Amniotic fluid content in children with kidney and urinary tract anomalies determines pre- and postnatal development.

BACKGROUND: Renal oligohydramnios (ROH) describes an abnormally low volume of amniotic fluid (AF) during pregnancy. ROH is mostly caused by congenital fetal kidney anomalies. The ROH diagnosis frequently implies an increased risk of peri- and postnatal fetal mortality and morbidity. The present study aimed to evaluate the impact of ROH on pre-and postnatal development in children with congenital kidney anomalies. METHODS: This retrospective study included 168 fetuses with anomalies in the kidney and urinary tract. Based on the amount of AF measured by ultrasound, patients were divided into three groups: normal amniotic fluid (NAF), amniotic fluid in the lower normal range (LAF), and ROH. These groups were compared with respect to prenatal sonographic parameters, perinatal outcomes, and postnatal outcomes. RESULTS: Among the 168 patients with congenital kidney anomalies, 26 (15%) had ROH, 132 (79%) had NAF, and 10 (6%) had LAF. Of the 26 families affected by ROH, 14 (54%) decided to terminate pregnancy. Of 10 live-born children in the ROH group, 6 (60%) survived the observation time; of these, 5/6 presented with chronic kidney disease, stages I-III, at their last examination. The main differences in postnatal development between the ROH group and the NAF and LAF groups were: restricted height and weight gain, respiratory issues, complicated feeding, and the presence of extrarenal malformations. CONCLUSIONS: ROH is not a mandatory indicator of severe postnatal kidney function impairment. However, children with ROH have complicated peri-and postnatal periods, due to the presence of concomitant malformations, which must be considered in prenatal care. A higher resolution version of the Graphical abstract is available as Supplementary information.

Rights and duties of genetic counsellors in Germany related to relatives at risk: comparative thoughts on the German Genetic Diagnostics Act.

Genetic testing has familial implications. Counsellors find themselves in (moral) conflict between medical confidentiality (towards the patient) and a potential right or even duty to warn at-risk relatives. Legal regulations vary between countries. English literature about German law is scarce. We reviewed the literature of relevant legal cases, focussing on German law, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. This article aims to familiarise counsellors with their responsibilities, compare the situation between countries and point out legally unresolved areas.According to the German Genetic Diagnostics Act (Gendiagnostikgesetz) in case of an 'avoidable or treatable' genetic disorder, geneticists ought to confine themselves to the obligated advice to the patient. Whether a breach of the duty of confidentiality can be justified in exceptional cases by 'necessity as justification' for actively informing relatives at risk remains legally unclear. In case of a 'neither avoidable nor treatable' genetic disease, geneticists should also refrain from actively informing relatives as the justifiable state of emergency does not permit to break the duty of confidentiality.

Quality assessment of automatically planned O-Ring linac SBRT plans for pelvic lymph node metastases, finding the optimal minimum target size by comparison with robotic SBRT.

PURPOSE: The purpose of this study is to assess the quality of automatic planned O-Ring Halcyon linac SBRT plans for pelvic lymph node metastases and to establish an absolute PTV volume threshold as a plan quality prediction criterion. Compliance of the plans to institutional SBRT plan evaluation criteria and differences in plan quality and treatment delivery times between Halcyon Linac and CyberKnife robotic SBRT were evaluated. METHODS: Twenty-one CyberKnife treatment plans were replanned for Halcyon. Prescription doses range was 26-40 Gy in mean three fractions. The mean/median planning target volume was 4.0/3.6 cm3 . Institutional criteria for the plan evaluation were: New Conformity Index (NCI), Conformity Index (CI), Modified Gradient Index (MGI), selectivity index reciprocal (PIV/TVPIV ), and the target coverage by prescription isodose (%PIV). Statistical analysis based on the receiver operating characteristic (ROC) curve was used to determine a plan quality predictor threshold of the PTV volume. Comparative analysis of normal tissue complication probabilities (NTCP) was used to assess the risk of toxicity in healthy tissues. RESULTS: Seventy-one percent (n = 15)/95% (n = 20) of Halcyon and 81% (n = 17)/100% (n = 21) of CK plans fulfilled all ideal/tolerance criteria. For PTVs above a found optimal threshold of 2.6 cm3 (71%, n = 15), no statistically significant difference was observed between the CI, NCI, PIV/TVPIV , and MGI indexes of both groups, while the coverage (%PIV) was statistically but not clinically significantly different between cohorts. Significantly shorter delivery times are expected with Halcyon. No significant differences in NTCP were observed. CONCLUSION: All but one automatically optimized Halcyon treatment plans demonstrated ideal or acceptable performance. PTV threshold of 2.6 cm3 can be used as decision criteria in clinical settings. The results of our study demonstrated the promising performance of the Halcyon for pelvic SBRT, although plan-specific QA is required to verify machine performance during plan delivery.

