Evaluation of the association between circulating IL-1ß and other inflammatory cytokines and incident atrial fibrillation in a cohort of postmenopausal women.

BACKGROUND: Inflammatory cytokines play a role in atrial fibrillation (AF). Interleukin (IL)-1ß, which is targeted in the treatment of ischemic heart disease, has not been well-studied in relation to AF. METHODS: Postmenopausal women from the Women's Health Initiative were included. Cox proportional hazards regression models were used to evaluate the association between log-transformed baseline cytokine levels and future AF incidence. Models were adjusted for body mass index, age, race, education, hypertension, diabetes, hyperlipidemia, current smoking, and history of coronary heart disease, congestive heart failure, or peripheral artery disease. RESULTS: Of 16,729 women, 3,943 developed AF over an average of 8.5 years. Racial and ethnic groups included White (77.4%), Black/African-American (16.1%), Asian (2.7%), American Indian/Alaska Native (1.0%), and Hispanic (5.5%). Baseline IL-1ß log continuous levels were not significantly associated with incident AF (HR 0.86 per 1 log [pg/mL] increase, P= .24), similar to those of other inflammatory cytokines, IL-7, IL-8, IL-10, IGF-1, and TNF-α. There were significant associations between C-reactive protein (CRP) and IL-6 with incident AF. CONCLUSIONS: In this large cohort of postmenopausal women, there was no significant association between IL-1ß and incident AF, although downstream effectors, CRP and IL-6, were associated with incident AF.

Risk factors for early development of cardiac allograft vasculopathy by intravascular ultrasound.

BACKGROUND: Cardiac allograft vasculopathy (CAV) is the leading cause of late graft loss. While there are numerous post-transplant factors which may increase the risk of the development of CAV, there is a paucity of data on the impact of donor-derived atherosclerosis (DA), early discontinuation of prednisone, and early initiation of proliferation signal inhibitors (PSI) as assessed by intravascular ultrasound (IVUS). METHODS: Retrospective single-center study of all adult transplant patients (2008-2017) with serial IVUS at baseline and annually for 5 years. DA was defined as a baseline maximal intimal thickness (MIT) ≥0.5 mm, and CAV development was defined as MIT ≥1 mm or an increase in MIT ≥0.5 mm at year 1 compared with baseline or an increase in 0.3 mm annually thereafter. Clinical risk factors for CAV were identified using multivariable hazard regression. Separate multistate models were applied to assess the association of prednisone discontinuation and PSI initiation and CAV. RESULTS: Of 282 patients screened, 186 patients had a 1-year angiogram. The mean age of those included in the cohort was 51 ± 11 years, 70% were male, 58% were Caucasian, and 27% were supported by a left ventricular assist device. Donor atherosclerosis was present in 40%. The cumulative incidence of CAV at 5 years is 41% in DA- vs. 59% in DA + (p = .012). Donor age was a strong predictor of DA (p = .016). Significant risk factors for CAV included male sex (HR = 4.141, p = .001), non-Caucasian race (HR = 1.98, p = .011), BMI < 18 kg/m2 (HR = 4.596, p = .042), longer ischemic time (HR = 1.374, p = .028), older donor age (HR = 1.158, p = .009), and rejection with hemodynamic compromise within the first year (HR = 2.858, p = .043). Prednisone discontinuation within 1 year was associated with a lower risk of CAV (HR 0.58 p = .047). Initiation of proliferation signal inhibitors (PSI) within 2 years resulted in fewer cases of CAV (HR 0.397 p < .001). CONCLUSION: In patients with an angiogram at 1 year, those with DA were significantly more likely to develop CAV. Lower incidence of CAV by IVUS was seen in patients who discontinued prednisone in the first year or had initiation of a PSI within two years of transplantation. Knowledge of early IVUS may allow a more tailored approach to patient management.

A novel therapy for an unusual problem: IL-1 receptor antagonist for recurrent post-transplant pericarditis.

