Persistence of Immunogenicity of a Purified Inactivated Zika Virus Vaccine Candidate in Healthy Adults: 2 Years of Follow-up Compared With Natural Infection.

BACKGROUND: We report 2-year persistence of immune response to Takeda's prophylactic purified formalin-inactivated whole Zika virus vaccine candidate (TAK-426) compared with that observed after natural infection. METHODS: A randomized, observer-blind, placebo-controlled, dose-selection, phase 1 trial was conducted in 18-49-year-old adults at 9 centers (7 in the United States, 2 in Puerto Rico) from 13 November 2017 to 24 November 2020. Primary objectives were safety, tolerability, and immunogenicity of 3 increasing doses of TAK-426 administered as 2 doses 28 days apart to flavivirus (FV)-naive and FV-primed adults. Here, we report on safety and persistence of immunity up to 2 years after primary vaccination with 10-µg TAK-426, the highest dose, and compare neutralizing antibody responses with those observed after natural infection. RESULTS: TAK-426 at 10-µg had an acceptable safety profile in FV-naive and FV-primed adults up to 24 months after dose 2. Seropositivity for neutralizing antibodies was 100% at 1 year, and 93.8% and 76.2% at 2 years in FV-naive and FV-primed groups, respectively. TAK-426 responses were comparable in magnitude and kinetics with those elicited by natural Zika virus infection. CONCLUSIONS: These results support the further clinical development of TAK-426 for both FV-naive and FV-primed populations. CLINICAL TRIALS REGISTRATION: NCT03343626.

Clinical Application of a Novel Genetic Risk Score for Ischemic Stroke in Patients With Cardiometabolic Disease.

BACKGROUND: Genome-wide association studies have identified single-nucleotide polymorphisms that are associated with an increased risk of stroke. We sought to determine whether a genetic risk score (GRS) could identify subjects at higher risk for ischemic stroke after accounting for traditional clinical risk factors in 5 trials across the spectrum of cardiometabolic disease. METHODS: Subjects who had consented for genetic testing and who were of European ancestry from the ENGAGE AF-TIMI 48 (Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation), SOLID-TIMI 52 (Stabilization of Plaques Using Darapladib), SAVOR-TIMI 53 (Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus), PEGASUS-TIMI 54 (Prevention of Cardiovascular Events in Patients With Prior Heart Attack Using Ticagrelor Compared to Placebo on a Background of Aspirin), and FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Patients With Elevated Risk) trials were included in this analysis. A set of 32 single-nucleotide polymorphisms associated with ischemic stroke was used to calculate a GRS in each patient and identify tertiles of genetic risk. A Cox model was used to calculate hazard ratios for ischemic stroke across genetic risk groups, adjusted for clinical risk factors. RESULTS: In 51 288 subjects across the 5 trials, a total of 960 subjects had an ischemic stroke over a median follow-up period of 2.5 years. After adjusting for clinical risk factors, a higher GRS was strongly and independently associated with increased risk for ischemic stroke (P trend=0.009). In comparison with individuals in the lowest third of the GRS, individuals in the middle and top tertiles of the GRS had adjusted hazard ratios of 1.15 (95% CI, 0.98-1.36) and 1.24 (95% CI 1.05-1.45) for ischemic stroke, respectively. Stratification into subgroups revealed that the performance of the GRS appeared stronger in the primary prevention cohort with an adjusted hazard ratio for the top versus lowest tertile of 1.27 (95% CI, 1.04-1.53), in comparison with an adjusted hazard ratio of 1.06 (95% CI, 0.81-1.41) in subjects with previous stroke. In an exploratory analysis of patients with atrial fibrillation and CHA2DS2-VASc score of 2, high genetic risk conferred a 4-fold higher risk of stroke and an absolute risk equivalent to those with CHA2DS2-VASc score of 3. CONCLUSIONS: Across a broad spectrum of subjects with cardiometabolic disease, a 32-single-nucleotide polymorphism GRS was a strong, independent predictor of ischemic stroke. In patients with atrial fibrillation but lower CHA2DS2-VASc scores, the GRS identified patients with risk comparable to those with higher CHA2DS2-VASc scores.

Edoxaban versus Warfarin in high-risk patients with atrial fibrillation: A comprehensive analysis of high-risk subgroups.

