Stereotactic radiosurgery for melanoma brain metastases: dose-size response relationship in the era of immunotherapy.

PURPOSE/OBJECTIVE(S): To determine, for intact melanoma brain metastases (MBM) treated with single-fraction stereotactic radiosurgery (SRS), whether planning parameter peripheral dose per lesion diameter (PDLDm, Gy/mm) and lesion control (LC) differs with versus without immunotherapy (IO). MATERIALS/METHODS: We performed a retrospective analysis of patients with intact MBM treated with SRS from 2008 to 2019. Cox-frailty models were constructed to include confounders selected by penalized Cox regression models with a LASSO selector. Interaction effect testing was used to determine whether a significant effect between IO and PDLDm could be demonstrated with respect to LC. RESULTS: The study cohort comprised 67 patients with 244 MBMs treated with SRS (30 patients with 122 lesions treated with both SRS and IO) were included. The logarithm of PDLDm was selected as a predictor of LC (HR 0.307, 95% CI 0.098-0.441), adjusting for IO receipt (HR 0.363, 95% CI 0.108-1.224). Interaction effect testing demonstrated a differential effect of PDLDm by IO receipt, with respect to LC (p = 0.048). Twelve-month LC rates for a 7.5 mm lesion receiving SRS (18 Gy) with IO versus without IO were 87.8% (95% CI 69.0-98.3%) versus 79.8% (95% CI 55.1-93.8%) respectively. CONCLUSION: PDLDm predicted LC in patients with small MBMs treated with single-fraction SRS. We found a differential effect of dose per lesion size and LC by immunotherapy receipt. Future studies are needed to determine whether lower doses of single-fraction SRS afford similarly effective LC for patients with small MBMs receiving immunotherapy.

Tumor infiltrating lymphocyte grade in Merkel cell carcinoma: relationships with clinical factors and independent prognostic value.

INTRODUCTION: Surrogate markers of the host immune response are not currently included in AJCC staging for Merkel cell carcinoma (MCC), and have not been consistently associated with clinical outcomes. We performed an analysis of a large national database to investigate tumor infiltrating lymphocyte (TIL) grade as an independent predictor of overall survival (OS) for patients with MCC and to characterize the relationship between TIL grade and other clinical prognostic factors. MATERIAL AND METHODS: The NCDB was queried for patients with resected, non-metastatic MCC with known TIL grade (absent, non-brisk and brisk). Multivariable Cox regression modeling was performed to define TIL grade as a predictor of OS adjusting for other relevant clinical factors. Multinomial, multivariable logistic regression was performed to characterize the relationship between TIL grade and other clinical prognostic factors. Multiple imputation was performed to account for missing data bias. RESULTS: Both brisk (HR 0.55, CI 0.36-0.83) and non-brisk (HR 0.77, CI 0.60-0.98) were associated with decreased adjusted hazard of death relative to absent TIL grade. Adverse clinical factors such as 1-3 positive lymph nodes, lymphovascular invasion (LVI) and immunosuppression were associated with increased likelihood of non-brisk TIL relative to absent TIL grade (p values <.05). Extracapsular extension (ECS) was associated with decreased likelihood of brisk TIL relative to absent TIL grade (p<.05). DISCUSSION: Histopathologic TIL grade was independently predictive for OS in this large national cohort. Significant differences in the likelihood of non-brisk or brisk TIL relative to absent grade were present with regards to LVI, ECS and immune status. TIL grade may be a useful prognostic factor to consider in addition to more granular characterization of TIL morphology and immunophenotype.

Cytochrome P450 1B1 contributes to increased blood pressure and cardiovascular and renal dysfunction in spontaneously hypertensive rats.

