Offspring sex modifies the association between early-pregnancy adiposity and 2-year-old physical activity-The Glowing Study.

BACKGROUND: Rodent models suggest that in utero exposure to under and overnutrition programs offspring physical activity (PA) behaviors. Such nexus has not been established in humans. This study evaluated the association of early pregnancy maternal adiposity with offspring PA at age 2 years (2-yo-PA) taking into consideration prenatal and postnatal factors. METHODS: Women (n = 153) were enrolled early in pregnancy (<10 weeks). At enrollment, maternal adiposity [air displacement plethysmography, fat mass index (FMI, kg/m2)] and PA (accelerometers, activity counts) were measured, and age, race, and education self-reported. Gestational weight gain was measured at the research facility. Offspring birthweight and sex were self-reported. At age 2 years, parental feeding practices (child feeding questionnaire) were assessed, whereas anthropometrics (length and weight) and physical activity (accelerometers) were objectively measured. Offspring body mass index z-scores were calculated. Generalized linear regression analysis modeled the association of maternal FMI and 2-yo-PA [average activity counts (AC)4/day]. RESULTS: In bivariate associations, 2-yo-PA did not associate with maternal FMI (ß = -0.22, CI = -0.73 to 0.29, p = 0.398). However, maternal FMI interacted with offspring sex in association with 2-yo-PA. Specifically, 2-yo-PA was lower in girls (ß = -1.14, CI = -2.1 to -0.18, p = 0.02) compared to boys when maternal FMI was ≥7 kg/m2. When stratified by sex, 2-yo-PA of girls negatively associated with maternal FMI (ß = -0.82, CI = -1.43 to 0.29, p = 0.009) while no association was found between maternal FMI and boy's PA (ß = 0.32, CI = -0.38 to 1.01, p = 0.376). CONCLUSIONS: The association of 2-yo-PA and early pregnancy maternal adiposity was modified by offspring sex. Offspring's physical activity decreased with increasing early pregnancy adiposity maternal in girls but not boys in second parity dyads.

Hands-Free Analytical Urine Testing Technology Validated for Drug-Facilitated Crime Investigations.

Forensic laboratories need quick and simple technology to improve turnaround times, while delivering reliable results. The goal of this study is first to create a simplified workflow to meet new Academy Standards Board requirements for urine testing in drug-facilitated crime investigations and, second, to create "ready-to-go", "hands-free" testing technology to further streamline analytical procedures. A first of its kind, the ToxBox forensic test kit is used to validate a single analytical procedure for opioids, benzodiazepines, cannabinoids, antidepressants, and several other drug classes. Method performance indicators follow accreditation requirements and include accuracy, precision, measurement uncertainty, calibration models, reportable range, sensitivity, specificity, carryover, interference, ion suppression/enhancement, and analyte stability. "Hands-free" testing platforms require the use of new suspended-state technology to stabilize NIST-traceable standards premanufactured at precise concentrations in the presence of sample preparation reagents. By suspending all reaction components in the solid state, with air gaps between the phases, reference standards and process controls are built in a "ready-to-go" format and stabilized for long-term storage in the presence of a sample matrix, ß-d-glucuronidase, and enzymatic buffers. "Hands-free" test kits are removed from storage, incubated at either ambient temperature or 60 °C, and assayed using validated methods. This is the first example of how complex forensic testing workflows can be streamlined with new "hands-free" testing strategies to meet analytical challenges associated with quantitative and confirmatory analyses.

Synthesis and biological evaluation of biaryl alkyl ethers as inhibitors of IDO1.

Starting from the dialkylaniline indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor lead 3 (IDO1 HeLa IC50 = 7.0 nM), an iterative process of synthesis and screening led to cyclized analog 21 (IDO1 HeLa IC50 = 3.6 nM) which maintained the high potency of 3 while addressing issues of lipophilicity, cytochrome P450 (CYP) inhibition, hERG (human potassium ion channel Kv11.1) inhibition, Pregnane X Receptor (PXR) transactivation, and oxidative metabolic stability. An x-ray crystal structure of a biaryl alkyl ether 11 bound to IDO1 was obtained. Consistent with our earlier results, compound 11 was shown to bind to the apo form of the enzyme.