Furthering climate-smart farming with the introduction of floating agriculture in Bangladeshi wetlands: Successes and limitations of an innovation transfer.

Although floating farming, a climate-smart practice, is a response to climate change challenges facing agriculture in wetland areas, the adoption of floating agriculture in Bangladesh wetland areas (also known as Haor) is slow. The purpose of our study was to identify the factors that motivate and barriers that inhibit the adoption of floating agriculture in the Haor region in Bangladesh's Kishoreganj district. To achieve our purpose, we used Roger's five-stage innovation-decision theory. We collected data from a sample of 120 Haor rural farmers using a quantitative questionnaire answered via a personal interview. We used a binary logistic regression to identify the factors that predict farmers' motivational actions in adopting floating agriculture. In addition, we rank ordered the data to identify the obstacles that prohibit farmers from implementing floating agriculture. The results demonstrate that education, training related to floating agriculture, credit received, communication behavior, trialability and observability, and complexity in practicing floating agriculture motivate farmers to adopt floating agriculture. The results also show that climatic factors (e.g., high waves and excessive rainfall, aquatic plant scarcity) and non-climatic factors (e.g., inadequate demonstration plots, conflict, and political power abuse) inhibit adoption of floating agriculture. Our study provides suggestions for increasing farmers' adoption of floating agriculture in wetland areas.

A bespoke health risk assessment methodology for the radiation protection of astronauts.

An alternative approach that is particularly suitable for the radiation health risk assessment (HRA) of astronauts is presented. The quantity, Radiation Attributed Decrease of Survival (RADS), representing the cumulative decrease in the unknown survival curve at a certain attained age, due to the radiation exposure at an earlier age, forms the basis for this alternative approach. Results are provided for all solid cancer plus leukemia incidence RADS from estimated doses from theoretical radiation exposures accumulated during long-term missions to the Moon or Mars. For example, it is shown that a 1000-day Mars exploration mission with a hypothetical mission effective dose of 1.07 Sv at typical astronaut ages around 40 years old, will result in the probability of surviving free of all types of solid cancer and leukemia until retirement age (65 years) being reduced by 4.2% (95% CI 3.2; 5.3) for males and 5.8% (95% CI 4.8; 7.0) for females. RADS dose-responses are given, for the outcomes for incidence of all solid cancer, leukemia, lung and female breast cancer. Results showing how RADS varies with age at exposure, attained age and other factors are also presented. The advantages of this alternative approach, over currently applied methodologies for the long-term radiation protection of astronauts after mission exposures, are presented with example calculations applicable to European astronaut occupational HRA. Some tentative suggestions for new types of occupational risk limits for space missions are given while acknowledging that the setting of astronaut radiation-related risk limits will ultimately be decided by the Space Agencies. Suggestions are provided for further work which builds on and extends this new HRA approach, e.g., by eventually including non-cancer effects and detailed space dosimetry.

Brønsted Acid-Catalyzed General Petasis Allylation and Isoprenylation of Unactivated Ketones.

