Viral vector-mediated transgene delivery with novel recombinase systems for targeting neuronal populations defined by multiple features.

A comprehensive understanding of neuronal diversity and connectivity is essential for understanding the anatomical and cellular mechanisms that underlie functional contributions. With the advent of single-cell analysis, growing information regarding molecular profiles leads to the identification of more heterogeneous cell types. Therefore, the need for additional orthogonal recombinase systems is increasingly apparent, as heterogeneous tissues can be further partitioned into increasing numbers of specific cell types defined by multiple features. Critically, new recombinase systems should work together with pre-existing systems without cross-reactivity in vivo. Here, we introduce novel site-specific recombinase systems based on ΦC31 bacteriophage recombinase for labeling multiple cell types simultaneously and a novel viral strategy for versatile and robust intersectional expression of any transgene. Together, our system will help researchers specifically target different cell types with multiple features in the same animal.

The Risk Evaluation and Mitigation Strategy (REMS) Public Dashboard: Improving Transparency of Regulatory Activities.

This brief paper aims to describe the Risk Evaluation and Mitigation Strategy (REMS) Public Dashboard launched by the US Food and Drug Administration (FDA) in December 2021. The FDA REMS Public Dashboard can be accessed through the REMS@FDA website. The dashboard was developed in Qlik Sense® to support a user-friendly interactive web-based tool that allows healthcare providers, patients, researchers, pharmaceutical companies, and regulators to readily access and visualize REMS information. The dashboard includes eight separate pages to capture information on all REMS, active REMS, REMS with elements to assure safe use, shared system REMS, REMS modifications, REMS revisions, released REMS, and REMS Summary; for REMS programs approved from 2008 to the present. Most of the pages allow users to choose different REMS characteristics to visualize and stratify the data by variables such as REMS approval time, application type, or REMS elements. This interactive platform is intended to allow users to quickly visualize trends over time and locate details of the REMS programs to inform emerging research and regulatory issues in the context of current drug safety. The FDA continues to explore ways to enhance public access of the REMS information in near real-time through the REMS Public Dashboard.

Trend changes of national zolpidem users and exposure cases after FDA drug safety communications.

PURPOSE: To evaluate the impact of FDA's 2013 zolpidem Drug Safety Communications (DSCs), which recommended lowering the initial dose to mitigate drowsiness, on national estimates of zolpidem users and zolpidem exposure cases. METHODS: We analyzed trend changes of national zolpidem users from the IQVIA Total Patient Tracker (TPT) and zolpidem exposure cases reported to the National Poison Data System (NPDS), 2009-2018. To control for time varying confounding, the adjusted trends were analyzed using simple and controlled interrupted time series (ITS). We also adjusted for seasonal changes. Three sedating antidepressants were used together as a control. RESULTS: The national estimates of high-dose zolpidem users in TPT decreased significantly in the month immediately post-DSC; the absolute level decrease was -12.51 (95% CI: -14.12, -10.89) per 10 000 U.S. population relative to sedating antidepressants. The trend continuously decreased post-DSC, resulting in a 59% overall decrease by the end of the study period. There was a larger decrease in high-dose zolpidem use in females than in males. There was a level decrease of zolpidem exposure cases in the NPDS immediately post-DSC, -0.37 absolute decline (95% CI, -0.53, -0.20) per 10 000 national zolpidem users; or -1.33 absolute decline (95% CI, -1.54, -1.13) per 1000 total NPDS exposure cases relative to sedating antidepressants. Similar patterns were observed for cases reporting drowsiness. The results from the single ITS and controlled ITS were similar. CONCLUSIONS: Zolpidem users and exposure cases decreased significantly post-DSC, suggesting practitioners and patients became aware of and responded to the zolpidem DSCs.

The Greatwall kinase safeguards the genome integrity by affecting the kinome activity in mitosis.

