Fracture incidence and fracture-related mortality decreased with decreases in population mobility during the early days of the COVID-19 pandemic: an epidemiological study.

INTRODUCTION: We investigated the impact of coronavirus disease 2019 (COVID-19) social distancing measures on fracture incidence and fracture-related mortality, as well as associations with population mobility. METHODS: In total, 47 186 fractures were analysed across 43 public hospitals from 22 November 2016 to 26 March 2020. Considering the smartphone penetration of 91.5% in the study population, population mobility was quantified using Apple Inc's Mobility Trends Report, an index of internet location services usage volume. Fracture incidences were compared between the first 62 days of social distancing measures and corresponding preceding epochs. Primary outcomes were associations between fracture incidence and population mobility, quantified by incidence rate ratios (IRRs). Secondary outcomes included fracture-related mortality rate (death within 30 days of fracture) and associations between emergency orthopaedic healthcare demand and population mobility. RESULTS: Overall, 1748 fewer fractures than projected were observed during the first 62 days of COVID-19 social distancing (fracture incidence: 321.9 vs 459.1 per 100 000 person-years, P<0.001); the relative risk was 0.690, compared with mean incidences during the same period in the previous 3 years. Population mobility exhibited significant associations with fracture incidence (IRR=1.0055, P<0.001), fracture-related emergency department attendances (IRR=1.0076, P<0.001), hospital admissions (IRR=1.0054, P<0.001), and subsequent surgery (IRR=1.0041, P<0.001). Fracture-related mortality decreased from 4.70 (in prior years) to 3.22 deaths per 100 000 person-years during the COVID-19 social distancing period (P<0.001). CONCLUSION: Fracture incidence and fracture-related mortality decreased during the early days of the COVID-19 pandemic; they demonstrated significant temporal associations with daily population mobility, presumably as a collateral effect of social distancing measures.

Treatment Efficacy Score-continuous residual cancer burden-based metric to compare neoadjuvant chemotherapy efficacy between randomized trial arms in breast cancer trials.

BACKGROUND: Difference in pathologic complete response (pCR) rate after neoadjuvant chemotherapy does not capture the impact of treatment on downstaging of residual cancer in the experimental arm. We developed a method to compare the entire distribution of residual cancer burden (RCB) values between clinical trial arms to better quantify the differences in cytotoxic efficacy of treatments. PATIENTS AND METHODS: The Treatment Efficacy Score (TES) reflects the area between the weighted cumulative distribution functions of RCB values from two trial arms. TES is based on a modified Kolmogorov-Smirnov test with added weight function to capture the importance of high RCB values and uses the area under the difference between two distribution functions as a statistical metric. The higher the TES the greater the shift to lower RCB values in the experimental arm. We developed TES from the durvalumab + olaparib arm (n = 72) and corresponding controls (n = 282) of the I-SPY2 trial. The 11 other experimental arms and control cohorts (n = 947) were used as validation sets to assess the performance of TES. We compared TES to Kolmogorov-Smirnov, Mann-Whitney, and Fisher's exact tests to identify trial arms with higher cytotoxic efficacy and assessed associations with trial arm level survival differences. Significance was assessed with a permutation test. RESULTS: In the validation set, TES identified arms with a higher pCR rate but was more accurate to identify regimens as less effective if treatment did not reduce the frequency of high RCB values, even if the pCR rate improved. The correlation between TES and survival was higher than the correlation between the pCR rate difference and survival. CONCLUSIONS: TES quantifies the difference between the entire distribution of pathologic responses observed in trial arms and could serve as a better early surrogate to predict trial arm level survival differences than pCR rate difference alone.

Predicted sensitivity to endocrine therapy for stage II-III hormone receptor-positive and HER2-negative (HR+/HER2-) breast cancer before chemo-endocrine therapy.

