with higher rates of mortality than previously known. The estimates from this study provide a robust framework for GBD and a valuable foundation for policy development, implementation, and evaluation around the world. Gates Foundation.

Violence against women and against children are human rights violations with lasting harms to survivors and societies at large. Intimate partner violence (IPV) and sexual violence against children (SVAC) are two major forms of such abuse. Despite their wide-reaching effects on individual and community health, these risk factors have not been adequately prioritised as key drivers of global health burden. Comprehensive x§and reliable estimates of the comparative health burden of IPV and SVAC are urgently needed to inform investments in prevention and support for survivors at both national and global levels. We estimated the prevalence and attributable burden of IPV among females and SVAC among males and females for 204 countries and territories, by age and sex, from 1990 to 2023, as part of the Global Burden of Diseases, Injuries, and Risk Factors Study 2023. We searched several global databases for data on self-reported exposure to IPV and SVAC and undertook a systematic review to identify the health outcomes associated with each of these risk factors. We modelled IPV and SVAC prevalence using spatiotemporal Gaussian process regression, applying data adjustments to account for measurement heterogeneity. We employed burden-of-proof methodology to estimate relative risks for outcomes associated with IPV and SVAC. These estimates informed the calculation of population attributable fractions, which were then used to quantify disability-adjusted life-years (DALYs) attributable to each risk factor. Globally, in 2023, we estimated that 608 million (95% uncertainty interval 518-724) females aged 15 years and older had ever been exposed to IPV, and 1·01 billion (0·764-1·48) individuals aged 15 years and older had experienced sexual violence during childhood. 18·5 million (8·74-30·0) DALYs were attributed to IPV among females and 32·2 million (16·4-52·5) DALYs were attributed to SVAC among males and females in 2023. IPV and SVAC were among the top contributors to the global disease burden in 2023, particularly among females aged 15-49 years, ranking as the fourth and fifth leading risk factors, respectively, for DALYs in this group. Among the eight health outcomes found to be associated with IPV, anxiety disorders and major depressive disorder were the leading causes of IPV-attributed DALYs, accounting for 5·43 million (-1·25 to 14·6) and 3·96 million (1·71 to 6·92) DALYs in 2023, respectively. SVAC was associated with 14 health outcomes, including mental health disorder, substance use disorder, and chronic and infectious disease outcomes. Self-harm and schizophrenia were the leading causes of SVAC-attributed burden, with SVAC accounting for 6·71 million (2·00 to 12·7) DALYs due to self-harm and 4·15 million (-1·92 to 13·1) DALYs due to schizophrenia in 2023. IPV and SVAC are substantial contributors to global health burden, and their health consequences span a variety of individual health outcomes. Importantly, mental health disorders account for the greatest share of disease burden among survivors. Investing in prevention of these avoidable risk factors has the potential to avert millions of DALYs and considerable premature mortality each year. Our findings represent strong evidence for global and national leaders to elevate IPV and SVAC among public health priorities. Sustained investments are needed to prevent IPV and SVAC and to implement interventions focused on supporting the complex social and health needs of survivors. Gates Foundation.

Volume 66 of the Annual Review of Pharmacology and Toxicology includes numerous articles that reveal evolving ideas and insights in pharmacology and toxicology. The major theme is new approaches, technology and techniques. New ideas include the use of systems biology, multiomics, and artificial intelligence to support wellness, prevention, early detection of disease, and precision medicine. Other reviews highlight new ideas and approaches to treat infectious diseases, including the repurposing of drugs approved for other indications and long-acting therapeutics. Related reviews emphasize aspects of global health. One review discusses psychedelics as therapeutics. Several reviews discuss advances in drug discovery modalities. Others relate to a variety of topics in toxicology, including aspects of mitochondrial biology, e-cigarettes, air pollution, microplastics, and nanoplastics. These reviews and others in this volume inform readers about recent advances in pharmacology and toxicology and show how both specialties continue to be vital for improving health and safety globally.

