Thesis (M.A.) -- University of Maryland, College Park, 2005.
Thesis research directed by: Dept. of Counseling and Personnel Services. Title from t.p. of PDF. Includes bibliographical references. ...Published by UMI Dissertation Services, Ann Arbor, Mich. Also available in paper.
The Work/Family Conflict Self-Efficacy Scale (WFC-SES) (Cinamon, 2003) was designed to measure an individual's beliefs in her or his ability to manage work-family and family-work conflict. The ...current study examines the factor structure, reliability, and validity estimates for the WFC-SES. In a sample of 159 working mothers, results showed evidence of satisfactory estimates of internal and external validity. Exploratory analysis suggests that work/family conflict self-efficacy may mediate the relationship between work/family conflict and outcomes such as work and family satisfaction and work stress. The WFC-SES may be used to better understand the role that self-efficacy can play in the relationship between conflict and negative outcomes.
Indoor pesticide exposure is a growing concern, particularly for pyrethroids, a commonly used class of pesticides. Pyrethroid concentrations may be especially high in homes of immigrant farm worker ...families, who often live in close proximity to agricultural fields and are faced with poor housing conditions, potentially causing high pest infestation and pesticide use. We investigate levels of pyrethroids in the house dust of farm worker family homes in a study of mothers and children living in Mendota, CA, within the population-based Mexican Immigration to California: Agricultural Safety and Acculturation (MICASA) Study. We present pesticide use data and levels of pyrethroid pesticides in indoor dust collected in 2009 as measured by questionnaires and a GC/MS analysis of the pyrethroids cis- and trans-permethrin, cypermethrin, deltamethrin, esfenvalerate and resmethrin in single dust samples collected from 55 households. Cis- and trans-permethrin had the highest detection frequencies at 67%, with median concentrations of 244 and 172ng/g dust, respectively. Cypermethrin was detected in 52% of the homes and had a median concentration of 186ng/g dust. Esfenvalerate, resmethrin and deltamethrin were detected in less than half the samples. We compared the pyrethroid concentrations found in our study to other studies looking at both rural and urban homes and daycares. Lower detection frequencies and/or lower median concentrations of cis- and trans-permethrin and cypermethrin were observed in our study as compared to those studies. However, deltamethrin, esfenvalerate and resmethrin were detected more frequently in the house dust from our study than in the other studies. Because households whose children had higher urinary pyrethroid metabolite levels were more likely to be analyzed in this study, a positive bias in our estimates of household pyrethroid levels may be expected. A positive association was observed with reported outdoor pesticide use and cypermethrin levels found in the indoor dust samples (rs=0.28, p=0.0450). There was also a positive association seen with summed pyrethroid levels in house dust and the results of a pesticide inventory conducted by field staff (rs=0.32, p=0.018), a potentially useful predictor of pesticide exposure in farm worker family homes. Further research is warranted to fully investigate the utility of such a measure.
•Farm worker family pesticide use and indoor pyrethroid levels were investigated.•Outdoor pesticide use and indoor pyrethroid levels were positively associated.•Indoor pyrethroid levels and a home pesticide inventory were positively associated.
The Cancer Genome Atlas analysis revealed that somatic EGFR, receptor tyrosine-protein kinase erbB-2 (ERBB2), Erb-B2 receptor tyrosine kinase 3 (ERBB3) and Erb-B2 receptor tyrosine kinase 4 (ERBB4) ...gene mutations (ERBB family mutations) occur alone or co-occur with somatic mutations in the gene encoding the phosphatidylinositol 3-kinase (PI3K) catalytic subunit (PIK3CA) in 19% of human epidermal growth factor receptor 2 (HER2)-positive breast cancers. Because ERBB family mutations can activate the PI3K/AKT pathway and likely have similar canonical signalling effects to PI3K pathway mutations, we investigated their combined impact on response to neoadjuvant HER2-targeted therapies.
Baseline tumour biopsies were available from 74 patients with HER2-positive breast cancer who were enrolled in the phase II TCHL neoadjuvant study (ICORG 10-05) assessing TCH (docetaxel, carboplatin, trastuzumab) (n = 38) versus TCL (docetaxel, carboplatin, lapatinib) (n = 10) versus TCHL (docetaxel, carboplatin, trastuzumab, lapatinib) (n = 40), each for six cycles. Activating mutations in PIK3CA and ERBB family genes were identified using mass spectrometry-based genotyping. Phosphatase and tensin homolog (PTEN) expression was assessed by immunohistochemistry.
