Prenatal cocaine exposure and self-reported behavioral adjustments from ages 12 to 21: environmental pathways.

BACKGROUND: In a birth-cohort study, we followed offspring with prenatal cocaine exposure (PCE) to investigate longitudinal associations of PCE with self-reported behavioral adjustment from early adolescence to emerging adulthood (EA). Environmental pathways (family functioning, non-kinship care, maltreatment) were specified as potential mediators of PCE. METHODS: Participants were 372 (190 PCE; 47% male), primarily Black, low socioeconomic status, enrolled at birth. Internalizing and externalizing behaviors were assessed using Youth Self-Report at ages 12 and 15 and Adult Self-Report at age 21. Extended random-intercept cross-lagged panel modeling was used to account for potential bidirectional relationships between internalizing and externalizing behaviors over time, examining potential mediators. RESULTS: Adjusting for covariates, significant indirect effects were found for each mediator at different ages. For family functioning, these were both internalizing (ß = 0.83, p = 0.04) and externalizing behaviors (ß = 1.58, p = 0.02) at age 12 and externalizing behaviors at age 15 (ß = 0.51, p = 0.03); for non-kinship care, externalizing behaviors at ages 12 (ß = 0.63, p = 0.02) and 15 (ß = 0.20, p = 0.03); and for maltreatment, both internalizing and externalizing behaviors at ages 15 (ß = 0.64, p = 0.02 for internalizing; ß = 0.50, p = 0.03 for externalizing) and 21 (ß = 1.39, p = 0.01 for internalizing; ß = 1.11, p = 0.01 for externalizing). Direct associations of PCE with internalizing and externalizing behaviors were not observed, nor cross-lagged relationships between internalizing and externalizing behaviors. CONCLUSIONS: Negative associations of PCE with behavioral adjustment persist into EA via environmental pathways, specifying intervention points to disrupt adverse pathways toward healthy development.

Treatment Patterns and Survival Outcomes in Patients With Breast Cancer on Medicaid, Pre- and Post-Expansion.

BACKGROUND: The objective of this study was to evaluate the impact of Medicaid expansion on breast cancer treatment and survival among Medicaid-insured women in Ohio, accounting for the timing of enrollment in Medicaid relative to their cancer diagnosis and post-expansion heterogeneous Medicaid eligibility criteria, thus addressing important limitations in previous studies. METHODS: Using 2011-2017 Ohio Cancer Incidence Surveillance System data linked with Medicaid claims data, we identified women aged 18 to 64 years diagnosed with local-stage or regional-stage breast cancer (n=876 and n=1,957 pre-expansion and post-expansion, respectively). We accounted for women's timing of enrollment in Medicaid relative to their cancer diagnosis, and flagged women post-expansion as Affordable Care Act (ACA) versus non-ACA, based on their income eligibility threshold. Study outcomes included standard treatment based on cancer stage and receipt of lumpectomy, mastectomy, chemotherapy, radiation, hormonal treatment, and/or treatment for HER2-positive tumors; time to treatment initiation (TTI); and overall survival. We conducted multivariable robust Poisson and Cox proportional hazards regression analysis to evaluate the independent associations between Medicaid expansion and our outcomes of interest, adjusting for patient-level and area-level characteristics. RESULTS: Receipt of standard treatment increased from 52.6% pre-expansion to 61.0% post-expansion (63.0% and 59.9% post-expansion in the ACA and non-ACA groups, respectively). Adjusting for potential confounders, including timing of enrollment in Medicaid, being diagnosed in the post-expansion period was associated with a higher probability of receiving standard treatment (adjusted risk ratio, 1.14 [95% CI, 1.06-1.22]) and shorter TTI (adjusted hazard ratio, 1.14 [95% CI, 1.04-1.24]), but not with survival benefits (adjusted hazard ratio, 1.00 [0.80-1.26]). CONCLUSIONS: Medicaid expansion in Ohio was associated with improvements in receipt of standard treatment of breast cancer and shorter TTI but not with improved survival outcomes. Future studies should elucidate the mechanisms at play.

Accounting for Medicaid expansion and regional policy and programs to advance equity in cancer prevention in the United States.

