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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.
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.
The 2023 iteration of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) estimated prevalence, incidence, and health burden for 375 diseases and injuries, including 12 mental disorders. We assess past, current, and emerging trends in the prevalence and burden of mental disorders across sexes and age groups, for 21 regions, 204 countries and territories, and by Socio-demographic Index (SDI) quintile, from 1990 to 2023. Mental disorders included in GBD 2023 were anxiety disorders, major depressive disorder, dysthymia, bipolar disorder, schizophrenia, autism spectrum disorders, conduct disorder, attention-deficit hyperactivity disorder, anorexia nervosa, bulimia nervosa, idiopathic developmental intellectual disability, and a residual category of other mental disorders. A literature review identified epidemiological data for each disorder. These were analysed via a Bayesian meta-regression to estimate prevalence by disorder, sex, age, location, and year. Disorder-specific prevalence was multiplied by disability weights representing the severity of health loss associated with each disorder to estimate years lived with disability (YLDs). Deaths due to anorexia nervosa were assessed with a Cause of Death Ensemble modelling strategy to estimate deaths by sex, age, location, and year, and then multiplied by the standard life expectancy at age of death to estimate years of life lost (YLLs). YLDs equalled disability-adjusted life-years (DALYs) for all mental disorders except anorexia nervosa (the only mental disorder considered as an underlying cause of death in GBD), for which DALYs represented the sum of YLDs and YLLs. We presented prevalence, deaths, YLDs, YLLs, and DALYs as counts, age-specific rates per 100 000 population, and age-standardised rates per 100 000 population. We estimated 1·17 billion (95% uncertainty interval 1·06-1·31) prevalent cases of mental disorders globally in 2023, equivalent to an age-standardised prevalence rate of 14 210·7 cases (12 849·5-15 940·1) per 100 000 population. These estimates represented a 95·5% (75·0-121·2) increase in prevalent cases and 24·2% (11·4-41·4) increase in age-standardised prevalence rate between 1990 and 2023. All mental disorders showed increases in prevalent cases between 1990 and 2023, while notable increases were seen in age-standardised prevalence rates for anxiety disorders, major depressive disorder, dysthymia, anorexia nervosa, bulimia nervosa, schizophrenia, and conduct disorder. There were an estimated 171 million (127-228) DALYs due to mental disorders globally across sex and age in 2023, equivalent to an age-standardised DALY rate of 2070·5 DALYs (1519·1-2750·5) per 100 000 population. Mental disorders contributed to 6·1% (4·8-7·6) of all-cause DALYs in 2023, making them the fifth leading cause of global DALYs (up from 12th in 1990). DALYs were almost entirely composed of YLDs. Mental disorders were the leading cause of YLDs in 2023 (up from second in 1990), explaining 17·3% (14·8-20·6) of all-cause global YLDs. Leading causes of mental disorder DALYs were anxiety disorders (ranked 11th among the 304 diseases and injuries at Level 4 of the GBD cause hierarchy), major depressive disorder (15th), and schizophrenia (41st). Globally in 2023, mental disorder age-standardised DALY rates were higher among females (2239·6 [1643·7-3014·1] per 100 000) than among males (1900·2 [1399·8-2510·8] per 100 000), and peaked in the 15-19 years age group (2617·3 [1850·6-3696·8] per 100 000). All locations showed increased mental disorder DALY rates in 2023 compared with 1990, ranging across countries and territories from 1302·4 (952·7-1683·7) per 100 000 in Viet Nam to 3555·8 (2661·9-4715·0) per 100 000 in the Netherlands. Across SDI quintiles, DALY rates ranged from 1853·0 (1352·1-2469·3) per 100 000 for middle SDI to 2184·1 (1606·1-2890·3) per 100 000 for high SDI. A significant health burden was imposed by mental disorders in all countries and territories in 2023, irrespective of the health resources available. In some instances, this burden has increased over time and is unevenly distributed across populations. Stronger surveillance systems, particularly in low-income and middle-income countries, are required. Additionally, we need more coordinated and inclusive policies to reduce the burden through early treatment and prevention, tailored to sex and age differences across locations. Responding to the mental health needs of our global population, especially those most vulnerable, is an obligation, not a choice. Gates Foundation, Queensland Health, and University of Queensland.
