IMPORTANCE Many patients receive suboptimal rehabilitation therapy doses after stroke owing to limited access to therapists and difficulty with transportation, and their knowledge about stroke is often limited. Telehealth can potentially address these issues.OBJECTIVES To determine whether treatment targeting arm movement delivered via a home-based telerehabilitation (TR) system has comparable efficacy with dose-matched, intensity-matched therapy delivered in a traditional in-clinic (IC) setting, and to examine whether this system has comparable efficacy for providing stroke education. DESIGN, SETTING, AND PARTICIPANTSIn this randomized, assessor-blinded, noninferiority trial across 11 US sites, 124 patients who had experienced stroke 4 to 36 weeks prior and had arm motor deficits (Fugl-Meyer [FM] score, 22-56 of 66) were enrolled between September 18, 2015, and December 28, 2017, to receive telerehabilitation therapy in the home (TR group) or therapy at an outpatient rehabilitation therapy clinic (IC group). Primary efficacy analysis used the intent-to-treat population.INTERVENTIONS Participants received 36 sessions (70 minutes each) of arm motor therapy plus stroke education, with therapy intensity, duration, and frequency matched across groups.MAIN OUTCOMES AND MEASURES Change in FM score from baseline to 4 weeks after end of therapy and change in stroke knowledge from baseline to end of therapy.RESULTS A total of 124 participants (34 women and 90 men) had a mean (SD) age of 61 ( 14) years, a mean (SD) baseline FM score of 43 (8) points, and were enrolled a mean (SD) of 18.7 (8.9) weeks after experiencing a stroke. Among those treated, patients in the IC group were adherent to 33.6 of the 36 therapy sessions (93.3%) and patients in the TR group were adherent to 35.4 of the 36 assigned therapy sessions (98.3%). Patients in the IC group had a mean (SD) FM score change of 8.36 (7.04) points from baseline to 30 days after therapy (P < .001), while those in the TR group had a mean (SD) change of 7.86 (6.68) points (P < .001). The covariate-adjusted mean FM score change was 0.06 (95% CI, -2.14 to 2.26) points higher in the TR group (P = .96). The noninferiority margin was 2.47 and fell outside the 95% CI, indicating that TR is not inferior to IC therapy. Motor gains remained significant when patients enrolled early (<90 days) or late (Ն90 days) after stroke were examined separately.CONCLUSIONS AND RELEVANCE Activity-based training produced substantial gains in arm motor function regardless of whether it was provided via home-based telerehabilitation or traditional in-clinic rehabilitation. The findings of this study suggest that telerehabilitation has the potential to substantially increase access to rehabilitation therapy on a large scale.

The zinc finger transcription factor Helios is critical for maintaining the identity, anergic phenotype, and suppressive activity of regulatory T cells. While it is an attractive target to enhance the efficacy of currently approved immunotherapies, no existing approaches can directly modulate Helios activity or abundance. Here, we report the structure-guided development of small molecules that recruit the E3 ubiquitin ligase substrate receptor Cereblon to Helios, thereby promoting its degradation. Pharmacological Helios degradation destabilized the anergic phenotype and reduced the suppressive activity of regulatory T cells, establishing a route towards Helios-targeting therapeutics. More generally, this study provides a framework for the development of small molecule degraders for previously unligandable targets by reprogramming E3 ligase substrate specificity.

Immunosuppression increases the risk of cancers associated with viral infection 1. In particular, squamous cell carcinoma (SCC) of the skin has a >100-fold increased risk in immunosuppressed patients and has been associated with beta human papillomavirus (β-HPV) infection 2-4. Previous studies, however, have failed to establish a causative role for HPVs in driving skin cancer development. Herein, we provide an alternative explanation for this association by demonstrating that the T cell immunity against commensal papillomaviruses suppresses skin cancer in immunocompetent hosts. The loss of this immunity, rather than the oncogenic effect of HPVs, is the reason for the markedly increased risk of skin cancer in immunosuppressed patients. To investigate the impact of papillomavirus on carcinogen-driven skin cancer, we colonized several Reprint and permissions information is available at www.nature.com/reprints.Users may view, print, copy, and download text and datamine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://