Stereoelectronic basis for the kinetic resolution of N-heterocycles with chiral acylating reagents.

The kinetic resolution of N-heterocycles with chiral acylating agents reveals a previously unrecognized stereoelectronic effect in amine acylation. Combined with a new achiral hydroxamate, this effect makes possible the resolution of various N-heterocycles by using easily prepared reagents. A transition-state model to rationalize the stereochemical outcome of this kinetic resolution is also proposed.

Novel dosimetric validation of a commercial CT scanner based deep learning automated contour solution for prostate radiotherapy.

PURPOSE: OAR delineation accuracy influences: (i) a patient's optimised dose distribution (PD), (ii) the reported doses (RD) presented at approval, which represent plan quality. This study utilised a novel dosimetric validation methodology, comprehensively evaluating a new CT-scanner-based AI contouring solution in terms of PD and RD within an automated planning workflow. METHODS: 20 prostate patients were selected to evaluate AI contouring for rectum, bladder, and proximal femurs. Five planning 'pipelines' were considered; three using AI contours with differing levels of manual editing (nominally none (AIStd), minor editing in specific regions (AIMinEd), and fully corrected (AIFullEd)). Remaining pipelines were manual delineations from two observers (MDOb1, MDOb2). Automated radiotherapy plans were generated for each pipeline. Geometric and dosimetric agreement of contour sets AIStd, AIMinEd, AIFullEd and MDOb2 were evaluated against the reference set MDOb1. Non-inferiority of AI pipelines was assessed, hypothesising that compared to MDOb1, absolute deviations in metrics for AI contouring were no greater than that from MDOb2. RESULTS: Compared to MDOb1, organ delineation time was reduced by 24.9 min (96 %), 21.4 min (79 %) and 12.2 min (45 %) for AIStd, AIMinEd and AIFullEd respectively. All pipelines exhibited generally good dosimetric agreement with MDOb1. For RD, median deviations were within ± 1.8 cm3, ± 1.7 % and ± 0.6 Gy for absolute volume, relative volume and mean dose metrics respectively. For PD, respective values were within ± 0.4 cm3, ± 0.5 % and ± 0.2 Gy. Statistically (p < 0.05), AIMinEd and AIFullEd were dosimetrically non-inferior to MDOb2. CONCLUSIONS: This novel dosimetric validation demonstrated that following targeted minor editing (AIMinEd), AI contours were dosimetrically non-inferior to manual delineations, reducing delineation time by 79 %.

Multi-institutional evaluation of a Pareto navigation guided automated radiotherapy planning solution for prostate cancer.

BACKGROUND: Current automated planning solutions are calibrated using trial and error or machine learning on historical datasets. Neither method allows for the intuitive exploration of differing trade-off options during calibration, which may aid in ensuring automated solutions align with clinical preference. Pareto navigation provides this functionality and offers a potential calibration alternative. The purpose of this study was to validate an automated radiotherapy planning solution with a novel multi-dimensional Pareto navigation calibration interface across two external institutions for prostate cancer. METHODS: The implemented 'Pareto Guided Automated Planning' (PGAP) methodology was developed in RayStation using scripting and consisted of a Pareto navigation calibration interface built upon a 'Protocol Based Automatic Iterative Optimisation' planning framework. 30 previous patients were randomly selected by each institution (IA and IB), 10 for calibration and 20 for validation. Utilising the Pareto navigation interface automated protocols were calibrated to the institutions' clinical preferences. A single automated plan (VMATAuto) was generated for each validation patient with plan quality compared against the previously treated clinical plan (VMATClinical) both quantitatively, using a range of DVH metrics, and qualitatively through blind review at the external institution. RESULTS: PGAP led to marked improvements across the majority of rectal dose metrics, with Dmean reduced by 3.7 Gy and 1.8 Gy for IA and IB respectively (p < 0.001). For bladder, results were mixed with low and intermediate dose metrics reduced for IB but increased for IA. Differences, whilst statistically significant (p < 0.05) were small and not considered clinically relevant. The reduction in rectum dose was not at the expense of PTV coverage (D98% was generally improved with VMATAuto), but was somewhat detrimental to PTV conformality. The prioritisation of rectum over conformality was however aligned with preferences expressed during calibration and was a key driver in both institutions demonstrating a clear preference towards VMATAuto, with 31/40 considered superior to VMATClinical upon blind review. CONCLUSIONS: PGAP enabled intuitive adaptation of automated protocols to an institution's planning aims and yielded plans more congruent with the institution's clinical preference than the locally produced manual clinical plans.

