Search

This report describes an approach to regional anaesthesia of the dorsal nerves of the penis in a Great Dane, as part of an anaesthetic protocol for surgical urethral resection and anastomosis. Bupivacaine (0.5%) was infiltrated around the left and right dorsal nerves of the penis, with ultrasound guidance. The locoregional approach was trans-perineal, with the ultrasound probe orientated at a right angle to the anus, at the level of the ischial symphysis. The described technique provided good visualisation of the urethra and dorsal arteries of the penis. No adverse events relating to the nerve blockade were encountered and no additional analgesia, other than the methadone premedication, was required intra-operatively. The locoregional approach was subsequently repeated on a cadaver using the same technique and, on dissection, demonstrated deposition of injectate next to the target neurovascular bundles. The technique described may provide a simple method of distal penile anaesthesia in the dog, where ultrasound is available.

Genomics of radiation-induced damage The potential adverse effects of exposures to radioactivity from nuclear accidents can include acute consequences such as radiation sickness, as well as long-term sequelae such as increased risk of cancer. There have been a few studies examining transgenerational risks of radiation exposure but the results have been inconclusive. Morton et al. analyzed papillary thyroid tumors, normal thyroid tissue, and blood from hundreds of survivors of the Chernobyl nuclear accident and compared them against those of unexposed patients. The findings offer insight into the process of radiation-induced carcinogenesis and characteristic patterns of DNA damage associated with environmental radiation exposure. In a separate study, Yeager et al. analyzed the genomes of 130 children and parents from families in which one or both parents had experienced gonadal radiation exposure related to the Chernobyl accident and the children were conceived between 1987 and 2002. Reassuringly, the authors did not find an increase in new germline mutations in this population. Science , this issue p. eabg2538 , p. 725

Purpose We examined if childhood socioeconomic status (SES) was related to adult leucocyte telomere length (TL) using the data of 361 African American (AA) participants from the GENE-FORECAST Study. We also assessed the mediating role of behavioral and psychosocial factors in the association between childhood SES and adult TL. Methods Childhood SES was assessed individually by using participant’s mother’s education and occupation, father’s education and occupation, parental home ownership, and family structure. TL was assessed using the quantitative polymerase chain reaction method. Information on potential confounders and mediators were collected. The associations of childhood SES with TL were assessed using multivariable linear regression models. We used path analysis to quantify and test the share of these associations that was statistically explained by each of the mediators (participant’s educational attainment, smoking status, physical activity, dietary habit, perceived stress, and depressive symptoms). Results Mother’s education was associated with longer average TL (β: 0.021; 95% CI: 0.001, 0.04, p=0.038) in confounder adjusted models. Once mediators were introduced in the model, the estimates were reduced and remained marginally significant (β: 0.017; 95% CI: −0.003, 0.038, p=0.061). According to path model, approximately 19% of the effect of mother’s education on TL (β: 0.004; 95% CI: −0.001, 0.01, p < 0.10) was mediated through participant’s own education level. No significant mediation effect was observed for any other mediators. Conclusions These data provide evidence that participant’s mother’s education was positively linked to adult TL in AA population. Participant’s own educational level partially explained this association.

PURPOSE Radiotherapy for childhood cancer is associated with elevated subsequent neoplasm (SN) risk, but the contribution of rare variants in DNA damage response and radiation sensitivity genes to SN risk is unknown. PATIENTS AND METHODS We conducted whole-exome sequencing in a cohort of childhood cancer survivors originally diagnosed during 1970 to 1986 (mean follow-up, 32.7 years), with reconstruction of doses to body regions from radiotherapy records. We identified patients who developed SN types previously reported to be related to radiotherapy (RT-SNs; eg, basal cell carcinoma [BCC], breast cancer, meningioma, thyroid cancer, sarcoma) and matched controls (sex, childhood cancer type/diagnosis, age, SN location, radiation dose, survival). Conditional logistic regression assessed SN risk associated with potentially protein-damaging rare variants (SnpEff, ClinVar) in 476 DNA damage response or radiation sensitivity genes with exact permutation-based P values using a Bonferroni-corrected significance threshold of P < 8.06 × 10−5. RESULTS Among 5,105 childhood cancer survivors of European descent, 1,108 (21.7%) developed at least 1 RT-SN. Out-of-field RT-SN risk, excluding BCC, was associated with homologous recombination repair (HRR) gene variants (patient cases, 23.2%; controls, 10.8%; odds ratio [OR], 2.6; 95% CI, 1.7 to 3.9; P = 4.79 × 10−5), most notably but nonsignificantly for FANCM (patient cases, 4.0%; matched controls, 0.6%; P = 9.64 × 10−5). HRR variants were not associated with likely in/near-field RT-SNs, excluding BCC (patient cases, 12.7%; matched controls, 12.9%; P = .92). Irrespective of radiation dose, risk for RT-SNs was also associated with EXO1 variants (patient cases, 1.8%; controls, 0.4%; P = 3.31 × 10−5), another gene implicated in DNA double-strand break repair. CONCLUSION In this large-scale discovery study, we identified novel associations between RT-SN risk after childhood cancer and potentially protein-damaging rare variants in genes involved in DNA double-strand break repair, particularly HRR. With replication, these results could affect screening recommendations for childhood cancer survivors and risk-benefit assessments of treatment approaches.

Background Myalgic Encephalomyelitis (ME) is a chronic condition whose status within medicine is the subject of on-going debate. Some medical professionals regard it as a contentious illness. Others report a lack of confidence with diagnosis and management of the condition. The genesis of this paper was a complaint, made by an ME patient, about their treatment by a general practitioner. In response to the complaint, Healthwatch Trafford ran a patient experience-gathering project. Method Data was collected from 476 participants (411 women and 65 men), living with ME from across the UK. Multinomial logistic regression investigated the predictive utility of length of time with ME; geographic location (i.e. Manchester vs. rest of UK); trust in GP; whether the patient had received a formal diagnosis; time taken to diagnosis; and gender. The outcome variable was number of GP visits per year. Results All variables, with the exception of whether the patient had received a formal diagnosis, were significant predictors. Conclusions Relationships between ME patients and their GPs are discussed and argued to be key to the effective delivery of care to this patient cohort. Identifying potential barriers to doctor patient interactions in the context of ME is crucial.

Background Oral microbiota may be related to pancreatic cancer risk because periodontal disease, a condition linked to multiple specific microbes, has been associated with increased risk of pancreatic cancer. We evaluated the association between oral microbiota and pancreatic cancer in Iran. Methods A total of 273 pancreatic adenocarcinoma cases and 285 controls recruited from tertiary hospitals and a specialty clinic in Tehran, Iran provided saliva samples and filled out a questionnaire regarding demographics and lifestyle characteristics. DNA was extracted from saliva and the V4 region of the 16S rRNA gene was PCR amplified and sequenced on the MiSeq. The sequencing data were processed using the DADA2 plugin in QIIME 2 and taxonomy was assigned against the Human Oral Microbiome Database. Logistic regression and MiRKAT models were calculated with adjustment for potential confounders. Results No association was observed for alpha diversity with an average of 91.11 (standard deviation [SD] 2.59) sequence variants for cases and 89.42 (SD 2.58) for controls. However, there was evidence for an association between beta diversity and case status. The association between the Bray‐Curtis dissimilarity and pancreatic cancer was particularly strong with a MiRKAT P‐value of .000142 and specific principal coordinate vectors had strong associations with cancer risk. Several specific taxa were also associated with case status after adjustment for multiple comparisons. Conclusion The overall microbial community appeared to differ between pancreatic cancer cases and controls. Whether these reflect differences evident before development of pancreatic cancer will need to be evaluated in prospective studies., Specific microbial taxa and periodontal pathogens have been found to be associated with pancreatic cancer in Western populations. In a case‐control study in Iran, we found distinct microbial communities in pancreatic cancer cases and controls in addition to associations with particular microbial taxa.

