High-Throughput Covalent Modifier Screening with Acoustic Ejection Mass Spectrometry.

Interests in covalent drugs have grown in modern drug discovery as they could tackle challenging targets traditionally considered "undruggable". The identification of covalent binders to target proteins typically involves directly measuring protein covalent modifications using high-resolution mass spectrometry. With a continually expanding library of compounds, conventional mass spectrometry platforms such as LC-MS and SPE-MS have become limiting factors for high-throughput screening. Here, we introduce a prototype high-resolution acoustic ejection mass spectrometry (AEMS) system for the rapid screening of a covalent modifier library comprising ∼10,000 compounds against a 50 kDa-sized target protein─Werner syndrome helicase. The screening samples were arranged in a 1536-well format. The sample buffer containing high-concentration salts was directly analyzed without any cleanup steps, minimizing sample preparation efforts and ensuring protein stability. The entire AEMS analysis process could be completed within a mere 17 h. An automated data analysis tool facilitated batch processing of the sample data and quantitation of the formation of various covalent protein-ligand adducts. The screening results displayed a high degree of fidelity, with a Z' factor of 0.8 and a hit rate of 2.3%. The identified hits underwent orthogonal testing in a biochemical activity assay, revealing that 75% were functional antagonists of the target protein. Notably, a comparative analysis with LC-MS showcased the AEMS platform's low risk of false positives or false negatives. This innovative platform has enabled robust high-throughput covalent modifier screening, featuring a 10-fold increase in library size and a 10- to 100-fold increase in throughput when compared with similar reports in the existing literature.

Nanoscale synthesis and affinity ranking.

Most drugs are developed through iterative rounds of chemical synthesis and biochemical testing to optimize the affinity of a particular compound for a protein target of therapeutic interest. This process is challenging because candidate molecules must be selected from a chemical space of more than 1060 drug-like possibilities 1 , and a single reaction used to synthesize each molecule has more than 107 plausible permutations of catalysts, ligands, additives and other parameters 2 . The merger of a method for high-throughput chemical synthesis with a biochemical assay would facilitate the exploration of this enormous search space and streamline the hunt for new drugs and chemical probes. Miniaturized high-throughput chemical synthesis3-7 has enabled rapid evaluation of reaction space, but so far the merger of such syntheses with bioassays has been achieved with only low-density reaction arrays, which analyse only a handful of analogues prepared under a single reaction condition8-13. High-density chemical synthesis approaches that have been coupled to bioassays, including on-bead 14 , on-surface 15 , on-DNA 16 and mass-encoding technologies 17 , greatly reduce material requirements, but they require the covalent linkage of substrates to a potentially reactive support, must be performed under high dilution and must operate in a mixture format. These reaction attributes limit the application of transition-metal catalysts, which are easily poisoned by the many functional groups present in a complex mixture, and of transformations for which the kinetics require a high concentration of reactant. Here we couple high-throughput nanomole-scale synthesis with a label-free affinity-selection mass spectrometry bioassay. Each reaction is performed at a 0.1-molar concentration in a discrete well to enable transition-metal catalysis while consuming less than 0.05 milligrams of substrate per reaction. The affinity-selection mass spectrometry bioassay is then used to rank the affinity of the reaction products to target proteins, removing the need for time-intensive reaction purification. This method enables the primary synthesis and testing steps that are critical to the invention of protein inhibitors to be performed rapidly and with minimal consumption of starting materials.

Life-course trajectories of body mass index from adolescence to old age: Racial and educational disparities.

No research exists on how body mass index (BMI) changes with age over the full life span and social disparities therein. This study aims to fill the gap using an innovative life-course research design and analytic methods to model BMI trajectories from early adolescence to old age across 20th-century birth cohorts and test sociodemographic variation in such trajectories. We conducted the pooled integrative data analysis (IDA) to combine data from four national population-based NIH longitudinal cohort studies that collectively cover multiple stages of the life course (Add Health, MIDUS, ACL, and HRS) and estimate mixed-effects models of age trajectories of BMI for men and women. We examined associations of BMI trajectories with birth cohort, race/ethnicity, parental education, and adult educational attainment. We found higher mean levels of and larger increases in BMI with age across more recent birth cohorts as compared with earlier-born cohorts. Black and Hispanic excesses in BMI compared with Whites were present early in life and persisted at all ages, and, in the case of Black-White disparities, were of larger magnitude for more recent cohorts. Higher parental and adulthood educational attainment were associated with lower levels of BMI at all ages. Women with college-educated parents also experienced less cohort increase in mean BMI. Both race and education disparities in BMI trajectories were larger for women compared with men.