Breastfeeding duration modifies the association between maternal weight status and offspring dietary palmitate oxidation.

BACKGROUND: Offspring of obese rodents develop a metabolic phenotype that favors fat deposition. Data regarding the impact of maternal obesity programing of offspring fuel usage in humans is scarce. OBJECTIVE: The objective of this study was to explore the association between maternal weight status and dietary palmitate oxidation (DPO) in 2-y-old offspring, taking into consideration potential confounders and modifiers. METHODS: Women (n = 56) were enrolled by the first trimester of gestation. Maternal physical activity (PA; measured with accelerometers) at enrollment and gestational weight gain (GWG) were measured. Offspring sex, race, and breastfeeding (BF) duration were self-reported. Human milk (HM) composition was determined at 6 mo postpartum. At age 2 y, dietary quality [healthy eating index (HEI)] and parental feeding practices [Child Feeding Questionnaire (CFQ)] were assessed. DPO in 2-y-olds (2-yo-DPO) was measured using deuterated palmitic acid. Generalized linear regression analysis was used to model the associations of 2-yo-DPO with maternal weight status [normal weight (NW), BMI <25 (in kg/m2) compared with excessive weight (EW), BMI ≥25]. RESULTS: DPO was higher in offspring of women with EW compared with NW (2.1 ± 1.2%/h compared with 1.4 ± 0.7%/h, P = 0.03). Maternal weight status interacted with BF duration in association with 2-yo-DPO (log ß: 0.05, P = 0.04). Specifically, 2-yo-DPO was higher in the EW compared with NW group if BF duration was ≥9 mo. HM insulin (log ß: 0.35, P = 0.002) and HM leptin (log ß: 0.81, P = 0.001) concentrations directly associated with 2-yo-DPO. PA (log ß: 0.06, P = 0.013), parental feeding restriction (log ß: 0.05, P < 0.0001), and male sex (log ß: 0.54, P < 0.001) were positively associated with 2-yo-DPO. HEI was negatively associated with 2-yo-DPO (log ß:-0.03, P < 0.0001). CONCLUSIONS: Higher 2-yo-DPO in offspring of women with EW compared with NW were driven by BF duration. Higher HM insulin and leptin concentrations in women with EW may explain these finding. More studies are needed to confirm these results. This trial was registered at clinicaltrials.gov as NCT03281850.

Static and Dynamic Balance Assessment in Healthy and Concussed Adolescent Athletes.

OBJECTIVE: The purpose of this study was to explore the utilization of the Y Balance Test (YBT) alongside the Balance Error Scoring System (BESS) during examination of healthy adolescent athletes (14-18 year old) as well as those with acute and chronic concussion. DESIGN: A repeated-measures study of balance in a cross-sectional convenience sample of adolescents participating in high-school athletics. SETTING: Data were collected on healthy athletes in their school setting for comparison purposes and on concussed athletes in the physical therapy rehabilitation center at the hospital. PARTICIPANTS: Participants were a convenience sample of male and female athletes between the ages of 14 to 18 year old [180 healthy (111 male, 69 female) and 44 (28 male, 16 female) with concussion]. ASSESSMENT OF RISK FACTORS: All participants were cleared for participation by preparticipation examination or by the treating sport medicine physician. MAIN OUTCOME MEASURES: Healthy athletes performed the YBT, a dynamic assessment of balance. Athletes with concussion also performed the BESS, a static assessment of balance. RESULTS: Means for each YBT reach direction were statistically different for both healthy males and females ( P < 0.05). Within both the acute and chronic subsets of the concussed sample, some participants performed over the median value for the BESS but not the YBT. CONCLUSIONS: These data may suggest that dynamic balance testing in conjunction with static balance testing could be valuable in both the acute and chronic phases of concussion to ensure a comprehensive assessment of the necessary balance skills for athletic play.

Cortical Morphometry is Associated with Neuropsychological Function in Healthy 8-Year-Old Children.

