Relative Hazard Research Articles

Effectiveness of Prophylactic Use of Hepatoprotectants for Tuberculosis Drug-Induced Liver Injury: A Population-Based Cohort Analysis Involving 6,743 Chinese Patients.

Background: Tuberculosis drug-induced liver injury (TB-DILI) is a common and potentially severe adverse drug reaction leading to treatment interruption and treatment failure. The real-world preventive effectiveness of hepatoprotective agents for DILI is not well described. The aim of the study was to evaluate the patterns of prophylactic therapies in real-world settings and risks of DILI among adult TB patients without known risk factors for DILI. Methods: This is a population-based retrospective cohort study of patients receiving first-line anti-tuberculosis drugs in the Chinese Center for Disease Control and Prevention (CDC) TB registry linked to the Ningbo Regional Health Care Database (NRHCD) between 2015 and 2020. The primary exposure was any use of chemopreventive agents including silymarin and/or glycyrrhetinic acid during the 30-day period prior to TB diagnosis (index date). The main outcome measure was the occurrence of newly onset DILI following TB treatment. Eligible patients were followed until the earliest of any DILI, treatment discontinuation, death, or end of the study period (30 June 2020). Marginal structural competing risk models and Cox models via inverse probability treatment weights using high-dimensional propensity scores were used to estimate subdistribution hazard risks (SHR) and 95% confidence intervals (CIs) for DILI risks, with adjustment for age, sex, TB-related characteristics, and comorbidities. Results: We identified a cohort of 6,743 adult patients with TB (mean age of 47.1 [SD 18.7] years; 65.80% male), of whom 2,886 (42.8%) patients received hepatoprotective agents. A total of 895 DILI events and 111 all-cause death events without DILI were observed over a median follow-up of 367 days post-TB diagnosis. The incidence rates of composite outcomes combining DILI and all-cause mortality were 248.9 and 222.3 per 1,000 person-years in the hepatoprotective agent exposed and unexposed groups (relative hazard ratio 1.35, 95% CI 1.11–1.64), respectively. The incidence rates of DILI were 223.7 and 196.1 per 1,000 person-years in the hepatoprotective agent exposed and unexposed groups (relative hazard ratio 1.38, 95% CI 1.12–1.71), respectively. Patients with any chemopreventive agent use had comparable liver function changes as evidenced by laboratory tests. Conclusion: A non-trivial number of adult patients received chemopreventive agents for TB-DILI. However, prophylactic utilization of hepatoprotective agents was not associated with a reduction in TB-DILI risks.

Prehospital synergy: Tranexamic acid and blood transfusion in patients at risk for hemorrhage.

Growing evidence supports improved survival with prehospital blood products. Recent trials show a benefit of prehospital tranexamic acid (TXA) administration in select subgroups. Our objective was to determine if receiving prehospital packed red blood cells (pRBC) in addition to TXA improved survival in injured patients at risk of hemorrhage. We performed a secondary analysis of all scene patients from the Study of Tranexamic Acid during Air and ground Medical Prehospital transport trial. Patients were randomized to prehospital TXA or placebo. Some participating EMS services utilized pRBC. Four resuscitation groups resulted: TXA, pRBC, pRBC+TXA, and neither. Our primary outcome was 30-day mortality and secondary outcome was 24-hour mortality. Cox regression tested the association between resuscitation group and mortality while adjusting for confounders. A total of 763 patients were included. Patients receiving prehospital blood had higher Injury Severity Scores in the pRBC (22 [10, 34]) and pRBC+TXA (22 [17, 36]) groups than the TXA (12 [5, 21]) and neither (10 [4, 20]) groups (p < 0.01). Mortality at 30 days was greatest in the pRBC+TXA and pRBC groups at 18.2% and 28.6% compared with the TXA only and neither groups at 6.6% and 7.4%, respectively. Resuscitation with pRBC+TXA was associated with a 35% reduction in relative hazards of 30-day mortality compared with neither (hazard ratio, 0.65; 95% confidence interval, 0.45-0.94; p = 0.02). No survival benefit was observed in 24-hour mortality for pRBC+TXA, but pRBC alone was associated with a 61% reduction in relative hazards of 24-hour mortality compared with neither (hazard ratio, 0.39; 95% confidence interval, 0.17-0.88; p = 0.02). For injured patients at risk of hemorrhage, prehospital pRBC+TXA is associated with reduced 30-day mortality. Use of pRBC transfusion alone was associated with a reduction in early mortality. Potential synergy appeared only in longer-term mortality and further work to investigate mechanisms of this therapeutic benefit is needed to optimize the prehospital resuscitation of trauma patients. Therapeutic/Care Management; Level III.

