Genomic loci influence patterns of structural covariance in the human brain.

Normal and pathologic neurobiological processes influence brain morphology in coordinated ways that give rise to patterns of structural covariance (PSC) across brain regions and individuals during brain aging and diseases. The genetic underpinnings of these patterns remain largely unknown. We apply a stochastic multivariate factorization method to a diverse population of 50,699 individuals (12 studies and 130 sites) and derive data-driven, multi-scale PSCs of regional brain size. PSCs were significantly correlated with 915 genomic loci in the discovery set, 617 of which are newly identified, and 72% were independently replicated. Key pathways influencing PSCs involve reelin signaling, apoptosis, neurogenesis, and appendage development, while pathways of breast cancer indicate potential interplays between brain metastasis and PSCs associated with neurodegeneration and dementia. Using support vector machines, multi-scale PSCs effectively derive imaging signatures of several brain diseases. Our results elucidate genetic and biological underpinnings that influence structural covariance patterns in the human brain.

Automated analysis of low-field brain MRI in cerebral malaria.

A central challenge of medical imaging studies is to extract biomarkers that characterize disease pathology or outcomes. Modern automated approaches have found tremendous success in high-resolution, high-quality magnetic resonance images. These methods, however, may not translate to low-resolution images acquired on magnetic resonance imaging (MRI) scanners with lower magnetic field strength. In low-resource settings where low-field scanners are more common and there is a shortage of radiologists to manually interpret MRI scans, it is critical to develop automated methods that can augment or replace manual interpretation, while accommodating reduced image quality. We present a fully automated framework for translating radiological diagnostic criteria into image-based biomarkers, inspired by a project in which children with cerebral malaria (CM) were imaged using low-field 0.35 Tesla MRI. We integrate multiatlas label fusion, which leverages high-resolution images from another sample as prior spatial information, with parametric Gaussian hidden Markov models based on image intensities, to create a robust method for determining ventricular cerebrospinal fluid volume. We also propose normalized image intensity and texture measurements to determine the loss of gray-to-white matter tissue differentiation and sulcal effacement. These integrated biomarkers have excellent classification performance for determining severe brain swelling due to CM.

Voxel-wise intermodal coupling analysis of two or more modalities using local covariance decomposition.

When individual subjects are imaged with multiple modalities, biological information is present not only within each modality, but also between modalities - that is, in how modalities covary at the voxel level. Previous studies have shown that local covariance structures between modalities, or intermodal coupling (IMCo), can be summarized for two modalities, and that two-modality IMCo reveals otherwise undiscovered patterns in neurodevelopment and certain diseases. However, previous IMCo methods are based on the slopes of local weighted linear regression lines, which are inherently asymmetric and limited to the two-modality setting. Here, we present a generalization of IMCo estimation which uses local covariance decompositions to define a symmetric, voxel-wise coupling coefficient that is valid for two or more modalities. We use this method to study coupling between cerebral blood flow, amplitude of low frequency fluctuations, and local connectivity in 803 subjects ages 8 through 22. We demonstrate that coupling is spatially heterogeneous, varies with respect to age and sex in neurodevelopment, and reveals patterns that are not present in individual modalities. As availability of multi-modal data continues to increase, principal-component-based IMCo (pIMCo) offers a powerful approach for summarizing relationships between multiple aspects of brain structure and function. An R package for estimating pIMCo is available at: https://github.com/hufengling/pIMCo.

Drug Adherence and Persistence of Patients with Moderate to Severe Psoriasis Treated with Biologic Medications in a US Commercially Insured Population.

