NovoTTF™-100A System (Tumor Treating Fields) transducer array layout planning for glioblastoma: a NovoTAL™ system user study.

BACKGROUND: Optune™, previously known as the NovoTTF-100A System™, generates Tumor Treating Fields (TTFields), an effective anti-mitotic therapy for glioblastoma. The system delivers intermediate frequency, alternating electric fields to the supratentorial brain. Patient therapy is personalized by configuring transducer array layout placement on the scalp to the tumor site using MRI measurements and the NovoTAL System. Transducer array layout mapping optimizes therapy by maximizing electric field intensity to the tumor site. This study evaluated physician performance in conducting transducer array layout mapping using the NovoTAL System compared with mapping performed by the Novocure in-house clinical team. METHODS: Fourteen physicians (7 neuro-oncologists, 4 medical oncologists, and 3 neurosurgeons) evaluated five blinded cases of recurrent glioblastoma and performed head size and tumor location measurements using a standard Digital Imaging and Communications in Medicine reader. Concordance with Novocure measurement and intra- and inter-rater reliability were assessed using relevant correlation coefficients. The study criterion for success was a concordance correlation coefficient (CCC) >0.80. RESULTS: CCC for each physician versus Novocure on 20 MRI measurements was 0.96 (standard deviation, SD ± 0.03, range 0.90-1.00), indicating very high agreement between the two groups. Intra- and inter-rater reliability correlation coefficients were similarly high: 0.83 (SD ±0.15, range 0.54-1.00) and 0.80 (SD ±0.18, range 0.48-1.00), respectively. CONCLUSIONS: This user study demonstrated an excellent level of concordance between prescribing physicians and Novocure in-house clinical teams in performing transducer array layout planning. Intra-rater reliability was very high, indicating reproducible performance. Physicians prescribing TTFields, when trained on the NovoTAL System, can independently perform transducer array layout mapping required for the initiation and maintenance of patients on TTFields therapy.

Enhancer-associated H3K4 methylation safeguards in vitro germline competence.

Germline specification in mammals occurs through an inductive process whereby competent cells in the post-implantation epiblast differentiate into primordial germ cells (PGC). The intrinsic factors that endow epiblast cells with the competence to respond to germline inductive signals remain unknown. Single-cell RNA sequencing across multiple stages of an in vitro PGC-like cells (PGCLC) differentiation system shows that PGCLC genes initially expressed in the naïve pluripotent stage become homogeneously dismantled in germline competent epiblast like-cells (EpiLC). In contrast, the decommissioning of enhancers associated with these germline genes is incomplete. Namely, a subset of these enhancers partly retain H3K4me1, accumulate less heterochromatic marks and remain accessible and responsive to transcriptional activators. Subsequently, as in vitro germline competence is lost, these enhancers get further decommissioned and lose their responsiveness to transcriptional activators. Importantly, using H3K4me1-deficient cells, we show that the loss of this histone modification reduces the germline competence of EpiLC and decreases PGCLC differentiation efficiency. Our work suggests that, although H3K4me1 might not be essential for enhancer function, it can facilitate the (re)activation of enhancers and the establishment of gene expression programs during specific developmental transitions.

Tumor Treating Fields Technology: Alternating Electric Field Therapy for the Treatment of Solid Tumors.

OBJECTIVE: To provide an overview of Tumor Treating Fields (TTFields) and the Optune device in the treatment of glioblastoma multiforme as well as discuss the evolution of TTFields technology for the treatment of different tumor types. DATA SOURCES: Peer reviewed publications, proceedings, and Internet-based resources. CONCLUSION: TTFields represent a unique technological modality for the effective treatment of glioblastoma multiforme and potentially other solid tumors. Oncology nurses are situated to play important roles as educators and advocates for patients and caregivers on the adherent use and management of this new and evolving treatment technology. IMPLICATIONS FOR NURSING PRACTICE: The increasing use of TTFields in cancer treatment draws attention to the expanding role for oncology nurses in the administration of this unique therapy. As an educator and advocate, the oncology nurse guides the cancer patient and caregiver through understanding the mechanism of action, initiation of TTFields treatment, and adjusting to the daily challenges of treatment administration, management of side effects, and optimizing compliance to treatment adherence to maximize treatment outcomes.