MRI of the Spine in Patients who Toe Walk: Is There a Role?

BACKGROUND: Little is known about the prevalence of intraspinal pathology in children who toe walk, but magnetic resonance imaging (MRI) may be part of the diagnostic workup. The purpose of this study was to examine the role of MRI for children who toe walk with a focus on the rate of positive findings and associated neurosurgical interventions performed for children with said MRI findings. METHODS: A single-center tertiary hospital database was queried to identify a cohort of 118 subjects with a diagnosis of toe walking who underwent spinal MRI during a 5-year period. Patient and MRI characteristics were summarized and compared between subjects with a major abnormality, minor abnormality, or no abnormality on MRI using multivariable logistic regression. Major MRI abnormalities included those with a clear spinal etiology, such as fatty filum, tethered cord, syrinx, and Chiari malformation, while minor abnormalities had unclear associations with toe walking. RESULTS: The most common primary indications for MRI were failure to improve with conservative treatment, severe contracture, and abnormal reflexes. The prevalence of major MRI abnormalities was 25% (30/118), minor MRI abnormalities was 19% (22/118), and normal MRI was 56% (66/118). Patients with delayed onset of toe walking were significantly more likely to have a major abnormality on MRI ( P =0.009). The presence of abnormal reflexes, severe contracture, back pain, bladder incontinence, and failure to improve with conservative treatment were not significantly associated with an increased likelihood of major abnormality on MRI. Twenty-nine (25%) subjects underwent tendon lengthening, and 5 (4%) underwent neurosurgical intervention, the most frequent of which was detethering and sectioning of fatty filum. CONCLUSIONS: Spinal MRI in patients who toe walk has a high rate of major positive findings, some of which require neurosurgical intervention. The most significant predictor of intraspinal pathology was the late onset of toe walking after the child had initiated walking. MRI of the spine should be considered by pediatric orthopedic surgeons in patients with toe walking who present late with an abnormal clinical course. LEVEL OF EVIDENCE: Level III Retrospective Comparative Study.

Informing Harmonization Decisions in Integrative Data Analysis: Exploring the Measurement Multiverse.

Combining datasets in an integrative data analysis (IDA) requires researchers to make a number of decisions about how best to harmonize item responses across datasets. This entails two sets of steps: logical harmonization, which involves combining items which appear similar across datasets, and analytic harmonization, which involves using psychometric models to find and account for cross-study differences in measurement. Embedded in logical and analytic harmonization are many decisions, from deciding whether items can be combined prima facie to how best to find covariate effects on specific items. Researchers may not have specific hypotheses about these decisions, and each individual choice may seem arbitrary, but the cumulative effects of these decisions are unknown. In the current study, we conducted an IDA of the relationship between alcohol use and delinquency using three datasets (total N = 2245). For analytic harmonization, we used moderated nonlinear factor analysis (MNLFA) to generate factor scores for delinquency. We conducted both logical and analytic harmonization 72 times, each time making a different set of decisions. We assessed the cumulative influence of these decisions on MNLFA parameter estimates, factor scores, and estimates of the relationship between delinquency and alcohol use. There were differences across paths in MNLFA parameter estimates, but fewer differences in estimates of factor scores and regression parameters linking delinquency to alcohol use. These results suggest that factor scores may be relatively robust to subtly different decisions in data harmonization, and measurement model parameters are less so.

Effects of Healthcare Organization Actions and Policies Related to COVID-19 on Perceived Organizational Support Among U.S. Internists: A National Study.

