Pathogenic Germline Variants in 10,389 Adult Cancers.

We conducted the largest investigation of predisposition variants in cancer to date, discovering 853 pathogenic or likely pathogenic variants in 8% of 10,389 cases from 33 cancer types. Twenty-one genes showed single or cross-cancer associations, including novel associations of SDHA in melanoma and PALB2 in stomach adenocarcinoma. The 659 predisposition variants and 18 additional large deletions in tumor suppressors, including ATM, BRCA1, and NF1, showed low gene expression and frequent (43%) loss of heterozygosity or biallelic two-hit events. We also discovered 33 such variants in oncogenes, including missenses in MET, RET, and PTPN11 associated with high gene expression. We nominated 47 additional predisposition variants from prioritized VUSs supported by multiple evidences involving case-control frequency, loss of heterozygosity, expression effect, and co-localization with mutations and modified residues. Our integrative approach links rare predisposition variants to functional consequences, informing future guidelines of variant classification and germline genetic testing in cancer.

Prediction of thirty-day morbidity and mortality after duodenal switch using an artificial neural network.

BACKGROUND: Understanding factors that increase risk of both mortality and specific measures of morbidity after duodenal switch (DS) is important in deciding to offer this weight loss operation. Artificial neural networks (ANN) are computational deep learning approaches that model complex interactions among input factors to optimally predict an outcome. Here, a comprehensive national database is examined for patient factors associated with poor outcomes, while comparing the performance of multivariate logistic regression and ANN models in predicting these outcomes. METHODS: 2907 DS patients from the 2019 Metabolic and Bariatric Surgery Accreditation and Quality Improvement Program database were assessed for patient factors associated with the previously validated composite endpoint of 30-day postoperative reintervention, reoperation, readmission, or mortality using bivariate analysis. Variables associated (P ≤ 0.05) with the endpoint were imputed in a multivariate logistic regression model and a three-node ANN with 20% holdback for validation. Goodness-of-fit was assessed using area under receiver operating curves (AUROC). RESULTS: There were 229 DS patients with the composite endpoint (7.9%), and 12 mortalities (0.4%). Associated patient factors on bivariate analysis included advanced age, non-white race, cardiac history, hypertension requiring 3 + medications (HTN), previous foregut/obesity surgery, obstructive sleep apnea (OSA), and higher creatinine (P ≤ 0.05). Upon multivariate analysis, independently associated factors were non-white race (odds ratio 1.40; P = 0.075), HTN (1.55; P = 0.038), previous foregut/bariatric surgery (1.43; P = 0.041), and OSA (1.46; P = 0.018). The nominal logistic regression multivariate analysis (n = 2330; R2 = 0.02, P < 0.001) and ANN (R2 = 0.06; n = 1863 [training set], n = 467 [validation]) models generated AUROCs of 0.619, 0.656 (training set) and 0.685 (validation set), respectively. CONCLUSION: Readily obtainable patient factors were identified that confer increased risk of the 30-day composite endpoint after DS. Moreover, use of an ANN to model these factors may optimize prediction of this outcome. This information provides useful guidance to bariatricians and surgical candidates alike.

Phase transitions in evolutionary dynamics.

Sharp changes in state, such as transitions from survival to extinction, are hallmarks of evolutionary dynamics in biological systems. These transitions can be explored using the techniques of statistical physics and the physics of nonlinear and complex systems. For example, a survival-to-extinction transition can be characterized as a non-equilibrium phase transition to an absorbing state. Here, we review the literature on phase transitions in evolutionary dynamics. We discuss directed percolation transitions in cellular automata and evolutionary models, and models that diverge from the directed percolation universality class. We explore in detail an example of an absorbing phase transition in an agent-based model of evolutionary dynamics, including previously unpublished data demonstrating similarity to, but also divergence from, directed percolation, as well as evidence for phase transition behavior at multiple levels of the model system's evolutionary structure. We discuss phase transition models of the error catastrophe in RNA virus dynamics and phase transition models for transition from chemistry to biochemistry, i.e., the origin of life. We conclude with a review of phase transition dynamics in models of natural selection, discuss the possible role of phase transitions in unraveling fundamental unresolved questions regarding multilevel selection and the major evolutionary transitions, and assess the future outlook for phase transitions in the investigation of evolutionary dynamics.