BACKGROUND: We proposed that a test for sensitivity to the adjuvant endocrine therapy component of treatment for patients with stage II-III breast cancer (SET2,3) should measure transcription related to estrogen and progesterone receptors (SETER/PR index) adjusted for a baseline prognostic index (BPI) combining clinical tumor and nodal stage with molecular subtype by RNA4 (ESR1, PGR, ERBB2, and AURKA). PATIENTS AND METHODS: Patients with clinically high-risk, hormone receptor-positive (HR+), human epidermal growth factor receptor 2 (HER2)-negative (HR+/HER2-) breast cancer received neoadjuvant taxane-anthracycline chemotherapy, surgery with measurement of residual cancer burden (RCB), and then adjuvant endocrine therapy. SET2,3 was measured from pre-treatment tumor biopsies, evaluated first in an MD Anderson Cancer Center (MDACC) cohort (n = 307, 11 years' follow-up, U133A microarrays), cut point was determined, and then independent, blinded evaluation was carried out in the I-SPY2 trial (n = 268, high-risk MammaPrint result, 3.8 years' follow-up, Agilent-44K microarrays, NCI Clinical Trials ID: NCT01042379). Primary outcome measure was distant relapse-free survival. Multivariate Cox regression models tested prognostic independence of SET2,3 relative to RCB and other molecular prognostic signatures, and whether other prognostic signatures could substitute for SETER/PR or RNA4 components of SET2,3. RESULTS: SET2,3 added independent prognostic information to RCB in the MDACC cohort: SET2,3 [hazard ratio (HR) 0.23, P = 0.004] and RCB (HR 1.77, P < 0.001); and the I-SPY2 trial: SET2,3 (HR 0.27, P = 0.031) and RCB (HR 1.68, P = 0.008). SET2,3 provided similar prognostic information irrespective of whether RCB-II or RCB-III after chemotherapy, and in both luminal subtypes. Conversely, RCB was most strongly prognostic in cancers with low SET2,3 status (MDACC P < 0.001, I-SPY2 P < 0.001). Other molecular signatures were not independently prognostic; they could effectively substitute for RNA4 subtype within the BPI component of SET2,3, but they could not effectively substitute for SETER/PR index. CONCLUSIONS: SET2,3 added independent prognostic information to chemotherapy response (RCB) and baseline prognostic score or subtype. Approximately 40% of patients with clinically high-risk HR+/HER2- disease had high SET2,3 and could be considered for clinical trials of neoadjuvant endocrine-based treatment.

Response of Aedes aegypti and Aedes albopictus (Diptera: Culicidae) Survival, Life History, and Population Growth to Oak Leaf and Acorn Detritus.

Aedes albopictus (Skuse) (Diptera: Culicidae) and Aedes aegypti (L.) (Diptera: Culicidae) are invasive container mosquitoes that are of potential medical importance in the southern United States. Seeds (acorns) and leaves from oak trees can contribute seasonally to the detritus of larval container habitats. Herein, we examined the effect of acorns and leaves from the southern live oak (Quercus virginiana Mill.), which has a concomitant range with these mosquitoes, on the population performance of Ae. aegypti and Ae. albopictus. Three levels of acorns and oak leaves were used (0.99, 1.98, and 7.94 g), along with two mixtures (leaf + acorn: 0.50 + 1.48 and 1.48 + 0.50 g). Tannins, secondary plant metabolites that effect herbivory, were measured across all treatment levels; nitrogen and carbon was also measured for detritus and representative females. Survival, female mass, development time, and λ' (per capita rate of population increase) were used to evaluate population performance of both species. Detritus amount but not type led to differences in tannins; however, these differences did not correspond to differences in performance. Acorns had higher carbon and C:N than leaves. Survival for both species was lower in medium amounts of acorns. Female mass varied with leaf amount, whereas development time differed between amounts of pure leaf and acorn. λ' was lowest in medium and high acorns compared with leaves or mixtures. Thus, acorns do appear to limit mosquito survival and affect population growth, suggesting that inputs of this common detritus type may negatively affect container Aedes production.

