Do You Want to Hear the Bad News? The Value of Diagnostic Tests for Alzheimer's Disease.

OBJECTIVE: The diagnosis of Alzheimer's disease (AD) remains difficult. Lack of diagnostic certainty or possible distress related to a positive result from diagnostic testing could limit the application of new testing technologies. The objective of this paper is to quantify respondents' preferences for obtaining AD diagnostic tests and to estimate the perceived value of AD test information. METHODS: Discrete-choice experiment and contingent-valuation questions were administered to respondents in Germany and the United Kingdom. Choice data were analyzed by using random-parameters logit. A probit model characterized respondents who were not willing to take a test. RESULTS: Most respondents indicated a positive value for AD diagnostic test information. Respondents who indicated an interest in testing preferred brain imaging without the use of radioactive markers. German respondents had relatively lower money-equivalent values for test features compared with respondents in the United Kingdom. CONCLUSIONS: Respondents preferred less invasive diagnostic procedures and tests with higher accuracy and expressed a willingness to pay up to €700 to receive a less invasive test with the highest accuracy.

A novel diagnostic test detects a low frequency of the hemicentin Gln5345Arg variant among Northern Irish age related macular degeneration patients.

Purpose: Age related macular degeneration (AMD) is a common cause of severe vision loss. Identification of genes involved in AMD will facilitate early detection and ultimately help to identify pathways for treatment for this disorder. The A16,263G mutation in the HEMICENTIN-1 gene produces a non-conservative substitution of arginine for glutamine at codon 5345 which has been implicated in familial AMD. The aim of this study is to develop a rapid diagnostic assay for the detection of this mutation and to evaluate its frequency in a sample of AMD patients. Methods: A primer probe set was designed from exon 104 of the HEMICENTIN-1 gene to differentiate between mutant and wild type alleles. A region spanning the mutation was amplified by PCR using a LightCycler (Roche Diagnostic). The mutation was then detected by melt curve analysis of the hybrid formed between the PCR product and a specific fluorescent probe. The frequency of the mutation within the Northern Ireland population was evaluated by assaying 508 affected AMD patients, 25 possibly affected and 163 controls. Results: This assay clearly discriminates between the A16,263G mutant and wild type HEMICENTIN-1 alleles. The wild type sequence has a single base mismatch with the probe which decreases the stability of the hybrid, resulting in a lower TM (TM=51.27 °C) than that observed for the perfectly matched mutant allele (TM=59.9 °C). The mutant allele was detected in only one of the 696 subjects, an affected AMD patient. Conclusions: We describe a rapid assay for the genotyping of the Gln5345Arg mutation using real-time fluorescence PCR to facilitate rapid processing of samples through combined amplification and detection steps. These characteristics are suitable for a clinical setting where high throughput diagnostic procedures are required. The frequency of this mutation within the Northern Ireland population has been estimated at 0.2%, concurring with previous findings that this mutation is a rare variant associated with AMD. A rapid diagnostic assay will facilitate a reliable and convenient evaluation of the frequency of the Gln5345Arg mutation and its association with AMD within other populations.

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.

Lichtheimia Infection in a Lymphoma Patient: Case Report and a Brief Review of the Available Diagnostic Tools

We describe the case of a patient with a T-lymphoblastic lymphoma whose disseminated mucormycosis was diagnosed with delay, and we address the diagnostic and therapeutic decision-making process and review the diagnostic workup of patients with potential IFD. The diagnosis was delayed despite a suggestive radiological presentation of the patient's pulmonary lesion. The uncommon risk profile (T-lymphoblastic lymphoma, short neutropenic phases) wrongly led to a low level of suspicion. The diagnosis was also hampered by the lack of indirect markers for infections caused by Mucorales, the low sensitivity of both fungal culture and panfungal PCR, and the limited availability of species-specific PCR. A high level of suspicion of IFD is needed, and aggressive diagnostic procedures should be promptly initiated even in apparently low-risk patients with uncommon presentations. The extent of the analytical workup should be decided on a case-by-case base. Diagnostic tests such as the galactomannan and β-D-glucan test and/or PCR on biological material followed by sequencing should be chosen according to their availability and after evaluation of their specificity and sensitivity. In high-risk patients, preemptive therapy with a broad-spectrum mould-active antifungal agent should be started before definitive diagnostic findings become available.

