Subtyping of intraductal papillary mucinous neoplasms – pitfalls of MUC1 immunohistochemistry

Intraductal papillary mucinous neoplasms (IPMNs) are precursor lesions of pancreatic ductal adenocarcinoma (PDAC). Current edition of WHO Classification of Tumors of the Digestive System recognizes four different subtypes (gastric, intestinal, pancreatobiliary, and oncocytic) and recommends analysis of mucin expression (MUC1, MUC2, MUC5AC, MUC6) as well as evaluation of architectural and cell differentiation patterns for correct classification. However, there is no consensus on MUC1 expression of IPMN‐lesions in the literature. Current recommendations are based on studies where antibodies against the core MUC1 protein or sialylated MUC1 (tumor associated MUC1), not the fully glycosylated MUC1 were used. We have recently reported that MUC1 is strongly expressed in both gastric and intestinal types IPMN specimens from the cystic wall, obtained by endoscopic ultrasound guided microbiopsy procedure. We have used a commercial MUC1 antibody, validated and recommended for diagnostic use, which recognizes fully glycosylated MUC1. Based on the above, we propose a revision of the WHO Classification, specifying that antibodies against tumor associated MUC1 should be used for IPMN subtyping.     

Intervention for arch obstruction after the Norwood procedure: Prevalence,associated factors,and practice variability

Objective

Arch obstruction after the Norwood procedure is common and contributes to mortality. We determined the prevalence, associated factors, and practice variability of arch reintervention and assessed whether arch reintervention is associated with mortality.

Intranasal hydromorphone for treatment of acute pain in children: A pilot study

ObjectivesWe aimed to describe the analgesic efficacy, duration of analgesia, and adverse event profile associated with intranasal hydromorphone in children with acute pain presenting to an emergency department.MethodsProspective dose titration pilot study of otherwise healthy children 4 to 17-years-old with moderate to severe pain who required a parenteral opioid. All patients received an initial intranasal hydromorophone dose of 0.03 mg/kg. The need for additional analgesia was assessed at 15 and 30 min; an additional 0.015 mg/kg was given at each assessment, if required. Need for rescue analgesic, pain intensity and adverse events were assessed until 6 h after hydromorphone administration or until patients were discharged, underwent a procedure to treat their painful condition, or received a rescue analgesic.ResultsWe enrolled 35 children. Fifteen, 11, and 9 children required a total dose of 0.03, 0.045, and 0.06 mg/kg, respectively. Patients in each dose group experienced an absolute decrease in pain score of ≥3/10 and percent reduction >40% within 5–15 min of completing dose-titration administration of hydromorphone. Duration of analgesia (i.e. time until rescue analgesic administered) >1 h was observed in 85.7% of patients. Patients not requiring rescue analgesics had mild or no pain until discharged or their painful conditions were treated. Three (8.6%) patients required a rescue analgesic <1 h after hydromorphone administration. There were no major adverse events.ConclusionsIntranasal hydromorphone led to rapid, clinically significant and frequently sustained decreases in pain intensity in children. No major adverse events were observed in this preliminary sample.Clinical Trials Registration Number: NCT02437669     

Quantitative Parameters of High-Frame-Rate Strain in Patients with Echocardiographically Normal Function

Recently, we developed a high-frame-rate echocardiographic imaging system capable of acquiring images at rates up to 2500 per second. High imaging rates were used to quantify longitudinal strain parameters in patients with echocardiographically normal function. These data can serve as a baseline for comparing strain parameters in disease states. The derived timing data also reveal the propagation of mechanical events in the left ventricle throughout the cardiac cycle. High-frame-rate echocardiographic images were acquired from 17 patients in the apical four-chamber view using Duke University's phased array ultrasound system, T5. B-Mode images were acquired at 500–1000 images per second by employing 16:1 or 32:1 parallel processing in receive, a scan depth ≤14 cm and an 80° field of view with a 3.5-MegaHertZ (MHz), 96-element linear array. The images were analyzed using a speckle tracking algorithm tailored for high-frame-rate echocardiographic images developed at Aalborg and Duke University. Four specific mechanical events were defined using strain curves from six regions along the myocardial contour of the left ventricle. The strain curves measure the local deformation events of the myocardium and are independent of the overall cardiac motion. We observed statistically significant differences in the temporal sequence among different myocardial segments for the first mechanical event described, myocardial tissue shortening onset (p < 0.01). We found that the spatial origin of tissue shortening was located near the middle of the interventricular septum in patients with echocardiographically normal function. The quantitative parameters defined here, based on high-speed strain measurements in patients with echocardiographically normal function, can serve as a means of assessing degree of contractile abnormality in the myocardium and enable the identification of contraction propagation. The relative timing pattern among specific events with respect to the Q wave may become an important new metric in assessing cardiac function and may, in turn, improve diagnosis and prognosis.     