BACKGROUND AND PURPOSE: Cortical development is essential for children's neurocognition. In this study, we evaluated how variations in cortical morphometry in normal children are associated with outcome differences in multiple domains of cognition. METHODS: Eight-year-old children were recruited for a brain MRI followed by a battery of neuropsychological assessments. The MRI scan included 3D-T1-weighted imaging for cortical morphometry in 34 regions defined by the Desikan atlas. The neuropsychological assessments included the Reynolds Intellectual Assessment Scales (RIAS) for IQ, Clinical Evaluation of Language Fundamentals (CELF-4) for language, Children's Memory Scale (CMS) for memory, Wide Range Achievement Test (WRAT-4) for academic skills, and Behavior Rating Inventory of Executive Function (BRIEF) for executive functions. The relationships between MRI measured cortical features, including gray matter volume, surface area, and cortical thickness for different brain regions and neuropsychological test scores, were evaluated using partial correlation analyses controlled for age and sex. RESULTS: RIAS/CELF-4/CMS/WRAT-4/BRIEF scores showed significant correlations (R: [.38-.44], P: [.005-.046]) with gray matter volume, surface area, or cortical thickness in multiple brain regions. Gray matter volume in the medial orbitofrontal/ventromedial prefrontal cortex appeared to be a sensitive marker for overall neurocognition as it significantly correlated with IQ, language, memory, and executive function behaviors. The superior temporal gyrus and banks of superior temporal sulcus appeared to be most sensitive to reflect overall language function as their cortical features consistently correlated with language-related test scores. CONCLUSIONS: Cortical morphometry significantly correlated with neuropsychological function in healthy children; certain regions/features may serve as sensitive imaging markers.

SPATIOTEMPORAL PARAMETERS OF ADOLESCENT GAIT WHEN PERFORMING A VISUOSPATIAL MEMORY TASK.

BACKGROUND: Accurate assessment of recovery following mild traumatic brain injury in adolescents can be difficult. When compared to single-task models, dual-task models that combine cognitive and motor demands may more accurately identify residual deficits that manifest during daily life and athletic play in adolescents with concussion. Previous studies have examined gait changes during a concurrent auditory task, or cognitive task. PURPOSE: The purpose of this study was to collect and present data from a sample of healthy 14-18 year old male and female athletes on spatiotemporal parameters of gait for walking with and without a concurrent visuospatial memory task presented on a hand-held tablet. STUDY DESIGN: A two-way repeated measures study of spatiotemporal gait parameters in a cross-sectional convenience sample of adolescent subjects participating in high school athletics. METHODS: Subjects comprised a total of 178 adolescent athletes (128 males; 50 females) ages 14-18 years old at six area high schools. Subjects were instructed to walk "how you normally do" on the GAITRite® portable gait analysis walkway for three undivided and three divided attention trials performing a visuospatial memory task on a hand-held tablet. RESULTS: Significant differences (p < 0.0001) were present between males and females during typical gait in each of the measured parameters except step length (p = 0.0715). Female participants walked with a significantly faster gait velocity (by 0.21 m/s) than male participants (p < 0.0001). The females spent a significantly smaller (-2.27%) percent of the gait cycle in double limb support (p < 0.0001) and a significantly greater (+1.10%) percent of the gait cycle in single limb support (p < 0.0001) than did the males. Both groups experienced a similar, dual-task cost during the divided attention trials (p < 0.0001) for each of the four gait parameters. Previous studies have shown that adults decrease their gait velocity by approximately 33% when performing a task on a hand-held device. The current study revealed that adolescents decreased their gait velocity by 8-9% by shortening their step length by 7.4 centimeters (p < 0.0001), increased the percent of the gait cycle spent in double limb support (2.73%, p < 0.0001) and decreased the percent of the gait cycle spent in single limb support (1.38%, p < 0.0001) during the dual-task. CONCLUSION: These data provide preliminary reference values specific to the adolescent population for the dual-task cost during a visuospatial memory task. More research is needed to determine the dual-task cost during a visuospatial memory task for adolescents with concussion. LEVEL OF EVIDENCE: 2b.

Increased foot strike variability in Parkinson's disease patients with freezing of gait.