Progression through mitosis is balanced by the timely regulation of phosphorylation and dephosphorylation events ensuring the correct segregation of chromosomes before cytokinesis. This balance is regulated by the opposing actions of CDK1 and PP2A, as well as the Greatwall kinase/MASTL. MASTL is commonly overexpressed in cancer, which makes it a potential therapeutic anticancer target. Loss of Mastl induces multiple chromosomal errors that lead to the accumulation of micronuclei and multilobulated cells in mitosis. Our analyses revealed that loss of Mastl leads to chromosome breaks and abnormalities impairing correct segregation. Phospho-proteomic data for Mastl knockout cells revealed alterations in proteins implicated in multiple processes during mitosis including double-strand DNA damage repair. In silico prediction of the kinases with affected activity unveiled NEK2 to be regulated in the absence of Mastl. We uncovered that, RAD51AP1, involved in regulation of homologous recombination, is phosphorylated by NEK2 and CDK1 but also efficiently dephosphorylated by PP2A/B55. Our results suggest that MastlKO disturbs the equilibrium of the mitotic phosphoproteome that leads to the disruption of DNA damage repair and triggers an accumulation of chromosome breaks even in noncancerous cells.

Using latent class analysis to identify the complex needs of youth on probation.

Youth involved with the juvenile justice system have higher rates of unmet social and psychological service needs than the general population. Yet, scant research has addressed the potentially complex needs of youth on probation. This study is thus a first step in improving our ability to promote positive youth development and improved outcomes from youth on probation. It uses administrative data on probation youth from FY2011-2013 in a mid-Atlantic state. We estimated latent class models based on the ordinal scoring (high, moderate, none/low) of the 25 subscales from a standardized assessment administered at intake. In order to test whether groups were distinct, we examined a range of variables, including the official risk classification and recidivism rates measured by officieal rearrests and reconvictions. We report the demographic differences between the estimated groups, as well as adverse childhood experiences, school and employment status, previous legal history, and substance use history. Ultimately, the seven-class model produced four groups that others have noted: a relatively low needs (lowest need), relatively high needs (complex needs), substance use service needs, and mental health service needs. The other three groups that emerged include two gender specific groups (one for male and one for female high-need groups) and a group with skills needs that lacks supportive and protective skills. The analyses will facilitate a better appreciation for the service needs of moderate risk youth. Youth on probation are not a uniform population; they reflect tremendous heterogeneity, and probation systems should embrace systemic responsivity to provide appropriate services to improve youth outcomes. Advancing efforts to provide a broader spectrum of services that address multi-morbid conditions can ensure that youth have opportunities to improve their quality of life during the period of supervision.

What Is the Association Between Articular Cartilage Damage and Subsequent THA 20 Years After Hip Arthroscopy for Labral Tears?

BACKGROUND: Few studies have examined long-term outcomes for patients after arthroscopic treatment for intraarticular hip conditions, and none have done so beyond 10 years postarthroscopy. Examining outcomes beyond 10 years is necessary to determine factors that contribute to conversion to THA in patients undergoing hip arthroscopy for labrochondral damage. QUESTIONS/PURPOSES: (1) What is hip survivorship free from THA in patients who underwent arthroscopic labral débridement, with or without chondroplasty at least 15 years before? (2) What factors are associated with conversion to THA after arthroscopic labral débridement, with or without chondroplasty? (3) Can these data be used to estimate the risk of conversion to THA based on patient- and hip-related factors? METHODS: Between 1989 and 2000, one surgeon performed 552 arthroscopic hip procedures for symptomatic labral tears, with or without associated articular cartilage damage. Of these, the hip status was known in 404 hips (73%) at a minimum of 15 years after the index procedure, with 20 of those patients having died during the followup period. During the study period, patients were offered hip arthroscopy for labral tears with mechanical symptoms, with or without underlying articular cartilage damage. Patient age, sex, acetabular and femoral head Outerbridge grade at surgery, and presence of labral tear were recorded. We determined survivorship free from THA using a Kaplan-Meier survivorship estimator. A stepwise multivariable logistic regression analysis was conducted to determine factors associated with the eventual conversion to THA after hip arthroscopy for labrochondral injuries. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated for all significant independent factors. Odds ratios for combinations of significant factors were used to create a risk assessment. RESULTS: The survivorship free from conversion to THA at 20 years was 59% (95% CI, 53-64. Factors that affected survival included age ≥ 40 years and the presence of combined femoral head and acetabular chondral damage. After controlling for confounding factors, we found that age ≥ 40 years (OR, 2.0; 95% CI, 1.2-3.4; p = 0.011), the absence of all chondral damage (OR, 0.1; 95% CI, 0.03-0.32; p < 0.001), the presence of acetabular damage with severe femoral head damage (OR, 5.0; 95% CI, 2.4-10.3; p < 0.001), and the presence of severe acetabular damage with femoral head damage (OR, 3.7; 95% CI, 2.0-6.8; p < 0.001) were associated with conversion to THA at long-term followup. Based on the calculated ORs, the probability of conversion to THA by 20 years postarthroscopic treatment for labrochondral injuries ranged from 12% (95% CI, 8-17) for a patient younger than 40 years with a Grade 0-II femoral and acetabular Outerbridge grade to 92% (95% CI, 86-95) for a patient older than 40 years with a Grade III-IV femoral and acetabular Outerbridge grade. CONCLUSIONS: Our study revealed that survivorship free from THA at 20 years after arthroscopic labral débridement was associated with both patient age at time of index procedure and, more importantly, the presence of combined femoral head and acetabular chondral damage. Patients should be counseled as to the increased probability of conversion to THA, depending on the health of their articular cartilage after surgery. Future studies should examine survivorship free from THA or clinical symptoms in patients undergoing hip arthroscopy with bone reshaping procedures or with labral repair or reconstruction up to and exceeding 20 years. LEVEL OF EVIDENCE: Level III, therapeutic study.