The Role of Individual-Level Socioeconomic Status on Nursing Home Placement Accounting for Neighborhood Characteristics.

OBJECTIVE: Independent living is desirable for many older adults. Although several factors such as physical and cognitive functions are important predictors for nursing home placement (NHP), it is also reported that socioeconomic status (SES) affects the risk of NHP. In this study, we aimed to examine whether an individual-level measure of SES is associated with the risk of NHP after accounting for neighborhood characteristics. DESIGN: A population-based study (Olmsted County, Minnesota, USA). SETTING AND PARTICIPANTS: Older adults (age 65+ years) with no prior history of NHP. METHODS: Electronic health records (EHR) were used to identify individuals with any NHP between April 1, 2012 (baseline date) and April 30, 2019. Association between the (HOUsing-based index of SocioEconomic Status (HOUSES) index, an individual-level SES measure based on housing characteristics of current residence, and risk of NHP was tested using random effects Cox proportional hazard model adjusting for area deprivation index (ADI), an aggregated SES measure that captures neighborhood characteristics, and other pertinent confounders such as age and chronic disease burden. RESULTS: Among 15,031 older adults, 3341 (22.2%) experienced NHP during follow-up period (median: 7.1 years). At baseline date, median age was 73 years old with 55% female persons, 91% non-Hispanic Whites, and median number of chronic conditions of 4. Accounting for pertinent confounders, the HOUSES index was strongly associated with risk of NHP (hazard ratio 1.89; 95% confidence interval 1.66‒2.15 for comparing the lowest vs highest quartiles), which was not influenced by further accounting for ADI. CONCLUSIONS AND IMPLICATIONS: This study demonstrates that an individual-level SES measure capturing current individual-specific socioeconomic circumstances plays a significant role for predicting NHP independent of neighborhood characteristics where they reside. This study suggests that older adults who are at higher risk of NHP can be identified by utilizing the HOUSES index and potential individual-level intervention strategies can be applied to reduce the risk for those with higher risk.

Paired Indoor and Outdoor Nitrogen Dioxide Associated With Childhood Asthma Outcomes in a Mixed Rural-Urban Setting: A Feasibility Study.

INTRODUCTION: Nitrogen dioxide (NO2) is known to be a trigger for asthma exacerbation. However, little is known about the role of seasonal variation in indoor and outdoor NO2 levels in childhood asthma in a mixed rural-urban setting of North America. METHODS: This prospective cohort study, as a feasibility study, included 62 families with children (5-17 years) that had diagnosed persistent asthma residing in Olmsted County, Minnesota. Indoor and outdoor NO2 concentrations were measured using passive air samples over 2 weeks in winter and 2 weeks in summer. We assessed seasonal variation in NO2 levels in urban and rural residential areas and the association with asthma control status collected from participants' asthma diaries during the study period. RESULTS: Outdoor NO2 levels were lower (median: 2.4 parts per billion (ppb) in summer, 3.9 ppb in winter) than the Environmental Protection Agency (EPA) annual standard (53 ppb). In winter, a higher level of outdoor NO2 was significantly associated with urban residential living area (P = .014) and lower socioeconomic status (SES) (P = .027). For both seasons, indoor NO2 was significantly higher (P < .05) in rural versus urban areas and in homes with gas versus electric stoves (P < .05). Asthma control status was not associated with level of indoor or outdoor NO2 in this cohort. CONCLUSIONS: NO2 levels were low in this mixed rural-urban community and not associated with asthma control status in this small feasibility study. Further research with a larger sample size is warranted for defining a lower threshold of NO2 concentration with health effect on asthma in mixed rural-urban settings.

Exploiting Acyl and Enol Azolium Intermediates via NHeterocyclic Carbene Catalyzed Reactions of Alpha-Reducible Aldehydes.