BACKGROUND: Adalimumab (ADA), certolizumab pegol (CER), etanercept (ETA), guselkumab (GUS), ixekizumab (IXE), secukinumab (SEC), and ustekinumab (UST) are biologic medications approved in the USA for the treatment of moderate to severe psoriasis. We examined drug adherence and persistence of patients with moderate to severe psoriasis who initiated these seven biologic medications. METHODS: Adult patients with ≥1 pharmacy/medical claim for any of the seven psoriasis medications and ≥1 diagnosis of psoriasis in the previous 6 months between July 1, 2014 and June 30, 2019 were selected from the IBM MarketScan® Commercial Claims and Encounters Database. The index date was defined as the date of the first prescription fill. Patients were required to have continuous health plan enrollment during the 6 months prior to their index date and ≥9 months after. Patients were grouped into seven study cohorts based upon their index biologic medication. Adherence was measured using the proportion of days covered (PDC) and defined by a PDC ≥80%. Adherence and persistence with index biologic medications were examined during fixed follow-up periods of 3, 6, and 9 months, with a subpopulation analysis carried out among patients with 12 months of follow-up. RESULTS: Among psoriasis patients with ≥9 months of continuous enrollment included in the study population, the number of those who initiated each biologic medication was 10,324 for ADA, 431 for CER, 3,092 for ETA, 821 for GUS, 1,766 for IXE, 4,132 for SEC, and 5,441 for UST. The mean age at the time of initiating biologic treatment was 46.9 years. During the 9-month follow-up period, the proportions of adherent patients (i.e., PDC ≥80%) were numerically higher among those treated with UST (59.9%) and GUS (56.9%), followed by those treated with SEC (46.1%), IXE (45.5%), ADA (44.7%), ETA (33.9%), and CER (22.0%). The proportions of patients who were persistent with their index biologic medication during the 9-month follow-up period were numerically higher among those treated with UST (70.1%) and GUS (67.8%), followed by those treated with IXE (47.3%), SEC (46.9%), ADA (28.7%), CER (14.8%), and ETA (10.7%). CONCLUSIONS: In this large healthcare claims database analysis of psoriasis patients treated with seven different biologic medications, adherence was numerically higher among those treated with UST or GUS. UST and GUS were also associated with numerically greater persistence.

Somatic, psychological and economic benefits of regular physical activity beginning in childhood.

Physical activity is a natural part of a healthy life-style, which should be nurtured from early childhood. Regular physical activity mitigates against the global problems of overweight and obesity, hypertension, anxiety and depression. It lowers the morbidity and mortality from cardiovascular disease and provides hope for sustainable economics to support an ageing population into their retirement. This is preventative health economics that can be achieved with integrated support from families, communities, health-care professionals and governments at all levels. At present, children lack the support of those responsible for them at a societal level to adequately protect them from the physical and emotional consequences of reduced physical activity.

A simple permutation-based test of intermodal correspondence.

Many key findings in neuroimaging studies involve similarities between brain maps, but statistical methods used to measure these findings have varied. Current state-of-the-art methods involve comparing observed group-level brain maps (after averaging intensities at each image location across multiple subjects) against spatial null models of these group-level maps. However, these methods typically make strong and potentially unrealistic statistical assumptions, such as covariance stationarity. To address these issues, in this article we propose using subject-level data and a classical permutation testing framework to test and assess similarities between brain maps. Our method is comparable to traditional permutation tests in that it involves randomly permuting subjects to generate a null distribution of intermodal correspondence statistics, which we compare to an observed statistic to estimate a p-value. We apply and compare our method in simulated and real neuroimaging data from the Philadelphia Neurodevelopmental Cohort. We show that our method performs well for detecting relationships between modalities known to be strongly related (cortical thickness and sulcal depth), and it is conservative when an association would not be expected (cortical thickness and activation on the n-back working memory task). Notably, our method is the most flexible and reliable for localizing intermodal relationships within subregions of the brain and allows for generalizable statistical inference.

Traveling to Receive Treatment for Extremity Soft Tissue Sarcomas: Is it worth the drive?

BACKGROUND: Regionalization of sarcoma care may improve outcomes. Concerns exist regarding the burdens of travel and its effects on care. We evaluate the presence of a "distance bias". METHODS: Retrospective cohort study of patients with extremity soft tissue sarcoma (stage I-III) within the NCDB. Travel distance (TD) and hospital volume (VOL) were categorized into quartiles. Alternating statistical models were used for analysis. RESULTS: 1,035 hospitals contributed 11,979 cases. Median and maximum VOL were 5 and 45 cases/year. VOL quartiles were "low-volume" (LV) (892 hospitals, < 3 cases/yr.), "intermediate low-volume" (ILV) (89, 3-5 cases/yr.), "intermediate high-volume" (IHV) (39, 6-12 cases/yr.), and "high-volume" (HV) (15, > 12 cases/yr.). TD quartiles: "short-travel" (ST) (< 8 mi), "intermediate-short travel" (IST) (8-17), "intermediate long-travel" (ILT) (18-49), and "long-travel" (LT) (> 50). VOL but not TD is associated with improved survival [HR 0.65 (CI 0.52-0.83)] and rate of R0 resection [1.87 (CI 1.4-2.5)] but has no effect on amputation rates. Matched analyses demonstrate similar results. CONCLUSIONS: Hospital volume but not distance traveled to treatment facility is associated with improved survival and R0 resections for extremity soft tissue sarcomas. Despite the inconveniences of travel, patients may benefit from treatment at high volume centers.

