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Background: Conditional survival estimates provide critical prognostic information for patients with advanced renal cell carcinoma (aRCC). Efficacy, safety, and conditional survival outcomes were assessed in CheckMate 214 (ClinicalTrials.gov identifier NCT02231749) with a minimum follow-up of 5 years. Methods: Patients with untreated aRCC were randomized to receive nivolumab (NIVO) (3 mg/kg) plus ipilimumab (IPI) (1 mg/kg) every 3 weeks for 4 cycles, then either NIVO monotherapy or sunitinib (SUN) (50 mg) daily (four 6-week cycles). Efficacy was assessed in intent-to-treat, International Metastatic Renal Cell Carcinoma Database Consortium intermediate-risk/poor-risk, and favorable-risk populations. Conditional survival outcomes (the probability of remaining alive, progression free, or in response 2 years beyond a specified landmark) were analyzed. Results: The median follow-up was 67.7 months; overall survival (median, 55.7 vs 38.4 months; hazard ratio, 0.72), progression-free survival (median, 12.3 vs 12.3 months; hazard ratio, 0.86), and objective response (39.3% vs 32.4%) benefits were maintained with NIVO+IPI versus SUN, respectively, in intent-to-treat patients (N = 550 vs 546). Point estimates for 2-year conditional overall survival beyond the 3-year landmark were higher with NIVO+IPI versus SUN (intent-to-treat patients, 81% vs 72%; intermediate-risk/poor-risk patients, 79% vs 72%; favorable-risk patients, 85% vs 72%). Conditional progression-free survival and response point estimates were also higher beyond 3 years with NIVO+IPI. Point estimates for conditional overall survival were higher or remained steady at each subsequent year of survival with NIVO+IPI in patients stratified by tumor programmed death ligand 1 expression, grade ≥3 immune-mediated adverse event experience, body mass index, and age. Conclusions: Durable clinical benefits were observed with NIVO+IPI versus SUN at 5 years, the longest phase 3 follow-up for a first-line checkpoint inhibitor-based combination in patients with aRCC. Conditional estimates indicate that most patients who remained alive or in response with NIVO+IPI at 3 years remained so at 5 years.

OBJECTIVES: Bedside delivery of discharge medications improves caregiver understanding and experience. Less is known about its impact on medication adherence. We aimed to improve antimicrobial adherence by increasing on-time first home doses for patients discharged from the pediatric hospital medicine service from 33% to 80% over 1 year via creation of a discharge medication delivery and counseling “Meds to Beds” (M2B) program. METHODS: Using sequential plan-do-study-act cycles, an interprofessional workgroup implemented M2B on select pediatric hospital medicine units at our quaternary children’s hospital from October 2017 through December 2018. Scripted telephone surveys were conducted with caregivers of patients prescribed antimicrobial agents at discharge. The primary outcome measure was on-time administration of the first home antimicrobial dose, defined as a dose given within the time of the inpatient dose equivalent plus 25%. Process measures primarily assessed caregiver report of barriers to adherence. Run charts, statistical process control charts, and inferential statistics were used for data analysis. RESULTS: Caregiver survey response rate was 35% (207 of 585). Median on-time first home antimicrobial doses increased from 33% to 67% (P < .001). Forty percent of M2B prescriptions were adjusted before discharge because of financial or insurance barriers. M2B participants reported significantly less difficulty in obtaining medications compared with nonparticipants (1% vs 17%, P < .001). CONCLUSIONS: The M2B program successfully increased parental report of timely administration of first home antimicrobial doses, a component of overall adherence. The program enabled providers to identify and resolve prescription problems before discharge. Importantly, caregivers reported reduced barriers to medication adherence.

In the United States, the Emergency Medical Services (EMS) has evolved and expanded over the past 50 years to provide critical care to patients outside of the hospital. EMS patients have a varied level of acuity, and the system is designed to meet their needs and adjust based on the situation at hand. The current prehospital system is comprised of various levels of certified and licensed providers and agencies to ensure the public gets the best care before arriving at a medical facility. EMS providers interact with many different professions to ensure there is continuity and top-level care provided to the patient. Interprofessional Education (IPE) incorporating simulation-based activities are necessary to expand the understanding about EMS and scope of practice as well as the potential impact on treating patients outside of the hospital. Expanding the knowledge and inclusion of EMS in IPE activities will help enhance the overall professional impression of the vital resource EMS can have in health care delivery. It will improve and extend the continuum of care to the initial entry of the patient into the healthcare system and integrate the role EMS providers have in improving patient safety and patient outcomes.

