Pneumonitis after Stereotactic Thoracic Radioimmunotherapy with Checkpoint Inhibitors: Exploration of the Dose-Volume-Effect Correlation.

Thoracic stereotactic body radiation therapy (SBRT) is extensively used in combination with immune checkpoint blockade (ICB). While current evidence suggests that the occurrence of pneumonitis as a side effect of both treatments is not enhanced for the combination, the dose-volume correlation remains unclear. We investigate dose-volume-effect correlations for pneumonitis after combined SBRT + ICB. We analyzed patient clinical characteristics and dosimetric data for 42 data sets for thoracic SBRT with ICB treatment (13) and without (29). Dose volumes were converted into 2 Gy equivalent doses (EQD2), allowing for dosimetric comparison of different fractionation regimes. Pneumonitis volumes were delineated and corresponding DVHs were analyzed. We noticed a shift towards lower doses for combined SBRT + ICB treatment, supported by a trend of smaller areas under the curve (AUC) for SBRT+ ICB (median AUC 1337.37 vs. 5799.10, p = 0.317). We present a DVH-based dose-volume-effect correlation method and observed large pneumonitis volumes, even with bilateral extent in the SBRT + ICB group. We conclude that further studies using this method with enhanced statistical power are needed to clarify whether adjustments of the radiation dose constraints are required to better estimate risks of pneumonitis after the combination of SBRT and ICB.

Acute Care Pediatric Nurse Practitioner: The 2018 Practice Analysis.

INTRODUCTION: Practice research serves as the certification framework for validating advanced practice roles and updating national qualifying examinations. This national study informed an update of the Certified Pediatric Nurse Practitioner - Acute Care (CPNP-AC) examination content outline. METHOD: A descriptive analysis of a survey completed in 2018 by 373 pediatric nurse practitioners (PNP) practicing as an acute care role (AC). RESULTS: Respondents were primarily females aged 25 to 34 years (35.4%) and formally educated as AC PNPs (84.2%) and held the CPNP-AC credential (98.9%). Most respondents (83.6%) practiced in urban areas and spent 84% of their time in direct patient care with 74% working in inpatient settings. The majority (87%) worked in subspecialty practice such as critical care (18.5%) and cardiac intensive care (12.3%). DISCUSSION: This is the fourth practice analysis of the AC PNP role that demonstrates continuous evolution in clinical practice, educational preparation, and subspecialty practice distribution.

Mouse Heterochromatin Adopts Digital Compaction States without Showing Hallmarks of HP1-Driven Liquid-Liquid Phase Separation.

The formation of silenced and condensed heterochromatin foci involves enrichment of heterochromatin protein 1 (HP1). HP1 can bridge chromatin segments and form liquid droplets, but the biophysical principles underlying heterochromatin compartmentalization in the cell nucleus are elusive. Here, we assess mechanistically relevant features of pericentric heterochromatin compaction in mouse fibroblasts. We find that (1) HP1 has only a weak capacity to form liquid droplets in living cells; (2) the size, global accessibility, and compaction of heterochromatin foci are independent of HP1; (3) heterochromatin foci lack a separated liquid HP1 pool; and (4) heterochromatin compaction can toggle between two "digital" states depending on the presence of a strong transcriptional activator. These findings indicate that heterochromatin foci resemble collapsed polymer globules that are percolated with the same nucleoplasmic liquid as the surrounding euchromatin, which has implications for our understanding of chromatin compartmentalization and its functional consequences.

Understanding Alcohol and Tobacco Consumption in Asexual Samples: A Mixed-Methods Approach.

Existing research suggests significant differences in alcohol and tobacco consumption trends according to one's sexual orientation. However, asexual people have not yet been included in these comparisons. In this mixed-methods, two-part study, we sought to compare group differences in alcohol and tobacco consumption among sexual orientations, focusing on asexual people, sexual people, and those in the "gray" area between asexual and sexual (i.e., "gray-asexual"). Data for Study 1 came from four British studies: National Surveys of Sexual Attitude and Lifestyles I, II, and III in 1990, 2000, and 2010 (NATSAL I, II, III) and Towards Better Sexual Health (TBSH) in 2000. Sample sizes for each study by gender are: NATSAL I-M: 1923 F: 3511; NATSAL II-M: 4604 F: 6031; NATSAL III-M: 6122 F: 7966; TBSH-M: 347 F: 552. Notably, asexual and gray-asexual respondents were found to consume significantly less alcohol and were more likely to abstain from drinking alcohol altogether, compared to allosexual respondents. Differences in tobacco consumption were only statistically significant for asexual respondents in two of three studies that included tobacco consumption. Each of the four studies also found that asexual and gray-asexual respondents were more likely to be non-drinkers (40.0-77.8%, asexual and 28.1-50.1% gray-asexual, non-drinkers, respectively) than allosexual respondents (10.2-27.2%, non-drinkers). Interviews conducted in Study 2 identified somatic, social, and psychological experiences and motivations that may shed light on the reasons for lower drinking frequencies among asexual individuals. Variability in alcohol consumption levels among asexual, lesbian, gay, and bisexual respondents, and the general population raises new questions about the motivations for why people consume alcohol.