Cancer is a leading cause of death globally. Accurate cancer burden information is crucial for policy planning, but many countries do not have up-to-date cancer surveillance data. To inform global cancer-control efforts, we used the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2023 framework to generate and analyse estimates of cancer burden for 47 cancer types or groupings by age, sex, and 204 countries and territories from 1990 to 2023, cancer burden attributable to selected risk factors from 1990 to 2023, and forecasted cancer burden up to 2050. Cancer estimation in GBD 2023 used data from population-based cancer registration systems, vital registration systems, and verbal autopsies. Cancer mortality was estimated using ensemble models, with incidence informed by mortality estimates and mortality-to-incidence ratios (MIRs). Prevalence estimates were generated from modelled survival estimates, then multiplied by disability weights to estimate years lived with disability (YLDs). Years of life lost (YLLs) were estimated by multiplying age-specific cancer deaths by the GBD standard life expectancy at the age of death. Disability-adjusted life-years (DALYs) were calculated as the sum of YLLs and YLDs. We used the GBD 2023 comparative risk assessment framework to estimate cancer burden attributable to 44 behavioural, environmental and occupational, and metabolic risk factors. To forecast cancer burden from 2024 to 2050, we used the GBD 2023 forecasting framework, which included forecasts of relevant risk factor exposures and used Socio-demographic Index as a covariate for forecasting the proportion of each cancer not affected by these risk factors. Progress towards the UN Sustainable Development Goal (SDG) target 3.4 aim to reduce non-communicable disease mortality by a third between 2015 and 2030 was estimated for cancer. In 2023, excluding non-melanoma skin cancers, there were 18·5 million (95% uncertainty interval 16·4 to 20·7) incident cases of cancer and 10·4 million (9·65 to 10·9) deaths, contributing to 271 million (255 to 285) DALYs globally. Of these, 57·9% (56·1 to 59·8) of incident cases and 65·8% (64·3 to 67·6) of cancer deaths occurred in low-income to upper-middle-income countries based on World Bank income group classifications. Cancer was the second leading cause of deaths globally in 2023 after cardiovascular diseases. There were 4·33 million (3·85 to 4·78) risk-attributable cancer deaths globally in 2023, comprising 41·7% (37·8 to 45·4) of all cancer deaths. Risk-attributable cancer deaths increased by 72·3% (57·1 to 86·8) from 1990 to 2023, whereas overall global cancer deaths increased by 74·3% (62·2 to 86·2) over the same period. The reference forecasts (the most likely future) estimate that in 2050 there will be 30·5 million (22·9 to 38·9) cases and 18·6 million (15·6 to 21·5) deaths from cancer globally, 60·7% (41·9 to 80·6) and 74·5% (50·1 to 104·2) increases from 2024, respectively. These forecasted increases in deaths are greater in low-income and middle-income countries (90·6% [61·0 to 127·0]) compared with high-income countries (42·8% [28·3 to 58·6]). Most of these increases are likely due to demographic changes, as age-standardised death rates are forecast to change by -5·6% (-12·8 to 4·6) between 2024 and 2050 globally. Between 2015 and 2030, the probability of dying due to cancer between the ages of 30 years and 70 years was forecasted to have a relative decrease of 6·5% (3·2 to 10·3). Cancer is a major contributor to global disease burden, with increasing numbers of cases and deaths forecasted up to 2050 and a disproportionate growth in burden in countries with scarce resources. The decline in age-standardised mortality rates from cancer is encouraging but insufficient to meet the SDG target set for 2030. Effectively and sustainably addressing cancer burden globally will require comprehensive national and international efforts that consider health systems and context in the development and implementation of cancer-control strategies across the continuum of prevention, diagnosis, and treatment. Gates Foundation, St Jude Children's Research Hospital, and St Baldrick's Foundation.
