Unit-Based Nurses' Development of a Couplet Care Acuity Scoring Tool.

OBJECTIVE: To evaluate content validity (CV) and interrater reliability (IRR) of an acuity scoring tool developed for the couplet care/postpartum/nursery patient population and to determine if there was agreement between supervisor or director scoring and staff scoring. DESIGN: A scoring tool to assess the acuity of the couplet care/postpartum/nursery patients was developed. SETTING: Two hospitals: one Level 2 hospital, one Level 3 hospital. Unit-based patient care councils participated in the development, and all couplet care nurses participated in scoring patients for testing. MEASUREMENTS: The final tool was evaluated for CV and IRR using expert review, universal agreement scores, and discriminant content validation. RESULTS: Regarding CV for the Couplet Care Acuity Scoring Tool, the average of the number of experts in agreement divided by the total number of experts across all items was 1.00. Regarding IRR, the intraclass correlation coefficient was 0.85, indicating that the tool is valid and reliable for the study sample. CONCLUSION: The tool was reliable and valid in this study. Future testing is needed with larger samples and different health care facilities.

Prophylactic Administration of Mesenchymal Stromal Cells Does Not Prevent Arrested Lung Development in Extremely Premature-Born Non-Human Primates.

Premature birth is a leading cause of childhood morbidity and mortality and often followed by an arrest of postnatal lung development called bronchopulmonary dysplasia. Therapies using exogenous mesenchymal stromal cells (MSC) have proven highly efficacious in term-born rodent models of this disease, but effects of MSC in actual premature-born lungs are largely unknown. Here, we investigated thirteen non-human primates (baboons; Papio spp.) that were born at the limit of viability and given a single, intravenous dose of ten million human umbilical cord tissue-derived MSC per kilogram or placebo immediately after birth. Following two weeks of human-equivalent neonatal intensive care including mechanical ventilation, lung function testing and echocardiographic studies, lung tissues were analyzed using unbiased stereology. We noted that therapy with MSC was feasible, safe and without signs of engraftment when administered as controlled infusion over 15 minutes, but linked to adverse events when given faster. Administration of cells was associated with improved cardiovascular stability, but neither benefited lung structure, nor lung function after two weeks of extrauterine life. We concluded that a single, intravenous administration of MSC had no short- to mid-term lung-protective effects in extremely premature-born baboons, sharply contrasting data from term-born rodent models of arrested postnatal lung development and urging for investigations on the mechanisms of cell-based therapies for diseases of prematurity in actual premature organisms.

Acuity Tools for the Antepartum and Neonatal Intensive Care Units.

PURPOSE: To evaluate content validity and interrater reliability for acuity tools developed for the antepartum and neonatal intensive care unit (NICU) patient population. STUDY DESIGN AND METHODS: Antepartum and NICU acuity tools were developed to better evaluate nurse staffing assignment equity and patient needs. Following several iterations with staff nurses and nurse leaders, content validity of the acuity tools was established via a panel of experts in each substantive area using the Content Validity Index. The final tools were then evaluated for interrater reliability using Intraclass Correlation. RESULTS: Content validity for the Antepartum Acuity Tool was S-CVI/Ave = 0.87 and for the NICU Acuity Tool was S-CVI/Ave = 0.98. Interrater Reliability for the Antepartum Acuity tool was ICC = 0.88, and the NICU Acuity Tool was ICC = 0.95. CLINICAL IMPLICATIONS: These tools have established content validity and interrater reliability and are appropriate for use in the antepartum and NICU settings to determine patient acuity and promote appropriate nurse-to-patient assignments.

AWHONN Members' Recommendations on What to Include in Updated Standards for Professional Registered Nurse Staffing for Perinatal Units.

OBJECTIVE: To solicit advice from members of the Association of Women's Health, Obstetric, and Neonatal Nurses (AWHONN) on what to include in an update of nurse staffing standards. DESIGN: Online, single-question survey with thematic analysis of responses. SETTING: Electronic survey link sent via e-mail. PARTICIPANTS: AWHONN members who shared their e-mail with the association and who responded to the survey (n = 1,813). MEASURES: Participants were asked to answer this single question: "The AWHONN (2010) Guidelines for Professional Registered Nurse Staffing for Perinatal Units are being updated. During their initial development, feedback from nearly 900 AWHONN members was extremely helpful in providing specific details for the nurse staffing guidelines. We'd really like to hear from you again. Please give the writing team your input. What should AWHONN consider when updating the AWHONN nurse staffing guidelines?" RESULTS: The e-mail was successfully delivered to 20,463 members; 8,050 opened the e-mail, and 3,050 opened the link to the survey. There were 1,892 responses. After removing duplicate and blank responses, 1,813 responses were available for analysis. They represented all hospital practice settings for maternity and newborn care and included nurses from small-volume and rural hospitals. Primary concerns of respondents centered on two aspects of patient acuity-the increasing complexity of clinical cases and the need to link nurse staffing standards to patient acuity. Other themes included maintaining current nurse-to-patient ratios, needing help with implementation in the context of economic challenges, and changing wording from "guidelines" to "standards" to promote widespread adoption. CONCLUSION: In a single-question survey, AWHONN members offered rich, detailed recommendations that were used in the updating of the AWHONN nurse staffing standards.