Zidovudine (ZDV) is a nucleoside reverse transcriptase inhibitor that could cause telomere shortening through inhibition of telomerase. We examined the association between in utero exposure to ZDV and telomere length at birth in HIV-exposed-uninfected (HEU) newborns.We selected 94 ZDV-exposed HEU children and 85 antiretroviral therapy (ART)-unexposed HEU children from the Surveillance Monitoring for ART Toxicities Study and the Women and Infants Transmission Study. We assessed relative telomere length in stored peripheral blood mononuclear cells taken in the first 7 days of life using quantitative polymerase chain reaction. We used linear regression to compare relative telomere length between ZDV-exposed and ART-unexposed children. We additionally evaluated relative telomere length according to maternal and infant characteristics.Relative telomere length was longer in ZDV-exposed children compared with ART-unexposed individuals (adjusted mean ratio difference 0.21, 95% confidence interval 0.15-0.28, P 0.001). We found an inverse correlation between maternal HIV RNA levels and infant relative telomere length (-0.06 per log10 copies, 95% confidence interval -0.08 to -0.03, P 0.001). Relative telomere length was not associated with maternal CD4 cell count, maternal age, gestational age, sex, sample storage time, or maternal substance use (P 0.05).Relative telomere length was longer in ZDV-exposed infants. This difference may reflect beneficial health effects of ART during pregnancy, as we observed an inverse association with maternal HIV RNA levels.

Background Pediatric cancers are the leading cause of death by disease in children despite improved survival rates overall. The contribution of germline genetic susceptibility to pediatric cancer survivors has not been extensively characterized. We assessed the frequency of pathogenic or likely pathogenic (P/LP) variants in 5451 long-term pediatric cancer survivors from the Childhood Cancer Survivor Study. Methods Exome sequencing was conducted on germline DNA from 5451 pediatric cancer survivors (cases who survived ≥5 years from diagnosis; n = 5105 European) and 597 European cancer-free adults (controls). Analyses focused on comparing the frequency of rare P/LP variants in 237 cancer-susceptibility genes and a subset of 60 autosomal dominant high-to-moderate penetrance genes, for both case-case and case-control comparisons. Results Of European cases, 4.1% harbored a P/LP variant in high-to-moderate penetrance autosomal dominant genes compared with 1.3% in controls (2-sided P = 3 × 10-4). The highest frequency of P/LP variants was in genes typically associated with adult onset rather than pediatric cancers, including BRCA1/2, FH, PALB2, PMS2, and CDKN2A. A statistically significant excess of P/LP variants, after correction for multiple tests, was detected in patients with central nervous system cancers (NF1, SUFU, TSC1, PTCH2), Wilms tumor (WT1, REST), non-Hodgkin lymphoma (PMS2), and soft tissue sarcomas (SDHB, DICER1, TP53, ERCC4, FGFR3) compared with other pediatric cancers. Conclusion In long-term pediatric cancer survivors, we identified P/LP variants in cancer-susceptibility genes not previously associated with pediatric cancer as well as confirmed known associations. Further characterization of variants in these genes in pediatric cancer will be important to provide optimal genetic counseling for patients and their families.

Genomics of radiation-induced damage The potential adverse effects of exposures to radioactivity from nuclear accidents can include acute consequences such as radiation sickness, as well as long-term sequelae such as increased risk of cancer. There have been a few studies examining transgenerational risks of radiation exposure but the results have been inconclusive. Morton et al. analyzed papillary thyroid tumors, normal thyroid tissue, and blood from hundreds of survivors of the Chernobyl nuclear accident and compared them against those of unexposed patients. The findings offer insight into the process of radiation-induced carcinogenesis and characteristic patterns of DNA damage associated with environmental radiation exposure. In a separate study, Yeager et al. analyzed the genomes of 130 children and parents from families in which one or both parents had experienced gonadal radiation exposure related to the Chernobyl accident and the children were conceived between 1987 and 2002. Reassuringly, the authors did not find an increase in new germline mutations in this population. Science , this issue p. eabg2538 , p. 725

Transitioning into the university environment can be both exciting and stressful for new and returning students alike. The pressure to perform well academically in an increasingly competitive environment, coupled with a vast array of lifestyle changes, can contribute to suboptimal wellbeing. Over recent years, uptake to wellbeing services within universities in the United Kingdom has grown given the concurrent rise in mental health difficulties reported. Higher education students now have to contend with a drastically altered learning landscape, owing to the discovery of novel coronavirus, Sars-Cov-2, otherwise referred to as COVID-19. In the United Kingdom, universities have moved to close their campuses to both students and non-essential staff in an effort to protect them from contracting the virus. The repercussions of these decisions have been monumental for the delivery of teaching, relationships and, importantly, the provision of student services. Ambiguity remains as to how teaching will be delivered for the forthcoming academic year. The uncertainty caused by the pandemic has yet to be considered in terms of student wellbeing and the new, mostly online, environments that students will be expected to navigate without their typical support networks. For the purpose of this paper, the concept of student wellbeing, a population level term concerned with positive emotions rather than diagnosed mental health conditions, will be considered in relation to the COVID-19 outbreak. The current paper performs a conceptual analysis on student wellbeing in United Kingdom universities with a specific lens on the psychosocial impact of the global COVID-19 outbreak. Given the unprecedented world that students now learn in, considering the impact of the pandemic on psychosocial outcomes delineates the novel challenges that researchers and practitioners must consider when implementing student wellbeing initiatives moving forward.

In the UK, there exists an important “action gap” between Government advice on measures necessary to counter the threat of COVID-19, and the behavior of a significant minority of the population. There are several reasons for this disconnect, including lack of message potency (i.e., credibility and congruence), inflexible/habitual behavior patterns, prevailing beliefs (i.e., vulnerability to, and seriousness of COVID-19), and individuals valuing personal concerns above general public health. For official messages to be effective and advice adhered to, strong, coherent “strategic narratives” are required. This article, using a psychological perspective, critically examined prevailing COVID-19 UK Government announcements during the lockdown (23/03/2020) and initial easing phase (10/05/2020). Specifically, it focused on important communication inconsistencies, and identified factors that may facilitate and create barriers to the adoption of essential public health directives. This included deliberation of factors that enhanced source impact, diminished the influence of message content, and the negative consequences of contrary information. Accordingly, this article proposes a framework for providing a unifying strategic narrative on COVID-19, one that helps to maximize the impact of key messages and promote effective behavior change. This framework places an emphasis on engaging the full range of actors and considers ways of reducing the efficacy of false information. The article provides recommendations that will potentially improve the reception of government policy and suggests how strategic narratives can harness the drivers of behavioral change needed to meet challenges such as COVID-19.

Background Dyskeratosis congenita (DC) is a rare genetic disorder of bone marrow failure inherited in an X-linked, autosomal dominant or autosomal recessive pattern. It has a wide array of clinical features and patients may be cared for by many medical sub specialties. The typical clinical features consist of lacy reticular skin pigmentation, nail dystrophy and oral leukoplakia. As the disease advances, patients may develop progressive bone marrow failure, pulmonary fibrosis, oesophageal stenosis, urethral stenosis, liver cirrhosis as well as haematological and solid malignancies. Several genes have been implicated in the pathogenesis of dyskeratosis congenita, with the dyskerin pseudouridine synthase 1 (DKC1) gene mutations being the X-linked recessive gene. Case presentation Herein, we report a 31-year-old male with history of recurrent febrile episodes who was found to have reticulate skin pigmentation interspersed with hypopigmented macules involving the face, neck and extremities, hyperkeratosis of palms and soles, nail dystrophy, leukoplakia of the tongue, premature graying of hair, watery eyes and dental caries. Several of his male relatives, including two maternal uncles and three maternal cousins were affected with a similar type of disease condition. Pedigree analysis suggested a possible X-linked pattern of inheritance. Genetic testing in the proband showed a novel hemizygous, non-synonymous likely pathogenic variant [NM_001363.4: c.1054A > G: p.Thr352Ala] in the PUA domain of the DKC1 gene. Quantitative polymerase chain reaction for relative telomere length measurements performed in the proband showed that he had very short telomeres [0.38, compared to a control median of 0.71 (range 0.44–1.19)], which is consistent with the DC diagnosis. Co-segregation analysis of the novel mutation and telomere length measurements in the extended family members could not be performed as they were unwilling to provide consent for testing. Conclusions The novel variant detected in the DKC1 gene adds further to the existing scientific literature on the genotype-phenotype correlation of DC, and has important implications for the clinical and molecular characterization of the disease.

