A Community-Engaged Approach to Understanding Suicide in a Small Rural County in Georgia: A Two-Phase Content Analysis of Individual and Focus Group Interviews.

Suicide is a significant public health problem, with disproportionate rates in rural areas. Rural communities face substantial structural and cultural barriers to suicide prevention. This study aimed to gain a deeper understanding of the need for suicide prevention and gauge the appropriateness of prevention efforts in the context of a rural Georgia county by leveraging existing community resources and knowledge. Twenty one-on-one, semi-structured interviews and two focus groups were conducted, with participants recruited via purposive snowball sampling. Data analysis included qualitative deductive and inductive content analysis from individual interviews and focus groups with community stakeholders. The findings highlight how rural contexts exacerbate drivers of death by suicide and how the substantial loss of community members to suicide contributes to the ongoing crisis and reduces available support. Access to mental health care often depended on a connection to an established public system such as schools, a military base, or Veterans Administration. There were perceived gaps in crisis and post-crisis services, with participants actively trying to address these gaps and build community support through coalition building. This study contributes knowledge to contextual drivers of suicide in rural areas beyond individual-level risk factors. Community-engaged suicide prevention research in rural areas is promising, but there is a need to develop interventions to best support coalition building and capacity development.

Rvi4 and Rvi15 are the same apple scab resistance genes.

The apple (Malus x domestica) scab (Venturia inaequalis) resistance genes Rvi4 and Rvi15 were mapped to a similar region on the top of linkage group 2 and both resistance genes elicit the same type of resistance reaction, i.e., a hypersensitive response; hence, it is suspected that the two genes may be the same. As the two resistance genes Rvi4 and Rvi15 are currently used in apple breeding, it is important to clarify whether the two resistance genes are the same or not. Several approaches were used to make this determination. First, the pedigree of the genotype GMAL 2473, the source of Rvi15, was reconstructed. GMAL 2473 was found to be an F1 of 'Russian seedling', the genotype, which is known to also be the source of Rvi4. Next, it was further demonstrated that 'Regia', a cultivar known to carry Rvi4 (and Rvi2), carries the same gene (Vr2-C), which was demonstrated to be the gene inducing Rvi15 resistance. Finally, it was shown that transgenic lines carrying Vr2-C are compatible with race 4 apple scab isolates. Taken all together, these results definitively demonstrate that Rvi4 and Rvi15 are the same resistance gene. For future studies, we suggest referring to this resistance with the first name that was assigned to this gene, namely Rvi4. Supplementary Information: The online version contains supplementary material available at 10.1007/s11032-023-01421-0.

Endoscopic Rhizotomy for Facetogenic Back Pain: A Review of the History, Financial Considerations, Patient Selection Criteria, and Clinical Outcomes.

BACKGROUND: Chronic back pain (CBP) is a condition that places a considerable burden on society, with several million people affected in the United States alone. Treatment options to address this problem and relieve CBP are constantly evolving, and one of the most promising treatment modalities for CBP that is refractory to conservative treatment options is endoscopic rhizotomy (ER). METHODS: A thorough search of the PubMed (MEDLINE) database was conducted to assess the full progression of ER from its earliest uses to present day in a historical narrative review of ER, with treatment of facetogenic pain as a model pathology. RESULTS: ER allows for direct visualization and ablation of sensory branches of the dorsal ramus to provide pain relief in up to 80% of patients faced with refractory CBP. This technique has been built upon since the early 20th century, and the novel endoscopic approach continues to gain popularity among physicians. Benefits of ER include superior postoperative median pain-free duration compared with traditional percutaneous radiofrequency ablation, as well as direct visualization of regional anatomy. Patient selection criteria for the procedure and a modest list of contraindications allow the use of ER as a viable treatment option for a significant population of patients suffering from CBP. Potential barriers to ER include high cost of the procedure, longer intraoperative time, and expensive proprietary equipment. CONCLUSIONS: ER is an effective treatment for refractory CBP with notable advantages. As the technology and popularity of this procedure progress, improvements in the cost, training, and intraoperative time may make it a favorable alternative to the current standard of care.

DNA profiling with the 20K apple SNP array reveals Malus domestica hybridization and admixture in M. sieversii, M. orientalis, and M. sylvestris genebank accessions.