Assessing natural infection with Zika virus in the southern house mosquito, Culex quinquefasciatus, during 2016 in Puerto Rico.

The epidemic of Zika in the Western hemisphere has led to intense investigations of all species important in the transmission of Zika virus (ZikV), including putative mosquito vectors. Although evidence points to Stegomyia (= Aedes) (Diptera: Culicidae) mosquitoes as the primary vectors in nature among humans, there remains the possibility that other common mosquito species may be implicated in the rapid spread of the virus. Herein, field-caught Culex quinquefasciatus (Diptera: Culicidae) collected during June 2016 in different neighbourhoods in San Juan, Puerto Rico were examined for the presence of natural infection with ZikV. Stegomyia aegypti (= Aedes aegypti) from the same locations were also analysed. None of the Cx. quinquefasciatus tested showed natural infection for ZikV, whereas S. aegypti tested positive at seven sites. The present results suggest that Cx. quinquefasciatus was not involved in the transmission of ZikV in San Juan, Puerto Rico in 2016.

Intraoperative factors associated with stranded source placement accuracy in low-dose-rate prostate brachytherapy.

PURPOSE: The quality of a low-dose rate prostate brachytherapy implant depends on the accurate placement of sources in their planned locations. This study investigates intraoperative factors that potentially contribute to stranded source placement inaccuracy in prostate brachytherapy. METHODS AND MATERIALS: Intraoperative video images of the brachytherapist's hand motions and needle insertions during the implant procedure were acquired for analysis. Using video analysis software, maximum and average needle insertion velocities were determined. The number of needle insertion attempts and the use of the brachytherapist's other hand to manipulate the needle direction were also recorded. Sources misplacements were analyzed using an ultrasound-based method described elsewhere. RESULTS: Fifteen patients agreed to undergo this study; 1619 125I seeds were inserted using 357 needles; 1197 seeds were confidently identified using ultrasound images and included in the analysis. The mean overall misplacement was 0.49 cm (0-2 cm, 95% CI = 0.47-0.51); 614 seeds were delivered with a single pass and 583 seeds with >1 passes (range 2-6). The mean maximum needle velocity was 12.34 cm s-1 (range 4-28 cm s-1) and mean average velocity was 4.76 cm s-1 (range 0.4-17.4 cm s-1); 747 seeds were delivered with manipulation of the needle. The generalized linear model test was used to analyze factors contributing to seed misplacement, and it was found that a maximum speed <12 cm s-1 was associated with a decrease in seed misplacement by 0.049 cm vs. a maximum speed >12 cm s-1, p = 0.0121). Other evaluated factors were found to have no statistically significant correlation with seed misplacement: average speed (p = 0.4947), manual manipulation of needle (p = 0.9264), and number of needle passes (p = 0.8907). CONCLUSIONS: This study identified that needles inserted with lower maximum velocity were associated with less seed misplacement. Manual manipulation of the needle, number of passes, and average speed did not show statistically significant correlation with seed misplacement.

Improvement in health-related quality of life in patients with haemophilia B treated with nonacog beta pegol, a new extended half-life recombinant FIX product.