Potential Health Impacts of Gamma-Frequency Sound in Server Room

Hearing degradation caused by an exposure to excessive noise is irreversible. Many of the other relative hazards that can be developed from noise-induced hearing loss are impaired communication with family and coworkers, social isolation, irritability, decreasing of self-esteem, anxiety, and loss of productivity. Hearing impairment is a significant health hazard that is naturally occurs with aging. Tinnitus is a disorder in hearing ability and can cause a ringing in the ear without a source for physical sound. More than 40 million people in the United States are suffering from tinnitus disorder. Fourteen percent of adults are suffering from chronic tinnitus, and 50% of normal adults with no clinically confirmed disorders in hearing ability experience subtle tinnitus in a silent environment. An exposure to excessive noise and the process of natural aging of people may increase the occurrence of Tinnitus. Tinnitus is a spontaneous auditory perception that is associated with the continued activity of the gamma frequency band (30 Hz - 80Hz). Server Room can be considered as a continuous source of gamma frequency. Server room running devices are generating a continuous noise that most of its power is allocated in the band of gamma frequency.

TP53 Mutant Versus Wild-Type Zebrafish Larvae Under Starvation Stress: Larvae Can Live Up to 17 Days Post-Fertilization Without Food.

In this study, an experimental protocol has been developed for comparing survival rates of mutant and wild-type zebrafish larvae under extreme starvation. Zebrafish larvae were placed in 96-well plates at fourth day postfertilization (dpf) and larvae were not fed at all from hatching to cease. Zdf1 zebrafish line was used, a strain carrying the (cancer) pathogenic TP53-M214K amino acid substitution. TP53-M214 corresponds to the human TP53-M246 and both residues are located on the DNA-binding domain of the p53 protein. Survival statistical analysis did not show any significant difference in the overall survival rates between homozygous mutant and wild-type larvae. When considering 15 dpf as the endpoint of the experiment (66% of larvae died), a borderline statistical significance was observed for the dominant model of inheritance (p = 0.015; relative hazard = 0.8320). Despite the fact yolk sac of larvae is depleted at 7-8 dpf, 34% of larvae survive until 15 dpf and 1.5% until 17 dpf. Concluding, three main results derive from this study: (1) pathogenic homozygous mutations in TP53 probably do not alter survival rates of zebrafish larvae under starvation; (2) zebrafish larvae can live up to 17 dpf without food, surviving only with their initial nutritional supplies; and (3) an easy and affordable protocol has been developed for estimating survival rates of zebrafish larvae under stressful conditions.

Actual Size Mismatch in Lung Transplantation for Restrictive Lung Disease

<h3>Purpose</h3> Donor to recipient <i>predicted</i> total lung capacity (TLC) ratio is increasingly used for size matching in lung transplantation. This can overlook significant reductions in the <i>actual</i> TLC frequently seen in restrictive lung diseases. Forced vital capacity (FVC) is a useful surrogate for actual TLC, with proportionate decreases with progression of restrictive conditions. Analyzing donor predicted:recipient actual FVC could better predict actual lung size mismatch. <h3>Methods</h3> The UNOS database was used to identify 7,572 patients with restrictive lung disease undergoing isolated bilateral lung transplantation from 2005 to 2021. Lung size mismatch was quantified by donor:recipient FVC ratio, and patients were divided into quintiles. Multivariable cox regression was used to assess the relationship between size mismatch and all-cause mortality, adjusting for patient, donor and center baseline characteristics including lung allocation score (LAS) and degree of recipient FVC decline. Restricted cubic splines were used to assess the non-linear relationship between the FVC ratio and relative mortality hazard. Median follow-up was 2.6 (range 0-15) years. <h3>Results</h3> The median age of the cohort was 59 (Interquartile range (IQR) 53-64) years, 32.5% (n=2,464) were female and the median LAS was 47.1 (IQR 39.7-67.3). The median FVC ratio was 2.4 (range 1.1-5.3). Overall unadjusted 10-year survival was 37.3% (95% confidence interval (CI) 35.5-39.2). The primary cause of death was graft failure in 19.0% (n=532) cases. The highest quintile of FVC ratio was an independent predictor of mortality in multivariable analysis (hazard ratio 1.2, 95% CI 1.1-1.4). Spline analysis indicated that an FVC ratio >3.45 predicted significantly worse survival (Figure 1), corresponding to the 1,043 (14%) most oversized patients. <h3>Conclusion</h3> Oversizing with respect to FVC results in worse long-term survival despite adjustment for baseline characteristics, emphasizing the importance of considering recipient actual TLC in donor-recipient matching.