Radiotherapy enhances uptake and efficacy of 90Y-cetuximab: A preclinical trial.

BACKGROUND AND PURPOSE: Systemic molecular radiotherapy utilizes internal irradiation by radionuclide-labeled tumor-targeting agents with the potential to destroy (micro-)metastases. However, doses that are applicable in solid tumors do not reach the levels nessecary for tumor control. Thus, the combination of molecular and external radiotherapy is a promising treatment strategy, as enhanced tumor doses can be delivered with and without minor overlapping toxicities. Here, we combined a 90Y-labeled anti-EGFR antibody (Cetuximab) with clinically relevant fractionated radiotherapy in a preclinical trial using head and neck squamous cell carcinoma xenograft tumors. MATERIALS AND METHODS: To model 90Y-Cetuximab uptake for treatment schedule optimization, FaDu-bearing mice were injected with near-infrared-labeled-Cetuximab at different time points during radiotherapy with differing doses. Cetuximab uptake was longitudinally followed by in vivo-optical imaging. Tumor control probability experiments with fractionated radiotherapy (30 fx, 6 weeks, 8 dose groups/ arm) in combination with 90Y-Cetuximab were performed to test the curative potential. RESULTS: Imaging of near-infrared-labeled-Cetuximab uptake revealed that low to moderate external beam doses can enhance antibody uptake. Using the optimized schedule, combination of molecular and external radiotherapy using 90Y-Cetuximab at a dose that did not result in permanent tumor inactivation in previous experiments, led to substantially increased tumor control compared to radiotherapy alone. CONCLUSION: Our results indicate that combination of radiolabeled therapeutics with clinically relevant fractionated radiotherapy has a remarkable potential to improve curative treatment outcome. Application of some radiation dose prior to injection may improve drug uptake and enable patient stratification and treatment personalization via a corresponding PET-tracer during therapy.

German population data for 18 X-STRs: a hexaplex PCR adding two clusters of X-STRs to the Argus X-12 set and expanding the German haplotype databases.

In kinship analysis, large data sets with estimated haplotype frequencies for marker clusters are very important for the likelihood calculation. Practical use of the X-STRs demonstrated that in some complex kinship cases, the marker set of the Investigator Argus X-12 kit can be insufficient. This study aimed to extend the German data base of the Argus X-12 kit (1037 haplotypes) and for a cluster in Xq21 (806 haplotypes) with additional 700 male haplotypes and to include a further cluster in Xp22.3 to complete the X-STR marker set for complex kinship cases.

Establishment and Characterisation of Heterotopic Patient-Derived Xenografts for Glioblastoma.

Glioblastoma is an aggressive brain tumour with a patient median survival of approximately 14 months. The development of innovative treatment strategies to increase the life span and quality of life of patients is hence essential. This requires the use of appropriate glioblastoma models for preclinical testing, which faithfully reflect human cancers. The aim of this study was to establish glioblastoma patient-derived xenografts (PDXs) by heterotopic transplantation of tumour pieces in the axillae of NMRI nude mice. Ten out of 22 patients' samples gave rise to tumours in mice. Their human origin was confirmed by microsatellite analyses, though minor changes were observed. The glioblastoma nature of the PDXs was corroborated by pathological evaluation. Latency times spanned from 48.5 to 370.5 days in the first generation. Growth curve analyses revealed an increase in the growth rate with increasing passages. The methylation status of the MGMT promoter in the primary material was maintained in the PDXs. However, a trend towards a more methylated pattern could be found. A correlation was observed between the take in mice and the proportion of Sox2+ cells (r = 0.49, p = 0.016) and nestin+ cells (r = 0.55, p = 0.007). Our results show that many PDXs maintain key features of the patients' samples they derive from. They could thus be used as preclinical models to test new therapies and biomarkers.