In the PSMAfore study, lutetium-177 [177Lu]Lu-PSMA-617 (vipivotide tetraxetan) significantly improved radiographic progression-free survival compared with change of androgen receptor pathway inhibitor (ARPI) in taxane-naive patients with prostate-specific membrane antigen (PSMA)-positive metastatic castration-resistant prostate cancer. Here, we present in-depth analyses of time to worsening of health-related quality of life (HRQOL) and pain, and time to first symptomatic skeletal events. PSMAfore, an open-label, randomised, phase 3 trial, was conducted at 74 investigator sites (including hospitals with nuclear medicine departments and the research facilities where patients were recruited) across 14 countries. Eligible patients had metastatic castration-resistant prostate cancer, were candidates for ARPI change after one progression on a previous ARPI, had at least one PSMA-positive and no exclusionary PSMA-negative metastatic lesions by gallium-68 [68Ga]Ga-PSMA-11 PET-CT, were aged 18 years or older, and had an Eastern Cooperative Oncology Group performance status of 0-1. Patients were randomly assigned (1:1) to [177Lu]Lu-PSMA-617 (7·4 GBq; every 6 weeks for six cycles) or ARPI change (oral abiraterone or enzalutamide per local labelling). The primary endpoint was radiographic progression-free survival. Secondary endpoints included time to worsening in self-reported HRQOL (assessed using the Functional Assessment of Cancer Therapy-Prostate [FACT-P] and EQ-5D-5L) and pain (assessed using the Brief Pain Inventory-Short Form [BPI-SF]) and time to the first symptomatic skeletal event. All analyses were done using the intention-to-treat principle. The study met the primary endpoint of radiographic progression-free survival (reported previously), and overall survival follow-up is ongoing; present analyses are from the third interim analysis of overall survival. This trial is registered with ClinicalTrials.gov, NCT04689828. Between June 15, 2021, and Oct 7, 2022, 468 patients (426 [91%] were White and 12 [3%] were Black or African American) were randomly assigned to [177Lu]Lu-PSMA-617 (n=234) or ARPI change (n=234). Median follow-up time from randomisation to the third interim analysis data cutoff date (Feb 27, 2024) was 24·11 months (IQR 20·24-27·60) in the [177Lu]Lu-PSMA-617 group and 24·13 months (20·24-27·37) in the ARPI change group. [177Lu]Lu-PSMA-617 delayed time to worsening in all assessed FACT-P, EQ-5D-5L, and BPI-SF scales and subscales versus ARPI change. In the [177Lu]Lu-PSMA-617 versus ARPI change groups, median time to worsening in FACT-P total score was 7·46 months (95% CI 6·08-8·54) versus 4·27 months (3·45-4·50; hazard ratio [HR] 0·61 [95% CI 0·50-0·75]), in EQ-5D-5L utility score was 6·28 months (4·70-7·89) versus 3·88 months (3·25-4·44; 0·67 [0·54-0·82]), and in BPI-SF pain intensity was 5·03 months (4·40-6·80) versus 3·65 months (3·09-4·37; 0·72 [0·59-0·88]). [177Lu]Lu-PSMA-617 also delayed symptomatic skeletal events versus ARPI change: median time to first symptomatic skeletal event was not reached (95% CI not estimable [NE]-NE) in the [177Lu]Lu-PSMA-617 group versus 17·97 months (14·26-NE) in the ARPI change group (HR 0·41 [0·26-0·63]). The most common grade 3 or worse treatment-emergent adverse event was anaemia (14 [6%] of 227 patients in the [177Lu]Lu-PSMA-617 group vs 16 [7%] of 232 patients in the ARPI change group). There were no treatment-related deaths in the [177Lu]Lu-PSMA-617 group and one in the ARPI change group (cerebrovascular accident). [177Lu]Lu-PSMA-617 might delay worsening of patient-reported outcomes and prevent symptomatic skeletal events versus ARPI change in taxane-naive patients with PSMA-positive metastatic castration-resistant prostate cancer whose disease has progressed once on a previous ARPI. Novartis.
T lymphocytes are central mediators of cardiovascular disease, driving myocardial injury in myocarditis, transplant rejection, post-infarct remodeling, atherosclerosis, and post-viral syndromes. Yet current imaging tools ([18F]FDG PET, somatostatin receptor tracers, CXCR4 PET, and cardiac MRI) offer only indirect or nonspecific measures of immune activity. The ability to noninvasively visualize and quantify T-cell infiltration and activation could transform diagnosis and management in cardio-immunology. Advances in immuno-PET have produced a growing arsenal of T-cell specific tracers. CD8-targeted agents (89Zr-Df-IAB22M2C) and small-molecule probes such as [18F]F-AraG have entered early clinical trials, demonstrating feasibility and safety in humans. Other tracers, including CD4- and CD3-directed antibodies, IL-2R and OX40 probes, checkpoint tracers (PD-1, CTLA-4), and granzyme B ligands, remain largely preclinical but show strong potential for cardiovascular translation. Applications span acute myocarditis, noninvasive transplant rejection surveillance, assessment of post-MI immune remodeling, plaque vulnerability in atherosclerosis, and systemic immune activation in long COVID. Compared with existing imaging modalities, T-cell PET offers cell-type specificity, quantitative longitudinal monitoring, and the capacity for whole-body immune mapping, particularly when integrated with total-body PET or hybrid PET/MR. Challenges include low T-cell density in the myocardium, tracer specificity, radiation burden, and the need for histopathologic validation. Future directions involve repurposing oncology tracers for cardiology, engineering antibody fragments with improved kinetics, and establishing T-cell PET as a mechanistic biomarker in cardiovascular clinical trials. With further innovation and validation, T-cell PET has the potential to evolve from an experimental tool into a clinically actionable modality, reshaping the management of immune-mediated heart disease.
