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With the advent of the Heliophysics/Geospace System Observatory (H/GSO), a complement of multi-spacecraft missions and ground-based observatories to study the space environment, data retrieval, analysis, and visualization of space physics data can be daunting. The Space Physics Environment Data Analysis System (SPEDAS), a grass-roots software development platform (www.spedas.org), is now officially supported by NASA Heliophysics as part of its data environment infrastructure. It serves more than a dozen space missions and ground observatories and can integrate the full complement of past and upcoming space physics missions with minimal resources, following clear, simple, and well-proven guidelines. Free, modular and configurable to the needs of individual missions, it works in both command-line (ideal for experienced users) and Graphical User Interface (GUI) mode (reducing the learning curve for first-time users). Both options have "crib-sheets," user-command sequences in ASCII format that can facilitate record-and-repeat actions, especially for complex operations and plotting. Crib-sheets enhance scientific interactions, as users can move rapidly and accurately from exchanges of technical information on data processing to efficient discussions regarding data interpretation and science. SPEDAS can readily query and ingest all International Solar Terrestrial Physics (ISTP)-compatible products from the Space Physics Data Facility (SPDF), enabling access to a vast collection of historic and current mission data. The planned incorporation of Heliophysics Application Programmer's Interface (HAPI) standards will facilitate data ingestion from distributed datasets that adhere to these standards. Although SPEDAS is currently Interactive Data Language (IDL)-based (and interfaces to Java-based tools such as Autoplot), efforts are under-way to expand it further to work with python (first as an interface tool and potentially even receiving an under-the-hood replacement). We review the SPEDAS development history, goals, and current implementation. We explain its "modes of use" with examples geared for users and outline its technical implementation and requirements with software developers in mind. We also describe SPEDAS personnel and software management, interfaces with other organizations, resources and support structure available to the community, and future development plans.Electronic supplementary materialThe online version of this article (10.1007/s11214-018-0576-4) contains supplementary material, which is available to authorized users.

Nurses spend more time with their patients than do other health care workers. Therefore, the spiritual needs of patients must be recognized as a domain of nursing care. Holism cannot exist without consideration of the spiritual aspects that create individuality and give meaning to people's lives. The purpose of this article is to provide nursing faculty with tools that may be used to develop spiritually knowledgeable nursing students who can overcome barriers to providing spiritual care to end-of-life patients. Our students were required to complete care maps to ensure they are prepared for patient care at the end of life. In this article, we present tools that faculty and students may use to complete the spiritual concept in care mapping. The literature on spirituality is reviewed, use of care mapping in nursing curricula is described, and our teaching approach to develop nursing students who are skilled at providing spiritual care is explained. Three case studies and care maps created by former students are also presented to demonstrate examples of spiritual competence. [ABSTRACT FROM AUTHOR]

Background: Coloboma is a rare congenital malformation in which part of the tissue that makes up the eye is missing and may cause visual impairment or blindness. Little is known about the epidemiology of this condition. Therefore, we obtained data from the Texas Birth Defects Registry on children identified with coloboma for the period 1999-2014., Methods: Using information on all live births from the same period, prevalence ratios (PRs) for selected demographic and clinical factors were used to estimate associations using Poisson regression among cases with coloboma. Coloboma cases were divided into subgroups to explore patterns of co-occurring defects and syndromes. All variables significant in unadjusted models (p < 0.05) were included in multivariable models to evaluate adjusted PRs (aPRs)., Results: We identified 1587 cases with coloboma, of whom 934 (58.8%) were nonsyndromic, and 474 (29.9%) were isolated. When considering all identified cases, factors associated with significant differences in prevalence included plurality (multiple vs. singleton aPR = 1.4, 95% CI: 1.1-1.8); maternal education (college or greater vs. less than high school aPR = 0.7, 95% CI: 0.6-0.9); maternal race/ethnicity (Hispanic vs. non-Hispanic White aPR = 0.9, 95% CI: 0.8-1.0); and maternal diabetes (yes vs. no aPR = 1.3, 95% CI: 1.0-1.6). There was a notable increase in the birth prevalence of coloboma during the study period (p-for-trend < 0.001). Effect estimates were similar across the different subgroups., Conclusion: In our large population, we identified several factors associated with the prevalence of coloboma. These findings may help define subgroups of women more likely to have children affected by coloboma, which could inform improved screening efforts., (© 2024 Wiley Periodicals LLC.)

Head and Neck Squamous Cell Carcinoma (HNSCC) comprises a diverse group of tumors with variable treatment response and prognosis. The tumor microenvironment (TME), which includes microbiome and immune cells, can impact outcomes. Here, we sought to relate the presence of specific microbes, gene expression, and tumor immune infiltration using tumor transcriptomics from The Cancer Genome Atlas (TCGA) and associate these with overall survival (OS). RNA sequencing (RNAseq) from HNSCC tumors in TCGA was processed through the exogenous sequences in tumors and immune cells (exotic) pipeline to identify and quantify low-abundance microbes. The detection of the Papillomaviridae family of viruses assessed HPV status. All statistical analyses were performed using R. A total of 499 RNAseq samples from TCGA were analyzed. HPV was detected in 111 samples (22%), most commonly Alphapapillomavirus 9 (90.1%). The presence of Alphapapillomavirus 9 was associated with improved OS [HR = 0.60 (95%CI: 0.40-0.89, p  = .01)]. Among other microbes, Yersinia pseudotuberculosis was associated with the worst survival (HR = 3.88; p  = .008), while Pseudomonas viridiflava had the best survival (HR = 0.05; p  = .036). Microbial species found more abundant in HPV- tumors included several gram-negative anaerobes. HPV- tumors had a significantly higher abundance of M0 ( p  < .001) and M2 macrophages ( p  = .035), while HPV+ tumors had more T regulatory cells ( p  < .001) and CD8+ T-cells ( p  < .001). We identified microbes in HNSCC tumor samples significantly associated with survival. A greater abundance of certain anaerobic microbes was seen in HPV tumors and pro-tumorigenic macrophages. These findings suggest that TME can be used to predict patient outcomes and may help identify mechanisms of resistance to systemic therapies.

Venus, lacking an intrinsic global dipole magnetic field, serves as a textbook example of an induced magnetosphere, formed by interplanetary magnetic fields (IMF) enveloping the planet. Yet, various aspects of its magnetospheric dynamics and planetary ion outflows are complex and not well understood. Here we analyze plasma and magnetic field data acquired during the fourth Venus flyby of the Parker Solar Probe (PSP) mission and show evidence for closed topology in the nightside and downstream portion of the Venus magnetosphere (i.e., the magnetotail). The formation of the closed topology involves magnetic reconnection-a process rarely observed at non-magnetized planets. In addition, our study provides an evidence linking the cold Venusian ion flow in the magnetotail directly to magnetic connectivity to the ionosphere, akin to observations at Mars. These findings not only help the understanding of the complex ion flow patterns at Venus but also suggest that magnetic topology is one piece of key information for resolving ion escape mechanisms and thus the atmospheric evolution across various planetary environments and exoplanets., (© 2024. The Author(s).)