Background: It is important to identify inherited bone marrow failure syndromes (IBMFS) in patients with aplastic anemia in order to provide appropriate therapy. IBMFS are diagnosed through genetic or other diagnostic testing but can also go unrecognized, particularly in adults who may lack classic IBMFS features. This is particularly critical in light of increasing identification of individuals with variants of uncertain significance (VUS) and those with single pathogenic variants in an autosomal recessive (AR) gene or X-linked recessive (XLR) gene in females (SPVR) ("carriers") during evaluation. In this study of patients diagnosed with acquired severe aplastic anemia (SAA), we evaluated putatively causal variants in IBMFS genes to determine the frequency of patients with an unrecognized IBMFS or SPVR and assessed their association with outcomes after hematopoietic cell transplant (HCT). Methods: We used pre-HCT blood samples and clinical data from the Transplant Outcomes in Aplastic Anemia study (TOAA; a collaboration between the National Cancer Institute and the Center for International Blood and Marrow Transplant Research). Germline whole exome sequencing was performed on 732 patients with acquired SAA who received HCT between 1991-2015. A total of 104 IBMFS genes, (51 autosomal dominant (AD), 46 AR, 3 both AR and AD, 4 XLR) were evaluated for both single nucleotide (SNV) and copy number variants (CNV). All variants were curated using ACMG/AMP criteria, and a subset were validated by Sanger sequencing. Variants classified as VUS according to ACMG/AMP criteria and with a damaging score prediction in 3 of 5 in silico meta-predictors were categorized as deleterious VUS. Patients were divided into 3 groups based on known inheritance patterns of identified genes into those with 1) unrecognized IBMFS 2) SPVR or 3) neither (presumed acquired SAA). For telomere biology genes with AD/AR inheritance, we used telomeres Results: We identified 309 variants of them 156 were pathogenic or likely pathogenic (P/LP) (112 (71.8%) loss of function SNVs, and 10 CNVs), and 153 were deleterious VUS. Patients with deleterious VUS did not have different survival compared with those with no variants, and these were not considered for designating unrecognized IBMFS and SPVR cases Our analysis showed that 6.7% (N=49/732) of patients had variants consistent with an unrecognized IBMFS; 22 were AR (21 compound heterozygous, 1 homozygous), 26 AD and 1 XLR. Approximately half of those patients (22/49, 45%) had P/LP variants in hematopoiesis genes, and 31% in telomere biology genes (Figure 1A). We identified 79 patients with an SPVR, most in SBDS and FANCM. Patients with an unrecognized IBMFS had worse overall survival when compared with patients with presumed acquired SAA (log-rank p=0.0098) (Figure 1B). Multivariable analysis confirmed this association (HR=2.11, 95% confidence interval (CI)=1.38-3.22, p=0.001). The observed survival difference was not mitigated by lower conditioning regimen intensity (HR=2.1, p=0.01 in myeloablative condition (MAC), and HR=2.3, p=0.016, in reduced intensity regimens (RIC)). Patients with an SPVR had no post-HCT survival difference than presumed acquired SAA regardless of conditioning regimen (overall HR=0.96, p=0.85; MAC HR=1.4, p=0.27; RIC HR=0.3, p=0.1). Conclusions: A sizable subset of patients (6.7%) with reported immune mediated acquired SAA had unrecognized inherited disorder and 33% were adults at HCT. Unrecognized IBMFS was associated with statistically significant poorer survival after HCT. In contrast, post-HCT survival in patients with an SPVR ("carriers") was not different than those with acquired SAA. This work underscores the importance of identifying SAA patients with clinically meaningful underlying inherited disorders to enable the use therapeutic approaches to minimize regimen toxicity and late complications. It further highlights that identification of a single pathogenic variant in an autosomal recessive gene or X-linked gene in females and VUS are associated with post-HCT survival similar to acquired SAA. Figure 1 Figure 1. Disclosures Paczesny: Medical University of South Carolina: Patents & Royalties: inventor on the ST2 bispecific antibody patent application. Lee: Kadmon: Research Funding; National Marrow Donor Program: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; JANSSEN: Other; AstraZeneca: Research Funding; Takeda: Research Funding; Novartis: Other: clinical trials, Research Funding; Syndax: Research Funding; Pfizer: Research Funding; Incyte: Research Funding.

Student engagement is an important predictor of success, retention and perseverance in higher education. This study used structural equation modelling to evaluate a gain cycle of future time perspective (FTP), positive emotion and student engagement derived from the broaden-andbuild theory (BBT). A second objective was to examine changes within study variables over time. Participants were 217 UK undergraduates sampled at two time points. Mean levels of\ud positive emotion and engagement decreased over time, whereas FTP increased. At both time points, FTP predicted higher engagement, and engagement predicted greater positive emotion levels. Positive emotion at Time 1 predicted increased levels of FTP, engagement and positive\ud emotion at Time 2. This was consistent with the ‘build’ hypothesis of BBT suggesting that positive emotions facilitate approach behaviour and the development of psychological resources. Findings indicate that interventions designed to enhance FTP and positive emotion\ud can facilitate student engagement and retention in higher education.

Positive behavioral support (PBS) employs applied behavioral analysis to enhance the quality of life of people who behave in challenging ways. PBS builds on the straightforward and intuitively appealing notion that if people know how to control their environments, they will have less need to behave in challenging ways. Accordingly, PBS focuses on the perspective of those who have behavioral issues, and assesses success via reduction in incidences of challenging behaviors. The qualitative research presented in this report approaches PBS from a different viewpoint and, using thematic analysis, considers the impact of PBS training on the lived experience of staff who deliver services. Thirteen support staff who work for a company supplying social care and supported living services for people with learning disabilities and complex needs in the northwest of England took part. Analysis of interviews identified five major themes. These were: (1) training: enjoyable and useful; (2) widening of perspective: different ways of thinking; (3) increased competence: better outcomes; (4) spill over into private lives: increased tolerance in relationships; and (5) reflecting on practice and moving to a holistic view: “I am aware that people…are not just being naughty.” These themes evidenced personal growth on the part of service providers receiving training. Explicitly, they demonstrated that greater awareness of PBS equipped recipients with an appropriate set of values, and the technical knowledge required to realize them.

Purpose Prolonged sitting is a major health concern, targeted via government policy and the proliferation of height-adjustable workstations and wearable technologies to encourage standing. Such interventions have the potential to influence energy balance and thus facilitate effective management of body/fat mass. It is therefore remarkable that the energy cost of sitting versus standing naturally remains unknown. Methods Metabolic requirements were quantified via indirect calorimetry from expired gases in 46 healthy men and women (age, 27 ± 12 yr; mass, 79.3 ± 14.7 kg; body mass index, 24.7 ± 3.1 kg·m -2, waist/hip, 0.81 ± 0.06) under basal conditions (i.e., resting metabolic rate) and then, in a randomized and counterbalanced sequence, during lying, sitting and standing. Critically, no restrictions were placed on natural/spontaneous bodily movements (i.e., fidgeting) to reveal the fundamental contrast between sitting and standing in situ while maintaining a comfortable posture. Results The mean (95% confidence interval [CI]) increment in energy expenditure was 0.18 (95% CI, 0.06-0.31 kJ·min -1) from resting metabolic rate to lying was 0.15 (95% CI, 0.03-0.27 kJ·min -1) from lying to sitting and 0.65 (95% CI, 0.53-0.77 kJ·min -1) from sitting to standing. An ancillary observation was that the energy cost of each posture above basal metabolic requirements exhibited marked interindividual variance, which was inversely correlated with resting heart rate for all postures (r = -0.5; -0.7 to -0.1) and positively correlated with self-reported physical activity levels for lying (r = 0.4; 0.1 to 0.7) and standing (r = 0.6; 0.3-0.8). Conclusions Interventions designed to reduce sitting typically encourage 30 to 120 min·d -1 more standing in situ (rather than perambulation), so the 12% difference from sitting to standing reported here does not represent an effective strategy for the treatment of obesity (i.e., weight loss) but could potentially attenuate any continued escalation of the ongoing obesity epidemic at a population level.

