Detection of Subclinical Rejection in Pediatric Kidney Transplantation: Current and Future Practices.

INTRODUCTION: The successes in the field of pediatric kidney transplantation over the past 60 years have been extraordinary. Year over year, there have been significant improvements in short-term graft survival. However, improvements in longer-term outcomes have been much less apparent. One important contributor has been the phenomenon of low-level rejection in the absence of clinical manifestations-so-called subclinical rejection (SCR). METHODS: Traditionally, rejection has been diagnosed by changes in clinical parameters, including but not limited to serum creatinine and proteinuria. This review examines the shortcomings of this approach, the effects of SCR on kidney allograft outcome, the benefits and drawbacks of surveillance biopsies to identify SCR, and new urine and blood biomarkers that define the presence or absence of SCR. RESULTS: Serum creatinine is an unreliable index of SCR. Surveillance biopsies are the method most utilized to detect SCR. However, these have significant drawbacks. New biomarkers show promise. These biomarkers include blood gene expression profiles and donor derived-cell free DNA; urine gene expression profiles; urinary cytokines, chemokines, and metabolomics; and other promising blood and urine tests. CONCLUSION: Specific emphasis is placed on studies carried out in pediatric kidney transplant recipients. TRIAL REGISTRATION: ClinicalTrials.gov: NCT03719339.

Clinical Value of Peripheral Blood Gene Expression Profile and dd-cfDNA for Identifying Persistent Rejection.

BACKGROUND: Persistent rejection is an increasingly recognized barrier to long-term kidney allograft survival. A noninvasive method to help identify patients with persistent rejection in need of biopsy would be valuable. METHODS: This was a post-hoc analysis of a multicenter observational study. Subjects that had a biopsy-proven acute rejection and had another biopsy within 9 months (270 days) and had a biopsy-paired biomarker sample were included. RESULTS: A total of 64 "index" rejections in 58 subjects with repeat biopsies were identified with a median time to repeat biopsy of 100 days. Persistent rejection was present in 61%; 69% of follow-up biopsies were performed in clinically stable patients. Peripheral blood gene expression profile (GEP) demonstrated 59% sensitivity, 76% specificity, PPV of 79%, and NPV of 54%. Donor-derived cell-free DNA (dd-cfDNA) demonstrated sensitivity of 62%, specificity of 86%, PPV of 88%, and NPV of 56%. For repeat biopsies within 90 days of rejection in clinically stable patients (63% of repeat biopsies), both GEP and dd-cfDNA had specificities and PPVs of 100%. GEP was more likely to be positive in TCMR, while dd-cfDNA was more likely to be positive in AMR. CONCLUSIONS: Both GEP and dd-cfDNA may have utility at identifying clinically stable patients with persistent rejection in need of biopsy, however they identify different types of rejection.

Multiple abnormal peripheral blood gene expression assay results are correlated with subsequent graft loss after kidney transplantation.

BACKGROUND: The aim of this study was to correlate peripheral blood gene expression profile (GEP) results during the first post-transplant year with outcomes after kidney transplantation. METHODS: We conducted a prospective, multicenter observational study of obtaining peripheral blood at five timepoints during the first post-transplant year to perform a GEP assay. The cohort was stratified based on the pattern of the peripheral blood GEP results: Tx-all GEP results normal, 1 Not-TX had one GEP result abnormal and >1 Not-TX two or more abnormal GEP results. We correlated the GEP results with outcomes after transplantation. RESULTS: We enrolled 240 kidney transplant recipients. The cohort was stratified into the three groups: TX n = 117 (47%), 1 Not-TX n = 59 (25%) and >1 Not-TX n = 64 (27%). Compared to the TX group, the >1 Not-TX group had lower eGFR (p < .001) and more chronic changes on 1-year surveillance biopsy (p = .007). Death censored graft survival showed inferior graft survival in the >1 Not-TX group (p < .001) but not in the 1 Not-TX group. All graft losses in the >1 Not-TX group occurred after 1-year post-transplant. CONCLUSIONS: We conclude that a pattern of persistently Not-TX GEP assay correlates with inferior graft survival.

A behavioral and modeling study of control algorithms underlying the translational optomotor response in larval zebrafish with implications for neural circuit function.

