Helping individuals with firearm injuries: A cluster randomized trial.

BACKGROUND: Patients with firearm injuries are at high risk of subsequent arrest and injury following hospital discharge. We sought to evaluate the effect of a 6-month joint hospital- and community-based low-intensity intervention on risk of arrest and injury among patients with firearm injuries. METHODS: We conducted a cluster randomized controlled trial, enrolling patients with firearm injuries who received treatment at Harborview Medical Center, the level 1 trauma center in Seattle, Washington, were 18 years or older at the time of injury, spoke English, were able to provide consent and a method of contact, and lived in one of the five study counties. The intervention consisted of hospital-based motivational interviewing, followed by a 6-month community-based intervention, and multiagency support. The primary outcome was the risk of subsequent arrest. The main secondary outcome was the risk of death or subsequent injury requiring treatment in the emergency department or hospitalization. RESULTS: Neither assignment to or engagement with the intervention, defined as having at least 1 contact point with the support specialist, was associated with risk of arrest at 2 years post-hospital discharge (relative risk for intervention assignment, 1.15; 95% confidence interval, 0.90-1.48; relative risk for intervention engagement, 1.07; 95% confidence interval, 0.74-2.19). There was similarly no association observed for subsequent injury. CONCLUSIONS: This study represents one of the first randomized controlled trials of a joint hospital- and community-based intervention delivered exclusively among patients with firearm injuries. The intervention was not associated with changes in risk of arrest or injury, a finding most likely due to the low intensity of the program. LEVEL OF EVIDENCE: Care management, level II.

The specificity and role of microglia in epileptogenesis in mouse models of tuberous sclerosis complex.

OBJECTIVE: Microglial abnormalities have been reported in pathologic specimens from patients with tuberous sclerosis complex (TSC), a genetic disorder characterized by epilepsy, intellectual disability, and autism. However, the pathogenic role of microglia in epilepsy in TSC is poorly understood, particularly whether microglia defects may be a primary contributor to epileptogenesis or are secondary to seizures or simply epiphenomena. In this study, we tested the hypothesis that Tsc1 gene inactivation in microglia is sufficient to cause epilepsy in mouse models of TSC. METHODS: Using a chemokine receptor, Cx3cr1, to target microglia, conventional Tsc1Cx3cr1-Cre CKO (conditional knockout) mice and postnatal-inducible Tsc1Cx3cr1-CreER CKO mice were generated and assessed for molecular and histopathologic evidence of microglial abnormalities, mechanistic target of rapamycin 1 (mTORC1) pathway activation, and epilepsy. RESULTS: Tsc1Cx3cr1-Cre CKO mice exhibited a high efficiency of microglia Tsc1 inactivation, mTORC1 activation, increased microglial size and number, and robust epilepsy, which were rapamycin-dependent. However, Cre reporter studies demonstrated that constitutive Cx3cr1 expression affected not only microglia, but also a large percentage of cortical neurons, confounding the role of microglia in epileptogenesis in Tsc1 Cx3cr1-Cre CKO mice. In contrast, postnatal inactivation of Tsc1 utilizing a tamoxifen-inducible Cx3cr1-CreER resulted in a more-selective microglia Tsc1 inactivation with high efficiency, mTORC1 activation, and increased microglial size and number, but no documented epilepsy. SIGNIFICANCE: Microglia abnormalities may contribute to epileptogenesis in the context of neuronal involvement in TSC mouse models, but selective Tsc1 gene inactivation in microglia alone may not be sufficient to cause epilepsy, suggesting that microglia have more supportive roles in the pathogenesis of seizures in TSC.

Efficacy of SERD/SERM Hybrid-CDK4/6 Inhibitor Combinations in Models of Endocrine Therapy-Resistant Breast Cancer.

PURPOSE: Endocrine therapy, using tamoxifen or an aromatase inhibitor, remains first-line therapy for the management of estrogen receptor (ESR1)-positive breast cancer. However, ESR1 mutations or other ligand-independent ESR1 activation mechanisms limit the duration of response. The clinical efficacy of fulvestrant, a selective estrogen receptor downregulator (SERD) that competitively inhibits agonist binding to ESR1 and triggers receptor downregulation, has confirmed that ESR1 frequently remains engaged in endocrine therapy-resistant cancers. We evaluated the activity of a new class of selective estrogen receptor modulators (SERM)/SERD hybrids (SSH) that downregulate ESR1 in relevant models of endocrine-resistant breast cancer. Building on the observation that concurrent inhibition of ESR1 and the cyclin-dependent kinases 4 and 6 (CDK4/6) significantly increased progression-free survival in advanced patients, we explored the activity of different SERD- or SSH-CDK4/6 inhibitor combinations in models of endocrine therapy-resistant ESR1(+) breast cancer. EXPERIMENTAL DESIGN: SERDs, SSHs, and the CDK4/6 inhibitor palbociclib were evaluated as single agents or in combination in established cellular and animal models of endocrine therapy-resistant ESR1(+) breast cancer. RESULTS: The combination of palbociclib with a SERD or an SSH was shown to effectively inhibit the growth of MCF7 cell or ESR1-mutant patient-derived tumor xenografts. In tamoxifen-resistant MCF7 xenografts, the palbociclib/SERD or SSH combination resulted in an increased duration of response as compared with either drug alone. CONCLUSIONS: A SERD- or SSH-palbociclib combination has therapeutic potential in breast tumors resistant to endocrine therapies or those expressing ESR1 mutations. See related commentary by DeMichele and Chodosh, p. 4999.

