Quality Comparison of 3 Tesla multiparametric MRI of the prostate using a flexible surface receiver coil versus conventional surface coil plus endorectal coil setup.

PURPOSE: To subjectively and quantitatively compare the quality of 3 Tesla magnetic resonance imaging of the prostate acquired with a novel flexible surface coil (FSC) and with a conventional endorectal coil (ERC). METHODS: Six radiologists independently reviewed 200 pairs of axial, high-resolution T2-weighted and diffusion-weighted image data sets, each containing one examination acquired with the FSC and one with the ERC, respectively. Readers selected their preferred examination from each pair and assessed every single examination using six quality criteria on 4-point scales. Signal-to-noise ratios were measured and compared. RESULTS: Two readers preferred FSC acquisition (36.5-45%) over ERC acquisition (13.5-15%) for both sequences combined, and four readers preferred ERC acquisition (41-46%). Analysis of pooled responses for both sequences from all readers shows no significant preference for FSC or ERC. Analysis of the individual sequences revealed a pooled preference for the FSC in T2WI (38.7% vs 17.8%) and for the ERC in DWI (50.9% vs 19.6%). Patients' weight was the only weak predictor of a preference for the ERC acquisition (p = 0.04). SNR and CNR were significantly higher in the ERC acquisitions (p<0.001) except CNR differentiating tumor lesions from benign prostate (p=0.1). CONCLUSION: Although readers have strong individual preferences, comparable subjective image quality can be obtained for prostate MRI with an ERC and the novel FSC. ERC imaging might be particularly valuable for sequences with inherently lower SNR as DWI and larger patients whereas the FSC is generally preferred in T2WI. FSC imaging generates a lower SNR than with an ERC.

How far have we come? Artificial intelligence for chest radiograph interpretation.

Due to recent advances in artificial intelligence, there is renewed interest in automating interpretation of imaging tests. Chest radiographs are particularly interesting due to many factors: relatively inexpensive equipment, importance to public health, commonly performed throughout the world, and deceptively complex taking years to master. This article presents a brief introduction to artificial intelligence, reviews the progress to date in chest radiograph interpretation, and provides a snapshot of the available datasets and algorithms available to chest radiograph researchers. Finally, the limitations of artificial intelligence with respect to interpretation of imaging studies are discussed.

Assessment of an ensemble of machine learning models toward abnormality detection in chest radiographs.

Respiratory diseases account for a significant proportion of deaths and disabilities across the world. Chest X-ray (CXR) analysis remains a common diagnostic imaging modality for confirming intra-thoracic cardiopulmonary abnormalities. However, there remains an acute shortage of expert radiologists, particularly in under-resourced settings, resulting in severe interpretation delays. These issues can be mitigated by a computer-aided diagnostic (CADx) system to supplement decision-making and improve throughput while preserving and possibly improving the standard-of-care. Systems reported in the literature or popular media use handcrafted features and/or data-driven algorithms like deep learning (DL) to learn underlying data distributions. The remarkable success of convolutional neural networks (CNN) toward image recognition tasks has made them a promising choice for automated medical image analyses. However, CNNs suffer from high variance and may overfit due to their sensitivity to training data fluctuations. Ensemble learning helps to reduce this variance by combining predictions of multiple learning algorithms to construct complex, non-linear functions and improve robustness and generalization. This study aims to construct and assess the performance of an ensemble of machine learning (ML) models applied to the challenge of classifying normal and abnormal CXRs and significantly reducing the diagnostic load of radiologists and primary-care physicians.

A novel stacked generalization of models for improved TB detection in chest radiographs.

Chest x-ray (CXR) analysis is a common part of the protocol for confirming active pulmonary Tuberculosis (TB). However, many TB endemic regions are severely resource constrained in radiological services impairing timely detection and treatment. Computer-aided diagnosis (CADx) tools can supplement decision-making while simultaneously addressing the gap in expert radiological interpretation during mobile field screening. These tools use hand-engineered and/or convolutional neural networks (CNN) computed image features. CNN, a class of deep learning (DL) models, has gained research prominence in visual recognition. It has been shown that Ensemble learning has an inherent advantage of constructing non-linear decision making functions and improve visual recognition. We create a stacking of classifiers with hand-engineered and CNN features toward improving TB detection in CXRs. The results obtained are highly promising and superior to the state-of-the-art.

