Median Date Research Articles

Hematopoietic Cell Transplantation with or without Sorafenib Maintenance for Patients with FLT3-ITD Acute Myeloid Leukemia in CR1

▪Introduction:Patients with acute myeloid leukemia (AML) with internal tandem duplications in the fms-like tyrosine kinase 3 receptor (FLT3-ITD) are at high risk for relapse despite allogeneic hematopoietic cell transplantation (HCT) in first remission (CR1).We have previously shown sorafenib, an oral FLT3/multikinase inhibitor, to be safe as maintenance therapy after HCT (BBMT 2014;20:2042). We performed a retrospective study to evaluate the impact of sorafenib maintenance on outcomes of adult patients with FLT3-ITD AML undergoing HCT in CR1.Methods:We identified consecutive patients (n=80) at 2 institutions with AML between 2008 and 2014, with FLT3-ITD at diagnosis, who underwent HCT in CR1. Patients given sorafenib in remission after HCT were in the "sorafenib" group, and others were the "control" group. We identified the median date of sorafenib initiation, and performed a landmark analysis including only controls alive without relapse at that date. The primary outcome was overall survival (OS). We performed multivariable analysis, accounting for age >60, conditioning intensity, NPM1 status, cytogenetic risk, and donor type, to estimate the impact of sorafenib maintenance on OS, disease-free survival (DFS), non-relapse mortality (NRM), and time to relapse from the estimated date of sorafenib initiation. Cumulative incidence of grade 2-4 acute GVHD (aGVHD) and chronic GVHD (cGVHD) requiring systemic immunosuppression were estimated from date of transplant.Results:We identified 26 sorafenib patients and 54 control patients. Median follow up was 22.1 mo. (range, 6.3-49.8) for survivors in the sorafenib group, and 37.5 mo. (range, 12.4-88.9) in the control group (p=0.020). The median time to sorafenib was 68 days after transplant; subsequent analysis therefore included 26 sorafenib patients and 41 control patients alive without relapse at day +68. There were no significant differences in patient characteristics (Table 1). Two patients in the control group had concomitant FLT3-TKD mutations.Patients on sorafenib had improved 2-year OS compared to controls in the landmark analysis (83% vs. 58%, p=0.019, Figure 1). In multivariable analysis, sorafenib maintenance significantly improved OS (HR for death 0.146, p=0.0047) and DFS (HR 0.091, p=0.0005). Of patients alive without relapse at d+68, sorafenib maintenance was associated with improved 2-year DFS (85% vs. 52%, p=0.0047) and lower 2-year cumulative incidence of relapse (9.5% vs. 41%, p=0.0065). After 68 days, 2 sorafenib patients and 4 controls developed aGVHD. There was no difference in 2-year NRM (5.7% vs. 7.6%, p=0.61) or cumulative cGVHD at 1 year (50% vs. 37%, p=0.31).Conclusions:Sorafenib maintenance after HCT is associated with significantly improved DFS and OS among patients with FLT3-ITD AML undergoing HCT in CR1, with no difference in GVHD or NRM. These findings suggest a potential benefit of sorafenib and possibly other FLT3 inhibitors after HCT for FLT3-ITD AML, and support a randomized controlled trial of FLT3 inhibition after HCT.Table 1Patient DemographicsControl n=41Sorafenib n=26P-valueAge (median, range)53 (25,72)54.5 (20,74)0.39HCT Age (median, range)53 (25,73)55 (20,74)0.44Gender (male, %)12 (29%)12 (46%)0.20Race (white, %)35 (85%)24 (92%)1.00ECOG at Diagnosis*0.4307 (39%)7 (50%)17 (39%)7 (50%)23 (17%)031 (6%)0Antecedant Disease0.58De Novo32 (78%)22 (85%)tAML4 (10%)3 (12%)Prior MDS or MPN5 (12%)1 (4%)Cytogenetic Risk1.00Favorable2 (5%)1 (4%)Intermediate35 (88%)23 (88%)Adverse3 (8%)2 (8%)NPM1 mut#20 (74%)14 (56%)0.25CEBPA mut (n)021.00Induction Treatment0.377+3 based induction39 (95%)23 (88%)Other induction2 (5%)3 (12%)TKI prior to HCT10 (24%)7 (27%)1.00ECOG at HCT+0.63013 (32%)6 (25%)118 (44%)14 (58%)210 (24%)4 (17%)HCT Intensity1.00Myeloablative23 (56%)14 (54%)Reduced intensity18 (44%)12 (46%)Donor Type0.49Matched36 (88%)21 (81%)Mismatched5 (12%)5 (19%)aGVHD prophylaxis0.61CNI and Methotrexate24 (59%)17 (65%)*Diagnosis ECOG missing in 23 control and 12 sorafenib patients#NPM1 testing performed on 27 control and 25 sorafenib patients+HCT ECOG missing in 2 sorafenib patients [Display omitted] [Display omitted] DisclosuresOff Label Use: Sorafenib for FLT3-ITD AML. Fathi:Takeda Pharmaceuticals International Co.: Research Funding; Agios: Membership on an entity's Board of Directors or advisory committees; Exelexis: Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees; Ariad: Consultancy; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Stone:Celator: Consultancy; Karyopharm: Consultancy; Pfizer: Consultancy; Celgene: Consultancy; AROG: Consultancy; Novartis: Research Funding; Abbvie: Consultancy; Sunesis: Consultancy, Other: DSMB for clinical trial; Amgen: Consultancy; Roche/Genetech: Consultancy; Merck: Consultancy; Juno: Consultancy; Agios: Consultancy. Soiffer:Gentium SpA/Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Chen:Bayer: Consultancy, Research Funding.

