Characterization of a new greenbug resistance gene Gb9 in a synthetic hexaploid wheat.

Greenbug [Schizaphis graminum (Rondani)] is a serious insect pest that not only damages cereal crops, but also transmits several destructive viruses. The emergence of new greenbug biotypes in the field makes it urgent to identify novel greenbug resistance genes in wheat. CWI 76364 (PI 703397), a synthetic hexaploid wheat (SHW) line, exhibits greenbug resistance. Evaluation of an F2:3 population from cross OK 14319 × CWI 76364 indicated that a dominant gene, designated Gb9, conditions greenbug resistance in CWI 76364. Selective genotyping of a subset of F2 plants with contrasting phenotypes by genotyping-by-sequencing identified 25 SNPs closely linked to Gb9 on chromosome arm 7DL. Ten of these SNPs were converted to Kompetitive allele-specific polymerase chain reaction (KASP) markers for genotyping the entire F2 population. Genetic analysis delimited Gb9 to a 0.6-Mb interval flanked by KASP markers located at 599,835,668 bp (Stars-KASP872) and 600,471,081 bp (Stars-KASP881) on 7DL. Gb9 was 0.5 cM distal to Stars-KASP872 and 0.5 cM proximal to Stars-KASP881. Allelism tests indicated that Gb9 is a new greenbug resistance gene which confers resistance to greenbug biotypes C, E, H, I, and TX1. TX1 is one of the most widely virulent biotypes and has overcome most known wheat greenbug resistance genes. The introgression of Gb9 into locally adapted wheat cultivars is of economic importance, and the KASP markers developed in this study can be used to tag Gb9 in cultivar development.

Complex adaptive systems-based framework for modeling the health impacts of climate change.

Introduction: Climate change is a global phenomenon with far-reaching consequences, and its impact on human health is a growing concern. The intricate interplay of various factors makes it challenging to accurately predict and understand the implications of climate change on human well-being. Conventional methodologies have limitations in comprehensively addressing the complexity and nonlinearity inherent in the relationships between climate change and health outcomes. Objectives: The primary objective of this paper is to develop a robust theoretical framework that can effectively analyze and interpret the intricate web of variables influencing the human health impacts of climate change. By doing so, we aim to overcome the limitations of conventional approaches and provide a more nuanced understanding of the complex relationships involved. Furthermore, we seek to explore practical applications of this theoretical framework to enhance our ability to predict, mitigate, and adapt to the diverse health challenges posed by a changing climate. Methods: Addressing the challenges outlined in the objectives, this study introduces the Complex Adaptive Systems (CAS) framework, acknowledging its significance in capturing the nuanced dynamics of health effects linked to climate change. The research utilizes a blend of field observations, expert interviews, key informant interviews, and an extensive literature review to shape the development of the CAS framework. Results and discussion: The proposed CAS framework categorizes findings into six key sub-systems: ecological services, extreme weather, infectious diseases, food security, disaster risk management, and clinical public health. The study employs agent-based modeling, using causal loop diagrams (CLDs) tailored for each CAS sub-system. A set of identified variables is incorporated into predictive modeling to enhance the understanding of health outcomes within the CAS framework. Through a combination of theoretical development and practical application, this paper aspires to contribute valuable insights to the interdisciplinary field of climate change and health. Integrating agent-based modeling and CLDs enhances the predictive capabilities required for effective health outcome analysis in the context of climate change. Conclusion: This paper serves as a valuable resource for policymakers, researchers, and public health professionals by employing a CAS framework to understand and assess the complex network of health impacts associated with climate change. It offers insights into effective strategies for safeguarding human health amidst current and future climate challenges.

Digital self-aligned focusing schlieren.

In this Letter, a digital self-aligned focusing schlieren (D-SAFS) system is introduced. This system uses a digital transparent micro liquid crystal display (µLCD), in combination with a linear polarizer, to act on the linear polarization state of light transmitted in both the forward and reverse directions, essentially acting as both the source and cutoff grids. The use of the µLCD display allows for on-the-fly changes to the cutoff pattern type, spatial frequency, and orientation. This eliminates the need to physically access the source/cutoff grid in order to optimize the instrument's sensitivity, which is necessary with a conventional self-aligned focusing schlieren (SAFS) system.

