Computable biomedical knowledge (CBK) is: “the result of an analytic and/or deliberative process about human health, or affecting human health, that is explicit, and therefore can be represented and ...reasned upon using logic, formal standards, and mathematical approaches.” Representing biomedical knowledge in a machine-interpretable, computable form increases its ability to be discovered, accessed, understood, and deployed. Computable knowledge artifacts can greatly advance the potential for implementation, reproducibility, or extension of the knowledge by users, who may include practitioners, researchers, and learners. Enriching computable knowledge artifacts may help facilitate reuse and translation into practice. Following the examples of 10 Simple Rules papers for scientific code, software, and applications, we present 10 Simple Rules intended to make shared computable knowledge artifacts more useful and reusable. These rules are mainly for researchers and their teams who have decided that sharing their computable knowledge is important, who wish to go beyond simply describing results, algorithms, or models via traditional publication pathways, and who want to both make their research findings more accessible, and to help others use their computable knowledge. These rules are roughly organized into 3 categories: planning, engineering, and documentation. Finally, while many of the following examples are of computable knowledge in biomedical domains, these rules are generalizable to computable knowledge in any research domain.
ABSTRACT
We report here the genetic basis for a form of progressive hereditary spastic paraplegia (SPG43) previously described in two Malian sisters. Exome sequencing revealed a homozygous missense ...variant (c.187G>C; p.Ala63Pro) in C19orf12, a gene recently implicated in neurodegeneration with brain iron accumulation (NBIA). The same mutation was subsequently also found in a Brazilian family with features of NBIA, and we identified another NBIA patient with a three‐nucleotide deletion (c.197_199del; p.Gly66del). Haplotype analysis revealed that the p.Ala63Pro mutations have a common origin, but MRI scans showed no brain iron deposition in the Malian SPG43 subjects. Heterologous expression of these SPG43 and NBIA variants resulted in similar alterations in the subcellular distribution of C19orf12. The SPG43 and NBIA variants reported here as well as the most common C19orf12 missense mutation reported in NBIA patients are found within a highly conserved, extended hydrophobic domain in C19orf12, underscoring the functional importance of this domain.
We report a Malian and Brazilian families affected with hereditary spastic paraplegia (SPG43) and “forme frustre” neurodegeneration with brain iron accumulation (NBIA), respectively. The same mutation (C19orf12, p.Ala63Pro) and haplotype were found in these families, but MRI scans showed no brain iron deposition in the Malian subjects. Heterologous expression of this SPG43 and NBIA variant resulted in alteration in the subcellular distribution of C19orf12. Further studies are needed to unravel other genetic or environmental factors underlining these phenotypic differences.
Some breast cancers have been shown to contain a small fraction of cells characterized by CD44⁺/CD24⁻/low cell-surface antigen profile that have high tumor-initiating potential. In addition, breast ...cancer cells propagated in vitro as mammospheres (MSs) have also been shown to be enriched for cells capable of self-renewal. In this study, we have defined a gene expression signature common to both CD44⁺/CD24⁻/low and MS-forming cells. To examine its clinical significance, we determined whether tumor cells surviving after conventional treatments were enriched for cells bearing this CD44⁺/CD24⁻/low-MS signature. The CD44⁺/CD24⁻/low-MS signature was found mainly in human breast tumors of the recently identified "claudin-low" molecular subtype, which is characterized by expression of many epithelial-mesenchymal-transition (EMT)-associated genes. Both CD44⁺/CD24⁻/low-MS and claudin-low signatures were more pronounced in tumor tissue remaining after either endocrine therapy (letrozole) or chemotherapy (docetaxel), consistent with the selective survival of tumor-initiating cells posttreatment. We confirmed an increased expression of mesenchymal markers, including vimentin (VIM) in cytokeratin-positive epithelial cells metalloproteinase 2 (MMP2), in two separate sets of postletrozole vs. pretreatment specimens. Taken together, these data provide supporting evidence that the residual breast tumor cell populations surviving after conventional treatment may be enriched for subpopulations of cells with both tumor-initiating and mesenchymal features. Targeting proteins involved in EMT may provide a therapeutic strategy for eliminating surviving cells to prevent recurrence and improve long-term survival in breast cancer patients.
Display omitted
•Largest available phylogeny of the Polemoniaceae with ∼89% of recognized species.•Presence of floral anthocyanins appears to increase speciation rate.•Autogamy does not appear to be ...an evolutionary.