The punctuated seaward migration of Pacific lamprey (Entosphenus tridentatus): environmental cues and implications for streamflow management

We investigated emigration timing of juvenile Pacific lamprey (Entosphenus tridentatus) over a 10-year period in the Sacramento River, California, USA. Emigration was punctuated with 90% of macrophthalmia in daily catches of at least 50 individuals. Macrophthalmia were observed primarily between November and May, with among-year variation in median emigration date over four times that of sympatric anadromous salmon. Our best model associating catch and environmental factors included days from rain event, temperature, and streamflow. We found strong evidence for an association of catch with days from rain events, a surrogate for streamflow, with 93% of emigrants caught during an event and the two subsequent days. Emigration was more likely during nighttime during subdaily sampling after accounting for the effects of factors significantly associated with daily catch. These results emphasize the importance of natural variation in streamflow regimes and provide insight for management practices that would benefit emigrating lampreys, such as synchronizing dam releases with winter and spring storms to reduce migration time, timing diversions to avoid entrainment during emigration windows, and ensuring streamflows are sufficient to reach the ocean, thereby avoiding mass stranding events.

Discovery of a secular trend in Cayo Santiago macaque reproduction.

Reproductive synchrony and the consequent clustering of births are hypothesized to be regulated by seasonal changes in rainfall and food availability. Such climate-related seasonality is, however, questionable in tropical populations occupying temporally invariant habitats year round. Using the long-term data of the Cayo Santiago rhesus macaques from 1973 to 2013, this study distinguishes synchrony (a greater than chance clustering of births) from seasonality (a cluster of births during a period of the year when abiotic conditions are favorable) and shows that females are highly synchronized (>72% of births in a 3-month period) but the effects of environmental zeitgebers on reproduction are overridden by biological factors. Specifically, biotic and abiotic factors including (i) loss of immature offspring; (ii) population density; (iii) age at delivery; (iv) rainfall; and (v) changes in colony management were modeled in relation to the annual onset of births and the median birth date. Females experiencing loss of immature offspring had an interbirth interval of <365 days in average and the proportion of these females increased up to 48% due to changes in colony management overtime, although reproductive synchrony increased with increasing population density. A secular trend in both the onset of births and the median date of birth is documented and the model predicts that the median birth date will advance across all calendar-based seasons by 2050. The secular trend in reproduction appears to be triggered by changes in the age at delivery of females, the absence of physiological constraints from maternal investment due to offspring loss, shorter interbirth interval, and a higher degree of coordination due to increasing population density. This study challenges the reproductive phenology previously described for rhesus macaques highlighting the importance of long-term studies in addressing the ultimate causes of reproductive synchrony.

Validation of International Classification of Diseases coding for bone metastases in electronic health records using technology-enabled abstraction.