Imaging caspase-3 activation as a marker of apoptosis-targeted treatment response in cancer.

PURPOSE: We tested whether positron emission tomography (PET) with the caspase-3-targeted isatin analog [(18)F]WC-4-116 could image caspase-3 activation in response to an apoptosis-inducing anticancer therapy. PROCEDURES: [(18)F]WC-4-116 uptake was determined in etoposide-treated EL4 cells. Biodistribution studies with [(18)F]WC-4-116 and [(18)F]ICMT-18, a non-caspase-3-targeted tracer, as well as [(18)F]WC-4-116 microPET imaging assessed responses in Colo205 tumor-bearing mice treated with death receptor 5 (DR5)-targeted agonist antibodies. Immunohistochemical staining and enzyme assays confirmed caspase-3 activation. Two-way analysis of variance or Student's t test assessed for treatment-related changes in tracer uptake. RESULTS: [(18)F]WC-4-116 increased 8 ± 2 fold in etoposide-treated cells. The [(18)F]WC-4-116 % ID/g also increased significantly in tumors with high caspase-3 enzyme activity (p < 0.05). [(18)F]ICMT-18 tumor uptake did not differ in tumors with high or low caspase-3 enzyme activity. CONCLUSIONS: [(18)F]WC-4-116 uptake in vivo reflects increased caspase-3 activation and may be useful for detecting caspase-3-mediated apoptosis treatment responses in cancer.

Click synthesis and biologic evaluation of (R)- and (S)-2-amino-3-[1-(2-[18F]fluoroethyl)-1H-[1,2,3]triazol-4-yl]propanoic acid for brain tumor imaging with positron emission tomography.

The (R)- and (S)-enantiomers of 2-amino-3-[1-(2-[18F]fluoroethyl)-1H-[1,2,3]triazol-4-yl]propanoic acid (4) were synthesized and evaluated in the rat 9L gliosarcoma brain tumor model using cell uptake assays, biodistribution studies, and micro-positron emission tomography (microPET). The (R)- and (S)-enantiomers of [18F]4 were radiolabeled separately using the click reaction in 57% and 51% decay-corrected yields, respectively. (S)-[18F]4 was a substrate for cationic amino acid transport and, to a lesser extent, system L transport in vitro. In vivo biodistribution studies demonstrated that (S)-[18F]4 provided higher tumor uptake and higher tumor to brain ratios (15:1 at the 30- and 60-minute time points) compared to the (R)-enantiomer (7:1 at the 30- and 60-minute time points). MicroPET studies with (S)-[18F]4 confirmed that this tracer provides good target to background ratios for both subcutaneous and intracranial 9L gliosarcoma tumors. Based on these results, the 1H-[1,2,3]triazole-substituted amino acid (S)-[18F]4 has promising PET properties for brain tumors and represents a novel class of radiolabeled amino acids for tumor imaging.

Oral mucosal reactivation rates of herpesviruses among HIV-1 seropositive persons.

Herpes simplex virus, cytomegalovirus and Epstein-Barr virus infections are prevalent among HIV-1 infected persons. The relationships between salivary shedding of these herpesviruses have not been characterized. Salivary samples were collected on a median of 61 consecutive days from 41 HIV-1 seropositive persons and tested for HSV-1, HSV-2, CMV and EBV. HSV was detected on 5%, CMV on 19% and EBV on 71% of the days of sampling. HSV shedding was not related to CMV or EBV shedding rates. Persons with EBV shedding rates >40% had CMV DNA detected in their saliva significantly more often than those with EBV shedding rates 200 cells/mm(3) were associated with lower frequency (P=0.02) and quantity (P=0.03) of CMV compared with CD4 counts

Long-term functional outcome after lateral patellar retinacular release in adolescents: an observational cohort study with minimum 5-year follow-up.

BACKGROUND: Lateral patellar retinacular release has been recommended for patients with patellar tilt, tight lateral retinaculum, patellar subluxation, patellar dislocation, and patellofemoral pain. Studies of long-term outcomes after lateral release are limited, especially for differing indications. HYPOTHESIS: Adolescents do well after lateral retinacular release in the 5- to 22-year time frame. METHODS: Patients having undergone lateral retinacular release between the years of 1981 and 1999 were contacted. Evaluation was by the Cincinnati and Lysholm scales and by level of satisfaction and need for reoperation. RESULTS: One hundred forty knees were studied. Mean age at operation was 15.4 years (SD, 2.7 years). Average follow-up was 8.5 (SD, 4.1 years; range, 5.2-22.5 years). Twenty-five patients had needed reoperation, indicating failure of the index operation. Kaplan-Meier survivorship was 78% at 15 years. Cincinnati and Lysholm scores indicated well-functioning knees in those not requiring reoperation. Overall satisfaction improved as time from operation increased. Comparisons were made between the group requiring reoperation and those who did not. Focus was placed on knees with patellar maltracking or tilt versus patellar instability and between males and females. No differences were found among groups for reoperation rate, level of satisfaction, average Lysholm score, or average Cincinnati score. There were no differences in demographics or outcome measures between patients with patellar instability and those with tilt. Instability patients trended toward higher reoperation rates than did tilt patients, but the difference was not significant. There were no differences between males and females. CONCLUSION: The majority of patients are satisfied with their knee 5 to 22 years after lateral patellar retinacular release and scored well on questions rating knee health and function.