A Half-Day Camp Program for Adolescents Affected by Childhood Cancer.

Background: Adolescents affected by childhood cancer experience various degrees of psychosocial distress, social isolation, and social support throughout the treatment process. Objective: To create and implement an evidence-based practice project consisting of a pilot half-day camp program to improve social support and connectedness for adolescents affected by childhood cancer. Methods: A pilot half-day camp program was implemented. Twenty adolescent patients, survivors, and siblings (ages 13-18 years) participated in the program. Participants provided basic demographic information and completed pretest, immediate posttest, and 4-week posttest surveys to assess their levels of social support and camp connectedness. Data were analyzed using descriptive statistics and two-tailed Wilcoxon signed-rank test. Results: All measures of social support in adolescent participants affected by childhood cancer trended upward following the conclusion of the program, then trended downward over time, with overall social support and family social support significantly decreasing over time postintervention. Camp connectedness was not significantly impacted by the program. Conclusions: Social support decreases as participants are further out from attending a half-day camp program. This pilot program demonstrated the feasibility of a short-term, local, cost-effective camp program that is scalable to larger groups. Implications for Nursing: Providers should refer adolescents affected by childhood cancer to camp programs for social support. More research is needed to determine if more frequent camp programs sustain a high level of social support in participants.

Genetics of cystogenesis in base-edited human organoids reveal therapeutic strategies for polycystic kidney disease.

In polycystic kidney disease (PKD), microscopic tubules expand into macroscopic cysts. Among the world's most common genetic disorders, PKD is inherited via heterozygous loss-of-function mutations but is theorized to require additional loss of function. To test this, we establish human pluripotent stem cells in allelic series representing four common nonsense mutations, using CRISPR base editing. When differentiated into kidney organoids, homozygous mutants spontaneously form cysts, whereas heterozygous mutants (original or base corrected) express no phenotype. Using these, we identify eukaryotic ribosomal selective glycosides (ERSGs) as PKD therapeutics enabling ribosomal readthrough of these same nonsense mutations. Two different ERSGs not only prevent cyst initiation but also limit growth of pre-formed cysts by partially restoring polycystin expression. Furthermore, glycosides accumulate in cyst epithelia in organoids and mice. Our findings define the human polycystin threshold as a surmountable drug target for pharmacological or gene therapy interventions, with relevance for understanding disease mechanisms and future clinical trials.

Impact of a Social Justice Course in Graduate Nursing Education.

BACKGROUND: Social justice and health equity are foundational concepts to the graduate-prepared nurse's role. However, the integration of these concepts into graduate nursing education has been unclear. PURPOSE: This study examined the impact of a newly created social justice course in a graduate nursing program. METHODS: The impact of the Health Equity and Social Justice course on students' values and attitudes toward social justice was investigated through analysis of quantitative and qualitative data generated in the course. RESULTS: Data were collected from 41 graduate nursing students. Findings demonstrated that students who completed the course had an increased endorsement of social justice values, goals, and behaviors. Students universally found the course to be transformational. CONCLUSIONS: A social justice course in graduate education can be transformational in shaping students' values and attitudes toward health equity and social justice.

Small Molecule Inhibitors of Activation-Induced Deaminase Decrease Class Switch Recombination in B Cells.

Activation-induced deaminase (AID) not only mutates DNA within the immunoglobulin loci to generate antibody diversity, but it also promotes development of B cell lymphomas. To tame this mutagen, we performed a quantitative high-throughput screen of over 90 000 compounds to see if AID activity could be mitigated. The enzymatic activity was assessed in biochemical assays to detect cytosine deamination and in cellular assays to measure class switch recombination. Three compounds showed promise via inhibition of switching in a transformed B cell line and in murine splenic B cells. These compounds have similar chemical structures, which suggests a shared mechanism of action. Importantly, the inhibitors blocked AID, but not a related cytosine DNA deaminase, APOBEC3B. We further determined that AID was continually expressed for several days after B cell activation to induce switching. This first report of small molecules that inhibit AID can be used to gain regulatory control over base editors.

Bland Embolization of Benign Liver Tumors: Review of the Literature and a Single Center Experience.