Telomeres are essential for chromosomal stability and markers of biological age. We evaluated the effect of pre-transplant short (10th percentile-for-age) or very short (5th or1st percentile-for-age) leucocyte telomere length on survival after unrelated donor haematopoietic cell transplantation (HCT) for acquired severe aplastic anaemia (SAA). Patient pre-transplant blood samples and clinical data were available at the Center for International Blood and Marrow Transplant Research. We used quantitative real time polymerase chain reaction to measure relative telomere length (RTL) in 490 SAA patients who received HCT between 1990 and 2013 (median age = 20 years). One hundred and twelve patients (22·86%) had pre-HCT RTL10th percentile-for-age, with the majority below the 5th percentile (N = 80, 71·43%). RTL10th percentile-for-age was associated with a higher risk of post-HCT mortality (hazard ratio [HR] = 1·78, 95% confidence interval [CI]=1·18-2·69, P = 0·006) compared with RTL ≥50th percentile; no survival differences were noted in longer RTL categories (P 0·10). Time-dependent effects for post-HCT mortality were only observed in relation to very short RTL; HR comparing RTL5th versus ≥5th percentile = 1·38, P = 0·15 for the first 12 months after HCT, and HR = 3·91, P 0·0001, thereafter, P-heterogeneity = 0·008; the corresponding HRs for RTL1st versus ≥1st percentile = 1·29, P = 0·41, and HR = 5·18, P 0·0001, P-heterogeneity = 0·005. The study suggests a potential role for telomere length in risk stratification of SAA patients in regard to their HCT survival.

The 1986 Chernobyl nuclear power plant accident increased papillary thyroid cancer (PTC) incidence in surrounding regions, particularly for 131I-exposed children. To investigate the contribution of environmental radiation to PTC characteristics and improve understanding of radiation-induced carcinogenesis, we analyzed genomic, transcriptomic, and epigenomic characteristics of 440 pathologically-confirmed fresh-frozen PTCs from Ukraine (359 with estimated childhood or in utero 131I exposure and 81 from unexposed children born after March 1987) and matched normal tissue (non-tumor thyroid tissue and/or blood). Mean age at PTC was 28.0 years (range: 10.0-45.6). Among 131I-exposed individuals, mean radiation dose was 250 mGy (range: 11.0-8,800). In multivariable models adjusted for age at PTC and sex, we observed radiation dose-dependent enrichment of fusion drivers (P=6.6 × 10−8), nearly all occurring in the MAPK pathway, as well as increases in small deletions (P=8.0 × 10−9) and simple/balanced structural variants (P=1.2 × 10−14). Further analyses demonstrated even stronger associations for those small deletions and simple/balanced structural variants that were clonal and bore hallmarks of non-homologous end-joining repair (deletions: P=4.9 × 10−31; simple/balanced structural variants: P=5.5 × 10−19). In contrast, radiation dose was not associated with subclonal small deletions (P=0.82) or subclonal simple/balanced structural variants (P=0.91). Additionally, radiation dose was not associated with TINS (locally templated insertions), which are characteristic of alt-end-joining repair (P=0.69). The effects of radiation on genomic alterations with more pronounced for those younger at exposure. Analyses generally were consistent with a linear radiation dose-response for all molecular characteristics except clonal small deletions. Analyses of transcriptomic and epigenomic features demonstrated strong associations with the PTC driver gene but not radiation dose. Our results point to DNA double-strand breaks as early carcinogenic events that subsequently enable PTC growth following environmental radiation exposure. Citation Format: Lindsay M. Morton, Danielle Karyadi, Chip Stewart, Tetiana Bogdanova, Eric Dawson, Mia Steinberg, Jieqiong Dai, Stephen Hartley, Sara Schonfeld, Joshua Sampson, Yosi Maruvka, Vidushi Kapoor, Dale Ramsden, Juan Carvajal-Garcia, Chuck Perou, Joel Parker, Marko Krznaric, Meredith Yeager, Joseph Boland, Amy Hutchinson, Belynda Hicks, Casey Dagnall, Julie Gastier-Foster, Jay Bowen, Olivia Lee, Mitchell Machiela, Elizabeth Cahoon, Alina Brenner, Kiyohiko Mabuchi, Vladimir Drozdovitch, Sergii Masiuk, Mykola Chepurny, Liudmyla Yu Zurnadzhy, Maureen Hatch, Amy Berrington de Gonzalez, Gerry Thomas, Mykola Tronko, Gad Getz, Stephen Chanock. Molecular characterization of papillary thyroid cancer in relation to ionizing radiation dose following the Chernobyl accident [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr PO-055.

Myotonic dystrophy type I (DM1) is an autosomal dominant disease of which clinical manifestations resemble premature aging. We evaluated the contribution of telomere length in pathogenesis in 361 DM1 patients (12 with serial measurements) and 223 unaffected relative controls using qPCR assay. While no differences in baseline leukocyte relative telomere length (RTL) was noted, the data suggested an accelerated RTL attrition in DM1 (discovery cohort: T/S change/year = -0.013 in DM1 vs. -0.005 in controls, P = 0.04); similar trend was noted in validation cohort. Further investigations are needed to examine the role of TL in the pathophysiology of DM1. The study was supported by the Intramural Research Program of the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health.

Background: The oral microbiota may be associated with lung cancer risk through direct mechanisms, including infection, immune responses, and periodontal disease, and through indirect mechanisms such as the modification of the oral microbiota by tobacco. We conducted a case-cohort study nested within three US prospective cohort studies to evaluate the association between oral microbiota ascertained years before a cancer diagnosis and risk of lung cancer. Methods: Incident lung cancer cases within the Agricultural Health Study (AHS; N=244), NIH-AARP Diet and Health Study (N=376), and the Prostate, Lung, Colorectum, and Ovarian Cancer Screening Trial (PLCO; N=700) who provided an oral wash sample were identified. The median time between oral sample collection and diagnosis was approximately 6.6 years, 3.4 years, and 4.5 years for AHS, NIH-AARP, and PLCO, respectively. A referent subcohort was randomly selected by strata of age, sex, and cigarette smoking history. We extracted DNA using the DSP DNA Virus Pathogen kit, and the V4 region of the 16S rRNA gene was PCR amplified and sequenced using the MiSeq. The sequencing data were processed using QIIME2 with the DADA2 plugin and we generated alpha and beta diversity metrics. Cox proportional hazards models were used to evaluate the hazard ratios (HR) and 95% confidence intervals (CI) for the association between the oral microbial measures and the risk of lung cancer with adjustment for known lung cancer risk factors, and estimates from the three cohorts were meta-analyzed. Results: Increased alpha diversity was associated with decreased lung cancer risk, although only the association with the Shannon Index reached statistical significance (HR for 5th quintile versus 1st quintile 0.74; 95% CI 0.60, 0.92) with no evidence of between-study heterogeneity (p = 0.5968). Specific principal coordinate vectors from the beta diversity matrices were also significantly associated with lung cancer risk, suggesting differing bacterial communities between future lung cancer cases. When stratified by histologic subtypes, the inverse association with alpha diversity was restricted to squamous cell carcinoma, with all alpha diversity metrics reaching statistical significance (e.g., Faith’s phylogenetic diversity HR for 5th quintile versus 1st quintile 0.57; 95% CI: 0.37, 0.87). Similarly, when stratified by smoking history, the inverse association with alpha diversity was restricted to former smokers (e.g., observed species HR for 5th quintile versus 1st quintile 0.63; 95% CI: 0.44, 0.89). Conclusions: In oral wash samples collected years before diagnosis, we found significant associations between both alpha and beta diversity metrics of the oral microbial communities and risk of lung cancer. Additional work is required to understand the associations by histologic subtype and smoking history. Citation Format: Emily Vogtmann, Xing Hua, Guoqin Yu, Autumn Hullings, Yunhu Wan, Casey L Dagnall, Kristine Jones, Belynda D. Hicks, Amy Hutchinson, Shalabh Suman, Bin Zhu, Barry Graubard, Mitchell H. Gail, J. Gregory Caporaso, William Wheeler, Dale Sandler, Laura E. Beane Freeman, Linda Liao, Neal D. Freedman, Neil Caporaso, Rashmi Sinha, Jianxin Shi, Christian C Abnet. The human oral microbiota and risk of lung cancer: An analysis of three prospective cohort studies [abstract]. In: Proceedings of the AACR Special Conference on the Microbiome, Viruses, and Cancer; 2020 Feb 21-24; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2020;80(8 Suppl):Abstract nr A39.

