The Nrf2 (nuclear factor E2 p45-related factor 2) transcription factor responds to diverse oxidative and electrophilic environmental stresses by circumventing repression by Keap1, translocating to the nucleus, and activating cytoprotective genes. Nrf2 responses provide protection against chemical carcinogenesis, chronic inflammation, neurodegeneration, emphysema, asthma and sepsis in murine models. Nrf2 regulates the expression of a plethora of genes that detoxify oxidants and electrophiles and repair or remove damaged macromolecules, such as through proteasomal processing. However, many direct targets of Nrf2 remain undefined. Here, mouse embryonic fibroblasts (MEF) with either constitutive nuclear accumulation (Keap1−/−) or depletion (Nrf2−/−) of Nrf2 were utilized to perform chromatin-immunoprecipitation with parallel sequencing (ChIP-Seq) and global transcription profiling. This unique Nrf2 ChIP-Seq dataset is highly enriched for Nrf2-binding motifs. Integrating ChIP-Seq and microarray analyses, we identified 645 basal and 654 inducible direct targets of Nrf2, with 244 genes at the intersection. Modulated pathways in stress response and cell proliferation distinguish the inducible and basal programs. Results were confirmed in an in vivo stress model of cigarette smoke-exposed mice. This study reveals global circuitry of the Nrf2 stress response emphasizing Nrf2 as a central node in cell survival response.

Virtual care, the use of videoconferencing technology to connect with patients, has become critical in providing continuing care for patients during the current COVID-19 pandemic. Virtual care has now been adopted by health care providers across the spectrum, including physicians, residents, nurse practitioners, nurses, and allied health care professionals. Virtual care is novel and nuanced compared to in-person care. Most of the health care providers who are delivering or expected to deliver virtual care have little to no prior experience with it. The nuances of virtual care involve regulatory standards, platforms, technology and troubleshooting, patient selection, etiquette, and workflow, all of which comprise critical points in the provision of health care. It is important to consistently deliver high-quality, equitable, and professional virtual care to inspire patients with the trust they need to continue follow-up of their care in these difficult times. We have been adopting virtual care in our clinical practice for over two years. In partnership with Canada Health Infoway, we have assembled a primer for virtual care that can serve as a guide for any health care provider in Canada and globally, with the goal of providing seamless transitions between in-person and virtual care.

Glioblastoma (GBM) is the most common and fatal primary central nervous system malignancy in adults with a median survival of less than 15 months. Surgery, radiation, and chemotherapy are the standard of care and provide modest benefits in survival, but tumor recurrence is inevitable. The poor prognosis of GBM has made the development of novel therapies targeting GBM of paramount importance. Immunotherapy via dendritic cells (DCs) has garnered attention and research as a potential strategy to boost anti-tumor immunity in recent years. As the “professional” antigen processing and presenting cells, DCs play a key role in the initiation of anti-tumor immune responses. Pre-clinical studies in GBM have shown long-term tumor survival and immunological memory in murine models with stimulation of DC activity with various antigens and costimulatory molecules. Phase I and II clinical trials of DC vaccines in GBM have demonstrated some efficacy in improving the median overall survival with minimal to no toxicity with promising initial results from the first Phase III trial. However, there remains no standardization of vaccines in terms of which antigens are used to pulse DCs ex vivo, sites of DC injection, and optimal adjuvant therapies. Future work with DC vaccines aims to elucidate the efficacy of DC-based therapy alone or in combination with other immunotherapy adjuvants in additional Phase III trials.

