Citations

Abstract Venomous snakebite is an important cause of preventable death. The World Health Organization (WHO) set a goal to halve snakebite mortality by 2030. We used verbal autopsy and vital registration data to model the proportion of venomous animal deaths due to snakes by location, age, year, and sex, and applied these proportions to venomous animal contact mortality estimates from the Global Burden of Disease 2019 study. In 2019, 63,400 people (95% uncertainty interval 38,900–78,600) died globally from snakebites, which was equal to an age-standardized mortality rate (ASMR) of 0.8 deaths (0.5–1.0) per 100,000 and represents a 36% (2–49) decrease in ASMR since 1990. India had the greatest number of deaths in 2019, equal to an ASMR of 4.0 per 100,000 (2.3-5.0). We forecast mortality will continue to decline, but not sufficiently to meet the WHO’s goals. Improved data collection should be prioritized to help target interventions, improve burden estimation, and monitor progress.

Background Atrial fibrillation (AF) is a major risk factor for mortality. The prevalence, clinical correlates, and prognostic impact of AF in Takotsubo syndrome (TTS) have not yet been investigated in a large patient cohort. This study aimed to investigate the prevalence, clinical correlates, and prognostic impact of AF in patients with TTS. Methods and Results Patients with TTS were enrolled from the International Takotsubo Registry, which is a multinational network with 26 participating centers in Europe and the United States. Patients were dichotomized according to the presence or absence of AF at the time of admission. Of 1584 patients with TTS, 112 (7.1%) had AF. The mean age was higher ( P <0.001), and there were fewer women ( P =0.046) in the AF than in the non‐AF group. Left ventricular ejection fraction was significantly lower ( P =0.001), and cardiogenic shock was more often observed ( P <0.001) in the AF group. Both in‐hospital ( P <0.001) and long‐term mortality ( P <0.001) were higher in the AF group. Multivariable Cox regression analysis revealed that AF was independently associated with higher long‐term mortality (hazard ratio, 2.31; 95% CI, 1.50–3.55; P <0.001). Among patients with AF on admission, 42% had no known history of AF before the acute TTS event, and such patients had comparable in‐hospital and long‐term outcomes compared with those with a history of AF. Conclusions In patients presenting with TTS, AF on admission is significantly associated with increased in‐hospital and long‐term mortality rates. Whether antiarrhythmics and/or cardioversion are beneficial in TTS with AF should thus be tested in a future trial. Registration URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01947621.

Background: Human induced pluripotent stem cells with normal (wild-type) or upregulated (overexpressed) levels of CCND2 (cyclin D2) expression were differentiated into cardiomyocytes (CCND2 WT CMs or CCND2 OE CMs, respectively) and injected into infarcted pig hearts. Methods: Acute myocardial infarction was induced by a 60-minute occlusion of the left anterior descending coronary artery. Immediately after reperfusion, CCND2 WT CMs or CCND2 OE CMs (3×10 7 cells each) or an equivalent volume of the delivery vehicle was injected around the infarct border zone area. Results: The number of the engrafted CCND2 OE CMs exceeded that of the engrafted CCND2 WT CMs from 6- to 8-fold, rising from 1 week to 4 weeks after implantation. In contrast to the treatment with the CCND2 WT CMs or the delivery vehicle, the administration of CCND2 OE CM was associated with significantly improved left ventricular function, as revealed by magnetic resonance imaging. This correlated with reduction of infarct size, fibrosis, ventricular hypertrophy, and cardiomyocyte apoptosis, and increase of vascular density and arterial density, as per histologic analysis of the treated hearts. Expression of cell proliferation markers (eg, Ki67, phosphorylated histone 3, and Aurora B kinase) was also significantly upregulated in the recipient cardiomyocytes from the CCND2 OE CM-treated than from the CCND2 WT CM-treated pigs. The cell proliferation rate and the hypoxia tolerance measured in cultured human induced pluripotent stem cell cardiomyocytes were significantly greater after treatment with exosomes isolated from the CCND2 OE CMs (CCND2 OE Exos) than from the CCND2 WT CMs (CCND2 WT Exos). As demonstrated by our study, CCND2 OE Exos can also promote the proliferation activity of postnatal rat and adult mouse cardiomyocytes. A bulk miRNA sequencing analysis of CCND2 OE Exos versus CCND2 WT Exos identified 206 and 91 miRNAs that were significantly upregulated and downregulated, respectively. Gene ontology enrichment analysis identified significant differences in the expression profiles of miRNAs from various functional categories and pathways, including miRNAs implicated in cell-cycle checkpoints (G2/M and G1/S transitions), or the mechanism of cytokinesis. Conclusions: We demonstrated that enhanced potency of CCND2 OE CMs promoted myocyte proliferation in both grafts and recipient tissue in a large mammal acute myocardial infarction model. These results suggest that CCND2 OE CMs transplantation may be a potential therapeutic strategy for the repair of infarcted hearts.