PURPOSE: We investigated the contribution of cytochrome P450 (CYP) 1B1 to hypertension and its pathogenesis by examining the effect of its selective inhibitor, 2,4,3',5'-tetramethoxystilbene (TMS), in spontaneously hypertensive rats (SHR). METHODS: Blood pressure (BP) was measured bi-weekly. Starting at 8 weeks, TMS (600 µg/kg, i.p.) or its vehicle was injected daily. At 14 weeks, samples were collected for measurement. RESULTS: TMS reversed increased BP in SHR (207 ± 7 vs. 129 ± 2 mmHg) without altering BP in Wistar-Kyoto rats. Increased CYP1B1 activity in SHR was inhibited by TMS (RLU: aorta, 5.4 ± 0.7 vs. 3.7 ± 0.7; heart, 6.0 ± 0.8 vs. 3.4 ± 0.4; kidney, 411 ± 45 vs. 246 ± 10). Increased vascular reactivity, cardiovascular hypertrophy, endothelial and renal dysfunction, cardiac and renal fibrosis in SHR were minimized by TMS. Increased production of reactive oxygen species and NADPH oxidase activity in SHR, were diminished by TMS. In SHR, TMS reduced increased plasma levels of nitrite/nitrate (46.4 ± 5.0 vs. 28.1 ± 4.1 µM), hydrogen-peroxide (36.0 ± 3.7 vs. 14.1 ± 3.8 µM), and thiobarbituric acid reactive substances (6.9 ± 1.0 vs. 3.4 ± 1.5 µM). Increased plasma levels of pro-inflammatory cytokines and catecholamines, and cardiac activity of extracellular signal-regulated kinase, p38 mitogen-activated protein kinase, c-Src tyrosine kinase, and protein kinase B in SHR were also inhibited by TMS. CONCLUSIONS: These data suggests that increased oxidative stress generated by CYP1B1 contributes to hypertension, increased cytokine production and sympathetic activity, and associated pathophysiological changes in SHR. CYP1B1 could be a novel target for developing drugs to treat hypertension and its pathogenesis.

Racial Variation in the Relationship of Glycemic Control with Fracture Risk in Elderly Patients with Diabetes.

We investigated racial variation in glycemic control (glycated hemoglobin A1c [HbA1c]) with fracture risk in geriatric patients with diabetes. Compared to an HbA1c of 7.0-7.9% [53-63 mmol/mol], HbA1c ≥9.0% [≥75 mmol/mol] was associated with increased fracture risk among Blacks and those of Unknown race only. This increase was attenuated in Blacks after accounting for the relative frequency of patient-provider interaction.

Effects of Differential Consequences on Choice Making in Students at Risk for Academic Failure.

Problem behavior can be reduced through choice making and use of preferred instructional activities. However, the opportunity to choose does not imply students are more engaged with instructional activities. The purpose of this study was to evaluate the effects of differential consequences on the on-task behavior of students within the context of teacher versus student selection of instructional activities. Students were exposed to two contingencies (i.e., escape + differential attention vs. escape + physical proximity) across two stimulus events (i.e., teacher vs. student choice of preferred instructional activities) using an alternating-treatments design within an A-B-A-B design. Choice of instructional activities increased on-task behavior during student-choice conditions compared to the teacher-choice conditions, but only when differential attention was provided. Differential attention was also more effective than physical proximity at increasing on-task behavior. Implications for practice and future research are discussed.

Prognostic factors and selection criteria in the retreatment of head and neck cancers.

OBJECTIVES: To determine predictors of treatment selection, outcome, and survival, we examined a cohort of previously irradiated head and neck squamous cell carcinoma (HNSCC) patients. MATERIALS AND METHODS: We retrospectively analyzed 100 patients at our institution who were treated for recurrent or second primary (RSP) HNSCC, focusing on subgroups receiving reirradiation (ReRT) alone and those undergoing surgical salvage (SS) with or without post-operative reirradiation therapy (POReRT). Logistic regression modeling was performed to identify factors predictive of retreatment modality. Cox regression modeling was used to determine prognostic factors for progression free survival (PFS) and overall survival (OS). RESULTS: ReRT alone was less likely in current smokers and neck recurrences, with reirradiation more likely in primary site recurrences. POReRT was significantly more likely in patients with positive surgical margins (PSM), neck dissection, or organ dysfunction. POReRT omission negatively impacted PFS when PSM (HR: 8.894, 95% CI: 1.742-45.403) and perineural invasion (PNI) (HR: 3.391, 95% CI: 1.140-10.089) were present. Tracheostomy was associated with worse OS, but ReRT alone and POReRT improved OS. PSM correlated with worse OS, regardless of whether POReRT was given (HR: 14.260, 95% CI: 2.064-98.547). CONCLUSION: This analysis confirms known factors for predicting outcome and shows nonsmoking status and primary site recurrence as predictors for ReRT alone. POReRT for PSM and PNI improves PFS. Tracheostomy patients are more likely to have ReRT due to acute toxicity not limiting treatment and POReRT improves OS compared to surgery alone. The presence of PSM negatively impacts survival which cannot be overcome by POReRT.

Varied effects of conventional antiepileptics on responding maintained by negative versus positive reinforcement.

