Predictors of Substance Use Initiation by Early Adolescence.

OBJECTIVE: Substance use initiation during early adolescence is associated with later development of substance use and mental health disorders. This study used various domains to predict substance use initiation, defined as trying any nonprescribed substance (e.g., alcohol, tobacco, cannabis), by age 12, using a large longitudinal data set. METHODS: Substance-naive youths from the Adolescent Brain Cognitive Development Study (ages 9-10; N=6,829) were followed for 3 years. A total of 420 variables were examined as predictors of substance use initiation, using a penalized logistic regression with elastic net; domains spanned demographic characteristics, self and peer involvement with substance use, parenting behaviors, mental and physical health, culture and environment, hormones, neurocognitive functioning, and structural neuroimaging. RESULTS: By age 12, 982 (14.4%) children reported substance initiation, with alcohol being the most common. Models with only self-report predictors had similar prediction performance to models adding hormones, neurocognitive factors, and neuroimaging predictors (AUCtest=0.66). Sociodemographic factors were the most robust predictors, followed by cultural and environmental factors, physical health factors, and parenting behaviors. The top predictor was a religious preference of Mormon (coefficient=-0.87), followed by a religious preference for Jewish (coefficient=0.32), and by Black youths (coefficient=-0.32). CONCLUSIONS: Sociodemographic variables were the most robust predictors of substance use initiation. Adding resource-intensive measures, including hormones, neurocognitive assessment, and structural neuroimaging, did not improve prediction of substance use initiation. The application of these large-scale findings in clinical settings could help to streamline and tailor prevention and early intervention efforts.

The impact of intraoperative N-acetylcysteine on opioid consumption following spine surgery: a randomized pilot trial.

Aim: N-acetylcysteine (NAC) decreases inflammation and could augment perioperative analgesia. Materials & methods: This prospective pilot trial examined postoperative opioid consumption at 12 h following intraoperative NAC. In phase I, 20 adults scheduled for posterior spine surgery were randomized to NAC (0, 50, 100 and 150 mg/kg) to determine the optimal dose. In phase II, 30 patients were randomized to placebo or NAC (150 mg/kg). Opioid consumption, pain ratings and time to opioid rescue were recorded. Results: Postoperative opioid consumption was reduced in the NAC group 19.3% at 12 h and 20% at 18 and 36 h. Opioid consumption was reduced 22-24% in the NAC group at all times after adjusting for intraoperative opioid administration. NAC subjects reported lower pain scores relative to placebo. Conclusion: Subjects randomized to NAC consumed less postoperative opioids and reported less pain versus placebo. Larger randomized controlled trials are needed to further evaluate NAC for analgesia. Clinical Trial Registration: NCT04562597 (ClinicalTrials.gov).

N-acetylcysteine (NAC) is a powerful anti-inflammatory drug used to treat some types of poisoning. It could help pain for patients after surgery. This study looked at how much pain medicine patients needed after back surgery when they received NAC or no drug (placebo). In the first 20 patients, people randomly received placebo or a small, medium or large dose of NAC (0, 50, 100, and 150 mg/kg) with five patients in each group. Since there were only a small number of patients, it was difficult to see any definite differences, and the next 30 patient patients randomly received placebo or the large dose of NAC (150 mg/kg). Patients that were given NAC received 16­22% less opioids in the first 2 days after surgery compared with those that were given placebo. NAC patients also took longer to request pain medications after surgery and reported lower pain scores in the first 2 days after surgery relative to placebo.

Who responds to a multi-component treatment for cannabis use disorder? Using multivariable and machine learning models to classify treatment responders and non-responders.