ObjectiveThe accuracy of bone metastases diagnostic coding based on International Classification of Diseases, ninth revision (ICD-9) is unknown for most large databases used for epidemiologic research in the US. Electronic health records (EHR) are the preferred source of data, but often clinically relevant data occur only as unstructured free text. We examined the validity of bone metastases ICD-9 coding in structured EHR and administrative claims relative to the complete (structured and unstructured) patient chart obtained through technology-enabled chart abstraction.Patients and methodsFemale patients with breast cancer with ≥1 visit after November 2010 were identified from three community oncology practices in the US. We calculated sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of bone metastases ICD-9 code 198.5. The technology-enabled abstraction displays portions of the chart to clinically trained abstractors for targeted review, thereby maximizing efficiency. We evaluated effects of misclassification of patients developing skeletal complications or treated with bone-targeting agents (BTAs), and timing of BTA.ResultsAmong 8,796 patients with breast cancer, 524 had confirmed bone metastases using chart abstraction. Sensitivity was 0.67 (95% confidence interval [CI] =0.63–0.71) based on structured EHR, and specificity was high at 0.98 (95% CI =0.98–0.99) with corresponding PPV of 0.71 (95% CI =0.67–0.75) and NPV of 0.98 (95% CI =0.98–0.98). From claims, sensitivity was 0.78 (95% CI =0.74–0.81), and specificity was 0.98 (95% CI =0.98–0.98) with PPV of 0.72 (95% CI =0.68–0.76) and NPV of 0.99 (95% CI =0.98–0.99). Structured data and claims missed 17% of bone metastases (89 of 524). False negatives were associated with measurable overestimation of the proportion treated with BTA or with a skeletal complication. Median date of diagnosis was delayed in structured data (32 days) and claims (43 days) compared with technology-assisted EHR.ConclusionTechnology-enabled chart abstraction of unstructured EHR greatly improves data quality, minimizing false negatives when identifying patients with bone metastases that may lead to inaccurate conclusions that can affect delivery of care.

Multi‐temporal scale changes of streamflow and sediment load in a loess hilly watershed of China

AbstractGlobal climate change and diverse human activities have resulted in distinct temporal–spatial variability of watershed hydrological regimes, especially in water‐limited areas. This study presented a comprehensive investigation of streamflow and sediment load changes on multi‐temporal scales (annual, flood season, monthly and daily scales) during 1952–2011 in the Yanhe watershed, Loess Plateau. The results indicated that the decreasing trend of precipitation and increasing trend of potential evapotranspiration and aridity index were not significant. Significant decreasing trends (p &lt; 0.01) were detected for both the annual and flood season streamflow, sediment load, sediment concentration and sediment coefficient. The runoff coefficient exhibited a significantly negative trend (p &lt; 0.01) on the flood season scale, whereas the decreasing trend on the annual scale was not significant. The streamflow and sediment load during July–August contributed 46.7% and 86.2% to the annual total, respectively. The maximum daily streamflow and sediment load had the median occurrence date of July 31, and they accounted for 9.7% and 29.2% of the annual total, respectively. All of these monthly and daily hydrological characteristics exhibited remarkable decreasing trends (p &lt; 0.01). However, the contribution of the maximum daily streamflow to the annual total progressively decreased (−0.07% year−1), while that of maximum daily sediment load increased over the last 60 years (0.08% year−1). The transfer of sloping cropland for afforestation and construction of check‐dams represented the dominant causes of streamflow and sediment load reductions, which also made the sediment grain finer. Copyright © 2015 John Wiley &amp; Sons, Ltd.

Reproductive trends of captive polar bears in North American zoos: a historical analysis

Despite the fact that nearly all captive polar bears ( Ursus maritimus ) are recommended for breeding, very few cubs are born each year and the rate of neonatal mortality is high. Animal caretakers tend to rely on anecdotal reports regarding reproductive events, such as timing of parturition, litter size and cub survival. To objectively document trends in polar bear reproduction during their tenure in North American zoos, this analysis utilised 99 years of records in the Polar Bear Studbook to characterise patterns in reproduction and cub survival. Factors evaluated included latitude, year of birth, parental demographics (age, origin (captive-born or wild-caught) and litter size), sex, survival, litter size and litter order. Between 1912 and 2010, 697 individuals (456 litters) were born at latitudes ranging from 25.90 to 52.94 oN. The average number of litters produced per year was 4.60 ± 0.51 with a range of zero to 18. The polar bear birth season lasted 106 days with mean and median birth dates of 29 November. Litter size was unaffected by any of the variables analysed: 52.7% of litters were singletons, 44.9% were twins and 2.4% were triplets. Older sires produced a higher proportion of male offspring than younger sires (P < 0.05). More than half of all individuals died prior to 30 days of age and 30.4% reached adulthood (four years). Cubs of captive-born parents lived longer than those of wild-caught parents (P < 0.05). Individuals born in litters of multiples were more likely to die as neonates than those born as singletons (P < 0.01) and individuals born to multiparous dams lived longer than those born to primiparous dams (P < 0.02). This study represents the largest analysis of captive polar bear reproduction conducted to date and may serve as a reference for individuals involved in the management and care of captive polar bears.