Brønsted acid-catalyzed general Petasis allylation and isoprenylation of unactivated ketones were developed by using o-hydroxyaniline and the corresponding pinacolyl boronic esters. This robust methodology provided access to a broad variety of quaternary homoallylic amines and dienyl amines in high yields, proved to be applicable to a gram-scale synthesis, and allowed the synthesis of a potentially bioactive quaternary homoallylic aminodiol.

Evaluating and expanding the European Union's protected-area network toward potential post-2020 coverage targets.

The Convention on Biological Diversity's (CBD) strategic plan will expire in 2020, but biodiversity loss is ongoing. Scientists call for more ambitious targets in the next agreement. The nature-needs-half movement, for example, has advocated conserving half of Earth to solve the biodiversity crisis, which has been translated to protecting 50% of each ecoregion. We evaluated current protection levels of ecoregions in the territory of one of the CBD's signatories, the European Union (EU). We also explored the possible enlargement of the Natura 2000 network to implement 30% or 50% ecoregion coverage in the EU member states' protected area (PA) network. Based on the most recent land-use data, we examined whether ecoregions have enough natural area left to reach such high coverage targets. We used a spatially explicit mixed integer programing model to estimate the least-cost expansion of the PA network based on 3 scenarios that put different emphasis on total conservation cost, ecological representation of ecosystems, or emphasize an equal share of the burden among member states. To realize 30% and 50% ecoregion coverage, the EU would need to add 6.6% and 24.2%, respectively, of its terrestrial area to its PA network. For all 3 scenarios, the EU would need to designate most recommended new PAs in seminatural forests and other semi- or natural ecosystems. Because 15 ecoregions did not have enough natural area left to implement the ecoregion-coverage targets, some member states would also need to establish new PAs on productive land, allocating the largest share to arable land. Thirty percent ecoregion coverage was met by protecting remaining natural areas in all ecoregions except 3, where productive land would also need to be included. Our results support discussions of higher ecoregions protection targets for post-2020 biodiversity frameworks.

Evaluación y Expansión de la Red de Áreas Protegidas de la Unión Europea hacia Objetivos Potenciales de Cobertura Post 2020 Resumen El plan estratégico del Convenio sobre la Diversidad Biológica (CBD) expirará en 2020, pero la pérdida de la biodiversidad continúa. Los científicos exigen objetivos más ambiciosos para el siguiente acuerdo. Por ejemplo, la corriente la-naturaleza-necesita-la-mitad ha abogado por la conservación de la mitad del planeta para resolver la crisis de la biodiversidad, lo que se ha traducido a la protección del 50% de cada ecoregión. Evaluamos los niveles actuales de protección de las ecoregiones en el territorio de uno de los signatarios de la CBD, la Unión Europea (UE). También exploramos el posible crecimiento de la red Natura 2000 para implementar una cobertura del 30% o 50% de las ecoregiones en la red de áreas protegidas (AP) de los estados miembros de la UE. Con base en los datos más recientes de uso de suelo, examinamos si las ecoregiones todavía tienen suficiente área natural como para alcanzar tales objetivos tan altos de cobertura. Usamos un modelo de programación entera mixta espacialmente explícito para estimar la expansión más asequible de la red de AP con base en tres escenarios que colocan un énfasis diferente sobre el costo total de la conservación, la representación ecológica de los ecosistemas o que enfaticen un porcentaje equitativo de la carga entre los estados miembros. Para alcanzar una cobertura del 30% y 50% de las ecoregiones, la UE necesitaría añadir 6.6% y 24.2%, respectivamente, de su área terrestre a la red de AP. Para los tres escenarios, la UE necesitaría designar la mayoría de las nuevas AP recomendadas en bosques seminaturales y en otros ecosistemas semi- o totalmente naturales. Debido a que 15 ecoregiones no tenían ya suficiente área natural para implementar los objetivos de cobertura de ecoregiones, algunos estados miembros también necesitarían establecer nuevas AP en suelo productivo, asignando la proporción mayor al suelo arable. La cobertura del 30% de las ecoregiones se alcanzó con la protección de las áreas naturales permanecientes en todas las ecoregiones salvo tres, en donde el suelo productivo también necesitaría estar incluido. Nuestros resultados respaldan las discusiones sobre objetivos más altos de protección de ecoregiones para los marcos de trabajo post 2020 para la biodiversidad.