BACKGROUND: Many studies compare state-level outcomes to estimate changes attributable to Medicaid expansion. However, it is imperative to conduct more granular, demographic-level analyses to inform current efforts on cancer prevention among low-income adults. Therefore, the authors compared the volume of patients with cancer and disease stage at diagnosis in Ohio, which expanded its Medicaid coverage in 2014, with those in Georgia, a nonexpansion state, by cancer site and health insurance status. METHODS: The authors used state cancer registries from 2010 to 2017 to identify adults younger than 64 years who had incident female breast cancer, cervical cancer, or colorectal cancer. Multivariable Poisson regression was conducted by cancer type, health insurance, and state to examine the risk of late-stage disease, adjusting for individual-level and area-level covariates. A difference-in-differences framework was then used to estimate the differences in risks of late-stage diagnosis in Ohio versus Georgia. RESULTS: In Ohio, the largest increase in all three cancer types was observed in the Medicaid group after Medicaid expansion. In addition, significantly reduced risks of late-stage disease were observed among patients with breast cancer on Medicaid in Ohio by approximately 7% and among patients with colorectal cancer on Medicaid in Ohio and Georgia after expansion by approximately 6%. Notably, the authors observed significantly reduced risks of late-stage diagnosis among all patients with colorectal cancer in Georgia after expansion. CONCLUSIONS: More early stage cancers in the Medicaid-insured and/or uninsured groups after expansion suggest that the reduced cancer burden in these vulnerable population subgroups may be attributed to Medicaid expansion. Heterogeneous risks of late-stage disease by cancer type highlight the need for comprehensive evaluation frameworks, including local cancer prevention efforts and federal health policy reforms. PLAIN LANGUAGE SUMMARY: This study looked at how Medicaid expansion affected cancer diagnosis and treatment in two states, Ohio and Georgia. The researchers found that, after Ohio expanded their Medicaid program, there were more patients with cancer among low-income adults on Medicaid. The study also found that, among people on Medicaid, there were lower rates of advanced cancer at the time of diagnosis for breast cancer and colon cancer in Ohio and for colon cancer in Georgia. These findings suggest that Medicaid expansion may be effective in reducing the cancer burden among low-income adults.

Increased Hazard Risk of First Malignancy in Adults with Undetectable Serum IgE: a Retrospective Cohort Study.

PURPOSE: The clinical relevance of IgE-deficiency is not established. Previous studies have postulated a relationship between absent serum IgE and the incidence of specific malignancies. We sought to examine the relationship between undetectable total serum IgE (< 3 IU/mL) and first malignancy, considering both general all-cause malignancy risk and risk of specific malignancy subtypes in adult subjects. METHODS: Retrospective cohort study at a single center of 39,965 adults aged 18 or older (median age 51, 65.1% female) with at least one serum total IgE measurement from 1998 to 2020. Analytics included chi2 table and logistic regression modeling of the main outcome measures, which include diagnosis of first malignancy and first diagnosis of specific malignancy subtype. RESULTS: Of the entire cohort, 2584 subjects (6.5%) developed a first malignancy and 2516 (6.3%) had an undetectable IgE. Of those with undetectable IgE levels, 8.9% developed a first malignancy versus 6.3% with detectable IgE measurements. After adjusting for risk factors, there was a significant association between undetectable IgE and risk/hazard of first malignancy (relative risk 1.49, 95% confidence interval (CI) 1.27-1.75) (hazard ratio 1.28, 95% CI 1.08-1.52). Results were similar in multiple sensitivity analyses. For type of malignancy developed, undetectable IgE was associated with increased risk of hematologic malignancy (relative risk 2.07, 95% CI 1.29-3.30) and skin malignancy (relative risk 1.52, 95% CI 1.13-2.05). CONCLUSION: Compared to individuals with detectable IgE levels, patients with undetectable total serum IgE had increased risk and hazard of first malignancy in general, and increased risk of hematologic malignancy in particular.

Community Members as Reviewers of Medical Journal Manuscripts: a Randomized Controlled Trial.

