Prolonged Hourly Neurologic Examinations are Associated with Increased Delirium and No Discernible Benefit in Mild/Moderate Geriatric Traumatic Brain Injury.

BACKGROUND: Serial neurologic examinations (NE) are routinely recommended in the ICU within the first 24 hours following a TBI. There are currently no widely accepted guidelines for the frequency of NE. Disruptions to the sleep-wake cycles increase the delirium rate. We aimed to evaluate whether there is a correlation between prolonged Q1-NE and development of delirium and to determine if this practice reduces the likelihood of missing the detection of a process requiring emergent intervention. METHODS: Retrospective analysis of patients with mild/moderate TBI, admitted to the ICU with serial-NE. Cohorts were stratified by the duration of exposure to Q1-NE, into Prolonged(≥24 h) and Not Prolonged(<24 h). Our primary outcomes of interest was delirium, evaluated using the Confusion Assessment Method (CAM-ICU), radiological progression from baseline images, neurological deterioration (focal neurological deficit, abnormal pupillary exam, or GCS decrease >2), and neurosurgical procedures. RESULTS: A total of 522 patients were included. No significant differences were found in demographics. Patients in the Prolonged Q1-NE group (26.1%) had higher ISS with similar AIS Head, and significantly higher delirium rate [59% vs 35%, p < .001], and a longer Hospital/ICU length of stay when compared to the Not Prolonged Q1-NE group. No neurosurgical interventions were found to be performed emergently as a result of findings on NE. Multivariate analysis demonstrated that Prolonged Q1-NE was the only independent risk factor associated with a 2.5-fold increase in delirium rate. The Number Needed to Harm for prolonged Q1-NE was 4. CONCLUSIONS: Geriatric patients with mild/moderate TBI exposed to Q1-NE for periods longer than 24 h had nearly a 3-fold increase in ICU-Delirium rate. One out of five patients exposed to prolonged Q1-NE is harmed by the development of delirium. No patients were found to directly benefit as a result of more frequent neurological examinations.

Conditional survival and long-term efficacy with nivolumab plus ipilimumab versus sunitinib in patients with advanced renal cell carcinoma.

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.

A Quality Improvement Initiative To Improve Postdischarge Antimicrobial Adherence.

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.

Faculty perceptions of student incivility in dental hygiene education.

PURPOSE/OBJECTIVE: Conflict and discourtesy between college students and faculty have become increasingly common in higher education. Fallout from uncivil student encounters can have numerous effects on educators' overall health and has been shown to negatively impact learning environments. This research assessed the severity and frequency of student incivility in dental hygiene education and explored the relationship uncivil behavior has on faculty feelings of confidence, career satisfaction, and longevity. METHODS: Cross-sectional survey research was conducted among dental hygiene educators (n = 601) in the United States and Canada using purposive and snowball sampling. The survey (47-item) was developed based on the literature and validated prior to administration. Spearman's correlation coefficient was used to assess the relationship between variables and mean item category scores and thematic analysis was used to identify themes for open-ended questions. RESULTS: Survey completion rate was 78% (n = 469). Behaviors ranked mildly uncivil, such as eating/drinking in class, occurred more frequently, and incivility had less impact on faculty confidence with increased age (r = -.19; P ≤ 0.01). The level of severity of behaviors did not impact educators; however, how often certain behaviors occurred had some effect. Contemptuous behaviors, such as using a disrespectful/sarcastic tone (r = .34, .32, .31; P ≤ 0.01), had the most impact. CONCLUSION: This study determined student incivility exists within dental hygiene education. Day-to-day, minor uncivil behaviors seemingly take a greater emotional toll than occasional, highly uncivil encounter. Understanding how faculty perceive these behaviors may influence development of management strategies, fostering a sense of career satisfaction for educators.

Urgent Care Transfers to an Academic Pediatric Emergency Department.

OBJECTIVES: The aim of this study was to investigate the hypothesis that a significant percentage of urgent care center to pediatric ED transfers can be discharged home without emergency department (ED) resource utilization. METHODS: A retrospective chart review was completed for a 6-month period on all patients transferred from urgent care centers. A data collection tool focusing on demographics, diagnoses, reason for transfer, ED resource utilization, ED disposition, and 72-hour ED return was used. Each encounter was classified as "urgent" or "nonurgent" based on resource utilization criteria. Descriptive statistics were reported for demographics, encounter data, and 72-hour ED return stratified by nonurgent versus urgent classification. Two-sample t, χ, and Fisher exact tests were used to assess differences in characteristics between the nonurgent and urgent groups. RESULTS: One hundred nine patients met inclusion criteria. Of these, 93 (85%) were discharged from the ED. Twenty nine (27%) of the transferred patients were discharged without ED resource utilization. Seventy-two-hour return was noted for only 1 patient who was again discharged at the subsequent encounter. CONCLUSIONS: A large proportion of patients transferred from urgent care centers were directly discharged from the ED without any ED resource utilization. Eliminating or reducing such transfers has the potential to limit the amount of nonurgent ED visits, thus producing cost savings and better patient care.

