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Background: Cell-penetrating peptides cross cell membrane barriers while carrying cargoes in a functional form. Our work identified two novel lung-targeting peptides, S7A and R11A. Here, we present studies on biodistribution, the cell types targeted, and an in vitro proof of application. Methods: Studies were performed in human bronchial epithelial cells (HBECs) with and without various endocytic inhibitors, and coincubation with fluorescently labeled transferrin or endocytic markers. Cyclic R11A (cR11A) was conjugated to siRNA duplexes and anti-viral activity against SARS-CoV-2 was tested. Biodistribution studies were performed by injecting wild-type mice with fluorescently labeled peptides, and various circulation times were allowed for, as well as cross-staining of lung sections or isolated single cells with various cellular markers, followed by fluorescence-activated cell sorting or confocal microscopy. Results: cR11A showed peak uptake in 15 min, with the highest uptake in airway epithelial type II (ATII) cells, followed by p63+ basal cells and ionocytes. Cyclization increased transduction efficiencies ~100-fold. Endocytosis studies showed a decrease in peptide uptake by pre-treatment with Pitstop2 but not Amiloride or Nystatin. Endocytic marker Lamp1 showed colocalization at the earliest time point, with the escape of the peptide from endocytic vesicles later. cR11A conjugated to ant-spike and anti-envelop proteins showed anti-viral effects with an EC90 of 0.6 μM and 1.0 µM, respectively. Conclusions: We have identified a novel peptide, cR11A, that targets ATII, basal cells, and ionocytes, the cyclization of which increased transduction efficiency in vitro and in vivo. The uptake mechanism appears to be via clathrin-mediated endocytosis with escape from endocytic vesicles. cR11A can act as a vector to deliver anti-viral siRNA to epithelial cells.

ABSTRACT Background and Aims Out‐of‐hospital cardiac arrest stands as the primary cause of worldwide mortality. Therefore, all healthcare workers must comprehensively understand and practically apply cardiopulmonary resuscitation (CPR). To address the paucity of literature on this subject, we conducted a nationwide survey among healthcare professionals in Pakistan. Methods This nationwide cross‐sectional study was based on an online questionnaire. The sample pool comprised healthcare professionals and medical students from all over Pakistan. The survey comprised 18 questions aimed to assess the comprehension of CPR, determine the source of their basic life support (BLS) training, and evaluate their competence in performing CPR in real‐life situations. Results The sample size consisted of 951 participants from Pakistan. A total of 712 responders (75%) reported having received CPR or CPR with an Automated External Defibrillator (AED) course, and the same percentage reported that their respective universities had organized the course. The responders reported that the BLS course was made mandatory in only 60% of cases. Most of the respondents were first‐year medical students (21%) and postgraduates (21%). Most of the respondents (78%) professed that the courses had been theoretical as well as practical, and 66% felt confident enacting CPR in out‐of‐hospital settings. Overall, no province was able to achieve a score of greater than 50% when assessed about their knowledge regarding cardiac arrest and CPR. Conclusion This study provides a detailed insight into Pakistan healthcare workers' CPR knowledge and perceptions belonging to different provinces, institutes, designations, and specialties. The participants reported being confident in performing CPR but demonstrated gaps when assessed regarding the revised guidelines and their performance in different scenarios. There is room for further research in overcoming the language barriers and other discrepancies faced by this study.

The radiotracer [ 68 Ga]Ga-NOTA-CTP was evaluated in healthy and diseased CD1 mice with myocardial infarction following ligation of the left anterior descending artery.