A model of radiation action based on nanodosimetry and the application to ultra-soft X-rays.

A radiation action model based on nanodosimetry is presented. It is motivated by the finding that the biological effects of various types of ionizing radiation lack a consistent relation with absorbed dose. It is postulated that the common fundamental cause of these effects is the production of elementary sublesions (DSB), which are created at a rate that is proportional to the probability to produce more than two ionisations within a volume of 10 base pairs of the DNA. The concepts of nanodosimetry allow for a quantitative characterization of this process in terms of the cumulative probability F2. The induced sublesions can interact in two ways to produce lethal damage. First, if two or more sublesions accumulate in a locally limited spherical volume of 3-10 nm in diameter, clustered DNA damage is produced. Second, consequent interactions or rearrangements of some of the initial damage over larger distances (~ µm) can produce additional lethal damage. From the comparison of theoretical predictions deduced from this concept with experimental data on relative biological effectiveness, a cluster volume with a diameter of 7.5 nm could be determined. It is shown that, for electrons, the predictions agree well with experimental data over a wide energy range. The only free parameter needed to model cell survival is the intersection cross-section which includes all relevant cell-specific factors. Using ultra-soft X-rays it could be shown that the energy dependence of cell survival is directly governed by the nanodosimetric characteristics of the radiation track structure. The cell survival model derived in this work exhibits exponential cell survival at a high dose and a finite gradient of cell survival at vanishing dose, as well as the dependence on dose-rate.

Phosphine-Catalyzed [4+1] Cycloadditions of Allenes with Methyl Ketimines, Enamines, and a Primary Amine.

Unprecedented phosphine-catalyzed [4+1] cycloadditions of allenyl imides have been discovered using various N-based substrates including methyl ketimines, enamines, and a primary amine. These transformations provide a one-pot access to cyclopentenoyl enamines and imines, or (chiral) γ-lactams through two geminal C-C bond or two C-N bond formations, respectively. Several P-based key intermediates including a 1,4-(bis)electrophilic α,ß-unsaturated ketenyl phosphonium species have been detected by 31 P NMR and HRMS analyses, which shed light on the postulated catalytic cycle. The synthetic utility of this new chemistry has been demonstrated through a gram-scaling up of the catalytic reaction as well as regioselective hydrogenation and double condensation to form cyclopentanoyl enamines and fused pyrazole building blocks, respectively.

Predictive factors for response to salvage stereotactic body radiotherapy in oligorecurrent prostate cancer limited to lymph nodes: a single institution experience.

BACKGROUND: In patients presenting with limited nodal recurrence following radical prostatectomy (RP), stereotactic body radiotherapy (SBRT) results might improve with a better case selection. METHODS: Single-institution retrospective analysis of patients presenting with 1-3 lymph node (LN) recurrences (N1 or M1a) on 18F-Choline PET/CT. Prior therapy included radical prostatectomy (RP) ± salvage radiotherapy (RT), in absence of any systemic therapy. Outcome parameters were biochemical response (BR), time to biochemical recurrence (TBR) and time interval between SBRT and androgen deprivation therapy start (TADT). Time to event endpoints was analysed using Kaplan-Meier method. Potential prognostic factors were examined using univariate proportional hazards regression for TADT and logistic regression for BR. The optimal cut-off point for LN size was calculated using the Contal and O'Quigley method. RESULTS: 25 patients fulfilling study criteria were treated with SBRT from January 2010 to January 2015 and retrospectively analysed. Median follow up was 18 months and median LN diameter 10.5 mm. SBRT was delivered to a median dose of 36 Gy in three fractions (range: 30-45 Gy). BR was reached in 52% of cases. Median TBR was 11.9 months and significantly longer in patients with larger LN (Hazard ratio [HR] = 0.87, P = 0.03). Using 14 mm as cut off for LN, median TBR was 10.8 months for patients with small LN (18 patients), and 21.2 months for patients with large LN (6 patients) (P unadjusted = 0.009; P adjusted = 0.099). ADT was started in 32% of patients after a median follow-up of 18 months. CONCLUSIONS: For PCa patients with 1-3 LN recurrence after RP (± salvage RT), SBRT might result in a better biochemical control when delivered to larger sized (≥ 14 mm) LN metastases. This study is hypothesis generating and results should be tested in a larger prospective trial.