GOAL: Perceived organizational support (POS) may promote healthcare worker mental health, but organizational factors that foster POS during the COVID-19 pandemic are unknown. The goals of this study were to identify actions and policies regarding COVID-19 that healthcare organizations can implement to promote POS and to evaluate the impact of POS on physicians' mental health, burnout, and intention to leave patient care. METHODS: We conducted a cross-sectional national survey with an online panel of internal medicine physicians from the American College of Physicians in September and October of 2020. POS was measured with a 4-item scale, based on items from Eisenberger's Perceived Organizational Support Scale that were adapted for the pandemic. Mental health outcomes and burnout were measured with short screening scales. PRINCIPAL FINDINGS: The response rate was 37.8% (N = 810). Three healthcare organization actions and policies were independently associated with higher levels of POS in a multiple linear regression model that included all actions and policies as well as potential confounding factors: opportunities to discuss ethical issues related to COVID-19 (ß (regression coefficient) = 0.74, p = .001), adequate access to personal protective equipment (ß = 1.00, p = .005), and leadership that listens to healthcare worker concerns regarding COVID-19 (ß = 3.58, p < .001). Sanctioning workers who speak out on COVID-19 safety issues or refuse pandemic deployment was associated with lower POS (ß = -2.06, p < .001). In multivariable logistic regression models, high POS was associated with approximately half the odds of screening positive for generalized anxiety, depression, post-traumatic stress disorder, burnout, and intention to leave patient care within 5 years. APPLICATIONS TO PRACTICE: Our results suggest that healthcare organizations may be able to increase POS among physicians during the COVID-19 pandemic by guaranteeing adequate personal protective equipment, making sure that leaders listen to concerns about COVID-19, and offering opportunities to discuss ethical concerns related to caring for patients with COVID-19. Other policies and actions such as rapid COVID-19 tests may be implemented for the safety of staff and patients, but the policies and actions associated with POS in multivariable models in this study are likely to have the largest positive impact on POS. Warning or sanctioning workers who refuse pandemic deployment or speak up about worker and patient safety is associated with lower POS and should be avoided. We also found that high degrees of POS are associated with lower rates of adverse outcomes. So, by implementing the tangible support policies positively associated with POS and avoiding punitive ones, healthcare organizations may be able to reduce adverse mental health outcomes and attrition among their physicians.

SAR towards indoline and 3-azaindoline classes of IDO1 inhibitors.

A novel series of IDO1 inhibitors have been identified with good IDO1 Hela cell and human whole blood activity. These inhibitors contain an indoline or a 3-azaindoline scaffold. Their structure-activity-relationship studies have been explored. Compounds 37 and 41 stood out as leads due to their good potency in IDO1 Hela assay, good IDO1 unbound hWB IC50s, reasonable unbound clearance, and good MRT in rat and dog PK studies.

Preoperative Considerations for Teenagers Undergoing Orthopaedic Surgery: VTE Prevention, Mental Health Assessment, Vaping, and Drug Addiction.

INTRODUCTION: Adolescents undergoing pediatric orthopaedic surgery typically experience an uncomplicated postoperative course. However, adolescence represents a unique transition period from pediatric to adult physiology. As a result, the astute pediatric orthopaedic surgeon will be aware of unique medical and social scenarios which are relevant to adolescents during the perioperative course including the risk of venous thromboembolism (VTE), prevalence of mental health conditions, and rising use of electronic cigarettes or "vaping" to consume nicotine and cannibas. DISCUSSION: Adolescents are at a greater risk of VTE after pediatric orthopaedic surgery. In particular, adolescent females with a family history of blood clotting disorders and those with a change in mobility after surgery should be considered for prophylaxis. The prevalence of adolescent mental health conditions including anxiety, depression, and behavioral issues is increasing in the United States. Higher levels of preoperative anxiety and the presence of mental health pathology are associated with slower recovery, higher levels of postoperative pain, and the increased likelihood for chronic pain. Several quick screening instruments are available to assess adolescents for preoperative anxiety risk, including the Visual Analogue Scale for Anxiety or the Amsterdam Perioperative Anxiety Information Scale. Unfortunately, electronic cigarettes have become increasingly popular for the consumption of nicotine and cannabis among adolescents. Preoperative use of combustive cigarettes (nicotine/cannabis) represents perioperative risks for induction/anesthesia, postoperative pain, and analgesia requirements and issues with delayed wound and fracture healing. CONCLUSIONS: VTE, underlying mental health conditions, and usage of nicotine and cannabis are clear detriments to the recovery and healing of adolescent patients following orthopaedic surgery. Therefore, standardized screening for adolescents before orthopaedic surgery is indicated to identify perioperative risk factors which have negative impacts on functional outcomes.