Background: Salivary duct carcinomas (SDC) are a rare and aggressive subtype of salivary gland neoplasm. They can present with distinct immunoprofiles, such as androgen receptor (AR) and HER-2/Neu-positivity. To date, no consensus exists on how to best manage this entity., Methods: All patients diagnosed with nonmetastatic AR+ SDC of the parotid from 2013 to 2019 treated with curative intent were included. Immunologic tumor profiling was conducted using 24 distinct markers. Kaplan-Meier analyses were used to estimate locoregional recurrence (LRR), distant control, and overall survival (OS)., Results: Fifteen patients were included. Nine (60%) patients presented with T4 disease and eight (53%) had positive ipsilateral cervical lymphadenopathy. Ten (67%) patients underwent trimodality therapy, including surgery followed by adjuvant radiation and concurrent systemic therapy. The median follow-up was 5.5 years (interquartile range, 4.8-6.1). The estimated 5-year rates of LRR, distant progression, and OS were 6%, 13%, and 87%, respectively., Conclusion: Despite only including AR+ SDC of the parotid, immunoprofiles, such as expression of HER-2, were highly variable, highlighting the potential to tailor systemic regimens based on individual histologic profiles in the future. Studies with larger patient numbers using tumor-specific molecular profiling and tumor heterogeneity analyses are justified to better understand the biology of these tumors. Molecularly informed treatment approaches, including the potential use of AR- and HER-2/Neu-directed therapies upfront in the definitive setting, may hold future promise to further improve outcomes for these patients.

Objectives: Patients with recurrent and metastatic head and neck cancer (HNC) have limited treatment options. 'QuadShot' (QS), a hypofractionated palliative radiotherapy regimen, can provide symptomatic relief and local control and may potentiate the effects of immune checkpoint inhibitors (ICIs). We compared outcomes of QS ± concurrent ICIs in the palliative treatment of HNC., Materials and Methods: We identified patients who received ≥three cycles of QS from 2017 to 2022 and excluded patients without post-treatment clinical evaluation or imaging. Outcomes for patients who received QS alone were compared to those treated with ICI concurrent with QS, defined as receipt of ICI within 4 weeks of QS., Results: Seventy patients were included, of whom 57% received concurrent ICI. Median age was 65.5 years (interquartile range [IQR]: 57.9-77.8), and 50% patients had received prior radiation to a median dose of 66 Gy (IQR: 60-70). Median follow-up was 8.8 months. Local control was significantly higher with concurrent ICIs (12-month: 85% vs. 63%, p = 0.038). Distant control (12-month: 56% vs. 63%, p = 0.629) and median overall survival (9.0 vs. 10.0 months, p = 0.850) were similar between the two groups. On multivariable analysis, concurrent ICI was a significant predictor of local control (HR for local failure: 0.238; 95% CI: 0.073-0.778; p = 0.018). Overall, 23% patients experienced grade 3 toxicities, which was similar between the two groups., Conclusions: The combination of QS with concurrent ICIs was well tolerated and significantly improved local control compared to QS alone. The median OS of 9.4 months compares favorably to historical controls for patients with HNC treated with QS. This approach represents a promising treatment option for patients with HNC unsuited for curative-intent treatment and warrants prospective evaluation.

Background: The increased incidence of human papillomavirus (HPV)-related cancers has motivated efforts to optimise treatment for these patients with excellent prognosis. Validation of surrogates for overall survival could expedite the investigation of new therapies. We sought to evaluate candidate intermediate clinical endpoints in trials assessing definitive treatment of p16-positive oropharyngeal cancer with chemotherapy or radiotherapy., Methods: We did a retrospective review of five multicentre, randomised trials (NRG/RTOG 9003, 0129, 0234, 0522, and 1016) that tested radiotherapy with or without chemotherapy in patients (aged ≥18 years) with p16-positive localised head or neck squamous-cell carcinomas. Eight intermediate clinical endpoints were considered as potential surrogates for overall survival: freedom from local progression, freedom from regional progression, freedom from distant metastasis, freedom from locoregional progression, freedom from any progression, locoregional progression-free survival, progression-free survival, and distant metastasis-free survival. We used a two-stage meta-analytical framework, which requires high correlation between the intermediate clinical endpoint and overall survival at the patient level (condition 1), and high correlation between the treatment effect on the intermediate clinical endpoint and the treatment effect on overall survival (condition 2). For both, an r 2 greater than 0·7 was used as criteria for clinically relevant surrogacy., Findings: We analysed 1373 patients with oropharyngeal cancer from May 9, 2020, to Nov 22, 2023. 1231 (90%) of patients were men, 142 (10%) were women, and 1207 (88%) were White, with a median age of 57 years (IQR 51-62). Median follow-up was 4·2 years (3·1-5·1). For the first condition, correlating the intermediate clinical endpoints with overall survival at the individual and trial level, the three composite endpoints of locoregional progression-free survival (Kendall's τ 0·91 and r 2 0·72), distant metastasis-free survival (Kendall's τ 0·93 and r 2 0·83), and progression-free survival (Kendall's τ 0·88 and r 2 0·70) were highly correlated with overall survival at the patient level and at the trial-group level. For the second condition, correlating treatment effects of the intermediate clinical endpoints and overall survival, the composite endpoints of locoregional progression-free survival (r 2 0·88), distant metastasis-free survival (r 2 0·96), and progression-free survival (r 2 0·92) remained strong surrogates. Treatment effects on the remaining intermediate clinical endpoints were less strongly correlated with overall survival., Interpretation: We identified locoregional progression-free survival, distant metastasis-free survival, and progression-free survival as surrogates for overall survival in p16-positive oropharyngeal cancers treated with chemotherapy or radiotherapy, which could serve as clinical trial endpoints., Funding: NRG Oncology Operations, NRG Oncology SDMC, the National Cancer Institute, Eli Lilly, Aventis, and the University of Michigan., Competing Interests: Declaration of interests LAG reports grant funding from the PROTEUS Consortium. JAB reports royalties or licenses from Bristol Myers Squibb, Eli Lilly, and Merck Serono; consulting fees from Cel-Sci, Merck Serano, and ICON; payment for lectures or presentations from Bristol Myers Squibb, Eli Lilly, Merck Serano, and Cel-Sci; and support for attending meetings or travel from Bristol Myers Squibb, Eli Lilly, and Merck Serono. MLG reports research funding from Genocea Biosciences, Bristol Myers Squibb, Genentech, Kura, Cullinan Labs, Agenus, LaRoche, NRG Oncology, and the University of Cincinnati; consulting fees from iTeos Therapeutics, Istari Oncology, LLX Solutions, OncLive Intellisphere, Seagen, Sensei Biotherapeutics, Kura Oncology, Coherus Biosciences, Mirati Therapeutics, BioNtech AG, Sensei Biotherapeutics, Caladrius Biosciences, Bristol Myers Squibb, Bicara Therapeutics, Bayer Healthcare Pharmaceutics, Genocea Biosciences, Shattuck Labs, EMD Serono, Debiopharm, Merck & Co, Ipsen Biopharmaceuticals, Gilead Sciences, Nektar Therapeutics, Eisai Medical Research, Roche, Roche Diagnostics, NewLink Genetics, Aspyrian Therapeutics, Amgen, TRM Oncology, AstraZeneca Pharmaceuticals, Celgene, and Exelixis; payment from OncLive and Roche; and support for meetings or travel for presentations from the American Association for Cancer Research, the American Society of Clinical Oncology, and the Society for Immunotherapy of Cancer. SK reports research funding from Merck, Bristol Myers Squibb, Castle Biosciences, and Regeneron; consulting fees from Merck, Bristol Myers Squibb, Regeneron, and Galera Therapeutics; and honorarium from Varian Medical Systems. Q-TL reports a leadership role as RTOG Group Chair for NRG Oncology and support from RTOG Foundation for attending meetings and travel. MM reports clinical trial drug support from Bristol Myers Squbb, and grant funding from the PROTEUS Consortium and Livestrong Foundation, advistory board of Adaptimmune. DLM reports a grant from the National Cancer Institute (3R01CA262388-02S1 NCI Diversity Supplement Award). EM reports a University of Michigan M-Cubed Grant (P30CA046592). JAR reports non-financial interests National Comprehensive Cancer Network Thyroid Cancer Panel and American Thyroid Association Guidelines Task Force. DIR reports payments from Merck to the Scientific Advisory Board for presentations. MJS reports consulting fees from Innovative Analytics. WAS reports a research grant from Georgia Research Alliance. PT-S reports NRG Oncology SDMC Grant from the National Cancer Institute (NCI). All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Background and Purpose: A bolus is required when treating scalp lesions with photon radiation therapy. Traditional bolus materials face several issues, including air gaps and setup difficulty due to irregular, convex scalp geometry. A 3D-milled bolus is custom-formed to match individual patient anatomy, allowing improved dose coverage and homogeneity. Here, we describe the creation process of a 3D-milled bolus and report the outcomes for patients with scalp malignancies treated with Volumetric Modulated Arc Therapy (VMAT) utilizing a 3D-milled bolus., Materials and Methods: Twenty-two patients treated from 2016 to 2022 using a 3D-milled bolus and VMAT were included. Histologies included squamous cell carcinoma ( n = 14, 64%) and angiosarcoma ( n = 8, 36%). A total of 7 (32%) patients were treated in the intact and 15 (68%) in the postoperative setting. The median prescription dose was 66.0 Gy (range: 60.0-69.96)., Results: The target included the entire scalp for 8 (36%) patients; in the remaining 14 (64%), the median ratio of planning target volume to scalp volume was 35% (range: 25-90%). The median dose homogeneity index was 1.07 (range: 1.03-1.15). Six (27%) patients experienced acute grade 3 dermatitis and one (5%) patient experienced late grade 3 skin ulceration. With a median follow-up of 21.4 months (range: 4.0-75.4), the 18-month rates of locoregional control and overall survival were 75% and 79%, respectively., Conclusions: To our knowledge, this is the first study to report the clinical outcomes for patients with scalp malignancies treated with the combination of VMAT and a 3D-milled bolus. This technique resulted in favorable clinical outcomes and an acceptable toxicity profile in comparison with historic controls and warrants further investigation in a larger prospective study.