Gender in clinical neuropsychology: practice survey trends and comparisons outside the specialty.

OBJECTIVE: This paper describes gender-related trends within clinical neuropsychology, based primarily on recurrent practice surveys within the specialty and, to a lesser extent, job-related information from medical specialties and the general U.S. labor market. METHOD: Chronological and cross-sectional analyses of professional practice survey data from 2005, 2010, and 2015 relevant to gender. As is common with survey data, descriptive analysis and independent samples t-tests were conducted. Longitudinal data allowed for examination of gender trends, as well as observations of change and stability of factors associated with gender, over time. RESULTS: Women have become dominant in number in clinical neuropsychology, and also comprise a vast majority of practitioners entering the specialty. Gender differences are noted in professional identity, work status, work settings, types of career satisfaction, and retirement expectations. Women are more likely to identify work environment and personal/family obstacles to aspects of career satisfaction. A gender pay gap was found at all time points and is not narrowing. As is true nationally, multiple factors appear related to the gender pay gap in clinical neuropsychology. CONCLUSIONS: Women in neuropsychology are now dominant in number, and their presence is strongly associated with specific practice patterns, such as greater institutional employment, less involvement in forensic practice, and strong involvement in pediatric practice, which may be maintaining the sizeable gender pay gap in neuropsychology. As the proportion of women neuropsychologists continues to increase, flexible work hours, and alternative means of remuneration may be needed to offset current disproportionate family-related responsibilities.

Current trends in managing oral mucositis.

Oral mucositis is an inflammatory and ulcerative process of the oral cavity that results from an assault on the epithelial mucous membrane tissue and most commonly is associated with the administration of radiotherapy and chemotherapy. The incidence of oral mucositis ranges from 15%-40% in patients receiving stomatotoxic chemotherapy or radiotherapy and 70%-90% in bone marrow recipients. Knowledge regarding the pathophysiology of oral mucositis has evolved and now guides practice. Assessment tools to measure the level of mucositis provide valuable data concerning the status of the oral cavity. No single oral assessment tool has been found to be appropriate in all clinical settings. Mucositis has a significant impact on patients' quality of life and treatment plan. Management of oral mucositis is aimed at minimizing this side effect and its subsequent sequelae. The strategies of care are geared toward early intervention and supportive care for patients at risk for developing mucositis and include specific targeted therapies for the management of debilitating side effects. This article provides an overview of the risk factors, pathophysiology, incidence, impact, clinical presentation, oral assessment tools, management strategies, and nursing implications related to oral mucositis.

The American Academy of Clinical Neuropsychology, National Academy of Neuropsychology, and Society for Clinical Neuropsychology (APA Division 40) 2015 TCN Professional Practice and 'Salary Survey': Professional Practices, Beliefs, and Incomes of U.S. Neuropsychologists.