We analyzed the effects of four conventional antiepileptic drugs (AEDs) - carbamazepine (CBZ), ethosuximide (ETH), phenytoin (PHT), and valproate (VPA) - on operant behavior maintained by negative or positive reinforcement contingencies. Rats were trained to lever press on a free-operant avoidance schedule or variable-interval (VI) schedule of appetitive reinforcement. Dose-effect functions were separately established on each reinforcement contingency for CBZ (12.5-100 mg/kg), ETH (25-200 mg/kg), PHT (12.5-50 mg/kg), and VPA (50-400 mg/kg). CBZ and PHT reduced responding on free-operant avoidance and VI appetitive reinforcement tasks, with positively reinforced behavior reduced at lower drug dosages than negatively reinforced responding. ETH and VPA reduced responding on the VI appetitive reinforcement task, but did not alter behavior maintained on the free-operant avoidance schedule. Our results suggest that conventional AEDs vary in their effect on operant behavior, depending on the type of reinforcement process maintaining responding.

Teaching preschool children to report suspicious packages to adults.

Law enforcement agencies stress that public reporting of terror-related crime is the predominant means for disrupting these actions. However, schools may be unprepared because the majority of the populace may not understand the threat of suspicious materials or what to do when they are found on school grounds. The purpose of this study was to systematically teach preschool children to identify and report suspicious packages across three experiments. In the first experiment, we used multiple exemplar training to teach children to identify the characteristics of safe and unsafe packages. In the second experiment, we taught participants to identify the locations where packages should be considered unsafe. Finally, in the third experiment, we used behavioral skills training to teach participants to avoid touching unsafe packages, leave the area where they were located, and report their discovery to an adult. Results suggest the participants quickly developed these skills. Implications for safety skills in young school children are discussed.

Computer-based insulin infusion protocol improves glycemia control over manual protocol.

OBJECTIVE: Hyperglycemia worsens clinical outcomes in critically ill patients. Precise glycemia control using intravenous insulin improves outcomes. To determine if we could improve glycemia control over a previous paper-based, manual protocol, authors implemented, in a surgical intensive care unit (SICU), an intravenous insulin protocol integrated into a care provider order entry (CPOE) system. DESIGN: Retrospective before-after study of consecutive adult patients admitted to a SICU during pre (manual protocol, 32 days) and post (computer-based protocol, 49 days) periods. MEASUREMENTS: Percentage of glucose readings in ideal range of 70-109 mg/dl, and minutes spent in ideal range of control during the first 5 days of SICU stay. RESULTS: The computer-based protocol reduced time from first glucose measurement to initiation of insulin protocol, improved the percentage of all SICU glucose readings in the ideal range, and improved control in patients on IV insulin for > or =24 hours. Hypoglycemia (<40 mg/dl) was rare in both groups. CONCLUSION: The CPOE-based intravenous insulin protocol improved glycemia control in SICU patients compared to a previous manual protocol, and reduced time to insulin therapy initiation. Integrating a computer-based insulin protocol into a CPOE system achieved efficient, safe, and effective glycemia control in SICU patients.

Glycemic control and fracture risk in elderly patients with diabetes.

AIMS: Elderly patients with diabetes are at increased fracture risk. Although long exposure to hyperglycemia may increase fracture risk via adverse effects on bone metabolism, tight glycemic control may increase risk via trauma subsequent to hypoglycemia. We tested the prospective relationship between glycemic control and fracture risk in 10,572 elderly patients (age ≥65) with diabetes. METHODS: Geriatric patients with diabetes were drawn from Vanderbilt University Medical Center's Electronic Health Record. Baseline was defined as age at first HbA1c after the latter of age 65 or ICD 9 code for diabetes. Cox analysis was used to test the relationship of updated mean HbA1c (average HbA1c over follow-up) with time to first fracture since baseline. HbA1c was categorized as follows: <6.5% [<48mmol/mol]; 6.5-6.9% [48-52mmol/mol]; 7-7.9% [53-63mmol/mol]; 8-8.9% [64-74 mmol-mol]; ≥9% [≥75mmol/mol]. The number of BMI measurements was used as a surrogate for relative frequency of outpatient visits, i.e. patient-provider contacts. RESULTS: During follow-up, there were 949 fracture events. HbA1c demonstrated a cubic relationship with fracture risk (p<0.05). In analyses accounting for age, sex, race, and number of BMI measures (a surrogate for patient-provider interaction), compared to an HbA1c of 7-7.9%, HRs (95% CIs) were: HbA1c<6.5% HR=0.97 (0.82-1.14), 6.5-6.9% HR=0.80 (0.66-0.97), 8-8.9% HR=1.13 (0.92-1.40), ≥9% HR=1.19 (0.93-1.54). CONCLUSIONS: An HbA1c of 6.5-6.9% is associated with the lowest risk of fracture in elderly patients with diabetes. Risk associated with an HbA1c ≥9% may be a marker of infrequent patient-provider interaction.

