Improved markers of prognosis are needed to stratify patients with early-stage colorectal cancer to refine selection of adjuvant therapy. The aim of the present study was to develop a biomarker of ...patient outcome after primary colorectal cancer resection by directly analysing scanned conventional haematoxylin and eosin stained sections using deep learning.
More than 12 000 000 image tiles from patients with a distinctly good or poor disease outcome from four cohorts were used to train a total of ten convolutional neural networks, purpose-built for classifying supersized heterogeneous images. A prognostic biomarker integrating the ten networks was determined using patients with a non-distinct outcome. The marker was tested on 920 patients with slides prepared in the UK, and then independently validated according to a predefined protocol in 1122 patients treated with single-agent capecitabine using slides prepared in Norway. All cohorts included only patients with resectable tumours, and a formalin-fixed, paraffin-embedded tumour tissue block available for analysis. The primary outcome was cancer-specific survival.
828 patients from four cohorts had a distinct outcome and were used as a training cohort to obtain clear ground truth. 1645 patients had a non-distinct outcome and were used for tuning. The biomarker provided a hazard ratio for poor versus good prognosis of 3·84 (95% CI 2·72–5·43; p<0·0001) in the primary analysis of the validation cohort, and 3·04 (2·07–4·47; p<0·0001) after adjusting for established prognostic markers significant in univariable analyses of the same cohort, which were pN stage, pT stage, lymphatic invasion, and venous vascular invasion.
A clinically useful prognostic marker was developed using deep learning allied to digital scanning of conventional haematoxylin and eosin stained tumour tissue sections. The assay has been extensively evaluated in large, independent patient populations, correlates with and outperforms established molecular and morphological prognostic markers, and gives consistent results across tumour and nodal stage. The biomarker stratified stage II and III patients into sufficiently distinct prognostic groups that potentially could be used to guide selection of adjuvant treatment by avoiding therapy in very low risk groups and identifying patients who would benefit from more intensive treatment regimes.
The Research Council of Norway.
There have been few studies of marijuana use before and after recreational marijuana legalization (RML) in affected states. We tested whether marijuana use rates increased more among college students ...in Oregon than in non-RML states following Oregon RML in July 2015. Repeated cross-sectional National College Health Assessment−II surveys were completed by random samples of students within participating colleges from 2008 to 2016. Data were from 4-year institutions that participated both before and after Oregon RML. Undergraduates (ages 18-26 years) from 2 institutions in Oregon (n = 7,412) and 123 institutions (n = 274,340) in non-RML U.S. states self-reported use of marijuana, tobacco, alcohol, and other drugs in the past 30 days. Mixed-effects regressions accounted for clustering of participants within institutions and controlled for individual-, context-, and institution-level factors as well as secular changes in substance use rates from 2008 to 2016. Following RML, Oregon students (compared to non-RML-state students) showed relative increases in rates of marijuana use (odds ratio OR = 1.29, 95% confidence interval CI: 1.13, 1.48, p = .0002, and decreases in tobacco use rates (OR = .71, 95% CI .60, .85, p < .0001). Changes in marijuana use after RML did not differ significantly for participants under and over age 21 years. Some study limitations would be addressed with higher survey response rates, inclusion of other Oregon institutions, and controls for marijuana and other substance policies. Still, findings are consistent with an effect of RML on rates of marijuana use among young adult college students, which may have important public health implications.
Background and Aims
Recreational marijuana legalization (RML) went into effect in Oregon in July 2015. RML is expected to influence marijuana use by adolescents and young adults in particular, and by ...those with a propensity for substance use. We sought to quantify changes in rates of marijuana use among college students in Oregon from pre‐ to post‐RML relative to college students in other states across the same time period.
Design
Repeated cross‐sectional survey data from the 2012–16 administrations of the Healthy Minds Study.
Setting
Seven 4‐year universities in the United States.
Participants
There were 10 924 undergraduate participants. One large public Oregon university participated in 2014 and 2016 (n = 588 and 1115, respectively); six universities in US states where recreational marijuana use was illegal participated both in 2016 and at least once between 2012 and 2015.
Measurements
Self‐reported marijuana use in the past 30 days (yes/no) was regressed on time (pre/post 2015), exposure to RML (i.e. Oregon students in 2016) and covariates using mixed‐effects logistic regression. Moderation of RML effects by recent heavy alcohol use was examined.
Findings
Rates of marijuana use increased from pre‐ to post‐2015 at six of the seven universities, a trend that was significant overall. Increases in rates of marijuana use were significantly greater in Oregon than in comparison institutions, but only among students reporting recent heavy alcohol use.
Conclusions
Rates of Oregon college students’ marijuana use increased (relative to that of students in other states) following recreational marijuana legislation in 2015, but only for those who reported recent heavy use of alcohol. Such alcohol misuse may be a proxy for vulnerabilities to substance use or lack of prohibitions (e.g. cultural) against it.