The impact of chronic kidney disease on lower extremity bypass outcomes in patients with critical limb ischemia

Objective

Patient selection for open lower extremity revascularization in patients with chronic kidney disease (CKD) remains a clinical challenge. This study investigates the impact of CKD on early graft failure, postoperative complications, and mortality in patients undergoing lower extremity bypass for critical limb ischemia.

Human subjects exploit a cognitive map for credit assignment

An influential reinforcement learning framework proposes that behavior is jointly governed by model-free (MF) and model-based (MB) controllers. The former learns the values of actions directly from past encounters, and the latter exploits a cognitive map of the task to calculate these prospectively. Considerable attention has been paid to how these systems interact during choice, but how and whether knowledge of a cognitive map contributes to the way MF and MB controllers assign credit (i.e., to how they revaluate actions and states following the receipt of an outcome) remains underexplored. Here, we examine such sophisticated credit assignment using a dual-outcome bandit task. We provide evidence that knowledge of a cognitive map influences credit assignment in both MF and MB systems, mediating subtly different aspects of apparent relevance. Specifically, we show MF credit assignment is enhanced for those rewards that are related to a choice, and this contrasted with choice-unrelated rewards that reinforced subsequent choices negatively. This modulation is only possible based on knowledge of task structure. On the other hand, MB credit assignment was boosted for outcomes that impacted on differences in values between offered bandits. We consider mechanistic accounts and the normative status of these findings. We suggest the findings extend the scope and sophistication of cognitive map-based credit assignment during reinforcement learning, with implications for understanding behavioral control.