Harmonizing altered measures in integrative data analysis: A methods analogue study.

In the current study, we used an analogue integrative data analysis (IDA) design to test optimal scoring strategies for harmonizing alcohol- and drug-use consequence measures with varying degrees of alteration across four study conditions. We evaluated performance of mean, confirmatory factor analysis (CFA), and moderated nonlinear factor analysis (MNLFA) scores based on traditional indices of reliability (test-retest, internal, and score recovery or parallel forms) and validity. Participants in the analogue study included 854 college students (46% male; 21% African American, 5% Hispanic/Latino, 56% European American) who completed two versions of the altered measures at two sessions, separated by 2 weeks. As expected, mean, CFA, and MNLFA scores all resulted in scales with lower reliability given increasing scale alteration (with less fidelity to formerly developed scales) and shorter scale length. MNLFA and CFA scores, however, showed greater validity than mean scores, demonstrating stronger relationships with external correlates. Implications for measurement harmonization in the context of IDA are discussed.

Practice Patterns for Management of Pediatric Femur Fractures in Low- and Middle-Income Countries.

BACKGROUND: Femoral shaft fractures in children are common in low and middle income countries. In high-income countries, patient age, fracture pattern, associated injuries, child/family socioeconomic status, and surgeon preference dictate fracture management. There is limited literature on treatment patterns for pediatric femur fractures in resource-limited settings. This study surveys surgeons from low (LIC), lower-middle (LMIC), and upper-middle income (UMIC) countries regarding treatment patterns for pediatric femur fractures. METHODS: Surgeons completed an electronic survey reporting surgeon demographics and treatment preference for pediatric femur fractures. Treatment preferences and indications for treatment were separated into 4 groups: infant (0 to 6 mo); toddler (7 mo to 4 y); child (5 to 12 y); adolescent (12 to 17 y). The survey was available in English, Spanish, and French. Analysis was completed with t test and χ test for continuous and categorical variables, respectively, and weighted Pearson correlation (P<0.05). RESULTS: Survey respondents consisted of 413 surgeons from 83 countries (20 LIC, 33 LMIC, 30 UMIC). The majority of respondents were fellowship trained (83%) most commonly in pediatrics (26%) and trauma (43%). Most treated >10 pediatric femur fractures per year (68%). Respondents reported treating infant femur fractures nonoperatively using Pavlik harness (19%), spica cast (60%), or traction with delayed spica cast (14%). Decreasing socioeconomic status was associated with higher nonoperative treatment rate in toddlers, children, and adolescents. Respondents commonly utilize bed rest and traction for child femur fractures in LICs (63%) and LMICs (65%) compared with UMICs (35%) (UMIC vs. LMIC P<0.001; UMIC vs. LIC P<0.001). Surgeries in children more commonly involve open reduction with internal fixation (UMIC 19%, LMIC 33%, LIC 40%; P<0.05 between UMIC-LMIC and UMIC-LIC). CONCLUSION: This is one of the largest surveys describing treatment patterns for pediatric femur fractures in low and middle income countries. Differences are evident including lower operative treatment rate in younger children and lower intramedullary fixation rates in older children. Future studies should investigate the value of treatment options in resource-limited settings. LEVEL OF EVIDENCE: Level II-prospective comparative study.

Bidirectional Relations between Witnessing Violence, Victimization, Life Events, and Physical Aggression among Adolescents in Urban Schools.

Although there is empirical evidence supporting associations between exposure to violence and engaging in physically aggressive behavior during adolescence, there is limited longitudinal research to determine the extent to which exposure to violence is a cause or a consequence of physical aggression, and most studies have not addressed the influence of other negative life events experienced by adolescents. This study examined bidirectional relations between physical aggression, two forms of exposure to violence-witnessing violence and victimization, and other negative life events. Participants were a sample of 2568 adolescents attending three urban public middle schools who completed measures of each construct every 3 months during middle school. Their mean age was 12.76 (SD = 0.98); 52% were female. The majority were African American (89%); 17% were Hispanic or Latino/a. Cross-lagged regression analyses across four waves of data collected within the same grade revealed bidirectional relations between witnessing violence and physical aggression, and between witnessing violence and negative life events. Although physical aggression predicted subsequent changes in victimization, victimization predicted changes in physical aggression only when witnessing violence was not taken into account. Findings were consistent across sex and grades. Overall, these findings highlight the need for interventions that break the connection between exposure to violence and aggression during adolescence.