BACKGROUND: To compare the efficacy and safety of edoxaban vs warfarin in high-risk subgroups. METHODS: ENGAGE AF-TIMI 48 was a multicenter randomized, double-blind, controlled trial in 21,105 patients with atrial fibrillation (AF) within 12 months and CHADS2 score >2 randomized to higher-dose edoxaban regimen (HDER) 60 mg/reduced 30 mg, lower-dose edoxaban regimen (LDER) 30 mg/reduced 15 mg, or warfarin, and followed for 2.8 years (median). The primary outcome for this analysis was the net clinical outcome (NCO), a composite of stroke/systemic embolism events, major bleeding, or death. Multivariable risk-stratification analysis was used to categorize patients by the number of high-risk features. RESULTS: The annualized NCO rates in the warfarin arm were highest in patients with malignancy (19.2%), increased fall risk (14.0%), and very-low body weight (13.5%). The NCO rates increased with the numbers of high-risk factors in the warfarin arm: 4.5%, 7.2%, 9.9% and 14.6% in patients with 0 to 1, 2, 3, and >4 risk factors, respectively (Ptrend <0.001). Versus warfarin, HDER was associated with significant reductions of NCO in most of the subgroups: elderly, patients with moderate renal dysfunction, prior stroke/TIA, of Asian race, very-low body weight, concomitant single antiplatelet therapy, and VKA-naïve. With more high-risk features (0->4+), the absolute risk reductions favoring edoxaban over warfarin increased: 0.3%->2.0% for HDER; 0.4%->3.4% for LDER vs warfarin (P = .065 and P < .001, respectively). CONCLUSIONS: While underuse of anticoagulation in high-risk patients with AF remains common, substitution of effective and safer alternatives to warfarin, such as edoxaban, represents an opportunity to improve clinical outcomes.

Meta-analysis and machine learning-augmented mixed effects cohort analysis of improved diets among 5847 medical trainees, providers and patients.

OBJECTIVE: We sought to produce the first meta-analysis (of medical trainee competency improvement in nutrition counseling) informing the first cohort study of patient diet improvement through medical trainees and providers counseling patients on nutrition. DESIGN: (Part A) A systematic review and meta-analysis informing (Part B) the intervention analysed in the world's largest prospective multi-centre cohort study on hands-on cooking and nutrition education for medical trainees, providers and patients. SETTINGS: (A) Medical educational institutions. (B) Teaching kitchens. PARTICIPANTS: (A) Medical trainees. (B) Trainees, providers and patients. RESULTS: (A) Of the 212 citations identified (n 1698 trainees), eleven studies met inclusion criteria. The overall effect size was 9·80 (95 % CI (7·15, 12·45) and 95 % CI (6·87, 13·85); P < 0·001), comparable with the machine learning (ML)-augmented results. The number needed to treat for the top performing high-quality study was 12. (B) The hands-on cooking and nutrition education curriculum from the top performing study were applied for medical trainees and providers who subsequently taught patients in the same curriculum (n 5847). The intervention compared with standard medical care and education alone significantly increased the odds of superior diets (high/medium v. low Mediterranean diet adherence) for residents/fellows most (OR 10·79, 95 % CI (4·94, 23·58); P < 0·001) followed by students (OR 9·62, 95 % CI (5·92, 15·63); P < 0·001), providers (OR 5·19, 95 % CI (3·23, 8·32), P < 0·001) and patients (OR 2·48, 95 % CI (1·38, 4·45); P = 0·002), results consistent with those from ML. CONCLUSIONS: The current study suggests that medical trainees and providers can improve patients' diets with nutrition counseling in a manner that is clinically and cost effective and may simultaneously advance societal equity.

Predicting Benefit From Evolocumab Therapy in Patients With Atherosclerotic Disease Using a Genetic Risk Score: Results From the FOURIER Trial.

BACKGROUND: The ability of a genetic risk score to predict risk in established cardiovascular disease and identify individuals who derive greater benefit from PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibition has not been established. METHODS: We studied 14 298 patients with atherosclerotic cardiovascular disease from the FOURIER trial (Further Cardiovascular Outcomes Researh With PCSK9 Inhibition in Subjects With Elevated Risk). A 27-single-nucleotide polymorphism genetic risk score defined low (quintile 1), intermediate (quintiles 2-4), and high (quintile 5) genetic risk. Patients were also categorized by major atherosclerotic risk factors including diabetes mellitus, hypertension, low-density lipoprotein cholesterol ≥100 mg/dl, and smoking; multiple (≥2) risk factors was considered high clinical risk. Outcomes consisted of major coronary events (coronary heart death, myocardial infarction, or coronary revascularization) and major vascular events (major coronary events and ischemic stroke). Median follow-up was 2.3 years. RESULTS: After we adjusted for clinical factors, the genetic risk score was associated with risk for both major vascular events (Ptrend=0.005) and major coronary events (Ptrend<0.0001). Individuals with intermediate and high genetic risk scores had 1.23- and 1.65-fold increased hazard for major coronary events, respectively. Elevated genetic risk was additive to major atherosclerotic risk factors and identified patients more likely to benefit from evolocumab. There was no benefit for major vascular events in patients without multiple clinical risk factors or high genetic risk (hazard ratio [HR], 1.02; absolute risk reduction [ARR], -0.2%, P=0.86). In contrast, there was a 13% relative risk reduction (HR, 0.87 [0.75-0.998], P=0.047) and a 1.4% ARR in patients with multiple clinical risk factors but without high genetic risk and a 31% relative risk reduction (HR, 0.69 [0.55-0.86], P=0.0012), and 4.0% ARR in patients with high genetic risk, irrespective of clinical risk (Ptrend for HR=0.017, ARR Ptrend=0.004). Patients with high genetic risk who received evolocumab had event rates similar to patients with a low burden of both genetic and clinical risk. CONCLUSION: Patients without multiple clinical risk factors or high genetic risk had a low event rate and did not appear to derive benefit from evolocumab over 2.3 years. Conversely, patients with multiple clinical risk factors but without high genetic risk had intermediate risk and intermediate risk reduction. Patients with high genetic risk, regardless of clinical risk, had a high event rate and derived the greatest relative and absolute benefit from evolocumab, which mitigated this risk.