e20520 Background: Cancer and respiratory failure (RF) are amongst leading causes of mortality in adults. This study investigates national trends in age-adjusted mortality rates (AAMRs) for cancer and RF in the United States from 1999 to 2023, focusing on disparities by gender, race, region, and rural-urban residence to inform public health strategies. Methods: This descriptive study analyzed data from the CDC WONDER database, of adults aged 25 and older. Mortality data were identified using ICD-10 codes C00–C97 (cancer) and J96 (RF). AAMRs per 100,000 population were calculated and stratified by gender, race/ethnicity, census region, urban-rural classification, and state. Temporal trends were analyzed using Joinpoint regression to estimate annual percent changes (APCs) with 95% confidence intervals (CIs). Statistical significance was set at p < 0.05. Results: From 1999 to 2023, total deaths of 1,263,368 attributed to cancer and RF (682,141 men, 581,227 women). AAMRs declined from 1999 to 2004 (APC = -1.5, 95% CI: -4.0 to -0.4), stabilized from 2004 to 2012 (APC = 0.8, 95% CI: 0.1 to 2.4), and increased from 2012 to 2023 (APC = 3.2, 95% CI: 2.9 to 3.8). Men experienced a greater initial decline (APC = -2.1, 1999–2004) but significant increases thereafter (APC = 3.0, 2012–2023), while women showed a slower decline followed by sharper increases (APC = 3.5, 2013–2023). Non-Hispanic Black populations initially declined (APC = -1.7, 1999–2003) but later increased significantly (APC = 3.0, 2014–2020). Hispanic/Latino populations declined (APC = -1.2, 1999–2009) before rising sharply (APC = 3.1, 2009–2020). American Indian or Alaska Native populations showed consistent increases (APC = 1.7, 1999–2020). Urban areas experienced initial declines (APC = -1.7, 1999–2004), followed by increases (APC = 2.4, 2011–2020). Non-metropolitan areas exhibited steeper increases (APC = 4.6, 2014–2020). Regionally, the West recorded the highest AAMR (24.0), followed by the Northeast (23.6), South (20.9), and Midwest (18.0). Mississippi had the highest state-level AAMR (36.3), while Wisconsin had the lowest (10.0). States in the top 90th percentile included Mississippi, Arkansas, and California, while Wisconsin, Minnesota, and Oregon were among the lowest. Conclusions: Cancer and RF mortality declined initially but have significantly increased in recent years. Disparities persist across gender, racial, and regional groups, underscoring the need for focused public health efforts and equitable resource distribution to address these trends.

e16076 Background: Gastric cancer is the fourth leading cause of global cancer deaths. Despite declining incidence and mortality, it remains a significant contributor to the global disease burden. This study analyzes regional gastric cancer DALYs and mortality trends from 1990-2021 using the GBD database. Methods: The regional DALYs and mortality rates per 100,000 individuals aged 70+ from GBD 2021 were analyzed, with trends from 1990 to 2021 evaluated using AAPC, and statistical significance assessed by p-values. Results: In 2021, the greatest Age-standardized DALYs rates were recorded in Andean Latin America, with 3068.04 per 100,000; the lowest was found in High-income North America with 386.08 per 100,000. The most significant increase of DALYs rate from 1990 to 2021 was in Southern Sub-Saharan Africa, (AAPC = -0.3068%; 95% CI: -0.3852 to -0.2234; p < 0.000001), while in Western Europe, the largest decline was noted (AAPC = -2.9999%; 95% CI: -3.0164 to -2.9841; p < 0.000001). Andean Latin America was the region with the highest Age-standardized mortality rates (ASMRs) in 2021, at 207.58 per 100,000 while High-income North America had the lowest at 27.18 per 100,000. In Western Sub-Saharan Africa, the ASMRs were rising with an AAPC of -0.2601% (95% CI: -0.2872 to -0.2368; p < 0.000001), while Western Europe had the highest decline with an AAPC of -2.7658% (95% CI: -2.7895 to -2.7471; p < 0.000001). Conclusions: The global burden of diseases from 1990 to 2021 is regional in nature. In 2021, DALYs and mortality were predominantly high in Andean Latin America and East Asia and notably low in High-income North America. DALYs have risen across Southern Sub-Saharan Africa over three decades, and mortality increased over Western Sub-Saharan Africa, while both declined sharply in Western Europe. These trends underscore the importance of regionalized health solutions. DALY per 100,000. Metric Region 1990 2021 AAPC (1990-2021) HIGHEST DISABILITY-ADJUSTED LIFE YEARS (DALYS) PER 100,000 Andean Latin America 4469.23 3068.04 -1.14 East Asia 5507.72 2958.98 -1.99 High Income Asia Pacific 4849.23 2130.43 -2.71 LOWEST DISABILITY-ADJUSTED LIFE YEARS (DALYS) PER 100,000 High Income North America 758.59 386.09 -2.22 Australasia 1116.91 567.32 -2.16 South Asia 794.81 680.50 -0.46 HIGHEST MORTALITY RATE PER 100,000 Andean Latin America 293.65 207.58 -1.04 East Asia 324.60 188.92 -1.72 High Income Asia Pacific 316.44 161.94 -2.22 LOWEST MORTALITY RATE PER 100,000 High Income North America 51.24 27.19 -2.02 Australasia 74.36 41.81 -1.85 South Asia 47.50 41.95 -0.39

