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.

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 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).

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).

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.

Alemtuzumab induction in renal transplantation.

BACKGROUND: There are few comparisons of antibody induction therapy allowing early glucocorticoid withdrawal in renal-transplant recipients. The purpose of the present study was to compare induction therapy involving alemtuzumab with the most commonly used induction regimens in patient populations at either high immunologic risk or low immunologic risk. METHODS: In this prospective study, we randomly assigned patients to receive alemtuzumab or conventional induction therapy (basiliximab or rabbit antithymocyte globulin). Patients were stratified according to acute rejection risk, with a high risk defined by a repeat transplant, a peak or current value of panel-reactive antibodies of 20% or more, or black race. The 139 high-risk patients received alemtuzumab (one dose of 30 mg, in 70 patients) or rabbit antithymocyte globulin (a total of 6 mg per kilogram of body weight given over 4 days, in 69 patients). The 335 low-risk patients received alemtuzumab (one dose of 30 mg, in 164 patients) or basiliximab (a total of 40 mg over 4 days, in 171 patients). All patients received tacrolimus and mycophenolate mofetil and underwent a 5-day glucocorticoid taper in a regimen of early steroid withdrawal. The primary end point was biopsy-confirmed acute rejection at 6 months and 12 months. Patients were followed for 3 years for safety and efficacy end points. RESULTS: The rate of biopsy-confirmed acute rejection was significantly lower in the alemtuzumab group than in the conventional-therapy group at both 6 months (3% vs. 15%, P<0.001) and 12 months (5% vs. 17%, P<0.001). At 3 years, the rate of biopsy-confirmed acute rejection in low-risk patients was lower with alemtuzumab than with basiliximab (10% vs. 22%, P=0.003), but among high-risk patients, no significant difference was seen between alemtuzumab and rabbit antithymocyte globulin (18% vs. 15%, P=0.63). Adverse-event rates were similar among all four treatment groups. CONCLUSIONS: By the first year after transplantation, biopsy-confirmed acute rejection was less frequent with alemtuzumab than with conventional therapy. The apparent superiority of alemtuzumab with respect to early biopsy-confirmed acute rejection was restricted to patients at low risk for transplant rejection; among high-risk patients, alemtuzumab and rabbit antithymocyte globulin had similar efficacy. (Funded by Astellas Pharma Global Development; INTAC ClinicalTrials.gov number, NCT00113269.).

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.

The emergency department action in smoking cessation (EDASC) trial: impact on cessation outcomes.

INTRODUCTION: The focus on acute care, time pressure, and lack of resources hamper the implementation of smoking cessation guidelines in the emergency department (ED). The purpose of this study was to determine whether an emergency nurse- initiated intervention based on the 5A's (Ask-Advise-Assess-Assist-Arrange) framework improves quit rates. METHODS: We conducted a pre-post implementation trial in 789 adult smokers who presented to two EDs in Iowa between August 13, 2008 and August 4, 2010. The intervention focused on improving delivery of the 5A's by ED nurses and physicians using academic detailing, charting/reminder tools, and group feedback. Performance of ED cessation counseling was measured using a 5A's composite score (ranging from 0 to 5). Smoking status was assessed by telephone interview at 3- and 6-month follow-up (with biochemical confirmation in those participants who reported abstinence at 6-month follow-up). RESULTS: Based on data from 650 smokers who completed the post-ED interview, there was a significant improvement in the mean 5A's composite score for emergency nurses during the intervention period at both hospitals combined (1.51 vs. 0.88, difference = 0.63, 95% confidence interval [CI] [0.41, 0.85]). At 6-month follow-up, 7-day point prevalence abstinence (PPA) was 6.8 and 5.1% in intervention and preintervention periods, respectively (adjusted odds ratio [OR] = 1.7, 95% CI [0.99, 2.9]). CONCLUSIONS: It is feasible to improve the delivery of brief smoking cessation counseling by ED staff. The observed improvements in performance of cessation counseling, however, did not translate into statistically significant improvements in cessation rates. Further improvements in the effectiveness of ED cessation interventions are needed.

Nursing interventions in a telemonitoring program.

