Ulcerated CRTC1::TRIM11 cutaneous tumor with metastases.

CRTC1::TRIM11 cutaneous tumor (CTCT) is a rare skin tumor of uncertain differentiation. In the 49 reported cases, only four cases showed regional or distant metastasis, but follow-up remains limited. Herein, we present a case of metastatic CTCT with ulceration, a histological feature that has not been previously described. A 75-year-old male with a 2-month history of toe ulceration underwent a shave biopsy, which showed a dermal nodular neoplasm that was immunoreactive for SOX10 and S100, negative for Melan-A, and was initially diagnosed as melanoma. Upon pathology review at our institution, the tumor was composed of intersecting fascicles and nests of epithelioid and spindle cells. Additional immunohistochemistry revealed immunoreactivity of the tumor for MiTF and NTRK and negativity for HMB-45 and PRAME. Next-generation sequencing identified CRTC1::TRIM11 fusion, leading to a revised diagnosis of CTCT. The patient proceeded to a toe amputation and sentinel lymph node (SLN) biopsy 5 months after the shave biopsy. The amputation showed residual CTCT and a focus on lymphovascular invasion. The SLN revealed multifocal subcapsular metastases. The patient was started on adjuvant nivolumab and showed biopsy-proven recurrence in the right inguinal lymph nodes and imaging findings suspicious for pulmonary metastases 8 months after the excision. In summary, we present a case of CTCT with ulceration and lymphovascular invasion. We also provide additional evidence that a subset of CTCT behaves aggressively. The optimal surgical and medical treatments are unknown.

Chromosome-scale genome assembly of bread wheat's wild relative Triticum timopheevii.

Wheat (Triticum aestivum) is one of the most important food crops with an urgent need for increase in its production to feed the growing world. Triticum timopheevii (2n = 4x = 28) is an allotetraploid wheat wild relative species containing the At and G genomes that has been exploited in many pre-breeding programmes for wheat improvement. In this study, we report the generation of a chromosome-scale reference genome assembly of T. timopheevii accession PI 94760 based on PacBio HiFi reads and chromosome conformation capture (Hi-C). The assembly comprised a total size of 9.35 Gb, featuring a contig N50 of 42.4 Mb and included the mitochondrial and plastid genome sequences. Genome annotation predicted 166,325 gene models including 70,365 genes with high confidence. DNA methylation analysis showed that the G genome had on average more methylated bases than the At genome. In summary, the T. timopheevii genome assembly provides a valuable resource for genome-informed discovery of agronomically important genes for food security.

Estimation of wound surface area: an evaluation of medical professionals' assessment in a plastic surgery unit.

The percentage of skin graft take following the resurfacing of burn injuries is routinely calculated in a subjective fashion, in order to make management decisions. Given the gravity of decisions made based on this clinical assessment of graft check, it is notable that limited research has been carried out on this subject. No standardised subjective assessment tools exist to measure surface area of graft take in a manner similar to that of Wallace's Rule of Nines or Lund and Browder. This study set out to examine the accuracy of visual assessments of graft take within the multidisciplinary team regularly making assessments of newly grafted burn wounds. A total of 15 digitally drawn images were used to assess 36 staff members' estimations of percentage of surface area. The results showed a wide variation in estimation in all staff types, including senior burns surgeons, who were found to underestimate surface area by as much as 30%. The British Burns Association has removed 'healing time' as an outcome measurement from its guidance, as it recognises how hard it is to make a standardised assessment of wound healing. This study demonstrates the difficulty in subjectively assessing surface area and makes some suggestions for further research and clinical applications of technology to aid assessment.

Clinical reporting for personalized cancer genomics requires extensive access to subscription-only literature.

Objective: Medical care for cancer is increasingly directed by genomic laboratory testing for alterations in the tumor genome that are significant for diagnosis, prognosis and therapy. Uniquely in medicine, providers must search the biomedical literature for each patient to determine the clinical significance of these alterations. Access to published scientific literature is frequently subject to high fees, with access limited to institutional subscriptions. We sought to investigate the degree to which the scientific literature is accessible to clinical cancer genomics providers, and the potential role of university and hospital system libraries in information access for cancer care. Methods: We identified 265 journals that were accessed during the interpretation and reporting of clinical test results from 1,842 cancer patients at the University Health Network (Toronto, Canada). We determined the degree of open access for this set of clinically important literature, and for any journals not available through open access we surveyed subscription access at seven academic hospital systems and at their affiliated universities. Results: This study found that nearly half (116/265) of journals have open access mandates that make articles freely available within one year of release. For the remaining subscription access journals, universities provided a uniformly high level of access, but access available through hospital system collections varied widely. Conclusion: This study highlights the importance of different modes of access to the use of the scientific literature in clinical practice and points to challenges that must be overcome as genomic medicine grows in scale and complexity.

