Targeting proprotein convertase subtilisin/kexin type 9 (PCSK9): from bench to bedside.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) has evolved as a pivotal enzyme in lipid metabolism and a revolutionary therapeutic target for hypercholesterolemia and its related cardiovascular diseases (CVD). This comprehensive review delineates the intricate roles and wide-ranging implications of PCSK9, extending beyond CVD to emphasize its significance in diverse physiological and pathological states, including liver diseases, infectious diseases, autoimmune disorders, and notably, cancer. Our exploration offers insights into the interaction between PCSK9 and low-density lipoprotein receptors (LDLRs), elucidating its substantial impact on cholesterol homeostasis and cardiovascular health. It also details the evolution of PCSK9-targeted therapies, translating foundational bench discoveries into bedside applications for optimized patient care. The advent and clinical approval of innovative PCSK9 inhibitory therapies (PCSK9-iTs), including three monoclonal antibodies (Evolocumab, Alirocumab, and Tafolecimab) and one small interfering RNA (siRNA, Inclisiran), have marked a significant breakthrough in cardiovascular medicine. These therapies have demonstrated unparalleled efficacy in mitigating hypercholesterolemia, reducing cardiovascular risks, and have showcased profound value in clinical applications, offering novel therapeutic avenues and a promising future in personalized medicine for cardiovascular disorders. Furthermore, emerging research, inclusive of our findings, unveils PCSK9's potential role as a pivotal indicator for cancer prognosis and its prospective application as a transformative target for cancer treatment. This review also highlights PCSK9's aberrant expression in various cancer forms, its association with cancer prognosis, and its crucial roles in carcinogenesis and cancer immunity. In conclusion, this synthesized review integrates existing knowledge and novel insights on PCSK9, providing a holistic perspective on its transformative impact in reshaping therapeutic paradigms across various disorders. It emphasizes the clinical value and effect of PCSK9-iT, underscoring its potential in advancing the landscape of biomedical research and its capabilities in heralding new eras in personalized medicine.

Classroom compositional effects on low-ability students' achievement in China.

Peer effects are at the center of educational policy debates regarding school choice, ability grouping, and instructional design. Though emerging empirical evidence suggests that positive peer effects exist, less is known about how it affects students with varying cognitive abilities. Using a nationally representative sample from China, we generated a student-level measure of classroom composition of peers based on cognitive ability to understand the benefits or pitfalls of placing low-ability students with heterogeneous or homogenous classmates. We conducted this analysis separately for grades seven and nine students after controlling for student background, family characteristics, and school endogeneity. We reaffirmed the overall positive-but small-peer effects on the performance rankings. Low-ability children scored much lower than their counterparts when they studied in cognitively diverse classrooms. However, this effect negates the overall positive impact of studying with high-ability peers and the pattern is consistent across rural and urban schools.

The muon Smasher's guide.

We lay out a comprehensive physics case for a future high-energy muon collider, exploring a range of collision energies (from 1 to 100 TeV) and luminosities. We highlight the advantages of such a collider over proposed alternatives. We show how one can leverage both the point-like nature of the muons themselves as well as the cloud of electroweak radiation that surrounds the beam to blur the dichotomy between energy and precision in the search for new physics. The physics case is buttressed by a range of studies with applications to electroweak symmetry breaking, dark matter, and the naturalness of the weak scale. Furthermore, we make sharp connections with complementary experiments that are probing new physics effects using electric dipole moments, flavor violation, and gravitational waves. An extensive appendix provides cross section predictions as a function of the center-of-mass energy for many canonical simplified models.

Cooperative guardian offenders and sentencing outcomes: Evidence from criminal sentencing documents of child trafficking crime in China.

BACKGROUND: Studies have revealed that guardians who sold their children for profit comprise the majority of child traffickers in China. Although sentencing disparity has been a focal topic in judicial studies, few scholars have investigated the influence of the guardian relationship on criminal sentencing for child trafficking. OBJECTIVE: The current study sought a better understanding of sentencing practices on child traffickers in China, focusing on the effects of the victim-offender relationship (VOR) and post-crime attitudes (PCAs) on sentencing outcomes. PARTICIPANTS AND SETTING: We retrieved all available sentencing documents related to "the trafficking of children" during the 2014-2016 period from China Judgments Online. The analytic dataset contained 844 child traffickers who were sentenced to a fixed term imprisonment. METHODS: A joint logistic and zero-truncated Poisson regression model was used to explore the main and interaction effects of VOR and PCAs on sentencing outcomes. RESULTS: Guardian offenders received sentences that were 12% shorter than those of non-guardians and were more likely to be given 60-month sentences, which is the minimum of the first statutory sentencing range. Guardian offenders who voluntarily surrendered also had a much higher chance of probation. The odds ratio of receiving probation for guardian offenders who surrendered was approximately three times higher than that of non-guardian offenders who did not surrender. Surrendering also reduced the sentence length of guardian offenders by 22%. CONCLUSIONS: Shorter sentences and a higher chance of probation suggest that the Chinese judicial system considers child trafficking crimes involving guardians to be low harm offenses that pose little danger to society. However, this practice of leniency for cooperative guardian offenders offers offenders pragmatic ways to avoid incarceration, and does not help to solve the problems of guardian offenders who really want to give up custody of their children.