On prognostic estimates of radiation risk in medicine and radiation protection.

The problem of expressing cumulative detrimental effect of radiation exposure is revisited. All conventionally used and computationally complex lifetime or time-integrated risks are based on current population and health statistical data, with unknown future secular trends, that are projected far into the future. It is shown that application of conventionally used lifetime or time-integrated attributable risks (LAR, AR) should be limited to exposures under 1 Gy. More general quantities, such as excess lifetime risk (ELR) and, to a lesser extent, risk of exposure-induced death (REID), are free of dose constraints, but are even more computationally complex than LAR and AR and rely on the unknown total radiation effect on demographic and health statistical data. Appropriate assessment of time-integrated risk of a specific outcome following high-dose (more than 1 Gy) exposure requires consideration of competing risks for other radiation-attributed outcomes and the resulting ELR estimate has an essentially non-linear dose response. Limitations caused by basing conventionally applied time-integrated risks on current population and health statistical data are that they are: (a) not well suited for risk estimates for atypical groups of exposed persons not readily represented by the general population; and (b) not optimal for risk projections decades into the future due to large uncertainties in developments of the future secular trends in the population-specific disease rates. Alternative disease-specific quantities, baseline and attributable survival fractions, based on reduction of survival chances are considered here and are shown to be very useful in circumventing most aspects of these limitations. Another main quantity, named as radiation-attributed decrease of survival (RADS), is recommended here to represent cumulative radiation risk conditional on survival until a certain age. RADS, historically known in statistical literature as "cumulative risk", is only based on the radiation-attributed hazard and is insensitive to competing risks. Therefore, RADS is eminently suitable for risk projections in emergency situations and for estimating radiation risks for persons exposed after therapeutic or interventional medical applications of radiation or in other highly atypical groups of exposed persons, such as astronauts.

Dependencies between maternal and fetal autonomic tone.

Background Disturbances in maternal physiology can cause changes in the fetal condition that may lead to impaired fetal development. Synchronous monitoring of cardiac autonomic tone via the assessment of the fetal and maternal heart rate (HR) and heart rate variability (HRV) may provide an appropriate diagnostic window. Methods Partial rank correlation coefficients between the maternal and fetal HR and HRV indices were calculated and verified by testing surrogate data in 315 magnetocardiographic (MCG) recordings from 141 healthy women pregnant with singleton fetuses [18+6 to 39+2 weeks gestational age (WGA)]. We assessed maternal self-perceived depression, anxiety and stress by means of the Depression, Anxiety, Stress Scales self-reporting instrument (DASS42G) questionnaire. Results The maternal HRV correlated positively with the fetal HRV, but negatively with the fetal HR. Correlation was |r|<0.2 in state-independent and gestational age (GA) <32 weeks, but |r|>0.2 in active sleep and GA ≥32 weeks. The DASS42G results correlated with the maternal HRV and HR, while the fetal HR and HRV were not influenced. Conclusion Correlations between maternal and fetal autonomic activation were statistically confirmed. They depend on the GA and active fetal state. As far as healthy subjects are concerned, maternal self-perceived stress, anxiety or depression is mirrored in maternal but not in fetal autonomic tone.

Whole-body dose equivalent including neutrons is similar for 6 MV and 15 MV IMRT, VMAT, and 3D conformal radiotherapy.