Heart transplant (HTx) recipients are at increased risk of pericardial disease. Idiopathic recurrent pericarditis has not been previously described following HTx. We describe a 35-year-old male who was admitted with pericarditis and moderate pericardial effusion 10 months after HTx. Two weeks before his admission, his prednisone had been tapered off. A thorough infectious workup and endomyocardial biopsy was unrevealing. He was started on colchicine with the addition of tapering prednisone regimen of 40 mg daily due to unresolved pain. Over the next several years, he had three recurrent episodes of pericarditis requiring re-initiation of prednisone with extensive investigations negative for rejection, autoimmune, and infectious causes. Cardiac MRI confirmed pericardial inflammation. Due to his recurrent course and inability to wean off prednisone, anakinra, an IL-1 receptor antagonist, was started at 100 mg sc daily. This allowed successful discontinuation of prednisone. He is now 34 months post-transplant without recurrence on anakinra and colchicine maintenance. Due to the overlap between idiopathic recurrent pericarditis and auto-inflammatory diseases, there is growing evidence for utilizing IL-1 receptor antagonists in this condition. While pericarditis is common in the HTx population, this is the first report of successful use of an IL-1 receptor blocker for pericarditis in this population.

Perks and Pitfalls of Performance-Linked Reimbursement for Novel Drugs: The Case of Sacubitril-Valsartan.

BACKGROUND: Rising drug costs have increased interest in performance-linked reimbursement (PLR) contracts that tie payment to patient outcomes. PLR is theoretically attractive to payers interested in reducing the risk of overpaying for expensive drugs, to manufacturers working to improve early drug adoption, and to patients seeking improved access. Multiple PLR contracts were developed for sacubitril-valsartan. We evaluated how the characteristics of a PLR contract influence its performance. METHODS: We used a published cost-effectiveness model of sacubitril-valsartan. We evaluated hypothetical PLR contracts that adjusted drug payment based on observed therapy effectiveness. Ideally, these contracts reduce the uncertainty around the value obtained with purchasing sacubitril-valsartan. By reducing the financial risk in covering an ineffective therapy, PLR incentivizes insurers to increase patient access. We measured the uncertainty in value as the SD of the incremental net monetary benefit (INMB), an estimate of therapy value incorporating costs and clinical benefits. We evaluated the change in INMB SD under a variety of different assumptions regarding contract design, therapy effectiveness, and population characteristics. RESULTS: Over 2 years, sacubitril-valsartan led to 0.042 additional quality-adjusted life-years at an incremental cost of $4916. Using a willingness-to-pay of $150 000 per quality-adjusted life-year, this led to a mean INMB across simulations of $1416 (SD, $1720). A PLR contract that adjusted payment based on cardiovascular mortality reduced the INMB SD moderately by 20.7% while a contract based on all-cause mortality was more effective (INMB SD reduction of 27.3%). A contract based on heart failure hospitalization reduction was ineffective. PLR effectiveness increased with greater uncertainty regarding therapy effectiveness or in sicker cohorts (eg, New York Heart Association Class III/IV heart failure). Contracts required precise estimates of treatment effect in addition to trust or verifiability between manufacturers and payers concerning patient selection. CONCLUSIONS: The development of accurate prospective estimates of treatment effectiveness using actual enrollee characteristics will be critical for successful PLR. If able to meet these requirements, PLRs could incentivize insurers to expand access to expensive treatments by reducing financial risk.

Cost-effectiveness of Empagliflozin in Patients With Heart Failure With Preserved Ejection Fraction.

