USP3 plays a critical role in the induction of innate immune tolerance.

Microbial products, such as lipopolysaccharide (LPS), can elicit efficient innate immune responses against invading pathogens. However, priming with LPS can induce a form of innate immune memory, termed innate immune "tolerance", which blunts subsequent NF-κB signaling. Although epigenetic and transcriptional reprogramming has been shown to play a role in innate immune memory, the involvement of post-translational regulation remains unclear. Here, we report that ubiquitin-specific protease 3 (USP3) participates in establishing "tolerance" innate immune memory through non-transcriptional feedback. Upon NF-κB signaling activation, USP3 is stabilized and exits the nucleus. The cytoplasmic USP3 specifically removes the K63-linked polyubiquitin chains on MyD88, thus negatively regulating TLR/IL1ß-induced inflammatory signaling activation. Importantly, cytoplasmic translocation is a prerequisite step for USP3 to deubiquitinate MyD88. Additionally, LPS priming could induce cytoplasmic retention and faster and stronger cytoplasmic translocation of USP3, enabling it to quickly shut down NF-κB signaling upon the second LPS challenge. This work identifies a previously unrecognized post-translational feedback loop in the MyD88-USP3 axis, which is critical for inducing normal "tolerance" innate immune memory.

Prescription drug monitoring programs and prescription pain medication misuse among U.S. high school students-2019.

BACKGROUND: Prescription drug monitoring programs (PDMPs) are state-level databases that track and inform prescribing practices to reduce prescription drug diversion and misuse. To our knowledge, only three studies have examined the impact of PDMPs on opioid-related outcomes among adolescents, and none have focused on prescription pain medication misuse among adolescents. METHODS: This study leveraged data from the 2019 National Youth Risk Behavior Survey (YRBS) to explore the associations between five categories of PDMP dimensions and the prevalence of self-reported prescription pain medication misuse. Demographic factors' associations with self-reported prescription pain medication misuse were also examined. RESULTS: In 2019, none of the PDMP dimensions were associated with self-reported prescription pain medication misuse among U.S. high school students, adjusting for gender, grade, race/ethnicity, and sexual orientation. CONCLUSIONS: None of the five PDMP dimensions were associated with lower prescription pain medication misuse, however further research is needed, especially as new YRBS data become available.

Associations between Adolescent Marijuana Use, Driving after Marijuana Use and Recreational Retail Sale in Colorado, USA.

OBJECTIVE: We investigated associations between the retail distribution of recreational marijuana in Colorado and (i) past 30-day marijuana use and (ii) driving after marijuana use (DAMU) among a representative sample of public high school students using four waves of data from a state surveillance system. METHODS: Past 30-day marijuana use was assessed among all sampled students (n = 85,336). DAMU was assessed among students 15 years or older who indicated driving (n = 47,518). Modified Poisson regression with robust variance estimates was used to estimate prevalence ratios (PR) comparing the pre-distribution (2013) and post-distribution (2015, 2017, 2019) periods for marijuana-related behaviors. Frequency of behavioral engagement was assessed using a multinomial approach. RESULTS: An estimated 20.3% of students engaged in past 30-day marijuana use and 10.5% of student drivers engaged in DAMU. Retail distribution of recreational marijuana was not significantly associated with the prevalence of any marijuana use or DAMU. However, it was associated with 1.16 (95% CI: 1.04-1.29) times the prevalence of using marijuana one or two times in the last 30 days, 1.27 (1.03, 1.55) times the prevalence of DAMU one time, and 0.82 (0.69, 0.98) times the prevalence of DAMU six or more times. No significant associations were observed for the remaining frequency categories. CONCLUSIONS: Approximately 1 in 10 students who drive reported DAMU. Varying prevalence in the frequency of past 30-day marijuana use and DAMU was observed following the retail distribution of recreational marijuana in Colorado. Care should be taken to properly educate adolescent drivers regarding the dangers of DAMU.