Precision medicine demands a shift from static, single-analyte diagnostics toward dynamic, systems-level understanding of health and disease. This review explores how the convergence of systems biology, multiomics, and artificial intelligence (AI) redefines biomarker discovery to drive early disease detection and personalized intervention. We highlight pioneering efforts that use longitudinal, multimodal data to map individual health trajectories and uncover early disease signals. Advances in AI, including machine learning and contextualization using knowledge graphs and digital twins, are accelerating clinical translation by enabling predictive, context-aware analyses. Real-world applications, including omics-informed diagnostics and digital health monitoring, demonstrate the potential of this approach to transform health care from reactive treatment to proactive wellness. These technologies also inform the development of targeted therapeutics that intervene earlier, personalize treatment, and potentially halt or reverse disease progression. We outline challenges, emerging solutions, and future directions that position AI-driven systems biology at the center of next-generation precision health.

Chronic inflammation is a common trait in the pathogenesis of several diseases of the gut, including inflammatory bowel disease and celiac disease. Control of the inflammatory response is crucial in these pathologies to avoid tissue destruction and loss of intestinal function. Over the last 50 years, the identification of the mechanisms and mediators involved in the acute phase of the inflammatory response, which is characterized by massive leukocyte recruitment, has led to a number of therapeutic options. New drugs targeting inflammatory flares are still under development. However, interest on the other end of the spectrum-the resolution and repair phases-has emerged, as promoting tissue functional repair may maintain remission and counteract the chronicity of the disease. This review aims to discuss the current and future pharmacological approaches to the treatment of chronic intestinal inflammation and the restoration of functional tissues.

The reviews in Volume 65 of the Annual Review of Pharmacology and Toxicology cover a wide variety of topics in pharmacology and toxicology focused upon the pathway from preclinical studies to clinical trials. Many of these reviews discuss the identification and validation of new therapeutic targets and/or novel therapeutic approaches. Examples include reviews that focus on the treatment of obesity, neuropsychiatric disorders, Parkinson's disease, substance use disorders, liver fibrosis, cardiac arrythmias, chronic intestinal inflammation, prostate cancer, immuno-oncology, sickle cell disease, and snakebite envenoming. Other topics include drug discovery of biologics, microphysiological systems, and human induced pluripotent stem cell-derived organoids and organ-on-chip technology integrated with artificial intelligence methodologies. Together, these and other reviews give new insights into the assessment of aspects of toxicology and provide readers a glimpse of advances in pharmacology and toxicology that we believe will advance health care and environmental safety.

Although plastic pollution and exposure to plastic-related compounds have received worldwide attention, health risks associated with micro- and nanoplastics (MNPs) are largely unknown. Emerging evidence suggests MNPs are present in human biofluids and tissue, including blood, breast milk, stool, lung tissue, and placenta; however, exposure assessment is limited and the extent of human exposure to MNPs is not well known. While there is a critical need to establish robust and scalable biomonitoring strategies to assess human exposure to MNPs and plastic-related chemicals, over 10,000 chemicals have been linked to plastic manufacturing with no existing standardized approaches to account for even a fraction of these exposures. This review provides an overview of the status of methods for measuring MNPs and associated plastic-related chemicals in humans, with a focus on approaches that could be adapted for population-wide biomonitoring and integration with biological response measures to develop hypotheses on potential health effects of plastic exposures. We also examine the exposure risks associated with the widespread use of chemical additives in plastics. Despite advancements in analytical techniques, there remains a pressing need for standardized measurement protocols and untargeted, high-throughput analysis methods to enable comprehensive MNP biomonitoring to identify key MNP exposures in human populations. This review aims to merge insights into the toxicological effects of MNPs and plastic additives with an evaluation of analytical challenges, advocating for enhanced research methods to fully assess, understand, and mitigate the public health implications of MNPs.

Long-acting (LA) therapeutics have emerged as a key component of infectious disease treatment and prevention strategies, their uptake fueled by the need to bridge notable gaps with short-acting drug formulations. In this review, we present the key drivers and summarize the enabling technologies. Focusing on infections with significant global disease burden (HIV, hepatitis B and C, tuberculosis, malaria, and COVID-19), the current state of knowledge on approved LA therapeutics and promising innovations currently in development are summarized. The potential role of LA therapeutics as countermeasures for diseases of pandemic potential and new approaches using computational modeling to accelerate their development for pediatric and perinatal health are discussed. Due to complexities in manufacturing, and the diversity of patent-protected technologies, barriers exist for global access to LA products and in upscaling intricate LA formulations. A multipronged strategic framework, including acceleration of equitable access through generic product manufacture, is proposed to realize the full potential of LA therapeutics for global health.