N-heterocyclic carbenes are well known for their role in catalyzing benzoin and Stetter reactions: the generation of acyl anion equivalents from simple aldehydes to react with a variety of electrophiles. However, when an aldehyde bearing a leaving group or unsaturation adjacent to the acyl anion equivalent is subjected to an NHC, a new avenue of reactivity is unlocked, leading to a number of novel transformations which can generate highly complex products from simple starting materials, many of which are assembled through unconventional bond disconnections. The field of these new reactions - those utilizing α-reducible aldehydes to access previously unexplored catalytic intermediates - has expanded rapidly in the past eight years. This review aims to provide the reader with a historical perspective on the underlying discoveries that led to the current state of the art, a mechanistic description of these reactions, and a summary of the recent advances in this area.

Role of geographic risk factors and social determinants of health in COVID-19 epidemiology: Longitudinal geospatial analysis in a midwest rural region.

Background: Studies examining the role of geographic factors in coronavirus disease-2019 (COVID-19) epidemiology among rural populations are lacking. Methods: Our study is a population-based longitudinal study based on rural residents in four southeast Minnesota counties from March through October 2020. We used a kernel density estimation approach to identify hotspots for COVID-19 cases. Temporal trends of cases and testing were examined by generating a series of hotspot maps during the study period. Household/individual-level socioeconomic status (SES) was measured using the HOUSES index and examined for association between identified hotspots and SES. Results: During the study period, 24,243 of 90,975 residents (26.6%) were tested for COVID-19 at least once; 1498 (6.2%) of these tested positive. Compared to other rural residents, hotspot residents were overall younger (median age: 40.5 vs 43.2), more likely to be minorities (10.7% vs 9.7%), and of higher SES (lowest HOUSES [SES] quadrant: 14.6% vs 18.7%). Hotspots accounted for 30.1% of cases (14.5% of population) for rural cities and 60.8% of cases (27.1% of population) for townships. Lower SES and minority households were primarily affected early in the pandemic and higher SES and non-minority households affected later. Conclusion: In rural areas of these four counties in Minnesota, geographic factors (hotspots) play a significant role in the overall burden of COVID-19 with associated racial/ethnic and SES disparities, of which pattern differed by the timing of the pandemic (earlier in pandemic vs later). The study results could more precisely guide community outreach efforts (e.g., public health education, testing/tracing, and vaccine roll out) to those residing in hotspots.

Highest densities of mountain hares (Lepus timidus) associated with ecologically restored bog but not grouse moorland management.

Over the last 20 years, ecological restoration of degraded habitats has become common in conservation practice. Mountain hares (Lepus timidus scoticus) were surveyed during 2017-2021 using 830 km of line transects in the Peak District National Park, England. Historically degraded bog areas were previously reported having low hare numbers. Following bog restoration, we found hare densities of 32.6 individuals km-2, notably higher than neighboring degraded (unrestored) bog with 24.4 hares km-2. Hare density on restored peatland was 2.7 times higher than on bogs managed for grouse shooting at 12.2 hares km-2 and 3.3 times higher than on heather moorland managed for grouse shooting at 10.0 hares km-2. Yearly estimates varied most on habitats managed for grouse, perhaps indicative of the impact of habitat management, for example, heather burning and/or possible hare culling to control potential tick-borne louping ill virus in gamebirds. Acid grassland used for sheep farming had a similar density to grouse moorland at 11.8 hares km-2. Unmanaged dwarf shrub heath had the lowest density at 4.8 hares km-2. Hare populations are characterized by significant yearly fluctuations, those in the study area increasing by 60% between 2017 and 2018 before declining by ca. 15% by 2020 and remaining stable to 2021. During an earlier survey in 2002, total abundance throughout the Peak District National Park was estimated at 3361 (95% CI: 2431-4612) hares. The present study estimated 3562 (2291-5624) hares suggesting a stable population over the last two decades despite fluctuations likely influenced by weather and anthropogenic factors. Mountain hares in the Peak District favored bog habitats and were associated with restored peatland habitat. Wildlife management should be cognizant of hare density variation between habitats, which may have implications for local extinction risk.

