Resistant Hypertension: Disease Burden and Emerging Treatment Options.

PURPOSE OF REVIEW: To define resistant hypertension (RHT), review its pathophysiology and disease burden, identify barriers to effective hypertension management, and to highlight emerging treatment options. RECENT FINDINGS: RHT is defined as uncontrolled blood pressure (BP) ≥ 130/80 mm Hg despite concurrent prescription of ≥ 3 or ≥ 4 antihypertensive drugs in different classes or controlled BP despite prescription of ≥ to 4 drugs, at maximally tolerated doses, including a diuretic. BP is regulated by a complex interplay between the renin-angiotensin-aldosterone system, the sympathetic nervous system, the endothelin system, natriuretic peptides, the arterial vasculature, and the immune system; disruption of any of these can increase BP. RHT is disproportionately manifest in African Americans, older patients, and those with diabetes and/or chronic kidney disease (CKD). Amongst drug-treated hypertensives, only one-quarter have been treated intensively enough (prescribed > 2 drugs) to be considered for this diagnosis. New treatment strategies aimed at novel therapeutic targets include inhibition of sodium-glucose cotransporter 2, aminopeptidase A, aldosterone synthesis, phosphodiesterase 5, xanthine oxidase, and dopamine beta-hydroxylase, as well as soluble guanylate cyclase stimulation, nonsteroidal mineralocorticoid receptor antagonism, and dual endothelin receptor antagonism. The burden of RHT remains high. Better use of currently approved therapies and integrating emerging therapies are welcome additions to the therapeutic armamentarium for addressing needs in high-risk aTRH patients.

D-methionine administered as late as 36 hours post-noise exposure rescues from permanent threshold shift and dose-dependently increases serum antioxidant levels.

OBJECTIVE: To elucidate D-methionine's (D-met) dose and time rescue parameters from steady-state or impulse noise-induced permanent threshold shift (PTS) and determine D-met rescue's influence on serum and cochlear antioxidant levels. DESIGN: Five D-met doses at 0, 50, 100, or 200 mg/kg/dose administered starting at 1, 24, or 36 hours post steady-state or impulse noise exposure. Auditory brainstem responses at baseline and 21 days post-noise measured PTS. Serum (superoxide dismutase [SOD], catalase [CAT],, glutathione reductaseand glutathione peroxidase [GPx]) and cochlear (Glutathione [GSH] and glutathione disulphide [GSSG]) antioxidant levels measured physiological impact. STUDY SAMPLE: Chinchillas (10/study group; 6-8/confirmatory groups). RESULTS: D-met significantly reduced PTS for impulse noise (100 mg [2, 6, 14 and 20 kHz]; 200 mg [2, 14 and 20 kHz]) and steady-state noise (all dosing groups, time parameters and tested frequencies). PTS reduction did not significantly vary by rescue time. D-met significantly increased serum SOD (100 and 200 mg for 24 hour rescue) and GPx (50 mg/kg at 24 hour rescue) at 21 days post-noise. Cochlear GSH and GSSG levels were unaffected relative to control. CONCLUSION: D-met rescues from steady-state and impulse noise-induced PTS even when administered up to 36 hours post-noise and dose-dependently influences serum antioxidant levels even 21 days post-noise. D-met's broad and effective dose/time window renders it a promising antioxidant rescue agent.

Oral D-methionine protects against cisplatin-induced hearing loss in humans: phase 2 randomized clinical trial in India.

Objective: This exploratory Phase 2 clinical trial is the first determining safety and efficacy of oral D-methionine (D-met) in reducing cisplatin-induced ototoxicity.Design: Randomised parallel double-blind placebo-controlled exploratory Phase 2 study.Study samples: Fifty adult cancer patients received oral D-met or placebo before each cisplatin dose. Physical examination, blood collection and audiometry occurred at baseline and subsequent visits plus post-treatment audiometry. After attrition, final analysis included 27 patients.Results: Significant treatment group by ear and time (baseline vs. post-treatment) interactions occurred at 10 kHz and 11.2 kHz. Placebo and D-met groups differed in threshold shift for left ear at 11.2 kHz (mean difference = 22.97 dB [9.59, 36.35]). Averaging across ears, placebo group showed significant threshold shifts from baseline to post-treatment at 10 kHz (mean shift= -13.65 dB [-21.32,-5.98]), 11.2 kHz (-16.15 dB [-25.19,-7.12]), and 12.5 kHz (-11.46 dB [-19.18,-3.74]) but not 8 kHz (-8.65 dB [-17.86, 0.55]). The D-met group showed no significant threshold shifts (8 kHz: -1.25 dB [-7.75, 5.25]; 10 kHz:-3.93 dB [-8.89, 1.03]; 11.2 kHz:-4.82 dB [-11.21, 1.57]; 12.5 kHz:-3.68 dB [-11.57, 4.21]). Side effects did not significantly differ between groups.Conclusion: Oral D-met reduces cisplatin-induced ototoxicity in humans.

