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Objective: The purpose of this study is to report our experience with interprofessional simulations, executed in a mock-up of a proposed perioperative space, that were designed to elicit valuable end-user feedback on the design of the perioperative space., Design: A styrofoam, life-sized model of a perioperative unit was constructed. Various medical professionals and support staff participated in interactive sessions, including workflow simulations, and provided feedback on the perioperative design. Based on participant feedback, the perioperative design was modified, and the styrofoam model was re-constructed. A second round of sessions was conducted, and the change in participant feedback was analyzed., Setting: This study took place under the auspices of the University of Pennsylvania in Philadelphia, Pennsylvania, within Penn Medicine., Participants: One-hundred and ninety-three medical professionals and front line operating room staff participated in the initial round of interactive sessions, and 134 participated in the second round (after re-construction)., Results: In the first round of simulations and interactive sessions, participants spent 560 hours engaging with the space. Modifications were then made to the perioperative design based on participant feedback, and a second round was conducted, in which participants spent 403 hours in the space. Floor plans for round 2 show significant changes compared with round 1, and mean design satisfaction scores for round 2 (3.78 ± 0.41) were significantly higher than for round 1 (3.61 ± 0.49) (p = 0.02). The quality of feedback was associated with the type of interactive session the user participated in., Conclusions: This study suggests that simulations and other interactive sessions, when executed in a mock-up of a proposed perioperative space, can elicit valuable end-user feedback that impacts the final design of the perioperative space and that would traditionally be difficult to obtain until after construction and move-in., (Copyright © 2018 Association of Program Directors in Surgery. All rights reserved.)

Objective: The aim of this study was to explore the relationship between resilience and coping in frontline nurses working in a healthcare system that has recently undergone a merger., Background: Hospital mergers are common in the current healthcare environment. Mergers can provide hospital nurses the opportunity to use and develop positive coping strategies to help remain resilient during times of change., Methods: An anonymous-survey, quantitative, exploratory, descriptive study design was used. Data were obtained from an electronic survey that was made available to all nurses working in a 3-hospital system located in the northeast., Results: Overall, the results showed that, when nurses reported using positive coping strategies, they report higher levels of resilience. The levels of resilience also varied from campus to campus. The campus that has been through 2 recent mergers reported the highest levels of resilience., Conclusion: This study suggests that, during times of change in the workplace, if nurses are encouraged to use positive coping strategies, they may have higher levels of resilience. This changing environment provides the clinical nurse specialists/clinical nurse educators the opportunity to foster and support frontline nurses in the use of healthy coping strategies and to help improve and maintain a high level of resilience, which is critical in today's healthcare environment.

Background: Use of force [UOF] by police can result in serious injuries and fatalities. The risk of significant injuries associated with different force modalities is poorly defined. We sought to determine the incidence of police UOF and compare the likelihood of significant injury with different force modalities., Methods: A prospective multicenter observational study of all UOF incidents was conducted via mandatory UOF investigations at three mid-sized police agencies over a two year period. Expert physicians reviewed police and medical records to determine injury severity using a priori injury severity stratification criteria., Results: There were 893 UOF incidents, representing a UOF rate of 0.086% of 1,041,737 calls for service (1 in 1167) and 0.78% of 114,064 criminal arrests(1 in 128). Suspects were primarily young (mean age, 31 years; range, 12-86 years) males (89%). The 1,399 force utilizations included unarmed physical force (n = 710, 51%), CEWs (504, 30%), chemical (88, 6.3%), canines (47, 3.4%), impact weapons (9, 0.6%), kinetic impact munitions (8, 0.6%), firearms (6, 0.4%), and other (27, 1.9%). Among 914 suspects, 898 (98%) sustained no or mild injury after police UOF. Significant (moderate or severe) injuries occurred in 16 (1.8%) subjects. Logistic regression analysis shows these are most associated with firearm and canine use. There was one fatality (0.1%) due to gunshots. No significant injuries occurred among 504 CEW uses (0%; 95% confidence interval, 0.0-0.9%). Of the 355 suspects transported to a medical facility, 78 (22%) were hospitalized. The majority of hospitalizations were unrelated to UOF (n = 59, 76%), whereas a minority (n = 19, 24%) were due to injuries related to police UOF., Conclusion: Police UOF is rare. When force is used officers most commonly rely on unarmed physical force and CEWs. Significant injuries are rare. Transport for medical evaluation is a poor surrogate for significant injury due to UOF., Level of Evidence: Epidemiological, level II.

Purpose: Programmed cell death ligand-1 (PD-L1)/programmed cell death-1 (PD-1) blockade has been unsuccessful in prostate cancer, with poor immunogenicity and subsequent low PD-L1 expression in prostate cancer being proposed as an explanation. However, recent studies indicate that a subset of prostate cancer may express significant levels of PD-L1. Furthermore, the androgen antagonist enzalutamide has been shown to upregulate PD-L1 expression in prostate cancer preclinical models. In this study, we evaluated the effect of neoadjuvant androgen deprivation therapy with abiraterone acetate plus prednisone and leuprolide (Neo-AAPL) on PD-L1 expression in prostate cancer. Experimental Design: Radical prostatectomy (RP) tissues were collected from 44 patients with intermediate- to high-risk prostate cancer who underwent RP after Neo-AAPL treatment. Untreated prostate cancer tissues were collected from 130 patients, including 44 matched controls for the Neo-AAPL cases. Tumor PD-L1 expression was detected by IHC using validated anti-PD-L1 antibodies. Tumor-infiltrating CD8 + cells were analyzed in trial cases and matched controls. Expression of DNA mismatch repair genes was examined in PD-L1-positive tumors. Results: Neo-AAPL-treated tumors showed a trend toward decreased PD-L1 positivity compared with matched controls (7% vs. 21% having ≥1% positive tumor cells; P = 0.062). Treated tumors also harbored significantly fewer tumor-infiltrating CD8 + cells ( P = 0.029). In 130 untreated prostate cancers, African American ethnicity, elevated serum PSA, and small prostate independently predicted tumor PD-L1 positivity. Loss of MSH2 expression was observed in 1 of 21 PD-L1-positive tumors. Conclusions: A subset of prostate cancer expresses PD-L1, which is not increased by Neo-AAPL treatment, indicating that combining Neo-AAPL treatment with PD-L1/PD-1 blockade may not be synergistic. Clin Cancer Res; 23(22); 6812-22. ©2017 AACR ., (©2017 American Association for Cancer Research.)