Background: Given the inverse relationship described previously between telomere content and thyroid subsequent malignant neoplasm (thyroid SMN) in survivors of childhood cancer, we investigated the relationship between known genetic determinants of leukocyte telomere length (LTL) and thyroid SMN among survivors. Methods: Leveraging data from a large, genotyped survivor cohort, the Childhood Cancer Survivor Study, we used a well-described genetic risk score method to estimate the HR for thyroid SMN among 5,324 genotyped survivors. Results: We identified 118 survivors with thyroid SMN and 5,206 without thyroid SMN. No association between genetically estimated LTL and risk for thyroid SMN was identified. Conclusions: Our results suggest that variation in common SNPs influencing LTL is not strongly associated with risk for thyroid SMN in survivors of childhood cancer. Impact: The previously observed inverse relationship between LTL and thyroid SMN risk in survivors of childhood cancer may be related to alternative molecular mechanisms and warrants further study.

Recent studies suggest improved survival in patients with severe aplastic anemia receiving hematopoietic cell transplant (HCT) from unrelated donors with longer telomeres. Here, we tested whether this effect is generalizable to patients with acute leukemia. From the Center for International Blood and Marrow Transplant Research (CIBMTR®) database, we identified 1097 patients who received 8/8 HLA-matched unrelated HCT for acute myeloid leukemia (AML) or acute lymphocytic leukemia (ALL) between 2004 and 2012 with myeloablative conditioning, and had pre-HCT blood sample from the donor in CIBMTR repository. The median age at HCT for recipients was 40 years (range ≤1-68), and 32 years for donors (range = 18-61). We used qPCR for relative telomere length (RTL) measurement, and Cox proportional hazard models for statistical analyses. In a discovery cohort of 300 patients, longer donor RTL (>25th percentile) was associated with reduced risks of relapse (HR = 0.62, p = 0.05) and acute graft-versus-host disease II-IV (HR = 0.68, p = 0.05), and possibly with a higher probability of neutrophil engraftment (HR = 1.3, p = 0.06). However, these results did not replicate in two validation cohorts of 297 and 488 recipients. There was one exception; a higher probability of neutrophil engraftment was observed in one validation cohort (HR = 1.24, p = 0.05). In a combined analysis of the three cohorts, no statistically significant associations (all p > 0.1) were found between donor RTL and any outcomes.

OBJECTIVES Gender-related factors can influence management decisions, treatment outcomes and the overall long-term wellbeing of people living with HIV (PLWH). The Women Against Viruses in Europe (WAVE) Working Group was established to promote the health and wellbeing of women living with HIV (WLWH). WAVE is part of the European AIDS Clinical Society (EACS) and organizes annual workshops to discuss different issues in the management of WLWH. METHODS In 2016, 34 WAVE members including community representatives, HIV clinicians and researchers met to discuss standards of care for WLWH and to review current guidelines. Participants focused on three different themes: (1) access to and engagement and retention in care; (2) monitoring of women on antiretroviral therapy and management of comorbidities; and (3) review of EACS treatment guidelines. RESULTS Five priority areas for optimizing the care of WLWH were identified: (1) psychosocial aspects of HIV diagnosis and care; (2) mental health and wellbeing; (3) pharmacokinetics, toxicity and tolerability of antiretroviral therapy; (4) coinfections and comorbidities; and (5) sexual and reproductive health. WAVE recommendations are provided for each of these areas, and gaps in knowledge and needs for changes in currently existing standards are discussed. CONCLUSIONS This position statement provides an overview of the key recommendations to optimize the care of WLWH that emerged during the 2016 WAVE workshop.

10028 Background: Radiotherapy for childhood cancer is associated with strikingly elevated risk for developing subsequent neoplasms (SNs). Whether mutations in DNA repair and radiation sensitivity genes modulate SN risks is largely unknown. Methods: We conducted whole-exome sequencing in 5105 long-term childhood cancer survivors of European descent (mean follow-up = 32.7 years). SnpEff and ClinVar identified potentially damaging rare variants in 476 DNA repair or radiation sensitivity genes. Conditional logistic regression assessed SN risk associated with these variants aggregated by gene or pathway (N = 155 with ≥5 carriers). Controls were matched on sex, childhood cancer type and diagnosis age, radiation dose to the SN site, and survival. Exact p-values were calculated by permutation. Analyses used all survivors or subsets stratified on radiation dose. Results: A total of 1108 (21.7%) survivors developed at least one SN type known to be related to ionizing radiation exposure (e.g., breast cancer, basal cell carcinoma, meningioma, thyroid cancer, sarcoma). Radiation-related SN risk was associated with homologous recombination (HR) gene variants for SN sites that received > 0- < 10 Gy (20.9% cases, 11.0% controls; odds ratio [OR] = 2.20, 95% confidence interval [CI] 1.52-3.18; P = 1.41x10-4), most notably for FANCM (3.1% cases, 0.5% controls; OR = 9.91, 95%CI 3.73-26.4; P = 2.85x10-4). For radiation-related SNs at sites with higher doses (≥10 Gy), associations were not observed for the HR pathway (14.4% cases, 12.4% controls, P = 0.17) but were observed for two individual genes implicated in double-strand DNA break repair, EXO1 (1.8% cases, 0.4% controls; OR = 6.50, 95%CI 3.49-12.1; P = 7.43x10-4) and NEIL3 (0% cases, 1.0% controls; P = 3.23x10-4). Conclusions: In this discovery study, we identified dose-specific novel associations between SN risk after radiotherapy for childhood cancer and potentially damaging rare variants in genes involved in double-strand DNA break repair, particularly HR. If replicated, these results could impact long-term screening of childhood cancer survivors and risk-benefit assessments of treatment approaches.