Achieved educational attainment, inherited genetic endowment for education, and obesity.

This study investigates two sources of education effects on obesity - achieved educational attainment and inherited genetic endowment for education. In doing so, we accomplish two goals. First, we assess the role of genetic confounding in the association between education and health. Second, we consider the heterogeneity in the extent to which genetic potential for education is realized, and we examine its impact on obesity. Data come from the National Longitudinal Study of Adolescent to Adult Health. Using a polygenic score approach, we find that, net of genetic confounding, holding a college degree is associated with a lower likelihood of obesity. Moreover, among individuals who hold a college degree, those with a high education polygenic score (a greater genetic propensity to succeed in education) are less likely to be obese than those with a relatively low education polygenic score. However, when individuals with a high education polygenic score do not have a college degree, their risk of obesity is similar to that of non-college-educated individuals with a low education polygenic score, suggesting that the effect of genetic endowment for education on obesity is conditional on college education.

Trajectories of COVID-19 vaccine intentions among U.S. adults: The role of race and ethnicity.

Research examining whether intentions to get a COVID-19 vaccine change over time is scarce. Moreover, the deep and pervasive history of medical racism in the U.S. has created a context in which some racial and ethnic groups exhibit greater levels of COVID-19 vaccine hesitancy; yet few researchers have attempted to determine whether these patterns persist with time. The purpose of this study was twofold: (a.) assess the role of time in COVID-19 vaccine intentions from April 2020 to January 2021, and (b.) examine whether race and ethnicity shape COVID-19 vaccine intention trajectories. Data were drawn from 9 waves of the Understanding America Study (n = 5023), a national probability panel study of U.S. adults. Multilevel logistic regression models were used to assess overall COVID-19 vaccine intention trajectories and trajectories by race and ethnicity. Results demonstrate intentions to get a COVID-19 vaccine significantly decreased from April 2020 to November 2020, but by January 2021, intentions to get a COVID-19 vaccine slightly increased. Findings also show trajectories significantly differed by racial and ethnic background. Asian/Pacific Islanders had the highest probability of likely getting a COVID-19 vaccine at baseline, followed by Whites and Latina/os. Black Americans exhibited the lowest probability of likely getting vaccinated, and, in most cases, the gap between Black Americans and other racial groups grew over time. Key findings from this study demonstrate that, among U.S. adults, time and race and ethnicity play significant roles in COVID-19 vaccine intentions. Understanding the role of time and race and racism in shaping COVID-19 vaccine intention trajectories can help government agencies and public health experts tasked with administrating vaccines better understand disparities in vaccine uptake.

Timing of parental incarceration and allostatic load: a developmental life course approach.

PURPOSE: We examined whether the timing of when a person experienced the loss of a parent to incarceration was significantly associated with allostatic load, a multisystem index of biological dysregulation. METHODS: Data were drawn from waves I and IV of National Longitudinal Study of Adolescent to Adult Health, a nationally representative sample of adolescents in 1994. The final analytic sample was restricted to responses with valid responses and valid sampling weights (n = 13,365). Survey-corrected negative binomial regressions were used to assess relationships between timings of parental incarceration and allostatic load. RESULTS: Compared with respondents with no history of parent incarceration, reporting the incarceration of a parent in childhood was associated with higher allostatic load scores, whereas losing a parent to incarceration in adulthood was associated with significantly lower allostatic load scores. CONCLUSIONS: The physiological consequences of parental incarceration are associated with the developmental period in which the incarceration occurred. The risk of biological dysregulation may be greatest among those who experience the loss of a parent to incarceration in childhood.

Smuggling of drugs by body packing: Evidence from Chinese sentencing documents.