BackgroundHospitalized patients are designated alternate level of care (ALC) when they no longer require hospitalization but discharge is delayed while they await alternate disposition or living arrangements. We assessed hospital costs and complications for general internal medicine (GIM) inpatients who had delayed discharge. In addition, we developed a clinical prediction rule to identify patients at risk for delayed discharge.MethodsWe conducted a retrospective cohort study of consecutive GIM patients admitted between 1 January 2015 and 1 January 2016 at a large tertiary care hospital in Canada. We compared hospital costs and complications between ALC and non-ALC patients. We derived a clinical prediction rule for ALC designation using a logistic regression model and validated its diagnostic properties.ResultsOf 4311 GIM admissions, 255 (6%) patients were designated ALC. Compared to non-ALC patients, ALC patients had longer median length of stay (30.85 vs. 3.95 days p < 0.0001), higher median hospital costs ($22,459 vs. $5003 p < 0.0001) and more complications in hospital (25.5% vs. 5.3% p < 0.0001) especially nosocomial infections (14.1% vs. 1.9% p < 0.0001). Sensitivity analyses using propensity score and pair matching yielded similar results. In a derivation cohort, seven significant risk factors for ALC were identified including age > =80 years, female sex, dementia, diabetes with complications as well as referrals to physiotherapy, occupational therapy and speech language pathology. A clinical prediction rule that assigned each of these predictors 1 point had likelihood ratios for ALC designation of 0.07, 0.25, 0.66, 1.48, 6.07, 17.13 and 21.85 for patients with 0, 1, 2, 3, 4, 5, and 6 points respectively in the validation cohort.ConclusionsDelayed discharge is associated with higher hospital costs and complication rates especially nosocomial infections. A clinical prediction rule can identify patients at risk for delayed discharge.

Objective To compare inhospital mortality of general internal medicine (GIM) patients bedspaced to off-service wards with GIM inpatients admitted to assigned GIM wards. Method A retrospective cohort study of consecutive GIM admissions between 1 January 2015 and 1 January 2016 was conducted at a large tertiary care hospital in Canada. Inhospital mortality was compared between patients admitted to off-service wards (bedspaced) and assigned GIM wards using a Cox proportional hazards model and a competing risk model. Sensitivity analyses included propensity score and pair matching based on GIM service team, workload, demographics, time of admission, reasons for admission and comorbidities. Results Among 3243 consecutive GIM admissions, more than a third (1125, 35%) were bedspaced to off-service wards with the rest (2118, 65%) admitted to assigned GIM wards. In hospital, 176 (5%) patients died: 88/1125 (8%) bedspaced patients and 88/2118 (4%) assigned GIM ward patients. Compared with assigned GIM wards patients, bedspaced patients had an HR of 3.42 (95% CI 2.23 to 5.26; P<0.0001) for inhospital mortality at admission, which then decreased by HR of 0.97 (95% CI 0.94 to 0.99; P=0.0133) per day in hospital. Competing risk models and sensitivity analyses using propensity scores and pair matching yielded similar results. Conclusions Bedspaced patients had significantly higher inhospital mortality than patients admitted to assigned GIM wards. The risk was highest at admission and subsequently declined. The results of this single centre study may not be generalisable to other hospitals and may be influenced by residual confounding. Despite these limitations, the relationship between bedspacing and patient outcomes requires investigation at other institutions to determine if this common practice represents a modifiable patient safety indicator.

Four hypotheses have been posited on the role of insulin in glucose-stimulated insulin secretion; available evidence has supported insulin as being 1) essential, 2) a positive modulator, 3) a negative modulator, or 4) not necessary. Because circulating insulin levels in mice, before or after intraperitoneal glucose injection, are sufficient to elicit insulin responses in insulinsensitive tissues, it is likely that ␤-cell insulin receptors are continuously exposed to stimulating concentrations of insulin. To determine whether constitutively secreted insulin is necessary for glucose-stimulated insulin secretion, CD1 male mouse islets were incubated for 30 min at 4°C in the absence (control) or presence of anti-insulin (1 g/ml) or anti-IgG (1 g/ml). Then islets were exposed to 3, 11, or 25 mmol/l glucose or to 20 mmol/l arginine. Nontreated islets exhibited first-and second-phase glucose-stimulated insulin secretion. Control and anti-IgG-treated islets, after a 5-min lag phase, increased their insulin secretion in 25 mmol/l glucose. Anti-insulin؊treated islets secreted insulin at a basal rate in 3 or 25 mmol/l glucose buffers. Insulin secretion stimulated by 20 mmol/l arginine was the same in islets pretreated with either antibody and showed no lag phase. Taken together, these data suggest that constitutively secreted insulin is required and sufficient for ␤-cells to maintain sensitivity to glucose.