In light of the success of blockbuster drugs for type 2 diabetes and obesity based on the GLP-1 hormone, drugmakers have concentrated their efforts on developing new and improved variations that address the route of administration, dosing, pathway selectivity, or polypharmacology. While some of these modifications have demonstrated improved efficacy in clinical studies and offered exciting opportunities for treating other diseases, drug-induced shifts to the conformational landscape of target receptors may have consequences for side effects. Our review summarizes advances in the understanding of the biochemistry, pharmacogenomics, and molecular pharmacology of incretins and their cognate receptors. We further highlight the current landscape of incretin mimetics and discuss how differences in compartmentalized pathway selectivity affect drug action and outcomes.

Pharmacogenetics (PGx) aims to optimize drug treatment outcomes by using a patient's genetic profile for individualized drug and dose selection. Currently, reactive and pretherapeutic single-gene PGx tests are increasingly applied in clinical practice in several countries and institutions. With over 95% of the population carrying at least one actionable PGx variant, and with drugs impacted by these genetic variants being in common use, pretherapeutic or preemptive PGx panel testing appears to be an attractive option for better-informed drug prescribing. Here, we discuss the current state of PGx panel testing and explore the potential for clinical implementation. We conclude that available evidence supports the implementation of pretherapeutic PGx panel testing for drugs covered in the PGx guidelines, yet identification of specific patient populations that benefit most and cost-effectiveness data are necessary to support large-scale implementation.

When I was young and pictured my future, it wasn't a path that could be determined a priori. The world was full of interesting things. Obtaining the qualifications to become a professor and a researcher was the easy part. The rest relied on being in the right place at the right moment and having the intuition to feel the importance of events we were witnessing. This is how I met my mentors and how my scientific partner and I came upon the paradox that caused us to propose the principle of biological inertia. This is also how we discovered that estrogens leached from plasticware were ruining our experiments, and thus we became "toxicologists by accident." Indeed, we were never formally trained in pharmacology or toxicology; however, our discovery that the estrogen nonylphenol leached from plastics made us pioneers of the new field of endocrine disruptors that encompasses endocrinology and toxicology.

Pregnant and lactating women have historically been excluded from clinical trials, limiting data on drug pharmacokinetics, safety, and efficacy in these populations. This knowledge gap stems from complex ethical, historical, and cultural factors, which previously categorized these women as vulnerable rather than protected participants. Recent legislative frameworks, including the FDA Pregnancy and Lactation Labeling Rule, have catalyzed efforts to include these populations in structured research. Quantitative pharmacology approaches using innovations such as physiologically based pharmacokinetic models support optimized trial designs, safer dosing regimens, and ethical research frameworks. Emerging technologies, including artificial intelligence, novel drug delivery mechanisms, and organ-on-chip models, further enhance insights into maternal-fetal drug exposure and drug exposures in breastfeeding infants. Integrating in vitro, ex vivo, in vivo, and clinical data and modeling approaches improves understanding of pregnancy-related physiological changes and their impact on drug outcomes, ultimately enabling appropriate and equitable pharmacotherapy for pregnant and breastfeeding women.

Genetically driven clinical trial enrichment has been proposed to accelerate and reduce the cost of developing new therapeutics. Usage of this approach has not been comprehensively reviewed. We searched Ovid MEDLINE, Embase, Web of Science, Cochrane Library, ClinicalTrials.gov, and WHO ICTRP for articles published between 2010 and 2023. Excluding absorption, distribution, metabolism, and elimination pharmacogenetic studies and anti-infectives, we found 95 completed, 4 terminated, and 22 ongoing prospective genetically enriched trials on 110 drugs for 48 nononcology, nonrare syndromic indications. Trial sizes ranged from 4 to 6,147 participants (median 72) and covered numerous disease areas, particularly neurology (30), metabolism (22), and psychiatry (17). Fifty-six completed studies (60%) met their primary end point. Overall, this scoping review demonstrates that genetically enriched trials are feasible and scalable across disease areas and provide critical information for further development, or attrition, of investigational drugs. Large, appropriately designed disease-, hospital-, or population-based biobanks will undoubtedly facilitate this type of precision drug development approach.