Osteoarthritis Increases the Frequency and Duration of Postoperative Hand Clinic Visits after Carpal Tunnel Release.

Background: Carpal tunnel syndrome affects up to 6% of the general population, and surgical intervention is often required to ameliorate symptoms. Osteoarthritis (OA) is a common condition that often coexists with carpal tunnel syndrome. We hypothesized that patients with preexisting OA use more healthcare resources after carpal tunnel release (CTR) than patients without arthritis. Methods: This was a retrospective cohort study at a single academic center between January 1, 2018 and November 1, 2021. Patients who underwent CTR were included. Preoperative carpal tunnel symptoms, diagnostic tests, medications, and concomitant OA were abstracted. Hand, wrist, and basal joint arthritis were specified. The primary outcome was healthcare utilization represented by duration and frequency of hand clinic and occupational therapy (OT) follow-up. In total, 312 hands were included. Multivariable analysis was performed. Results: The average duration of hand clinic follow-up among patients without arthritis was 25.3 days compared with 87.1 days for patients with any arthritis (P = 0.0375) and 172 days for patients with wrist arthritis (P = 0.012). The average number of postoperative surgeon visits was increased in patients with hand arthritis, with an average of 2.3 visits versus 1.34 visits for patients without arthritis (P = 0.003). Both the number of OT visits and the duration of OT follow-up did not differ between cohorts. Conclusion: After CTR, patients with preexisting OA use more healthcare resources than patients without OA.

Characterization of Quantitative Trait Loci for Leaf Rust Resistance in the Uzbekistani Wheat Landrace Teremai Bugdai.

Leaf rust, caused by Puccinia triticina, is a major cause of wheat yield losses globally, and novel leaf rust resistance genes are needed to enhance wheat leaf rust resistance. Teremai Bugdai is a landrace from Uzebekistan that is highly resistant to many races of P. triticina in the United States. To unravel leaf rust resistance loci in Teremai Bugdai, a recombinant inbred line (RIL) population of Teremai Bugdai × TAM 110 was evaluated for response to P. triticina race Pt54-1 (TNBGJ) and genotyped using single nucleotide polymorphism (SNP) markers generated by genotyping-by-sequencing (GBS). Quantitative trait loci (QTL) analysis using 5,130 high-quality GBS-SNPs revealed three QTLs, QLr-Stars-2DS, QLr-Stars-6BL, and QLr.Stars-7BL, for leaf rust resistance in two experiments. QLr-Stars-2DS, which is either a new Lr2 allele or a new resistance locus, was delimited to an ∼19.47-Mb interval between 46.4 and 65.9 Mb on 2DS and explained 31.3 and 33.2% of the phenotypic variance in the two experiments. QLr-Stars-6BL was mapped in an ∼84.0-kb interval between 719.48 and 719.56 Mb on 6BL, accounting for 33 to 36.8% of the phenotypic variance in two experiments. QLr.Stars-7BL was placed in a 350-kb interval between 762.41 and 762.76 Mb on 7BL and explained 4.4 to 5.3% of the phenotypic variance. Nine GBS-SNPs flanking these QTLs were converted to kompetitive allele specific PCR (KASP) markers, and these markers can be used to facilitate their introgression into locally adapted wheat lines.

Modified Frailty Index predicts postoperative complications following adult-acquired buried penis surgery: A retrospective cohort study.

