Risk of Cerebrovascular Events in 178 962 Five-Year Survivors of Cancer Diagnosed at 15 to 39 Years of Age: The TYACSS (Teenage and Young Adult Cancer Survivor Study)

Background: Survivors of teenage and young adult (TYA) cancer are at risk of cerebrovascular events, but the magnitude of and extent to which this risk varies by cancer type, decade of diagnosis, age at diagnosis and attained age remains uncertain. This is the largest ever cohort study to evaluate the risks of hospitalisation for a cerebrovascular event among long-term survivors of TYA cancer. Methods:The population-based Teenage and Young Adult Cancer Survivor Study (N=178,962) was linked to Hospital Episode Statistics data for England to investigate the risks of hospitalisation for a cerebrovascular event among 5-year survivors of cancer diagnosed when aged 15-39 years. Observed numbers of first hospitalisations for cerebrovascular events were compared to that expected from the general population using standardised hospitalisation ratios (SHR) and absolute excess risks (AER) per 10,000 person-years. Cumulative incidence was calculated with death considered a competing risk. Results: Overall, 2,782 cancer survivors were hospitalised for a cerebrovascular event—40% higher than expected (SHR=1.4, 95% confidence interval [CI]=1.3-1.4). Survivors of central nervous system (CNS) tumours (SHR=4.6, CI=4.3-5.0), head & neck tumours (SHR=2.6, CI=2.2-3.1) and leukaemia (SHR=2.5, CI=1.9-3.1) were at greatest risk. Males had a significantly higher AER than females (AER=7 versus 3), especially among head & neck tumour survivors (AER=30 versus 11). By age 60, 9%, 6% and 5% of CNS tumour, head & neck tumour, and leukaemia survivors, respectively, had been hospitalised for a cerebrovascular event. Beyond age 60, every year 0.4% of CNS tumour survivors were hospitalised for a cerebral infarction (versus 0.1% expected. Whereas at any age, every year 0.2% of head & neck tumour survivors were hospitalised for a cerebral infarction 7 (versus 0.06% expected). Conclusions: Survivors of a CNS tumour, head & neck tumour, and leukaemia are particularly at risk of hospitalisation for a cerebrovascular event. The excess risk of cerebral infarction among CNS tumour survivors increases with attained age. For head & neck tumour survivors this excess risk remains high across all ages. These groups of survivors, and in particular males, should be considered for surveillance of cerebrovascular risk factors and potential pharmacological interventions for cerebral infarction prevention

Risk of subsequent primary neoplasms in survivors of adolescent and young adult cancer (Teenage and Young Adult Cancer Survivor Study): a population-based, cohort study.

Background Few studies have investigated the risks of subsequent primary neoplasms after adolescent and young adult (AYA) cancer. We investigated the risks of specific subsequent primary neoplasms after each of 16 types of AYA cancer. Methods The Teenage and Young Adult Cancer Survivor Study is a population-based cohort of 200 945 survivors of cancer diagnosed when aged 15–39 years in England and Wales from Jan 1, 1971, to Dec 31, 2006. The cohort was established using cancer registrations from the Office for National Statistics and the Welsh Cancer registry. Follow-up was from 5-year survival until the first occurrence of death, emigration, or study end date (Dec 31, 2012). In this analysis, we focus on the risk of specific subsequent primary neoplasms after 16 types of AYA cancer: breast; cervical; testicular; Hodgkin lymphoma (female); Hodgkin lymphoma (male); melanoma; CNS (intracranial); colorectal; non-Hodgkin lymphoma; thyroid; soft-tissue sarcoma; ovarian; bladder; other female genital; leukaemia; and head and neck cancer. We report absolute excess risks (AERs; per 10 000 person-years) and cumulative incidence of specific types of subsequent primary neoplasm after each type of AYA cancer. Findings During the 2 631 326 person-years of follow-up (median follow-up 16·8 years, IQR 10·5–25·2), 12 321 subsequent primary neoplasms were diagnosed in 11 565 survivors, most frequently among survivors of breast cancer, cervical cancer, testicular cancer, and Hodgkin lymphoma. AERs of any subsequent primary neoplasms were 19·5 per 10 000 person-years (95% CI 17·4–21·5) in survivors of breast cancer, 10·2 (8·0–12·4) in survivors of cervical cancer, 18·9 (16·6–21·1) in survivors of testicular cancer, 55·7 (50·4–61·1) in female survivors of Hodgkin lymphoma, and 29·9 (26·3–33·6) in male survivors of Hodgkin lymphoma. The cumulative incidence of all subsequent primary neoplasms 35 years after diagnosis was 11·9% (95% CI 11·3–12·6) in survivors of breast cancer, 15·8% (14·8–16·7) in survivors of cervical cancer, 20·2% (18·9–21·5) in survivors of testicular cancer, 26·6% (24·7–28·6) in female survivors of Hodgkin lymphoma, and 16·5% (15·2–18·0) in male survivors of Hodgkin lymphoma. In patients who had survived at least 30 years from diagnosis of cervical cancer, testicular cancer, Hodgkin lymphoma in women, breast cancer, and Hodgkin lymphoma in men, we identified a small number of specific subsequent primary neoplasms that account for 82%, 61%, 58%, 45%, and 41% of the total excess number of neoplasms, respectively. Lung cancer accounted for a notable proportion of the excess number of neoplasms across all AYA groups investigated. Interpretation Our finding that a small number of specific subsequent primary neoplasms account for a large percentage of the total excess number of neoplasms in long-term survivors of cervical, breast, and testicular cancer, and Hodgkin lymphoma provides an evidence base to inform priorities for clinical long-term follow-up. The prominence of lung cancer after each of these AYA cancers indicates the need for further work aimed at preventing and reducing the burden of this cancer in future survivors of AYA cancer. Funding Cancer Research UK, National Institute for Health Research, Academy of Medical Sciences, and Children with Cancer UK

