CD4 Phenotypes Are Associated with Reduced Expansion of Tumor-Infiltrating Lymphocytes in Melanoma Patients Treated with Adoptive Cell Therapy.

Tumor-infiltrating lymphocyte (TIL) adoptive cell therapy is effective in treating malignant melanoma, but its success relies on the adequate ex vivo expansion of TIL. To assess correlates of TIL expansion, CD4+ and CD8+ TIL were analyzed by RNA sequencing (RNA-seq) and chromatin immunoprecipitation sequencing of acetylated histone 3. Patients were grouped into "TIL high" and "TIL low" based on division at the median number of TIL infused.

Implementation of Home-Based Telerehabilitation of Patients With Stroke in the United States: Protocol for a Realist Review.

Background: Stroke is a common cause of mortality and morbidity. Insufficient and untimely rehabilitation has been associated with inadequate recovery. Telerehabilitation provides an opportunity for timely and accessible services for individuals with stroke, especially in remote areas.

PhenoComb: a discovery tool to assess complex phenotypes in high-dimensional single-cell datasets.

Motivation: High-dimensional cytometry assays can simultaneously measure dozens of markers, enabling the investigation of complex phenotypes. However, as manual gating relies on previous biological knowledge, few marker combinations are often assessed. This results in complex phenotypes with the potential for biological relevance being overlooked.

Clinical and immune correlate results from a phase 1b study of the histone deacetylase inhibitor mocetinostat with ipilimumab and nivolumab in unresectable stage III/IV melanoma.

Checkpoint immunotherapies (CPIs) have improved outcomes for metastatic melanoma patients, with objective response rates to combination ipilimumab and nivolumab of ~58%. Preclinical data suggest that histone deacetylase (HDAC) inhibition enhances antitumor immune activity and may augment CPI. In a phase Ib open-label pilot trial (NCT03565406), patients with therapy-naive metastatic melanoma were treated with the class I/IV HDAC inhibitor mocetinostat orally three times a week in combination with nivolumab and ipilimumab every 3 weeks for 12 weeks followed by 12-week maintenance cycles of nivolumab every 2 weeks and mocetinostat at the same dose and schedule as induction.

Evaluation of the Impact of on Seed Production in California.

The impact of the capitulum weevil on seed production was examined at two field sites in central California. The study occurred in 1993-1995 during the early phases of the biological control program on and before the current guild of capitulum insects had become widespread. Results showed that adult feeding on early flower buds resulted in 60-70% of buds failing to develop.

Nivolumab and ipilimumab are associated with distinct immune landscape changes and response-associated immunophenotypes.

BACKGROUNDThe reshaping of the immune landscape by nivolumab (NIVO) and ipilimumab (IPI) and its relation to patient outcomes is not well described.METHODSWe used high-parameter flow cytometry and a computational platform, CytoBrute, to define immunophenotypes of up to 15 markers to assess peripheral blood samples from metastatic melanoma patients receiving sequential NIVO > IPI or IPI > NIVO (Checkmate-064).RESULTSThe 2 treatments were associated with distinct immunophenotypic changes and had differing profiles associated with response.

Low prevalence of clinical decision support to calculate caloric and fluid intake for infants in the neonatal intensive care unit.

Background: Clinical decision support (CDS) improves nutrition delivery for infants in the neonatal intensive care unit (NICU), however, the prevalence of CDS to support nutrition is unknown.

Methods: Online surveys, with telephone and email validation of responses, were administered to NICU clinicians in the Children's Hospital Neonatal Consortium (CHNC). We determined and compared the availability of CDS to calculate calories and fluid received in the prior 24 h, stratified by enteral and parenteral intake, using McNemar's test.

HDAC6 selective inhibition of melanoma patient T-cells augments anti-tumor characteristics.