Risks for Public Health and Social Infrastructure in Russian Arctic under Climate Change and Permafrost Degradation

This study analyzes the risks to public health and life quality in the conditions of permafrost degradation caused by the ongoing climate change in the Russian Arctic. There are more than 200 Siberian anthrax cattle burial grounds in the Russian permafrost regions. Permafrost degradation poses the risks of thawing of frozen carcasses of the infected animals and propagation of infectious diseases. Permafrost degradation leads to infiltration of toxic waste in the environment. Such waste contains mercury, which migrates into the rivers and forms methylmercury (MeHg) in fish. Other risks associated with permafrost degradation include damage to the existing social infrastructure (housing, health-care facilities, roads, etc.). Various risks to public well-being that emerge because of permafrost degradation were addressed in this study. Relative hazard indices were developed and calculated to characterize the probability of outbreaks of Siberian anthrax in the future. These indices linked the rates of permafrost degradation and the number of Siberian anthrax cattle burials to the potential hazard of re-emergence of Siberian anthrax among local populations in 70 municipal districts under the ongoing warming. The expected damage to public housing, health-care facilities, and motorways was assessed. Accessibility of health care in various regions of the Russian Arctic was analyzed. The economic costs associated with various scenarios of possible destruction of residential buildings, health-care facilities, and roads built on permafrost were estimated.

Association of Pentachlorophenol with Fetal Risk of Prolonged Bradycardia: A Systematic Review and Meta-Analysis.

Objective This study explored the systematic evaluation and meta-analysis of different concentrations of PCP on the risk of long-term bradycardia in fetuses. Methods Cochrane Library, Embase, PubMed, China Biomedical Literature Service, CNCNKI, and Wanfang database were computerized to collect all case-control studies on the association between variety classes and different concentrations of environmental pollutant gas to fetal of prolonged bradycardia. After evaluating the quality of the inclusion study and extracting valid data, meta-analysis was performed using Stata15 software. Relative hazards were calculated using the Mantel-Haenszel method and the random effect model, and P values and I2 values were used for heterogeneity evaluation. When heterogeneity occurs, subgroup analysis and sensitivity analysis were used to explore the sources. Results A total of 15 studies were included, including 1202 patients with fetal of prolonged bradycardia and 1380 in the control population. Meta-analysis showed that there was no statistical difference in PCP < 0.1 mg/L between the experimental group and control group (OR = 1.03, 95% CI (0.62, 1.72), P=0.90, I2 = 0%, Z = 0.13), but there was a statistical difference in PCP > 5 mg/L (OR = 1.73, 95% CI (1.15, 2.58), P=0.008, I2 = 0%, Z = 2.65), PCP > 10 mg/L (OR = 1.75, 95% CI (1.19, 2.57), P=0.004, I2 = 14%, Z = 2.85), and PCP >15 mg/L (OR = 2.02, 95% CI (1.38, 2.95), P=0.0003, I2 = 77%, Z = 3.61). Conclusion In this study, we found that different concentrations of PCP increased the risk of long-term bradycardia in fetuses, and the risk coefficient increased with the increase of PCP concentration.

Impact of the COVID-19 Pandemic and Public Restrictions on Outcomes After Catheter Ablation of Atrial Fibrillation.