The reproductive biology of the Syrian Woodpecker Dendrocopos syriacus in a newly colonized area of south-eastern Poland

In 2003–2006, 73 Syrian Woodpecker nests were studied in a 305-km2 area of the agricultural landscape in SE Poland. The median egg-laying date was found to be 12 May and the median fledging date was 20 June (the earliest laying date was April 24 and the latest fledging date was July 25). Females laid from two to seven eggs (median 5.0 eggs, n = 56). An average of 4.4 young hatched per nest (SD = 1.18, median 5, maximum 6, n = 41) after 9–13 days of incubation (median 10 days, n = 37). Two to six nestlings left successful nests (median 4, n = 37) after 24–30 days (median 27, n = 36), with a mean of 2.8 (SD = 2.24, median 3, n = 56) young fledging per nest. The main reason for the loss of young observed in 31 % of the Syrian Woodpecker broods was nest parasitism by starlings. These results suggest that the process and dynamics of the range expansion of the Syrian Woodpecker are influenced by a higher reproductive output of Syrian Woodpeckers at the extremities of its range as compared to that of the rest of the Syrian Woodpecker population.

Telemedicine in care homes in Airedale, Wharfedale and Craven

Purpose – The purpose of this paper is to observe and analyse the effects of the use of telemedicine in care homes on the use of acute hospital resources. Design/methodology/approach – The study was an uncontrolled retrospective observational review of data on emergency hospital admissions and Emergency Department (ED) visits for care home residents in Airedale, Wharfedale and Craven. Acute hospital activity for residents was observed before and after the installation of telemedicine in 27 care homes. Data from a further 21 care homes that did not use telemedicine were used as a control group, using the median date of telemedicine installation for the “before and after” period. Patient outcomes were not considered. Findings – Care homes with telemedicine showed a 39 per cent reduction in the costs of emergency admissions and a 45 per cent reduction in ED attendances after telemedicine installation. In the control group reductions were 31 and 31 per cent, respectively. The incremental difference in costs between the two groups of care homes was almost £1.2 million. The cost of telemedicine to care commissioners was £177,000, giving a return on investment over a 20-month period of £6.74 per £1 spent. Research limitations/implications – The results should be interpreted carefully. There is inherent bias as telemedicine was deployed in care homes with the highest use of acute hospital resources and there were some methodological limitations due to poor data. Nevertheless, controlling the data as much as possible and adopting a cautious approach to interpretation, it can be concluded that the use of telemedicine in these care homes was cost-effective. Originality/value – There are very few telemedicine studies focused on care homes.

A Model for Predicting Spring Emergence of Monochamus saltuarius (Coleoptera: Cerambycidae) from Korean white pine, Pinus koraiensis.

Monochamus saltuarius Gebler is a vector that transmits the pine wood nematode, Bursaphelenchus xylophilus, to Korean white pine, Pinus koraiensis, in Korea. To reduce the damage caused by this nematode in pine forests, timely control measures are needed to suppress the cerambycid beetle population. This study sought to construct a forecasting model to predict beetle emergence based on spring temperature. Logs of Korean white pine were infested with M. saltuarius in 2009, and the infested logs were overwintered. In February 2010, infested logs were then moved into incubators held at constant temperature conditions of 16, 20, 23, 25, 27, 30 or 34°C until all adults had emerged. The developmental rate of the beetles was estimated by linear and nonlinear equations and a forecasting model for emergence of the beetle was constructed by pooling data based on normalized developmental rate. The lower threshold temperature for development was 8.3°C. The forecasting model relatively well predicted the emergence pattern of M. saltuarius collected from four areas in northern Republic of Korea. The median emergence dates predicted by the model were 2.2-5.9 d earlier than the observed median dates.

Abstract P3-06-02: Exploratory analysis of single gene predictive biomarkers in TransHERA DASL cohort reveals that C8A mRNA expression is prognostic of outcome and predictive of benefit of trastuzumab