Background: Dual antiplatelet therapy is used to reduce the risk of thromboembolic complications in neuroendovascular surgery. However, the predictive utility of preoperative platelet-sensitivity testing for decreasing bleed risk in patients undergoing endovascular neurointervention remains unclear., Objective: We conducted a systematic review and meta-analysis to illustrate the association between platelet response and risk of hemorrhagic complications from neuroendovascular surgery, examine the efficacy of the VerifyNow platelet reactivity unit (PRU) assay in predicting hemorrhagic outcomes, and assess whether a clinically useful threshold for platelet response can be defined to standardize guidelines., Methods: PubMed, Embase, and Scopus were searched. Articles were screened for relevance by title and abstract, followed by full text., Results: Of 735 resultant articles, 17 studies of 2084 patients undergoing neuroendovascular intervention were included. Diagnoses included both intracranial and extracranial pathologies, of which 37.8% were treated with flow diversion, 22.4% with stent-assisted coil embolization, 14.3% with intracranial stenting, 12.8% with simple coil embolization, 5.8% with balloon-assisted coil embolization, 2.0% with extracranial stenting, and 4.8% with an alternate method. Precisely, 52.9% (9 out of 17) of studies determined platelet hyperresponse to be an independent predictor of postoperative hemorrhagic complications, with 11.8% (2 out of 17) of studies reporting a similar but non-statistically significant trend. 35.3% (6 out of 17) of studies found no relationship between platelet response and postoperative hemorrhagic complications. The estimated clinical threshold for PRU to prevent hemorrhagic complications varied considerably across studies (range: <46-118 PRU). Meta-analysis found platelet hyperresponse to have more than a 3-fold increased risk of hemorrhagic complications compared to normoresponders (relative risk = 3.2, p  = 0.001)., Conclusion: Although this meta-analysis shows the predictive utility of the P2Y12 assay for postoperative hemorrhagic complications in neuroendovascular surgery, the optimal therapeutic threshold for minimizing bleeding risk is still uncertain. To better understand the utility of the P2Y12 assay in the perioperative period, further prospective research is needed., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Despite the heavily debated use of routine platelet-function testing, the VerifyNow Platelet Reactivity Unit (PRU) assay has been increasingly adopted as standard of care for assessing risk of postoperative thromboembolic complications of neuroendovascular surgery., Objective: We conducted a systematic review and meta-analysis to examine the relationship between platelet response and risk of ischemic events from neuroendovascular surgery, assess the efficacy of point-of-care platelet-function testing in predicting thromboembolic outcomes, and assess whether a clinically useful threshold for platelet response can be defined in order to standardize guidelines., Methods: PubMed, Embase, and Scopus were searched. Following deduplication, articles were first screened for relevance by title and abstract, followed by full text., Results: Of 735 resultant articles, 22 studies consisting of 3266 patients undergoing neuroendovascular intervention were included. Diagnoses included both intracranial and extracranial pathologies, of which 45.8% were treated with flow diversion, 16.4% with stent-assisted coil embolization, 15.8% with intracranial stenting, 12.0% with simple coil embolization, 3.4% with balloon-assisted coil embolization, 3.6% with extracranial stenting, and 3.0% with an alternate method. 54.5% (12/22) of studies determined platelet hyporesponse to be an independent predictor of postoperative thromboembolic complications, with 27.3% (6/22) of studies reporting a similar, but non-statistically significant trend. 18.2% (4/22) of studies found no relationship between platelet response and postoperative thromboembolic complications. The estimated clinical threshold for PRU to prevent thromboembolic complications varied greatly across studies (Range: > 144-295 PRU). Meta-analysis found platelet hyporesponse to have a 2.23-fold increased risk of thromboembolic complications compared to normoresponders (RR = 2.23, P = 0.03)., Conclusion: While PRU demonstrates a significant predictive value for postoperative thromboembolic complications of neuroendovascular surgery, the target therapeutic threshold for minimizing ischemic events remains unclear. Further studies, such as large multicenter cohorts of the existing data, are needed to standardize guidelines., Competing Interests: Declaration of conflicting interestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Phenomenon : Ad hoc entrustment decisions reflect a clinical supervisor's estimation of the amount of supervision a trainee needs to successfully complete a task in the moment. These decisions have important consequences for patient safety, trainee learning, and preparation for independent practice. Determinants of these decisions have previously been described but have not been well described for acute care contexts such as critical care and emergency medicine. The ad hoc entrustment of trainees caring for vulnerable patient populations is a high-stakes decision that may differ from other contexts. Critically ill patients and children are vulnerable patient populations, making the ad hoc entrustment of a pediatric critical care medicine (PCCM) fellow a particularly high-stakes decision. This study sought to characterize how ad hoc entrustment decisions are made for PCCM fellows through faculty ratings of vignettes. The authors investigated how acuity, relationship, training level, and task interact to influence ad hoc entrustment decisions. Approach : A survey containing 16 vignettes that varied by four traits (acuity, relationship, training level, and task) was distributed to U.S. faculty of pediatric critical care fellowships in 2020. Respondents determined an entrustment level for each case and provided demographic data. Entrustment ratings were dichotomized by "high entrustment" versus "low entrustment" (direct supervision or observation only). The authors used logistic regression to evaluate the individual and interactive effects of the four traits on dichotomized entrustment ratings. Findings : One hundred seventy-eight respondents from 30 institutions completed the survey (44% institutional response rate). Acuity, relationship, and task all significantly influenced the entrustment level selected but did not interact. Faculty most frequently selected "direct supervision" as the entrustment level for vignettes, including for 24% of vignettes describing fellows in their final year of training. Faculty rated the majority of vignettes (61%) as "low entrustment." There was no relationship between faculty or institutional demographics and the entrustment level selected. Insights : As has been found in summative entrustment for pediatrics, internal medicine, and surgery trainees, PCCM fellows often rated at or below the "direct supervision" level of ad hoc entrustment. This may relate to declining opportunities to practice procedures, a culture of low trust propensity among the specialty, and/or variation in interpretation of entrustment scales.