INTRODUCTION: Freezing of gait (FOG) is a debilitating, late motor complication of Parkinson's disease (PD) that occurs in 50-80% of patients. Gait freezing significantly worsens quality of life by decreasing mobility and increasing falls. Studies have shown that patients with episodic freezing episodes also have deficits in continuous gait. We evaluated whether there was an objective gait correlate to the increased stumbling reported by many patients with gait freezing. METHODS: PD subjects and healthy controls (HC) were enrolled after IRB approval. Subjects with more than 1 fall/day or a Montreal Cognitive Assessment score <10 were excluded. Subjects walked at their normal pace, 8 lengths of a 20 × 4 foot pressure-sensor mat. Data was collected and analyzed using PKMAS software (Protokinetics) and statistical analysis performed using SPSS 22 (IBM). RESULTS: 72 age matched subjects (22 PD FOG, 27 PD no-FOG, and 23 HC) were enrolled. Disease duration and Hoehn & Yahr scores were not significantly different between the PD groups. Mean dimensions of foot strike were not significantly different between groups, but PD FOG subjects had increased step-to-step variability in foot strike as measured by the percent coefficient of variation (%CV) in foot strike length compared to PD no-FOG and HC, independent of stride velocity. In PD no-FOG subjects, fallers also had higher variability in foot strike length compared to non-fallers. CONCLUSION: PD subjects with FOG had increased variability in foot strike suggesting that in addition to stride length variability, foot strike variability could contribute to imbalance leading to falls.

Development of a series of novel o-phenylenediamine-based indoleamine 2,3-dioxygenase 1 (IDO1) inhibitors.

A novel series of o-phenylenediamine-based inhibitors of indoleamine 2,3-dioxygenase (IDO) has been identified. IDO is a heme-containing enzyme, overexpressed in the tumor microenvironment of many cancers, which can contribute to the suppression of the host immune system. Synthetic modifications to a previously described diarylether series resulted in an additional degree of molecular diversity which was exploited to afford compounds that demonstrated significant potency in the HeLa human cervical cancer IDO1 assay. .

Practice-Based Versus Telemedicine-Based Collaborative Care for Depression in Rural Federally Qualified Health Centers: A Pragmatic Randomized Comparative Effectiveness Trial.

(Reprinted with permission from American Journal of Psychiatry 2013; 170:414-425).

Pilocarpine-induced status epilepticus in mice: A comparison of spectral analysis of electroencephalogram and behavioral grading using the Racine scale.

Pilocarpine-induced status epilepticus (SE) is a widely used seizure model in mice, and the Racine scale has been used to index seizure intensity. The goal of this study was to analyze electroencephalogram (EEG) quantitatively using fast Fourier transformation (FFT) and statistically evaluate the correlation of electrographic seizures with convulsive behaviors. Simultaneous EEG and video recordings in male mice in a mixed genetic background were conducted and pilocarpine was administered intraperitoneally to induce seizures. The videos were graded using the Racine scale and the root-mean-square (RMS) power analysis of EEG was performed with Sirenia Seizure Pro software. We found that the RMS power was very weakly correlated with convulsive behavior induced by pilocarpine. Convulsive behaviors appeared long before electrographic seizures and showed a strong negative correlation with theta frequency activity and a moderate positive correlation with gamma frequency activity. Racine scores showed moderate correlations with RMS power across multiple frequency bands during the transition from first electrographic seizure to SE. However, there was no correlation between Racine scores and RMS power during the SE phase except a weak correlation with RMS power in the theta frequency. Our analysis reveals limitations of the Racine scale as a primary index of seizure intensity in status epilepticus, and demonstrates a need for quantitative analysis of EEG for an accurate assessment of seizure onset and severity.

Longitudinal evaluation of compressor/nebulizer performance.