BACKGROUND: The use of telemonitoring of patients with chronic illness in their homes is growing. Current literature does not describe what types of patient problems are addressed by nurses in these programs and what actions are taken in response to identified problems. This study defined and analyzed patient problems and nursing actions delivered in a telemonitoring program focused on chronic disease management. SUBJECTS AND METHODS: Data were drawn from a clinical trial that evaluated telemonitoring in patients with comorbid diabetes and hypertension. Using study patient records, patient problems and nursing actions were coded using an inductive approach. RESULTS: In total, 2,336 actions were coded for 68 and 65 participants in two intervention groups. The most frequent reasons for contact were reporting information to the primary care provider and lifestyle information related to diabetes and hypertension (e.g., diet, smoking cessation, foot care, and social contacts). The most frequent mode of contact was the study sending a letter to a participant. CONCLUSIONS: Detailed descriptions of interventions delivered facilitate analysis of the unique contributions of nurses in the expanding market of telemonitoring, enable identification of the appropriate number and combination of interventions needed to improve outcomes, and make possible more systematic translation of findings to practice. Furthermore, this information can inform calculation of appropriate panel sizes for care managers and the competencies needed to provide this care.

Outcomes of a home telehealth intervention for patients with diabetes and hypertension.

BACKGROUND: Home telehealth programs often focus on a single disease, yet many patients who need monitoring have multiple conditions. This study evaluated secondary outcomes from a clinical trial evaluating the efficacy of home telehealth to improve outcomes of patients with co-morbid diabetes and hypertension. SUBJECTS AND METHODS: A single-center randomized controlled clinical trial compared two remote monitoring intensity levels (low and high) and usual care in patients with type 2 diabetes and hypertension being treated in primary care. Secondary outcomes assessed were knowledge (diabetes, hypertension, medications), self-efficacy, adherence (diabetes, medications), and patient perceptions of the intervention mode. RESULTS: Knowledge scores improved in the high-intensity intervention group participants, but upon further analysis, we found the intervention effect was not mediated by gain in knowledge. No significant differences were found across the groups in self-efficacy, adherence, or patient perceptions of the intervention mode. CONCLUSIONS: Home telehealth can enhance detection of key clinical symptoms that occur between regular physician visits. While our intervention improved glycemic and blood pressure control, the mechanism of the effect for this improvement was not clear.

Effectiveness of home telehealth in comorbid diabetes and hypertension: a randomized, controlled trial.

BACKGROUND: Increased emphasis is being placed on the critical need to control hypertension (HTN) in patients with diabetes. OBJECTIVE: The objective of this study was to evaluate the efficacy of a nurse-managed home telehealth intervention to improve outcomes in veterans with comorbid diabetes and HTN. DESIGN: A single-center, randomized, controlled clinical trial design comparing two remote monitoring intensity levels and usual care in patients with type 2 diabetes and HTN being treated in primary care was used. MEASUREMENTS: Primary outcomes were hemoglobin A1c and systolic blood pressure (SBP); secondary outcome was adherence. RESULTS: Intervention subjects experienced decreased A1c during the 6-month intervention period compared with the control group, but 6 months after the intervention was withdrawn, the intervention groups were comparable with the control group. For SBP, the high-intensity subjects had a significant decrease in SBP compared with the other groups at 6 months and this pattern was maintained at 12 months. Adherence improved over time for all groups, but there were no differences among the three groups. LIMITATIONS: Subjects had relatively good baseline control for A1c and SBP; minorities and women were underrepresented. CONCLUSIONS: Home telehealth provides an innovative and pragmatic approach to enhance earlier detection of key clinical symptoms requiring intervention. Transmission of education and advice to the patient on an ongoing basis with close surveillance by nurses can improve clinical outcomes in patients with comorbid chronic illness.

Resistance/reactance level.

Psychotherapists from all professions and perspectives periodically struggle to effectively manage a patient's resistance to change. This article provides definitions and examples of patient-treatment matching applied to patient resistance or reactance. We report the results from an original meta-analysis of 12 select studies (N = 1,102) on matching therapist directiveness to patient reactance. Our findings support the hypothesis that patients exhibiting low levels of trait-like resistance respond better to directive types of treatment, while patients with high levels of resistance respond best to nondirective treatments (d = .82). Limitations of the research reviewed are noted, and practice recommendations are advanced.

Patient perceptions of a remote monitoring intervention for chronic disease management.

Use of telecommunications technology to provide remote monitoring for people with chronic disease is becoming increasingly accepted as a means to improve patient outcomes and reduce resource use. The purpose of this project was to evaluate patient perceptions of a nurse-managed remote monitoring intervention to improve outcomes in veterans with comorbid diabetes and hypertension. Postintervention evaluation data were collected using a 12-item questionnaire and an open-ended question. Participants rated the program as generally positive on the questionnaire, but responses to the open-ended question revealed criticisms and suggestions for improvement not captured on the questionnaire. Interviewing participants in these programs may offer richer data for identifying areas for program improvement.