Structural and Functional Characterization of the LPS Transporter LptDE from Gram-Negative Pathogens.

Incorporation of lipopolysaccharide (LPS) into the outer membrane of Gram-negative bacteria is essential for viability, and is accomplished by a two-protein complex called LptDE. We solved crystal structures of the core LptDE complexes from Yersinia pestis, Klebsiella pneumoniae, Pseudomonas aeruginosa, and a full-length structure of the K. pneumoniae LptDE complex. Our structures adopt the same plug and 26-strand ß-barrel architecture found recently for the Shigella flexneri and Salmonella typhimurium LptDE structures, illustrating a conserved fold across the family. A comparison of the only two full-length structures, SfLptDE and our KpLptDE, reveals a 21° rotation of the LptD N-terminal domain that may impart flexibility on the trans-envelope LptCAD scaffold. Utilizing mutagenesis coupled to an in vivo functional assay and molecular dynamics simulations, we demonstrate the critical role of Pro231 and Pro246 in the function of the LptD lateral gate that allows partitioning of LPS into the outer membrane.

Impact of the 2009 influenza A (H1N1) pandemic on healthcare workers at a tertiary care center in New York City.

BACKGROUND AND OBJECTIVE: Assessing the impact of 2009 influenza A (H1N1) on healthcare workers (HCWs) is important for pandemic planning. METHODS: We retrospectively analyzed employee health records of HCWs at a tertiary care center in New York City with influenza-like illnesses (ILI) and confirmed influenza from March 31, 2009, to February 28, 2010. We evaluated HCWs' clinical presentations during the first and second wave of the pandemic, staff absenteeism, exposures among HCWs, and association between high-risk occupational exposures to respiratory secretions and infection. RESULTS: During the pandemic, 40% (141/352) of HCWs with ILI tested positive for influenza, representing a 1% attack rate among our 13,066 employees. HCWs with influenza were more likely to have fever, cough, and tachycardia. When compared with the second wave, cases in the first wave were sicker and at higher risk of exposure to patients' respiratory secretions (P=.049). HCWs with ILI--with and without confirmed influenza--missed on average 4.7 and 2.7 work days, respectively (P=.001). Among HCWs asked about working while ill, 65% (153/235) reported they did so (mean, 2 days). CONCLUSIONS: HCWs in the first wave had more severe ILI than those in the second wave and were more likely to be exposed to patients' respiratory secretions. HCWs with ILI often worked while ill. Timely strategies to educate and support HCWs were critical to managing this population during the pandemic.

Structural basis of functional group activation by sulfotransferases in complex metabolic pathways.

Sulfated molecules with diverse functions are common in biology, but sulfonation as a method to activate a metabolite for chemical catalysis is rare. Catalytic activity was characterized and crystal structures were determined for two such "activating" sulfotransferases (STs) that sulfonate ß-hydroxyacyl thioester substrates. The CurM polyketide synthase (PKS) ST domain from the curacin A biosynthetic pathway of Moorea producens and the olefin synthase (OLS) ST from a hydrocarbon-producing system of Synechococcus PCC 7002 both occur as a unique acyl carrier protein (ACP), ST, and thioesterase (TE) tridomain within a larger polypeptide. During pathway termination, these cyanobacterial systems introduce a terminal double bond into the ß-hydroxyacyl-ACP-linked substrate by the combined action of the ST and TE. Under in vitro conditions, CurM PKS ST and OLS ST acted on ß-hydroxy fatty acyl-ACP substrates; however, OLS ST was not reactive toward analogues of the natural PKS ST substrate bearing a C5-methoxy substituent. The crystal structures of CurM ST and OLS ST revealed that they are members of a distinct protein family relative to other prokaryotic and eukaryotic sulfotransferases. A common binding site for the sulfonate donor 3'-phosphoadenosine-5'-phosphosulfate was visualized in complexes with the product 3'-phosphoadenosine-5'-phosphate. Critical functions for several conserved amino acids in the active site were confirmed by site-directed mutagenesis, including a proposed glutamate catalytic base. A dynamic active-site flap unique to the "activating" ST family affects substrate selectivity and product formation, based on the activities of chimeras of the PKS and OLS STs with exchanged active-site flaps.