INTRODUCTION: Health-related quality of life (HRQoL) of individuals with haemophilia has greatly improved with the use of factor replacement and routine prophylaxis. AIM: To explore the HRQoL of individuals with haemophilia B treated with nonacog beta pegol, an extended half-life recombinant factor IX, in a single-blind, randomized multinational phase III pivotal trial (paradigm(™) 2) and its open-label extension (paradigm(™) 4). METHODS: In the pivotal trial, adolescents and adults with haemophilia B were allocated to 28-week on-demand treatment or randomized to 52 weeks of prophylaxis with 10 or 40 IU kg(-1) nonacog beta pegol administered every seven days. In the extension trial, patients could continue on the same treatment or switch to the alternate dosing regimen at any time. HRQoL was assessed with the HAEMO-QOL/HAEM-A-QOL age-specific questionnaires and the EQ-5D. RESULTS: In the pivotal trial, adults receiving 40 IU kg(-1) prophylaxis reported significant improvements in the 'HAEM-A-QOL Total' score (-6.4 ± 8.5, P = 0.017) and in 'Sport' (-15.3 ± 8.5, P = 0.020), 'Feeling' (-15.2 ± 18.3, P = 0.010) and 'Partnership' (-9.6 ± 15.5, P = 0.046) domain scores; no significant improvements were seen in the other arms. At the pivotal trial end, fewer patients reported problems in the EQ-5D 'Mobility' and 'Pain/Discomfort' dimensions, in particular those receiving prophylaxis. In the extension trial, adult patients switching from 10 to 40 IU kg(-1) prophylaxis showed significant improvements in 'HAEM-A-QOL Total' score (-12.5 ± 8.7, P = 0.016) and 'Physical health' domain (-23.1 ± 14.4, P = 0.016). CONCLUSION: Prophylactic treatment with nonacog beta pegol 40 IU kg(-1) once weekly leads to HRQoL benefits in individuals with haemophilia B; this might be related to fewer bleeding episodes and higher FIX activity levels.

Disruption of insulin receptor function inhibits proliferation in endocrine-resistant breast cancer cells.

The insulin-like growth factor (IGF) system is a well-studied growth regulatory pathway implicated in breast cancer biology. Clinical trials testing monoclonal antibodies directed against the type I IGF receptor (IGF1R) in combination with estrogen receptor-α (ER) targeting have been completed, but failed to show benefits in patients with endocrine-resistant tumors compared to ER targeting alone. We have previously shown that the closely related insulin receptor (InsR) is expressed in tamoxifen-resistant (TamR) breast cancer cells. Here we examined if inhibition of InsR affected TamR breast cancer cells. InsR function was inhibited by three different mechanisms: InsR short hairpin RNA, a small InsR-blocking peptide, S961 and an InsR monoclonal antibody (mAb). Suppression of InsR function by these methods in TamR cells successfully blocked insulin-mediated signaling, monolayer proliferation, cell cycle progression and anchorage-independent growth. This strategy was not effective in parental cells likely because of the presence of IGFR /InsR hybrid receptors. Downregulation of IGF1R in conjunction with InsR inhibition was more effective in blocking IGF- and insulin-mediated signaling and growth in parental cells compared with single-receptor targeting alone. Our findings show TamR cells were stimulated by InsR and were not sensitive to IGF1R inhibition, whereas in tamoxifen-sensitive parental cancer cells, the presence of both receptors, especially hybrid receptors, allowed cross-reactivity of ligand-mediated activation and growth. To suppress the IGF system, targeting of both IGF1R and InsR is optimal in endocrine-sensitive and -resistant breast cancer.

Estimation of Contaminant Loads from the Sacramento-San Joaquin River Delta to San Francisco Bay.

Contaminant concentrations from the Sacramento-San Joaquin River watershed were determined in water samples mainly during flood flows in an ongoing effort to describe contaminant loads entering San Francisco Bay, CA, USA. Calculated PCB and total mercury loads during the 6-year observation period ranged between 3.9 and 19 kg/yr and 61 and 410 kg/yr, respectively. Long-term average PCB loads were estimated at 7.7 kg/yr and total mercury loads were estimated at 200 kg/yr. Also monitored were PAHs, PBDEs (two years of data), and dioxins/furans (one year of data) with average loads of 392, 11, and 0.15/0.014 (OCDD/OCDF) kg/yr, respectively. Organochlorine pesticide loads were estimated at 9.9 kg/yr (DDT), 1.6 kg/yr (chlordane), and 2.2 kg/yr (dieldrin). Selenium loads were estimated at 16 300 kg/yr. With the exception of selenium, all average contaminant loads described in the present study were close to or below regulatory load allocations established for North San Francisco Bay.

UNBLOCK: an open-label, dose-finding, pharmacokinetic and safety study of bivalirudin in children with deep vein thrombosis.

