Citations

Abstract Rationale Workers’ exposure to metalworking fluid (MWF) has been associated with respiratory disease. Objectives As part of a public health investigation of a manufacturing facility, we performed a cross-sectional study using paired environmental and human sampling to evaluate the cross-pollination of microbes between the environment and the host and possible effects on lung pathology present among workers. Methods Workplace environmental microbiota were evaluated in air and MWF samples. Human microbiota were evaluated in lung tissue samples from workers with respiratory symptoms found to have lymphocytic bronchiolitis and alveolar ductitis with B-cell follicles and emphysema, in lung tissue samples from control subjects, and in skin, nasal, and oral samples from 302 workers from different areas of the facility. In vitro effects of MWF exposure on murine B cells were assessed. Measurements and Main Results An increased similarity of microbial composition was found between MWF samples and lung tissue samples of case workers compared with control subjects. Among workers in different locations within the facility, those that worked in the machine shop area had skin, nasal, and oral microbiota more closely related to the microbiota present in the MWF samples. Lung samples from four index cases and skin and nasal samples from workers in the machine shop area were enriched with Pseudomonas, the dominant taxa in MWF. Exposure to used MWF stimulated murine B-cell proliferation in vitro, a hallmark cell subtype found in the pathology of index cases. Conclusions Evaluation of a manufacturing facility with a cluster of workers with respiratory disease supports cross-pollination of microbes from MWF to humans and suggests the potential for exposure to these microbes to be a health hazard.

Abstract Purpose: TNF-related apoptosis inducing ligand (TRAIL) expression by immune cells contributes to antitumor immunity. A naturally occurring splice variant of TRAIL, called TRAILshort, antagonizes TRAIL-dependent cell killing. It is unknown whether tumor cells express TRAILshort and if it impacts antitumor immunity. Experimental Design: We used an unbiased informatics approach to identify TRAILshort expression in primary human cancers, and validated those results with IHC and ISH. TRAILshort-specific mAbs were used to determine the effect of TRAILshort on tumor cell sensitivity to TRAIL, and to immune effector cell dependent killing of autologous primary tumors. Results: As many as 40% of primary human tumors express TRAILshort by both RNA sequencing and IHC analysis. By ISH, TRAILshort expression is present in tumor cells and not bystander cells. TRAILshort inhibition enhances cancer cell lines sensitivity to TRAIL-dependent killing both in vitro and in immunodeficient xenograft mouse models. Immune effector cells isolated from patients with B-cell malignancies killed more autologous tumor cells in the presence compared with the absence of TRAILshort antibody (P < 0.05). Conclusions: These results identify TRAILshort in primary human malignancies, and suggest that TRAILshort blockade can augment the effector function of autologous immune effector cells. See related commentary by de Miguel and Pardo, p. 5546

Abstract Ultrasound-guided percutaneous ethanol ablation procedures for locoregional recurrences in papillary thyroid carcinoma (PTC) can be repeatedly performed over years. Skin metastases (SM) from PTC generally portend a lethal prognosis. Our patient case report demonstrates the innovative use in low-risk PTC (LRPTC) of treatment modalities designed to prevent neck re-explorations and capable of eliminating both locoregional recurrences and SM. In 2004, a 48-year-old man presented with neck nodal metastases due to PTC. He underwent a near-total thyroidectomy and nodal dissection, confirming an 8-mm PTC involving 2 ipsilateral node metastases. Postoperatively, he received 2 doses of radioactive iodine (RAI) for remnant uptake (cumulative dose 338 mCi); posttherapy scanning was unrevealing. In 2007, he underwent right neck dissection for further node metastases. In 2008, a guided biopsy confirmed a level IV node metastasis. He was referred to our institution for ethanol ablation. Two node metastases were ablated and subsequently disappeared. During 2010-2016, he developed an additional 6 node metastases, which were treated with ethanol ablation; all disappeared on high-resolution sonography. FDG-PET-CT scans in 2009 and 2016 were negative for distant spread. In 2016, a SM in his right neck was removed by dermatologic surgery. In 2017-2018, 2 further SM were excised with negative margins, one after Mohs surgery. He has now been disease-free for 20 months. In conclusion, despite 3 neck surgeries and 2 RAI therapies, our patient repeatedly developed both locoregional recurrences and SM. All 11 disease foci were eliminated with minimally invasive procedures which should more often be considered as effective treatment options in LRPTC.