Accessibility, availability, and quality of online information for US radiation oncology residencies.

PURPOSE: Radiation oncology (RO) residency applicants commonly use Internet resources for information on residency programs. The purpose of this study is to assess the accessibility, availability, and quality of online information for RO graduate medical education. METHODS AND MATERIALS: Accessibility of online information was determined by surveying databases for RO residency programs within the Fellowship Residency Electronic Interactive Data Access System (FREIDA) of the American Medical Association, the Accreditation Council for Graduate Medical Education (ACGME), and Google search. As of June 30, 2015, websites were assessed for presence, accessibility, and overall content availability based on a 55-item list of desired features based on 13 program features important to previously surveyed applicants. Quality scoring of available content was performed based on previously published Likert scale variables deemed desirable to RO applicants. Quality score labels were given based on percentage of desired information presented. RESULTS: FREIDA and ACGME databases listed 89% and 98% of program websites, respectively, but only 56% and 52% of links routed to a RO department-specific website, respectively. Google search obtained websites for 98% of programs and 95% of links routed to RO department-specific websites. The majority of websites had program descriptions (98%) and information on staff. However, resident information was more limited (total number [42%], education [47%], previous residents [28%], positions available [35%], contact information [13%]). Based on quality scoring, program websites contained only 47% of desired information on average. Only 13% of programs had superior websites containing 80% or more of desired information. CONCLUSIONS: Compared with Google, the FREIDA and ACGME program databases provide limited access to RO residency websites. The overall information availability and quality of information within RO residency websites varies widely. Applicants and programs may benefit from improved content accessibility and quality from US RO program websites in the residency application process.

Nociceptor and age specific effects of REM sleep deprivation induced hyperalgesia.

REM sleep deprivation (REMSD) has been shown to increase rates of negatively reinforced operant behavior, but not operant responding maintained by positive reinforcement. The reason for this differential effect is currently unknown. We hypothesize that REMSD can increase sensitivity to noxious stimuli. In the present study, we sought to determine if REMSD was associated with a change in response to noxious heat (i.e., altered nociceptive sensitivity). Two groups of rats, aged 6 and 22 months, were subjected to hotplate algesia testing at two different temperatures (44 and 52 degrees C). Initially, baseline numbers of responses and total response time were obtained at 44 degrees C. Animals then were exposed to 48 h of REMSD or control conditions. The frequency and duration of hindpaw responses (licking and guarding) increased for young animals only after REMSD and none of the control conditions. Old rats showed increased duration of nocifensive responding after REMSD and tank control conditions without a change in the number of responses at 44 degrees C. Latency to first nocifensive response was significantly longer in the 44 degrees C hotplate tests, but decreased to levels observed throughout the 52 degrees C hotplate tests following REMSD and TC conditions. These findings suggest that REMSD increases nociceptive sensitivity under conditions of sustained, selective C nociceptor activation (42 degrees C), but not under conditions of phasic A-delta activation (52 degrees C). The findings also indicate that age can be a significant variable in REMSD studies.

Possible role for the 5-HT1A receptor in the behavioral effects of REM sleep deprivation on free-operant avoidance responding in rat.

RATIONALE: REM sleep deprivation (REMSD) has been shown to increase rates of free-operant avoidance responding. Depletion of 5-hydroxytryptamine (5-HT, serotonin) levels produces similar effects on responding. OBJECTIVE: We studied whether the pharmacological activation of the 5-HT1A receptor would produce effects on avoidance responding similar to REMSD and depleted 5-HT levels. METHODS: Rats were trained to lever press on a free-operant avoidance task. Dose-effect functions were established for 8-OH-DPAT (a 5-HT1A receptor agonist) (0.1-1.0 mg/kg) and WAY 100635 (a 5-HT1A receptor antagonist) (0.1-1.0 mg/kg). Rats were then exposed to REMSD (48 h) or equivalent control conditions, and then administered 8-OH-DPAT (0.6 mg/kg) and/or WAY 100635 (0.025-0.1 mg/kg). RESULTS: Injections of 8-OH-DPAT increased rates of avoidance responding in a dose-dependent manner, while WAY 100635 did not alter responding. The effect of 8-OH-DPAT was antagonized by pre-injection of WAY 100635. REMSD and injections of 8-OH-DPAT increased rates of avoidance responding and the effects of both manipulations were reversed by pre-injection of WAY 100635. CONCLUSIONS: Activation of the 5-HT1A receptor may be a mechanism by which REMSD increases rates of free-operant avoidance responding.