OBJECTIVE: The current survey updated professional practice and income information pertaining to clinical neuropsychology. METHODS: Doctoral-level members of the American Academy of Clinical Neuropsychology, Division 40 (Clinical Neuropsychology) of the American Psychological Association, and the National Academy of Neuropsychology and other neuropsychologists, as well as postdoctoral trainees in the Association of Postdoctoral Programs in Clinical Neuropsychology and at other training sites were invited to participate in a web-based survey in early 2015. The sample of 1777 respondents, of whom 1579 were doctoral-level practitioners and 198 were postdoctoral trainees, was larger than the prior 2010 income and practice survey. RESULTS: The substantial proportional change in gender has continued, with women now a clear majority in the postdoctoral trainee sample as well as in the practitioner sample. Dissimilar from the median age trajectory of American Psychological Association members, the median age of clinical neuropsychologists remains essentially unchanged since 1989, indicating a substantial annual influx of young neuropsychologists. The question of whether the Houston Conference training model has become an important influence in the specialty can now be considered settled in the affirmative among postdoctoral trainees and practitioners. Testing assistant usage remains commonplace, and continues to be more common in institutions. The vast majority of clinical neuropsychologists work full-time and very few are unemployed and seeking employment. The numbers of neuropsychologists planning to retire in the coming 5-10 years do not suggest a "baby boomer" effect or an unexpected bolus of planned retirements in the next 10 years that would be large enough to be worrisome. Average length of time reported for evaluations appears to be increasing across time. The most common factors affecting evaluation length were identified, with the top three being: (1) goal of evaluation, (2) stamina/health of examinee, and (3) age of examinee. Pediatric specialists remain more likely than others to work part-time, more likely to work in institutions, report lower incomes than respondents with a lifespan professional identity, and are far more likely to be women. Incomes continue to vary considerably by years of clinical practice, work setting, amount of forensic practice, state, and region of country. Neurologists are the number one referral source in institutions and in private practice, as well as for pediatric, adult, and lifespan practitioners. Learning disability is no longer among the top five conditions seen by pediatric neuropsychologists; traumatic brain injury and seizure disorder are common reasons for clinical evaluations at all age ranges. There is a continued increase in forensic practice and a clear consensus on the use of validity testing. There is a substantial interest in subspecialization board certification, with the greatest interest evident among postdoctoral trainees. Income satisfaction, job satisfaction, and work-life balance satisfaction are higher for men. Job satisfaction varies across general work setting and across age range of practice. Work-life balance satisfaction is moderately correlated with income satisfaction and job satisfaction. Again in this five-year interval survey, a substantial majority of respondents reported increased incomes, despite experiencing substantial negative practice effects related to changes in the US health care system. Numerous breakdowns related to income and professional activities are provided. CONCLUSIONS: Professional practice survey information continues to provide valuable perspectives regarding consistency and change in the activities, beliefs, and incomes of US clinical neuropsychologists.

Properties of the type B histone acetyltransferase Hat1: H4 tail interaction, site preference, and involvement in DNA repair.

The Hat1 histone acetyltransferase catalyzes the acetylation of H4 at lysines 5 and 12, the same sites that are acetylated in newly synthesized histone H4. By performing histone acetyltransferase (HAT) assays on various synthetic H4 N-terminal peptides, we have examined the interactions between Hat1 and the H4 tail domain. It was found that acetylation requires the presence of positively charged amino acids at positions 8 and 16 of H4, positions that are normally occupied by lysine; however, lysine per se is not essential and can be replaced by arginine. In contrast, replacing Lys-8 and -16 of H4 with glutamines reduces acetylation to background levels. Similarly, phosphorylation of Ser-1 of the H4 tail depresses acetylation by both yeast Hat1p and the human HAT-B complex. These results strongly support the model proposed by Ramakrishnan and colleagues for the interaction between Hat1 and the H4 tail (Dutnall, R. N., Tafrov, S. T., Sternglanz, R., and Ramakrishnan, V. (1998) Cell 94, 427-438) and may have implications for the genetic analysis of histone acetylation. It was also found that Lys-12 of H4 is preferentially acetylated by human HAT-B, in further agreement with the proposed model of H4 tail binding. Finally, we have demonstrated that deletion of the hat1 gene from the fission yeast Schizosaccharomyces pombe causes increased sensitivity to the DNA-damaging agent methyl methanesulfonate in the absence of any additional mutations. This is in contrast to results obtained with a Saccharomyces cerevisiae hat1Delta strain, which must also carry mutations of the acetylatable lysines of H3 for heightened methyl methanesulfonate sensitivity to be observed. Thus, although the role of Hat1 in DNA damage repair is evolutionarily conserved, the ability of H3 acetylation to compensate for Hat1 deletion appears to be more variable.

An initial report of sleep disturbance in inactive inflammatory bowel disease.