The optomotor response (OMR) is central to the locomotory behavior in diverse animal species including insects, fish and mammals. Furthermore, the study of the OMR in larval zebrafish has become a key model system for investigating the neural basis of sensorimotor control. However, a comprehensive understanding of the underlying control algorithms is still outstanding. In fish it is often assumed that the OMR, by reducing average optic flow across the retina, serves to stabilize position with respect to the ground. Yet the degree to which this is achieved, and how it could emerge from the intermittent burst dynamics of larval zebrafish swimming, are unclear. Here, we combine detailed computational modeling with a new approach to free-swimming experiments in which we control the amount of visual feedback produced by a given motor effort by varying the height of the larva above a moving grid stimulus. We develop an account of underlying feedback control mechanisms that describes both the bout initiation process and the control of swim speed during bouts. We observe that the degree to which fish stabilize their position is only partial and height-dependent, raising questions about its function. We find the relative speed profile during bouts follows a fixed temporal pattern independent of absolute bout speed, suggesting that bout speed and bout termination are not separately controlled. We also find that the reverse optic flow, experienced when the fish is swimming faster than the stimulus, plays a minimal role in control of the OMR despite carrying most of the sensory information about self-movement. These results shed new light on the underlying dynamics of the OMR in larval zebrafish and will be crucial for future work aimed at identifying the neural basis of this behavior.

Combining Blood Gene Expression and Cellfree DNA to Diagnose Subclinical Rejection in Kidney Transplant Recipients.

BACKGROUND AND OBJECTIVES: Subclinical acute rejection is associated with poor outcomes in kidney transplant recipients. As an alternative to surveillance biopsies, noninvasive screening has been established with a blood gene expression profile. Donor-derived cellfree DNA (cfDNA) has been used to detect rejection in patients with allograft dysfunction but not tested extensively in stable patients. We hypothesized that we could complement noninvasive diagnostic performance for subclinical rejection by combining a donor-derived cfDNA and a gene expression profile assay. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We performed a post hoc analysis of simultaneous blood gene expression profile and donor-derived cfDNA assays in 428 samples paired with surveillance biopsies from 208 subjects enrolled in an observational clinical trial (Clinical Trials in Organ Transplantation-08). Assay results were analyzed as binary variables, and then, their continuous scores were combined using logistic regression. The performance of each assay alone and in combination was compared. RESULTS: For diagnosing subclinical rejection, the gene expression profile demonstrated a negative predictive value of 82%, a positive predictive value of 47%, a balanced accuracy of 64%, and an area under the receiver operating curve of 0.75. The donor-derived cfDNA assay showed similar negative predictive value (84%), positive predictive value (56%), balanced accuracy (68%), and area under the receiver operating curve (0.72). When both assays were negative, negative predictive value increased to 88%. When both assays were positive, positive predictive value increased to 81%. Combining assays using multivariable logistic regression, area under the receiver operating curve was 0.81, significantly higher than the gene expression profile (P<0.001) or donor-derived cfDNA alone (P=0.006). Notably, when cases were separated on the basis of rejection type, the gene expression profile was significantly better at detecting cellular rejection (area under the receiver operating curve, 0.80 versus 0.62; P=0.001), whereas the donor-derived cfDNA was significantly better at detecting antibody-mediated rejection (area under the receiver operating curve, 0.84 versus 0.71; P=0.003). CONCLUSIONS: A combination of blood-based biomarkers can improve detection and provide less invasive monitoring for subclinical rejection. In this study, the gene expression profile detected more cellular rejection, whereas donor-derived cfDNA detected more antibody-mediated rejection.

Efficacy and safety of bleselumab in kidney transplant recipients: A phase 2, randomized, open-label, noninferiority study.