Pronator teres accessorius: A new variant in flexor antebrachial musculature.

Muscles of flexor compartment of forearm have a common origin from medial epicondyle of humerus. Additional bellies of flexor muscles are commonly reported but presence of supernumerary muscles is an infrequent phenomenon. The present study describes an unusual muscle mass in flexor compartment of forearm simulating pronator teres. During routine dissection the upper limb of a 50 years old male cadaver, a supernumerary muscle was found on left side of the upper limb in the flexor compartment. The origin of the muscle was 2cm wide and aponeurotic in nature and attached to an oblique line extending from the inferior surface of the medial epicondyle and the medial surface of the trochlea. It was inserted on an oblique line 2.5cm wide on the radius in area between supinator superiorly and flexor digitorum profundus inferiorly. Existence of accessory muscles, which connect flexor muscles, could be explained embryologically by incomplete cleavage of flexor mass during development. The flexor muscles of the forearm develop from the flexor mass which subsequently divides into two layers: superficial and deep. The deep layer gives rise to flexor digitorum superficialis, flexor digitorum profundus and flexor pollicis longus. These supernumerary muscles are extremely rare entities and probably represent deranged embryological development or the process of atavism in which the anomalous part persist for a longer time in the tree of evolution.

Bilateral clavicular attachment of omohyoid muscle.

Omohyoid muscle present in cervical region is of particular importance to anatomists as it defines anteriorly the carotid triangle and divides the posterior cervical triangle. It has superior and inferior bellies and an intermediate common tendon. Like sternohyoid, sternothyroid and thyrohyoid muscles, omohyoid is also an infrahyoid muscle, but it differs from them in its course. The infrahyoid muscles are formed from a muscle primordium occurring in the anterior cervical area. Anderson (Anderson, 1881) theorized that the superior belly of the omohyoid muscle is a true infrahyoid muscle, whereas the inferior belly most likely shares a common embryology with the subclavius muscle. In the present study, during routine dissection in the neck region of an adult male cadaver of 50 years age, an anomalous origin of inferior belly of omohyoid with absence of intermediate tendon was observed bilaterally. It was arising from clavicle on both sides. Both the muscle bellies were measured from the lateral end of fascial sling. The inferior belly of omohyoid extending from the lateral margin of sling to clavicular surface was measured 3.3cm in length on left side and 3.6cm on right side. The omohyoid is important in neck dissections because it is considered as an ideal landmark for level III and IV lymph node metastases. Knowledge of variations of this muscle is very important for surgeries in neck region because of its close relation to the internal jugular vein and brachial plexus. Its crucial relationship to vascular structures in the neck makes it an important landmark during neck surgeries.

A prospective genome-wide study of prostate cancer metastases reveals association of wnt pathway activation and increased cell cycle proliferation with primary resistance to abiraterone acetate-prednisone.

Background: Genomic aberrations have been identified in metastatic castration-resistant prostate cancer (mCRPC), but molecular predictors of resistance to abiraterone acetate/prednisone (AA/P) treatment are not known. Patients and methods: In a prospective clinical trial, mCRPC patients underwent whole-exome sequencing (n = 82) and RNA sequencing (n = 75) of metastatic biopsies before initiating AA/P with the objective of identifying genomic alterations associated with resistance to AA/P. Primary resistance was determined at 12 weeks of treatment using criteria for progression that included serum prostate-specific antigen measurement, bone and computerized tomography imaging and symptom assessments. Acquired resistance was determined using the end point of time to treatment change (TTTC), defined as time from enrollment until change in treatment from progressive disease. Associations of genomic and transcriptomic alterations with primary resistance were determined using logistic regression, Fisher's exact test, single and multivariate analyses. Cox regression models were utilized for determining association of genomic and transcriptomic alterations with TTTC. Results: At 12 weeks, 32 patients in the cohort had progressed (nonresponders). Median study follow-up was 32.1 months by which time 58 patients had switched treatments due to progression. Median TTTC was 10.1 months (interquartile range: 4.4-24.1). Genes in the Wnt/ß-catenin pathway were more frequently mutated and negative regulators of Wnt/ß-catenin signaling were more frequently deleted or displayed reduced mRNA expression in nonresponders. Additionally, mRNA expression of cell cycle regulatory genes was increased in nonresponders. In multivariate models, increased cell cycle proliferation scores (≥ 50) were associated with shorter TTTC (hazard ratio = 2.11, 95% confidence interval: 1.17-3.80; P = 0.01). Conclusions: Wnt/ß-catenin pathway activation and increased cell cycle progression scores can serve as molecular markers for predicting resistance to AA/P therapy.

