Investigation of the Human Brain Metabolome to Identify Potential Markers for Early Diagnosis and Therapeutic Targets of Alzheimer’s Disease

A study combining high resolution mass spectrometry (liquid chromatography-quadrupole time-of-flight-mass spectrometry, UPLC-QTof-MS) and chemometrics for the analysis of post-mortem brain tissue from subjects with Alzheimer’s disease (AD) (n = 15) and healthy age-matched controls (n = 15) was undertaken. The huge potential of this metabolomics approach for distinguishing AD cases is underlined by the correct prediction of disease status in 94–97% of cases. Predictive power was confirmed in a blind test set of 60 samples, reaching 100% diagnostic accuracy. The approach also indicated compounds significantly altered in concentration following the onset of human AD. Using orthogonal partial least-squares discriminant analysis (OPLS-DA), a multivariate model was created for both modes of acquisition explaining the maximum amount of variation between sample groups (Positive Mode-R2 = 97%; Q2 = 93%; root mean squared error of validation (RMSEV) = 13%; Negative Mode-R2 = 99%; Q2 = 92%; RMSEV = 15%). In brain extracts, 1264 and 1457 ions of interest were detected for the different modes of acquisition (positive and negative, respectively). Incorporation of gender into the model increased predictive accuracy and decreased RMSEV values. High resolution UPLC-QTof-MS has not previously been employed to biochemically profile post-mortem brain tissue, and the novel methods described and validated herein prove its potential for making new discoveries related to the etiology, pathophysiology, and treatment of degenerative brain disorders.

Optical coherence tomography for the diagnosis of neovascular age-related macular degeneration: a systematic review

The purpose is to study the diagnostic performance of optical coherence tomography (OCT) and alternative diagnostic tests for neovascular age-related macular degeneration (nAMD). Methods employed are as follows:systematic review and meta-analysis; Index test: OCT including time-domain (TD-OCT) and the most recently developed spectral domain (SD-OCT); comparator tests: visual acuity, clinical evaluation (slit lamp), Amsler chart, colour fundus photographs, infra-red reflectance, red-free images/blue reflectance, fundus autofluorescence imaging (FAF), indocyanine green angiography (ICGA), preferential hyperacuity perimetry (PHP), and microperimetry; reference standard: fundus fluorescein angiography. Databases searched included MEDLINE, MEDLINE In Process, EMBASE, Biosis, SCI, the Cochrane Library, DARE, MEDION, and HTA database. Last literature searches: March 2013. Risk of bias assessed using QUADAS-2. Meta-analysis models were fitted using hierarchical summary receiver operating characteristic (HSROC) curves. Twenty-two studies (2 abstracts and 20 articles) enrolling 2124 participants were identified, reporting TD-OCT (12 studies), SD-OCT (1 study), ICGA (8 studies), PHP (3 studies), Amsler grid, colour fundus photography and FAF (1 study each). Most studies were considered to have a high risk of bias in the patient selection (55%, 11/20), and flow and timing (40%, 8/20) domains. In a meta-analysis of TD-OCT studies, sensitivity and specificity (95% CI) were 88% (46–98%) and 78% (64–88%), respectively. There was insufficient information to undertake meta-analysis for other tests. TD-OCT is a sensitive test for detecting nAMD, although specificity was only moderate. Data on SD-OCT are sparse. Diagnosis of nAMD should not rely solely on OCT.

Optical coherence tomography for the diagnosis, monitoring and guiding of treatment for neovascular age-related macular degeneration:a systematic review and economic evaluation

BACKGROUND: Age-related macular degeneration is the most common cause of sight impairment in the UK. In neovascular age-related macular degeneration (nAMD), vision worsens rapidly (over weeks) due to abnormal blood vessels developing that leak fluid and blood at the macula.

OBJECTIVES: To determine the optimal role of optical coherence tomography (OCT) in diagnosing people newly presenting with suspected nAMD and monitoring those previously diagnosed with the disease.

DATA SOURCES: Databases searched: MEDLINE (1946 to March 2013), MEDLINE In-Process & Other Non-Indexed Citations (March 2013), EMBASE (1988 to March 2013), Biosciences Information Service (1995 to March 2013), Science Citation Index (1995 to March 2013), The Cochrane Library (Issue 2 2013), Database of Abstracts of Reviews of Effects (inception to March 2013), Medion (inception to March 2013), Health Technology Assessment database (inception to March 2013).