Comparison of Events Across Bleeding Scales in the ENGAGE AF-TIMI 48 Trial.

BACKGROUND: Numerous scales exist for the classification of major bleeding events. Limited data compare the most commonly used bleeding scales within a single at-risk cohort of patients with atrial fibrillation. Here, we analyze bleeding outcomes according to the ISTH (International Society on Thrombosis and Hemostasis), TIMI (Thrombolysis in Myocardial Infarction), GUSTO (Global Usage of Strategies to Open Occluded Arteries), and BARC (Bleeding Academic Research Consortium) bleeding scales in the ENGAGE AF (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation)-TIMI 48 trial (NCT00781391) of edoxaban versus warfarin. METHODS: A total of 21 105 patients with atrial fibrillation at risk for stroke (CHADS2 score ≥2) were enrolled in the ENGAGE AF-TIMI 48 trial comparing warfarin with a higher- (60/30 mg daily) or lower- (30/15 mg daily) dose edoxaban regimen. Median follow-up was 2.8 years. Bleeding events occurring among on-treatment patients were examined. Annualized event rates were calculated by the ISTH, TIMI, GUSTO, and BARC scales and compared across treatment arms. Cox proportional hazards for a first bleeding event of each type were calculated for higher-dose edoxaban regimen vs warfarin and lower-dose edoxaban regimen versus warfarin. RESULTS: A total of 10 311 bleeding events were reported. In a comparison of the most severe events in each scale, ISTH major bleeding was the most common (n=1289), followed by TIMI major (n=548), GUSTO severe/life-threatening (n=347), and BARC 3c+5 (n=276) bleeding. Lower bleeding risk with edoxaban compared with warfarin was seen regardless of bleeding scale (higher-dose edoxaban regimen range: hazard ratio [HR], 0.47 [95% CI, 0.35-0.62] for BARC 3c+5 versus HR, 0.80 [95% CI, 0.71-0.91] for ISTH major; lower-dose edoxaban regimen range: HR, 0.32 [95% CI, 0.23-0.45] for BARC 3c+5 versus HR, 0.47 [95% CI, 0.41-0.55] for ISTH major). Furthermore, a gradient of more pronounced risk reduction with edoxaban was observed with greater severity of first bleeding event (higher-dose edoxaban regimen: HR, 0.47 [95% CI, 0.35-0.62] for BARC 3c+5 bleeds versus HR, 0.86 [95% CI, 0.81-0.91] for any BARC bleed; lower-dose edoxaban regimen: HR, 0.32 [95% CI, 0.23-0.45] for BARC 3c+5 bleeds versus HR, 0.68 [95% CI, 0.63-0.72] for any BARC bleed). The direction of this trend was consistent for both gastrointestinal bleeding and nongastrointestinal bleeding. CONCLUSIONS: Among patients with atrial fibrillation at risk for stroke, there was a >4-fold difference in the frequency of the most severe bleeding events across commonly used bleeding scales. Furthermore, the relative safety of edoxaban compared with warfarin tended to increase with greater severity of bleeding. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT00781391.

Performance of the ABC Scores for Assessing the Risk of Stroke or Systemic Embolism and Bleeding in Patients With Atrial Fibrillation in ENGAGE AF-TIMI 48.