BACKGROUND AND AIMS: Treatments for cannabis use disorder (CUD) have limited efficacy and little is known about who responds to existing treatments. Accurately predicting who will respond to treatment can improve clinical decision-making by allowing clinicians to offer the most appropriate level and type of care. This study aimed to determine whether multivariable/machine learning models can be used to classify CUD treatment responders versus non-responders. METHODS: This secondary analysis used data from a National Drug Abuse Treatment Clinical Trials Network multi-site outpatient clinical trial in the United States. Adults with CUD (n = 302) received 12 weeks of contingency management, brief cessation counseling and were randomized to receive additionally either (1) N-Acetylcysteine or (2) placebo. Multivariable/machine learning models were used to classify treatment responders (i.e. two consecutive negative urine cannabinoid tests or a 50% reduction in days of use) versus non-responders using baseline demographic, medical, psychiatric and substance use information. RESULTS: Prediction performance for various machine learning and regression prediction models yielded area under the curves (AUCs) >0.70 for four models (0.72-0.77), with support vector machine models having the highest overall accuracy (73%; 95% CI = 68-78%) and AUC (0.77; 95% CI = 0.72, 0.83). Fourteen variables were retained in at least three of four top models, including demographic (ethnicity, education), medical (diastolic/systolic blood pressure, overall health, neurological diagnosis), psychiatric (depressive symptoms, generalized anxiety disorder, antisocial personality disorder) and substance use (tobacco smoker, baseline cannabinoid level, amphetamine use, age of experimentation with other substances, cannabis withdrawal intensity) characteristics. CONCLUSIONS: Multivariable/machine learning models can improve on chance prediction of treatment response to outpatient cannabis use disorder treatment, although further improvements in prediction performance are likely necessary for decisions about clinical care.

Relationship Between Palliative Care Consults and Outcomes of Pediatric Surgical Patients During Terminal Admissions.

Background: Pediatric patients often undergo surgery during terminal admissions. However, the involvement and timing of palliative care consults in caring for these patients has not been readily described. Objective: To describe the presence and timing of palliative care consults for pediatric patients who undergo surgical procedures during terminal admissions. Design: Retrospective cohort study using data from the electronic health record. Setting and Participants: Pediatric patients who underwent at least one surgical procedure during a terminal admission at an urban, quaternary hospital in the United States from January 1, 2016 to December 31, 2021. Main Outcomes and Measures: Patients' medical, surgical, and admission-level characteristics were abstracted. Associations were evaluated between these characteristics and the occurrence and timing of a palliative care consult relative to surgery and death. Results: Of 134 patients, 84% received a palliative care consult during their terminal admission. Approximately 36% of consults occurred before surgery, and 12% were within one day of death. Children without a palliative care consult were more likely than children with a consult to die during surgery (19.1% vs. 2.7%, p = 0.02), have surgery within 24 hours of death (52.4% vs. 15.9%, p < 0.001), and undergo a full resuscitation attempt (47.6% vs. 12.4%, p = 0.002). Receipt of a palliative care consultation did not differ by patient sex, reported race and ethnicity, language, insurance, or income level. Conclusions and Relevance: Palliative care consults support high-quality end-of-life care for children and impact perioperative outcomes, including intensity of surgical care and resuscitation in the final hours of life.

CHRNA5-A3-B4 and DRD2 Genes and Smoking Cessation Throughout Adulthood: A Longitudinal Study of Women.

INTRODUCTION: Smoking cessation is more than 50% heritable. Genetic studies of smoking cessation have been limited by short-term follow-up or cross-sectional design. AIMS AND METHODS: This study tests single nucleotide polymorphism (SNP) associations with cessation during long-term follow-up throughout adulthood in women. The secondary aim tests whether genetic associations differ by smoking intensity. Associations between 10 SNPs in CHRNA5, CHRNA3, CHRNB2, CHRNB4, DRD2, and COMT and the probability of smoking cessation over time were evaluated in two longitudinal cohort studies of female nurses, the Nurses' Health Study (NHS) (n = 10 017) and NHS-2 (n = 2793). Participant follow-up ranged from 2 to 38 years with data collected every 2 years. RESULTS: Women with the minor allele of either CHRNA5 SNP rs16969968 or CHRNA3 SNP rs1051730 had lower odds of cessation throughout adulthood [OR = 0.93, p-value = .003]. Women had increased odds of cessation if they had the minor allele of CHRNA3 SNP rs578776 [OR = 1.17, p-value = .002]. The minor allele of DRD2 SNP rs1800497 was associated with lower odds of cessation in moderate-to-heavy smokers [OR = 0.92, p-value = .0183] but increased odds in light smokers [OR = 1.24, p-value = .096]. CONCLUSIONS: Some SNP associations with short-term smoking abstinence observed in prior studies were shown in the present study to persist throughout adulthood over decades of follow-up. Other SNP associations with short-term abstinence did not persist long-term. The secondary aim findings suggest genetic associations may differ by smoking intensity. IMPLICATIONS: The results of the present study expand on previous studies of SNP associations in relation to short-term smoking cessation to demonstrate some of these SNPs were associated with smoking cessation throughout decades of follow-up, whereas other SNP associations with short-term abstinence did not persist long-term. The rate of relapse to smoking remains high for several years after quitting smoking, and many smokers experience multiple quit attempts and relapse episodes throughout adulthood. Understanding genetic associations with long-term cessation has potential importance for precision medicine approaches to long-term cessation management.

