Feasibility of internal-source tracking with C-arm CT/SPECT imaging with limited-angle projection data for online in vivo dose verification in brachytherapy: A Monte Carlo simulation study.

PURPOSE: The current protocol for use of the image-guided adaptive brachytherapy (IGABT) procedure entails transport of a patient between the treatment room and the 3-D tomographic imaging room after implantation of the applicators in the body, which movement can cause position displacement of the applicator. Moreover, it is not possible to track 3-D radioactive source movement inside the body, even though there can be significant inter- and intra-fractional patient-setup changes. In this paper, therefore, we propose an online single-photon emission computed tomography (SPECT) imaging technique with a combined C-arm fluoroscopy X-ray system and attachable parallel-hole collimator for internal radioactive source tracking of every source position in the applicator. METHODS AND MATERIALS: In the present study, using Geant4 Monte Carlo (MC) simulation, the feasibility of high-energy gamma detection with a flat-panel detector for X-ray imaging was assessed. Further, a parallel-hole collimator geometry was designed based on an evaluation of projection image quality for a 192Ir point source, and 3-D limited-angle SPECT-image-based source-tracking performances were evaluated for various source intensities and positions. RESULTS: The detector module attached to the collimator could discriminate the 192Ir point source with about 3.4% detection efficiency when including the total counts in the entire deposited energy region. As the result of collimator optimization, hole size, thickness, and length were determined to be 0.5, 0.2, and 45 mm, respectively. Accordingly, the source intensities and positions also were successfully tracked with the 3-D SPECT imaging system when the C-arm was rotated within 110° in 2 seconds. CONCLUSIONS: We expect that this system can be effectively implemented for online IGABT and in vivo patient dose verification.

Circulating RNA Profiling in Postreperfusion Plasma From Kidney Transplant Recipients.

BACKGROUND: Ischemia/reperfusion injury (IRI) is inevitable in kidney transplantation (KT) and may lead to impaired tubular epithelial cell function and reduce graft function and survival. Renal IRI is a complex cellular and molecular event; therefore, investigating the genetic or molecular pathways associated with the early phase of KT would improve our understanding of IRI in KT. MicroRNAs (miRNAs) play a critical role in various pathologic events associated with IRI. METHODS: We compared the expression profile of miRNAs extracted from 2 blood plasma samples, 1 from periphery and the other form gonadal veins immediately after reperfusion, in a total 5 cases of KT. RESULTS: We observed that the total RNA yield was higher in postreperfusion plasma and that a subset of miRNAs was upregulated (miR-let-7a-3p, miR-143-3p, and miR-214-3p) or downregulated (let-7d-3p, let-7d-3p, miR-1246, miR-1260b, miR-1290, and miR-130b-3p) in postreperfusion plasma. Gene ontology analyses revealed that these subsets target different biological functions. Twenty-four predicted genes were commonly targeted by the upregulated miRNAs, and gene ontology enrichment and pathway analyses revealed that these were associated with various cellular activities such as signal transduction or with components such as exosomes and membranous organelles. CONCLUSION: We present 2 subsets of miRNAs that were differentially upregulated or downregulated in postreperfusion plasma. Our findings may enhance our understanding of miRNA-mediated early molecular events related to IRI in KT.

Monte Carlo methods for device simulations in radiation therapy.

Monte Carlo (MC) simulations play an important role in radiotherapy, especially as a method to evaluate physical properties that are either impossible or difficult to measure. For example, MC simulations (MCSs) are used to aid in the design of radiotherapy devices or to understand their properties. The aim of this article is to review the MC method for device simulations in radiation therapy. After a brief history of the MC method and popular codes in medical physics, we review applications of the MC method to model treatment heads for neutral and charged particle radiation therapy as well as specific in-room devices for imaging and therapy purposes. We conclude by discussing the impact that MCSs had in this field and the role of MC in future device design.

Expansion of CD45RA-FOXP3++ regulatory T cells is associated with immune tolerance in patients with combined kidney and bone marrow transplantation.

