Comparative effectiveness of third doses of mRNA-based COVID-19 vaccines in US veterans.

Vaccination against SARS-CoV-2 has been effective in reducing the burden of severe disease and death from COVID-19. Third doses of mRNA-based vaccines have provided a way to address waning immunity and broaden protection against emerging SARS-CoV-2 variants. However, their comparative effectiveness for a range of COVID-19 outcomes across diverse populations is unknown. We emulated a target trial using electronic health records of US veterans who received a third dose of either BNT162b2 or mRNA-1273 vaccines between 20 October 2021 and 8 February 2022, during a period that included Delta- and Omicron-variant waves. Eligible veterans had previously completed an mRNA vaccine primary series. We matched recipients of each vaccine in a 1:1 ratio according to recorded risk factors. Each vaccine group included 65,196 persons. The excess number of events over 16 weeks per 10,000 persons for BNT162b2 compared with mRNA-1273 was 45.4 (95% CI: 19.4, 84.7) for documented infection, 3.7 (2.2, 14.1) for symptomatic COVID-19, 10.6 (5.1, 19.7) for COVID-19 hospitalization, 2.0 (-3.1, 6.3) for COVID-19 intensive care unit admission and 0.2 (-2.2, 4.0) for COVID-19 death. After emulating a second target trial of veterans who received a third dose between 1 January and 1 March 2022, during a period restricted to Omicron-variant predominance, the excess number of events over 9 weeks per 10,000 persons for BNT162b2 compared with mRNA-1273 was 63.2 (95% CI: 15.2, 100.7) for documented infection. The 16-week risks of COVID-19 outcomes were low after a third dose of mRNA-1273 or BNT162b2, although risks were lower with mRNA-1273 than with BNT162b2, particularly for documented infection.

Comparative Safety of BNT162b2 and mRNA-1273 Vaccines in a Nationwide Cohort of US Veterans.

Importance: The risk of adverse events has been found to be low for participants receiving the BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna Inc) vaccines in randomized trials. However, a head-to-head comparison of their safety for a broader range of potential adverse events over longer follow-up and in larger and more diverse populations is lacking, to our knowledge. Objective: To compare the head-to-head safety in terms of risk of adverse events of the BNT162b2 and mRNA-1273 vaccines in the national health care databases of the US Department of Veterans Affairs, the largest integrated health care system in the US. Design, Setting, and Participants: In this cohort study, the electronic health records of US veterans who received a first dose of the BNT162b2 or mRNA-1273 vaccine between January 4 and September 20, 2021, were used. Recipients of each vaccine were matched in a 1:1 ratio according to their risk factors. Exposures: Vaccination with either the BNT162b2 vaccine, with a second dose scheduled 21 days later, or the mRNA-1273 vaccine, with a second dose scheduled 28 days later. Main Outcomes and Measures: A large panel of potential adverse events was evaluated; the panel included neurologic events, hematologic events, hemorrhagic stroke, ischemic stroke, myocardial infarction, other thromboembolic events, myocarditis or pericarditis, arrhythmia, kidney injury, appendicitis, autoimmune events, herpes zoster or simplex, arthritis or arthropathy, and pneumonia. Risks over 38 weeks were estimated using the Kaplan-Meier estimator. Results: Among 433 672 persons included in the matched vaccine groups, the median age was 69 years (IQR, 60-74 years), 93% of individuals were male, and 20% were Black. Estimated 38-week risks of adverse events were generally low after administration of either the BNT162b2 or the mRNA-1273 vaccine. Compared with the mRNA-1273 group, the BNT162b2 group had an excess per 10 000 persons of 10.9 events (95% CI, 1.9-17.4 events) of ischemic stroke, 14.8 events (95% CI, 7.9-21.8 events) of myocardial infarction, 11.3 events (95% CI, 3.4-17.7 events) of other thromboembolic events, and 17.1 events (95% CI, 8.8-30.2 events) of kidney injury. Estimates were largely similar among subgroups defined by age (<40, 40-69, and ≥70 years) and race (Black, White), but there were higher magnitudes of risk differences of ischemic stroke among older persons and White persons, kidney injury among older persons, and other thromboembolic events among Black persons. Small-magnitude differences between the 2 vaccines were seen within 42 days of the first dose, and few differences were seen within 14 days of the first dose. Conclusions and Relevance: The findings of this cohort study suggest that there were few differences in risk of adverse events within 14 days of the first dose of either the BNT162b2 or the mRNA-1273 vaccine and small-magnitude differences within 42 days of the first dose. The 38-week risks of adverse events were low in both vaccine groups, although risks were lower for recipients of the mRNA-1273 vaccine than for recipients of the BNT162b2 vaccine. Although the primary analysis was designed to detect safety events unrelated to SARS-CoV-2 infection, the possibility that these differences may partially be explained by a lower effectiveness of the BNT162b2 vaccine in preventing the sequelae of SARS-CoV-2 infection compared with the mRNA-1273 vaccine could not be ruled out. These findings may help inform decision-making in future vaccination campaigns.