This study assessed the efficacy and safety of the anti-CD40 monoclonal antibody bleselumab (ASKP1240) in de novo kidney transplant recipients over 36 months posttransplant. Transplant recipients were randomized (1:1:1) to standard of care (SoC: 0.1 mg/kg per day immediate-release tacrolimus [IR-TAC]; target minimum blood concentration [Ctrough ] 4-11 ng/mL plus 1 g mycophenolate mofetil [MMF] twice daily) or bleselumab (200 mg on days 0/7/14/28/42/56/70/90, and monthly thereafter) plus either MMF or IR-TAC (0.1 mg/kg per day; target Ctrough 4-11 ng/mL days 0-30, then 2-5 ng/mL). All received basiliximab induction (20 mg pretransplant and on days 3-5 posttransplant) and corticosteroids. One hundred thirty-eight transplant recipients received ≥1 dose of study drug (SoC [n = 48]; bleselumab + MMF [n = 46]; bleselumab + IR-TAC [n = 44]). For the primary endpoint (incidence of biopsy-proven acute rejection [BPAR] at 6 months), bleselumab + IR-TAC was noninferior to SoC (difference 2.8%; 95% confidence interval [CI] -8.1% to 13.8%), and bleselumab + MMF did not demonstrate noninferiority to SoC (difference 30.7%; 95% CI 15.2%-46.2%). BPAR incidence slightly increased through month 36 in all groups, with bleselumab + IR-TAC continuing to demonstrate noninferiority to SoC. Bleselumab had a favorable benefit-risk ratio. Most treatment-emergent adverse events were as expected for kidney transplant recipients (ClinicalTrials.gov NCT01780844).

A randomized, phase 1b study of the pharmacokinetics, pharmacodynamics, safety, and tolerability of bleselumab, a fully human, anti-CD40 monoclonal antibody, in kidney transplantation.

This study evaluated the safety, tolerability, pharmacokinetics, and pharmacodynamics of various doses of the anti-CD40 monoclonal antibody bleselumab (ASKP1240) in de novo kidney transplant recipients receiving concomitant standard immunosuppression over 90 days posttransplant. Transplant recipients were randomized (1:1:1:1:1) to bleselumab 50 mg, 100 mg, 200 mg, or 500 mg, or placebo, in addition to standard maintenance immunosuppression. The primary pharmacokinetic endpoints were AUCinf , Cmax , and AUClast . The primary pharmacodynamic endpoint was B cell CD40 receptor occupancy over time. Overall, 50 kidney transplant recipients were randomized; 45 received their randomized treatment (bleselumab [n = 37] or placebo [n = 8]). AUCinf and AUClast demonstrated a more than dose-proportional increase in the range of 50-500 mg, and Cmax increased linearly with increasing dose. Maximal receptor occupancy for B cell CD40 was reached at all dose levels and was prolonged as dose increased. No kidney transplant recipients experienced cytokine release syndrome or a thromboembolic event. Treatment-emergent anti-bleselumab antibodies were found in one kidney transplant recipient in the bleselumab 50 mg group; these were detected only at Day 7. Overall, bleselumab demonstrated nonlinear pharmacokinetics and dose-dependent prolonged B cell CD40 receptor occupancy and was well tolerated at all doses (ClinicalTrials.gov: NCT01279538).

Imbalanced sphingolipid signaling is maintained as a core proponent of a cancerous phenotype in spite of metabolic pressure and epigenetic drift.

Tumor heterogeneity may arise through genetic drift and environmentally driven clonal selection for metabolic fitness. This would promote subpopulations derived from single cancer cells that exhibit distinct phenotypes while conserving vital pro-survival pathways. We aimed to identify significant drivers of cell fitness in pancreatic adenocarcinoma (PDAC) creating subclones in different nutrient formulations to encourage differential metabolic reprogramming. The genetic and phenotypic expression profiles of each subclone were analyzed relative to a healthy control cell line (hTert-HPNE). The subclones exhibited distinct variations in protein expression and lipid metabolism. Relative to hTert-HPNE, PSN-1 subclones uniformly maintained modified sphingolipid signaling and specifically retained elevated sphingosine-1-phosphate (S1P) relative to C16 ceramide (C16 Cer) ratios. Each clone utilized a different perturbation to this pathway, but maintained this modified signaling to preserve cancerous phenotypes, such as rapid proliferation and defense against mitochondria-mediated apoptosis. Although the subclones were unique in their sensitivity, inhibition of S1P synthesis significantly reduced the ratio of S1P/C16 Cer, slowed cell proliferation, and enhanced sensitivity to apoptotic signals. This reliance on S1P signaling identifies this pathway as a promising drug-sensitizing target that may be used to eliminate cancerous cells consistently across uniquely reprogrammed PDAC clones.

Chemistry Has No Nationality.