Characteristics of Patients Initiating Guselkumab for Plaque Psoriasis in the Symphony Health Claims Database.

Guselkumab is approved by the Food and Drug Administration for the treatment of moderate-to-severe plaque psoriasis. However, characteristics of patients initiating guselkumab in a real-world setting are not well characterized. The present study described baseline characteristics of patients with psoriasis initiating guselkumab in the first year after approval using data from the Symphony Health Claims database. Adult patients with psoriasis with ≥1 claim for guselkumab between 7/13/2017 and 7/2/2018 were included. The index date was defined as the date of the first pharmacy claim for guselkumab. Outcomes of interest included demographics, frequency of prior biologic and non-biologic psoriasis treatments, and frequency of diagnoses or procedures during the year before guselkumab initiation (baseline period). A total of 1,520 patients were included. Mean age was 51.2 (SD 13.4) years and 53.7% of patients were female. During the baseline period, 63.9% of patients had ≥1 biologic drug claim and 66.9% were prescribed topical corticosteroids/combinations. The most common non-psoriasis diagnoses among patients with ≥1 medical claim were hypertension (25.1%), type 2 diabetes (13.4%), and hyperlipidemia (13.4%). The most common procedures reflected routine medical care. These findings describing the baseline characteristics of patients initiating guselkumab provide insights regarding variables that may impact observed treatment outcomes and may ultimately help with treatment decision making. J Drugs Dermatol. 2021;20(10):1127-1131. doi:10.36849/JDD.6024.

Upfront resection versus neoadjuvant therapy for T1/T2 pancreatic cancer.

BACKGROUND: The role of neoadjuvant therapy remains controversial for resectable pancreatic neoplasms. We evaluated treatment outcomes for T1/T2 tumors. METHODS: Retrospective study of patients with T1/T2 (Stage I-II) pancreatic cancer within the NCDB. Treatment-sequence variables were used for classification: "surgery + chemotherapy" (S+C), "chemotherapy + surgery" (C+S), "surgery only" (SO), and "chemotherapy only" (CO). RESULTS: 13 412 patients were included; the majority had T2 tumors. 8 490 received upfront surgery; 4 922 preoperative chemotherapy. In the surgery branch, 5 684 received surgery and chemotherapy (S+C); 2 806 did not receive chemotherapy (SO). Of those intended to receive preoperative chemotherapy, 3 804 received only chemotherapy (CO); 1 118 proceeded to surgery (C+S). Median survival for S+C and C+S groups was similar (25.9 vs 26.2) [HR 0.92, p= 0.41]. Compared to the CO group, the SO group had improved median survival (13.5 vs. 10.8) [HR 0.63, p<0.001]. Branched analyses demonstrated improved median and 5-year (20.8% vs 12.7%) survival for patients receiving upfront resection [HR 0.77, p<0.001]. CONCLUSION: Patients with T1/T2 pancreatic cancer have similar survival irrespective of the timing of chemotherapy and surgery, if they receive both. Upfront resection ensures surgery is delivered, increasing the possibility of long-term survival.

Better Defining the Role of Total Neoadjuvant Radiation: Changing Paradigms in Locally Advanced Pancreatic Cancer.

