Poziotinib treatment in patients with HER2-positive advanced breast cancer who have received prior anti-HER2 regimens.

PURPOSE: Poziotinib is an irreversible pan-inhibitor of the human epidermal growth factor receptor (HER) that has shown acceptable tolerability and antitumor activity in phase I and II trials in patients with advanced solid tumors. In the present open-label, multicenter phase II study, we demonstrate safety, tolerability, and preliminary efficacy data from two different dosing schedules in patients with HER2-positive advanced breast cancer. PATIENTS AND METHODS: Patients who had received at least two prior HER2-directed therapy lines for advanced disease, received 24 mg poziotinib on an intermittent dosing schedule (cohort 1) or 16 mg poziotinib once daily on a continuous dosing schedule (cohort 2). The primary endpoint was overall response rate (ORR). Secondary endpoints were progression-free survival (PFS), disease control rate (DCR), and time to progression (TTP). Secondary endpoints additionally included safety and pharmacokinetics. RESULTS: A total of 67 patients were enrolled. The ORR was 30% in both groups (p = 0.98). DCR was 60% vs 78% (p = 0.15) and median PFS and TTP were 4.1 vs 4.9 months (both p = 0.30) for cohorts 1 and 2, respectively. The most common treatment related adverse events (AEs) of any grade included diarrhea (88% vs 85%, p = 0.76), rash (88% vs 88%, p = 0.96), and stomatitis (64% vs 56%, p = 0.52), with grade 3-4 diarrhea occurring in 33% vs 32% of patients (p = 0.93) and grade 3-4 rash in 27% vs 35% of patients (p = 0.48) in cohort 1 vs cohort 2, respectively. CONCLUSION: Poziotinib demonstrated evidence of clinical activity in patients with pre-treated HER2-positive advanced breast cancer, although high levels of toxicity may preclude further studies at this time.

Poziotinib in Treatment-Naive NSCLC Harboring HER2 Exon 20 Mutations: ZENITH20-4, A Multicenter, Multicohort, Open-Label, Phase 2 Trial (Cohort 4).

INTRODUCTION: ERBB2 or HER2 alterations are found in approximately 2% to 5% of NSCLCs; most are exon 20 insertion mutations. The efficacy and safety of poziotinib, an oral tyrosine kinase inhibitor, were assessed in patients with treatment-naive NSCLC whose tumors harbor HER2 exon 20 insertions. METHODS: ZENITH20 is an open-label, multicohort, multicenter, global, phase 2 trial. ZENITH20-C4 enrolled treatment-naive patients with NSCLC with tumors harboring HER2 exon 20 insertions. Poziotinib was administered 16 mg once daily (QD) or 8 mg twice daily (BID). The primary end point was objective response rate (ORR) by independent central review. Secondary and exploratory end points included disease control rate, duration of response, progression-free survival, and safety. RESULTS: A total of 80 patients (16 mg QD, n = 47; 8 mg BID, n = 33) were treated in ZENITH20-C4. ORR was 39% (95% confidence interval [CI]: 28%-50%; 31 of 80), with a disease control rate of 73% (95% CI: 61%-82%; 58 of 80); 80% of the patients experienced tumor reduction. Median duration of response was 5.7 (95% CI: 4.6-11.9) months, and median progression-free survival was 5.6 (95% CI: 5.4-7.3) months. The most common grade 3 treatment-related adverse events were rash (QD, 45%; BID, 39%), stomatitis (QD, 21%; BID, 15%), and diarrhea (QD, 15%; BID, 21%). Among all subtypes of HER2 exon 20 insertions, seven patients (9%) harboring tumors with G778_P780dupGSP had the best clinical outcomes (ORR, 71%). CONCLUSIONS: Poziotinib was found to have clinically meaningful efficacy with a manageable toxicity profile for patients with treatment-naive NSCLC harboring HER2 exon 20 mutations.

Poziotinib in Non-Small-Cell Lung Cancer Harboring HER2 Exon 20 Insertion Mutations After Prior Therapies: ZENITH20-2 Trial.