The USDA-ARS National Plant Germplasm System (NPGS) apple collection in Geneva, NY, USA maintains accessions of the primary Malus domestica (Suckow) Borkh. progenitor species M. sieversii (Ledeb.) M. Roem., M. orientalis Uglitzk., and M. sylvestris (L.) Mill. Many of these accessions originated from seeds that were collected from wild populations in the species' centers of diversity. Some of these accessions have fruit phenotypes that suggest recent M. domestica hybridization, which if true would represent crop contamination of wild species populations and mislabeled species status of NPGS accessions. Pedigree connections and admixture between M. domestica and its progenitor species can be readily identified with apple SNP array data, despite such arrays not being designed for these purposes. To investigate species purity, most (463 accessions) of the NPGS accessions labeled as these three progenitor species were genotyped using the 20K apple SNP array. DNA profiles obtained were compared with a dataset of more than 5000 unique M. domestica apple cultivars. Only 212 accessions (151 M. sieversii, 26 M. orientalis, and 35 M. sylvestris) were identified as "pure" species representatives because their DNA profiles did not exhibit genotypic signatures of recent hybridization with M. domestica. Twenty-one accessions (17 M. sieversii, 1 M. orientalis, and 3 M. sylvestris) previously labeled as wild species were instead fully M. domestica. Previously unrealized hybridization and admixture between wild species and M. domestica was identified in 230 accessions (215 M. sieversii, 9 M. orientalis, and 6 M. sylvestris). Among these species-mislabeled accessions, 'Alexander', 'Gold Reinette', 'Charlamoff', 'Rosmarina Bianca', and 'King of the Pippins' were the most frequently detected M. domestica parents or grandparents. These results have implications for collection management, including germplasm distribution, and might affect conclusions of previous research focused on these three progenitor species in the NPGS apple collection. Specifically, accessions received from the NPGS for breeding and genomics, genetics, and evolutionary biology research might not be truly representative of their previously assigned species.

Phase 2 Study of Neoadjuvant FGFR Inhibition and Androgen Deprivation Therapy Prior to Prostatectomy.

BACKGROUND: Disease recurrence is common following prostatectomy in patients with localised prostate cancer with high-risk features. Although androgen deprivation therapy increases the rates of organ-confined disease and negative surgical margins, there is no significant benefit on disease recurrence. Multiple lines of evidence suggest that (Fibroblast Growth Factor/Fibroblast Growth Factor Receptor) FGF/FGFR-signalling is important in supporting prostate epithelial cell survival in hostile conditions, including acute androgen deprivation. Given the recent availability of oral FGFR inhibitors, we investigated whether combination therapy could improve tumour response in the neo-adjuvant setting. METHODS: We conducted an open label phase II study of the combination of erdafitinib (3 months) and androgen deprivation therapy (4 months) in men with localised prostate cancer with high-risk features prior to prostatectomy using a Simon's 2 stage design. The co-primary endpoints were safety and tolerability and pathological response in the prostatectomy specimen. The effect of treatment on residual tumours was explored by global transcriptional profiling with RNA-sequencing. RESULTS: Nine patients were enrolled in the first stage of the trial. The treatment combination was poorly tolerated. Erdafitinib treatment was discontinued early in six patients, three of whom also required dose interruptions/reductions. Androgen deprivation therapy for 4 months was completed in all patients. The most common adverse events were hyperphosphataemia, taste disturbance, dry mouth and nail changes. No patients achieved a complete pathological response, although patients who tolerated erdafitinib for longer had smaller residual tumours, associated with reduced transcriptional signatures of epithelial cell proliferation. CONCLUSIONS: Although there was a possible enhanced anti-tumour effect of androgen deprivation therapy in combination with erdafitnib in treatment naïve prostate cancer, the poor tolerability in this patient population prohibits the use of this combination in this setting.

Different Shades of Kale-Approaches to Analyze Kale Variety Interrelations.