e16074 Background: Gastric cancer is a malignant disease characterized by the uncontrolled growth of cells in the stomach lining. It is a global health concern with regional variation in incidence and prevalence. This study examines the national mortality trends in adults aged 70 years and older from 1990 to 2021. Methods: GBD data was analysed to assess the mortality rates of Gastric cancer in individuals aged ≥ 70 years. The Estimated Annual Percentage Change (EAPC) was used to evaluate trends from 1990 to 2021, with p-values determining statistical significance. Results: From 1990 to 2021, the global prevalence of Gastric cancer increased, peaking in 2021. Japan recorded the highest prevalence (621.7379, UI: 525.93, 675.74), followed by the Republic of Korea and China.In 2021, Bolivia (Plurinational State of) had the highest mortality rate (309.7, CI: 400.9, 240.6), slightly lower than its 1990 rate (445.35, CI: 539.58, 362.14), which was the highest that year. Mongolia (303.15, CI: 378.8, 226.2) and Cabo Verde (265.1, CI: 322.6, 206.8) followed. The lowest mortality rates were observed in Morocco (20.9, CI: 25.9, 15.0), Namibia (20.93, CI: 25.93, 16.4), and Nigeria (23.27, CI: 32.3, 19.2).Countries with the largest EAPC increases included Egypt (0.98, CI: 1.84, -0.22), Honduras (0.31, CI: 0.7, -0.01), and Lesotho (0.16, CI: 0.597, -0.16). The greatest declines were seen in Austria (-0.72, CI: -0.68, -0.74), Czechia (-0.69, CI: -0.64, -0.74), and Hungary (-0.67, CI: -0.607, -0.72). Conclusions: Mortality rates associated with Gastric Cancer among individuals aged 70 and older increased globally from 1990 to 2021, notably in Egypt, Honduras and Lesotho, emphasizing the need for improved prevention, management, and research on underlying disparities. Mortality percent changes. Metric Region 1990 2021 EAPC with 95% CI (1990-2021) HIGHEST MORTALITY PERCENT CHANGE Egypt 30.43 60.44 0.98 (1.84, -0.22) Honduras 140.76 184.48 0.31 (0.7, -0.01) Lesotho 77.18 90.26 0.16 (0.59, -0.16) LOWEST MORTALITY PERCENT CHANGE Austria 177.25 49.48 -0.72 (-0.68, -0.74) Czechia 168.73 51.51 -0.69 (-0.64, -0.74) Hungary 184.88 60.55 -0.67 (0.607, -0.72)

e16237 Background: Alcohol use (AU) and Liver cell carcinoma (LCC) are significant contributors to adult mortality worldwide. Examining trends and disparities in AU and LCC-related deaths is essential for understanding public health challenges and formulating targeted interventions. This study investigates national mortality patterns related to AU and LCC in the United States from 1999 to 2023, emphasizing demographic, geographic, and temporal disparities. Methods: This descriptive analysis used the CDC WONDER database (1999–2023) to identify AU-related deaths (ICD-10 codes E24.4, F10, G32.2, G62.1, G72.1, I42.6, K70, K85.2, K86.0, R78.0, T51, X65, Y15) and LCC (ICD-10 code C22.0) in adults aged 25 and older. Age-adjusted mortality rates (AAMRs) per 1,000,000 individuals were calculated, stratified by gender, race/ethnicity, census region, urban-rural classification, and state. Trends were analyzed using Joinpoint regression to compute annual percent changes (APCs) and 95% confidence intervals (CIs). Statistical significance was set at p < 0.05, and analyses adhered to STROBE guidelines. Results: From 1999 to 2023, a total of 21,007 deaths were attributed to LCC and AU (Men: 18,836 Women: 2,171). AAMRs showed a stable trend from 1999 to 2003 (APC: 0.0; 95% CI: -8.7 to 4.9) but increased significantly from 2003 to 2019 (APC: 6.1; 95% CI: 5.7 to 7.4), stabilizing from 2019 to 2023 (APC: -0.6; 95% CI: -3.2 to 1.3). Men's AAMRs decreased from 1999 to 2003 (APC: -1.1; 95% CI: -10.4 to 3.4), then rose sharply from 2003 to 2019 (APC: 6.1; 95% CI: 5.6 to 7.1). For women, AAMRs increased significantly, particularly between 2013 and 2017 (APC: 12.4; 95% CI: -9.5 to 25.1). Non-Hispanic Black and White populations experienced notable increases in AAMRs, while Hispanic people showed an initial decline followed by an increase post-2004 (APC: 4.7; 95% CI: 3.7 to 7.9). The West had the highest regional AAMR (5.3; 95% CI: 5.2 to 5.5), while the Northeast recorded the lowest (2.1; 95% CI: 2.0 to 2.2). New Mexico had the highest state AAMR (8.4; 95% CI: 7.4 to 9.4), and Mississippi the lowest (1.2; 95% CI: 0.9 to 1.5). AAMRs rose more sharply in non-metropolitan areas from 1999-2020 (APC: 6.6; 95% CI: 5.9 to 7.8) compared to metropolitan regions from 2004 to 2020 (APC: 5.4; 95% CI: 4.9 to 6.5). Conclusions: AU and LCC-related mortality rates have increased significantly since 2003, with distinct gender, racial, and geographic disparities. Men and rural populations faced higher mortality increases, with notable variations across states and regions. These findings underscore the need for focused public health efforts to mitigate these disparities and address the growing burden of LCC and AU-related mortality.