Mortality by race among low-income adults with early-onset insulin-treated diabetes.

OBJECTIVE: To determine if long-term mortality rates in early-onset insulin-treated diabetes differ by race among adults of similar socioeconomic status. RESEARCH DESIGN AND METHODS: A total of 391 (299 African Americans, 92 whites) mostly low-income adults 40-79 years of age with insulin-treated diabetes diagnosed before 30 years of age were recruited from community health centers in the southeast U.S. Cox models were used to estimate hazard ratios (HRs) of all-cause mortality among African Americans compared with whites. Additionally, standardized mortality ratios (SMRs) were used to compare the mortality experience of the individuals with diabetes with both national and general community health center sex- and race-specific population norms. RESULTS: Mean age at diabetes diagnosis and cohort entry, respectively, was 21 and 50 years in African Americans and 19 and 51 years in whites. During an average of 6.7 years of follow-up, 29% of African Americans and 35% of whites died. In multivariable analysis, no significant mortality difference was observed among African Americans compared with whites (HR 0.83 [95% CI 0.53-1.30]; P=0.51). Compared with the race-specific U.S. general population, SMRs for those with diabetes were 5.7 in African Americans and 11.7 in whites. However, when compared with the same source population (i.e., the community health center population), SMRs were 3.5 and 3.7 in African Americans and whites, respectively. CONCLUSIONS: Elevated mortality persists in men and women with long duration of early-onset insulin-treated diabetes, but given survival to 40 years of age and similarly low economic status and access to health care, our data do not suggest a racial disparity in mortality.

Serotonin2A/C receptors mediate the aggressive phenotype of TLX gene knockout mice.

Deleting the tailless (TLX) gene in mice produces a highly aggressive phenotype yet to be characterized in terms of heterozygous animals or neurotransmitter mechanisms. We sought to establish pharmacological control over aggression and study the role of serotonin (5-HT)(2A/C) receptors in mediating changes in aggression. We analyzed aggression in mice heterozygous (+/-) or homozygous (-/-) for the TLX gene and wild-types (+/+) using a resident-intruder paradigm. No +/+ mice were aggressive, 36% of +/- TLX and 100% of -/- TLX mice showed aggression. Dose-effect functions were established for clozapine (0.1-1.5mg/kg, ip), ketanserin (0.3-1.25 mg/kg, ip), and (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane [(±)DOI] (0.5-2.0 mg/kg, ip). Injecting clozapine decreased the frequency and duration of attacks for +/- TLX and -/- TLX mice. Clozapine did not decrease grooming in either +/- TLX or -/- TLX mice but may have increased locomotion for -/- TLX mice. Injecting ketanserin, a 5-HT(2A/C) receptor antagonist, produced differential decreases in frequency and latency to aggression between genotypes and corresponding increases in locomotor behavior. Injecting (±)DOI, a 5-HT(2A/C) receptor agonist, increased the frequency and duration of attacks, decreased the latency to attacks, and decreased locomotion in +/- and -/- TLX mice. Results of the current study suggest aggression displayed by TLX null and heterozygous mice involves 5-HT(2A/C) receptors.

Mortality among low-income African Americans and whites with diabetes.