PURPOSE: Insertion mutations in Erb-b2 receptor tyrosine kinase 2 gene (ERBB2 or HER2) exon 20 occur in 2%-5% of non-small-cell lung cancers (NSCLCs) and function as an oncogenic driver. Poziotinib, a tyrosine kinase inhibitor, was evaluated in previously treated patients with NSCLC with HER2 exon 20 insertions. METHODS: ZENITH20, a multicenter, multicohort, open-label phase II study, evaluated poziotinib in patients with advanced or metastatic NSCLC. In cohort 2, patients received poziotinib (16 mg) once daily. The primary end point was objective response rate evaluated by independent review committee (RECIST v1.1); secondary outcome measures were disease control rate, duration of response, progression-free survival, and safety and tolerability. Quality of life was assessed. RESULTS: Between October 2017 and March 2021, 90 patients with a median of two prior lines of therapy (range, 1-6) were treated. With a median follow-up of 9.0 months, objective response rate was 27.8% (95% CI, 18.9 to 38.2); 25 of 90 patients achieved a partial response. Disease control rate was 70.0% (95% CI, 59.4 to 79.2). Most patients (74%) had tumor reduction (median reduction 22%). Median progression-free survival was 5.5 months (95% CI, 3.9 to 5.8); median duration of response was 5.1 months (95% CI, 4.2 to 5.5). Clinical benefit was seen regardless of lines and types of prior therapy, presence of central nervous system metastasis, and types of HER2 mutations. Grade 3 or higher treatment-related adverse events included rash (48.9%), diarrhea (25.6%), and stomatitis (24.4%). Most patients had poziotinib dose reductions (76.7%), with median relative dose intensity of 71.5%. Permanent treatment discontinuation because of treatment-related adverse events occurred in 13.3% of patients. CONCLUSION: Poziotinib demonstrates antitumor activity in previously treated patients with HER2 exon 20 insertion NSCLC.

Double-Blind, Randomized, Placebo-controlled Studies Evaluating Apaziquone (E09, Qapzola™) Intravesical Instillation Post Transurethral Resection of Bladder Tumors for the Treatment of Low-risk Non-Muscle Invasive Bladder Cancer.

BACKGROUND: Guidelines recommend a single postoperative instillation of intravesical chemotherapy within 24 hours of transurethral resection of bladder tumors (TURBT) in patients with low- and intermediate-risk non-muscle invasive bladder cancer (NMIBC) to reduce recurrence risk. OBJECTIVE: To evaluate the 2-year recurrence rate (2-YRR) of bladder cancer in randomized patients with Ta, G1-G2 histology who receive TURBT plus apaziquone versus TURBT plus placebo. METHODS: Two nearly identical Phase 3, multinational, randomized, double-blind, placebo-controlled trials were conducted in patients with histologically confirmed Ta, G1-G2 NMIBC (Target Population) to evaluate the efficacy/safety of a single instillation of apaziquone post-TURBT. A single intravesical instillation of apaziquone (4 mg/40 mL) or placebo was administered within 6 hours post-TURBT. The primary and secondary efficacy endpoints were 2-YRR and time to recurrence (TTR) respectively. RESULTS: Overall, 1614 patients were enrolled, including 1146 patients in the Target Population. Individually, the two studies did not meet statistical significance for 2-YRR (38.0% vs 44.6% ; 39.7% vs. 46.3%). Because apaziquone is rapidly metabolized in blood, a post hoc subgroup analysis was performed by time window of drug instillation post-TURBT. Patients who had drug instilled in the time window 60±30 minutes post-TURBT demonstrated 20.3% and 20.8% reduction in 2-YRR and 56% (HR = 0.44) and 45% (HR = 0.55) reduction in hazards for TTR in two studies respectively. Apaziquone was well tolerated with minimal toxicity. CONCLUSIONS: Two identical Phase 3 studies supported the safety of apaziquone (4 mg/40 mL) administered as a single intravesical instillation post-TURBT and identified efficacy when instilled within 60±30-minutes time interval which requires further study.

Inter- and intra-subject variability of nitric oxide levels in leukocyte subpopulations.