Role of ADHD in the Co-Occurrence Between Heavy Alcohol Use and Depression Trajectories in Adulthood.

BACKGROUND: Attention-deficit/hyperactivity disorder (ADHD) is associated with greater heavy alcohol use and depressive symptoms in adulthood. Yet, few studies have investigated whether childhood ADHD predicts an increased association between heavy drinking and depression in adulthood when this co-occurrence becomes more common. We examined associations among heavy alcohol use and depression longitudinally from ages 21 to 29 and whether these associations differed for those with or without childhood ADHD, as well as for those with or without persistent ADHD in adulthood. METHODS: Data were from the Pittsburgh ADHD Longitudinal Study, a prospective cohort of children diagnosed with ADHD and demographically similar individuals without ADHD histories. ADHD symptoms in adulthood were self- and parent reported; depressive symptoms and frequency of drinking 5 or more drinks in a single drinking occasion were self-reported and measured at 5 time-points from ages 21 to 29. Depression and alcohol use were modeled in a multiple-group, parallel process longitudinal growth model. RESULTS: The slopes of heavy alcohol use and depression were significantly and positively associated from ages 25 to 29 but not at the younger ages. Although the strength of these associations did not differ by group (with or without ADHD, childhood or adulthood), the slopes of depression and heavy drinking at the older ages were highly variable and individuals with ADHD showed significantly faster growth in depression from ages 25 to 29. CONCLUSIONS: Due to the strengthening association between heavy drinking and depression for adults in their late 20s, and increasing depression for adults with ADHD histories, individuals with ADHD may be at greater risk for co-occurring depression and binge drinking. Negative reinforcement-related alcohol use may strengthen as these individuals age toward the fourth decade of life. More rigorous testing of this possibility is warranted.

ISSLS PRIZE IN BIOENGINEERING SCIENCE 2019: biomechanical changes in dynamic sagittal balance and lower limb compensatory strategies following realignment surgery in adult spinal deformity patients.

STUDY DESIGN: A longitudinal cohort study. OBJECTIVE: To define a set of objective biomechanical metrics that are representative of adult spinal deformity (ASD) post-surgical outcomes and that may forecast post-surgical mechanical complications. Current outcomes for ASD surgical planning and post-surgical assessment are limited to static radiographic alignment and patient-reported questionnaires. Little is known about the compensatory biomechanical strategies for stabilizing sagittal balance during functional movements in ASD patients. METHODS: We collected in-clinic motion data from 15 ASD patients and 10 controls during an unassisted sit-to-stand (STS) functional maneuver. Joint motions were measured using noninvasive 3D depth mapping sensor technology. Mathematical methods were used to attain high-fidelity joint-position tracking for biomechanical modeling. This approach provided reliable measurements for biomechanical behaviors at the spine, hip, and knee. These included peak sagittal vertical axis (SVA) over the course of the STS, as well as forces and muscular moments at various joints. We compared changes in dynamic sagittal balance (DSB) metrics between pre- and post-surgery and then separately compared pre- and post-surgical data to controls. RESULTS: Standard radiographic and patient-reported outcomes significantly improved following realignment surgery. From the DSB biomechanical metrics, peak SVA and biomechanical loads and muscular forces on the lower lumbar spine significantly reduced following surgery (- 19 to - 30%, all p < 0.05). In addition, as SVA improved, hip moments decreased (- 28 to - 65%, all p < 0.05) and knee moments increased (+ 7 to + 28%, p < 0.05), indicating changes in lower limb compensatory strategies. After surgery, DSB data approached values from the controls, with some post-surgical metrics becoming statistically equivalent to controls. CONCLUSIONS: Longitudinal changes in DSB following successful multi-level spinal realignment indicate reduced forces on the lower lumbar spine along with altered lower limb dynamics matching that of controls. Inadequate improvement in DSB may indicate increased risk of post-surgical mechanical failure. These slides can be retrieved under Electronic Supplementary Material.

