Educational development between faculty and administration

This essay employs Identity Theory to explore the professional identities of educational developers, arguing that it is important to pay attention to the different saliences, or weights, that developers attach to the faculty and administrative sides of their identities

Integration of Sensory and Reward Information during Perceptual Decision-Making in Lateral Intraparietal Cortex (LIP) of the Macaque Monkey

Single neurons in cortical area LIP are known to carry information relevant to both sensory and value-based decisions that are reported by eye movements. It is not known, however, how sensory and value information are combined in LIP when individual decisions must be based on a combination of these variables. To investigate this issue, we conducted behavioral and electrophysiological experiments in rhesus monkeys during performance of a two-alternative, forced-choice discrimination of motion direction (sensory component). Monkeys reported each decision by making an eye movement to one of two visual targets associated with the two possible directions of motion. We introduced choice biases to the monkeys' decision process (value component) by randomly interleaving balanced reward conditions (equal reward value for the two choices) with unbalanced conditions (one alternative worth twice as much as the other). The monkeys' behavior, as well as that of most LIP neurons, reflected the influence of all relevant variables: the strength of the sensory information, the value of the target in the neuron's response field, and the value of the target outside the response field. Overall, detailed analysis and computer simulation reveal that our data are consistent with a two-stage drift diffusion model proposed by Diederich and Bussmeyer [1] for the effect of payoffs in the context of sensory discrimination tasks. Initial processing of payoff information strongly influences the starting point for the accumulation of sensory evidence, while exerting little if any effect on the rate of accumulation of sensory evidence

2017 update of the WSES guidelines for emergency repair of complicated abdominal wall hernias

Emergency repair of complicated abdominal wall hernias may be associated with worsen outcome and a significant rate of postoperative complications. There is no consensus on management of complicated abdominal hernias. The main matter of debate is about the use of mesh in case of intestinal resection and the type of mesh to be used. Wound infection is the most common complication encountered and represents an immense burden especially in the presence of a mesh. The recurrence rate is an important topic that influences the final outcome. A World Society of Emergency Surgery (WSES) Consensus Conference was held in Bergamo in July 2013 with the aim to define recommendations for emergency repair of abdominal wall hernias in adults. This document represents the executive summary of the consensus conference approved by a WSES expert panel. In 2016, the guidelines have been revised and updated according to the most recent available literature.Peer reviewe

A prenylated dsRNA sensor protects against severe COVID-19

Inherited genetic factors can influence the severity of COVID-19, but the molecular explanation underpinning a genetic association is often unclear. Intracellular antiviral defenses can inhibit the replication of viruses and reduce disease severity. To better understand the antiviral defenses relevant to COVID-19, we used interferon-stimulated gene (ISG) expression screening to reveal that OAS1, through RNase L, potently inhibits SARS-CoV-2. We show that a common splice-acceptor SNP (Rs10774671) governs whether people express prenylated OAS1 isoforms that are membrane-associated and sense specific regions of SARS-CoV-2 RNAs, or only express cytosolic, nonprenylated OAS1 that does not efficiently detect SARS-CoV-2. Importantly, in hospitalized patients, expression of prenylated OAS1 was associated with protection from severe COVID-19, suggesting this antiviral defense is a major component of a protective antiviral response

Effect of Lenalidomide (LEN) Exposure on AML-Free Survival and Overall Survival in LEN-Treated Patients (Pts) with IPSS Low- or Intermediate-1-Risk Myelodysplastic Syndromes (MDS) with Del(5q)