•Emerging adults may be especially sensitive to recreational marijuana legalization (RML)•Substance use trends from 2008 to 2018 were investigated in a national college sample.•RML was linked to ...decreased binge drinking prevalence among students age 21 and older.•RML was associated with increased sedative misuse among minors.•RML effects are not limited to marijuana use, and depend on substance and age group.
Young adult college students may be particularly sensitive to recreational marijuana legalization (RML). Although evidence indicates the prevalence of marijuana use among college students increased after states instituted RML, there have been few national studies investigating changes in college students’ other substance use post-RML.
The cross-sectional National College Health Assessment-II survey was administered twice yearly from 2008 to 2018 at four-year colleges and universities. Participants were 18–26 year old undergraduates attending college in states that did (n = 243,160) or did not (n = 624,342) implement RML by 2018. Outcome variables were self-reported nicotine use, binge drinking, illicit drug use, and misuse of prescription stimulants, sedatives, and opioids. Other variables included individual and contextual covariates, and institution-reported institutional and community covariates. Publicly available information was used to code state RML status at each survey administration.
Accounting for state differences and time trends, RML was associated with decreased binge drinking prevalence among college students age 21 and older OR (95% CI) = 0.91 (0.87 − 0.95), p < .0001 and increased sedative misuse among minors OR (95% CI) = 1.20 (1.09 − 1.32), p = .0003. RML did not disrupt secular trends in other substance use.
In the context of related research showing national increases in college students’ marijuana use prevalence and relative increases following state RML, we observed decreases in binge drinking and increases in sedative use that both depended on age. Findings support some specificity in RML-related changes in substance use trends and the importance of individual factors.
Summary Background Antiangiogenic agents have established efficacy in the treatment of metastatic colorectal cancer. We investigated whether bevacizumab could improve disease-free survival in the ...adjuvant setting after resection of the primary tumour. Methods For the open-label, randomised, controlled QUASAR 2 trial, which was done at 170 hospitals in seven countries, we recruited patients aged 18 years or older with WHO performance status scores of 0 or 1 who had undergone potentially curative surgery for histologically proven stage III or high-risk stage II colorectal cancer. Patients were randomly assigned (1:1) to receive eight 3-week cycles of oral capecitabine alone (1250 mg/m2 twice daily for 14 days followed by a break for 7 days) or the same regimen of oral capecitabine plus 16 cycles of 7·5 mg/kg bevacizumab by intravenous infusion over 90 min on day 1 of each cycle. Randomisation was done by a computer-generated schedule with use of minimisation with a random element stratified by age, disease stage, tumour site, and country. The study was open label and no-one was masked to treatment assignment. The primary endpoint was 3-year disease-free survival, assessed in the intention-to-treat population. Toxic effects were assessed in patients who received at least one dose of randomised treatment. This trial is registered with the ISRCTN registry, number ISRCTN45133151. Findings Between April 25, 2005, and Oct 12, 2010, 1952 eligible patients were enrolled, of whom 1941 had assessable data (968 in the capecitabine alone group and 973 in the capecitabine and bevacizumab group). Median follow-up was 4·92 years (IQR 4·00–5·16). Disease-free survival at 3 years did not differ between the groups (75·4%, 95% CI 72·5–78·0 in the capecitabine and bevacizumab group vs 78·4%, 75·7–80·9 in the capecitabine alone group; hazard ratio 1·06, 95% CI 0·89–1·25, p=0·54). The most common grade 3–4 adverse events were hand–foot syndrome (201 21% of 963 in the capecitabine alone group vs 257 27% of 959 in the capecitabine and bevacizumab group) and diarrhoea (102 11% vs 104 11%), and, with the addition of bevacizumab, expected increases were recorded in all-grade hypertension (320 33% vs 75 8%), proteinuria (197 21% vs 49 5%), and wound healing problems (30 3% vs 17 2%). 571 serious adverse events were reported (221 with capecitabine alone and 350 with capecitabine and bevacizumab). Most of these were gastrointestinal (n=245) or cardiovascular (n=169). 23 deaths within 6 months of randomisation were classified as being related to treatment, eight in the capecitabine alone group and 15 in the capecitabine and bevacizumab group. Interpretation The addition of bevacizumab to capecitabine in the adjuvant setting for colorectal cancer yielded no benefit in the treatment of an unselected population and should not be used. Funding Roche.