Abstract HERA is an international multi-center randomized trial comparing 1 or 2 years trastuzumab, given every 3 weeks, with observation in women with HER2+ breast cancer after standard neoadjuvant or adjuvant chemotherapy. From December 2001 to June 2005, 5102 patients were randomized. Comparing 1 year trastuzumab with observation at 8 years of follow-up, statistically significant differences in disease-free survival (DFS) and overall survival, despite crossover to trastuzumab of observation arm patients, were found. No benefit in DFS of 2 years compared to 1 year trastuzumab was found[Goldhirsch 2013]. To determine possible predictive single-gene biomarkers, an exploratory ITT analysis, with DFS as the primary endpoint, was conducted using mRNA expression data from 610 TransHERA FFPE samplesprofiled on Illumina Whole-Genome DASL cubic spline normalization was applied to the data. Outcome was obtained from the HERA database with 8 years median follow-up and clinical cut-off date April 12, 2012. Characteristics were well balanced between treatment groups. The exploratory analysis of 20,464 genes using DFS as the endpoint identified C8A as a possible biomarker that is prognostic and predictive of response to treatment. Cox regression was used to model DFS, with the interaction term between treatment and C8A as a continuous and a categorical variable split on the cohort mean. The observation arm consists of 199 samples with 66 events and the trastuzumab arm(1&amp;2-year combined) of 411 samples with 108 events. A statistically significant interaction between C8A mRNA and treatment was detected (p&amp;lt;0.001), indicating that C8A mRNA is predictive of response to trastuzumab treatment. For the C8A low subgroup (mRNA expression lower than the cohort mean) no significant treatment benefit is observed (p=0.73). On the other hand for the C8A high subgroup, patients in the trastuzumab arm experience a lower hazard of a DFS event by almost 75% compared to patients from the observation arm (HR=0.25; 95%CI:0.15-0.43, p&amp;lt;0.001). A significant prognostic effect of C8A mRNA is also observed (p&amp;lt;0.001) in the observation arm, where for the C8A high group the hazard of a DFS event is three times the respective hazard of the C8A low group (HR-=3.27; 95%CI:2.01-5.32, p&amp;lt;0.001). C8A is a member of the membrane attack complex and is part of the innate immune system. C8A inserts into the membrane of the target cell and binds with multiple copies of the pore-forming C9 leading to cell lysis. From the GeneAtlas, C8A is highly expressed in liver tissue suggesting an advantage for tumors with high expression of C8A and innate immune response. The Cancer Cell Line Encyclopedia indicates a wide range of C8A mRNA expression. C8A as a single gene biomarker that is prognostic of DFS and predictive of benefit from trastuzumab has the potential to improve the standard of care in HER2+ breast cancer. Understanding the advantage of over expression of C8A related to the innate immune response can give insight into the mechanisms that drive cancer. We note with caution that this finding is the result of an exploratory analysis and is being pursued in additional trastuzumab cohorts for further validation. Citation Format: Scooter Willis, Varvara Polydoropoulou, Zoi Tsourti, Urania Dafni, Brandon Young, Bradley Long, Pradip De, Nandini Dey, Casey Williams, Mitch Dowsett, Brian Leyland-Jones. Exploratory analysis of single gene predictive biomarkers in TransHERA DASL cohort reveals that C8A mRNA expression is prognostic of outcome and predictive of benefit of trastuzumab [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-06-02.

Prognostic factors of perinatal short-term outcome in severe placental insufficiency using Doppler sonography to assess end-diastolic absent and reverse blood flow in umbilical arteries

Significant placental insufficiency, indicated by Doppler ultrasound findings of absent or reverse end-diastolic flow velocities (AREDV), is associated with increased morbidity and mortality. Analysis of blood flow in the ductus venosus should assist in early intrauterine recognition of threatened foetuses. 58 high-risk pregnancies with umbilical AREDV were repeatedly examined (n=364). Doppler findings were correlated with neonatal signs of deterioration (ratio of normoblasts to leukocytes, pH, base excess, Apgar score), as well as short-term morbidity [need for intubation, duration of assisted respiration, evidence of respiratory distress syndrome (RDS), bronchopulmonary dysplasia (BPD), necrotising enterocolitis (NEC), intraventricular haemorrhage (IVH grade III+IV)] against the analysis of the blood flow findings (normal or increased pulsitility, absence or reverse end-diastolic flow) in the umbilical arteries (AU), the middle cerebral arteries (ACM) and ductus venosus (DV) relating these to birth weight and the duration of the pregnancy. The median period of observation was 12.8 days, 48% of the foetuses showed an abnormal ductus venosus flow and 26% an absent venous or reverse end-diastolic flow. The median date of delivery was 30 weeks, with a mean birth weight of 816 g. 93% were live births with 12% dying postnatally. Although the criteria for postnatal morbidity (BPD, NEC, IVH III+IV) and mortality did not correlate with changes in arterial and venous Doppler parameters in our group, there was a significant relationship between the normoblast count, known to be a marker of chronic hypoxia. The Apgar 10 minte score, umbilical arterial pH and base excess were correlated with changes in the DV flow curves. Healthy survival started, irrespective of arterial or venous blood flow criteria, from 27+0 weeks of pregnancy. If born between 27.0 and 30+6 weeks, the infants were more likely to be healthy the less the blood flow had been compromised. A birth weight of 590 g (sensitivity 62.5%; specificity 93.5%) and gestational age of 28+5 weeks (sensitivity 87.5%; specificity 90.3%) were shown to be cut-off points between healthy survival and survival with serious neonatal complications.