Nanomedicine targets iron metabolism for cancer therapy.

Iron is an essential element for cell proliferation and homeostasis by engaging in cell metabolism including DNA synthesis, cell cycle, and redox cycling; however, iron overload could contribute to tumor initiation, proliferation, metastasis, and angiogenesis. Therefore, manipulating iron metabolisms, such as using iron chelators, transferrin receptor 1 (TFR1) Abs, and cytotoxic ligands conjugated to transferrin, has become a considerable strategy for cancer therapy. However, there remain major limitations for potential translation to the clinic based on the regulation of iron metabolism in cancer treatment. Nanotechnology has made great advances for cancer treatment by improving the therapeutic potential and lowering the side-effects of the proved drugs and those under various stages of development. Early studies that combined nanotechnology with therapeutic means for the regulation of iron metabolism have shown certain promise for developing specific treatment options based on the intervention of cancer iron acquisition, transportation, and utilization. In this review, we summarize the current understanding of iron metabolism involved in cancer and review the recent advances in iron-regulatory nanotherapeutics for improved cancer therapy. We also envision the future development of nanotherapeutics for improved treatment for certain types of cancers.

Antidepressant exposures associated with exploratory behavior among young children reported to United States poison control centers, 2000-2020.

PURPOSE: This study investigates characteristics and trends of antidepressant exposures among children <6 years old related to exploratory behavior reported to US poison control centers. METHODS: Using data from the National Poison Data System for 2000-2020, population-based annual exposure rates by sex, antidepressant category, serious medical outcome, and health care facility admission were analyzed and odds ratios to assess associations of exposure type and antidepressant category with medical outcome and admission were calculated. RESULTS: There were 215 909 first-ranked unintentional exploratory exposures involving antidepressants among children <6 years old during the study period, averaging 10 281 annually. Most cases were <3 years old (77.8%), involved a single substance (86.9%), and did not receive treatment at a health care facility (57.6%); however, 7.9% were admitted and 3.4% had serious medical outcomes, including 13 deaths. SSRIs were involved in 56.9% of all cases. Compared with SSRIs, bupropion (OR: 5.22, 95% CI: 4.68-5.82), TCAs (OR: 3.74, 95% CI: 3.44-4.07), SNRIs (OR: 2.39, 95% CI: 2.11-2.71), and lithium salts (OR: 2.00, 95% CI: 1.63-2.46) were more likely to be associated with a serious medical outcome. TCAs were the first-ranked substance in 7 of the 13 deaths. CONCLUSIONS: Although most unintentional antidepressant exposures related to pediatric exploratory behavior were inconsequential, an important minority of cases required admission to a HCF or had a serious medical outcome, including 13 deaths. Therefore, increased efforts to prevent these exposures among young children are needed, including public education and improved medication packaging.

Motor vehicle-related electric scooter injuries in the US: A descriptive analysis of NEISS data.

INTRODUCTION: The introduction of scooter-share programs across the United States has led to an increased incidence of electronic scooter (e-scooter) injuries presenting to emergency departments (EDs). As legislation begins to push scooters from the sidewalk to the street, injuries resulting from collisions between e-scooters and motor vehicles are an important, but poorly characterized consideration. This study leverages data from a national injury surveillance system to characterize e-scooter versus motor vehicle collisions resulting in ED presentation. METHODS: This study utilizes data from the National Electronic Injury Surveillance System (NEISS). NEISS was queried for e-scooter-related injuries from January 1st, 2015 through December 31st, 2019. Injuries were characterized as motor vehicle-related (MV-involved) or non-motor-vehicle-related (MV-uninvolved) based on a manual review by the study investigators. Weighted tabular analyses were used to characterize both types of e-scooter injuries across demographic, diagnostic, and event-related factors. RESULTS: Over the study period an estimated 60,554 (95% CI: 37,525-84,594) injuries were treated in US EDs. Approximately 19% of these injuries involved motor vehicles. Those sustaining MV-involved injuries were significantly younger (p = 0.01), with a higher proportion of males injured (p = 0.01). Additionally, when compared to MV-uninvolved injuries, a significantly higher proportion of those with MV-involved injuries were admitted to the hospital for treatment (8.8% vs. 14.6%, p < 0.01). MV-involved injuries occurred primarily in the street (96.3%), while MV-uninvolved injuries were split across streets (44.0%), at one's home (~20%), and on public property (~20%) (p < 0.01). CONCLUSIONS: Electric scooter injuries involving a motor vehicle differed from those that did not across several key categories. As e-scooters and motor vehicles start to share the road more frequently, greater consideration should be made regarding how these two modes of transportation interact with each other. The promotion of thoughtful e-scooter legislation and infrastructure changes could help promote safer travel.