D-methionine immediate and continued rescue after noise exposure does not prevent temporary threshold shift but alters cochlear and serum antioxidant levels.

OBJECTIVE: Determine if D-methionine (D-met) rescue prevents temporary threshold shift (TTS) from steady-state or impulse noise and determine D-met's impact on serum and cochlear antioxidant levels. DESIGN: D-met at 50, 100 or 200 mg/kg/doses were administered 0, 6 and 18 hours-post noise. ABRs at baseline and 24 hours post-noise measured TTS. Serum (SOD, CAT, GR, GPx) and cochlear (GSH, GSSG) antioxidant levels measured physiological influence. Three control groups, with impulse or steady-state or without noise, were saline-injected. STUDY SAMPLE: Ten Chinchillas/group. RESULTS: D-met rescue did not significantly reduce TTS or impact serum CAT, SOD, GPx or GR levels vs. noise-exposed control groups, but TTS was greater in all groups relative to no-noise controls. D-met significantly elevated CAT at 50 mg/kg vs. steady-state controls and SOD at 200 mg/kg vs. impulse noise controls. D-met significantly reduced cochlear GSH/GSSG ratios in the 100 mg/kg D-met group vs. impulse noise controls. CONCLUSIONS: While D-met rescue has reduced permanent threshold shift in previous studies, it did not reduce TTS in this study. However, D-met rescue did alter selective serum and cochlear oxidative state changes 24 hours post-noise relative to controls. Results demonstrate TTS studies do not always predict PTS protection in otoprotectant experimental designs.

Systemic White Blood Cell Count as a Biomarker for Malignant Cerebral Edema in Large Vessel Ischemic MCA Stroke.

OBJECTIVES: Large middle cerebral artery (MCA) strokes remain a major cause for mortality and morbidity all over the world, and therefore early identification of patients with the highest risk for malignant cerebral edema is crucial for early intervention. Neutrophils to lymphocytes ratio (NLR) and peripheral total white blood cell (WBC) count are inflammatory markers done routinely for all patients, and this study evaluated the use of NLR and elevated white blood cell count within the first 24 h of MCA ischemic stroke onset, with the absence of significant hemorrhagic transformation, to predict malignant cerebral edema. MATERIALS AND METHODS: A total of 156 patients with large MCA strokes were included. We collected demographic, clinical, radiological data, and NLR and WBCs within the first 24 h from admission.We excluded patients who had any underlying infections diagnosed 7 days before or within 72 h after admission. We used a body temp of 38 C or more, abnormal CXR or abnormal urine analysis within the first 72 h to exclude patients with possible infections.We excluded immune-compromised patients and patients on steroid therapy. We compared the NLR and WBC count in patients who developed malignant cerebral edema versus the patients who did not. NLR > 3.5 and < 3.5 was used for comparison. We then conducted multivariate logistic regression models to explore the relationship between cerebral edema, WBCs and NLR count simultaneously. RESULTS: NLR, WBC, radiological involvement of more than 50% of MCA territory infarction on presentation, hyperdense MCA sign, and NIH stroke scale were all significantly higher in patients with malignant cerebral edema within the first 24 h. Using univariate logistic regression, NLR performs better than WBC when predicting the occurrence of malignant cerebral edema (AUC = 0.74 vs. 0.62). However, NIH stroke scale scores, and radiological involvement of more than 50% of MCA territory infarction on the first 24 h of presentation on CT scan both showed better discriminative performance for malignant cerebral edema than NLR (AUC = 0.84 and 0.76, respectively). When combined, NLR > 3.5 paired with the NIH stroke scale score had the best predictive performance (AUC = 0.87). CONCLUSION: NLR > 3.5 can be used for early prognostication in patients with large vessel MCA ischemic strokes with no significant hemorrhagic transformation within the first 24 h regardless if they had reperfusion therapy or not. Combining NLR of > 3.5 in addition to high NIHSS provided the best predictive model in our study. Further studies are needed to further develop the best predictive model in diverse populations.