Temporal patterns in adult salmon migration timing across southeast Alaska

Pacific salmon migration timing can drive population productivity, ecosystem dynamics, and human harvest. Nevertheless, little is known about long-term variation in salmon migration timing for multiple species across broad regions. We used long-term data for five Pacific salmon species throughout rapidly warming southeast Alaska to describe long-term changes in salmon migration timing, interannual phenological synchrony, relationships between climatic variation and migratory timing, and to test whether long-term changes in migration timing are related to glaciation in headwater streams. Temporal changes in the median date of salmon migration timing varied widely across species. Most sockeye populations are migrating later over time (11 of 14), but pink, chum, and especially coho populations are migrating earlier than they did historically (16 of 19 combined). Temporal trends in duration and interannual variation in migration timing were highly variable across species and populations. The greatest temporal shifts in the median date of migration timing were correlated with decreases in the duration of migration timing, suggestive of a loss of phenotypic variation due to natural selection. Pairwise interannual correlations in migration timing varied widely but were generally positive, providing evidence for weak region-wide phenological synchrony. This synchrony is likely a function of climatic variation, as interannual variation in migration timing was related to climatic phenomenon operating at large- (Pacific decadal oscillation), moderate- (sea surface temperature), and local-scales (precipitation). Surprisingly, the presence or the absence of glaciers within a watershed was unrelated to long-term shifts in phenology. Overall, there was extensive heterogeneity in long-term patterns of migration timing throughout this climatically and geographically complex region, highlighting that future climatic change will likely have widely divergent impacts on salmon migration timing. Although salmon phenological diversity will complicate future predictions of migration timing, this variation likely acts as a major contributor to population and ecosystem resiliency in southeast Alaska.

Climate Change and Flowering Phenology in Worcester County, Massachusetts

Premise of research. Flowering times are sensitive indicators of climate change. This study explores important methodological issues in the use of samples of phenological records, quantifies change in flowering times, and examines causes of variability among species.Methodology. I used Monte Carlo simulations to explore effects of sample size on estimates of phenological statistics. I documented 60 yr of change in temperature and flowering times of forbs in Worcester County, Massachusetts, a largely nonurban area, using a combination of herbarium specimens and observations, and I tested several hypotheses using these data. I also compared changes in flowering times in eastern North America from several published studies.Pivotal results. Average spring temperatures increased 1.4°C (0.24°C/decade) during the last 60 yr. Mean and median flowering dates were most robust for small sample sizes, while early and late flowering dates and ranges were least stable. Mean flowering time advanced 2.9 d (0.4°C/decade), with greatest advances in early-flowering species. The predicted advance for a spring-flowering species was 4–10 d (0.6°–1.5°C/decade) using different models, corresponding to 2.5–6.3 d/°C of springtime warming. Flowering advanced more in species with shorter blooming periods than in species with longer blooming periods. Flowering advance was unaffected by a species’ native status and by whether it was locally increasing or declining. Phenological advances reported for the same species in different studies showed no significant correlation.Conclusions. Advances in flowering times were comparable to those in other north temperate studies, as was the large change in spring-flowering species. Contrary to other studies, phenological changes were unrelated to a species’ native status and to changes in species frequency. Results of simulations and comparisons across studies suggest that sampling error may contribute substantially to reported variation among species.

Effects of organ removal on trade‐offs between sexual and clonal reproduction in the stoloniferous herb Duchesnea indica

AbstractResource allocation patterns and trade‐off between sexual and clonal reproduction in clonal plants have been extensively studied, but little is known about effects of organ removal on the trade‐offs in clonal plants. To examine the effects, we conducted an experiment with the stoloniferous herb Duchesnea indica in which we removed plant organs like roots, flowers, or fruits. Removing roots significantly increased number of ramets and biomass allocation to stolons, but decreased number of fruits. Removing flowers or fruits greatly increased number of ramets and biomass allocation to stolons and roots, but decreased spacer length, number of fruits, and fruits set. Onset and median date of flowering phenology of D. indica shifted after flowers, fruits, or roots were removed. These results may indicate that removing organs can affect trade‐off between sexual and clonal reproduction of D. indica.