A competent healthcare simulation technology specialist (HSTS) exudes both managerial and leadership skills. Both are important to building a robust and high functioning simulation program. Techniques to evolve leadership effectiveness can be obtained in a formal educational environment and also through informal mechanisms. A future leader should further develop their knowledge, skills, and abilities through lifelong learning as it greatly improves the effectiveness of the HSTS to grow well beyond their initial desire and passion. In the end, leadership is a valuable skill that expands the effectiveness of the team and the simulation program.

The complex health care needs of today's society require health care professionals to work as a collaborative team. Safe, quality health care depends on the ability of the health care team to cooperate, communicate, and share skills and knowledge appropriately. Interprofessional education provides a collaborative approach for the development and mastery of these competencies. Simulation-based experiential learning is recognized as an effective way to promote interprofessional education teamwork.

There is a lack of appropriate services to manage youth with comorbid mental health problems and violence risks. To address this gap, we implemented a forensic satellite clinic in a youth mental health service. This paper characterises offending histories among 45 young patients referred to the clinic, and compares them with matched clinical controls (n = 45). Levels of prior risk taking and aggression were prominent among referred patients. Forensic cases and controls did not differ on demographic and clinical variables, with the exception of psychiatric inpatient admissions, which were higher among referred patients. Group differences were observed for prior offending variables (e.g., physical aggression), which were significantly higher among referred patients than controls. Findings suggest that referrals were made to the clinic based on challenging and aggressive behaviour rather than specific clinical characteristics. The role of specialist assessment, treatment and management of violence risks in youth mental health services are discussed.

Aim: There is a significant relationship between experiencing a severe mental illness, particularly psychosis, and exhibiting violent or offending behaviour. Reducing, if not preventing, the risks of violence among patients of mental health services is clinically warranted, but models to address this are limited. Methods: We provide a rationale for, and service description of, a pilot forensic satellite clinic embedded within an early intervention service for patients with emerging psychosis, mood disorder and/or personality disorders. The core elements of the programme and its implementation are described, and demographic, clinical and risk data are presented for the patients assessed during the clinic's pilot phase. Results: A total of 54 patients were referred, 45 of whom were subsequently assessed via primary or secondary consultation. The majority of patients were male, with psychosis (40%) or major depressive disorder (31%) as the most common diagnoses. Illicit substance use in the sample was common, as was previous aggression (81%) and prior criminal offences (51%). Most referrals related to assessing and managing violent behaviour (64%) and violent/homicidal ideation (38%). On the basis of the risk assessments, 71% of patients were rated as medium to high risk of offending. Conclusion: Assessing and managing risks of violent offending among young patients are both clinically indicated for a proportion of patients and feasible via a forensic outreach model. Given the proliferation of early psychosis services worldwide, the issue of managing, and ideally preventing, patient risk of violence will almost certainly have wide application. However, a comprehensive evaluation of this model is required to ultimately determine the effectiveness of this approach for improving patient outcomes. Language: en

Background:dmissions to secure mental health services aim to treat both mental illness and the offending behaviour of service users. Dialectical Behaviour Therapy (DBT) is an emerging therapy within secure services for personality disordered service users. This pilot study explores the impact DBT had with female patients located in a secure service in Wales.Aims:To identify any treatment benefits of DBT for a sample of female forensic patients in Wales.Methods:DBT was adapted to meet the needs of the forensic setting and patient needs. Measures exploring anger, anxiety, depression, hopelessness and social problem solving were gathered from participants pre and post intervention.Results:Results indicated significant reduction in post intervention ratings for depression, hopelessness and anxiety, with large effect sizes in the desired direction reported on other measures, excluding social problem solving.Conclusions and implications for practice:DBT appears to have had a greater impact on the affective experiences of participants and less impact on the cognitive processes related to social problem solving. Findings are discussed in terms of clinical practice significance.

Nursing home administration is seeing high turnover and low entrance into the profession. Face-to-face interviews were conducted with thirty NH administrators and coded using qualitative analytical techniques. It was found that constrained autonomy contributes to job dissatisfaction in the nursing home administrator profession, and that autonomy contributes to increased satisfaction and may lower administrator turnover.

Mast cells play a critical role in host defense against a number of pathogens. Increased mast cell infiltration has been described in allergic asthma, in rheumatoid arthritis, and during helminthes infection. Despite the importance of mast cells in allergic disease and defense against infection, little is known about the mechanisms by which mast cells migrate to various tissues under steady state conditions or during infection or inflammation. Here, we show that activation of c-Kit by its ligand, stem cell factor (SCF), cooperates with α4 integrin in inducing directed migration of mast cells on fibronectin. A reduction in migration and activation of a small G protein, Rac, was observed in mast cells derived from class IA phosphoinositide-3 kinase (PI-3kinase)–deficient mice in response to SCF stimulation and in mast cells expressing the dominant-negative Rac (RacN17), as well as in mast cells deficient in the hematopoietic-specific small G protein, Rac2. In addition, a PI-3kinase inhibitor inhibited α4- as well as SCF-induced migration in a dose-dependent fashion. In contrast, a mitogen-activated protein kinase (MAPK) inhibitor had little effect. Consistent with the pharmacologic results, abrogating the binding of the p85α subunit of class IA PI-3kinase to c-Kit also resulted in inhibition of SCF-induced migration on fibronectin. These genetic and biochemical data demonstrate that both c-Kit and α4 integrin signaling are linked to class IA PI-3kinase and Rac pathways and regulate integrin-directed (haptotactic) migration in mast cells.