Development and initial testing of a new socioeconomic status measure based on housing data.

Socioeconomic status (SES) has been associated with many health outcomes. Commonly used datasets such as medical records often lack data on SES but do include address information. The authors sought to determine whether an SES measure derived from housing characteristics is associated with other SES measures and outcomes known to be associated with SES. The data come from a telephone survey of parents/guardians of children aged 1-17 years who resided in Olmsted County, Minnesota, and Jackson County, Missouri. Seven variables related to housing and six neighborhood characteristics obtained from local government assessor's offices in Olmsted County, Minnesota, were appended to survey responses. An SES index derived from housing characteristics (hereafter, HOUSES) was constructed using principal components factor analysis. For criterion validity, we assessed Pearson's correlation coefficients between HOUSES and other SES measures, including self-reported parents' educational levels, income, Hollingshead Index, and Nakao-Treas Index. For construct validity, we determined the association between HOUSES and outcomes, risks of low birth weight, overweight, and smoking exposure at home. We applied HOUSES to subjects in another community by formulating HOUSES from housing data of subjects in Jackson County, Missouri, using the same statistical algorithm as HOUSES for subjects in Olmsted County, Minnesota. We found that HOUSES had modest to good correlation with other SES measures. Overall, as hypothesized, HOUSES was inversely associated with outcome measures assessed among subjects from both counties. HOUSES may be a useful surrogate measure of individual SES in epidemiologic research, especially when SES measures for individuals are not available.

Role of Geographic Risk Factors in COVID-19 Epidemiology: Longitudinal Geospatial Analysis.

OBJECTIVE: To perform a geospatial and temporal trend analysis for coronavirus disease 2019 (COVID-19) in a Midwest community to identify and characterize hot spots for COVID-19. PARTICIPANTS AND METHODS: We conducted a population-based longitudinal surveillance assessing the semimonthly geospatial trends of the prevalence of test confirmed COVID-19 cases in Olmsted County, Minnesota, from March 11, 2020, through October 31, 2020. As urban areas accounted for 84% of the population and 86% of all COVID-19 cases in Olmsted County, MN, we determined hot spots for COVID-19 in urban areas (Rochester and other small cities) of Olmsted County, MN, during the study period by using kernel density analysis with a half-mile bandwidth. RESULTS: As of October 31, 2020, a total of 37,141 individuals (30%) were tested at least once, of whom 2433 (7%) tested positive. Testing rates among race groups were similar: 29% (black), 30% (Hispanic), 25% (Asian), and 31% (white). Ten urban hot spots accounted for 590 cases at 220 addresses (2.68 cases per address) as compared with 1843 cases at 1292 addresses in areas outside hot spots (1.43 cases per address). Overall, 12% of the population residing in hot spots accounted for 24% of all COVID-19 cases. Hot spots were concentrated in neighborhoods with low-income apartments and mobile home communities. People living in hot spots tended to be minorities and from a lower socioeconomic background. CONCLUSION: Geographic and residential risk factors might considerably account for the overall burden of COVID-19 and its associated racial/ethnic and socioeconomic disparities. Results could geospatially guide community outreach efforts (eg, testing/tracing and vaccine rollout) for populations at risk for COVID-19.

Factors associated with willingness to wear a mask to prevent the spread of COVID-19 in a Midwestern Community.