Clinical trials involving anti-programmed cell death protein-1 (anti-PD-1) failed to demonstrate improved overall survival in glioblastoma (GBM) patients. This may be due to the expression of alternative checkpoints such as B- and T- lymphocyte attenuator (BTLA) on several immune cell types including regulatory T cells. Murine GBM models indicate that there is significant upregulation of BTLA in the tumor microenvironment (TME) with associated T cell exhaustion. We investigate the use of antibodies against BTLA and PD-1 on reversing immunosuppression and increasing long-term survival in a murine GBM model. C57BL/6 J mice were implanted with the murine glioma cell line GL261 and randomized into 4 arms: (i) control, (ii) anti-PD-1, (iii) anti-BTLA, and (iv) anti-PD-1 + anti-BTLA. Kaplan–Meier curves were generated for all arms. Flow cytometric analysis of blood and brains were done on days 11 and 16 post-tumor implantation. Tumor-bearing mice treated with a combination of anti-PD-1 and anti-BTLA therapy experienced improved overall long-term survival (60%) compared to anti-PD-1 (20%) or anti-BTLA (0%) alone ( P = .003). Compared to monotherapy with anti-PD-1, mice treated with combination therapy also demonstrated increased expression of CD4+ IFN-γ ( P < .0001) and CD8+ IFN-γ ( P = .0365), as well as decreased levels of CD4+ FoxP3+ regulatory T cells on day 16 in the brain ( P = .0136). This is the first preclinical investigation into the effects of combination checkpoint blockade with anti-PD-1 and anti-BTLA treatment in GBM. We also show a direct effect on activated immune cell populations such as CD4+ and CD8 + T cells and immunosuppressive regulatory T cells through this combination therapy.

OBJECTIVE Frailty—the state defined by decreased physiological reserve and increased vulnerability to physiological stress—is exceedingly common in oncology patients. Given the palliative nature of spine metastasis surgery, it is imperative that patients be healthy enough to tolerate the physical insult of surgery. In the present study, the authors compared the association of two frailty metrics and the widely used Charlson Comorbidity Index (CCI) with postoperative morbidity in spine metastasis patients. METHODS A retrospective cohort of patients who underwent operations for spinal metastases at a comprehensive cancer center were identified. Data on patient demographic characteristics, disease state, medical comorbidities, operative details, and postoperative outcomes were collected. Frailty was measured with the modified 5-item frailty index (mFI-5) and metastatic spinal tumor frailty index (MSTFI). Outcomes of interest were length of stay (LOS) greater than the 75th percentile of the cohort, nonroutine discharge, and the occurrence of ≥ 1 postoperative complication. RESULTS In total, 322 patients were included (mean age 59.5 ± 12 years; 56.9% of patients were male). The mean ± SD LOS was 11.2 ± 9.9 days, 44.5% of patients had nonroutine discharge, and 24.0% experienced ≥ 1 postoperative complication. On multivariable analysis, increased frailty on mFI-5 and MSTFI was independently predictive of all three outcomes: prolonged LOS (OR 1.67 per point, 95% CI 1.06–2.63, p = 0.03; and OR 1.63 per point, 95% CI 1.29–2.05, p < 0.01, respectively), nonroutine discharge (OR 2.65 per point, 95% CI 1.74–4.04, p < 0.01; and OR 1.69 per point, 95% CI 1.36–2.11, p < 0.01), and ≥ 1 complication (OR 1.95 per point, 95% CI 1.23–3.09, p = 0.01; and OR 1.41 per point, 95% CI 1.12–1.77, p < 0.01). CCI was found to be independently predictive of only the occurrence of ≥ 1 postoperative complication (OR 1.45 per point, 95% CI 1.22–1.72, p < 0.01). CONCLUSIONS Frailty measured with either mFI-5 or MSTFI scores was a more robust independent predictor of adverse postoperative outcomes than the more widely used CCI. Both mFI-5 and MSTFI were significantly associated with prolonged LOS, higher complication rates, and nonroutine discharge. Further investigation in a prospective multicenter cohort is merited.