Introduction: Infants in neonatal intensive care units require painful and noxious stimuli as part of their care. Judicious use of analgesic medications, including opioids, is necessary. However, these medications have long- and short-term side effects, including potential neurotoxicity. This quality improvement project’s primary aim was to decrease opioid exposure by 33% in the first 14 days of life for infants less than 1,250 g at birth within 12 months. Methods: A multidisciplinary care team used Define, Measure, Analyze, Improve, Control methodology to identify root causes of the quality gap including: (1) inconsistent reporting of objective pain scales; (2) variable provider prescribing patterns; and (3) variable provider bedside assessment of pain. These root causes were addressed by two interventions: (1) standardized reporting of the premature infant pain profile scores and (2) implementation of an analgesia management pathway. Results: Mean opioid exposure, measured in morphine equivalents, in infants less than 1,250 g at birth during their first 14 days of life decreased from 0.64 mg/kg/d (95% confidence interval 0.41–0.87) at baseline to 0.08 mg/kg/d (95% confidence interval 0.03–0.13) during the postintervention period (P < 0.001). There was no statistical difference in rates of days to full feedings, unintentional extubations, or central line removals between epochs. Conclusions: Following the implementation of consistent pain score reporting and an analgesia management pathway, opioid exposure in the first 14 days of life for infants less than 1,250 g was significantly reduced by 88%, exceeding the project aim.

Abstract Background: Awareness of burnout has led residency programs to seek interventions to promote well-being, resiliency, camaraderie and social network development. Limited evidence exists on the efficacy of specific interventions. This study evaluated the efficacy of an emergency medicine residency program’s semi-annual retreat using serial administration of the Maslach burnout index and resident well-being survey.Methods: Surveys were administered to all emergency medicine residents (n=25) in July 2018 and before and after fall 2018 and winter 2019 retreats. Retreats included a meal, team building, and social networking opportunities (bowling, softball, snow tubing, and sledding). Comparisons of responses between baseline, pre-retreat, and post-retreat were evaluated using two-sample t, Wilcoxon rank sum, and Fisher exact tests. Results: Sixteen emergency medicine residents (64%) responded at baseline. Response rates on subsequent surveys ranged from 14 (56%) to 21 (84%). Nineteen percent of residents exhibited burnout at baseline. This peaked at 36% pre-winter retreat. Burnout decreased after each retreat (fall: 29% to 6%, winter: 36% to 13%). Mean Maslach burnout index subscores for emotional exhaustion (13 to 9) and depersonalization (7 to 5) decreased from baseline to post-fall retreat, but neither changed significantly over the entire study period (emotional exhaustion: 13 to 12, depersonalization: 7 to 6). Resident well-being survey pre- and post-retreat responses were similar on all items.Conclusion: Meaningful, but not statistically significant differences were detected on the Maslach burnout index and resident well-being survey in association with a retreat. Mean emotional exhaustion, depersonalization and burnout decreased after retreats. Larger studies would provide further insight into the significance of these trends.

Background: Little is known about the impact of socioeconomic status (SES) as a key element of social determinants of health on intensive care unit (ICU) outcomes for adults. Objective: We assessed whether a validated individual SES index termed HOUSES (HOUsing-based SocioEconomic status index) derived from housing features was associated with short-term outcomes of critical illness including ICU mortality, ICU-free days, hospital-free days, and ICU readmission. Methods: We performed a population-based cohort study of adult patients living in Olmsted County, Minnesota, admitted to 7 intensive care units at Mayo Clinic from 2011 to 2014. We compared outcomes between the lowest SES group (HOUSES quartile 1 [Q1]) and the higher SES group (HOUSES Q2-4). We stratified the cohort based on age (<50 years old and ≥50 years old). Results: Among 4134 eligible patients, 3378 (82%) patients had SES successfully measured by the HOUSES index. Baseline characteristics, severity of illness, and reason for ICU admission were similar among the different SES groups as measured by HOUSES except for larger number of intoxications and overdoses in younger patients from the lowest SES. In all adult patients, there were no overall differences in mortality, ICU-free days, hospital-free days, or ICU readmissions in patients with higher SES compared to lower SES. Among older patients (>50 years), those with higher SES (HOUSES Q2-4) compared to those with lower SES (HOUSES Q1) had lower mortality rates (hazard ratio = 0.72; 95% CI: 0.56-0.93; adjusted P = .01), increased ICU-free days (mean 1.08 days; 95% CI: 0.34-1.84; adjusted P = .004), and increased hospital-free days (mean 1.20 days; 95% CI: 0.45-1.96; adjusted P = .002). There were no differences in ICU readmission rates (OR = 0.74; 95% CI: 0.55-1.00; P = .051). Conclusion: Individual-level SES may be an important determinant or predictor of critical care outcomes in older adults. Housing-based socioeconomic status may be a useful tool for enhancing critical care research and practice.

