Comparative effectiveness of perioperative physical activity in older adults with lung cancer and their family caregivers: design of a multicenter pragmatic randomized trial.

BACKGROUND: With a median age at diagnosis of 70, lung cancer remains a significant public health challenge for older Americans. Surgery is a key component in treating most patients with non-metastatic lung cancer. These patients experience postoperative pain, fatigue, loss of respiratory capacity, and decreased physical function. Data on quality of life (QOL) in older adults undergoing lung cancer surgery is limited, and few interventions are designed to target the needs of older adults and their family caregivers (FCGs). The primary aim of this comparative effectiveness trial is to determine whether telephone-based physical activity coaching before and after surgery will be more beneficial than physical activity self-monitoring alone for older adults and their FCGs. METHODS: In this multicenter comparative effectiveness trial, 382 older adults (≥ 65 years) with lung cancer and their FCGs will be recruited before surgery and randomized to either telephone-based physical activity coaching or physical activity self-monitoring alone. Participants allocated to the telephone-based coaching comparator will receive five telephone sessions with coaches (1 pre and 4 post surgery), an intervention resource manual, and a wristband pedometer. Participants in the self-monitoring only arm will receive American Society of Clinical Oncology (ASCO) physical activity information and wristband pedometers. All participants will be assessed at before surgery (baseline), at discharge, and at days 30, 60, and 180 post-discharge. The primary endpoint is the 6-minute walk test (6MWT) at 30 days post-discharge. Geriatric assessment, lower extremity function, self-reported physical function, self-efficacy, and QOL will also be assessed. DISCUSSION: The trial will determine whether this telephone-based physical activity coaching approach can enhance postoperative functional capacity and QOL outcomes for older adults with lung cancer and their FCGs. Trial results will provide critical findings to inform models of postoperative care for older adults with cancer and their FCGs. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT06196008.

Effective stakeholder engagement: design and implementation of a clinical trial (SWOG S1415CD) to improve cancer care.

BACKGROUND: The Fred Hutchinson Cancer Research Center has engaged an External Stakeholder Advisory Group (ESAG) in the planning and implementation of the TrACER Study (S1415CD), a five-year pragmatic clinical trial assessing the effectiveness of a guideline-based colony stimulating factor standing order intervention. The trial is being conducted by SWOG through the National Cancer Institute Community Oncology Research Program in 45 clinics. The ESAG includes ten patient partners, two payers, two pharmacists, two guideline experts, four providers and one medical ethicist. This manuscript describes the ESAG's role and impact on the trial. METHODS: During early trial development, the research team assembled the ESAG to inform plans for each phase of the trial. ESAG members provide feedback and engage in problem solving to improve trial implementation. Each year, members participate in one in-person meeting, web conferences and targeted email discussion. Additionally, they complete a survey that assesses their satisfaction with communication and collaboration. The research team collected and reviewed stakeholder input from 2014 to 2018 for impact on the trial. RESULTS: The ESAG has informed trial design, implementation and dissemination planning. The group advised the trial's endpoints, regimen list and development of cohort and usual care arms. Based on ESAG input, the research team enhanced patient surveys and added pharmacy-related questions to the component application to assess order entry systems. ESAG patient partners collaborated with the research team to develop a patient brochure and study summary for clinic staff. In addition to identifying recruitment strategies and patient-oriented platforms for publicly sharing results, ESAG members participated as co-authors on this manuscript and a conference poster presentation highlighting stakeholder influence on the trial. The annual satisfaction survey results suggest that ESAG members were satisfied with the methods, frequency and target areas of their engagement in the trial during project years 1-3. CONCLUSIONS: Diverse stakeholder engagement has been essential in optimizing the design, implementation and planned dissemination of the TrACER Study. The lessons described in the manuscript may assist others to effectively partner with stakeholders on clinical research.

LOEYS-DIETZ SYNDROME: PERIOPERATIVE ANESTHESIA CONSIDERATIONS.