Functional workspace and patient-reported outcomes improve after reverse and total shoulder arthroplasty.

BACKGROUND: Low-cost motion analysis systems (LCMASs) have emerged as easy and practical methods to measure the functional workspace (FWS). Thus, we ventured to apply an LCMAS, the Kinect2 gaming camera, to evaluate the FWS in patients with shoulder osteoarthritis (OA) and patients who underwent total shoulder arthroplasty (TSA) or reverse total shoulder arthroplasty (RTSA). METHODS: A cross-sectional study of participants with OA (n = 53), TSA (n = 70), and RTSA (n = 34) was performed. The FWS as measured by an LCMAS, the American Shoulder and Elbow Surgeons (ASES) Standardized Shoulder Assessment Form score, and the Patient-Reported Outcomes Measurement Information System (PROMIS) score were collected. For participants who underwent TSA or RTSA, the FWS was evaluated at 6, 12, and 24 months postoperatively. The correlation of the FWS with the ASES score and PROMIS score was determined. Significance was set at P < .05. RESULTS: Patients who underwent TSA or RTSA had a significantly higher FWS than patients with shoulder OA at almost all time points. Patients who underwent TSA had a significantly higher FWS than patients who underwent RTSA at 24 months after surgery. PROMIS and ASES scores showed strong correlations with the FWS in patients who underwent TSA (R = 0.75 [P < .001] and R = 0.83 [P < .001], respectively) and RTSA (R = 0.84 [P < .001] and R = 0.73 [P < .001], respectively). CONCLUSION: The FWS measured by an LCMAS is an easy and low-cost method to quantify the reachable space of the hand in patients and shows strong correlations with patient-reported outcome measures. This may be a useful tool to assess upper-extremity range of motion before and after shoulder arthroplasty.

The Increasing Diversity and Complexity of Family Structures for Adolescents.

The structure of adolescents' families, and thus parental forms, in the United States, have become more heterogeneous and fluid over the past several decades. These changes are due to increases in never-married, single parents, divorce, cohabitation, same-sex parenting, multi-partnered fertility, and co-residence with grandparents. We document current diversity and complexity in adolescents' families as important context for rethinking future parenting theory and research. We also discuss how understandings of adolescents' families are somewhat limited by current methods used to measure characteristics of families. We recommend social network and profile-based methods as alternatives to capturing key dimensions of family structure and processes. Understanding the diversity of households and families in which adolescents are raised can improve theory and research on parenting.

Bipolar Bone Loss in Patients With Anterior Shoulder Dislocation: A Comparison of Adolescents Versus Adult Patients.

PURPOSE: To compare bipolar bone loss by evaluating the degree of glenoid bone loss, Hill-Sachs lesion size, and glenoid track in adolescents and adults with shoulder dislocations. METHODS: We performed a retrospective review between 2012 and 2016 of surgical and nonsurgical patients with a history of anterior shoulder dislocations (primary or recurrent) who underwent magnetic resonance imaging of the affected shoulder. The exclusion criteria included multidirectional instability, prior surgery, and posterior dislocation. Patients were grouped into 2 groups: adolescents (aged 10-19 years) and adults (aged ≥20 years). The groups were compared regarding measures of glenoid bone loss (best-fit circle technique) and Hill-Sachs lesion size (medial margin of rotator cuff footprint to medial margin of Hill-Sachs lesion). If the medial margin of a Hill-Sachs lesion was within the glenoid track, it was defined as on track; if it was more medial than the glenoid track, it was defined as off track. RESULTS: We identified 45 adolescents (mean age, 16.1 years) and 30 adults (mean age, 28.9 years) with anterior shoulder dislocations. There was no significant difference in percentage of bone loss between adolescents (mean, 8.4%) and adults (mean, 9.9%; P = .23). There was no significant difference in Hill-Sachs lesion size between adolescents (mean, 12.7 mm) and adults (mean, 9.9 mm; P = .12). There were 12 patients with off-track lesions. Off-track lesions were present in 11 of 45 adolescents (24.4%) and 1 of 30 adults (3.3%). Adolescents had an increased risk of having an off-track lesion (odds ratio, 9.38; 95% confidence interval, 1.14-77.1). A subgroup analysis identified multiple dislocations as an independent risk factor for an off-track lesion (odds ratio, 4.15; 95% confidence interval, 0.85-20.23). CONCLUSIONS: This study shows that adolescence and a history of multiple dislocations are independent risk factors for a greater likelihood of glenoid off-track lesions. The findings support the use of bipolar assessment of shoulder dislocators, especially in adolescents and multiple dislocators. LEVEL OF EVIDENCE: Level III, retrospective comparative study.