BACKGROUND: This study was designed to better define the role of radiation (Neo-Rad) in addition to neoadjuvant multiagent chemotherapy (NAT) for the treatment of locally advanced pancreatic cancer. METHODS: Retrospective cohort study using the NCDB. Individuals with AJCC clinical T3/T4 pancreatic carcinoma who underwent resection and multiagent chemotherapy were included. Kaplan-Meier, logistic-regression, and Cox proportional-hazard models were used for analysis. RESULTS: A total of 2703 patients were included; 2039 had T3 and 664 had T4 tumors, and 1092 (40.4%) received Neo-Rad. Median follow-up was 22.5 months. During the study period, there was increased use of NAT and a decline in the use of Neo-Rad. Addition of Neo-Rad did not affect 30-day (2.51% vs. 3.24%, p = 0.272) or 90-day mortality (5.23% vs. 6.38%, p = 0.216). Neo-Rad was not associated with improved overall survival on univariable (25.95 vs. 24.7 months, p = 0.202), or multivariable analyses (hazard ratio [HR] 0.94; 95% confidence interval [CI] 0.85-1.05). Time from diagnosis to definitive surgery was increased by Neo-Rad (204 vs. 115 days, p < 0.001). Neo-Rad was associated with increased pathologic downstaging in T3 (32.8% vs. 14.4%) (odds ratio [OR] 2.90; 95% CI 2.30-3.66) and T4 tumors (88.9% vs. 77.8%) (OR 2.29; 95% CI 1.44-3.67); complete pathologic response (5.3% vs. 1.6%) (OR 2.89; 95% CI 1.73-4.83), and increased R0 resection rates (85.7% vs. 76.8%) (OR 1.79; 95% CI 1.44-2.23). CONCLUSIONS: The use of neoadjuvant therapy is increasing for the treatment of locally advanced pancreatic cancer. The addition of radiation to neoadjuvant chemotherapy is associated with improved antineoplastic effectiveness (downstaging, complete pathologic response), surgical resection (R0 rates), but has no effect on overall survival.

A simple matrix to predict treatment success and long-term survival among patients undergoing pancreatectomy.

BACKGROUND: A more accurate measure of long-term survival among patients who have undergone a successful resection for pancreatic adenocarcinoma may be computed by accounting for time already survived during the initial treatment window. METHODS: Patients diagnosed with pancreatic adenocarcinoma, from 2004 through 2013, were identified from the American College of Surgeons National Cancer Database (NCDB). A risk-stratification matrix was constructed including age, histopathologic factors and the use of adjuvant therapy, given successful treatment and survival at 3-month following diagnosis. RESULTS: A total of 25,897 patients (50% male, 53% >65 years of age) presented with stage I-III pancreatic cancer. The majority of patients had tumors >2 cm size (82%), grade I/II (65%), lymphatic invasion (LI) (66%), and negative margins (76%). A survival advantage for adjuvant therapy was observed among all patients, independent of their risk-profile. For example, a patient ≤65 years of age, with early stage cancer (size ≤2 cm, grade I/II, -ve LI, -ve margins) who received adjuvant therapy had a 62% probability of being alive beyond three years (95%CI = 59%-66%). In contrast, the survival probability decreased to 53% (95%CI = 59%-66%) without adjuvant therapy. CONCLUSIONS: These results provide surgeons and patients with more accurate information regarding long-term survival, as well as the benefit of opting for adjuvant therapy after successful pancreatic surgery.

Procedure-based postoperative risk prediction using NSQIP data.

BACKGROUND: The National Surgical Quality Improvement Program (NSQIP) has proposed using procedure-based hierarchical models to predict adverse outcomes, but it is not clear whether this approach was used to develop the NSQIP "Surgical Risk Calculator". We therefore wished to demonstrate how procedure-based hierarchical models can be constructed and to describe their results. METHODS: NSQIP data from 2015 were used to construct statistical models predicting 30-day postoperative mortality and morbidity, using two-level logistic regression with preoperative patient-level variables as fixed effects and procedure-specific codes as a random intercept. Model performance was validated using NSQIP data from 2014. RESULTS: NSQIP for 2015 contained records for 885,502 patients, of whom 8986 died (1.0%) and 104,836 suffered a complication (11.8%). Complete model specifications and results are presented, including odds ratios for patient-level variable effects and random procedure effects. Most comorbidities were associated with increased morbidity and mortality, but overweight and obesity were associated with lower risk. Odds ratios for individual procedures ranged from 0.117 to 10.85 for mortality and from 0.615 to 8.09 for morbidity. Validation C-statistics were 0.940 for the mortality model and 0.833 for the morbidity model; Brier Scores were 0.0086 and 0.085, respectively. Graphs for 20 quantiles showed good conformity of observed and predicted risk. CONCLUSIONS: Procedure-based hierarchical logistic regression models of NSQIP outcomes had satisfactory overall performance statistics. Model specifications and results are provided for criticism and improvement, and several possible refinements are suggested.