Exome Sequencing of Extended Families with Alzheimer's Disease Identifies Novel Genes Implicated in Cell Immunity and Neuronal Function.

OBJECTIVE: Alzheimer's disease (AD) is a neurodegenerative disorder for which more than 20 genetic loci have been implicated to date. However, studies demonstrate not all genetic factors have been identified. Therefore, in this study we seek to identify additional rare variants and novel genes potentially contributing to AD. METHODS: Whole exome sequencing was performed on 23 multi-generational families with an average of eight affected subjects. Exome sequencing was filtered for rare, nonsynonymous and loss-of-function variants. Alterations predicted to have a functional consequence and located within either a previously reported AD gene, a linkage peak (LOD>2), or clustering in the same gene across multiple families, were prioritized. RESULTS: Rare variants were found in known AD risk genes including AKAP9, CD33, CR1, EPHA1, INPP5D, NME8, PSEN1, SORL1, TREM2 and UNC5C. Three families had five variants of interest in linkage regions with LOD>2. Genes with segregating alterations in these peaks include CD163L1 and CLECL1, two genes that have both been implicated in immunity, CTNNA1, which encodes a catenin in the cerebral cortex and MIEF1, a gene that may induce mitochondrial dysfunction and has the potential to damage neurons. Four genes were identified with alterations in more than one family include PLEKHG5, a gene that causes Charcot-Marie-Tooth disease and THBS2, which promotes synaptogenesis. CONCLUSION: Utilizing large families with a heavy burden of disease allowed for the identification of rare variants co-segregating with disease. Variants were identified in both known AD risk genes and in novel genes.

Targeted sequencing of ABCA7 identifies splicing, stop-gain and intronic risk variants for Alzheimer disease.

Several variants in the gene ABCA7 have been identified as potential causal variants for late-onset Alzheimer's disease (LOAD). In order to replicate these findings, and search for novel causal variants, we performed targeted sequencing of this gene in cohorts of non-Hispanic White (NHW) and African-American (AA) LOAD cases and controls. We sequenced the gene ABCA7 in 291 NHW LOAD cases and 103 controls. Variants were prioritized for rare, damaging variants and previously reported variants associated with LOAD, and were follow-up genotyped in 4076 NHW and 1157 AA cases and controls. We confirm three previously associated ABCA7 risk variants and extend two of these associations to other populations, an intronic variant in NHW (P=3.0×10-3) (originally reported in a Belgian population), and a splice variant originally associated in the Icelandic population, which was significantly associated in the NHW cohort (P=1.2×10-6) and nominally associated in the AA cohort (P=0.017). We also identify a 3'-UTR splice variant that segregates in four siblings of one family and is nominally associated with LOAD (P=0.040). Multiple variants in ABCA7 contribute to LOAD risk.

Is suppression of apoptosis a new therapeutic target in sepsis?

Sepsis remains as a leading cause of death in critically ill patients. Unfortunately, there have been very few successful specific therapeutic agents that can significantly reduce the attributable mortality and morbidity of sepsis. Developing novel therapeutic strategies to improve outcomes of sepsis remains an important focus of ongoing research in the field of critical care medicine. Apoptosis has recently been identified as an important mechanism of cell death and evidence suggests that prevention of cell apoptosis can improve survival in animal models of sepsis and endotoxaemia. In this review article, we summarise the critical role of apoptosis of the immune cells in the pathophysiology of sepsis and propose that blocking cell-signaling pathways leading to apoptosis may present a promising specific therapy for sepsis. Various methods to inhibit apoptosis including the cell surface Fas receptor pathway inhibitors, caspase inhibitors, over-expression of anti-apoptotic genes and small interfering ribonucleic acid therapy are discussed.