BACKGROUND: The ABC (age, biomarker, clinical history)-stroke and ABC-bleeding risk scores incorporate clinical variables and cardiovascular biomarkers to estimate risk of stroke or systemic embolic events and bleeding, respectively, in patients with atrial fibrillation. These scores have been proposed for routine clinical use, but their performance in external cohorts remains uncertain. METHODS: ENGAGE AF-TIMI 48 (Effective Anticoagulation With Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48) was a multinational randomized trial of the oral factor Xa inhibitor edoxaban in patients with atrial fibrillation and a CHADS2 score ≥2. We performed a nested prospective biomarker study in 8705 patients, analyzing baseline high-sensitivity troponin T (hsTnT), NT-proBNP (N-terminal B-type natriuretic peptide), and growth differentiation factor-15 (GDF-15), as well as in serial samples after 12 months. The ABC-stroke (age, prior stroke/transient ischemic attack, hsTnT, NT-proBNP) and ABC-bleeding (age, prior bleeding, hemoglobin, hsTnT, and GDF-15) scores were tested. Hazard ratios were adjusted for estimated glomerular filtration rate and the components of the CHA2DS2-VASc and HAS-BLED scores, respectively. Discrimination and reclassification were compared with these established scores. RESULTS: Median baseline hsTnT, NT-proBNP, and GDF-15 levels were 13.7 ng/L (25th-75th percentiles, 9.6-20.4 ng/L), 811 pg/mL (386-1436 pg/mL), and 1661 pg/mL (1179-2427 pg/mL), respectively. Elevated hsTnT, NT-proBNP, and GDF-15 were independently associated with higher rates of stroke or systemic embolic events, and elevated hsTnT and GDF-15 were independently associated with higher rates of major bleeding ( P<0.001 for each). The ABC-stroke and ABC-bleeding scores were well calibrated and yielded higher c indexes than the CHA2DS2-VASc score for stroke or systemic embolic events (0.67 [95% CI, 0.65-0.70] versus 0.59 [95% CI, 0.57-0.62]; P<0.001) and HAS-BLED score for major bleeding (0.69 [95% CI, 0.66-0.71] versus 0.62 [95% CI, 0.60-0.64]; P<0.001), respectively. The ABC-stroke and ABC-bleeding scores stratified patients within CHA2DS2-VASc and HAS-BLED risk categories ( P<0.001 for both). Patients with ABC-bleeding scores predicting a high 1-year risk of bleeding (>2%) derived greater benefit from treatment with edoxaban compared with warfarin. CONCLUSIONS: The ABC-stroke and ABC-bleeding scores evaluated in this anticoagulated clinical trial cohort were well calibrated and outperformed the CHA2DS2-VASc and HAS-BLED scores, respectively. These scores may help identify patients most likely to derive a benefit from treatment with non-vitamin K antagonist oral anticoagulants. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00781391.

Two Clinical Prediction Tools to Improve Tuberculosis Contact Investigation.

BACKGROUND: Efficient contact investigation strategies are needed for the early diagnosis of tuberculosis (TB) disease and treatment of latent TB infections. METHODS: Between September 2009 and August 2012, we conducted a prospective cohort study in Lima, Peru, in which we enrolled and followed 14 044 household contacts of adults with pulmonary TB. We used information from a subset of this cohort to derive 2 clinical prediction tools that identify contacts of TB patients at elevated risk of progressing to active disease by training multivariable models that predict (1) coprevalent TB among all household contacts and (2) 1-year incident TB among adult contacts. We validated the models in a geographically distinct subcohort and compared the relative utilities of clinical decisions based on these tools to existing strategies. RESULTS: In our cohort, 296 (2.1%) household contacts had coprevalent TB and 145 (1.9%) adult contacts developed incident TB within 1 year of index patient diagnosis. We predicted coprevalent disease using information that could be readily obtained at the time an index patient was diagnosed and predicted 1-year incident TB by including additional contact-specific characteristics. The area under the receiver operating characteristic curves for coprevalent TB and incident TB were 0.86 (95% confidence interval [CI], .83-.89]) and 0.72 (95% CI, .67-.77), respectively. These clinical tools give 5%-10% higher relative utilities than existing methods. CONCLUSIONS: We present 2 tools that identify household contacts at high risk for TB disease based on reportable information from patient and contacts alone. The performance of these tools is comparable to biomarkers that are both more costly and less feasible than this approach.

Nitric Oxide Decreases Acute Kidney Injury and Stage 3 Chronic Kidney Disease after Cardiac Surgery.

RATIONALE: No medical intervention has been identified that decreases acute kidney injury and improves renal outcome at 1 year after cardiac surgery. OBJECTIVES: To determine whether administration of nitric oxide reduces the incidence of postoperative acute kidney injury and improves long-term kidney outcomes after multiple cardiac valve replacement requiring prolonged cardiopulmonary bypass. METHODS: Two hundred and forty-four patients undergoing elective, multiple valve replacement surgery, mostly due to rheumatic fever, were randomized to receive either nitric oxide (treatment) or nitrogen (control). Nitric oxide and nitrogen were administered via the gas exchanger during cardiopulmonary bypass and by inhalation for 24 hours postoperatively. MEASUREMENTS AND MAIN RESULTS: The primary outcome was as follows: oxidation of ferrous plasma oxyhemoglobin to ferric methemoglobin was associated with reduced postoperative acute kidney injury from 64% (control group) to 50% (nitric oxide group) (relative risk [RR], 0.78; 95% confidence interval [CI], 0.62-0.97; P = 0.014). Secondary outcomes were as follows: at 90 days, transition to stage 3 chronic kidney disease was reduced from 33% in the control group to 21% in the treatment group (RR, 0.64; 95% CI, 0.41-0.99; P = 0.024) and at 1 year, from 31% to 18% (RR, 0.59; 95% CI, 0.36-0.96; P = 0.017). Nitric oxide treatment reduced the overall major adverse kidney events at 30 days (RR, 0.40; 95% CI, 0.18-0.92; P = 0.016), 90 days (RR, 0.40; 95% CI, 0.17-0.92; P = 0.015), and 1 year (RR, 0.47; 95% CI, 0.20-1.10; P = 0.041). CONCLUSIONS: In patients undergoing multiple valve replacement and prolonged cardiopulmonary bypass, administration of nitric oxide decreased the incidence of acute kidney injury, transition to stage 3 chronic kidney disease, and major adverse kidney events at 30 days, 90 days, and 1 year. Clinical trial registered with ClinicalTrials.gov (NCT01802619).