Impact of chronic kidney disease on in-hospital outcomes and readmission rate after edge-to-edge transcatheter mitral valve repair.

BACKGROUND: Transcatheter mitral valve repair (TMVR) is a treatment option for patients with 3+ or greater mitral regurgitation who cannot undergo mitral valve surgery. Outcomes in patients with chronic kidney disease (CKD) and end stage renal disease (ESRD) are unclear. We sought to evaluate the TMVR in-hospital outcomes, readmission rates and its impact on kidney function. METHODS: Data from 2016 National Readmission Database was used to obtain all patients who underwent TMVR. Patients were classified by their CKD status: no CKD, CKD, or ESRD. The primary outcomes were: in-hospital mortality, 30- and 90-day readmission rate, and change in CKD status on readmission. Multivariable logistic regression analysis was used to assess in-hospital, readmission outcomes and kidney function stage. RESULTS: A total of 4,645 patients were assessed (mean age 78.5 ± 10.3 years). In-hospital mortality was higher in patients with CKD (4.0%, odds ratio [OR]:2.01 [95% CI, confidence interval: 1.27-3.18]) and ESRD (6.6%, OR: 6.38 [95% CI: 1.49-27.36]) compared with non-CKD (2.4%). 30-day readmission rate was higher in ESRD versus non-CKD patients (17.8% vs. 10.4%, OR: 2.24 [95% CI: 1.30-3.87]) as was 90-day readmission (41.2% vs. 21% OR: 2.51 [95% CI:1.70-3.72]). Kidney function improved in 25% of patients with CKD stage 3 and in 50% with CKD stage 4-5 at 30-and 90-day readmission. Incidence of AKI, major bleeding, and respiratory failure were higher in CKD group. CONCLUSIONS: Patients with CKD and ESRD have worse outcomes and higher readmission rate after TMVR. In patients who were readmitted after TMVR, renal function improved in some patients, suggesting that TMVR could potentially improve CKD stage.

Risk Factors for Infection After Minor Dermatologic Procedures: A Case-Control Study.

BACKGROUND: There are limited published data regarding the incidence and risk factors for infection after minor dermatologic procedures, such as skin biopsy, shave, and curettage. Prior studies of infection risk after dermatologic procedures have often not specified the method of preparation of local anesthetic. OBJECTIVE: To assess the incidence and risk factors for infection after minor procedures performed in a general dermatology clinic using buffered lidocaine prepared in office. MATERIALS AND METHODS: In this retrospective case-control study, the medical record was searched for cases of infection after skin biopsies, shaves, conventional excisions, and destructions performed in a general dermatology clinic over a 4-year period. Patient and procedure characteristics were compared with uninfected controls. RESULTS: Of 9,031 procedures performed during the study period, there were 34 infections (0.4%). The odds of infection for procedures on the arm and leg were 5.29 and 9.28 times higher, respectively, than those on the head/neck. There was no significant effect of age, sex, smoking, immunosuppression, diabetes, or anticoagulation. CONCLUSION: The incidence of infection is low after minor dermatologic procedures performed with local anesthesia using buffered lidocaine prepared in office. There is a higher risk of infection on the arm and leg compared with the head and neck.

Endovascular Thrombolysis or Thrombectomy for Cerebral Venous Thrombosis: Study of Nationwide Inpatient Sample 2004-2014.