BackgroundHere we aimed to analyze changes in the outcomes of atrial fibrillation (AF) catheter ablation (AFCA) during the coronavirus disease 2019 (COVID-19) pandemic and examine the relationship between rhythm outcomes and the stringency of government social distancing measures.MethodsWe included 453 patients who underwent de novo AFCA between May 2018 and October 2019 (pre-COVID-19 era) and 601 between November 2019 and April 2021 (COVID-19 era). The primary outcome was late recurrence, defined as any episode of AF or atrial tachycardia documented after a 3-month blanking period. A multivariable Cox regression analysis was performed to estimate the relative hazards of AF recurrence in the two eras.ResultsIn the study population (24.3% women; median age, 60 years), 660 (62.6%) patients had paroxysmal AF. Among those with paroxysmal AF, the late recurrence rate was significantly lower in the COVID-19 era than in the pre-COVID-19 era [9.4% vs. 17.0%, respectively, log-rank P = 0.004; adjusted hazard ratio (HR) 0.56, 95% confidence interval (CI) 0.35–0.90] during a median follow-up of 11 months. In patients with persistent AF, the late recurrence rate did not significantly differ between the pre-COVID-19 and COVID-19 era groups (18.9% vs. 21.5%, respectively; log-rank P = 0.523; adjusted HR 0.84, 95% CI 0.47–1.53) during the median follow-up of 11 months.ConclusionA decrease in AF recurrence after catheter ablation was observed in patients with paroxysmal AF during the COVID-19 outbreak, whereas no change was observed in those with persistent AF.

Relation between Relative Hazard Rates and Residual Divergence with some Applications to Reliability Analysis

Relation between Relative Hazard Rates and Residual Divergence with some Applications to Reliability Analysis

Association Between Preoperative Fibrinogen-to-Albumin Ratio and All-Cause Mortality After Off-Pump Coronary Artery Bypass Grafting: A Retrospective Observational Study.

The fibrinogen-to-albumin ratio (FAR) is a recently introduced prognostic marker for patients with coronary artery disease. The present study investigated whether the FAR is associated with clinical outcome after off-pump coronary artery bypass grafting (OPCAB). We retrospectively reviewed 1759 patients who underwent OPCAB (median duration of follow-up, 46 months). To evaluate the association between FAR and mortality in OPCAB patients, time-dependent coefficient Cox regression analyses were used to assess the association between FAR and all-cause mortality. In multivariable time-dependent coefficient Cox regression analyses, preoperative FAR was an independent risk factor for all-cause mortality after OPCAB (adjusted hazard ratio, 1.051; 95% confidence interval, 1.021-1.082). In the restricted cubic spline function curve of the multivariable-adjusted relationship between the preoperative FARs, a linear increase in the relative hazard for all-cause mortality was observed as the FAR increased (P = .001). A higher FAR is associated with increased all-cause mortality after OPCAB. The preoperative FAR could be a prognostic factor for predicting higher mortality after OPCAB.

A new survival analysis model in adjuvant Tamoxifen-treated breast cancer patients using manifold-based semi-supervised learning

Breast cancer researchers are very interested in studying and analyzing the survival time of patients. However, choosing the appropriate model for survival time analysis is the main challenge in the survival analysis of these patients. Using a dataset of patients with breast cancer, a new survival analysis model is proposed in this study. First, using the Cox-PH model, the whole selected data was categorized into high-risk and low-risk groups. The classified data was given to the AFT model in the next step to estimate the survival time. In some instances, the value of the metabolic status of the Tamoxifen feature was missing. Next, using the information obtained from the first and second steps, in the proposed Manifold-based semi-supervised learning module, the value of missing data was estimated. Using all labeled data, the final survival analysis was performed, and the relative hazard obtained. The comparison of the proposed model via other previous models in survival analysis demonstrates that the proposed model is 26% more accurate than when only the Cox-PH model was used and 28% more accurate than when only the AFT model was used in the testing set. Furthermore, the findings demonstrate that when the Manifold-based SSL model was used in the learning module, the accuracy was 19% higher than the Co-training SSL method and 12% higher than the SVMSSL method. The advantages of the proposed survival analysis method are high capability for identifying the survival risk classes of the patient and high predictive accuracy for the relative hazard.

Abstract MP66: Prediabetes, Diabetes By Age Of Onset And Subsequent Risk Of Dementia