OBJECTIVES: Simultaneous transplantation of a solid organ and bone marrow from the same donor is a possible means of achieving transplant tolerance. Here, we attempted to identify biomarkers that indicate transplant tolerance for discontinuation of immunosuppressants in combined kidney and bone marrow transplantation (CKBMT). METHODS: Conventional kidney transplant (KT) recipients (n = 20) and CKBMT recipients (n = 6) were included in this study. We examined various immunological parameters by flow cytometry using peripheral blood mononuclear cells (PBMCs), including the frequency and phenotype of regulatory T (Treg) cell subpopulations. We also examined the suppressive activity of the Treg cell population in the setting of mixed lymphocyte reaction (MLR) with or without Treg cell depletion. RESULTS: Among six CKBMT recipients, three successfully discontinued immunosuppressants (tolerant group) and three could not (non-tolerant group). The CD45RA-FOXP3++ Treg cell subpopulation was expanded in CKBMT recipients compared to conventional kidney transplant patients, and this was more obvious in the tolerant group than the non-tolerant group. In addition, high suppressive activity of the Treg cell population was observed in the tolerant group. The ratio of CD45RA-FOXP3++ Treg cells to CD45RA-FOXP3+ cells indicated good discrimination between the tolerant and non-tolerant groups. CONCLUSION: Thus, our findings propose a biomarker that can distinguish CKBMT patients who achieve transplant tolerance and are eligible for discontinuation of immunosuppressants and may provide insight into tolerance mechanisms in CKBMT.

Contributors to reduced life expectancy among Native Americans in the Four Corners States.

To assess trends in life expectancy and the contribution of specific causes of death to Native American-White longevity gaps in the Four Corners states, we used death records from the National Center for Health Statistics and population estimates from the U.S. Census Bureau from 1999-2017 to generate period life tables and decompose racial gaps in life expectancy. Native American-White life expectancy gaps narrowed between 2001 and 2012 but widened thereafter, reaching 4.92 years among males and 2.06 years among females in 2015. The life expectancy disadvantage among Native American males was primarily attributable to motor vehicle accidents (0.96 years), liver disease (1.22 years), and diabetes (0.78 years). These causes of deaths were also primary contributors to the gap among females, forming three successive waves of mortality that occurred in young adulthood, midlife, and late adulthood, respectively, among Native American males and females. Interventions to reduce motor vehicle accidents in early adulthood, alcohol-related mortality in midlife, and diabetes complications at older ages could reduce Native American-White longevity disparities in the Four Corners states.

Gestational Age at Birth and Risk of Developmental Delay: The Upstate KIDS Study.

OBJECTIVE: The aim of this study is to model the association between gestational age at birth and early child development through 3 years of age. STUDY DESIGN: Development of 5,868 children in Upstate KIDS (New York State; 2008-2014) was assessed at 7 time points using the Ages and Stages Questionnaire (ASQ). The ASQ was implemented using gestational age corrected dates of birth at 4, 8, 12, 18, 24, 30, and 36 months. Whether children were eligible for developmental services from the Early Intervention Program was determined through linkage. Gestational age was based on vital records. Statistical models adjusted for covariates including sociodemographic factors, maternal smoking, and plurality. RESULTS: Compared with gestational age of 39 weeks, adjusted odds ratios (aOR) and 95% confidence intervals of failing the ASQ for children delivered at <32, 32-34, 35-36, 37, 38, and 40 weeks of gestational age were 5.32 (3.42-8.28), 2.43 (1.60-3.69), 1.38 (1.00-1.90), 1.37 (0.98-1.90), 1.29 (0.99-1.67), 0.73 (0.55-0.96), and 0.51 (0.32-0.82). Similar risks of being eligible for Early Intervention Program services were observed (aOR: 4.19, 2.10, 1.29, 1.20, 1.01, 1.00 [ref], 0.92, and 0.78 respectively for <32, 32-34, 37, 38, 39 [ref], 40, and 41 weeks). CONCLUSION: Gestational age was inversely associated with developmental delays for all gestational ages. Evidence from our study is potentially informative for low-risk deliveries at 39 weeks, but it is notable that deliveries at 40 weeks exhibited further lower risk.