Importance: Patients with locally advanced non-human papillomavirus (HPV) head and neck cancer (HNC) carry an unfavorable prognosis. Chemoradiotherapy (CRT) with cisplatin or anti-epidermal growth factor receptor (EGFR) antibody improves overall survival (OS) of patients with stage III to IV HNC, and preclinical data suggest that a small-molecule tyrosine kinase inhibitor dual EGFR and ERBB2 (formerly HER2 or HER2/neu) inhibitor may be more effective than anti-EGFR antibody therapy in HNC., Objective: To examine whether adding lapatinib, a dual EGFR and HER2 inhibitor, to radiation plus cisplatin for frontline therapy of stage III to IV non-HPV HNC improves progression-free survival (PFS)., Design, Setting, and Participants: This multicenter, phase 2, double-blind, placebo-controlled randomized clinical trial enrolled 142 patients with stage III to IV carcinoma of the oropharynx (p16 negative), larynx, and hypopharynx with a Zubrod performance status of 0 to 1 who met predefined blood chemistry criteria from October 18, 2012, to April 18, 2017 (median follow-up, 4.1 years). Data analysis was performed from December 1, 2020, to December 4, 2020., Intervention: Patients were randomized (1:1) to 70 Gy (6 weeks) plus 2 cycles of cisplatin (every 3 weeks) plus either 1500 mg per day of lapatinib (CRT plus lapatinib) or placebo (CRT plus placebo)., Main Outcomes and Measures: The primary end point was PFS, with 69 events required. Progression-free survival rates between arms for all randomized patients were compared by 1-sided log-rank test. Secondary end points included OS., Results: Of the 142 patients enrolled, 127 (median [IQR] age, 58 [53-63] years; 98 [77.2%] male) were randomized; 63 to CRT plus lapatinib and 64 to CRT plus placebo. Final analysis did not suggest improvement in PFS (hazard ratio, 0.91; 95% CI, 0.56-1.46; P = .34) or OS (hazard ratio, 1.06; 95% CI, 0.61-1.86; P = .58) with the addition of lapatinib. There were no significant differences in grade 3 to 4 acute adverse event rates (83.3% [95% CI, 73.9%-92.8%] with CRT plus lapatinib vs 79.7% [95% CI, 69.4%-89.9%] with CRT plus placebo; P = .64) or late adverse event rates (44.4% [95% CI, 30.2%-57.8%] with CRT plus lapatinib vs 40.8% [95% CI, 27.1%-54.6%] with CRT plus placebo; P = .84)., Conclusion and Relevance: In this randomized clinical trial, dual EGFR-ERBB2 inhibition with lapatinib did not appear to enhance the benefit of CRT. Although the results of this trial indicate that accrual to a non-HPV HNC-specific trial is feasible, new strategies must be investigated to improve the outcome for this population with a poor prognosis., Trial Registration: ClinicalTrials.gov Identifier: NCT01711658.

Purpose: The transition from pediatric to adult care can be complex and difficult to navigate for adolescents with cerebral palsy (CP). We aimed to assess the current state of transitional care for young persons with CP and delineate guidelines for best practice with opportunities for intervention., Methods: A systematic review was conducted using PRISMA guidelines to search PubMed, Embase, and Scopus databases. Articles were screened for relevance via title and abstract prior to full-text review., Results: Of 3151 resultant articles, 27 observational studies were included. Fourteen (52%) studies assessed clinical outcomes of patients with CP during and post-transition. Transition-associated poor outcomes included housing instability, unemployment, difficulty forming relationships, increased hospital admission rates, and decreased use of rehabilitation services. Factors associated with improved outcomes included family participation, promotion of self-efficacy, and meeting the adult team before transition. Nine (33%) studies conducted interviews with transition-age persons with CP. Key themes were a lack of transition preparedness, difficulty navigating the adult system, gaps in seamless care, and limited accessibility to specialists and environments suitable for patients with complex care needs. Four (15%) studies examined features of current transition services. Perceived barriers included poor communication within health service teams, limited adult providers accepting CP patients, and the lack of financial resources for specialized care. There was no standardized transition tool or approach., Conclusion: These findings underscore the importance of a planned transition process in optimizing long-term medical and psychosocial outcomes for persons with CP. Further research, including translational, team-based, and community-engaged research, are needed., (© 2023. The Author(s).)

Background: Moyamoya disease (MMD) is an occlusive arteriopathy leading to stroke. Progressive if left untreated, revascularization surgery has become the mainstay of treatment. Although clinical and radiographic outcomes of MMD after intervention are well-characterized, cognitive outcomes in pediatric patients remain unclear. We aimed to examine postoperative cognitive outcomes in children with MMD, examine factors associated with cognitive changes after intervention, and define the effect of revascularization surgery on cognitive outcomes., Methods: A systematic review was conducted following PRISMA guidelines searching PubMed, Embase, and Scopus databases. Articles met inclusion criteria if they studied pediatric patients undergoing revascularization surgery for MMD and examined cognitive outcomes either qualitatively or quantitatively. All data extracted from included articles was examined descriptively., Results: Of 1091 resultant articles, 12 articles containing 446 patients were included. Surgery was associated with maintained or improved full scale intellectual quotient (IQ), performance IQ, perceptual IQ, memory quotient and verbal memory. However, 70% of patients had impaired cognitive function, with associated poor school performance. Improvements in cognition were associated with increased cerebral blood flow, particularly to the middle cerebral artery, due to the development of collaterals. Female sex, shorter duration from symptom onset to surgery, and surgery after age 7 were predictive of cognitive improvement. Completed ischemic stroke prior to surgery was associated with poorer cognitive outcomes., Conclusions: Although children with MMD have improved cognitive outcomes following revascularization overall, a distinct subset experience cognitive impairment. Consideration of patient-specific and treatment-related factors is important to enable proper risk stratification and inform management approaches., (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Deep brain stimulation (DBS) can be a life-changing intervention for patients with Parkinson's disease (PD), but its success is largely dependent on precise lead placement. The subthalamic nucleus (STN) is one of the most common surgical targets of DBS, but the close anatomical and physiological resemblance of the STN to the mediocaudal red nucleus renders these landmarks difficult to distinguish., Observations: We present an atypical case in which targeted localization of the STN resulted in symptoms pathognomonic of rubrospinal tract (RST) stimulation. A 79-year-old female with a 12-year history of right-hand resting tremor due to medically refractory PD presented for asleep bilateral STN-DBS surgery. Right STN intraoperative testing revealed left hand and elbow flexion contractures, initially suggestive of corticospinal tract activation, despite imaging studies demonstrating reasonable lead placement in the central dorsolateral STN. The lead was moved anteromedially near the medial border of the STN, but stimulation at this location revealed similar but more robust flexor hand and arm contractures, without any extraocular muscle involvement. Thus, activation of the RST was suspected., Lessons: Isolated activation of the RST is possible during STN-DBS surgery. Its identification can help avoid false localization and suboptimal lead placement.