Radioresistance of KRAS/TP53-mutated lung cancer can be overcome by radiation dose escalation or EGFR tyrosine kinase inhibition in vivo.

Recent clinical data have linked KRAS/TP53 comutation (mut) to resistance to radiotherapy (RT), but supporting laboratory in vivo evidence is lacking. In addition, the ability of different radiation doses, with/without epidermal growth factor receptor (EGFR)-directed treatment, to achieve local tumor control as a function of KRAS status is unknown. Here, we assessed clonogenic radiation survival of a panel of annotated lung cancer cell lines. KRASmut/TP53mut was associated with the highest radioresistance in nonisogenic and isogenic comparisons. To validate these findings, isogenic TP53mut NCI-H1703 models, KRASmut or wild-type (wt), were grown as heterotopic xenografts in nude mice. A clinical RT schedule of 30 fractions over 6 weeks was employed. The dose that controlled 50% of tumors (TCD50 ) was calculated. The TCD50 for KRASwt/TP53mut xenografts was 43.1 Gy whereas KRASmut/TP53mut tumors required a 1.9-fold higher TCD50 of 81.4 Gy. The EGFR inhibitor erlotinib radiosensitized KRASmut but not KRASwt cells and xenografts. The TCD50 associated with adding erlotinib to RT was 58.8 Gy for KRASmut, that is, a ~1.4-fold dose enhancement. However, the EGFR antibody cetuximab did not have a radiosensitizing effect. In conclusion, we demonstrate for the first time that KRASmut in a TP53mut background confers radioresistance when studying a clinical RT schedule and local control rather than tumor growth delay. Despite the known unresponsiveness of KRASmut tumors to EGFR inhibitors, erlotinib radiosensitized KRASmut tumors. Our data highlight KRAS/TP53 comutation as a candidate biomarker of radioresistance that can be at least partially reversed by dose escalation or the addition of a targeted agent.

Residual gammaH2AX foci in head and neck squamous cell carcinomas as predictors for tumour radiosensitivity: Evaluation in pre-clinical xenograft models and clinical specimens.

BACKGROUND AND PURPOSE: Predictive biomarkers can be instrumental to treatment individualisation of cancer patients and improve therapy outcome. Residual γH2AX foci represent a promising biomarker to predict tumour radiosensitivity. In this pre-clinical study, the slope of the dose-response curve was evaluated for its predictive relevance in head and neck squamous cell carcinoma xenografts (HNSCC). Additionally, the feasibility of the translated assay was tested in a clinical setting in patient derived HNSCC samples, and associations between residual γH2AX foci and clinical parameters were analysed. MATERIALS AND METHODS: Seven HNSCC xenografts models (FaDu, SAS, SKX, UT-SCC-5, UT-SCC-14, UT-SCC-45, XF354) were used. Tumour bearing NMRI nude mice were randomly distributed to five treatment arms (0-8 Gy). Residual γH2AX foci (24 h post irradiation) were counted by visual scoring in a micromilieu dependent manner (assessed with BrdU and pimonidazole). The local tumour control values measured as TCD50 (tumour control dose 50%) have previously been published. Patient derived HNSCC biopsies were cultivated ex vivo for 24 h including 4 h of pimonidazole and BrdU treatment, subsequently irradiated with 0-8 Gy and fixed after 24 h. RESULTS: In the pre-clinical study, the dose-response curve slopes negatively correlated with the tumour control dose after fractionated irradiation (TCD50,fx, R2 = 0.63, p = 0.032) and after single dose irradiation under homogeneous hypoxia (TCD50,SD,clamp, R2 = 0.66, p = 0.027). The γH2AX assay in clinical HNSCC samples showed a dose-response relationship, with the values of the slopes ranging from 0.099 Gy-1 to 0.920 Gy-1 (coefficient of variation = 52.8%). Slopes derived from patients were in the same ranges as the sensitive, moderate and resistant models of the pre-clinical study. Statistical analysis revealed a significant negative correlation between the slope and the patients' age (R2 = 0.65, p = 0.001). CONCLUSION: These results further support the promise of the slope of the residual γH2AX foci dose-response as a biomarker for radiosensitivity. In the clinical samples, the variation in the slopes reveals patients' specific repair capacities, which could hold potential value for treatment individualisation.

Recognition and Management of Sepsis in the Obstetric Patient.