Understanding Antenatal Genetics Services in Sri Lanka: Current Landscape of Screening and Diagnostic Services and Contextual Factors Influencing Their Availability and Uptake

Background: Too little information is available on Sri Lanka’s current capacity to provide community genetic services—antenatal genetic services in particular—to understand whether building that capacity could further improve and reduce disparity in maternal and child health. This qualitative research project seeks to gather information on congenital disorders, routine antenatal care, and the current state of antenatal screening testing services within that routine antenatal to assess the feasibility of and the need for scaling up antenatal genetics services in Sri Lanka. Methods: Nineteen key informant (KI) interviews were conducted with stakeholders in antenatal care and genetic services. Seven focus group discussions were held with a total of 56 Public Health Midwives (PHMs), the health workers responsible for antenatal care at the field level. Transcripts for all interviews and FGDs were analyzed for key themes, and themes were categorized to address the specific aims of the project. Results: Antenatal genetic services play a minor role in antenatal care, with screening and diagnostic procedures available in the private sector and paid for out-of-pocket. KIs and PHMs expect that demand for antenatal genetic services will increase as patients’ purchasing power and knowledge grow but note that prohibitive abortion laws limit the ability of patients to act on test results. Genetic services compete for limited financial and human resources in the free public health system, and inadequate information on the prevalence of congenital disorders limits the ability to understand whether funding for services related to those disorders should be increased. A number of alternatives to scaling up antenatal genetic services within the free health system might be better suited to the Sri Lankan structural and social context. Conclusions: Scaling up antenatal genetic services within the public health system is not feasible in the current financial, legal, and human resource context. Yet current availability and utilization patterns contribute to regional and economic disparities, suggesting that stasis will not bring continued improvements in maternal and child health. More information on the burden of congenital disorders is necessary to fully understand if and how antenatal genetic service availability should be increased in Sri Lanka, but even before that information is gathered, examination of policies for patient referral, termination of pregnancy, and government support for individuals with genetic disease are steps that might bring extend improvements and reduce disparity in maternal and child health.

Detection of a novel mutation in the CACNA1A gene

Familial hemiplegic migraine (FHM) is a rare autosomal dominant subtype of migraine with aura. It is divided into three subtypes FHM1, FHM2 and FHM3, which are caused by mutations in the CACNA1A, ATP1A2 and SCN1A genes respectively. As part of a regular diagnostic service, we investigated 168 patients with FHM symptoms. Samples were tested for mutations contained within the CACNA1A gene. Some tested samples (4.43%) showed an FHM1 mutation, with five of the mutations found in exon 5, one mutation in exon 16 and one in exon 17. Four polymorphisms were also detected, one of which occurred in a large percentage of samples (14.88%). The exon 16 2094G>A polymorphism, however, has been found to occur in healthy Caucasian control populations up to a frequency of 16% and is not considered to be significantly associated with FHM. A finding of significance, found in a single patient, was the detection of a novel mutation in exon 5 that results in a P225H change. The affected individual was an 8-year-old female. The exact phenotypic effect of this mutation is unknown, and further studies are needed to understand the pathophysiology of this mutation in FHM1. New information will allow for diagnostic procedures to be constantly updated, thus improving accuracy of diagnosis. It is possible that new information will also aid the development of new therapeutic agents for the treatment of FHM.

Experimental evidences in bearing diagnostics for traction system of high speed trains

Rolling element bearings are the most critical components in the traction system of high speed trains. Monitoring their integrity is a fundamental operation in order to avoid catastrophic failures and to implement effective condition based maintenance strategies. Generally, diagnostics of rolling element bearings is usually performed by analyzing vibration signals measured by accelerometers placed in the proximity of the bearing under investigation. Several papers have been published on this subject in the last two decades, mainly devoted to the development and assessment of signal processing techniques for diagnostics. The experimental validation of such techniques has been traditionally performed by means of laboratory tests on artificially damaged bearings, while their actual effectiveness in specific industrial applications, particularly in rail industry, remains scarcely investigated. This paper is aimed at filling this knowledge gap, by addressing the diagnostics of bearings taken from the service after a long term operation on the traction system of a high speed train. Moreover, in order to test the effectiveness of the diagnostic procedures in the environmental conditions peculiar to the rail application, a specific test-rig has been built, consisting of a complete full-scale train traction system, able to reproduce the effects of wheeltrack interaction and bogie-wheelset dynamics. The results of the experimental campaign show that suitable signal processing techniques are able to diagnose bearing failures even in this harsh and noisy application. Moreover, the most suitable location of the sensors on the traction system is proposed, in order to limit their number.