Importance: Squamous cell carcinoma of the head and neck (HNSCC) is prevalent globally and in the US. Management, particularly after disease recurrence, can be challenging, and exploring additional treatment modalities, such as therapeutic cancer vaccines, may offer an opportunity to improve outcomes in this setting., Observations: This review provides an overview of the clinical efficacy of different treatment modalities that are currently available for the treatment of recurrent and metastatic HNSCC, including checkpoint inhibitors and targeted therapies, with a detailed summary of the numerous T-cell vaccines that have been studied in the setting of HNSCC, as well as a detailed summary of B-cell therapeutic vaccines being investigated for various malignant tumors., Conclusions and Relevance: The findings of this review suggest that several therapeutic T-cell and B-cell vaccines, which have been recently developed and evaluated in a clinical setting, offer a promising treatment modality with the potential to improve outcomes for patients with recurrent and metastatic HNSCC.

Purpose/Objective(s): Microbiome has been shown to affect tumorigenesis by promoting inflammation. However, the association between the upper aerodigestive microbiome and head and neck squamous cell carcinoma (HNSCC) is not well established. Hypoxia is a modifiable factor associated with poor radiation response. Our study analyzed the HNSCC tumor samples from The Cancer Genome Atlas (TCGA) to investigate the relationship between different HNSCC tumor subsites, hypoxia, and local tumor microbiome composition. Results: A total of 357 patients were included [Oral cavity (OC) = 226, Oropharynx (OPx) = 53, and Larynx/Hypopharynx (LHPx) = 78], of which 12.8%, 71.7%, and 10.3%, respectively, were HPV positive. The mean (SD) hypoxia scores were 30.18 (11.10), 24.31 (14.13), and 29.53 (12.61) in OC, OPx, and LHPx tumors, respectively, with higher values indicating greater hypoxia. The hypoxia score was significantly higher for OC tumors compared to OPx (p = 0.044) and LHPx (p = 0.002). There was no significant correlation between hypoxia and HPV status. Pseudomonas sp. in OC, Actinomyces sp. and Sulfurimonas sp. in OPx, and Filifactor, Pseudomonas and Actinomyces sp. in LHPx had the strongest association with the hypoxia score. Materials/Methods: Tumor RNAseq samples from TCGA were processed, and the R package “tmesig” was used to calculate gene expression signature, including the Buffa hypoxia (BH) score, a validated hypoxia signature using 52 hypoxia-regulated genes. Microbe relative abundances were modeled with primary tumor location and a high vs. low tertile BH score applying a gamma-distributed generalized linear regression using the “stats” package in R, with adjusted p-value < 0.05 considered significant. Conclusions: In our study, oral cavity tumors were found to be more hypoxic compared to other head and neck subsites, which could potentially contribute to their radiation resistance. For each subsite, distinct microbial populations were over-represented in hypoxic tumors in a subsite-specific manner. Further studies focusing on an association between microbiome, hypoxia, and patient outcomes are warranted.

In situ measurements of ionospheric and thermospheric temperatures are experimentally challenging because orbiting spacecraft typically travel supersonically with respect to the cold gas and plasma. We present O 2 + temperatures in Mars' ionosphere derived from data measured by the SupraThermal And Thermal Ion Composition instrument onboard the Mars Atmosphere and Volatile EvolutioN spacecraft. We focus on data obtained during nine special orbit maneuvers known as Deep Dips, during which MAVEN lowered its periapsis altitude from the nominal 150 to 120 km for 1 week in order to sample the ionospheric main peak and approach the homopause. We use two independent techniques to calculate ion temperatures from the measured energy and angular widths of the supersonic ram ion beam. After correcting for background and instrument response, we are able to measure ion temperatures as low as 100 K with associated uncertainties as low as 10%. It is theoretically expected that ion temperatures will converge to the neutral temperature at altitudes below the exobase region (∼180-200 km) due to strong collisional coupling; however, no evidence of the expected thermalization is observed. We have eliminated several possible explanations for the observed temperature difference between ions and neutrals, including Coulomb collisions with electrons, Joule heating, and heating caused by interactions with the spacecraft. The source of the energy maintaining the high ion temperatures remains unclear, suggesting that a fundamental piece of physics is missing from existing models of the Martian ionosphere., (© 2021. The Authors.)

Background: Positron emission tomography/computed tomography (PET/CT) in staging of advanced oropharyngeal squamous cell carcinoma (OPSCC) and at 3 months posttreatment (PETpost) is often utilized to assess response. The significance of lymph node vs primary site treatment response is incompletely understood., Methods: We reviewed 230 patients treated with radiation therapy. PETpost response was graded at primary and nodal sites and correlated with survival., Results: Median age was 58, and 83% were p16-positive. Median follow-up was 24.3 months. Nodal response at PETpost predicted improved 2-year local recurrence-free survival (LRFS) (93% vs 72%, P =.004), 2-year disease-free survival (DFS) (80% vs 61.3%, P =.021), and 2-year overall survival (OS) (89% vs 83%, P =.051), while primary response only predicted improved 2-year LRFS (91% vs 76% P = .035)., Conclusion: In OPSCC patients, both nodal and primary response at 3 months on PET/CT predicted for improved LRFS, but only nodal response predicted DFS and OS., (© 2020 Wiley Periodicals, Inc.)

