Mechanisms of within-session sequential behavior in pigeons.

Correctly and efficiently selecting among options is critical to the organization of behavior across different time scales (minutes, days, seasons). As a result, understanding the mechanisms underlying the sequential behavior of animals has been a long-standing aim. In three experiments, four pigeons were tested in a four-choice simultaneous color discrimination. Across a session, they had to sequentially select a colored stimulus, and the correct color changed over four 24-trial phases (A→B→C→D). After learning this ABCD within-session sequence, tests identified that both timing and outcome feedback mechanisms contributed to the organization of pigeons' behavior. Different representational mechanisms are considered as accounts for the pigeons' observed sequential behavior.

Does Real Age Feedback Really Motivate Us to Change our Lifestyle? Results from an Online Experiment.

We set out to research the causal impact of Real Age feedback, a popular tool on health and lifestyle platforms, on health behaviors. We ran an online experiment where participants were randomly assigned a Real Age that differed in both direction (older or younger) and magnitude (much or slightly) from their passport age, or to a control condition where they received no Real Age feedback. We measured the impact of Real Age feedback on motivation to begin a healthier lifestyle, interest in taking a Real Age test, and percentage click-rate on an optional health link. We found that younger Real Age feedback was associated with higher interest. In addition, participants who received a slightly older Real Age were significantly less motivated to begin a healthier lifestyle compared to not only those who received a much younger or much older Real Age, but also to those in the control condition, suggesting a backfire effect. This effect remained even after accounting for participant health, demographics, and other psychological correlates to motivation. Real Age tests may backfire and demotivate people, and the positive effects they may have on psychological states may not outweigh the negative effects. Though promising, we caution using Real Age tests in their current form as stand-alone interventions to get people motivated.

Thoughts and beliefs of healthcare workers regarding the coronavirus disease 2019 (COVID-19) vaccine and which messaging themes might affect vaccine confidence and recommendation of the vaccine.

We surveyed healthcare workers within the Duke Antimicrobial Stewardship Outreach Network (DASON) to describe beliefs regarding coronavirus disease 2019 (COVID-19) vaccination and their decision-making process behind vaccination recommendations. In contrast to the type of messaging that appealed most on a personal level to the healthcare workers, they preferred a more generic message emphasizing safety and efficacy when making vaccination recommendations.

Intratumoral expression of IL-12 from lentiviral or RNA vectors acts synergistically with TLR4 agonist (GLA) to generate anti-tumor immunological memory.

Systemic interleukin-12 (IL12) anti-tumor therapy is highly potent but has had limited utility in the clinic due to severe toxicity. Here, we present two IL12-expressing vector platforms, both of which can overcome the deficiencies of previous systemic IL12 therapies: 1) an integrating lentiviral vector, and 2) a self-replicating messenger RNA formulated with polyethyleneimine. Intratumoral administration of either IL12 vector platform resulted in recruitment of immune cells, including effector T cells and dendritic cells, and the complete remission of established tumors in multiple murine models. Furthermore, concurrent intratumoral administration of the synthetic TLR4 agonist glucopyranosyl lipid A formulated in a stable emulsion (GLA-SE) induced systemic memory T cell responses that mediated complete protection against tumor rechallenge in all survivor mice (8/8 rechallenged mice), whereas only 2/6 total rechallenged mice treated with intratrumoral IL12 monotherapy rejected the rechallenge. Taken together, expression of vectorized IL12 in combination with a TLR4 agonist represents a varied approach to broaden the applicability of intratumoral immune therapies of solid tumors.

Within-session dynamics of categorical and memory mechanisms in pigeons.

The current experiments used categorical mid-session reversal (MSR) to examine how eight pigeons utilized categorical and item-specific mechanisms to learn and solve a novel variation of this task. Employing a fixed order of trial-unique pictorial items from two categories (flowers and cars) on each simultaneous discrimination trial, categorical and item-specific information was available during each session's 80 trials. Choices to one category were rewarded for the first 40 trials, after which the correct category was reversed (e.g., car correct early → flower correct late). This procedure selectively impacts the time-modulated utility of categorical identification, but leaves exclusively item-specific information intact. Results revealed that categorical control emerged rapidly and before item-specific memorization, which came after extended experience. Both types of control occurred within a session, with control modulated by their time-based relative utility. The implications for the timing, ordering, and attention by animals to categorical and item-specific information is considered.