BACKGROUND: Direct thrombin inhibitors offer potential advantages over unfractionated heparin but have been poorly studied in children. OBJECTIVES: To determine appropriate dosing of bivalirudin in children and adolescents and the relationship between activated partial thromboplastin time (APTT) and plasma bivalirudin concentration. PATIENTS/METHODS: The UNBLOCK (UtilizatioN of BivaLirudin On Clots in Kids) study was an open-label, single-arm, dose-finding, pharmacokinetic, safety and efficacy study of bivalirudin for the acute treatment of deep vein thrombosis (DVT) in children aged 6 months to 18 years. Drug initiation consisted of a bolus dose (0.125 mg kg(-1) ) followed by continuous infusion (0.125 mg kg h(-1) ). Dose adjustments were based on the APTT, targeting a range of 1.5-2.5 times each patient's baseline APTT. Safety was assessed by specific bleeding endpoints and efficacy by repeat imaging at 48-72 h and 25-35 days. RESULTS: Eighteen patients completed the study. Following the bolus dose and the initial infusion rate, most patients' APTT values were within the target range. The infusion rate bivalirudin correlated more closely with drug concentration than the APTT. At 48-72 h, nine (50%) patients had complete or partial thrombus resolution, increasing to 16 (89%) at 25-35 days. No major and one minor bleeding event occurred. CONCLUSIONS: Bivalirudin demonstrated reassuring safety and noteworthy efficacy in terms of early clot resolution in children and adolescents with DVT. Although a widely available and familiar monitoring tool, the APTT correlates poorly with plasma bivalirudin concentration, possibly limiting its utility in managing pediatric patients receiving bivalirudin for DVT.

Progesterone receptor-B enhances estrogen responsiveness of breast cancer cells via scaffolding PELP1- and estrogen receptor-containing transcription complexes.

Progesterone and estrogen are important drivers of breast cancer proliferation. Herein, we probed estrogen receptor-α (ER) and progesterone receptor (PR) cross-talk in breast cancer models. Stable expression of PR-B in PR-low/ER+ MCF7 cells increased cellular sensitivity to estradiol and insulin-like growth factor 1 (IGF1), as measured in growth assays performed in the absence of exogenous progestin; similar results were obtained in PR-null/ER+ T47D cells stably expressing PR-B. Genome-wide microarray analyses revealed that unliganded PR-B induced robust expression of a subset of estradiol-responsive ER target genes, including cathepsin-D (CTSD). Estradiol-treated MCF7 cells stably expressing PR-B exhibited enhanced ER Ser167 phosphorylation and recruitment of ER, PR and the proline-, glutamate- and leucine-rich protein 1 (PELP1) to an estrogen response element in the CTSD distal promoter; this complex co-immunoprecipitated with IGF1 receptor (IGFR1) in whole-cell lysates. Importantly, ER/PR/PELP1 complexes were also detected in human breast cancer samples. Inhibition of IGF1R or phosphoinositide 3-kinase blocked PR-B-dependent CTSD mRNA upregulation in response to estradiol. Similarly, inhibition of IGF1R or PR significantly reduced ER recruitment to the CTSD promoter. Stable knockdown of endogenous PR or onapristone treatment of multiple unmodified breast cancer cell lines blocked estradiol-mediated CTSD induction, inhibited growth in soft agar and partially restored tamoxifen sensitivity of resistant cells. Further, combination treatment of breast cancer cells with both onapristone and IGF1R tyrosine kinase inhibitor AEW541 was more effective than either agent alone. In summary, unliganded PR-B enhanced proliferative responses to estradiol and IGF1 via scaffolding of ER-α/PELP1/IGF1R-containing complexes. Our data provide a strong rationale for targeting PR in combination with ER and IGF1R in patients with luminal breast cancer.

Behavioral differences among four co-occurring species of container mosquito larvae: effects of depth and resource environments.