Blood loss associated with lower-extremity total joint arthroplasty (TJA) often results in anemia and the need for red blood cell transfusions (RBCTs). This article reports on a quality improvement initiative aimed at improving blood management strategies in patients undergoing TJA. A multifaceted intervention (preoperative anemia assessment, use of tranexamic acid, discouragement of autologous preoperative blood collection, restrictive RBCT protocols) was implemented. The results were stratified into 3 intervention periods: 1, pre; 2, peri; and 3, post. Fractional logistic regression was used to describe differences between various intervention periods. During the study period, 2511 patients underwent TJA. Compared with the preintervention period, there was 81.8% decrease in total units of RBCT during the postintervention period. Using activity-based costing (~$1000/unit), the annualized saving in RBC expenditure was $480 000. A multidisciplinary approach can be successful and sustainable in reducing RBCT and its associated costs for patients undergoing TJA.

Objective: The Chief Nurse National Health Service Wales initiated a national survey of acute and community hospital patients in Wales to identify the prevalence of pressure ulcers and incontinence-associated dermatitis., Methods: Teams of two nurses working independently assessed the skin of each inpatient who consented to having their skin observed., Results: Over 28 September 2015 to 2nd October 2015, 8365 patients were assessed across 66 hospitals with 748 (8.9%) found to have pressure ulcers. Not all patients had their skin inspected with all mental health patients exempt from this part of the audit along with others who did not consent or were too ill. Of the patients with pressure ulcers, 593 (79.3%) had their skin inspected with 158 new pressure ulcers encountered that were not known to ward staff, while 152 pressure ulcers were incorrectly categorised by the ward teams. Incontinence-associated dermatitis was encountered in 360 patients (4.3%), while medical device-related pressure ulcers were rare (n=33). The support surfaces used while patients were in bed were also recorded to provide a baseline against which future changes in equipment procurement could be assessed. The presence of other wounds was also recorded with 2537 (30.3%) of all hospital patients having one or more skin wounds., Conclusions: This survey has demonstrated that although complex, it is feasible to undertake national surveys of pressure ulcers, incontinence-associated dermatitis and other wounds providing comprehensive and accurate data to help plan improvements in wound care across Wales., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

The American Academy of Otolaryngology-Head and Neck Surgery Foundation has published a supplement to this issue of Otolaryngology-Head and Neck Surgery featuring the "Clinical Practice Guideline: Benign Paroxysmal Positional Vertigo (Update)." To assist in implementing the guideline recommendations, this article summarizes the rationale, purpose, and key action statements. The 14 recommendations developed emphasize diagnostic accuracy and efficiency, reducing the inappropriate use of vestibular suppressant medications, decreasing the inappropriate use of ancillary testing, and increasing the appropriate therapeutic repositioning maneuvers. An updated guideline is needed due to new clinical trials, new systematic reviews, and the lack of consumer participation in the initial guideline development group.

Objective: This plain language summary serves as an overview in explaining benign paroxysmal positional vertigo, abbreviated BPPV. This summary applies to patients ≥18 years old with a suspected or potential diagnosis of BPPV and is based on the 2017 "Clinical Practice Guideline: Benign Paroxysmal Positional Vertigo (Update)." The evidence-based guideline includes research to support more effective diagnosis and treatment of BPPV. The guideline was developed as a quality improvement opportunity for managing BPPV by creating clear recommendations to use in medical practice.

Objective: To compare neurodevelopmental outcomes at 2-3 years in extremely premature outborn and inborn infants., Design: Population-based retrospective cohort study., Setting: Geographically defined area of New South Wales (NSW) and the Australian Capital Territory (ACT) served by a network of 10 neonatal intensive care units (NICUs)., Patients: All premature infants <29 weeks gestation born between 1998 and 2004 in the setting., Intervention: At 2-3 years, corrected age, 1473 children were assessed with either the Griffiths Mental Developmental Scales (GMDS) or the Bayley Scales of Infant Development (BSID-II)., Main Outcome Measure: Moderate/severe functional disability (FD) defined as: developmental delay (GMDS general quotient (GQ) or BSID-II mental developmental index (MDI)) > 2 standard deviations (SD) below the mean; cerebral palsy (CP) requiring aids; sensorineural or conductive deafness (requiring amplification); or bilateral blindness (visual acuity <6/60 in better eye)., Results: At 2-3 years, moderate/severe functional disability does not appear to be significantly different between outborn and inborn infants (adjusted OR 0.782; 95% CI 0.424-1.443). However, there were a significant number of outborn infants lost to follow up (23.3% versus 42.9%)., Conclusion: In this cohort, at 2-3 years follow up neurodevelopmental outcome does not appear to be significantly different between outborn and inborn infants. These results should be interpreted with caution given the limitation of this study.

Self-direction has emerged worldwide as a promising practice for persons with serious mental health conditions and as a means toward creating more person-centered service systems. In self-direction, service users control an individualized budget, purchasing goods or services that can help them achieve personal recovery goals. This Open Forum describes an international learning exchange meeting, held in September 2015, in which experts in self-direction and mental health from seven nations convened for sharing best practices, discussing challenges, and laying the groundwork for a learning community to support the continued development of self-direction. Meeting participants identified three themes that represent next steps toward ensuring that the promise of self-direction is realized. First, self-direction involves creating a culture shift for value-based systems change. Second, people with lived experience must be involved and supported at every level, including direct support, leadership, and oversight. Third, stakeholder communication about self-direction's impact is critical.