BACKGROUND AND PURPOSE: 15% of cerebral venous thrombosis (CVT) patients have poor outcomes despite anticoagulation. Uncontrolled studies suggest that endovascular approaches may benefit such patients. In this study, we analyze Nationwide Inpatient Sample (NIS) data to evaluate the safety and efficacy of endovascular therapy (ET) versus medical management in CVT. We also examined the yearly trends of ET utilization in the United States. METHODS: International Classification of Diseases, Ninth Revision, Clinical Modification codes were utilized to identify CVT patients who received ET. To make the data nationally representative, weights were applied per NIS recommendations. Since ET was not randomly assigned to patients and was likely to be influenced by disease severity, propensity score weighting methods were utilized to correct for this treatment selection bias. Outcome variables included in-hospital mortality and discharge disposition. To determine if our primary outcomes were associated with ET, we used weighted multivariable logistic regression analyses. RESULTS: Of the 49,952 estimated CVT cases, 48,704 (97%) received medical management and 1248 (3%) received ET (mechanical thrombectomy [MT] alone, N = 269 [21%], MT ± thrombolysis, N = 297 [24%], and thrombolysis alone, N = 682 [55%]). Patients who received ET were older with more CVT associated complications including venous infarct, intracranial hemorrhage, coma, seizure, and cerebral edema. There was a significant yearly rise in the use of ET, with a trend favoring MT versus thrombolysis alone. ET was independently associated with an increased risk of death (odds ratio 1.96, 95% confidence interval 1.15-3.32). CONCLUSIONS: Patients receiving ET experienced higher mortality after adjusting for age and CVT associated complications. Large, well designed prospective randomized trials are warranted for further evaluation of the safety and efficacy of ETs.

Inferring infection hazard in wildlife populations by linking data across individual and population scales.

Our ability to infer unobservable disease-dynamic processes such as force of infection (infection hazard for susceptible hosts) has transformed our understanding of disease transmission mechanisms and capacity to predict disease dynamics. Conventional methods for inferring FOI estimate a time-averaged value and are based on population-level processes. Because many pathogens exhibit epidemic cycling and FOI is the result of processes acting across the scales of individuals and populations, a flexible framework that extends to epidemic dynamics and links within-host processes to FOI is needed. Specifically, within-host antibody kinetics in wildlife hosts can be short-lived and produce patterns that are repeatable across individuals, suggesting individual-level antibody concentrations could be used to infer time since infection and hence FOI. Using simulations and case studies (influenza A in lesser snow geese and Yersinia pestis in coyotes), we argue that with careful experimental and surveillance design, the population-level FOI signal can be recovered from individual-level antibody kinetics, despite substantial individual-level variation. In addition to improving inference, the cross-scale quantitative antibody approach we describe can reveal insights into drivers of individual-based variation in disease response, and the role of poorly understood processes such as secondary infections, in population-level dynamics of disease.

Detecting signals of chronic shedding to explain pathogen persistence: Leptospira interrogans in California sea lions.

Identifying mechanisms driving pathogen persistence is a vital component of wildlife disease ecology and control. Asymptomatic, chronically infected individuals are an oft-cited potential reservoir of infection, but demonstrations of the importance of chronic shedding to pathogen persistence at the population-level remain scarce. Studying chronic shedding using commonly collected disease data is hampered by numerous challenges, including short-term surveillance that focuses on single epidemics and acutely ill individuals, the subtle dynamical influence of chronic shedding relative to more obvious epidemic drivers, and poor ability to differentiate between the effects of population prevalence of chronic shedding vs. intensity and duration of chronic shedding in individuals. We use chronic shedding of Leptospira interrogans serovar Pomona in California sea lions (Zalophus californianus) as a case study to illustrate how these challenges can be addressed. Using leptospirosis-induced strands as a measure of disease incidence, we fit models with and without chronic shedding, and with different seasonal drivers, to determine the time-scale over which chronic shedding is detectable and the interactions between chronic shedding and seasonal drivers needed to explain persistence and outbreak patterns. Chronic shedding can enable persistence of L. interrogans within the sea lion population. However, the importance of chronic shedding was only apparent when surveillance data included at least two outbreaks and the intervening inter-epidemic trough during which fadeout of transmission was most likely. Seasonal transmission, as opposed to seasonal recruitment of susceptibles, was the dominant driver of seasonality in this system, and both seasonal factors had limited impact on long-term pathogen persistence. We show that the temporal extent of surveillance data can have a dramatic impact on inferences about population processes, where the failure to identify both short- and long-term ecological drivers can have cascading impacts on understanding higher order ecological phenomena, such as pathogen persistence.

Epidemiological models to control the spread of information in marine mammals.