Refinement of the Superomedial Pedicle Technique: A New Approach to Breast Reshaping Following Reduction.

INTRODUCTION: We present an alteration of the superomedial pedicle technique in breast reduction to control lateral fullness and create a more natural and contoured breast during reshaping. This approach has been adopted by the senior author (NC) in 79 patients over the past 4 years. METHODS: A wise pattern skin incision is used, and the nipple-areola complex (NAC) is maintained on a de-epithelialized superomedial pedicle. Instead of fully releasing the pedicle from the lateral parenchyma for rotation and inset, a bridge of tissue between the pedicle on its most posterior aspect and the lateral pillar is maintained. Key holding sutures are subsequently placed in Scarpa's fascia for reshaping. RESULTS: We find that with this refinement, the connection with the lateral pillar pulls the lateral parenchyma medially and superiorly when the pedicle is rotated into its new position, adding a natural curve to the side. The superior medial pedicle is still attached in its postero-lateral aspect to the lateral pillar and theoretically, will provide an even more robust vascular supply to the NAC. In our series, three patients developed minor skin healing issues amenable to treatment with dressings. No one suffered from nipple loss or other serious complications, and no dog ear revisions were required. CONCLUSIONS: We present a simple alteration of the superomedial pedicle technique that we believe results in improved breast contouring. Our experience suggests that this simple adaptation is safe, effective, and reproducible. LEVEL OF EVIDENCE IV: 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 .

Clinical outcome and biomarker assessments of a multi-centre phase II trial assessing niraparib with or without dostarlimab in recurrent endometrial carcinoma.

This multi-centre, non-randomized, open-label, phase II trial (NCT03016338), assessed niraparib monotherapy (cohort 1, C1), or niraparib and dostarlimab (cohort 2, C2) in patients with recurrent serous or endometrioid endometrial carcinoma. The primary endpoint was clinical benefit rate (CBR), with ≥5/22 overall considered of interest. Secondary outcomes were safety, objective response rate (ORR), duration of response, progression free survival and overall survival. Translational research was an exploratory outcome. Potential biomarkers were evaluated in archival tissue by immunohistochemistry and next generation sequencing panel. In C1, 25 patients were enrolled, and CBR was 20% (95% CI: 9-39) with median clinical benefit duration of 5.3 months. The ORR was 4% (95% CI: 0-20). In C2, 22 patients were enrolled, and the CBR was 31.8% (95% CI: 16-53) with median clinical benefit duration of 6.8 months. The ORR was 14% (95% CI: 3-35). No new safety signals were detected. No significant association was detected between clinical benefit and IHC markers (PTEN, p53, MMR, PD-L1), or molecular profiling (PTEN, TP53, homologous recombination repair genes). In conclusion, niraparib monotherapy did not meet the efficacy threshold. Niraparib in combination with dostarlimab showed modest activity.

Whole-genome sequencing uncovers the structural and transcriptomic landscape of hexaploid wheat/Ambylopyrum muticum introgression lines.

Wheat is a globally vital crop, but its limited genetic variation creates a challenge for breeders aiming to maintain or accelerate agricultural improvements over time. Introducing novel genes and alleles from wheat's wild relatives into the wheat breeding pool via introgression lines is an important component of overcoming this low variation but is constrained by poor genomic resolution and limited understanding of the genomic impact of introgression breeding programmes. By sequencing 17 hexaploid wheat/Ambylopyrum muticum introgression lines and the parent lines, we have precisely pinpointed the borders of introgressed segments, most of which occur within genes. We report a genome assembly and annotation of Am. muticum that has facilitated the identification of Am. muticum resistance genes commonly introgressed in lines resistant to stripe rust. Our analysis has identified an abundance of structural disruption and homoeologous pairing across the introgression lines, likely caused by the suppressed Ph1 locus. mRNAseq analysis of six of these introgression lines revealed that novel introgressed genes are rarely expressed and those that directly replace a wheat orthologue have a tendency towards downregulation, with no discernible compensation in the expression of homoeologous copies. This study explores the genomic impact of introgression breeding and provides a schematic that can be followed to characterize introgression lines and identify segments and candidate genes underlying the phenotype. This will facilitate more effective utilization of introgression pre-breeding material in wheat breeding programmes.

