Does Conceptual Abstraction Moderate Whether Past Moral Deeds Motivate Consistency or Compensatory Behavior? A Registered Replication and Extension of Conway and Peetz (2012).

A long-standing debate in psychology concerns whether doing something good or bad leads to more of the same or the opposite. Conway and Peetz proposed that conceptual abstraction moderates if past moral deeds lead to consistent or compensatory behavior. Although cited 384 times across disciplines, we did not find any direct replications. It was also unclear how increases or decreases from one's baseline prosociality might underlie the effect. A large-scale experiment (N = 5,091) in the registered report format tested Conway and Peetz's original hypothesis. The hypothesized interaction was not replicated: conceptual abstraction did not moderate the effect of recalling moral vs. immoral behavior on prosocial intentions. Our results show that recalling moral behavior led to higher prosocial intentions than recalling either immoral or neutral behavior, irrespective of recalling from the recent or distant past. Thus, the current research found no evidence for compensatory moral behavior, only for positive moral consistency.

Evaluation of a Patient Education Game Design Activity.

BACKGROUND: Game-based learning has been used in pharmacy education settings with the instructor developing a game for students to play to enhance learning. However, there is a paucity of data about health sciences students designing a game themselves to further their understanding of a complex topic. The purpose of this study was to describe and assess a game design activity focused on patient education of anticoagulants in a pharmacotherapy skills laboratory setting. INNOVATION: Second-year pharmacy students enrolled in a pharmacotherapy skills laboratory course worked in teams in a one-hour active learning activity to design a game intended to educate patients about their medication. A pre/post analysis of student attitudes about game-based learning and the activity, as well as knowledge, was conducted. FINDINGS: The large majority of students (80.5%) agreed that the activity was an effective way to develop patient education strategies. Through the survey and free-response questions, students reported that the game design activity facilitated positive group collaboration and allowed students to take the perspective of their patients. Students also requested additional time to complete the activity. Knowledge assessment scores of key patient education points increased from 66.5% prior to the activity to 71.5% one week following the activity (p<0.05). CONCLUSION: The game design activity served as a novel teaching method for pharmacy students to actively learn about anticoagulant medications while developing an innovative patient education strategy. Although there was an increase in knowledge scores, students highlighted the impact on group collaboration and taking the perspective of their patients.

Exploring the role of task success in implicit motor adaptation.

Although implicit motor adaptation is driven by sensory-prediction errors (SPEs), recent work has shown that task success modulates this process. Task success has typically been defined as hitting a target, which signifies the goal of the movement. Visuomotor adaptation tasks are uniquely situated to experimentally manipulate task success independently from SPE by changing the target size or the location of the target. These two, distinct manipulations may influence implicit motor adaptation in different ways, so, over four experiments, we sought to probe the efficacy of each manipulation. We found that changes in target size, which caused the target to fully envelop the cursor, only affected implicit adaptation for a narrow range of SPE sizes, while jumping the target to overlap with the cursor more reliably and robustly affected implicit adaptation. Taken together, our data indicate that, while task success exerts a small effect on implicit adaptation, these effects are susceptible to methodological variations. Future investigations of the effect of task success on implicit adaptation could benefit from employing target jump manipulations instead of target size manipulations.NEW & NOTEWORTHY Recent work has suggested that task success, namely, hitting a target, influences implicit motor adaptation. Here, we observed that implicit adaptation is modulated by target jump manipulations, where the target abruptly "jumps" to meet the cursor; however, implicit adaptation was only weakly modulated by target size manipulations, where a static target either envelops or excludes the cursor. We discuss how these manipulations may exert their effects through different mechanisms.

Teaching Tissue Repair Through an Inquiry-Based Learning Bioadhesives Module.