For patients ineligible for cisplatin with definitive radiotherapy (CP-CRT) for locally advanced head and neck squamous cell carcinoma (LA-HNSCC), concurrent cetuximab (C225-RT) is a popular substitute. Carboplatin-based chemoradiation (CB-CRT) is another option; however, relative efficacies of CP-CRT, CB-CRT and C225-RT are unclear, particularly in the human papillomavirus (HPV)-unrelated population. We identified 316 patients with stage III-IVB cancers of the oropharynx (24.7%), larynx (58.2%) and hypopharynx (17.1%) undergoing definitive C225-RT (N = 61), CB-CRT (N = 74) or CP-CRT (N = 181). Kaplan-Meier and cumulative incidence functions were generated to estimate overall survival (OS), locoregional failure (LRF) and distant metastasis (DM). Cox proportional hazards were used to determine the association of survival endpoints with clinical characteristics. Respectively, 3-year cumulative incidences for CP-CRT, CB-CRT and C225-RT were: LRF (0.19, 0.18 and 0.48, p ≤ 0.001), DM (0.17, 0.12 and 0.25, p = 0.32). Kaplan-Meier estimates for 3 year OS were: CP-CRT: 71%; CB-CRT: 59% and C225-RT: 54%; p = 0.0094. CP-CRT (hazard ratio [HR] 0.336; 95% confidence interval [CI] 0.203-0.557, p < 0.01) and CB-CRT (HR 0.279; 95% CI 0.141-0.551, p < 0.01) were associated with reduced hazard for LRF on multivariable analysis. CP-CRT (HR 0.548; 95% CI 0.355-0.845, p < 0.01) and CB-CRT (HR 0.549; 95% CI 0.334-0.904, p = 0.02) were associated with a reduced hazard for death on multivariable analysis. Propensity matching confirmed reduced hazards with a combined CP/CB-CRT group compared to C225-RT for LRF: HR 0.384 (p = 0.018) and OS: HR 0.557 (p = 0.045) and CB-CRT group compared to C225-RT for LRF: HR 0.427 (p = 0.023). In conclusion, CB-CRT is an effective alternative to CP-CRT in HPV-unrelated LA-HNSCC with superior locoregional control and OS compared to C225-RT., (© 2019 UICC.)

The refilling of the lunar wake is relatively well explained by the theory of 1-D plasma expansion into a vacuum; however, the field-aligned wake potential is not a directly measured quantity, and thus, a statistical analysis of wake potentials at high altitudes has not been previously performed. In this study, we obtain the wake potential by comparing the field-aligned electron distributions inside and outside of the lunar wake measured by the two probes of the Acceleration, Reconnection, Turbulence, and Electrodynamics of Moon's Interaction with the Sun (ARTEMIS) mission. The derived potentials from ARTEMIS data vary with solar wind electron temperature and bulk flow velocity as the theory predicts. We also expand the 1-D plasma theory to 2-D in the plane of the interplanetary magnetic field and the solar wind velocity to examine how a tilted interplanetary magnetic field affects the wake potential structure. As the expansion time for the two sides of the wake differs, a wake potential asymmetry is developed in our model. This asymmetry is confirmed by the data-derived wake potentials. Moreover, ambipolar electric fields are obtained from both the modeled and data-derived wake potentials and show good agreement. Lastly, we examine the effects of the solar wind strahl-electron population on the wake potential structure, which appears to cause a net potential difference across the lunar shadow. This may imply that the disturbance of the wake plasma expansion extends farther outside the wake than previous plasma-expansion theories have predicted.

The clinical impact of lymph node dissection extent remains undetermined in the contemporary setting, as reflected in care pattern variations. Despite some series demonstrating a direct relationship between number of lymph nodes identified and detection of nodal involvement, the correlation between lymph node yield and disease control or survival outcomes remains unclear. Patients with clinically localized prostate cancer, pre-RP PSA <30, and pT2-3a/N0 disease at RP were retrospectively identified from two databases for inclusion. Those who received pre- or post-RP radiotherapy or hormone therapy were excluded. Kaplan-Meier method was employed for survival probability estimation. Cox regression models were used to assess bRFS differences between subsets. From 2002 to 2010, 667 eligible patients were identified. The median age was 61 yrs. (range, 43-76), with median PSA 5.6 ng/dL (0.9-28.0). At RP, most patients had pT2c (64%) disease with Gleason Score (GS) ≤6 (43%) or 7 (48%); 218 (33%) patients had positive margins (M+). At median clinical and PSA follow-up of 96 and 87 months, respectively, 146 patients (22%) experienced PSA failure with an estimated bRFS of 81%/76% at 5/8 years. For patients who underwent LND, univariable analysis identified PSA (at diagnosis), higher GS (≥7, at biopsy or RP), intermediate/high risk stratification, M+ as adversely associated with bRFS (all p < 0.01). A higher number of LNs excised was not associated with improved bRFS for the entire cohort (HR = 0.97, p = 0.27), nor for any clinical risk stratum, biopsy GS, or RP GS subgroup. This study did not demonstrate an association between LN yield and bRFS in patients with clinically localized pT2-3a/pN0 prostate cancer managed with RP alone, either in the entire population or with substratification by clinical risk stratum or GS.

We have implemented a parameterization for forming ice in large-scale cirrus clouds that accounts for the changes in updrafts associated with a spectrum of waves acting within each time step in the model. This allows us to account for the frequency of homogeneous and heterogeneous freezing events that occur within each time step of the model and helps to determine more realistic ice number concentrations as well as changes to ice number concentrations. The model is able to fit observations of ice number at the lowest temperatures in the tropical tropopause but is still somewhat high in tropical latitudes with temperatures between 195°K and 215°K. The climate forcings associated with different representations of heterogeneous ice nuclei (IN or INPs) are primarily negative unless large additions of IN are made, such as when we assumed that all aircraft soot acts as an IN. However, they can be close to zero if it is assumed that all background dust can act as an INP irrespective of how much sulfate is deposited on these particles. Our best estimate for the forcing of anthropogenic aircraft soot in this model is -0.2 ± 0.06 W/m 2 , while that from anthropogenic fossil/biofuel soot is -0.093 ± 0.033 W/m 2 . Natural and anthropogenic open biomass burning leads to a net forcing of -0.057 ± 0.05 W/m 2 .

A new satellite remote sensing method is described whereby the sensitivity of thermal infrared wave resonance absorption to small ice crystals is exploited to estimate cirrus cloud ice particle number concentration N, effective diameter D e , and ice water content IWC. This method uses co-located observations from the Infrared Imaging Radiometer (IIR) and from the CALIOP ( Cloud and Aerosol Lidar with Orthogonal Polarization ) lidar aboard the CALIPSO ( Cloud-Aerosol Lidar and Infrared Pathfinder Satellite Observation) polar orbiting satellite, employing IIR channels at 10.6 μm and 12.05 μm. Using particle size distributions measured over several flights of the TC4 (Tropical Composition, Cloud and Climate Coupling) and the mid-latitudes SPARTICUS (Small Particles in Cirrus) field campaigns, we show for the first time that N/IWC is tightly related to β eff ; the ratio of effective absorption optical depths at 12.05 μm and 10.6 μm. Relationships developed from in situ aircraft measurements are applied to β eff derived from IIR measurements to retrieve N. This satellite remote sensing method is constrained by measurements of β eff from the IIR and is by essence sensitive to the smallest ice crystals. Retrieval uncertainties are discussed, including uncertainties related to in situ measurement of small ice crystals (D < 15 µm), which are studied through comparisons with IIR β eff . The method is applied here to single-layered semi-transparent clouds having a visible optical depth between about 0.3 and 3, where cloud base temperature is ≤ 235 K. Two years of CALIPSO data have been analyzed for the years 2008 and 2013, with the dependence of cirrus cloud N and D e on altitude, temperature, latitude, season (winter vs. summer) and topography (land vs. ocean) described. The results for the mid-latitudes show a considerable dependence on season. In the high latitudes, N tends to be highest and D e smallest, whereas the opposite is true for the tropics. The frequency of occurrence of these relatively thick cirrus clouds exhibited a strong seasonal dependence in the high latitudes, with the occurrence frequency during Arctic winter being at least twice that of any other season. Processes that could potentially explain some of these micro-and macroscopic cloud phenomena are discussed.