PURPOSE: This study investigates the difference in whole-body dose equivalent between 6 and 15 MV image-guided radiotherapy (IGRT) for the treatment of a rhabdomyosarcoma in the prostate. METHODS: A previously developed model for stray radiation of the primary beam was improved and used to calculate the photon dose and photon energy in the out-of-field region for a radiotherapy patient. The dose calculated by the treatment planning system was fused with the model-calculated out-of-field dose, resulting in a whole-body photon dose distribution. The peripheral neutron dose equivalent was calculated using an analytical model from the literature. A daily cone beam CT dose was added to the neutron and photon dose equivalents. The calculated 3D dose distributions were compared to independent measurements conducted with thermoluminescence dosimeters and an anthropomorphic phantom. The dose contributions from the IGRT treatments of three different techniques applied with two nominal X-ray energies were compared using dose equivalent volume histograms (DEVHs). RESULTS: The calculated and measured out-of-field whole-body dose equivalents for the IGRT treatments agreed within (9 ± 10) % (mean and type A SD). The neutron dose equivalent was a minor contribution to the total out-of-field dose up to 50 cm from the isocenter. Further from the isocenter, head leakage was dominating inside the patient body, whereas the neutron dose equivalent contribution was important close to the surface. There were small differences between the whole-body DEVHs of the 6 and 15 MV treatments applied with the same technique, although the single scatter contributions showed large differences. Independent of the beam energy, the out-of-field dose of the volumetric-modulated arc therapy (VMAT) treatment was significantly lower than the dynamic intensity-modulated radiation therapy (IMRT) treatment. CONCLUSION: The calculated whole-body dose helped to understand the importance of the dose contributions in different areas of the patient. Regarding radiation protection of the patient for IGRT treatments, the choice of beam energy is not important, whereas the treatment technique has a large influence on the out-of-field dose. If the patient is treated with intensity-modulated beams, VMAT should be used instead of dynamic IMRT in terms of radiation protection of the patient. In general, the developed models for photon and neutron dose equivalent calculation can be used for any patient geometry, tumor location, and linear accelerator.

Farmer Perceptions of Climate Change, Observed Trends and Adaptation of Agriculture in Pakistan.

Farmers' willingness and ability to adapt agricultural systems depend on their knowledge about changes in climate and perceived risks of extreme events. Using cross-sectional data of 450 farmers collected from three agro-ecological zones of Punjab, Pakistan, this study investigates farmer perceptions of climate change and their agreement with observed climatic trends. In addition, this study explores the correlation between different adaptation stages (perceptions, intentions, and adaptation) and their key drivers using a Multivariate Probit Model. This study also explores the adaptation measures adopted by farmers. The results of the study show that the perceptions of increasing mean temperature match well with locally recorded data. However, a discrepancy is found in some cases between farmer perceptions of rainfall changes and local climate records. Moreover, education, experience, land tenure, land holdings, extension, cooperation, access to weather forecasting, and marketing information are the factors influencing the three adaptation stages. A strong association is found among the three adaptation stages. Particularly, the study confirms the hypothesis that accurate perceptions lead to stronger adaptation intentions compared to underestimated or no perceptions. Further, farmers prefer basic adaptation measures including changing crop varieties, input use and planting dates over advanced measures, such as planting shade trees, soil conservation, and crop diversification. The study recommends providing farmers, especially small landholders and tenants, easy access to information, institutional services and training on the use of advanced measures to reduce negative impacts of climate change at the farm level.

Intensity-modulated radiation therapy dose prescription and reporting: Sum and substance of the International Commission on Radiation Units and Measurements Report 83 for veterinary medicine.

