REAP-2 is an interactive dose-response curve estimation tool for Robust and Efficient Assessment of drug Potency. It provides user-friendly dose-response curve estimation for in vitro studies and conducts statistical testing for model comparisons with a redesigned user interface. We also make a major update of the underlying estimation method with penalized beta regression, which demonstrates great reliability and accuracy in dose estimation and uncertainty quantification. In this note, we describe the method and implementation of REAP-2 with a highlight on potency estimation and drug comparison.

The purpose of this study was to examine possible pathways by which genetic risk associated with externalizing is transmitted in families. We used molecular data to disentangle the genetic and environmental pathways contributing to adolescent externalizing behavior in a sample of 1,111 adolescents (50% female; 719 European and 392 African ancestry) and their parents from the Collaborative Study on the Genetics of Alcoholism. We found evidence for genetic nurture such that parental externalizing polygenic scores were associated with adolescent externalizing behavior, over and above the effect of adolescents’ own externalizing polygenic scores. Mediation analysis indicated that parental externalizing psychopathology partly explained the effect of parental genotype on children’s externalizing behavior. We also found evidence for evocative gene-environment correlation, whereby adolescent externalizing polygenic scores were associated with lower parent–child communication, less parent–child closeness, and lower parental knowledge, controlling for parental genotype. These effects were observed among participants of European ancestry but not African ancestry, likely due to the limited predictive power of polygenic scores across ancestral background. These results demonstrate that in addition to genetic transmission, genes influence offspring behavior through the influence of parental genotypes on their children’s environmental experiences, and the role of children’s genotypes in shaping parent–child relationships.

Background: A non-operative approach has been favoured for elderly patients with lumbar spondylolisthesis due to a perceived higher risk with surgery. However, most studies have used an arbitrary age cut-off to define “elderly.” We hypothesized that frailty is an independent predictor of morbidity after surgery for lumbar spondylolisthesis. Methods: The American College of Surgeons National Surgical Quality Improvement Program (NSQIP) database for years 2010 to 2018 was used. Patients who received posterior lumbar spine decompression with or without posterior fusion instrumented fusion for degenerative lumbar spondylolisthesis were included. The primary outcome was major complication. Secondary outcomes were readmission, reoperation, and discharge to location other than home. Logistic regression analysis was done to investigate the association between outcomes and frailty. Results: There were 15 658 patients in this study. The mean age was 62.5 years (SD 12.2). Frailty, as measured by the Modified Frailty Index-5 was significantly associated with increased risk of major complication, unplanned readmission, reoperation, and non-home discharge. Increasing frailty was associated with increasing risk of morbidity. Conclusions: Frailty is independently associated with higher risk of morbidity after posterior surgery in patients with lumbar spondylolisthesis. These data are of significance to clinicians in planning treatment for these patients.

Many studies demonstrate that marriage protects against risky alcohol use and moderates genetic influences on alcohol outcomes; however, previous work has not considered these effects from a developmental perspective or in high-risk individuals. These represent important gaps, as it cannot be assumed that marriage has uniform effects across development or in high-risk samples. We took a longitudinal developmental approach to examine whether marital status was associated with heavy episodic drinking (HED), and whether marital status moderated polygenic influences on HED. Our sample included 937 individuals (53.25% female) from the Collaborative Study on the Genetics of Alcoholism who reported their HED and marital status biennially between the ages of 21 and 25. Polygenic risk scores (PRS) were derived from a genome-wide association study of alcohol consumption. Marital status was not associated with HED; however, we observed pathogenic gene-by-environment effects that changed across young adulthood. Among those who married young (age 21), individuals with higher PRS reported more HED; however, these effects decayed over time. The same pattern was found in supplementary analyses using parental history of alcohol use disorder as the index of genetic liability. Our findings indicate that early marriage may exacerbate risk for those with higher polygenic load.

While China's Constitution says everyone is treated equally before the law, employment discrimination continues to exist. This paper breaks new ground by analysing a quantitative survey of more than 10,000 lesbian, gay, bisexual, transgender and intersex (LGBTI) people, the largest dataset of its kind to date in China. Only 5.1 per cent of respondents were completely open about their gender and sexuality at work. More than one-fifth reported experiencing negative treatment in the workplace. Transgender and intersex people reported higher rates of negative treatment, as did respondents with lower educational levels and lower incomes and those residing in towns. Employer policies against discrimination were rare, but when in place, they were significantly associated with less negative treatment. These findings highlight an almost completely neglected segment of the workforce and document discriminatory experiences that could be addressed by changes in discrimination law and by employer policies and practices related to diversity and inclusion.