Loeys-Dietz syndrome (LDS) is a rare autosomal dominant disease related to genetic mutations in receptors for the cytokine transforming growth factor-receptor type 1 (TGFB-R1) or 2 gene (TGFB-R2) on the cell surface. LDS results in abnormal protein synthesis and dysfunctional connective tissue, which can result in unique cardiovascular anesthesia challenges related to perioperative management. Patients with LDS may manifest hypertelorism, bifid uvula or cleft palate, and arterial tortuosity. Virtually all LDS patients show some type of abnormal skin findings and bleeding tendency. These patients may show a rapid progression of aortic dilation, regurgitation, and a propensity towards rupture and/or dissection at a much earlier age and smaller aneurysm size. LDS patients who require surgical intervention require meticulous vigilance from the anesthesiologist. We describe a 26 year old patient with documented LDS type 1 who presented for repair of an ascending/root aneurysm in this case report. Recognition of LDS and intra-operative management of the cardiovascular manifestations of this disease is paramount in ensuring successful surgical outcome and to limit morbidity and mortality.

Thermal Death Kinetics of Conogethes Punctiferalis (Lepidoptera: Pyralidae) as Influenced by Heating Rate and Life Stage.

Thermal death kinetics of Conogethes punctiferalis (Guenée) (Lepidoptera: Pyralidae) at different life stages, heating rate, and temperature is essential for developing postharvest treatments to control pests in chestnuts. Using a heating block system (HBS), the most heat-tolerant life stage of C. punctiferalis and the effects of heating rate (0.1, 0.5, 1, 5, and 10°C/min) on insect mortality were determined. The thermal death kinetic data of fifth-instar C. punctiferalis were obtained at temperatures between 44 and 50°C at a heating rate of 5°C/min. The results showed that the relative heat tolerance of C. punctiferalis was found to be fifth instars>pupae> third instars> eggs. To avoid the enhanced thermal tolerance of C. punctiferalis at low heating rates (0.1 or 0.5°C/min), a high heating rate of 5°C/min was selected to simulate the fast radio frequency heating in chestnuts and further determine the thermal death kinetic data. Thermal death curves of C. punctiferalis followed a 0th-order kinetic reaction model. The minimum exposure time to achieve 100% mortality was 55, 12, 6, and 3 min at 44, 46, 48, and 50°C, respectively. The activation energy for controlling C. punctiferalis was 482.15 kJ/mol with the z value of 4.09°C obtained from the thermal death-time curve. The information provided by thermal death kinetics for C. punctiferalis is useful in developing effective postharvest thermal treatment protocols for disinfesting chestnuts.

An evaluation of stakeholder engagement in comparative effectiveness research: lessons learned from SWOG S1415CD.

Aim: Stakeholder engagement is central to comparative effectiveness research yet there are gaps in definitions of success. We used a framework developed by Lavallee et al. defining effective engagement criteria to evaluate stakeholder engagement during a pragmatic cluster-randomized trial. Methods: Semi-structured interviews were developed from the framework and completed to learn about members' experiences. Interviews were analyzed in a deductive approach for themes related to the effective engagement criteria. Results: Thirteen members participated and described: respect for ideas, time to achieve consensus, access to information and continuous feedback as areas of effective engagement. The primary criticism was lack of diversity. Discussion: Feedback was positive, particularly among themes of respect, trust and competence, and led to development of a list of best practices for engagement. The framework was successful for evaluating engagement. Conclusion: Standardized frameworks allow studies to formally evaluate their stakeholder engagement approach and develop best practices for future research.

What is this article about? This article is about the evaluation of how effective the stakeholder engagement was in a comparative effectiveness research (CER) study funded by the Patient Centered Outcomes Research Institute (PCORI). The research team found a framework (developed by Lavalle et al.) that defined six different criteria for effective stakeholder engagement, and used that criteria to complete semi-structured interviews with the stakeholders involved with our study. These interviews were reviewed to determine what stakeholder engagement processes were successful and helped provide a list of best practices for stakeholder engagement for other researchers doing CER. What were the results? Stakeholders highlighted respect for their ideas, time to achieve consensus, easy access to information and a continuous feedback loop between study team and stakeholders as effective engagement processes. What do the results mean? These results can help other researchers doing CER learn best practices to implement from the outset of a study to best engage stakeholders in their research. The results also show that having a standardized framework to evaluate stakeholder engagement is important and allows for research teams to formally evaluate their engagement approach and learn what was successful and where there are areas for improvement in future studies.

Patient Knowledge and Expectations About Return of Genomic Results in a Biomarker-Driven Master Protocol Trial (SWOG S1400GEN).