Abstract Introduction: The efficacy and safety of LEN in red blood cell (RBC) transfusion-dependent pts with International Prognostic Scoring System (IPSS)-defined Low- or Intermediate-1-risk MDS and del(5q) was assessed in 2 large pivotal trials; protocol-defined dose modifications due to adverse events were required in the majority of LEN-treated pts (MDS-003 [List A, et al. N Engl J Med. 2006;355:1456-65] and MDS-004 [Fenaux P, et al. Blood. 2011;118:3765-76]). Previously we have shown that achievement of cytogenetic response (CyR) with LEN is associated with LEN dose and with achieving RBC transfusion-independence and improved acute myeloid leukemia (AML)-free survival. The current analysis evaluates the impact of actual LEN exposure, including induction-type dosing in Cycle 1 and subsequent dose reductions for LEN-associated cytopenias, and CyR on AML-free survival and overall survival (OS) in lower-risk MDS pts with del(5q) treated in the MDS-003 and MDS-004 studies. Methods: This analysis includes pooled data from pts who were treated with LEN in MDS-003 and MDS-004. Pts received LEN at one of the following starting doses and schedules: 5 mg/day, days 1-28 (MDS-004); 10 mg/day, days 1-21 (MDS-003 and MDS-004); or 10 mg/day, days 1-28 (MDS-003); all given in 28-day cycles. LEN dose reductions related to adverse events (NCI CTCAE v3.0) of grade ≥ 3 (MDS-003) or grade 4 thrombocytopenia or neutropenia (MDS-004) were predefined in the study protocols. Full dose modification guidelines for MDS-004 have been published previously (Fenaux P, et al. Blood. 2011;118:3765-76). Dose interruptions were not considered. AML-free survival and OS were estimated by the Kaplan-Meier method with differences evaluated by the log-rank test. Univariate and multivariable Cox proportional hazards models were used to identify predictive factors for AML-free survival and OS. CyR and LEN dose reduction were analyzed as time-varying covariates. Results: Among the 286 LEN-treated pts from MDS-003 and MDS-004, median total doses in Cycle 1 were 245, 210, 280, and 140 mg in the 10 mg (MDS-003: 10 mg × 28 days), 10 mg (MDS-003: 10 mg × 21 days), 10 mg (MDS-004: 10 mg × 21 days), and 5 mg (MDS-004: 5 mg × 28 days) treatment groups, respectively. Median total times on LEN were 364, 385, 510, and 273 days, respectively, and median times to first dose reduction were 53, 63, 54, and 63 days across the treatment groups, respectively. AML-free survival and OS were significantly longer in pts who received > 210 mg versus ≤ 210 mg in Cycle 1 of therapy (log-rank P = 0.0005 and P = 0.0002, respectively). In multivariable analyses, higher total LEN dose in Cycle 1, analyzed as a continuous variable, was significantly associated with improved AML-free survival (hazard ratio [HR] 0.97; P = 0.033) and OS (HR 0.97; P = 0.036) (Table). Sensitivity analyses showed total dose in Cycles 1-3 to be significant, but total dose in Cycle 1 was a better predictor. In the same model, the occurrence of LEN dose reduction was significantly associated with improved AML-free survival (HR 0.54; P < 0.001) and OS (HR 0.56; P = 0.001) (Table) and was strongly associated with longer duration on study (P < 0.001). Conclusions: In this pooled analysis of LEN-treated pts with MDS and del(5q) from the pivotal MDS-003 and MDS-004 trials, the total cumulative LEN dose actually received in Cycle 1 was a significant predictor of AML-free survival and OS; this is likely mediated through clone suppression, evidenced by the association with CyR. Long-term outcomes were significantly improved in LEN-treated pts who had received early cumulative exposure using 10 mg daily and longer duration through dose modifications. These findings support the use of LEN 10 mg as the recommended induction starting dose, and the importance of dose reductions as required to maximize treatment duration and optimize response and survival outcomes in these pts with lower-risk MDS with del(5q). Disclosures Sekeres: Celgene Corporation: Membership on an entity's Board of Directors or advisory committees; TetraLogic: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees. Swern:Celgene Corporation: Employment, Equity Ownership. List:Celgene Corporation: Honoraria, Research Funding. Fenaux:Novartis: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding. Sugrue:Celgene Corporation: Employment, Equity Ownership