Transarterial embolization has shown promise as a safe, effective, and less invasive treatment modality for benign liver lesions (hemangioma, focal nodular hyperplasia (FNH), and hepatic adenoma (HA)) with fewer complications compared to surgical intervention. There is no consensus regarding the most appropriate embolization material(s) for the treatment of benign liver tumors. The purpose of this study was to review the current literature regarding the transarterial embolization of benign liver tumors and to share our single center experience. This was a non-blinded, retrospective, single-institution review of the bland embolization of benign liver tumors. Clinical data and imaging before and after embolization were used to evaluate lesion response to transarterial embolization. Twelve patients were included in the study. Five patients with six hemangiomas were treated. Pain was a presenting complaint in all five of these patients. The median change in tumor volume was -12.4% and ranged from -30.1% to +42.3%. One patient with two FNH lesions was treated, and both lesion volumes decreased by more than 50%. Six patients with 10 adenomas were treated. Pain was a presenting complaint in three patients, and five patients had a lesion >5 cm. The median change in tumor volume was -67.0% and ranged from -92.9% to +65.8%. Bland transarterial embolization of liver hemangiomas, FNH, and HA can be an effective and minimally invasive treatment modality to control the size and/or symptoms of these lesions. There is a variable response depending on tumor type and the embolization materials used.

Targeting G542X CFTR nonsense alleles with ELX-02 restores CFTR function in human-derived intestinal organoids.

BACKGROUND: Promoting full-length protein production is a requisite step to address some of the remaining unmet medical need for those with Cystic Fibrosis (CF) nonsense alleles. ELX-02 promotes read-through of mRNA transcripts bearing nonsense mutations, including the most common CF nonsense allele G542X, in several different preclinical models including human bronchial epithelial cells. Here we evaluate ELX-02 mediated read-through using the CFTR-dependent Forskolin-induced swelling (FIS) assay across a selection of G542X genotype patient derived organoids (PDOs). METHODS: CFTR functional restoration was evaluated in ELX-02 treated G542X homozygous and heterozygous PDOs in the CFTR-dependent FIS assay. CFTR mRNA abundance and integrity were evaluated by qPCR and Nanostring analysis while PDO protein was detected by capillary based size-exclusion chromatography. RESULTS: PDOs homozygous for G542X or heterozygous with a second minimally functional allele had significantly increased CFTR activity with ELX-02 in a dose-dependent fashion across a variety of forskolin induction concentrations. The functional increases are similar to those obtained with tezacaftor/ivacaftor in F508del homozygous PDOs. Increased CFTR C- and B-band protein was observed in accordance with increased function. In addition, ELX-02 treatment of a G542X/G542X PDO results in a 5-fold increase in CFTR mRNA compared with vehicle treated, resulting in normalization of CFTR mRNA as measured via Nanostring. CONCLUSIONS: These data with ELX-02 in PDOs are consistent with previous G542X model evaluations. These results also support the on-going clinical evaluation of ELX-02 as a read-through agent for CF caused by the G542X allele.

ELX-02 Generates Protein via Premature Stop Codon Read-Through without Inducing Native Stop Codon Read-Through Proteins.

ELX-02 is a clinical stage, small-molecule eukaryotic ribosomal selective glycoside acting to induce read-through of premature stop codons (PSCs) that results in translation of full-length protein. However, improved read-through at PSCs has raised the question of whether native stop codon (NSC) fidelity would be impacted. Here, we compare read-through by ELX-02 in PSC and NSC contexts. DMS-114 cells containing a PSC in the TP53 gene were treated with ELX-02 and tested for increased nuclear p53 protein expression while also monitoring two other proteins for NSC read-through. Additionally, blood samples were taken from healthy subjects pre- and post-treatment with ELX-02 (0.3-7.5 mg/kg). These samples were processed to collect white blood cells and then analyzed by western blot to identify native and potentially elongated proteins from NSC read-through. In a separate experiment, lymphocytes cultivated with vehicle or ELX-02 (20 and 100 µg/ml) were subjected to proteomic analysis. We found that ELX-02 produced significant read-through of the PSC found in TP53 mRNA in DMS-114 cells, resulting in increased p53 protein expression and consistent with decreased nonsense-mediated mRNA degradation. NSC read-through protein products were not observed in either DMS-114 cells or in clinical samples from subjects dosed with ELX-02. The number of read-through proteins identified by using proteomic analysis was lower than estimated, and none of the NSC read-through products identified with >2 peptides showed dose-dependent responses to ELX-02. Our results demonstrate significant PSC read-through by ELX-02 with maintained NSC fidelity, thus supporting the therapeutic utility of ELX-02 in diseases resulting from nonsense alleles. SIGNIFICANCE STATEMENT: ELX-02 produces significant read-through of premature stop codons leading to full-length functional protein, demonstrated here by using the R213X mutation in the TP53 gene of DMS-114 cells. In addition, three complementary techniques suggest that ELX-02 does not promote read-through of native stop codons at concentrations that lead to premature stop codon read-through. Thus, ELX-02 may be a potential therapeutic option for nonsense mutation-mediated genetic diseases.