Health care Resource Utilization and Migraine Disability Along the Migraine Continuum Among Patients Treated for Migraine.

OBJECTIVE: To examine the disability, health care resource utilization, and direct annual costs among patients with migraine, categorized according to the number of headache days experienced in the past month. BACKGROUND: Migraine exists on a continuum of different attack frequencies and associated levels of disability. People with migraine have increased health care utilization and incur substantially more direct costs than those without the disease. While the broad implications of migraine are evident, there is a need to comprehensively describe the impact of headache frequency on the burden of illness. DESIGN/METHODS: Data from a cross-sectional, self-administered, Internet-based survey of respondents recruited from the US National Health and Wellness Survey panel were assessed. Adults who had self-reported migraine diagnosis or migraine symptoms in the past 3 months were grouped by their frequency of headache days in the past month: low-frequency episodic migraine (LFEM, <4 days), moderate-frequency episodic migraine (MFEM, 4-9 days), high-frequency episodic migraine (HFEM, 10-14 days), and chronic migraine (CM, ≥15 days). Headache-related disability was determined from the Headache Impact Test (HIT-6) scores, and health care resource utilization was assessed by the number of ER visits, hospitalizations, and visits to health care practitioners (HCPs) in the past 12 months. The estimated annual direct costs were calculated from the number of each type of visit and all-cause cost data from the 2014 Medical Expenditure Panel Survey. RESULTS: A total of 1347 patients (LFEM, n = 813; MFEM, n = 301; HFEM, n = 105; CM, n = 128) were included. Patient groups differed significantly by comorbidity index, education and income level, alcohol consumption, and insurance type. Overall, patients with LFEM had the least disability and lowest health care utilization and direct costs. Patients with CM scored 3.7 points (adjusted mean score [95% confidence interval, CI] 68.2 [67.3, 69.0] points) higher on HIT-6 compared with those in the LFEM group (64.5 points [64.1, 64.8]), while those with HFEM and MFEM scored 2.4 (66.8 points [65.9, 67.8]) and 2.3 (66.7 points [66.2, 67.3]) points higher, respectively (all, P < .001). The CM and MFEM groups reported significantly more HCP visits ([mean ± standard error] CM: 7.03 ± 0.83; MFEM: 5.34 ± 0.42; vs LFEM: 3.48 ± 0.18; both, P < .001) and migraine-related hospitalizations (CM: 0.06 ± 0.03; MFEM: 0.05 ± 0.02; vs LFEM: 0.02 ± 0.01; both, P < .05) than the LFEM group. There were significant differences in the total direct costs between the CM and MFEM groups compared with the LFEM group (CM: $3155 ± $609; MFEM: $2721 ± $342; vs LFEM: $1560 ± $118; both, P < .001), with differences largely driven by costs of HCP visits. CONCLUSIONS: In patients with migraine, as the number of headache days increased, so did the burden of disease (disability, health care utilization, and direct costs). Elucidating the burden associated with EM and CM has implications for guiding treatment decisions and management of patients with migraine.

Roles of NGAL and MMP-9 in the tumor microenvironment and sensitivity to targeted therapy.

Various, diverse molecules contribute to the tumor microenvironment and influence invasion and metastasis. In this review, the roles of neutrophil gelatinase-associated lipocalin (NGAL) and matrix metalloproteinase-9 (MMP-9) in the tumor microenvironment and sensitivity to therapy will be discussed. The lipocalin family of proteins has many important functions. For example when NGAL forms a complex with MMP-9 it increases its stability which is important in cancer metastasis. Small hydrophobic molecules are bound by NGAL which can alter their entry into and efflux from cells. Iron transport and storage are also influenced by NGAL activity. Regulation of iron levels is important for survival in the tumor microenvironment as well as metastasis. Innate immunity is also regulated by NGAL as it can have bacteriostatic properties. NGAL and MMP-9 expression may also affect the sensitivity of cancer cells to chemotherapy as well as targeted therapy. Thus NGAL and MMP-9 play important roles in key processes involved in metastasis as well as response to therapy. This article is part of a Special Issue entitled: Tumor Microenvironment Regulation of Cancer Cell Survival, Metastasis, Inflammation, and Immune Surveillance edited by Peter Ruvolo and Gregg L. Semenza.