Change in Left Ventricular Ejection Fraction With Coronary Artery Revascularization and Subsequent Risk for Adverse Cardiovascular Outcomes.

BACKGROUND: Coronary revascularization is recommended to treat ischemic cardiomyopathy. However, the relations of revascularization-associated ejection fraction (EF) change to subsequent outcomes have not been elucidated. METHODS: In 10 071 veterans (mean age 67 years; 1% women; 15% non-White) who underwent a first percutaneous coronary intervention (PCI) or coronary artery bypass grafting between January 1, 1995, and December 31, 2010, and had prerevascularization and postrevascularization EF measured, we calculated delta-EF (postprocedure EF-preprocedure EF). We related delta-EF as a continuous measure and as categories (≤-5, -5

Comparative Effectiveness of BNT162b2 and mRNA-1273 Vaccines in U.S. Veterans.

BACKGROUND: The messenger RNA (mRNA)-based vaccines BNT162b2 and mRNA-1273 are more than 90% effective against coronavirus disease 2019 (Covid-19). However, their comparative effectiveness for a range of outcomes across diverse populations is unknown. METHODS: We emulated a target trial using the electronic health records of U.S. veterans who received a first dose of the BNT162b2 or mRNA-1273 vaccine between January 4 and May 14, 2021, during a period marked by predominance of the SARS-CoV-2 B.1.1.7 (alpha) variant. We matched recipients of each vaccine in a 1:1 ratio according to their risk factors. Outcomes included documented severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, symptomatic Covid-19, hospitalization for Covid-19, admission to an intensive care unit (ICU) for Covid-19, and death from Covid-19. We estimated risks using the Kaplan-Meier estimator. To assess the influence of the B.1.617.2 (delta) variant, we emulated a second target trial that involved veterans vaccinated between July 1 and September 20, 2021. RESULTS: Each vaccine group included 219,842 persons. Over 24 weeks of follow-up in a period marked by alpha-variant predominance, the estimated risk of documented infection was 5.75 events per 1000 persons (95% confidence interval [CI], 5.39 to 6.23) in the BNT162b2 group and 4.52 events per 1000 persons (95% CI, 4.17 to 4.84) in the mRNA-1273 group. The excess number of events per 1000 persons for BNT162b2 as compared with mRNA-1273 was 1.23 (95% CI, 0.72 to 1.81) for documented infection, 0.44 (95% CI, 0.25 to 0.70) for symptomatic Covid-19, 0.55 (95% CI, 0.36 to 0.83) for hospitalization for Covid-19, 0.10 (95% CI, 0.00 to 0.26) for ICU admission for Covid-19, and 0.02 (95% CI, -0.06 to 0.12) for death from Covid-19. The corresponding excess risk (BNT162b2 vs. mRNA-1273) of documented infection over 12 weeks of follow-up in a period marked by delta-variant predominance was 6.54 events per 1000 persons (95% CI, -2.58 to 11.82). CONCLUSIONS: The 24-week risk of Covid-19 outcomes was low after vaccination with mRNA-1273 or BNT162b2, although risks were lower with mRNA-1273 than with BNT162b2. This pattern was consistent across periods marked by alpha- and delta-variant predominance. (Funded by the Department of Veterans Affairs and others.).

Early Convalescent Plasma Therapy and Mortality Among US Veterans Hospitalized With Nonsevere COVID-19: An Observational Analysis Emulating a Target Trial.