BACKGROUND: Inhaled medications are the mainstay of treatment for maintenance of lung health in patients with cystic fibrosis (CF). Compressor/nebulizer units are used an average of 100-120 min/d by patients with CF. Each compressor/nebulizer has unique flow/pressure characteristics that affect particle size distribution and drug output rate. Few data are available regarding longitudinal performance of compressor/nebulizers. We hypothesized that their use over a 24-wk period under conditions similar to those of patients with CF would affect their performance. METHODS: Four new units of compressor/reusable nebulizers from 3 brands (Pari Vios/Pari LC Plus, Pulmo-Aide 5650D/Viox, and Inspiration Elite/SideStream Plus) commonly used by patients with CF were tested. Compressor/nebulizers were operated for 1 h twice daily 5 d/wk for 24 wk. Compressor flow/pressure characteristics were measured every 6 wk. Maximal flow was recorded without and with the nebulizer (MF and MF/NEB, respectively). Pressure was recorded at zero flow (MP) and at MF/NEB (P/NEB). Particle size distribution, inhaled mass (IM), and IM in respirable range were evaluated at baseline and every 12 wk. RESULTS: Vios had statistically significant declines in MP and P/NEB at each measurement compared with baseline (45.8 and 32.6 psi for MP and 16.7 and 14.3 psi for P/NEB at wk 0 and 24, respectively, P < .05), but other compressors did not. MF and MF/NEB were stable over time but significantly varied among brands. Vios had the greatest slope of flow/pressure relationship (Vios > Pulmo-Aide > Inspiration Elite). Two Vios units stopped working at wk 11 and 24, respectively. All compressors maintained baseline IM, IM in respirable range, and aerosol characteristics. CONCLUSIONS: Long-term use of compressor/nebulizers in a regimen similar to that of patients with CF affected their performance. Pari Vios was the most affected brand, with declines in MP and P/NEB and 2 units that stopped working. Measurement of MF and MF/NEB could help identify compressors that are likely to fail.

Practice-based versus telemedicine-based collaborative care for depression in rural federally qualified health centers: a pragmatic randomized comparative effectiveness trial.

OBJECTIVE: Practice-based collaborative care is a complex evidence-based practice that is difficult to implement in smaller primary care practices that lack on-site mental health staff. Telemedicine-based collaborative care virtually co-locates and integrates mental health providers into primary care settings. The objective of this multisite randomized pragmatic comparative effectiveness trial was to compare the outcomes of patients assigned to practice-based and telemedicine-based collaborative care. METHOD: From 2007 to 2009, patients at federally qualified health centers serving medically underserved populations were screened for depression, and 364 patients who screened positive were enrolled and followed for 18 months. Those assigned to practice-based collaborative care received evidence-based care from an on-site primary care provider and a nurse care manager. Those assigned to telemedicine-based collaborative care received evidence-based care from an on-site primary care provider and an off-site team: a nurse care manager and a pharmacist by telephone, and a psychologist and a psychiatrist via videoconferencing. The primary clinical outcome measures were treatment response, remission, and change in depression severity. RESULTS: Significant group main effects were observed for both response (odds ratio=7.74, 95% CI=3.94-15.20) and remission (odds ratio=12.69, 95% CI=4.81-33.46), and a significant overall group-by-time interaction effect was observed for depression severity on the Hopkins Symptom Checklist, with greater reductions in severity over time for patients in the telemedicine-based group. Improvements in outcomes appeared to be attributable to higher fidelity to the collaborative care evidence base in the telemedicine-based group. CONCLUSIONS: Contracting with an off-site telemedicine-based collaborative care team can yield better outcomes than implementing practice-based collaborative care with locally available staff.

Atrial fibrillation following autologous stem cell transplantation in patients with multiple myeloma: incidence and risk factors.

OBJECTIVES: Atrial fibrillation (AF) often develops in patients with multiple myeloma following autologous stem cell transplantation (ASCT), but the exact incidence of, and the risk factors for AF have not been described. In this study, we sought to determine the incidence of AF in patients with multiple myeloma undergoing ASCT. METHODS: Patients who received ASCT for multiple myeloma between January 2000 and December 2009 were identified using the ICD-9 codes for multiple myeloma and ASCT, and formed the basis of this report. RESULTS: The study included 278 patients (mean age, 63 ± 9.5 years). A total of 75 (27%) patients developed AF at a mean duration of 14.8 days following ASCT. On multiple regression analysis, baseline renal dysfunction (odds ratio 15.2 [confidence interval 5.08-45.6]), left ventricular systolic dysfunction (9.55 [2.78-32.79]), dilated left atrium on echocardiogram (4.97 [1.8-13.78]), and hypertension (3.6 [1.36-9.52]) were significantly associated with the development of AF after ASCT. The presence of light-chain secretion (0.21 [0.07-0.6]) was associated with a lower incidence of AF. Age, gender, and race were not significantly associated with the development of AF after ASCT. CONCLUSIONS: AF is very frequent in patients with multiple myeloma when they receive ASCT. The presence of abnormal renal function, left ventricular systolic dysfunction, dilated left atrium, or hypertension at baseline identifies patients at high risk of developing AF following ASCT.