Prostate-specific membrane antigen (PSMA) radioligands used for PET imaging of prostate cancer (PCa) have variable urinary excretion. The prostate bed region is an important site of disease localization where intense bladder activity may obscure lesion detection. We performed a comparative analysis of bladder activity across different PSMA radioligands and investigated the impact of furosemide administration on reducing bladder activity. We analyzed the PSMA PET/CT images of patients with PCa who were imaged with 68Ga-PSMA-11 with/without 20 mg furosemide, 18F-PSMA-1007, 18F-DCFPyL, 18F-rhPSMA-7.3 with/without 20 mg furosemide. We determined and compared bladder volume and bladder activity level using mean and maximum standardized uptake values (SUVmean and SUVmax) between PET scans obtained with the different PSMA radioligands using an ANOVA or Kruskal-Wallis test, as appropriate. We also determined the association between the bladder activity level versus bladder volume using Spearman correlation. 210 PSMA PET/CT studies were reviewed, including 50, 20, 20, 28, 42, and 50 completed with 18F-PSMA-1007 without furosemide, 18F-rhPSMA-7.3 without furosemide, 18F-rhPSMA-7.3 with furosemide, 68Ga-PSMA-11 without furosemide, 68Ga-PSMA-11 with furosemide, and 18F-DCFPyL without furosemide, respectively. The median bladder SUVmean (range) without furosemide were: 1.75 (0.4-6.4) [18F-PSMA-1007], 10.00 (1.9-140.0) [18F-rhPSMA-7.3], 15.92 (2.0-106.0) [68Ga-PSMA-11], and 25.7 (7.9-87.6) [18F-DCFPyL], (P<0.001). With 20 mg furosemide co-administered with the radiotracer, there was a significant decline in bladder activity level (median SUVmean of 10.00 (1.9-140.0) to 2.95 (0.8-17.6) for 18F-rhPSMA-7.3 and 15.92 (2.0-106.0) to 10.21 (2.6-281.3) for 68Ga-PSMA-11 and a significant increase in bladder volume, P<0.05. There was a significant negative correlation between bladder SUVmax and bladder volume for the entire cohort, P=0.008, r=-0.181. There is variation in the bladder radioactivity between the different PSMA radioligands for PCa PET imaging, with 18F-PSMA-1007 demonstrating the lowest, 68Ga-PSMA-11 and 18F-DCFPyL the highest, and 18F-rhPSMA-7.3 intermediate bladder activity level. Administration of 20 mg furosemide produces a significant reduction in bladder activity and an increase in bladder volume. With 20 mg furosemide, bladder activity of 18F-rhPSMA-7.3 approaches that of 18F-PSMA-1007.
Gallium-68 labeled fibroblast activation protein inhibitor ([68Ga]Ga-FAPI-04) can be visualized just 15 min post-injection. However, the appearance of imaging at 15 and 60 min remains unclear. This study aimed to explore the relationship between quantitative values in [68Ga]Ga-FAPI-04 PET, specifically at 15 and 60 minutes post-injection, in patients with various tumor. We enrolled 30 patients with cancer who underwent [68Ga]Ga-FAPI-04 PET/CT scan between January 2021 and February 2025 at our institute. Image acquisition was performed using a PET/CT scanner at 15 min and 60 min after [68Ga]Ga-FAPI-04 injection. The maximum, mean and peak standardized uptake value (SUVmax, SUVmean and SUVpeak), tumor-to-liver ratio (TLR), and uptake tumor volume (UTV) were measured in the region of interest of the target lesion, liver SUVmean (SUVliver) was also measured. Correlation coefficients of the between-image variables were evaluated by Spearman's rank correlation test. Agreement between the variables was evaluated by Bland-Altman plots with 95% limits of agreement. The SUVmax, SUVmean, SUVpeak and UTV in tumors of all examinations were decreased from 15 min to 60 min. The SUVmax, SUVmean, SUVpeak, TLR, and UTV at 15 min and 60 min were highly correlated (rs = 0.945, 0.949, 0.959, 0.943, and 0.958; P < 0.001). The 95% limits of agreement ranged from -27.8 to 29.1 with a mean of 0.7 and -24.1 to 29.5 with a mean of 2.7 for SUVmax and SUVmean, respectively. Other PET metrics demonstrated that all limits are above ± 30% between 15 min and 60 min. We observed a high correlation between the quantitative values at 15 min and 60 min. Meanwhile, 15 min and 60 min [68Ga]Ga-FAPI-04 PET SUVmax and SUVmean have clinically acceptable reproducibility, and 15 min scan is feasible for all patients, but SUVpeak, TLR and UTV should not be used interchangeably.
