The ability to silence the activity of genetically specified neurons in a temporally precise fashion would open up the ability to investigate the causal role of specific cell classes in neural computations, behaviors, and pathologies. Here we show that members of the class of light-driven outward proton pumps can mediate very powerful, safe, multiple-color silencing of neural activity. The gene archaerhodopsin-31 (Arch) from Halorubrum sodomense enables near-100% silencing of neurons in the awake brain when virally expressed in mouse cortex and illuminated with yellow light. Arch mediates currents of several hundred picoamps at low light powers, and supports neural silencing currents approaching 900 pA at light powers easily achievable in vivo. In addition, Arch spontaneously recovers from light-dependent inactivation, unlike light-driven chloride pumps that enter long-lasting inactive states in response to light. These properties of Arch are appropriate to mediate the optical silencing of significant brain volumes over behaviourally-relevant timescales. Arch function in neurons is well tolerated because pH excursions created by Arch illumination are minimized by self-limiting mechanisms to levels comparable to those mediated by channelrhodopsins2,3 or natural spike firing. To highlight how proton pump ecological and genomic diversity may support new innovation, we show that the blue-green light-drivable proton pump from the fungus Leptosphaeria maculans4 (Mac) can, when expressed in neurons, enable neural silencing by blue light, thus enabling alongside other developed reagents the potential for independent silencing of two neural populations by blue vs. red light. Light-driven proton pumps thus represent a high-performance and extremely versatile class of “optogenetic” voltage and ion modulator, which will broadly empower new neuroscientific, biological, neurological, and psychiatric investigations.

SUMMARYThe presence of dark melanin (eumelanin) within human epidermis represents one of the strongest predictors of low skin cancer risk. Topical rescue of eumelanin synthesis, previously achieved in “redhaired” Mc1r-deficient mice, demonstrated significant protection against UV damage. However, application of a topical strategy for human skin pigmentation has not been achieved, largely due to the greater barrier function of human epidermis. Salt-inducible kinase (SIK) has been demonstrated to regulate MITF, the master regulator of pigment gene expression, through its effects on CRTC and CREB activity. Here, we describe the development of small-molecule SIK inhibitors that were optimized for human skin penetration, resulting in MITF upregulation and induction of melanogenesis. When topically applied, pigment production was induced in Mc1r-deficient mice and normal human skin. These findings demonstrate a realistic pathway toward UV-independent topical modulation of human skin pigmentation, potentially impacting UV protection and skin cancer risk.

Warmth is a characteristic but nondiagnostic feature of cellulitis. We assessed the diagnostic utility of skin surface temperature in differentiating cellulitis from pseudocellulitis. Adult patients presenting to the emergency department of a large urban hospital with presumed cellulitis were enrolled. Patients were randomized to dermatology consultation (n = 40) versus standard of care (n = 32). Thermal images of affected and unaffected skin were obtained for each patient. Analysis was performed on dermatology consultation patients to establish a predictive model for cellulitis, which was then validated in the other cohort. Of those evaluated by dermatology consultation, pseudocellulitis was diagnosed in 28%. Cellulitis patients had an average maximum affected skin temperature of 34.1°C, which was 3.7°C warmer than the corresponding unaffected area (95% confidence interval = 2.7-4.8°C, P < 0.00001). Pseudocellulitis patients had an average maximum affected temperature of 31.5°C, which was 0.2°C warmer than the corresponding unaffected area (95% confidence interval = -1.1 to 1.5°C, P = 0.44). Temperature differences between sites were greater in cellulitis patients than in pseudocellulitis patients (3.7 vs. 0.2°C, P = 0.002). A logistic regression model showed that a temperature difference of 0.47°C or greater conferred a 96.6% sensitivity, 45.5% specificity, 82.4% positive predictive value, and 83.3% negative predictive value for cellulitis diagnosis. When validated in the other cohort, this model gave the correct diagnosis for 100% of patients with cellulitis and 50% of those with pseudocellulitis. A difference threshold of 0.47°C or greater between affected and unaffected skin showed an 87.5% accuracy in cellulitis diagnosis.

IMPORTANCE Each year, cellulitis leads to 650 000 hospital admissions and is estimated to cost $3.7 billion in the United States. Previous literature has demonstrated a high misdiagnosis rate for cellulitis, which results in unnecessary antibiotic use and health care cost. OBJECTIVE To determine whether dermatologic consultation decreases duration of hospital stay or intravenous antibiotic treatment duration in patients with cellulitis. DESIGN, SETTING, AND PARTICIPANTS This randomized clinical trial was conducted in a large urban tertiary care hospital between October 2012 and January 2017, with 1-month follow-up duration. Patients were randomized to the control group, which received the standard of care (ie, treatment by primary medicine team), or the intervention group, which received dermatology consultation. Medical chart review of demographic information and hospital courses was performed. Adult patients hospitalized with presumed diagnosis of cellulitis were eligible. A total of 1300 patients were screened, 1125 were excluded, and 175 were included. Statistical analysis was employed to identify significant outcome differences between the 2 groups. INTERVENTIONS Dermatology consultation within 24 hours of hospitalization. MAIN OUTCOMES AND MEASURES Length of hospital stay and duration of intravenous antibiotic treatment. RESULTS Of 175 participants, 70 (40%) were women and 105 (60%) were men. The mean age was 58.8 years. Length of hospital stay was not statistically different between the 2 groups. The duration of intravenous antibiotic treatment (<4 days: 86.4% vs 72.5%; absolute difference, 13.9%; 95% CI, 1.9%-25.9%; P = .04) and duration of total antibiotic treatment was significantly lower in patients who had early dermatology consultation (<10 days: 50.6% vs 32.5%; absolute difference, 18.1%; 95% CI, 3.7%-32.5%; P = .01). Clinical improvement at 2 weeks was significantly higher for those in the intervention group (79 [89.3%] vs 59 [68.3%]; absolute difference, 21.0%; 95% CI, 9.3%-32.7%; P < .001). There was no significant difference in 1-month readmission rate between the groups (4 [4.5%] vs 6 [6.9%]; absolute difference, −2.4%; 95% CI, −9.3% to 4.5%; P = .54). In the intervention group, the rate of cellulitis misdiagnosis was 30.7% (27 of 88 participants). Among the entire cohort, 101 (57.7%) patients were treated with courses of antibiotics longer than what is recommended by guidelines. CONCLUSIONS AND RELEVANCE Early dermatologic consultation can improve outcomes in patients with suspected cellulitis by identifying alternate diagnoses, treating modifiable risk factors, and decreasing length of antibiotic treatment. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01706913