PURPOSE: Biomarker-driven master protocols represent a new paradigm in oncology clinical trials, but their complex designs and wide-ranging genomic results returned can be difficult to communicate to participants. The objective of this pilot study was to evaluate patient knowledge and expectations related to return of genomic results in the Lung Cancer Master Protocol (Lung-MAP). METHODS: Eligible participants with previously treated advanced non-small-cell lung cancer were recruited from patients enrolled in Lung-MAP. Participants completed a 38-item telephone survey ≤ 30 days from Lung-MAP consent. The survey assessed understanding about the benefits and risks of Lung-MAP participation and knowledge of the potential uses of somatic testing results returned. Descriptive statistics and odds ratios for associations between demographic factors and correct responses to survey items were assessed. RESULTS: From August 1, 2017, to June 30, 2019, we recruited 207 participants with a median age of 67, 57.3% male, and 94.2% White. Most participants "strongly/somewhat agreed" with statements that they "received enough information to understand" Lung-MAP benefits (82.6%) and risks (69.5%). In items asking about potential uses of Lung-MAP genomic results, 87.0% correctly indicated that the results help to select cancer treatment, but < 20% correctly indicated that the results are not used to confirm cancer diagnosis, would not reveal risk of developing diseases besides cancer, and would not indicate if family members had increased cancer risk. There were no associations between sociodemographic factors and proportions providing correct responses. CONCLUSION: In a large National Clinical Trials Network biomarker-driven master protocol, most participants demonstrated incorrect knowledge and expectations about the uses of genomic results provided in the study despite most indicating that they had enough information to understand benefits and risks.

Sprouty1 is a critical regulator of GDNF/RET-mediated kidney induction.

Intercellular signaling molecules and their receptors, whose expression must be tightly regulated in time and space, coordinate organogenesis. Regulators of intracellular signaling pathways provide an additional level of control. Here we report that loss of the receptor tyrosine kinase (RTK) antagonist, Sprouty1 (Spry1), causes defects in kidney development in mice. Spry1(-/-) embryos have supernumerary ureteric buds, resulting in the development of multiple ureters and multiplex kidneys. These defects are due to increased sensitivity of the Wolffian duct to GDNF/RET signaling, and reducing Gdnf gene dosage correspondingly rescues the Spry1 null phenotype. We conclude that the function of Spry1 is to modulate GDNF/RET signaling in the Wolffian duct, ensuring that kidney induction is restricted to a single site. These results demonstrate the importance of negative feedback regulation of RTK signaling during kidney induction and suggest that failures in feedback control may underlie some human congenital kidney malformations.

Brief communication: Preoperative anticoagulant activity after bridging low-molecular-weight heparin for temporary interruption of warfarin.

BACKGROUND: Preoperative low-molecular-weight heparin (LMWH) is often used when warfarin therapy is interrupted for surgery. OBJECTIVE: To determine the preoperative anticoagulant activity of LMWH following a standardized "bridging" regimen. DESIGN: Prospective cohort study. SETTING: Single university hospital. PATIENTS: Consecutive patients who had warfarin therapy interrupted before an invasive procedure. INTERVENTION: Enoxaparin, 1 mg/kg of body weight, twice daily. The last dose was administered the evening before surgery. MEASUREMENTS: Blood anti-factor Xa heparin levels measured shortly before surgery. RESULTS: Preoperative anti-Xa heparin levels were obtained in 80 patients at an average of 14 hours after the last dose of enoxaparin was administered. The average anti-Xa heparin level was 0.6 U/mL. The anti-Xa heparin level, measured shortly before surgery, was 0.5 U/mL or greater in 54 (68%) patients and 1.0 U/mL or greater in 13 (16%) patients. A shorter interval since the last dose (P < 0.001) and a higher body mass index (P = 0.001) were associated with higher preoperative anti-Xa heparin levels. LIMITATIONS: The small sample size limits accurate estimates of the frequency of the clinical outcomes. A single regimen of LMWH was evaluated. CONCLUSIONS: Anti-Xa heparin levels often remain high at the time of surgery if a last dose of a twice-daily regimen of LMWH is given the evening before surgery.

The relationship between domestic violence and animal abuse: an Australian study.