The role of thrombopoietin (Tpo) in promoting hematopoiesis has been extensively studied in late fetal, neonatal, and adult mice. However, the effects of Tpo on early yolk sac hematopoiesis have been largely unexplored. We examined whole embryos or the cells isolated from embryo proper and yolk sacs and identified both Tpo and c-mpl (Tpo receptor) mRNA transcripts in tissues as early as embryonic day 6.5 (E6.5). Presomite whole embryos and somite-staged yolk sac and embryo proper cells were plated in methylcellulose cultures and treated with selected hematopoietic growth factors in the presence or absence of Tpo. Tpo alone failed to promote colony-forming unit (CFU) formation. However, in the presence of other growth factors, Tpo caused a substantial dose-dependent reduction in primitive and definitive erythroid CFU growth in cultures containing E7.5 and E8.0 whole embryos and E8.25 to 9.5 yolk sac–derived cells. Meanwhile, Tpo treatment resulted in a substantial dose-dependent increase in CFU-mixed lineage (CFU-Mix) and CFU-megakaryocyte (CFU-Meg) formation in cultures containing cells from similar staged tissues. Addition of Tpo to cultures of sorted E9.5 yolk sac c-Kit+CD34+ hematopoietic progenitors also inhibited erythroid CFU growth but augmented CFU-Mix and CFU-Meg activity. Effects of Tpo on CFU growth were blocked in the presence of a monoclonal antibody with Tpo-neutralizing activity but not with control antibody. Thus, under certain growth factor conditions, Tpo directly inhibits early yolk sac erythroid CFU growth but facilitates megakaryocyte and mixed lineage colony formation.

Two alternatively spliced stem cell factor (SCF) transcripts encode protein products, which differ in the duration of membrane presentation. One form, soluble SCF (S-SCF) gets rapidly processed to yield predominantly secreted protein. The other form, membrane-associated SCF (MA-SCF) lacks the primary proteolytic cleavage site but is cleaved slowly from an alternate site, and thus represents a more stable membrane form of SCF. Mutants of SCF that lack the expression of MA-SCF (Steel-dickie) or possess a defect in its presentation (Steel17H) manifest deficiencies in erythroid cell development. In this study, we have compared the consequence(s) of activating Kit, the receptor for SCF by MA-SCF with S-SCF, and an obligate membrane-restricted (MR) form of SCF (MR-SCF) on erythroid cell survival, proliferation, cell cycle progression, and the activation of p38 and ERK MAP kinase pathways. Activation of Kit by MR-SCF was associated with a significantly lower incidence of apoptosis and cell death in erythroid cells compared to either other isoform. MR- or MA-SCF–induced stimulation of erythroid cells resulted in similar and significantly greater proliferation and cell cycle progression compared to soluble SCF. The increase in proliferation and cell cycle progression via MA- or MR-SCF stimulation correlated with sustained and enhanced activation of p38 and ERK MAP kinase pathways. In addition, MR- or MA-SCF–induced proliferation was more sensitive to the inhibitory effects of ERK inhibitor compared to S-SCF–induced proliferation. In contrast, soluble SCF-induced proliferation was more sensitive to the inhibitory effects of p38 inhibitor compared with MR- or MA-SCF. These results suggest that different isoforms of SCF may use different biochemical pathways in stimulation of survival and/or proliferation of erythroid cells.

An acquired chromosomal translocation, t(8;13)(p11;q11-12), observed in a distinctive type of stem cell leukemia/lymphoma syndrome, leads to the fusion of the 5′ portion of ZNF198 and the 3′ portion of FGFR1. ZNF198–FGFR1 fusion transcripts encode 4 to 10 zinc fingers, a proline-rich region, and the intracellular portion of the FGFR1 (fibroblast growth factor receptor 1) receptor tyrosine kinase. We demonstrate that the ZNF198 proline-rich region constitutes a novel self-association domain. When fused to the intracellular domain of FGFR1, the ZNF198 proline-rich region is sufficient to cause oligomerization, FGFR1 tyrosine kinase activation, and transformation of Ba/F3 cells to IL-3 independent growth.