BACKGROUND: Early convalescent plasma transfusion may reduce mortality in patients with nonsevere coronavirus disease 2019 (COVID-19). METHODS: This study emulates a (hypothetical) target trial using observational data from a cohort of US veterans admitted to a Department of Veterans Affairs (VA) facility between 1 May and 17 November 2020 with nonsevere COVID-19. The intervention was convalescent plasma initiated within 2 days of eligibility. Thirty-day mortality was compared using cumulative incidence curves, risk differences, and hazard ratios estimated from pooled logistic models with inverse probability weighting to adjust for confounding. RESULTS: Of 11 269 eligible person-trials contributed by 4755 patients, 402 trials were assigned to the convalescent plasma group. Forty and 671 deaths occurred within the plasma and nonplasma groups, respectively. The estimated 30-day mortality risk was 6.5% (95% confidence interval [CI], 4.0%-9.7%) in the plasma group and 6.2% (95% CI, 5.6%-7.0%) in the nonplasma group. The associated risk difference was 0.30% (95% CI, -2.30% to 3.60%) and the hazard ratio was 1.04 (95% CI, .64-1.62). CONCLUSIONS: Our target trial emulation estimated no meaningful differences in 30-day mortality between nonsevere COVID-19 patients treated and untreated with convalescent plasma. Clinical Trials Registration. NCT04545047.

Pharmacoepidemiology, Machine Learning, and COVID-19: An Intent-to-Treat Analysis of Hydroxychloroquine, With or Without Azithromycin, and COVID-19 Outcomes Among Hospitalized US Veterans.

Hydroxychloroquine (HCQ) was proposed as an early therapy for coronavirus disease 2019 (COVID-19) after in vitro studies indicated possible benefit. Previous in vivo observational studies have presented conflicting results, though recent randomized clinical trials have reported no benefit from HCQ among patients hospitalized with COVID-19. We examined the effects of HCQ alone and in combination with azithromycin in a hospitalized population of US veterans with COVID-19, using a propensity score-adjusted survival analysis with imputation of missing data. According to electronic health record data from the US Department of Veterans Affairs health care system, 64,055 US Veterans were tested for the virus that causes COVID-19 between March 1, 2020 and April 30, 2020. Of the 7,193 veterans who tested positive, 2,809 were hospitalized, and 657 individuals were prescribed HCQ within the first 48-hours of hospitalization for the treatment of COVID-19. There was no apparent benefit associated with HCQ receipt, alone or in combination with azithromycin, and there was an increased risk of intubation when HCQ was used in combination with azithromycin (hazard ratio = 1.55; 95% confidence interval: 1.07, 2.24). In conclusion, we assessed the effectiveness of HCQ with or without azithromycin in treatment of patients hospitalized with COVID-19, using a national sample of the US veteran population. Using rigorous study design and analytic methods to reduce confounding and bias, we found no evidence of a survival benefit from the administration of HCQ.

Phenome-wide association of 1809 phenotypes and COVID-19 disease progression in the Veterans Health Administration Million Veteran Program.

BACKGROUND: The risk factors associated with the stages of Coronavirus Disease-2019 (COVID-19) disease progression are not well known. We aim to identify risk factors specific to each state of COVID-19 progression from SARS-CoV-2 infection through death. METHODS AND RESULTS: We included 648,202 participants from the Veteran Affairs Million Veteran Program (2011-). We identified characteristics and 1,809 ICD code-based phenotypes from the electronic health record. We used logistic regression to examine the association of age, sex, body mass index (BMI), race, and prevalent phenotypes to the stages of COVID-19 disease progression: infection, hospitalization, intensive care unit (ICU) admission, and 30-day mortality (separate models for each). Models were adjusted for age, sex, race, ethnicity, number of visit months and ICD codes, state infection rate and controlled for multiple testing using false discovery rate (≤0.1). As of August 10, 2020, 5,929 individuals were SARS-CoV-2 positive and among those, 1,463 (25%) were hospitalized, 579 (10%) were in ICU, and 398 (7%) died. We observed a lower risk in women vs. men for ICU and mortality (Odds Ratio (95% CI): 0.48 (0.30-0.76) and 0.59 (0.31-1.15), respectively) and a higher risk in Black vs. Other race patients for hospitalization and ICU (OR (95%CI): 1.53 (1.32-1.77) and 1.63 (1.32-2.02), respectively). We observed an increased risk of all COVID-19 disease states with older age and BMI ≥35 vs. 20-24 kg/m2. Renal failure, respiratory failure, morbid obesity, acid-base balance disorder, white blood cell diseases, hydronephrosis and bacterial infections were associated with an increased risk of ICU admissions; sepsis, chronic skin ulcers, acid-base balance disorder and acidosis were associated with mortality. CONCLUSIONS: Older age, higher BMI, males and patients with a history of respiratory, kidney, bacterial or metabolic comorbidities experienced greater COVID-19 severity. Future studies to investigate the underlying mechanisms associated with these phenotype clusters and COVID-19 are warranted.