OBJECTIVE: To identify motivators and barriers to wearing a mask to prevent COVID-19. PARTICIPANTS AND METHODS: An anonymous, online survey of adults from Southeastern Minnesota conducted August 2020. We assessed willingness to wear a mask and its associations with socio-demographics, COVID-19-related factors and prevention behaviors using multivariable ordinal logistic regression. RESULTS: Of 7,786 respondents (78% women, 51% rural), 9% reported 'not at all willing', 27% 'willing', and 64% 'very willing' to wear a mask. Factors independently associated with willingness to wear a mask were: urban residence (OR = 1.23, 95% CI 1.05-1.44, p = 0.009); college degree or greater (OR 1.42, CI 1.05-1.93, p = 0.025); age (18-29 years OR 1.29, CI 01.02-1.64, p = 0.038; 30-39 OR = 1.37, CI 1.12-1.69, p = 0.003; 60-69 OR = 1.44, CI 1.09-1.91, p = 0.011; 70-89 OR 2.09, CI 1.32-3.37, p = 0.002; 40-49 reference group); and (all p < 0.001) democratic party affiliation (OR 1.79, CI 1.40-2.29), correct COVID-19 knowledge (OR 1.50, CI 1.28-1.75), 5 + COVID-19 prevention behaviors (OR 2.74, CI 1.98-3.81), positive perceived impacts for wearing a mask (OR 1.55, 1.52-1.59), perceived COVID-19 severity (OR 2.1, CI 1.44-3.1), and greater stress (OR 1.03, CI 1.02-1.04), and trust in the Centers for Disease Control (CDC) (OR 1.78, CI 1.45 -2.19). CONCLUSION: Results from this sample of SEMN residents suggest interventions to enhance COVID-19 knowledge, positive expectations for mask wearing, and trust in the CDC are warranted. Research is needed to understand cultural and other barriers and facilitators among sub-populations, e.g., rural residents less willing to wear a mask.

Artificial intelligence-assisted clinical decision support for childhood asthma management: A randomized clinical trial.

RATIONALE: Clinical decision support (CDS) tools leveraging electronic health records (EHRs) have been an approach for addressing challenges in asthma care but remain under-studied through clinical trials. OBJECTIVES: To assess the effectiveness and efficiency of Asthma-Guidance and Prediction System (A-GPS), an Artificial Intelligence (AI)-assisted CDS tool, in optimizing asthma management through a randomized clinical trial (RCT). METHODS: This was a single-center pragmatic RCT with a stratified randomization design conducted for one year in the primary care pediatric practice of the Mayo Clinic, MN. Children (<18 years) diagnosed with asthma receiving care at the study site were enrolled along with their 42 primary care providers. Study subjects were stratified into three strata (based on asthma severity, asthma care status, and asthma diagnosis) and were blinded to the assigned groups. MEASUREMENTS: Intervention was a quarterly A-GPS report to clinicians including relevant clinical information for asthma management from EHRs and machine learning-based prediction for risk of asthma exacerbation (AE). Primary endpoint was the occurrence of AE within 1 year and secondary outcomes included time required for clinicians to review EHRs for asthma management. MAIN RESULTS: Out of 555 participants invited to the study, 184 consented for the study and were randomized (90 in intervention and 94 in control group). Median age of 184 participants was 8.5 years. While the proportion of children with AE in both groups decreased from the baseline (P = 0.042), there was no difference in AE frequency between the two groups (12% for the intervention group vs. 15% for the control group, Odds Ratio: 0.82; 95%CI 0.374-1.96; P = 0.626) during the study period. For the secondary end points, A-GPS intervention, however, significantly reduced time for reviewing EHRs for asthma management of each participant (median: 3.5 min, IQR: 2-5), compared to usual care without A-GPS (median: 11.3 min, IQR: 6.3-15); p<0.001). Mean health care costs with 95%CI of children during the trial (compared to before the trial) in the intervention group were lower than those in the control group (-$1,036 [-$2177, $44] for the intervention group vs. +$80 [-$841, $1000] for the control group), though there was no significant difference (p = 0.12). Among those who experienced the first AE during the study period (n = 25), those in the intervention group had timelier follow up by the clinical care team compared to those in the control group but no significant difference was found (HR = 1.93; 95% CI: 0.82-1.45, P = 0.10). There was no difference in the proportion of duration when patients had well-controlled asthma during the study period between the intervention and the control groups. CONCLUSIONS: While A-GPS-based intervention showed similar reduction in AE events to usual care, it might reduce clinicians' burden for EHRs review resulting in efficient asthma management. A larger RCT is needed for further studying the findings. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02865967.

Mobile home residence as a risk factor for adverse events among children in a mixed rural-urban community: A case for geospatial analysis.