This study explored neutralization as a process of graduated desensitization, providing a theoretical link between the opposing tenets of neutralisation theory and the subcultural theory of criminal behaviour Participants were 95 adult male offenders who were categorised according to type of offence (personal or property) and level of offending involvement (low or high). Offenders' excuse acceptance and offence approval were examined for S offence situations. The results indicated offenders' excuse acceptance varied as a function of their level of involvement in crime. Specifically, for property offence situations, low-involvement property offenders reported higher excuse acceptance than did high-involvement property offenders, whereas for personal offence situations, low-involvement personal offenders reported higher excuse acceptance than did high-involvement personal offenders. This finding partially supported the graduated desensitization hypothesis, providing an empirical link between neutralisation and the subcultural theory of criminal behaviour

CONTEXT: Implantable cardioverter defibrillator (ICD) therapy with backup ventricular pacing increases survival in patients with life-threatening ventricular arrhythmias. Most currently implanted ICD devices provide dual-chamber pacing therapy. The most common comorbid cause for mortality in this population is congestive heart failure. OBJECTIVE: To determine the efficacy of dual-chamber pacing compared with backup ventricular pacing in patients with standard indications for ICD implantation but without indications for antibradycardia pacing. DESIGN: The Dual Chamber and VVI Implantable Defibrillator (DAVID) Trial, a single-blind, parallel-group, randomized clinical trial. SETTING AND PARTICIPANTS: A total of 506 patients with indications for ICD therapy were enrolled between October 2000 and September 2002 at 37 US centers. All patients had a left ventricular ejection fraction (LVEF) of 40% or less, no indication for antibradycardia pacemaker therapy, and no persistent atrial arrhythmias. INTERVENTIONS: All patients had an ICD with dual-chamber, rate-responsive pacing capability implanted. Patients were randomly assigned to have the ICDs programmed to ventricular backup pacing at 40/min (VVI-40; n = 256) or dual-chamber rate-responsive pacing at 70/min (DDDR-70; n = 250). Maximal tolerated medical therapy for left ventricular dysfunction, including angiotensin-converting enzyme inhibitors and beta-blockers, was prescribed to all patients. MAIN OUTCOME MEASURE: Composite end point of time to death or first hospitalization for congestive heart failure. RESULTS: One-year survival free of the composite end point was 83.9% for patients treated with VVI-40 compared with 73.3% for patients treated with DDDR-70 (relative hazard, 1.61; 95% confidence interval [CI], 1.06-2.44). The components of the composite end point, mortality of 6.5% for VVI-40 vs 10.1% for DDDR-70 (relative hazard, 1.61; 95% CI, 0.84-3.09) and hospitalization for congestive heart failure of 13.3% for VVI-40 vs 22.6% for DDDR-70 (relative hazard, 1.54; 95% CI, 0.97-2.46), also trended in favor of VVI-40 programming. CONCLUSION: For patients with standard indications for ICD therapy, no indication for cardiac pacing, and an LVEF of 40% or less, dual-chamber pacing offers no clinical advantage over ventricular backup pacing and may be detrimental by increasing the combined end point of death or hospitalization for heart failure.

Two alternatively spliced stem cell factor (SCF) transcripts encode protein products, which differ in the duration of membrane presentation. One form, soluble SCF (S-SCF) gets rapidly processed to yield predominantly secreted protein. The other form, membrane-associated SCF (MA-SCF) lacks the primary proteolytic cleavage site but is cleaved slowly from an alternate site, and thus represents a more stable membrane form of SCF. Mutants of SCF that lack the expression of MA-SCF (Steel-dickie) or possess a defect in its presentation (Steel(17H)) manifest deficiencies in erythroid cell development. In this study, we have compared the consequence(s) of activating Kit, the receptor for SCF by MA-SCF with S-SCF, and an obligate membrane-restricted (MR) form of SCF (MR-SCF) on erythroid cell survival, proliferation, cell cycle progression, and the activation of p38 and ERK MAP kinase pathways. Activation of Kit by MR-SCF was associated with a significantly lower incidence of apoptosis and cell death in erythroid cells compared to either other isoform. MR- or MA-SCF-induced stimulation of erythroid cells resulted in similar and significantly greater proliferation and cell cycle progression compared to soluble SCF. The increase in proliferation and cell cycle progression via MA- or MR-SCF stimulation correlated with sustained and enhanced activation of p38 and ERK MAP kinase pathways. In addition, MR- or MA-SCF-induced proliferation was more sensitive to the inhibitory effects of ERK inhibitor compared to S-SCF-induced proliferation. In contrast, soluble SCF-induced proliferation was more sensitive to the inhibitory effects of p38 inhibitor compared with MR- or MA-SCF. These results suggest that different isoforms of SCF may use different biochemical pathways in stimulation of survival and/or proliferation of erythroid cells.