A systematic review of genetic variation within nicotinic acetylcholine receptor genes and cigarette smoking cessation.

BACKGROUND: Nicotine produces its effects by binding to nicotinic acetylcholine receptors (nAChRs). Variants of genes encoding properties of nAChRs are candidates for affecting likelihood of smoking cessation. METHODS: A systematic review was conducted summarizing evidence of associations between single nucleotide polymorphisms (SNPs) of nAChR genes and smoking cessation. From 24 articles meeting inclusion criteria, summary odds ratios (ORs) for associations between nine SNPs and smoking cessation were calculated from 26 studies (N = 233-29,072) stratified by gene, ancestry, study design, and pharmacotherapy; SNPs in linkage disequilibrium were pooled. Results for a tenth SNP from two GWAS were summarized. RESULTS: People of European ancestry with minor alleles of CHRNA5 rs16969968 and CHRNA3 rs1051730 had longer time to cessation [HR = 0.90, 95 % CI 0.88 - 0.92 (n = 2 studies)] and lower odds of cessation [OR = 0.88, 95 % CI 0.80 - 0.97 (n = 5 cohort studies), OR = 0.64, 95 % CI 0.45 - 0.90 (n = 4 placebo arms)]. Risk of persistent smoking associated with these alleles was attenuated in smokers receiving nicotine replacement therapy (NRT). Recipients of bupropion alone or with NRT with these alleles had higher, though not statistically significant, odds of cessation. Results for CHRNA5 rs588765 and rs680244 were similar to rs16969968/rs1051730 findings. Evidence was limited for other SNPs. CONCLUSION: Evidence consistently indicates the minor alleles of four SNPs within CHRNA3 or CHRNA5 are risk alleles for cessation failure. Analysis by pharmacotherapy revealed bupropion may be the most efficacious intervention for people with these alleles.

Safety, immunological effects and clinical response in a phase I trial of umbilical cord mesenchymal stromal cells in patients with treatment refractory SLE.

BACKGROUND: Reports of clinical improvement following mesenchymal stromal cell (MSC) infusions in refractory lupus patients at a single centre in China led us to perform an explorative phase I trial of umbilical cord derived MSCs in patients refractory to 6 months of immunosuppressive therapy. METHODS: Six women with a SLEDAI >6, having failed standard of care therapy, received one intravenous infusion of 1×106 MSCs/kg of body weight. They maintained their current immunosuppressives, but their physician was allowed to adjust corticosteroids initially for symptom management. The clinical endpoint was an SRI of 4 with no new British Isles Lupus Activity Guide (BILAG) As and no increase in Physician Global Assessment score of >0.3 with tapering of prednisone to 10 mg or less by 20 weeks. RESULTS: Of six patients, five (83.3%; 95% CI 35.9% to 99.6%) achieved the clinical endpoint of an SRI of 4. Adverse events were minimal. Mechanistic studies revealed significant reductions in CD27IgD double negative B cells, switched memory B cells and activated naïve B cells, with increased transitional B cells in the five patients who met the endpoint. There was a trend towards decreased autoantibody levels in specific patients. Two patients had increases in their Helios+Treg cells, but no other significant T cell changes were noted. GARP-TGFß complexes were significantly increased following the MSC infusions. The B cell changes and the GARP-TGFß increases significantly correlated with changes in SLEDAI scores. CONCLUSION: This phase 1 trial suggests that umbilical cord (UC) MSC infusions are very safe and may have efficacy in lupus. The B cell and GARP-TGFß changes provide novel insight into mechanisms by which MSCs may impact disease. TRIAL REGISTRATION NUMBER: NCT03171194.

Association of Patient Factors and Follow-Up in an International Volunteer Cleft Lip and Palate Repair Clinic in El Salvador.