"… Our job is to make absolutely sure that the needs of science are made very clear to government, and are emphasised again and again and again. Because I really believe that strong science benefits everyone. It's not just scientists who benefit: we all benefit from scientific discoveries, and a country with a strong base in science will have a strong knowledge economy …" Read more in the Editorial by Sir John Holman and Edwin Silvester.

Psychometric Properties of Patient-Facing eHealth Evaluation Measures: Systematic Review and Analysis.

BACKGROUND: Significant resources are being invested into eHealth technology to improve health care. Few resources have focused on evaluating the impact of use on patient outcomes A standardized set of metrics used across health systems and research will enable aggregation of data to inform improved implementation, clinical practice, and ultimately health outcomes associated with use of patient-facing eHealth technologies. OBJECTIVE: The objective of this project was to conduct a systematic review to (1) identify existing instruments for eHealth research and implementation evaluation from the patient's point of view, (2) characterize measurement components, and (3) assess psychometrics. METHODS: Concepts from existing models and published studies of technology use and adoption were identified and used to inform a search strategy. Search terms were broadly categorized as platforms (eg, email), measurement (eg, survey), function/information use (eg, self-management), health care occupations (eg, nurse), and eHealth/telemedicine (eg, mHealth). A computerized database search was conducted through June 2014. Included articles (1) described development of an instrument, or (2) used an instrument that could be traced back to its original publication, or (3) modified an instrument, and (4) with full text in English language, and (5) focused on the patient perspective on technology, including patient preferences and satisfaction, engagement with technology, usability, competency and fluency with technology, computer literacy, and trust in and acceptance of technology. The review was limited to instruments that reported at least one psychometric property. Excluded were investigator-developed measures, disease-specific assessments delivered via technology or telephone (eg, a cancer-coping measure delivered via computer survey), and measures focused primarily on clinician use (eg, the electronic health record). RESULTS: The search strategy yielded 47,320 articles. Following elimination of duplicates and non-English language publications (n=14,550) and books (n=27), another 31,647 articles were excluded through review of titles. Following a review of the abstracts of the remaining 1096 articles, 68 were retained for full-text review. Of these, 16 described an instrument and six used an instrument; one instrument was drawn from the GEM database, resulting in 23 articles for inclusion. None included a complete psychometric evaluation. The most frequently assessed property was internal consistency (21/23, 91%). Testing for aspects of validity ranged from 48% (11/23) to 78% (18/23). Approximately half (13/23, 57%) reported how to score the instrument. Only six (26%) assessed the readability of the instrument for end users, although all the measures rely on self-report. CONCLUSIONS: Although most measures identified in this review were published after the year 2000, rapidly changing technology makes instrument development challenging. Platform-agnostic measures need to be developed that focus on concepts important for use of any type of eHealth innovation. At present, there are important gaps in the availability of psychometrically sound measures to evaluate eHealth technologies.

Implementing smoking cessation guidelines for hospitalized Veterans: Cessation results from the VA-BEST trial.

PURPOSE: To examine the impact of a nurse-initiated tobacco cessation intervention focused on providing guideline-recommended care to hospitalized smokers. DESIGN: Pre-post quasi-experimental trial. SETTING: General medical units of four US Department of Veterans Affairs hospitals. SUBJECTS: 898 adult Veteran smokers (503 and 395 were enrolled in the baseline and intervention periods, respectively). INTERVENTION: The intervention included academic detailing, adaptation of the computerized medical record, patient self-management support, and organizational support and feedback. MEASURES: The primary outcome was self-reported 7-day point prevalence abstinence at six months. ANALYSIS: Tobacco use was compared for the pre-intervention and intervention periods with multivariable logistic regression using generalized estimating equations to account for clustering at the nurse level. Predictors of abstinence at six months were investigated with best subsets regression. RESULTS: Seven-day point prevalence abstinence during the intervention period did not differ significantly from the pre-intervention period at either three (adjusted odds ratio (AOR) and 95% confidence interval (CI95)=0.78 [0.51-1.18]) or six months (AOR=0.92; CI95=0.62-1.37). Predictors of abstinence included baseline self-efficacy for refraining from smoking when experiencing negative affect (p=0.0004) and perceived likelihood of staying off cigarettes following discharge (p<0.0001). CONCLUSIONS: Tobacco use interventions in the VA inpatient setting likely require more substantial changes in clinician behavior and enhanced post-discharge follow-up to improve cessation outcomes.