Importance: In the Empagliflozin Outcome Trial in Patients With Chronic Heart Failure With Preserved Ejection Fraction (EMPEROR-Preserved), empagliflozin significantly reduced hospitalizations for heart failure while improving patient-reported health status compared with placebo. The long-term cost-effectiveness of empagliflozin among patients who have heart failure with preserved ejection fraction (HFpEF) remains unclear. Objective: To estimate the cost-effectiveness of empagliflozin in patients with HFpEF. Design, Setting, and Participants: This cost-effectiveness analysis performed from October 2021 to April 2022 included a Markov model using estimates of treatment efficacy, event probabilities, and utilities from EMPEROR-Preserved and published literature. Costs were derived from national surveys and pricing data sets. Quality of life was imputed from a heart failure-specific quality-of-life measure. Two analyses were performed, with and without a treatment effect on cardiovascular mortality. Subgroup analyses were based on diabetes status, ejection fraction, and health status impairment due to heart failure. The model reproduced the event rates and risk reduction with empagliflozin observed in EMPEROR-Preserved over 26 months of follow-up; future projections extended across the lifetime of patients. Exposures: Empagliflozin or standard of care. Main Outcomes and Measures: Hospitalizations for heart failure, life-years, quality-adjusted life-years (QALYs), lifetime costs, and lifetime incremental cost-effectiveness ratio. Results: A total of 5988 patients were included in the analysis, with a mean age of 72 years, New York Heart Association class II to IV heart failure, and left ventricular ejection fraction greater than 40%. At the Federal Supply Schedule price of $327 per month, empagliflozin yielded 0.06 additional QALYs and $26 257 incremental costs compared with standard of care, producing a cost per QALY gained of $437 442. Incremental costs consisted of total drug costs of $29 586 and savings of $3329 from reduced hospitalizations for heart failure. Cost-effectiveness was similar across subgroups. The results were most sensitive to the monthly cost, quality-of-life benefit, and mortality effect of empagliflozin. A price reduction to $153 per month, incremental utility of 0.02, or 8% reduction in cardiovascular mortality would bring empagliflozin to $180 000 per QALY gained, the threshold for intermediate value. Using Medicare Part D monthly pricing of $375 after rebates and $511 before rebates, empagliflozin would remain low value at $509 636 and $710 825 per QALY gained, respectively. Cost-effectiveness estimates were robust to variation in the frequency and disutility of heart failure hospitalizations. Conclusions and Relevance: In this economic evaluation, based on current cost-effectiveness benchmarks, empagliflozin provides low economic value compared with standard of care for HFpEF, largely due to its lack of efficacy on mortality and small benefit on quality of life.

Cost-effectiveness and system-wide impact of using Hepatitis C-viremic donors for heart transplant.

BACKGROUND: The advent of direct-acting antiviral therapy for Hepatitis C (HCV) has made using HCV-viremic donors a viable strategy to address the donor shortage in heart transplantation. We employed a large-scale simulation to evaluate the impact and cost-effectiveness of using HCV-viremic donors for heart transplant. METHODS: We simulated detailed histories from time of listing until death for the real-world cohort of all adults listed for heart transplant in the United States from July 2014 to June 2019 (n = 19,346). This population was imputed using historical data and captures "real-world" heterogeneity in geographic and clinical characteristics. We estimated the impact of an intervention in which all candidates accept HCV+ potential donors (n = 472) on transplant volume, waitlist outcomes, and lifetime costs and quality-adjusted life years (QALYs). RESULTS: The intervention produced 232 more transplants, 132 fewer delistings due to deterioration, and 50 fewer waitlist deaths within this 5-year cohort and reduced wait times by 3% to 11% (varying by priority status). The intervention was cost-effective, adding an average of 0.08 QALYs per patient at a cost of $124 million ($81,892 per QALY). DAA therapy and HCV care combined account for 11% this cost, with the remainder due to higher costs of transplant procedures and routine post-transplant care. The impact on transplant volume varied by blood type and region and was correlated with donor-to-candidate ratio (ρ = 0.71). CONCLUSIONS: Transplanting HCV+ donor hearts is likely to be cost-effective and improve waitlist outcomes, particularly in regions and subgroups experiencing high donor scarcity.

County-Level Factors Associated With Cardiovascular Mortality by Race/Ethnicity.