Mosquito larvae often exhibit different behaviors depending on the aspects of the aquatic environment, including the presence of different physical factors and detrital food sources. Regardless of these physical differences, different genera also devote different amounts of time to different behaviors. To determine if differences existed among four focal mosquito species (Aedes albopictus (Singh), Aedes triseriatus (Say), Culex quinquefasciatus (Say), Culex coronator Dyar & Knab), we recorded behaviors under different food environments (animal detritus, leaf detritus, and inoculum + inert material) and depths (shallow and deep). Based on past work, we predicted that larval mosquitoes in the genus Culex would spend more time filtering or resting at the surface of containers, whereas Aedes mosquitoes would spend more time browsing on surfaces. Behaviors were recorded for 30 min and were used to generate instantaneous scan census of behavior (thrashing, browsing, and resting or filtering) and locations (top, middle, bottom, wall, and detritus) of each larva every minute. There were significant differences in behaviors among the three detritus types and the four species (Culex generally different than Aedes), as well as a significant interaction between depth and detritus type. Consistent with predictions, Culex species spent more time filtering or resting, whereas Aedes larvae spent more time browsing on detritus. However, all four species changed their behavior similarly among the different environments, and Cx. coronator exhibited some similar behaviors as the two Aedes species. These behavioral differences may aid in explaining performance differences between different species and outcomes of interspecific encounters, which in turn can affect adult emergence and patterns of disease.

Interspecific competition of a new invasive mosquito, Culex coronator, and two container mosquitoes, Aedes albopictus and Cx. quinquefasciatus (Diptera: Culicidae), across different detritus environments.

The mosquito Culex coronator (Dyar and Knab) (Diptera: Culicidae) has undergone rapid range expansion in the United States since 2003, with its historical distribution in the southwest expanding eastward to the Atlantic coast. Although Cx. coronator nominally use small natural aquatic habitats for development, the use of containers (e.g., tires) makes it potentially important as container invasive. To determine the potential ecological effects of Cx. coronator on resident container species, we conducted a laboratory experiment to assess its competitive ability with two common tire-inhabiting species, Aedes albopictus (Skuse) and Culex quinquefasciatus (Say) (Diptera: Culicidae). Larvae were reared under a factorial design with each species alone and in combination (Cx. coronator + Ae. albopictus, Cx. coronator + Cx. quinquefasciatus) across three different resource environments (leaf detritus only, animal detritus only, animal + leaf). Mosquito performance (survival, adult male and female mass, and development time) was measured for each species across treatments. Female Cx. coronator developed slowest when grown with Ae. albopictus, or when grown with leaves only regardless of species combinations; similar patterns emerged for males although species effects were restricted to mass. Few differences were evident in performance for male and female Cx. coronator across detritus environments when grown with Cx. quinquefasciatus. Cx. quinquefasciatus did not vary in mass or development time in the presence of Cx. coronator compared with when grown alone. Ae. albopictus female mass was 15% lower in the presence of Cx. coronator. Survival of Cx. coronator was highest in animal and leaf detritus containers, although survival was generally lower when larvae were grown with Ae. albopictus. These findings suggest that the performance of Cx. coronator is similar to that of Cx. quinquefasciatus but it suffers in the presence of Ae. albopictus under some resource environments.

Influence of resource levels, organic compounds and laboratory colonization on interspecific competition between the Asian tiger mosquito Aedes albopictus (Stegomyia albopicta) and the southern house mosquito Culex quinquefasciatus.