BACKGROUND: Given that patients with morbid obesity are predisposed to frailty, we sought to determine whether the 5-Factor Modified Frailty Index (mFI-5) predicts postoperative complications following surgery for adult-acquired buried penis, and secondarily, to compare the mFI-5 to body mass index (BMI) and American Society of Anesthesiologists (ASA) status as preoperative risk stratification measures. METHODS: We included all patients who underwent surgical management for adult-acquired buried penis at an academic Level I trauma center between 2015 and 2023. A manual chart review was performed to collect data on patient demographics, modified frailty index variables, intraoperative data, postoperative outcomes, and complications. RESULTS: A total of 55 patients underwent surgical repair of adult-acquired buried penis, with 26 experiencing postoperative complications (47.3%). Univariable regression analyses revealed that the mFI-5 was a significant predictor of postoperative complications (odds ratio [OR] 3.40, 95% confidence interval [CI]: 1.56-7.42, p = .002), ongoing postoperative urinary problems (OR 2.03, 95% CI: 1.02-4.05, p = .045), patient dissatisfaction with outcomes (OR 3.29, 95% CI: 1.35-8.02, p = .009), and persistent postoperative symptoms (OR 2.42, 95% CI: 1.10-5.35, p = .029). There was no significant association between ASA classification and postoperative complications (OR 1.59, 95% CI:.544-4.63, p = .398). Multivariable analysis demonstrated that the mFI-5 was an independent predictor of postoperative complications (OR 5.34, 95% CI: 1.80-15.9, p = .003) when controlling for BMI and age. CONCLUSION: The mFI-5 is an independent predictor of postoperative complications in patients undergoing surgical repair of adult-acquired buried penis. The simplicity of the index permits efficient preoperative risk stratification of adult-acquired buried penis patients and provides important counseling information that may not be reflected by age or BMI alone.

Epidemiology and healthcare utilization of First Nations peoples living with spinal cord injury in Alberta: an observational study to explore health inequities.

STUDY DESIGN: Retrospective observational cohort study. OBJECTIVES: Estimate spinal cord injury (SCI) prevalence in First Nations and non-First Nations populations and compare healthcare utilization as an indirect marker of health inequities. SETTING: Alberta, Canada. METHODS: We created a prevalent adult SCI cohort by identifying cases between April 1, 2002 and December 31, 2017 who were followed for common SCI complications and location of healthcare access from January 1, 2018 to December 31, 2019 using administrative data sources housed within Alberta Health Services (AHS). First Nations and non-First Nations SCI cohorts were divided into SCI etiology: traumatic SCI (TSCI) and non-traumatic SCI (NTSCI). Statistical analyses compared prevalence, demographics, healthcare utilization, and SCI complication rates. A secondary analysis was performed using case matching for demographics, injury type, injury level, and comorbidities. RESULTS: TSCI prevalence: 248 and 117 per 100,000 in First Nations and non-First Nations cohorts, respectively. NTSCI prevalence: 74 and 50 per 100,000 in First Nations and non-First Nations cohorts, respectively. Visit rates were higher in the TSCI First Nations cohort for visits to General Practitioner (GP), Emergency Department (ED), inpatient visits, and inpatient days with higher complication rates due to pulmonary, genitourinary, skin, and 'other' causes after case matching. Visits rates were higher in the NTSCI First Nations cohort for GP and specialists without differences in complication types after case matching. CONCLUSIONS: Significant differences exist between First Nations and non-First Nations cohorts living with SCI in Alberta, suggesting healthcare inequities against First Nations Peoples in this province.

Colinear focused laser differential interferometry and self-aligned focusing schlieren.

A colinear focused laser differential interferometer (FLDI) and self-aligned focusing schlieren (SAFS) system has been assembled and tested in the laboratory, using a turbulent jet of compressed air issuing from a small needle nozzle to provide a high frequency density object. Measurements verified that the coupling of the SAFS system onto the optical axis of the FLDI system had negligible influence on the FLDI system's data, including tests that assessed the influence of the inclusion of dichroic mirrors, dichroic mirror reflection angle, dichroic mirror positioning relative to the Wollaston prisms of the FLDI system, and SAFS light propagation direction. A qualitative comparison of the focusing ability of the two systems was made, and FLDI power spectral density estimates and SAFS spectral proper orthogonal decomposition were used for quantitative comparisons of the acoustic frequency of the jet, with good agreement between the two. The success of the system integration and resulting jet testing demonstrates the utility of this colinear, simultaneous FLDI/SAFS measurement system.

Core and Advanced Thoracic Imaging Curricula to Guide Residency and Fellowship Training: A Framework From the Canadian Society of Thoracic Radiology.