Role of active nitrogen molecules in progression of septic shock.

INTRODUCTION: Active nitrogen molecules are formed as a result of cell metabolism. They are essential for cell metabolism, but when produced in excess, they contribute to the pathogenesis of several disease processes. These nitrogen molecules play an important role in vascular instability of septic shock. This study was planned to detect the role of active nitrogen molecules in the progression of septic shock. MATERIALS AND METHODS: Blood samples were collected from 118 critically ill patients admitted in ICU and from 95 healthy relatives accompanying the patients. Patients were categorized into three groups: systemic inflammatory response syndrome (n = 54), sepsis (n = 35) and septic shock (n = 29). Plasma total nitrite (nitrites and nitrates), cytokines like tumour necrosis factor-α (TNF-α) and plasma lactate were measured to assess inflammatory activity and severity of septic shock. RESULTS: High plasma levels of nitrite and nitrate (No2-/No3-) were observed in critically ill patients (mean level 78.92 µmol/l in sepsis and 97.20 µmol/l in septic shock). Mean plasma TNF-α level in sepsis was 213.50 pg/ml and septic shock was 227.38 pg/ml. CONCLUSION: Plasma No2-/No3- and TNF-α levels were high in patients with sepsis and septic shock, which increased with severity of sepsis.

Gene-PUFA interactions and obesity risk.

Although there are indications for modulatory effects of PUFA on associations between SNP and obesity risk, scientific evidence in human subjects is still scarce. The present analyses investigated interaction effects between SNP in candidate genes for obesity and PUFA in erythrocyte membranes on obesity risk. Within the second Bavarian Food Consumption Survey (cross-sectional, population-based), 568 adults provided blood samples. Fatty acid composition of erythrocyte membranes was analysed by means of GC. Genotyping was performed for twenty-one genes, including cytokines, adipokines, neurotransmitters and transcription factors. In addition, plasma IL-6 concentrations were analysed. For the statistical analysis, a logistic regression model assuming additive genetic effects was chosen. About 20 % of the study participants were classified as obese (BMI ≥ 30 kg/m(2)). Several significant gene-PUFA interactions were found, indicating regulatory effects of PUFA by gene variants of IL-2, IL-6, IL-18, TNF receptor family member 1B and 21, leptin receptor and adiponectin on obesity risk. After stratification by genotype, the strongest effects were found for rs2069779 (IL-2) and all tested PUFA as well as for rs1800795 (IL-6) and linoleic or arachidonic acid. The obesity risk of minor allele carriers significantly decreased with increasing fatty acid content. The genetic PUFA-IL-6 interaction was also reflected in plasma IL-6 concentrations. If replicated in a prospective study with sufficient statistical power, the results would indicate a beneficial effect of high PUFA supply for a substantial proportion of the population with respect to obesity risk.

TMEM132D, a new candidate for anxiety phenotypes: evidence from human and mouse studies.

The lifetime prevalence of panic disorder (PD) is up to 4% worldwide and there is substantial evidence that genetic factors contribute to the development of PD. Single-nucleotide polymorphisms (SNPs) in TMEM132D, identified in a whole-genome association study (GWAS), were found to be associated with PD in three independent samples, with a two-SNP haplotype associated in each of three samples in the same direction, and with a P-value of 1.2e-7 in the combined sample (909 cases and 915 controls). Independent SNPs in this gene were also associated with the severity of anxiety symptoms in patients affected by PD or panic attacks as well as in patients suffering from unipolar depression. Risk genotypes for PD were associated with higher TMEM132D mRNA expression levels in the frontal cortex. In parallel, using a mouse model of extremes in trait anxiety, we could further show that anxiety-related behavior was positively correlated with Tmem132d mRNA expression in the anterior cingulate cortex, central to the processing of anxiety/fear-related stimuli, and that in this animal model a Tmem132d SNP is associated with anxiety-related behavior in an F2 panel. TMEM132D may thus be an important new candidate gene for PD as well as more generally for anxiety-related behavior.

Ecotoxicity of a brominated flame retardant (tetrabromobisphenol A) and its derivatives to aquatic organisms.