BACKGROUND: Community members may provide useful perspectives on manuscripts submitted to medical journals. OBJECTIVE: To determine the impact of community members reviewing medical journal manuscripts. DESIGN: Randomized controlled trial involving 578 original research manuscripts submitted to two medical journals from June 2018 to November 2021. PARTICIPANTS: Twenty-eight community members who were trained, supervised, and compensated. INTERVENTIONS: A total of 289 randomly selected control manuscripts were reviewed by scientific reviewers only. And 289 randomly selected intervention manuscripts were reviewed by scientific reviewers and one community member. Journal editorial teams used all reviews to make decisions about acceptance, revision, or rejection of manuscripts. MAIN MEASURES: Usefulness of reviews to editors, content of community reviews, and changes made to published articles in response to community reviewer comments. KEY RESULTS: Editor ratings of community and scientific reviews averaged 3.1 and 3.3, respectively (difference 0.2, 95% confidence interval [CI] 0.1 to 0.3), on a 5-point scale where a higher score indicates a more useful review. Qualitative analysis of the content of community reviews identified two taxonomies of themes: study attributes and viewpoints. Study attributes are the sections, topics, and components of manuscripts commented on by reviewers. Viewpoints are reviewer perceptions and perspectives on the research described in manuscripts and consisted of four major themes: (1) diversity of study participants, (2) relevance to patients and communities, (3) cultural considerations and social context, and (4) implementation of research by patients and communities. A total of 186 community reviewer comments were integrated into 64 published intervention group articles. Viewpoint themes were present more often in 66 published intervention articles compared to 54 published control articles (2.8 vs. 1.7 themes/article, difference 1.1, 95% CI 0.4 to 1.8). CONCLUSIONS: With training, supervision, and compensation, community members are able to review manuscripts submitted to medical journals. Their comments are useful to editors, address topics relevant to patients and communities, and are reflected in published articles. TRIAL REGISTRATION: ClinicalTrials.gov NCT03432143.

Post-Affordable Care Act Improvements in Cancer Stage Among Ohio Medicaid Beneficiaries Resulted From an Increase in Stable Coverage.

BACKGROUND: The mechanisms underlying improvements in early-stage cancer at diagnosis following Medicaid expansion remain unknown. We hypothesized that Medicaid expansion allowed for low-income adults to enroll in Medicaid before cancer diagnosis, thus increasing the number of stably-enrolled relative to those who enroll in Medicaid only after diagnosis (emergently-enrolled). METHODS: Using data from the 2011-2017 Ohio Cancer Incidence Surveillance System and Medicaid enrollment files, we identified individuals diagnosed with incident invasive breast (n=4850), cervical (n=1023), and colorectal (n=3363) cancer. We conducted causal mediation analysis to estimate the direct effect of pre- (vs. post-) expansion on being diagnosed with early-stage (-vs. regional-stage and distant-stage) disease, and indirect (mediation) effect through being in the stably- (vs. emergently-) enrolled group, controlling for individual-level and area-level characteristics. RESULTS: The percentage of stably-enrolled patients increased from 63.3% to 73.9% post-expansion, while that of the emergently-enrolled decreased from 36.7% to 26.1%. The percentage of patients with early-stage diagnosis remained 1.3-2.9 times higher among the stably-than the emergently-enrolled group, both pre-expansion and post-expansion. Results from the causal mediation analysis showed that there was an indirect effect of Medicaid expansion through being in the stably- (vs. emergently-) enrolled group [risk ratios with 95% confidence interval: 1.018 (1.010-1.027) for breast cancer, 1.115 (1.064-1.167) for cervical cancer, and 1.090 (1.062-1.118) for colorectal cancer. CONCLUSION: We provide the first evidence that post-expansion improvements in cancer stage were caused by an increased reliance on Medicaid as a source of stable insurance coverage.

Continuous-time causal mediation analysis.

While causal mediation analysis has seen considerable recent development for a single measured mediator (M) and final outcome (Y), less attention has been given to repeatedly measured M and Y. Previous methods have typically involved discrete-time models that limit inference to the particular measurement times used and do not recognize the continuous nature of the mediation process over time. To overcome such limitations, we present a new continuous-time approach to causal mediation analysis that uses a differential equations model in a potential outcomes framework to describe the causal relationships among model variables over time. A connection between the differential equation models and standard repeated measures models is made to provide convenient model formulation and fitting. A continuous-time extension of the sequential ignorability assumption allows for identifiable natural direct and indirect effects as functions of time, with estimation based on a two-step approach to model fitting in conjunction with a continuous-time mediation formula. Novel features include a measure of an overall mediation effect based on the "area between the curves," and an approach for predicting the effects of new interventions. Simulation studies show good properties of estimators and the new methodology is applied to data from a cohort study to investigate sugary drink consumption as a mediator of the effect of socioeconomic status on dental caries in children.