Bioadhesives are an important class of biomaterials for wound healing, hemostasis, and tissue repair. To develop the next generation of bioadhesives, there is a societal need to teach trainees about their design, engineering, and testing. This study designed, implemented, and evaluated a hands-on, inquiry-based learning (IBL) module to teach bioadhesives to undergraduate, master's, and PhD/postdoctoral trainees. Approximately 30 trainees across three international institutions participated in this IBL bioadhesives module, which was designed to last approximately 3 h. This IBL module was designed to teach trainees about how bioadhesives are used for tissue repair, how to engineer bioadhesives for different biomedical applications, and how to assess the efficacy of bioadhesives. The IBL bioadhesives module resulted in significant learning gains for all cohorts; whereby, trainees scored an average of 45.5% on the pre-test assessment and 69.0% on the post-test assessment. The undergraduate cohort experienced the greatest learning gains of 34.2 points, which was expected since they had the least theoretical and applied knowledge about bioadhesives. Validated pre/post-survey assessments showed that trainees also experienced significant improvements in scientific literacy from completing this module. Similar to the pre/post-test, improvements in scientific literacy were most significant for the undergraduate cohort since they had the least amount of experience with scientific inquiry. Instructors can use this module, as described, to introduce undergraduate, master's, and PhD/postdoctoral trainees to principles of bioadhesives.

Exploring the role of task success in implicit motor adaptation.

We learn to improve our motor skills using different forms of feedback: sensory-prediction error, task success, and reward/punishment. While implicit motor adaptation is driven by sensory-prediction errors, recent work has shown that task success modulates this process. Task success is often confounded with reward, so we sought to determine if the effects of these two signals on adaptation can be dissociated. To address this question, we conducted five experiments that isolated implicit learning using error-clamp visuomotor reach adaptation paradigms. Task success was manipulated by changing the size and position of the target relative to the cursor providing visual feedback, and reward expectation was established using monetary cues and auditory feedback. We found that neither monetary cues nor auditory feedback affected implicit adaptation, suggesting that task success influences implicit adaptation via mechanisms distinct from conventional reward-related processes. Additionally, we found that changes in target size, which caused the target to either exclude or fully envelop the cursor, only affected implicit adaptation for a narrow range of error sizes, while jumping the target to overlap with the cursor more reliably and robustly affected implicit adaptation. Taken together, our data indicate that, while task success exerts a small effect on implicit adaptation, these effects are susceptible to methodological variations and unlikely to be mediated by reward.

Real-World Outcomes of Proprotein Convertase Subtilisin Kexin-9 Inhibitor Use.

ABSTRACT: Although the proprotein convertase subtilisin kexin-9 inhibitors (PCSK9i) were shown to significantly lower low-density lipoprotein and reduce atherosclerotic cardiovascular disease events in clinical trials, there is a dearth of use data on these agents in real-world settings. This study compares PCSK9i use in a population of real-world patients with atherosclerotic cardiovascular disease or familial hypercholesterolemia. This was a matched cohort study of adult patients who were dispensed a PCSK9i along with adult patients who did not receive a PCSK9i. PCSK9i patients were matched on a propensity to have received a PCSK9i score up to 1:10 to non-PCSK9i patients. The primary outcomes were changes in cholesterol levels. Secondary outcomes included a composite outcome of all-cause mortality, major cardiovascular events, and ischemic strokes along with health care utilization during follow-up. Adjusted conditional, multivariate Cox proportional hazards, and negative binomial modeling were performed. Ninety-one PCSK9i patients were matched to 840 non-PCSK9i patients. Seventy-one percent of PCSK9i patients either discontinued or switched PCSK9i therapy. PCSK9i patients had greater median reductions in low-density lipoprotein (-73.0 mg/dL vs. -30.0 mg/dL) and total (-77.0 vs. -31.0) cholesterol (both P < 0.001). No adjusted between-group differences in the composite outcome or individual components of the composite outcome were identified (all P > 0.05). PCSK9i patients had a lower rate of medical office visits during follow-up (adjusted incidence rate ratio = 0.61, P = 0.019). These findings support the effectiveness of PCSK9i therapy in real-world settings but suggest that use may be limited by PCSK9i adverse reactions and patient cost barriers.