Arctic sea ice: use of observational data and model hindcasts to refine future projections of ice extent

This manuscript presents an evaluation of global climate models to guide future projections of Arctic sea ice extent (SIE). Thirty-five model simulations from Coupled Model Intercomparison Project, Phase 5 were examined to select model subsets using comparison to observational data (1979–2013). The study extends previous work by highlighting the seasonality of sea ice trends, utilizing a multi-step selection process to demonstrate how the timing of an ice-free Arctic varies with the hindcast performance of the models, and extending the analysis to include sudden ice loss events (SILE). Although the models' trends for the historical period are generally smaller than observed, the models' projected trends show a similar seasonality, largest in September and smallest in March to April. A multi-step evaluation process is applied to obtain progressively smaller subsets of the best-performing models. As the number of models retained becomes smaller, the simulated historical trend becomes larger and the median date of a projected ice-free Arctic becomes earlier. An examination of SILE through the historical period and model projections from 2014 through 2099 shows that SILE can account for between half and all of the future net loss of SIE. We created an application for exploring sea ice data: http://spark.rstudio.com/uafsnap/sea_ice_coverage/.

Sex-specific migration patterns and population trends of Skylarks Alauda arvensis ringed during autumn migration in southern Italy

The autumn migration of Skylarks Alauda arvensis along the southern Tyrrhenian coast of Italy from 1998 until 2014 is described, with respect to timing and phenology, sex-specific migration patterns and population trends. In total, 21,610 fully grown birds were captured and ringed, using mist nets, from October to mid November. The frequency distribution of wing length shows a clear bimodality due to sexual dimorphism, with males having longer wings than females. Wing length was used to determine sex in 20,622 individuals using Harding–Cassie plots: 57.1% were identified as females, 38.3% as males and 4.6% were undetermined. Autumn migration of Skylarks peaked during the second and third 10-day periods of October. Females migrated earlier than males: the median date of migration, based on combined data for all years, was 19 October for females and 25 October for males. The main migration period, expressed as the interquartile range, fell between 12 and 26 October for females and between 17 and 29 October for males. Based on capture numbers, we infer a fairly stable population migrating through the Volturno Plain, but with significant year-to-year fluctuations.

From Mediterranean to Scandinavia—timing and body mass condition in four long distance migrants

In spring, long-distance migrants are considered to adopt a time-minimizing strategy to promote early arrival at breeding sites. The phenology of spring migration was examined and compared between two insular stopover sites in Greece and Sweden for Icterine Warbler, Wood Warbler, Spotted Flycatcher and Collared Flycatcher. All of them migrate due north which means that some proportion of birds that pass through Greece are heading to Scandinavia. The Collared Flycatcher had the earliest and the Icterine Warbler the latest arrival time. The differences in median dates between Greece and Sweden were 3–4 weeks and the passages in Sweden were generally more condensed in time. The average overall speed estimates were very similar and varied between 129 and 137 km/d. In most of the species higher speed estimates were associated with years when birds arrived late in Greece. After crossing continental Europe birds arrive at the Swedish study site with significantly higher body masses compared to when they arrive in Greece and this might indicate a preparation for arriving at breeding grounds with some overload.

Paediatric HIV treatment failure: a silent epidemic.

Paediatric antiretroviral treatment (ART) failure is an under-recognized issue that receives inadequate attention in the field of paediatrics and within HIV treatment programmes. With paediatric ART failure rates ranging from 19.3% to over 32% in resource limited settings, a comprehensive evaluation of the causes of failure along with approaches to address barriers to treatment adherence are urgently needed.In partnership with the local Department of Health, a pilot programme has been established by Medecins Sans Frontieres (MSF) in Khayelitsha, South Africa, to identify and support paediatric HIV patients with high viral loads and potential treatment failure. Through detailed clinical and psychosocial evaluations and adherence support with an innovative counselling model, treatment barriers are identified and addressed.Demographic and clinical characteristics from the cohort show a delayed median start date for ART, prolonged viraemia including a large number of patients who have never achieved viral load (VL) suppression, a low rate of regimen changes despite failure, and a high percentage of pre-adolescent and adolescent patients who have not gone through the disclosure process.Stemming this epidemic of paediatric treatment failure requires programmatic responses to high viral loads in children, starting with improved “case finding” of previously undiagnosed HIV-infected children and adolescents. Viral load testing needs to be prioritized over CD4 count monitoring, and flagging systems to identify high VL results should be developed in clinics. Clinicians must understand that successful treatment begins with good adherence, and that simple adherence support strategies can often dramatically improve adherence. Moreover, appropriate adherence counselling should begin not when the child fails to respond to treatment. Establishing good adherence from the beginning of treatment, and supporting ongoing adherence during the milestones in these children's lives is key to sustaining treatment success in this vulnerable HIV-infected patient population.