Abstract Background Blood flow restriction (BFR) therapy is an emerging addition to rehabilitative programs that allows patients to increase strength at lower loads over shorter time periods. Therefore, we conducted a study to evaluate the safety and efficacy of a rehabilitation program using BFR to a traditional rehabilitation protocol following operative fixation of distal radius fractures. Methods A randomized controlled study was conducted comparing a standardized rehabilitation protocol alone to a combined protocol with the use of BFR therapy in patients treated with volar plate fixation following a displaced distal radius fracture. The same exercises done in the control group were performed by the BFR group with a restrictive tourniquet in place. Patients were followed with serial radiographs to ensure fracture stability. Outcome measures included wrist range of motion, grip strength, pinch strength, visual analog scale (VAS) pain scores at rest and during activity, patient rated wrist evaluation scores (PRWE), and disabilities of the arm, shoulder, and hand scores. Results Nine patients were randomized and enrolled within the BFR group (n = 5) and control (n = 4) groups. Patients within the BFR group had a significantly greater reduction in pain with activity over the course of the rehabilitation program. Additionally, the BFR group had a significant improvement in PRWE scores during the 8-week rehabilitation program. There was no difference in radiographic measures after initiation of BFR, and all patients tolerated therapy without noted complications. Conclusion BFR therapy is safe and well tolerated after operatively treated distal radius fractures. The addition of BFR therapy can result in quicker reduction in pain with activity and improvement in patient disability when used early following operative management of a distal radius fracture. Level of Evidence This is a Level 1, prognostic study.

Background and Purpose: Periventricular white matter hyperintensities (WMH; PVWMH) and deep WMH (DWMH) are regional classifications of WMH and reflect proposed differences in cause. In the first study, to date, we undertook genome-wide association analyses of DWMH and PVWMH to show that these phenotypes have different genetic underpinnings. Methods: Participants were aged 45 years and older, free of stroke and dementia. We conducted genome-wide association analyses of PVWMH and DWMH in 26,654 participants from CHARGE (Cohorts for Heart and Aging Research in Genomic Epidemiology), ENIGMA (Enhancing Neuro-Imaging Genetics Through Meta-Analysis), and the UKB (UK Biobank). Regional correlations were investigated using the genome-wide association analyses -pairwise method. Cross-trait genetic correlations between PVWMH, DWMH, stroke, and dementia were estimated using LDSC. Results: In the discovery and replication analysis, for PVWMH only, we found associations on chromosomes 2 ( NBEAL ), 10q23.1 ( TSPAN14/FAM231A ), and 10q24.33 ( SH3PXD2A). In the much larger combined meta-analysis of all cohorts, we identified ten significant regions for PVWMH: chromosomes 2 (3 regions), 6, 7, 10 (2 regions), 13, 16, and 17q23.1. New loci of interest include 7q36.1 ( NOS3 ) and 16q24.2. In both the discovery/replication and combined analysis, we found genome-wide significant associations for the 17q25.1 locus for both DWMH and PVWMH. Using gene-based association analysis, 19 genes across all regions were identified for PVWMH only, including the new genes: CALCRL (2q32.1), KLHL24 (3q27.1), VCAN (5q27.1), and POLR2F (22q13.1). Thirteen genes in the 17q25.1 locus were significant for both phenotypes. More extensive genetic correlations were observed for PVWMH with small vessel ischemic stroke. There were no associations with dementia for either phenotype. Conclusions: Our study confirms these phenotypes have distinct and also shared genetic architectures. Genetic analyses indicated PVWMH was more associated with ischemic stroke whilst DWMH loci were implicated in vascular, astrocyte, and neuronal function. Our study confirms these phenotypes are distinct neuroimaging classifications and identifies new candidate genes associated with PVWMH only.

The NCCN Guidelines for Cervical Cancer provide recommendations for diagnostic workup, staging, and treatment of patients with the disease. These NCCN Guidelines Insights focus on recent updates to the guidelines, including changes to first- and second-line systemic therapy recommendations for patients with recurrent or metastatic disease, and emerging evidence on a new histopathologic classification system for HPV-related endocervical adenocarcinoma.