Telomeres are essential for chromosomal stability and markers of biological age. We evaluated the effect of abnormal telomere biology on survival after unrelated donor hematopoietic cell transplant (HCT) for acquired severe aplastic anemia (SAA). Patient pre-transplant blood samples, and clinical and outcome data were available at the Center for International Blood and Marrow Transplant Research. We used qPCR to measure relative telomere length (RTL) and whole exome sequencing to identify patients with pathogenic (P) or likely pathogenic (LP) variants in telomere biology disorder (TBD) related genes. Cox proportional hazard models were used for survival analysis. The study included 490 SAA patients who received HCT between 1990 and 2013 at a median age of 20 years. Eighty patients (16.3%) had pre-HCT RTL 0.10 for all other categories). A similar high mortality risk was found in patients with P/LP TBD-related variants (HR=2.0, 95% CI=1.28-3.15, p=0.003). A time-dependent effect for post-HCT mortality was only observed in relation to RTL (HR for RTL

Some freeway and expressway interchanges contain an interior option lane in which traffic in that lane can choose to exit or remain on the route at the split. The 2009 Manual on Uniform Traffic Control Devices requires that either the Overhead Arrow per Lane or the diagrammatic guide sign designs be used for all multilane exits at major interchanges that have an optional exit lane that also carries the through route. However, some practitioners believe that it is cost-prohibitive and unnecessary to install Overhead Arrow per Lane guide signs at minor interchanges. Given the benefits of Overhead Arrow per Lane guide signs, a condensed version of an Overhead Arrow per Lane guide sign is needed for use where a full Overhead Arrow per Lane guide sign is not a reasonable option. A truncated version of the sign, which could be displayed on existing cantilever structures, would eliminate the expense of installing larger structures while still reaping the benefits of the Arrow per Lane sign concept. This study identified five signing alternatives for potential use at minor and intermediate interchanges with multilane exits and an option lane. Participants viewed videos of either Overhead Arrow per Lane guide signs or one of the four truncated alternatives. Participants were asked to indicate which lanes they could use to exit in some scenarios and which to use to proceed through in other scenarios. Participants typically understood the alternatives that provided information about both through and exiting traffic (80% comprehension), whereas alternatives that provided information about exiting traffic, with little to no information about through traffic, resulted in relatively low comprehension (38%).

Telomeres are tandem nucleotide repeats and a protein complex located at the end of the chromosomes maintaining genomic stability. Their potential as a predictive biomarker for outcomes after allogeneic hematopoietic cell transplant (HCT) in hematologic malignancies is still unclear. From the Center for International Blood and Marrow Transplant Research we randomly selected 536 acute leukemia patients from those who underwent myeloablative 8/8 HLA-matched unrelated donor HCT between 2005 and 2012 and who had an available pre-HCT blood sample in the repository. Relative telomere length (RTL) was measured by real-time quantitative PCR. We used Kaplan-Meier and competing risk estimators to calculate survival probability and cumulative incidence, respectively, across patient RTL tertiles. Cox proportional hazard regression was used for adjusted analyses. The study included 396 acute myeloid leukemia (AML) and 140 acute lymphoblastic leukemia (ALL) patients. Median age at HCT was 41 years (range, .5 to 66), and median follow-up for survivors was 5.1 years (range, .4 to 8.3). Significant inverse correlations between age and RTL were observed in patients with AML (r = -.44, P .0001) and ALL (r = -.48, P .0001). Patients with ALL had longer RTL than those with AML (.48 versus .43, respectively); the difference was not statistically significant after adjusting for patient age (P = .96). Pre-HCT RTL in acute leukemia patients was not statistically significantly associated with overall survival (HR for longest RTL compared with shortest, .91; 95% CI, .65 to 1.28), disease-free survival (HR, .90; 95% CI, .64 to 1.25), transplant-related mortality (HR, .97; 95% CI, .60 to 1.59), incidence of relapse (HR, .89; 95% CI, .56 to 1.40), neutrophil engraftment (HR, 1.06; 95% CI, .85 to 1.32), or grades II to IV acute graft-versus-host disease (HR, 1.11; 95% CI, .81 to 1.53), grades III-IV acute graft-versus-host disease (HR, .92; 95% CI, .54 to 1.59), and chronic graft-versus-host disease (HR, 1.10; 95% CI, .81 to 1.50). In this study, recipient pre-HCT RTL had no prognostic role in post-transplant outcomes in acute leukemia patients.

Specific service signs provide motorists with business identification information along freeway approaches to interchanges. The Manual on Uniform Traffic Control Devices limits the number of these signs along an interchange approach to four and the number of logo panels per sign to six, although there are continuing requests to increase the number of panels allowed per sign. The present research evaluated specific service signs with four, six, or nine panels per sign and with all logo-based panels or all text-based panels. Participants were asked to determine whether a particular business was present on a sign. Mean reaction times indicated that for nine-panel signs, younger drivers took approximately 2.2 s to determine correctly the presence of a business, while older drivers took approximately 2.9 s. In considering drivers of all ages, an increase from six to nine panels brings mean reaction times from 1.8 s to 2.5 s for text signs and from 1.9 s to 2.5 s for logo signs. In a second task, participants were given 2 s to view each sign before reporting the businesses present on the sign. Participants reported three to four businesses on average, regardless of the number of panels on the sign. Considering the generally accepted standard that eye glances away from the forward roadway for greater than 2 s are unsafe, the study concluded that the benefit of providing more service information is presumably not great enough to outweigh the risk of information overload and driver distraction.

Background Childhood cancer survivors treated with chest-directed radiotherapy have substantially elevated risk for developing breast cancer. Although genetic susceptibility to breast cancer in the general population is well studied, large-scale evaluation of breast cancer susceptibility after chest-directed radiotherapy for childhood cancer is lacking. Methods We conducted a genome-wide association study of breast cancer in female survivors of childhood cancer, pooling two cohorts with detailed treatment data and systematic, long-term follow-up: the Childhood Cancer Survivor Study and St. Jude Lifetime Cohort. The study population comprised 207 survivors who developed breast cancer and 2774 who had not developed any subsequent neoplasm as of last follow-up. Genotyping and subsequent imputation yielded 16 958 466 high-quality variants for analysis. We tested associations in the overall population and in subgroups stratified by receipt of lower than 10 and 10 or higher gray breast radiation exposure. We report P values and pooled per-allele risk estimates from Cox proportional hazards regression models. All statistical tests were two-sided. Results Among survivors who received 10 or higher gray breast radiation exposure, a locus on 1q41 was associated with subsequent breast cancer risk (rs4342822, nearest gene PROX1 , risk allele frequency in control subjects [RAF controls ] = 0.46, hazard ratio = 1.92, 95% confidence interval = 1.49 to 2.44, P = 7.09 × 10 -9 ). Two rare variants also showed potentially promising associations (breast radiation ≥10 gray: rs74949440, 11q23, TAGLN , RAF controls = 0.02, P = 5.84 × 10 -8

We previously showed an association between donor leukocyte relative telomere length (RTL) and post-hematopoietic cell transplantation (HCT) survival in patients with severe aplastic anemia (SAA) who received bone marrow grafts at ages

Introduction: There is a growing body of evidence within the healthcare community which suggests that developing feelings of compassion can have a profound impact on physical and psychological health. This is an important area of work, and initial research with non-professional groups has found that practicing compassion through a variety of experiential practices and meditations can lead to higher levels of compassion for others, sensitivity to suffering, motivation to help, and altruism. This study examines outcome measures following a three day introductory workshop on Compassionate Focused Therapy provided for healthcare providers and educators. The aim of the research was to explore whether the training would increase self-compassion and reduce self-criticism and self-persecution. Method: Twenty-eight participants consisting of three groups ‘nurses/midwives’, ‘counsellors/psychotherapists’ and ‘other healthcare providers’ completed the Self-Compassion Scale and Functions of Self-Criticising/Attacking Scale pre and post-training. Results: Results reveal an overall statistically significant increase in self-compassion and statistically significant reduction in self-critical judgement post-training. There was no statistically significant reduction in self-persecution or self-correction scores post-training. Discussion: Developing self-compassion and compassionately responding to our own ‘self-critic’ may lead the way forward in the development of more compassionate care amongst healthcare professionals. Practical Implications: Training people in compassion based exercises may bring changes in levels of self-compassion and self-critical judgement. The findings are exciting in that they suggest the potential benefits of training healthcare providers and educators in compassion focused practices.