Pharmacokinetics, Pharmacodynamics, and Safety of ASP015K (Peficitinib), a New Janus Kinase Inhibitor, in Healthy Subjects.

Two randomized, double-blind, placebo-controlled studies are reported that had the objective to evaluate the pharmacokinetics, pharmacodynamics, and safety of ASP015K (peficitinib), a Janus kinase (JAK) inhibitor, in healthy subjects. The single-dose study included 7 male groups (3-300 mg) and 2 female groups (30 or 200 mg), n = 8/group (6 on ASP015K and 2 on placebo in each group). The multiple-dose study included 1 female and 3 male groups, n = 12/group (9 on ASP015K and 3 on placebo in each group), who received ASP015K (30 mg) or placebo every 12 hours (twice a day) for 14 days. In the single-dose study, plasma ASP015K concentration increased dose-proportionally. Food increased ASP015K exposure (AUCinf ) by 27%. Mean peak JAK inhibition increased with dose, from 6% at 4 hours (median) following ASP015K 3 mg to 93% (range, 89%-98%) at 2 hours (median) after ASP015K 300 mg. In the multiple-dose study, ASP015K plasma exposure reached steady state by day 3. On day 14, mean ASP015K peak concentration was 38%-65% higher than after the first dose; peak JAK inhibition following 100 or 200 mg twice daily was >85%. The most common adverse events (AEs) were neutropenia, headache, and abdominal pain; no serious AEs occurred. The safety findings at pharmacologically effective doses of ASP015K support further clinical development.

"Let Me Get You a Nicotine Patch": Nurses' Perceptions of Implementing Smoking Cessation Guidelines for Hospitalized Veterans.

Many hospitalized smokers do not receive guideline-recommended tobacco treatment, but little is known about the perceptions of inpatient nurses with regard to tobacco treatment. We used a sequential explanatory mixed methods design to help explain the findings of an academic detailing intervention trial on the inpatient medicine units of four Veterans Affairs (VA) hospitals. We surveyed 164 nurses and conducted semistructured interviews in a purposeful sample of 33 nurses with different attitudes toward cessation counseling. Content analysis was used to inductively characterize the issues raised by participants. Emerging themes were categorized using the knowledge-attitudes-behavior framework of guideline adherence. Knowledge-related and attitudinal barriers included perceived lack of skills in cessation counseling and skepticism about the effectiveness of cessation guidelines in hospitalized veterans. Nurses also reported multiple behavioral and organizational barriers to guideline adherence: resistance from patients, insufficient time and resources, the presence of smoking areas on VA premises, and lack of coordination with primary care. VA hospitals should train inpatient staff how to negotiate behavior change, integrate cessation counseling into nurses' workflow, develop alternative referral mechanisms for post-discharge cessation counseling, and adopt hospital policies to promote inpatient abstinence.

Assessment of tacrolimus absorption from the human intestinal tract: open-label, randomized, 4-way crossover study.

BACKGROUND: Tacrolimus is an established immunosuppressant used for the prevention and treatment of allograft rejection in solid organ transplantation. An immediate-release oral formulation of tacrolimus has been commercially available since 1994 that is administered orally BID. To improve the compliance and quality of life of transplant patients, a once-daily modified release (MR) formulation is an attractive option. However, to be successful, the drug of interest must be sufficiently well absorbed from the distal region of the gastrointestinal tract. OBJECTIVE: To facilitate the development of an MR formulation, we investigated the absorption of tacrolimus from different regions of the human gastrointestinal tract, proximal and distal small bowels, and ascending colon. METHODS: The study was performed as an open-label, randomized, 4-way crossover design in 6 healthy white male subjects. For each subject, 1 mg (2 mg/mL) of tacrolimus solution in polyethylene glycol 400 was administered to each location in the gastrointestinal tract via a site-specific radiolabeled delivery capsule, which can release tacrolimus solution at specific sites of the gastrointestinal tract. Real-time visualization of capsule location and tacrolimus release at each target site was performed by using γ-scintigraphy. Blood samples were collected to determine tacrolimus levels in the blood. The pharmacokinetic parameters Cmax, Tmax after the capsule activation, AUC0-24, and mean residence time were determined from the concentration-time profiles. RESULTS: Ten healthy male subjects underwent dosing. Six subjects completed all 4 treatments. Three adverse events (mild headache [n = 1], small amount of blood in stool [n = 1], and mild syncopal episode [n = 1]) that were possibly study drug related were reported in 3 different subjects. Tacrolimus was absorbed from not only the small intestine but also from the colonic region of the gastrointestinal tract. Although AUC0-24 values revealed some site-specific absorption tendencies, the mean AUC0-24 values obtained were similar regardless of the location of tacrolimus release from the capsule. CONCLUSIONS: Tacrolimus was absorbed from the duodenum to the colon in these male subjects, although differences were observed in the value of AUC0-24, possibly due to variation in cytochrome P450 3A4 activity in the intestine. Although this study was conducted in small group of healthy fasting men, the present results indicate that tacrolimus is suitable for MR formulation development due to a wide absorption window throughout the intestine in humans.