In a national "real-life" treatment population, we show that the wide availability of the novel treatment modalities ICB and BRAF-targeted therapy has significantly improved the survival of patients with stage 4 melanoma. Our findings additionally suggest that there are opportunities for expanding coverage and access to these novel immunotherapies in community practice.

IMPORTANCE Calciphylaxis is a rare skin disease with high morbidity and mortality that frequently affects patients with renal disease. Hypercoagulable conditions are frequently observed in both patients with calciphylaxis and those with chronic kidney disease (CKD), complicating our understanding of which hypercoagulable conditions are specific to calciphylaxis. OBJECTIVE To identify hypercoagulable conditions that are risk factors for developing calciphylaxis while controlling for CKD. DESIGN, SETTING, AND PARTICIPANTS This was a case-control study, comparing the hypercoagulability status of patients with calciphylaxis and with renal disease with that of a matched control population at 2 large urban academic hospitals in Boston, Massachusetts. Retrospective medical record review of laboratory values was performed to identify patients with hypercoagulable conditions. Case and control patients were further stratified based on both severity of CKD and warfarin. Patients with a dermatologic diagnosis of calciphylaxis between 2006 and 2014 and concomitant CKD were included as cases (n = 38). Three controls (n = 114) per case patient with CKD were included, and were matched by age, sex, and race. MAIN OUTCOMES AND MEASURES The rate of various hypercoagulable states (ie, antithrombin III [ATIII] deficiency, protein C and S deficiency, factor V Leiden mutation, prothrombin gene mutation [G20210A], elevated factor VIII level, lupus anticoagulant, anti-IgG or IgM cardiolipin antibodies, heparin-induced thrombocytopenia antibodies, and elevation of homocysteine) in patients with calciphylaxis compared with their matched controls. RESULTS Of the calciphylaxis cohort, 28 (58%) were female and 18 (55%) were non-Hispanic white. Among all patients, lupus anticoagulant (13 [48%] positive in cases vs 1 [5%] in controls; P = .001), protein C deficiency (9 [50%] vs 1 [8%]; P = .02), and combined thrombophilias (18 [62%] vs 10 [31%]; P = .02) were found to be significantly associated with calciphylaxis. In a subanalysis of patients with stage 5 CKD, only lupus anticoagulant (12 [53%] vs 9 [0%]; P = .01) and combined thrombophilia (15 [63%] vs 1 [8%]; P = .004) remained significantly associated with calciphylaxis. In a separate subanalysis of warfarin-unexposed patients, only lupus anticoagulant (7 [50%] vs 1 [6%]; P = .01) and protein C deficiency (5 [46%] vs 10 [0%]; P = .04) remained significantly associated with calciphylaxis. CONCLUSIONS AND RELEVANCE Presence of lupus anticoagulant and combined thrombophilias are risk factors for the development of calciphylaxis in patients with late-stage renal disease. Clinicians should be aware of these associations in patients with impaired kidney function and may consider increased screening and appropriate anticoagulation treatment to reduce the risk of calciphylaxis development.

Background Biologic therapy is effective for treatment of moderate-to-severe psoriasis but may be associated with an increased risk for serious infection. Objective To estimate the serious infection rate among patients with psoriasis treated with biologic as compared with nonbiologic systemic agents within a community-based health care delivery setting. Methods We identified 5889 adult Kaiser Permanente Northern California health plan members with psoriasis who had ever been treated with systemic therapies and calculated the incidence rates and 95% confidence intervals (CIs) for serious infections over 29,717 person-years of follow-up. Adjusted hazard ratios (aHRs) were calculated using Cox regression. Results Adjusting for age, sex, race or ethnicity, and comorbidities revealed a significantly increased risk for overall serious infection among patients treated with biologics as compared with those treated with nonbiologics (aHR, 1.31; 95% CI, 1.02–1.68). More specifically, there was a significantly elevated risk for skin and soft tissue infection (aHR, 1.75; 95% CI, 1.19–2.56) and meningitis (aHR, 9.22; 95% CI, 1.77–48.10) during periods of active biologic use. Limitations Risk associated with individual drugs was not examined. Conclusion We found an increased rate of skin and soft tissue infections among patients with psoriasis treated with biologic agents. There also was a signal suggesting increased risk for meningitis. Clinicians should be aware of these potential adverse events when prescribing biologic agents.

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