Objective: To characterize the direct and indirect association of prediabetes with dementia risk and to examine the age at diabetes onset and subsequent risk of dementia. Methods: At baseline (1990-1992), prediabetes was defined based on HbA1C 5.7-6.4% among people without a history of diagnosed diabetes or medication use for diabetes; diabetes was defined based on self-reported physician diagnosis or diabetes medication use or HbA1C level of 6.5% or greater. Incident diabetes with the same definition during the follow-up was included as a time-varying variable. Incident dementia was ascertained using surveillance, interviews and adjudication. Survival analysis used age as the time scale using an origin at age 50 and left and right censoring. Adjustment models included sex, race, education, APOE, BMI, smoking status, alcohol use, physical activity, total cholesterol, HDL cholesterol and hypertension. Results: Among the 13,388 participants, 2314 (17.3%) had prediabetes and 1798 (13.4%) had diabetes at baseline. Before adjusting for incident diabetes, the adjusted hazard ratios of dementia were 2.35 (95% CI: 1.99, 2.76) and 1.13 (95% CI: 1.02, 1.25) for diabetes and prediabetes compared to no diabetes in the fully adjusted model. After adding incident diabetes, the excess risk of dementia for prediabetes decreased by ~50% and the association was not significant. The relative hazards of dementia were 3.16 (95% CI: 2.15, 4.66), 1.64 (95% CI: 1.36, 1.97), 1.29 (95% CI: 1.14, 1.47) and 1.06 (95% CI: 0.89, 1.28) for diabetes with age onset at &lt; 60, 60-69, 70-79 and 80-93, respectively (Table). Conclusion: Midlife diabetes and prediabetes are associated with excess hazard of dementia and death. Earlier age of onset of diabetes shows a strong dose response with higher dementia hazard. Much of the risk of dementia in pre-diabetes is explained by intervening incidence of clinical diabetes. Dementia prevention efforts would benefit from preventing or delaying the progression of prediabetes to diabetes.

Retromolar trigone squamous cell carcinoma: A population-based analysis of survival

ObjectivesTo evaluate the difference in overall survival (OS) in patients with retromolar trigone squamous cell carcinoma (RMT SCC) treated with surgery alone versus surgery plus postoperative radiotherapy (PORT) versus surgery plus postoperative chemoradiotherapy (POCRT). Materials and MethodsRetrospective cohort study of patients from 1,500 US facilities reporting to the National Cancer Database (NCDB) registry. Participants were adult patients treated with surgery as primary treatment modality for RMT SCC (n = 2,877). Exposures were primary definitive surgery versus surgery + PORT versus surgery + POCRT. Outcomes included OS after diagnosis and treatment of RMT SCC. A multivariate Cox proportional hazards model was constructed to compare survival between the three treatment modalities. Subgroup analysis was performed by T classification and overall staging. ResultsThere were 1,415 (50%) patients treated with surgery alone, 870 (30%) patients treated with surgery + PORT, and 572 (20%) treated with surgery + POCRT. Treatment with surgery + PORT was associated with improved OS compared to surgery alone (relative hazard: 1.25, 95% CI: 1.01, 1.54, p = 0.042). Patients treated with surgery + POCRT also had improved OS compared with surgery alone (relative hazard: 1.89, 95% CI 1.45, 2.43, p < 0.001). Patients with T3/4 tumors had improved OS when treated with surgery + PORT (relative hazard 1.39, 95% CI: 1.05, 1.84, p = 0.022) or surgery + POCRT (relative hazard 2.27, 95% CI: 1.66, 3.15, p < 0.001). Patients with T1 or T2 disease had no significant difference in survival in both the surgery + PORT (p = 0.331) and surgery + POCRT treatment groups (p = 0.134). Therefore, there was no difference in OS for patients with stage I or II disease treated with surgery + PORT (p = 0.451), nor with surgery + POCRT (p = 0.853). ConclusionTreatment with surgery + PORT +/- chemotherapy appears to be associated with significantly improved OS compared to surgery alone for advanced RMT SCCa.

Calcaneal quantitative ultrasound is associated with all-cause and cardiovascular disease mortality independent of hip bone mineral density