The Polarized Electrons for Polarized Positrons experiment at the injector of the Continuous Electron Beam Accelerator Facility has demonstrated for the first time the efficient transfer of polarization from electrons to positrons produced by the polarized bremsstrahlung radiation induced by a polarized electron beam in a high-Z target. Positron polarization up to 82% have been measured for an initial electron beam momentum of 8.19  MeV/c, limited only by the electron beam polarization. This technique extends polarized positron capabilities from GeV to MeV electron beams, and opens access to polarized positron beam physics to a wide community.

This study set out to explore the saving behavior, barriers, and facilitators along with effects of participating in a consumer-directed care program among people with disabilities in the state of West Virginia (N = 29). Results suggest that respondents were able to save money through the program to enable them to purchase goods and services they needed to enhance their welfare and quality of life. Generally, items saved for fell into 3 broad categories: household equipment, individual functioning, and home modification. Facilitators and barriers to saving were also indicated and so were the benefits of program participation. Program and policy implications are presented.

White-tailed deer (Odocoileus virginianus) are commonly exposed to disease agents that affect livestock but environmental factors that predispose deer to exposure are unknown for many pathogens. We trapped deer during winter months on two study areas (Northern Forest and Eastern Farmland) in Wisconsin from 2010 to 2013. Deer were tested for exposure to six serovars of Leptospira interrogans (grippotyphosa, icterohaemorrhagiae, canicola, bratislava, pomona, and hardjo), bovine viral diarrhea virus (BVDV-1 and BVDV-2), infectious bovine rhinotracheitis virus (IBR), and parainfluenza 3 virus (PI3). We used logistic regression to model potential intrinsic (e.g., age, sex) and extrinsic (e.g., land type, study site, year, exposure to multiple pathogens) variables we considered biologically meaningful to exposure of deer to livestock pathogens. Deer sampled in 2010-2011 did not demonstrate exposure to BVDV, so we did not test for BVDV in subsequent years. Deer had evidence of exposure to PI3 (24.7%), IBR (7.9%), Leptospira interrogans serovar pomona (11.7%), L. i. bratislava (1.0%), L. i. grippotyphosa (2.5%) and L. i. hardjo (0.3%). Deer did not demonstrate exposure to L. interrogans serovars canicola and icterohaemorrhagiae. For PI3, we found that capture site and year influenced exposure. Fawns (n = 119) were not exposed to L. i. pomona, but land type was an important predictor of exposure to L. i. pomona for older deer. Our results serve as baseline exposure levels of Wisconsin white-tailed deer to livestock pathogens, and helped to identify important factors that explain deer exposure to livestock pathogens.

Introduction: Bariatric surgery has proven safe and effective for long-term weight loss in morbidly obese patients. Readmissions within 30 days of discharge have become an important metric for quality of care. Sleeve gastrectomy is a common bariatric procedure, but data regarding early readmission is sparse. The purpose of this study is to determine what, if any, demographic or technical factors influence returns to the hospital or readmission following sleeve gastrectomy., Methods: All laparoscopic sleeve gastrectomies (n = 200) performed at a single community hospital from February 2009 to November 2012 were retrospectively reviewed. Demographic, technical, length of stay, return to Emergency Department (ED) and readmission data were gathered for each patient. The data were analyzed to determine what factors were related to early return to the Emergency Department or readmission., Results: Demographics were similar to other studies, with a male to female ratio of 1:4. Patients returning to the ED or readmitted within 30 days were statistically younger than those not returning. None of the other demographic, social, technical, or comorbid conditions considered were associated with a statistically significant risk of readmission or return to the ED within 30 days., Conclusion: Although the only statistically significant difference among the groups studied was age, trends toward significance exist in minority ethnicity and comorbid asthma. These factors have been associated with increased complications in other types of surgery. Larger, multi-institutional studies are needed to further evaluate these and other risk factors for readmission following bariatric surgery.

Background: Use of social media has become widespread across the United States. Although businesses have invested in social media to engage consumers and promote products, less is known about the extent to which hospitals are using social media to interact with patients and promote health., Objective: The aim was to investigate the relationship between hospital social media extent of adoption and utilization relative to hospital characteristics., Methods: We conducted a cross-sectional review of hospital-related activity on 4 social media platforms: Facebook, Twitter, Yelp, and Foursquare. All US hospitals were included that reported complete data for the Centers for Medicare and Medicaid Services Hospital Consumer Assessment of Healthcare Providers and Systems survey and the American Hospital Association Annual Survey. We reviewed hospital social media webpages to determine the extent of adoption relative to hospital characteristics, including geographic region, urban designation, bed size, ownership type, and teaching status. Social media utilization was estimated from user activity specific to each social media platform, including number of Facebook likes, Twitter followers, Foursquare check-ins, and Yelp reviews., Results: Adoption of social media varied across hospitals with 94.41% (3351/3371) having a Facebook page and 50.82% (1713/3371) having a Twitter account. A majority of hospitals had a Yelp page (99.14%, 3342/3371) and almost all hospitals had check-ins on Foursquare (99.41%, 3351/3371). Large, urban, private nonprofit, and teaching hospitals were more likely to have higher utilization of these accounts., Conclusions: Although most hospitals adopted at least one social media platform, utilization of social media varied according to several hospital characteristics. This preliminary investigation of social media adoption and utilization among US hospitals provides the framework for future studies investigating the effect of social media on patient outcomes, including links between social media use and the quality of hospital care and services.

The literature supports family presence during cardiopulmonary resuscitation (CPR) and its many perceived benefits for patients and their families. It also suggests that, overall, health care professionals are supportive of this practice. There have not been any published studies to date that have looked at the perception of family presence from the multidisciplinary resuscitation or code team's perspective. The purpose of this study was to describe the multidisciplinary care provider's understanding and perceived barriers of family presence during CPR in an academic medical center. This study is a quantitative, exploratory, descriptive study that utilized survey methodology. The sample included all members of an urban academic medical center's resuscitation response team. The study findings reveal that, overall, code team members feel that family members should be allowed to remain at the bedside during CPR but that challenges exist including education deficits and mixed feelings that may result from family presence; the study participants caring for neonates and children were more favorable to family presence during CPR than their adult counterparts. Barriers remain related to family presence during resuscitation. Education is needed for all members of the health care team to facilitate collaborative changes in resuscitation practices. Education should include information regarding institutional policies, methods for incorporating family members into the code process, and interventions to support the psychosocial needs of family members.