BACKGROUND: In China, body packing as a means of transporting drugs was firstly found in Yunnan province in an area that shares a border with the Golden Triangle in late 1970s. Since then, drug trafficking cases that utilize body packing as the primary mode of transportation have increased substantially. Due to a scarcity of data, however, the scope and nature of such criminal activity is not thoroughly understood. This study provides a new approach to the analysis of body packing by digitizing and analyzing court sentencing documents in China from 2006-2016. METHODOLOGY: This study implements network analysis and descriptive statistics to identify the structures of drug trafficking routes involving body packing in China and aims to provide a comprehensive examination of body packing activity, including the pattern of geographic routes and the characteristics of captured body packers. A generalized inflated negative binomial model is also used to investigate the effects of legal and extra-legal factors on the length of sentence for captured body packers. RESULTS: We identified three types of trafficking routes involving body packing: intra-provincial, inter-provincial, and international. Our results showed that heroin and methamphetamine are the two primary drugs trafficked by captured body packers. Network analysis revealed that among body packing routes, there are three major hubs that serve as the primary origin for the trafficking -Yunnan, Sichuan, and Myanmar- and three potential authorities- Guangdong, Xinjiang, and Sichuan-which serve as the common destinations of the drug routes. Consistent with previous studies, our research also demonstrated that heavier punishments are given in cases that involve a larger quantity of drugs and repeat offenders. Offenders who fall into special groups, such as pregnant/lactating women, the disabled, or minors, receive more lenient sentences. In addition, our analysis further revealed that the logic behind longer sentences for those offenders who confessed as opposed to those who did not, is possibly due to the concentration of imprisonment values at fifteen years, as many of the confessed body packers are sentenced to the maximum fixed term of imprisonment. CONCLUSION: By narrowing the gap in knowledge on the topic of body packing, our analysis provides evidence-based strategies for fighting against body packing, specifically by identifying geographical patterns and the profiles of captured body packers.

Elevated Risk of Radiation Therapy-Associated Second Malignant Neoplasms in Young African-American Women Survivors of Stage I-IIIA Breast Cancer.

PURPOSE: To estimate the effect of radiation therapy (RT) on nonbreast second malignant neoplasms (SMNs) in young women survivors of stage I-IIIA breast cancer. METHODS AND MATERIALS: Women aged 20 to 44 years who received a diagnosis of stage I-IIIA breast cancer (1988-2008) were identified in the Surveillance, Epidemiology, and End Results 9 registries. Bootstrapping approach and competing-risk proportional hazards models were used to evaluate the effect of RT on nonbreast SMN risk. The analysis was repeated in racial subgroups. Radiotolerance score analysis of normal airway epithelium was performed using Gene Expression Omnibus (GEO) data sets. RESULTS: Within records of 30,003 women with primary breast cancer, 20,516 eligible patients were identified, including 2,183 African Americans (AAs) and 16,009 Caucasians. The 25-year cumulative incidences of SMN were 5.2% and 3.6% (RT vs no-RT) for AAs, with 12.8-year and 17.4-year (RT vs no-RT) median follow-up (hazard ratio [HR] = 1.81; 95% bootstrapping confidence interval [BCI], 1.02-2.50; P < .05), respectively, and 6.4% and 5.9% (RT vs no-RT) for Caucasians with 14.3-year and 18.1-year (RT vs no-RT) median follow-up (HR = 1.10; 95% BCI, 0.61-1.40; P > .05), respectively. The largest portion of excess RT-related SMN risk was lung cancer (AA: HR = 2.08, 95% BCI, 1.02-5.39, P < .05; Caucasian: HR = 1.50, 95% BCI, 0.84-5.38, P > .05). Subpopulation Treatment Effect Pattern Plot (STEPP) analysis revealed higher post-RT nonbreast SMN risk in those 20 to 44 years of age, with larger HRs for RT in AAs. Radiotolerance score (RTS) of normal airway epithelium from young AA women was significantly lower than that from young Caucasian women (P = .038). CONCLUSIONS: With a projected 25-year follow-up, RT is associated with elevated risk of nonbreast SMNs, particularly second lung cancer, in young women survivors of stage I-IIIA breast cancer. Nonbreast SMNs associated with RT are higher in AA women than Caucasian women.

The School Contextual Effect of Sexual Debut on Sexual Risk-Taking: A Joint Parameter Approach.