Association Of Cytogenetic Response (CyR) With RBC Transfusion-Independence (RBC-TI) and AML-Free Survival In Lenalidomide (LEN)-Treated Patients (Pts) With IPSS Low-/Int-1-Risk Myelodysplastic Syndromes (MDS) With Del(5q)

Abstract Introduction The efficacy and safety of LEN in RBC transfusion-dependent pts with International Prognostic Scoring System (IPSS) Low- or Intermediate (Int)-1-risk MDS with del(5q) was assessed in 2 large, multicenter studies (MDS-003 [List A, et al. N Engl J Med. 2006;355:1456-65] and MDS-004 [Fenaux P, et al. Blood. 2011;118:3765-76]). RBC-TI for ≥ 8 weeks and CyR was achieved in 51–67% and 25–73% of pts treated with LEN, respectively. In a multivariate analysis, achievement of RBC-TI ≥ 26 weeks with LEN was associated with a significantly reduced risk of acute myeloid leukemia (AML) progression and death (MDS-004). To further understand the effects of LEN in lower-risk del(5q) MDS pts treated in the MDS-003 and MDS-004 studies, we analyzed the association of CyR with RBC-TI ≥ 26 weeks and AML-free survival. Methods Of the 286 pts from the MDS-003 and MDS-004 studies who received LEN from study start, 181 were evaluable for both CyR and RBC-TI ≥ 26 weeks, and included in the current analysis (88 pts from MDS-003 and 93 pts from MDS-004). Cytogenetic studies by central review were performed at baseline, and at weeks 24 and 48 (MDS-003); or at week 24 and every 24 weeks thereafter (MDS-004). CyR rates were assessed using International Working Group 2000 criteria and compared with rates of RBC-TI ≥ 26 weeks. CyR and AML-free survival (Kaplan-Meier method) were assessed by baseline cytogenetic complexity [isolated del(5q), del(5q) + 1 additional abnormality, and del(5q) + > 1 additional abnormality]. A univariate Cox proportional hazards model identified factors associated with AML-free survival. CyR and RBC-TI ≥ 26 weeks were included as time varying covariates, and IPSS-R was included as a categorical variable. A best multivariate model was chosen by fitting all possible models, including all covariates with P < 0.1 in the univariate model, and using the Akaike information criterion. Results Of the 181 pts, 130 had isolated del(5q), 32 had del(5q) + 1 additional abnormality, 14 had del(5q) + > 1 additional abnormality, and 5 pts had missing cytogenetics at baseline. Median age was 68 years (range 36–89) and 73% of pts were female. Median baseline hemoglobin level was 8.0 g/dL (range 3.6–11.0) and median RBC transfusion burden was 6 units/8 weeks (range 1.0–25.0). A total of 103 pts (56.9%) achieved a CyR (complete + partial response). The likelihood of a CyR was increased in pts who achieved RBC-TI ≥ 26 weeks compared with those who did not: 71% versus 29%, respectively (hazard ratio [HR] 2.3; 95% confidence interval 1.56–3.41). RBC-TI ≥ 26 weeks preceded CyR, with median times to RBC-TI ≥ 26 weeks and CyR of 29 days (range 2–343) and 148 days (range 56–707), respectively. However, this may have been dependent on the timing of bone marrow aspirates. CyR rates were comparable across the isolated del(5q) and del(5q) + 1 additional abnormality groups (59% vs 63%; P = 0.736), but lower in the del(5q) + > 1 additional abnormality group compared to these 2 groups combined (29% vs 60%; P = 0.023) (Table). In pts with isolated del(5q) and del(5q) + 1 additional abnormality, CyR was associated with a 41% (P = 0.019) and 58% (P = 0.056) reduction, respectively, in the risk of AML or death compared with no CyR. In all cytogenetic groups, median AML-free survival was longer in those who achieved CyR compared with non-responders, although it was not statistically significant in pts with del(5q) + > 1 additional abnormality (Table). In a multivariate Cox proportional hazard model, factors associated with AML-free survival were CyR (HR 0.58; P = 0.023), RBC-TI ≥ 26 weeks (HR 0.34; P < 0.0001), lower IPSS-R categorization (P = 0.018), female gender (HR 0.44; P = 0.0004), and younger age (HR 1.03 for each additional year; P = 0.008). Conclusion In IPSS-defined Low- or Int-1-risk MDS pts with del(5q), achievement of CyR with LEN was associated with a RBC-TI ≥ 26 weeks response and a reduced risk of AML or death in pts with isolated del(5q) and del(5q) + 1 abnormality. Due to small sample size, further studies are needed to evaluate the effect of LEN in the del(5q) + > 1 additional abnormality group. These data provide evidence for LEN as a disease-modifying agent in RBC transfusion-dependent pts with Low- or Int-1-risk MDS and del(5q). Disclosures: Sekeres: Celgene: Membership on an entity’s Board of Directors or advisory committees; Amgen: Membership on an entity’s Board of Directors or advisory committees. Swern:Celgene: Employment, Equity Ownership. Giagounidis:Celgene: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees. List:Celgene: Serve on Celgene Data Safety & Monitoring Committee Other. Schlegelberger:Celgene: Consultancy. Fenaux:Celgene: Honoraria. Shiansong Li:Celgene: Employment, Equity Ownership. Sugrue:Celgene: Employment, Equity Ownership

