Deep learning convolutional neural networks (CNN) may facilitate melanoma detection, but data comparing a CNN’s diagnostic performance to larger groups of dermatologists are lacking.
Google’s ...Inception v4 CNN architecture was trained and validated using dermoscopic images and corresponding diagnoses. In a comparative cross-sectional reader study a 100-image test-set was used (level-I: dermoscopy only; level-II: dermoscopy plus clinical information and images). Main outcome measures were sensitivity, specificity and area under the curve (AUC) of receiver operating characteristics (ROC) for diagnostic classification (dichotomous) of lesions by the CNN versus an international group of 58 dermatologists during level-I or -II of the reader study. Secondary end points included the dermatologists’ diagnostic performance in their management decisions and differences in the diagnostic performance of dermatologists during level-I and -II of the reader study. Additionally, the CNN’s performance was compared with the top-five algorithms of the 2016 International Symposium on Biomedical Imaging (ISBI) challenge.
In level-I dermatologists achieved a mean (±standard deviation) sensitivity and specificity for lesion classification of 86.6% (±9.3%) and 71.3% (±11.2%), respectively. More clinical information (level-II) improved the sensitivity to 88.9% (±9.6%, P=0.19) and specificity to 75.7% (±11.7%, P<0.05). The CNN ROC curve revealed a higher specificity of 82.5% when compared with dermatologists in level-I (71.3%, P<0.01) and level-II (75.7%, P<0.01) at their sensitivities of 86.6% and 88.9%, respectively. The CNN ROC AUC was greater than the mean ROC area of dermatologists (0.86 versus 0.79, P<0.01). The CNN scored results close to the top three algorithms of the ISBI 2016 challenge.
For the first time we compared a CNN’s diagnostic performance with a large international group of 58 dermatologists, including 30 experts. Most dermatologists were outperformed by the CNN. Irrespective of any physicians’ experience, they may benefit from assistance by a CNN’s image classification.
This study was registered at the German Clinical Trial Register (DRKS-Study-ID: DRKS00013570; https://www.drks.de/drks_web/).
Lenalidomide acts by a novel drug mechanism—modulation of the substrate specificity of the CRL4CRBN E3 ubiquitin ligase. In multiple myeloma, lenalidomide induces the ubiquitination of IKZF1 and ...IKZF3 by CRL4CRBN. Subsequent proteasomal degradation of these transcription factors kills multiple myeloma cells. In del(5q) myelodysplastic syndrome, lenalidomide induces the degradation of CK1α, which preferentially affects del(5q) cells because they express this gene at haploinsufficient levels. In the future, modulation of ubiquitin ligase function may enable us to target previously “undruggable” proteins.
In historical attempts to treat morning sickness, use of the drug thalidomide led to the birth of thousands of children with severe birth defects. Despite their teratogenicity, thalidomide and ...related IMiD drugs are now a mainstay of cancer treatment; however, the molecular basis underlying the pleiotropic biology and characteristic birth defects remains unknown. Here we show that IMiDs disrupt a broad transcriptional network through induced degradation of several C
H
zinc finger transcription factors, including SALL4, a member of the
-like family of developmental transcription factors. Strikingly, heterozygous loss of function mutations in
result in a human developmental condition that phenocopies thalidomide-induced birth defects such as absence of thumbs, phocomelia, defects in ear and eye development, and congenital heart disease. We find that thalidomide induces degradation of SALL4 exclusively in humans, primates, and rabbits, but not in rodents or fish, providing a mechanistic link for the species-specific pathogenesis of thalidomide syndrome.
Background
While the excisional biopsy and histological examination of suspicious lesions remains the current gold standard for diagnosing cutaneous melanoma (CM), there is a demand for more ...objective and non‐invasive examination methods that may support clinicians in their decision when to biopsy or not.
Methods
This review is based on publications and guidelines retrieved by a selective search in PubMed and MEDLINE and focused on non‐invasive diagnostic strategies for detecting melanoma.
Results
Ten different non‐invasive techniques were compared with regard to applicability, status of development, and resources necessary for introduction into clinical routine (dermoscopy, sequential digital dermoscopy, total body photography, computer‐aided multispectral digital analysis, electrical impedance spectroscopy, Raman spectroscopy, reflectance confocal microscopy, multiphoton tomography, stepwise two‐photon‐laser spectroscopy, quantitative dynamic infrared imaging). In an effort to create a classification based on our analyses, we suggest to differentiate i) tools for screening of patients in daily clinical routine, ii) tools for examination of a restricted number of preselected lesions that produce an automated diagnostic score, iii) tools for examination of a restricted number of preselected lesions at specialized centers requiring extensive training, iv) devices at an experimental stage of development.