RATIONALE: A well-defined curriculum with goals and objectives is an inherent part of every radiology training program. MATERIALS AND METHODS: Following a needs assessment, the Canadian Society of Thoracic Radiology Education Committee developed a thoracic imaging curriculum using a mixed- method approach, complimentary to the cardiac curriculum published as a separate document. RESULTS: The Thoracic Imaging Curriculum consists of two separate yet complimentary parts: a Core Curriculum, aimed at residents in-training, with the main goal of building a strong foundational knowledge, and an Advanced Curriculum, designed to build upon the core knowledge and guide a more in-depth subspecialty training. CONCLUSION: The curricular frameworks aim to enhance the educational experience of residents and fellows and provide an educational framework for clinical supervisors and residency and fellowship program directors. SUMMARY STATEMENT: The Canadian Society of Thoracic Radiology championed the creation of Cardiovascular and Thoracic Imaging curricula encompassing clinical knowledge and technical, communication, and decision-making skills with the goal of providing direction to a strong foundational knowledge for residents and to guide specialty training for fellowship programs.

Topographic hydro-conditioning to resolve surface depression storage and ponding in a fully distributed hydrologic model.

Land surface depressions play a central role in the transformation of rainfall to ponding, infiltration and runoff, yet digital elevation models (DEMs) used by spatially distributed hydrologic models that resolve land surface processes rarely capture land surface depressions at spatial scales relevant to this transformation. Methods to generate DEMs through processing of remote sensing data, such as optical and light detection and ranging (LiDAR) have favored surfaces without depressions to avoid adverse slopes that are problematic for many hydrologic routing methods. Here we present a new topographic conditioning workflow, Depression-Preserved DEM Processing (D2P) algorithm, which is designed to preserve physically meaningful surface depressions for depression-integrated and efficient hydrologic modeling. D2P includes several features: (1) an adaptive screening interval for delineation of depressions, (2) the ability to filter out anthropogenic land surface features (e.g., bridges), (3) the ability to blend river smoothing (e.g., a general downslope profile) and depression resolving functionality. From a case study in the Goodwin Creek Experimental Watershed, D2P successfully resolved 86% of the ponds at a DEM resolution of 10 m. Topographic conditioning was achieved with minimum impact as D2P reduced the number of modified cells from the original DEM by 51% compared to a conventional algorithm. Furthermore, hydrologic simulation using a D2P processed DEM resulted in a more robust characterization on surface water dynamics based on higher surface water storage as well as an attenuated and delayed peak streamflow.

"The Impact of Neighborhood and Socioeconomic Disparities on Distal Radius Fracture Follow-Up Adherence: A Retrospective Cohort Study".

BACKGROUND: The aims of this retrospective cohort study were to assess if the Area Deprivation Index (ADI), a novel neighborhood-level socioeconomic disparities metric, is associated with follow-up non-adherence, and secondarily, determine the individual-level socioeconomic factors associated with follow-up non-adherence after treatment of distal radius fractures (DRF). METHODS: We included all patients who underwent non-operative and operative management of DRF at an academic level I trauma center between 2019 and 2021. A manual chart review was performed to collect data on ADI, sociodemographic factors, injury characteristics, conservative and surgical interventions, and healthcare utilization. RESULTS: There was a significant, weak negative Spearman-ranked correlation between ADI state deciles and clinic attendance rates (rs(220) = -.144; [95% CI: -.274, -.009] p = .032). Socioeconomic factors associated with significant differences in clinic attendance rates were having a spouse or partner (protective) (p = .007), Medicaid insurance (p = .013), male sex (p = .023), and current smokers (p = .026). Factors associated with differences in no show rates were having spouse or partner (OR .326; [95% CI: .123 - .867] p = .025), Medicaid insurance (OR 7.78; [95% CI: 2.15 - 28.2] p = .002), male sex (OR 4.09; [95% CI: 1.72 - 9.74] p = .001), and cigarette use (OR 5.07; [95% CI: 1.65 - 15.6] p = .005). CONCLUSIONS: ADI has a weak, negative correlation with clinic attendance rates following DRF treatment. Significant disparities in clinic follow-up adherence exist between patients with different marital status, insurances, sexes, and cigarette use.

National Core and Advanced Cardiac Imaging Curricula: A Framework From the Canadian Society of Thoracic Radiology Education Committee.

