Snidervaughan3508

As many as 1 in 10 patients experience dyspnea at hospital admission but the relationship between dyspnea and patient outcomes is unknown. We sought to determine whether dyspnea on admission predicts outcomes.We conducted a retrospective cohort study in a single, academic medical center. We analysed 67 362 consecutive hospital admissions with available data on dyspnea, pain, and outcomes. As part of the Initial Patient Assessment by nurses, patients rated "breathing discomfort" using a 0 to 10 scale, (10="unbearable"). Patients reported dyspnea at the time of admission and recalled dyspnea experienced in the 24 h prior to admission. Outcomes included in-hospital mortality, 2-year mortality, length of stay, need for rapid response system activation, transfer to the intensive care unit, discharge to extended care, and 7- and 30-day all cause readmission to the same institution.Patients who reported any dyspnea were at an increased risk of death during that hospital stay; the greater the dyspnea, the greater the risk of death (dyspnea=0, 0.8% in-hospital mortality; dyspnea=1-3, 2.5% mortality; dyspnea ≥4, 3.7% mortality, p less then 0.001). After adjustment for patient comorbidities, demographics, and severity of illness, increasing dyspnea remained associated with inpatient mortality (dyspnea 1-3, aOR 2.1, 95% CI 1.7-2.6; dyspnea ≥4, aOR 3.1, 95% CI 2.4-3.9). Pain did not predict increased mortality. Patients reporting dyspnea also used more hospital resources, were more likely to be readmitted, and were at increased risk of death within 2 years (dyspnea=1-3 adjusted HR 1.5, 95% CI 1.3-1.6; dyspnea ≥4 adjusted HR 1.7, 95% CI 1.5-1.8).We found that dyspnea of any rating was associated with an increased risk of death. Dyspnea can be rapidly collected by nursing staff, which may allow for better monitoring or interventions that could reduce mortality and morbidity.

Prenatal vitamin D

supplementation has been linked to reduced risk of early life asthma/recurrent wheeze. This protective effect appears to be influenced by variations in the 17q21 functional SNP rs12936231 of the child, which regulates the expression of

and for which the high-risk CC-genotype is associated with early-onset asthma. However, this does not fully explain the differential effects of supplementation. We investigated the influence of maternal rs12936231 genotype variation on the protective effect of prenatal vitamin D

supplementation against offspring asthma/recurrent wheeze.

We determined the rs12936231 genotype of mother-child pairs from two randomised-controlled trials the Vitamin D Antenatal Asthma Reduction Trial (VDAART, n=613) and the Copenhagen Prospective Studies on Asthma in Childhood 2010 (COPSAC

, n=563) to examine the effect of maternal genotype variation on offspring asthma/recurrent wheeze at age 0-3 years between groups who received high-dose prenatal vitamin D

supplementation

placebo.

Offspring of mothers with low-risk GG-genotype or GC-genotype who received high-dose vitamin D

supplementation had a significantly reduced risk of asthma/recurrent wheeze when compared to the placebo group (hazard ratio [HR], 0.54; 95% confidence interval [CI], 0.37-0.77; p<0.001 for VDAART and HR, 0.56; 95% CI, 0.35-0.92; p=0.021 for COPSAC

), whereas no difference was observed among the offspring of mothers with high-risk CC-genotype (HR, 1.05; 95% CI, 0.61-1.84; p=0.853 for VDAART and HR, 1.11; 95% CI, 0.54-2.28; p=0.785 for COPSAC

).

Maternal 17q21 genotype has an important influence on the protective effects of prenatal vitamin D

supplementation against offspring asthma/recurrent wheeze.

Maternal 17q21 genotype has an important influence on the protective effects of prenatal vitamin D3 supplementation against offspring asthma/recurrent wheeze.

Myocarditis is a highly morbid complication of immune checkpoint inhibitor (ICI) use that remains inadequately characterized. The QRS duration and the QTc interval are standardized electrocardiographic measures that are prolonged in other cardiac conditions; however, there are no data on their utility in ICI myocarditis.

From an international registry, ECG parameters were compared between 140 myocarditis cases and 179 controls across multiple time points (pre-ICI, on ICI prior to myocarditis, and at the time of myocarditis). The association between ECG values and major adverse cardiac events (MACE) was also tested.

Both the QRS duration and QTc interval were similar between cases and controls prior to myocarditis. When compared with controls on an ICI (93±19 ms) or to baseline prior to myocarditis (97±19 ms), the QRS duration prolonged with myocarditis (110±22 ms, p<0.001 and p=0.009, respectively). https://www.selleckchem.com/ In contrast, the QTc interval at the time of myocarditis (435±39 ms) was not increased compared with pre-myocarditis baseline (422±27 ms, p=0.42). A prolonged QRS duration conferred an increased risk of subsequent MACE (HR 3.28, 95% CI 1.98 to 5.62, p<0.001). After adjustment, each 10 ms increase in the QRS duration conferred a 1.3-fold increase in the odds of MACE (95% CI 1.07 to 1.61, p=0.011). Conversely, there was no association between the QTc interval and MACE among men (HR 1.33, 95% CI 0.70 to 2.53, p=0.38) or women (HR 1.48, 95% CI 0.61 to 3.58, p=0.39).

The QRS duration is increased in ICI myocarditis and is associated with increased MACE risk. Use of this widely available ECG parameter may aid in ICI myocarditis diagnosis and risk-stratification.

