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he crosstalk between tumor cells and microenvironment. CONCLUSIONS Taken together, our results show that melanoma-specific bcl-2 controls an IL-1β-driven axis of macrophage diversion that establishes tumor microenvironmental conditions favoring melanoma development. Interfering with this pathway might provide novel therapeutic strategies. © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.BACKGROUND Adoptive cellular therapy (ACT) is a promising treatment for synovial sarcoma (SS) with reported response rates of over 50%. However, more work is needed to obtain deeper and more durable responses. SS has a 'cold' tumor immune microenvironment with low levels of major histocompatibility complex (MHC) expression and few T-cell infiltrates, which could represent a barrier toward successful treatment with ACT. We previously demonstrated that both MHC expression and T-cell infiltration can be increased using systemic interferon gamma (IFN-γ), which could improve the efficacy of ACT for SS. CASE PRESENTATION We launched a phase I trial incorporating four weekly doses of IFN-γ in an ACT regimen of high-dose cyclophosphamide (HD Cy), NY-ESO-1-specific T cells, and postinfusion low-dose interleukin (IL)-2. Two patients were treated. While one patient had significant tumor regression and resultant clinical benefit, the other patient suffered a fatal histiocytic myocarditis. Therefore, this cohort was terminated for safety concerns. CONCLUSION We describe a new and serious toxicity of immunotherapy from IFN-γ combined with HD Cy-based lymphodepletion and low-dose IL-2. While IFN-γ should not be used concurrently with HD Cy or with low dose IL-2, IFN-γ may still be important in sensitizing SS for ACT. Future studies should avoid using IFN-γ during the immediate period before/after cell infusion. TRIAL REGISTRATION NUMBERS NCT04177021, NCT01957709, and NCT03063632. © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.BACKGROUND Avelumab, a human anti-programmed death-ligand 1 immunoglobulin G1 monoclonal antibody, showed favorable efficacy and safety in patients with metastatic Merkel cell carcinoma (mMCC) in the phase II JAVELIN Merkel 200 trial, leading to approval in multiple countries. We describe real-world experience with avelumab in patients with mMCC from an expanded access program. METHODS Eligible patients had mMCC and progressive disease during or after chemotherapy or were ineligible for chemotherapy or clinical trial participation. Patients received an initial 3-month supply of avelumab (administered as 10 mg/kg intravenously every 2 weeks until progressive disease or unacceptable toxicity); resupply was allowed following complete response, partial response, stable disease, or clinical benefit per physician assessment. RESULTS Between December 15, 2015, and March 4, 2019, 558 of 620 requests from 38 countries were medically approved, and 494 patients received avelumab. Among 240 evaluable patients, the objective response rate was 46.7% (complete response in 22.9%, including 3 of 16 potentially immunocompromised patients), and the disease control rate was 71.2%. The median duration of treatment in evaluable patients with response was 7.9 months (range, 1.0-41.7) overall and 5.2 months (range, 3.0-13.9) in immunocompromised patients. No new safety signals were identified. The expanded access program closed for new requests on December 31, 2018, as required after regulatory approval; benefitting patients continued to receive avelumab. CONCLUSIONS The avelumab expanded access program for patients with mMCC demonstrated efficacy and safety in a real-world setting, consistent with the results from JAVELIN Merkel 200, and provided a treatment for patients with limited options. © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.BACKGROUND Frailty increases risk for complications after total joint arthroplasty (TJA). Whether this association is influenced by anesthetic administered is unknown. We hypothesized that use of neuraxial (spinal or epidural) anesthesia is associated with better outcomes compared with general anesthesia, and that the effect of anesthesia type on outcomes differs by frailty status. see more METHODS This single-institution cohort study included all patients (≥50 years) from January 2005 through December 2016 undergoing unilateral, primary and revision TJA. Using multivariable Cox regression, we assessed relationships between anesthesia type, a preoperative frailty deficit index (FI) categorized as non-frail (FI 0.20), and complications (mortality, infection, wound complications/hematoma, reoperation, dislocation, and periprosthetic fracture) within 1 year after surgery. Interactions between anesthesia type and frailty were tested, and stratified models were presented when an interaction (p less then 0.1) was observed. RESULTS Among 18 458 patients undergoing TJA, more patients were classified as frail (21.5%) and vulnerable (36.2%) than non-frail (42.3%). Anesthesia type was not associated with complications after adjusting for age, joint, and revision type. However, in analyzes stratified by frailty, vulnerable patients under neuraxial block had less mortality (HR=0.49; 95% CI 0.27 to 0.89) and wound complications/hematoma (HR=0.71; 95% CI 0.55 to 0.90), whereas no difference in risk by anesthesia type was observed among patients found non-frail or frail. CONCLUSIONS Neuraxial anesthesia use among vulnerable patients was associated with improved survival and less wound complications. Calculating preoperative frailty prior to TJA informs perioperative risk and enhances shared-decision making for selection of anesthesia type. © American Society of Regional Anesthesia & Pain Medicine 2020. No commercial re-use. See rights and permissions. Published by BMJ.Systemic sclerosis sine scleroderma (ssSSc) is a rare variant of systemic sclerosis, with only one pediatric case reported in the medical literature to date. Pulmonary arterial hypertension as the presenting feature of ssSSc is extremely rare, even in adults, and so far has never been reported in children. We report, for the first time, a case of pediatric ssSSc in a 3-year-old girl, who presented with interstitial lung disease and pulmonary hypertension. The patient was prescribed early aggressive pulmonary vasodilators combined with anti-inflammatory medications. The clinical response was good, and her current condition at 12 years of age is remarkable, considering the high mortality rates reported in adults. We underscore the importance of early aggressive treatment in future cases of similar presentation. Copyright © 2020 by the American Academy of Pediatrics.see more