BACKGROUND: In countries which lack robust health care systems, congenital conditions such as cleft lip and/or palate deformities are often untreated in certain individuals. Many volunteer organizations have stepped in to fill this gap but certain factors, such as continuity of care, are yet to be studied for these clinics. METHODS: This is a retrospective cohort study of 167 pediatric patients with cleft lip and/or palate residing in El Salvador treated by a nongovernmental organizations between 2011 and 2020. This data was used in univariate and multivariable models to associate particular patient factors to their likelihood of following up to their annual clinic visits. RESULTS: Each 1-year increase in duration of follow-up was associated with a 27% decrease in the odds of attending a visit. In addition, 33.7% of cleft lip and 49.7% of cleft palate/cleft lip and palate patients returned at least once. Males had 36% higher odds of attending a return visit compared with females but this difference was not statistically significant. Time spent travelling to the clinic had no effect on follow-up rates. CONCLUSION: Nongovernmental organizations utilizing a diagonal care model should consider using more strategies to maximize continuity of care by increasing communication with patients and emphasizing the need of following up during clinic visits. Continued and increased collaboration with the local team is also of great importance.

Point-of-Care Ultrasound to Assess Gastric Content in Pediatric Emergency Department Procedural Sedation Patients.

OBJECTIVES: There is debate regarding the timing of procedural sedation and analgesia (PSA) in relation to fasting status. Point-of-care ultrasound (POCUS) provides the ability to measure gastric content and is being used as a surrogate for aspiration risk in anesthesia. We sought to evaluate the gastric content of pediatric emergency department (PED) patients undergoing PSA using POCUS. METHODS: We performed a prospective observational study using a convenience sample of pediatric patients undergoing PSA between July 1, 2018, and June 30, 2019. Following a brief history, gastric content was measured using POCUS in both supine and right lateral decubitus positions at 2-hour intervals until the time of PSA. Qualitative content and calculated volume were classified based on the Perlas Model of anesthesia "Risk" assessment. RESULTS: Ninety-three patients were enrolled with 61.3% male and mean age of 6.5 years. Gastric content was determined in 92 patients. There were 79.3% that had "high risk" content at the time of PSA, with a median fasting time of 6.25 hours and no serious adverse events. Fasting duration had a weak to moderate ability to predict "risk" category (area under the curve = 0.73), with no patient (n = 17) who underwent multiple evaluations awaiting PSA progressing from "high" to "low risk." CONCLUSIONS: The majority of PED patients undergoing PSA at our institution had "high risk" gastric content with no clinically significant change occurring during serial evaluations. This calls into question the utility of delaying PSA based upon fasting status and lends support to a more comprehensive risk-benefit approach when planning pediatric PSA.

Nicotine Metabolism Predicted by CYP2A6 Genotypes in Relation to Smoking Cessation: A Systematic Review.

INTRODUCTION: Identifying genetic factors associated with smoking cessation could inform precision cessation interventions. Of major interest is genetic variation in nicotine metabolism, largely predicted by CYP2A6 variations. AIMS AND METHODS: We conducted a systematic literature review to summarize the population-based evidence of the association between CYP2A6 and smoking cessation. In the 12 studies meeting the inclusion criteria, the known functional metabolic effect of CYP2A6 variants was used to classify nicotine metabolism as normal (>75% metabolic activity), intermediate (50.1%-75% activity), slow (25%-50% activity), and poor (<25% activity). Summary odds ratios of smoking cessation were calculated across metabolic groups, stratified by ancestry and whether participants received pharmacotherapy or placebo/no treatment. RESULTS: Among untreated people of European ancestry (n = 4 studies), those with CYP2A6 reduced metabolism were more likely to quit smoking than those with normal metabolism (Summary OR = 2.05, 95% CI 1.23 to 3.42) and the likelihood of cessation increased as nicotine metabolism decreased. Nicotine replacement therapy attenuated the association at end-of-treatment, while bupropion modified the association such that intermediate/slow metabolizers were less likely to quit than normal metabolizers (Summary OR = 0.86, 95% CI 0.79 to 0.94). Among untreated Asian people (n = 3 studies), results differed compared with those with European ancestry: those with slow metabolism were less likely to have quit smoking than normal metabolizers (Summary OR = 0.52, 95% CI 0.38 to 0.71). Evidence for people of African ancestry (n = 1 study) suggested the CYP2A6 association with cessation may differ compared with those of European ancestry. CONCLUSIONS AND IMPLICATIONS: Most studies included in this review were of European ancestry populations; these showed slower nicotine metabolism was associated with increased likelihood of smoking cessation in a dose-related manner. Pharmacotherapy appeared to attenuate or modify this association among people of European ancestry, but it is unclear whether the change in the association remains consistent after treatment ceases. This finding has implications for precision medicine cessation interventions. Based on only a few studies of people of Asian or African ancestry, the association between CYP2A6 variants and cessation may differ from that observed among those of European ancestry, but more evidence is needed.