Background Persistent racial/ethnic disparities in cardiovascular disease (CVD) mortality are partially explained by healthcare access and socioeconomic, demographic, and behavioral factors. Little is known about the association between race/ethnicity-specific CVD mortality and county-level factors. Methods and Results Using 2017 county-level data, we studied the association between race/ethnicity-specific CVD age-adjusted mortality rate (AAMR) and county-level factors (demographics, census region, socioeconomics, CVD risk factors, and healthcare access). Univariate and multivariable linear regressions were used to estimate the association between these factors; R2 values were used to assess the factors that accounted for the greatest variation in CVD AAMR by race/ethnicity (non-Hispanic White, non-Hispanic Black, and Hispanic/Latinx individuals). There were 659 740 CVD deaths among non-Hispanic White individuals in 2698 counties; 100 475 deaths among non-Hispanic Black individuals in 717 counties; and 49 493 deaths among Hispanic/Latinx individuals across 267 counties. Non-Hispanic Black individuals had the highest mean CVD AAMR (320.04 deaths per 100 000 individuals), whereas Hispanic/Latinx individuals had the lowest (168.42 deaths per 100 000 individuals). The highest CVD AAMRs across all racial/ethnic groups were observed in the South. In unadjusted analyses, the greatest variation (R2) in CVD AAMR was explained by physical inactivity for non-Hispanic White individuals (32.3%), median household income for non-Hispanic Black individuals (24.7%), and population size for Hispanic/Latinx individuals (28.4%). In multivariable regressions using county-level factor categories, the greatest variation in CVD AAMR was explained by CVD risk factors for non-Hispanic White individuals (35.3%), socioeconomic factors for non-Hispanic Black (25.8%), and demographic factors for Hispanic/Latinx individuals (34.9%). Conclusions The associations between race/ethnicity-specific age-adjusted CVD mortality and county-level factors differ significantly. Interventions to reduce disparities may benefit from being designed accordingly.

Cost-effectiveness of Dapagliflozin for Treatment of Patients With Heart Failure With Reduced Ejection Fraction.

Importance: In the Dapagliflozin and Prevention of Adverse Outcomes in Heart Failure (DAPA-HF) trial, dapagliflozin was shown to reduce cardiovascular mortality and hospitalizations due to heart failure while improving patient-reported health status. However, the cost-effectiveness of adding dapagliflozin therapy to standard of care (SOC) is unknown. Objective: To estimate the cost-effectiveness of dapagliflozin therapy among patients with chronic heart failure with reduced ejection fraction (HFrEF). Design, Setting, and Participants: This Markov cohort cost-effectiveness model used estimates of therapy effectiveness, transition probabilities, and utilities from the DAPA-HF trial and other published literature. Costs were derived from published sources. Patients with HFrEF included subgroups based on diabetes status and health status impairment due to heart failure. We compiled parameters from the literature including DAPA-HF, on which our model is based, and many other sources from December 2019 to February 27, 2021. We performed our analysis in February 2021. Exposures: Dapagliflozin or SOC. Main Outcomes and Measures: Hospitalizations for heart failure, life-years, quality-adjusted life-years (QALYs), costs, and the cost per QALY gained (incremental cost-effectiveness ratio). Results: In the model, dapagliflozin therapy yielded a mean of 0.78 additional life-years and 0.46 additional QALYs compared with SOC at an incremental cost of $38 212, resulting in a cost per QALY gained of $83 650. The cost per QALY was similar for patients with or without diabetes and for patients with mild or moderate impairment of health status due to heart failure. The cost-effectiveness was most sensitive to estimates of the effect on mortality and duration of therapy effectiveness. If the cost of dapagliflozin decreased from $474 to $270 (43% decline), the cost per QALY gained would drop below $50 000. Conclusions and Relevance: These findings suggest that dapagliflozin provides intermediate value compared with SOC, based on American College of Cardiology/American Heart Association benchmarks. Additional data regarding the magnitude of mortality reduction would improve the precision of cost-effectiveness estimates.

Trends in Readmission and Mortality Rates Following Heart Failure Hospitalization in the Veterans Affairs Health Care System From 2007 to 2017.