CIViCdb 2022: evolution of an open-access cancer variant interpretation knowledgebase.

CIViC (Clinical Interpretation of Variants in Cancer; civicdb.org) is a crowd-sourced, public domain knowledgebase composed of literature-derived evidence characterizing the clinical utility of cancer variants. As clinical sequencing becomes more prevalent in cancer management, the need for cancer variant interpretation has grown beyond the capability of any single institution. CIViC contains peer-reviewed, published literature curated and expertly-moderated into structured data units (Evidence Items) that can be accessed globally and in real time, reducing barriers to clinical variant knowledge sharing. We have extended CIViC's functionality to support emergent variant interpretation guidelines, increase interoperability with other variant resources, and promote widespread dissemination of structured curated data. To support the full breadth of variant interpretation from basic to translational, including integration of somatic and germline variant knowledge and inference of drug response, we have enabled curation of three new Evidence Types (Predisposing, Oncogenic and Functional). The growing CIViC knowledgebase has over 300 contributors and distributes clinically-relevant cancer variant data currently representing >3200 variants in >470 genes from >3100 publications.

The 17-gene stemness score associates with relapse risk and long-term outcomes following allogeneic haematopoietic cell transplantation in acute myeloid leukaemia.

A 17-gene stemness (LSC17) score determines risk in acute myeloid leukaemia patients treated with standard chemotherapy regimens. The present study further analysed the impact of the LSC17 score at diagnosis on outcomes following allogeneic haematopoietic cell transplantation (HCT). Out of 452 patients with available LSC17 score, 123 patients received allogeneic HCT. Transplant outcomes, including overall (OS), leukaemia-free survival (LFS), relapse incidence (RI) and non-relapse mortality (NRM), were compared according to the LSC17 scored group. The patients with a low LSC17 score had higher OS (56.2%) and LFS (54.4%) at 2 years compared to patients with high LSC17 score (47.2%, p = 0.0237 for OS and 46.0%, p = 0.0181 for LFS). The low LSC17 score group also had a lower relapse rate at 2 years (12.7%) compared to 25.3% in the high LSC17 score group (p = 0.017), but no difference in NRM (p = 0.674). Worse outcomes in the high LSC17 score group for OS, LFS and relapse were consistently observed across all stratified sub-groups. The use of more intensive conditioning did not improve outcomes for either group. In contrast, chronic graft-versus-host-disease was associated with more favourable outcomes in both groups. The 17-gene stemness score is highly prognostic for survival and relapse risk following allogeneic HCT.

Learning the "Science of the Art of Prescribing": From Evidence-based Algorithms to Individualized Medicine in Psychiatric Care.

The purpose of this review is to highlight the limitations of the traditional diagnosis/evidence-based symptom reduction paradigm and advocate for an individualized medicine approach that incorporates psychological and relational aspects of prescribing in addition to the objective patient presentation. Potential barriers, challenges, and proposed future directions for improving education in psychological and relational aspects of prescribing are discussed. Psychological aspects of prescribing, as recently spelled out in the field of psychodynamic psychopharmacology, are generally acknowledged as important, but they do not have a well-defined position in contemporary residency training throughout North America. While residents receive in-depth exposure to diverse aspects of what to prescribe in their psychopharmacological training, and they work with patients' subjective and relational meaning and the quality of the therapeutic alliance in their psychotherapy rotations, an integrated approach to how to prescribe is generally lacking. Despite many legitimate challenges, the authors suggest that teaching an integrated approach that incorporates objective, subjective, and relational factors in the provision of psychopharmacology and utilizing evidence-based principles of individualized care should be prioritized in both residency training and the provision of psychiatric treatment as a whole.

Assessing the Potential of Using the Langdon 5D(5B) Substitution Line for the Introgression of Aegilops tauschii Into Durum Wheat.