Development of integrated prompt gamma imaging and positron emission tomography system for in vivo 3-D dose verification: a Monte Carlo study.

An accurate knowledge of in vivo proton dose distribution is key to fully utilizing the potential advantages of proton therapy. Two representative indirect methods for in vivo range verification, namely, prompt gamma (PG) imaging and positron emission tomography (PET), are available. This study proposes a PG-PET system that combines the advantages of these two methods and presents detector geometry and background reduction techniques optimized for the PG-PET system. The characteristics of the secondary radiations emitted by a water phantom by interaction with a 150 MeV proton beam were analysed using Geant4.10.00, and the 2-D PG distributions were obtained and assessed for different detector geometries. In addition, the energy window (EW), depth-of-interaction (DOI), and time-of-flight (TOF) techniques are proposed as the background reduction techniques. To evaluate the performance of the PG-PET system, the 3-D dose distribution in the water phantom caused by two proton beams of energies 80 MeV and 100 MeV was verified using 16 optimal detectors. The thickness of the parallel-hole tungsten collimator of pitch 8 mm and width 7 mm was determined as 200 mm, and that of the GAGG scintillator was determined as 30 mm, by an optimization study. Further, 3-7 MeV and 2-7 MeV were obtained as the optimal EWs when the DOI and both the DOI and TOF techniques were applied for data processing, respectively; the detector performances were improved by about 38% and 167%, respectively, compared with that when applying only the 3-5 MeV EW. In this study, we confirmed that the PG distribution can be obtained by simply combining the 2-D parallel hole collimator and the PET detector module. In the future, we will develop an accurate 3-D dose evaluation technique using deep learning algorithms based on the image sets of dose, PG, and PET distributions for various proton energies.

Integrated whole liver histologic analysis of the allogeneic islet distribution and characteristics in a nonhuman primate model.

The most obvious method to observe transplanted islets in the liver is direct biopsy, but the distribution and location of the best biopsy site in the recipient's liver are poorly understood. Islets transplanted into the whole liver of five diabetic cynomolgus monkeys that underwent insulin-independent survival for an extended period of time after allo-islet transplantation were analyzed for characteristics and distribution tendency. The liver was divided into segments (S1-S8), and immunohistochemistry analysis was performed to estimate the diameter, beta cell area, and islet location. Islets were more distributed in S2 depending on tissue size; however, the number of islets per tissue size was high in S1 and S8. Statistical analysis revealed that the characteristics of islets in S1 and S8 were relatively similar to other segments despite various transplanted islet dosages and survival times. In conclusion, S1, which exhibited high islet density and reflected the overall characteristics of transplanted islets, can be considered to be a reasonable candidate for a liver biopsy site in this monkey model. The findings obtained from the five monkey livers with similar anatomical features to human liver can be used as a reference for monitoring transplanted islets after clinical islet transplantation.

Inducing Transient Mixed Chimerism for Allograft Survival Without Maintenance Immunosuppression With Combined Kidney and Bone Marrow Transplantation: Protocol Optimization.

BACKGROUND: Tolerance induction is an important goal in the field of organ transplantation. We have sequentially modified our conditioning regimen for induction of donor-specific tolerance in recipients of major histocompatibility complex-mismatched combined kidney and bone marrow transplantation (CKBMT). METHODS: From December 2011 to May 2017, 8 major histocompatibility complex-mismatched patients received CKBMT. The initial conditioning regimen (protocol 1) consisted of cyclophosphamide (CP), rituximab, rabbit antithymocyte globulin, and thymic irradiation. Tacrolimus and steroids were used for the maintenance of immunosuppression (IS). RESULTS: This regimen was complicated by transient acute kidney injury, which has been the major clinical feature of engraftment syndrome and side effects of CP, although one of 2 subjects successfully discontinued his IS for 14 months. The conditioning regimen was modified by reducing the CP dose and adding fludarabine (protocol 2). The final modification was reducing the fludarabine and rabbit antithymocyte globulin doses (protocol 3). Mixed chimerism, detected by the short tandem repeat method, was achieved transiently in all subjects for 3-20 weeks. Among the 3 subjects treated with protocol 2, IS was successfully discontinued for >35 months in one subject, but the other 2 subjects suffered from severe BK virus-associated nephritis. All 3 subjects treated with protocol 3 tolerated the protocol well and have successfully discontinued IS for >4-41 months. Interestingly, de novo donor-specific antibody was not detected in any subject during all the follow-up periods. CONCLUSIONS: Our clinical trial has shown that long-term renal allograft survival without maintenance IS can be achieved by induction of mixed chimerism following CKBMT.

