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.

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.

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. .

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.

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.

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.

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.

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.

Second generation tetrahydroquinoline-based protein farnesyltransferase inhibitors as antimalarials.

Substituted tetrahydroquinolines (THQs) have been previously identified as inhibitors of mammalian protein farnesyltransferase (PFT). Previously we showed that blocking PFT in the malaria parasite led to cell death and that THQ-based inhibitors are the most potent among several structural classes of PFT inhibitors (PFTIs). We have prepared 266 THQ-based PFTIs and discovered several compounds that inhibit the malarial enzyme in the sub- to low-nanomolar range and that block the growth of the parasite (P. falciparum) in the low-nanomolar range. This body of structure-activity data can be rationalized in most cases by consideration of the X-ray structure of one of the THQs bound to mammalian PFT together with a homology structural model of the malarial enzyme. The results of this study provide the basis for selection of antimalarial PFTIs for further evaluation in preclinical drug discovery assays.

A randomized trial of telemedicine-based collaborative care for depression.

BACKGROUND: Evidence-based practices designed for large urban clinics are not necessarily portable into smaller isolated clinics. Implementing practice-based collaborative care for depression in smaller primary care clinics presents unique challenges because it is often not feasible to employ on-site psychiatrists. OBJECTIVE: The purpose of the Telemedicine Enhanced Antidepressant Management (TEAM) study was to evaluate a telemedicine-based collaborative care model adapted for small clinics without on-site psychiatrists. DESIGN: Matched sites were randomized to the intervention or usual care. PARTICIPANTS: Small VA Community-based outpatient clinics with no on-site psychiatrists, but access to telepsychiatrists. In 2003-2004, 395 primary care patients with PHQ9 depression severity scores > or = 12 were enrolled, and followed for 12 months. Patients with serious mental illness and current substance dependence were excluded. MEASURES: Medication adherence, treatment response, remission, health status, health-related quality of life, and treatment satisfaction. RESULTS: The sample comprised mostly elderly, white, males with substantial physical and behavioral health comorbidity. At baseline, subjects had moderate depression severity (Hopkins Symptom Checklist, SCL-20 = 1.8), 3.7 prior depression episodes, and 67% had received prior depression treatment. Multivariate analyses indicated that intervention patients were more likely to be adherent at both 6 (odds ratio [OR] = 2.1, p = .04) and 12 months (OR = 2.7, p = .01). Intervention patients were more likely to respond by 6 months (OR = 2.0, p = .02), and remit by 12 months (OR = 2.4, p = .02). Intervention patients reported larger gains in mental health status and health-related quality of life, and reported higher satisfaction. CONCLUSIONS: Collaborative care can be successfully adapted for primary care clinics without on-site psychiatrists using telemedicine technologies.

Hypertabastic survival model.

A new two-parameter probability distribution called hypertabastic is introduced to model the survival or time-to-event data. A simulation study was carried out to evaluate the performance of the hypertabastic distribution in comparison with popular distributions. We then demonstrate the application of the hypertabastic survival model by applying it to data from two motivating studies. The first one demonstrates the proportional hazards version of the model by applying it to a data set from multiple myeloma study. The second one demonstrates an accelerated failure time version of the model by applying it to data from a randomized study of glioma patients who underwent radiotherapy treatment with and without radiosensitizer misonidazole. Based on the results from the simulation study and two applications, the proposed model shows to be a flexible and promising alternative to practitioners in this field.

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).

Risk profiles for four types of work-related injury among hospital employees: a case-control study.

In this retrospective case-control study, researchers examined risk factors for four types of work-related injury (WRI) in hospital employees. Data were collected from employee health charts and computer databases (N = 2050) and analyzed using logistic regression. Study results showed that strain injuries were related to increased age, increased body mass index (BMI), and maintenance, custodial, and direct-caregiver employment types. Repetitive motion injuries were related to increased BMI and clerical and custodial employment types. Exposure/reaction injuries were related to increased age, increased BMI, and maintenance, custodial, and direct-caregiver employment types. Contact/assault injuries were related to increased age, increased BMI, and maintenance, custodial, and direct-caregiver employment types. All injury types were most often related to female gender and full-time employment status. Reformulating policies to improve screening, prevention, and education for those at risk for certain injury types may limit WRI occurrences and costs.

Factors associated with work-related injury among hospital employees: a case-control study.

The Central Arkansas Veterans Healthcare System (CAVHS) spends $1 million annually on occupational illnesses and injuries. To address the problem of injuries among hospital employees, a retrospective case-control study was conducted to examine select risk factors for work-related injuries (WRI) among CAVHS employees. Study methods included a review of employee health charts and computer and manual databases from 1997 to 2002 (N = 2,050). The researchers found that WRI increased with age; WRI occurred more often in women than in men; WRI was greater among maintenance and custodial staff compared to direct caregivers, and less among clerical staff; WRI occurred less often in part-time than full-time staff; and WRI increased with increasing body mass index. Developing standards, guidelines, and policies for preplacement screening, preventive measures, training, and education may help to minimize WRI and associated costs.

Protein farnesyltransferase inhibitors exhibit potent antimalarial activity.

New therapeutics to combat malaria are desperately needed. Here we show that the enzyme protein farnesyltransferase (PFT) from the malaria parasite Plasmodium falciparum (P. falciparum) is an ideal drug target. PFT inhibitors (PFTIs) are well tolerated in man, but are highly cytotoxic to P. falciparum. Because of their anticancer properties, PFTIs comprise a highly developed class of compounds. PFTIs are ideal for the rapid development of antimalarials, allowing "piggy-backing" on previously garnered information. Low nanomolar concentrations of tetrahydroquinoline (THQ)-based PFTIs inhibit P. falciparum PFT and are cytotoxic to cultured parasites. Biochemical studies suggest inhibition of parasite PFT as the mode of THQ cytotoxicity. Studies with malaria-infected mice show that THQ PFTIs dramatically reduce parasitemia and lead to parasite eradication in the majority of animals. These studies validate P. falciparum PFT as a target for the development of antimalarials and describe a potent new class of THQ PFTIs with antimalaria activity.