Comparing web-based video interventions to enhance university student willingness to donate organs: A randomized controlled trial.

BACKGROUND: The efficacy of video interventions to increase organ donation willingness remains unclear. METHODS: Three-arm web-based randomized controlled trial involving 2261 students at 3 northeastern Ohio universities. Intervention students watched a live-action (n = 755) or animated (n = 753) donation video. Control students (n = 753) viewed wellness information from the Centers for Disease Control and Prevention (CDC). The primary outcome was proportion of students who visited their state electronic donor registry to consent. The secondary outcome was intervention quality. Logistic regression assessed the effects of interventions on visiting the state registry to provide donation consent while controlling for baseline variables. RESULTS: Students in the live-action video arm visited their state registry more frequently than students in the CDC arm (OR = 1.86, 95% CI = 1.20-2.88). There was no difference between students in the animated video and CDC arms (OR = 1.10, 95% CI = 0.69-1.76). The quality of the live-action video was rated lower than the animated video and the CDC text (75% ± 18, 84% ± 16, 80% ± 16, respectively; P < 0.001). CONCLUSION: Students who watched the live-action video were more willing to visit their electronic donor registry to register as organ donors, but rated it lower in satisfaction. Future work should identify the most potent components of organ donation interventions.

Quantifying the Time Used for Renal Dietitian's Responsibilities: A Pilot Study.

OBJECTIVE: The purpose of this study was to quantify how dialysis dietitians spend their time and whether the activities that were most frequent varied based on the ratio of patient to full-time equivalent (FTE) dietitian. METHODS: This study is a cross-sectional, observational, time-and-motion study carried out using the Work Activity Measurement by Activity Timing software/method for time recording. This study was carried out in 14 dialysis centers in and around Cleveland, Ohio. Fourteen registered dietitian nutritionists participated in this study. The mean time/experience of these nutritionists in dietetics was 26.6 ± 8.5 years. Percent of time in direct care (e.g., patient interaction) versus indirect care (e.g., documentation and plans of care, professional communication) versus other responsibilities (e.g., administrative work, education of self or others). RESULTS: The mean number of tasks recorded per 3-hour observation session was 38.3 ± 14.0, including 18.5 ± 7.7 indirect care tasks, 7.7 ± 6.2 direct care tasks, and 9.7 ± 5.4 other tasks. The mean number of unique patients seen per observation session was 6.9 ± 5.4; the mean direct care time per patient encounter was 6.95 ± 4.05 minutes. Indirect care took the highest proportion of observed time, 56.0 ± 22.2%, followed by direct care, 24.9 ± 18.8%. Increasing the ratio of patient to FTE had a moderate negative correlation with the percent of time spent in direct patient care (r = -0.35, P = .21), but there was no relationship between the ratio of patient to FTE and direct care time per patient (r = 0.02, P = .94). CONCLUSION: About 25% of dietitians' time was available for direct patient care. This is much less than that reported in previous studies and may not be sufficient to improve the nutritional status. Limitations of our study include a small sample size from a single region. Further work is needed to understand the balance of responsibilities among renal dietitians and their impact on patient outcomes.

Bayesian Causal Mediation Analysis with Multiple Ordered Mediators.

Causal mediation analysis provides investigators insight into how a treatment or exposure can affect an outcome of interest through one or more mediators on causal pathway. When multiple mediators on the pathway are causally ordered, identification of mediation effects on certain causal pathways requires a sensitivity parameter to be specified. A mixed model-based approach was proposed in the Bayesian framework to connect potential outcomes at different treatment levels, and identify mediation effects independent of a sensitivity parameter, for the natural direct and indirect effects on all causal pathways. The proposed method is illustrated in a linear setting for mediators and outcome, with mediator-treatment interactions. Sensitivity analysis was performed for the prior choices in the Bayesian models. The proposed Bayesian method was applied to an adolescent dental health study, to see how social economic status can affect dental caries through a sequence of causally ordered mediators in dental visit and oral hygiene index.