Three-Dimensional Printed Biopatches With Conductive Ink Facilitate Cardiac Conduction When Applied to Disrupted Myocardium

BACKGROUND: Reentrant ventricular arrhythmias are a major cause of sudden death in patients with structural heart disease. Current treatments focus on electrically homogenizing regions of scar contributing to ventricular arrhythmia with ablation or altering conductive properties using antiarrhythmic drugs. The high conductivity of carbon nanotubes may allow restoration of conduction in regions where impaired electrical conduction results in functional abnormalities. We propose a new concept for arrhythmia treatment using a stretchable, flexible biopatch with conductive properties to attempt to restore conduction across regions in which activation is disrupted.METHODS: Carbon nanotube patches composed of nanofibrillated cellulose/single-walled carbon nanotube ink 3-dimensionally printed in conductive patterns onto bacterial nanocellulose were developed and evaluated for conductivity, flexibility, and mechanical properties. The patches were applied on 6 canines to epicardium before and after surgical disruption. Electroanatomic mapping was performed on normal epicardium, then repeated over surgically disrupted epicardium, and then finally with the patch applied passively.RESULTS: We developed a 3-dimensional printable carbon nanotube ink complexed on bacterial nanocellulose that was (1) expressable through 3-dimensional printer nozzles, (2) electrically conductive, (3) flexible, and (4) stretchable. Six canines underwent thoracotomy, and, during epicardial ventricular pacing, mapping was performed. We demonstrated disruption of conduction after surgical incision in all 6 canines based on activation mapping. The patch resulted in restored conduction based on mapping and assessment of conduction direction and velocities in all canines.CONCLUSIONS: We have demonstrated 3-dimensional custom-printed electrically conductive carbon nanotube patches can be surgically manipulated to improve cardiac conduction when passively applied to surgically disrupted epicardial myocardium in canines

Conditional Survival in Patients with Del(5q) Myelodysplastic Syndromes Treated with Lenalidomide