Background: Therapies targeting anti-tumor T-cell responses have proven successful in the treatment of a variety of malignancies. However, as most patients still fail to respond, approaches to augment immunotherapeutic efficacy are needed. Here, we investigated the ability of histone deacetylase 6 (HDAC6)-selective inhibitors to decrease immunosuppression and enhance immune function of melanoma patient T-cells in ex vivo cultures.

High-Parameter Single-Cell Analysis.

Thousands of transcripts and proteins confer function and discriminate cell types in the body. Using high-parameter technologies, we can now measure many of these markers at once, and multiple platforms are now capable of analysis on a cell-by-cell basis. Three high-parameter single-cell technologies have particular potential for discovering new biomarkers, revealing disease mechanisms, and increasing our fundamental understanding of cell biology.

Association of Tumor Microenvironment T-cell Repertoire and Mutational Load with Clinical Outcome after Sequential Checkpoint Blockade in Melanoma.

To understand prognostic factors for outcome between differentially sequenced nivolumab and ipilimumab in a randomized phase II trial, we measured T-cell infiltration and PD-L1 by IHC, T-cell repertoire metrics, and mutational load within the tumor. We used next-generation sequencing (NGS) and assessed the association of those parameters with response and overall survival. Immunosequencing of the T-cell receptor β-chain locus (TCRβ) from DNA of 91 pretreatment tumor samples and an additional 22 pairs of matched pre- and posttreatment samples from patients who received nivolumab followed by ipilimumab (nivo/ipi), or the reverse (ipi/nivo), was performed to measure T-cell clonality and fraction.

Energy and Protein Intake During the Transition from Parenteral to Enteral Nutrition in Infants of Very Low Birth Weight.

Objective: To evaluate the association between nutrition delivery practices and energy and protein intake during the transition from parenteral to enteral nutrition in infants of very low birth weight (VLBW).

Study Design: This was a retrospective analysis of 115 infants who were VLBW from a regional neonatal intensive care unit. Changes in energy and protein intake were estimated during transition phase 1 (0% enteral); phase 2 (>0, ≤33.

Decreased Suppression and Increased Phosphorylated STAT3 in Regulatory T Cells are Associated with Benefit from Adjuvant PD-1 Blockade in Resected Metastatic Melanoma.

Purpose: PD-1 blockade induces durable responses in patients with metastatic melanoma and prolongs relapse-free survival in patients with resected melanoma; however, current biomarkers do not consistently associate with patient responses. In this study, we investigated the impact of nivolumab therapy on peripheral blood regulatory T cells (Treg) and its relation to patient outcomes.

Experimental Design: Peripheral blood Tregs and conventional CD4 T cells from patients with resected high-risk melanoma treated with adjuvant nivolumab were assessed for gene expression changes by RNA-seq.

Redesigning Transplant Organ Labeling to Prevent Patient Harm and Organ Loss.

Background: In 2012, the Health Resources and Services Administration and the United Network for Organ Sharing launched the "Electronic Tracking and Transportation" (ETT) project, in response to "labeling and packaging issues" being a frequently reported safety incident. This article describes an improvement project conducted as part of this United Network for Organ Sharing project.

Methods: An interdisciplinary team conducted a Process Failure Modes and Effects Analysis, laboratory simulations of organ labeling during procurement, and a heuristic evaluation of a label software application to inform the design of TransNet, a system that uses barcode technology at the point of organ recovery.

Immediate and long-term effects of a team-based quality improvement training programme.

Background: Although many studies of quality improvement (QI) education programmes report improvement in learners' knowledge and confidence, the impact on learners' future engagement in QI activities is largely unknown and few studies report project measures beyond completion of the programme.

Method: We developed the Academy for Quality and Safety Improvement (AQSI) to prepare individuals, across multiple departments and professions, to lead QI. The 7-month programme consisted of class work and team-based project work.

The class I/IV HDAC inhibitor mocetinostat increases tumor antigen presentation, decreases immune suppressive cell types and augments checkpoint inhibitor therapy.