Abstract Aims Acute pulmonary disorders are known physical triggers of takotsubo syndrome (TTS). This study aimed to investigate prevalence of acute pulmonary triggers in patients with TTS and their impact on outcomes. Methods and results Patients with TTS were enrolled from the International Takotsubo Registry and screened for triggering factors and comorbidities. Patients were categorized into three groups (acute pulmonary trigger, chronic lung disease, and no lung disease) to compare clinical characteristics and outcomes. Of the 1670 included patients with TTS, 123 (7%) were identified with an acute pulmonary trigger, and 194 (12%) had a known history of chronic lung disease. The incidence of cardiogenic shock was highest in patients with an acute pulmonary trigger compared with those with chronic lung disease or without lung disease (17% vs. 10% vs. 9%, P = 0.017). In-hospital mortality was also higher in patients with an acute pulmonary trigger than in the other two groups, although not significantly (5.7% vs. 1.5% vs. 4.2%, P = 0.13). Survival analysis demonstrated that patients with an acute pulmonary trigger had the worst long-term outcome (P = 0.002). The presence of an acute pulmonary trigger was independently associated with worse long-term mortality (hazard ratio 2.12, 95% confidence interval 1.33–3.38; P = 0.002). Conclusions The present study demonstrates that TTS is related to acute pulmonary triggers in 7% of all TTS patients, which accounts for 21% of patients with physical triggers. The presence of acute pulmonary trigger is associated with a severe in-hospital course and a worse long-term outcome.

Abstract Background: Androgen receptor (AR) is expressed in 60%-90% of breast cancers. The role of AR in breast cancer largely depends on estrogen receptor (ER) status and remains controversial. In ER+ cancers, AR expression is associated with improved prognosis. Enzalutamide (ENZ), an AR antagonist, impairs AR signaling, inhibits ER+/AR+ breast cancer cell proliferation and has been shown to mitigate resistance to anti-estrogen therapies. A recent study identified that RAD140, an AR agonist, suppressed the growth of ER+/AR+ breast cancer via stimulating AR signaling, resulting in down regulation of ERα. Both AR agonists and antagonists are effective in treating ER+ breast cancers. Identifying the subgroup of patients who most likely will benefit from an individual drug is important in clinical practice. Here, we sought to characterize the relative AR to ER levels and their relationships to drug response in ER+ breast cancers.Methods: We evaluated AR and ER expression levels among 68 samples with ER+ breast cancers. On each tumor, IHC staining for AR and ER were performed and results were scored by multiplying the percentage of positive cells by the intensity. TCGA-RPPA (reverse phase protein array) dataset was used to verify AR protein distribution in ER+ cancers. We created MCF7 and T47D cells with doxycycline-inducible AR and ER expression system to manipulate the relative AR to ER ratios and determined the antitumor activity of ENZ and RAD140 by cell proliferation assays. The levels of AR and ER in cells were measured by western blot. Linear regression was used to test the association between dose-response area under curve (AUC) and AR, ER levels. Drug preference was modeled against AR/ER expression levels (AR/ER ratios) using logistic regression.Results: Among 68 ER+ breast cancers, 69.12% were AR-positive. More than 2/3 cases (48 of 68) had more ER than AR expressed. The AR to ER ratios varied from 0 to 6. In the TCGA cohort, 84.15% of 347 ER+ patients had AR/ER ratios less than 1.The range of AR to ER ratios in TCGA dataset were comparable with our data (0.004 to 4.210). In our cell line models, the AR/ER ratios were controlled between 0.19 to 4.05. We found that the AUC of RAD140 was negatively associated with AR protein levels (P=0.008) and AR/ER ratios (P=0.013), and not significantly associated with ER expression levels. On the other hand, the AUC of ENZ was significantly negatively associated with ER protein (P=0.0016) but postiviely associated with AR/ER ratio (p=0.037). Preferred treatment comparing efficacy of the two drug can be best determined at extremes of AR/ER ratios. Using clinically relevant dosages, our model predicted that ENZ (10µM) would be a preferred treatment choice and have a better treatment efficacy compared with RAD140 when the AR/ER ratio was ≤ 0.42, whereas RAD140 (1µM) would be the preferred choice with a better treatment efficacy compared with ENZ when AR/ER ratios were ≥ 3.1 The efficacy preference of the two drugs are equivocal for AR/ER ratios between 0.42 and 3.10. Conclusion: We developed preclinical models using AR and ER expression levels to predict AR-targeting drug response. The results support the use of RAD140 in AR high patients and those with an AR/ER ratio &gt;3.10, and enzalutamide in AR low patients and those with an AR/ER ratio &lt;0.42. Equipoise on choice of drug was found for AR/ER ratios of 0.42-3.10. RAD140 and enzalutamide are compelling candidates for monotherapy or combination with anti-estrogen therapies in ER+/AR+ breast cancer. Future clinical validation of the models and therapeutic effect is warranted. Citation Format: Lixuan Wei, Huanyao Gao, Jia Yu, Duan Liu, Huan Zhang, Thanh Nguyen, Marie R Passow, Jodi M Carter, Richard M Weinshilboum, James N Ingle, Liewei Wang. Computational modeling of androgen receptor (AR) and estrogen receptor as predictive biomarkers of response to AR agonists and antagonists [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS5-36.