Abstract Introduction: Although trial results can be used to develop prognostic models for patient survival that are useful at the beginning of treatment, their accuracy as patients continue to receive therapy may decrease. With attention increasingly focused on defining treatment value and providing effective patient care, we evaluated how survival among patients with myelodysplastic syndromes (MDS) changes over time while on treatment. This analysis used conditional probability to address the practical question: what is the probability of a patient surviving y months after he/she has already survived x months since starting treatment with lenalidomide? Methods: This analysis evaluated lenalidomide-treated patients with lower-risk MDS and del(5q) from the MDS-003 and MDS-004 studies (List A, et al. N Engl J Med. 2006;355:1456-65; Fenaux P, et al. Blood. 2011;118:3765-76). We calculated the probability of a patient surviving an additional 6, 9, 12, 18, 24, or 30 months on-treatment with lenalidomide after having received lenalidomide for an initial 3, 6, 9, 12, or 18 months. The conditional probability of surviving an additional y months was calculated as OS (x +y)/OS (x) within the Kaplan Meier survival framework. Results: Of 286 lenalidomide-treated patients with MDS included in this analysis, 70% were women, median age was 69 years (range 36-95), and median time from diagnosis 2.7 years (range 0.1-29.2). Isolated del(5q) was present in 70% of patients and 73% were classified as having International Prognostic Scoring System (IPSS)-defined Low- or Intermediate-1-risk disease. The median transfusion burden for the population was 6 red blood cell (RBC) units/8 weeks (range 1-25). Within 3 months of starting treatment with lenalidomide, 139 of 286 patients became RBC transfusion-independent (defined as ≥ 8 consecutive weeks without RBC transfusions); 79, 123, and 139 patients were transfusion-independent by 1, 2, and 3 months, respectively. Of 286 patients, 242, 193, 165, 149, and 114 received lenalidomide for at least 3, 6, 9, 12, and 18 months, respectively. The conditional probability of lenalidomide-treated patients (regardless of response status) surviving an additional 6, 9, 12, 18, 24, or 30 months after receiving lenalidomide for the above treatment periods is presented in Table 1. The conditional probability values of a patient surviving an additional 6, 9, 12, 18, 24, or 30 months were similar regardless of initial lenalidomide treatment period. The conditional probability of surviving an additional 30 months after specific periods of lenalidomide treatment for patients stratified by Revised-IPSS (IPSS-R) group is shown in Figure 1. For patients in the IPSS-R Very Low/Low-risk and Intermediate-risk groups, the conditional probabilities of surviving an additional 30 months after 18 months of lenalidomide treatment were 59.8% and 55.2%, respectively. As expected, the conditional survival was lower in the High/Very High-risk group; even in these higher-risk patients, however, conditional probability of surviving an additional 30 months after 18 months of lenalidomide treatment was 26.7%. Conclusions: Irrespective of initial treatment duration, the conditional probability of survival of MDS patients on lenalidomide remains remarkably consistent while on treatment for up to 18 months. Patients with lower-risk del(5q) MDS who had received up to 18 months of lenalidomide still had a > 55% conditional probability of surviving an additional 30 months on treatment. The ability to adjust survival estimates on the basis of time elapsed since starting therapy is clinically meaningful in counseling patients with lower-risk del(5q) MDS, and may be informative when planning healthcare resource use. Table 1. Conditional probability of survival after initial lenalidomide treatment period Time since initiation of lenalidomide, months n Conditional probability of additional survival, % 6 months 9 months 12 months 18 months 24 months 30 months 3 242 93.7 88.9 83.6 75.4 67.4 60.9 6 193 92.3 86.8 81.8 74.7 66.0 59.7 9 165 89.3 84.0 80.4 71.9 65.0 57.6 12 149 88.6 84.8 81.0 71.5 64.7 56.9 18 114 91.4 85.6 80.7 73.0 64.2 56.0 Disclosures List: Celgene Corporation: Honoraria, Research Funding. Giagounidis:Celgene Corporation: Honoraria. Hellström-Lindberg:Celgene Corporation: Research Funding. Shiansong Li:Celgene Corporation: Employment, Equity Ownership. Swern:Celgene Corporation: Employment, Equity Ownership. Sugrue:Celgene Corporation: Employment, Equity Ownership. Fenaux:Janssen: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Sekeres:Celgene Corporation: Membership on an entity's Board of Directors or advisory committees