SummaryOsteoporosis has been linked with increased risk of cardiovascular disease previously. However, few studies have detailed bone and vascular information. In a prospective study of older women, we demonstrated heel quantitative ultrasound measures were associated with increased cardiovascular and all-cause mortality, independent of established cardiovascular risk factors.IntroductionOsteoporosis and low bone mineral density (BMD) have been previously linked to cardiovascular disease (CVD) and mortality. Calcaneal quantitative ultrasound (QUS) is used to evaluate bone material properties, especially in older women. However, it is uncertain whether it is related to risk of mortality. This study was aimed to investigate the association between calcaneal QUS measurements and 15-year all-cause and CVD mortality in 1404 older women (mean age 75.2 ± 2.7 years).MethodsOne thousand four hundred four older women, participants of Calcium Intake Fracture Outcome study (CAIFOS), had calcaneal bone measured at baseline (1998) and followed for 15 years. The primary outcomes, any deaths, and deaths attributable to cardiovascular causes ascertained by using linked data were obtained from Western Australia data linkage system.ResultsOver the 15 years of follow-up (17,955 person years), 584 of the women died, and 223 from CVD. For every standard deviation (SD), reduction in broadband ultrasound attenuation (BUA) in minimally and multivariable-adjusted model including cardiovascular risk factors increased relative hazards for all-cause (multivariable-adjusted HR 1.15; 95%CI: 1.06–1.26, p = 0.001) and CVD mortality (multivariable-adjusted HR 1.20; 95%CI: 1.04–1.38, p = 0.010). Such relationships also persisted when hip BMD was included in the model (all-cause mortality HR 1.19; 95%CI: 1.07–1.33, p = 0.002; CVD mortality HR 1.28; 95%CI: 1.07–1.53, p = 0.008).ConclusionBUA is associated with all-cause and CVD mortality in older women independent of BMD and established CVD risk factors. Understanding why and how these are related may provide further insights about the bone-vascular nexus as well as therapeutic targets benefiting both systems.

In Professional Male Soccer Players, Time-Loss Groin Injury Is More Associated With the Team Played for Than With Training/Match-Play Duration.

To investigate the relationship between training/match-play duration and time-loss groin injury in professional male soccer players, and to determine whether previously identified intrinsic risk factors influenced this relationship. Prospective cohort study. A total of 579 professional male soccer players were prospectively followed from July 2013 to June 2015. Time-loss groin injuries and individual training and match-play duration were recorded using standardized surveillance methods. Acute training/match-play duration and chronic training/match-play duration were considered as interacting variables. Nonlinear Cox regression analysis (modeled using restricted cubic splines), clustered by player identification number, examined the relationship between training/match-play duration and groin injury. Previously identified intrinsic risk factors of previous groin injury and eccentric adduction strength were included in the multivariable regression analysis. There was no clinically meaningful relationship between training/match-play duration and groin injury risk. Team played for had the strongest influence on groin injury risk (relative log hazard ratio -2.28 to 0.97). Groin injury risk was highest when accumulated chronic and acute training duration was also highest, but large confidence intervals indicate considerable uncertainty around this finding. Previous groin injury and eccentric adduction strength were not associated with groin injury risk when training/match-play duration and team were included in the model. In professional male soccer players, there was no clinically meaningful relationship between groin injury risk and training/match-play duration. Team played for either protected against or increased groin injury risk, indicating that team-related factors not measured in this study had greater effect on groin injury risk than training/match-play duration. J Orthop Sports Phys Ther 2022;52(4):217-223. Epub 5 Feb 2022. doi:10.2519/jospt.2022.10845.

A population-based cohort approach to assess excess mortality due to the spread of COVID-19 in Italy, January-May 2020.

To assess the impact of the COVID-19 pandemic on all-cause mortality in Italy during the first wave of the epidemic, taking into consideration the geographical heterogeneity of the spread of COVID-19. This study is a retrospective, population-based cohort study using national statistics throughout Italy. Survival analysis was applied to data aggregated by day of death, age groups, sex, and Italian administrative units (107 provinces). We applied Cox models to estimate the relative hazards (RH) of excess mortality, comparing all-cause deaths in 2020 with the expected deaths from all causes in the same time period. The RH of excess deaths was estimated in areas with a high, moderate, and low spread of COVID-19. We reported the estimate also restricting the analysis to the period of March-April 2020 (first peak of the epidemic). The study population consisted of 57,204,501 individuals living in Italy as of January 1, 2020. The number of excess deaths was 36,445, which accounts for 13.4% of excess mortalities from all causes during January-May 2020 (i.e., RH = 1.134; 95% confidence interval (CI): 1.129-1.140). In the macro-area with a relatively higher spread of COVID-19 (i.e., incidence rate, IR): 450-1,610 cases per 100,000 residents), the RH of excess deaths was 1.375 (95% CI: 1.364-1.386). In the area with a relatively moderate spread of COVID-19 (i.e., IR: 150-449 cases) it was 1.049 (95% CI: 1.038-1.060). In the area with a relatively lower spread of COVID-19 (i.e., IR: 30-149 cases), it was 0.967 (95% CI: 0.959-0.976). Between March and April (peak months of the first wave of the epidemic in Italy), we estimated an excess mortality from all causes of 43.5%. The RH of all-cause mortality for increments of 500 cases per 100,000 residents was 1.352 (95% CI: 1.346-1.359), corresponding to an increase of about 35%. Our analysis, making use of a population-based cohort model, estimated all-cause excess mortality in Italy taking account of both time period and of COVID-19 geographical spread. The study highlights the importance of a temporal/geographic framework in analyzing the risk of COVID-19-epidemy related mortality.