REVIEW METHODS: Types of studies: direct/indirect studies reporting diagnostic outcomes.

INDEX TEST: time domain optical coherence tomography (TD-OCT) or spectral domain optical coherence tomography (SD-OCT).

COMPARATORS: clinical evaluation, visual acuity, Amsler grid, colour fundus photographs, infrared reflectance, red-free images/blue reflectance, fundus autofluorescence imaging, indocyanine green angiography, preferential hyperacuity perimetry, microperimetry. Reference standard: fundus fluorescein angiography (FFA). Risk of bias was assessed using quality assessment of diagnostic accuracy studies, version 2. Meta-analysis models were fitted using hierarchical summary receiver operating characteristic curves. A Markov model was developed (65-year-old cohort, nAMD prevalence 70%), with nine strategies for diagnosis and/or monitoring, and cost-utility analysis conducted. NHS and Personal Social Services perspective was adopted. Costs (2011/12 prices) and quality-adjusted life-years (QALYs) were discounted (3.5%). Deterministic and probabilistic sensitivity analyses were performed.

RESULTS: In pooled estimates of diagnostic studies (all TD-OCT), sensitivity and specificity [95% confidence interval (CI)] was 88% (46% to 98%) and 78% (64% to 88%) respectively. For monitoring, the pooled sensitivity and specificity (95% CI) was 85% (72% to 93%) and 48% (30% to 67%) respectively. The FFA for diagnosis and nurse-technician-led monitoring strategy had the lowest cost (£39,769; QALYs 10.473) and dominated all others except FFA for diagnosis and ophthalmologist-led monitoring (£44,649; QALYs 10.575; incremental cost-effectiveness ratio £47,768). The least costly strategy had a 46.4% probability of being cost-effective at £30,000 willingness-to-pay threshold.

LIMITATIONS: Very few studies provided sufficient information for inclusion in meta-analyses. Only a few studies reported other tests; for some tests no studies were identified. The modelling was hampered by a lack of data on the diagnostic accuracy of strategies involving several tests.

CONCLUSIONS: Based on a small body of evidence of variable quality, OCT had high sensitivity and moderate specificity for diagnosis, and relatively high sensitivity but low specificity for monitoring. Strategies involving OCT alone for diagnosis and/or monitoring were unlikely to be cost-effective. Further research is required on (i) the performance of SD-OCT compared with FFA, especially for monitoring but also for diagnosis; (ii) the performance of strategies involving combinations/sequences of tests, for diagnosis and monitoring; (iii) the likelihood of active and inactive nAMD becoming inactive or active respectively; and (iv) assessment of treatment-associated utility weights (e.g. decrements), through a preference-based study.

STUDY REGISTRATION: This study is registered as PROSPERO CRD42012001930.

FUNDING: The National Institute for Health Research Health Technology Assessment programme.

The role of Optical Coherence Tomography (OCT) for the diagnosis, monitoring, and guiding of treatment for neovascular Age-related Macular Degeneration (nAMD): an evidence synthesis study

Purpose:To determine the optimal role of OCT in diagnosing and monitoring nAMD (detecting disease activity and the need for further anti-VEGF treatment).
Methods:Systematic review. Major electronic databases and websites were searched. Studies were included if they reported the diagnostic performance of time domain or spectral domain OCT (or selected other tests) against a reference standard of ophthalmologist-interpreted fluorescein angiography in people with newly suspected or previously diagnosed nAMD. Risk of bias was assessed by two independent investigators using QUADAS-2. Summary receiver operating characteristic (SROC) curves were produced for each test given sufficient data.
Results:3700 titles/abstracts were screened, and 120 (3.2%) were selected for full-text assessment. A total of 22 studies were included (17 on diagnosis, 7 monitoring, and 3 both). From 15 studies reporting OCT data, sensitivity and specificity ranged from 59% to 100% and 27% to 100%, respectively.
Conclusions:The reported diagnostic performance of OCT showed large variability. The methodological quality of most studies was sub-optimal.

Long-term health-related quality of life of prostate cancer survivors varies by primary treatment. Results from the PiCTure (Prostate Cancer Treatment, your experience) study

PURPOSE: Men are living longer with prostate cancer. In a two-country study, we investigated the health-related quality of life (HRQoL) of prostate cancer survivors up to 18 years post-diagnosis.