OBJECTIVE: To estimate mortality rates and risk factors for mortality in a low-socioeconomic status (SES) population of African Americans and whites with diabetes. RESEARCH DESIGN AND METHODS: We determined mortality among African Americans and whites aged 40-79 years with (n = 12,498) and without (n = 49,914) diabetes at entry into a cohort of participants recruited from government-funded community health centers. Multivariable Cox analysis was used to estimate mortality hazard ratios (HRs) (95% CI) among those with versus those without diabetes and among those with diabetes according to patient characteristics. RESULTS: During follow-up (mean 5.9 years), 13.5% of those with and 7.3% of those without diabetes died. All-cause mortality risk was higher among those with versus without diabetes for both African Americans (HR 1.84 [95% CI 1.71-1.99]) and whites (1.80 [1.58-2.04]), although among those with diabetes, mortality was lower among African Americans than whites (0.78 [0.69-0.87]). Mortality risk increased with duration of diabetes and was greater among patients on insulin therapy and reporting histories of cardiovascular disease (CVD), hypertension, and stroke. The HRs associated with these multiple risk factors tended to be similar by sex and race, with the exception of a differentially higher impact of prevalent CVD on mortality among African Americans (interaction P value = 0.03), despite a lower baseline prevalence of CVD. CONCLUSIONS: In this population with similarly low SES and access to health care, strong and generally similar predictors of mortality were identified for African Americans and whites with diabetes, with African Americans at a moderately but significantly lower mortality risk.

Moderating effects of autism on parent views of genetic screening for aggression.

Advances in gene-environment interaction research have revealed genes that are associated with aggression. However, little is known about parent perceptions of genetic screening for behavioral symptoms like aggression as opposed to diagnosing disabilities. These perceptions may influence future research endeavors involving genetic linkage studies to behavior, including proactive approaches for parents to avoid events leading to aggression. The purpose of this study was to solicit the perspectives of parents who have children with autism about screening for genes associated with aggression, compared to responses from those who have children without disabilities and those planning to have children. Parents of children with autism were more likely to support screening and the use of the results to seek treatment if necessary. Results are discussed in the context of surveillance screening and systematic early intervention for behavioral symptoms related to autism. The results may provide insight for clincians, researchers, policymakers, and advocacy groups related to diagnosing and treating aggression in people with autism.

Mortality experience of a low-income population with young-onset diabetes.

OBJECTIVE: In young-onset diabetes, insulin therapy status is a rough marker of diabetes type. We describe the mortality experience of a low-income, predominantly minority population with diabetes diagnosed before age 30 years, stratified by insulin therapy. RESEARCH DESIGN AND METHODS: A total of 1,098 adults aged 40-79 years (median 49) diagnosed with diabetes before age 30 years and 49,914 without diabetes were recruited from community health centers. Individuals with diabetes were categorized by insulin therapy at baseline: group A, insulin therapy only; group B, insulin therapy and an oral hypoglycemic agent; and group C, no insulin therapy. Cox models were used to compute hazard ratios (HRs) and 95% CI for cause-specific mortality based on both underlying and contributing causes of death from death certificates. RESULTS: During follow-up (mean 3.9 years), 15.0, 12.5, and 7.3% of groups A, B, and C, respectively, and 4.6% without diabetes died. Compared with individuals without diabetes, HRs (CI) for all-cause mortality were 4.3 (3.4-5.6), 4.2 (2.8-6.3), and 2.0 (1.4-2.8) in groups A, B, and C, respectively. The leading cause of death was renal failure (end-stage renal disease [ESRD]) in group A, ESRD and coronary artery disease (CAD) in group B, and CAD in group C and individuals without diabetes. HRs for these conditions were at least twice as high as the HRs for all-cause mortality, reaching 17.3 (10.2-29.3), 17.9 (8.3-38.7), and 5.1 (2.3-11.7) in groups A, B, and C, respectively, for ESRD. CONCLUSIONS: Excess mortality persists among people with young-onset diabetes of long duration, with ESRD and CAD as the leading contributors to mortality.

Aggression as positive reinforcement in people with intellectual disabilities.

From an applied behavior-analytic perspective, aggression in people with intellectual disabilities is mostly maintained by social reinforcement consequences. However, nonsocial consequences have also been identified in functional assessments on aggression. Behaviors producing their own reinforcement have been labeled "automatic" or "nonsocial" in the behavior-analytic literature, a label that bares a striking resemblance to biobehavioral explanations of reward-seeking behaviors. Biobehavioral studies have revealed that aggression activates the same endogenous brain mechanisms as primary reinforcers like food. Therefore, integrating brain-environment explanations would result in a better understanding of the functional mechanisms associated with nonsocial aggression. The purpose of this paper was to explore aggression as a reinforcing consequence for reinforcement-seeking behaviors in people with intellectual disabilities. First, the literature establishing aggression as reinforcement for arbitrary responding will be reviewed. Next, the reward-related biological process associated with aggression was described. Finally, the paper discusses what might be done to assess and treat aggression maintained by nonsocial reinforcement.