Institutions' adherence to protocol, quality assurance, and radiation parameter reporting are key to adequately interpret and compare treatment outcomes in radiation oncology. In 2017, the editorial board for Veterinary Radiology & Ultrasound adapted author guidelines on "technical information for radiation therapy (RT)". These guidelines provide a framework to report the RT treatment process in manuscripts resulting from veterinary clinical trials. In spite of this framework, however, in implementing IMRT, we have identified different "interpretations" of the extended prescription and reporting recommendations of the International Commission on Radiation Units and Measurements (ICRU 83), even within our small team. In the following commentary review, we provide a short summary of various detailed aspects of the ICRU 83 recommended (IMRT) prescription and reporting, including (a) absorbed target dose specification and prescription, (b) homogeneity and conformity, and (c) reporting of absorbed dose in organs at risk. In particular, we want to share our thoughts on possible dangers of noncompliance in adhering to protocol, prescription, and reporting. As veterinary IMRT publications still sparsely adhere to the recommendations of the ICRU, we were motivated to summarize the recommendations to facilitate appropriate reporting for IMRT in future veterinary studies.

Diastereodivergent Asymmetric 1,3-Dipolar Cycloaddition of Azomethine Ylides and ß-Fluoroalkyl Vinylsulfones: Low Copper(II) Catalyst Loading and Theoretical Studies.

A CuII -catalyzed asymmetric 1,3-dipolar cycloaddition using ß-fluoroalkyl alkenyl arylsulfones as dipolarophiles and glycine/alanine iminoesters as azomethine ylide precursors has been developed. Remarkably, a catalyst loading as low as 0.5 mol % is highly efficient. Accordingly, a wide range of enantioenriched 3-fluoroalkyl pyrrolidines, as well as Δ2 -pyrroline and pyrrole derivatives, are generated in good to excellent yields with high asymmetric induction. This synthetic approach is diastereodivergent in that exo-adducts could be converted into the corresponding exo'-adducts by 1,8-diazabicyclo[5.4.0]undec-7-ene mediated epimerization at C2 of the pyrrolidine core. The free-energy profiles from DFT calculations suggest the Michael addition of the 1,3-dipole to be the rate- and enantiodetermining step, and the origin of stereoselectivity is studied by means of the noncovalent interaction (NCI) analysis.

Tumour size can have an impact on the outcomes of epidemiological studies on second cancers after radiotherapy.

Obtaining a correct dose-response relationship for radiation-induced cancer after radiotherapy presents a major challenge for epidemiological studies. The purpose of this paper is to gain a better understanding of the associated uncertainties. To accomplish this goal, some aspects of an epidemiological study on breast cancer following radiotherapy of Hodgkin's disease were simulated with Monte Carlo methods. It is demonstrated that although the doses to the breast volume are calculated by one treatment plan, the locations and sizes of the induced secondary breast tumours can be simulated and, based on these simulated locations and sizes, the absorbed doses at the site of tumour incidence can also be simulated. For the simulations of point dose at tumour site, linear and non-linear mechanistic models which predict risk of cancer induction as a function of dose were applied randomly to the treatment plan. These simulations provided for each second tumour and each simulated tumour size the predicted dose. The predicted-dose-response-characteristic from the analysis of the simulated epidemiological study was analysed. If a linear dose-response relationship for cancer induction was applied to calculate the theoretical doses at the simulated tumour sites, all Monte-Carlo realizations of the epidemiological study yielded strong evidence for a resulting linear risk to predicted-dose-response. However, if a non-linear dose-response of cancer induction was applied to calculate the theoretical doses, the Monte Carlo simulated epidemiological study resulted in a non-linear risk to predicted-dose-response relationship only if the tumour size was small (< 1.5 cm). If the diagnosed breast tumours exceeded an average diameter of 1.5 cm, an applied non-linear theoretical-dose-response relationship for second cancer falsely resulted in strong evidence for a linear predicted-dose relationship from the epidemiological study realizations. For a typical distribution of breast cancer sizes, the model selection probability for a resulting predicted-dose linear model was 61% although a non-linear theoretical-dose-response relationship for cancer induction had been applied. The results of this study, therefore, provide evidence that the shapes of epidemiologically obtained dose-response relationships for cancer induction can be biased by the finite size of the diagnosed second tumour, even though the epidemiological study was done correctly.