PIK3CA and/or ERBB family mutations were detected in 23 (31.1%) tumour samples tested, whereas PTEN expression was low in 31.1% of cases tested. Mutation frequency was similar in each treatment arm (31.3% in TCH arm, 30% in TCL arm and 31.3% in TCHL arm) and was not influenced by oestrogen receptor (ER) status (27.6% in ER-negative patients, 33.3% in ER-positive patients) or progesterone receptor (PR) status (32.6% in PR-negative patients, 29% in PR-positive patients). There was no significant difference in pathological complete response (pCR) rates between 47 patients with wild-type (WT) tumours and 22 patients whose tumours carried mutations (in either PIK3CA or ERBB family genes) (42.5% vs. 54.5%; p = 0.439). Similarly, there was no significant difference in pCR rates between patients with PIK3CA/ERBB family mutated/PTEN-low (i.e., PI3K-activated) tumours and patients without PI3K activation (50% vs. 44%; p = 0.769). However, in the TCHL (but not the TCH) group, the pCR rate was higher for 9 patients with PIK3CA/ERBB family mutated tumours than for 20 patients with PIK3CA/ERBB family WT tumours (77.8% vs. 35%; p = 0.05).
Our results indicate that patients who receive neoadjuvant TCHL and have PIK3CA/ERBB family mutated tumours may be more likely to have a pCR than patients with WT tumours.
ClinicalTrials.gov, NCT01485926 . Registered on 2 December 2011.
Purpose
A 3-biomarker homologous recombination deficiency (HRD) score is a key component of a currently FDA-approved companion diagnostic assay to identify HRD in patients with ovarian cancer using a ...threshold score of ≥ 42, though recent studies have explored the utility of a lower threshold (GIS ≥ 33). The present study evaluated whether the ovarian cancer thresholds may also be appropriate for major breast cancer subtypes by comparing the genomic instability score (GIS) distributions of
BRCA1/2
-deficient estrogen receptor–positive breast cancer (ER + BC) and triple-negative breast cancer (TNBC) to the GIS distribution of
BRCA1/2-
deficient ovarian cancer.
Methods
Ovarian cancer and breast cancer (ER + BC and TNBC) tumors from ten study cohorts were sequenced to identify pathogenic
BRCA1/2
mutations, and GIS was calculated using a previously described algorithm. Pathologic complete response (pCR) to platinum therapy was evaluated in a subset of TNBC samples. For TNBC, a threshold was set and threshold validity was assessed relative to clinical outcomes.
Results
A total of 560 ovarian cancer, 805 ER + BC, and 443 TNBC tumors were included. Compared to ovarian cancer, the GIS distribution of
BRCA1/2
-deficient samples was shifted lower for ER + BC (p = 0.015), but not TNBC (p = 0.35). In the subset of TNBC samples, univariable logistic regression models revealed that GIS status using thresholds of ≥ 42 and ≥ 33 were significant predictors of response to platinum therapy.
Conclusions
This study demonstrated that the GIS thresholds used for ovarian cancer may also be appropriate for TNBC, but not ER + BC. GIS thresholds in TNBC were validated using clinical response data to platinum therapy.
Hospitalized children with medical complexity (CMC) are at high risk of medical errors. Their families are an underutilized source of hospital safety data. We evaluated safety concerns from families ...of hospitalized CMC and patient/parent characteristics associated with family safety concerns.
We conducted a 12-month prospective cohort study of English- and Spanish-speaking parents/staff of hospitalized CMC on 5 units caring for complex care patients at a tertiary care children's hospital. Parents completed safety and experience surveys predischarge. Staff completed surveys during meetings and shifts. Mixed-effects logistic regression with random intercepts controlling for clustering and other patient/parent factors evaluated associations between family safety concerns and patient/parent characteristics.
A total of 155 parents and 214 staff completed surveys (>89% response rates). 43% (n = 66) had ≥1 hospital safety concerns, totaling 115 concerns (1-6 concerns each). On physician review, 69% of concerns were medical errors and 22% nonsafety-related quality issues. Most parents (68%) reported concerns to staff, particularly bedside nurses. Only 32% of parents recalled being told how to report safety concerns. Higher education (adjusted odds ratio 2.94, 95% confidence interval 1.21-7.14, P = .02) and longer length of stay (3.08 1.29-7.38, P = .01) were associated with family safety concerns.
Although parents of CMC were infrequently advised about how to report safety concerns, they frequently identified medical errors during hospitalization. Hospitals should provide clear mechanisms for families, particularly of CMC and those from disadvantaged backgrounds, to share safety concerns. Actively engaging patients/families in reporting will allow hospitals to develop a more comprehensive, patient-centered view of safety.
