Immunomodulatory agents lenalidomide and pomalidomide co-stimulate T cells by inducing degradation of T cell repressors Ikaros and Aiolos via modulation of the E3 ubiquitin ligase complex CRL4(CRBN.).

Cereblon (CRBN), the molecular target of lenalidomide and pomalidomide, is a substrate receptor of the cullin ring E3 ubiquitin ligase complex, CRL4(CRBN) . T cell co-stimulation by lenalidomide or pomalidomide is cereblon dependent: however, the CRL4(CRBN) substrates responsible for T cell co-stimulation have yet to be identified. Here we demonstrate that interaction of the transcription factors Ikaros (IKZF1, encoded by the IKZF1 gene) and Aiolos (IKZF3, encoded by the IKZF3 gene) with CRL4(CRBN) is induced by lenalidomide or pomalidomide. Each agent promotes Aiolos and Ikaros binding to CRL4(CRBN) with enhanced ubiquitination leading to cereblon-dependent proteosomal degradation in T lymphocytes. We confirm that Aiolos and Ikaros are transcriptional repressors of interleukin-2 expression. The findings link lenalidomide- or pomalidomide-induced degradation of these transcriptional suppressors to well documented T cell activation. Importantly, Aiolos could serve as a proximal pharmacodynamic marker for lenalidomide and pomalidomide, as healthy human subjects administered lenalidomide demonstrated Aiolos degradation in their peripheral T cells. In conclusion, we present a molecular model in which drug binding to cereblon results in the interaction of Ikaros and Aiolos to CRL4(CRBN) , leading to their ubiquitination, subsequent proteasomal degradation and T cell activation.

Facilitators and barriers to continuing healthcare after jail: a community-integrated program.

A cooperative, community-oriented "public health model of correctional healthcare" was developed to address the needs of persons temporarily displaced into jail from the community, and to improve the health and safety of the community. It emphasizes 5 key elements: early detection, effective treatment, education, prevention, and continuity of care. In the program, physicians and case managers are "dually based"-they work both at the jail and at community healthcare centers. This, together with discharge planning, promotes continuity of care for inmates with serious and chronic medical conditions. This report characterizes the health status and healthcare in this group, and identifies facilitators and barriers to engagement in primary medical and mental health care after release from jail.

Resumption of smoking after release from a tobacco-free correctional facility.

Approximately 70% of incarcerated people smoke tobacco, and an estimated 12% of all smokers in the United States leave correctional facilities annually. Many facilities prohibit smoking, but no published study has measured the relapse to tobacco after release. In a study of 200 people with chronic health conditions reentering the community from jail, 165 (83%) were cigarette smokers. Of these, 129 were interviewed at 1 and/or 6 months after release. Self-reported sustained abstinence rates were 37.3% at the end of the first day, 17.7% for the first week, 13.7% for 1 month, and 3.1% for 6 months. These abstinence rates are lower than those reported after military basic training and medical hospitalization but similar to rates after inpatient psychiatric and addiction programs. More efforts and resources are needed to determine successful tobacco cessation interventions during incarceration and after release.

A cost-effectiveness evaluation of a jail-based chlamydia screening program for men and its impact on their partners in the community.

BACKGROUND: Few cost-effectiveness evaluations of screening men in jails for chlamydia have been published, and none have evaluated the cost-effectiveness of providing partner notification services to the partners of chlamydia-infected inmates. GOAL: The goal of this study was to evaluate the cost-effectiveness of the chlamydia screening and partner notification programs for men conducted by a Massachusetts jail compared with 3 hypothetical alternatives. STUDY DESIGN: Using jail cost and testing data, we used decision analyses to compare the cost and effectiveness of universal screening, age-based screening with 2 age cutoffs, and testing of symptomatic inmates at intake using treated cases of chlamydia and gonorrhea as the primary outcome. We also evaluated the cost-effectiveness of adding partner notification to these alternatives. RESULTS: Universal screening was the most effective and expensive alternative. Age-based screening would have identified slightly fewer cases at half the cost of universal screening. The net cost of partner notification was low. Assuming high sequelae costs in female partners made partner notification a cost-saving intervention. CONCLUSIONS: Age-based screening could lower costs without substantially sacrificing effectiveness. Notifying partners of infected inmates was a cost-effective adjunct to screening inmates.