Pentaerythrityltetranitrate (PETN) improves utero- and feto-placental Doppler parameters in pregnancies with impaired utero-placental perfusion in mid-gestation - a secondary analysis of the PETN-pilot trial.

AIM: In pregnancies complicated by impaired utero-placental perfusion, pentaeritrithyltetranitrate (PETN) has been shown to reduce the risk of severe fetal growth restriction (FGR) and perinatal death by 39%. The effect is most likely related to the vasodilatative influence of PETN. To assess its impact on utero-placental and fetal perfusion, we analyzed the Doppler parameters measured during the PETN pilot-trial. METHODS: One hundred and eleven pregnancies presenting impaired utero-placental resistance at mid-gestation were included in the trial. Fifty-four women received PETN, while 57 received a placebo. Doppler velocimetry measurements were monitored biweekly. Statistical analysis was performed using a mixed linear model. RESULTS: Within the first week of treatment, the mean pulsatility index (PI) of the uterine artery (UtA) dropped more prominently in the PETN group [-0.20, 95% confidence interval (CI): -0.34 to -0.05, P=0.007). The adjusted relative risk (RR) for abnormal cerebro-placental ratio (CPR) was significantly reduced by PETN [RR 0.412 (95% CI: 0.181-0.941)]. Kaplan-Meier analysis demonstrates the postponement of absent end-diastolic flow (AED), absent or reverse end-diastolic flow (ARED), brain sparing and abnormal cerebroplacental ratio (CPR) in the PETN group. CONCLUSION: The demonstrated effect of PETN on utero-placental and feto-placental perfusion strengthens the evidence for a positive impact in pregnancies complicated by impaired placental perfusion and might explain the effect on neonatal outcome, as shown in the PETN-pilot trial.

Formal Allylic C(sp3)-H Bond Activation of Alkenes Triggered by a Sodium Amide.

The catalytic use of a sodium amide has been exploited for formal allylic C(sp3)-H bond activation of alkenes under mild conditions. Subsequent C-C bond formations with imines have proceeded in high yields with complete regioselectivity and excellent geometric selectivity. Aromatic cyano, chloro, and bromo functionalities are tolerated by the transition metal-free catalyst. Complex amines bearing a C═C double bond and distinct heteroaromatic units have been prepared in a single step. The critical importance of sodium versus other s-, p-, d-, and f-block metals as well as metal-free systems has been revealed. In addition, two catalytically active sodium-based intermediates were detected by NMR and HRMS analyses.

The probabilities of one- and multi-track events for modeling radiation-induced cell kill.

In view of the clinical importance of hypofractionated radiotherapy, track models which are based on multi-hit events are currently reinvestigated. These models are often criticized, because it is believed that the probability of multi-track hits is negligible. In this work, the probabilities for one- and multi-track events are determined for different biological targets. The obtained probabilities can be used with nano-dosimetric cluster size distributions to obtain the parameters of track models. We quantitatively determined the probabilities for one- and multi-track events for 100, 500 and 1000 keV electrons, respectively. It is assumed that the single tracks are statistically independent and follow a Poisson distribution. Three different biological targets were investigated: (1) a DNA strand (2 nm scale); (2) two adjacent chromatin fibers (60 nm); and (3) fiber loops (300 nm). It was shown that the probabilities for one- and multi-track events are increasing with energy, size of the sensitive target structure, and dose. For a 2 × 2 × 2 nm3 target, one-track events are around 10,000 times more frequent than multi-track events. If the size of the sensitive structure is increased to 100-300 nm, the probabilities for one- and multi-track events are of the same order of magnitude. It was shown that target theories can play a role for describing radiation-induced cell death if the targets are of the size of two adjacent chromatin fibers or fiber loops. The obtained probabilities can be used together with the nano-dosimetric cluster size distributions to determine model parameters for target theories.