Post-operative non-steroidal anti-inflammatory drug use for pain in infant and paediatric cardiac surgery patients.

BACKGROUND: Pain control is an important element of care for patients after surgery, leading to better outcomes, quicker transitions to recovery, and improvement in quality of life. The purpose of this study was to evaluate the safety and efficacy of non-steroidal anti-inflammatory drugs in children after cardiac surgery. MATERIALS AND METHODS: Patients between the ages of 1 month and 18 years of age, who received intravenous or oral non-steroidal anti-inflammataory drugs after cardiac surgery, from November 2015 until September 2017 were included in this study. The primary endpoints were non-steroidal anti-inflammataory drug-associated renal dysfunction and post-operative bleeding. Secondary endpoints examined the effect of non-steroidal anti-inflammataory drug use on total daily dose of narcotics, number of intravenous PRN narcotic doses received, and pain assessment score. Data were analysed using descriptive statistics for frequencies and ranges. Multivariate analysis was performed to measure the association of all predictors and outcomes. Wilcoxon singed-rank test was performed for secondary outcomes. RESULTS: There was no association between the incidence of renal dysfunction and the use of or duration of non-steroidal anti-inflammataory drugs; in addition no association was found with increased chest tube output. There was a statistically significant reduction of patients' median Face, Legs, Activity, Cry, Consolability (FLACC) scores (2-0; p = 0.003), seen within first 24 hours after initiation of ketorolac, and a significant reduction of morphine requirements seen from day 1 to day 2 (0.3 mg/kg versus 0.1 mg/kg; p < 0.001) and number of as-needed doses. CONCLUSION: Non-steroidal anti-inflammataory drugs in paediatric cardiac surgery patients are safe and effective for post-operative pain management.

The utility of guaiac stool testing in the detection of gastrointestinal complications in infants with critical congenital heart disease.

BACKGROUND: Guaiac stool testing has been routinely used as a method to detect gastrointestinal complications in infants with critical congenital heart disease (CHD); however, the sensitivity and specificity have not been established. METHODS: A retrospective chart review was performed investigating the presence of heme-positive stools and subsequent gastrointestinal complications as well as time to goal caloric intake and radiograph exposure. RESULTS: The presence of heme-positive stools was not a statistically significant factor in patients with critical CHD that experienced gastrointestinal complications. Additionally, patients with heme-positive stools did undergo more abdominal X-rays than those with heme-negative stools. CONCLUSIONS: The routine use of guaiac stool testing in infants with critical CHD is not a predictor of possible gastrointestinal complications and leads to more radiograph exposure for the patient. Close clinical monitoring can be used to evaluate feeding tolerance in infants with critical CHD.

Cancer Cells with Alternative Lengthening of Telomeres Do Not Display a General Hypersensitivity to ATR Inhibition.

Telomere maintenance is a hallmark of cancer as it provides cancer cells with cellular immortality. A significant fraction of tumors uses the alternative lengthening of telomeres (ALT) pathway to elongate their telomeres and to gain an unlimited proliferation potential. Since the ALT pathway is unique to cancer cells, it represents a potentially valuable, currently unexploited target for anti-cancer therapies. Recently, it was proposed that ALT renders cells hypersensitive to ataxia telangiectasia- and RAD3-related (ATR) protein inhibitors (Flynn et al., Science 347, 273). Here, we measured the response of various ALT- or telomerase-positive cell lines to the ATR inhibitor VE-821. In addition, we compared the effect of the inhibitor on cell viability in isogenic cell lines, in which ALT was active or suppressed. In these experiments, a general ATR inhibitor sensitivity of cells with ALT could not be confirmed. We rather propose that the observed variations in sensitivity reflect differences between cell lines that are unrelated to ALT.

Specificity, propagation, and memory of pericentric heterochromatin.

The cell establishes heritable patterns of active and silenced chromatin via interacting factors that set, remove, and read epigenetic marks. To understand how the underlying networks operate, we have dissected transcriptional silencing in pericentric heterochromatin (PCH) of mouse fibroblasts. We assembled a quantitative map for the abundance and interactions of 16 factors related to PCH in living cells and found that stably bound complexes of the histone methyltransferase SUV39H1/2 demarcate the PCH state. From the experimental data, we developed a predictive mathematical model that explains how chromatin-bound SUV39H1/2 complexes act as nucleation sites and propagate a spatially confined PCH domain with elevated histone H3 lysine 9 trimethylation levels via chromatin dynamics. This "nucleation and looping" mechanism is particularly robust toward transient perturbations and stably maintains the PCH state. These features make it an attractive model for establishing functional epigenetic domains throughout the genome based on the localized immobilization of chromatin-modifying enzymes.