Solar/Argos PTTs contradict ring-recovery analyses: Woodcocks wintering in Spain are found to breed further east than previously stated

The development of increasingly small devices for the satellite tracking of small birds allows us to explore aspects of avian migration that have never been studied before. Here, we provide the results of using 12- and 9.5-g platform transmitter terminals (PTTs) to track game birds of 300–385 g. Attaching PTTs to 20 Woodcocks (Scolopax rusticola), wintering in Spain from 2006 to 2012, allowed us to explore (1) migration strategies (timing, velocity and stopovers), (2) the identity of the breeding grounds; (3) inter-year site fidelity to wintering grounds. We provide details of the route, speed and timing of migration and the location of remote breeding sites that were unknown prior to this study. The departure from winter quarters (median date) was completed by 20 March. The spring migration period lasted 40 days, and our birds were found to travel from >5,000 to >10,000 km, with a mean total migratory speed (i.e., including stopovers) of 170 km/day. Woodcocks followed fairly direct routes of migration. Stopover duration tended to be shortened when birds were closer to their breeding areas, which were located further east than previously stated. The only bird that provided long-term data (>1 year) was observed to return to the same wintering area, suggesting high winter site fidelity. The use of small PTTs opens new research lines related to the study and management of small to medium-sized migratory birds.

Clinical Features of Heparin-Induced Thrombocytopenia Diagnosed By Lumi-Aggregometry

Background: Heparin-induced thrombocytopenia (HIT) is associated with anti-platelet factor-4 (PF4)/heparin antibodies that activate platelets, resulting in thrombocytopenia and a pro-thrombotic state. At our institution antibody-mediated platelet activation is demonstrated by lumi-aggregometry, which is a method previously validated against the gold standard serotonin-release assay (SRA). Lumi-aggregometry does not involve radioactive isotopes, which is its major advantage over the SRA. The clinical course of HIT diagnosed via SRA and ELISA has been previously described, and clinical prediction tools such as the 4-T score were validated using these diagnostic tests. However, the clinical picture of HIT diagnosed by lumi-aggregometry has not been previously described.Aims: The objective of this study is to describe the clinical and laboratory presentation of patients diagnosed with HIT by lumi-aggregometry.Methods: Patients with clinically suspected HIT and quantitative anti-PF4 IgG-specific ELISA OD ≥0.400 (Gen-Probe, San Diego) received confirmatory HIT testing by lumi-aggregometry. Briefly, HIT antibody-induced activation of washed healthy donor platelets was tested at therapeutic (0.1U/mL and 0.5U/mL) and high (100U/mL) porcine heparin concentration. The degree of platelet activation was quantitated luminographically based on the light flash reaction of ATP (released from platelet dense-granules) with luciferin luciferase reagent. A ratio of therapeutic to high heparin luminescence amplitude of >5.0 and platelet aggregation at therapeutic, but not high, concentrations was considered a positive result. The results of assays performed by our regional HIT testing referral laboratory from June 2009 to July 2012 were reviewed to identify patients with positive HIT testing by lumi-aggregometry. Patient records were retrospectively reviewed to obtain predefined data on baseline patient characteristics, heparin exposure, platelet counts, and thrombotic events occurring in the 5 days preceding or the 30 days following the date of positive HIT testing.Results: We identified 43 patients diagnosed with HIT by lumi-aggregometry (median age 68.0, 49% male) while under the care of local academic (46%) or urban community hospitals (37.2% medical; 53.5% surgical; 9.3% intensive care). Median baseline platelet count was 187 (14-349). Median date of platelet drop post-heparin exposure was 6 days (range 3-14) in patients without prior heparin exposure or platelet transfusions (Figure 1). Platelet drop >50% and platelet nadir ≥20x109/L were present in the majority of patients (Table 1). Thrombocytopenia occurred prior to (70.5%) or the same day (23.5%) as thrombosis in 16/17 patients with serial platelet counts who developed HIT-associated thromboembolism.Conclusion: Patients diagnosed with HIT by lumi-aggregometry present with similar findings to those described in SRA-confirmed HIT. These findings lend support to the use of lumi-aggregometry as an accurate diagnostic assay for the clinico-pathologic syndrome of HIT. [Display omitted] Table 1Percentage platelet drop from baseline and platelet nadirPercent platelet dropPlatelet nadir>50%30-50%<30%≥20 x 109/L283210-19 x 109/L510<10 x 109/L110 DisclosuresSzkotak:Alexion Pharmaceuticals: Research Funding. Sandhu:Celgene: Honoraria; Jansen: Honoraria; Novartis: Honoraria.