METHODS: Postal questionnaires were administered in 2012 to 6559 prostate cancer (ICD10 C61) survivors 2-18 years post-diagnosis, identified through population-based cancer registries in Ireland. HRQoL was measured using QLQ-C30 and QLQ-PR25. HRQoL, functional and symptom scores were compared by primary treatment(s) using multiple linear regression.

RESULTS: Fifty-four percent responded (n = 3348). After controlling for socio-demographic and clinical factors, global HRQoL varied significantly by primary treatment (p < 0.001); compared to radical prostatectomy (RP), survivors who received androgen deprivation therapy alone (ADT; p < 0.001) or external beam radiotherapy (EBRT) without concurrent ADT (p = 0.001) had significantly lower global HRQoL. The global HRQoL of men who received brachytherapy (p = 0.157), EBRT with concurrent ADT (p = 0.940) or active surveillance/watchful waiting (p = 0.388) was not significantly different from men treated with RP. There were statistically and clinically significant differences in general (fatigue, pain, dyspnoea, appetite loss, constipation, diarrhoea, financial difficulties) and disease-specific symptoms (sexual, urinary, bowel, ADT) by primary treatment. Fatigue and insomnia scores were high for survivors in all treatment groups.

CONCLUSIONS: Prostate cancer survivors' long-term HRQoL varied with primary treatment.

IMPLICATIONS OF CANCER SURVIVORS: Population-based information regarding statistically and clinically significant treatment effects on long-term global HRQoL, symptom burden and functionality should be provided during treatment decision-making. Screening for symptoms and utilising interventions during long-term follow-up may improve survivors' HRQoL.

Diagnostic value of surgical lung biopsy: comparison with clinical and radiological diagnosis

OBJECTIVE: To determine overall and disease-related accuracy of the clinical/imagiological evaluation for pulmonary infiltrates of unknown aetiology, compared with the pathological result of the surgical lung biopsy (SLB) and to evaluate the need for the latter in this setting. METHODS: We conducted a retrospective review of the experiences of SLB in 366 consecutive patients during the past 5 years. The presumptive diagnosis was based on clinical, imagiological and non-invasive or minimally invasive diagnostic procedures and compared with the gold standard of histological diagnosis by SLB. We considered five major pathological groups: diffuse parenchymal lung disease (DPLD), primitive neoplasms, metastases, infectious disease and other lesions. Patients with previous histological diagnosis were excluded. RESULTS: In 56.0% of patients (n=205) clinical evaluation reached a correct diagnosis, in 42.6% a new diagnosis was established (n=156) by the SLB, which was inconclusive in 1.4% (n=5). The pre-test probability for each disease was 85% for DPLD, 75% for infectious disease, 64% for primitive neoplasms and 60% for metastases. Overall sensitivity, specificity, positive and negative predictive values for the clinical/radiological diagnosis were 70%, 90%, 62% and 92%, respectively. For DPLD: 67%, 90%, 76% and 85%; primitive neoplasms: 47%, 90%, 46% and 90%; metastases: 99%, 79%, 60% and 99%; infectious disease 38%, 98%, 53% and 96%. CONCLUSIONS: Despite a high sensitivity and specificity of the clinical and imagiological diagnosis, the positive predictive value was low, particularly in the malignancy group. SLB should be performed in pulmonary infiltrates of unknown aetiology because the clinical/imagiological assessment missed and/or misdiagnosed an important number of patients.

Diagnostic et traitement des infections d'implants orthopédiques [Update on implant related infections in orthopaedic surgery. Diagnosis and treatment]

Infections associated with implants are increasingly important in modem medicine. Biofilms are the cause that these infections are more difficult to diagnose and to cure. Particularly low-grade infections are difficult to distinguish from aseptic failure, because they often present with early loosening and persisting pain. For an accurate diagnosis, clinical signs and symptoms, laboratory markers of infection, microbiology, histology and imaging examinations are needed. The treatment goal is eradication of infection and an optimal functional result. Successful treatment requires adequate surgical procedure combined with long-term antimicrobial therapy, ideally with an agent acting on biofilms.