Several North American studies have found a connection between domestic violence and animal abuse. This article reports on the first Australian research to examine this connection. A group of 102 women recruited through 24 domestic violence services in the state of Victoria and a nondomestic violence comparison group (102 women) recruited from the community took part in the study. Significantly higher rates of partner pet abuse, partner threats of pet abuse, and pet abuse by other family members were found in the violent families compared with the nondomestic violence group. As hypothesized, children from the violent families were reported by their mothers to have witnessed and committed significantly more animal abuse than children from the nonviolent families. Logistic regression analyses revealed, for the group as a whole, that a woman whose partner had threatened the pets was 5 times more likely to belong to the intimate partner violence group.

How important is patient-to-patient transmission in extended-spectrum beta-lactamase Escherichia coli acquisition.

BACKGROUND: Extended-spectrum beta-lactamase (ESBL)-producing Escherichia coli is an emerging pathogen. The causal role of antibiotic selective pressure versus patient-to-patient transmission has not been assessed. The objective of this study was to quantify the amount of patient-to-patient transmission among patients who acquire an ESBL-producing E coli infection using perianal surveillance cultures in an intensive care unit (ICU) population. METHODS: A prospective cohort of patients admitted between September 1, 2001, and September 1, 2004, to the medical and surgical ICUs at a tertiary care hospital was studied. Patients had perianal cultures on admission, weekly, and upon discharge. Strain typing by pulsed-field gel electrophoresis (PFGE) and epidemiologic criteria were used to quantify the amount of patient-to-patient transmission. RESULTS: There were 1806 patients admitted to the ICUs. There were 74 patients who had ESBL-producing E coli on admission to the ICU and 23 patients who acquired ESBL-producing E coli. Among these 23 patients, there were 14 PFGE types, and 3 (13%) patient acquisitions were defined as patient-to-patient transmission by similar PFGE type and overlapping time in the hospital. CONCLUSION: Our data suggest that patient-to-patient transmission is not an important cause of the acquisition of ESBL-producing E coli colonization in the ICU setting.

Large-scale phenome analysis defines a behavioral signature for Huntington's disease genotype in mice.

Rapid technological advances for the frequent monitoring of health parameters have raised the intriguing possibility that an individual's genotype could be predicted from phenotypic data alone. Here we used a machine learning approach to analyze the phenotypic effects of polymorphic mutations in a mouse model of Huntington's disease that determine disease presentation and age of onset. The resulting model correlated variation across 3,086 behavioral traits with seven different CAG-repeat lengths in the huntingtin gene (Htt). We selected behavioral signatures for age and CAG-repeat length that most robustly distinguished between mouse lines and validated the model by correctly predicting the repeat length of a blinded mouse line. Sufficient discriminatory power to accurately predict genotype required combined analysis of >200 phenotypic features. Our results suggest that autosomal dominant disease-causing mutations could be predicted through the use of subtle behavioral signatures that emerge in large-scale, combinatorial analyses. Our work provides an open data platform that we now share with the research community to aid efforts focused on understanding the pathways that link behavioral consequences to genetic variation in Huntington's disease.

Abacavir expanded access program for adult patients infected with human immunodeficiency virus type 1.

Expanded access programs (EAPs) provide medication to patients with life-threatening, treatment-refractory illnesses before regulatory approval and allow the acquisition of safety information. A 2-part, multisite EAP to evaluate abacavir, a carbocyclic nucleoside reverse-transcriptase inhibitor for use in combination antiretroviral therapy, was conducted. The EAP involved >13,000 adults infected with human immunodeficiency virus type 1 (HIV-1) who no longer responded to commercially available treatment regimens. Part A (open-label trials) examined the efficacy, safety, and tolerance of abacavir, and part B (provision of abacavir through expanded access) assessed only the occurrence of serious adverse events. By month 2 of abacavir-containing treatment, plasma HIV-1 RNA levels decreased by > or =0.5 log(10) in 31.4% of patients, and 5.6% of the patients had HIV-1 RNA levels decrease to <400 copies/mL. Drug-related serious adverse events were reported by 7.7% of patients, the most common of which were nausea, skin rash, diarrhea, malaise or fatigue, and fever. Approximately 4.6% of patients experienced a hypersensitivity reaction that was possibly drug related. Overall, the types and incidences of adverse events reported in the abacavir EAP were similar to those reported in phase 2 and 3 clinical trials evaluating abacavir.

Lamivudine 300 mg QD versus continued lamivudine 150 mg BID with stavudine and a protease inhibitor in suppressed patients.

