Multiscale quantification of morphological heterogeneity with creation of a predictor of longer survival in glioblastoma

Intratumor heterogeneity is a main cause of the dismal prognosis of glioblastoma (GBM). Yet, there remains a lack of a uniform assessment of the degree of heterogeneity. With a multiscale approach, we addressed the hypothesis that intratumor heterogeneity exists on different levels comprising traditional regional analyses, but also innovative methods including computer-assisted analysis of tumor morphology combined with epigenomic data. With this aim, 157 biopsies of 37 patients with therapy-naive IDH-wildtype GBM were analyzed regarding the intratumor variance of protein expression of glial marker GFAP, microglia marker Iba1 and proliferation marker Mib1. Hematoxylin and eosin stained slides were evaluated for tumor vascularization. For the estimation of pixel intensity and nuclear profiling, automated analysis was used. Additionally, DNA methylation profiling was conducted separately for the single biopsies. Scoring systems were established to integrate several parameters into one score for the four examined modalities of heterogeneity (regional, cellular, pixel-level and epigenomic). As a result, we could show that heterogeneity was detected in all four modalities. Furthermore, for the regional, cellular and epigenomic level, we confirmed the results of earlier studies stating that a higher degree of heterogeneity is associated with poorer overall survival. To integrate all modalities into one score, we designed a predictor of longer survival, which showed a highly significant separation regarding the OS. In conclusion, multiscale intratumor heterogeneity exists in glioblastoma and its degree has an impact on overall survival. In future studies, the implementation of a broadly feasible heterogeneity index should be considered.     

Noise characterization of “effective quiet” areas on a U.S. Navy aircraft carrier

The purpose of this investigation was to characterize noise levels in spaces designated as “effective quiet” areas on a U.S. Navy aircraft carrier. Noise dosimetry samples were collected in 15 designated spaces, representing 15 noise measurements, while at-sea during airwing carrier qualifications. Equivalent sound level (L_eq) measurements were collected during flight operations (L_{eq (flt ops)}), non-flight operations (L_{eq (non-flt ops)}), and over 24-hr periods (L_{eq (24-hr)}). These data were compared to the 70 dBA American Conference of Governmental Industrial Hygienists (ACGIH^®) Threshold Limit Value (TLV^®) for “effective quiet” areas intended for temporary threshold shift recovery when personnel live and work in a potentially noise hazardous environment for periods greater than 24?hr. The monitored areas were selected based on personnel occupancy/use during off-duty time periods. Areas were classified by either (1) leisure areas that included mess (eating areas), gyms, lounges, an internet cafe, and the fantail social area or (2) berthing (sleeping) areas. The L_eq measurements in decibels “A” weighted (dBA) were compared to determine significant differences between L_{eq (flt ops)}, L_{eq (non-flt ops)}, and L_{eq (24-hr)} and were compared between leisure area and berthing area. Measured noise levels according to time period ranged as follows: (1) L_{eq (24-hr)}: 70.8–105.4 dBA; (2) L_{eq (flt ops)}: 70–101.2 dBA; and (3) L_{eq (non-flt ops)}: 39.4–104.6 dBA. All area measurements over the 24-hr period and during flight operations and 46.7% of the areas during the non-flight operation time period exceeded the “effective quiet” 70 dBA ACGIH TLV. Mean L_eqs were 15 dBA higher during flight operations compared to non-flight operations in “effective quiet” areas (p?=?0.001). The L_eqs in leisure areas were significantly higher than berthing areas by approximately 21 dBA during non-flight operation periods (p?=?0.001). Results suggest noise levels in “effective quiet” areas frequented by aircraft carrier personnel during off-duty hours when at-sea may inhibit auditory recovery from occupational noise exposures that occur on-duty.     

Maîtrise des risques liés à la production des fluides de dialyse dans une unité de télédialyse

Objective

The “Centre Hospitalier Francois Dunan” is located on an isolated island and ensures patients care in hemodialysis thanks to telemedicine support. Many research studies have demonstrated the importance of hemodialysis fluids composition to reduce morbidity in patients on chronic hemodialysis. The aim of this study was to identify the risks inherent in the production of dialysis fluids in a particular context, in order to set up an improvement action plan to improve risk control on the production of dialysis fluids.