RATIONALE: Well-defined curriculum with goals and objectives is an inherent part of every radiology residency program. MATERIALS AND METHODS: Following a needs assessment, the Canadian Society of Thoracic Radiology education committee developed a cardiac imaging curriculum using a mixed method collaborative approach. RESULTS: The Cardiovascular Imaging Curricula consist each of two separate yet complimentary granular parts: a Core Curriculum, aimed at residents in-training, with the main goal of building a strong foundational knowledge and an Advanced Curriculum, designed to build upon the core knowledge and guide a more in-depth fellowship subspecialty training. CONCLUSION: The curricular frameworks aim to enhance the educational experience of trainees (residents and fellows) and provide an educational framework for clinical supervisors and residency and fellowship program directors. SUMMARY STATEMENT: The Canadian Society of Thoracic Radiology (CSTR) championed the creation of Cardiovascular and Thoracic Imaging curricula encompassing clinical knowledge and technical, communication, and decision-making skills with the goal of providing direction to a strong foundational knowledge for residents and to guide specialty training for fellowship programs.

Rise Above the Competition: How Do Plastic Surgery Residency Applicants with NCAA Experience Fare in the Residency Match?

BACKGROUND: The integrated plastic surgery residency match continues to be highly competitive. Every year, some candidates are former NCAA athletes. While it is challenging to balance academic and athletic responsibilities, participation in NCAA sports may be predictive of continued success. OBJECTIVES: This study aimed to evaluate the impact of participation in collegiate athletics on applicant anticipated rank and academic success. METHODS: All applications received from 2017 to 2020 at a single institution were reviewed for participation in NCAA athletics (Division I-III). Our primary outcome of interest was applicant anticipated rank by letter of reference writers. Applications were also examined for demographic information, membership in AOA, number of research publications, and USMLE board certification examination scores. RESULTS: After reviewing 885 applications, 61 applicants (6.89%) were former NCAA athletes. Former NCAA involvement was associated with the highest effect on anticipated ranking (- 0.22, p=0.001). Former NCAA involvement demonstrated the highest odds of receiving an anticipated ranking in the top 5 (OR 1.83, p=0.025). We found no significant difference in research productivity between the two groups, including first authorships or USMLE Step 1 board certification exam scores. A significant difference was seen in race distribution, with forty-five (80.4%) of athlete applicants identifying as Caucasian, while 430 (56.5%) of non-athletes identified as Caucasian (p=0.012). CONCLUSION: Former athletes applying to become integrated plastic surgery residents overcome the challenges of balancing athletic and academic pursuits with a higher anticipated rank in the integrated plastic surgery match while having comparable academic achievement. Former collegiate athletes have demonstrated greater success in and after residency. Former NCAA participation demonstrated the highest odds of receiving a top-5 rank. Former NCAA applicants showed no difference in academic productivity LEVEL OF EVIDENCE V: Case series study. This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors   www.springer.com/00266 .

Insurance Status Predicts Hand Therapy Adherence Following Flexor Tendon Repair: A Retrospective Cohort Study".

BACKGROUND: Many patients are not adherent to hand therapy rehabilitation following surgical repair of traumatic flexor tendon injuries, which can negatively affect surgical outcomes and long-term hand function. We aimed to identify the factors that predict patient non-adherence to hand therapy following flexor tendon repair surgery. METHODS: This retrospective cohort study included 154 patients who underwent surgical repair of flexor tendon injuries at a level I trauma center between January 2015 and January 2020. A manual chart review was performed to collect demographic data, insurance status, injury characteristics, and details of the postoperative course including health care utilization. RESULTS: Factors significantly associated with occupational therapy no-shows included Medicaid insurance (OR, 8.35; 95% CI, 2.91 to 24.0; p < 0.001), self-identified Black race (OR, 7.28; 95% CI, 1.78 to 29.7; p = 0.006), and current cigarette smoker status (OR, 2.69; 95% CI, 1.18 to 6.15; p = 0.019). Patients without insurance attended 73.8% of their OT visits and patients with Medicaid attended 72.0% of their visits, which were significantly lower rates than those with private insurance 90.7% (p=0.026 and p=0.001, respectively). Patients with Medicaid were 8 times more likely to seek emergency department care postoperatively than patients with private insurance (p=0.002). CONCLUSIONS: Significant disparities in hand therapy adherence following flexor tendon repair surgery exist between patients with different insurance statuses, races, and tobacco use. Understanding these disparities can help providers identify at-risk patients to improve hand therapy utilization and postoperative outcomes.