Low pH immobilizes and kills human leukocytes and prevents transmission of cell-associated HIV in a mouse model

BACKGROUND: Both cell-associated and cell-free HIV virions are present in semen and cervical secretions of HIV-infected individuals. Thus, topical microbicides may need to inactivate both cell-associated and cell-free HIV to prevent sexual transmission of HIV/AIDS. To determine if the mild acidity of the healthy vagina and acid buffering microbicides would prevent transmission by HIV-infected leukocytes, we measured the effect of pH on leukocyte motility, viability and intracellular pH and tested the ability of an acidic buffering microbicide (BufferGel(®)) to prevent the transmission of cell-associated HIV in a HuPBL-SCID mouse model. METHODS: Human lymphocyte, monocyte, and macrophage motilities were measured as a function of time and pH using various acidifying agents. Lymphocyte and macrophage motilities were measured using video microscopy. Monocyte motility was measured using video microscopy and chemotactic chambers. Peripheral blood mononuclear cell (PBMC) viability and intracellular pH were determined as a function of time and pH using fluorescent dyes. HuPBL-SCID mice were pretreated with BufferGel, saline, or a control gel and challenged with HIV-1-infected human PBMCs. RESULTS: Progressive motility was completely abolished in all cell types between pH 5.5 and 6.0. Concomitantly, at and below pH 5.5, the intracellular pH of PBMCs dropped precipitously to match the extracellular medium and did not recover. After acidification with hydrochloric acid to pH 4.5 for 60 min, although completely immotile, 58% of PBMCs excluded ethidium homodimer-1 (dead-cell dye). In contrast, when acidified to this pH with BufferGel, a microbicide designed to maintain vaginal acidity in the presence of semen, only 4% excluded dye at 10 min and none excluded dye after 30 min. BufferGel significantly reduced transmission of HIV-1 in HuPBL-SCID mice (1 of 12 infected) compared to saline (12 of 12 infected) and a control gel (5 of 7 infected). CONCLUSION: These results suggest that physiologic or microbicide-induced acid immobilization and killing of infected white blood cells may be effective in preventing sexual transmission of cell-associated HIV

Cardiac Mortality Among 200 000 Five-Year Survivors of Cancer Diagnosed at 15 to 39 Years of Age: The Teenage and Young Adult Cancer Survivor Study

BACKGROUND: Survivors of teenage and young adult cancer are acknowledged as understudied. Little is known about their long-term adverse health risks, particularly of cardiac disease that is increased in other cancer populations where cardiotoxic treatments have been used. METHODS: The Teenage and Young Adult Cancer Survivor Study cohort comprises 200 945 5-year survivors of cancer diagnosed at 15 to 39 years of age in England and Wales from 1971 to 2006, and followed to 2014. Standardized mortality ratios, absolute excess risks, and cumulative risks were calculated. RESULTS: Two thousand sixteen survivors died of cardiac disease. For all cancers combined, the standardized mortality ratios for all cardiac diseases combined was greatest for individuals diagnosed at 15 to 19 years of age (4.2; 95% confidence interval, 3.4-5.2) decreasing to 1.2 (95% confidence interval, 1.1-1.3) for individuals aged 35 to 39 years (2P for trend <0.0001). Similar patterns were observed for both standardized mortality ratios and absolute excess risks for ischemic heart disease, valvular heart disease, and cardiomyopathy. Survivors of Hodgkin lymphoma, acute myeloid leukaemia, genitourinary cancers other than bladder cancer, non-Hodgkin lymphoma, lung cancer, leukaemia other than acute myeloid, central nervous system tumour, cervical cancer, and breast cancer experienced 3.8, 2.7, 2.0, 1.7, 1.7, 1.6, 1.4, 1.3 and 1.2 times the number of cardiac deaths expected from the general population, respectively. Among survivors of Hodgkin lymphoma aged over 60 years, almost 30% of the total excess number of deaths observed were due to heart disease. CONCLUSIONS: This study of over 200 000 cancer survivors shows that age at cancer diagnosis was critical in determining subsequent cardiac mortality risk. For the first time, risk estimates of cardiac death after each cancer diagnosed between the ages of 15 and 39 years have been derived from a large population-based cohort with prolonged follow-up. The evidence here provides an initial basis for developing evidence-based follow-up guidelines