Evaluating the Minimal Clinically Important Difference of the King's Sarcoidosis Questionnaire in a Multicenter Prospective Study.

Rationale: Improvement of quality of life (QoL) in patients with sarcoidosis is an important goal of management. The King's Sarcoidosis Questionnaire (KSQ) and Patient Global Assessment (PGA) are instruments that have been used in sarcoidosis.Objectives: We defined the minimal clinically important difference (MCID) as the within-patient clinically meaningful change threshold and determined the MCID of KSQ general health (KSQ GH), KSQ lung, and PGA using both anchor and distribution methods. The discriminatory properties of these MCIDs relative to other QoL instruments were then determined.Methods: Patients with sarcoidosis recruited from six centers in the United States were prospectively studied. Initially and at 6 months, patients completed a series of QoL questionnaires, including the St. George's Respiratory Questionnaire (SGRQ), Short Form 36 (SF-36), Fatigue Assessment Scale (FAS), Sarcoidosis Assessment Tool (SAT), KSQ, and PGA, and spirometry. For the anchor method, receiver operator characteristic curves were used to determine the MCID for improvement or worsening. The distribution method using half of the standard deviation was calculated for KSQ GH, KSQ lung, and PGA.Results: Of the 325 patients enrolled in the study, 271 completed the 6-month evaluation. At 6 months, approximately half of patients were worse and 30% were improved based on previously established MCID values for the SGRQ, SF-36, and FAS. There were no discordant cases. There were significant correlations between the KSQ GH, KSQ lung, and PGA and most parameters assessed. The best correlations were with the SGRQ, SF-36, and FAS, which have established MCID values. Using anchor analysis, we found that most of the domains of SGRQ and SF-36 were able to determine the significant MCIDs for all three variables. These MCIDs were similar to those determined by the half least square method. We propose an MCID of 8 for the KSQ GH, an MCID of 4 for the KSQ lung, and an MCID of 2 for the PGA because these values captured >90% of parameters studied. These MCID values discriminated between changes in other QoL instruments.Conclusions: The determination of MCID values for KSQ lung, KSQ GH, and PGA may prove useful for clinical practice as well as clinical trials.

Therapeutic efficacy of PD1/PDL1 blockade in B16 melanoma is greatly enhanced by immunization with dendritic cell-targeting lentiviral vector and protein vaccine.

While immune checkpoint inhibition is rapidly becoming standard of care in many solid tumors, immune checkpoint inhibitors (ICIs) fail to induce clinical responses in many patients, presumably due to insufficient numbers of tumor-specific T cells in the tumor milieu. To this end, immunization protocols using viral vectors expressing tumor-associated antigens are being explored to induce T cell responses that synergize with ICIs. However, the optimal combination of vaccine and immune checkpoint regimen remains undefined. Here, a dendritic cell-targeting lentiviral vector (ZVex®) expressing the endogenous murine tyrosinase-related protein 1 (mTRP1), or the human tumor antigen NY-ESO-1, was explored as monotherapy or heterologous prime-boost (HPB) vaccine regimen together with recombinant tumor antigen in the murine B16 melanoma model. PD1/PDL1 blockade significantly enhanced ZVex/mTRP1, but not ZVex/NY-ESO-1, induced immune responses in mice, whereas the opposite effect was observed with anti-CTLA4 antibody. Anti-tumor efficacy of anti-PD1, but not anti-PDL1 or anti-CTLA4, was significantly enhanced by ZVex/mTRP1 and HPB vaccination. These results suggest mechanistic differences in the effect of checkpoint blockade on vaccine-induced immune and anti-tumor responses against self versus non-self tumor antigens, possibly due to tolerance and state of exhaustion of anti-tumor T cells.

Spatial midsession reversal learning in rats: Effects of egocentric Cue use and memory.