Characterization of Post-Operative Opioid Use Following Total Joint Arthroplasty.

BACKGROUND: The purpose of our study is to examine post-operative opioid use in total hip arthroplasty (THA) and total knee arthroplasty (TKA) patients and describe factors associated with the need for refill prescriptions. METHODS: Using online prescription information, we calculated the number of filled prescriptions, total morphine equivalent dose (MED) and quantity of pills, and date of last opioid prescription (days) for 197 TKA and 186 THA patients. Patients were classified based on refill status. Opioid data were compared between TKA and THA patients. Relationships between comorbidities and refill status were examined. RESULTS: Number of prescriptions (P < .001), total quantity (P < .001) and MED (P < .001), and days on opioids (P < .001) were greater for TKA patients. TKA patients required more refills (P < .001) for a greater quantity of pills (P = .007). The presence of a comorbidity (P = .003) or anxiety/depression (P = .004) were correlated with refills for TKA patients only. A comorbidity increased the risk of refills by 3.1 times, while anxiety/depression had a 2.5 times greater risk of refills. CONCLUSION: Compared to THA patients, TKA patients were twice as likely to require refill opioid prescriptions and were prescribed a greater total MED for a longer period of time post-operatively. Patients undergoing TKA who present with a comorbidity or are currently being treated for anxiety or depression are more likely to require a refill.

Trajectories of Economic Disconnection among Families in the Child Welfare System.

This study examined economic disconnection, an extreme case of economic exclusion in which families lack both employment and cash assistance, among families in the child welfare system. To build hypotheses about the intersection of the child welfare system and economic disconnection we used a multilevel framework that considers federal policy, local practice, and processes within families. We hypothesized that child welfare intervention has the potential to be a mechanism of economic inclusion or exclusion for vulnerable families, with implications for family reunification. We utilized a novel administrative data set containing data from three state agencies to construct income histories of parents relative to their child's placement in foster care (N = 15,159 parents). We identified eight trajectories using group-based trajectory modeling. About two-thirds of parents experience economic disconnection over a three-year period; these families are least likely to reunify. Although providing economic resources to families is typically beyond the scope of child welfare, efforts to minimize the negative impact of child placement on parents' economic connection is likely to improve both the economic inclusion of poor families and family reunification.

Dual-System Families: Cash Assistance Sequences of Households Involved with Child Welfare.