PURPOSE: To compare the efficacy (sustained virologic suppression) and safety/tolerability of a switch to lamivudine 300 mg once daily (QD) versus continued lamivudine 150 mg twice daily (BID) in virologically suppressed patients (HIV-1 RNA <400 copies/mL for > or =3 months) on stable (> or =6 months) therapy with lamivudine 150 mg BID plus stavudine and either indinavir or nelfinavir. METHOD: Eighty-nine suppressed patients > or =18 years old with CD4 counts >50 cells/mm(3) were enrolled in this phase II, open-label, multicenter, randomized, stratified (by pretrial protease inhibitor [PI]), parallel-group clinical trial. Eighty-one patients received either lamivudine 300 mg QD (n = 39) or 150 mg BID (n = 42) with their pretrial stavudine/PI regimens for 24 weeks. RESULTS: A high rate of virologic suppression was sustained with both regimens throughout the trial. At week 24, intent-to-treat:exposed (missing = failure) analyses showed no statistically significant differences in the percentage of patients with HIV-1 RNA <400 copies/mL (95% [QD] vs. 90% [BID]) or <50 copies/mL (82% [QD] vs. 81% [BID]) or in the median change from baseline in CD4 counts (+42 cells/mm(3) [QD] vs. +22 cells/mm(3) [BID]). Both regimens were well tolerated. No patient experienced virologic failure, clinical disease progression, or a drug-related serious adverse event during the trial. Self-reported medication adherence was high in both groups. CONCLUSION: Patients who experience virologic suppression with a regimen of lamivudine 150 mg BID in combination with stavudine/PI can maintain that suppression by continuing their regimen or switching to lamivudine 300 mg QD and continuing the other components. Adverse event profiles were comparable among treatment regimens, and no new safety concerns were raised.

Pharmacodynamic effects of zidovudine 600 mg once/day versus 300 mg twice/day in therapy-naïve patients infected with human immunodeficiency virus.

STUDY OBJECTIVE: To compare the virologic activity of zidovudine monotherapy administered as 600 mg once/day versus 300 mg twice/day. DESIGN: Phase II, randomized (1:1), open-label study. SETTING: Thirteen medical centers in the United States. PATIENTS: Thirty-two antiretroviral-naive patients infected with human immunodeficiency virus (HIV). INTERVENTION: Patients were administered either zidovudine 600 mg every 24 hours (16 patients) or 300 mg every 12 hours (16 patients) for 13 days. MEASUREMENTS AND MAIN RESULTS: Plasma HIV-1 RNA concentration was measured daily. Study end points were between-group differences in change from baseline of log10-transformed HIV-1 RNA and in rates of viral load decline measured by the slope of HIV-1 RNA over time. At baseline, mean HIV-1 RNA was similar in the once/day and twice/day groups (4.33 and 4.40 log10 copies/ml, respectively). At day 14, a trend toward lower mean reduction in HIV-1 RNA from baseline was observed in the once/day group (-0.585, 95% confidence interval [CI] -0.728 to -0.442 log10 copies/ml) compared with the twice/day group (-0.849, 95% CI -1.067 to -0.630 log10 copies/ml, p=0.056). Viral load reduction also tended to be slower in the once/day group, as indicated by the smaller slope of viral load decline in the once/day group than in the twice/day group during days 1-14 (-0.045 vs -0.065 logic copies/ml/day, p=0.065). Both zidovudine regimens were similarly well tolerated. CONCLUSION: Zidovudine 600 mg once/day has antiviral activity, although less pronounced and more slowly achieved than that seen with zidovudine 300 mg twice/day. No differences were observed between the two treatment groups with respect to safety profile or tolerability

Predicting sex offender institutional adjustment and treatment compliance using the personality assessment inventory.

This study examined the utility of the Personality Assessment Inventory (PAI) to identify prison inmates in a mandatory sex offender treatment program prone to engage in institutional misconduct. Archival PAI and institutional disciplinary data were coded for 137 inmates in treatment for an average of 1.59 years. The Antisocial Features scale predicted various forms of general and major infractions (e.g., verbal aggression), with no other scales providing any incremental validity beyond this measure. The Treatment Rejection scale was uniquely but modestly correlated (r=.14) with treatment noncompliance, even though such infractions were rare in this sample.