Identification of a Novel Pm65 Allele Conferring a Wide Spectrum of Resistance to Powdery Mildew in Wheat Accession PI 351817.

Powdery mildew is caused by the highly adaptive biotrophic fungus Blumeria graminis f. sp. tritici infecting wheat worldwide. Novel powdery mildew resistance genes are urgently needed that can be used rapidly in wheat cultivar development with minimal disruption of trait advances elsewhere. PI 351817 is a German cultivar exhibiting a wide spectrum of resistance to B. graminis f. sp. tritici isolates collected from different wheat-growing regions of the United States. Evaluation of an F2 population and 237 F2:3 lines derived from OK1059060-2C14 × PI 351817 for responses to B. graminis f. sp. tritici isolate OKS(14)-B-3-1 identified a single dominant gene, designated Pm351817, for powdery mildew resistance in PI 351817. Using bulked segregant analysis (BSA) and simple sequence repeat (SSR) markers, Pm351817 was mapped in the terminal region of the long arm of chromosome 2A. Deep sequencing of the genotyping-by-sequencing libraries of the two parental lines identified a set of single-nucleotide polymorphism (SNP) markers in the 2AL candidate gene region. Those SNP markers was subsequently converted to Kompetitive allele-specific PCR (KASP) markers for genotyping the mapping population. Linkage analysis delimited Pm351817 to a 634-kb interval between Stars-KASP656 (771,207,512 bp) and Stars-KASP662 (771,841,609 bp) on 2AL, based on the Chinese Spring reference sequence IWGSC RefSeq v 2.1. Tests of allelism indicated that Pm351817 is located at the Pm65 locus. Pm351817 shows resistance to all B. graminis f. sp. tritici isolates used in this study and can be used to enhance powdery mildew resistance in the United States. KASP markers flanking Pm351817 can be used to select Pm351817 in wheat breeding programs after further tests for polymorphism.

Toward improved sediment management and coastal resilience through efficient permitting in California.

The value of sediment for helping coastal habitats and infrastructure respond to sea level rise is widely recognized. Across the country, coastal managers are seeking ways to beneficially use sediment sourced from dredging and other projects to counter coastal erosion and protect coastal resources. However, these projects are difficult to permit and have been slow to actualize. This paper draws on interviews with sediment managers and regulators in California to explore the challenges and opportunities for habitat restoration and beach nourishment within the current permitting regime. We find that permits are costly, difficult to obtain, and sometimes stand as a barrier to more sustainable and adaptive sediment management. We next characterize streamlining approaches and describe entities and ongoing efforts within California that apply them. Finally, we conclude that to keep pace with coastal losses due to climate change impacts, efforts toward efficient permitting must be accelerated and approaches diversified to support coastal resilience practices state-wide, in a timeframe that will allow coastal managers to innovate and adapt.

Making Headway in Surgical Education at Home and Abroad: Use of an Inexpensive Three-Dimensional Learning Model to Improve Plastic Surgery Resident Confidence in Mohs Defect Assessment and Closure Planning.

BACKGROUND: The development of simulation, particularly low-cost models, has become a focus of interest within plastic surgery education. Current simulators for Mohs reconstruction are either expensive or not reusable. The authors hypothesize that using a Styrofoam head model during an interactive teaching session will positively affect plastic surgery trainee comfort in designing Mohs reconstructive options. METHODS: A cohort of integrated plastic surgery residents at a single institution performed a preactivity questionnaire to obtain baseline comfort in defect assessment and design for five Mohs defects. They subsequently underwent an interactive learning session and were instructed to design flaps on life-size Styrofoam heads with feedback from the senior author (M.L.B.). A postactivity questionnaire was completed to assess improvement in comfort in defect assessment and flap design. Three attending surgeons then compared trainee designs with the senior author's design to assess accuracy. All surveys were based on a five-point Likert scale. RESULTS: When analyzing all defects, average postactivity scores increased by 0.63 (SD, ±0.24) ( P = 0.008). Junior residents ( n = 8) had a greater increase in average score responses [mean, 1.07 (0.5 to 1.75)] compared with senior residents ( n = 9) [mean, 0.27 (0 to 1)] ( P < 0.001). When assessed by senior-level surgeons, senior residents had significantly greater accuracy in design for each defect ( P < 0.05) except cheek advancement flap ( P = 0.08). CONCLUSION: Participation in an interactive educational activity using a Styrofoam head model demonstrated significant improvements in trainee assessment and design of reconstructive options for Mohs defects.