Dual-system families, those involved with the child welfare system and receiving public cash assistance, may be more vulnerable than families only connected to either of the two systems. This study advances our understanding of the heterogeneous and dynamic cash assistance histories of dual-system families in the post-welfare reform era. With merged administrative data from [state name removed] over the period 1998 to 2009, we use cluster analysis to group month-to-month sequences of cash assistance use among households over the 37-month period surrounding child removal. Close to two thirds of families who received any assistance either had a short spell of Temporary Assistance for Needy Families (TANF) or lost TANF. Smaller percentages had steady support. Families who lose assistance are less likely than average to reunify while those who connect to benefits are more likely, suggesting coordination between systems may serve dual-system families well.

Adolescent (Mis)Perceptions About Nicotine Addiction: Results From a Mixed-Methods Study.

PURPOSE: Despite evidence that adolescents become addicted to nicotine even after limited use, adolescents believe they can experiment with or smoke cigarettes for a few years and easily quit. The goal of this study was to examine adolescents' understanding of the definition and process of nicotine addiction using a mixed-methods approach.Method A total of 367 adolescents with and without smoking experience rated the perceived risk for addiction, still being a smoker in 5 years, and ability to quit smoking. A subsample of adolescents (N= 41) were interviewed about their conceptualization and understanding of nicotine addiction. Within-participants analyses of variance were conducted to assess differences in perceptions of addiction across the three scenarios; thematic analyses of interviews were conducted to assess adolescents' understanding of addiction.Results Adolescents rated their perceived risk for addiction, still being a smoker in 5 years, and ability to quit as significantly different from one another for three different scenarios (F= 7.81, 47.78, and 70.27, respectively;p< .001). Seven themes describing how youth conceptualize and understand addiction emerged from the interview data, including skepticism and uncertainty about addiction, how smoking makes a person feel, and family and friends' experiences. CONCLUSION: While adolescents have received the message that cigarettes are addictive, they are uncertain regarding the definition of addiction and have not recognized that addiction means experiencing difficulty quitting and continuing to smoke longer than expected. Findings suggest the need for comprehensive messaging regarding nicotine addiction in educational, clinical, and intervention settings and for product warning messages aimed at reducing and preventing tobacco use.

Labeling and the effect of adolescent legal system involvement on adult outcomes for foster youth aging out of care.

This study uses labeling theory to examine the role that adolescent legal system involvement may play in initiating a process of social exclusion, leading to higher levels of adult criminal activities among foster youth who have aged out of care. We used data from the Midwest Evaluation of the Adult Functioning of Former Foster Youth (Midwest Study), a prospective study that sampled 732 youth from Illinois, Iowa, and Wisconsin as they were preparing to leave the foster care system at ages 17 or 18. The youth were interviewed again at ages 19, 21, and 23 or 24. We used structural equation modeling to examine pathways to self-reported adult criminal behaviors from juvenile legal system involvement. The path model indicated that legal system involvement as a juvenile was associated with a lower likelihood of having a high school diploma at age 19, which was associated with a reduced likelihood of employment and increased criminal activities at age 21. Legal system involvement is more common among foster youth aging out of care, and this legal system involvement appears to contribute to a process of social exclusion by excluding former foster youth from conventional opportunities.

A National Asian-Language Smokers' Quitline--United States, 2012-2014.

INTRODUCTION: Until recently, in-language telephone quitline services for smokers who speak Asian languages were available only in California. In 2012, the Centers for Disease Control and Prevention (CDC) funded the national Asian Smokers' Quitline (ASQ) to expand this service to all states. The objective of this study was to examine characteristics of ASQ callers, how they heard about the quitline, and their use of the service. METHODS: Characteristics of callers from August 2012 through July 2014 were examined by using descriptive statistics. We examined demographics, cigarette smoking status, time to first cigarette, how callers heard about the quitline, and service use (receipt of counseling and medication) by using ASQ intake and administrative data. We analyzed these data by language and state. RESULTS: In 2 years, 5,771 callers from 48 states completed intake; 31% were Chinese (Cantonese or Mandarin), 38% were Korean, and 31% were Vietnamese. More than 95% of all callers who used tobacco were current daily cigarette smokers at intake. About 87% of ASQ callers were male, 57% were aged 45 to 64 years, 48% were uninsured, and educational attainment varied. Most callers (54%) were referred by newspapers or magazines. Nearly all eligible callers (99%) received nicotine patches. About 85% of smokers enrolled in counseling; counseled smokers completed an average of 4 sessions. CONCLUSION: ASQ reached Chinese, Korean, and Vietnamese speakers nationwide. Callers were referred by the promotional avenues employed by ASQ, and most received services (medication, counseling, or both). State quitlines and local organizations should consider transferring callers and promoting ASQ to increase access to cessation services.