Abstract
Background
Mobility training is a complex intervention and recovery post-stroke is multidimensional. AVERT DOSE aims to define optimal early intervention regimens for people with mild to ...moderate ischaemic stroke.
Methods
AVERT DOSE (ACTRN:12619000557134) is an international randomised trial that will recruit >2,500 patients. Randomisation is to two groups according to stroke severity. Patients are then randomised to one of four mobility training regimens in each strata and the intervention is delivered for up to 14-days. Primary Outcome: Identification of the intervention regimen that results in higher proportion of favourable outcome at 3-months post-stroke.
Results
In Ireland, 4 sites are actively recruiting (1,2,3 and 7), one completing training (4) and two finalising ethical approval and contracts (5,6). Eighteen patients have been recruited to date in Ireland, and over 400 internationally. Trial set-up has proven complex with processes and requirements differing significantly across Irish sites. Time to ethics approval has ranged from 10-months to over 3-years. The novel status of this trial as a non-drug/medical device trial, but rather rehabilitation trial, had led to discussion in relation to the need for a trial EU representative. Staff recruitment and retention challenges have proven to be a significant barrier to recruitment in recent months. The development of an Irish Avert Dose group to collaboratively address challenges and provide peer support has proven very successful in both supporting sites to reach recruitment stage and throughout the stages of screening, recruitment, intervention and blind assessment.
Conclusion
Undertaking rehabilitation research against the backdrop of a global pandemic and increasing staffing challenges requires a determined, problem-solving approach. Irish sites have embraced this opportunity to answer an important stroke research question. Health and social care professionals have displayed innovation and competence in steering clinical research and this should improve future rehabilitation trial readiness. Trial recruitment is expected to gain pace as more Irish and international sites are approved.
Abstract
Dual Bcl-2/Bcl-x
L
inhibitors are expected to deliver therapeutic benefit in many haematological and solid malignancies, however, their use is limited by tolerability issues. AZD4320, a ...potent dual Bcl-2/Bcl-x
L
inhibitor, has shown good efficacy however had dose limiting cardiovascular toxicity in preclinical species, coupled with challenging physicochemical properties, which prevented its clinical development. Here, we describe the design and development of AZD0466, a drug-dendrimer conjugate, where AZD4320 is chemically conjugated to a PEGylated poly-lysine dendrimer. Mathematical modelling was employed to determine the optimal release rate of the drug from the dendrimer for maximal therapeutic index in terms of preclinical anti-tumour efficacy and cardiovascular tolerability. The optimised candidate is shown to be efficacious and better tolerated in preclinical models compared with AZD4320 alone. The AZD4320-dendrimer conjugate (AZD0466) identified, through mathematical modelling, has resulted in an improved therapeutic index and thus enabled progression of this promising dual Bcl-2/Bcl-x
L
inhibitor into clinical development.
Patients with severe coronavirus disease 2019 (COVID-19) develop a febrile pro-inflammatory cytokinemia with accelerated progression to acute respiratory distress syndrome (ARDS). Here we report the ...results of a phase 2, multicenter, randomized, double-blind, placebo-controlled trial of intravenous (IV) plasma-purified alpha-1 antitrypsin (AAT) for moderate to severe ARDS secondary to COVID-19 (EudraCT 2020-001391-15).
Patients (n = 36) were randomized to receive weekly placebo, weekly AAT (Prolastin, Grifols, S.A.; 120 mg/kg), or AAT once followed by weekly placebo. The primary endpoint was the change in plasma interleukin (IL)-6 concentration at 1 week. In addition to assessing safety and tolerability, changes in plasma levels of IL-1β, IL-8, IL-10, and soluble tumor necrosis factor receptor 1 (sTNFR1) and clinical outcomes were assessed as secondary endpoints.
Treatment with IV AAT resulted in decreased inflammation and was safe and well tolerated. The study met its primary endpoint, with decreased circulating IL-6 concentrations at 1 week in the treatment group. This was in contrast to the placebo group, where IL-6 was increased. Similarly, plasma sTNFR1 was substantially decreased in the treatment group while remaining unchanged in patients receiving placebo. IV AAT did not definitively reduce levels of IL-1β, IL-8, and IL-10. No difference in mortality or ventilator-free days was observed between groups, although a trend toward decreased time on ventilator was observed in AAT-treated patients.
In patients with COVID-19 and moderate to severe ARDS, treatment with IV AAT was safe, feasible, and biochemically efficacious. The data support progression to a phase 3 trial and prompt further investigation of AAT as an anti-inflammatory therapeutic.
ECSA-2020-009; Elaine Galwey Research Bursary.
PDF