Long-term follow-up of a phase III clinical trial comparing tacrolimus extended-release/MMF, tacrolimus/MMF, and cyclosporine/MMF in de novo kidney transplant recipients.

BACKGROUND: In a phase III, open-label, comparative, noninferiority study, 638 subjects receiving de novo kidney transplants were randomized to one of three treatment arms: tacrolimus extended-release (Astagraf XL) qd, tacrolimus (Prograf) bid, or cyclosporine (CsA) bid. All subjects received basiliximab induction, mycophenolate mofetil, and corticosteroids. Safety and efficacy follow-up data through 4 years are reported. METHODS: Evaluations included patient and graft survival, study drug discontinuations, laboratory values including renal function and development of new-onset diabetes after transplantation, concomitant medications, and adverse events. RESULTS: At study termination, 129 Astagraf XL, 113 Prograf, and 79 CsA patients had continued follow-up. Demographic and baseline characteristics were similar in all arms. Four-year Kaplan-Meier estimates of patient survival in the Astagraf XL, Prograf, and CsA groups were 93.2, 91.2, and 91.7%, respectively, while graft survival was 84.7, 82.7, and 83.9%, respectively. At least one serious adverse event was reported in the majority of patients in each group during the study (65.9% Astagraf XL, 69.8% Prograf, and 65.6% CsA). Renal function was not significantly different between Astagraf XL and Prograf. HgbA1c levels were collected every 6 months; the 4-year Kaplan-Meier estimate for incidence of HgbA1c levels ≥ 6.5% was significantly higher for both tacrolimus formulations compared to CsA; 41.1% (Astagraf XL), 33.6% (Prograf), and 21.3% (CsA). CONCLUSIONS: In this 4-year follow-up report, patients receiving Astagraf XL and Prograf showed comparable efficacy and safety profiles, with a higher incidence of new-onset diabetes after transplantation but superior renal function compared to patients receiving CsA.

Implementation of smoking cessation guidelines in the emergency department: a qualitative study of staff perceptions.

BACKGROUND: The US Public Health Service smoking cessation practice guideline specifically recommends that physicians and nurses strongly advise their patients who use tobacco to quit, but the best approach for attaining this goal in the emergency department (ED) remains unknown. The aim of this study was to characterize emergency physicians' (EPs) and nurses' (ENs) perceptions of cessation counseling and to identify barriers and facilitators to implementation of the 5 A's framework (Ask-Advise-Assess-Assist-Arrange) in the ED. METHODS: We conducted semi-structured, face-to-face interviews of 11 EPs and 19 ENs following a pre-post implementation trial of smoking cessation guidelines in two study EDs. We used purposeful sampling to target EPs and ENs with different attitudes toward cessation counseling, based on their responses to a written survey (Decisional Balance Questionnaire). Conventional content analysis was used to inductively characterize the issues raised by study participants and to construct a coding structure, which was then applied to study transcripts. RESULTS: The main findings of this study converged upon three overarching domains: 1) reactions to the intervention; 2) perceptions of patients' receptivity to cessation counseling; and 3) perspectives on ED cessation counseling and preventive care. ED staff expressed ambivalence toward the implementation of smoking cessation guidelines. Both ENs and EPs agreed that the delivery of smoking cessation counseling is important, but that it is not always practical in the ED on account of time constraints, the competing demands of acute care, and resistance from patients. Participants also called attention to the need for improved role clarity and teamwork when implementing the 5 A's in the ED. CONCLUSIONS: There are numerous challenges to the implementation of smoking cessation guidelines in the ED. ENs are generally willing to take the lead in offering brief cessation counseling, but their efforts need to be reinforced by EPs. ED systems need to address workflow, teamwork, and practice policies that facilitate prescription of smoking cessation medication, referral for cessation counseling, and follow-up in primary care. The results of this qualitative evaluation can be used to guide the design of future ED intervention studies. TRIAL REGISTRATION: ClinicalTrials.gov registration number NCT00756704.