Regulated Phosphosignaling Associated with Breast Cancer Subtypes and Druggability.

Aberrant phospho-signaling is a hallmark of cancer. We investigated kinase-substrate regulation of 33,239 phosphorylation sites (phosphosites) in 77 breast tumors and 24 breast cancer xenografts. Our search discovered 2134 quantitatively correlated kinase-phosphosite pairs, enriching for and extending experimental or binding-motif predictions. Among the 91 kinases with auto-phosphorylation, elevated EGFR, ERBB2, PRKG1, and WNK1 phosphosignaling were enriched in basal, HER2-E, Luminal A, and Luminal B breast cancers, respectively, revealing subtype-specific regulation. CDKs, MAPKs, and ataxia-telangiectasia proteins were dominant, master regulators of substrate-phosphorylation, whose activities are not captured by genomic evidence. We unveiled phospho-signaling and druggable targets from 113 kinase-substrate pairs and cascades downstream of kinases, including AKT1, BRAF and EGFR. We further identified kinase-substrate-pairs associated with clinical or immune signatures and experimentally validated activated phosphosites of ERBB2, EIF4EBP1, and EGFR. Overall, kinase-substrate regulation revealed by the largest unbiased global phosphorylation data to date connects driver events to their signaling effects.

Militaries and global health: peace, conflict, and disaster response.

Many countries show a growing willingness to use militaries in support of global health efforts. This Series paper summarises the varied roles, responsibilities, and approaches of militaries in global health, drawing on examples and case studies across peacetime, conflict, and disaster response environments. Militaries have many capabilities applicable to global health, ranging from research, surveillance, and medical expertise to rapidly deployable, large-scale assets for logistics, transportation, and security. Despite this large range of capabilities, militaries also have limitations when engaging in global health activities. Militaries focus on strategic, operational, and tactical objectives that support their security and defence missions, which can conflict with humanitarian and global health equity objectives. Guidelines-both within and outside militaries-for military engagement in global health are often lacking, as are structured opportunities for military and civilian organisations to engage one another. We summarise policies that can help close the gap between military and civilian actors to catalyse the contributions of all participants to enhance global health.

GenomeVIP: a cloud platform for genomic variant discovery and interpretation.

Identifying genomic variants is a fundamental first step toward the understanding of the role of inherited and acquired variation in disease. The accelerating growth in the corpus of sequencing data that underpins such analysis is making the data-download bottleneck more evident, placing substantial burdens on the research community to keep pace. As a result, the search for alternative approaches to the traditional "download and analyze" paradigm on local computing resources has led to a rapidly growing demand for cloud-computing solutions for genomics analysis. Here, we introduce the Genome Variant Investigation Platform (GenomeVIP), an open-source framework for performing genomics variant discovery and annotation using cloud- or local high-performance computing infrastructure. GenomeVIP orchestrates the analysis of whole-genome and exome sequence data using a set of robust and popular task-specific tools, including VarScan, GATK, Pindel, BreakDancer, Strelka, and Genome STRiP, through a web interface. GenomeVIP has been used for genomic analysis in large-data projects such as the TCGA PanCanAtlas and in other projects, such as the ICGC Pilots, CPTAC, ICGC-TCGA DREAM Challenges, and the 1000 Genomes SV Project. Here, we demonstrate GenomeVIP's ability to provide high-confidence annotated somatic, germline, and de novo variants of potential biological significance using publicly available data sets.

CharGer: clinical Characterization of Germline variants.