Motor learning without movement.

Prediction errors guide many forms of learning, providing teaching signals that help us improve our performance. Implicit motor adaptation, for instance, is thought to be driven by sensory prediction errors (SPEs), which occur when the expected and observed consequences of a movement differ. Traditionally, SPE computation is thought to require movement execution. However, recent work suggesting that the brain can generate sensory predictions based on motor imagery or planning alone calls this assumption into question. Here, by measuring implicit motor adaptation during a visuomotor task, we tested whether motor planning and well-timed sensory feedback are sufficient for adaptation. Human participants were cued to reach to a target and were, on a subset of trials, rapidly cued to withhold these movements. Errors displayed both on trials with and without movements induced single-trial adaptation. Learning following trials without movements persisted even when movement trials had never been paired with errors and when the direction of movement and sensory feedback trajectories were decoupled. These observations indicate that the brain can compute errors that drive implicit adaptation without generating overt movements, leading to the adaptation of motor commands that are not overtly produced.

Deleting Mecp2 from the cerebellum rather than its neuronal subtypes causes a delay in motor learning in mice.

Rett syndrome is a devastating childhood neurological disorder caused by mutations in MECP2. Of the many symptoms, motor deterioration is a significant problem for patients. In mice, deleting Mecp2 from the cortex or basal ganglia causes motor dysfunction, hypoactivity, and tremor, which are abnormalities observed in patients. Little is known about the function of Mecp2 in the cerebellum, a brain region critical for motor function. Here we show that deleting Mecp2 from the cerebellum, but not from its neuronal subtypes, causes a delay in motor learning that is overcome by additional training. We observed irregular firing rates of Purkinje cells and altered heterochromatin architecture within the cerebellum of knockout mice. These findings demonstrate that the motor deficits present in Rett syndrome arise, in part, from cerebellar dysfunction. For Rett syndrome and other neurodevelopmental disorders, our results highlight the importance of understanding which brain regions contribute to disease phenotypes.

Flat-dose granulocyte colony-stimulating factor evaluation after autologous hematopoietic stem cell transplant in multiple myeloma patients: Does one dose fit all?

INTRODUCTION: The current recommended granulocyte-colony stimulating factor (G-CSF) dose after autologous hematopoietic stem cell transplant (autoHSCT) in multiple myeloma patients is 5 mcg/kg/day administered subcutaneously until engraftment. Recently, our institution changed practice from weight-based to flat-dose G-CSF. The purpose of this study was to assess the impact of flat-dose G-CSF on time to engraftment among multiple myeloma patients of different weight groups. METHODS: Retrospective chart review was completed for adult patients with multiple myeloma who underwent autoHSCT from March 2018 through August 2019. Data collected included time to neutrophil engraftment, total length of hospitalization, length of stay post-transplant, time to platelet engraftment, use of intravenous fluconazole or acyclovir, parenteral nutrition use, incidence of febrile neutropenia, antibiotic use, and death. Differences in outcomes were compared between patients ≤80 kg versus those >80 kg. A secondary analysis was completed for patients ≤100 kg versus those >100 kg. RESULTS: There was no difference in time to neutrophil engraftment between weight groups (≤80 kg versus >80 kg: median = 12 days, p = 0.22; ≤100 kg versus >100 kg: median = 12 days, p = 0.52). There was a significant difference in intravenous fluconazole and acyclovir use between groups, with more use in the lower weight groups (≤80 kg versus >80 kg: 12 patients versus 10 patients p = 0.02; ≤100 kg versus >100 kg: 19 patients versus 3 patients p = 0.04). No significant differences were found for any other outcomes. CONCLUSION: Utilizing a flat-dose of G-CSF for patients after autoHSCT does not appear to negatively affect patient outcomes. Institutions may benefit from using the 300 mcg dose of G-CSF for multiple myeloma patients after autoHSCT.