The mosquitoes Aedes albopictus (Stegomyia albopicta) (Skuse) and Culex quinquefasciatus (Say) (Diptera: Culicidae) are common inhabitants of tyres and other artificial containers, which constitute important peridomestic mosquito breeding habitats. We tested the hypotheses that interspecific resource competition between the larvae of these species is asymmetrical, that the concentration of chemicals associated with decomposing detritus affects the competitive outcomes of these species, and that wild and colonized strains of Cx. quinquefasciatus are affected differently by competition with Ae. albopictus. We conducted two laboratory competition experiments wherein we measured survivorship and estimated population growth (λ') in both species under multiple mixed-species densities. Under varying resource levels, competition was asymmetrical: Ae. albopictus caused competitive reductions or exclusions of Cx. quinquefasciatus under conditions of limited resources. In a second experiment, which used both wild and colonized strains of Cx. quinquefasciatus, organic chemical compounds associated with decomposing detritus did not affect the competitive outcome. The colonized strain of Cx. quinquefasciatus had greater survivorship and adult mass, and faster development times than the wild strain, but both strains were similarly affected by competition with Ae. albopictus. Competition between these species may have important consequences for vector population dynamics, especially in areas in which tyres and artificial containers constitute the majority of mosquito breeding habitats.

Platelet function defects in adolescents with heavy menstrual bleeding.

Platelet function defects (PFD) are reported to occur frequently in adult women with heavy menstrual bleeding (HMB). Few studies on adolescent HMB report varying incidence rates (2-44%) for PFD. We reviewed our institutional experience in detecting and managing PFD in adolescent HMB. Postmenarchial girls and adolescents with HMB seen at our institution undergo a comprehensive bleeding disorder work-up by paediatric haematology and paediatric gynaecology providers. Whole blood platelet aggregometry (WBPA) is performed as a second tier test after excluding thrombocytopaenia, coagulation factor deficiencies and Von Willebrand disease (VWD). We retrospectively reviewed the medical records of adolescents with HMB seen between June 2009 and November 2010, as approved by the Institutional Review Board. Patient demographics, clinical features, laboratory results, therapy details and patient outcome information were analysed. Overall, 114 postmenarchial girls and adolescents with HMB were evaluated; 68 patients (59%) had WBPA study performed. Nineteen patients (28%) had at least one aggregation or secretion defect; 12 (18%) had two or more such defects. Treatment included hormonal therapy (13/19; 68%), antifibrinolytic agents (8/19; 42%) and intra-nasal DDAVP (3/19; 16%). Thirteen patients (81%) had improved outcome (median follow-up--15.6 months; range of 1-66 months). In this study, PFD were identified in nearly one-third of girls with HMB, with the majority of these having two or more defects as identified by WBPA. Further prospective studies are needed to better define the prevalence and address appropriate management of HMB and other bleeding complications of PFD in adolescents.

Implications of saline concentrations for the performance and competitive interactions of the mosquitoes Aedes aegypti (Stegomyia aegypti) and Aedes albopictus (Stegomyia albopictus).

Aedes albopictus (Stegomyia albopictus) (Diptera: Culicidae) has probably supplanted Aedes aegypti (Stegomyia aegypti) throughout most of its historical range in the U.S.A., although Ae. aegypti still exists in large coastal cities in southern Florida. We measured salt concentrations in field containers along an axis perpendicular to the coast and examined intraspecific outcomes in these species under different salt concentrations in a factorial study using varying intra- and interspecific densities in different conditions of salinity to order to determine if salt could mitigate the documented competitive superiority of Ae. albopictus. Salt in field containers declined away from the coast, with maximal values similar to our lower salt concentrations. Egg hatching and short-term survival of pupae and late instars were not affected by salt concentrations; survival of early instars of both species decreased at higher concentrations. In high salt conditions, Ae. aegypti achieved higher survival. In the longterm experiment, both species displayed longer development times. Salt did not affect interactions for either species; Ae. aegypti survived in the highest salt conditions, regardless of density. The tolerance of Ae. aegypti to high salt concentrations may allow it to use coastal containers, although because salt did not mediate interspecific interactions between Ae. aegypti and Ae. albopictus, the ultimate effects of salt on the coexistence of these species or exclusion of either species remain unknown.

Analysis of intraprostatic therapeutic effects in prostate cancer patients using [(11)C]-choline pet/ct after external-beam radiation therapy.