SUMMARY: CharGer (Characterization of Germline variants) is a software tool for interpreting and predicting clinical pathogenicity of germline variants. CharGer gathers evidence from databases and annotations, provided by local tools and files or via ReST APIs, and classifies variants according to ACMG guidelines for assessing variant pathogenicity. User-designed pathogenicity criteria can be incorporated into CharGer's flexible framework, thereby allowing users to create a customized classification protocol. AVAILABILITY AND IMPLEMENTATION: Source code is freely available at https://github.com/ding-lab/CharGer and is distributed under the GNU GPL-v3.0 license. Software is also distributed through the Python Package Index (PyPI) repository. CharGer is implemented in Python 2.7 and is supported on Unix-based operating systems. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Database of evidence for precision oncology portal.

Summary: A database of curated genomic variants with clinically supported drug therapies and other oncological annotations is described. The accompanying web portal provides a search engine with two modes: one that allows users to query gene, cancer type, variant type or position for druggable mutations, and another to search for and to visualize, on three-dimensional protein structures, putative druggable sites that cluster with known druggable mutations. Availability and implementation: http://dinglab.wustl.edu/depo.

The cost of love: financial consequences of insecure attachment in antisocial youth.

BACKGROUND: Knowing that your parent or caregiver will be there for you in times of emotional need and distress is a core aspect of the human experience of feeling loved and being securely attached. In contrast, an insecure attachment pattern is found in many antisocial youth and is related to less sensitive caregiving. Such youth are often distrustful of adults and authority figures, and are at high risk of poor outcomes. As they become adults, they require extensive health, social and economic support, costing society ten times more than their well-adjusted peers. However, it is not known whether insecure attachment itself is associated with higher costs in at-risk youth, independently of potential confounders, nor whether cost differences are already beginning to emerge early in adolescence. METHODS: Sample: A total of 174 young people followed up aged 9-17 years (mean 12.1, SD 1.8): 85 recruited with moderate antisocial behaviour (80th percentile) from a school screen aged 4-6 years; 89 clinically referred with very high antisocial behaviour (98th percentile) aged 3-7 years. MEASURES: Costs by detailed health economic and service-use interview; attachment security to mother and father from interview; diagnostic interviews for oppositional and conduct problems; self-reported delinquent behaviour. RESULTS: Costs were greater for youth insecurely attached to their mothers (secure £6,743, insecure £10,199, p = .001) and more so to fathers (secure £1,353, insecure £13,978, p < .001). These differences remained significant (mother p = .019, father p < .001) after adjusting for confounders, notably family income and education, intelligence and antisocial behaviour severity. CONCLUSIONS: Attachment insecurity is a significant predictor of public cost in at-risk youth, even after accounting for covariates. Since adolescent attachment security is influenced by caregiving quality earlier in childhood, these findings add support to the public health case for early parenting interventions to improve child outcomes and reduce the financial burden on society.

Acute Pancreatitis in a Patient with Maple Syrup Urine Disease: A Management Paradox.

Maple syrup urine disease (MSUD) is an inborn error of metabolism that causes elevated leucine in the setting of acute illnesses. We describe an 8-year-old boy with MSUD who developed acute pancreatitis and subsequent leucinosis. This case highlights the complexities of fluid management in patients with MSUD.

A Clinical Decision Rule to Identify Emergency Department Patients at Low Risk for Acute Coronary Syndrome Who Do Not Need Objective Coronary Artery Disease Testing: The No Objective Testing Rule.

