Computerized Prediction of Radiological Observations Based on Quantitative Feature Analysis: Initial Experience in Liver Lesions

We propose a computerized framework that, given a region of interest (ROI) circumscribing a lesion, not only predicts radiological observations related to the lesion characteristics with 83.2% average prediction accuracy but also derives explicit association between low-level imaging features and high-level semantic terms by exploiting their statistical correlation. Such direct association between semantic concepts and low-level imaging features can be leveraged to build a powerful annotation system for radiological images that not only allows the computer to infer the semantics from diverse medical images and run automatic reasoning for making diagnostic decision but also provides “human-interpretable explanation” of the system output to facilitate better end user understanding of computer-based diagnostic decisions. The core component of our framework is a radiological observation detection algorithm that maximizes the low-level imaging feature relevancy for each high-level semantic term. On a liver lesion CT dataset, we have implemented our framework by incorporating a large set of state-of-the-art low-level imaging features. Additionally, we included a novel feature that quantifies lesion(s) present within the liver that have a similar appearance as the primary lesion identified by the radiologist. Our framework achieved a high prediction accuracy (83.2%), and the derived association between semantic concepts and imaging features closely correlates with human expectation. The framework has been only tested on liver lesion CT images, but it is capable of being applied to other imaging domains.     

From the Cover: PNAS Plus: The essential gene set of a photosynthetic organism

Synechococcus elongatus PCC 7942 is a model organism used for studying photosynthesis and the circadian clock, and it is being developed for the production of fuel, industrial chemicals, and pharmaceuticals. To identify a comprehensive set of genes and intergenic regions that impacts fitness in S. elongatus, we created a pooled library of ∼250,000 transposon mutants and used sequencing to identify the insertion locations. By analyzing the distribution and survival of these mutants, we identified 718 of the organism’s 2,723 genes as essential for survival under laboratory conditions. The validity of the essential gene set is supported by its tight overlap with well-conserved genes and its enrichment for core biological processes. The differences noted between our dataset and these predictors of essentiality, however, have led to surprising biological insights. One such finding is that genes in a large portion of the TCA cycle are dispensable, suggesting that S. elongatus does not require a cyclic TCA process. Furthermore, the density of the transposon mutant library enabled individual and global statements about the essentiality of noncoding RNAs, regulatory elements, and other intergenic regions. In this way, a group I intron located in tRNA^Leu, which has been used extensively for phylogenetic studies, was shown here to be essential for the survival of S. elongatus. Our survey of essentiality for every locus in the S. elongatus genome serves as a powerful resource for understanding the organism’s physiology and defines the essential gene set required for the growth of a photosynthetic organism.Determining the sets of genes necessary for survival of diverse organisms has helped to identify the fundamental processes that sustain life across an array of environments (1). This research has also served as the starting point for efforts by synthetic biologists to design organisms from scratch (2, 3). Despite the importance of essential gene sets, they have traditionally been challenging to gather because of the difficulty of observing mutations that result in lethal phenotypes. More recently, the pairing of transposon mutagenesis with next generation sequencing, referred to collectively as transposon sequencing (Tn-seq), has resulted in a dramatic advance in the identification of essential gene sets (4–7). The key characteristic of Tn-seq is the use of high-throughput sequencing to screen for the fitness of every transposon mutant in a pooled population to measure each mutation’s impact on survival. These data can be used to quantitatively ascertain the effect of loss-of-function mutations at any given locus, intragenic or intergenic, in the conditions under which the library is grown (8). Essential gene sets for 42 diverse organisms distributed across all three domains have now been defined, largely through the use of Tn-seq (9). A recently developed variation on Tn-seq, random barcode transposon site sequencing (RB-TnSeq) (10), further minimizes the library preparation and sequencing costs of whole-genome mutant screens.Despite the proliferation of genome-wide essentiality screens, a complete essential gene set has yet to be defined for a photosynthetic organism. A collection of phenotyped Arabidopsis thaliana mutants has been created but extends to only one-tenth of Arabidopsis genes (11). In algae, efforts are underway to produce a Tn-seq–like system in Chlamydomonas reinhardtii; however, the mutant library currently lacks sufficient saturation to determine gene essentiality (12). To date, the essential genes for photoautotrophs have only been estimated by indirect means, such as by comparative genomics (13). The absence of experimentally determined essential gene sets in photosynthetic organisms, despite their importance to the environment and industrial production, is largely because of the difficulty and time required for genetic modification of these organisms.Cyanobacteria comprise an extensively studied and ecologically important photosynthetic phylum. They are responsible for a large portion of marine primary production and have played a foundational role in research to decipher the molecular components of photosynthesis (14, 15). Synechococcus elongatus PCC 7942 is a particularly well-studied member of this phylum because of its genetic tractability and streamlined genome (16). As a result, it has been developed as a model photosynthetic organism and a production platform for a number of fuel products and high-value chemicals (17). Despite the importance of S. elongatus for understanding photosynthesis and industrial production, 40% of its genes have no functional annotation, and only a small portion of those that do have been studied experimentally.Here, we use RB-TnSeq, a method that pairs high-density transposon mutagenesis and pooled mutant screens, to probe the S. elongatus genome for essential genes and noncoding regions. We categorized 96% of 2,723 genes in S. elongatus as either essential (lethal when mutated), beneficial (growth defect when mutated), or nonessential (no phenotype when mutated) under standard laboratory conditions. Furthermore, we determined the genome-wide essentiality of noncoding RNAs (ncRNAs), regulatory regions, and intergenic regions. Our investigation has produced an extensive analysis of the loci essential for the growth of a photosynthetic organism and developed a powerful genomic tool that can be used for additional screens under a wide array of ecologically and industrially relevant growth conditions.     