An extensive body of psychological and neuroscientific literature on dual-system reinforcement learning (RL) indicates that behavior is governed by two distinct systems (1–17)—a rigid, retrospective model-free (MF) system (18, 19) and a flexible, prospective model-based (MB) system (18, 20). Unlike an MF system, which tends to repeat actions with a past history of success, an MB system relies on a cognitive map (CM) (21), that is, a model detailing the structure of a decision-making environment, including how states, actions, observations, and rewards are linked, to predict the impact of action choice on potential future rewards. Recent research highlights competitive and cooperative interactions between these systems, including speed accuracy trade-offs (22), reliability-based arbitration (1, 23), and a plan-to-habit strategy (24), with a focus on a prospective-planning role served by the MB system during choice. Recently, we demonstrated another influence of a CM (and thus, as we described it there, MB processes) in guiding credit assignment (CA) to MF action-values (i.e., affecting how MF values of actions and states are updated as reward-outcomes are received) (25). However, by design, this influence was limited to unraveling the resolution of state uncertainty for MF purposes, leaving broader aspects of the contribution of CM-based processes to CA unexplored.Here, we consider two potential complementary CM-based modulators of CA. Both concern the causal structure of the relationship between options and outcomes. One involves the “relatedness” of actual outcomes to an enacted choice, a retrospective effect of a CM on MF CA. The second involves the “importance” of potential outcomes during the deliberation process preceding a choice, a prospective effect of a CM on MB CA.“Relatedness” arises out of a complexity in assigning credit when information about streams of rewards is provided that depends only partly on the actions taken (unlike situations that involve simple lotteries, for instance, when an action is directly followed by the reward it occasions). An MF system, lacking structural causal knowledge, is disposed to assign credit naively to a choice based on the entire collection of ensuing outcomes, irrespective of whether these outcomes were caused by, or related to, an actual initiating action choice. By contrast, knowledge stored as a CM can guide MF CA to favor action-related outcomes.Take an example of a trader who deliberates purchasing one of two available mutual funds: X, which invests in companies A and B, or Y, which invests in companies A and C. Assume the trader opts for X and then later receives positive information about companies B and D. The trader might assign credit in an MF manner to her/his past action (“buy X”), updating the action’s cached value on the basis that positive consequences followed that choice. However, only one component of those positive consequences (that concerning company B) actually related to the choice of fund X. We propose that MF CA is modulated by a CM such that a change in the action’s value will be affected mostly by information about company B. More generally, relatedness depends on a causal attribution of rewards to actions (26).We consider a second modulator of CA, termed “importance,” as a form of attentional effect. When deliberating between several choice options, and taking into account their prospective outcomes, it is often the case that certain outcomes (which we dub “unimportant”) should not determine choice, as they are common to all choice options. In contrast, other (“important”) outcomes are distinctive to some choice options but not to others, and these should be the main determinants of choice. A CM will contain this type of information and direct attention to the latter alone. We consider the possibility that when the outcomes of the choice are observed, those that garnered more attention at choice are favored in learning.Consider our previous example where information about companies B and D triggers a CA process that leads to positive revaluation of these companies—a process useful for future MB financial decisions related to these companies. We propose this CA process can be biased by CM-based deliberations during choice. Notably, the values of companies B and C were “important” in the trader’s MB deliberation process (choosing a fund), as each is unique to one fund. The values of companies A and D, on the other hand, are less important, as these are either common to both choice options (A) or altogether absent (D). We hypothesize that representations of “important” components in a CM are activated more strongly during choice, leading to them being revalued more when information about choice outcomes are subsequently realized. Thus, ceteris paribus, the increase in the trader’s evaluation of company B will be higher than for company D, given the positive information. This evaluation is then exploited by MB planning processes for future choices.To test these hypotheses, we developed a variant of our previously described dual-outcome bandit task (25). Participants chose between pairs of bandits (i.e., lotteries) that led to different outcomes and received a stream of reward feedback pertaining to choice-related, choice-unrelated, important, and unimportant outcomes. Critically, there are two ways to value bandits in this task. An MF controller treats each bandit holistically, and, as described above, an MB controller predicts the values of the bandits from knowledge of the outcomes to which the bandits lead as provided by a putative CM. This distinction in the structure of evaluations can then be generalized to the apportioning of credit. We consider CA to a bandit to take the form of an MF credit assignment (MFCA; since the MF system makes decisions directly based on these values). Similarly, we consider CA to the outcomes associated with the bandits to be an MB credit assignment (MBCA). To put this another way, the main distinction between MFCA and MBCA in our task is that the former pertains to a revaluation of actions, while the latter pertains to a revaluation of latent causes for these actions (i.e., the ensuing outcomes).In support of our hypothesis that MFCA is guided by a CM, we found evidence that credit for choice-related and -unrelated outcomes is assigned to actions in a different manner. We show information about rewards actually related to chosen actions alone positively impact on the value of those actions. Information about rewards not related to chosen actions, on the other hand, have an opposite effect. Second, we found that MBCA was greater for choice outcomes that were “important” compared to “unimportant” during choice deliberations. We discuss mechanistic and normative accounts of these results.     

Temporal Expectation Hastens Decision Onset But Does Not Affect Evidence Quality

The ability to predict the timing of forthcoming events, known as temporal expectation, has a strong impact on human information processing. Although there is growing consensus that temporal expectations enhance the speed and accuracy of perceptual decisions, it remains unclear whether they affect the decision process itself, or non-decisional (sensory/motor) processes. Here, healthy human participants (N = 21; 18 female) used predictive auditory cues to anticipate the timing of low-contrast visual stimuli they were required to detect. Modeling of the behavioral data using a prominent sequential sampling model indicated that temporal expectations speeded up non-decisional processes but had no effect on decision formation. Electrophysiological recordings confirmed and extended this result: temporal expectations hastened the onset of a neural signature of decision formation but had no effect on its build-up rate. Anticipatory α band power was modulated by temporal expectation and co-varied with intrinsic trial-by-trial variability in behavioral and neural signatures of the onset latency of the decision process. These findings highlight how temporal predictions optimize our interaction with unfolding sensory events.SIGNIFICANCE STATEMENT Temporal expectation enhances performance, but the locus of this effect remains debated. Here, we contrasted the two dominant accounts: enhancement through (1) expedited decision onset, or (2) an increase in the quality of sensory evidence. We manipulated expectations about the onset of a dim visual target using a temporal cueing paradigm, and probed the locus of the expectation effect with two complementary approaches: drift diffusion modeling (DDM) of behavior, and estimation of the onset and progression of the decision process from a supramodal accumulation-to-bound signal in simultaneously measured EEG signals. Behavioral modeling and neural data provided strong, converging evidence for an account in which temporal expectations enhance perception by speeding up decision onset, without affecting evidence quality.