Aegilops tauschii, the D-genome donor of hexaploid wheat, provides a source of genetic variation that could be used for tetraploid (durum) wheat improvement. In addition to the genes for wheat quality on the D-genome, which differentiate between bread and durum wheats in terms of end-use properties, genes coding for resistances to biotic and abiotic stresses are also present on the D-genome which would be useful in durum wheat. The introgression of Ae. tauschii into durum wheat, however, requires cytogenetic manipulation to induce homoeologous chromosome pairing to promote recombination. For this purpose, the introgression of Ae. tauschii into durum wheat was performed through a bridge cross of the wild species to the Langdon 5D(5B) disomic substitution line that lacks the Ph1 locus present on chromosome 5B, followed by a cross of the F1 to the durum wheat cultivar Om Rabi 5. Subsequent generations were self-fertilized, and these were screened for D-genome introgressions using (i) D-genome-specific Kompetitive Allele-Specific PCR (KASP) markers and (ii) KASP markers polymorphic between the 5D chromosomes of wheat, present in the Langdon 5D(5B) substitution line, and of Ae. tauschii. Homozygous introgression lines were confirmed using genomic and fluorescence in situ hybridization. The results showed that the use of the Langdon 5D(5B) disomic substitution line did not promote D-genome introgression across all linkage groups with only a limited success in the introgression of Ae. tauschii 5D segments into durum wheat.

Identification of Fusarium Head Blight Resistance in Triticum timopheevii Accessions and Characterization of Wheat-T. timopheevii Introgression Lines for Enhanced Resistance.

A diverse panel of wheat wild relative species was screened for resistance to Fusarium head blight (FHB) by spray inoculation. The great majority of species and accessions were susceptible or highly susceptible to FHB. Accessions of Triticum timopheevii (P95-99.1-1), Agropyron desertorum (9439957), and Elymus vaillantianus (531552) were highly resistant to FHB while additional accessions of T. timopheevii were found to be susceptible to FHB. A combination of spray and point inoculation assessments over two consecutive seasons indicated that the resistance in accession P95-99.1-1 was due to enhanced resistance to initial infection of the fungus (type 1 resistance), and not to reduction in spread (type 2 resistance). A panel of wheat-T. timopheevii (accession P95-99.1-1) introgression lines was screened for FHB resistance over two consecutive seasons using spray inoculation. Most introgression lines were similar in susceptibility to FHB as the wheat recipient (Paragon) but substitution of the terminal portion of chromosome 3BS of wheat with a similar-sized portion of 3G of T. timopheevii significantly enhanced FHB resistance in the wheat background.

Introgression of the Triticum timopheevii Genome Into Wheat Detected by Chromosome-Specific Kompetitive Allele Specific PCR Markers.

Triticum timopheevii (2n = 28, A t A t GG) is a tetraploid wild relative species with great potential to increase the genetic diversity of hexaploid wheat Triticum aestivum (2n = 42, AABBDD) for various important agronomic traits. A breeding scheme that propagated advanced backcrossed populations of wheat-T. timopheevii introgression lines through further backcrossing and self-fertilisation resulted in the generation of 99 introgression lines (ILs) that carried 309 homozygous segments from the A t and G subgenomes of T. timopheevii. These introgressions contained 89 and 74 unique segments from the A t and G subgenomes, respectively. These overlapping segments covered 98.9% of the T. timopheevii genome that has now been introgressed into bread wheat cv. Paragon including the entirety of all T. timopheevii chromosomes via varying sized segments except for chromosomes 3A t , 4G, and 6G. Homozygous ILs contained between one and eight of these introgressions with an average of three per introgression line. These homozygous introgressions were detected through the development of a set of 480 chromosome-specific Kompetitive allele specific PCR (KASP) markers that are well-distributed across the wheat genome. Of these, 149 were developed in this study based on single nucleotide polymorphisms (SNPs) discovered through whole genome sequencing of T. timopheevii. A majority of these KASP markers were also found to be T. timopheevii subgenome specific with 182 detecting A t subgenome and 275 detecting G subgenome segments. These markers showed that 98% of the A t segments had recombined with the A genome of wheat and 74% of the G genome segments had recombined with the B genome of wheat with the rest recombining with the D genome of wheat. These results were validated through multi-colour in situ hybridisation analysis. Together these homozygous wheat-T. timopheevii ILs and chromosome-specific KASP markers provide an invaluable resource to wheat breeders for trait discovery to combat biotic and abiotic stress factors affecting wheat production due to climate change.

The Relationship Between Medical Diagnoses, Risk Perceptions, and Social Distancing Compliance: An Analysis of Data from the Toledo Adolescent Relationships Study.