Dose reduction using digital fluoroscopy versus digital subtraction angiography in endovascular aneurysm repair: A prospective randomized trial.

OBJECTIVE: Endovascular aneurysm repair (EVAR) can result in high radiation dose to patients and operators. This prospective randomized study aimed to assess whether patient radiation dose sustained during EVAR could be decreased by predominantly using digital fluoroscopy (DF) vs the standard technique using digital subtraction angiography (DSA). METHODS: Between February 2011 and June 2017, patients with EVAR of infrarenal abdominal aortic aneurysms were prospectively enrolled and randomly assigned to a standard treatment DSA cohort or a DF cohort in which two or fewer DSA acquisitions were allowed for confirmatory imaging. Primary end points included dose-area product (DAP) and cumulative air kerma. Secondary end points included technical success and conversion to DSA standard treatment (if DF was inadequate for visualization). RESULTS: For all 43 patients enrolled (26 in the DF cohort, 17 in the DSA cohort), technical success was 100%. Of the 26 DF patients, 5 (19%) required conversion to the DSA cohort. In an intention-to-treat analysis, mean DAP was significantly lower in the DF cohort than in the DSA cohort (132 vs 174 Gy·cm2; P = .04). When patients were separated by number of DSA acquisitions (two or fewer vs three or more), mean DAP decreased 41% (109 vs 185 Gy·cm2; P = .005) and cumulative air kerma decreased 40% (578 vs 964 mGy; P = .004). CONCLUSIONS: In most patients (81%), DF or limited DSA was adequate for visualization during EVAR. In both intention-to-treat DF and limited-DSA cohorts, mean DAP was significantly decreased. If image quality allows, a DF-only or limited-DSA approach to EVAR decreases radiation dose.

Investigating neutron activated contrast agent imaging for tumor localization in proton therapy: a feasibility study for proton neutron gamma-x detection (PNGXD).

Proton neutron gamma-x detection (PNGXD) is a novel imaging concept being investigated for tumor localization during proton therapy that uses secondary neutron interactions with a gadolinium contrast agent (GDCA) to produce characteristic photons within the 40-200 keV energy region. The purpose of this study is to experimentally investigate the feasibility of implementing this procedure by performing experimental measurements on a passive double scattering proton treatment unit. Five experimental measurements were performed with varying concentrations and irradiation conditions. Photon spectra were measured with a 25 mm2, 1 mm thick uncollimated X-123 CdTe spectrometer. For a 10.4 Gy administration on a 100 ml volume phantom with 10 mg g-1 Gd solution placed in a water phantom, 1129 ± 184 K-shell Gd counts were detected. For an administered dose of 21 Gy and the same Gd solution measured in air, resulted in 3296 ± 256 counts. A total of 1094 ± 171, 421 ± 150 and 23 ± 141 K-shell Gd counts were measured for Gd concentrations of 10 mg g-1, 1 mg g-1 and 0 mg g-1 for 7 Gy dose in air. The signal to noise ratio for these five measurements were: 7, 15, 6, 3, and 0.2, respectively. The spectrum contained 43 keV K α and 49 keV K ß peaks, however a small amount of 79.5 and 181.9 keV prompt gamma rays were detected from gadolinium neutron capture. This discrepancy is due to a drop in the intrinsic detection efficiency of the CdTe spectrometer over this energy range. The measurements were compared with Monte-Carlo simulation to determine the contributions of Gd neutron capture from internal and external neutrons on a passive scattering proton therapy unit and to investigate the discrepancy in detected characteristic x-rays versus prompt gamma rays.

Correction to: Factors driving adaptive radiation in plants of oceanic islands: a case study from the Juan Fernández Archipelago.

The article Factors driving adaptive radiation in plants of oceanic islands: a case study from the Juan Fernández Archipelago, written by Koji Takayama, Daniel J. Crawford, Patricio López­Sepúlveda, Josef Greimler, Tod F. Stuessy was originally published electronically on the publisher's internet portal (currently SpringerLink) on 13 March 2018 without open access.

Reflections on 50 Years of Pediatric Neuroscience Nursing.

Throughout the past 50 years, the role of the neuroscience nurse has become more specialized as we continue to keep pace with new innovations and improvement in care for our patients. This is evident when reviewing the hundreds of articles that have been published in the Journal of Neuroscience Nursing over the last half-century. These authors have had a tremendous influence over neuroscience nursing through dissemination of their expert knowledge. This article will review the areas of pediatric hydrocephalus, brain tumors, and epilepsy and the role neuroscience nurses have played in the advancement of these specialties.