We use observations from the Mars Atmosphere and Volatile EvolutioN(MAVEN) mission to show how superthermal electron fluxes and crustal magnetic fields affect ion densities in the nightside ionosphere of Mars. We find that, due to electron impact ionization, high electron fluxes significantly increase the CO 2 + , O + , and O 2 + densities below 200 km, but only modestly increase the NO + density. High electron fluxes also produce distinct peaks in the CO 2 + , O + , and O 2 + altitude profiles. We also find that superthermal electron fluxes are smaller near strong crustal magnetic fields. Consequently, nightside ion densities are also smaller near strong crustal fields because they decay without being replenished by electron impact ionization. Furthermore, the NO + / O 2 + ratio is enhanced near strong crustal fields because, in the absence of electron impact ionization, O 2 + is converted into NO + and not replenished. Our results show that electron impact ionization is a significant source of CO 2 + , O + , and O 2 + in the nightside ionosphere of Mars.

Background: The purpose of this study was to determine whether a "high-risk" subpopulation of low-grade (Gleason score ≤6) prostate cancer defined by lower prostate-specific antigen (PSA) relapse-free survival (bRFS) might be identified within a large population of men who underwent radical prostatectomy (RP) alone, with mature follow-up., Patients and Methods: Patients were retrospectively identified for inclusion by cT1-2 prostate cancer managed with RP alone. Exclusion criteria were: Gleason score ≥7 at RP, any pre- or post-RP radiotherapy or hormone therapy, or PSA follow-up <12 months. The Kaplan-Meier method was used for survival estimates; recursive partitioning by conditional inference analysis was applied to identify variables associated with bRFS., Results: From 2002 through 2010, 284 eligible patients were identified. Median age was 60 years (range, 44-76 years), 233 (82%) were cT1c, and median PSA was 5.3 ng/dL (92% ≤10). The median biopsy to RP interval was 50 days (range, 11-410, with 97% <180 days). Eighty patients (28%) had positive margin (M+). At a median follow-up of 92.6 months (range, 16.9-160.9, with 45% followed ≥ 8 years), 32 patients (11%) had PSA failure, with an estimated 8-year bRFS rate of 89%. In univariate analysis, M+, extraprostatic extension, detectable initial post-RP PSA, and longer biopsy to RP interval were significantly associated with lower bRFS. M+ and longer biopsy to RP interval remained significant in multivariable analysis. Recursive partitioning analysis identified M+ as the only stratification factor, with 8-year bRFS estimates of 74% versus 95% for M+ versus margin-negative., Conclusion: Gleason score ≤6 prostate cancer managed using RP alone is associated with high rates of bRFS; however, margin positivity predicts early PSA failure rates in >20% of patients., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: The current standard of care for men with muscle-invasive bladder cancer is radical cystoprostatectomy (RCP). One-third of RCP specimens demonstrate incidental prostate cancer, primarily reported in small series with limited follow-up. The aim of this study is to report mature outcomes, including patterns of failure and disease-specific recurrence rates, and survival, for a large cohort of men with incidental prostate cancer at RCP performed at a tertiary referral center., Methods: This retrospective study describes cancer control and survival rates for men who underwent RCP for bladder cancer and were found incidentally to have prostate cancer. Analysis of patient-, tumor-, and treatment-specific factors were analyzed for association with disease control and survival endpoints., Results: Between 2002 and 2010, 94 patients with incidental discovery of prostate cancer postRCP were identified for inclusion in this study. Forty-five patients (45%) underwent RCP for recurrent (rather than initial presentation of) bladder carcinoma. At a median follow-up of 40.3 months (71.2 months for survivors; range, 8.9-155.5 months), 42 patients were alive without recurrence and 52 patients had died (25 associated with disease). The estimated 5-year bladder cancer disease-free, urinary tract malignancy disease-free, and prostate specific antigen (PSA) relapse-free survivals were 76% [95% confidence interval (CI), 65-84%], 64% (52-74%), and 97% (79-100%), respectively. The estimated 5-year urinary tract malignancy-specific and overall survivals were 61% (49-71%) and 52% (41-62%), respectively. Univariate analysis demonstrated associations between pathologic T/N-stage and nodal ratio with bladder cancer disease-free, urinary tract malignancy disease-specific, and overall survivals, with patient age at diagnosis as an additional adverse factor associated with overall survival. Multivariate analysis confirmed pN-stage and age as independently associated with worse survival., Conclusion: For men undergoing RCP for bladder cancer, the present study suggests that incidentally discovered prostate cancers, irrespective of pathologic stage, Gleason score, or clinical significance, do not impact 5-year disease control or survival outcomes.

Radiation therapy indications in the postprostatectomy setting are evolving. Several retrospective series have identified a number of "high-risk" pathologic features associated with an elevated risk of disease recurrence after radical prostatectomy. More recently, several randomized phase III trials demonstrated superior biochemical relapse-free survival for adjuvant radiation therapy after prostatectomy for patients with these high-risk pathologic features, including positive margin status, extraprostatic extension, and/or seminal vesicle invasion. These series further suggested improvement in distant metastasis control and overall survival after 15 years. However, not all patients with high-risk features experience disease recurrence after surgery alone, and some subsets of patients experience suboptimal disease control and survival despite immediate postoperative radiotherapy. Furthermore, some patients without high-risk features will develop recurrence. The present review discusses the current data and potential future directions to improve individualization of therapy after prostatectomy., (Copyright © 2016 Elsevier Inc. All rights reserved.)

The objective of this study was to assess potential functional attenuation or inactivation of the intra-S checkpoint during melanoma development. Proliferating cultures of skin melanocytes, fibroblasts, and melanoma cell lines were exposed to increasing fluences of UVC and intra-S checkpoint responses were quantified. Melanocytes displayed stereotypic intra-S checkpoint responses to UVC qualitatively and quantitatively equivalent to those previously demonstrated in skin fibroblasts. In comparison with fibroblasts, primary melanocytes displayed reduced UVC-induced inhibition of DNA strand growth and enhanced degradation of p21Waf1 after UVC, suggestive of enhanced bypass of UVC-induced DNA photoproducts. All nine melanoma cell lines examined, including those with activating mutations in BRAF or NRAS oncogenes, also displayed proficiency in activation of the intra-S checkpoint in response to UVC irradiation. The results indicate that bypass of oncogene-induced senescence during melanoma development was not associated with inactivation of the intra-S checkpoint response to UVC-induced DNA replication stress., (© 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Planetary auroras reveal the complex interplay between an atmosphere and the surrounding plasma environment. We report the discovery of low-altitude, diffuse auroras spanning much of Mars' northern hemisphere, coincident with a solar energetic particle outburst. The Imaging Ultraviolet Spectrograph, a remote sensing instrument on the Mars Atmosphere and Volatile Evolution (MAVEN) spacecraft, detected auroral emission in virtually all nightside observations for ~5 days, spanning nearly all geographic longitudes. Emission extended down to ~60 kilometer (km) altitude (1 microbar), deeper than confirmed at any other planet. Solar energetic particles were observed up to 200 kilo--electron volts; these particles are capable of penetrating down to the 60 km altitude. Given minimal magnetic fields over most of the planet, Mars is likely to exhibit auroras more globally than Earth., (Copyright © 2015, American Association for the Advancement of Science.)

