Doctor of Philosophy

dissertationThis study was designed in two sequential phases; 1) to describe the career paths of experienced nurses related to the intention to leave direct patient care and decisions associated with changing or advancing their education, and 2) to explore how pregnancy, childbirth, and mothering young children impact the lives of nurses working in direct patient care. A multimethod qualitative design with two qualitative components, QUAL1 → QUAL2, was utilized. Study participants were female nurses educated in the United States and licensed in Utah from 6 to 12 years. The QUAL1 core component consisted of unstructured interviews (n = 39), the results of which were used to form the QUAL2 sequential component of semistructured interviews (n = 45). Findings from QUAL1 revealed that mothering responsibilities and family obligations strongly influenced nurses with regard to career decisions and educational advancement. Organizational impacts such as lack of employer appreciation and inflexible scheduling/lack of control over the schedule by the nurse led to a "tipping point" for nurses, and to thoughts of intention to leave and ultimately resignation from their position. The second phase of the study focused on the nurse when pregnant and working in direct patient care and/or while having young children at home. Results revealed that there are distinct physical and emotional challenges and hardships experienced by female nurses. There were few accommodations in workload for pregnancy, and few supports, and major challenges regarding breastfeeding. Financial necessity, and the satisfaction derived from working in patient care, kept nurses working at the bedside

The diagnostic accuracy of two human epididymis protein 4 (HE4) testing systems in combination with CA125 in the differential diagnosis of ovarian masses

Background: Cancer antigen 125 (CA125) is the best known single tumor marker for ovarian cancer (OC). We investigated whether the additional information of the human epididymis protein 4 (HE4) improves diagnostic accuracy. Methods: We retrospectively analyzed preoperative sera of 109 healthy women, 285 patients with benign ovarian masses (cystadenoma: n = 78, leimyoma: n = 66, endometriosis: n = 52, functional ovarian cysts: n = 79, other: n = 10), 16 low malignant potential (LMP) ovarian tumors and 125 OC (stage 1: 22, II: 15, III: 78, IV: 10). CA 125 was analyzed using the ARCHITECT system, HE4 using the ARCHITECT(a) system and EIA(e) technology additionally. Results: The lowest concentrations of CA125 and HE4 were observed in healthy individuals, followed by patients with benign adnexal masses and patients with LMP tumors and OC. The area under the curve (AUC) for the differential diagnosis of adnexal masses of CA 125 alone was not significantly different to HE4 alone in premenopausal (CA 125: 86.7, HE4(a): 82.6, HE4(e): 81.6% p > 0.05) but significantly different in postmenopausal {[}CA125: 93.4 vs. HE4(a): 88.3 p = 0.023 and vs. HE4(e): 87.8% p=0.012] patients. For stage I OC, HE4 as a single marker was superior to CA 125, which was the best single marker in stage H-IV. The combination of CA 125 and HE4 using risk of malignancy algorithm (ROMA) gained the highest sensitivity at 95% specificity for the differential diagnosis of adnexal masses {[}CA 125: 70.9, HE4(a): 67.4, HE4(e): 66.0, ROMA(a): 76.6 and ROMA(e): 74.5%], especially in stage I OC {[}CA 125: 27.3, HE4(a): 40.9, HE4(e): 40.9, ROMA(a): 45.5 and ROMA(e): 45.5%]. Conclusions: CA 125 is still the best single marker in the diagnosis of OC. HE4 alone and even more the combined analysis of CA 125 and HE4 using ROMA improve the diagnostic accuracy of adnexal masses, especially in early OC

Preventive health examinations: protocol for a prospective cross-sectional study of German employees aged 45 to 59 years (Ü45-check)

Objective: Early identification of health-related risk factors is of great importance for maintaining workability. Screening examinations can help to detect diseases at an early stage and provide more needs-based recommendations. This study aims (1) to assess the individual need for prevention or rehabilitation based on preventive health examinations compared to a questionnaire survey, (2) to assess the results of the preventive health examinations compared to the Risk Index – Disability Pension (RI-DP), (3) to assess the results of the questionnaire survey compared to the RI-DP, (4) to assess the general health status of the sample (target population > 1,000) in German employees aged 45–59, (5) to identify the most common medical conditions. A further study question aims, and (6) to investigate the general health status of the specific occupational groups. Methods: Comprehensive diagnostics including medical examination, anamnesis, anthropometric measurements, bioelectrical impedance analysis (BIA), handgrip strength, resting electrocardiogram (ECG), resting blood pressure, pulse wave velocity (PWV), and laboratory blood analyses added by a questionnaire are conducted. The research questions are analyzed in an exploratory manner. Results and conclusion: We expect that the results will allow us to formulate recommendations regarding screening for prevention and rehabilitation needs on a more evidence-based level. Clinical Trial Registration: DRKS ID: DRKS00030982.Peer Reviewe