Bans on Cellphone Use While Driving and Traffic Fatalities in the United States.

BACKGROUND: As of January 2020, 18 of 50 US states comprehensively banned almost all handheld cellphone use while driving, 3 states and the District of Columbia banned calling and texting, 27 states banned texting on a handheld cellphone, and 2 states had no general cellphone ban for all drivers. However, it remains unknown whether these bans were associated with fewer traffic deaths and whether comprehensive handheld bans are more effective than isolated calling or texting bans. We evaluated whether cellphone bans were associated with fewer driver, non-driver, and total fatalities nationally. METHODS: We conducted a longitudinal panel analysis of traffic fatality rates by state, year, and quarter. Population-based rate ratios and 95% CIs were estimated comparing state-quarters with and without cellphone bans. RESULTS: From 1999 through 2016, 616,289 persons including 344,003 drivers died in passenger vehicle crashes in the United States. Relative to no ban, comprehensive handheld bans were associated with lower driver fatality rates (adjusted rate ratio aRR = 0.93, 95% CI = 0.90, 0.97) but not for non-driver fatalities (aRR = 1.01, 95% CI = 0.95, 1.07) or total fatalities (aRR = 0.98, 95% CI = 0.94, 1.01). We found no differences in driver fatalities for calling-only bans (aRR = 1.00, 95% CI = 0.97, 1.03), texting-only bans (aRR = 1.02, 95% CI = 0.99, 1.05), texting plus phone-manipulating bans (aRR = 0.99, 95% CI = 0.93, 1.04), or calling and texting bans (aRR = 0.98, 95% CI = 0.88, 1.09). CONCLUSIONS: Comprehensive handheld bans were associated with fewer driver fatalities.

A cross-sectional study of characteristics of bicyclist upper and lower extremity injuries in bicycle-vehicle crashes in Ohio, United States, 2013-2017.

BACKGROUND: Extremity injury is one of the most common injury types for bicyclists. Extremity injury can lead to long-term disability and contribute to adverse health-related quality of life and prolonged absence from work. OBJECTIVES: The objectives of our study were to identify crash factors associated with bicyclist upper and lower extremity injury and characterize type of extremity injury by bicyclist age category. METHODS: We linked the 2013-2017 Ohio police accident report and hospital databases. The logistic regression model was used to model the odds of sustaining upper or lower extremity injury among bicyclists involved in bicycle-vehicle crashes. Bicyclist upper and lower extremity injury were further described by the detailed injured body regions (e.g., forearm and elbow or lower leg) and the nature of injury (e.g., superficial or fracture). RESULTS: Bicyclists 65 years or older had higher odds (odds ratio [OR] = 1.46, 95% confidence interval [CI]: 1.03-2.08) of sustaining upper extremity injury, bicyclists aged 3-14 years (OR = 1.34, 95% CI: 1.09-1.66) and 15-24 years (OR = 1.24, 95% CI: 1.03-1.49) had higher odds of sustaining lower extremity injury, compared to bicyclists 25-44 years old. In addition, colder weather, bicyclist sex, and intersection-related crashes were associated with bicyclists' odds of sustaining upper or lower extremity injury. Compared to individuals under 65 years old, bicyclists 65 years or older had a higher percentage of injury to the wrist, hand and finger, or knee. Bicyclists aged 65 years or older also had a higher percentage of fractures. CONCLUSIONS: Our study has identified important factors that were associated with bicyclists' odds of sustaining an extremity injury. Based on these findings, targeted educational efforts and interventions can be implemented to prevent bicyclists from these injuries.