Bicyclo((aryl)methyl)benzamides as inhibitors of GlyT1.

A series of isoquinuclidine benzamides as glycine uptake inhibitors for the treatment of schizophrenia are described. Potency, lipophilicity, and intrinsic human microsomal clearance were parameters for optimization. Potency correlated with the nature of the ortho substituents of the benzamide ring, and reductions in lipophilicity could be achieved through heteroatom incorporation in the benzamide and pendant phenyl moieties. Improvements in human CLint were achieved through changes in ring size and the N-alkyl group of the isoquinuclidine itself, with des-alkyl derivatives (40-41, 44) demonstrating the most robust microsomal stability. Dimethylbenzamide 9 was tested in a mouse MK801 LMA assay and had a statistically significant attenuation of locomotor activity at 3 and 10 µmol/kg compared to control.

Structural Equation Modeling to Explore Patient to Staff Ratios as an Explanatory Factor for Variation in Dialysis Facility Outcomes.

OBJECTIVE: Patient to staff ratios vary based on facility characteristics, and therefore have been proposed as an explanatory factor for the variation in dialysis facility outcomes. This analysis tested that hypothesis. DESIGN AND METHODS: Observational study using Dialysis Facility Report data. Reported staff numbers from the Annual Facility Survey were converted to full time equivalents (FTE). Subsequently, ratios were created for patients per FTE registered dietitian (RD), social worker, nurse, and patient care technician. Bivariate associations and structural equation modeling (SEM) were used to explore relationships between these ratios and patient outcomes: standardized mortality ratio and standardized hospitalization rate, when also considering the impact of non-modifiable facility characteristics (region, chain, profit status). Our focus was on RD staffing; therefore we also included serum phosphorus and normalized protein catabolic ratio in the model, and also conducted a sub-analysis of the 198 facilities that exceeded the KDOQI maximum of 150 patients:FTE RD. SUBJECTS: Dialysis centers in the US with at least 30 adult patients and no pediatric patients. 4035 facilities had complete data for the proposed variables. MAIN OUTCOME MEASURE: Standardized mortality ratio and standardized hospitalization rate were the primary outcomes. RESULTS: The mean and standard deviation for patients per FTE staff were 90.0 ± 34.0, 88.7 ± 32.8, 17.1 ± 20.5 and 11.9 ± 7.0 for RDs, social workers, nurses, and technicians, respectively. Facility characteristics impacted staffing in bivariate analyses and SEM. The only significant paths from staffing ratio to outcomes were for patient:FTE social worker to SMR (standardized beta = -0.09, 95% CI -0.13, -0.04) and Patients:FTE RD to SHR Days (standardized beta = 0.04, 95% CI 0.001, 0.09). In the sub-analysis, there were no significant paths from staffing to outcomes. CONCLUSIONS: This study did not provide evidence that patient per staff ratios explain variation in dialysis facility outcomes. While there are some important bivariate relationships, these disappear in more complex models. Future research should investigate the impacts of staffing ratios on individual patients, to overcome the possible ecological fallacy.

Pharmacological property optimization for allosteric ligands: A medicinal chemistry perspective.

New strategies to potentially improve drug safety and efficacy emerge with allosteric programs. Biased allosteric modulators can be designed with high subtype selectivity and defined receptor signaling endpoints, however, selecting the most meaningful parameters for optimization can be perplexing. Historically, "potency hunting" at the expense of physicochemical and pharmacokinetic optimization has led to numerous tool compounds with excellent pharmacological properties but no path to drug development. Conversely, extensive physicochemical and pharmacokinetic screening with only post hoc bias and allosteric characterization has led to inefficacious compounds or compounds with on-target toxicities. This field is rapidly evolving with new mechanistic understanding, changes in terminology, and novel opportunities. The intent of this digest is to summarize current understanding and debates within the field. We aim to discuss, from a medicinal chemistry perspective, the parameter choices available to drive SAR.

Failure mode and effects analysis: A community practice perspective.