Managing risks of violence in a youth mental health service: a service model description.

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.

Single-dose effects of isosorbide mononitrate alone or in combination with losartan on central blood pressure.

Antihypertensive drugs can have different effects on central and brachial blood pressures, which may affect outcomes. Nitric oxide donors have acute effects on central blood pressure but have not been assessed with renin-angiotensin system blockade. Thirteen patients with prehypertensive/Stage 1 hypertension were randomized to five single-dose treatments separated by ≤4 days using a double-blind, crossover study design: angiotensin receptor blocker (ARB) losartan 100 mg, isosorbide mononitrate (ISMN) 60 mg, losartan 100 mg + ISMN 15 mg, losartan 100 mg + ISMN 60 mg, and placebo. Central and brachial blood pressures were measured throughout 10 hours. Mean placebo-subtracted decrease from baseline in augmentation index (AIx) approximately 1% for losartan 100 mg, 26% for ISMN 60 mg, 19% for losartan 100 mg + ISMN 15 mg, and 24% for losartan 100 mg + ISMN 60 mg. Administered with losartan 100 mg or alone, ISMN lowered AIx, demonstrating that acute effects of a nitrate donor are much larger than those of an ARB even when administered with an ARB. Differences from placebo were statistically significant except for losartan 100 mg. AIx is a good biomarker of acute hemodynamic effects of nitric oxide in prehypertensive/Stage 1 hypertension.

Dog colonoscopy model for predicting human colon absorption.

PURPOSE: This study was conducted to develop and validate a dog colon model that predicts colon permeability in humans. METHODS: The following compounds were studied: Class 1 highly soluble (HS)/highly permeable (HP): aminophylline, propranolol, CP-409092; Class 2 LS/HP: nifedipine; trovafloxacin, sertraline; Class 3 HS/LP: azithromycin, atenolol, CP-331684, CP-424391; Class 4 LS/LP: CJ-13610. Administration to dogs was made 30 cm cranial to the anal sphincter with a lubricated Schott Model VFS-5 flexible endoscope. The bioavailability of the compound following the colon administration in dogs, relative to the same formulation administered orally (relative bioavailability), was determined. RESULTS: Except for atenolol, a small hydrophillic molecule, the relative bioavailability from administration to the colon of the dog correlated well with the following compound properties: high solubility and high, passive permeability > high solubility, low permeability > low solubility, high, passive permeability approximately low solubility, low permeability. CONCLUSION: The dog colon model is proposed as a surrogate for human intubation studies when the controlled release candidate falls in BCS Classes 2 (LS/HP), 3 (HS/LP), and 4 (LS/LP). However, no human intubation or dog colon studies are required for Class 1 (HS/HP), as these compounds are likely to be well absorbed from the colon.

The significance of autonomy in the nursing home administrator profession: a qualitative study.

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.

Genetic evidence for convergence of c-Kit- and alpha4 integrin-mediated signals on class IA PI-3kinase and the Rac pathway in regulating integrin-directed migration in mast cells.

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 alpha4 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 alpha4- 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 p85alpha 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 alpha4 integrin signaling are linked to class IA PI-3kinase and Rac pathways and regulate integrin-directed (haptotactic) migration in mast cells.

Thrombopoietin promotes mixed lineage and megakaryocytic colony-forming cell growth but inhibits primitive and definitive erythropoiesis in cells isolated from early murine yolk sacs.

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.

Lymphoproliferative defects in mice lacking the expression of neurofibromin: functional and biochemical consequences of Nf1 deficiency in T-cell development and function.

Ras plays an essential role in lymphocyte development and function. However, in vivo consequence(s) of regulation of Ras activity by guanosine triphosphatase (GTPase)-activating proteins (GAPs) on lymphocyte development and function are not known. In this study we demonstrate that neurofibromin, the protein encoded by the NF1 tumor suppressor gene functions as a GAP for Ras in T cells. Loss of Nf1 in T cells results in enhanced Ras activation, which is associated with thymic and splenic hyperplasia, and an increase in the absolute number of immature and mature T-cell subsets compared with control mice. Interestingly, in spite of a profound T-cell expansion and higher thymidine incorporation in unstimulated Nf1-deficient T cells, T-cell receptor and interleukin-2 receptor-mediated proliferation of thymocytes and mature T cells was substantially reduced compared with control mice. Collectively, these results identify neurofibromin as a GAP for Ras in T cells for maintaining immune homeostasis in vivo.

Role of p38 and ERK MAP kinase in proliferation of erythroid progenitors in response to stimulation by soluble and membrane isoforms of stem cell factor.

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.