Design, synthesis and structure-activity relationships of novel biarylamine-based Met kinase inhibitors.

Biarylamine-based inhibitors of Met kinase have been identified. Lead compounds demonstrate nanomolar potency in Met kinase biochemical assays and significant activity in the Met-driven GTL-16 human gastric carcinoma cell line. X-ray crystallography revealed that these compounds adopt a bioactive conformation, in the kinase domain, consistent with that previously seen with 2-pyridone-based Met kinase inhibitors. Compound 9b demonstrated potent in vivo antitumor activity in the GTL-16 human tumor xenograft model.

Discovery of N-(4-(2-amino-3-chloropyridin-4-yloxy)-3-fluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (BMS-777607), a selective and orally efficacious inhibitor of the Met kinase superfamily.

Substituted N-(4-(2-aminopyridin-4-yloxy)-3-fluoro-phenyl)-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamides were identified as potent and selective Met kinase inhibitors. Substitution of the pyridine 3-position gave improved enzyme potency, while substitution of the pyridone 4-position led to improved aqueous solubility and kinase selectivity. Analogue 10 demonstrated complete tumor stasis in a Met-dependent GTL-16 human gastric carcinoma xenograft model following oral administration. Because of its excellent in vivo efficacy and favorable pharmacokinetic and preclinical safety profiles, 10 has been advanced into phase I clinical trials.

Discovery of pyrrolopyridine-pyridone based inhibitors of Met kinase: synthesis, X-ray crystallographic analysis, and biological activities.

Conformationally constrained 2-pyridone analogue 2 is a potent Met kinase inhibitor with an IC50 value of 1.8 nM. Further SAR of the 2-pyridone based inhibitors of Met kinase led to potent 4-pyridone and pyridine N-oxide inhibitors such as 3 and 4. The X-ray crystallographic data of the inhibitor 2 bound to the ATP binding site of Met kinase protein provided insight into the binding modes of these inhibitors, and the SAR of this series of analogues was rationalized. Many of these analogues showed potent antiproliferative activities against the Met dependent GTL-16 gastric carcinoma cell line. Compound 2 also inhibited Flt-3 and VEGFR-2 kinases with IC50 values of 4 and 27 nM, respectively. It possesses a favorable pharmacokinetic profile in mice and demonstrates significant in vivo antitumor activity in the GTL-16 human gastric carcinoma xenograft model.

Discovery of orally active pyrrolopyridine- and aminopyridine-based Met kinase inhibitors.

A series of acylurea analogs derived from pyrrolopyridine and aminopyridine scaffolds were identified as potent inhibitors of Met kinase activity. The SAR at various positions of the two kinase scaffolds was investigated. These studies led to the discovery of compounds 3b and 20b, which demonstrated favorable pharmacokinetic properties in mice and significant antitumor activity in a human gastric carcinoma xenograft model.

Identification of pyrrolo[2,1-f][1,2,4]triazine-based inhibitors of Met kinase.

An amide library derived from the pyrrolo[2,1-f][1,2,4]triazine scaffold led to the identification of modest inhibitors of Met kinase activity. Introduction of polar side chains at C-6 of the pyrrolotriazine core provided significant improvements in in vitro potency. The amide moiety could be replaced with acylurea and malonamide substituents to give compounds with improved potency in the Met-driven GTL-16 human gastric carcinoma cell line. Acylurea pyrrolotriazines with substitution at C-5 demonstrated single digit nanomolar kinase activity. X-ray crystallography revealed that the C-5 substituted pyrrolotriazines bind to the Met kinase domain in an ATP-competitive manner.