Worsening Renal Function during Index Hospitalization Does Not Predict Prognosis in Heart Failure with Preserved Ejection Fraction Patients.

INTRODUCTION: Worsening renal function (WRF) predicts poor prognosis in patients with left ventricular systolic dysfunction. The effect of WRF in heart failure with preserved ejection fraction (HFpEF) is unclear. OBJECTIVE: The objective of this study was to determine whether WRF during index hospitalization for HFpEF is associated with increased death or readmission for heart failure. METHODS: National Veterans Affairs electronic medical data recorded between January 1, 2002, and December 31, 2014, were screened to identify index hospitalizations for HFpEF using an iterative algorithm. Patients were divided into 3 groups based on changes in serum Cr (sCr) during this admission. WRF was defined as a rise in sCr ≥0.3 mg/dL. Group 1 had no evidence of WRF, group 2 had transient WRF, and group 3 had persistent WRF at the time of discharge. RESULTS: A total of 10,902 patients with index hospitalizations for HFpEF were identified (mean age 72, 97% male). Twenty-nine percent had WRF during this hospital admission, with 48% showing recovery of sCr and 52% with no recovery at discharge. The mortality rate over a mean follow-up duration of 3.26 years was 72%. Compared to group 1, groups 2 and 3 showed no significant difference in risk of death from any cause (hazard ratio [HR] = 0.95 [95% confidence interval [CI]: 0.87, 1.03] and 1.02 [95% CI: 0.93, 1.11], respectively), days hospitalized for any cause (incidence density ratio [IDR] = 1.01 [95% CI: 0.92, 1.11] and 1.01 [95% CI: 0.93, 1.11], respectively), or days hospitalized for heart failure (IDR = 0.94 [95% CI: 0.80, 1.10] and 0.94 [95% CI: 0.81, 1.09], respectively) in analyses adjusted for covariates affecting renal function and outcomes. CONCLUSIONS: While there is a high incidence of WRF during index hospitalizations for HFpEF, WRF is not associated with an increased risk of death or hospitalization. This suggests that WRF alone should not influence decisions regarding heart failure management.

Association of pulse rate with outcomes in heart failure with reduced ejection fraction: a retrospective cohort study.

BACKGROUND: In a real-world setting, the effect of pulse rate measured at the time of diagnosis and serially during follow-up and management, on outcomes in heart failure with reduced ejection fraction (HFrEF), has not been well-studied. Furthermore, how beta-blockade use in a real-world situation modifies this relation between pulse rate and outcomes in HFrEF is not well-known. Hence, we identified a large, national, real-world cohort of HFrEF to examine the association of pulse rate and outcomes. METHODS: Using Veterans Affairs (VA) national electronic health records we identified incident HFrEF cases between 2006 and 2012. We examined the associations of both baseline and serially measured pulse rates, with mortality and days hospitalized per year for heart failure and for any cause, using crude and multivariable Cox proportional hazards and Poisson or negative binomial models, respectively. The exposure was examined as continuous, dichotomous, and categorical. Post-hoc analyses addressed the interaction of pulse rate and beta-blocker target dose. RESULTS: We identified 51,194 incident HFrEF cases (67 ± 12 years, 98% male, 77% white. A significant positive, near linear relationship was observed for both baseline and serially measured pulse rates with all-cause mortality, all-cause hospitalization and heart failure hospitalization after adjusting for covariates including beta-blocker use. Patients who had a pulse rate ≥ 70 bpm in the past 6 months had 36% (95% CI: 31-42%), 25% (95% CI: 19-32%), and 51% (95% CI: 33-72%) increased rates of mortality, all-cause hospitalization, and heart failure hospitalization, respectively, compared to patients with pulse rates < 70 bpm. A minority of subjects (15%) were treated with guideline directed beta blockade ≥50% of recommended target dose, among whom better outcomes were seen compared to those who did not achieve target dose in patients with pulse rates both above and below 70 beats per minute. CONCLUSIONS: High pulse rate, both at the time of diagnosis and during follow-up, is strongly associated with increased risk of adverse outcomes in HFrEF patients, independent of the use of beta-blockers. In a real-world setting, the majority of HFrEF patients do not achieve target dose of beta-blockade; greater use of strategies to reduce heart rate may improve outcomes in HFrEF.