Accounting for adaptation and intensity in projecting heat wave-related mortality.

BACKGROUND: How adaptation and intensity of heat waves affect heat wave-related mortality is unclear, making health projections difficult. METHODS: We estimated the effect of heat waves, the effect of the intensity of heat waves, and adaptation on mortality in 209 U.S. cities with 168 million people during 1962-2006. We improved the standard time-series models by incorporating the intensity of heat waves using excess heat factor (EHF) and estimating adaptation empirically using interactions with yearly mean summer temperature (MST). We combined the epidemiological estimates for heat wave, intensity, and adaptation with the Coupled Model Intercomparison Project Phase 5 (CMIP5) multi-model dataset to project heat wave-related mortality by 2050. RESULTS: The effect of heat waves increased with its intensity. Adaptation to heat waves occurred, which was shown by the decreasing effect of heat waves with MST. However, adaptation was lessened as MST increased. Ignoring adaptation in projections would result in a substantial overestimate of the projected heat wave-related mortality (by 277-747% in 2050). Incorporating the empirically estimated adaptation into projections would result in little change in the projected heat wave-related mortality between 2006 and 2050. This differs regionally, however, with increasing mortality over time for cities in the southern and western U.S. but decreasing mortality over time for the north. CONCLUSIONS: Accounting for adaptation is important to reduce bias in the projections of heat wave-related mortality. The finding that the southern and western U.S. are the areas that face increasing heat-related deaths is novel, and indicates that more regional adaptation strategies are needed.

A novel risk prediction score in atrial fibrillation for a net clinical outcome from the ENGAGE AF-TIMI 48 randomized clinical trial.

AIMS: The choice between initiating a non-vitamin K antagonist oral anticoagulant (NOAC) and a vitamin K antagonist (VKA) in patients with atrial fibrillation (AF) may be challenging. To assist in this decision, we developed a risk score to identify patients for whom a therapeutic benefit of NOACs over VKA is predicted. METHODS AND RESULTS: ENGAGE AF-TIMI 48 was a randomized clinical trial of edoxaban vs. warfarin in 21 105 patients with AF. Cox proportional hazard models identified factors associated with a serious net clinical outcome (NCO) of disabling stroke, life-threatening bleeding, and all-cause mortality in VKA naïve patients from the warfarin arm. These were used to develop an integer risk score. Performance was assessed by C-indices and validation by bootstrapping. Kaplan-Meier analyses were stratified by three score categories and treatment arm. Over a median of 2.7 years, 457 NCO events occurred in 2898 patients with a total person-time of 7549.5 years (6.05%/year). The risk prediction model (C = 0.693) for the NCO was translated into a 17-point integer score, with annualized event rates for the low, intermediate, and high-risk categories in the warfarin arm of 3.5%, 9.9%, and 20.8%, respectively. Therapeutic benefit of higher- and lower-dose edoxaban over warfarin was demonstrated in the high- and intermediate-risk, with equal benefit in the low-risk categories (P-interaction 0.008 and 0.014, respectively). CONCLUSION: In VKA naive patients with AF, the TIMI-AF score can assist in the prediction of a poor composite outcome and guide selection of anticoagulant therapy by identifying a differential clinical benefit with a NOAC or VKA.

Ambient Temperature and Sudden Infant Death Syndrome in the United States.

BACKGROUND: Sudden infant death syndrome (SIDS) is a leading cause of infant mortality in the United States. While thermal stress is implicated in many risk factors for SIDS, the association between ambient temperature and SIDS remains unclear. METHODS: We obtained daily individual-level infant mortality data and outdoor temperature data from 1972 to 2006 for 210 US cities. We applied a time-stratified case-crossover analysis to determine the effect of ambient temperature on the risk of SIDS by season. We stratified the analysis by race, infant age, and climate. RESULTS: There were a total of 60,364 SIDS cases during our study period. A 5.6°C (10°F) higher daily temperature on the same day was associated with an increased SIDS risk of 8.6% (95% confidence interval [CI] = 3.6%, 13.8%) in the summer, compared with a 3.1% decrease (95% CI = -5.0%, -1.3%) in the winter. Summer risks were greater among black infants (18.5%; 95% CI = 9.3%, 28.5%) than white infants (3.6%; 95% CI = -2.3%, 9.9%), and among infants 3-11 months old (16.9%; 95% CI = 8.9%, 25.5%) than infants 0-2 months old (2.7%; 95% CI = -3.5%, 9.2%). The temperature-SIDS association was stronger in climate clusters in the Midwest and surrounding northern regions. CONCLUSIONS: Temperature increases were associated with an elevated risk of SIDS in the summer, particularly among infants who were black, 3 months old and older, and living in the Midwest and surrounding northern regions.