Chronic cannabis smoking-enriched oral pathobiont drives behavioral changes, macrophage infiltration, and increases ß-amyloid protein production in the brain.

BACKGROUND: Little is known about chronic cannabis smoking-associated oral microbiome and its effects on central nervous system (CNS) functions. METHODS: In the current study, we have analyzed the saliva microbiome in individuals who chronically smoked cannabis with cannabis use disorder (n = 16) and in non-smoking controls (n = 27). The saliva microbiome was analyzed using microbial 16S rRNA sequencing. To investigate the function of cannabis use-associated oral microbiome, mice were orally inoculated with live Actinomyces meyeri, Actinomyces odontolyticus, or Neisseria elongata twice per week for six months, which mimicked human conditions. FINDINGS: We found that cannabis smoking in humans was associated with oral microbial dysbiosis. The most increased oral bacteria were Streptococcus and Actinomyces genus and the most decreased bacteria were Neisseria genus in chronic cannabis smokers compared to those in non-smokers. Among the distinct species bacteria in cannabis smokers, the enrichment of Actinomyces meyeri was inversely associated with the age of first cannabis smoking. Strikingly, oral exposure of Actinomyces meyeri, an oral pathobiont, but not the other two control bacteria, decreased global activity, increased macrophage infiltration, and increased ß-amyloid 42 protein production in the mouse brains. INTERPRETATION: This is the first study to reveal that long-term oral cannabis exposure is associated oral enrichment of Actinomyces meyeri and its contributions to CNS abnormalities.

Effect of leg lift on stroke volume index in children 11-17 years old before and after induction of general anesthesia.

BACKGROUND: Fluid administration in ERAS is one component which anesthesiologists have control. Change in stroke volume index (SVI) is used to assess fluid responsiveness. This study sought the effect of perioperative fluid responsiveness in pediatric patients. The Cheetah NICOM™ (noninvasive CO monitor) was employed because of correlation with other CO monitors. AIMS: The Cheetah NICOM™ is an FDA-approved device in adults. Its indications in children are unknown. 24 enrolled patients (age 11-17) were ASA 1 or 2 without cardiopulmonary disease. The study examined changes in SVI, HR, SBP, and DBP between the semi-recumbent and legs lifted positions, both awake and after anesthesia. METHODS: Each patient had baseline vital signs measured and fluid responsiveness determined with the Cheetah NICOM™ monitor. Stroke volume index (SVI) was measured in both the semi-recumbent position and after passive leg lift. Measurements were repeated immediately after induction of general anesthesia. Twenty-one of 24 patients received inhalation induction with sevoflurane and three patients received intravenous propofol followed by sevoflurane. Airway management included intubation in 19 of 24 and a laryngeal mask airway (LMA) in five of 24 patients. RESULTS: There was a 25% increase in SVI after leg lift from 54.8 ml/m2 to 68.0 ml/m2 in awake patients (p < 0.001). Diastolic pressure decreased by 15.4% from 67.9 mm Hg to 58.2 mm Hg from semi-recumbent position and leg lift, respectively (p = .004). No significant change in heart rate or SBP was found. Following induction, patient SVI increased with leg lift by 25.6% from 42.6 ml/m2 to 53.5 ml/m2 after leg lift (p = .003). Heart rate decreased by 9.3% and SBP increased 2.8% with leg lift. CONCLUSIONS: 96% of normal 11-17-year-old children were fluid responsive while awake and 79% after induction of general anesthesia.

Impedance planimetry values for predicting clinical response following peroral endoscopic myotomy.