Effects of mutations in Wnt/ß-catenin, hedgehog, Notch and PI3K pathways on GSK-3 activity-Diverse effects on cell growth, metabolism and cancer.

Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase that participates in an array of critical cellular processes. GSK-3 was first characterized as an enzyme that phosphorylated and inactivated glycogen synthase. However, subsequent studies have revealed that this moon-lighting protein is involved in numerous signaling pathways that regulate not only metabolism but also have roles in: apoptosis, cell cycle progression, cell renewal, differentiation, embryogenesis, migration, regulation of gene transcription, stem cell biology and survival. In this review, we will discuss the roles that GSK-3 plays in various diseases as well as how this pivotal kinase interacts with multiple signaling pathways such as: PI3K/PTEN/Akt/mTOR, Ras/Raf/MEK/ERK, Wnt/beta-catenin, hedgehog, Notch and TP53. Mutations that occur in these and other pathways can alter the effects that natural GSK-3 activity has on regulating these signaling circuits that can lead to cancer as well as other diseases. The novel roles that microRNAs play in regulation of the effects of GSK-3 will also be evaluated. Targeting GSK-3 and these other pathways may improve therapy and overcome therapeutic resistance.

Perioperative chemotherapy versus postoperative chemoradiotherapy in patients with resectable gastric/gastroesophageal junction adenocarcinomas: A survival analysis of 5058 patients.

BACKGROUND: Both perioperative chemotherapy (PECT) and postoperative chemoradiotherapy (POCRT) have a significant survival advantage over surgery alone for the treatment of patients with gastric cancer. However, to the best of our knowledge, these regimens have not been compared in a randomized clinical trial. The purpose of the current observational study was to compare overall survival among patients receiving PECT versus POCRT for the treatment of gastric/gastroesophageal junction (GEJ) adenocarcinomas. METHODS: Patients with resected clinical American Joint Committee on Cancer TNM stage II or III adenocarcinomas of the stomach or GEJ from 2004 through 2013 were identified utilizing the National Cancer Data Base. Hazard ratios (HRs), 95% confidence intervals, and P values were computed using a Cox proportional hazards procedure. Multivariable models were adjusted for treatment regimen, age, race, ethnicity, tumor size, TNM stage, Charlson comorbidity index, and tumor grade. RESULTS: Patients receiving PECT had a 72% survival advantage compared with those treated with POCRT (5058 patients; HR, 0.58 [adjusted P<.0001]). The 5-year actuarial survival rate for PECT was 44% compared with 38% for POCRT. A statistically significant survival advantage for PECT also was observed when the analysis was stratified by clinical stage of disease (stage II [3192 patients]: adjusted HR, 0.79 [P = .041]; and stage III [1866 patients]: adjusted HR, 0.49 [P<.0001]). This benefit was greatest among patients with lymph node-positive disease who converted to lymph node-negative status with PECT. CONCLUSIONS: In this large series of patients with stage II/III resected gastric/GEJ adenocarcinomas from >1500 American College of Surgeons Commission on Cancer-accredited facilities, patients receiving PECT were shown to survive longer than those receiving POCRT. Cancer 2017;123:2909-17. © 2017 American Cancer Society.

The defence-associated transcriptome of hexaploid wheat displays homoeolog expression and induction bias.

Bread wheat (Triticum aestivum L.) is an allopolyploid species containing three ancestral genomes. Therefore, three homoeologous copies exist for the majority of genes in the wheat genome. Whether different homoeologs are differentially expressed (homoeolog expression bias) in response to biotic and abiotic stresses is poorly understood. In this study, we applied a RNA-seq approach to analyse homoeolog-specific global gene expression patterns in wheat during infection by the fungal pathogen Fusarium pseudograminearum, which causes crown rot disease in cereals. To ensure specific detection of homoeologs, we first optimized read alignment methods and validated the results experimentally on genes with known patterns of subgenome-specific expression. Our global analysis identified widespread patterns of differential expression among homoeologs, indicating homoeolog expression bias underpins a large proportion of the wheat transcriptome. In particular, genes differentially expressed in response to Fusarium infection were found to be disproportionately contributed from B and D subgenomes. In addition, we found differences in the degree of responsiveness to pathogen infection among homoeologous genes with B and D homoeologs exhibiting stronger responses to pathogen infection than A genome copies. We call this latter phenomenon as 'homoeolog induction bias'. Understanding how homoeolog expression and induction biases operate may assist the improvement of biotic stress tolerance in wheat and other polyploid crop species.