A novel modeling framework for ordinal data defined by collapsed counts.

Adolescent alcohol use is a serious public health concern. Despite advances in the theoretical conceptualization of pathways to alcohol use, researchers are limited by the statistical techniques currently available. Researchers often fit linear models and restrictive categorical models (e.g., proportional odds models) to ordinal data with many response categories defined by collapsed count data (0 drinking days, 1-2 days, 3-6 days, etc.). Consequently, existing models ignore the underlying count process, resulting in disjoint between the construct of interest and the models being fitted. Our proposed ordinal modeling approach overcomes this limitation by explicitly linking ordinal responses to a suitable underlying count distribution. In doing so, researchers can use maximum likelihood estimation to fit count models to ordinal data as if they had directly observed the underlying discrete counts. The usefulness of our ordinal negative binomial and ordinal zero-inflated negative binomial models is verified by simulation studies. We also demonstrate our approach using real empirical data from the 2010 National Survey of Drug Use and Health. Results show the benefit of the proposed ordinal modeling framework compared with existing methods.

Modulating the interaction between CDK2 and cyclin A with a quinoline-based inhibitor.

A new class of quinoline-based kinase inhibitors has been discovered that both disrupt cyclin dependent 2 (CDK2) interaction with its cyclin A subunit and act as ATP competitive inhibitors. The key strategy for discovering this class of protein-protein disrupter compounds was to screen the monomer CDK2 in an affinity-selection/mass spectrometry-based technique and to perform secondary assays that identified compounds that bound only to the inactive CDK2 monomer and not the active CDK2/cyclin A heterodimer. Through a series of chemical modifications the affinity (Kd) of the original hit improved from 1 to 0.005µM.

A Moderated Nonlinear Factor Model for the Development of Commensurate Measures in Integrative Data Analysis.

Integrative data analysis (IDA) is a methodological framework that allows for the fitting of models to data that have been pooled across two or more independent sources. IDA offers many potential advantages including increased statistical power, greater subject heterogeneity, higher observed frequencies of low base-rate behaviors, and longer developmental periods of study. However, a core challenge is the estimation of valid and reliable psychometric scores that are based on potentially different items with different response options drawn from different studies. In Bauer and Hussong (2009) we proposed a method for obtaining scores within an IDA called moderated nonlinear factor analysis (MNLFA). Here we move significantly beyond this work in the development of a general framework for estimating MNLFA models and obtaining scale scores across a variety of settings. We propose a five step procedure and demonstrate this approach using data drawn from n=1972 individuals ranging in age from 11 to 34 years pooled across three independent studies to examine the factor structure of 17 binary items assessing depressive symptomatology. We offer substantive conclusions about the factor structure of depression, use this structure to compute individual-specific scale scores, and make recommendations for the use of these methods in practice.

Latent growth factors as predictors of distal outcomes.

A currently overlooked application of the latent curve model (LCM) is its use in assessing the consequences of development patterns of change-that is as a predictor of distal outcomes. However, there are additional complications for appropriately specifying and interpreting the distal outcome LCM. Here, we develop a general framework for understanding the sensitivity of the distal outcome LCM to the choice of time coding, focusing on the regressions of the distal outcome on the latent growth factors. Using artificial and real-data examples, we highlight the unexpected changes in the regression of the slope factor which stand in contrast to prior work on time coding effects, and develop a framework for estimating the distal outcome LCM at a point in the trajectory-known as the aperture-which maximizes the interpretability of the effects. We also outline a prioritization approach developed for assessing incremental validity to obtain consistently interpretable estimates of the effect of the slope. Throughout, we emphasize practical steps for understanding these changing predictive effects, including graphical approaches for assessing regions of significance similar to those used to probe interaction effects. We conclude by providing recommendations for applied research using these models and outline an agenda for future work in this area. (PsycInfo Database Record (c) 2024 APA, all rights reserved).