Serial sodium values and adverse outcomes in heart failure with preserved ejection fraction.

OBJECTIVE: The purpose of our study is to examine whether serial measurements of serum sodium values after diagnosis identify a higher-risk subset of patients with heart failure with preserved ejection fraction. METHODS: We identified 50,932 subjects with HFpEF with 759,577 recorded sNa measurements (mean age 72 ±â€¯11 years) using a validated algorithm in the VA national database from 2002 to 2012. We examined the association of repeated measures of sNa with mortality using a multivariable Cox proportional hazards model. RESULTS: After a median follow-up of 2.9 years (IQR: 1.2-5.4), 19,011 deaths occurred. After adjusting for age, sex, race, BMI, glomerular filtration rate, potassium, coronary artery disease, hypertension, hyperlipidemia, atrial fibrillation, pulmonary disease, diabetes, anemia, and medications, we found J-shaped associations of serum sodium with mortality. HRs for all-cause mortality were 2.48 (95% CI: 2.38-2.60) for the sNA 115.00-133.99 category; and 1.40 (95% CI: 1.35-1.46) for the sNA 143.00-175.00 category compared to the 137.01-140.99 category (ref). We used generalized estimating equation-based negative binomial regression to compute the incidence density ratios (IDR) to examine days hospitalized for heart failure and for all causes. There were a total of 1,275,614 days of all-cause hospitalization and 104,006 days of heart-failure hospitalization. The IDRs for the lowest sNA group were 2.03 (95% CI: 1.90-2.18) for all-cause hospitalization and 1.73 (95% CI: 1.39-2.16) for heart-failure hospitalization. CONCLUSIONS: Our findings suggest that monitoring of serum sodium values during longitudinal follow-up can identify HFpEF patients at risk of adverse outcomes.

Relationship between intra-operative vein graft treatment with DuraGraft® or saline and clinical outcomes after coronary artery bypass grafting.

BACKGROUND: Saphenous vein grafts (SVGs) remain the most often used conduits for coronary bypass grafting (CABG). Progressive intimal hyperplasia contributes to vein-graft disease and vein-graft failure (VGF). We compared the impact of intraoperative preservation of SVGs in a storage solution (DuraGraft®) versus heparinized saline on VGF-related outcomes after CABG. METHODS: From 1996 to 2004, 2436 patients underwent isolated CABG with ≥ 1 SVG. SVGs were consecutively treated with DuraGraft in 1036 patients (2001-2004) and heparinized saline in 1400 patients (1996-1999). Short- (< 30 days) and long-term (≥ 1000 days) outcomes were assessed using repeat revascularization (primary end point), and major adverse cardiac events (MACE) consisting of the composite of death, nonfatal myocardial infarction, or repeat revascularization. RESULTS: Mean follow-up in the DuraGraft group was 8.5 ± 4.2 years and 9.9 ± 5.6 years in controls. Short-term event rates were low and generally did not differ between groups. DuraGraft was associated with a 45% lower occurrence of nonfatal myocardial infarction after 1000 days (hazard ratio 0.55, 95% CI 0.41-0.74; P < 0.0001). There was 35% and 19% lower long-term risk for revascularization (HR 0.65, 95% CI 0.44-0.97; P = 0.037) and MACE (HR 0.81, 95% CI 0.70-0.94; P = 0.0051), respectively, after DuraGraft. Mortality was comparable between both groups at 1, 5, and 10 years. There was no statistically significant association between DuraGraft exposure and time to death starting at 30 or 1000 days (HR 0.91, 95% CI 0.76-1.09; P = 0.29). CONCLUSION: In this study, intraoperative treatment of SVGs with DuraGraft was associated with a lower risk of long-term adverse events suggesting that efficient intraoperative SVG treatment may reduce VGF-related complications post-CABG. These data warrant randomized clinical trials to validate these findings.

Prognostic Significance of Baseline Serum Sodium in Heart Failure With Preserved Ejection Fraction.