The midsession reversal task has been used to investigate behavioral flexibility and cue use in non-human animals, with results indicating differences in the degree of control by environmental cues across species. For example, time-based control has been found in rats only when tested in a T-maze apparatus and under specific conditions in which position and orientation (i.e., egocentric) cues during the intertrial interval could not be used to aid performance. Other research in an operant setting has shown that rats often produce minimal errors around the reversal location, demonstrating response patterns similar to patterns exhibited by humans and primates in this task. The current study aimed to reduce, but not eliminate, the ability for rats to utilize egocentric cues by placing the response levers on the opposite wall of the chamber in relation to the pellet dispenser. Results showed that rats made minimal errors prior to the reversal, suggesting time-based cues were not controlling responses, and that they switched to the second correct stimulus within a few trials after the reversal event. Video recordings also revealed highly structured patterns of behavior by the majority of rats, which often differed depending on which response was reinforced. We interpret these findings as evidence that rats are adept at utilizing their own egocentric cues and that these cues, along with memory for the recent response-reinforcement contingencies, aid in maximizing reinforcement over the session.

Within-session reversal learning in rhesus macaques (Macaca mulatta).

In a midsession reversal (MSR) task, animals are typically presented with a simple, simultaneous discrimination (S1+, S2-) where contingencies are reversed (S1-, S2+) half-way through each session. This paradigm creates multiple, relevant cues that can aid in maximizing overall reinforcement. Recent research has shown that pigeons show systematic anticipatory and perseverative errors across the session, which increase as a function of proximity to the reversal trial. This behavior has been theorized to indicate primary control by temporal cues across the session, instead of the cues provided by recent reinforcement history that appear to control behavior shown by humans. Rats, however, appear to be guided by recent reinforcement history when tested in an operant context, thereby demonstrating behavior that parallels that seen in humans, but they appear to be guided by temporal cues when tested in an open-field apparatus, showing behavior more akin to that seen in pigeons. We tested rhesus macaques (Macaca mulatta) on the MSR with a computerized simultaneous visual discrimination to assess whether they would show errors indicative of control by time or by recent reinforcement history. When a single reversal point occurred midsession, rhesus macaques showed no anticipation of the reversal and a similar level of perseveration to rats tested in an operant setting. Nearly identical results also were observed when the monkeys were trained with a single, variable reversal point or with multiple, variable reversal points within a session. These results indicate that temporal cues are not guiding response flexibility in rhesus macaque visual discrimination.

Dynamic cue use in pigeon mid-session reversal.

The systematic anticipation and preservation errors produced by pigeons around the reversal point in midsession reversal (MSR) learning experiments suggest that an internal time estimation cue, instead of a more efficient external cue provided by reinforcement, controls behavior over the course of a session. The current experiments examined the role and effectiveness of other external cues in the MSR task. In Experiment 1, providing differential outcomes based on response key location produced fewer errors prior to, but not after, the reversal as compared with a non-differential outcomes condition. Experiment 2a used alternating differentially colored ITIs (cued sessions) or dark ITIs (un-cued sessions) during each half of the session. The ITI cues improved switch efficiency both prior to and after the reversal. Experiment 2b introduced probe trials around the reversal, testing ITI color cues added to un-cued sessions or removed from cued sessions. Results showed control by the ITI cues when they were available and control by the time-based cue when they were unavailable. This suggests both cues were being simultaneously processed when available and that the cues could also independently provide sufficient information about future reinforcement. In Experiment 2c, ITI cues were inserted as probe trials in the opposite half of the session (miscues). The closer such miscue trials were to the reversal, the more the ITI cues exerted control over behavior. Together, these results indicate that as the utility of internal temporal cues is reduced, the use of external visual cues increases. These results have implications for the way in which cues dynamically shift in controlling behavior over time based on their relative rates of utility, and are discussed in light of an occasion setting perspective.

The Organization of Behavior Over Time: Insights from Mid-Session Reversal.