STUDY OBJECTIVE: We derive a clinical decision rule for ongoing investigation of patients who present to the emergency department (ED) with chest pain. The rule identifies patients who are at low risk of acute coronary syndrome and could be discharged without further cardiac testing. METHODS: This was a prospective observational study of 2,396 patients who presented to 2 EDs with chest pain suggestive of acute coronary syndrome and had normal troponin and ECG results 2 hours after presentation. Research nurses collected clinical data on presentation, and the primary endpoint was diagnosis of acute coronary syndrome within 30 days of presentation to the ED. Logistic regression analyses were conducted on 50 bootstrapped samples to identify predictors of acute coronary syndrome. A rule was derived and diagnostic accuracy statistics were computed. RESULTS: Acute coronary syndrome was diagnosed in 126 (5.3%) patients. Regression analyses identified the following predictors of acute coronary syndrome: cardiac risk factors, age, sex, previous myocardial infarction, or coronary artery disease and nitrate use. A rule was derived that identified 753 low-risk patients (31.4%), with sensitivity 97.6% (95% confidence interval [CI] 93.2% to 99.5%), negative predictive value 99.6% (95% CI 98.8% to 99.9%), specificity 33.0% (95% CI 31.1% to 35.0%), and positive predictive value 7.5% (95% CI 6.3% to 8.9%) for acute coronary syndrome. This was referred to as the no objective testing rule. CONCLUSION: We have derived a clinical decision rule for chest pain patients with negative early cardiac biomarker and ECG testing results that identifies 31% at low risk and who may not require objective testing for coronary artery disease. A prospective trial is required to confirm these findings.

Utility of Routine Exercise Stress Testing among Intermediate Risk Chest Pain Patients Attending an Emergency Department.

BACKGROUND: To assess the utility of routine exercise stress testing (EST) in patients at intermediate risk of acute coronary syndrome (ACS) according to the Heart Foundation of Australia/Cardiac Society of Australia and New Zealand (HFA/CSANZ) guidelines. METHOD: Prospective observational study of patients presenting to the Emergency Department (ED) with chest pain suggestive of ACS between November 2008 and July 2014. Participants included 1205 patients who presented to the ED with chest pain suggestive of ACS and who met the HFA/CSANZ intermediate risk criteria. The outcome was diagnosis of ACS occurring on presentation or within 30 days of presentation to the ED. ACS included acute myocardial infarction and unstable angina pectoris. RESULTS: Twenty (1.66%) of the intermediate risk patients were diagnosed with ACS. Of the 777 patients who underwent EST, eight had ACS. EST identified all ACS cases except for one patient with a negative test, who was ultimately diagnosed with ACS following angiography. 164 patients deemed inappropriate to undergo EST underwent an alternative form of objective testing, of which 12 were positive for ACS. 264 patients underwent no objective testing. CONCLUSION: EST stratifies intermediate risk patients to a near zero short-term risk of ACS. However, the overall yield of EST within this group of patients is extremely low. Intermediate risk patients with normal zero and six hour biomarkers have a very low probability of ACS, and over half of these patients ultimately diagnosed with ACS in this group were deemed unsuitable for EST anyway. Future research should focus on the identification of patients who do not require EST and the inclusion of routine EST within the HFA/CSANZ guidelines should be reconsidered.

Regulation of the Src kinase-associated phosphoprotein 55 homologue by the protein tyrosine phosphatase PTP-PEST in the control of cell motility.

PTP-PEST is a cytosolic ubiquitous protein tyrosine phosphatase (PTP) that contains, in addition to its catalytic domain, several protein-protein interaction domains that allow it to interface with several signaling pathways. Among others, PTP-PEST is a key regulator of cellular motility and cytoskeleton dynamics. The complexity of the PTP-PEST interactome underscores the necessity to identify its interacting partners and physiological substrates in order to further understand its role in focal adhesion complex turnover and actin organization. Using a modified yeast substrate trapping two-hybrid system, we identified a cytosolic adaptor protein named Src kinase-associated phosphoprotein 55 homologue (SKAP-Hom) as a novel substrate of PTP-PEST. To confirm PTP-PEST interaction with SKAP-Hom, in vitro pull down assays were performed demonstrating that the PTP catalytic domain and Proline-rich 1 (P1) domain are respectively binding to the SKAP-Hom Y260 and Y297 residues and its SH3 domain. Subsequently, we generated and rescued SKAP-Hom-deficient mouse embryonic fibroblasts (MEFs) with WT SKAP-Hom, SKAP-Hom tyrosine mutants (Y260F, Y260F/Y297F), or SKAP-Hom SH3 domain mutant (W335K). Given the role of PTP-PEST, wound-healing and trans-well migration assays were performed using the generated lines. Indeed, SKAP-Hom-deficient MEFs showed a defect in migration compared with WT-rescued MEFs. Interestingly, the SH3 domain mutant-rescued MEFs showed an enhanced cell migration corresponding potentially with higher tyrosine phosphorylation levels of SKAP-Hom. These findings suggest a novel role of SKAP-Hom and its phosphorylation in the regulation of cellular motility. Moreover, these results open new avenues by which PTP-PEST regulates cellular migration, a hallmark of metastasis.