The large use of tetrabromobisphenol A (B(4)BPA) in common products (plastics, electric and electronic equipments) has raised concern about its ecotoxicity. Physical and bio-degradations may lead to the formation of tetrabromobisphenol A derivatives like tri- (B(3)BPA), di- (B(2)BPA), monobromobisphenol A (B(1)BPA) and bisphenol A (BPA). However, little is known about the toxicity of these brominated derivatives. An appraisal on the ecotoxicity of B(4)BPA and its derivatives was carried out with several bioassays representing organisms (bacteria, algae, micro-invertebrates and fish) of different taxonomic groups present in aquatic ecosystems. Endpoint values showed that B(4)BPA was significantly less toxic than the other chemicals when tested with the Microtox and algal asssays. A similar trend was observed with other bioassays for BPA. One of the brominated derivatives was particularly toxic: B(2)BPA. The LuminoTox assay and the rainbow trout hepatocytes assay reported the most significant toxicity for this derivative. Its toxicity was also significantly higher than the other compounds barring B(3)BPA when tested with the micro-crustacean test.

Variations in tryptophan hydroxylase 2 linked to decreased serotonergic activity are associated with elevated risk for metabolic syndrome in depression.

Major depression and the metabolic syndrome (MetS) are interacting clinical conditions influenced by genetic susceptibility. For both disorders, impaired serotonergic neurotransmission in specific brain areas has been suggested. This led us to investigate whether variants in the gene coding for tryptophan hydroxylase 2 (TPH2), the brain-specific and rate-limiting enzyme for serotonin biosynthesis, might be predictive for an increased liability for the development of MetS in depressed patients. In a case-control study consisting of 988 patients with recurrent unipolar depression (RUD) and 1023 psychiatric healthy controls, MetS components were ascertained according to the International Diabetes Foundation criteria. A total of 41 single nucleotide polymorphisms fully covering the TPH2 gene region were genotyped in stage 1 (300 patients/300 controls), resulting in significant genetic associations of polymorphisms located in exon 7 and intron 8 of TPH2 and the occurrence of MetS in depressed patients after correction for age, gender and multiple testing (51 RUD-MetS/179 RUD-non-MetS). We were able to confirm the significant association of rs17110690 in stage 2 (688 patients/723 controls; 110 RUD-MetS/549 RUD-non-MetS) and to link risk-genotypes and risk-haplotypes for MetS to lower TPH2 mRNA expression and to lower 5-hydroxyindoleacetic acid levels in cerebrospinal fluid previously reported in functional studies. Our findings suggest that TPH2 polymorphisms characterize a subgroup of depressed patients who are especially prone to develop metabolic disorders induced by a genotype-dependent impairment of serotonergic neurotransmission. Identifying depressed patients at high risk for MetS using genetic variants could have direct clinical impact on individualized disease management and prevention strategies.

Incidence and factors related to flare-ups in a graduate endodontic programme.

AIM: To investigate the incidence and factors related to endodontic flare-ups in nonsurgical root canal treatment (NSRCT) cases completed by graduate endodontic residents at University of Pennsylvania, USA. METHODOLOGY: Residents at University of Pennsylvania enter all clinical patient records into an electronic database called PennEndo database. Analysis of records of 6580 patients treated from September 2000 to July 2005 revealed a total of 26 patients with flare-ups (0.39%). Patients were categorized to have undergone flare-up when they attended for an unscheduled visit and active treatment, and when they suffered from severe pain and or swelling after initiation or continuation of NSRCT. SAS software was used to develop a logistic regression model with flare-up as a dependent variable. Independent variables included in the model were: history of previous pain, one vs. two visit NSRCT, periapical diagnosis, tooth type, rotary versus hand instrumentation, and lateral versus vertical compaction of gutta-percha. RESULTS: The odds for developing a flare-up in teeth with a periapical radiolucency were 9.64 times greater than teeth without a periapical radiolucency (P = 0.0090). There was no statistically significant difference in flare-ups between one and two visits NSRCT. The odds of developing a flare-up increased 40 fold when NSRCT was completed in three or more visits. However, this result may have been confounded by addition of an unscheduled visit in patients suffering from flare-ups. Other independent variables did not have any statistically significant correlations. CONCLUSIONS: A low percentage of patients experienced flare-ups during NSRCT procedures. The presence of a periapical lesion was the single most important predictor of flare-ups during NSRCT.