BACKGROUND: The purpose of this study was to evaluate the relationship between serum sodium at the time of diagnosis and long term clinical outcomes in a large national cohort of patients with heart failure with preserved ejection fraction. METHODS AND RESULTS: We studied 25 440 patients with heart failure with preserved ejection fraction treated at Veterans Affairs medical centers across the United States between 2002 and 2012. Serum sodium at the time of heart failure diagnosis was analyzed as a continuous variable and in categories as follows: low (115.00-134.99 mmol/L), low-normal (135.00-137.99 mmol/L), referent group (138.00-140.99 mmol/L), high normal (141.00-143.99 mmol/L), and high (144.00-160.00 mmol/L). Multivariable Cox regression and negative binomial regression were performed to estimate hazard ratios (95% confidence interval [CI]) and incidence density ratios (95% CI) for the associations of serum sodium with mortality and hospitalizations (heart failure and all-cause), respectively. The average age of patients was 70.8 years, 96.2% were male, and 14% were black. Compared with the referent group, low, low-normal, and high sodium values were associated with 36% (95% CI, 28%-44%), 6% (95% CI, 1%-12%), and 9% (95% CI, 1%-17%) higher risk of all-cause mortality, respectively. Low and low-normal serum sodium were associated with 48% (95% CI, 10%-100%) and 38% (95% CI, 8%-77%) higher risk of number of days of heart failure hospitalizations per year, and with 44% (95% CI, 32%-56%) and 18% (95% CI, 10%-27%) higher risk of number of days of all-cause hospitalizations per year, respectively. CONCLUSIONS: Both elevated and reduced serum sodium, including values currently considered within normal range, are associated with adverse outcomes in patients with heart failure with preserved ejection fraction.

Development and validation of a heart failure with preserved ejection fraction cohort using electronic medical records.

BACKGROUND: Heart failure (HF) with preserved ejection fraction (HFpEF) comprises nearly half of prevalent HF, yet is challenging to curate in a large database of electronic medical records (EMR) since it requires both accurate HF diagnosis and left ventricular ejection fraction (EF) values to be consistently ≥50%. METHODS: We used the national Veterans Affairs EMR to curate a cohort of HFpEF patients from 2002 to 2014. EF values were extracted from clinical documents utilizing natural language processing and an iterative approach was used to refine the algorithm for verification of clinical HFpEF. The final algorithm utilized the following inclusion criteria: any International Classification of Diseases-9 (ICD-9) code of HF (428.xx); all recorded EF ≥50%; and either B-type natriuretic peptide (BNP) or aminoterminal pro-BNP (NT-proBNP) values recorded OR diuretic use within one month of diagnosis of HF. Validation of the algorithm was performed by 3 independent reviewers doing manual chart review of 100 HFpEF cases and 100 controls. RESULTS: We established a HFpEF cohort of 80,248 patients (out of a total 1,155,376 patients with the ICD-9 diagnosis of HF). Mean age was 72 years; 96% were males and 12% were African-Americans. Validation analysis of the HFpEF algorithm had a sensitivity of 88%, specificity of 96%, positive predictive value of 96%, and a negative predictive value of 87% to identify HFpEF cases. CONCLUSION: We developed a sensitive, highly specific algorithm for detecting HFpEF in a large national database. This approach may be applicable to other large EMR databases to identify HFpEF patients.

A Team-Based Online Game Improves Blood Glucose Control in Veterans With Type 2 Diabetes: A Randomized Controlled Trial.

OBJECTIVE: Rigorous evidence is lacking whether online games can improve patients' longer-term health outcomes. We investigated whether an online team-based game delivering diabetes self-management education (DSME) to patients via e-mail or mobile application (app) can generate longer-term improvements in hemoglobin A1c (HbA1c). RESEARCH DESIGN AND METHODS: Patients (n = 456) on oral diabetes medications with HbA1c ≥58 mmol/mol were randomly assigned between a DSME game (with a civics booklet) and a civics game (with a DSME booklet). The 6-month games sent two questions twice weekly via e-mail or mobile app. Participants accrued points based on performance, with scores posted on leaderboards. Winning teams and individuals received modest financial rewards. Our primary outcome measure was HbA1c change over 12 months. RESULTS: DSME game patients had significantly greater HbA1c reductions over 12 months than civics game patients (-8 mmol/mol [95% CI -10 to -7] and -5 mmol/mol [95% CI -7 to -3], respectively; P = 0.048). HbA1c reductions were greater among patients with baseline HbA1c >75 mmol/mol: -16 mmol/mol [95% CI -21 to -12] and -9 mmol/mol [95% CI -14 to -5] for DSME and civics game patients, respectively; P = 0.031. CONCLUSIONS: Patients with diabetes who were randomized to an online game delivering DSME demonstrated sustained and meaningful HbA1c improvements. Among patients with poorly controlled diabetes, the DSME game reduced HbA1c by a magnitude comparable to starting a new diabetes medication. Online games may be a scalable approach to improve outcomes among geographically dispersed patients with diabetes and other chronic diseases.