Enzyme-Linked Immunosorbent Assay and Serologic Responses to Pneumocystis jiroveci

Seroepidemiologic studies of Pneumocystis pneumonia (PCP) in humans have been limited by inadequate reagents. We have developed an enzyme-linked immunosorbent assay (ELISA) using three overlapping recombinant fragments of the human Pneumocystis major surface glycoprotein (MsgA, MsgB, and MsgC) for analysis of antibody responses in HIV-positive patients and healthy blood donors. HIV-positive patients had significantly higher antibody levels to all Msg fragments. Furthermore, HIV-positive patients who experienced a previous episode of PCP (PCP-positive) had higher level of antibodies to MsgC than patients who never had PCP. A significant association was found between ELISA antibody level and reactivity by Western blot in HIV-positive patients, especially those who were PCP-positive. Thus, this ELISA will be useful in studying serum antibody responses to Pneumocystis in different human populations

Circulating exosomes inhibit B cell proliferation and activity

(1) Background: Head and neck squamous cell carcinoma (HNSCC) is characterized by a distinctive suppression of the anti-tumor immunity, both locally in the tumor microenvironment (TME) and the periphery. Tumor-derived exosomes mediate this immune suppression by directly suppressing T effector function and by inducing differentiation of regulatory T cells. However, little is known about the effects of exosomes on B cells. (2) Methods: Peripheral B cells from healthy donors and HNSCC patients were isolated and checkpoint receptor expression was analyzed by flow cytometry. Circulating exosomes were isolated from the plasma of HNSCC patients (n = 21) and healthy individuals (n = 10) by mini size-exclusion chromatography. B cells from healthy individuals were co-cultured with isolated exosomes for up to 4 days. Proliferation, viability, surface expression of checkpoint receptors, and intracellular signaling were analyzed in B cells by flow cytometry. (3) Results: Expression of the checkpoint receptors PD-1 and LAG3 was increased on B cells from HNSCC patients. The protein concentration of circulating exosomes was increased in HNSCC patients as compared to healthy donors. Both exosomes from healthy individuals and HNSCC patients inhibited B cell proliferation and survival, in vitro. Surface expression of inhibitory and stimulatory checkpoint receptors on B cells was modulated in co-culture with exosomes. In addition, an inhibitory effect of exosomes on B cell receptor (BCR) signaling was demonstrated in B cells. (4) Conclusions: Plasma-derived exosomes show inhibitory effects on the function of healthy B cells. Interestingly, these inhibitory effects are similar between exosomes from healthy individuals and HNSCC patients, suggesting a physiological B cell inhibitory role of circulating exosomes

Does safety climate moderate the influence of staffing adequacy and work conditions on nurse injuries?

Hospital nurses have one of the highest work-related injury rates in the United States. Yet, approaches to improving employee safety have generally focused on attempts to modify individual behavior through enforced compliance with safety rules and mandatory participation in safety training. We examined a theoretical model that investigated the impact on nurse injuries (back injuries and needlesticks) of critical structural variables (staffing adequacy, work engagement, and work conditions) and further tested whether safety climate moderated these effects. A longitudinal, non-experimental, organizational study, conducted in 281 medical-surgical units in 143 general acute care hospitals in the United States. Work engagement and work conditions were positively related to safety climate, but not directly to nurse back injuries or needlesticks. Safety climate moderated the relationship between work engagement and needlesticks, while safety climate moderated the effect of work conditions on both needlesticks and back injuries, although in unexpected ways. DISCUSSION AND IMPACT ON INDUSTRY: Our findings suggest that positive work engagement and work conditions contribute to enhanced safety climate and can reduce nurse injuries

IKK phosphorylates Huntingtin and targets it for degradation by the proteasome and lysosome

Expansion of the polyglutamine repeat within the protein Huntingtin (Htt) causes Huntington's disease, a neurodegenerative disease associated with aging and the accumulation of mutant Htt in diseased neurons. Understanding the mechanisms that influence Htt cellular degradation may target treatments designed to activate mutant Htt clearance pathways. We find that Htt is phosphorylated by the inflammatory kinase IKK, enhancing its normal clearance by the proteasome and lysosome. Phosphorylation of Htt regulates additional post-translational modifications, including Htt ubiquitination, SUMOylation, and acetylation, and increases Htt nuclear localization, cleavage, and clearance mediated by lysosomal-associated membrane protein 2A and Hsc70. We propose that IKK activates mutant Htt clearance until an age-related loss of proteasome/lysosome function promotes accumulation of toxic post-translationally modified mutant Htt. Thus, IKK activation may modulate mutant Htt neurotoxicity depending on the cell's ability to degrade the modified species