Comparative study of human and cynomolgus T-cell depletion with rabbit anti-thymocyte globulin (rATG) treatment-for dose adjustment in a non-human primate kidney transplantation model.

Rabbit-antithymocyte globulin (rATG) is commonly used in kidney transplantation (KT) as an induction agent and is also commonly used in non-human primate (NHP) KT models. However, the optimal dose has not been reported. In this study, we evaluated which cumulative dose of rATG was most appropriate for transplantation in NHPs. Cynomolgus monkeys were treated with intravenous 5 mg/kg rATG (Thymoglobulin®, Genzyme Ltd., UK) twice, on days 0 and 2 (a total of 10 mg/kg, n=2), or 4 times, on days 0, 1, 2, and 3 (a total of 20 mg/kg, n=6). In addition, we performed allo-KT in cynomolgus monkeys (n=4) with a cumulative 20 mg/kg dose of rATG with optimized dosing for induction therapy. We further compared immune cells, including naïve, central memory, and effector memory T cells, in reconstituted distributions in human KT patients (n=22). The kinetics of lymphocytes showed a rapid decrease at day 1 that was maintained for 2 weeks in the 20 mg/kg rATG group, while lymphocyte depletion was not maintained for more than 1 week in the 10 mg/kg rATG group. During the early period of rATG treatment in the NHP-KT model, the frequency of total T cells in the 20 mg/kg group showed a pattern of depletion similar with that of KT patients treated with rATG (1.5 mg/kg, 3 days). However, the pattern of reconstituted T cell subpopulations was different, as the number of effector memory cells rebounded in the NHP-KT model. These data indicate that lymphocyte-depletion induced by rATG was influenced by cumulative dose, and that an rATG dose of 20 mg/kg is suitable for induction therapy in renal transplantation in cynomolgus monkeys compared to human KT.

Cyclophosphamide and fludarabine monophosphate dose optimization for the non-myeloablative condition in non-human primates to induce transient mixed chimerism via bone marrow transplantation.

Bone marrow preconditioning using cyclophosphamide (CP) is generally used for bone marrow transplantation (BMT). However, because of CP's hepatotoxicity and nephrotoxicity, additional fludarabine (FDR) administration and a reduced dose of CP are used for reduced-intensity preconditioning. Recently, preclinical studies using non-human primates (NHPs) were performed to induce immune tolerance after solid organ transplantation by conducting BMT simultaneously. However, dose optimization of CP and FDR for BMT preconditioning in cynomolgus monkeys has not been conducted. Therefore, the objective of this study was to evaluate the efficacy and tolerability of induction protocols using different doses of CP and FDR. Our results showed that relatively low-dose CP (30 mg/kg×2) combined with additional high-dose FDR (60 mg/m2×4) was associated with sufficient suppression in periphery as well as in bone marrow compared with high-dose CP (60 mg/kg×2) combined with low-dose FDR (30 mg/m2×4) and did not show hepatic or renal toxicity. CD34+ stem cells were also well suppressed with both doses. Therefore, we concluded that the combination of 60 mg/kg of CP with 240 mg/m2 of FDR can be used effectively and safely for non-myeloablative preconditioning for BMT in cynomolgus monkeys.

Monte Carlo simulation of a 2D dynamic multileaf collimator to improve the plan quality in radiotherapy plan: a proof-of-concept study.