Identification, validation and biological characterisation of novel glioblastoma tumour microenvironment subtypes: implications for precision immunotherapy.

BACKGROUND: New precision medicine therapies are urgently required for glioblastoma (GBM). However, to date, efforts to subtype patients based on molecular profiles have failed to direct treatment strategies. We hypothesised that interrogation of the GBM tumour microenvironment (TME) and identification of novel TME-specific subtypes could inform new precision immunotherapy treatment strategies. MATERIALS AND METHODS: A refined and validated microenvironment cell population (MCP) counter method was applied to >800 GBM patient tumours (GBM-MCP-counter). Specifically, partition around medoids (PAM) clustering of GBM-MCP-counter scores in the GLIOTRAIN discovery cohort identified three novel patient clusters, uniquely characterised by TME composition, functional orientation markers and immune checkpoint proteins. Validation was carried out in three independent GBM-RNA-seq datasets. Neoantigen, mutational and gene ontology analysis identified mutations and uniquely altered pathways across subtypes. The longitudinal Glioma Longitudinal AnalySiS (GLASS) cohort and three immunotherapy clinical trial cohorts [treatment with neoadjuvant/adjuvant anti-programmed cell death protein 1 (PD-1) or PSVRIPO] were further interrogated to assess subtype alterations between primary and recurrent tumours and to assess the utility of TME classifiers as immunotherapy biomarkers. RESULTS: TMEHigh tumours (30%) displayed elevated lymphocyte, myeloid cell immune checkpoint, programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 transcripts. TMEHigh/mesenchymal+ patients featured tertiary lymphoid structures. TMEMed (46%) tumours were enriched for endothelial cell gene expression profiles and displayed heterogeneous immune populations. TMELow (24%) tumours were manifest as an 'immune-desert' group. TME subtype transitions upon recurrence were identified in the longitudinal GLASS cohort. Assessment of GBM immunotherapy trial datasets revealed that TMEHigh patients receiving neoadjuvant anti-PD-1 had significantly increased overall survival (P = 0.04). Moreover, TMEHigh patients treated with adjuvant anti-PD-1 or oncolytic virus (PVSRIPO) showed a trend towards improved survival. CONCLUSIONS: We have established a novel TME-based classification system for application in intracranial malignancies. TME subtypes represent canonical 'termini a quo' (starting points) to support an improved precision immunotherapy treatment approach.

Weighted kernels improve multi-environment genomic prediction.

Crucial to variety improvement programs is the reliable and accurate prediction of genotype's performance across environments. However, due to the impactful presence of genotype by environment (G×E) interaction that dictates how changes in expression and function of genes influence target traits in different environments, prediction performance of genomic selection (GS) using single-environment models often falls short. Furthermore, despite the successes of genome-wide association studies (GWAS), the genetic insights derived from genome-to-phenome mapping have not yet been incorporated in predictive analytics, making GS models that use Gaussian kernel primarily an estimator of genomic similarity, instead of the underlying genetics characteristics of the populations. Here, we developed a GS framework that, in addition to capturing the overall genomic relationship, can capitalize on the signal of genetic associations of the phenotypic variation as well as the genetic characteristics of the populations. The capacity of predicting the performance of populations across environments was demonstrated by an overall gain in predictability up to 31% for the winter wheat DH population. Compared to Gaussian kernels, we showed that our multi-environment weighted kernels could better leverage the significance of genetic associations and yielded a marked improvement of 4-33% in prediction accuracy for half-sib families. Furthermore, the flexibility incorporated in our Bayesian implementation provides the generalizable capacity required for predicting multiple highly genetic heterogeneous populations across environments, allowing reliable GS for genetic improvement programs that have no access to genetically uniform material.