Background While there is a long history of measuring death and disability from injuries, modern research methods must account for the wide spectrum of disability that can occur in an injury, and must provide estimates with sufficient demographic, geographical and temporal detail to be useful for policy makers. The Global Burden of Disease (GBD) 2017 study used methods to provide highly detailed estimates of global injury burden that meet these criteria. Methods In this study, we report and discuss the methods used in GBD 2017 for injury morbidity and mortality burden estimation. In summary, these methods included estimating cause-specific mortality for every cause of injury, and then estimating incidence for every cause of injury. Non-fatal disability for each cause is then calculated based on the probabilities of suffering from different types of bodily injury experienced. Results GBD 2017 produced morbidity and mortality estimates for 38 causes of injury. Estimates were produced in terms of incidence, prevalence, years lived with disability, cause-specific mortality, years of life lost and disability-adjusted life-years for a 28-year period for 22 age groups, 195 countries and both sexes. Conclusions GBD 2017 demonstrated a complex and sophisticated series of analytical steps using the largest known database of morbidity and mortality data on injuries. GBD 2017 results should be used to help inform injury prevention policy making and resource allocation. We also identify important avenues for improving injury burden estimation in the future.

Several antiepileptic drugs (AEDs) have US Food and Drug Administration (FDA) approval for use as mood stabilizers in bipolar disorder (BD), but not all BD patients respond to these AED mood stabilizers (AED‐MSs). To identify genetic polymorphisms that contribute to the variability in AED‐MS response, we performed a discovery genome‐wide association study (GWAS) of 199 BD patients from the Mayo Clinic Bipolar Disorder Biobank. Most of these patients had been treated with the AED‐MS valproate/divalproex and/or lamotrigine. AED‐MS response was assessed using the Alda scale, which quantifies clinical improvement while accounting for potential confounding factors. We identified two genome‐wide significant single‐nucleotide polymorphism (SNP) signals that mapped to the THSD7A (rs78835388, P = 7.1E‐09) and SLC35F3 (rs114872993, P = 3.2E‐08) genes. We also identified two genes with statistically significant gene‐level associations: ABCC1 (P = 6.7E‐07; top SNP rs875740, P = 2.0E‐6), and DISP1 (P = 8.9E‐07; top SNP rs34701716, P = 8.9E‐07). THSD7A SNPs were previously found to be associated with risk for several psychiatric disorders, including BD. Both THSD7A and SLC35F3 are expressed in excitatory/glutamatergic and inhibitory/γ‐aminobutyric acidergic (GABAergic) neurons, which are targets of AED‐MSs. ABCC1 is involved in the transport of valproate and lamotrigine metabolites, and the SNPs in ABCC1 and DISP1 with the strongest evidence of association in our GWAS are strong splicing quantitative trait loci in the human gut, suggesting a possible influence on drug absorption. In conclusion, our pharmacogenomic study identified novel genetic loci that appear to contribute to AED‐MS treatment response, and may facilitate precision medicine in BD.