BACKGROUND: There is an increased prevalence of gastrointestinal symptoms, peptic ulcer disease, and colon cancer in night-shiftworkers, whose sleep is commonly disrupted. Sleep complaints are an extrapyramidal symptom of irritable bowel syndrome (IBS). Sleep disruption may contribute to increased medical morbidity by weakening the ability of the immune system to protect against endotoxins-this pathway could be of potential importance to the pathogenesis and/or clinical course of inflammatory bowel disease (IBD), a chronic immunoinflammatory gastrointestinal disorder associated with marked reductions in quality of life. This is the first study to comprehensively examine sleep concerns in patients with IBD. METHODS: Sixteen patients with biopsy-proven inactive IBD (8 with Crohn disease and 8 with ulcerative colitis), 9 patients with IBS, and 7 healthy controls completed the Pittsburgh Sleep Quality Index, Epworth Sleepiness Scale, Inflammatory Bowel Disease Questionnaire, SF-12, and a single overnight polysomnogram. Polysomnography and arousals were scored according to standard criteria. Multivariate analyses were used to compare subjective and objective sleep parameters between groups and to identify associations between sleep complaints and quality of life. RESULTS: Patients with IBD did not seem to significantly differ from patients with IBS, who have established sleep complaints. On polysomnography, total sleep time differentiated the 3 groups well, with the IBS and IBD groups appearing numerically similar. Whereas IBS and IBD groups were similar with respect to observed sleep parameters, IBS patients did report the most concerns, consistent with earlier research suggesting that hyperarousal and perceptual differences may contribute to symptom reporting. CONCLUSION: Sleep parameters greatly influenced quality of life in both groups and highlight the need to address sleep concerns as part of IBD management.

Modifications of H3 and H4 during chromatin replication, nucleosome assembly, and histone exchange.

Histone posttranslational modifications that accompany DNA replication, nucleosome assembly, and H2A/H2B exchange were examined in human tissue culture cells. Through microsequencing analysis and chromatin immunoprecipitation, it was found that a subset of newly synthesized H3.2/H3.3 is modified by acetylation and methylation at sites that correlate with transcriptional competence. Immunoprecipitation experiments suggest that cytosolic predeposition complexes purified from cells expressing FLAG-H4 contain H3/H4 dimers, not tetramers. Studies of the deposition of newly synthesized H2A/H2B onto replicating and nonreplicating chromatin demonstrated that H2A/H2B exchange takes place in chromatin regions that contain acetylated H4; however, there is no single pattern of H4 acetylation that accompanies exchange. H2A/H2B exchange is also largely independent of the deposition of replacement histone variant, H3.3. Finally, immunoprecipitation of nucleosomes replicated in the absence of de novo nucleosome assembly showed that histone modifications do not prevent the transfer of parental histones to newly replicated DNA and thus have the potential to serve as means of epigenetic inheritance. Our experiments provide an in-depth analysis of the "histone code" associated with chromatin replication and dynamic histone exchange in human cells.

Facilitating Self-Management of Substance Use Disorders with Online Counseling: The Intervention and Study Design.

This paper describes a pilot study using online counseling for court-involved parents who have been charged with child abuse and neglect related to substance use. All families resided in the medically underserved area of Newark, New Jersey and were recruited from halfway houses and the Family Court. The sample consisted of 30 participants randomly assigned to control (n=15) and experimental (n=15) groups. Of the participants, 83% were Black, 13% were White, and 3% were Hispanic. The control group had access to usual face-to-face treatment at a local treatment center where typical court-ordered offenders were referred. Usual face-to-face treatment often involved being wait-listed for periods of months even for a detox bed. The experimental group had immediate access to the online counseling intervention. The online counseling software and the live counseling components of the intervention were developed with a stages of change theoretical framework. Preliminary findings show promise for the feasibility of online interventions for underserved populations.

In vitro analysis of histone acetyltransferase activity.

Interest in histone acetylation has risen dramatically in recent years. In the following report, we present methods for the analysis of histone acetyltransferase activity in vitro. Protocols are described for radiolabeling histone proteins and N-terminal "tail" peptides, and for the analysis of acetylation by immunoblotting. Techniques for acetylating immobilized histone peptides are also described.