Support for distracted driving laws: An analysis of adolescent drivers from the Traffic Safety Culture Index from 2011 to 2017.

INTRODUCTION: Adolescent drivers are often the focus of traffic safety legislation as they are at increased risk for crash-related injury and death. However, the degree to which adolescents support distracted driving laws and factors contributing to their support are relatively unknown. Using a large, nationally weighted sample of adolescent drivers in the United States, we assessed if perceived threat from other road users' engagement in distracted driving, personal engagement in distracted driving behaviors, and the presence of state distracted driving laws was associated with support for distracted driving laws. METHODS: The sample included 3565 adolescents (aged 16-18) who participated in the Traffic Safety Culture Index survey from 2011 to 2017. A modified Poisson regression model with robust errors was fit to the weighted data to examine support for distracted driving laws. Models included age, gender, year, state distracted driving laws, personal engagement in distracted driving behavior, and perceived threat from other road users' engaging in distracted driving. RESULTS: Approximately 87% of adolescents supported a law against texting and emailing compared to 66% who supported a universal handheld cellphone law. Support for distracted driving legislation was associated with greater perceived threat of other road users engaging in distracted driving while accounting for personal engagement in distracted driving, state distracted driving laws, and developmental covariates. DISCUSSION: Greater understanding of the factors behind legislative support is needed. Public health interventions focused on effectively translating the risks of cellphone use while driving and effective policy will further improve the traffic safety culture.

Road traffic injury mortality and morbidity by country development status, 2011-2017.

PURPOSE: This research examined road traffic injury mortality and morbidity disparities across of country development status, and discussed the possibility of reducing country disparities by various actions to accelerate the pace of achieving Sustainable Development Goals target 3.6 - to halve the number of global deaths and injuries from road traffic accidents by 2020. METHODS: Data for road traffic mortality, morbidity, and socio-demographic index (SDI) were extracted by country from the estimates of the Global Burden of Disease study, and the implementation of the three types of national actions (legislation, prioritized vehicle safety standards, and trauma-related post-crash care service) were extracted from the Global Status Report on Road Safety by World Health Organization. We fitted joinpoint regression analysis to identify and quantify the significant rate changes from 2011 to 2017. RESULTS: Age-adjusted road traffic mortality decreased substantially for all the five SDI categories from 2011 to 2017 (by 7.52%-16.08%). Age-adjusted road traffic mortality decreased significantly as SDI increased in the study time period, while age-adjusted morbidity generally increased as SDI increased. Subgroup analysis by road user yielded similar results, but with two major differences during the study period of 2011 to 2017: (1) pedestrians in the high SDI countries experienced the lowest mortality (1.68-1.90 per 100,000 population) and morbidity (110.45-112.72 per 100,000 population for incidence and 487.48-491.24 per 100,000 population for prevalence), and (2) motor vehicle occupants in the high SDI countries had the lowest mortality (4.07-4.50 per 100,000 population) but the highest morbidity (428.74-467.78 per 100,000 population for incidence and 1025.70-1116.60 per 100,000 population for prevalence). Implementation of the three types of national actions remained nearly unchanged in all five SDI categories from 2011 to 2017 and was consistently stronger in the higher SDI countries than in the lower SDI countries. Lower income nations comprise the heaviest burden of global road traffic injuries and deaths. CONCLUSION: Global road traffic deaths would decrease substantially if the large mortality disparities across country development status were reduced through full implementation of proven national actions including legislation and law enforcement, prioritized vehicle safety standards and trauma-related post-crash care services.