Immunotherapy plays a pivotal role in the treatment of colorectal cancer (CRC). PD-L1 has been identified to be a significant biomarker of response to treatment. The assessment of PD-L1 presently depends on biopsy samples - a problem that may be resolved with the help of a molecular imaging approach. This study devised and evaluated an 18F-and 89Zr-labelled albumin-binding PD-L1-targeted VHH for potential diagnostic imaging in CRC models. PD-L1 expression was initially validated in HCT-116 cell-derived xenografts and CRC20-PDX tumors. An albumin-binding moiety was conjugated to a PD-L1-targeted VHH to construct SN-2D01. The 18F-labeled SN-2D01 was prepared using the AlF-RESCA chelation strategy and the probe was modified with DFO for a 89Zr radiolabeling process. The evaluation of [18F]F-SN-2D01 and [89Zr]Zr-SN-2D01 through PET imaging was performed on the two tumor models and a quantitative analysis of tumor uptake for each tracer. Ultimately, a biodistribution study of [89Zr]Zr-SN-2D01 at 120 h post-injection (p.i.) was performed in both tumor models. The HCT-116 cell-derived xenografts and CRC20-PDX tumors were both PD-L1-positive, with a higher expression observed in lesions from CRC20-PDX versus HCT-116 tumors. The 2 h p.i. of [18F]F-SN-2D01 PET showed clear visualization of HCT-116 and CRC20-PDX tumors, with tracer mostly cleared via hepatic and renal excretion. In PET imaging with [89Zr]Zr-SN-2D01, the tumor uptake in both HCT-116 and CRC20-PDX slowly increased from 24 h to 120 h p.i, which peaked at 120 h. Biodistribution at 120 h showed tumor uptake of 11.49 ± 1.32 %ID/g for the CRC20-PDX model and 8.12 ± 1.54 %ID/g for the HCT-116 model. In summary, we presented two PET probes to visualize PD-L1. Of these, [89Zr]Zr-SN-2D01 was found to have significant capability to evaluate PD-L1 expression in CRC. The PD-L1-targeted SN-2D01 may provide a new approach in radionuclide therapy targeting PD-L1 in CRC.
18F-Fluciclovine positron emission tomography (PET) was FDA-approved in the U.S. in 2016 and was the most sensitive imaging modality for prostate cancer (PC) until the approval of prostate-specific membrane antigen (PSMA) PET in 2020. However, providers' reasons for ordering 18F-Fluciclovine PET/CT (FluPET) in practice and impact on patient care remain poorly defined. This prospective registry at a tertiary academic center describes patterns of FluPET use and outcomes prior to the FDA approval of PSMA PET in December 2020. Providers ordering FluPET for patients with PC were surveyed before, ≤2 weeks after, and ≥1 year after imaging to assess reasons for obtaining FluPET, projected treatment plan, changes in plan due to FluPET findings, and toxicity attributable to the change in treatment plan. Baseline patient characteristics, FluPET results, and longitudinal outcomes were collected. Between 12/2018-09/2021, 62 patients with localized PC (8.1%), biochemical recurrence (BCR; 80.6%), non-metastatic castration-resistant PC (CRPC) (3.2%), metastatic castration-sensitive PC (3.2%), or metastatic CRPC (4.8%) were enrolled and underwent FluPET. Most scans (90.3%) were performed prior to the FDA approval of PSMA PET 12/2020. FluPET was most often obtained to guide local salvage or metastasis-directed therapies (90.3%); other reasons (non-exclusive) were initial staging (9.6%) or clarifying equivocal lesions from other imaging (9.6%). FluPET detected ≥1 PC lesion in 74.2% of patients. After FluPET, 48.4% of providers reported changing treatment plans, which was more likely when FluPET was positive (60.9% vs 12.5%, P<0.001), and often involved initiation of systemic therapy (19.4%). Treatment changes were reported in 57% of patients with BCR1 and 48.2% of patients with BCR2. In contrast, only 20% of patients with distant metastatic disease had a change in treatment. Among patients in the BCR1 and BCR2 cohort, treatment plan changes were associated with a median time to next treatment that was not reached after a median follow-up of 67.6 months. There was no statistically significant difference in overall survival between patients with biochemical recurrence (BCR) who did and did not have a treatment plan change. A year after FluPET, reported potential toxicities from treatment plan changes were minimal. FluPET was utilized across the disease spectrum of PC, primarily to guide local salvage or metastasis-directed therapies, given its improved sensitivity for detecting prostate bed recurrence due to the slow physiologic excretion of 18F-fluciclovine. Notably, a positive FluPET frequently prompted initiation of systemic therapy; however, the clinical benefit of such management remains uncertain. Moreover, providers often selected multiple, sometimes conflicting, treatment plans following FluPET, reflecting uncertainty in translating imaging findings into definitive management decisions. A larger, prospective registry using PSMA PET with a requirement for providers to select a single post-scan treatment strategy is warranted to better assess whether imaging-guided treatment changes improve clinical outcomes.