A cerebello-olivary signal for negative prediction error is sufficient to cause extinction of associative motor learning.

The brain generates negative prediction error (NPE) signals to trigger extinction, a type of inhibitory learning that is responsible for suppressing learned behaviors when they are no longer useful. Neurons encoding NPE have been reported in multiple brain regions. Here, we use an optogenetic approach to demonstrate that GABAergic cerebello-olivary neurons can generate a powerful NPE signal, capable of causing extinction of conditioned motor responses on its own.

Single-Unit Extracellular Recording from the Cerebellum During Eyeblink Conditioning in Head-Fixed Mice.

This chapter presents a method for performing in vivo single-unit extracellular recordings and optogenetics during an associative, cerebellum-dependent learning task in head-fixed mice. The method uses a cylindrical treadmill system that reduces stress in the mice by allowing them to walk freely, yet it provides enough stability to maintain single-unit isolation of neurons for tens of minutes to hours. Using this system, we have investigated sensorimotor coding in the cerebellum while mice perform learned skilled movements.

Insights into the epidemiological link between biting flies and pemphigus foliaceus in southeastern Brazil.

BACKGROUND: Black fly and sandfly bites are related to the endemicity of pemphigus foliaceus (PF); however, an immune reaction against the salivary proteins from these flies still requires confirmation in the case of PF patients living in southeastern Brazil. PURPOSE: To georeference the distribution of Simuliidae (Diptera: Simuliidae) and Phlebotominae (Diptera: Psychodidae) and of PF cases in the northeastern region of São Paulo State, and to assess the humoral immune response against salivary gland extracts (SGEs) from biting flies in PF patients, relatives, and neighbours. METHODS: PF patients' medical information recorded between 1965 and 2014 were obtained from the database of the University Hospital. Data on the distribution of fly species were collected from scientific reports and epidemiological databases. Spatial maps relating the distribution of biting flies with PF cases were plotted. Serum IgG antibodies against the SGEs from Simulium nigrimanum, Nyssomyia neivai, and Aedes aegypti (as control) were determined by ELISA. RESULTS: Two hundred and eighty-five PF cases were distributed in 60 municipalities with a prevalence of 57.5 per million inhabitants, revealing well-defined geographical clusters. S. nigrimanum and N. neivai specimens were registered in eight (13.3%) and 26 (43.3%) of these municipalities, respectively. PF patients, and their relatives presented higher levels of IgG against the SGEs of S. nigrimanum and N. neivai (P<0.001 for both), but not against the SGE from A. aegypti (P=0.115 and P=0.552, respectively), as compared to controls. IgG against the SGEs from S. nigrimanum and N. neivai but not against the SGE from A. aegypti correlated with levels of anti-Desmoglein 1 in PF patients (r=0.3848, P=0.039; and r=0.416, P=0.022, respectively). CONCLUSION: An epidemiological link between biting flies and PF in southeastern Brazil is proposed, implying a possible role of the salivary proteins from these flies in PF etiopathogenesis.

Family study of monozygotic twins affected by pemphigus vulgaris.

Rare are the family studies that include siblings affected by pemphigus vulgaris (PV) and in whom HLA class II alleles are related. HLA-DR and -DQ genotyping and profiling of antibodies against desmogleins (Dsg) 1 and Dsg3 were performed in ten members of a family including monozygotic twins affected by PV. The twin sisters were heterozygotes; they presented the haplotypes most commonly associated with increased susceptibility to PV (DRB1∗04:02-DQA1∗03:01-DQB1∗03:02 and DRB1∗14:04-DQA1∗01:01-DQB1∗05:03). Their parents and five siblings had only one or none of these two haplotypes in combination with the alleles or haplotypes associated with resistance to PV (DRB1∗07:01-DQA1∗02:01-DQB1∗02:02 and DRB1∗13:01-DQA1∗01:03-DQB1∗06:03). Only the monozygotic twins presented IgG antibodies against both Dsg1 and Dsg3. According to our knowledge based on a review of published literature on the topic, this is the first report of PV affecting monozygotic twins.