Developmental effects on sleep–wake patterns in infants receiving a cow’s milk-based infant formula with an added prebiotic blend: A Randomized Controlled Trial

Background Few studies have evaluated nutritive effects of prebiotics on infant behavior state, physiology, or metabolic status. Methods In this double-blind randomized study, infants (n = 161) received cow’s milk-based infant formula (Control) or similar formula with an added prebiotic blend (polydextrose and galactooligosaccharides [PDX/GOS]) from 14–35 to 112 days of age. Infant wake behavior (crying/fussing, awake/content) and 24-h sleep–wake actograms were analyzed (Baseline, Days 70 and 112). Salivary cortisol was immunoassayed (Days 70 and 112). In a subset, exploratory stool 16S ribosomal RNA-sequencing was analyzed (Baseline, Day 112). Results One hundred and thirty-one infants completed the study. Average duration of crying/fussing episodes was similar at Baseline, significantly shorter for PDX/GOS vs. Control at Day 70, and the trajectory continued at Day 112. Latency to first and second nap was significantly longer for PDX/GOS vs. Control at Day 112. Cortisol awakening response was demonstrated at Days 70 and 112. Significant stool microbiome beta-diversity and individual taxa abundance differences were observed in the PDX/GOS group. Conclusions Results indicate faster consolidation of daytime waking state in infants receiving prebiotics and support home-based actigraphy to assess early sleep–wake patterns. A prebiotic effect on wake organization is consistent with influence on the gut–brain axis and warrants further investigation. Impact Few studies have evaluated nutritive effects of prebiotics on infant behavior state, cortisol awakening response, sleep–wake entrainment, and gut microbiome. Faster consolidation of daytime waking state was demonstrated in infants receiving a prebiotic blend in infant formula through ~4 months of age. Shorter episodes of crying were demonstrated at ~2 months of age (time point corresponding to age/developmental range associated with peak crying) in infants receiving formula with added prebiotics. Results support home-based actigraphy as a suitable method to assess early sleep–wake patterns. Prebiotic effect on wake organization is consistent with influence on the gut–brain axis and warrants further investigation

Measurement of D-s(+) and D-s(*+) production in B meson decays and from continuum e(+)e(-) annihilation at √s=10.6 GeV

This is the pre-print version of the Article. The official published version can be accessed from the links below. Copyright @ 2002 APSNew measurements of Ds+ and Ds*+ meson production rates from B decays and from qq̅ continuum events near the Υ(4S) resonance are presented. Using 20.8 fb-1 of data on the Υ(4S) resonance and 2.6 fb-1 off-resonance, we find the inclusive branching fractions B(B⃗Ds+X)=(10.93±0.19±0.58±2.73)% and B(B⃗Ds*+X)=(7.9±0.8±0.7±2.0)%, where the first error is statistical, the second is systematic, and the third is due to the Ds+→φπ+ branching fraction uncertainty. The production cross sections σ(e+e-→Ds+X)×B(Ds+→φπ+)=7.55±0.20±0.34pb and σ(e+e-→Ds*±X)×B(Ds+→φπ+)=5.8±0.7±0.5pb are measured at center-of-mass energies about 40 MeV below the Υ(4S) mass. The branching fractions ΣB(B⃗Ds(*)+D(*))=(5.07±0.14±0.30±1.27)% and ΣB(B⃗Ds*+D(*))=(4.1±0.2±0.4±1.0)% are determined from the Ds(*)+ momentum spectra. The mass difference m(Ds+)-m(D+)=98.4±0.1±0.3MeV/c2 is also measured.This work was supported by DOE and NSF (USA), NSERC (Canada), IHEP (China), CEA and CNRS-IN2P3 (France), BMBF (Germany), INFN (Italy), NFR (Norway), MIST (Russia), and PPARC (United Kingdom). Individuals have received support from the Swiss NSF, A. P. Sloan Foundation, Research Corporation, and Alexander von Humboldt Foundation