e16456 Background: Gastric cancer is one of the significant contributors of mortality and morbidity, especially in older patients. Analyzing national trends in the Disability adjust life years (DALY) helps identify the evolving burden of this disease among patients older than 70 years and highlights the regions requiring particular interventions. Methods: Using Global burden of disease data from 2021, national DALY rates per 100,000 people aged 70 and over with gastric cancer were assessed. The Estimated Annual Percentage Change (EAPCs) with p value taken as a statistical measure of significance, was used to evaluate trends from 1990 to 2021. Results: The analysis displays considerable contrasts in the trends of gastric cancer burden across nations. From 1990 to 2021, a rising trend in DALY EAPC was seen in Egypt (1.01883; 95% CI: -0.1931- 1.958) followed by Honduras (0.3262; 95% CI: 0.0177- 0.7456) and Lesotho (0.2253; 95% CI:-0.1326- 0.6995). Conversely, Austria (-0.7368; 95% CI: -0.7646 to -0.7087), Republic of Korea (-0.7095; 95% CI: -0.7620 to -0.6442) and Singapore (-0.6923; 95% CI: -0.7286 to -0.6553) reported a prominent decline in DALY EAPCs, reflecting significant progress in reducing burden. The DALY rates in 2021 also varied dramatically among nations. Highest DALY rate was observed in Bolivia (4882.7; 95% CI:3782.9- 6349.7) underscoring highest impact on healthcare system. Conversely, Morocco (329.69; 95% CI: 234.64- 410.12) recorded lowest DALY rate indicating comparatively better disease control or lower incidence. Conclusions: While some nations demonstrate remarkable progress in mitigating the burden of gastric cancer, others still face significant challenges. Highest increase in EAPC in Egypt, Honduras and Lesotho whereas significant decline in Austria, Korea, and Singapore indicates areas of target public health efforts. Future research should focus on understanding the causes of these disparities and evaluating the impact of interventions across it. DALY and EPAC. Country 2021 DALY rate EAPC(1990-2021) EAPC, 95% CI Egypt 1272.146 1.018834(highest) -0.193 to 1.959 Honduras 2880.563 0.32617 0.018 to 0.746 Lesotho 1555.79 0.225384 -0.133 to 0.699 Singapore 806.6098 -0.692396 -0.729 to -0.655 Republic of Korea 1961.151 -0.709502 -0.762 to -0.644 Austria 662.5105 -0.736826(lowest) -0.765 to -0.709 Morocco 410.1227(lowest) -0.17817 -0.387 to 0.097 Bolivia 4882.718(highest) -0.32185 -0.473 to -0.103