Socially transmitted wildlife behaviours that create human-wildlife conflict are an emerging problem for conservation efforts, but also provide a unique opportunity to apply principles of infectious disease control to wildlife management. As an example, California sea lions (Zalophus californianus) have learned to exploit concentrations of migratory adult salmonids below the fish ladders at Bonneville Dam, impeding endangered salmonid recovery. Proliferation of this foraging behaviour in the sea lion population has resulted in a controversial culling programme of individual sea lions at the dam, but the impact of such culling remains unclear. To evaluate the effectiveness of current and alternative culling strategies, we used network-based diffusion analysis on a long-term dataset to demonstrate that social transmission is implicated in the increase in dam-foraging behaviour and then studied different culling strategies within an epidemiological model of the behavioural transmission data. We show that current levels of lethal control have substantially reduced the rate of social transmission, but failed to effectively reduce overall sea lion recruitment. Earlier implementation of culling could have substantially reduced the extent of behavioural transmission and, ultimately, resulted in fewer animals being culled. Epidemiological analyses offer a promising tool to understand and control socially transmissible behaviours.

Identification of migratory bird flyways in North America using community detection on biological networks.

Migratory behavior of waterfowl populations in North America has traditionally been broadly characterized by four north-south flyways, and these flyways have been central to the management of waterfowl populations for more than 80 yr. However, previous flyway characterizations are not easily updated with current bird movement data and fail to provide assessments of the importance of specific geographical regions to the identification of flyways. Here, we developed a network model of migratory movement for four waterfowl species, Mallard (Anas platyrhnchos), Northern Pintail (A. acuta), American Green-winged Teal (A. carolinensis), and Canada Goose (Branta canadensis), in North America, using bird band and recovery data. We then identified migratory flyways using a community detection algorithm and characterized the importance of smaller geographic regions in identifying flyways using a novel metric, the consolidation factor. We identified four main flyways for Mallards, Northern Pintails, and American Green-winged Teal, with the flyway identification in Canada Geese exhibiting higher complexity. For Mallards, flyways were relatively consistent through time. However, consolidation factors revealed that for Mallards and Green-winged Teal, the presumptive Mississippi flyway was potentially a zone of high mixing between other flyways. Our results demonstrate that the network approach provides a robust method for flyway identification that is widely applicable given the relatively minimal data requirements and is easily updated with future movement data to reflect changes in flyway definitions and management goals.

Evolving the Role of Black Race in Hypertension Therapeutics.

Black race has been used to guide antihypertensive drug selection for Black patients based on predominant between race (same drug) and intra-race (different drugs) BP response patterns. Accordingly, thiazide diuretics and calcium antagonists have been recommended over renin angiotensin system (RAS) inhibitors (angiotensin receptor blockers, angiotensin converting enzyme inhibitors) and beta blockers for Black patients. Current antihypertensive drug prescribing reflects historical guidance as calcium antagonist and thiazide diuretics are prescribed more and RAS blockers less in Black than White patients. Hypertension control rates in Blacks, lag those for Whites despite their greater use of combination drug therapy and lesser use of monotherapy. This is also true across drug regimens containing any of the four recommended classes for initial therapy as well as for evidence-based combination drug therapy (calcium antagonist or thiazide diuretic + RAS blocker) regimens for which there is no known racial disparity in BP response. Current recommendations acknowledge the need for combination drug therapy in most, especially in Black patients. One exemplar comprehensive hypertension control program achieved > 80% control rates in Black and White patients with minimal racial disparity while utilizing a race-agnostic therapeutic algorithm. Black patients manifest robust, if not outsized, BP responses to diet/lifestyle modifications. Importantly, race neither appears to be a necessary nor sufficient consideration for selection of effective drug therapy. Accordingly, we urge the initiation of adequately intense race-agnostic drug therapy coupled with greater emphasis on diet/lifestyle modifications for Black patients as the cornerstone of a race-informed approach to hypertension therapeutics.

Preloaded D-methionine protects from steady state and impulse noise-induced hearing loss and induces long-term cochlear and endogenous antioxidant effects.