Assessment of nitric oxide (NO) dynamics in immune cells, commonly measured using NO surrogates such as inducible nitric oxide synthase (iNOS) rather than NO itself, has been effective in understanding pathophysiology across a wide range of diseases. Although the intracellular measurement of NO is now feasible, many technical issues remain unresolved. The principle aim of our study was to determine the effect of storage time of whole blood on nitric oxide (NO) level expression in leukocytes. This is important because immune cells remain chemically dynamic even after they are removed from the circulation, and the impact of storage time must be known to optimally quantify the effect of a disease or condition on NO dynamics in circulating leukocytes. We measured NO levels using the fluorescent probe, diaminofluorescein (DAF-2DA), and flow cytometry in monocytes, neutrophils, and natural killer cells from healthy subjects immediately after blood draw (Time 0) and 30, 60, and 120 min following the blood draw. There was no significant difference among the 4 study time points in NO (DAF-2) levels, though there was wide intra-subject variability at all time points. Using LPS stimulation, we compared iNOS (the more traditional surrogate marker of NO dynamics) with NO (by DAF-2) in natural killer cells and monocytes and, we found no difference in the response patterns. In summary, we did find that within a 2-hour interval from blood draw to sample processing, there was a remarkably wide intra-subject variability in expression of intracellular NO (DAF-2) in leukocytes of healthy individuals at baseline and over time. The mechanism(s) for these differences are not known but could clearly confound efforts to detect changes in NO metabolism in white blood cells. We speculate that rapid pulsatility of NO could explain the wide variability seen.

Simultaneously Occurring Elevated Metabolic States Expose Constraints in Maximal Levels of Oxygen Consumption in the Oviparous Snake Lamprophis fuliginosus.

African house snakes (Lamprophis fuliginosus) were used to compare the metabolic increments associated with reproduction, digestion, and activity both individually and when combined simultaneously. Rates of oxygen consumption ([Formula: see text]) and carbon dioxide production ([Formula: see text]) were measured in adult female (nonreproductive and reproductive) and adult male snakes during rest, digestion, activity while fasting, and postprandial activity. We also compared the endurance time (i.e., time to exhaustion) during activity while fasting and postprandial activity in males and females. For nonreproductive females and males, our results indicate that the metabolic increments of digestion (∼3-6-fold) and activity while fasting (∼6-10-fold) did not interact in an additive fashion; instead, the aerobic scope associated with postprandial activity was 40%-50% lower, and animals reached exhaustion up to 11 min sooner. During reproduction, there was no change in digestive [Formula: see text], but aerobic scope for activity while fasting was 30% lower than nonreproductive values. The prioritization pattern of oxygen delivery exhibited by L. fuliginosus during postprandial activity (in both males and females) and for activity while fasting (in reproductive females) was more constrained than predicted (i.e., instead of unchanged [Formula: see text], peak values were 30%-40% lower). Overall, our results indicate that L. fuliginosus's cardiopulmonary system's capacity for oxygen delivery was not sufficient to maintain the metabolic increments associated with reproduction, digestion, and activity simultaneously without limiting aerobic scope and/or activity performance.

Cardiopulmonary Exercise Testing in Children and Adolescents with High Body Mass Index.

Consensus has yet to be achieved on whether obesity is inexorably tied to poor fitness. We tested the hypothesis that appropriate reference of cardiopulmonary exercise testing (CPET) variables to lean body mass (LBM) would eliminate differences in fitness between high-BMI (≥ 95th percentile, n = 72, 50% female) and normal-BMI (< 85th percentile, n = 142, 49% female), otherwise-healthy children and adolescents typically seen when referencing body weight. We measured body composition with dual x-ray absorptiometry (DXA) and CPET variables from cycle ergometry using both peak values and submaximal exercise slopes (peak VO2, ΔVO2/ΔHR, ΔWR/ΔHR, ΔVO2/ΔWR, and ΔVE/ΔVCO2). In contrast to our hypothesis, referencing to LBM tended to lessen, but did not eliminate, the differences (peak VO2 [p < .004] and ΔVO2/ΔHR [p < .02]) in males and females; ΔWR/ΔHR differed between the two groups in females (p = .041) but not males (p = .1). The mean percent predicted values for all CPET variables were below 100% in the high-BMI group. The pattern of CPET abnormalities suggested a pervasive impairment of O2 delivery in the high-BMI group (ΔVO2/ΔWR was in fact highest in normal-BMI males). Tailoring lifestyle interventions to the specific fitness capabilities of each child (personalized exercise medicine) may be one of the ways to stem what has been an intractable epidemic.

Cerebral and Muscle Tissue Oxygenation During Incremental Cycling in Male Adolescents Measured by Time-Resolved Near-Infrared Spectroscopy.