The multiple meanings of global health governance: a call for conceptual clarity.

BACKGROUND: The term global health governance (GHG) is now widely used, with over one thousand works published in the scholarly literature, almost all since 2002. Amid this rapid growth there is considerable variation in how the term is defined and applied, generating confusion as to the boundaries of the subject, the perceived problems in practice, and the goals to be achieved through institutional reform. METHODOLOGY: This paper is based on the results of a separate scoping study of peer reviewed GHG research from 1990 onwards which undertook keyword searches of public health and social science databases. Additional works, notably books, book chapters and scholarly articles, not currently indexed, were identified through Web of Science citation searches. After removing duplicates, book reviews, commentaries and editorials, we reviewed the remaining 250 scholarly works in terms of how the concept of GHG is applied. More specifically, we identify what is claimed as constituting GHG, how it is problematised, the institutional features of GHG, and what forms and functions are deemed ideal. RESULTS: After examining the broader notion of global governance and increasingly ubiquitous term "global health", the paper identifies three ontological variations in GHG scholarship - the scope of institutional arrangements, strengths and weaknesses of existing institutions, and the ideal form and function of GHG. This has produced three common, yet distinct, meanings of GHG that have emerged - globalisation and health governance, global governance and health, and governance for global health. CONCLUSIONS: There is a need to clarify ontological and definitional distinctions in GHG scholarship and practice, and be critically reflexive of their normative underpinnings. This will enable greater precision in describing existing institutional arrangements, as well as serve as a prerequisite for a fuller debate about the desired nature of GHG.

Rural-urban disparities and trends in utilization of palliative care services among US patients with metastatic breast cancer.

PURPOSE: To assess trends and rural-urban disparities in palliative care utilization among patients with metastatic breast cancer. METHODS: We analyzed data from the 2004-2019 National Cancer Database. Palliative care services, including surgery, radiotherapy, systemic therapy, and/or other pain management, were provided to control pain or alleviate symptoms; utilization was dichotomized as "yes/no." Rural-urban residence, defined by the US Department of Agriculture Economic Research Service's Rural-Urban Continuum Codes, was categorized as "rural/urban/metropolitan." Multivariable logistic regression was used to examine rural-urban differences in palliative care use. Adjusted odds ratios (AORs) and 95% confidence intervals (CIs) were calculated. FINDINGS: Of 133,500 patients (mean age 62.4 [SD = 14.2] years), 86.7%, 11.7%, and 1.6% resided in metropolitan, urban, and rural areas, respectively; 72.5% were White, 17.0% Black, 5.8% Hispanic, and 2.7% Asian. Overall, 20.3% used palliative care, with a significant increase from 15.6% in 2004-2005 to 24.5% in 2008-2019 (7.0% increase per year; p-value for trend <0.001). In urban areas, 23.3% received palliative care, compared to 21.0% in rural and 19.9% in metropolitan areas (p < 0.001). After covariate adjustment, patients residing in rural (AOR = 0.84; 95% CI: 0.73-0.98) or metropolitan (AOR = 0.85, 95% CI: 0.80-0.89) areas had lower odds of having used palliative care than those in urban areas. CONCLUSIONS: In this national, racially diverse sample of patients with metastatic breast cancer, the utilization of palliative care services increased over time, though remained suboptimal. Further, our findings highlight rural-urban disparities in palliative care use and suggest the potential need to promote these services while addressing geographic access inequities for this patient population.