Patient doses in ct, dental cone beam ct and projection radiography in Finland, with emphasis on paediatric patients

Diagnostic radiology represents the largest man-made contribution to population radiation doses in Europe. To be able to keep the diagnostic benefit versus radiation risk ratio as high as possible, it is important to understand the quantitative relationship between the patient radiation dose and the various factors which affect the dose, such as the scan parameters, scan mode, and patient size. Paediatric patients have a higher probability for late radiation effects, since longer life expectancy is combined with the higher radiation sensitivity of the developing organs. The experience with particular paediatric examinations may be very limited and paediatric acquisition protocols may not be optimised. The purpose of this thesis was to enhance and compare different dosimetric protocols, to promote the establishment of the paediatric diagnostic reference levels (DRLs), and to provide new data on patient doses for optimisation purposes in computed tomography (with new applications for dental imaging) and in paediatric radiography. Large variations in radiation exposure in paediatric skull, sinus, chest, pelvic and abdominal radiography examinations were discovered in patient dose surveys. There were variations between different hospitals and examination rooms, between different sized patients, and between imaging techniques; emphasising the need for harmonisation of the examination protocols. For computed tomography, a correction coefficient, which takes individual patient size into account in patient dosimetry, was created. The presented patient size correction method can be used for both adult and paediatric purposes. Dental cone beam CT scanners provided adequate image quality for dentomaxillofacial examinations while delivering considerably smaller effective doses to patient compared to the multi slice CT. However, large dose differences between cone beam CT scanners were not explained by differences in image quality, which indicated the lack of optimisation. For paediatric radiography, a graphical method was created for setting the diagnostic reference levels in chest examinations, and the DRLs were given as a function of patient projection thickness. Paediatric DRLs were also given for sinus radiography. The detailed information about the patient data, exposure parameters and procedures provided tools for reducing the patient doses in paediatric radiography. The mean tissue doses presented for paediatric radiography enabled future risk assessments to be done. The calculated effective doses can be used for comparing different diagnostic procedures, as well as for comparing the use of similar technologies and procedures in different hospitals and countries.

MicroRNAs in breast cancer progression and DNA damage response

Os tumores de mama são caracterizados pela sua alta heterogeneidade. O câncer de mama é uma doença complexa, que possui o seu desenvolvimento fortemente influenciado por fatores ambientais, combinada a uma progressiva acumulação de mutações genéticas e desregulação epigenética de vias críticas. Alterações nos padrões de expressão gênica podem ser resultado de uma desregulação no controle de eventos epigenéticos, assim como, na regulação pós-transcricional pelo mecanismo de RNA de interferência endógeno via microRNA (miRNA). Estes eventos são capazes de levar à iniciação, à promoção e à manutenção da carcinogênese, como também ter implicações no desenvolvimento da resistência à terapia Os miRNAs formam uma classe de RNAs não codificantes, que durante os últimos anos surgiram como um dos principais reguladores da expressão gênica, através da sua capacidade de regular negativamente a atividade de RNAs mensageiros (RNAms) portadores de uma seqüencia parcialmente complementar. A importância da regulação mediada por miRNAs foi observada pela capacidade destas moléculas em regular uma vasta gama de processos biológicos incluindo a proliferação celular, diferenciação e a apoptose. Para avaliar a expressão de miRNAs durante a progressão tumoral, utilizamos como modelo experimental a série 21T que compreende 5 linhagens celulares originárias da mesma paciente diagnosticada com um tumor primário de mama do tipo ErbB2 e uma posterior metástase pulmonar. Essa série é composta pela linhagem obtida a partir do tecido normal 16N, pelas linhagens correspondentes ao carcinoma primário 21PT e 21NT e pelas linhagens obtidas um ano após o diagnóstico inicial, a partir da efusão pleural no sítio metastatico 21MT1 e 21MT2. O miRNAoma da série 21T revelou uma redução significativa nos níveis de miR-205 e nos níveis da proteina e-caderina e um enriquecimento do fator pró-metastático ZEB-1 nas células 21MT. Considerando a importância dos miRNAs na regulação da apoptose, e que a irradiação em diferentes espectros é comumente usada em procedimentos de diagnóstico como mamografia e na radioterapia, avaliamos a expressão de miRNAs após irradiação de alta e baixa energia e do tratamento doxorrubicina. Para os ensaios foram utilizados as linhagens não tumorais MCF-10A e HB-2 e as linhagens de carcinoma da mama MCF-7 e T-47D. Observou-se que raios-X de baixa energia são capazes de promover quebras na molécula do DNA e apoptose assim como, alterar sensivelmente miRNAs envolvidos nessas vias como o let-7a, miR-34a e miR-29b. No que diz respeito à resposta a danos genotóxicos, uma regulação positiva sobre a expressão de miR-29b, o qual em condições normais é regulado negativamente foi observada uma regulação positiva sobre miR-29b expressão após todos os tratamentos em células tumorais. Nossos resultados indicam que miR-29b é um possível biomarcador de estresse genotóxico e que miR-205 pode participar no potencial metastático das células 21T.

Diagnosing child sex abuse: A research challenge.