Background: The purpose of this study is to compare 1-year postoperative clinical outcomes between posterior instrumented fusion with (P/TLIF) and without (PLF) interbody fusion in patients with isthmic spondylolisthesis. Methods: This is a multi-centre retrospective study using the Canadian Spine Outcomes and Research Network. Adult patients who received surgical management for isthmic spondylolisthesis were included in this study. The primary outcome was change in Oswestry Disability Index at 1-year. Secondary outcomes were change in EQ-5D, SF-12 PCS, back pain, leg pain, estimated blood loss, length of surgery, length of stay, rate of transfusions and adverse events. Descriptive statistics, Student t-test, Chi-Squared test, and stepwise multivariable regression were used for analysis. Results: A total of 300 patients (252 P/TLIF, 48 PLF) were included in this study. The mean age was 50 years. The P/TLIF group had poorer baseline leg pain scores (t=2.02, p=0.01). There were no significant differences in primary and secondary outcomes between the two groups. Addition of interbody fusion was not a significant variable in the stepwise multivariable regression analysis. Conclusions: There were no significant differences in clinical outcomes at 1 year. Addition of interbody fusion was not associated with higher complication rates or length of stay.

Background: Cervical spondylotic myelopathy is a degenerative condition with a variable clinical course. We aim to quantify the sources of potential delay in management and understand how the timing of these events may affect quality of life measures. Methods: The Canadian Spine Outcomes Research Network Registry was used to identify patients older than 18 years of age and have received cervical decompression surgery from January 1, 2013 to March 1, 2016. The primary outcome was the Short Form-12 Physical Component Score at 12-month follow-up. Four time groups were identified: 1) duration of symptoms, 2) time awaiting surgical consult, 3) time spent monitoring symptoms, and 4) time awaiting surgery. -Multivariate regression was used for analysis. Results: A total of 208 patients were identified. The mean age was 59.5 years. 61.53% of patients had symptoms for >12 months at initial consult. Mean time awaiting surgical consult, monitoring symptoms, and awaiting surgery was 77.2, 60.9, and 46.9 days, respectively. Time awaiting surgery (β=-0.032, p=0.04) was a significant factor for change in Physical Component Score. Conclusions: We found time awaiting surgery to be a significant factor on PSC score at 12-month follow-up. Increased time awaiting surgery may result in negative impacts on quality of life outcomes.

In Hong Kong, universal varicella vaccination started in July 2014. Before this, children could receive varicella vaccine via the private market. We analysed the epidemiology of varicella and zoster before universal vaccination. We estimated varicella vaccination coverage through surveys in preschool children. We estimated the burden of varicella and zoster with varicella notifications from 1999/00 to 2013/14, Accident and Emergency Department (A&E) attendance and inpatient admissions to public hospitals from 2004/05 to 2013/14. We fitted a catalytic model to serological data on antibodies against varicella-zoster virus to estimate the force of infection. We found that varicella vaccination coverage gradually increased to about 50% before programme inception. In children younger than 5 years, the annual rate of varicella notifications, varicella admission and zoster A&E attendance generally declined. The annual notification, A&E attendance and hospitalisation rate of varicella and zoster generally increased for individuals between 10 and 59 years old. Varicella serology indicated an age shift during the study period towards a higher proportion of infections in slightly older individuals, but the change was most notable before vaccine licensure. In conclusion, we observed a shift in the burden of varicella to slightly older age groups with a corresponding increase in incidence but it cannot necessarily be attributed to private market vaccine coverage alone. Increasing varicella vaccination uptake in the private market might affect varicella transmission and epidemiology, but not to the level of interrupting transmission.