Genetics and the clinical response to warfarin and edoxaban: findings from the randomised, double-blind ENGAGE AF-TIMI 48 trial.

BACKGROUND: Warfarin is the most widely used oral anticoagulant worldwide, but serious bleeding complications are common. We tested whether genetic variants can identify patients who are at increased risk of bleeding with warfarin and, consequently, those who would derive a greater safety benefit with a direct oral anticoagulant rather than warfarin. METHODS: ENGAGE AF-TIMI 48 was a randomised, double-blind trial in which patients with atrial fibrillation were assigned to warfarin to achieve a target international normalised ratio of 2·0-3·0, or to higher-dose (60 mg) or lower-dose (30 mg) edoxaban once daily. A subgroup of patients was included in a prespecified genetic analysis and genotyped for variants in CYP2C9 and VKORC1. The results were used to create three genotype functional bins (normal, sensitive, and highly sensitive responders to warfarin). This trial is registered with ClinicalTrials.gov, number NCT00781391. FINDINGS: 14,348 patients were included in the genetic analysis. Of 4833 taking warfarin, 2982 (61·7%) were classified as normal responders, 1711 (35·4%) as sensitive responders, and 140 (2·9%) as highly sensitive responders. Compared with normal responders, sensitive and highly sensitive responders spent greater proportions of time over-anticoagulated in the first 90 days of treatment (median 2·2%, IQR 0-20·2; 8·4%, 0-25·8; and 18·3%, 0-32·6; ptrend<0·0001) and had increased risks of bleeding with warfarin (sensitive responders hazard ratio 1·31, 95% CI 1·05-1·64, p=0·0179; highly sensitive responders 2·66, 1·69-4·19, p<0·0001). Genotype added independent information beyond clinical risk scoring. During the first 90 days, when compared with warfarin, treatment with edoxaban reduced bleeding more so in sensitive and highly sensitive responders than in normal responders (higher-dose edoxaban pinteraction=0·0066; lower-dose edoxaban pinteraction=0·0036). After 90 days, the reduction in bleeding risk with edoxaban versus warfarin was similarly beneficial across genotypes. INTERPRETATION: CYP2C9 and VKORC1 genotypes identify patients who are more likely to experience early bleeding with warfarin and who derive a greater early safety benefit from edoxaban compared with warfarin. FUNDING: Daiichi Sankyo.

Edoxaban vs warfarin in patients with nonvalvular atrial fibrillation in the US Food and Drug Administration approval population: An analysis from the Effective Anticoagulation with Factor Xa Next Generation in Atrial Fibrillation-Thrombolysis in Myocardial Infarction 48 (ENGAGE AF-TIMI 48) trial.

BACKGROUND: Edoxaban is a specific anti-Xa inhibitor that, in comparison to warfarin, has been found to be noninferior for the prevention of stroke or systemic embolism (SSE) and to reduce bleeding significantly in patients with nonvalvular atrial fibrillation (AF). The US Food and Drug Administration (FDA) approved the higher-dose edoxaban regimen (60/30 mg) in patients with AF and a creatinine clearance of ≤95 mL/min. We report for the first time the clinical characteristics, efficacy, and safety of the FDA-approved population in the ENGAGE AF--TIMI 48 trial. METHODS: The patients included had been treated with either warfarin or edoxaban 60/30 mg and had a creatinine clearance of ≤95 mL/min. The primary efficacy was SSE, and the principal safety end point was major bleeding (International Society on Thrombosis and Haemostasis classification). Median follow-up was 2.8 years. RESULTS: Patients in the FDA-approved cohort were older, were more likely female, and had higher CHADS2 and HAS-BLED scores, as compared with patients not included in the FDA label. The primary end point occurred in 1.63%/y with edoxaban vs 2.02%/y with warfarin (hazard ratio [HR] 0.81, 95% CI 0.67-0.97, P = .023). Edoxaban significantly reduced the rate of hemorrhagic stroke (HR 0.47, 95% CI 0.31-0.72, P < .001) and cardiovascular death (HR 0.84, 95% CI 0.73-0.97, P = .015). Ischemic stroke rates were similar between the treatment groups (1.31%/y vs 1.39%/y, P = .97). Major bleeding was significantly lower with edoxaban (3.16%/y vs 3.77%/y; HR 0.84, 95% CI 0.72-0.98, P = .023). CONCLUSION: In the FDA-approved cohort of the ENGAGE AF--TIMI 48 trial, treatment with edoxaban 60/30 mg was superior to warfarin in the prevention of SSE and significantly reduced cardiovascular death and bleeding, especially fatal bleeding and hemorrhagic stroke.