BACKGROUND: Given the significant health effects, we assessed geospatial patterns of adverse events (AEs), defined as physical or sexual abuse and accidents or poisonings at home, among children in a mixed rural-urban community. METHODS: We conducted a population-based cohort study of children (<18 years) living in Olmsted County, Minnesota, to assess geographic patterns of AEs between April 2004 and March 2009 using International Classification of Diseases, Ninth Revision codes. We identified hotspots by calculating the relative difference between observed and expected case densities accounting for population characteristics (; hotspot ≥ 0.33) using kernel density methods. A Bayesian geospatial logistic regression model was used to test for association of subject characteristics (including residential features) with AEs, adjusting for age, sex, and socioeconomic status (SES). RESULTS: Of the 30,227 eligible children (<18 years), 974 (3.2%) experienced at least one AE. Of the nine total hotspots identified, five were mobile home communities (MHCs). Among non-Hispanic White children (85% of total children), those living in MHCs had higher AE prevalence compared to those outside MHCs, independent of SES (mean posterior odds ratio: 1.80; 95% credible interval: 1.22-2.54). MHC residency in minority children was not associated with higher prevalence of AEs. Of addresses requiring manual correction, 85.5% belonged to mobile homes. CONCLUSIONS: MHC residence is a significant unrecognized risk factor for AEs among non-Hispanic, White children in a mixed rural-urban community. Given plausible outreach difficulty due to address discrepancies, MHC residents might be a geographically underserved population for clinical care and research.

Practical synthesis of a p38 MAP kinase inhibitor.

p38 MAP kinase inhibitors have attracted considerable interest as potential agents for the treatment of inflammatory diseases. Herein, we describe a concise and efficient synthesis of inhibitor 1 that is based on a phthalazine scaffold. Highlights of our approach include a practical synthesis of a 1,6-disubstituted phthalazine building block 24 as well as the one-pot formation of boronic acid 27. Significant synthetic work to understand the reactivity principles of the intermediates helped in selection of the final synthetic route. Subsequent optimization of the individual steps of the final sequence led to a practical synthesis of 1.

Spatio-temporal comparison of pertussis outbreaks in Olmsted County, Minnesota, 2004-2005 and 2012: a population-based study.

OBJECTIVE: Two pertussis outbreaks occurred in Olmsted County, Minnesota, during 2004-2005 and 2012 (5-10 times higher than other years), with significantly higher incidence than for the State. We aimed to assess whether there were similar spatio-temporal patterns between the two outbreaks. SETTING: Olmsted County, Minnesota, USA PARTICIPANTS: We conducted a population-based retrospective cohort study of all Olmsted County residents during the 2004-2005 and 2012 outbreaks, including laboratory-positive pertussis cases. PRIMARY OUTCOME MEASURE: For each outbreak, we estimated (1) age-specific incidence rate using laboratory-positive pertussis cases (numerator) and the Rochester Epidemiology Project Census (denominator), a medical record-linkage system for virtually all Olmsted County residents, and (2) pertussis case density using kernel density estimation to identify areas with high case density. To account for population size, we calculated relative difference of observed density and expected density based on age-specific incidence. RESULTS: We identified 157 and 195 geocoded cases in 2004-2005 and 2012, respectively. Incidence was the highest among adolescents (ages 11 to <14 years) for both outbreaks (9.6 and 7.9 per 1000). The 2004-2005 pertussis outbreak had higher incidence in winter (52% of cases) versus summer in 2012 (53%). We identified a consistent area with higher incidence at the beginning (ie, first quartile) of two outbreaks, but it was inconsistent for later quartiles. The relative difference maps for the two outbreaks suggest a greater role of neighbourhood population size in 2012 compared with 2004-2005. CONCLUSIONS: Comparing spatio-temporal patterns between two pertussis outbreaks identified a consistent geographical area with higher incidence of pertussis at the beginning of outbreaks in this community. This finding can be tested in future outbreaks, and, if confirmed, can be used for identifying epidemiological risk factors clustered in such areas for geographically targeted intervention.

Evaluating the application of Pareto navigation guided automated radiotherapy treatment planning to prostate cancer.