Near-infrared spectroscopy has long been used to measure tissue-specific O2 dynamics in exercise, but most published data have used continuous wave devices incapable of quantifying absolute Hemoglobin (Hb) concentrations. We used time-resolved near-infrared spectroscopy to study exercising muscle (Vastus Lateralis, VL) and prefrontal cortex (PFC) Hb oxygenation in 11 young males (15.3 ± 2.1 yrs) performing incremental cycling until exhaustion (peak VO2 = 42.7 ± 6.1 ml/min/kg, mean peak power = 181 ± 38 W). Time-resolved near-infrared spectroscopy measurements of reduced scattering (µs´) and absorption (µa) at three wavelengths (759, 796, and 833 nm) were used to calculate concentrations of oxyHb ([HbO2]), deoxy Hb ([HbR]), total Hb ([THb]), and O2 saturation (stO2). In PFC, significant increases were observed in both [HbO2] and [HbR] during intense exercise. PFC stO2% remained stable until 80% of total exercise time, then dropped (-2.95%, p = .0064). In VL, stO2% decreased until peak time (-6.8%, p = .01). Segmented linear regression identified thresholds for PFC [HbO2], [HbR], VL [THb]. There was a strong correlation between timing of second ventilatory threshold and decline in PFC [HbO2] (r = .84). These findings show that time-resolved near-infrared spectroscopy can be used to study physiological threshold phenomena in children during maximal exercise, providing insight into tissue specific hemodynamics and metabolism.

Cost comparison of robotic-assisted laparoscopic hysterectomy versus standard laparoscopic hysterectomy.

The aim of the study was to assess if the cost of robotic-assisted total laparoscopic hysterectomy is similar to the cost of standard laparoscopic hysterectomy when performed by surgeons past their initial learning curve. A retrospective chart review of all hysterectomies was performed for benign indications without concomitant major procedures at Orange Coast Memorial Medical Center (OCMMC) and Saddleback Memorial Medical Center between January 1, 2013 and September 30, 2013. Robotic-assisted total laparoscopic hysterectomies (RTLH) and standard laparoscopic hysterectomies (LAVH and TLH) were compared. Data analyzed included only those hysterectomies performed by surgeons past their initial learning curve (minimum of 30 previous robotic cases). The primary outcome was the direct total cost of patient's hospitalization related to hysterectomy. The secondary outcomes were estimated blood loss, surgery time, and days in hospital post-surgery. A multiple linear regression model was applied to evaluate the difference between RTLH and LAVH/TLH in hospital cost, blood loss, and surgery time, while adjusting for hospital, patient's age, body mass index (BMI), whether or not the patient had previous abdominal/pelvic surgery, and uterine weight. The χ (2) test was applied to examine the association between hospital stay and surgery type. There were 93 hysterectomies (5 LAVH, 88 RTLH) performed at OCMMC and 90 hysterectomies (6 LAVH, 17 TLH, 67 RTLH) performed at Saddleback Memorial Medical Center. The hospitalization total cost result showed that, after adjusting for hospital, age, BMI, previous abdominal/pelvic surgery, and uterine weight, RTLH was not significantly more expensive than LAVH/TLH (mean diff. = $283.1, 95 % CI = [-569.6, 1135.9]; p = 0.51) at the 2 study hospitals. However, the cost at OCMMC was significantly higher than Saddleback Memorial Medical Center (mean diff. = $2008.7, 95 % CI = [1380.6, 2636.7]; p < 0.0001); and the cost increased significantly with uterine weight (ß = 3.8, 95 % CI = [2.3, 5.3]; p < 0.0001). Further analysis showed significantly less blood loss (mean diff. = -78.5 ml, 95 % CI = [-116.8, -40.3]; p < 0.0001) and shorter surgery time (mean diff. = -21.9 min., 95 % CI = [-39.6, -4.2]; p = 0.016) for RTLH versus LAVH/TLH. There was no significant association between hospital stay and surgery type (p = 0.43). After adjusting for patient-level covariates, there was no statistically significant cost difference of performing robotically assisted laparoscopic hysterectomy versus standard laparoscopic hysterectomy when performed by surgeons past their initial learning curve at two community hospitals.

Patterns of oxygen consumption during simultaneously occurring elevated metabolic states in the viviparous snake Thamnophis marcianus.