A risk prediction model for xerostomia: a retrospective cohort study.

OBJECTIVE: We investigated the prevalence of xerostomia in dental patients and built a xerostomia risk prediction model by incorporating a wide range of risk factors. MATERIALS AND METHODS: Socio-demographic data, past medical history, self-reported dry mouth and related symptoms were collected retrospectively from January 2010 to September 2013 for all new dental patients. A logistic regression framework was used to build a risk prediction model for xerostomia. External validation was performed using an independent data set to test the prediction power. RESULTS: A total of 12 682 patients were included in this analysis (54.3%, females). Xerostomia was reported by 12.2% of patients. The proportion of people reporting xerostomia was higher among those who were taking more medications (OR = 1.11, 95% CI = 1.08-1.13) or recreational drug users (OR = 1.4, 95% CI = 1.1-1.9). Rheumatic diseases (OR = 2.17, 95% CI = 1.88-2.51), psychiatric diseases (OR = 2.34, 95% CI = 2.05-2.68), eating disorders (OR = 2.28, 95% CI = 1.55-3.36) and radiotherapy (OR = 2.00, 95% CI = 1.43-2.80) were good predictors of xerostomia. For the test model performance, the ROC-AUC was 0.816 and in the external validation sample, the ROC-AUC was 0.799. CONCLUSION: The xerostomia risk prediction model had high accuracy and discriminated between high- and low-risk individuals. Clinicians could use this model to identify the classes of medications and systemic diseases associated with xerostomia.

Pathologic complete response to intralesional interleukin-2 therapy associated with improved survival in melanoma patients with in-transit disease.

PURPOSE: Melanoma patients with in-transit disease have a high mortality rate despite various treatment strategies. The aim of this study was to validate the role of intralesional interleukin (IL)-2, to understand its mechanism of action, and to better understand factors that may influence its response. METHODS: We retrospectively collected the clinicopathological data of 31 consecutive patients who presented to a tertiary care cancer center for treatment of in-transit melanoma with intralesional IL-2. Kaplan-Meier survival curves and multivariable Cox regression analysis were performed. Immunohistochemistry (IHC) was used to better understand the immune response to localized IL-2 therapy. Targeted next-generation sequencing was performed to genomically characterize the tumors. RESULTS: Ten patients (10/31, 32 %) achieved a pathologic complete response (pCR), 17/21 (55 %) had a partial response, and 4/21 (19 %) had progressive disease on treatment. pCR to IL-2 therapy was associated with overall survival (log-rank p = 0.004) and improved progression-free survival (PFS) [adjusted hazard ratio (HR) 0.11; 95 % CI 0.02-0.47; p = 0.003). A higher CD8+ T cell infiltrate was identified in in-transit lesions with a pCR compared with the other lesions (mean IHC score 3.78 vs. 2.61; p = 0.01). Patients with an elevated CD8+ infiltrate demonstrated an improved PFS (unadjusted HR 0.08; 95 % CI 0.01-0.52; p = 0.008). CONCLUSIONS: Thirty-two percent of patients achieved pCR with intralesional IL-2 therapy and had a significantly improved PFS compared with the rest of the cohort, which may be explained by a systemic CD8+ T-cell response.

Microvesicle-associated microRNA expression is altered upon particulate matter exposure in healthy workers and in A549 cells.

Cardiovascular disease risk has been consistently linked with particulate matter (PM) exposure. Cell-derived microvesicles (MVs) are released into plasma and transfer microRNAs (miRNAs) between tissues. MVs can be produced by the respiratory system in response to proinflammatory triggers, enter the circulatory system and remotely modify gene expression in cardiovascular tissues. However, whether PM affects MV signaling has never been investigated. In this study, we evaluated expression of microRNAs contained within plasma MVs upon PM exposure both in vivo and in vitro. In the in vivo study, we isolated plasma MVs from healthy steel plant workers before and after workplace PM exposure. We measured the expression of 88 MV-associated miRNAs by real-time polymerase chain reaction. To assess a possible source of the MV miRNAs identified in vivo, we measured their miRNA expression in PM-treated A549 pulmonary cell lines in vitro. MiRNA profiling of plasma MVs showed 5.62- and 13.95-fold increased expression of miR-128 and miR-302c, respectively, after 3 days of workplace PM exposure (P < 0.001). According to Ingenuity Pathway Analysis, miR-128 is part of coronary artery disease pathways, and miR-302c is part of coronary artery disease, cardiac hypertrophy and heart failure pathways. In vitro experiments confirmed a dose-dependent expression of miR-128 in MVs released from A549 cells after 6 h of PM treatment (P = 0.030). MiR-302c was expressed neither from A549 cells nor in reference lung RNA. These results suggest novel PM-activated molecular mechanisms that may mediate the effects of air pollution and could lead to the identification of new diagnostic and therapeutic interventions.