Quantitative ultrasound imaging during shear wave propagation for application related to breast cancer diagnosis

Dans le contexte de la caractérisation des tissus mammaires, on peut se demander ce que l’examen d’un attribut en échographie quantitative (« quantitative ultrasound » - QUS) d’un milieu diffusant (tel un tissu biologique mou) pendant la propagation d’une onde de cisaillement ajoute à son pouvoir discriminant. Ce travail présente une étude du comportement variable temporel de trois paramètres statistiques (l’intensité moyenne, le paramètre de structure et le paramètre de regroupement des diffuseurs) d’un modèle général pour l’enveloppe écho de l’onde ultrasonore rétrodiffusée (c.-à-d., la K-distribution homodyne) sous la propagation des ondes de cisaillement. Des ondes de cisaillement transitoires ont été générés en utilisant la mèthode d’ imagerie de cisaillement supersonique ( «supersonic shear imaging » - SSI) dans trois fantômes in-vitro macroscopiquement homogènes imitant le sein avec des propriétés mécaniques différentes, et deux fantômes ex-vivo hétérogénes avec tumeurs de souris incluses dans un milieu environnant d’agargélatine. Une comparaison de l’étendue des trois paramètres de la K-distribution homodyne avec et sans propagation d’ondes de cisaillement a montré que les paramètres étaient significativement (p < 0,001) affectès par la propagation d’ondes de cisaillement dans les expériences in-vitro et ex-vivo. Les résultats ont également démontré que la plage dynamique des paramétres statistiques au cours de la propagation des ondes de cisaillement peut aider à discriminer (avec p < 0,001) les trois fantômes homogènes in-vitro les uns des autres, ainsi que les tumeurs de souris de leur milieu environnant dans les fantômes hétérogénes ex-vivo. De plus, un modéle de régression linéaire a été appliqué pour corréler la plage de l’intensité moyenne sous la propagation des ondes de cisaillement avec l’amplitude maximale de déplacement du « speckle » ultrasonore. La régression linéaire obtenue a été significative : fantômes in vitro : R2 = 0.98, p < 0,001 ; tumeurs ex-vivo : R2 = 0,56, p = 0,013 ; milieu environnant ex-vivo : R2 = 0,59, p = 0,009. En revanche, la régression linéaire n’a pas été aussi significative entre l’intensité moyenne sans propagation d’ondes de cisaillement et les propriétés mécaniques du milieu : fantômes in vitro : R2 = 0,07, p = 0,328, tumeurs ex-vivo : R2 = 0,55, p = 0,022 ; milieu environnant ex-vivo : R2 = 0,45, p = 0,047. Cette nouvelle approche peut fournir des informations supplémentaires à l’échographie quantitative statistique traditionnellement réalisée dans un cadre statique (c.-à-d., sans propagation d’ondes de cisaillement), par exemple, dans le contexte de l’imagerie ultrasonore en vue de la classification du cancer du sein.

Microcalcification evaluation in computer assisted diagnosis for digital mammography

In order to develop applications for z;isual interpretation of medical images, the early detection and evaluation of microcalcifications in digital mammograms is verg important since their presence is often associated with a high incidence of breast cancers. Accurate classification into benign and malignant groups would help improve diagnostic sensitivity as well as reduce the number of unnecessa y biopsies. The challenge here is the selection of the useful features to distinguish benign from malignant micro calcifications. Our purpose in this work is to analyse a microcalcification evaluation method based on a set of shapebased features extracted from the digitised mammography. The segmentation of the microcalcifications is performed using a fixed-tolerance region growing method to extract boundaries of calcifications with manually selected seed pixels. Taking into account that shapes and sizes of clustered microcalcifications have been associated with a high risk of carcinoma based on digerent subjective measures, such as whether or not the calcifications are irregular, linear, vermiform, branched, rounded or ring like, our efforts were addressed to obtain a feature set related to the shape. The identification of the pammeters concerning the malignant character of the microcalcifications was performed on a set of 146 mammograms with their real diagnosis known in advance from biopsies. This allowed identifying the following shape-based parameters as the relevant ones: Number of clusters, Number of holes, Area, Feret elongation, Roughness, and Elongation. Further experiments on a set of 70 new mammogmms showed that the performance of the classification scheme is close to the mean performance of three expert radiologists, which allows to consider the proposed method for assisting the diagnosis and encourages to continue the investigation in the sense of adding new features not only related to the shape