As drivers continue to purchase electric vehicles, there is an increasing demand for electric vehicle charging stations and, consequently, signing for these stations. Previous research evaluated a sign which was recommended to the Manual on Uniform Traffic Control Devices (MUTCD) team for addition to the MUTCD; however there remained concerns that drivers’ perceptions of electric vehicle charging stations signs had not been adequately addressed. The present research focused on driver comprehension and perceived risk of electric shock in regard to two electric vehicle charging station signs. Members of the driving public completed a computer-based survey which consisted of open-ended questions, rating tasks, and ranking tasks. Drivers did not necessarily associate a risk of electric shock with electric vehicle charging stations. In fact, nearly 100 percent reported that they would feel comfortable using a public electric vehicle charging station. When asked specifically about the risk of electric shock, statistically significant differences in sign alternatives arose only in the risk of electric shock implied by the sign. Further, drivers perceived the risk of shock from using an electric vehicle charging station as lower than many commonly used items which contain an electric charge (e.g., toaster, hair dryer, and extension cord). Given that both alternatives were well comprehended, either sign is suitable for use.

This paper documents a research project that evaluated proposed new traffic signs to ensure that the signs were effective when human factors requirements were taken into consideration. The following sign messages were selected for symbol development and evaluation: combination horizontal alignment–advisory speed, congestion ahead, cross-street preferential lane warning, do not enter, do not pass, electric-vehicle charging station, fallen rocks, flagger ahead, low-shoulder warning, maximum width, no left turn ahead, railroad crossing on leg of roundabout, road narrows, survey crew, trolley crossing, uneven lanes, and winery. The team conducted 96 surveys to determine driver comprehension and legibility for each alternative sign design. The surveys were administered to the general driving public at the Turner–Fairbank Highway Research Center in McLean, Virginia. On the basis of driver input and the results of the comprehension and legibility testing, the research team provided recommendations on symbols that should be included in the next edition of the Manual on Uniform Traffic Control Devices.

Background: Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children and has one of the poorest survival rates among all pediatric cancers. The two major histologic subtypes of RMS are embryonal (eRMS) and alveolar (aRMS), which display differences in terms of age-incidence patterns and somatic mutations. Approximately 10% of RMS cases are associated with germline mutations in known cancer predisposition genes (e.g., TP53, NF1), but very little is known about the genetic susceptibility to the ~90% of RMS cases that are sporadic. We conducted the first multi-institutional genome-wide association study (GWAS) of RMS in 727 cases and 3,384 controls. Methods: Phase 1 of the GWAS included 421 RMS cases from Children's Oncology Group clinical trials, Texas Children's Hospital, and the Universidad de Navarra. Controls (n=2,763) were cancer-free individuals included in previous studies at the National Cancer Institute (NCI). Phase 2 included 306 cases from the Childhood Cancer Survivor Study and 621 independent controls from NCI. Genotypes were generated using the Illumina OmniExpress or the HumanOmni5Exome array and imputed based on the 1000 Genomes Project. Analyses were restricted to those of European (EUR) ancestry, and controls were matched to the cases based on principal components and genotype platform. Assuming an additive genetic model in SNPTEST, we used multivariable logistic regression models to estimate the odds ratio (OR), 95% confidence interval (CI), and P value for each variant on RMS overall and by two RMS subtypes: eRMS and aRMS. Results: After quality control filtering and assessment of population substructure, there were 555 combined EUR RMS cases and 1,561 controls, which included: 1) 278 cases and 1,112 controls in phase 1; and 2) 277 cases and 449 controls in phase 2. In the combined set, we identified a new locus at chromosome 11p15.2 that was strongly associated with an increased risk of aRMS and significant at the genome-wide level (OR=2.3, P=2.2x10-8). Results were consistent across studies: phase 1 OR=2.3, 95% CI 1.7-3.2; and phase 2 OR=2.3, 95% CI 1.2-4.5. The top variant, rs12785926, mapped to an intron in the PSMA1 (proteasome subunit alpha 1) gene. Based on data from GTEx, rs12785926 is significantly associated with RRAS2 expression across multiple tissues. RRAS2 is involved in cell proliferation and is somatically mutated in several tumors. When evaluating eRMS and RMS overall in the combined set, there were no variants significant at the genome-wide level. Conclusion: In the first GWAS of pediatric RMS, we identified a susceptibility locus associated with the more aggressive aRMS subtype that has a poorer prognosis. Additional replication analyses are underway using DNA obtained from archived newborn blood spots linked to population-based cancer registries, as well as other institutional cohorts. Further investigation will advance understanding of RMS etiology and biology. Citation Format: Philip J. Lupo, Libby Morimoto, Eric Karlins, Xiaorong Shao, Lindsay M. Morton, Michael E. Scheurer, Smita Bhatia, Leslie L. Robison, Gregory T. Armstrong, Simone Hettmer, Javed Khan, Stephen J. Chanock, Neal D. Freedman, Kathleen Wyatt, Belynda D. Hicks, Meredith Yeager, Casey L. Dagnall, Shengchao A. Li, Stephen X. Skapek, Douglas S. Hawkins, Catherine Metayer, Lisa Mirabello. A genome-wide scan identifies a new locus associated with pediatric rhabdomyosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2966.

SYNOPSIS In recent years there has been considerable interest in the performance of wind schemes; this article presents a definitive account of an analysis of the capacity factors for UK wind farms between 1998 and 2005 in relation to annual average wind speed.

There are nearly 450 operational nuclear fission reactors around the world, providing 16% of the world's electricity and cutting CO2 emissions by one billion tonnes a year. Britain's 23 operational reactors at 12 nuclear power stations provide over 20% of the country's electricity, though all but four will close within 10 years. This paper reviews the current state of the nuclear power industry and reports on the new generations of fission reactor design currently being researched and developed. It concludes that the future of electricity generation from nuclear fission in the UK lies in the deployment of an evolutionary ‘Generation III’ design to replace the current fleet of reactors, and for further research into revolutionary ‘Generation IV’ reactors.

Livestock farms produce manure, and this has a high potential for pollution. Alternative, environmentally acceptable disposal routes with potential financial benefits might lie in the development of biomass-to-energy schemes, which often provide fertiliser as a by-product. Two options are being seriously considered by industry in Europe: centralised anaerobic digestion (AD) and direct combustion. This paper outlines the use of resource mapping to assist in the siting of centralised AD schemes; similar techniques may also be used to site other types of biomass to energy schemes, including direct combustion of farm manures. The paper uses a study in the UK to show how resource mapping and analysis can be used to identify sources of collectable farmyard manure in order to determine the potential for AD plants. With the forthcoming introduction of the European Commission (EC) Integrated Pollution Prevention and Control (IPPC) Directive, this could prove a valuable tool to highlight the priority areas where the potential for pollution could be a problem.

This paper presents the systematic characterization of the molecular beam epitaxy (MBE) process to quantitatively model the effects of process conditions on film qualities. A five-layer, undoped AlGaAs and InGaAs single quantum well structure grown on a GaAs substrate is designed and fabricated. Six input factors (time and temperature for oxide removal, substrate temperatures for AlGaAs and InGaAs layer growth, beam equivalent pressure of the As source and quantum well interrupt time) are examined by means of a fractional factorial experiment. Defect density, X-ray diffraction, and photoluminescence are characterized by a static response model developed by training back-propagation neural networks. In addition, two novel approaches for characterized reflection high-energy electron diffraction (RHEED) signals used in the real-time monitoring of MBE are developed. In the first technique, principal component analysis is used to reduce the dimensionality of the RHEED data set, and the reduced RHEED data set is used to train neural nets to model the process responses. A second technique uses neural nets to model RHEED intensity signals as time series, and matches specific RHEED patterns to ambient process conditions. In each case, the neural process models exhibit good agreement with experimental results.

We present for the first time a three-dimensional (3D) Si CMOS interconnection system consisting of three layers of optically interconnected hybrid integrated Si CMOS transceivers. The transceivers were fabricated using 0.8-/spl mu/m digital Si CMOS foundry circuits and were integrated with long wavelength InP-based emitters and detectors for through-Si vertical optical interconnections. The optical transmitter operated with a digital input and optical output with operation speeds up to 155 Mb/s. The optical receiver operated with an external optical input and a digital output up to 155 Mb/s. The transceivers were stacked to form 3D through-Si vertical optical interconnections and a fabricated three layer stack demonstrated optical interconnections between the three layers with operational speed of 1 Mb/s and bit-error rate of 10/sup -9/.