Pollinator-mediated selection is a major driver of evolution in flowering plants, contributing to the vast diversity of floral features. Despite long-standing interest in floral variation and the evolution of pollination syndromes in Polemoniaceae, the evolution of floral traits and known pollinators has not been investigated in an explicit phylogenetic context. Here we explore macroevolutionary patterns of both pollinator specificity and three floral traits long considered important determinants of pollinator attraction across the most comprehensive species-level phylogenetic tree yet produced for the family. The presence of floral chlorophyll is reconstructed as the ancestral character state of the family, even though the presence of floral anthocyanins is the most prevalent floral pigment in extant taxa. Mean corolla length and width of the opening of the floral tube are correlated, and both appear to vary with pollinator type. The evolution of pollination systems appears labile, with multiple gains and losses of selfing and conflicting implications for patterns of diversification. Explicit testing of diversification models rejects the hypothesis that selfing is an evolutionary dead-end. This study begins to disentangle the individual components that comprise pollination syndromes and lays the foundation for future work on the genetic mechanisms that control each trait.
Mutations in DNA repair genes are associated with aggressive prostate cancer (PCa).
To assess whether germline mutations are associated with grade reclassification (GR) in patients undergoing active ...surveillance (AS).
Two independent cohorts of PCa patients undergoing AS; 882 and 329 patients from Johns Hopkins and North Shore, respectively.
Germline DNA was sequenced for DNA repair genes, including BRCA1/2 and ATM (three-gene panel). Pathogenicity of mutations was defined according to the American College of Medical Genetics guidelines. Association of mutation carrier status and GR was evaluated by a competing risk analysis.
Of 1211, 289 patients experienced GR; 11 of 26 with mutations in a three-gene panel and 278 of 1185 noncarriers; adjusted hazard ratio (HR)=1.96 (95% confidence interval CI=1.004–3.84, p=0.04). Reclassification occurred in six of 11 carriers of BRCA2 mutations and 283 of 1200 noncarriers; adjusted HR=2.74 (95% CI=1.26–5.96, p=0.01). The carrier rates of pathogenic mutations in the three-gene panel, and BRCA2 alone, were significantly higher in those reclassified (3.8% and 2.1%, respectively) than in those not reclassified (1.6% and 0.5%, respectively; p=0.04 and 0.03, respectively). Carrier rates for BRCA2 were greater for those reclassified from Gleason score (GS) 3+3 at diagnosis to GS ≥4+3 (4.1% vs 0.7%, p=0.01) versus GS 3+4 (2.1% vs 0.6%; p=0.03). Results are limited by the small number of mutation carriers and an intermediate end point.
Mutation status of BRCA1/2 and ATM is associated with GR among men undergoing AS.
Men on active surveillance with inherited mutations in BRCA1/2 and ATM are more likely to harbor aggressive prostate cancer.
Men with inherited mutations in DNA repair genes (BRCA1/2 and ATM) have a greater risk of grade reclassification on active surveillance (AS) than those without. Mutation status can help inform decisions for AS.
Chronic hepatitis C virus (HCV) infection with advanced cirrhosis or post‐liver transplantation recurrence represents a high unmet medical need with no approved therapies effective across all HCV ...genotypes. The open‐label ALLY‐1 study assessed the safety and efficacy of a 60‐mg once‐daily dosage of daclatasvir (pan‐genotypic NS5A inhibitor) in combination with sofosbuvir at 400 mg once daily (NS5B inhibitor) and ribavirin at 600 mg/day for 12 weeks with a 24‐week follow‐up in two cohorts of patients with chronic HCV infection of any genotype and either compensated/decompensated cirrhosis or posttransplantation recurrence. Patients with on‐treatment transplantation were eligible to receive 12 additional weeks of treatment immediately after transplantation. The primary efficacy measure was sustained virologic response at posttreatment week 12 (SVR12) in patients with a genotype 1 infection in each cohort. Sixty patients with advanced cirrhosis and 53 with posttransplantation recurrence were enrolled; HCV genotypes 1 (76%), 2, 3, 4, and 6 were represented. Child‐Pugh classifications in the advanced cirrhosis cohort were 20% A, 53% B, and 27% C. In patients with cirrhosis, 82% (95% confidence interval CI, 67.9%‐92.0%) with genotype 1 infection achieved SVR12, whereas the corresponding rates in those with genotypes 2, 3, and 4 were 80%, 83%, and 100%, respectively; SVR12 rates were higher in patients with Child‐Pugh class A or B, 93%, versus class C, 56%. In transplant recipients, SVR12 was achieved by 95% (95% CI, 83.5%‐99.4%) and 91% of patients with genotype 1 and 3 infection, respectively. Three patients received peritransplantation treatment with minimal dose interruption and achieved SVR12. There were no treatment‐related serious adverse events. Conclusion: The pan‐genotypic combination of daclatasvir, sofosbuvir, and ribavirin was safe and well tolerated. High SVR rates across multiple HCV genotypes were achieved by patients with post‐liver transplantation recurrence or advanced cirrhosis. (Hepatology 2016;63:1493‐1505)
Effective, practical, nonpharmacologic therapies are needed to treat menopause-related insomnia symptoms in primary and women's specialty care settings.