e16423 Background: Pancreatic cancer (PC) is one of the most aggressive malignancies, disproportionately affecting older adults. Leveraging data from the Global Burden of Disease (GBD), this study investigates gender-specific trends in disability-adjusted life years (DALYs) and mortality rates for PC among adults aged 70 and older from 1990 to 2021. Methods: DALYs and mortality rates associated with PC were extracted for both genders from the GBD-2021 study from 1990 to 2021. The Annual Percentage Change (APC) and the Average Annual Percentage Change (AAPC) were calculated, along with 95% confidence intervals (CI), to assess the statistical significance of the trends using the p-value. Results: In 1990, DALY rates were 837.25 for men and 711.95 for women, increasing to 950.68 and 768.31, respectively, by 2021. Mortality rates followed a similar pattern: men’s rates rose from 52.05 in 1990 to 61.37 in 2021, while women’s increased from 47.31 to 53.40. Men consistently experienced higher burdens than women. The AAPC analysis revealed that men exhibited a steeper rise in both DALYs and mortality rates associated with PC compared to women over the past three decades. Notably, the gender disparity was more evident in DALYs (+0.1929%) than in mortality rates (+0.1358%), with all AAPC values demonstrating statistical significance (p < 0.000001). Following the APC analysis, additional significant trends were identified. Among males, DALY rates demonstrated the most pronounced increase between 1997 and 2021 (APC: 0.5397, 95% CI: 0.5118, 0.5645), whereas in females, the most significant rise occurred from 1990 to 1993 (APC: 0.6593, 95% CI: 0.3608, 1.1016). Conversely, the slowest increase in DALY rates among females was observed between 1993 and 2003 (APC: 0.0925, 95% CI: -0.2053, 0.1641). For mortality rates, the most notable rise in males was observed between 2007 and 2010 (APC: 1.2314, 95% CI: 1.0292, 1.3195), while females experienced their sharpest escalation from 1990 to 1994 (APC: 0.6891, 95% CI: 0.4322, 1.0720). In contrast, the slowest rate of progression in mortality among females occurred between 1993 and 2002 (APC: 0.1736, 95% CI: 0.0180, 0.2368). Conclusions: Over the past three decades, men have experienced a significantly more pronounced rise in DALYs and mortality rates related to PC compared to women.These findings highlight the urgent need for gender-specific interventions to address the growing burden of PC in aging populations. Trends in DALY and mortality rates per 100,000 by gender (1990-2021). Metrics Gender 1990 2021 APC (1990-2021) Daly Rates per 100,000 Male 837.25 950.68 0.4422 Female 711.9 768.31 0.2493 Mortality Rates per 100,000 Male 52.05 61.37 0.5366 Female 47.31 53.40 0.4008

e16420 Background: Pancreatic cancer (PC) typically follows an indolent course and is often diagnosed at an advanced stage, contributing to its high mortality rate, particularly among older adults. Its aggressive nature makes it a significant global health burden, causing substantial mortality across nations. This analysis investigates national mortality trends in adults aged 70 years and older from 1990 to 2021, utilizing data from the Global Burden of Disease (GBD) Study. Methods: We utilized data from the GBD-Study 2021 to report the number of cases and age-standardized rates (per 100,000 population) of PC. To assess mortality trends from 1990 to 2021, we calculated the estimated annual percentage change (EAPC) along with corresponding 95%confidence intervals (CI), providing a robust evaluation of temporal patterns. Results: Over the past three decades, deaths attributable to PC have shown a significant increase globally. In 1990, the United States of America (USA) reported the highest number of PC-related deaths, followed by China and Japan. By 2021, however, China surpassed the USA, becoming the leading contributor to PC mortality, with Japan maintaining its position as the third highest.In 2021, the United Arab Emirates reported the highest mortality rate (148.15), which was more than double its 1990 rate (70.71). The Principality of Monaco (140.87) and Uruguay (129.39) held the second and third highest mortality rates, respectively. The lowest mortality rates were recorded in Mozambique (8.18), Malawi (8.98), and Sao Tome and Principe (9.01).Countries with the largest increases in the EAPC included Turkmenistan (EAPC: 15.16, 95% CI: 10.92, 21.02), Republic of Cabo Verde (EAPC: 13.60, 95% CI: 8.56, 19.48), and Mongolia (EAPC: 4.80, 95% CI: 3.11, 7.26). In contrast, the greatest declines were observed in the Republic of San Marino (EAPC: -0.32, 95% CI: -0.52, -0.07), Guam (EAPC: -0.27, 95% CI: -0.41, -0.13), and Greenland (EAPC: -0.24, 95% CI: -0.44, 0.007). Conclusions: Globally, mortality rates associated with PC among individuals aged 70 and older increased from 1990 to 2021, with particularly notable rises in Turkmenistan, Republic of Cabo Verde, and Mongolia. These findings underscore the critical need for enhanced prevention strategies, improved management, and research to address underlying disparities. Mortality percent change. Metric Region 1990 2021 EAPC with 95% CI (1990-2021) Highest mortality percent change Turkmenistan 1.19 19.34 15.16 (10.92, 21.02) Republic of Cabo Verde 6.47 94.55 13.60 (8.56, 19.48) Mongolia 10.21 59.24 4.80 (3.11, 7.26) Lowest mortality percent change Republic of San Marino 89.48 60.47 -0.32 (-0.52, -0.07) Guam 32.46 23.51 -0.27 (-0.41, -0.13) Greenland 169.52 127.96 -0.24 (-0.44, 0.007)