Self-medication and related terms: a conceptual reflection

Introduction: self-medication has become a growing practice in the world population. This phenomenon has been promoted as a form of self-care, with a positive impact on reducing spending in health systems, however there is concern about the potential negative effects related to inadequate diagnosis and treatment, which can affect health of individuals. This dual perception of the phenomenon is partly related to a variety of terms and concepts used, that make difficult its theoretical and empirical approach. Harmonization of the definitions involved is required in order to make adequate epidemiological comparisons. Objectives: analyze the concept of self medication and related terms from the definitions in the literature of the subject. Conclusions: in the last four decades it has been an evolution of both the wording and the definitions related to self-medication, from a very simple concept that implies the absence of prescription, to more complex ones that encompass very diverse behaviors, even those mediated by an act of prescription but not followed or not completed by the patient. Additionally the conceptual proliferation seen, justify the ordering of the terms related to self-medication. This paper presents a proposal for classification in four groups: a. self-medication, b. self care, c. pharmaceutical preparations and medicines, and d. prescription. This proposal should facilitate the exploration and analysis of the phenomenon and allow future theoretical approaches.

Genes related to sex steroids, neural growth, and social-emotional behavior are associated with autistic traits, empathy, and Asperger syndrome

Genetic studies of autism spectrum conditions (ASC) have mostly focused on the "low functioning" severe clinical subgroup, treating it as a rare disorder. However, ASC is now thought to be relatively common ( approximately 1%), and representing one end of a quasi-normal distribution of autistic traits in the general population. Here we report a study of common genetic variation in candidate genes associated with autistic traits and Asperger syndrome (AS). We tested single nucleotide polymorphisms in 68 candidate genes in three functional groups (sex steroid synthesis/transport, neural connectivity, and social-emotional responsivity) in two experiments. These were (a) an association study of relevant behavioral traits (the Empathy Quotient (EQ), the Autism Spectrum Quotient (AQ)) in a population sample (n=349); and (b) a case-control association study on a sample of people with AS, a "high-functioning" subgroup of ASC (n=174). 27 genes showed a nominally significant association with autistic traits and/or ASC diagnosis. Of these, 19 genes showed nominally significant association with AQ/EQ. In the sex steroid group, this included ESR2 and CYP11B1. In the neural connectivity group, this included HOXA1, NTRK1, and NLGN4X. In the socio-responsivity behavior group, this included MAOB, AVPR1B, and WFS1. Fourteen genes showed nominally significant association with AS. In the sex steroid group, this included CYP17A1 and CYP19A1. In the socio-emotional behavior group, this included OXT. Six genes were nominally associated in both experiments, providing a partial replication. Eleven genes survived family wise error rate (FWER) correction using permutations across both experiments, which is greater than would be expected by chance. CYP11B1 and NTRK1 emerged as significantly associated genes in both experiments, after FWER correction (P<0.05). This is the first candidate-gene association study of AS and of autistic traits. The most promising candidate genes require independent replication and fine mapping.

Knowledge about sports-related concussion: is the message getting through to coaches and trainers?

Aim The need for accurate diagnosis and appropriate return-to-play decisions following a concussion in sports has prompted the dissemination of guidelines to assist managing this condition. This study aimed to assess whether key messages within these guidelines are reflected in the knowledge of coaches and sports trainers involved in community sport. Methods An online knowledge survey was widely promoted across Australia in May–August 2012 targeting community Australian Football (AF) and Rugby League (RL) coaches and sports trainers. 260 AF coaches, 161 AF sports trainers, 267 RL coaches and 228 RL sports trainers completed the survey. Knowledge scores were constructed from Likert scales and compared across football codes and respondent groups. Results General concussion knowledge did not differ across codes but sports trainers had higher levels than did coaches. There were no significant differences in either concussion symptoms or concussion management knowledge across codes or team roles. Over 90% of respondents correctly identified five of the eight key signs or symptoms of concussion. Fewer than 50% recognised the increased risk of another concussion following an initial concussion. Most incorrectly believed or were uncertain that scans typically show damage to the brain after a concussion occurs. Fewer than 25% recognised, and >40% were uncertain that younger players typically take longer to recover from concussion than adults. Conclusions The key messages from published concussion management guidelines have not reached community sports coaches and sports trainers. This needs to be redressed to maximise the safety of all of those involved in community sport.