Brassica oleracea is a vegetable crop with an amazing morphological diversity. Among the various crops derived from B. oleracea, kale has been in the spotlight globally due to its various health-benefitting compounds and many different varieties. Knowledge of the existing genetic diversity is essential for the improved breeding of kale. Here, we analyze the interrelationships, population structures, and genetic diversity of 72 kale and cabbage varieties by extending our previous diversity analysis and evaluating the use of summed potential lengths of shared haplotypes (SPLoSH) as a new method for such analyses. To this end, we made use of the high-density Brassica 60K SNP array, analyzed SNPs included in an available Brassica genetic map, and used these resources to generate and evaluate the information from SPLoSH data. With our results we could consistently differentiate four groups of kale across all analyses: the curly kale varieties, Italian, American, and Russian varieties, as well as wild and cultivated types. The best results were achieved by using SPLoSH information, thus validating the use of this information in improving analyses of interrelations in kale. In conclusion, our definition of kale includes the curly varieties as the kales in a strict sense, regardless of their origin. These results contribute to a better understanding of the huge diversity of kale and its interrelations.

A new method to reconstruct the direction of parent-offspring duo relationships using SNP array data and its demonstration on ancient and modern cultivars in the outcrossing species malus × domestica.

Unordered parent-offspring (PO) relationships are an outstanding issue in pedigree reconstruction studies. Resolution of the order of these relationships would expand the results, conclusions, and usefulness of such studies; however, no such PO order resolution (POR) tests currently exist. This study describes two such tests, demonstrated using SNP array data in the outcrossing species apple (Malus × domestica) on a PO relationship of known order ("Keepsake" as a parent of "Honeycrisp") and two PO relationships previously ordered only via provenance information. The first test, POR-1, tests whether some of the extended haplotypes deduced from homozygous SNP calls from one individual in an unordered PO duo are composed of recombinant haplotypes from accurately phased SNP genotypes from the second individual. If so, the first individual would be the offspring of the second individual, otherwise the opposite relationship would be present. The second test, POR-2, does not require phased SNP genotypes and uses similar logic as the POR-1 test, albeit in a different approach. The POR-1 and POR-2 tests determined the correct relationship between "Keepsake" and "Honeycrisp". The POR-2 test confirmed "Reinette Franche" as a parent of "Nonpareil" and "Brabant Bellefleur" as a parent of "Court Pendu Plat". The latter finding conflicted with the recorded provenance information, demonstrating the need for these tests. The successful demonstration of these tests suggests they can add insights to future pedigree reconstruction studies, though caveats, like extreme inbreeding or selfing, would need to be considered where relevant.

Comparative analysis of infectious complications with outpatient vs. inpatient care for adults with high-risk myeloid neoplasm receiving intensive induction chemotherapy.

We recently reported an early hospital discharge (EHD) care strategy following intensive acute myeloid leukemia (AML)-like chemotherapy is safe. To evaluate its impact on infectious outcomes, we compared all adults treated from 8/1/2014 to 7/31/2018 discharging within 72 h of completing chemotherapy (EHD) with hospitalized patients (controls) across 354 induction and 259 post-remission cycles. While overall outcomes were similar, gram-positive bacteremias were more common in EHD patients than control (p<.001), although they received fewer days of IV antimicrobials (p< .001). Notably, cumulative infection risks in EHD patients were similar after induction and post-remission therapy. In multivariable analysis, only EHD status was independently associated with risk for gram-positive bacteremia (p= .01), whereas the only independent risk factor for fungal infection was fluconazole (vs. posaconazole) use (p< .001). The observation of increased rates of gram-positive bacteremias with EHD identifies improvements in catheter management as one area to further increase the safety of this care approach.

The use of shared haplotype length information for pedigree reconstruction in asexually propagated outbreeding crops, demonstrated for apple and sweet cherry.