What are the mechanisms by which behavior is organized sequentially over time? The recently developed mid-session reversal (MSR) task offers new insights into this fundamental question. The typical MSR task is arranged to have a single reversed discrimination occurring in a consistent location within each session and across sessions. In this task, we examine the relevance of time, reinforcement, and other factors as the switching cue in the sequential modulation of control in MSR. New analyses also highlight some of the potential mechanisms underlying this serially organized behavior. MSR provides new evidence and we offer some ideas about how cues interact to compete for the control of behavior within and across sessions. We suggest that MSR is an excellent preparation for studying the competition among psychological states and their resolution toward action.

Who are the real bird brains? Qualitative differences in behavioral flexibility between dogs (Canis familiaris) and pigeons (Columba livia).

Pigeons given a simultaneous spatial discrimination reversal, in which a single reversal occurs at the midpoint of each session, consistently show anticipation prior to the reversal as well as perseveration after the reversal, suggesting that they use a less effective cue (time or trial number into the session) than what would be optimal to maximize reinforcement (local feedback from the most recent trials). In contrast, rats (Rattus norvegicus) and humans show near-optimal reversal learning on this task. To determine whether this is a general characteristic of mammals, in the present research, pigeons (Columba livia) and dogs (Canis familiaris) were tested with a simultaneous spatial discrimination mid-session reversal. Overall, dogs performed the task more poorly than pigeons. Interestingly, both pigeons and dogs employed what resembled a timing strategy. However, dogs showed greater perseverative errors, suggesting that they may have relatively poorer working memory and inhibitory control with this task. The greater efficiency shown by pigeons with this task suggests they are better able to time and use the feedback from their preceding choice as the basis of their future choice, highlighting what may be a qualitative difference between the species.

Partial Meal Replacement Plan and Quality of the Diet at 1 Year: Action for Health in Diabetes (Look AHEAD) Trial.

BACKGROUND: Little is known about diet quality with a reduced-energy, low-fat, partial meal replacement plan, especially in individuals with type 2 diabetes. The Action for Health in Diabetes (Look AHEAD) trial implemented a partial meal replacement plan in the Intensive Lifestyle Intervention. OBJECTIVE: To compare dietary intake and percent meeting fat-related and food group dietary recommendations in Intensive Lifestyle Intervention and Diabetes Support and Education groups at 12 months. DESIGN: A randomized controlled trial comparing Intensive Lifestyle Intervention with Diabetes Support and Education at 0 and 12 months. PARTICIPANTS/SETTING: From 16 US sites, the first 50% of participants (aged 45 to 76 years, overweight or obese, with type 2 diabetes) were invited to complete dietary assessments. Complete 0- and 12-month dietary assessments (collected between 2001 and 2004) were available for 2,397 participants (46.6% of total participants), with 1,186 randomized to Diabetes Support and Education group and 1,211 randomized to Intensive Lifestyle Intervention group. MAIN OUTCOME MEASURES: A food frequency questionnaire assessed intake: energy; percent energy from protein, fat, carbohydrate, polyunsaturated fatty acids, and saturated fats; trans-fatty acids; cholesterol; fiber; weekly meal replacements; and daily servings from food groups from the Food Guide Pyramid. STATISTICAL ANALYSES PERFORMED: Mixed-factor analyses of covariance, using Proc MIXED with a repeated statement, with age, sex, race/ethnicity, education, and income controlled. Unadjusted χ² tests compared percent meeting fat-related and food group recommendations at 12 months. RESULTS: At 12 months, Intensive Lifestyle Intervention participants had a significantly lower fat and cholesterol intake and greater fiber intake than Diabetes Support and Education participants. Intensive Lifestyle Intervention participants consumed more servings per day of fruits; vegetables; and milk, yogurt, and cheese; and fewer servings per day of fats, oils, and sweets than Diabetes Support and Education participants. A greater percentage of Intensive Lifestyle Intervention participants than Diabetes Support and Education participants met fat-related and most food group recommendations. Within Intensive Lifestyle Intervention, a greater percentage of participants consuming two or more meal replacements per day than participants consuming less than one meal replacement per day met most fat-related and food group recommendations. CONCLUSIONS: The partial meal replacement plan consumed by Intensive Lifestyle Intervention participants was related to superior diet quality.