Impact of investigations in general practice on timeliness of referral for patients subsequently diagnosed with cancer: analysis of national primary care audit data

Background:

For patients with symptoms of possible cancer who do not fulfil the criteria for urgent referral, initial investigation in primary care has been advocated in the United Kingdom and supported by additional resources. The consequence of this strategy for the timeliness of diagnosis is unknown.

Methods:

We analysed data from the English National Audit of Cancer Diagnosis in Primary Care on patients with lung (1494), colorectal (2111), stomach (246), oesophagus (513), pancreas (327), and ovarian (345) cancer relating to the ordering of investigations by the General Practitioner and their nature. Presenting symptoms were categorised according to National Institute for Health and Care Excellence (NICE) guidance on referral for suspected cancer. We used linear regression to estimate the mean difference in primary-care interval by cancer, after adjustment for age, gender, and the symptomatic presentation category.

Results:

Primary-care investigations were undertaken in 3198/5036 (64%) of cases. The median primary-care interval was 16 days (IQR 5–45) for patients undergoing investigation and 0 days (IQR 0–10) for those not investigated. Among patients whose symptoms mandated urgent referral to secondary care according to NICE guidelines, between 37% (oesophagus) and 75% (pancreas) were first investigated in primary care. In multivariable linear regression analyses stratified by cancer site, adjustment for age, sex, and NICE referral category explained little of the observed prolongation associated with investigation.

Interpretation:

For six specified cancers, investigation in primary care was associated with later referral for specialist assessment. This effect was independent of the nature of symptoms. Some patients for whom urgent referral is mandated by NICE guidance are nevertheless investigated before referral. Reducing the intervals between test order, test performance, and reporting can help reduce the prolongation of primary-care intervals associated with investigation use. Alternative models of assessment should be considered.     

Prevalence of bruxism and temporomandibular disorders among orphans in southeast Uganda: A gender and age comparison

Objectives: The aims of the current study were: (1) to assess the prevalence of oral habits, bruxism, and temporomandibular disorders (TMDs) among children living in Uganda; (2) to establish whether parafunctional activities are associated with TMDs; and (3) to examine the possible impact of gender and age on the prevalence of bruxism, oral habits, and TMDs.

Methods: This study included 153 children aged 6–17 years. The study consisted of a questionnaire and a clinical examination.

Results: TMDs were moderately prevalent (35%). Parafunctional habits were performed by 93% of the participants. When performed extensively, they were significantly related to myalgia. No gender or age significant differences were found.

Conclusions: 1. Only extensive masticatory parafunctional oral activity is significantly related to myalgia. 2. Gender and age had no impact on the prevalence of bruxism, oral habits, or TMDs. 3. Sleep and awake bruxism were not related to anamnestic symptoms or clinical findings in TMD.     

ETS rearrangements in prostate cancer

Prostate cancer is a clinically and molecularly heterogeneous disease. Understanding the biologic underpinning of prostate cancer is necessary to best determine how biology is associated with the risk of disease progression and how this understanding might provide insight into the development of novel therapeutic approaches. The focus of this review is on the recently identified common ETS and non-ETS gene rearrangements in prostate cancer. Although multiple molecular alterations have been detected in prostate cancer, a basic understanding of gene fusion prostate cancer should help explain the clinical and biologic diversity, providing a rationale for a molecular subclassification of the disease.     

Maternal mortality and impact of dengue in Southeast Brazil: an ecological study, 2001-2005

The aim of this study was to explore the distribution of reproductive outcomes following dengue virus infection during pregnancy (2001-2005). An ecological epidemiological study was conducted in all counties with more than 80,000 inhabitants in Southeast Brazil. The study explored the correlation between dengue incidence rates in women 15-39 years of age and selected mortality indicators (maternal, fetal, perinatal, neonatal, early neonatal, and infant) in these counties, and Spearman correlation coefficients were calculated. A positive correlation was observed between median dengue incidence in women 15-39 years of age and median maternal mortality (r = 0.88; 95%CI: 0.51; 1.00), with a determination coefficient R2 = 0.78. The correlation between dengue incidence in childbearing-age women and reproductive outcomes in Southeast Brazil suggests that dengue infection during pregnancy can negatively impact its outcome and increase maternal mortality.     

Taking refuge from modernity: 21st century hermits

Idiopathic environmental intolerances, such as ‘multiple chemical sensitivity’ and ‘electrosensitivity,’ can drastically affect the quality of life of those affected. A proportion of severely affected patients remove themselves from modern society, to live in isolation away from the purported causal agent of their ill health. This is not a new phenomenon; reports of hermits extend back to the 3^rd century AD. We conducted a literature review of case reports relating to ancient hermits and modern day reclusion resulting from idiopathic environmental intolerance, in order to explore whether there are similarities between these two groups and whether the symptoms of these ‘illnesses of modernity’ are simply a present-day way of reaching the end-point of reclusion. Whilst there were some differences between the cases, recurring themes in ancient and modern cases included: dissatisfaction with society, a compulsion to flee, reports of a constant struggle and a feeling of fighting against the establishment. The similarities which exist between the modern-day cases and the historical hermits may provide some insight into the extreme behaviours exhibited by this population. The desire to retreat from society in order to escape from harm has existed for many centuries, but in different guises.