Epidural Steroid Injections for Radiculopathy and/or Back Pain in Children and Adolescents: A Retrospective Cohort Study With a Prospective Follow-Up.

BACKGROUND AND OBJECTIVES: Epidural steroid injections (ESIs) are commonly performed for adults with spinal pain and/or radiculopathy. Previous pediatric ESI case series were not identified by literature review. The primary aim of this study was to examine the safety and provisional outcomes of pediatric ESIs. METHODS: With institutional review board approval, medical records were reviewed for patients aged 9 to 20 years receiving a first ESI at Boston Children's Hospital from 2003 through 2013. A subset of patients completed a Web-based follow-up questionnaire. Descriptive statistics included frequencies, medians, interquartile ranges, and Kaplan-Meier methods. Statistical comparisons were made using Wilcoxon rank sum, χ2, Fisher exact, and Cox proportional hazards regression analyses. RESULTS: A total of 224 patients aged 9 to 20 years underwent 428 ESIs. One hundred seventy-four (76.0%) patients had a lumbar disc herniation with radiculopathy; the others had a spectrum of other spinal disorders. There were no serious adverse events, hospitalizations, dural punctures, or nerve injuries. During follow-up, 69 (41.6%) of 166 previously nonoperated lumbar disc plus radiculopathy patients underwent discectomy at a median time of 128 days (interquartile range, 76-235 days) after first injection. Degrees of straight-leg raising at presentation was significantly associated with subsequent discectomy. On follow-up, patients who did and did not undergo discectomy had low pain scores and high function scores. CONCLUSIONS: Children and adolescents can receive ESIs under conscious sedation with good safety. Further prospective studies may better define the role for these injections in the comprehensive management of pediatric spinal pain disorders.

Neosaxitoxin in Rat Sciatic Block: Improved Therapeutic Index Using Combinations with Bupivacaine, with and without Epinephrine.

BACKGROUND: Neosaxitoxin (NeoSTX) is a site-1 sodium channel blocker undergoing clinical trials as a prolonged-duration local anesthetic. Rat sciatic block and intravenous infusion models were used to assess efficacy and local and systemic toxicities for NeoSTX in saline (NeoSTX-Saline), bupivacaine (Bup), and their combination (NeoSTX-Bup). Exploratory studies evaluated the effects of addition of epinephrine to NeoSTX-Bup (NeoSTX-Bup-Epi). METHODS: Rats received percutaneous sciatic blocks with escalating doses of NeoSTX-Saline or NeoSTX-Bup. Sensory-nocifensive block was assessed using modified hotplate and Von Frey filaments. Motor-proprioceptive function was assessed by extensor postural thrust. Nerves were examined histologically after 7 days and scored on the Estebe-Myers scale. Median lethal dose was estimated for NeoSTX-Saline and in combinations. Accidental intravenous overdose was simulated in isoflurane-anesthetized, spontaneously breathing rats receiving NeoSTX-Saline (n = 6), Bup (n = 7), or NeoSTX-Bup (n = 13), with respiratory, hemodynamic, and electrocardiographic endpoints. Additional groups received blocks with NeoSTX-Bup-Epi (n = 80). Investigators were blinded for behavioral and histologic studies. RESULTS: NeoSTX-Bup produced more prolonged sensory and motor block compared with NeoSTX-Saline or Bup. NeoSTX-Bup-Epi further prolonged median time to near-complete recovery for 3 µg/kg NeoSTX-Bup (hotplate: 48 vs. 6 h, P < 0.001). With sciatic injections, addition of Bup did not worsen the systemic toxicity (median lethal dose) compared with NeoSTX-Saline. Intravenous NeoSTX-Saline infusion had significantly longer times to apnea, first arrhythmia, and asystole compared with Bup (P < 0.001 for each). Histologic injury scores overall were low for all groups, with median scores of 0 (interquartile range, 0 to 0) on a 5-point scale. CONCLUSION: NeoSTX-Bup and NeoSTX-Bup-Epi hold promise for prolonged-duration local anesthesia.