Pesticide concentrations in frog tissue and wetland habitats in a landscape dominated by agriculture.

Habitat loss and exposure to pesticides are likely primary factors contributing to amphibian decline in agricultural landscapes. Conservation efforts have attempted to restore wetlands lost through landscape modifications to reduce contaminant loads in surface waters and providing quality habitat to wildlife. The benefits of this increased wetland area, perhaps especially for amphibians, may be negated if habitat quality is insufficient to support persistent populations. We examined the presence of pesticides and nutrients in water and sediment as indicators of habitat quality and assessed the bioaccumulation of pesticides in the tissue of two native amphibian species Pseudacris maculata (chorus frogs) and Lithobates pipiens (leopard frogs) at six wetlands (3 restored and 3 reference) in Iowa, USA. Restored wetlands are positioned on the landscape to receive subsurface tile drainage water while reference wetlands receive water from overland run-off and shallow groundwater sources. Concentrations of the pesticides frequently detected in water and sediment samples were not different between wetland types. The median concentration of atrazine in surface water was 0.2 µg/L. Reproductive abnormalities in leopard frogs have been observed in other studies at these concentrations. Nutrient concentrations were higher in the restored wetlands but lower than concentrations thought lethal to frogs. Complex mixtures of pesticides including up to 8 fungicides, some previously unreported in tissue, were detected with concentrations ranging from 0.08 to 1,500 µg/kg wet weight. No significant differences in pesticide concentrations were observed between species, although concentrations tended to be higher in leopard frogs compared to chorus frogs, possibly because of differences in life histories. Our results provide information on habitat quality in restored wetlands that will assist state and federal agencies, landowners, and resource managers in identifying and implementing conservation and management actions for these and similar wetlands in agriculturally dominated landscapes.

Autonomous stimulation of cancer cell plasticity by the human NKG2D lymphocyte receptor coexpressed with its ligands on cancer cells.

The stimulatory NKG2D receptor on lymphocytes promotes tumor immune surveillance by targeting ligands selectively induced on cancer cells. Progressing tumors counteract by employing tactics to disable lymphocyte NKG2D. This negative dynamic is escalated as some human cancer cells co-opt expression of NKG2D, thereby complementing the presence of its ligands for autonomous stimulation of oncogenic signaling. Clinical association data imply relationships between cancer cell NKG2D and metastatic disease. Here we show that NKG2D promotes cancer cell plasticity by induction of phenotypic, molecular, and functional signatures diagnostic of the epithelial-mesenchymal transition, and of stem-like traits via induction of Sox9, a key transcriptional regulator of breast stem cell maintenance. These findings obtained with model breast tumor lines and xenotransplants were recapitulated by ex vivo cancer cells from primary invasive breast carcinomas. Thus, NKG2D may have the capacity to drive high malignancy traits underlying metastatic disease.

Fiber intake and plasminogen activator inhibitor-1 in type 2 diabetes: Look AHEAD (Action for Health in Diabetes) trial findings at baseline and year 1.

Plasminogen activator inhibitor 1 (PAI-1) is elevated in obese individuals with type 2 diabetes and may contribute, independently of traditional factors, to increased cardiovascular disease risk. Fiber intake may decrease PAI-1 levels. We examined the associations of fiber intake and its changes with PAI-1 before and during an intensive lifestyle intervention (ILI) for weight loss in 1,701 Look AHEAD (Action for Health in Diabetes) participants with dietary, fitness, and PAI-1 data at baseline and 1 year. Look AHEAD was a randomized cardiovascular disease trial in 5,145 overweight/obese patients with type 2 diabetes, comparing ILI (goal of ≥7% reduction in baseline weight) with a control arm of diabetes support and education. ILI participants were encouraged to consume vegetables, fruits, and grain products low in sugar and fat. At baseline, median fiber intake was 17.9 g/day. Each 8.3 g/day higher fiber intake was associated with a 9.2% lower PAI-1 level (P=0.008); this association persisted after weight and fitness adjustments (P=0.03). Higher baseline intake of fruit (P=0.019) and high-fiber grain and cereal (P=0.029) were related to lower PAI-1 levels. Although successful in improving weight and physical fitness at 1 year, the ILI in Look AHEAD resulted in small increases in fiber intake (4.1 g/day, compared with -2.35 g/day with diabetes support and education) that were not related to PAI-1 change (P=0.34). Only 31.3% of ILI participants (39.8% of women, 19.1% of men) met daily fiber intake recommendations. Increasing fiber intake in overweight/obese individuals with diabetes interested in weight loss is challenging. Future studies evaluating changes in fiber consumption during weight loss interventions are warranted.