Acclimatization across space and time in the effects of temperature on mortality: a time-series analysis.

BACKGROUND: Climate change has increased the days of unseasonal temperature. Although many studies have examined the association between temperature and mortality, few have examined the timing of exposure where whether this association varies depending on the exposure month even at the same temperature. Therefore, we investigated monthly differences in the effects of temperature on mortality in a study comprising a wide range of weather and years, and we also investigated heterogeneity among regions. METHODS: We analyzed 38,005,616 deaths from 148 cities in the U.S. from 1973 through 2006. We fit city specific Poisson regressions to examine the effect of temperature on mortality separately for each month of the year, using penalized splines. We used cluster analysis to group cities with similar weather patterns, and combined results across cities within clusters using meta-smoothing. RESULTS: There was substantial variation in the effects of the same temperature by month. Heat effects were larger in the spring and early summer and cold effects were larger in late fall. In addition, heat effects were larger in clusters where high temperatures were less common, and vice versa for cold effects. CONCLUSIONS: The effects of a given temperature on mortality vary spatially and temporally based on how unusual it is for that time and location. This suggests changes in variability of temperature may be more important for health as climate changes than changes of mean temperature. More emphasis should be placed on warnings targeted to early heat/cold temperature for the season or month rather than focusing only on the extremes.

A New Hybrid Spatio-Temporal Model For Estimating Daily Multi-Year PM2.5 Concentrations Across Northeastern USA Using High Resolution Aerosol Optical Depth Data.

BACKGROUND: The use of satellite-based aerosol optical depth (AOD) to estimate fine particulate matter (PM2.5) for epidemiology studies has increased substantially over the past few years. These recent studies often report moderate predictive power, which can generate downward bias in effect estimates. In addition, AOD measurements have only moderate spatial resolution, and have substantial missing data. METHODS: We make use of recent advances in MODIS satellite data processing algorithms (Multi-Angle Implementation of Atmospheric Correction (MAIAC), which allow us to use 1 km (versus currently available 10 km) resolution AOD data. We developed and cross validated models to predict daily PM2.5 at a 1×1km resolution across the northeastern USA (New England, New York and New Jersey) for the years 2003-2011, allowing us to better differentiate daily and long term exposure between urban, suburban, and rural areas. Additionally, we developed an approach that allows us to generate daily high-resolution 200 m localized predictions representing deviations from the area 1×1 km grid predictions. We used mixed models regressing PM2.5 measurements against day-specific random intercepts, and fixed and random AOD and temperature slopes. We then use generalized additive mixed models with spatial smoothing to generate grid cell predictions when AOD was missing. Finally, to get 200 m localized predictions, we regressed the residuals from the final model for each monitor against the local spatial and temporal variables at each monitoring site. RESULTS: Our model performance was excellent (mean out-of-sample R2=0.88). The spatial and temporal components of the out-of-sample results also presented very good fits to the withheld data (R2=0.87, R2=0.87). In addition, our results revealed very little bias in the predicted concentrations (Slope of predictions versus withheld observations = 0.99). CONCLUSION: Our daily model results show high predictive accuracy at high spatial resolutions and will be useful in reconstructing exposure histories for epidemiological studies across this region.

Predicting Efficacy of a Purified Inactivated Zika Virus Vaccine in Flavivirus-Naïve Humans Using an Immunological Correlate of Protection in Non-Human Primates.

A traditional phase 3 clinical efficacy study for a Zika vaccine may be unfeasible because of the current low transmission of Zika virus (ZIKV). An alternative clinical development approach to evaluate Zika vaccine efficacy (VE) is therefore required, delineated in the US FDA's Accelerated Approval Program for licensure, which utilizes an anti-Zika neutralizing antibody (Zika NAb) titer correlated with non-human primate (NHP) protection as a surrogate endpoint. In this accelerated approval approach, the estimation of VE would be inferred from the percentage of phase 3 trial participants achieving the established surrogate endpoint. We provide a statistical framework to predict the probability of protection for human participants vaccinated with a purified inactivated ZIKV vaccine (TAK-426), in the absence of VE measurements, using NHP data under a single-correlate model. Based on a logistic regression (LR) with bias-reduction model, a probability of 90% protection in humans is expected with a ZIKV NAb geometric mean titer (GMT) ≥ 3.38 log10 half-maximal effective concentration (EC50). The predicted probability of protection of TAK-426 against ZIKV infection was determined using the two-parameter LR model that fit the calculated VE in rhesus macaques and the flavivirus-naïve phase 1 trial participants' ZIKV NAb GMTs log10 EC50, measured by a ZIKV reporter virus particle assay, at 1 month post dose 2. The TAK-426 10 µg dose predicted a probability of protection from infection of 98% among flavivirus-naïve phase 1 trial participants.