Suicide-related over-the-counter analgesic exposures reported to United States poison control centers, 2000-2018.

PURPOSE: To investigate suicide-related over-the-counter (OTC) analgesic medication exposures among individuals ≥6 years old reported to United States (US) poison control centers. METHODS: Data from the National Poison Data System for the years 2000-2018 were retrospectively analyzed. RESULTS: From 2000 to 2018, US poison control centers recorded 549 807 suicide-related cases involving OTC analgesics, including 327 781 cases (59.6%) admitted to the hospital and 1745 deaths (0.3%). Most cases involved a single substance (67.5%) and occurred among females (72.7%) and individuals 6-19 years old (49.7%). Overall, the rate of exposures increased significantly by 33.5% from 2000 to 2018, primarily driven by the increasing exposure rate among 6- to 19-year-old females. From 2000 to 2018, exposure rates for acetaminophen and ibuprofen increased, while that for acetylsalicylic acid decreased. Additionally, the proportion of cases resulting in a serious medical outcome or healthcare facility admission increased for all types of OTC analgesics. Acetaminophen and acetylsalicylic acid accounted for 48.0% and 18.5% of cases, respectively, and 64.5% and 32.6% of deaths, respectively. Both acetaminophen and acetylsalicylic acid had greater odds of healthcare facility admission (ORs 2.56 and 2.63, respectively) and serious medical outcomes (ORs 2.54 and 4.90, respectively) compared with ibuprofen. CONCLUSIONS: The rate of suicide-related OTC analgesic cases is increasing. Acetaminophen and acetylsalicylic acid cases are associated with greater morbidity and mortality. Prevention efforts should include implementing unit-dose packaging requirements and restrictions on package sizes and purchase quantities for acetaminophen and acetylsalicylic acid products to reduce access to large quantities of these analgesics.

Changes in reporting for unintentional injury deaths, United States of America.

OBJECTIVE: To quantify how changes in reporting of specific causes of death and of selecting underlying cause from among multiple causes of death contribute to trends in mortality from unintentional injury in Americans aged 65 years or older. METHODS: We extracted age-standardized unintentional injury mortality data in the United States Centers for Disease Control and Prevention online databases from 1999 to 2016. We used an attribution method to calculate two indicators: the proportion of mortality with specific codes out of all mortality; and the proportion of mortality with underlying cause of death selected from multiple causes of death. We conducted a linear regression to examine the changes over time in these proportions and in reported and age-adjusted mortality. FINDINGS: From 1999 through 2016, the proportion of cause-specific unintentional injury mortality in this age group increased from 74% in 1999 (136.9 out of 185.0 per 100 000 population) to 85% in 2016 (143.0 out of 169.1 per 100 000 population) based on multiple causes of death codes. The proportions of mortality with underlying cause of death selected out of multiple causes of death rose in all specific causes of unintentional injury except motor vehicle crash. Age-standardized mortality attributed to reporting changes increased steadily between 1999 and 2016. The increases for overall unintentional injury, fall, motor vehicle crash, suffocation, poisoning and fire or hot object were 24.2, 13.5, 2.1, 2.3, 1.6 and 0.4 deaths per 100 000 persons, respectively. CONCLUSION: Changes in data reporting affect trends in overall and specific unintentional injury mortality over time for older Americans.

Performance of Between-study Heterogeneity Measures in the Cochrane Library.