Patients belonging to some racial, ethnic, and socioeconomic groups are at risk of receiving suboptimal pain management. This study identifies health care provider attitudes, knowledge, and practices regarding the treatment of chronic pain in vulnerable patient populations and assesses whether a certified continuing medical education (CME) intervention can improve knowledge in this area. Survey responses revealed several knowledge gaps, including a lack of knowledge that the undertreatment of pain is more common in minority patients than others. Respondents identified language barriers, miscommunication, fear of medication diversion, and financial barriers as major obstacles to optimal pain management for this patient population. Participants who completed a CME-certified activity on pain management disparities demonstrated increased confidence in caring for disadvantaged patients, but only 1 of 3 knowledge items improved. Understanding clinician factors that underlie suboptimal pain management is necessary to develop effective strategies to overcome disparities and improve quality of care for patients with chronic pain., (© 2013 by the American College of Medical Quality.)

Background: Amyotrophic lateral sclerosis is a fatal neurodegenerative disease with few therapeutic options. Mild obesity is associated with greater survival in patients with the disease, and calorie-dense diets increased survival in a mouse model. We aimed to assess the safety and tolerability of two hypercaloric diets in patients with amyotrophic lateral sclerosis receiving enteral nutrition., Methods: In this double-blind, placebo-controlled, randomised phase 2 clinical trial, we enrolled adults with amyotrophic lateral sclerosis from participating centres in the USA. Eligible participants were aged 18 years or older with no history of diabetes or liver or cardiovascular disease, and who were already receiving percutaneous enteral nutrition. We randomly assigned participants (1:1:1) using a computer-generated list of random numbers to one of three dietary interventions: replacement calories using an isocaloric tube-fed diet (control), a high-carbohydrate hypercaloric tube-fed diet (HC/HC), or a high-fat hypercaloric tube-fed diet (HF/HC). Participants received the intervention diets for 4 months and were followed up for 5 months. The primary outcomes were safety and tolerability, analysed in all patients who began their study diet. This trial is registered with ClinicalTrials.gov, number NCT00983983., Findings: Between Dec 14, 2009, and Nov 2, 2012, we enrolled 24 participants, of whom 20 started their study diet (six in the control group, eight in the HC/HC group, and six in the HF/HC group). One patient in the control group, one in the HC/HC group, and two in the HF/HC group withdrew consent before receiving the intervention. Participants who received the HC/HC diet had a smaller total number of adverse events than did those in the other groups (23 in the HC/HC group vs 42 in the control group vs 48 in the HF/HC group; overall, p=0.06; HC/HC vs control, p=0.06) and significantly fewer serious adverse events than did those on the control diet (none vs nine; p=0.0005). Fewer patients in the HC/HC group discontinued their study diet due to adverse events (none [0%] of eight in the HC/HC group vs three [50%] of six in the control group). During the 5 month follow-up, no deaths occurred in the nine patients assigned to the HC/HC diet compared with three deaths (43%) in the seven patients assigned to the control diet (log-rank p=0.03). Adverse events, tolerability, deaths, and disease progression did not differ significantly between the HF/HC group and the control group., Interpretation: Our results provide preliminary evidence that hypercaloric enteral nutrition is safe and tolerable in patients with amyotrophic lateral sclerosis, and support the study of nutritional interventions in larger randomised controlled trials at earlier stages of the disease., Funding: Muscular Dystrophy Association, National Center for Research Resources, National Institutes of Health, and Harvard NeuroDiscovery Center., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Although urothelial carcinoma (UC) of the urinary bladder generally portends a favorable prognosis, metastatic tumors often follow an aggressive clinical course. DNA was extracted from 40 μm of formalin-fixed, paraffin-embedded (FFPE) sections from 35 stage IV UCs that had relapsed and progressed after primary surgery and conventional chemotherapy. Next-generation sequencing (NGS) was performed on hybridization-captured, adaptor ligation-based libraries for 3320 exons of 182 cancer-related genes plus 37 introns from 14 genes frequently rearranged in cancer to at an average sequencing depth of 1164 × and evaluated for all classes of genomic alterations (GAs). Actionable GAs were defined as those impacting the selection of targeted anticancer therapies on the market or in registered clinical trials. A total of 139 GAs were identified, with an average of 4.0 GAs per tumor (range 0-10), of which 78 (56%) were considered actionable, with an average of 2.2 per tumor (range 0-7). Twenty-nine (83%) cases harbored at least one actionable GA including: PIK3CA (9 cases; 26%); CDKN2A/B (8 cases; 23%); CCND1 (5 cases; 14%); FGFR1 (5 cases; 14%); CCND3 (4 cases; 11%); FGFR3 (4 cases; 11%); MCL1 (4 cases; 11%); MDM2 (4 cases; 11%); EGFR (2 cases, 6%); ERBB2 (HER2/neu) (2 cases, 6%); NF1 (2 cases, 6%) and TSC1 (2 cases, 6%). Notable additional alterations included TP53 (19 cases, 54%) and RB1 (6 cases; 17%). Genes involved in chromatin modification were altered by nonsense mutation, splice site mutation or frameshift indel in a mutually exclusive manner in nearly half of all cases including KDM6A (10 cases; 29%) and ARID1A (7 cases; 20%). Comprehensive NGS of 35 UCs of the bladder revealed a diverse spectrum of actionable GAs in 83% of cases, which has the potential to inform treatment decisions for patients with relapsed and metastatic disease.