PURPOSE: To report our early experiences with failure mode and effects analysis (FMEA) in a community practice setting. METHODS: The FMEA facilitator received extensive training at the AAPM Summer School. Early efforts focused on department education and emphasized the need for process evaluation in the context of high profile radiation therapy accidents. A multidisciplinary team was assembled with representation from each of the major department disciplines. Stereotactic radiosurgery (SRS) was identified as the most appropriate treatment technique for the first FMEA evaluation, as it is largely self-contained and has the potential to produce high impact failure modes. Process mapping was completed using breakout sessions, and then compiled into a simple electronic format. Weekly sessions were used to complete the FMEA evaluation. Risk priority number (RPN) values > 100 or severity scores of 9 or 10 were considered high risk. The overall time commitment was also tracked. RESULTS: The final SRS process map contained 15 major process steps and 183 subprocess steps. Splitting the process map into individual assignments was a successful strategy for our group. The process map was designed to contain enough detail such that another radiation oncology team would be able to perform our procedures. Continuous facilitator involvement helped maintain consistent scoring during FMEA. Practice changes were made responding to the highest RPN scores, and new resulting RPN scores were below our high-risk threshold. The estimated person-hour equivalent for project completion was 258 hr. CONCLUSIONS: This report provides important details on the initial steps we took to complete our first FMEA, providing guidance for community practices seeking to incorporate this process into their quality assurance (QA) program. Determining the feasibility of implementing complex QA processes into different practice settings will take on increasing significance as the field of radiation oncology transitions into the new TG-100 QA paradigm.

Sensitivity analyses for parametric causal mediation effect estimation.

Causal mediation analysis uses a potential outcomes framework to estimate the direct effect of an exposure on an outcome and its indirect effect through an intermediate variable (or mediator). Causal interpretations of these effects typically rely on sequential ignorability. Because this assumption is not empirically testable, it is important to conduct sensitivity analyses. Sensitivity analyses so far offered for this situation have either focused on the case where the outcome follows a linear model or involve nonparametric or semiparametric models. We propose alternative approaches that are suitable for responses following generalized linear models. The first approach uses a Gaussian copula model involving latent versions of the mediator and the final outcome. The second approach uses a so-called hybrid causal-observational model that extends the association model for the final outcome, providing a novel sensitivity parameter. These models, while still assuming a randomized exposure, allow for unobserved (as well as observed) mediator-outcome confounders that are not affected by exposure. The methods are applied to data from a study of the effect of mother education on dental caries in adolescence.

Effects of a Video on Organ Donation Consent Among Primary Care Patients: A Randomized Controlled Trial.

BACKGROUND: Low organ donation rates remain a major barrier to organ transplantation. OBJECTIVE: We aimed to determine the effect of a video and patient cueing on organ donation consent among patients meeting with their primary care provider. DESIGN: This was a randomized controlled trial between February 2013 and May 2014. SETTING: The waiting rooms of 18 primary care clinics of a medical system in Cuyahoga County, Ohio. PATIENTS: The study included 915 patients over 15.5 years of age who had not previously consented to organ donation. INTERVENTIONS: Just prior to their clinical encounter, intervention patients (n = 456) watched a 5-minute organ donation video on iPads and then choose a question regarding organ donation to ask their provider. Control patients (n = 459) visited their provider per usual routine. MAIN MEASURES: The primary outcome was the proportion of patients who consented for organ donation. Secondary outcomes included the proportion of patients who discussed organ donation with their provider and the proportion who were satisfied with the time spent with their provider during the clinical encounter. KEY RESULTS: Intervention patients were more likely than control patients to consent to donate organs (22 % vs. 15 %, OR 1.50, 95%CI 1.10-2.13). Intervention patients were also more likely to have donation discussions with their provider (77 % vs. 18 %, OR 15.1, 95%CI 11.1-20.6). Intervention and control patients were similarly satisfied with the time they spent with their provider (83 % vs. 86 %, OR 0.87, 95%CI 0.61-1.25). LIMITATION: How the observed increases in organ donation consent might translate into a greater organ supply is unclear. CONCLUSION: Watching a brief video regarding organ donation and being cued to ask a primary care provider a question about donation resulted in more organ donation discussions and an increase in organ donation consent. Satisfaction with the time spent during the clinical encounter was not affected. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01697137.