Importance: The Centers for Medicare & Medicaid Services and the Veterans Affairs Health Care System provide incentives for hospitals to reduce 30-day readmission and mortality rates. In contrast with the large body of evidence describing readmission and mortality in the Medicare system, it is unclear how heart failure readmission and mortality rates have changed during this period in the Veterans Affairs Health Care System. Objectives: To evaluate trends in readmission and mortality after heart failure admission in the Veterans Affairs Health Care System, which had no financial penalties, in a decade involving focus on heart failure readmission reduction (2007-2017). Design, Setting, and Participants: This cohort study used data from all Veterans Affairs-paid heart failure admissions from January 2007 to September 2017. All Veterans Affairs-paid hospital admissions to Veterans Affairs and non-Veterans Affairs facilities for a primary diagnosis of heart failure were included, when the admission was paid for by the Veterans Affairs. Data analyses were conducted from October 2018 to March 2020. Exposures: Admission for a primary diagnosis of heart failure at discharge. Main Outcomes and Measures: Thirty-day all-cause readmission and mortality rates. Results: A total of 164 566 patients with 304 374 hospital admissions were included. Among the 304 374 hospital admissions between 2007 and 2017, 298 260 (98.0%) were for male patients, and 195 205 (64.4%) were for white patients. The mean (SD) age was 70.8 (11.5) years. The adjusted odds ratio of 30-day readmission declined throughout the study period to 0.85 (95% CI, 0.83-0.88) in 2015 to 2017 compared with 2007 to 2008. The adjusted odds ratio of 30-day mortality remained stable, with an adjusted odds ratio of 1.01 (95% CI, 0.96-1.06) in 2015 to 2017 compared with 2007 to 2008. Stratification by left ventricular ejection fraction showed similar readmission reduction trends and no significant change in mortality, regardless of strata. Conclusions and Relevance: In this analysis of an integrated health care system that provided guidance and nonfinancial incentives for reducing readmissions, such as public reporting of readmission rates, risk-adjusted 30-day readmission declined despite inclusion of clinical variables in risk adjustment, but mortality did not decline. Future investigations should focus on evaluating the effectiveness of specific approaches to readmission reduction to inform efficient and effective application in individual health systems, hospitals, and practices.

Association of Diagnostic Coding-Based Frailty and Outcomes in Patients With Heart Failure: A Report From the Veterans Affairs Health System.

Background The aim of this study was to determine whether frailty is associated with increased admission and mortality risk in the setting of heart failure. Methods and Results This retrospective cohort analysis included patients treated within the Veterans Affairs Health System who had International Classification of Diseases, Ninth Revision (ICD-9) codes for heart failure on 2 or more dates over a 2-year period. The clinical variables identifiable in claims data, such as demographic variables and markers of physical and cognitive dysfunction, were used to identify patients meeting the frailty phenotype. Of 388 785 extracted patients with coding of heart failure between 2015 and 2018, 163 085 patients (41.9%) with ejection fraction (EF) measurement were included in the present analysis (38.3% with reduced EF and 61.7% with preserved EF). There were 16 660 patients (10.2%) who were identified as frail (9.1% in heart failure with reduced EF and 10.9% in heart failure with preserved EF). Frail patients were older, more often depressed, and were likely to have been admitted in the previous year. One-year all-cause mortality rate was 9.7% and 28.1%, and admission rate was 58.1% and 79.5% for nonfrail and frail patients, respectively. Frailty was associated with mortality and admission risk compared with the nonfrail group (adjusted odds ratio [OR], 1.71; 95% CI, 1.65-1.77 for mortality; adjusted OR, 1.29; 95% CI, 1.24-1.34 for admission) independent of EF. Conclusions Frailty based on diagnostic coding was associated with particularly higher risk of mortality despite adjustment for known clinical variables. Our findings underscore the importance of nontraditional parameters in the prognostic assessment.

Prognostic Implications of Early and Midrange Readmissions After Acute Heart Failure Hospitalizations: A Report From a Japanese Multicenter Registry.