Cartilage Status at Time of Arthroscopy Predicts Failure in Patients With Hip Dysplasia.

The purpose of our study was to determine whether chondral damage at the time of arthroscopy predicted conversion to THA in patients with dysplasia. We identified 166 patients with dysplasia who underwent hip arthroscopy. Forty-seven went on to receive THA. The articular cartilage of three regions of the acetabulum and femoral head were assessed for signs of chondral damage (absent, mild, or severe]). A stepwise multivariable logistic regression analysis revealed mild damage on the posterior femoral head (P=0.001) and severe damage on the anterior acetabulum (P=0.007) made a significant contribution to the predictor. The presence of mild posterior femoral head chondral changes was indicative of more global cartilage damage in this series of patients. Our findings show that chondral damage on the posterior femoral head and anterior acetabulum is a strong predictor of ultimate conversion to THA in dysplastic patients.

Risk factors of future smoking among Thai youth: a secondary analysis of the Thai Global Youth Tobacco Survey.

The study aimed to identify the risk factors for future smoking among Thai youth aged 13 to 15 years (seventh to ninth grade). Data from the nationally representative 2005 Thai Global Youth Tobacco Survey (n = 15 774) were analyzed using descriptive statistics and logistic regression. Among nonsmoking Thai youth, boys were much more likely to have intention of future smoking (odds ratio [OR] = 0.56, 95% confidence interval [CI] = 0.37-0.84). Younger youth were more likely to be cigarette smokers in the future (OR = 0.70, 95% CI = 0.56-0.88). Youth having the intention of smoking from a friend's cigarette offer were 5.29 times more likely to have intention of future smoking, compared with those who did not (95% CI = 3.75-7.46). Understanding and targeting youth at higher risk for future smoking can provide for a lowering of the youth smoking rate in Thailand and contribute to the country's continued efforts in effective youth tobacco control.

Pro-tobacco influences and susceptibility to smoking cigarettes among middle and high school students--United States, 2011.

PURPOSE: Smoking is a leading cause of cancer, and most smokers begin during adolescence. We examined the proportion of adolescents exposed to pro-tobacco advertising and assessed the association between this exposure and susceptibility to smoking. METHODS: Data from the 2011 National Youth Tobacco Survey were used to calculate the proportion of susceptible middle school (MS) and high school (HS) students exposed to pro-tobacco advertisements through stores, magazines, and the Internet. Following previous work, susceptibility to smoking cigarettes was defined as "never smoked but open to trying cigarettes." RESULTS: In 2011, 81.5% of MS students and 86.9% of HS students were exposed to tobacco advertisements in stores; 48.2% of MS students and 54.0% of HS students were exposed to such advertising in magazines. Exposure to tobacco advertisements on the Internet was similar for MS (40.8%) and HS students (40.2%). Of those surveyed, 22.5% of MS students and 24.2% of HS students were susceptible to trying cigarettes. Exposure to magazine advertising declined from 71.8% in 2000 to 46.1% in 2009 among susceptible MS students; however, exposure increased to 55.4% in 2011. Tobacco advertising seen through the Internet among susceptible HS students increased from 25.9% in 2000 to 44.7% in 2011. CONCLUSIONS: Adolescents continue to be exposed to pro-tobacco advertisements. Adolescents susceptible to smoking are more likely to report exposure to pro-tobacco advertisements. In addition to continued monitoring, more effective interventions to eliminate youth exposure to pro-tobacco marketing are needed.

Smoking beliefs and behavior among youth in South Korea, Taiwan, and Thailand.