Fragment-assisted hit investigation involving integrated HTS and fragment screening: Application to the identification of phosphodiesterase 10A (PDE10A) inhibitors.

Fragment-based drug design (FBDD) relies on direct elaboration of fragment hits and typically requires high resolution structural information to guide optimization. In fragment-assisted drug discovery (FADD), fragments provide information to guide selection and design but do not serve as starting points for elaboration. We describe FADD and high-throughput screening (HTS) campaign strategies conducted in parallel against PDE10A where fragment hit co-crystallography was not available. The fragment screen led to prioritized fragment hits (IC50's ∼500µM), which were used to generate a hypothetical core scaffold. Application of this scaffold as a filter to HTS output afforded a 4µM hit, which, after preparation of a small number of analogs, was elaborated into a 16nM lead. This approach highlights the strength of FADD, as fragment methods were applied despite the absence of co-crystallographical information to efficiently identify a lead compound for further optimization.

Causal mediation analysis with a latent mediator.

Health researchers are often interested in assessing the direct effect of a treatment or exposure on an outcome variable, as well as its indirect (or mediation) effect through an intermediate variable (or mediator). For an outcome following a nonlinear model, the mediation formula may be used to estimate causally interpretable mediation effects. This method, like others, assumes that the mediator is observed. However, as is common in structural equations modeling, we may wish to consider a latent (unobserved) mediator. We follow a potential outcomes framework and assume a generalized structural equations model (GSEM). We provide maximum-likelihood estimation of GSEM parameters using an approximate Monte Carlo EM algorithm, coupled with a mediation formula approach to estimate natural direct and indirect effects. The method relies on an untestable sequential ignorability assumption; we assess robustness to this assumption by adapting a recently proposed method for sensitivity analysis. Simulation studies show good properties of the proposed estimators in plausible scenarios. Our method is applied to a study of the effect of mother education on occurrence of adolescent dental caries, in which we examine possible mediation through latent oral health behavior.

Dietary intake of calcium and magnesium and the metabolic syndrome in the National Health and Nutrition Examination (NHANES) 2001-2010 data.

Higher dietary intakes of Mg and Ca, individually, have been associated with a decreased risk for the metabolic syndrome (MetSyn). Experimental studies suggest that a higher intra-cellular ratio of Ca:Mg, which may be induced by a diet high in Ca and low in Mg, may lead to hypertension and insulin resistance. However, no previous epidemiological studies have examined the effects of the combined intake of Mg and Ca on MetSyn. Thus, we evaluated the association between dietary intakes of Ca and Mg (using 24-h recalls), independently and in combination, and MetSyn in the National Health and Nutrition Examination Study 2001-2010 data, which included 9148 adults (4549 men and 4599 women), with complete information on relevant nutrient, demographic, anthropometric and biomarker variables. We found an inverse association between the highest (>355 mg/d) v. the lowest (<197 mg/d) quartile of Mg and MetSyn (OR 0.70; 95% CI 0.57, 0.86). Women who met the RDA for both Mg (310-320 mg/d) and Ca (1000-1200 mg/d) had the greatest reduced odds of MetSyn (OR 0.59; 95% CI 0.45, 0.76). In men, meeting the RDA for Mg (400-420 mg/d) and Ca (1000-1200 mg/d), individually or in combination, was not associated with MetSyn; however, men with intakes in the highest quartile for Mg (≥ 386 mg/d) and Ca (≥ 1224 mg/d) had a lower odds of MetSyn (OR 0.74; 95% CI 0.59, 0.93). Our results suggest that women who meet the RDA for Mg and Ca have a reduced odds of MetSyn but men may require Ca levels higher than the RDA to be protected against MetSyn.

Discovery of a series of aryl-N-(3-(alkylamino)-5-(trifluoromethyl)phenyl)benzamides as TRPA1 antagonists.

We describe the discovery and advancement of a novel series of TRPA1 antagonist having an aryl-N-(3-(alkylamino)-5-(trifluoromethyl)phenyl)benzamide scaffold. The physical and in vitro DMPK profiles are discussed.