Background: The health belief model suggests that individuals' beliefs affect behaviors associated with health. This study examined whether Ohioans' pre-existing medical health diagnoses affected their belief about personal health risk and their compliance with social distancing during the coronavirus disease 2019 (COVID-19) pandemic. Prior research examining physical and mental diagnoses and social distancing compliance is nearly nonexistent. We examined whether physical and mental health diagnoses influenced individuals' beliefs that their health is at risk and their adherence with social distancing guidelines. Methods: The study used longitudinal cohort data from the Toledo Adolescent Relationships Study (TARS) (n = 790), which surveyed Ohioans prior to and during the COVID-19 pandemic. Dependent variables included belief that an individual's own health was at risk and social distancing compliance. Independent variables included physical and mental health diagnoses, pandemic-related factors (fear of COVID-19, political beliefs about the pandemic, friends social distance, family social distance, COVID-19 exposure), and sociodemographic variables (age, gender, race/ethnicity, educational level). Results: Individuals who had a pre-existing physical health diagnosis were more likely to believe that their personal health was at risk during the pandemic but were not more likely to comply with social distancing guidelines. In contrast, individuals who had a pre-existing mental health diagnosis were more compliant with social distancing guidelines but were not more likely to believe their personal health was at risk. Individuals who expressed greater fear of COVID-19 believed their health is more at risk than those who expressed lower levels of fear. Conclusion: Health considerations are important to account for in assessments of responses to the pandemic, beliefs about personal health risk, and social distancing behavior. Additional research is needed to understand the divergence in the findings regarding physical health, beliefs about personal health risk, and social distancing compliance. Further, research is needed to understand how mental health issues impact decision-making related to social distancing compliance.

Turnaround Times in Melanoma BRAF Testing and the Impact on the Initiation of Systemic Therapy at a Single Tertiary Care Cancer Center.

PURPOSE: The identification of BRAF mutations in melanoma enables targeted therapy and improves patient outcomes. Barriers to BRAF molecular testing affect the quality of care and therapeutic options. METHODS: This retrospective study mapped BRAF testing timelines in adult patients with melanoma at the Princess Margaret Cancer Centre to identify obstacles to timely BRAF reporting and its impact on the initiation of therapy. RESULTS: Sixty-six cases were included. The median time between BRAF request and result was 12 days (95% CI, 8 to 15) when the BRAF test was ordered by pathology, compared with 20 days (95% CI, 16 to 23) if the test was requested by another specialist (P < .001). When the BRAF test and biopsy were performed within the same institution, the BRAF median turnaround time (TAT) was 13 days (95% CI, 6 to 19) compared with 19 days (95% CI, 16 to 21) if the sample was transferred from another institution (P = .02). Forty-seven patients received systemic therapy, and 20 had metastatic disease. In the metastatic subgroup, if the BRAF result was available at the first medical oncology visit, the initiation of treatment was 20 days (95% CI, 9.6 to 30.3), but was delayed to 31 days (95% CI, 10.8 to 51.1) if the BRAF result was not available (P = .03). CONCLUSION: This study showed variations in BRAF test results in TAT. One factor affecting this timeline is the transfer time, which can be streamlined by pathology reflex testing. Delays in TAT affect the timing and type of therapeutic intervention, especially in patients with stage IV disease.

Identifying variation for N-use efficiency and associated traits in amphidiploids derived from hybrids of bread wheat and the genera Aegilops, Secale, Thinopyrum and Triticum.

Future genetic progress in wheat grain yield will depend on increasing biomass and this must be achieved without commensurate increases in nitrogen (N) fertilizer inputs to minimize environmental impacts. In recent decades there has been a loss of genetic diversity in wheat through plant breeding. However, new genetic diversity can be created by incorporating genes into bread wheat from wild wheat relatives. Our objectives were to investigate amphidiploids derived from hybrids of bread wheat (Triticum aestivum L.) and related species from the genera Aegilops, Secale, Thinopyrum and Triticum for expression of higher biomass, N-use efficiency (NUE) and leaf photosynthesis rate compared to their bread wheat parents under high and low N conditions. Eighteen amphidiploid lines and their bread wheat parents were examined in high N (HN) and low N (LN) treatments under glasshouse conditions in two years. Averaged across years, grain yield reduced by 38% under LN compared to HN conditions (P = 0.004). Three amphidiploid lines showed positive transgressive segregation compared to their bread wheat parent for biomass per plant under HN conditions. Positive transgressive segregation was also identified for flag-leaf photosynthesis both pre-anthesis and post-anthesis under HN and LN conditions. For N uptake per plant at maturity positive transgressive segregation was identified for one amphidiploid line under LN conditions. Our results indicated that introgressing traits from wild relatives into modern bread wheat germplasm offers scope to raise biomass and N-use effciency in both optimal and low N availability environments.