Pedigree information is of fundamental importance in breeding programs and related genetics efforts. However, many individuals have unknown pedigrees. While methods to identify and confirm direct parent-offspring relationships are routine, those for other types of close relationships have yet to be effectively and widely implemented with plants, due to complications such as asexual propagation and extensive inbreeding. The objective of this study was to develop and demonstrate methods that support complex pedigree reconstruction via the total length of identical by state haplotypes (referred to in this study as "summed potential lengths of shared haplotypes", SPLoSH). A custom Python script, HapShared, was developed to generate SPLoSH data in apple and sweet cherry. HapShared was used to establish empirical distributions of SPLoSH data for known relationships in these crops. These distributions were then used to estimate previously unknown relationships. Case studies in each crop demonstrated various pedigree reconstruction scenarios using SPLoSH data. For cherry, a full-sib relationship was deduced for 'Emperor Francis, and 'Schmidt', a half-sib relationship for 'Van' and 'Windsor', and the paternal grandparents of 'Stella' were confirmed. For apple, 29 cultivars were found to share an unknown parent, the pedigree of the unknown parent of 'Cox's Pomona' was reconstructed, and 'Fameuse' was deduced to be a likely grandparent of 'McIntosh'. Key genetic resources that enabled this empirical study were large genome-wide SNP array datasets, integrated genetic maps, and previously identified pedigree relationships. Crops with similar resources are also expected to benefit from using HapShared for empowering pedigree reconstruction.

Loss of SNAI2 in Prostate Cancer Correlates With Clinical Response to Androgen Deprivation Therapy.

PURPOSE: Androgen receptor (AR) signaling is important in prostate cancer progression, and therapies that target this pathway have been the mainstay of treatment for advanced disease for over 70 years. Tumors eventually progress despite castration through a number of well-characterized mechanisms; however, little is known about what determines the magnitude of response to short-term pathway inhibition. METHODS: We evaluated a novel combination of AR-targeting therapies (degarelix, abiraterone, and bicalutamide) and noted that the objective patient response to therapy was highly variable. To investigate what was driving treatment resistance in poorly responding patients, as a secondary outcome we comprehensively characterized pre- and post-treatment samples using both whole-genome and RNA sequencing. RESULTS: We find that resistance following short-term treatment differs molecularly from typical progressive castration-resistant disease, associated with transcriptional reprogramming, to a transitional epithelial-to-mesenchymal transition (EMT) phenotype rather than an upregulation of AR signaling. Unexpectedly, tolerance to therapy appears to be the default state, with treatment response correlating with the prevalence of tumor cells deficient for SNAI2, a key regulator of EMT reprogramming. CONCLUSION: We show that EMT characterizes acutely resistant prostate tumors and that deletion of SNAI2, a key transcriptional regulator of EMT, correlates with clinical response.

Financial Implications of Early Hospital Discharge After AML-Like Induction Chemotherapy: A 4-Year Retrospective Analysis.

BACKGROUND: Early hospital discharge (EHD) after intensive acute myeloid leukemia (AML) induction chemotherapy has become routine at the University of Washington/Seattle Cancer Care Alliance over the past several years. We assessed the financial implications of EHD over the first 4 years after its broad adoption for patients with AML and other high-grade myeloid neoplasms undergoing AML-like induction chemotherapy. PATIENTS AND METHODS: We retrospectively compared charges between 189 patients with EHD who received all postinduction inpatient/outpatient care within our care system between August 2014 and July 2018 and 139 medically matched control patients who remained hospitalized for logistical reasons. Charges from the day of initial discharge (patients with EHD) or end of chemotherapy (control patients) until blood count recovery, additional chemotherapy or care transition, hospital discharge (for control patients only), an elapse of 42 days, or death were extracted from financial databases and separated into categories: facility/provider, emergency department, transfusions, laboratory, imaging, pharmacy, and miscellaneous. RESULTS: Combined charges averaged $4,157/day (range, $905-$13,119/day) for patients with EHD versus $9,248/day (range, $4,363-$48,522/day) for control patients (P<.001). The EHD cohort had lower mean facility/provider, transfusion, laboratory, and pharmacy charges but not imaging or miscellaneous charges. During readmissions, there was no statistically significant difference in daily inpatient charges between the EHD and control cohorts. After multivariable adjustment, average charges were $3,837/day lower for patients with EHD (P<.001). CONCLUSIONS: Together with previous data from our center showing that EHD is safe and associated with reduced healthcare resource utilization, this study further supports this care approach for AML and other high-grade myeloid neoplasms if infrastructure is available to enable close outpatient follow-up.

Integration of Infinium and Axiom SNP array data in the outcrossing species Malus × domestica and causes for seemingly incompatible calls.