C-X-C chemokine receptor 4 (CXCR4) is a G protein-coupled receptor implicated in immune regulation, tumor progression, and therapy resistance. In lymphoma, CXCR4 overexpression promotes malignant cell survival via microenvironmental retention and activation of pro-survival pathways, correlating with poor prognosis. Its extracellular localization makes it a strong candidate for selective molecular imaging and targeted therapy. This review summarizes recent advances in CXCR4-targeted agents for lymphoma. Peptide-based radiotracers (68Ga-Pentixafor, [18F]AlF-NOTA-QHY-04, [68Ga]Ga-BL02) and small molecules ([64Cu]AMD3100, [18F]MCFB) offer high specificity and favorable pharmacokinetics for positron emission tomography (PET) and single photon emission computed tomography (SPECT) imaging. Therapeutic strategies include peptide antagonists (BL-8040, Balixafortide), radioligand therapies ([177Lu]Pentixather, [177Lu]Lu-BL02), small-molecule inhibitors (Plerixafor, WK1), and monoclonal antibodies (PF-06747143, Ulocuplomab, LY2624587). These approaches have demonstrated efficacy in reducing tumor burden and enhancing chemosensitivity. Key challenges include off-target uptake due to physiological CXCR4 expression and compensatory signaling via CXCR7. Future directions involve dual-receptor targeting, nanoparticle-based delivery, and integration into precision oncology for both hematologic and solid tumors.
A growing number of advanced neuroimaging studies have been used to evaluate the nature of consciousness. Such studies have focused on various states of consciousness as well as ways of inducing altered states of consciousness. Various states of consciousness include the normal waking state, sleep states, the brain under anesthesia, and the impact of disorders such as seizures or schizophrenia. The induction of altered states of consciousness includes practices such as meditation or the use of psychoactive substances leading to psychedelic effects. This paper reviews some of the relevant research and then considers some of limitations and challenges for studying consciousness with neuroimaging, particularly via positron emission tomography (PET), single photon emission computed tomography (SPECT), and advanced magnetic resonance imaging (MRI) modalities.
This report describes the 18F-sodium fluoride (18F-NaF) and 18F-fluorodeoxyglucose (18F-FDG) PET/CT imaging of spinal instrumentation incidentally found in a 71-year-old male with extensive degenerative spinal disease. Hardware was noted at L5-S1, a common site of lumbar degeneration and cause of radiculopathy. 18F-NaF showed intense focal uptake at the instrumentation site, while 18F-FDG demonstrated minimal uptake. These findings suggest remodeling of bone (18F-NaF) at the site of instrumentation in the setting of benign physiological metabolic activity (18F-FDG). Other signs of structural deterioration were observed in the cervical and thoracic regions, such as osteophytes and ossification of the posterior longitudinal ligament. We present these findings in the context of a literature review of published studies that utilized 18F-NaF or 18F-FDG PET imaging for the assessment and monitoring of patients with spinal instrumentation.
To predict bilateral renal curves and glomerular filtration rate (GFR) following unsuccessful tracer injection in SPECT renal dynamic imaging using a Transformer model, thereby obviating the need for repeat examinations. We retrospectively studied patients who underwent repeat imaging post-extravasation (2015-2025). Patient height, weight, serum creatinine, urea, uric acid, and renal dynamic curves were used as inputs to develop a Transformer deep learning model for calibrating curves and predicting GFR. Following injection extravasation during SPECT renal dynamic imaging, the proposed model achieved a high overall alignment with the ground truth curves (Median R2>0.93). However, performance variability was observed, with a small subset of outliers showing poor fit (minimum R2<0) due to complex noise artifacts. For the left kidney, the model achieved an R2 of 0.9288, with 91.78% of predictions falling within a clinically acceptable tolerance of ±5 ml/min of the ground truth. Similarly, for the right kidney, the R2 reached 0.9216, with an accuracy rate of 93.15% based on the same tolerance threshold. It is important to note that the ±5 ml/min criterion was used strictly as a statistical threshold to define 'clinical accuracy' and did not involve any modification of the predicted values. In conclusion, a Transformer model can accurately calibrate and predict bilateral renal curves and GFR values after injection extravasation in SPECT renal dynamic imaging, potentially enhancing clinical workflow efficiency and diagnostic accuracy.