Conclusion
None of the discussed examination techniques is able to provide a definite and final diagnosis or to completely replace the histopathological examination. Up to date, the need for fully automated devices offering a complete skin cancer screening has not been satisfied.
Purpose
The purpose of this study was to utilize a novel functional test system to facilitate determining the time of return to sports following ACL reconstruction.
Methods
Sixty-nine patients with ...unilateral ACL reconstruction were included in this pilot study. All the patients performed a standardized test battery consisting of one- and two-legged stability tests, counter movement jumps, speedy jumps, plyometric jumps and a quick feed test. The first test was administered on average 170.7 ± 75.1 days post-operatively, and the retest was administered on average 239.1 ± 79.7 days post-operatively. The values of the subtests were compared with the normative data of healthy gender- and age-matched controls to determine the functional capacities of patients following ACL reconstruction.
Results
After the first and second test, 15.9 and 17.4 % of the patients met the criteria for a “return to non-competitive sports”. One patient fulfilled the criteria for a “return to competitive sports” after the second test battery. The most limiting factor was a poor LSI value of <90 % if the dominant leg was involved and <80 % if the non-dominant leg was involved.
Conclusion
This test battery demonstrates that, in terms of neuromuscular abilities, most patients, compared to healthy controls, are most likely not ready for a safe return to sports, even 8 months post-operatively. This should be considered in the future to determine when it is safe to return to sports and should avoid a premature return to competitive sports.
Level of evidence
III.
Salmonella can survive for long periods under extreme desiccation conditions. This stress tolerance poses a risk for food safety, but relatively little is known about the molecular and cellular ...regulation of this adaptation mechanism. To determine the genetic components involved in Salmonella's cellular response to desiccation, we performed a global transcriptomic analysis comparing S. enterica serovar Typhimurium cells equilibrated to low water activity (aw 0.11) and cells equilibrated to high water activity (aw 1.0). The analysis revealed that 719 genes were differentially regulated between the two conditions, of which 290 genes were up-regulated at aw 0.11. Most of these genes were involved in metabolic pathways, transporter regulation, DNA replication/repair, transcription and translation, and, more importantly, virulence genes. Among these, we decided to focus on the role of sopD and sseD. Deletion mutants were created and their ability to survive desiccation and exposure to aw 0.11 was compared to the wild-type strain and to an E. coli O157:H7 strain. The sopD and sseD mutants exhibited significant cell viability reductions of 2.5 and 1.3 Log (CFU/g), respectively, compared to the wild-type after desiccation for 4 days on glass beads. Additional viability differences of the mutants were observed after exposure to aw 0.11 for 7 days. E. coli O157:H7 lost viability similarly to the mutants. Scanning electron microscopy showed that both mutants displayed a different morphology compared to the wild-type and differences in production of the extracellular matrix under the same conditions. These findings suggested that sopD and sseD are required for Salmonella's survival during desiccation.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
The growing amount of high dimensional biomolecular data has spawned new statistical and computational models for risk prediction and disease classification. Yet, many of these methods do not yield ...biologically interpretable models, despite offering high classification accuracy. An exception, the top-scoring pair (TSP) algorithm derives parameter-free, biologically interpretable single pair decision rules that are accurate and robust in disease classification. However, standard TSP methods do not accommodate covariates that could heavily influence feature selection for the top-scoring pair. Herein, we propose a covariate-adjusted TSP method, which uses residuals from a regression of features on the covariates for identifying top scoring pairs. We conduct simulations and a data application to investigate our method, and compare it to existing classifiers, LASSO and random forests.
Our simulations found that features that were highly correlated with clinical variables had high likelihood of being selected as top scoring pairs in the standard TSP setting. However, through residualization, our covariate-adjusted TSP was able to identify new top scoring pairs, that were largely uncorrelated with clinical variables. In the data application, using patients with diabetes (n = 977) selected for metabolomic profiling in the Chronic Renal Insufficiency Cohort (CRIC) study, the standard TSP algorithm identified (valine-betaine, dimethyl-arg) as the top-scoring metabolite pair for classifying diabetic kidney disease (DKD) severity, whereas the covariate-adjusted TSP method identified the pair (pipazethate, octaethylene glycol) as top-scoring. Valine-betaine and dimethyl-arg had, respectively, ≥ 0.4 absolute correlation with urine albumin and serum creatinine, known prognosticators of DKD. Thus without covariate-adjustment the top-scoring pair largely reflected known markers of disease severity, whereas covariate-adjusted TSP uncovered features liberated from confounding, and identified independent prognostic markers of DKD severity. Furthermore, TSP-based methods achieved competitive classification accuracy in DKD to LASSO and random forests, while providing more parsimonious models.