BACKGROUND: There is growing interest in developing impedance planimetry as a tool to enhance the clinical outcomes for endoscopic and surgical management of achalasia. The primary aim of this study was to determine whether impedance planimetry measurements can predict clinical response and reflux following peroral endoscopic myotomy (POEM). METHODS: A multicenter cohort study of patients with achalasia undergoing POEM was established from prospective databases and retrospective chart reviews. Patients who underwent impedance planimetry before and after POEM were included. Clinical response was defined as an Eckardt score of ≤ 3. Tenfold cross-validated area under curve (AUC) values were established for the different impedance planimetry measurements associated with clinical response and reflux development. RESULTS: Of the 290 patients included, 91.7 % (266/290) had a clinical response and 39.4 % (108/274) developed reflux following POEM. The most predictive impedance planimetry measurements for a clinical response were: percent change in cross-sectional area (%ΔCSA) and percent change in distensibility index (%ΔDI), with AUCs of 0.75 and 0.73, respectively. Optimal cutoff values for %ΔCSA and %ΔDI to determine a clinical response were a change of 360 % and 272 %, respectively. Impedance planimetry values were much poorer at predicting post-POEM reflux, with AUCs ranging from 0.40 to 0.62. CONCLUSION: Percent change in CSA and distensibility index were the most predictive measures of a clinical response, with a moderate predictive ability. Impedance planimetry values for predicting reflux following POEM showed weak predictive capacity.

Intraoperative vasopressors in head and neck free flap reconstruction.

INTRODUCTION: Historically, there were concerns vasopressors impair free flap outcomes, but recent studies suggest vasopressors are safe. Here we investigate this controversy by (1) evaluating vasopressors' effect on head and neck free-flap survival and surgical complications, and (2) performing soft tissue and bony subset analysis. PATIENTS AND METHODS: Post hoc analysis was performed of a single-blinded, prospective, randomized clinical trial at a tertiary care academic medical center involving patients ≥18 years old undergoing head and neck free flap reconstruction over a 16-month period. Patients were excluded if factors prevented accurate FloTrac™ use. Patients were randomized to traditional volume-based support, or goal-directed support including vasopressor use. Primary data was obtained by study personnel through intraoperative data recording and postoperative medical record review. RESULTS: Forty-one and 38 patients were randomized to traditional and pressor-based algorithms, respectively. Flap survival was 95% (75/79). There was no significant difference between the pressor-based and traditional protocols' flap failure (1/38 [3%] vs. 3/41 [7%], RR 0.36, 95% CI of RR 0.04-3.31, p = .63) or flap-related complications (12/38 [32%] vs. 18/41 [44%], RR 0.72, 95% CI 0.40-1.29, p = .36) Soft tissue flaps had surgical complication rates of 12/30 (40%) and 9/27 (33%) for traditional and pressor-based protocols, respectively. Bony flaps had surgical complication rates of 6/11 (55%), and 3/11 (27%) for traditional and pressor-based protocols, respectively. CONCLUSIONS: Intraoperative goal-directed vasopressor administration during head and neck free flap reconstruction does not appear to increase the rate of flap complications or failures.

Biomonitoring of emerging DINCH metabolites in pregnant women in charleston, SC: 2011-2014.

Due to the mounting evidence that phthalates, specifically di-2-ethylhexyl phthalate and dibutyl phthalate, produce adverse endocrine effects in humans and wildlife, the use of other chemicals as replacements has increased. One of the most commonly encountered phthalate replacements is di(isononyl)cyclohexane-1,2-dicarboxylate (DINCH). Currently, little is known about the prevalence of human exposure, bioactivity, and endocrine disrupting potential of DINCH. We sampled urine from 100 pregnant women during the second trimester of pregnancy living in Charleston, SC between 2011 and 2014 and measured the following DINCH metabolites by LC-MS/MS: cyclohexane-1,2-dicarboxylic acid-mono(hydroxy-isononyl) ester (OH-MINCH), cyclohexane-1,2-dicarboxylic acid-mono(oxo-isononyl) ester (oxo-MINCH), and cyclohexane-1,2-dicarboxylic acid-monocarboxy isooctyl ester (cx-MINCH). These metabolites were also tested on human estrogen receptor alpha and progesterone receptor beta transactivation assays in vitro. OH-MINCH was detected in 98% of urine samples. The specific gravity-adjusted median (interquartile range) OH-MINCH concentration was 0.20 (0.25) ng/mL, and concentrations were significantly higher in African American women compared to Caucasian women (p = 0.01). DINCH metabolite concentrations were consistent between years, and they did not exhibit estrogenic or progestogenic activity in vitro. Human exposure to these emerging compounds should continue to be monitored, especially in vulnerable populations, to ensure the replacement of phthalates by DINCH is not a case of regrettable substitution.