BACKGROUND AND PURPOSE: Current automated planning methods do not allow for the intuitive exploration of clinical trade-offs during calibration. Recently a novel automated planning solution, which is calibrated using Pareto navigation principles, has been developed to address this issue. The purpose of this work was to clinically validate the solution for prostate cancer patients with and without elective nodal irradiation. MATERIALS AND METHODS: For 40 randomly selected patients (20 prostate and seminal vesicles (PSV) and 20 prostate and pelvic nodes (PPN)) automatically generated volumetric modulated arc therapy plans (VMATAuto) were compared against plans created by expert dosimetrists under clinical conditions (VMATClinical) and no time pressures (VMATIdeal). Plans were compared through quantitative comparison of dosimetric parameters and blind review by an oncologist. RESULTS: Upon blind review 39/40 and 33/40 VMATAuto plans were considered preferable or equal to VMATClinical and VMATIdeal respectively, with all deemed clinically acceptable. Dosimetrically, VMATAuto, VMATClinical and VMATIdeal were similar, with observed differences generally of low clinical significance. Compared to VMATClinical, VMATAuto reduced hands-on planning time by 94% and 79% for PSV and PPN respectively. Total planning time was significantly reduced from 22.2 mins to 14.0 mins for PSV, with no significant reduction observed for PPN. CONCLUSIONS: A novel automated planning solution has been evaluated, whose Pareto navigation based calibration enabled clinical decision-making on trade-off balancing to be intuitively incorporated into automated protocols. It was successfully applied to two sites of differing complexity and robustly generated high quality plans in an efficient manner.

Utilisation of Pareto navigation techniques to calibrate a fully automated radiotherapy treatment planning solution.

BACKGROUND AND PURPOSE: Current automated radiotherapy planning solutions do not allow for the intuitive exploration of different treatment options during protocol calibration. This work introduces an automated planning solution, which aims to address this problem through incorporating Pareto navigation techniques into the calibration process. MATERIALS AND METHODS: For each tumour site a set of planning goals is defined. Utilising Pareto navigation techniques an operator calibrates the solution through intuitively exploring different treatment options: selecting the optimum balancing of competing planning goals for the given site. Once calibrated, fully automated plan generation is possible, with specific algorithms implemented to ensure trade-off balancing of new patients is consistent with that during calibration. Using the proposed methodology the system was calibrated for prostate and seminal vesicle treatments. The resultant solution was validated through quantitatively comparing the dose distribution of automatically generated plans (VMATAuto) against the previous clinical plan, for ten randomly selected patients. RESULTS: VMATAuto yielded statistically significant improvements in: PTV conformity indices, high dose bladder metrics, mean bowel dose, and the majority of rectum dose metrics. Of particular note was the reduction in mean rectum dose (median 25.1 Gy vs. 27.5 Gy), rectum V24.3Gy (median 41.1% vs. 46.4%), and improvement in the conformity index for the primary PTV (median 0.86 vs. 0.79). Dosimetric improvements were not at the cost of other dose metrics. CONCLUSIONS: An automated planning methodology with a Pareto navigation based calibration has been developed, which enables the complex balancing of competing trade-offs to be intuitively incorporated into automated protocols.

Facilitating permeability of landscapes impacted by roads for protected amphibians: patterns of movement for the great crested newt.

Amphibian populations are highly vulnerable to road mortality and habitat fragmentation caused by road networks. Wildlife road tunnels are considered the most promising road mitigation measure for amphibians yet generally remain inadequately monitored, resulting in mixed success rates in the short-term and uncertain conservation benefits in the long-term. We monitored a complex multi-tunnel and fence system over five years and investigated the impact of the scheme on movement patterns of two newt species, including the largest known UK population of the great crested newt (Triturus cristatus), a European Protected Species. We used a stage descriptive approach based on capture positions to quantify newt movement patterns. Newt species successfully used the mitigation but the system constituted a bottleneck to movements from the fences to the tunnels. Crossing rates varied widely among years and were skewed towards autumn dispersal rather than spring breeding migration. There was a substantial negative bias against adult male great crested newts using the system. This study indicates that road tunnels could partially mitigate wider connectivity loss and fragmentation at the landscape scale for newt species. However, the observed bottleneck effects and seasonal bias could have population-level effects which must be better understood, especially for small populations, so that improvements can be made. Current requirements for monitoring mitigation schemes post-implementation are probably too short to assess their effectiveness in maintaining connectivity and to adequately understand their population-level impacts.