The QRS duration is increased in ICI myocarditis and is associated with increased MACE risk. Use of this widely available ECG parameter may aid in ICI myocarditis diagnosis and risk-stratification.

Although intravesical BCG is the standard treatment of high-grade non-muscle invasive bladder cancer (NMIBC), response rates remain unsatisfactory. In preclinical models, rapamycin enhances BCG vaccine efficacy against tuberculosis and the killing capacity of γδ T cells, which are critical for BCG's antitumor effects. Here, we monitored immunity, safety, and tolerability of rapamycin combined with BCG in patients with NMIBC.

A randomized double-blind trial of oral rapamycin (0.5 or 2.0 mg daily) versus placebo for 1 month was conducted in patients with NMIBC concurrently receiving 3 weekly BCG instillations (NCT02753309). The primary outcome was induction of BCG-specific γδ T cells, measured as a percentage change from baseline. Post-BCG urinary cytokines and immune cells were examined as surrogates for local immune response in the bladder. Secondary outcomes measured were adverse events (AEs) and tolerability using validated patient-reported questionnaires.

Thirty-one patients were randomized (11 placeents with NMIBC. Rapamycin enhances BCG-specific γδ T cell immunity and boosts urinary cytokines during BCG treatment. Further study is needed to determine long-term rapamycin safety, tolerability and effects on BCG efficacy.

Four weeks of 0.5 and 2.0 mg oral rapamycin daily is safe and tolerable in combination with BCG for patients with NMIBC. Rapamycin enhances BCG-specific γδ T cell immunity and boosts urinary cytokines during BCG treatment. Further study is needed to determine long-term rapamycin safety, tolerability and effects on BCG efficacy.Immune checkpoint inhibitors (ICIs) have improved overall survival for cancer patients, however, optimal duration of ICI therapy has yet to be defined. Given ICIs were first used to treat patients with metastatic melanoma, a condition that at the time was incurable, little attention was initially paid to how much therapy would be needed for a durable response. As the early immunotherapy trials have matured past 10 years, a significant per cent of patients have demonstrated durable responses; it is now time to determine whether patients have been overtreated, and if durable remissions can still be achieved with less therapy, limiting the physical and financial toxicity associated with years of treatment. Well-designed trials are needed to identify optimal duration of therapy, and to define biomarkers to predict who would benefit from shorter courses of immunotherapy. Here, we outline key questions related to health, financial and societal toxicities of over treating with ICI and present four unique clinical trials aimed at exposing criteria for early cessation of ICI. Taken together, there is a serious liability to overtreating patients with ICI and future work is warranted to determine when it is safe to stop ICI.

Low-density lipoprotein receptor-related protein 1b (encoded by

) is a putative tumor suppressor, and preliminary evidence suggests

mutated cancers may have improved outcomes with immune checkpoint inhibitors (ICI).

We conducted a multicenter, retrospective pan-cancer analysis of patients with

alterations treated with ICI at Duke University, Johns Hopkins University (JHU) and University of Michigan (UM). The primary objective was to assess the association between overall response rate (ORR) to ICI and pathogenic or likely pathogenic (P/LP)

alterations compared with

variants of unknown significance (VUS). Secondary outcomes were the associations with progression-free survival (PFS) and overall survival (OS) by

status.

We identified 101 patients (44 Duke, 35 JHU, 22 UM) with

alterations who were treated with ICI. The most common tumor types by alteration (P/LP vs VUS%) were lung (36% vs 49%), prostate (9% vs 7%), sarcoma (5% vs 7%), melanoma (9% vs 0%) and breast cancer (3% vs 7%). The ORR for patients with

P/LP versus VUS alterations was 54% and 13%, respectively (OR 7.5, 95% CI 2.9 to 22.3, p=0.0009). P/LP

alterations were associated with longer PFS (HR 0.42, 95% CI 0.26 to 0.68, p=0.0003) and OS (HR 0.62, 95% CI 0.39 to 1.01, p=0.053). These results remained consistent when excluding patients harboring microsatellite instability (MSI) and controlling for tumor mutational burden (TMB).

This multicenter study shows significantly better outcomes with ICI therapy in patients harboring P/LP versus VUS

alterations, independently of TMB/MSI status. Further mechanistic and prospective validation studies are warranted.

This multicenter study shows significantly better outcomes with ICI therapy in patients harboring P/LP versus VUS LRP1B alterations, independently of TMB/MSI status. Further mechanistic and prospective validation studies are warranted.

Current immunotherapies including checkpoint blockade therapy have limited success rates in certain types of cancers. Identification of alternative checkpoint molecules for the development of effective strategies for tumor immunotherapy is urgently needed. Immunoglobulin-like transcript 4 (ILT4) is an immunosuppressive molecule expressed in both myeloid innate cells and malignant tumor cells. However, the role of tumor-derived ILT4 in regulating cancer biology and tumor immunity remains unclear.

ILT4 expression in tumor cells and patient samples was determined by real-time PCR, flow cytometry, and immunohistochemistry. T cell senescence induced by tumor was evaluated using multiple markers and assays. Moreover, metabolic enzyme and signaling molecule expression and lipid droplets in tumor cells were determined using real-time PCR, western blot and oil red O staining, respectively. Loss-of-function and gain-of-function strategies were used to identify the causative role of ILT4 in tumor-induced T cell senescence.