The growth in comparative effectiveness research and evidence-based medicine has increased attention to systematic reviews and meta-analyses. Meta-analysis synthesizes and contrasts evidence from multiple independent studies to improve statistical efficiency and reduce bias. Assessing heterogeneity is critical for performing a meta-analysis and interpreting results. As a widely used heterogeneity measure, the I statistic quantifies the proportion of total variation across studies that is caused by real differences in effect size. The presence of outlying studies can seriously exaggerate the I statistic. Two alternative heterogeneity measures, the (Equation is included in full-text article.)and (Equation is included in full-text article.)have been recently proposed to reduce the impact of outlying studies. To evaluate these measures' performance empirically, we applied them to 20,599 meta-analyses in the Cochrane Library. We found that the (Equation is included in full-text article.)and (Equation is included in full-text article.)have strong agreement with the I, while they are more robust than the I when outlying studies appear.

Hand-held cell phone use while driving legislation and observed driver behavior among population sub-groups in the United States.

BACKGROUND: Cell phone use behaviors are known to vary across demographic sub-groups and geographic locations. This study examined whether universal hand-held calling while driving bans were associated with lower road-side observed hand-held cell phone conversations across drivers of different ages (16-24, 25-59, ≥60 years), sexes, races (White, African American, or other), ruralities (suburban, rural, or urban), and regions (Northeast, Midwest, South, and West). METHODS: Data from the 2008-2013 National Occupant Protection Use Survey were merged with states' cell phone use while driving legislation. The exposure was presence of a universal hand-held cell phone ban at time of observation. Logistic regression was used to assess the odds of drivers having a hand-held cell phone conversation. Sub-groups differences were assessed using models with interaction terms. RESULTS: When universal hand-held cell phone bans were effective, hand-held cell phone conversations were lower across all driver demographic sub-groups and regions. Sub-group differences existed among the sexes (p-value, <0.0001) and regions (p-value, 0.0003). Compared to states without universal hand-held cell phone bans, the adjusted odds ratio (aOR) of a driver hand-held phone conversation was 0.34 [95% confidence interval (CI): 0.28, 0.41] for females versus 0.47 (CI 0.40, 0.55) for males and 0.31 (CI 0.25, 0.38) for drivers in Western states compared to 0.47 (CI 0.30, 0.72) in the Northeast and 0.50 (CI 0.38, 0.66) in the South. CONCLUSIONS: The presence of universal hand-held cell phone bans were associated lower hand-held cell phone conversations across all driver sub-groups and regions. Hand-held phone conversations were particularly lower among female drivers and those from Western states when these bans were in effect. Public health interventions concerning hand-held cell phone use while driving could reasonably target all drivers.

Traffic Fatalities in West Virginia and the Remaining United States, 2008-2012.

Purpose: Research has shown that Appalachia has a higher traffic fatality rate than the non-Appalachian United States. This study compared traffic fatality rates in West Virginia to the rest of the United States. Methods: Fatality Analysis Reporting System and Census data from 2008-2012 were used to calculate traffic fatality rates. Poisson regression was used to model rate ratios stratified by age, sex, rurality, and transportation type, as well as rate ratios per licensed driver, vehicles registered and miles travelled. Results: The West Virginia traffic fatality rate was 71% higher that the United States. Fatality rates per-capita were elevated for vehicle passengers and drivers of passenger vehicles, and large trucks. In contrast, rates for pedestrians and bicyclists were lower that the rest of the country. Conclusion: Public health intervention and further research are likely needed to discern reasons as to why this disparity exists in West Virginia.

Brief Report: The Association of Graduated Driver Licensing with Nondriver Transport-related Injuries Among Adolescents.

BACKGROUND: As a phased approach to initiating driving, graduated driver licensing restricts driving by young drivers with the aim of reducing crashes. It might increase riding with parents or on buses, which might be safer, or walking or biking, which might be more dangerous. We examined whether it increases nondriver injuries, and whether it reduces total injuries combining drivers and nondrivers. METHODS: We conducted longitudinal analyses of 1995-2012 traffic injuries from 43 states. Using Poisson mixed regression, we estimated adjusted rate ratios for visible, incapacitating, and fatal injury. RESULTS: Among 16 year olds, graduated driver licensing was associated with reduced passenger injuries (adjusted rate ratio 0.93, 95% confidence interval: 0.89, 0.97). It was not associated with increased injuries as bus riders, pedestrians, or bicyclists among 16- or 17-year olds. It was associated with a 10% reduction in total injuries among 16-year olds, but not 17-year olds. CONCLUSION: Graduated driver licensing was associated with reduced passenger injuries and total injuries.