Snakes exhibit large factorial increments in oxygen consumption during digestion and physical activity, and long-lasting sub-maximal increments during reproduction. Under natural conditions, all three physiological states may occur simultaneously, but the integrated response is not well understood. Adult male and female checkered gartersnakes (Thamnophis marcianus) were used to examine increments in oxygen consumption (i.e. V̇(O2)) and carbon dioxide production (i.e. V̇(CO2)) associated with activity (Act), digestion (Dig) and post-prandial activity (Act+Dig). For females, we carried out these trials in the non-reproductive state, and also during the vitellogenic (V) and embryogenic (E) phases of a reproductive cycle. Endurance time (i.e. time to exhaustion, TTE) was recorded for all groups during Act and Act+Dig trials. Our results indicate that male and non-reproductive female T. marcianus exhibit significant increments in V̇(O2) during digestion (∼5-fold) and activity (∼9-fold), and that Act+Dig results in a similar increment in V̇(O2) (∼9- to 10-fold). During reproduction, resting V̇(O2) increased by 1.6- to 1.7-fold, and peak increments during digestion were elevated by 30-50% above non-reproductive values, but values associated with Act and Act+Dig were not significantly different from non-reproductive values. During Act+Dig, endurance time remained similar for all of the groups in the present study. Overall, our results indicate that prioritization is the primary pattern of interaction in oxygen delivery exhibited by this species. We propose that the metabolic processes associated with digestion, and perhaps reproduction, are temporarily compromised during activity.

Assessment of Dosing and Patient Factors on the Efficacy of Warfarin Following Total Joint Replacement.

The purpose of this study was to determine the percentage of patients discharged with a subtherapeutic INR <1.8 using our institutions inpatient warfarin dosing nomogram following total joint arthroplasty (TJA). We examined predisposing risk factors for a subtherapeutic discharge (INR <1.8), including increased body weight, age, gender, end stage renal disease (ESRD), smoking, and peri-operative transfusion. Chart review identified 249 patients for study inclusion. Logistic regression (LR) was used to identify associated risk factors for a subtherapeutic INR (<1.8) on day of discharge. The majority of patients (58.6%, 146 of 249) following TJA surgery were found to have a subtherapeutic INR level (INR<1.8) at discharge (mean length of stay 2.6 days). Multivariate LR analysis found that weight greater than 180 lbs. (OR 2.08, CI 1.09, 3.98, P=0.027) was found to increase the odds of a subtherapeutic INR on day of discharge. Our results were not significant for weight 20% beyond ideal body weight, age (>65y), gender, peri-operative transfusion, smoking, ESRD or autoimmune disease. A patient's body weight influences response to warfarin following TJA. An inpatient warfarin dosing nomogram that takes into account a patient's weight should be used to reduce the risk of subtherapeutic INR levels in obese TJA patients.

Quantification of Aerosol Hydrofluoroalkane HFA-134a Elimination in the Exhaled Human Breath Following Inhaled Corticosteroids Administration.

Inhaled corticosteroids (ICS) and ß2-agonists are the primary pharmacotherapies of asthma management. However, suboptimal medication compliance is common in asthmatics and is associated with increased morbidity. We hypothesized that exhaled breath measurements of the aerosol used in the inhaled medications might prove useful as surrogate marker for asthma medication compliance. To explore this, 10 healthy controls were recruited and randomly assigned to ICS (Flovent HFA) or short acting bronchodilators (Proventil HFA). Both inhalers contain HFA-134a as aerosol propellant. Exhaled breath sampling and pulmonary function tests were performed prior to the inhaler medication dispersion, immediately after inhalation, then at 2, 4, 6, 8, 24, and 48 hours postadministration. At baseline, mean (SD) levels of HFA-134a in the breath were 252 (156) pptv. Immediately after inhalation, HFA-134a breath levels increased to 300 × 10(6) pptv and were still well above ambient levels 24 hours postadministration. The calculated ratio of forced expiratory volume in 1 second over forced vital capacity did not change over time following inhaler administration. This study demonstrates, for the first time, that breath HFA-134a levels can be used to assess inhaler medication compliance. It may also be used to evaluate how effectively the medicine is delivered.

Vigorous Exercise Can Cause Abnormal Pulmonary Function in Healthy Adolescents.