BACKGROUND: Single nucleotide polymorphism (SNP) array technology has been increasingly used to generate large quantities of SNP data for use in genetic studies. As new arrays are developed to take advantage of new technology and of improved probe design using new genome sequence and panel data, a need to integrate data from different arrays and array platforms has arisen. This study was undertaken in view of our need for an integrated high-quality dataset of Illumina Infinium® 20 K and Affymetrix Axiom® 480 K SNP array data in apple (Malus × domestica). In this study, we qualify and quantify the compatibility of SNP calling, defined as SNP calls that are both accurate and concordant, across both arrays by two approaches. First, the concordance of SNP calls was evaluated using a set of 417 duplicate individuals genotyped on both arrays starting from a set of 10,295 robust SNPs on the Infinium array. Next, the accuracy of the SNP calls was evaluated on additional germplasm (n = 3141) from both arrays using Mendelian inconsistent and consistent errors across thousands of pedigree links. While performing this work, we took the opportunity to evaluate reasons for probe failure and observed discordant SNP calls. RESULTS: Concordance among the duplicate individuals was on average of 97.1% across 10,295 SNPs. Of these SNPs, 35% had discordant call(s) that were further curated, leading to a final set of 8412 (81.7%) SNPs that were deemed compatible. Compatibility was highly influenced by the presence of alternate probe binding locations and secondary polymorphisms. The impact of the latter was highly influenced by their number and proximity to the 3' end of the probe. CONCLUSIONS: The Infinium and Axiom SNP array data were mostly compatible. However, data integration required intense data filtering and curation. This work resulted in a workflow and information that may be of use in other data integration efforts. Such an in-depth analysis of array concordance and accuracy as ours has not been previously described in the literature and will be useful in future work on SNP array data integration and interpretation, and in probe/platform development.

A DNA test for high incidence of soft scald and soggy breakdown postharvest disorders in Malus domestica Borkh.

The 'Honeycrisp' apple, an economically important cultivar and breeding parent, is prone to soft scald and soggy breakdown postharvest physiological disorders. Phenotypic evaluation of soft scald is time consuming and costly, making it an excellent target for DNA-informed breeding. The objective of this study was to develop a DNA test for a soft scald and soggy breakdown quantitative trait locus (QTL) on linkage group two (LG2) that was characterized in a previous study. 'Honeycrisp' is homozygous for the undesirable high disorder incidence haplotype (HDI) at this QTL. In this study, sixteen single nucleotide polymorphism markers were evaluated for their associations with the HDI haplotype in a set of 132 unique cultivars and important breeding parents. A DNA test was successfully developed utilizing KASP™ (Kompetitive Allele Specific PCR) chemistry to identify the number of HDI haplotypes in individuals. This test had a 100% accuracy for detecting homozygous unfavorable HDI individuals and has an expected 88% accuracy over all three haplotype copy groups across the evaluated germplasm. This DNA test is a promising tool for minimizing the chances of selecting individuals that exhibit high incidence of soft scald postharvest disorder in 'Honeycrisp'-related germplasm. Supplementary Information: The online version contains supplementary material available at 10.1007/s11032-021-01245-w.

The utility of magnetic resonance imaging in prostate cancer diagnosis in the Australian setting.

Objectives: To investigate the utility of Magnetic Resonance Imaging (MRI) for prostate cancer diagnosis in the Australian setting. Patients and methods: All consecutive men who underwent a prostate biopsy (transperineal or transrectal) at Royal Melbourne Hospital between July 2017 to June 2019 were included, totalling 332 patients. Data were retrospectively collected from patient records. For each individual patient, the risk of prostate cancer diagnosis at biopsy based on clinical findings was determined using the European Randomized study of Screening for Prostate Cancer (ERSPC) risk calculator, with and without incorporation of MRI findings. Results: MRI has good diagnostic accuracy for clinically significant prostate cancer. A PI-RADS 2 or lower finding has a negative predictive value of 96% for clinically significant cancer, and a PI-RADS 3, 4 or 5 MRI scan has a sensitivity of 93%. However, MRI has a false negative rate of 6.5% overall for clinically significant prostate cancers. Pre- biopsy MRI may reduce the number of unnecessary biopsies, as up to 50.0% of negative or ISUP1 biopsies have MRI PI-RADS 2 or lower. Incorporation of MRI findings into the ERSPC calculator improved predictive performance for all prostate cancer diagnoses (AUC 0.77 vs 0.71, P = .04), but not for clinically significant cancer (AUC 0.89 vs 0.87, P = .37). Conclusion: MRI has good sensitivity and negative predictive value for clinically significant prostate cancers. It is useful as a pre-biopsy tool and can be used to significantly reduce the number of unnecessary prostate biopsies. However, MRI does not significantly improve risk predictions for clinically significant cancers when incorporated into the ERSPC risk calculator.