We hypothesized that next-generation sequencing could reveal actionable genomic alterations (GAs) and potentially expand treatment options for patients with advanced adenoid cystic carcinoma (ACC). Genomic profiling using next-generation sequencing was performed on hybridization-captured, adapter ligation libraries derived from 28 relapsed and metastatic formalin-fixed paraffin-embedded ACC. The 3230 exons of 182 cancer-related genes and 37 introns of 14 genes frequently rearranged in cancer were fully sequenced using the Illumina HiSeq 2000. All classes of GAs were evaluated. Actionable GAs were defined as those impacting targeted anticancer therapies on the market or in registered clinical trials. A total of 44 GAs were identified in the 28 ACC tumors, with 12 of 28 (42.9%) of tumors harboring at least 1 potentially actionable GA. The most common nonactionable GAs were identified in KD6MA (5 cases; 18%), ARID1A (4 cases; 14%), RUNX1 (2 cases; 7%), and MYC (2 cases; 7%). Actionable GAs included NOTCH1 (3 cases; 11%), MDM2 (2 cases; 7%), PDGFRA (2 cases; 7%), and CDKN2A/B (p16) (2 cases; 7%). Other potentially actionable GAs identified in a single case included: mutations in AKT1, BAP1, EGFR, and PIK3CA, homozygous deletion of FBXW7, and amplifications of CDK4, FGFR1, IGF1R, KDR, KIT, and MCL1. The frequency of GA in ACC is lower than that seen in the more common solid tumors. Comprehensive genomic profiling of ACC can identify actionable GAs in a subset of patients that could influence therapy for these difficult-to-treat progressive neoplasms.

As more clinically relevant cancer genes are identified, comprehensive diagnostic approaches are needed to match patients to therapies, raising the challenge of optimization and analytical validation of assays that interrogate millions of bases of cancer genomes altered by multiple mechanisms. Here we describe a test based on massively parallel DNA sequencing to characterize base substitutions, short insertions and deletions (indels), copy number alterations and selected fusions across 287 cancer-related genes from routine formalin-fixed and paraffin-embedded (FFPE) clinical specimens. We implemented a practical validation strategy with reference samples of pooled cell lines that model key determinants of accuracy, including mutant allele frequency, indel length and amplitude of copy change. Test sensitivity achieved was 95-99% across alteration types, with high specificity (positive predictive value >99%). We confirmed accuracy using 249 FFPE cancer specimens characterized by established assays. Application of the test to 2,221 clinical cases revealed clinically actionable alterations in 76% of tumors, three times the number of actionable alterations detected by current diagnostic tests.

The majority of lower leg ulceration has a venous component. Compression therapy is the "Gold Standard" to reverse venous hypertension and heal venous ulceration. Over recent years, new compression systems have evolved which means greater choice for patients. This describes venous disease and assessment and treatment choices. Case studies are also presented.

Background: Mutations in SOD1 cause 13% of familial amyotrophic lateral sclerosis. In the SOD1 Gly93Ala rat model of amyotrophic lateral sclerosis, the antisense oligonucleotide ISIS 333611 delivered to CSF decreased SOD1 mRNA and protein concentrations in spinal cord tissue and prolonged survival. We aimed to assess the safety, tolerability, and pharmacokinetics of ISIS 333611 after intrathecal administration in patients with SOD1-related familial amyotrophic lateral sclerosis., Methods: In this randomised, placebo-controlled, phase 1 trial, we delivered ISIS 333611 by intrathecal infusion using an external pump over 11·5 h at increasing doses (0·15 mg, 0·50 mg, 1·50 mg, 3·00 mg) to four cohorts of eight patients with SOD1-positive amyotrophic lateral sclerosis (six patients assigned to ISIS 333611, two to placebo in each cohort). We did the randomisation with a web-based system, assigning patients in blocks of four. Patients and investigators were masked to treatment assignment. Participants were allowed to re-enrol in subsequent cohorts. Our primary objective was to assess the safety and tolerability of ISIS 333611. Assessments were done during infusion and over 28 days after infusion. This study was registered with Clinicaltrials.gov, number NCT01041222., Findings: Seven of eight (88%) patients in the placebo group versus 20 of 24 (83%) in the ISIS 333611 group had adverse events. The most common events were post-lumbar puncture syndrome (3/8 [38%] vs 8/24 [33%]), back pain (4/8 [50%] vs 4/24 [17%]), and nausea (0/8 [0%] vs 3/24 [13%]). We recorded no dose-limiting toxic effects or any safety or tolerability concerns related to ISIS 333611. No serious adverse events occurred in patients given ISIS 333611. Re-enrolment and re-treatment were also well tolerated., Interpretation: This trial is the first clinical study of intrathecal delivery of an antisense oligonucleotide. ISIS 333611 was well tolerated when administered as an intrathecal infusion. Antisense oligonucleotides delivered to the CNS might be a feasible treatment for neurological disorders., Funding: The ALS Association, Muscular Dystrophy Association, Isis Pharmaceuticals., (Copyright © 2013 Elsevier Ltd. All rights reserved.)

Background: Severe congenital neutropenia type 4 (SCN4) is an autosomal recessive disorder caused by mutations in the third subunit of the enzyme glucose-6-phosphatase (G6PC3). Its core features are congenital neutropenia and a prominent venous skin pattern, and affected individuals have variable birth defects. Oculocutaneous albinism type 4 (OCA4) is caused by autosomal recessive mutations in SLC45A2., Methods: We report a sister and brother from Newfoundland, Canada with complex phenotypes. The sister was previously reported by Cullinane et al., 2011. We performed homozygosity mapping, next generation sequencing and conventional Sanger sequencing to identify mutations that cause the phenotype in this family. We have also summarized clinical data from 49 previously reported SCN4 cases with overlapping phenotypes and interpret the medical histories of these siblings in the context of the literature., Results: The siblings' phenotype is due in part to a homozygous mutation in G6PC3, [c.829C > T, p.Gln277X]. Their ages are 38 and 37 years respectively and they are the oldest SCN4 patients published to date. Both presented with congenital neutropenia and later developed Crohn disease. We suggest that the latter is a previously unrecognized SCN4 manifestation and that not all affected individuals have an intellectual disability. The sister also has a homozygous mutation in SLC45A2, which explains her severe oculocutaneous hypopigmentation. Her brother carried one SLC45A2 mutation and was diagnosed with "partial OCA" in childhood., Conclusions: This family highlights that apparently novel syndromes can in fact be caused by two known autosomal recessive disorders.