RATIONALE: Although exercise-induced bronchoconstriction is more common in adolescents with asthma, it also manifests in healthy individuals without asthma. The steady-state exercise protocol is widely used and recommended by the American Thoracic Society (ATS) as a method to diagnose exercise-induced bronchoconstriction. Airway narrowing in response to exercise is thought to be related to airway wall dehydration secondary to hyperventilation. More rigorous exercise protocols may have a role in detecting exercise-induced bronchoconstriction in those who otherwise have a normal response to steady-state exercise challenge. OBJECTIVES: The objective of this study was to determine the effect of two different exercise protocols--a constant work rate protocol and a progressive ramp protocol--on pulmonary function testing in healthy adolescents. We hypothesized that vigorous exercise protocols would lead to reductions in lung function in healthy adolescents. METHODS: A total of 56 healthy adolescents (mean age, 15.2 ± 3.3 [SD] years) were recruited to perform two exercise protocols: constant work rate exercise test to evaluate for exercise-induced bronchoconstriction (as defined by ATS) and standardized progressive ramp protocol. Pulmonary function abnormalities were defined as a decline from baseline in FEV1 of greater than 10%. MEASUREMENTS AND MAIN RESULTS: Ten participants (17.8%) had a significant drop in FEV1. Among those with abnormal lung function after exercise, three (30%) were after the ATS test only, five (50%) were after the ramp test only, and two (20%) were after both ATS and ramp tests. CONCLUSION: Healthy adolescents demonstrate subtle bronchoconstriction after exercise. This exercise-induced bronchoconstriction may be detected in healthy adolescents via constant work rate or the progressive ramp protocol. In a clinical setting, ramp testing warrants consideration in adolescents suspected of having exercise-induced bronchoconstriction and who have normal responses to steady-state exercise testing.

Arabic validation of the Pelvic Organ Prolapse/Incontinence Sexual Questionnaire, IUGA-Revised (PISQ-IR).

INTRODUCTION AND HYPOTHESIS: Our aim was to translate then assess the reliability of the culturally adapted Pelvic Organ Prolapse/Incontinence Sexual Function Questionnaire, International Urogynecological Association (IUGA)-Revised (PISQ-IR) to assess sexual health among Arabic-speaking women with pelvic floor disorders. METHODS: PISQ-IR was modified to consider cultural characteristics of the Middle East. The final reliability study included 172 women with urinary incontinence (UI) and/or pelvic organ prolapse (POP). Participants completed the questionnaire twice: at enrollment and 2 weeks later. RESULTS: Among sexually active women, good internal consistency was observed for five of the six scales in the adapted instrument: Global Quality (Cronbach's coefficient α = 0.86), Condition Impact (α = 0.87), Desire (α = 0.82), Condition Specific (α = 0.74), and Partner Related (α = 0.75). Internal consistency was acceptable for the Arousal Orgasm subscale (α = 0.66). However, among not sexually active women, internal consistency was poor (α <0.6) for all four scales. Lin's concordance correlation coefficient measuring agreement between test and retest measurements [Lin's concordance correlation coefficient (CCC); a value of 1 represents perfect agreement] ranged from 0.81 to 0.87 for the not sexually active scales, except for condition impact (CCC = 0.63.) For sexually active women, CCC was typically stronger, ranging from 0.85 to 0.96. CONCLUSIONS: PISQ-IR questionnaire is easy to administer and reliable for assessing sexual function in sexually active Arabic women with POP and UI, but internal consistency is poor for Arabic women not sexually active.

Reliability and application variability of a commercially available infrared videonystagmography unit.

PURPOSE: Nystagmus is a condition of involuntary eye movement. The causes for nystagmus may be congenital, idiopathic, or acquired. Considerable debate exists on the therapeutic potential of various surgical techniques. Currently, there are neither standardized protocols nor devices to record quantitative data on patients with clinical nystagmus undergoing various procedures at multiple centers to facilitate randomized prospective clinical trials. METHODS: The authors evaluated the reliability and variability of a commercially available infrared videonystagmography unit by recording eye movement waveforms elicited from normal volunteers (n = 117, 13 patients, 9 trials) by different examiners (A, B, and C). Five movement characteristics were examined, including saccadic latency, velocity and precision, and pursuit gain and velocity. RESULTS: The overall test/retest variability was low, where the median coefficient of variation of the three testers for all five eye movement categories was less than 15%, and less than 10% of the coefficients of variation calculated were more than 20%. However, there was a significant difference in interobserver variability for all outcomes, except saccade latency. CONCLUSIONS: The between-tester analysis was found to have greater variability than the test/retest reliability analysis. Future studies at multiple sites using videonystagmography measurements should aim to have each patient repeatedly tested by the same tester. In anticipation of multicenter, randomized, prospective clinical trials of surgical procedures for nystagmus, standardized protocols for nystagmographic data collection and analysis must be validated both within and among participating centers.