Theranostics is an interesting area of cancer research that describes the use of radiotracers to first diagnose and then treat cancer. By coupling a radioisotope to an agent that selectively targets malignant cells, one can distribute focused radiation to disease sites. There are a variety of different radiopharmaceutical vectors that have been utilized in this way, such as peptides, small molecules and antibodies. Because antibodies bind to highly specific antigens, radioimmunotherapy (RIT) offers a promising route to precisely targeted treatments with reduced systemic toxicity compared to conventional radiotherapy. Beta (β)-emitting isotopes (e.g., 131I, 90Y) have been more commonly coupled in RIT, but the use of alpha (α)-emitters (e.g., 225Ac, 212Pb), for RIT (α-RIT) has rising popularity due to their shorter tissue range and higher linear energy transfer. These characteristics decrease off-target effects in neighboring tissues and increase tumor cell destruction, respectively. However, there are several challenges to RIT. The production of daughter isotopes from α decay makes dosimetric assessments difficult and could potentially cause off target toxicities. Additionally, whole antibodies tend to accumulate in liver tissue and have long biological clearance times, which may cause excess radiation to the blood, marrow and liver. Yet, there are a variety of α-RIT agents currently in development to treat prostate cancer, hematologic malignancies, and other solid tumors. Many agents show promise, like 227Th-epratuzumab, a CD22-targeting antibody used in the treatment of relapsed or refractory acute myeloid leukemia (R/R AML). While notoriously deadly and difficult to treat, the disease control rate in patients with R/R AML taking 227Th-epratuzumab was 38%. Like many α-RIT therapies, follow-up studies are needed to continue to improve efficacy. Strategies to widen the therapeutic indices of these agents have been investigated such as pretargeting, use of antibody fragments, chelator optimization and combination therapies. This review describes the current landscape and clinical progress of targeted α radioimmunotherapy.
Monoamine oxidase B (MAO-B) is a key astrocytic biomarker implicated in neuro-inflammation and neurodegenerative diseases. This study reports the development and evaluation of novel fluorine-18 (18F) PET radiotracers for selective MAO-B imaging by exploiting deuteration strategies to address metabolic instability of existing probes. A literature compound [18F]GEH200449 ([18F]4) was synthesized through redesigned labeling precursor, and its deuterated analogue, [18F]4-D2, was prepared to improve metabolic stability. Systematic evaluation using PET imaging, radiometabolite analysis, and autoradiography was performed. While both tracers demonstrated favorable blood-brain barrier penetration, they didn't exhibit region-specific binding consistent with MAO-B distribution in vivo. Furthermore, [18F]4 underwent substantial metabolic degradation in both central and peripheral compartments, and deuteration failed to provide significant stabilization in [18F]4-D2. Autoradiography further revealed non-selective binding of [18F]4-D2 to both MAO isoforms. Overall, the translational potential of [18F]4 and [18F]4-D2 remains limited by poor metabolic stability and insufficient target selectivity. Future tracer design should focus on pharmacophore optimization to achieve reliable and selective MAO-B PET imaging.
In Singapore, there are plans to release radiological reports to patients directly, potentially before their physician clinic visits. While several studies have researched this policy in Caucasian-majority populations, there is scarce data for Asian-majority populations. This study aims to understand the perceptions of releasing radiological reports directly to patients before their clinic visit, by surveying physicians and patients at a major tertiary hospital in Singapore. Voluntary surveys were fielded to English-proficient patients who presented for select cross-sectional imaging, as well as physicians working at the hospital between March and July 2024. Statistical analysis was performed using Pearson's χ2 test and multivariate linear regression with a two-tailed statistical significance value of 0.05. An institutional review board waiver of consent was received. Analyzing 280 physician and 137 patient responses showed significant differences in agreement across all questions (p < 0.0001). Patients favored, and physicians opposed, the direct release of results. Subgroup analysis revealed significant differences (p < 0.05) between tertiary and pre-tertiary educated patients. Tertiary-educated patients highlighted presumed better understanding of radiological reports (53.6% vs. 25%), less confusion (16.5% vs. 37.5%), felt that the report would better prepare them for the clinic visit (79.4% vs. 47.5%), and increased understanding of their medical condition (79.4% vs. 50%). Wide differences in opinion on direct release of radiological reports, especially as education levels rise, need to be addressed. A "one-size-fits-all" approach does not suit our population, and physicians play a vital role by advocating for patients, helping them navigate complex medical terminology, and the increasingly complex medical landscape.
The metabotropic glutamate receptor 3 (mGluR3) is a G-protein-coupled receptor (GPCR) involved in modulating glutamatergic neurotransmission and maintaining neural homeostasis. By inhibiting adenylyl cyclase activity, mGluR3 negatively modulates the activity of adenylyl cyclase via Gi/o protein coupling, reducing cyclic AMP (cAMP) levels and modulating downstream signaling pathways. Dysfunction of mGluR3 is associated with a range of neurological and psychiatric disorders, including depression, autism, cognitive impairment, bipolar affective disorder, schizophrenia, and neurodegenerative diseases. Despite its therapeutic relevance, no selective mGluR3 positron emission tomography (PET) radioligand is currently available to image this target in vivo. In this study, we report the radiosynthesis and preclinical evaluation of [18F]VU6010572 - a novel PET tracer based on a therapeutical drug candidate. VU6010572 exhibits potent binding affinity (IC50 = 39.9 nM) and exceptional selectivity (>100-fold over other mGluR subtypes). Radiolabeling with fluorine-18 yielded [18F]VU6010572 with high radiochemical yield (48%, decay-corrected) and molar activity (59 GBq/µmol). While in vitro autoradiography demonstrated heterogeneous brain distribution, dynamic PET imaging in rodents revealed reasonable brain uptake in vivo yet modest binding specificity and rapid brain washout. While these findings support the potential of [18F]VU6010572 as a lead structure, further medicinal chemistry optimization is warranted to enhance the metabolic and pharmacokinetic properties.