Background Past research in population health trends has shown that injuries form a substantial burden of population health loss. Regular updates to injury burden assessments are critical. We report Global Burden of Disease (GBD) 2017 Study estimates on morbidity and mortality for all injuries. Methods We reviewed results for injuries from the GBD 2017 study. GBD 2017 measured injury-specific mortality and years of life lost (YLLs) using the Cause of Death Ensemble model. To measure non-fatal injuries, GBD 2017 modelled injury-specific incidence and converted this to prevalence and years lived with disability (YLDs). YLLs and YLDs were summed to calculate disability-adjusted life years (DALYs). Findings In 1990, there were 4 260 493 (4 085 700 to 4 396 138) injury deaths, which increased to 4 484 722 (4 332 010 to 4 585 554) deaths in 2017, while age-standardised mortality decreased from 1079 (1073 to 1086) to 738 (730 to 745) per 100 000. In 1990, there were 354 064 302 (95% uncertainty interval: 338 174 876 to 371 610 802) new cases of injury globally, which increased to 520 710 288 (493 430 247 to 547 988 635) new cases in 2017. During this time, age-standardised incidence decreased non-significantly from 6824 (6534 to 7147) to 6763 (6412 to 7118) per 100 000. Between 1990 and 2017, age-standardised DALYs decreased from 4947 (4655 to 5233) per 100 000 to 3267 (3058 to 3505). Interpretation Injuries are an important cause of health loss globally, though mortality has declined between 1990 and 2017. Future research in injury burden should focus on prevention in high-burden populations, improving data collection and ensuring access to medical care.

Background: Nonrheumatic valvular diseases are common; however, no studies have estimated their global or national burden. As part of the Global Burden of Disease Study 2017, mortality, prevalence, and disability-adjusted life-years (DALYs) for calcific aortic valve disease (CAVD), degenerative mitral valve disease, and other nonrheumatic valvular diseases were estimated for 195 countries and territories from 1990 to 2017. Methods: Vital registration data, epidemiologic survey data, and administrative hospital data were used to estimate disease burden using the Global Burden of Disease Study modeling framework, which ensures comparability across locations. Geospatial statistical methods were used to estimate disease for all countries, because data on nonrheumatic valvular diseases are extremely limited for some regions of the world, such as Sub-Saharan Africa and South Asia. Results accounted for estimated level of disease severity as well as the estimated availability of valve repair or replacement procedures. DALYs and other measures of health-related burden were generated for both sexes and each 5-year age group, location, and year from 1990 to 2017. Results: Globally, CAVD and degenerative mitral valve disease caused 102 700 (95% uncertainty interval [UI], 82 700–107 900) and 35 700 (95% UI, 30 500–42 500) deaths, and 12.6 million (95% UI, 11.4 million–13.8 million) and 18.1 million (95% UI, 17.6 million–18.6 million) prevalent cases existed in 2017, respectively. A total of 2.5 million (95% UI, 2.3 million–2.8 million) DALYs were estimated as caused by nonrheumatic valvular diseases globally, representing 0.10% (95% UI, 0.09%–0.11%) of total lost health from all diseases in 2017. The number of DALYs increased for CAVD and degenerative mitral valve disease between 1990 and 2017 by 101% (95% UI, 79%–117%) and 35% (95% UI, 23%–47%), respectively. There is significant geographic variation in the prevalence, mortality rate, and overall burden of these diseases, with highest age-standardized DALY rates of CAVD estimated for high-income countries. Conclusions: These global and national estimates demonstrate that CAVD and degenerative mitral valve disease are important causes of disease burden among older adults. Efforts to clarify modifiable risk factors and improve access to valve interventions are necessary if progress is to be made toward reducing, and eventually eliminating, the burden of these highly treatable diseases.