We extended TSP-based methods to account for covariates, via a simple, easy to implement residualizing process. Our covariate-adjusted TSP method identified metabolite features, uncorrelated from clinical covariates, that discriminate DKD severity stage based on the relative ordering between two features, and thus provide insights into future studies on the order reversals in early vs advanced disease states.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Calcium/calmodulin-dependent protein kinase II (CaMKII) is thought to be a critical mediator of neuronal plasticity that links transiently triggered Ca
2+ signals to persistent changes in neuronal ...physiology. In one of its roles, CaMKII is an essential player in the
N-methyl-D-aspartate receptor-mediated increase in conductance at glutamatergic synapses, a process described as long-term potentiation, which serves as a common model for neuronal plasticity and memory. Recent studies have used genetic, biochemical, live cell imaging and mathematical modeling approaches to investigate neuronal CaMKII and have led to a model of the molecular steps of CaMKII translocation and activation that can explain its role in neuronal plasticity.
Recent studies, using biochemical, genetic and mathematical modeling, reveal the mechanisms behind CaMKII translocation and activation that lead to synaptic plasticity.
Adults with chronic kidney disease (CKD) are hospitalized more frequently than those without CKD, but the magnitude of this excess morbidity and the factors associated with hospitalizations are not ...well known.
Data from 3,939 participants enrolled in the Chronic Renal Insufficiency Cohort (CRIC) Study between 2003 and 2008 at 7 clinical centers in the United States were used to estimate primary causes of hospitalizations, hospitalization rates, and baseline participant factors associated with all-cause, cardiovascular, and non-cardiovascular hospitalizations during a median follow up of 9.6 years. Multivariable-adjusted Poisson regression was used to identify factors associated with hospitalization rates, including demographics, blood pressure, estimated glomerular filtration rate (eGFR), and proteinuria. Hospitalization rates in CRIC were compared with rates in the Nationwide Inpatient Sample (NIS) from 2012. Of the 3,939 CRIC participants, 45.1% were female, and 41.9% identified as non-Hispanic black, with a mean age of 57.7 years, and the mean eGFR is 44.9 ml/min/1.73m2. CRIC participants had an unadjusted overall hospitalization rate of 35.0 per 100 person-years (PY) 95% CI: 34.3 to 35.6 and 11.1 per 100 PY 95% CI: 10.8 to 11.5 for cardiovascular-related causes. All-cause, non-cardiovascular, and cardiovascular hospitalizations were associated with older age (≥65 versus 45 to 64 years), more proteinuria (≥150 to <500 versus <150 mg/g), higher systolic blood pressure (≥140 versus 120 to <130 mmHg), diabetes (versus no diabetes), and lower eGFR (<60 versus ≥60 ml/min/1.73m2). Non-Hispanic black (versus non-Hispanic white) race/ethnicity was associated with higher risk for cardiovascular hospitalization rate ratio (RR) 1.25, 95% CI: 1.16 to 1.35, p-value < 0.001, while risk among females was lower RR 0.89, 95% CI: 0.83 to 0.96, p-value = 0.002. Rates of cardiovascular hospitalizations were higher among those with ≥500 mg/g of proteinuria irrespective of eGFR. The most common causes of hospitalization were related to cardiovascular (31.8%), genitourinary (8.7%), digestive (8.3%), endocrine, nutritional or metabolic (8.3%), and respiratory (6.7%) causes. Hospitalization rates were higher in CRIC than the NIS, except for non-cardiovascular hospitalizations among individuals aged >65 years. Limitations of the study include possible misclassification by diagnostic codes, residual confounding, and potential bias from healthy volunteer effect due to its observational nature.
In this study, we observed that adults with CKD had a higher hospitalization rate than the general population that is hospitalized, and even moderate reductions in kidney function were associated with elevated rates of hospitalization. Causes of hospitalization were predominantly related to cardiovascular disease, but other causes contributed, particularly, genitourinary, digestive, and endocrine, nutritional, and metabolic illnesses. High levels of proteinuria were observed to have the largest association with hospitalizations across a wide range of kidney function levels.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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