The leaf width of a multileaf collimator (MLC) determines the dose conformity to the target volume. The objective of this study was to investigate the feasibility of a two-dimensional dynamic MLC (2DDMLC) to improve the treatment plan quality with a fixed leaf width. The treatment head of the Clinac™ linear accelerator with the Millennium 120™ MLC was modelled with the Geant4 (for GEometry ANd Tracking) tollkit using the Monte Carlo (MC) method. The 2DDMLC produces a beam aperture by moving the MLC bank vertically to the leaf movement. Thus, the effect of the 2DDMLC motion on beam divergence and beam fluence resolution was evaluated by comparing the dose distributions between the conventional MLC motion and the 2DDMLC. Finally, the 2DDMLC was employed for dynamic conformal arc therapy for 13 brain cancer patients. The dose-volumetric parameters, including the dose delivered to 98% of the target volume (D 98%), percent volume given 20% of the prescribed dose (V 20%), and conformity index (CI) were compared with those of the conventional MLC. For the 6 MV beam of the MC model, the depth dose and lateral dose distribution differed by less than 2% between the simulation and measurement. The 2DDMLC did not significantly influence beam divergence and sharpened the beam. In clinical use, the dose delivered to the target was almost identical between the 2DDMLC and conventional MLC (D 98% = 29.74 Gy versus 29.71 Gy, p  = 0.18). The CI was improved with the use of the 2DDMLC (CI = 1.49 versus 1.47, p  = 0.14). Moreover, irradiation of normal tissue was reduced with the 2DDMLC compared with conventional MLC (V 20% = 17.22% versus 17.45%, p  < 0.001). The 2DDMLC improved the dose conformity to the target volume and reduced the irradiation of the normal tissue compared with the conventional MLC.

Development of accurate dose evaluation technique of X-ray inspection for quality assurance of semiconductor with Monte Carlo simulation.

Since higher dose delivered to a semiconductor leads to more functional loss to the device, accurate dose evaluation of the semiconductor is very important to reduce the defect rate during x-ray inspection. The aim of this study is to develop the technique to accurately evaluate the absorbed dose to the semiconductor using the Monte Carlo method. The x-ray radiographic system was modeled based on the Geant4 Monte Carlo tool-kit. The Monte Carlo commissioning was performed by comparing the energy spectrum between the simulation and measurement. The dose evaluation technique for the semiconductor was developed, and the dose delivered to the semiconductor device was evaluated according to various x-ray energies. The energy spectrum of the x-ray beam simulated with Geant4 was validated with the experiment using the CdTe detector for various x-ray beams. The accurate dose to the semiconductor component was assessed according to various x-ray energies. The x-rays of 25 keV energy delivered the highest dose to the silicon die, while the 67.5 keV showed the minimum dose to the die. It was observed that the higher energy over about 70 keV also increased the dose with the scattered photons produced in the solder ball and circuit board. The technique to accurately determine the absorbed dose in the semiconductor was suggested and the x-ray energy deliver the high dose to the semiconductor die was assessed. These results could be fundamentally used to reduce the dose in semiconductor and defect rate in x-ray inspection.

Development of advanced skin dose evaluation technique using a tetrahedral-mesh phantom in external beam radiotherapy: a Monte Carlo simulation study.

Incorrect prediction of skin dose in external beam radiotherapy (EBR) can have normal tissue complication such as acute skin desquamation and skin necrosis. The absorbed dose of skin should be evaluated within basal layer, placed between the epidermis and dermis layers. However, current treatment planning systems (TPS) cannot correctly define the skin layer because of the limitation of voxel resolution in computed tomography (CT). Recently, a new tetrahedral-mesh (TM) phantom was developed to evaluate radiation dose realistically. This study aims to develop a technique to evaluate realistic skin dose using the TM phantom in EBR. The TM phantom was modeled with thin skin layers, including the epidermis, basal layer, and dermis from CT images. Using the Geant4 toolkit, the simulation was performed to evaluate the skin dose according to the radiation treatment conditions. The skin dose was evaluated at a surface depth of 50 µm and 2000 µm. The difference in average skin dose between depths was up to 37%, depending on the thickness and region of the skin to be measured. The results indicate that the skin dose has been overestimated when the skin is evaluated using commercial TPS. Although it is not possible with traditional TPS, our skin dose evaluation technique can realistically express the absorbed dose at thin skin layers from a patient-specific phantom.