Variable selection methods for identifying predictor interactions in data with repeatedly measured binary outcomes.

INTRODUCTION: Identifying predictors of patient outcomes evaluated over time may require modeling interactions among variables while addressing within-subject correlation. Generalized linear mixed models (GLMMs) and generalized estimating equations (GEEs) address within-subject correlation, but identifying interactions can be difficult if not hypothesized a priori. We evaluate the performance of several variable selection approaches for clustered binary outcomes to provide guidance for choosing between the methods. METHODS: We conducted simulations comparing stepwise selection, penalized GLMM, boosted GLMM, and boosted GEE for variable selection considering main effects and two-way interactions in data with repeatedly measured binary outcomes and evaluate a two-stage approach to reduce bias and error in parameter estimates. We compared these approaches in real data applications: hypothermia during surgery and treatment response in lupus nephritis. RESULTS: Penalized and boosted approaches recovered correct predictors and interactions more frequently than stepwise selection. Penalized GLMM recovered correct predictors more often than boosting, but included many spurious predictors. Boosted GLMM yielded parsimonious models and identified correct predictors well at large sample and effect sizes, but required excessive computation time. Boosted GEE was computationally efficient and selected relatively parsimonious models, offering a compromise between computation and parsimony. The two-stage approach reduced the bias and error in regression parameters in all approaches. CONCLUSION: Penalized and boosted approaches are effective for variable selection in data with clustered binary outcomes. The two-stage approach reduces bias and error and should be applied regardless of method. We provide guidance for choosing the most appropriate method in real applications.

Grading Aortic Valve Stenosis With Dimensionless Index During Pre-cardiopulmonary Bypass Transesophageal Echocardiography: A Comparison With Transthoracic Echocardiography.

OBJECTIVE: The authors hypothesized that grading valvular aortic stenosis (AS) with dimensionless index (DI) during intraoperative pre-cardiopulmonary bypass (pre-CPB) transesophageal echocardiography (TEE) would match the grade of AS during preoperative transthoracic echocardiography (TTE) for the same patients more often than when using peak velocity (Vp), mean pressure gradient (PGm), or aortic valve area (AVA). DESIGN: Retrospective, observational. SETTING: Single university hospital. PARTICIPANTS: The participants in this study included 123 cardiac surgical patients with any degree of AS, who underwent open cardiac surgery between 2010 and 2016 at the Medical University of South Carolina and had Vp, PGm, AVA, and DI values available from reporting databases or archived imaging. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: When using DI, pre-CPB TEE grading of AS severity was 1 grade higher 21.1% of the time and 1 grade lower 13.0% of the time compared with TTE, for an overall disagreement rate of 34.1%. The overall disagreement rates between pre-CPB TEE and TTE for Vp, PGm, and AVA were 39.8%, 33.3%, and 33.3%, respectively. CONCLUSIONS: The authors could not demonstrate that DI was better than Vp, PGm, or AVA at matching AS grades between intraoperative pre-CPB TEE and preoperative TTE. When DI was used, pre-CPB TEE was more likely to overestimate than underestimate the severity of AS compared with TTE. However, when Vp or PGm was used, pre-CPB TEE was more likely to underestimate the severity of AS compared with TTE. A comprehensive approach without overemphasis on 1 parameter should be used for AS assessment by intraoperative TEE.

Association of Very Early Serum Levels of S100B, Glial Fibrillary Acidic Protein, Ubiquitin C-Terminal Hydrolase-L1, and Spectrin Breakdown Product with Outcome in ProTECT III.