Sepsis is one of the principal causes of maternal mortality in obstetrics. Physiologic changes that occur during pregnancy create a vulnerable environment, predisposing pregnant patients to the development of sepsis. Furthermore, these changes can mask sepsis indicators normally seen in the nonobstetric population, making it difficult to recognize and treat sepsis in a timely manner. The use of maternal-specific early warning tools for sepsis identification and knowledge of appropriate interventions and their effects on the mother and fetus can help clinicians obtain the best patient outcomes in acute care settings. This article outlines the signs and symptoms of sepsis in obstetric patients and discusses treatment options used in critical care settings.

EGFR-amplification plus gene expression profiling predicts response to combined radiotherapy with EGFR-inhibition: A preclinical trial in 10 HNSCC-tumour-xenograft models.

BACKGROUND AND PURPOSE: Improvement of the results of radiotherapy by EGFR inhibitors is modest, suggesting significant intertumoural heterogeneity of response. To identify potential biomarkers, a preclinical trial was performed on ten different human squamous cell carcinoma xenografts of the head and neck (HNSCC) studying in vivo and ex vivo the effect of fractionated irradiation and EGFR inhibition. Local tumour control and tumour growth delay were correlated with potential biomarkers, e.g. EGFR gene amplification and radioresponse-associated gene expression profiles. MATERIAL AND METHODS: Local tumour control 120days after end of irradiation was determined for fractionated radiotherapy alone (30f, 6weeks) or after simultaneous EGFR-inhibition with cetuximab. The EGFR gene amplification status was determined using FISH. Gene expression analyses were performed using an in-house gene panel. RESULTS: Six out of 10 investigated tumour models showed a significant increase in local tumour control for the combined treatment of cetuximab and fractionated radiotherapy compared to irradiation alone. For 3 of the 6 responding tumour models, an amplification of the EGFR gene could be demonstrated. Gene expression profiling of untreated tumours revealed significant differences between amplified and non-amplified tumours as well as between responder and non-responder tumours to combined radiotherapy and cetuximab. CONCLUSION: The EGFR amplification status, in combination with gene expression profiling, may serve as a predictive biomarker for personalized interventional strategies regarding combined treatment of cetuximab and fractionated radiotherapy and should, as a next step, be clinically validated.

Sepsis in Obstetrics: Pathophysiology and Diagnostic Definitions.

In spite of many medical breakthroughs, sepsis continues to be challenging to identify, treat, and successfully resolve, including among the obstetric population. Sepsis is the result of an overactive, complex inflammatory response that is not completely understood. Currently there are no nationally agreed-upon criteria for systemic inflammatory response syndrome or sepsis in pregnant or peripartum women, as the physiologic changes of pregnancy have not been taken into consideration.This article is the first in a series of three that discuss the importance of sepsis and septic shock in pregnancy. The focus of this article is to understand the proposed pathophysiology of sepsis and new definitions associated with sepsis and septic shock. Knowledge of these conditions can assist in better identification of sepsis in the obstetric population.

Sepsis in Obstetrics: Clinical Features and Early Warning Tools.

Morbidity and mortality associated with sepsis has gained widespread attention on a local, state, and national level, yet, it remains a complicated disorder that can be difficult to identify in a timely manner. Sepsis in obstetric patients further complicates the diagnosis as alterations in physiology related to pregnancy can mask sepsis indicators normally seen in the general population. If early signs of sepsis go unrecognized, septic shock can develop, leading to organ dysfunction and potential death. Maternal early warning tools have been designed to assist clinicians in recognizing early indications of illness. Through use of clinical pathway-specific tools, disease processes may be detected early, subsequently benefitting patients with aggressive treatment management and intervention.This article is the second in a series of three that discuss the importance of sepsis and septic shock in pregnancy. Risk factors, causes of sepsis, signs and symptoms, and maternal early warning tools are discussed.

Randomized Controlled Trial of Use of the Peanut Ball During Labor.

PURPOSE: The purpose of this study was to evaluate the efficacy of peanut ball use on duration of first stage labor and pushing time in women who were scheduled for elective induction of labor at ≥39 weeks gestation and planning an epidural. STUDY DESIGN AND METHODS: In this randomized controlled trial, women having labor induction and planning a labor epidural were assigned (1:1) to one of two groups: one group used a peanut ball and one group did not. Outcome variables were time spent in first stage labor and time spent pushing. Factors included group assignment (peanut ball, no peanut ball), parity (primiparous, multiparous), and race. Age and maximum oxytocin dose served as covariates. RESULTS: Among women having elective induction with epidural analgesia, use of a peanut ball reduced first stage labor duration for primiparous patients significantly more than multiparous patients, p = 0.018. There was no significant difference in the reduction of length of first stage labor for multiparous women, p = 0.057 with use of the peanut ball. Peanut ball use did not alter length of pushing time for either group, p > 0.05. CLINICAL IMPLICATIONS: Use of peanut balls may reduce total labor time to a greater degree in primiparous patients than multiparous patients having elective induction at ≥39 weeks with epidural analgesia.