Systemic delivery of P42 peptide: a new weapon to fight Huntington's disease.

BACKGROUND: In Huntington's disease (HD), the ratio between normal and mutant Huntingtin (polyQ-hHtt) is crucial in the onset and progression of the disease. As a result, addition of normal Htt was shown to improve polyQ-hHtt-induced defects. Therefore, we recently identified, within human Htt, a 23aa peptide (P42) that prevents aggregation and polyQ-hHtt-induced phenotypes in HD Drosophila model. In this report, we evaluated the therapeutic potential of P42 in a mammalian model of the disease, R6/2 mice. RESULTS: To this end, we developed an original strategy for P42 delivery, combining the properties of the cell penetrating peptide TAT from HIV with a nanostructure-based drug delivery system (Aonys® technology), to form a water-in-oil microemulsion (referred to as NP42T) allowing non-invasive per mucosal buccal/rectal administration of P42. Using MALDI Imaging Mass Spectrometry, we verified the correct targeting of NP42T into the brain, after per mucosal administration. We then evaluated the effects of NP42T in R6/2 mice. We found that P42 (and/or derivatives) are delivered into the brain and target most of the cells, including the neurons of the striatum. Buccal/rectal daily administrations of NP42T microemulsion allowed a clear improvement of behavioural HD-associated defects (foot-clasping, rotarod and body weights), and of several histological markers (aggregation, astrogliosis or ventricular areas) recorded on brain sections. CONCLUSIONS: These data demonstrate that NP42T presents an unprecedented protective effect, and highlight a new therapeutic strategy for HD, associating an efficient peptide with a powerful delivery technology.

Phase behavior of reverse microemulsions based on Peceol(®).

The phase diagram of the four component system Peceol®/lecithin/ethanol/water was studied at 25°C and at a fixed fraction of ethanol. It shows an isotropic W/O microemulsion phase, biphasic liquid system and Liquid crystalline phases. The stabilizing effect of lecithin with the fluidifying effect of ethanol on the microemulsion based on long chain glycerides provides an effective combination to solubilize a large amount of water. Some structural transitions in the phase diagram were investigated as a function of water content using conductivity, rheology, Karl Fisher titration, optical microscopy and SAXS measurements. The results show no change in the microstructure of the isotropic liquid upon phase separation in the liquid biphasic area. However, in the water rich region, migration of ethanol to the external aqueous phase at the expense of the saturated microemulsion promotes the formation of liquid crystalline phases. As a function of water content, the structural change to the liquid crystalline phases follows: isotropic phase L2 → Inverted hexagonal phase H2 → Inverted hexagonal H2/lamellar Lα phases.

Liquid interface functionalized by an ion extractant: the case of Winsor III microemulsions.

The present work shows for the first time that tributylphosphate (TBP), the major ion extractant used in the reprocessing of spent nuclear fuel, acts efficiently as a cosurfactant in the formation of three-phase microemulsions. The system is composed of water, dodecane, TBP, and an extremely hydrophilic sugar surfactant, n-octyl-ß-glucoside. The investigation of the three-phase region (Winsor III), the so-called "fish-cut" diagrams, revealed that TBP exhibits cosurfactant behavior comparable to that of classical cosurfactants n-pentanol and n-hexanol. Upon increasing the cosurfactant/surfactant molar ratio, TBP appears to be more efficient than single-chain alcohols in raising the spontaneous curvature of the adsorbed surfactant film toward oil. This is a direct consequence of the different lateral packing of TBP and n-pentanol or n-hexanol in the mixed surfactant film, with TBP having three alkyl chains and so a higher hydrophobic volume than those n-alcohols. This property is underlined by the interfacial film composition, which is determined by the chemical analysis of the excess phases. It gives a surfactant to cosurfactant molar ratio of 1:1 for TBP and 1:3 for n-hexanol. Moreover, the local microstructure of the microemulsion becomes dependent on the addition of salt when n-alcohol is replaced by TBP. A specific salt effect is also observed and rationalized in terms of the complexing property of TBP and Hofmeister's effects. Treatment of the small-angle neutron scattering (SANS) data gives access to (i) the length scales characterizing the microemulsions (i.e., the persistence length, ξ, and aqueous or organic domain sizes, D*) and (ii) the specific surface, Σ. It results that a subtle change is highlighted in the TBP microemulsion structure, in terms of connectivity, according to the type of salt added.