BACKGROUND: Previous research has identified individual and school-level characteristics that are associated with sexual risk-taking, but the impact of school-level mechanisms on sexual risk-taking is not well understood. We examine the aggregated effects that early sex at the school level have on risky sexual behaviors. METHODS: We use 3 waves of data from the National Longitudinal Study of Adolescent Health. An individual's first sexual intercourse before age 15 was recorded along with various risky sexual behaviors at debut. Two variables at respondent's later stage of life were also included: having sex in exchange for drugs or money, and contraction of sexually transmitted disease (STD). Longitudinal analysis was conducted using a joint parameter model that tested unobserved school effects on individual behaviors simultaneously. RESULTS: An increase in early sexual initiation at the school level was associated with higher probability of sexual debut, along with increased involvement in sexual risk-taking controlling for student family background. CONCLUSIONS: School behavioral mechanisms are directly related to sexual health behaviors among youth. Our findings have implications for school-based interventions, education programs, and the role of parents.

Gender differences in trajectories of alcohol use from ages 13 to 33 across Latina/o ethnic groups.

BACKGROUND: Research examining alcohol use trajectories among Latina/os is scarce. Further, prior findings on alcohol use by ethnic group and gender is mixed. The purpose of this study was twofold: (a.) to examine developmental trajectories for two types of alcohol (drunkenness and heavy drinking) use across four Latina/o ethnic groups (Cubans, Puerto Ricans, Central/South American, and Mexican Americans) and, (b.) to examine the role of gender and ethnicity in developmental trajectories of drunkenness and heavy drinking among Latina/os. METHODS: Data were drawn from Waves I-IV of the National Longitudinal Study of Adolescent to Adult Health. The sample consisted of 1670 Latina/os that were followed from adolescence into adulthood. Multi-level logistic regression models were used to estimate drunkenness and heavy drinking trajectories and trajectories by gender. RESULTS: indicate that, for all four ethnic groups examined, the probability of drunkenness and heavy drinking gradually increased in adolescence, peaked in "emerging adulthood", and decreased as they transitioned into adulthood. Findings also show divergent age trajectories by gender, but patterns varied across ethnicity and alcohol use outcome. CONCLUSIONS: Key findings from this study demonstrate that among Latina/os, there are critical developmental periods for reported drunkenness and heavy drinking in the last 12 months, and that ethnicity and gender play substantial roles in the development of hazardous alcohol use over the life course.

Parental involvement, adolescents' self-determined learning and academic achievement in Urban China.

Self-determined learning is essential to academic success. The motivational resources development model argues that parents promote academic success in their children indirectly by nurturing self-determined learner. In this study, applying a structural equation modelling and using data collected from 8th graders in Zhuhai, China (n = 1009) in 2012, we aim to answer 2 research questions: (a) What forms of parental involvement are highly correlated with self-determined learning and (b) Can self-determined learning fully mediate the relationship between parental involvement and students' academic performance? We find that parental leisure involvement is positively and significantly associated with the development of self-determined learning, which in turn is significantly and positively correlated with academic achievement. Parental provision of structure or parental academic assistance is not significantly associated with students' self-regulation and students' academic achievement.

Social isolation, drunkenness, and cigarette use among adolescents.

INTRODUCTION: This study compares isolated to sociable youth to investigate the relations between different network types of social isolation and alcohol and cigarette use. METHODS: Using data from the National Longitudinal Study of Adolescent to Adult Health we developed a network measure that includes various types of social isolation. Types of social isolation were operationalized as socially avoidant, actively isolated, and socially disinterested, with sociable youth as the reference category. Random effects ordinal logit models were fit to estimate the association between different types of social isolation and drunkenness and cigarette use. RESULTS: Different types of social isolation had varying effects on drunkenness and cigarette use. On the one hand, socially disinterested youth were at an increased risk for drunkenness and cigarette use. On the other hand, socially avoidant youth had lower odds of drunkenness and no significant differences in cigarette use when compared to sociable youth. Actively isolated youth showed no differences in drunkenness and cigarette use. CONCLUSIONS: The role played by marginalized social positions in youth substance use is an important yet overlooked problem. This study can contribute to better targeted and more effective health behavior prevention efforts for vulnerable adolescents.

Peer Influence, Genetic Propensity, and Binge Drinking: A Natural Experiment and a Replication.

The authors draw data from the College Roommate Study (ROOM) and the National Longitudinal Study of Adolescent Health to investigate gene-environment interaction effects on youth binge drinking. In ROOM, the environmental influence was measured by the precollege drinking behavior of randomly assigned roommates. Random assignment safeguards against friend selection and removes the threat of gene-environment correlation that makes gene-environment interaction effects difficult to interpret. On average, being randomly assigned a drinking peer as opposed to a nondrinking peer increased college binge drinking by 0.5-1.0 episodes per month, or 20%-40% the average amount of binge drinking. However, this peer influence was found only among youths with a medium level of genetic propensity for alcohol use; those with either a low or high genetic propensity were not influenced by peer drinking. A replication of the findings is provided in data drawn from Add Health. The study shows that gene-environment interaction analysis can uncover social-contextual effects likely to be missed by traditional sociological approaches.