The apple REFPOP-a reference population for genomics-assisted breeding in apple.

Breeding of apple is a long-term and costly process due to the time and space requirements for screening selection candidates. Genomics-assisted breeding utilizes genomic and phenotypic information to increase the selection efficiency in breeding programs, and measurements of phenotypes in different environments can facilitate the application of the approach under various climatic conditions. Here we present an apple reference population: the apple REFPOP, a large collection formed of 534 genotypes planted in six European countries, as a unique tool to accelerate apple breeding. The population consisted of 269 accessions and 265 progeny from 27 parental combinations, representing the diversity in cultivated apple and current European breeding material, respectively. A high-density genome-wide dataset of 303,239 SNPs was produced as a combined output of two SNP arrays of different densities using marker imputation with an imputation accuracy of 0.95. Based on the genotypic data, linkage disequilibrium was low and population structure was weak. Two well-studied phenological traits of horticultural importance were measured. We found marker-trait associations in several previously identified genomic regions and maximum predictive abilities of 0.57 and 0.75 for floral emergence and harvest date, respectively. With decreasing SNP density, the detection of significant marker-trait associations varied depending on trait architecture. Regardless of the trait, 10,000 SNPs sufficed to maximize genomic prediction ability. We confirm the suitability of the apple REFPOP design for genomics-assisted breeding, especially for breeding programs using related germplasm, and emphasize the advantages of a coordinated and multinational effort for customizing apple breeding methods in the genomics era.

Experiences of Unmet Need and Access to Supportive Care for Men Receiving Androgen Deprivation Therapy for Prostate Cancer: A Bi-national Study.

OBJECTIVE: The number of men affected by incurable prostate cancer is expected to increase worldwide. Research is needed to enable men to share their experiences of unmet supportive care needs in current care delivery. We aimed to identify the most frequently reported domains of unmet supportive care needs, levels of anxiety, depression, distress, health-related quality of life, and to identify any perceived barriers to receiving supportive care. DATA SOURCES: Men diagnosed with prostate cancer who had received a minimum of 6 months of ADT were recruited into a cross-sectional study. Participants completed standardised questionnaires; clinical and demographic data was also collected. CONCLUSION: Two hundred seventy-two patients were invited, and 102 participated. No statistically significant differences were found between participant scores from Australia and UK in relation to anxiety and depression, exercise, health-related quality of life, or distress scores. Perceived barriers include service delivery related to information provision and difficulties in the navigation of complex care systems. IMPLICATIONS FOR NURSING PRACTICE: Men affected by prostate cancer receiving ADT reported unmet supportive care needs, specifically related to sexual, informational, and psychological aspects of care. Mapping future trajectories of needs and identifying men at high risk can significantly improve timely and tailored interventions.

Global Regulatory DNA Potentiation by SMARCA4 Propagates to Selective Gene Expression Programs via Domain-Level Remodeling.

The human genome encodes millions of regulatory elements, of which only a small fraction are active within a given cell type. Little is known about the global impact of chromatin remodelers on regulatory DNA landscapes and how this translates to gene expression. We use precision genome engineering to reawaken homozygously inactivated SMARCA4, a central ATPase of the human SWI/SNF chromatin remodeling complex, in lung adenocarcinoma cells. Here, we combine DNase I hypersensitivity, histone modification, and transcriptional profiling to show that SMARCA4 dramatically increases both the number and magnitude of accessible chromatin sites genome-wide, chiefly by unmasking sites of low regulatory factor occupancy. By contrast, transcriptional changes are concentrated within well-demarcated remodeling domains wherein expression of specific genes is gated by both distal element activation and promoter chromatin configuration. Our results provide a perspective on how global chromatin remodeling activity is translated to gene expression via regulatory DNA.