Population-Based Analysis of Completion Lymphadenectomy in Intermediate-Thickness Melanoma.

BACKGROUND: Multicenter selective lymphadenectomy trial 1 (MSLT-I) defined the prognostic and potential therapeutic values of sentinel lymph node biopsy (SLNB) for intermediate-thickness melanoma. The role of completion lymphadenectomy (CLND) is, however, unclear and the subject of the ongoing MSLT-II trial. METHODS: From 2003 to 2012, patients with tumors 1-4 mm thick with positive SLNB were identified in the Surveillance Epidemiology and End Results Program registry. The patients were divided into two groups: group 1 (CLND) and group 2 (observation). RESULTS: The study enrolled 2172 patients, the majority of whom were white and male with extremity primaries, no ulceration, Clark level 4 invasion, and nodes 2.01-4.0 mm deep. In the univariate analysis, CLND was associated with lower mean age, male gender, primary site, number of positive nodes, and geographic region (p < 0.05). In the multivariate analysis, male gender [odds ratio (OR), 1.27] and geographic area (Michigan OR, 2.31; Iowa OR, 1.69) were associated with CLND (p < 0.05). In the survival analysis, male gender, primary site, ulceration, Clark level, and depth and number of positive nodes were associated with survival (p < 0.05), but CLND was not (p = 0.83). In the Cox regression analysis, the relationship between male gender [hazard ratio (HR), 1.14], primary site trunk versus extremity (HR, 1.3), ulceration (HR, 1.79), Clark level (2 vs. 4 HR, 3.51; 2 vs. 5 HR, 6.48), depth (HR, 1.43) and number of nodes (1 vs. 2: HR, 1.23; 1 vs. ≥3: HR, 2.52) persisted (p < 0.05). However, when CLND was included in this model, it was not associated with improved survival. CONCLUSIONS: Age, gender, and geographic area predict the likelihood of CLND. In this retrospective study, CLND did not add survival benefit.

The Fusarium crown rot pathogen Fusarium pseudograminearum triggers a suite of transcriptional and metabolic changes in bread wheat (Triticum aestivum L.).

Background and Aims: Fusarium crown rot caused by the fungal pathogen Fusarium pseudograminearum is a disease of wheat and barley, bearing significant economic cost. Efforts to develop effective resistance to this disease have been hampered by the quantitative nature of resistance and a lack of understanding of the factors associated with resistance and susceptibility. Here, we aimed to dissect transcriptional responses triggered in wheat by F. pseudograminearum infection. Methods: We used an RNA-seq approach to analyse host responses during a compatible interaction and identified >2700 wheat genes differentially regulated after inoculation with F. pseudograminearum . The production of a few key metabolites and plant hormones in the host during the interaction was also analysed. Key Results: Analysis of gene ontology enrichment showed that a disproportionate number of genes involved in primary and secondary metabolism, signalling and transport were differentially expressed in infected seedlings. A number of genes encoding pathogen-responsive uridine-diphosphate glycosyltransferases (UGTs) potentially involved in detoxification of the Fusarium mycotoxin deoxynivalenol (DON) were differentially expressed. Using a F. pseudograminearum DON-non-producing mutant, DON was shown to play an important role in virulence during Fusarium crown rot. An over-representation of genes involved in the phenylalanine, tryptophan and tyrosine biosynthesis pathways was observed. This was confirmed through metabolite analyses that demonstrated tryptamine and serotonin levels are induced after F. pseudograminearum inoculation. Conclusions: Overall, the observed host response in bread wheat to F. pseudograminearum during early infection exhibited enrichment of processes related to pathogen perception, defence signalling, transport and metabolism and deployment of chemical and enzymatic defences. Additional functional analyses of candidate genes should reveal their roles in disease resistance or susceptibility. Better understanding of host responses contributing to resistance and/or susceptibility will aid the development of future disease improvement strategies against this important plant pathogen.