Genetic bio-ancestry and social construction of racial classification in social surveys in the contemporary United States.

Self-reported race is generally considered the basis for racial classification in social surveys, including the U.S. census. Drawing on recent advances in human molecular genetics and social science perspectives of socially constructed race, our study takes into account both genetic bio-ancestry and social context in understanding racial classification. This article accomplishes two objectives. First, our research establishes geographic genetic bio-ancestry as a component of racial classification. Second, it shows how social forces trump biology in racial classification and/or how social context interacts with bio-ancestry in shaping racial classification. The findings were replicated in two racially and ethnically diverse data sets: the College Roommate Study (N = 2,065) and the National Longitudinal Study of Adolescent Health (N = 2,281).

Social capital and self-rated health among middle-aged and older adults in China: a multilevel analysis.

This study examined the association between social capital, at both the individual and the community level, and self-rated health among older adults in China. Using data from the 2008 Pilot Survey of China Health and Retirement Longitudinal Study, a series of multilevel logistic models were estimated in SAS 9.2. The association between social capital and self-rated health was examined among 996 adults aged 45 or older from two provinces in China, while controlling for demographic characteristics and socioeconomic variables. Our results suggest the significant association between certain aspects of social capital, at both the individual and the community level, and self-rated health. The individual-level social capital in the form of perceived help in the future and the social capital of community in the form of the availability of amenities and associations within the community were significantly related to self-rated health. A significant cross-level interaction effect between individual- and community-level social capital was also observed.

The dopamine transporter gene, a spectrum of most common risky behaviors, and the legal status of the behaviors.

This study tests the specific hypothesis that the 9R/9R genotype in the VNTR of the dopamine transporter gene (DAT1) exerts a general protective effect against a spectrum of risky behaviors in comparison to the 10R/9R and 10R/10R genotypes, drawing on three-time repeated measures of risky behaviors in adolescence and young adulthood on about 822 non-Hispanic white males from the Add Health study. Our data have established two empirical findings. The first is a protective main effect in the DAT1 gene against risky behaviors. The second finding is that the protective effect varies over age, with the effect prominent at ages when a behavior is illegal and the effect largely vanished at ages when the behavior becomes legal or more socially tolerated. Both the protective main effect and the gene-lifecourse interaction effect are replicated across a spectrum of most common risky behaviors: delinquency, variety of sexual partners, binge drinking, drinking quantity, smoking quantity, smoking frequency, marijuana use, cocaine use, other illegal drug use, and seatbelt non-wearing. We also compared individuals with the protective genotype and individuals without it in terms of age, physical maturity, verbal IQ, GPA, received popularity, sent popularity, church attendance, two biological parents, and parental education. These comparisons indicate that the protective effect of DAT1*9R/9R cannot be explained away by these background characteristics. Our work demonstrates how legal/social contexts can enhance or reduce a genetic effect on risky behaviors.

Gene-Environment Interactions: Peers' Alcohol Use Moderates Genetic Contribution to Adolescent Drinking Behavior.

Social context is increasingly recognized as essential for understanding complex human outcomes even among geneticists who focus on genetic influences. These outcomes typically involve multiple genes, multiple environmental factors, and the interactions between the two. In this paper, we propose a conceptual framework for gene-environment interaction and show how the interaction can be tested empirically using a sample of MZ twin, DZ twins, and full siblings. We test the hypothesis that the genetic contribution to adolescent drinking depends on the drinking behavior of their friends, using a sample of clusters of siblings and their friends from Add Health. Our analysis has yielded evidence supporting the gene-environment interaction hypothesis. High levels of alcohol use by one's best friend or among one's friends tend to bring about higher levels of genetic contribution to alcohol use. Lower levels of alcohol use by one's best friend or among one's friends tend to suppress the level of genetic contribution to alcohol use. Our findings suggest that friend behavior might be a particularly important environmental moderator of the expression of genetic disposition for adolescent drug use, smoking, dietary habits, and risky sexual behavior. Subsequent studies of these behaviors that use non-DNA twin samples or DNA measures of genetic variants should investigate peer influence as a significant environmental moderator.