Sensitivity to self-administered cocaine within the lateral preoptic-rostral lateral hypothalamic continuum.

The lateral preoptic-rostral lateral hypothalamic continuum (LPH) receives projections from the nucleus accumbens and is believed to be one route by which nucleus accumbens signaling affects motivated behaviors. While accumbens firing patterns are known to be modulated by fluctuating levels of cocaine, studies of the LPH's drug-related firing are absent from the literature. The present study sought to electrophysiologically test whether drug-related tonic and slow-phasic patterns exist in the firing of LPH neurons during a free-access cocaine self-administration task. Results demonstrated that a majority of neurons in the LPH exhibited changes in both tonic and slow-phasic firing rates during fluctuating drug levels. During the maintenance phase of self-administration, 69.6% of neurons exhibited at least a twofold change in tonic firing rate when compared to their pre-drug firing rates. Moreover, 54.4% of LPH neurons demonstrated slow-phasic patterns, specifically "progressive reversal" patterns, which have been shown to be related to pharmacological changes across the inter-infusion interval. Firing rate was correlated with calculated drug level in 58.7% of recorded cells. Typically, a negative correlation between drug level and firing rate was observed, with a majority of neurons showing decreases in firing during cocaine self-administration. A small percentage of LPH neurons also exhibited correlations between locomotor behavior and firing rate; however, correlations with drug level in these same neurons were always stronger. Thus, the weak relationships between LPH firing and locomotor behaviors during cocaine self-administration do not account for the observed changes in firing. Overall, these findings suggest that a proportion of LPH neurons are sensitive to fluctuations in cocaine concentration and may contribute to neural activity that controls drug taking.

Distractibility during episodic retrieval is exacerbated by perturbation of left ventrolateral prefrontal cortex.

The presence of irrelevant external stimuli during the retrieval of long-term memory (LTM) has a negative impact on the fidelity of recollected details. Top-down control processes that both guide the selection of internal information relevant to LTM goals and resolve interference on retrieval from irrelevant external information have been associated with the same region in left ventrolateral prefrontal cortex (VLPFC). The current study examined a causal role of the left VLPFC in memory performance when external distraction (i.e., visual stimuli irrelevant to the current task goals) was presented during retrieval of LTM. Immediately after functional perturbation of the left VLPFC with 1-Hz repetitive transcranial magnetic stimulation, participants' memory was tested when their eyes were closed and when their eyes were open and irrelevant visual stimuli were presented. The results showed that visual distraction diminished LTM performance based on an objective measure of recollection and that perturbation of left VLPFC exacerbated the disruptive effect. This is the first evidence of a direct role of the left VLPFC in diminishing the impact of distraction on recollection, elucidating neural mechanisms that are critically involved in how we reconstruct the past while navigating the external environment.

Recombinant human parainfluenza virus type 2 with mutations in V that permit cellular interferon signaling are not attenuated in non-human primates.

The HPIV2 V protein inhibits type I interferon (IFN) induction and signaling. To manipulate the V protein, whose coding sequence overlaps that of the polymerase-associated phosphoprotein (P), without altering the P protein, we generated an HPIV2 virus in which P and V are expressed from separate genes (rHPIV2-P+V). rHPIV2-P+V replicated like HPIV2-WT in vitro and in non-human primates. HPIV2-P+V was modified by introducing two separate mutations into the V protein to create rHPIV2-L101E/L102E and rHPIV2-Delta122-127. In contrast to HPIV2-WT, both mutant viruses were unable to degrade STAT2, leaving virus-infected cells susceptible to IFN. Neither mutant, nor HPIV2-WT, induced significant amounts of IFN-beta in infected cells. Surprisingly, neither rHPIV2-L101E/L102E nor rHPIV2-Delta122-127 was attenuated in two species of non-human primates. This indicates that loss of HPIV2's ability to inhibit IFN signaling is insufficient to attenuate virus replication in vivo as long as IFN induction is still inhibited.