PURPOSE: The objective of the present study was to analyze, with relatively high sensitivity and specificity, uptake properties of [(11)C]-choline in prostate cancer patients by means of positron-emission tomography (pet)/computed tomography (ct) imaging using objectively defined pet parameters to test for statistically significant changes before, during, and after external-beam radiation therapy (ebrt) and to identify the time points at which the changes occur. METHODS: The study enrolled 11 patients with intermediate-risk prostate cancer treated with ebrt, who were followed for up to 12 months after ebrt. The [(11)C]-choline pet scans were performed before treatment (baseline); at weeks 4 and 8 of ebrt; and at 1, 2, 3, 6, and 12 months after ebrt. RESULTS: Analysis of [(11)C]-choline uptake in prostate tissue before treatment resulted in a maximum standardized uptake value (suvmax) of 4.0 ± 0.4 (n = 11) at 40 minutes after injection. During week 8 of ebrt, the suvmax declined to 2.9 ± 0.1 (n = 10, p < 0.05). At 2 and 12 months after ebrt, suvmax values were 2.3 ± 0.3 (n = 10, p < 0.01) and 2.2 ± 0.2 (n = 11, p < 0.001) respectively, indicating that, after ebrt, maximum radiotracer uptake in the prostate was significantly reduced. Similar effects were observed when analyzing the tumour:muscle ratio (tmr). The tmr declined from 7.4 ± 0.6 (n = 11) before ebrt to 6.1 ± 0.4 (n = 11, nonsignificant) during week 8 of ebrt, to 5.6 ± 0.03 (n = 11, p < 0.05) at 2 months after ebrt, and to 4.4 ± 0.4 (n = 11, p < 0.001) at 12 months after ebrt. CONCLUSIONS: Our study demonstrated that intraprostatic [(11)C]-choline uptake in the 11 analyzed prostate cancer patients significantly declined during and after ebrt. The pet parameters SUVmax and tmr also declined significantly. These effects can be detected during radiation therapy and up to 1 year after therapy. The prognostic value of these early and statistically significant changes in intraprostatic [(11)C]-choline pet avidity during and after ebrt are not yet established. Future studies are indicated to correlate changes in [(11)C]-choline uptake parameters with long-term biochemical recurrence to further evaluate [(11)C]-choline pet changes as a possible, but currently unproven, biomarker of response.

Dosimetry study of [I-131] and [I-125]- meta-iodobenz guanidine in a simulating model for neuroblastoma metastasis.

The physical properties of I-131 may be suboptimal for the delivery of therapeutic radiation to bone marrow metastases, which are common in the natural history of neuroblastoma. In vitro and preliminary clinical studies have implied improved efficacy of I-125 relative to I-131 in certain clinical situations, although areas of uncertainty remain regarding intratumoral dosimetry. This prompted our study using human neuroblastoma multicellular spheroids as a model of metastasis. 3D dose calculations were made using voxel-based Medical Internal Radiation Dosimetry (MIRD) and dose-point-kernel (DPK) techniques. Dose distributions for I-131 and I-125 labeled mIBG were calculated for spheroids (metastases) of various sizes from 0.01 cm to 3 cm diameter, and the relative dose delivered to the tumors was compared for the same limiting dose to the bone marrow. Based on the same data, arguments were advanced based upon the principles of tumor control probability (TCP) to emphasize the potential theoretical utility of I-125 over I-131 in specific clinical situations. I-125-mIBG can deliver a higher and more uniform dose to tumors compared to I-131 mIBG without increasing the dose to the bone marrow. Depending on the tumor size and biological half-life, the relative dose to tumors of less than 1 mm diameter can increase several-fold. TCP calculations indicate that tumor control increases with increasing administered activity, and that I-125 is more effective than I-131 for tumor diameters of 0.01 cm or less. This study suggests that I-125-mIBG is dosimetrically superior to I-131-mIBG therapy for small bone marrow metastases from neuroblastoma. It is logical to consider adding I-125-mIBG to I-131-mIBG in multi-modality therapy as these two isotopes could be complementary in terms of their cumulative dosimetry.