Background Although 30-day readmission is thought to be an important quality indicator in patients with hospitalized heart failure, its prognostic impact and comparison of patients who were readmitted beyond 30 days has not been investigated. We assessed early (0-30 days) versus midrange (31-90 days) readmission in terms of incidence and distribution, and elucidated whether the timing of readmission could have a different prognostic significance. Methods and Results We examined patients with hospitalized heart failure registered in the WET-HF (West Tokyo Heart Failure) registry. The primary outcomes analyzed were all-cause death and HF readmission. Data of 3592 consecutive patients with hospitalized heart failure (median follow-up, 2.0 years [interquartile range, 0.8-3.1 years]; 39.6% women, mean age 73.9±13.3 years) were analyzed. Within 90 days after discharge, HF readmissions occurred in 11.1% patients. Of them, patients readmitted within 30 and 31 to 90 days after discharge accounted for 43.1% and 56.9%, respectively. Independent predictors of 30- and 90-day readmission were almost identical, and after adjustment, readmission for HF within 90 days (including both early and midrange readmission) was an independent predictor of subsequent all-cause death (hazard ratio, 2.36; P<0.001). Among 90-day readmitted patients, the time interval from discharge to readmission was not significantly associated with subsequent all-cause death. Conclusions Among patients readmitted within 90 days after index hospitalization discharge, ≈60% of readmission events occurred beyond 30 days. Patients readmitted within 90 days had a higher risk of long-term mortality, regardless of the temporal proximity of readmission to the index hospitalization.

Finding missed cases of familial hypercholesterolemia in health systems using machine learning.

Familial hypercholesterolemia (FH) is an underdiagnosed dominant genetic condition affecting approximately 0.4% of the population and has up to a 20-fold increased risk of coronary artery disease if untreated. Simple screening strategies have false positive rates greater than 95%. As part of the FH Foundation's FIND FH initiative, we developed a classifier to identify potential FH patients using electronic health record (EHR) data at Stanford Health Care. We trained a random forest classifier using data from known patients (n = 197) and matched non-cases (n = 6590). Our classifier obtained a positive predictive value (PPV) of 0.88 and sensitivity of 0.75 on a held-out test-set. We evaluated the accuracy of the classifier's predictions by chart review of 100 patients at risk of FH not included in the original dataset. The classifier correctly flagged 84% of patients at the highest probability threshold, with decreasing performance as the threshold lowers. In external validation on 466 FH patients (236 with genetically proven FH) and 5000 matched non-cases from the Geisinger Healthcare System our FH classifier achieved a PPV of 0.85. Our EHR-derived FH classifier is effective in finding candidate patients for further FH screening. Such machine learning guided strategies can lead to effective identification of the highest risk patients for enhanced management strategies.

Validity of Performance and Outcome Measures for Heart Failure.

Background Numerous quality metrics for heart failure (HF) care now exist based on process and outcome. What remains unclear, however, is if the correct quality metrics are being emphasized. To determine the validity of certain measures, we compared correlations between measures and reliability over time. Measures assessed include guideline-recommended ß-blocker (BB), any BB, angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker, mineralocorticoid receptor antagonist, and hydralazine/isosorbide dinitrate (in blacks) use among candidates, 30-day mortality, 1-year mortality, and 30-day readmission. Methods and Results This was an observational cohort analysis using chart review and electronic resources for 55 735 patients from 102 Veterans Affairs medical centers hospitalized with HF from 2008 to 2013. Assessments of convergent validity and reliability were performed. Significant correlations were found between in-hospital rates of ACE inhibitor use and the following measures: BB use, 30-day mortality, and 1-year mortality. Guideline-recommended BB use was also significantly correlated with mineralocorticoid receptor antagonists, 30-day mortality, and 1-year mortality. There was no correlation between 30-day readmission rates and any therapy or mortality. Measure reliability over time was seen for guideline-recommended BBs ( r=0.57), mineralocorticoid receptor antagonists ( r=0.50), 30-day mortality ( r=0.29), and 1-year mortality ( r=0.31). ACE inhibitor and readmission rates were not reliable measures over time. Conclusions BB use, ACE inhibitor use, mortality, and mineralocorticoid receptor antagonist use are valid measures of HF quality. Thirty-day readmission rate did not seem to be a valid measure of HF quality of care. If the goal is to identify high-quality HF care, the emphasis on decreasing readmission rates might be better directed towards improving usage of the recommended therapies.

Novel Therapies for Familial Hypercholesterolemia.