This study was designed to evaluate the safety and tolerability of single doses of CK-2017357, an orally bioavailable fast skeletal muscle troponin activator, in patients with amyotrophic lateral sclerosis (ALS), and to explore pharmacodynamic markers related to strength, endurance, and function. Sixty-seven patients with ALS received single doses of placebo, CK-2017357 at 250 mg and 500 mg in random order, separated by one week. Safety measures assessments were performed, as well as tests of pulmonary function, limb muscle strength and endurance, and global impression of change. Pharmacokinetics of both CK-2017357 and riluzole were studied. Sixty-three patients completed all three dosing periods. CK-2017357 was well tolerated, with dizziness and general fatigue being the most frequent adverse events. Both patients and investigators perceived a dose-dependent benefit of CK-2017357 as measured by global impression of change. Maximum voluntary ventilation and submaximal handgrip endurance also improved. Only small changes were seen in maximal strength. In conclusion, single doses of 250 mg and 500 mg of CK-2017357 were safe and well tolerated by patients with ALS. Measures of endurance appear to be improved in a dose-related fashion, and both patients and investigators perceived a global benefit. Further study of this agent is warranted.

Background: Idiopathic pulmonary fibrosis (IPF) is an adult-onset Idiopathic Interstitial Pneumonia (IIP) usually diagnosed between age 50 to 70 years. Individuals with Familial Pulmonary Fibrosis (FPF) have at least one affected first or second-degree relative and account for 0.5-20% of cases., Methods: We ascertained and collected DNA samples from a large population-based cohort of IPF patients from Newfoundland, Canada. For each proband, a family history was documented and medical records were reviewed. Each proband was classified as familial (28 patients) or sporadic (50 patients) and all 78 probands were screened for variants in four highly penetrant, adult-onset PF genes (SFTPC, SFTPA2, TERT,TERC)., Results: Seventy-eight IPF probands were enrolled of whom 28 (35.9%) had a positive family history. These 28 familial patients led to the recruitment of an additional 49 affected relatives (total of 77 FPF patients). By age 60 years, 42% of the familial cohort had been diagnosed with PF compared with only 16% of the sporadic patient collection (χ2 = 8.77, p = 0.003). Mean age of diagnosis in the familial group was significantly younger than the sporadic group (61.4 years vs. 66.6 yrs, p = 0.012) with a wider age range of diagnosis (19-92 years compared with 47-82 years). Thirty-three of 77 (42.8%) FPF patients had a tissue diagnosis and all but five had usual interstitial pneumonia histology. Compared with other published case series, the familial IIP histologies were more homogeneous. Three of 28 familial probands (10.7%) and none of the 50 sporadic probands had pathogenic variants in the four genes tested. All three familial probands had mutations in TERT. Other phenotypes associated with telomerase deficiency were present in these families including cirrhosis, bone marrow hypoplasia and premature graying. Telomere length assays were performed on mutation carriers from two families and confirmed telomere-related deficiency., Conclusion: The proportion of familial cases in our cohort is higher than any previously reported estimate and we suggest that this is due to the fact that Newfoundland cohort is ethnically homogeneous and drawn from a founder population. In our patient collection, diagnosis with IPF prior to age 45 years predicted familial disease. In two of the three TERT mutation families, the pedigree appearance is consistent with genetic anticipation. In the other 25 FPF families negative for mutations in known PF genes, we did not identify other telomerase associated medical problems (bone marrow dysfunction, cirrhosis) and we hypothesize that there are novel PF genes segregating in our population.

A recent report detailed the occurrence of both somatic and constitutional variants in the GALNT12 gene, located at 9q22.33, in some colorectal cancer (CRC) patients. In this study, we investigate the occurrence of inherited deleterious variants in GALNT12 in 118 families referred to a cancer genetics clinic. We discovered two deleterious variants (c.907G>A (p.Asp303Asn); c.1187A>G (p.Tyr396Cys)) in 4/118 probands. The variants, which were not found in 149 control individuals (P = 0.0376), cosegregate with CRC and/or adenomatous polyps in other family members. The probability by chance that cosegregation of c.907G>A with CRC and/or adenomatous polyps occurred, in the two pedigrees combined, was 1.56%. Although this study does not provide irrefutable evidence that GALNT12 variants are highly penetrant alleles that predispose to CRC in the majority of unexplained hereditary CRC families, it does provide additional evidence to support an important role of these variants in a proportion of this considerable high-risk group., (© 2012 Wiley Periodicals, Inc.)

Background: Patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer have a higher risk of locoregional recurrence (LRR), even in the setting of early stage, lymph node-negative disease. In this sequential, retrospective study, the authors evaluated whether adjuvant trastuzumab was associated with reduced LRR in women with lymph node-negative, HER2-positive disease who received breast-conservation therapy (BCT)., Methods: By using an institutional database, 197 women were identified who had lymph node-negative, HER2-positive breast cancer measuring ≤5 cm diagnosed between 2002 and 2008 and who received BCT, including whole-breast irradiation. Two cohorts were compared: 70 women who did not receive trastuzumab (the no-trastuzumab cohort) and 102 women who did receive trastuzumab (the trastuzumab cohort). Kaplan-Meier methods were used to estimate LRR-free survival., Results: The 2 cohorts were similar in age, tumor size, histology, and hormone receptor status. Chemotherapy was received by 73% of the no-trastuzumab cohort and by 100% of the trastuzumab cohort. In both groups, 99% of patients completed radiotherapy with a median dose of 60 Gray. The median recurrence-free follow-up was 86 months for the no-trastuzumab cohort and 47 months for the trastuzumab cohort. The 3-year LRR-free survival rate was 90% (95% confidence interval, 83%-97%) for the no-trastuzumab cohort and 99% (95% confidence interval, 97%-100%) for the trastuzumab cohort. In the no-trastuzumab cohort, LRR occurred in 7 patients (median time to LRR, 14 months). In the trastuzumab cohort, there was 1 LRR at 14 months., Conclusions: Even among women with lower risk breast cancer, the relatively high locoregional failure rates associated with positive HER2 status could be reduced markedly with adjuvant trastuzumab chemotherapy. Within 3 years, a 10% LRR rate without trastuzumab and a 1% LRR rate with trastuzumab were observed in women with lymph node-negative disease who received BCT., (Copyright © 2011 American Cancer Society.)