Modelling studies of the hazards posed by liquid hydrogen use in civil aviation

As part of the ENABLEH2 project, modelling studies have been carried out to examine liquid hydrogen release and dispersion behaviour for different LH2 aircraft and airport infrastructure leak/spill accident scenarios. The FLACS CFD model has been used to simulate the potential hazard effects following an accidental LH2 leak, including the extent of the flammable LH2 clouds formed, magnitude of explosion overpressures and pool fire radiation hazards. A comparison has also been made between the relative hazard consequences of using LH2 with conventional Jet A/A-1 fuel. The results indicate that in the event of accidental fuel leak/spill LH2 has some safety advantages over Jet A/A-1 but will also introduce additional hazards not found with Jet A/A-1 that will need to be carefully managed and mitigated against.

Abstract 104: A Step In The Wrong Direction: The Lack Of Drug Subsidies Drives Patients To Switch From Direct Oral Anticoagulants To Warfarin

Background: Direct oral anticoagulants (DOACs) are superior to warfarin in preventing ischemic stroke from nonvalvular atrial fibrillation (AF). Transitioning from a DOAC to warfarin is rarely medically indicated. The frequency and determinants of switching from DOAC to warfarin, including the potential influence of cost, are not known. Objective: Examine the impact of financial assistance available through Medicaid prescription coverage or low-income subsidy programs on likelihood of switching to warfarin after initiating a DOAC. Methods: We identified patients in the Medicare 5% sample who initiated a DOAC from 2015 to 2017. Patients were eligible if they were age 65 or older, had AF diagnosis, had no oral anticoagulant use during the prior 12 months, and were enrolled in a Medicare Prescription Plan for at least 12 months prior to first oral anticoagulant. Patients who switched to warfarin after an initial DOAC were identified, and their characteristics were evaluated in bivariable and multivariable analyses using Cox regression to adjust for potential confounders and censor for death or end of the observation period. Results: Of 27,151 eligible patients,16,599 (61%), 8,930 (33%), and 1,622 (6%) initiated apixaban, rivaroxaban, and dabigatran, respectively. 30% (8,110) initiated a low dose DOAC. A total of 1,481 (5.5%) switched to warfarin sometime during the follow-up period. The median time to first warfarin dose among patients who switched was 153 days. Overall, 14% of patients were eligible for Medicaid prescription coverage and an additional 8.8% were eligible for other drug subsidies; these patients were significantly less likely to switch to warfarin, compared to other patients (3.4%, 4.1%, 5.8% of patients with Medicaid coverage, other drug subsidies, or neither). After risk adjustment, the relative hazard of switching to warfarin was 0.57 (95% confidence interval (CI): 0.47-0.68) and 0.69 (95% CI: 0.56-0.85), for patients with Medicaid coverage or drug subsidy, respectively, compared to other patients. Conclusions: The financial burden of DOACs may contribute to patients switching to warfarin, despite guideline recommendations. Financial assistance may facilitate evidenced-based best practices in stroke prevention.

Prognostic Impact of Left Ventricular Ejection Fraction in Patients With Moderate Aortic Regurgitation: Potential Implications for Treatment Decision-Making.