The association between graduated driver licensing laws and travel behaviors among adolescents: an analysis of US National Household Travel Surveys.

BACKGROUND: Young novice drivers have crash rates higher than any other age group. To address this problem, graduated driver licensing (GDL) laws have been implemented in the United States to require an extended learner permit phase, and create night time driving or passenger restrictions for adolescent drivers. GDL allows adolescents to gain experience driving under low-risk conditions with the aim of reducing crashes. The restricted driving might increase riding with parents or on buses, which might be safer, or walking or biking, which might be more dangerous. We examined whether GDL increases non-driver travels, and whether it reduces total travels combining drivers and non-drivers. METHODS: We used data from the US National Household Travel Survey for the years 1995-1996, 2001-2002, and 2008-2009 to estimate the adjusted ratio for the number of trips and trip kilometers made by persons exposed to a GDL law, compared with those not exposed. RESULTS: Adolescents aged 16 years had fewer trips and kilometers as drivers when exposed to a GDL law: ratio 0.84 (95 % confidence interval (CI) 0.71, 1.00) for trips; 0.79 (0.63, 0.98) for kilometers. For adolescents aged 17 years, the trip ratio was 0.94 (0.83, 1.07) and the kilometers ratio 0.80 (0.63, 1.03). There was little association between GDL laws and trips or kilometers traveled by other methods: ratio 1.03 for trips and 1.00 for kilometers for age 16 years, 0.94 for trips and 1.07 for kilometers for age 17. CONCLUSIONS: If these associations are causal, GDL laws reduced driving kilometers by about 20 % for 16 and 17 year olds, and reduced the number of driving trips by 16 % among 16 year olds. GDL laws showed little relationship with trips by other methods.

The association of graduated driver licensing with miles driven and fatal crash rates per miles driven among adolescents.

BACKGROUND: Graduated driver licensing (GDL) laws are associated with reduced crash rates per person-year among adolescents. It is unknown whether adolescents crash less per miles driven or drive less under GDL policies. METHODS: We used data from the US National Household Travel Survey and Fatality Analysis Reporting System for 1995-1996, 2001-2002 and 2008-2009. We compared adolescents subject to GDL laws with those not by estimating adjusted IRRs for being a driver in a crash with a death per person-year (aIRRpy) and per miles driven (aIRRm), and adjusted miles driven ratios (aMR) controlling for changes in rates over time. RESULTS: Comparing persons subject to GDL policies with those not, 16 year olds had fewer fatal crashes per person-year (aIRRpy 0.63, 95% CI 0.47 to 0.91), drove fewer miles (aMR 0.79, 95% CI 0.63 to 0.98) and had lower crash rates per miles driven (aIRRm 0.83, 95% CI 0.65 to 1.06). For age 17, the aIRRpy was 0.83 (95% CI 0.60 to 1.17), the aMR 0.80 (95% CI 0.63 to 1.03) and the aIRRm 1.03 (95% CI 0.80 to 1.35). For age 18, the aIRRpy was 0.93 (95% CI 0.72 to 1.19), the aMR 0.92 (95% CI 0.77 to 1.09) and the aIRRm 1.01 (95% CI 0.84 to 1.23). CONCLUSIONS: If these associations are causal, GDL laws reduced crashes per person-year by about one-third among 16 year olds; half the reduction was due to fewer crashes per miles driven and half to less driving. For ages 17 and 18, there was no evidence of reduced crash rates per miles driven.