A Phase 1, Dose-escalation, Double-blind, Block-randomized, Controlled Trial of Safety and Efficacy of Neosaxitoxin Alone and in Combination with 0.2% Bupivacaine, with and without Epinephrine, for Cutaneous Anesthesia.

BACKGROUND: Neosaxitoxin (NeoSTX) is a site-1 sodium channel blocker that produces prolonged local anesthesia in animals and humans. Under a Food and Drug Administration-approved phase 1 Investigational New Drug trial, the authors evaluated safety and efficacy of NeoSTX alone and combined with 0.2% bupivacaine (Bup) with and without epinephrine. METHODS: The authors conducted a double-blind, randomized, controlled trial involving healthy male volunteers aged 18 to 35 yr receiving two 10-ml subcutaneous injections. Control sites received Bup. In part 1, active sites received (1) 5 to 40 µg NeoSTX+Saline (NeoSTX-Saline), (2) 5 to 40 µg NeoSTX+Bup (NeoSTX-Bup), or (3) placebo (Saline). In part 2, active sites received 10 or 30 µg NeoSTX+Bup+Epinephrine (NeoSTX-Bup-Epi) or placebo. Primary outcome measures were safety and adverse events associated with NeoSTX. Secondary outcomes included clinical biochemistry, NeoSTX pharmacokinetics, and cutaneous hypoesthesia. RESULTS: A total of 84 subjects were randomized and completed the two-part trial with no serious adverse events or clinically significant physiologic impairments. Perioral numbness and tingling increased with NeoSTX dose for NeoSTX-Saline and NeoSTX-Bup. All symptoms resolved without intervention. NeoSTX-Bup-Epi dramatically reduced symptoms compared with other NeoSTX combinations (tingling: 0 vs. 70%, P = 0.004; numbness: 0 vs. 60%, P = 0.013) at the same dose. Mean peak plasma NeoSTX concentration for NeoSTX-Bup-Epi was reduced at least two-fold compared with NeoSTX-Saline and NeoSTX-Bup (67 ± 14, 134 ± 63, and 164 ± 81 pg/ml, respectively; P = 0.016). NeoSTX-Bup showed prolonged cutaneous block duration compared with Bup, NeoSTX-Saline, or placebo, at all doses. Median time to near-complete recovery for 10 µg NeoSTX-Bup-Epi was almost five-fold longer compared with Bup (50 vs. 10 h, P = 0.007). CONCLUSION: NeoSTX combinations have a tolerable side effect profile and appear promising for prolonged local anesthesia.

Thyroid hormone regulates hepatic expression of fibroblast growth factor 21 in a PPARalpha-dependent manner.

Thyroid hormone has profound and diverse effects on liver metabolism. Here we show that tri-iodothyronine (T3) treatment in mice acutely and specifically induces hepatic expression of the metabolic regulator fibroblast growth factor 21 (FGF21). Mice treated with T3 showed a dose-dependent increase in hepatic FGF21 expression with significant induction at doses as low as 100 microg/kg. Time course studies determined that induction is seen as early as 4 h after treatment with a further increase in expression at 6 h after injection. As FGF21 expression is downstream of the nuclear receptor peroxisome proliferator-activated receptor alpha (PPARalpha), we treated PPARalpha knock-out mice with T3 and found no increase in expression, indicating that hepatic regulation of FGF21 by T3 in liver is via a PPARalpha-dependent mechanism. In contrast, in white adipose tissue, FGF21 expression was suppressed by T3 treatment, with other T3 targets unaffected. In cell culture studies with an FGF21 reporter construct, we determined that three transcription factors are required for induction of FGF21 expression: thyroid hormone receptor beta (TRbeta), retinoid X receptor (RXR), and PPARalpha. These findings indicate a novel regulatory pathway whereby T3 positively regulates hepatic FGF21 expression, presenting a novel therapeutic target for diseases such as non-alcoholic fatty liver disease.