Objectives: The purpose of this study, in a sample of preschool children (ages 3-5 years; N = 47), was to evaluate the feasibility of scheduled analgesic dosing following outpatient tonsillectomy in order to optimize pain management., Methods: Parents were instructed to give their child acetaminophen with hydrocodone (167 mg/5 mL) every 4 hours around the clock for the first 3 days following surgery. Parents recorded ratings of their child's pain with/without swallowing using the Faces, Legs, Activity, Cry, and Consolability (FLACC) behavioral pain scale, pain relief ratings, and severity of analgesic side effects in a home diary. Audiotaped interviews were conducted with parents to document descriptions of their experiences in managing their child's pain at home., Results: Mean FLACC scores with/without swallowing were less than two at each measurement time and pain relief scores increased over time. Total analgesic dose decreased, and the number of missed doses increased over the first 3 days after surgery. Moderate-to-severe daytime sedation, nausea, vomiting, and constipation were reported by parents., Discussion: Study results suggest that acetaminophen with hydrocodone is effective in relieving preschool children's pain following tonsillectomy and that parental adherence to a scheduled analgesic regimen decreases over time. Time-contingent dosing was associated with moderate to severe side effects and should be addressed in discharge teaching with parents. Findings provide insight into parents' perspective of pain management at home following tonsillectomy and methods for relieving their child's pain., (Wiley Periodicals, Inc.)

Purpose: To describe the incidence and epidemiology of pediatric idiopathic epilepsy (IE) in Newfoundland and Labrador., Methods: All children in Newfoundland and Labrador aged 0-15 years with IE were ascertained through the provincial neurology clinic at the Janeway Child Health Centre. Family history, medical history and blood samples were obtained from probands and relatives. Two genes, SCN1A and KCNQ2, were screened for mutations by direct sequencing., Results: The mean annual incidence of IE for the population of children living in the Avalon region of Newfoundland from 2000 to 2004 was 107 per 100,000. This rate is approximately three-fold greater than rates reported in other developed countries. Of 117 families with IE eligible for study, 86 (74%) provided detailed pedigree data. Multiple different epilepsy phenotypes were identified. Fifty-five families (64%) had a positive family history. Eight of these had family histories compatible with autosomal dominant (AD) inheritance and these families lived in five different geographic isolates. DNA was obtained from 21 families (79 individuals). The two previously identified mutations in Newfoundland families with epilepsy were sequenced and excluded as pathogenic sites in all but one family which had a mutation in SCN1A., Conclusion: The incidence of IE is high in the Avalon Peninsula of Newfoundland and the rate of familial disease is high throughout the province of Newfoundland and Labrador. The distribution of familial and AD IE in different geographic isolates, together with the clinical heterogeneity of disease suggests substantial genetic heterogeneity. It is likely that other novel mutations will be identified in this population., (Copyright © 2011 Elsevier B.V. All rights reserved.)

In Pennsylvania on February 16, 2006, a New York City resident collapsed with rigors and was hospitalized. On February 21, the Centers for Disease Control and Prevention and the New York City Department of Health and Mental Hygiene were notified that Bacillus anthracis had been identified in the patient's blood. Although the patient's history of working with dried animal hides to make African drums indicated the likelihood of a natural exposure to aerosolized anthrax spores, bioterrorism had to be ruled out first. Ultimately, this case proved to be the first case of naturally occurring inhalational anthrax in 30 years. This article describes the epidemiologic and environmental investigation to identify other cases and persons at risk and to determine the source of exposure and scope of contamination. Because stricter regulation of the importation of animal hides from areas where anthrax is enzootic is difficult, public healthcare officials should consider the possibility of future naturally occurring anthrax cases caused by contaminated hides. Federal protocols are needed to assist in the local response, which should be tempered by our growing understanding of the epidemiology of naturally acquired anthrax. These protocols should include recommended methods for reliable and efficient environmental sample collection and laboratory testing, and environmental risk assessments and remediation.

Objectives: To determine the effectiveness of around-the-clock (ATC) analgesic administration, with or without nurse coaching, compared with standard care with as needed (PRN) dosing in children undergoing outpatient tonsillectomy., Methods: Children 6 to 15 years of age were randomized to receive acetaminophen and hydrocodone (167 mg/2.5 mg/5 mL) for 3 days after surgery: Group A (N=39)-every 4 hours PRN, with standard postoperative instructions; Group B (N=34)-every 4 hours ATC, with standard postoperative instructions, without nurse coaching; and Group C (N=40)-every 4 hours ATC, with standard postoperative instructions, with coaching. Parents completed a medication log, and recorded the presence and severity of opioid-related adverse effects and children's reports of pain intensity using a 0 to 10 numeric rating scale., Results: No differences were found in analgesic administration or pain intensity scores between the 2 ATC groups. Therefore, they were combined for comparison with the PRN group. Children in the ATC group received more analgesic than those in the PRN group (P<0.0001). Children in the PRN group had higher pain intensity scores compared to children in the ATC group, both at rest (P=0.017) and with swallowing (P=0.017). Pain intensity scores for both groups were higher in the morning compared with the evening (P<0.0001). With the exception of constipation, scheduled analgesic dosing did not increase the frequency or severity of opioid-related adverse effects., Discussion: Scheduled dosing of acetaminophen and hydrocodone is more effective than PRN dosing in reducing pain intensity in children after tonsillectomy. Nurse coaching does not impact parent's adherence to ATC dosing.