Repeated Acquisition in the Morris Swim Task: Effects of MDMA, Methamphetamine and Methylphenidate.

Acute effects of methylenedioxymethamphetamine (MDMA), methamphetamine (MA) and methylphenidate (MPD) were studied using a within-subject, repeated acquisition/performance procedure adapted to the Morris Swim Task. To investigate place learning, the acquisition component consisted of a hidden platform that varied in location across experimental sessions. As a control for drug effects not specific to acquisition, a performance component was included in which the hidden platform was in the same pool location in every experimental session. All three drugs increased escape latencies and swim distances in dose-dependent fashion. However, impairment in the acquisition component was generally observed only at doses that also produced impairment in the performance component, suggesting that effects were not selective to place learning. None of the drugs produced enhancement of learning or performance at any dose. Taken together, the results suggest that acute exposure to these psychomotor stimulants produce global impairment of performance in the Morris task, rather than specific deficits in place learning.

Midsession reversals with pigeons: visual versus spatial discriminations and the intertrial interval.

Discrimination reversal learning has been used as a measure of species flexibility in dealing with changes in reinforcement contingency. In the simultaneous-discrimination, midsession-reversal task, one stimulus (S1) is correct for the first half of the session, and the other stimulus (S2) is correct for the second half. After training, pigeons show a curious pattern of choices: They begin to respond to S2 well before the reversal point (i.e., they make anticipatory errors), and they continue to respond to S1 well after the reversal (i.e., they make perseverative errors). That is, pigeons appear to be using the passage of time or the number of trials into the session as a cue to reverse, and are less sensitive to the feedback at the point of reversal. To determine whether the nature of the discrimination or a failure of memory for the stimulus chosen on the preceding trial contributed to the pigeons' less-than-optimal performance, we manipulated the nature of the discrimination (spatial or visual) and the duration of the intertrial interval (5.0 or 1.5 s), in order to determine the conditions under which pigeons would show efficient reversal learning. The major finding was that only when the discrimination was spatial and the intertrial interval was short did the pigeons perform optimally.

Findings from an online behavioural weight management programme provided with or without a fortified diet beverage.

The present multi-centre randomised weight-loss trial evaluated the efficacy of a low-intensity 12-week online behavioural modification programme, with or without a fortified diet beverage using a 2 × 2 factorial design. A total of 572 participants were randomised to: (1) an online basic lifestyle information (OBLI) intervention, consisting of one online informational class about tips for weight management; (2) an online behavioural weight management (OBWM) intervention, entailing 12 weekly online classes focused on weight-loss behaviour modification; (3) an OBLI intervention plus a fortified diet cola beverage (BEV) containing green tea extract (total catechin 167 mg), soluble fibre dextrin (10 g) and caffeine (100 mg) (OBLI+BEV); (4) OBWM+BEV. Assessments included height, weight, dual-energy X-ray absorptiometry-derived body composition, and waist circumference (WC). Attrition was 15·7 %. Intention-to-treat (ITT) models demonstrated a main effect for type of Internet programme, with those assigned to the OBWM condition losing significantly more weight (F= 7·174; P= 0·008) and fat mass (F= 4·491; P= 0·035) than those assigned to the OBLI condition. However, there was no significant main effect for the OBWM condition on body fat percentage (F= 2·906; P= 0·089) or WC (F= 3·351; P= 0·068), and no significant main effect for beverage use or significant interactions between factors in ITT models. A 12-week, low-intensity behaviourally based online programme produced a greater weight loss than a basic information website. The addition of a fortified diet beverage had no additional impact.