Genome-wide association for major depressive disorder: a possible role for the presynaptic protein piccolo.

Major depressive disorder (MDD) is a common complex trait with enormous public health significance. As part of the Genetic Association Information Network initiative of the US Foundation for the National Institutes of Health, we conducted a genome-wide association study of 435 291 single nucleotide polymorphisms (SNPs) genotyped in 1738 MDD cases and 1802 controls selected to be at low liability for MDD. Of the top 200, 11 signals localized to a 167 kb region overlapping the gene piccolo (PCLO, whose protein product localizes to the cytomatrix of the presynaptic active zone and is important in monoaminergic neurotransmission in the brain) with P-values of 7.7 x 10(-7) for rs2715148 and 1.2 x 10(-6) for rs2522833. We undertook replication of SNPs in this region in five independent samples (6079 MDD independent cases and 5893 controls) but no SNP exceeded the replication significance threshold when all replication samples were analyzed together. However, there was heterogeneity in the replication samples, and secondary analysis of the original sample with the sample of greatest similarity yielded P=6.4 x 10(-8) for the nonsynonymous SNP rs2522833 that gives rise to a serine to alanine substitution near a C2 calcium-binding domain of the PCLO protein. With the integrated replication effort, we present a specific hypothesis for further studies.

IL2RA and IL7RA genes confer susceptibility for multiple sclerosis in two independent European populations.

Multiple sclerosis (MS) is the most common chronic inflammatory neurologic disorder diagnosed in young adults and, due to its chronic course, is responsible for a substantial economic burden. MS is considered to be a multifactorial disease in which both genetic and environmental factors intervene. The well-established human leukocyte antigen (HLA) association does not completely explain the genetic impact on disease susceptibility. However, identification and validation of non-HLA-genes conferring susceptibility to MS has proven to be difficult probably because of the small individual contribution of each of these genes. Recently, associations with two single nucleotide polymorphisms (SNPs) in the IL2RA gene (rs12722489, rs2104286) and one SNP in the IL7RA gene (rs6897932) have been reported by several groups. These three SNPs were genotyped in a French and a German population of MS patients using the hME assay by the matrix-assisted laser desorption/ionization time of flight technology (Sequenom, San Diego, CA, USA). We show that these SNPs do contribute to the risk of MS in these two unrelated European MS patient populations with odds ratios varying from 1.1 to 1.5. The discovery and validation of new genetic risk factors in independent populations may help toward the understanding of MS pathogenesis by providing valuable information on biological pathways to be investigated.

Mandibular canal variant: a case report.

The mandibular canal transmits the inferior alveolar artery, vein and the inferior alveolar nerve. From an embryological perspective, there might be three inferior dental nerves innervating three groups of mandibular teeth. During rapid prenatal growth and remodeling in the ramus region there is spread of intramembranous ossification that eventually forms the mandibular canal. Occurrence of bifid/trifid mandibular canals in some patients is secondary to incomplete fusion of these three nerves. Various types of bifid mandibular canals have been classified according to anatomical location and configuration. This case report highlights an unusual variant of the mandibular canal.

Estimating the long-term impact of a prophylactic human papillomavirus 16/18 vaccine on the burden of cervical cancer in the UK.

To predict the public health impact on cervical disease by introducing human papillomavirus (HPV) vaccination in the United Kingdom, we developed a mathematical model that can be used to reflect the impact of vaccination in different countries with existing screening programmes. Its use is discussed in the context of the United Kingdom. The model was calibrated with published data. The impact of vaccination on cervical cancer and deaths, precancerous lesions and screening outcomes were estimated for a vaccinated cohort of 12-year-old girls, among which it is estimated that there would be a reduction of 66% in the prevalence of high-grade precancerous lesions and a 76% reduction in cervical cancer deaths. Estimates for various other measures of the population effects of vaccination are also presented. We concluded that it is feasible to forecast the potential effects of HPV vaccination in the context of an existing national screening programme. Results suggest a sizable reduction in the incidence of cervical cancer and related deaths. Areas for future research include investigation of the beneficial effects of HPV vaccination on infection transmission and epidemic dynamics, as well as HPV-related neoplasms in other sites.