Purpose: To describe the spectrum of clinical disease in a mutliplex family with an autosomal dominant form of generalized epilepsy with febrile seizures plus (GEFS+) and determine its genetic etiology., Methods: Medical and family history was obtained on 11 clinically affected individuals and their relatives across three generations through medical chart review and home visits. A candidate gene approach including haplotype analysis and direct sequencing was used., Results: An epilepsy-associated haplotype was identified on 2q24. Direct sequencing of the entire SCN1A gene identified seven sequence variants. However, only one of these, c.1162 T>C, was not found in population controls. This transition in exon 8 of SCN1A predicts a substitution (Y388H) of a highly conserved tyrosine residue in the loop between transmembrane segments S5 and S6 of the sodium channel protein (Na(v)1.1). Clinical features in mutation carriers of this novel missense mutation were highly variable, ranging from febrile seizures to severe refractory epilepsy., Conclusion: A novel missense mutation in the pore-forming region of the sodium channel gene SCN1A causes GEFS+ with a variable phenotype that includes mood and anxiety disorders, as well as ataxia, expanding the GEFS+ spectrum to include neuropsychiatric disease.

Educators, challenged to measure clinical competency impartially in Advanced Health Assessment courses, have used Objective Structured Clinical Examination (OSCE) and standardized patients (SP). Faculty-trained laypersons act as patients (SP) for students in a clinical laboratory setting using a standardized, scripted scenario. Students typically are evaluated during the examination and receive instant feedback from the SP. There has been little evidence that supports this as the best way to measure student's clinical competency. This study's purpose was to compare outcomes of graduate nursing students completing a traditional methods Health Assessment course to those students using OSCE and SPs. Problem-based Learning Theory guided the quasi-experimental study that included 37 students divided into research and control groups. There were statistically significant differences between the two groups for the final practical examination grades, clinical preceptor evaluations, satisfaction scores, and self-evaluations of skills at the course's end. Research group's course scores were higher than the control group. There was no difference between group's self-evaluation for their current assessment skills. This intervention had a positive impact on students' outcomes. Educators should incorporate SPs and OSCE to improve clinical competency scores, course satisfaction, and preceptor evaluations. Future studies should include a longitudinal design and qualitative student feedback.

This paper reports the results of a qualitative study of nurses' ethical decision-making. Focus groups of nurses in diverse practice contexts were used as a means to explore the meaning of ethics and the enactment of ethical practice. The findings centre on the metaphor ofa moral horizon--the horizon representing "the good" towards which the nurses were navigating.The findings suggest that currents within the moral climate of nurses' work significantly influence nurses' progress towards their moral horizon. All too often the nurses found themselves navigating against a current characterized by the privileging of biomedicine and a corporate ethos. Conversely, a current of supportive colleagues as well as professional guidelines and standards and ethics education helped them to move towards their horizon.The implications for nursing practice and for our understanding of ethical decision-making are discussed.

Empirical evidence on the role financial institutions and home and community-based interventions play in influencing asset building among persons with disabilities is scarce. This article contributes to this effort directed at understanding such effects by exploring patterns of and barriers to use of banking services offered by the credit union that has enrolled persons with disabilities in Iowa under a home and community-based services waivers program. It is suggested that although banking services are not used by the majority of program participants, the credit union model has appeal. It provides an opportunity for people with disabilities to build savings for the purchase of goods and services that enhance their independence and productivity.

The Cash and Counseling Demonstration and Evaluation (CCDE) tested one of the most autonomous forms of consumer direction for personal assistance services. In the winter of 1996/97, Arkansas, Florida, New Jersey, and New York each received grants to develop and implement CCDE. While Arkansas, Florida, and New Jersey were successful in their efforts of implementing CCDE, New York was unable to do so. Using elements of Hasenfeld and Brock's (1991) political economy policy implementation model, the following sections describe two primary interactions between key policy implementation instruments and internal and external stakeholders that made New York's participation in CCDE not possible. This case study also provides some lessons for other states interested in developing Cash and Counseling models.

Patient-professional communication is a critically important element of effective chronic illness care. However, the dynamics of health care communication in supporting self-care management and effective coping with various chronic diseases is not well understood. The present study examined health care communication from the perspective of 38 patients with four distinct chronic conditions: end-stage renal disease (ESRD), non-insulin dependent diabetes mellitus (NIDDM), multiple sclerosis (MS), and fibromyalgia (FM). Analysis revealed the dimensions of courtesy, respect, and engagement to be inherent in communication priorities across conditions. However, distinct "disease worlds" among and between these chronic conditions illuminated salient differences within these dimensions, thereby illustrating the way in which relevant variables such as legitimacy, the availability of conventional treatments, and lifestyle implications shape the meaning of health care communication. The findings enlarge upon patient-centered approaches to health care communication and inform further analysis of the interactional dynamics associated with chronic conditions., (Copyright 2003 Elsevier Ireland Ltd.)

Background: While contemporary ethical theory is of tremendous value to nursing, the extent to which such theory has been informed by the concerns and practices of nurses has been limited., Purpose: With a view to complementing extant ethical theory, a study was undertaken to explore, from the perspective of nurses, the meaning of ethics and the enactment of ethical practice in nursing., Design and Methods: Located in the interpretive/constructivist paradigm, using an emergent design, this inquiry employed focus groups to collect the data. Eighty-seven nurses from a wide range of practice settings were interviewed in 19 focus groups of three to nine nurses each., Findings: The nurses described ethics in their practice as both a way of being and a process of enactment. They described drawing on a wide range of sources of moral knowledge in a dynamic process of developing awareness of themselves as moral agents. Enacting moral agency involved working in a shifting moral context, and working in-between their own values and those of the organizations in which they worked, in-between their own values and those of others, and in-between competing values and interests., Conclusions: Analysis of the experiences and concerns of the nurses offered new understanding of ethics in nursing and direction for the development of ethical theory pertinent to nursing practice.

This paper reports the results of a qualitative study of nurses' ethical decision-making. Focus groups of nurses in diverse practice contexts were used as a means to explore the meaning of ethics and the enactment of ethical practice. The findings centre on the metaphor of a moral horizon--the horizon representing "the good" towards which the nurses were navigating. The findings suggest that currents within the moral climate of nurses' work significantly influence nurses' progress towards their moral horizon. All too often, the nurses found themselves navigating against a current characterized by the privileging of biomedicine and a corporate ethos. Conversely, a current of supportive colleagues as well as professional guidelines and standards and ethics education helped them to move towards their horizon. The implications for nursing practice and for our understanding of ethical decision-making are discussed.