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.

Postadmission dehydration: risk factors, indicators, and outcomes.

Detecting and treating dehydration in hospitalized patients is critical because of the adverse outcomes associated with this condition. Using a case-control design, this study estimated the incidence, risk factors, and outcomes of dehydration in hospitalized adults. The overall incidence rate for developing one of three ICD-9 codes for dehydration during a hospital stay was 3.5%. Cases and controls differed significantly on a number of clinical variables on admission; a large percentage of patients may have had dehydration on admission to the hospital. Mortality rates at 30 and 180 days postdischarge were significantly higher when dehydration was present. Patients may be discharged to rehabilitation settings in a dehydrated state, which prolongs recovery. Despite the increased risk for dehydration and higher rates of hospitalization in older populations, little systematic research has addressed the risk factors for and indicators of dehydration in hospitalized patients.

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.

Optimizing tacrolimus therapy in the maintenance of renal allografts: 12-month results.

BACKGROUND: The determination of optimal tacrolimus (TAC) trough levels is needed to prevent adverse effects of calcineurin inhibitors. METHODS: Stable transplant recipients currently receiving cyclosporine (CsA) were assigned randomly (1:1:1) to continue CsA (target trough level of 50-250 ng/mL); or convert to "reduced" TAC (target trough level 3.0-5.9 ng/mL) or "standard" TAC (target trough level 6.0-8.9 ng/mL). RESULTS: At 12 months, there was a significant improvement in renal function in the reduced TAC versus CsA group with lower serum creatinine (P=0.004) and cystatin C (P<0.001), and higher estimated creatinine clearance (P=0.017). However, there were no statistically significant differences in any renal parameter in the standard TAC versus CsA group. Total and low-density lipoprotein cholesterol were significantly reduced in both TAC groups versus the CsA group (P<0.001). Patient and graft survival and episodes of biopsy-confirmed acute rejection were similar for all treatment groups, and no statistically significant differences were observed between groups in the incidence of new-onset diabetes or cardiac conditions, or in the prevalence of hyperglycemia, hypertension, or hyperlipidemia among patients who did not have these conditions at baseline. Alopecia developed more commonly among TAC-treated patients than CsA-treated patients (P<0.001). CONCLUSIONS: Compared with CsA continuation, conversion to reduced TAC target trough concentrations resulted in significantly improved renal function without increasing the risk of rejection. Conversion to TAC, regardless of target concentration, resulted in improved serum lipid profiles in kidney transplant recipients at 12 months.

Conversion from cyclosporine to tacrolimus in patients at risk for chronic renal allograft failure: 60-month results of the CRAF Study.

BACKGROUND: This study compared the long-term effects of switching from cyclosporine to tacrolimus on the incidence, progression, and severity of chronic renal allograft failure in patients with elevated serum creatinine levels. METHODS: Patients were assigned randomly (2:1) to switch to tacrolimus or remain on cyclosporine. Tacrolimus was initiated at 1/50th of the cyclosporine dose or 0.15 mg/kg/day, whichever dose was lower, to maintain trough concentrations between 5 and 15 ng/mL. Cyclosporine doses were adjusted to achieve trough concentrations between 100 and 300 ng/mL. RESULTS: At 60 months, the median change from baseline in serum creatinine was -0.2 mg/dL in the tacrolimus group and 0.3 mg/dL in the cyclosporine group (P=0.003). Median change in estimated creatinine clearance was 1.2 mL/min in the tacrolimus group and -4.1 mL/min in the cyclosporine group (P=0.019). The incidence of new-onset diabetes, hyperglycemia, hypertension, lymphoma, and malignancies was generally low and comparable between groups. Fewer patients in the tacrolimus group than in the cyclosporine group developed new cardiac conditions (11% vs. 28%, P=0.004), had low-density lipoprotein (LDL) cholesterol values more than 130 mg/dL (29% vs. 57%, P=0.002), or developed hyperlipidemia (24% vs. 67%, P=0.046) during the 60-month follow-up period. Despite these changes, patient and graft survival were similar for both groups. CONCLUSION: Switching from cyclosporine to tacrolimus resulted in improved renal function and a reduction in the occurrence of new-onset cardiac conditions and hyperlipidemia, with no increase in the incidence of new-onset diabetes or new-onset hyperglycemia. However, after 5 years there was no impact on patient or graft survival.