Compliant substrates allow a new approach to the growth of strained epitaxial layers, in which part of the strain is accommodated in the substrate. In this article, compliant substrates are discussed and a new compliant substrate technology based on bonded thin film substrates is introduced. This technology has several advantages over previously published methods, including the ability to pattern both the top and bottom of the material. A new concept enabled by this compliant substrate technology,strain-modulated epitaxy, will be introduced. Using this technique, the properties of the semiconductor material can be controlled laterally across a substrate. Results of two experiments are presented in which low composition InxGa1−xAs was grown by molecular beam epitaxy on GaAs compliant substrates at thicknesses both greater than and less than the conventional critical thickness. It was found that for t > tc, there was an inhibition of defect production in the epitaxial films grown on the compliant substrates as compared to those grown on conventional reference substrates. For t < tc, photoluminescence and x-ray diffraction show the compliant substrates to be of excellent quality and uniformity as compared to conventional substrates.

SYNOPSIS This paper is a follow-up to “Compiling Renewable Energy Statistics” which appeared in Volume 13 of this journal. The paper argued the need for a project aimed at compiling information on renewable energy schemes running throughout the UK, and went on to describe the Renewable Energy STATisticS (RESTATS) database which was being developed and managed by ETSU. Since the project began, data are now collected from a variety of sources, including other databases and updated annually for publication in the Digest of UK Energy Statistics (DUKES). Future plans for RESTATS involve incorporating the database into a single system being set up to consolidate all renewable energy data held by ETSU; in addition, opportunities for using Geographic Information Systems (GIs) to assist in surveys and promoting results are being investigated. RESTATS is arguably the most reliable means by which the success of the UK renewables programme can be both measured and monitored.

Introduction. A recent study showed that receiving a hematopoietic cell transplant (HCT) from donors with long leukocyte relative telomere length (RTL) was associated with improved survival in patients with severe aplastic anemia who primarily received bone marrow grafts at age Methods. From the Center for International Blood and Marrow Transplant Research (CIBMTR®) database, we identified 1,097 patients who received unrelated HCT for acute myeloid leukemia (AML) or acute lymphocytic leukemia (ALL) and fulfilled the following criteria: 1) HCT between 2004 and 2012, 2) available pre-HCT blood sample for the donor, 3) 8/8 HLA matching, and 3) myeloablative conditioning. We used qPCR to measure RTL; 1084 samples completed testing (597 measured at Telomere Diagnostics, Inc. and 487 at the Cancer Genomics Research Laboratory, NCI). Telomere Diagnostics samples were randomly divided into discovery (n=300) and validation (n=297) cohorts; the NCI samples served as a 2nd validation cohort (N=500). Cox proportional hazard models were used for statistical analyses. All analyses were adjusted for donor age together with clinical factors that met statistical inclusion criteria in a multivariate model. Donor RTL was categorized into short (≤25th percentile based on cohort-specific distribution), or long otherwise. Follow-up ended in November 2014. Results. All patient demographics, disease- and HCT-related characteristics were similar in the discovery, 1st, and 2nd validation cohorts with the exception of graft source (peripheral blood stem cells in 67%, 60%, and 70%, respectively, p=0.008), and year of HCT (0%, 0%, and 37% between 2008-2012, respectively, p0.3) were found between donor telomere length and any outcomes. Conclusions. Donor telomere length is not associated with outcomes in unrelated donor HCT for patients with acute leukemia. Table. Impact of donor RTL comparing the three longest quartiles to the shortest quartile. Table. Impact of donor RTL comparing the three longest quartiles to the shortest quartile. Disclosures Loftus: Telomere Diagnostics, Inc.: Consultancy. Friedman:Telomere Diagnostics, Inc.: Consultancy. Buturovic:Clinical Persona: Consultancy. Blauwkamp:Telomere Diagnostics, Inc.: Employment. Shelton:Telomere Diagnostics, Inc.: Employment.

Background Telomere shortening is an important molecular event in hepatocellular carcinoma (HCC) initiation; however, its role in HCC progression and prognosis is less clear. Our study aimed to examine the association of telomere length with survival of patients with HCC. Methods We measured telomere length in tumor and adjacent non-tumor tissues from 126 persons with HCC in the United States (U.S.) who were followed for mortality outcomes. Relative telomere length (RTL) was measured by a monochrome multiplex quantitative polymerase chain reaction assay. Multivariable Cox proportional hazards modeling was used to calculate hazard ratios (HRs) and 95% CIs for the association between telomere length and all-cause mortality. We also examined associations between telomere length and patient characteristics using multiple linear regression. Results During a mean follow-up of 6.0 years, 79 deaths occurred among 114 individuals for whom survival data were available. The ratio of RTL in tumor relative to non-tumor tissue was greater for individuals with regional or distant stage tumors (0.97) than localized stage tumors (0.77), and for individuals with grade III or IV tumors (0.95) than grade II (0.88) or grade I (0.67) tumors. An RTL ratio ≥1 was not associated with survival (HR 0.92, 95% CI 0.55, 1.55) compared to a ratio

Background: Telomeres play an important role in the maintenance of chromosomal stability. It has been previously reported that telomere length is shortened in hepatocellular carcinoma (HCC) compared to paired non-tumor tissue. However, most studies have been conducted in high-risk regions such as Asia. To date, no prior study has examined telomere length and HCC in the United States, a low risk region where HCC etiology may differ from that of high risk regions. Methods: We measured telomere length in 127 paired tumor and non-tumor tissue samples from persons with HCC in Iowa, Hawaii and Connecticut. Formalin-fixed, paraffin-embedded tissues were collected at the time of diagnosis. Relative telomere length was measured by a monochrome multiplex quantitative PCR assay. The Wilcoxon signed-rank test was used to compare telomere length between tumor and paired non-tumor tissues. Cox proportional hazards modeling was used to estimate the association between telomere length and mortality, adjusting for age at diagnosis, sex, and tumor stage and size at diagnosis. Results: Of the 127 pairs of samples, telomere length was shorter in the tumor in 88 pairs (69%), longer in the tumor in 33 pairs (26%) and the same length in the tumor and non-tumor tissue in 6 pairs (5%). Overall, the HCC tissues had statistically significantly shorter telomere length than their matched non-tumor tissues (p < 0.01). The proportion of pairs in which the tumor telomere was shorter than non-tumor was higher among those with localized stage tumors (81%) compared to those with regional or distant stage tumors (50%) (p < 0.01 after adjusting for age at diagnosis, sex, and source of the case). In addition, we observed a 119% higher risk of mortality (adjusted relative risk 2.19) among persons whose tumors had shorter telomeres than their non-tumor tissue, compared to persons whose tumors had longer telomeres; however, the confidence interval was relatively wide (0.94-5.12). Conclusion: Using tissue samples from persons with HCC in the United States, we found that telomere length was shorter in tumor tissue compared to paired non-tumor tissue, especially among localized stage tumors. In addition, there was a suggestion that tumor telomere shortening might be associated with higher risk of mortality. Together, these results may provide insight into the role of biological mechanisms associated with telomere shortening and into the prognosis of HCC in lower risk populations. Citation Format: Baiyu Yang, Fatma M. Shebl, Lawrence R. Sternberg, Andrew C. Warner, David E. Kleiner, Daniel C. Edelman, Allison Gomez, Casey L. Dagnall, Belynda D. Hicks, Sean F. Altekruse, Brenda Y. Hernandez, Charles F. Lynch, Paul S. Meltzer, Katherine A. McGlynn. Shortened telomere length in hepatocellular carcinoma in the United States. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 818.