OBJECTIVE: Determine effective preloading timepoints for D-methionine (D-met) otoprotection from steady state or impulse noise and impact on cochlear and serum antioxidant measures. DESIGN: D-met started 2.0-, 2.5-, 3.0-, or 3.5- days before steady-state or impulse noise exposure with saline controls. Auditory brainstem response (ABRs) measured from 2 to 20 kHz at baseline and 21 days post-noise. Samples were then collected for serum (SOD, CAT, GR, GPx) and cochlear (GSH, GSSG) antioxidant levels. STUDY SAMPLE: Ten Chinchillas per group. RESULTS: Preloading D-met significantly reduced ABR threshold shifts for both impulse and steady state noise exposures but with different optimal starting time points and with differences in antioxidant measures. For impulse noise exposure, the 2.0, 2.5, and 3.0 day preloading start provide significant threshold shift protection at all frequencies. Compared to the saline controls, serum GR for the 3.0 and 3.5 day preloading groups was significantly increased at 21 days with no significant increase in SOD, CAT or GPx for any impulse preloading time point. Cochlear GSH, GSSG, and GSH/GSSG ratio were not significantly different from saline controls at 21 days post noise exposure. For steady state noise exposure, significant threshold shift protection occurred at all frequencies for the 3.5, 3.0 and 2.5 day preloading start times but protection only occurred at 3 of the 6 test frequencies for the 2.0 day preloading start point. Compared to the saline controls, preloaded D-met steady-state noise groups demonstrated significantly higher serum SOD for the 2.5-3.5 day starting time points and GPx for the 2.5 day starting time but no significant increase in GR or CAT for any preloading time point. Compared to saline controls, D-met significantly increased cochlear GSH concentrations in the 2 and 2.5 day steady-state noise exposed groups but no significant differences in GSSG or the GSH/GSSG ratio were noted for any steady state noise-exposed group. CONCLUSIONS: The optimal D-met preloading starting time window is earlier for steady state (3.5-2.5 days) than impulse noise (3.0-2.0). At 21 days post impulse noise, D-met increased serum GR for 2 preloading time points but not SOD, CAT, or GpX and not cochlear GSH, GSSG or the GSH/GSSG ratio. At 21 days post steady state noise D-met increased serum SOD and GPx at select preloading time points but not CAT or GR. However D-met did increase the cochlear GSH at select preloading time points but not GSSG or the GSH/GSSG ratio.

Adverse Health Outcomes Associated With Refractory and Treatment-Resistant Hypertension in the Chronic Renal Insufficiency Cohort.

Refractory hypertension (RfH) is a severe phenotype of antihypertension treatment failure. Treatment-resistant hypertension (TRH), a less severe form of difficult-to-treat hypertension, has been associated with significantly worse health outcomes. However, no studies currently show how health outcomes may worsen upon progression to RfH. RfH and TRH were studied in 3147 hypertensive participants in the CRIC (Chronic Renal Insufficiency Cohort study). The hypertensive phenotype (ie, no TRH or RfH, TRH, or RfH) was identified at the baseline visit, and health outcomes were monitored at subsequent visits. Outcome risk was compared using Cox proportional hazards models with time-varying covariates. A total of 136 (4.3%) individuals were identified with RfH at baseline. After adjusting for participant characteristics, individuals with RfH had increased risk for the composite renal outcome across all study years (50% decline in estimated glomerular filtration rate or end-stage renal disease; hazard ratio for study years 0-10=1.73 [95% CI, 1.42-2.11]) and the composite cardiovascular disease outcome during later study years (stroke, myocardial infarction, or congestive heart failure; hazard ratio for study years 0-3=1.25 [0.91-1.73], for study years 3-6=1.50 [0.97-2.32]), and for study years 6-10=2.72 [1.47-5.01]) when compared with individuals with TRH. There was no significant difference in all-cause mortality between those with refractory versus TRH. We provide the first evidence that RfH is associated with worse long-term health outcomes compared with TRH.

Serious Adverse Events Cluster in Participants Experiencing the Primary Composite Cardiovascular Endpoint: A Post Hoc Analysis of the SPRINT Trial.

BACKGROUND: Intensively treated participants in the SPRINT study experienced fewer primary cardiovascular composite study endpoints (CVD events) and lower mortality, although 38% of participants experienced a serious adverse event (SAE). The relationship of SAEs with CVD events is unknown. METHODS: CVD events were defined as either myocardial infarction, acute coronary syndrome, decompensated heart failure, stroke, or death from cardiovascular causes. Cox models were utilized to understand the occurrence of SAEs with CVD events according to baseline atherosclerotic cardiovascular disease (ASCVD) risk. RESULTS: SAEs occurred in 96% of those experiencing a CVD event but only in 34% (P < 0.001) of those not experiencing a CVD event. Occurrence of SAEs monotonically increased across the range of baseline ASCVD risk being approximately twice as great in the highest compared with the lowest risk category. SAE occurrence was strongly associated with ASCVD risk but was similar within risk groups across treatment arms. In adjusted Cox models, experiencing a CVD event was the strongest predictor of SAEs in all risk groups. By the end of year 1, the hazard ratios for the low, middle, and high ASCVD risk tertiles, and baseline clinical CVD group were 2.56 (95% CI = 1.39-4.71); 2.52 (1.63-3.89); 3.61 (2.79-4.68); 1.86 (1.37-2.54), respectively-a trend observed in subsequent years until study end. Intensive treatment independently predicted SAEs only in the second ASVCD risk tertile. CONCLUSIONS: The occurrence of SAEs is multifactorial and mostly related to prerandomization patient characteristics, most prominently ASCVD risk, which, in turn, relates to in-study CVD events.