Infectious Outcomes from Renal Tumor Ablation: Prophylactic Antibiotics or Not?

INTRODUCTION: Variability exists among institutions and physicians regarding the use of prophylactic antibiotics for ablation of renal tumors. The literature was reviewed for infectious complications vis-à-vis the reported use of prophylactic antibiotics for tumor ablation of renal neoplasms. MATERIALS AND METHODS: PubMed was searched for articles reporting radiofrequency ablation, cryoablation, and microwave ablation of renal masses, both by percutaneous and laparoscopic approaches. Data regarding potentially infectious outcomes, prophylactic antibiotic use or not, patient information, lesion characteristics, and procedural specifics were extracted from relevant articles. RESULTS: Fifty-one articles met the inclusion criteria. Potentially infectious complications occurred in 74/6952 patients (1.06%) if fever is included, but only 29 patients (0.42%) if fever is excluded. Prophylactic antibiotics were reported in 373 patients and were not mentioned in 6579 patients. The incidence of fever was higher with the laparoscopic radiofrequency ablation and cryoablation compared to the percutaneous approach (p < 0.001). CONCLUSION: Prophylactic antibiotics seldom are used and/or reported in renal tumor ablation, and when they are, the antibiotic regimens vary widely. Even so, infectious complications in renal tumor ablation are uncommon. The similar and very low rates of infectious outcomes among ablation types and the two access approaches (laparoscopic and percutaneous) suggest that prophylactic antibiotics for routine renal tumor ablation are unnecessary.

Endovascular Retrieval of an Embolized Atrial Septal Occluder Device From the Abdominal Aorta.

Patent foramen ovale (PFO) is a common heart condition in adults. Closure with a septal occluder device is a safe, well-established treatment option with excellent clinical outcomes. One rare complication of percutaneous PFO closure is embolization of the device to the heart chambers or distal vasculature. Most device migrations are recognized during or shortly after implantation. While many endovascular retrievals of migrated devices are successful, there are still a high percentage of surgical interventions performed. We report a case of a septal occluder device that embolized to the abdominal aorta and was discovered 7 days after implantation. Endovascular techniques with a snare and endobronchial forceps were used to retrieve the device safely.

Factors driving adaptive radiation in plants of oceanic islands: a case study from the Juan Fernández Archipelago.

Adaptive radiation is a common evolutionary phenomenon in oceanic islands. From one successful immigrant population, dispersal into different island environments and directional selection can rapidly yield a series of morphologically distinct species, each adapted to its own particular environment. Not all island immigrants, however, follow this evolutionary pathway. Others successfully arrive and establish viable populations, but they remain in the same ecological zone and only slowly diverge over millions of years. This transformational speciation, or anagenesis, is also common in oceanic archipelagos. The critical question is why do some groups radiate adaptively and others not? The Juan Fernández Islands contain 105 endemic taxa of angiosperms, 49% of which have originated by adaptive radiation (cladogenesis) and 51% by anagenesis, hence providing an opportunity to examine characteristics of taxa that have undergone both types of speciation in the same general island environment. Life form, dispersal mode, and total number of species in progenitors (genera) of endemic angiosperms in the archipelago were investigated from literature sources and compared with modes of speciation (cladogenesis vs. anagenesis). It is suggested that immigrants tending to undergo adaptive radiation are herbaceous perennial herbs, with leaky self-incompatible breeding systems, good intra-island dispersal capabilities, and flexible structural and physiological systems. Perhaps more importantly, the progenitors of adaptively radiated groups in islands are those that have already been successful in adaptations to different environments in source areas, and which have also undergone eco-geographic speciation. Evolutionary success via adaptive radiation in oceanic islands, therefore, is less a novel feature of island lineages but rather a continuation of tendency for successful adaptive speciation in lineages of continental source regions.

Mutations along a TET2 active site scaffold stall oxidation at 5-hydroxymethylcytosine.

Ten-eleven translocation (TET) enzymes catalyze stepwise oxidation of 5-methylcytosine (mC) to yield 5-hydroxymethylcytosine (hmC) and the rarer bases 5-formylcytosine (fC) and 5-carboxylcytosine (caC). Stepwise oxidation obscures how each individual base forms and functions in epigenetic regulation, and prompts the question of whether TET enzymes primarily serve to generate hmC or are adapted to produce fC and caC as well. By mutating a single, conserved active site residue in human TET2, Thr1372, we uncovered enzyme variants that permit oxidation to hmC but largely eliminate fC and caC. Biochemical analyses, combined with molecular dynamics simulations, elucidated an active site scaffold that is required for wild-type (WT) stepwise oxidation and that, when perturbed, explains the mutants' hmC-stalling phenotype. Our results suggest that the TET2 active site is shaped to enable higher-order oxidation and provide the first TET variants that could be used to probe the biological functions of hmC separately from fC and caC.