Correlation between beta-2-glycoprotein I gene polymorphism and anti-beta-2 glycoprotein I antibodies in patients with multibacillary leprosy.

Antiphospholipid antibodies, such as anti-beta2-glycoprotein I (beta2GPI), are present in multibacillary leprosy (MB) patients; however, MB patients do not usually present with antiphospholipid antibody syndrome (APS), which is characterized by thromboembolic phenomena (TEP). Rare cases of TEP occur in leprosy patients, but the physiopathology of this condition remains unclear. In this case-control study, we examined whether single-nucleotide polymorphisms (SNPs) of the beta2GPI gene contributed to the risk of leprosy and APS co-morbidity. SNPs Ser88Asn, Leu247Val, Cys306Gly and Trp316Ser were identified in 113 Brazilian leprosy patients. Additionally, anti-beta2GPI antibodies and plasma concentrations of beta2GPI were quantified. The Ser88Asn, Cys306Gly and Trp316Ser SNPs were not risk factors for APS in leprosy. A higher frequency of Val/Val homozygosity was observed in leprosy patients compared to controls (36 vs. 5%; P < 0.001). Forty-two percent of MB and 17% of paucibacillary leprosy patients were positive for anti-beta2GPI IgM (P = 0.014). There was no correlation between SNP Ser88Asn or Cys306Gly and anti-beta2GPI antibody levels. In MB patients with positive anti-beta2GPI IgM, the frequency of Val/Val homozygosity was higher than in controls (32 vs. 15%; P = 0.042). The frequency of the mutant allele Ser316 was higher in MB patients with positive rather than negative anti-beta2GPI IgM levels (6 vs. 0%; P = 0.040) and was greater than in the control group (6 vs. 1%; P = 0.034). The studied polymorphisms did not influence the plasma concentrations of beta2GPI. These results suggest that Leu247Val and Trp316Ser SNPs may represent genetic risk factors for anti-beta2GPI antibody production in MB patients.

Recombinant human parainfluenza virus type 2 vaccine candidates containing a 3' genomic promoter mutation and L polymerase mutations are attenuated and protective in non-human primates.

Previously, we identified several attenuating mutations in the L polymerase protein of human parainfluenza virus type 2 (HPIV2) and genetically stabilized those mutations using reverse genetics [Nolan SM, Surman S, Amaro-Carambot E, Collins PL, Murphy BR, Skiadopoulos MH. Live-attenuated intranasal parainfluenza virus type 2 vaccine candidates developed by reverse genetics containing L polymerase protein mutations imported from heterologous paramyxoviruses. Vaccine 2005;39(23):4765-74]. Here we describe the discovery of an attenuating mutation at nucleotide 15 (15(T-->C)) in the 3' genomic promoter that was also present in the previously characterized mutants. We evaluated the properties of this promoter mutation alone and in various combinations with the L polymerase mutations. Amino acid substitutions at L protein positions 460 (460A or 460P) or 948 (948L), or deletion of amino acids 1724 and 1725 (Delta1724), each conferred a temperature sensitivity (ts) phenotype whereas the 15(T-->C) mutation did not. The 460A and 948L mutations each contributed to restricted replication in the lower respiratory tract of African green monkeys, but the Delta1724 mutation increased attenuation only in certain combinations with other mutations. We constructed two highly attenuated viruses, rV94(15C)/460A/948L and rV94(15C)/948L/Delta1724, that were immunogenic and protective against challenge with wild-type HPIV2 in African green monkeys and, therefore, appear to be suitable for evaluation in humans.