An Examination of Changes in Emotion Co-Regulation Among Mother and Child Dyads During the Strange Situation.

The present study applied State Space Grid analysis to describe how preschooler-mother dyads co-regulate emotion in the Strange Situation. Second-to-second mother and child affect during pre-separation play (baseline) and the final reunion (post perturbation) episodes of the Strange Situation were coded for 80 dyads. Change in emotion co-regulation across the two Strange Situation episodes was examined with linear mixed models for groups with secure and insecure classifications. The groups did not differ at baseline. Change in content-specific emotion co-regulation but not content-free emotion co-regulation was found to be significantly different within and between groups. Both secure and insecure dyads reduced the time spent in positive interaction but increased the time in negative interaction across two episodes; the change in secure dyads was less pronounced than in the insecure dyads. After the separation, secure dyads had more positive interactions and fewer negative interactions compared to insecure dyads. Results highlight how secure dyads adapted to the stressful change, whereas insecure dyads were more reactive and less resilient to the stress of the study's brief imposed separation.

The clinical translation gap in child health exercise research: a call for disruptive innovation.

In children, levels of play, physical activity, and fitness are key indicators of health and disease and closely tied to optimal growth and development. Cardiopulmonary exercise testing (CPET) provides clinicians with biomarkers of disease and effectiveness of therapy, and researchers with novel insights into fundamental biological mechanisms reflecting an integrated physiological response that is hidden when the child is at rest. Yet the growth of clinical trials utilizing CPET in pediatrics remains stunted despite the current emphasis on preventative medicine and the growing recognition that therapies used in children should be clinically tested in children. There exists a translational gap between basic discovery and clinical application in this essential component of child health. To address this gap, the NIH provided funding through the Clinical and Translational Science Award (CTSA) program to convene a panel of experts. This report summarizes our major findings and outlines next steps necessary to enhance child health exercise medicine translational research. We present specific plans to bolster data interoperability, improve child health CPET reference values, stimulate formal training in exercise medicine for child health care professionals, and outline innovative approaches through which exercise medicine can become more accessible and advance therapeutics across the broad spectrum of child health.

Altered insulin response to an acute bout of exercise in pediatric obesity.

Pediatric obesity typically induces insulin resistance, often later evolving into type 2 diabetes. While exercise, enhancing insulin sensitivity, is broadly used to prevent this transition, it is unknown whether alterations in the exercise insulin response pattern occur in obese children. Therefore, we measured exercise insulin responses in 57 healthy weight (NW), 20 overweight (OW), and 56 obese (Ob) children. Blood samples were drawn before and after 30 min of intermittent (2 min on, 1 min off) cycling at ~80% VO2max. In a smaller group (14 NW, 6 OW, 15 Ob), a high-fat meal was ingested 45 min preexercise. Baseline glycemia was similar and increased slightly and similarly in all groups during exercise. Basal insulin (pmol/L) was significantly higher in Ob vs. other groups; postexercise, insulin increased in NW (+7± 3) and OW (+5 ± 8), but decreased in Ob (-15±5, p < .0167 vs. NW). This insulin drop in Ob was disproportionately more pronounced in the half of Ob children with higher basal insulin (Ob-H). In all groups, high-fat feeding caused a rapid rise in insulin, promptly corrected by exercise. In Ob, however, insulin rose again 30 min postexercise. Our data indicates a distinct pattern of exercise-induced insulin modulation in pediatric obesity, possibly modulated by basal insulin concentrations.

NON-HOMOGENEOUS POISSON PROCESS MODEL FOR GENETIC CROSSOVER INTERFERENCE.

The genetic crossover interference is usually modeled with a stationary renewal process to construct the genetic map. We propose two non-homogeneous, also dependent, Poisson process models applied to the known physical map. The crossover process is assumed to start from an origin and to occur sequentially along the chromosome. The increment rate depends on the position of the markers and the number of crossover events occurring between the origin and the markers. We show how to obtain parameter estimates for the process and use simulation studies and real Drosophila data to examine the performance of the proposed models.