Abstract The consequences in adulthood of bullying, teasing, and other peer victimization experiences in childhood rarely have been considered in prospective studies. Studies of peer victimization ...are mixed regarding whether negative outcomes are explained by pre-existing child vulnerabilities. Furthermore, replication of prior studies with broader definitions and other methods and demographic groups is needed. Based on mother, father, and teacher reports at ages 10–12 years, we classified American boys (n = 206) from higher delinquency neighborhoods as perpetrators of teasing, victims, perpetrator–victims, or uninvolved ( n = 26, 35, 29, and 116, respectively). Family income, parent and child depressive symptoms, and child antisocial behavior served as controls. Boys were assessed to age 34 years for suicide-attempt history (including death) and adult (ages 20–32 years) suicidal ideation, depressive symptoms, alcohol use, patterned tobacco and illicit drug use, and arrest. Relative to uninvolved boys, means or odds were higher for: suicide attempt among perpetrator–victims; all three groups for depressive symptoms and clinically significant symptoms; arrest for perpetrators and perpetrator–victims; number of arrests and violent arrest among perpetrator–victims; and patterned tobacco use among perpetrators and perpetrator–victims. With childhood vulnerabilities controlled, however, odds remained higher only for suicide attempt among perpetrator–victims, and criminal arrest and patterned tobacco use among perpetrators. Overall, childhood involvement in teasing predicted serious adverse outcomes in adulthood, in some cases beyond childhood risks. Programs that prevent peer victimization and identify already involved individuals for additional services may have positive impacts on the diverse public health problems of suicide, crime, depression, and tobacco use.
Six original research papers were submitted to this Special Section to address questions regarding the intergenerational transmission of risk for cannabis and other substance use. Study teams ...recruited youth in Iowa, Washington, Oregon, New York, and Arizona in the 1980s-1990s, assessed them into adulthood, and recruited their partners and offspring for another study. All of the studies assessed substance use in 2 or more generations. Other strengths in this section include the strong representation of fathers, the demographic diversity of the samples as a whole, and the demonstrations of varied statistical and replication approaches. The findings highlight features of parental histories of cannabis use during adolescence that are associated with their children's risk for cannabis use and factors that explain or weaken intergenerational similarities. Two groups of prevention scholars also offered commentaries on the implications of these studies for prevention and training, and collaboration. It is hoped that the Special Section will stimulate new hypotheses, replications, and communication among etiological and prevention researchers. Furthermore, the papers highlight that the familial transmission of substance use risk should be taken into account more fully in the design of prevention programs to maximize impacts for youth as well as their future offspring.
Poor effortful control is a key temperamental factor underlying behavioral problems. The bidirectional association of child effortful control with both positive parenting and negative discipline was ...examined from ages approximately 3 to 13-14 years, involving five time points, and using data from parents and children in the Oregon Youth Study-Three Generational Study (N = 318 children from 150 families). Based on a dynamic developmental systems approach, it was hypothesized that there would be concurrent associations between parenting and child effortful control and bidirectional effects across time from each aspect of parenting to effortful control and from effortful control to each aspect of parenting. It was also hypothesized that associations would be more robust in early childhood, from ages 3 to 7 years, and would diminish as indicated by significantly weaker effects at the older ages, 11-12 to 13-14 years. Longitudinal feedback or mediated effects were also tested. The findings supported (a) stability in each construct over multiple developmental periods; (b) concurrent associations, which were significantly weaker at the older ages;
Preventing adolescent pregnancy is a national research priority that has had limited success. In the present study, the authors examined whether Multidimensional Treatment Foster Care (MTFC) relative ...to intervention services as usual (group care GC) decreased pregnancy rates among juvenile justice girls mandated to out-of-home care. Girls (13-17 years of age) with histories of criminal referrals (
Mdn
= 10) were randomly assigned to MTFC (
n
= 81) or GC (
n
= 85) as part of 2 randomized controlled trials. Pregnancy histories were assessed from baseline through 24 months. Fewer postbaseline pregnancies were reported for MTFC girls (26.9%) than for GC girls (46.9%)-an effect that remained significant after controlling for baseline criminal referrals, pregnancy history, and sexual activity. MTFC has previously been shown to decrease arrest and lock-up rates. The present findings support the long-term preventive effects of MTFC on adolescent girls' pregnancy rates. Findings are consistent with the notion that programs that target delinquency by impacting general risk behavior pathways and contexts may more successfully prevent teen pregnancy than those that directly target sexual behaviors.
We evaluated how applying post-stratification sampling weights to National College Health Assessment II (NCHA-II) data affects estimates of substance use prevalence and tests of medical and ...recreational marijuana legalization (MML and RML) effects. Participants/Methods: We constructed weights for Fall 2015 and Spring 2016 surveys (n = 90,503) using population information on U.S. undergraduates' gender and race/ethnicity and three institutional characteristics (region, city population, public/private). We estimated substance use prevalence (e.g., e-cigarettes, prescription opioid misuse) and compared 30-day marijuana use rates in states with RML, MML, or neither policy. Results: When unweighted versus weighted data were used, prevalence estimates did not differ appreciably; conclusions from logistic regressions were similar (weighted 30-day marijuana use rates among undergraduates in RML, MML, and non-ML states were 30.0%, 20.3%, and 16.3%, respectively) but effect sizes differed. Conclusions: The value of using weighted NCHA-II data depends on the analysis and the precision required for the research questions.
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