The Brightest Young Star Clusters in NGC 5253

67 pages; 11 figures; 7 tables. Accepted for publication in the Astrophysical JournalThe nearby dwarf starburst galaxy NGC5253 hosts a number of young, massive star clusters, the two youngest of which are centrally concentrated and surrounded by thermal radio emission (the `radio nebula'). To investigate the role of these clusters in the starburst energetics, we combine new and archival Hubble Space Telescope images of NGC5253 with wavelength coverage from 1500 Ang to 1.9 micron in 13 filters. These include H-alpha, P-beta, and P-alpha, and the imaging from the Hubble Treasury Program LEGUS (Legacy Extragalactic UV Survey). The extraordinarily well-sampled spectral energy distributions enable modeling with unprecedented accuracy the ages, masses, and extinctions of the 9 optically brightest clusters (M_V < -8.8) and the two young radio nebula clusters. The clusters have ages ~1-15 Myr and masses ~1x10^4 - 2.5x10^5 M_sun. The clusters' spatial location and ages indicate that star formation has become more concentrated towards the radio nebula over the last ~15 Myr. The most massive cluster is in the radio nebula; with a mass 2.5x10^5 M_sun and an age ~1 Myr, it is 2-4 times less massive and younger than previously estimated. It is within a dust cloud with A_V~50 mag, and shows a clear nearIR excess, likely from hot dust. The second radio nebula cluster is also ~1 Myr old, confirming the extreme youth of the starburst region. These two clusters account for about half of the ionizing photon rate in the radio nebula, and will eventually supply about 2/3 of the mechanical energy in present-day shocks. Additional sources are required to supply the remaining ionizing radiation, and may include very massive stars.Based on observations made with the NASA/ESA Hubble Space Telescope, obtained at the Space Telescope Science Institute, which is operated by the Association of Universities for Research in Astronomy, Inc., under NASA contract NAS 5-26555. These observations are associated with program # 13364. Support for program # 13364 was provided by NASA through a grant from the Space Telescope Science Institute. Based also on observations made with the NASA/ESA Hubble Space Telescope, and obtained from the Hubble Legacy Archive, which is a collaboration between the Space Telescope Science Institute (STScI/NASA), the Space Telescope European Coordinating Facility (ST-ECF/ESA) and the Canadian Astronomy Data Centre (CADC/NRC/CSA). This research has made use of the NASA/IPAC Extragalactic Database (NED) which is operated by the Jet Propulsion Laboratory, California Institute of Technology, under contract with the National Aeronautics and Space Administration. Part of this work was conducted while D.C. was a Raymond and Beverley Sackler Distinguished Visitor at the Institute of Astronomy, University of Cambridge (UK), and an Overseas Fellow at the Churchill College (Cambridge, UK). D.C. acknowledges the kind hospitality of both the Institute and the College. A.S.E. was supported by the Taiwan, R.O.C. Ministry of Science and Technology grant MoST 102-2119-M-001-MY3. M.F. acknowledges support by the Science and Technology Facilities Council [grant number ST/L00075X/1]. D.A.G. kindly acknowledges financial support by the German Research Foundation (DFG) through grant GO 1659/3-2. E.Z. acknowledges research funding from the Swedish Research Council (project 2011-5349)

Fungal associates of the lodgepole pine beetle, Dendroctonus murrayanae

Bark beetles are well known vectors of ophiostomatoid fungi including species of Ophiostoma, Grosmannia and Ceratocystis. In this study, the most common ophiostomatoid fungi associated with the lodgepole pine beetle, Dendroctonus murrayanae, were characterized. Pre-emergent and post-attack adult beetles were collected from lodgepole pines at four sites in British Columbia, Canada. Fungi were isolated from these beetles and identified using a combination of morphology and DNA sequence comparisons of five gene regions. In all four populations, Grosmannia aurea was the most common associate (74–100% of all beetles) followed closely by Ophiostoma abietinum (29–75%). Other fungi isolated, in order of their relative prevalence with individual beetles were an undescribed Leptographium sp. (0–13%), Ophiostoma ips (0–15%), Ophiostoma piliferum (0–11%), a Pesotum sp. (0–11%) and Ophiostoma floccosum (0–1%). Comparisons of the DNA sequences of Leptographium strains isolated in this study, with ex-type isolates of G. aurea, Grosmannia robusta, Leptographium longiclavatum, and Leptographium terebrantis, as well as with sequences from GenBank, revealed a novel lineage within the Grosmannia clavigera complex. This lineage included some of the D. murrayane isolates as well as several isolates from previous studies referred to as L. terebrantis. However, the monophyly of this lineage is not well supported and a more comprehensive study will be needed to resolve its taxonomic status as one or more novel taxa.National Science Foundation grant OISE-0434171 awarded to DLS, Natural Resources Canada, Canadian Forest Service Mountain Pine Beetle Initiative Grant to ALC, members of the Tree Co-operative Programme, the THRIP initiative of the Department of Trade and Industry, South Africa