Combination therapy with c-met inhibitor and TRAIL enhances apoptosis in dedifferentiated liposarcoma patient-derived cells.

BACKGROUND: Liposarcoma (LPS) is a tumor derived from adipose tissue, and has the highest incidence among soft tissue sarcomas. Dedifferentiated liposarcoma (DDLPS) is a malignant tumor with poor prognosis. Recurrence and metastasis rates in LPS remain high even after chemotherapy and radiotherapy following complete resection. Therefore, the development of advanced treatment strategies for LPS is required. In the present study, we investigated the effect of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) treatment, and of combination treatment using TRAIL and a c-Met inhibitor on cell viability and apoptosis in LPS and DDLPS cell lines of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) treatment, and of combination treatment using TRAIL and a c-Met inhibitor. METHODS: We analyzed cell viability after treatment with TRAIL and a c-Met inhibitor by measuring CCK8 and death receptor 5 (DR5) expression levels via fluorescence activated cell sorting (FACS) in both sarcoma cell lines and DDLPS patient-derived cells (PDCs). Moreover, we validated the effects of TRAIL alone and in combination with c-Met inhibitor on apoptosis in LPS cell lines and DDLPS PDCs via FACS. RESULTS: Our results revealed that combination treatment with a c-Met inhibitor and human recombinant TRAIL (rhTRAIL) suppressed cell viability and induced cell death in both sarcoma cell lines and DDLPS PDCs, which showed varying sensitivities to rhTRAIL alone. Also, we confirmed that treatment with a c-Met inhibitor upregulated DR5 levels in sarcoma cell lines and DDLPS PDCs. In both TRAIL-susceptible and TRAIL-resistant cells subjected to combination treatment, promotion of apoptosis was dependent on DR5 upregulation. CONCLUSION: From these results, our findings validated that DR5 up-regulation caused by combination therapy with a c-Met inhibitor and rhTRAIL enhanced TRAIL sensitization and promoted apoptosis. We propose the use of this approach to overcome TRAIL resistance and serve as a novel treatment strategy for clinical trials.

Determining the energy spectrum of clinical linear accelerator using an optimized photon beam transmission protocol.

PURPOSE: The complex beam delivery techniques for patient treatment using a clinical linear accelerator (linac) may result in variations in the photon spectra, which can lead to dosimetric differences in patients that cannot be accounted for by current treatment planning systems (TPSs). Therefore, precise knowledge of the fluence and energy spectrum (ES) of the therapeutic beam is very important. However, owing to the high energy and flux of the beam, the ES cannot be measured directly, and validation of the spectrum modeled in the TPS is difficult. The aim of this study is to develop an efficient beam transmission measurement procedure for accurately reconstructing the ES of a therapeutic x-ray beam generated by a clinical linac. METHODS: The attenuation of a 6 MV photon beam from an Elekta Synergy Platform clinical linac through different thicknesses of graphite and lead was measured using an ion chamber. The response of the ion chamber as a function of photon energy was obtained using the Monte Carlo (MC) method in the Geant4 simulation code. Using the curves obtained in the photon beam transmission measurements and the ion chamber energy response, the ES was reconstructed using an iterative algorithm based on a mathematical model of the spectrum. To evaluate the accuracy of the spectrum reconstruction method, the reconstructed ES (ESrecon ) was compared to that determined by the MC simulation (ESMC ). RESULTS: The ion chamber model in the Geant4 simulation was well validated by comparing the ion chamber perturbation factors determined by the TRS-398 calibration protocol and EGSnrc; the differences were within 0.57%. The number of transmission measurements was optimized to 10 for efficient spectrum reconstruction according to the rate of increase in the spectrum reconstruction accuracy. The distribution of ESrecon obtained using the measured transmission curves was clearly similar to the reference, ESMC , and the dose distributions in water calculated using ESrecon and ESMC were similar within a 2% local difference. However, in a heterogeneous medium, the dose discrepancy between them was >5% when a complex beam delivery technique composed of 171 control points was used. CONCLUSIONS: The proposed measurement procedure required a total time of approximately 1 h to obtain and analyze 20 transmission measurements. In addition, it was confirmed that the transmission curve of high-Z materials influences the accuracy of spectrum reconstruction more than that of low-Z materials. A well-designed transmission measurement protocol suitable for clinical environments could be an essential tool for better dosimetric accuracy in patient treatment and for periodic verification of the beam quality.