BACKGROUND: Beliefs about smoking are important predictors of smoking behavior among adolescents, and adolescents who hold positive beliefs about the benefits of smoking are at an increased risk of smoking initiation. An alarming fact is the rising smoking prevalence in Asian countries, particularly the increasing trend in smoking during adolescence. PURPOSE: This cross-sectional study examined smoking beliefs and behavior among a nationally representative sample of youth in South Korea, Taiwan, and Thailand. METHODS: Descriptive statistics, linear regression, and logistic regression methods were used to analyze data from 13-15-year-old adolescents who participated in the 2005 Global Youth Tobacco Survey (GYTS) in South Korea (N = 4,765) and Thailand (N = 15,420) and the 2007 GYTS in Taiwan (N = 3,955). RESULTS: The rate of ever smoking among youth was similar in all three countries and ranged from 26.7 to 28.0 %. The prevalence of current smoking among youth in Thailand (11.4 %) was nearly double the prevalence in South Korea (6.6 %) and Taiwan (6.5 %). Pro-tobacco advertising exposure, as well as older ages, was a positive and significant predictor of positive beliefs about smoking among youth in all three countries. Additionally, youth who reported increased positive smoking-related beliefs, greater pro-tobacco advertising exposure, and were male were more likely to be current smokers in all three countries. CONCLUSION: Results suggest that greater attention be directed to understanding beliefs and attitudes about smoking among youth. Exploring the relationship between these factors and smoking behavior can provide a strong starting point in the development of effective smoking prevention interventions and tobacco control policies in this region.

Multiple jeopardy: poor, economically disconnected, and child welfare involved.

Although the welfare literature reveals a growing number of parents who are economically disconnected, meaning neither employed nor receiving cash assistance, little is known about the prevalence and impacts of disconnection among child welfare-involved parents. This study took advantage of a statewide survey of child welfare-involved parents to examine economic disconnection in this population and to explore the relationship between disconnection and parent engagement in child welfare. One fifth of the sample reported that they were economically disconnected, with several patterns differentiating disconnected caregivers from those who received benefits or earned income through employment. Disconnected caregivers were younger and more frequently had children in out-of-home placements as opposed to receiving services in home than economically connected caregivers. They also reported higher unmet needs for basic services, such as housing and medical care, but were more likely to report financial help from their informal network. Finally, disconnected caregivers reported lower engagement in child welfare services even when controlling for demographic characteristics, chronic psychosocial risk factors, placement status, and maltreatment type. The findings document economic disconnection among child welfare-involved parents and raise important questions about the implications of disconnection for families and for child welfare outcomes.

What does it take to be a smoker? Adolescents' characterization of different smoker types.

INTRODUCTION: Studies have demonstrated that clinical- and research-based definitions of who a smoker is and what constitutes smoking often differ from adolescent-derived definitions, which can be problematic for effective intervention and prevention efforts. We investigated how adolescents define different smoker types (nonsmoker, smoker, regular smoker, addicted smoker, heavy smoker, experimental smoker, casual smoker, and social smoker) using multiple indicators of smoking behaviors, including frequency, amount, place, and length of time cigarette smoking, and whether differences exist by smoking experience. METHODS: Quantitative and qualitative methods were used to analyze data from a cohort of adolescents (N = 372) in northern California. RESULTS: We found differences in how adolescents characterized smoker types based on their own smoking experience. Ever-smokers tended to have a greater flexibility in determining what constituted nonsmoking and heavy smoking, while never-smokers had much narrower definitions. Results also indicated that adolescents may mistakenly associate nicotine addiction with a high frequency and amount of cigarette use as 74.3% characterized an addicted smoker as having smoked for a few years or more. In addition, there was a considerable amount of overlap in definitions between different smoker types, particularly among the smoker-regular smoker, addicted smoker-heavy smoker, and casual smoker-social smoker pairs. CONCLUSION: Health communication strategies for youth smoking prevention need to address the wide variability and overlap in how adolescents define different smoker types. Greater attention should be directed to understanding the nuances of how adolescents define smoking in order to maximize the effectiveness of youth-centered smoking prevention and cessation messages.

History of hip arthroscopy: challenges and opportunities.

Hip arthroscopy began with resection of pathologies and later progressed to repair of different tissues. There is an increasing impetus for reconstruction of biologic joints; although this has occurred with other joints, hip arthroscopic procedures are now headed in this direction. Thus, despite considerable initial challenges, multiple opportunities are now available in this fertile field.