To evaluate the efficacy of telephone-based ...cognitive behavioral therapy for insomnia (CBT-I) vs menopause education control (MEC).
A single-site, randomized clinical trial was conducted from September 1, 2013, to August 31, 2015, in western Washington State among 106 perimenopausal or postmenopausal women aged 40 to 65 years with moderate insomnia symptoms (Insomnia Severity Index ISI score, ≥12) and 2 or more daily hot flashes. Blinded assessments were conducted at baseline, 8, and 24 weeks postrandomization. An intent-to-treat analysis was conducted.
Six CBT-I or MEC telephone sessions in 8 weeks. Participants submitted weekly electronic sleep diaries and received group-specific written educational materials. The CBT-I sessions included sleep restriction, stimulus control, sleep hygiene education, cognitive restructuring, and behavioral homework; MEC sessions provided information about menopause and women's health.
Primary outcome was scores on the ISI (score range, 0-28; scores ≥15 indicate moderate to severe insomnia). Secondary outcome was scores on the Pittsburgh Sleep Quality Index (score range, 0-21; higher scores indicate worse sleep quality). Additional outcomes included sleep and hot flash diary variables and hot flash interference.
At 8 weeks, ISI scores had decreased 9.9 points among 53 women receiving CBT-I (mean SD age, 55.0 3.5 years) and 4.7 points among 53 women receiving MEC (age, 54.7 4.7 years), a mean between-group difference of 5.2 points (95% CI, -6.1 to -3.3; P < .001). Pittsburgh Sleep Quality Index scores decreased 4.0 points in women receiving CBT-I and 1.4 points in women receiving MEC, a mean between-group difference of 2.7 points (95% CI, -3.9 to -1.5; P < .001). Significant group differences were sustained at 24 weeks. At 8 and 24 weeks, 33 of 47 women (70%) and 37 of 44 (84%) in the CBT-I group, respectively, had ISI scores in the no-insomnia range compared with 10 of 41 (24%) and 16 of 37 (43%) in the MEC group, respectively. The CBT-I group also had greater improvements in diary-reported sleep latency, wake time, and sleep efficiency. There were no between-group differences in frequency of daily hot flashes, but hot flash interference was significantly decreased at 8 weeks for the CBT-I group (-15.7; 95% CI, -20.4 to -11.0) compared with the MEC group (-7.1; 95% CI, -14.6 to 0.4) (P = .03), differences that were maintained at 24 weeks for the CBT-I group (-22.8; 95% CI, -28.6 to -16.9) and MEC group (-11.6; 95% CI, -19.4 to -3.8) (P = .003).
Telephone-based CBT-I improved sleep in perimenopausal and postmenopausal women with insomnia and hot flashes. Results support further development and testing of centralized CBT-I programs for treating menopausal insomnia.
clinicaltrials.gov Identifier: NCT01936441.
Severe alcoholic hepatitis (sAH) is associated with a poor prognosis. There is no proven effective treatment for sAH, which is why early transplantation has been increasingly discussed. ...Hepatoblastoma‐derived C3A cells express anti‐inflammatory proteins and growth factors and were tested in an extracorporeal cellular therapy (ELAD) study to establish their effect on survival for subjects with sAH. Adults with sAH, bilirubin ≥8 mg/dL, Maddrey's discriminant function ≥ 32, and Model for End‐Stage Liver Disease (MELD) score ≤ 35 were randomized to receive standard of care (SOC) only or 3‐5 days of continuous ELAD treatment plus SOC. After a minimum follow‐up of 91 days, overall survival (OS) was assessed by using a Kaplan‐Meier survival analysis. A total of 203 subjects were enrolled (96 ELAD and 107 SOC) at 40 sites worldwide. Comparison of baseline characteristics showed no significant differences between groups and within subgroups. There was no significant difference in serious adverse events between the 2 groups. In an analysis of the intent‐to‐treat population, there was no difference in OS (51.0% versus 49.5%). The study failed its primary and secondary end point in a population with sAH and with a MELD ranging from 18 to 35 and no upper age limit. In the prespecified analysis of subjects with MELD < 28 (n = 120), ELAD was associated with a trend toward higher OS at 91 days (68.6% versus 53.6%; P = .08). Regression analysis identified high creatinine and international normalized ratio, but not bilirubin, as the MELD components predicting negative outcomes with ELAD. A new trial investigating a potential benefit of ELAD in younger subjects with sufficient renal function and less severe coagulopathy has been initiated. Liver Transplantation 24 380–393 2018 AASLD.
PDF