In response to DNA damage, the E2F1 transcription factor is phosphorylated at serine 31 (serine 29 in mouse) by the ATM or ATR kinases, which promotes E2F1 protein stabilization. Phosphorylation of E2F1 also leads to the recruitment of E2F1 to sites of DNA damage, where it functions to enhance DNA repair. To study the role of this E2F1 phosphorylation event in vivo, a knock-in mouse model was generated, in which serine 29 was mutated to alanine. The S29A mutation impairs E2F1 stabilization in response to ultraviolet (UV) radiation and doxorubicin treatment, but has little effect on the expression of E2F target genes. The apoptotic and proliferative responses to acute UV radiation exposure are also similar between wild-type and E2f1(S29A/) (S29A) mice. As expected, the S29A mutation prevents E2F1 association with damaged DNA and reduces DNA repair efficiency. Moreover, E2f1(S29A/) (S29A) mice display increased sensitivity to UV-induced skin carcinogenesis. This knock-in mouse model thus links the ability of E2F1 to directly promote DNA repair with the suppression of tumor development., (©2014 American Association for Cancer Research.)

Xiphophorus fish and interspecies hybrids represent long-standing models to study the genetics underlying spontaneous and induced tumorigenesis. The recent release of the Xiphophorus maculatus genome sequence will allow global genetic regulation studies of genes involved in the inherited susceptibility to UVB-induced melanoma within select backcross hybrids. As a first step toward this goal, we report results of an RNA-Seq approach to identify genes and pathways showing modulated transcription within the skin of X. maculatus Jp 163 B upon UVB exposure. X. maculatus Jp 163 B were exposed to various doses of UVB followed by RNA-Seq analysis at each dose to investigate overall gene expression in each sample. A total of 357 genes with a minimum expression change of 4-fold (p-adj<0.05) were identified as responsive to UVB. The molecular genetic response of Xiphophorus skin to UVB exposure permitted assessment of; (1) the basal expression level of each transcript for each skin sample, (2) the changes in expression levels for each gene in the transcriptome upon exposure to increasing doses of UVB, and (3) clusters of genes that exhibit similar patterns of change in expression upon UVB exposure. These data provide a foundation for understanding the molecular genetic response of fish skin to UVB exposure., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Induction of pyrimidine dimers in DNA by solar UV radiation has drastic effects on microorganisms. To better define the nature of these DNA photoproducts in marine bacterioplankton and eukaryotes, a study was performed during a cruise along a latitudinal transect in the Pacific Ocean. The frequency of all possible cyclobutane pyrimidine dimers, pyrimidine (6-4) pyrimidone photoproducts (64PPs) and their related Dewar valence isomers (DEWs) was determined by high-performance liquid chromatography-mass spectrometry. Studied samples were bacterioplankton and eukaryotic fractions isolated from sea water either collected before sunrise or exposed to ambient sunlight from sunrise to sunset. Isolated DNA dosimeters were also exposed to daily sunlight for comparison purposes. A first major result was the observation in all samples of large amounts of DEWs, a class of photoproducts rarely considered outside photochemical studies. Evidence was obtained for a major role of UVA in the formation of these photoisomerization products of 64PPs. Considerations on the ratio between the different classes of photoproducts in basal and induced DNA damage suggests that photoenzymatic repair (PER) is an important DNA repair mechanism used by marine microorganisms occupying surface seawater in the open ocean. This result emphasizes the biological role of DEWs which are very poor substrate for PER., (© 2014 Society for Applied Microbiology and John Wiley & Sons Ltd.)

Using the Xiphophorus fish melanoma model, we show a strong male bias for sunlight-induced malignant melanoma, consistent with that seen in the human population. To examine underlying factors, we exposed adult X. couchianus fish to a single, sublethal dose of UVB and measured circulating sex steroid hormones and expression of associated hormone receptor genes over a 24-h period. We found that a single exposure had profound effects on circulating levels of steroid hormones with significant decreases for all free sex steroids at 6 and 24 h and increases in conjugated 2-estradiol and 11-ketotestosterone at 6 and 24 h, respectively. Whereas ARα expression increased in male and female skin, neither ARβ nor either of the ERs showed significant responses to UVB in either sex. The rapid response of male androgens and their receptors in the skin after UVB irradiation implicates hormones in the male bias of skin cancer and suggests that the photoendocrine response immediately after UV exposure may be relevant to melanomagenesis., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

This study compared biological responses of normal human fibroblasts (NHF1) to three sources of ultraviolet radiation (UVR), emitting UVC wavelengths, UVB wavelengths, or a combination of UVA and UVB (solar simulator; emission spectrum, 94.3% UVA and 5.7% UVB). The endpoints measured were cytotoxicity, intra-S checkpoint activation, inhibition of DNA replication and mutagenicity. Results show that the magnitude of each response to the indicated radiation sources was best predicted by the density of DNA cyclobutane pyrimidine dimers (CPD). The density of 6-4 pyrimidine-pyrimidone photoproducts was highest in DNA from UVC-irradiated cells (14% of CPD) as compared to those exposed to UVB (11%) or UVA-UVB (7%). The solar simulator source, under the experimental conditions described here, did not induce the formation of 8-oxo-7,8-dihydroguanine in NHF1 above background levels. Taken together, these results suggest that CPD play a dominant role in DNA damage responses and highlight the importance of using endogenous biomarkers to compare and report biological effects induced by different sources of UVR., (© 2013 The American Society of Photobiology.)

Over the past 25 years, the use of polyclonal and monoclonal antibodies to quantify DNA damage has burgeoned. Immunoassays offer distinct advantages over other analytical procedures currently used to measure DNA damage including adaptability, sensitivity, and selectivity. This combination of attributes allows for the development of powerful analytical techniques to visualize and quantify specific types of DNA damage in cells, tissue, and organisms exposed to subtoxic levels of xenobiotics with distinct advantages over the other procedures in the analysis of DNA damage in human and environmental samples. Radioimmunoassay (RIA) is readily applied to a variety of biological materials and has typically been used to measure DNA damage in cell and organ cultures, tissue sections and biopsies, buccal cells, bone marrow aspirates, peripheral blood lymphocytes, and urine. Here we describe the use of a very sensitive RIA for the specific quantitation of cyclobutane dimers and (6-4) photoproducts in DNA extracted from mammalian cells and tissues.

Unlike breast and prostate cancers, the nature and sequence of critical genetic and epigenetic events involved in the initiation and progression of melanoma are not well understood. A contributing factor to this dilemma, especially given our current understanding of the importance of UV light in melanoma etiology, is the lack of quality UV-inducible melanoma animal models. In this study we elaborate on the capability of UV light to induce cutaneous malignant melanomas (CMM) in Xiphophorus fishes, which were previously found to develop melanomas after acute neonatal UVB irradiation. In two separate tumorigenesis experiments, we exposed adult Xiphophorus hybrids to either acute UVB irradiations (5 consecutive daily treatments) or chronic solar irradiations (continuous UVA/UVB treatment for 9 months). Acute adult UVB irradiation resulted in the significant induction of melanomas, and moreover, this induction rate is equivalent to that of animals exposed to acute neonatal UVB irradiation. This study represents the first evidence that acute adult UVB irradiation, in the absence of any early life exposures, induces CMM. Similar to the findings conducted on other divergent melanoma models, including HGF/SF transgenic mice and Monodelphis domestica, prolonged chronic solar UV was not a factor in melanomagenesis., (Copyright © 2011 Elsevier Inc. All rights reserved.)