Low screening rates and high prevalence of osteoporosis in cirrhosis: A real-world retrospective analysis.

BACKGROUND: Patients with cirrhosis are at increased risk for osteoporosis, and those who suffer a fracture are at high risk for mortality. Despite this, osteoporosis is often overlooked and undertreated. This study aimed to evaluate osteoporosis screening, management, and adverse osteoporosis medication events in patients with cirrhosis. METHODS: We performed a retrospective chart review of adult outpatients with compensated and decompensated cirrhosis seen in single health system over a 6-year period. Patient demographics, liver and bone health comorbidities, DEXA scan results, and medications were abstracted. RESULTS: In total, 5398 patients met criteria. The cohort was predominately white (79.1%) and older (age 59). 44.4% were female. 64.6% had decompensated cirrhosis. Median MELD-Na score was 12.8. 23.5% had a DEXA scan ordered, approximately 50% completed this test. Patients who were older, female, white, with more severe liver disease, and other osteoporosis risk factors were more likely to have a DEXA scan ordered. 48.5% of patients had osteopenia and 30.2% had osteoporosis on DEXA scan. Only 22.6% of patients with osteoporosis received treatment, most commonly oral bisphosphonates. Oral bisphosphonate prescription was not associated with variceal bleeding (8.4% without vs. 4.8% with, p = 0.487). CONCLUSION: A minority of patients with cirrhosis were screened for osteoporosis. The majority screened had osteopenia or osteoporosis on DEXA scan. Less than a quarter of patients with osteoporosis were started on treatment. Real-world experience of oral bisphosphonate use did not reveal higher rates of gastrointestinal bleeding. There is room for improvement in all aspects of bone health care in cirrhosis.

Prediction of 30-Day Morbidity and Mortality After Conversion of Sleeve Gastrectomy to Roux-en-Y Gastric Bypass: Use of an Artificial Neural Network.

BACKGROUND: Conversion of sleeve gastrectomy to Roux-en-Y gastric bypass is indicated primarily for unsatisfactory weight loss or gastroesophageal reflux disease (GERD). This study aimed to use a comprehensive database to define predictors of 30-day reoperation, readmission, reintervention, or mortality. An artificial neural network (ANN) was employed to optimize prediction of the composite endpoint (occurrence of 1+ morbid event). METHODS: Areview of 8895 patients who underwent conversion for weight-related or GERD-related indications was performed using the 2021 MBSAQIP national dataset. Demographics, comorbidities, laboratory values, and other factors were assessed for bivariate and subsequent multivariable associations with the composite endpoint (P ≤ .05). Factors considered in the multivariable model were imputed into a three-node ANN with 20% randomly withheld for internal validation, to optimize predictive accuracy. Models were compared using receiver operating characteristic (ROC) curve analysis. RESULTS: 39% underwent conversion for weight considerations and 61% for GERD. Rates of 30-day reoperation, readmission, reintervention, mortality, and the composite endpoint were 3.0%, 7.1%, 2.1%, .1%, and 9.1%, respectively. Of the nine factors associated with the composite endpoint on bivariate analysis, only non-white race (P < .001; odds ratio 1.4), lower body-mass index (P < .001; odds ratio .22), and therapeutic anticoagulation (P = .001; odds ratio 2.0) remained significant upon multivariable analysis. Areas under ROC curves for the multivariable regression, ANN training, and validation sets were .587, .601, and .604, respectively. DISCUSSION: Identification of risk factors for morbidity after conversion offers critical information to improve patient selection and manage postoperative expectations. ANN models, with appropriate clinical integration, may optimize prediction of morbidity.