Serotonin Syndrome in Pregnancy.

Millions of people take selective serotonin reuptake inhibitors (SSRIs) for depression and anxiety, so nurses and other clinicians need to be aware of the potential for serotonin toxicity and serotonin syndrome. These conditions can occur when women taking SSRIs are given additional medications in the labor and birth or postpartum settings. Symptoms can have an acute onset and can include delirium, fever and hypertension. Understanding the mechanism and symptoms of serotonin syndrome can lead to timely treatment of this unusual condition.

γH2AX assay in ex vivo irradiated tumour specimens: A novel method to determine tumour radiation sensitivity in patient-derived material.

PURPOSE: To establish a clinically applicable protocol for quantification of residual γH2AX foci in ex vivo irradiated tumour samples and to apply this method in a proof-of-concept feasibility study to patient-derived tumour specimens. MATERIAL AND METHODS: Evaluation of γH2AX foci formation and disappearance in excised FaDu tumour specimens after (a) different incubation times in culture medium, 4Gy irradiation and fixation after 24h (cell recovery), (b) 10h medium incubation, 4Gy irradiation and fixation after various time points (double strand break repair kinetics), and (c) 10h medium incubation, irradiation with graded single radiation doses and fixation after 24h (dose-response). The optimised protocol was applied to patient-derived samples of seminoma, prostate cancer and glioblastoma multiforme. RESULTS: Post excision or biopsy, tumour tissues showed stable radiation-induced γH2AX foci values in oxic cells after >6h of recovery in medium. Kinetics of foci disappearance indicated a plateau of residual foci after >12h following ex vivo irradiation. Fitting the dose-response of residual γH2AX foci yielded slopes comparable with in situ irradiation of FaDu tumours. Significant differences in the slopes of ex vivo irradiated patient-derived tumour samples were found. CONCLUSION: A novel clinically applicable method to quantify residual γH2AX foci in ex vivo irradiated tumour samples was established. The first clinical results suggest that this method allows to distinguish between radiosensitive and radioresistant tumour types. These findings support further translational evaluation of this assay to individualise radiation therapy.

Developing protocols for obstetric emergencies.

There is potential for important steps to be missed in emergency situations, even in the presence of many health care team members. Developing a clear plan of response for common emergencies can ensure that no tasks are redundant or omitted, and can create a more controlled environment that promotes positive health outcomes. A multidisciplinary team was assembled in a large community hospital to create protocols that would help ensure optimum care and continuity of practice in cases of postpartum hemorrhage, shoulder dystocia, emergency cesarean surgical birth, eclamptic seizure and maternal code. Assignment of team roles and responsibilities led to the evolution of standardized protocols for each emergency situation.

Collaborative genetic mapping of 12 forensic short tandem repeat (STR) loci on the human X chromosome.

A large number of short tandem repeat (STR) markers spanning the entire human X chromosome have been described and established for use in forensic genetic testing. Due to their particular mode of inheritance, X-STRs often allow easy and informative haplotyping in kinship analyses. Moreover, some X-STRs are known to be tightly linked so that, in combination, they constitute even more complex genetic markers than each STR taken individually. As a consequence, X-STRs have proven particularly powerful in solving complex cases of disputed blood relatedness. However, valid quantification of the evidence provided by X-STR genotypes in the form of likelihood ratios requires that the recombination rates between markers are exactly known. In a collaborative family study, we used X-STR genotype data from 401 two- and three-generation families to derive valid estimates of the recombination rates between 12 forensic markers widely used in forensic testing, namely DXS10148, DXS10135, DXS8378 (together constituting linkage group I), DXS7132, DXS10079, DXS10074 (linkage group II), DXS10103, HPRTB, DXS10101 (linkage group III), DXS10146, DXS10134 and DXS7423 (linkage group IV). Our study is the first to simultaneously allow for mutation and recombination in the underlying likelihood calculations, thereby obviating the bias-prone practice of excluding ambiguous transmission events from further consideration. The statistical analysis confirms that linkage groups I and II are transmitted independently from one another whereas linkage groups II, III and IV are characterised by inter-group recombination fractions that are notably smaller than 50%. Evidence was also found for recombination within all four linkage groups, with recombination fraction estimates ranging as high as 2% in the case of DXS10146 and DXS10134.