Estimating prevalence and test accuracy in disease ecology: How Bayesian latent class analysis can boost or bias imperfect test results.

Obtaining accurate estimates of disease prevalence is crucial for the monitoring and management of wildlife populations but can be difficult if different diagnostic tests yield conflicting results and if the accuracy of each diagnostic test is unknown. Bayesian latent class analysis (BLCA) modeling offers a potential solution, providing estimates of prevalence levels and diagnostic test accuracy under the realistic assumption that no diagnostic test is perfect.In typical applications of this approach, the specificity of one test is fixed at or close to 100%, allowing the model to simultaneously estimate the sensitivity and specificity of all other tests, in addition to infection prevalence. In wildlife systems, a test with near-perfect specificity is not always available, so we simulated data to investigate how decreasing this fixed specificity value affects the accuracy of model estimates.We used simulations to explore how the trade-off between diagnostic test specificity and sensitivity impacts prevalence estimates and found that directional biases depend on pathogen prevalence. Both the precision and accuracy of results depend on the sample size, the diagnostic tests used, and the true infection prevalence, so these factors should be considered when applying BLCA to estimate disease prevalence and diagnostic test accuracy in wildlife systems. A wildlife disease case study, focusing on leptospirosis in California sea lions, demonstrated the potential for Bayesian latent class methods to provide reliable estimates under real-world conditions.We delineate conditions under which BLCA improves upon the results from a single diagnostic across a range of prevalence levels and sample sizes, demonstrating when this method is preferable for disease ecologists working in a wide variety of pathogen systems.

Linking longitudinal and cross-sectional biomarker data to understand host-pathogen dynamics: Leptospira in California sea lions (Zalophus californianus) as a case study.

Confronted with the challenge of understanding population-level processes, disease ecologists and epidemiologists often simplify quantitative data into distinct physiological states (e.g. susceptible, exposed, infected, recovered). However, data defining these states often fall along a spectrum rather than into clear categories. Hence, the host-pathogen relationship is more accurately defined using quantitative data, often integrating multiple diagnostic measures, just as clinicians do to assess their patients. We use quantitative data on a major neglected tropical disease (Leptospira interrogans) in California sea lions (Zalophus californianus) to improve individual-level and population-level understanding of this Leptospira reservoir system. We create a "host-pathogen space" by mapping multiple biomarkers of infection (e.g. serum antibodies, pathogen DNA) and disease state (e.g. serum chemistry values) from 13 longitudinally sampled, severely ill individuals to characterize changes in these values through time. Data from these individuals describe a clear, unidirectional trajectory of disease and recovery within this host-pathogen space. Remarkably, this trajectory also captures the broad patterns in larger cross-sectional datasets of 1456 wild sea lions in all states of health but sampled only once. Our framework enables us to determine an individual's location in their time-course since initial infection, and to visualize the full range of clinical states and antibody responses induced by pathogen exposure. We identify predictive relationships between biomarkers and outcomes such as survival and pathogen shedding, and use these to impute values for missing data, thus increasing the size of the useable dataset. Mapping the host-pathogen space using quantitative biomarker data enables more nuanced understanding of an individual's time course of infection, duration of immunity, and probability of being infectious. Such maps also make efficient use of limited data for rare or poorly understood diseases, by providing a means to rapidly assess the range and extent of potential clinical and immunological profiles. These approaches yield benefits for clinicians needing to triage patients, prevent transmission, and assess immunity, and for disease ecologists or epidemiologists working to develop appropriate risk management strategies to reduce transmission risk on a population scale (e.g. model parameterization using more accurate estimates of duration of immunity and infectiousness) and to assess health impacts on a population scale.