Implementing Best Evidence in Smoking Cessation Treatment for Hospitalized Veterans: Results from the VA-BEST Trial.

BACKGROUND: Although the US Department of Veterans Affairs (VA) has promoted adherence to smoking cessation guidelines since 1997, hospitalized smokers do not consistently receive assistance in quitting. METHODS: In a pre-post guideline implementation trial on the inpatient medicine units of four VA hospitals, the effectiveness of a multimodal intervention (enhanced academic detailing, modification of the nursing admission template, patient education materials and quitline referral, practice facilitation and staff feedback) changing practice behavior was evaluated. Peridischarge interviews were conducted with 824 patients to assess receipt of nurses' and physicians' delivery of the 5A's (Ask, Advise, Assess, Assist, Arrange) in hospitalized smokers. RESULTS: Subjects were significantly more likely to have received each of the 5A's from a nurse during the postimplementation period (except for "advise to quit"). More patients were assisted in quitting (75% versus 56%, adjusted odds ratio [OR] = 2.3, 95% confidence interval [CI] = 1.6, 3.1) and had follow-up arranged (23% versus 18%, adjusted OR = 1.5, 95% CI = 1.0, 2.2) by a nurse during the postimplementation period. However, unadjusted results showed no improvement in seven-day point prevalence abstinence at six-month follow-up (13.5% versus 13.9%). Nurses' self-efficacy in cessation counseling, as measured in a survey of 166 unit nurses, improved following guideline implementation. DISCUSSION: A multifaceted intervention including enhanced academic detailing is an effective strategy for improving the delivery of smoking cessation services in medical inpatients. To promote long-term cessation, more intensive interventions are needed to ensure that motivated smokers receive guideline-recommended treatment (including pharmacotherapy and referral to outpatient cessation counseling).

Implementing smoking cessation guidelines for hospitalized veterans: effects on nurse attitudes and performance.

BACKGROUND: A minority of hospitalized smokers actually receives assistance in quitting during hospitalization or cessation counseling following discharge. This study aims to determine the impact of a guideline-based intervention on 1) nurses' delivery of the 5A's (Ask-Advise-Assess-Assist-Arrange follow-up) in hospitalized smokers, and 2) nurses' attitudes toward the intervention. METHODS: We conducted a pre-post guideline implementation trial involving 205 hospitalized smokers on the inpatient medicine units at one US Department of Veterans Affairs (VA) medical center. The intervention included: 1) academic detailing of nurses on delivery of brief cessation counseling, 2) modification of the admission form to facilitate 5A's documentation, and 3) referral of motivated inpatients to receive proactive telephone counseling. Based on subject interviews, we calculated a nursing 5A's composite score for each patient (ranging from 0 to 9). We used linear regression with generalized estimating equations to compare the 5A's composite score (and logistic regression to compare individual A's) across periods. We compared 29 nurses' ratings of their self-efficacy and decisional balance ("pros" and "cons") with regard to cessation counseling before and after guideline implementation. Following implementation, we also interviewed a purposeful sample of nurses to assess their attitudes toward the intervention. RESULTS: Of 193 smokers who completed the pre-discharge interview, the mean nursing 5A's composite score was higher after guideline implementation (3.9 vs. 3.1, adjusted difference 1.0, 95 % CI 0.5-1.6). More patients were advised to quit (62 vs. 48 %, adjusted OR = 2.1, 95 % CI = 1.2-3.5) and were assisted in quitting (70 vs. 45 %, adjusted OR = 2.9, 95 % CI = 1.6-5.3) by a nurse during the post-implementation period. Nurses' attitudes toward cessation counseling improved following guideline implementation (35.3 vs. 32.7 on "pros" subscale, p = 0.01), without significant change on the "cons" subscale. CONCLUSIONS: A multifaceted intervention including academic detailing and adaptation of the nursing admission template is an effective strategy for improving nurses' delivery of brief cessation counseling in medical inpatients.