Cardiovascular disease family history and risk of pregnancy loss.

PURPOSE: To determine whether family history of cardiovascular disease (CVD) is a risk factor for pregnancy loss, given potential shared etiology, including vascular mechanisms involved in reproduction and placentation. METHODS: In a prospective study, first-degree family histories were self-reported before pregnancy among women with 1-2 previous losses. Women were followed for up to 6 menstrual cycles while attempting pregnancy and through pregnancy. Pregnancies were ascertained by urinary human chorionic gonadotropin and confirmed by ultrasound. Risk ratios and 95% confidence intervals for pregnancy loss were estimated using weighted Poisson regression models with robust standard errors adjusted for covariates including prepregnancy body mass index and sociodemographics. RESULTS: Of 1228 women enrolled, 742 had a clinically confirmed pregnancy, and of these, 18% experienced a clinical pregnancy loss. Forty six percent of women reported family history of CVD, diabetes, hypertension, or hypercholesterolemia/dyslipidemia. Family history of CVD was not associated with the risk of pregnancy loss overall (1.01; 95% confidence interval: 0.64, 1.59) or among women with 2 previous losses (1.05; 0.51, 2.17). Family history of hypertension was also not associated with pregnancy loss (0.98; 0.65, 1.46). CONCLUSIONS: Family history of CVD is not providing additional information helpful in determining the risk of subsequent pregnancy loss in an at-risk group.

Development of a Geant4-based independent patient dose validation system with an elaborate multileaf collimator simulation model.

Despite the improvements in the dose calculation models of the commercial treatment planning systems (TPS), their ability to accurately predict patient dose is still limited. One of the limitations is caused by the simplified model of the multileaf collimator (MLC). The aim of this study was to develop a Monte Carlo (MC) method-based independent patient dose validation system with an elaborate MLC model for more accurate dose evaluation. Varian Clinac 2300 IX was simulated using Geant4 toolkits, after which MC commissioning with measurements was performed to validate the simulation model. A DICOM-RT interface was developed to obtain the beam delivery conditions including the hundreds of MLC motions. Finally, the TPS dose distributions were compared with the MC dose distributions for water phantom cases and a patient case. Our results show that the TPS overestimated the absolute abutting leakage dose in the closed MLC field, with about 20% more of the maximum dose than that of the MC calculation. For water phantom cases, the dose distributions inside the target region were almost identical with the dose difference of less than 2%, while the dose near the edge of the target shows difference about 10% between Geant4 and TPS due to geometrical differences in MLC model. For the patient analysis, the Geant4 and TPS doses of all organs were matched well within 1.4% of the prescribed dose. However, for organs located in areas with high ratio of leaf pairs with distances less than 10 mm leaf pair (LP(<10mm) ), the maximum dose of TPS was overestimated by about 3% of the prescribed dose. These dose comparison results demonstrate that our system for calculating the patient dose is quite accurate. Furthermore, if the MLC sequences in treatment plan have a large ratio of LP(short) , more than 3% dose difference in normal tissue could be seen.

Maternal polycystic ovarian syndrome and offspring growth: the Upstate KIDS Study.