Checkpoint inhibitor therapy has led to major treatment advances for several cancers including non-small cell lung cancer (NSCLC). Despite this, a significant percentage of patients do not respond or develop resistance. Potential mechanisms of resistance include lack of expression of programmed death ligand 1 (PD-L1), decreased capacity to present tumor antigens, and the presence of an immunosuppressive tumor microenvironment.

Predictors of responses to immune checkpoint blockade in advanced melanoma.

Immune checkpoint blockers (ICB) have become pivotal therapies in the clinical armamentarium against metastatic melanoma (MMel). Given the frequency of immune related adverse events and increasing use of ICB, predictors of response to CTLA-4 and/or PD-1 blockade represent unmet clinical needs. Using a systems biology-based approach to an assessment of 779 paired blood and tumor markers in 37 stage III MMel patients, we analyzed association between blood immune parameters and the functional immune reactivity of tumor-infiltrating cells after ex vivo exposure to ICB.

T cells lacking HDAC11 have increased effector functions and mediate enhanced alloreactivity in a murine model.

Histone acetylation and the families of enzymes responsible for controlling these epigenetic marks have been implicated in regulating T-cell maturation and phenotype. Here, we demonstrate a previously undefined role of histone deacetylase 11 (HDAC11) in regulating T-cell effector functions. Using EGFP-HDAC11 transgenic reporter mice, we found that HDAC11 expression was lower in effector relative to naive and central memory T-cell populations, and activation of resting T cells resulted in its decreased expression.

Verbal Communication During Airway Management and Emergent Endotracheal Intubation: Observations of Team Behavior Among Multi-institutional Pediatric Intensive Care Unit In Situ Simulations.

Objective: To assess health-care teams' verbal communication, an observable teamwork behavior, during simulations involving pediatric emergency airway management and intubation.

Methods: We conducted video-recorded, risk-informed in situ simulations at 5 hospitals with pediatric intensive care units in the Chicago, Illinois, area. Clinicians participated in their clinical roles (eg, attending physician, bedside nurse) and had access to hospital operational systems (eg, electronic health record, medical imaging, laboratory services).

Applying the WHO conceptual framework for the International Classification for Patient Safety to a surgical population.

Objective: Efforts to improve patient safety are challenged by the lack of universally agreed upon terms. The International Classification for Patient Safety (ICPS) was developed by the World Health Organization for this purpose. This study aimed to test the applicability of the ICPS to a surgical population.

Baseline characteristics of African Americans in the Systolic Blood Pressure Intervention Trial.

The Systolic Blood Pressure Intervention Trial (SPRINT) will compare treatment to a systolic blood pressure goal of <120 mm Hg to treatment to the currently recommended goal of <140 mm Hg for effects on incident cardiovascular, renal, and neurologic outcomes including cognitive decline. The objectives of this analysis are to compare baseline characteristics of African American (AA) and non-AA SPRINT participants and explore factors associated with uncontrolled blood pressure (BP) by race. SPRINT enrolled 9361 hypertensive participants aged older than 50 years.

HDAC Inhibition Upregulates PD-1 Ligands in Melanoma and Augments Immunotherapy with PD-1 Blockade.

Expression of PD-1 ligands by tumors and interaction with PD-1-expressing T cells in the tumor microenvironment can result in tolerance. Therapies targeting this coinhibitory axis have proven clinically successful in the treatment of metastatic melanoma, non-small cell lung cancer, and other malignancies. Therapeutic agents targeting the epigenetic regulatory family of histone deacetylases (HDAC) have shown clinical success in the treatment of some hematologic malignancies.

A rater training protocol to assess team performance.

Introduction: Simulation-based methodologies are increasingly used to assess teamwork and communication skills and provide team training. Formative feedback regarding team performance is an essential component. While effective use of simulation for assessment or training requires accurate rating of team performance, examples of rater-training programs in health care are scarce.