New-onset diabetes after transplantation (NODAT): an evaluation of definitions in clinical trials.

BACKGROUND: New-onset diabetes after transplantation (NODAT) occurs commonly. Prior NODAT definitions have been inconsistent. Based on the American Diabetic Association criteria, we propose a new approach to defining NODAT. METHODS: Analysis of 1416 at-risk transplant recipients was performed. Data from three de novo Astellas registration transplant studies (two kidney and one liver) evaluated NODAT in 634 at-risk patients receiving tacrolimus, 630 at-risk patients receiving tacrolimus extended release, and 152 at-risk patients receiving cyclosporine. NODAT was defined as a composite endpoint consisting of first occurrence of one of four parameters: (i) two fasting plasma glucose levels ≥ 126 mg/dL (≥ 7.0 mmol/L) ≥ 30 days apart, (ii) oral hypoglycemic agent use for ≥ 30 consecutive days, (iii) insulin therapy for ≥ 30 consecutive days, and (iv) hemoglobin A1c ≥ 6.5%. We evaluated each of the above parameters, as well as the composite endpoint, in an attempt to establish an appropriate clinical approach to the diagnosis of NODAT. RESULTS: The composite definition results in a 1-year NODAT incidence of 30% to 37% in kidney and 44% to 45% in liver transplant recipients treated with tacrolimus. NODAT incidence was significantly higher with tacrolimus than cyclosporine; there was no difference between the two tacrolimus formulations. CONCLUSIONS: Based on these analyses, the proposed composite definition for NODAT, incorporating broader criteria, is recommended for clinical trials. Appropriate definitions of NODAT allow for a better understanding of the incidence of this complication and may result in earlier initiation of therapy with improved long-term outcomes.

Acute rejection characteristics from a prospective, randomized, double-blind, placebo-controlled multicenter trial of early corticosteroid withdrawal.

BACKGROUND: This report characterizes acute rejection and rejection outcomes in subjects randomized to continuous corticosteroid therapy (CCS) or early corticosteroid withdrawal (CSWD; 7 days after transplantation) in the Astellas Blinded CSWD Trial. METHODS: The Astellas Blinded CSWD Trial was a 5-year, prospective, multicenter, randomized, double-blind trial of early CCS withdrawal in 386 kidney transplant recipients (195 CCS and 191 CSWD). Tacrolimus and mycophenolate mofetil were required as well as either rabbit antithymocyte globulin or interleukin-2 receptor antibody induction. Biopsy-confirmed acute rejection (BCAR) was grade 1A or higher by Banff criteria. This report also provides borderline changes (BL) that did not meet Banff grade 1A included with BCAR (BCAR+BL). RESULTS: BCAR+BL was 25 (12.8%) in CCS group and 42 (22.0%) in CSWD group (P=0.022). Early BCAR+BL (first 90 days after transplantation) was less frequent in CCS (n=5 [2.6%]) than in CSWD (n=22 [11.5%]; P<0.001). Among non-African-American subjects, early BCAR+BL occurred more often in CSWD (n=20 [12.7%]) versus CCS (n=2 [1.3%]; P<0.001). Late acute rejection (>2 years) occurred more often in African-American subjects in CCS (n=5 [13.9%]) than in CSWD (n=0; P=0.056). Risk factors were CSWD (hazard ratio [HR], 4.72; P<0.002) and human leukocyte antigen mismatch (HR, 1.48; P<0.005) for early BCAR+BL and CSWD (HR, 1.9; P<0.02), human leukocyte antigen mismatch (HR, 1.2; P<0.01), and age (HR, 0.97; P<0.002) for 5-year rejection. The HR for graft loss associated with BCAR+BL was 8.8. CONCLUSIONS: BCAR+BL may occur more frequently during the early period after transplantation under an early CSWD regimen with tacrolimus plus induction compared with CCS, particularly among non-African-Americans.