Post-harvest entomology research in the United States Department of Agriculture-Agricultural Research Service.

This is a review of current post-harvest entomology research conducted by the Agricultural Research Service, the research branch of the US Department of Agriculture. The review covers both durable and perishable commodities. Research on biochemistry, genetics, physiology, monitoring and control of insects infesting stored grain, dried fruits and nuts, and processed commodities is reviewed. Research on development of quarantine treatments, particularly for fruit flies, is also reviewed, including research on thermal and irradiation treatments and a discussion of risk management for quarantine pests. Two areas of research are covered more extensively: a project to map the genome of the red flour beetle, Tribolium castaneum, and the use of near-infrared spectroscopy for detection of hidden infestations in grain, quantification of insect fragments in food, determination of quality in dried fruits, identification of insect species and age-grading insects. Future research directions are identified.

Molecular epidemiology of community-associated methicillin-resistant Staphylococcus aureus in the genomic era: a cross-sectional study.

Methicillin-resistant Staphylococcus aureus (MRSA) is a leading cause of healthcare-associated infections and significant contributor to healthcare cost. Community-associated-MRSA (CA-MRSA) strains have now invaded healthcare settings. A convenience sample of 97 clinical MRSA isolates was obtained from seven hospitals during a one-week period in 2010. We employed a framework integrating Staphylococcus protein A typing and full-genome next-generation sequencing. Single nucleotide polymorphisms were analyzed using phylodynamics. Twenty-six t002, 48 t008, and 23 other strains were identified. Phylodynamic analysis of 30 t008 strains showed ongoing exponential growth of the effective population size the basic reproductive number (R0) ranging from 1.24 to 1.34. No evidence of hospital clusters was identified. The lack of phylogeographic clustering suggests that community introduction is a major contributor to emergence of CA-MRSA strains within hospitals. Phylodynamic analysis provides a powerful framework to investigate MRSA transmission between the community and hospitals, an understanding of which is essential for control.

Deficits in a Simple Visual Go/No-go Discrimination Task in Two Mouse Models of Huntington's Disease.

Huntington's disease (HD), a devastating neurodegenerative disorder caused by a CAG repeat expansion on the HTT gene located on chromosome 4, is associated with a characteristic pattern of progressive cognitive dysfunction known to involve early deficits in executive function. A modified Go/No-go successive discrimination task was designed to assess the type of online response control/executive function known to be disrupted in patients with HD. The present studies show that this simple discrimination assay revealed early and robust deficits in two mouse models of HD, the zQ175 KI mouse (deficits from 28 weeks of age) and the R6/2 mouse, carrying ~240 CAG repeats (deficits from 9 weeks of age). These deficits are not due to gross motor dysfunction in the test animals, but instead appear to measure some inability to inhibit responding in the HD mouse models, suggesting this assay may measure deficits in underlying attentional and/or behavioral inhibition processes. Accordingly, this assay may be well suited to evaluation of simple deficits in cognitive function in mouse HD models, providing a potential platform for preclinical screening.

A mixed fixed ratio/progressive ratio procedure reveals an apathy phenotype in the BAC HD and the z_Q175 KI mouse models of Huntington's disease.

Apathy, characterized by generally reduced interest in and likelihood to perform goal-directed actions, is a recognized symptom of Huntington's disease (HD), a devastating neurological disorder caused by a CAG repeat expansion of the Htt gene located on chromosome 4. The present experiments used a modified progressive ratio task that incorporated a fixed-ratio schedule of reinforcement component to assess consummatory behavior, and a progressive-ratio schedule component that required increasing numbers of lever-presses for successive reinforcers (0.01 ml of evaporated milk). The studies revealed an apathetic phenotype in two mouse models of HD, with decreased response rates either overall or only at higher ratio requirements in the progressive-ratio component relative to wild-type controls. Based on the procedure used (within-session fixed- and progressive-ratio components), it is proposed that an observed phenotype can be ascribed either specifically to reduced motivation to work for food reinforcement or more generally to deficits in consummatory behavior. This procedure provides a simple means to assess this type of phenotype in rodents, with issues in consummatory vs. incentive motivation reflected in general alterations in fixed- versus progressive alterations on an escalating-ratio schedules respectively, providing translational measures of the amotivation/apathy construct of the human realm to the homologous construct of incentive motivation in preclinical models of human disease.