Background:The prognostic impact and optimal treatment of left ventricular systolic dysfunction in patients with moderate aortic regurgitation (AR) remain unknown. We aimed to assess the prognostic value of left ventricular ejection fraction (LVEF) in patients with moderate AR and explore the potential benefits of aortic valve intervention (AVI).Methods:In total, 1,211 consecutive patients with moderate AR (jet width, 25–64% of LV outflow tract; vena contracta, 0.3–0.6 cm; regurgitant volume, 30–59 mL/beat; regurgitant fraction, 30–49%; effective regurgitation orifice, 0.10–0.29 cm2) prospectively registered between April and June 2018 at 46 academic hospitals were included. The primary outcome was a composite of death or hospitalization for heart failure (HHF). The optimal LVEF threshold for predicting the primary outcome was determined through the penalized spline shape and maximally selected rank statistics.Results:During the 2-year follow-up, 125 deaths or HHF occurred. In the penalized splines, the relative hazard of death or HHF monotonically increased with decreasing LVEF. In the multivariate analysis, LVEF ≤55% was identified as the best threshold for independently predicting death or HHF under medical treatment (adjusted hazard ratio [HR]: 2.18; 95% confidence interval [CI] 1.38–3.42; P = 0.001), with substantial incremental values (integrated discrimination improvement index = 0.018, P = 0.030; net reclassification improvement index = 0.225, P = 0.006; likelihood ratio test P < 0.001). Among patients with LVEF 35–55%, AVI within 6 months of diagnosis was associated with a reduced risk of death or HHF compared with medical treatment alone (adjusted HR: 0.15; 95% CI: 0.04–0.50; P = 0.002), whereas this benefit was markedly attenuated when LVEF was ≤35% (adjusted HR: 0.65; 95% CI: 0.21–1.97; P = 0.441, P-interaction = 0.010) or >55% (adjusted HR: 0.40; 95% CI: 0.14–1.15; P = 0.089, P-interaction = 0.723).Conclusions:LVEF is an independent and incremental prognostic factor in patients with moderate AR, with LVEF ≤55% being a robust marker of poor prognosis. Patients with LVEF 35–55% may benefit from early surgical correction of moderate AR. Further studies are warranted to validate our findings in a randomized setting.Registration:China Valvular Heart Disease Study (China-VHD study, NCT03484806); clinicaltrials.gov/ct2/show/NCT03484806.

Clinical effects of durability of immunosuppression in virologically suppressed ART-initiating persons with HIV in Latin America. A retrospective cohort study

SummaryBackgroundClinical outcomes are rarely studied in virologically suppressed people living with HIV (PWH) and incomplete CD4 recovery. To explore whether time living with severe immunosuppression predict clinical outcomes better than baseline or time updated CD4, we estimated the association between cumulative percentage of time with CD4 <200 cells/μL during viral suppression (VS) (%tCD4<200), and mortality and comorbidities during 2000–2019.MethodsIn a retrospective cohort analysis, we followed PWH initiating ART in Latin America from first VS (HIV-RNA<200 copies/μL) to death, virological failure or loss to follow-up. We fit Cox models to estimate risk of death and/or AIDS-defining and serious non-AIDS-defining events (ADE and SNADE -cancer, cardiovascular, liver, and renal diseases) by %tCD4<200 (continuous variable). We predicted survival probabilities for each event and calculated risks of hypothetical cases of different %tCD4<200.FindingsIn 8,369 patients with 34·9 months of follow-up (median, IQR: 16·7, 69·1), 4,274 (51%) started ART with CD4<200 cells/μL. Median %tCD4<200 was 0% (IQR: 0, 15%). We identified 195 (2·3%) deaths and 584 (7·2%) patients with ADE/SNADE. For an increased %tCD4<200 of 15% (e.g., 15% vs. 0%), the adjusted relative hazard (aHR) of death was 1·27 (95% confidence interval [CI]: 1·19 − 1·35), of ADE/SNADE was 1·13 (95%CI: 1·09 − 1·17), of SNADE was 0·96 (95%CI: 0·89 − 1·02) and of death/ADE/SNADE was 1·11 (95%CI: 1·07 − 1·14). Estimates were similar after adjusting for time updated CD4 count.InterpretationIn virologically suppressed PWH, increased time living with severe immunosuppression had an increased risk of death and ADE/SNADE in this Latin American cohort, independently of time updated CD4 count.FundingThis work was supported by the NIH-funded Caribbean, Central and South America network for HIV epidemiology (CCASAnet, U01AI069923), a member cohort of the International Epidemiologic Databases to Evaluate AIDS (leDEA). This award is funded by the following institutes: Eunice Kennedy Shriver National Institute Of Child Health & Human Development (NICHD), National Cancer Institute (NCI), National Institute Of Allergy And Infectious Diseases (NIAID), National Institute Of Mental Health (NIMH), the National Heart, Lung, and Blood Institute (NHLBI), the National Institute on Alcohol Abuse and Alcoholism (NIAAA), the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), and the Fogarty International Center (FIC). Specific funding was provided from the Fogarty International Center (FIC) for lead author, Yanink Caro-Vega, for the Fogarty-IeDEA Mentorship Program (FIMP).