Radiolabeled folate derivatives have been extensively investigated for positron emission tomography (PET) imaging of ovarian cancer due to the frequent overexpression of folate receptor α (FRα). However, clinical translation has been hindered, at least in part, by suboptimal tumor uptake of FRα-targeted radiotracers. In this study, we developed and characterized a 68Ga-labeled heterodimeric radiotracer, 68Ga-folate-KR, designed to concurrently target FRα and human epidermal growth factor receptor 2 (HER2), another receptor commonly overexpressed in ovarian cancer. Transcriptomics analysis confirmed the co-upregulation of FOLR1 and HER2 in ovarian cancer tissues relative to normal ovarian tissue, supporting the rationale for dual-receptor targeting. In vitro binding assays demonstrated specific binding of 68Ga-folate-KR to both receptors. PET imaging and biodistribution studies in SKOV3 tumor-bearing mice revealed significantly enhanced tumor uptake and improved tumor-to-nontumor contrast compared to the monomeric radiotracers 68Ga-folate and 68Ga-KR. Competitive blocking experiments further confirmed the in vivo dual-receptor targeting capability of 68Ga-folate-KR. Collectively, our results highlight that 68Ga-folate-KR enables more sensitive PET detection of ovarian cancer xenografts. With further optimization, dual-receptor-targeted radiotracers hold promise for clinical translation in both lesion detection and therapy response monitoring in ovarian cancer.
The AI-CVD initiative aims to extract actionable insights from coronary artery calcium (CAC) scans beyond the traditional CAC score. Although AI-derived cardiac chamber volumes predict atrial fibrillation (AF) and stroke, the long-term prognostic value of chamber ratios is less established. We evaluated the predictive value of AI-derived left atrial volume index and related chamber ratios (left atrial [LA]/right atrial [RA], LA/left ventricular) from routine CAC scans for incident AF and stroke, and their incremental value beyond established risk scores. Pooled participant-level data from 2 prospective cohorts, the MESA (Multi-Ethnic Study of Atherosclerosis, 2000-2002, n=5670) and the FHS (Framingham Heart Study Offspring cohort, 1998-2001, n=1142), were analyzed. Primary outcomes were incident AF and incident stroke. AI-enabled volumetry (AutoChamber, AI-CVD platform) quantified cardiac chamber metrics from noncontrast CAC scans. Cox proportional hazards models, net reclassification improvement, time-dependent area under the curve, calibration metrics, and least absolute shrinkage and selection operator regression were applied to evaluate predictive performance. Over a median 17-year follow-up, 1302 participants developed AF, and 365 experienced stroke events. Individuals in the ≥95th percentile of chamber metrics had a significantly increased risk. Adjusted hazard ratios for AF were 2.66 (95% CI, 2.23-3.17) for left atrial volume index, 2.04 (95% CI, 1.71-2.45) for LA/left ventricular (LV) ratio, and 1.87 (95% CI, 1.55-2.26) for LA/RA ratio. For stroke, corresponding hazard ratios were 1.96 (95% CI, 1.38-2.77), 1.64 (95% CI, 1.15-2.33), and 1.83 (95% CI, 1.29-2.59), respectively. AI-derived metrics improved reclassification beyond Cohorts for Heart and Aging Research in Genomic Epidemiology Atrial Fibrillation risk score and Framingham Stroke Risk Profile, with greatest improvements for AF from left atrial volume index (net reclassification improvement, 0.48) and stroke from LA/RA ratio (net reclassification improvement, 0.39), driven mainly by nonevent classification. Although discrimination improvements (area under the curve ) were modest, chamber measurements substantially improved Framingham Stroke Risk Profile calibration (slope, 0.448 to 0.834-0.902). Among all chamber metrics (including volumes and ratios), the least absolute shrinkage and selection operator identified left atrial volume index as the strongest predictor for AF, and LA/RA ratio as the strongest for stroke. AI-enabled left atrial volumetric and ratio-based metrics derived opportunistically from CAC scans provide incremental predictive value for AF and stroke prediction.