The global population breathes unsafe levels of pollutants. In recent years, electronic cigarettes (e-cigs) have become a significant source of particulate matter (PM), which causes injurious effects across organ systems. E-cig users and bystanders are exposed to concentrated aerosols, commonly called vapor, that we now know can have harmful long-term consequences due to PM and chemicals contained within. E-cigs are diverse in design, and e-liquids vary dramatically, making it difficult to draw broad conclusions from studies of different devices, brands, and flavors. With the rise in popularity of e-cigs, it is important to define the health effects across the body. In this comprehensive review, we dissect and summarize the known organ-specific effects of e-cigs, including underlying molecular mechanisms. Notably, e-cig aerosols broadly cause increased cytokine release and oxidative stress, which are associated with a heightened risk of organ dysfunction. We also highlight ways to minimize harmful e-cig constituents to develop safer products.

The use of pharmaceuticals has grown substantially and their consequential release via wastewaters poses a potential threat to aquatic and terrestrial environments. While transportation prediction models for aquatic environments are well established, they cannot be universally extrapolated to terrestrial systems. Pharmaceuticals and their metabolites are, for example, readily detected in the excreta of terrestrial organisms (including humans). Furthermore, the trophic transfer of pharmaceuticals to and from food webs is often overlooked, which in turn highlights a public health concern and emphasizes the pressing need to elucidate how today's potpourri of pharmaceuticals affect the terrestrial system, their biophysical behaviors, and their interactions with soil metazoans. This review explores the existing knowledge base of pharmaceutical exposure sources, mobility, persistence, (bio)availability, (bio)accumulation, (bio)magnification, and trophic transfer of pharmaceuticals through the soil and terrestrial food chains.

G protein-coupled receptors (GPCRs) are a superfamily of transmembrane signal transducers that facilitate the flow of chemical signals across membranes. GPCRs are a desirable class of drug targets, and the activation and deactivation dynamics of these receptors are widely studied. Multidisciplinary approaches for studying GPCRs, such as downstream biochemical signaling assays, cryo-electron microscopy structural determinations, and molecular dynamics simulations, have provided insights concerning conformational dynamics and signaling mechanisms. However, new approaches including biosensors that use luminescence- and fluorescence-based readouts have been developed to investigate GPCR-related protein interactions and dynamics directly in cellular environments. Luminescence- and fluorescence-based readout approaches have also included the development of GPCR biosensor platforms that utilize enabling technologies to facilitate multiplexing and miniaturization. General principles underlying the biosensor platforms and technologies include scalability, orthogonality, and kinetic resolution. Further application and development of GPCR biosensors could facilitate hit identification in drug discovery campaigns. The goals of this review are to summarize developments in the field of GPCR-related biosensors and to discuss the current available technologies.

Atrial fibrillation (AF) is a common arrhythmia with a tremendous impact on quality of life and mortality. Its prevalence continues to rise alongside the increasing obesity and type 2 diabetes epidemics, raising a need for improved therapeutic strategies and a better understanding of the factors and mechanisms that drive metabolic disease-associated AF. To this end, the link between AF and metabolic disease is being increasingly explored in observational, clinical, and experimental studies. Chronic inflammation is a hallmark of metabolic disease, and multiple studies have also demonstrated a strong relationship between AF and inflammation. In this review, we discuss recent advances in our understanding of the mechanisms governing the development of AF in the context of metabolism and inflammation, related concepts in therapeutic development, and a novel role for calcitonin in AF.

Pharmacogenetic variation is common and an established driver of response for many drugs. There has been tremendous progress in pharmacogenetics knowledge over the last 30 years and in clinical implementation of that knowledge over the last 15 years. But there have also been many examples where translation has stalled because of the lack of available data sets for discovery or validation research. The recent availability of data from very large cohorts with linked genetic, electronic health record, and other data promises new opportunities to advance pharmacogenetics research. This review presents the stages from pharmacogenetics discovery to widespread clinical adoption using prominent gene-drug pairs that have been implemented into clinical practice as examples. We discuss the opportunities that the All of Us Research Program and other large biorepositories with genomic and linked electronic health record data present in advancing and accelerating the translation of pharmacogenetics into clinical practice.