Different modes of retrovirus restriction by human APOBEC3A and APOBEC3G in vivo.

The apolipoprotein B editing complex 3 (A3) cytidine deaminases are among the most highly evolutionarily selected retroviral restriction factors, both in terms of gene copy number and sequence diversity. Primate genomes encode seven A3 genes, and while A3F and 3G are widely recognized as important in the restriction of HIV, the role of the other genes, particularly A3A, is not as clear. Indeed, since human cells can express multiple A3 genes, and because of the lack of an experimentally tractable model, it is difficult to dissect the individual contribution of each gene to virus restriction in vivo. To overcome this problem, we generated human A3A and A3G transgenic mice on a mouse A3 knockout background. Using these mice, we demonstrate that both A3A and A3G restrict infection by murine retroviruses but by different mechanisms: A3G was packaged into virions and caused extensive deamination of the retrovirus genomes while A3A was not packaged and instead restricted infection when expressed in target cells. Additionally, we show that a murine leukemia virus engineered to express HIV Vif overcame the A3G-mediated restriction, thereby creating a novel model for studying the interaction between these proteins. We have thus developed an in vivo system for understanding how human A3 proteins use different modes of restriction, as well as a means for testing therapies that disrupt HIV Vif-A3G interactions.

Estrogen receptor ß ligand therapy activates PI3K/Akt/mTOR signaling in oligodendrocytes and promotes remyelination in a mouse model of multiple sclerosis.

The identification of a drug that stimulates endogenous myelination and spares axon degeneration during multiple sclerosis (MS) could potentially reduce the rate of disease progression. Using experimental autoimmune encephalomyelitis (EAE), a mouse model of MS, we have previously shown that prophylactic administration of the estrogen receptor (ER) ß ligand 2,3-bis(4-hydroxyphenyl)-propionitrile (DPN) decreases clinical disease, is neuroprotective, stimulates endogenous myelination, and improves axon conduction without altering peripheral cytokine production or reducing central nervous system (CNS) inflammation. Here, we assessed the effects of therapeutic DPN treatment during peak EAE disease, which represents a more clinically relevant treatment paradigm. In addition, we investigated the mechanism of action of DPN treatment-induced recovery during EAE. Given that prophylactic and therapeutic treatments with DPN during EAE improved remyelination-induced axon conduction, and that ER (α and ß) and membrane (m)ERs are present on oligodendrocyte lineage cells, a direct effect of treatment on oligodendrocytes is likely. DPN treatment of EAE animals resulted in phosphorylated ERß and activated the phosphatidylinositol 3-kinase (PI3K)/serine-threonine-specific protein kinase (Akt)/mammalian target of rapamycin (mTOR) signaling pathway, a pathway required for oligodendrocyte survival and axon myelination. These results, along with our previous studies of prophylactic DPN treatment, make DPN and similar ERß ligands immediate and favorable therapeutic candidates for demyelinating disease.

Attenuation of corpus callosum axon myelination and remyelination in the absence of circulating sex hormones.

Sex differences in the structure and organization of the corpus callosum (CC) can be attributed to genetic, hormonal or environmental effects, or a combination of these factors. To address the role of gonadal hormones on axon myelination, functional axon conduction and immunohistochemistry analysis of the CC in intact, gonadectomized and hormone-replaced gonadectomized animals were used. These groups were subjected to cuprizone diet-induced demyelination followed by remyelination. The myelinated component of callosal compound action potential was significantly decreased in ovariectomized and castrated animals under normal myelinating condition. Compared to gonadally intact cohorts, both gonadectomized groups displayed more severe demyelination and inhibited remyelination. Castration in males was more deleterious than ovariectomy in females. Callosal conduction in estradiol-supplemented ovariectomized females was significantly increased during normal myelination, less attenuated during demyelination, and increased beyond placebo-treated ovariectomized or intact female levels during remyelination. In castrated males, the non-aromatizing steroid dihydrotestosterone was less efficient than testosterone and estradiol in restoring normal myelination/axon conduction and remyelination to levels of intact males. Furthermore, in both sexes, estradiol supplementation in gonadectomized groups increased the number of oligodendrocytes. These studies suggest an essential role of estradiol to promote efficient CC myelination and axon conduction in both sexes.