Natural history of perinatal and infantile hypophosphatasia: A retrospective study

Objective: To report clinical characteristics and medical history data obtained retrospectively for a large cohort of pediatric patients with perinatal and infantile hypophosphatasia. Study design: Medical records from academic medical centers known to diagnose and/or treat hypophosphatasia were reviewed. Patients born between 1970 and 2011 with hypophosphatasia and any of the following signs/symptoms at age <6 months were eligible: vitamin B6–dependent seizures, respiratory compromise, or rachitic chest deformity (NCT01419028). Patient demographics and characteristics, respiratory support requirements, invasive ventilator–free survival, and further complications of hypophosphatasia were followed for up to the first 5 years of life. Results: Forty-eight patients represented 12 study sites in 7 countries; 13 patients were alive, and 35 were dead (including 1 stillborn). Chest deformity, respiratory distress, respiratory failure (as conditioned by the eligibility criteria), failure to thrive, and elevated calcium levels were present in >70% of patients between birth and age 5 years. Vitamin B6–dependent seizures and respiratory distress and failure were associated significantly (P <.05)with the risk of early death. Serum alkaline phosphatase activity in all 41 patients tested (mean [SD]: 18.1 [15.4]U/L)was below the mean lower limit of normal of the reference ranges of the various laboratories (88.2 U/L). Among the 45 patients with relevant data, 29 had received respiratory support, of whom 26 had died at the time of data collection. The likelihood of invasive ventilator–free survival for this cohort decreased to 63% at 3 months, 54% at 6 months, 31% at 12 months, and 25% at 5 years. Conclusions: Patients with perinatal or infantile hypophosphatasia and vitamin B6–dependent seizures, with or without significant respiratory distress or chest deformities, have high morbidity and mortality in the first 5 years of life. Trial registration: ClinicalTrials.gov: NCT01419028

Long term outcomes and causal modelling of compulsory inpatient and outpatient mental health care using Norwegian registry data: protocol for a controversies in psychiatry research project

Objectives: Compulsory mental health care includes compulsory hospitalisation and outpatient commitment with medication treatment without consent. Uncertain evidence of the effects of compulsory care contributes to large geographical variations and a controversy on its use. Some argue that compulsion can rarely be justified and should be reduced to an absolute minimum, while others claim compulsion can more frequently be justified. The limited evidence base has contributed to variations in care that raise issues about the quality/appropriateness of care as well as ethical concerns. To address the question whether compulsory mental health care results in superior, worse or equivalent outcomes for patients, this project will utilise registry‐ based longitudinal data to examine the effect of compulsory inpatient and outpatient care on multiple outcomes, including suicide and overall mortality; emergency care/injuries; crime and victimisation; and participation in the labour force and welfare dependency. Methods: By using the natural variation in health providers' preference for compulsory care as a source of quasi‐randomisation we will estimate causal effects of compulsory care on short‐ and long‐term trajectories. Conclusions: This project will provide valuable insights for service providers and policy makers in facilitating high quality clinical care pathways for a high risk population group

Global 3-D Simulations of the Triple Oxygen Isotope Signature Δ17O in Atmospheric CO2

The triple oxygen isotope signature Δ¹⁷O in atmospheric CO₂, also known as its “¹⁷O excess,” has been proposed as a tracer for gross primary production (the gross uptake of CO₂ by vegetation through photosynthesis). We present the first global 3-D model simulations for Δ¹⁷O in atmospheric CO₂ together with a detailed model description and sensitivity analyses. In our 3-D model framework we include the stratospheric source of Δ¹⁷O in CO₂ and the surface sinks from vegetation, soils, ocean, biomass burning, and fossil fuel combustion. The effect of oxidation of atmospheric CO on Δ¹⁷O in CO2 is also included in our model. We estimate that the global mean Δ¹⁷O (defined as Δ¹⁷O = ln( ¹⁷O + 1) − RL · ln( ¹⁸O + 1) with RL = 0.5229) of CO₂ in the lowest 500 m of the atmosphere is 39.6 per meg, which is ∼20 per meg lower than estimates from existing box models. We compare our model results with a measured stratospheric Δ¹⁷O in CO₂ profile from Sodankylä (Finland), which shows good agreement. In addition, we compare our model results with tropospheric measurements of Δ¹⁷O in CO₂ from Göttingen (Germany) and Taipei (Taiwan), which shows some agreement but we also find substantial discrepancies that are subsequently discussed. Finally, we show model results for Zotino (Russia), Mauna Loa (United States), Manaus (Brazil), and South Pole, which we propose as possible locations for future measurements of Δ¹⁷O in tropospheric CO₂ that can help to further increase our understanding of the global budget of Δ¹⁷O in atmospheric CO₂