Rapid risk-stratification of patients with acute traumatic brain injury (TBI) would inform management decisions and prognostication. The objective of this serum biomarker study (Biomarkers of Injury and Outcome [BIO]-Progesterone for Traumatic Brain Injury, Experimental Clinical Treatment [ProTECT]) was to test the hypothesis that serum biomarkers of structural brain injury, measured at a single, very early time-point, add value beyond relevant clinical covariates when predicting unfavorable outcome 6 months after moderate-to-severe acute TBI. BIO-ProTECT utilized prospectively collected samples obtained from subjects with moderate-to-severe TBI enrolled in the ProTECT III clinical trial of progesterone. Serum samples were obtained within 4 h after injury. Glial fibrillary acidic protein (GFAP), S100B, αII-spectrin breakdown product of molecular weight 150 (SBDP150), and ubiquitin C-terminal hydrolase-L1 (UCH-L1) were measured. The association between log-transformed biomarker levels and poor outcome, defined by a Glasgow Outcome Scale-Extended (GOS-E) score of 1-4 at 6 months post-injury, were estimated via logistic regression. Prognostic models and a biomarker risk score were developed using bootstrapping techniques. Of 882 ProTECT III subjects, samples were available for 566. Each biomarker was associated with 6-month GOS-E (p < 0.001). Compared with a model containing baseline patient variables/characteristics, inclusion of S100B and GFAP significantly improved prognostic capacity (p ≤ 0.05 both comparisons); conversely, UCH-L1 and SBDP did not. A final predictive model incorporating baseline patient variables/characteristics and biomarker data (S100B and GFAP) had the best prognostic capability (area under the curve [AUC] = 0.85, 95% confidence interval [CI]: CI 0.81-0.89). Very early measurements of brain-specific biomarkers are independently associated with 6-month outcome after moderate-to-severe TBI and enhance outcome prediction.

Development of a novel cell-based assay to diagnose recurrent focal segmental glomerulosclerosis patients.

Definitive diagnosis of glomerular disease requires a kidney biopsy, an invasive procedure that may not be safe or feasible to perform in all patients. We developed a noninvasive, accurate, and economical diagnostic assay with easy commercial adaptability to detect recurrent focal segmental glomerulosclerosis (rFSGS) after kidney transplant. Since FSGS involves podocyte damage and death, our approach involved mRNA profiling of cultured podocytes treated with plasma from patients with rFSGS to identify upregulated genes involved in podocyte damage. For concept validation, three upregulated pro-apoptotic candidate genes (IL1ß, BMF, and IGFBP3) were selected, and their promoter regions were cloned into a luciferase-based reporter vector and transfected into podocytes to generate stable podocyte cell lines. Strikingly, when exposed to rFSGS patient plasma, these cell lines showed increased reporter activity; in contrast, no reporter activity was noted with plasma from patients with non-recurrent FSGS or membranous nephropathy. Area under the receiver operating characteristics curves (AUCs) for models discriminating between rFSGS and other nephropathies (non-recurrent FSGS and membranous nephropathy) and between rFSGS and non-recurrent FSGS ranged from 0.81 to 0.86, respectively. Estimated sensitivities and specificities for the diagnosis of rFSGS were greater than 80% for the IL1ß and BMF cell lines, and were slightly lower for the IGFBP3 cell line. Importantly, the novel approach outlined here for the diagnosis of rFSGS is widely applicable to the design of sensitive and specific diagnostic/prognostic assays for other glomerular diseases.

An Analytic Approach Using Candidate Gene Selection and Logic Forest to Identify Gene by Environment Interactions (G × E) for Systemic Lupus Erythematosus in African Americans.

Development and progression of many human diseases, such as systemic lupus erythematosus (SLE), are hypothesized to result from interactions between genetic and environmental factors. Current approaches to identify and evaluate interactions are limited, most often focusing on main effects and two-way interactions. While higher order interactions associated with disease are documented, they are difficult to detect since expanding the search space to all possible interactions of p predictors means evaluating 2p - 1 terms. For example, data with 150 candidate predictors requires considering over 1045 main effects and interactions. In this study, we present an analytical approach involving selection of candidate single nucleotide polymorphisms (SNPs) and environmental and/or clinical factors and use of Logic Forest to identify predictors of disease, including higher order interactions, followed by confirmation of the association between those predictors and interactions identified with disease outcome using logistic regression. We applied this approach to a study investigating whether smoking and/or secondhand smoke exposure interacts with candidate SNPs resulting in elevated risk of SLE. The approach identified both genetic and environmental risk factors, with evidence suggesting potential interactions between exposure to secondhand smoke as a child and genetic variation in the ITGAM gene associated with increased risk of SLE.