BACKGROUND: Polycystic ovarian syndrome (PCOS) is the most common cause of female infertility and is associated with higher levels of circulating androgens. Exposure to higher levels of androgens in utero may be a risk factor for obesity among children of women with PCOS. METHODS: We examined whether maternal PCOS was associated with differences in offspring growth and obesity in the Upstate KIDS study, a prospective cohort study of infants born in New York State (excluding New York City) oversampled for fertility treatments and multiple births. Measurements of offspring length/height and weight were recorded at doctor's visits through 3 years of age. PCOS diagnosis was self-reported by mothers at baseline. We used linear mixed models with robust SEs to estimate differences in growth by maternal PCOS exposure. We used logistic regression to examine whether infants experienced rapid weight gain at 4, 9 and 12 months. Growth measures were reported by 4098 mothers for 4949 children (1745 twins). Of these, 435 mothers (10.6%) had a diagnosis of PCOS. RESULTS: Compared with children born to mothers without PCOS, children of mothers with PCOS did not have significant differences in weight (4.81 g, 95% CI -95.1 to 104.7), length/height (0.18 cm, 95% CI -0.16 to 0.52) and body mass index (-0.14 kg/m2, 95% CI -0.30 to 0.01) through 3 years of age. We also observed no association between maternal PCOS and offspring rapid weight gain. CONCLUSIONS: Overall, we found little evidence to suggest that maternal PCOS influences early childhood growth in this large, prospective cohort study.

Maternal polycystic ovarian syndrome and early offspring development.

STUDY QUESTION: Is maternal polycystic ovarian syndrome (PCOS) associated with developmental delays in offspring? SUMMARY ANSWER: Offspring of mothers with PCOS were at higher risk of failure on the Ages and Stages Questionnaire (ASQ). WHAT IS KNOWN ALREADY: There is growing evidence that offspring of mothers with PCOS may be at higher risk for developmental disorders due to potential exposure to hyperandrogenism and insulin resistance. Few studies exist regarding maternal PCOS and early childhood development in the USA. STUDY DESIGN, SIZE, DURATION: The Upstate KIDS Study is a population-based prospective cohort study of infants born between 2008 and 2010 in New York State (excluding New York City), originally designed to study-and finding no impact of-infertility treatment exposure on child development. Children were followed up to 36 months of age. In all, 4453 mothers completed one or more developmental screening instruments for 5388 children (35.5% twins) up to 36 months of age. PARTICIPANTS/MATERIALS, SETTING, METHODS: In our study, 458 mothers (10.3%) reported a healthcare provider's diagnosis of PCOS, as well as the related treatment received, on the baseline study questionnaire. Parents completed the ASQ on their child's development at 4, 8, 12, 18, 24, 30 and 36 months of age to assess fine motor, gross motor, communication, personal-social functioning and problem-solving cognitive domains. We used generalized linear mixed models to estimate odds ratios (OR) between PCOS diagnosis and failures in the ASQ adjusted for maternal age, race, BMI, education, marital status, smoking, alcohol consumption, diabetes, insurance and plurality. MAIN RESULTS AND THE ROLE OF CHANCE: Diagnosis of PCOS was associated with increased risk of the offspring failing the fine motor domain (adjusted odds ratio (aOR) = 1.77; 95% CI: 1.09, 2.89), largely driven by higher risk in female singletons (aOR = 2.23; 1.16, 4.29). Twins of mothers with PCOS had higher risk of failing the communication (aOR = 1.94; 1.19, 3.18) and personal-social functioning (aOR = 1.76; 1.12, 2.77) domains compared to twins born to mothers without PCOS. Compared to offspring of women without PCOS, offspring of women who reported receiving no treatment for their PCOS had a stronger association with failing the ASQ (aOR = 1.68; 0.95, 2.75) than the association among offspring of women who reported PCOS treatment (aOR = 1.16; 0.79, 1.73). LIMITATIONS, REASONS FOR CAUTION: Further study is needed to confirm the role of maternal PCOS in early offspring development with provider-validated diagnosis of PCOS. WIDER IMPLICATIONS OF THE FINDINGS: If confirmed, these findings suggest that offspring of women with PCOS may be at increased risk for developmental delay. STUDY FUNDING/COMPETING INTEREST(S): Supported by the Intramural Research Program of the Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD; contracts HHSN275201200005C, #HHSN267200700019C). Authors have no competing interests to declare. TRIAL REGISTRATION NUMBER: Not applicable.