Background: Oligodendroglioma (ODG), a molecularly defined subtype of glioma, is a treatment responsive, slow growing tumour strongly associated with IDH mutation and 1p19q co-deletion. Mutations in Capicua (CIC), located on chromosome 19q, have been found in up to 70% of IDH mutated, 1p19q co-deleted ODGs; suggesting that loss or altered function of CIC may be crucially associated with ODG’s unique biology. CIC and ATXN1L have previously been implicated in neurodegeneration, however, this interaction has not been studied in cancer. Methods: Transcriptome profiling of CIC knockout HEK293 cell lines generated using CRISPR was performed using microarray. CIC and ATXN1L interaction was confirmed using immunoprecipitation and immunofluorescence. Transcript and protein changes of CIC targets were tested using RT-qPCR and Western blot following ATXN1L siRNA knockdown. Results: Transcriptomic profiling of CIC knockout cell lines resulted in a list of candidate CIC target genes validated against clinical samples. Immunoprecipitation and immunofluorescence confirmed CIC and ATXN1L interaction. Derepression of candidate CIC targets at transcript and protein levels was seen upon siRNA knockdown of ATXN1L. Conclusions: The interaction between CIC and ATXN1L is necessary for the repression of CIC target genes, including known oncogenes. Further research into the relationship between CIC and ATXN1L may lead potentially novel avenues of therapeutic approaches for less favorable gliomas.

Introduction: Developing structured online educational curricula that meet learner needs is challenging. Thrombosis and bleeding are areas of innovation and change in emergency medicine. We aimed to determine the learning needs of the Free Open Access Medical education (FOAM) community with the subsequent goal of developing structured curricula to meet them. Methods: A Massive Online Needs Assessment (MONA) was conducted to determine the perceived and unperceived educational needs in thrombosis and bleeding. The survey was designed by a multidisciplinary team of experts and was open from September 20 to December 10, 2016. The survey requested limited demographic information and contained questions to identify topics of interest. Respondents’ baseline knowledge and unperceived needs were assessed using 5 case scenarios containing 3 questions each. Knowledge gaps were defined a priori as topics where <50% of participants answered correctly. Results: We received 198 complete responses by staff physicians (n=109), residents (n=46), medical students (n=29) and allied health professionals (n=14) from 20 countries. 116/198 responses were from people working in emergency medicine. Topics of interest to participants included choice of anticoagulants, interruption of anticoagulation, management of bleeding and monitoring anticoagulation. Knowledge gaps were identified in 4 main areas including interruption of anticoagulation, management of bleeding (including reversal of anticoagulation and massive transfusion), inherited thrombophilia, and screening for malignancy in acute thrombosis. Conclusion: We have identified six priority topics to cover in our future online Thrombosis and Bleeding curriculum by surveying the online medical community. Although perceived and unperceived needs showed high congruence, two priority topics were only identified by assessing unperceived needs.

Introduction/Innovation Concept: The boom in online educational resources for medical education over the past decade has changed how physicians learn and keep up to date with new literature. While nearly all emergency medicine residents use online resources, few of these resources were designed to target knowledge gaps. Novel methods are required to identify learning needs to allow the targeted development of learner-centered curricula. Methods: A multidisciplinary team attempted to determine the feasibility of conducting a Massive Online Needs Assessment (MONA) to assess the perceived and unperceived educational needs in thrombosis and bleeding. An open, online survey was launched via Google Forms and disseminated using the online educational resource CanadiEM.org and social media platforms Twitter and Facebook with the goal of reaching participants of the Free Open Access Medical education (FOAM) community. Curriculum, Tool, or Material: The survey was designed to identify knowledge gaps and contained demographic, free text, and multiple choice questions. It took individuals approximately 30 minutes to complete and was incentivized with entry into a draw for one of four $250 Amazon Gift cards. Feasibility was defined a priori as 150 responses from at least 4 specialties in 4 or more countries. This sample was deemed the minimum number required to identify knowledge gaps (defined as <50% correct answers). The survey was open from September 20 to December 10, 2016. We received 198 complete responses from 20 countries. Respondents included staff physicians (n=109), residents (n=46), medical students (n=29), nurses (n=8), paramedics (n=4), a pharmacist (n=1) and a physician assistant (n=1). The survey entry page hosted on CanadiEM.org received page views from 866 unique IP addresses. As such, a conservative approximation of the completion rate per unique viewer was 22% (198/866). Conclusion: It is feasible to use a MONA to collect data on the perceived and unperceived needs of an online community. Such needs assessments could be used to make online resources more learner-centered.