OPINION STATEMENT: Both HeFH and HoFH require dietary and lifestyle modification. Pharmacotherapy of adult HeFH patients is largely driven by the American Heart Association (AHA) algorithm. A high-potency statin is started initially with a goal low-density lipoprotein cholesterol (LDL-C) reduction of >50 %. The LDL-C target is adjusted to <100 or <70 mg/dL in subjects with coronary artery disease (CAD) with ezetimibe being second line. If necessary, a third adjunctive therapy, such as a PSCK9 inhibitor (not yet approved in children) or bile acid-binding resin, can be added. Finally, LDL-C apheresis can be considered in patients with LDL-C >300 mg/dL (or >200 mg/dL with significant CAD, although now approved for LDL-C as low as 160 mg/dL with CAD). Due to the early, severe LDL-C elevation in HoFH patients, concerning natural history, rarity of the condition, and nuances of treatment, all HoFH patients should be treated at a pediatric or adult center with HoFH experience. LDL-C apheresis should be considered as early as 5 years of age. However, apheresis availability and tolerability is limited and pharmacotherapy is required. Generally, the AHA algorithm with reference to the European Atherosclerosis Society Consensus Panel recommendations is reasonable with all patients initiated on high-dose, high-potency statin, ezetimibe, and bile acid-binding resins. In most, additional LDL-C lowering is required with PCSK9 inhibitors and/or lomitapide or mipomersen. Liver transplantation can also be considered at experienced centers as a last resort.

Spatiotemporal Analysis of Malaria in Urban Ahmedabad (Gujarat), India: Identification of Hot Spots and Risk Factors for Targeted Intervention.

The world population, especially in developing countries, has experienced a rapid progression of urbanization over the last half century. Urbanization has been accompanied by a rise in cases of urban infectious diseases, such as malaria. The complexity and heterogeneity of the urban environment has made study of specific urban centers vital for urban malaria control programs, whereas more generalizable risk factor identification also remains essential. Ahmedabad city, India, is a large urban center located in the state of Gujarat, which has experienced a significant Plasmodium vivax and Plasmodium falciparum disease burden. Therefore, a targeted analysis of malaria in Ahmedabad city was undertaken to identify spatiotemporal patterns of malaria, risk factors, and methods of predicting future malaria cases. Malaria incidence in Ahmedabad city was found to be spatially heterogeneous, but temporally stable, with high spatial correlation between species. Because of this stability, a prediction method utilizing historic cases from prior years and seasons was used successfully to predict which areas of Ahmedabad city would experience the highest malaria burden and could be used to prospectively target interventions. Finally, spatial analysis showed that normalized difference vegetation index, proximity to water sources, and location within Ahmedabad city relative to the dense urban core were the best predictors of malaria incidence. Because of the heterogeneity of urban environments and urban malaria itself, the study of specific large urban centers is vital to assist in allocating resources and informing future urban planning.

Surveillance for malaria elimination in Swaziland: a national cross-sectional study using pooled PCR and serology.

BACKGROUND: To guide malaria elimination efforts in Swaziland and other countries, accurate assessments of transmission are critical. Pooled-PCR has potential to efficiently improve sensitivity to detect infections; serology may clarify temporal and spatial trends in exposure. METHODOLOGY/PRINCIPAL FINDINGS: Using a stratified two-stage cluster, cross-sectional design, subjects were recruited from the malaria endemic region of Swaziland. Blood was collected for rapid diagnostic testing (RDT), pooled PCR, and ELISA detecting antibodies to Plasmodium falciparum surface antigens. Of 4330 participants tested, three were RDT-positive yet false positives by PCR. Pooled PCR led to the identification of one P. falciparum and one P. malariae infection among RDT-negative participants. The P. falciparum-infected participant reported recent travel to Mozambique. Compared to performing individual testing on thousands of samples, PCR pooling reduced labor and consumable costs by 95.5%. Seropositivity was associated with age ≥20 years (11·7% vs 1·9%, P<0.001), recent travel to Mozambique (OR 4.4 [95% CI 1.0-19.0]) and residence in southeast Swaziland (RR 3.78, P<0.001). CONCLUSIONS: The prevalence of malaria infection and recent exposure in Swaziland are extremely low, suggesting elimination is feasible. Future efforts should address imported malaria and target remaining foci of transmission. Pooled PCR and ELISA are valuable surveillance tools for guiding elimination efforts.