Early intervention in myelofibrosis and impact on outcomes: A pooled analysis of the COMFORT-I and COMFORT-II studies

Background

In a pooled analysis of the phase 3 Controlled Myelofibrosis Study With Oral JAK Inhibitor Treatment I (COMFORT-I) and COMFORT-II clinical trials, adult patients with intermediate-2 or high-risk myelofibrosis who received oral ruxolitinib at randomization or after crossover from placebo or best available therapy (BAT) had improved overall survival (OS).

Methods

This post hoc analysis of pooled COMFORT data examined relevant disease outcomes based on the disease duration (≤12 or >12 months from diagnosis) before ruxolitinib initiation.

Results

The analysis included 525 patients (ruxolitinib: ≤12 months, n = 84; >12 months, n = 216; placebo/BAT: ≤12 months, n = 66; >12 months, n = 159); the median age was 65.0–70.0 years. Fewer thrombocytopenia and anemia events were observed among patients who initiated ruxolitinib treatment earlier. At Weeks 24 and 48, the spleen volume response (SVR) was higher for patients who initiated ruxolitinib earlier (47.6% vs. 32.9% at Week 24, p = .0610; 44.0% vs. 26.9% at Week 48, p = .0149). In a multivariable analysis of factors associated with spleen volume reduction, a logistic regression model that controlled for confounding factors found that a significantly greater binary reduction was observed among patients with shorter versus longer disease duration (p = .022). At Week 240, OS was significantly improved among patients who initiated ruxolitinib earlier (63% [95% CI, 51%‒73%] vs. 57% [95% CI, 49%‒64%]; hazard ratio, 1.53; 95% CI, 1.01‒2.31; p = .0430). Regardless of disease duration, a longer OS was observed for patients who received ruxolitinib versus those who received placebo/BAT.

Conclusions

These findings suggest that earlier ruxolitinib initiation for adult patients with intermediate-2 and high-risk myelofibrosis may improve clinical outcomes, including fewer cytopenia events, durable SVR, and prolonged OS.

Plain Language Summary

• Patients with myelofibrosis, a bone marrow cancer, often do not live as long as the general population. These patients may also have an enlarged spleen and difficult symptoms such as fatigue.
• Two large clinical trials showed that patients treated with the drug ruxolitinib lived longer and had improved symptoms compared to those treated with placebo or other standard treatments.
• Here it was examined whether starting treatment with ruxolitinib earlier (i.e., within a year of diagnosis) provided benefits versus delaying treatment.
• Patients who received ruxolitinib within a year of diagnosis lived longer and experienced fewer disease symptoms than those whose treatment was delayed.

     

The case for a medication first approach to the treatment of opioid use disorder

Background: The opioid addiction and overdose crisis continues to ravage communities across the U.S. Maintenance pharmacotherapy using buprenorphine or methadone is the most effective intervention for Opioid Use Disorder (OUD), yet few have immediate and sustained access to these medications. Objectives: To address lack of medication access for people with OUD, the Missouri Department of Mental Health began implementing a Medication First (Med First) treatment approach in its publicly-funded system of comprehensive substance use disorder treatment programs. Methods: This Perspective describes the four principles of Med First, which are based on evidence-based guidelines. It draws conceptual comparisons between the Housing First approach to chronic homelessness and the Med First approach to pharmacotherapy for OUD, and compares state certification standards for substance use disorder (SUD) treatment (the traditional approach) to Med First guidelines for OUD treatment. Finally, the Perspective details how Med First principles have been practically implemented. Results: Med First principles emphasize timely access to maintenance pharmacotherapy without requiring psychosocial services or discontinuation for any reason other than harm to the client. Early results regarding medication utilization and treatment retention are promising. Feedback from providers has been largely favorable, though clinical- and system-level obstacles to effective OUD treatment remain. Conclusion: Like the Housing First model, Medication First is designed to decrease human suffering and activate the strengths and capacities of people in need. It draws on decades of research and facilitates partnerships between psychosocial and medical treatment providers to offer effective and life-saving care to persons with OUD.