Child sex abuse increasingly is recognised as a societal problem that can no longer be ignored. In this paper definitions, prevalence, trends, assessment, and available diagnostic procedures are described and critically evaluated. It is argued that the lack of reliable diagnostic procedures remains one of the main difficulties in dealing effectively with the detrimental effects of CSA on the child or adult. The research challenge to find effective alternative procedures is outlined.

ESCMID* guideline for the diagnosis and management of Candida diseases 2012: developing European guidelines in clinical microbiology and infectious diseases.

The process to develop a guideline in a European setting remains a challenge. The ESCMID Fungal Infection Study Group (EFISG) successfully achieved this endeavour. After two face-to-face meetings, numerous telephone conferences, and email correspondence, an ESCMID task force (basically composed of members of the Society's Fungal Infection Study Group, EFISG) finalized the ESCMID diagnostic and management/therapeutic guideline for Candida diseases. By appreciating various patient populations at risk for Candida diseases, four subgroups were predefined, mainly ICU patients, paediatric, HIV/AIDS and patients with malignancies including haematopoietic stem cell transplantation. Besides treatment recommendations, the ESCMID guidelines provide guidance for diagnostic procedures. For the guidelines, questions were formulated to phrase the intention of a given recommendation, for example, outcome. The recommendation was the clinical intervention, which was graded by a score of A-D for the 'Strength of a recommendation'. The 'level of evidence' received a score of I-III. The author panel was approved by ESCMID, European Organisation for Research and Treatment of Cancer, European Group for Blood and Marrow Transplantation, European Society of Intensive Care Medicine and the European Confederation of Medical Mycology. The guidelines followed the framework of GRADE and Appraisal of Guidelines, Research, and Evaluation. The drafted guideline was presented at ECCMID 2011 and points of discussion occurring during that meeting were incorporated into the manuscripts. These ESCMID guidelines for the diagnosis and management of Candida diseases provide guidance for clinicians in their daily decision-making process.

Sudden cardiac death in forensic medicine - Swiss recommendations for a multidisciplinary approach.

Sudden cardiac death (SCD) is by definition unexpected and cardiac in nature. The investigation is almost invariably performed by a forensic pathologist. Under these circumstances the role of the forensic pathologist is twofold: (1.) to determine rapidly and efficiently the cause and manner of death and (2.) to initiate a multidisciplinary process in order to prevent further deaths in existing family members. If the death is determined to be due to "natural" causes the district attorney in charge often refuses further examinations. However, additional examinations, i.e. extensive histopathological investigations and/or molecular genetic analyses, are necessary in many cases to clarify the cause of death. The Swiss Society of Legal Medicine created a multidisciplinary working group together with clinical and molecular geneticists and cardiologists in the hope of harmonising the approach to investigate SCD. The aim of this paper is to close the gap between the Swiss recommendations for routine forensic post-mortem cardiac examination and clinical recommendations for genetic testing of inherited cardiac diseases; this is in order to optimise the diagnostic procedures and preventive measures for living family members. The key points of the recommendations are (1.) the forensic autopsy procedure for all SCD victims under 40 years of age, (2.) the collection and storage of adequate samples for genetic testing, (3.) communication with the families, and (4.) a multidisciplinary approach including cardiogenetic counselling.

Facteurs de risque modifiables associés à l’incidence, l’élimination et la prévalence d’infections intra-mammaires chez la vache laitière en lactation

La mammite subclinique est un problème de santé fréquent et coûteux. Les infections intra-mammaires (IIM) sont souvent détectées à l’aide de mesures du comptage des cellules somatiques (CCS). La culture bactériologique du lait est cependant requise afin d’identifier le pathogène en cause. À cause de cette difficulté, pratiquement toutes les recherches sur la mammite subclinique ont été centrées sur la prévalence d’IIM et les facteurs de risque pour l’incidence ou l’élimination des IIM sont peu connus. L’objectif principal de cette thèse était d’identifier les facteurs de risque modifiables associés à l’incidence, l’élimination et la prévalence d’IIM d’importance dans les troupeaux laitiers Canadiens. En premier lieu, une revue systématique de la littérature sur les associations entre pratiques utilisées à la ferme et CCS a été réalisée. Les pratiques de gestion constamment associées au CCS ont été identifiées et différentiées de celles faisant l’objet de rapports anecdotiques. Par la suite, un questionnaire bilingue a été développé, validé, et utilisé afin de mesurer les pratiques de gestion d’un échantillon de 90 troupeaux laitiers canadiens. Afin de valider l’outil, des mesures de répétabilité et de validité des items composant le questionnaire ont été analysées et une évaluation de l’équivalence des versions anglaise et française a été réalisée. Ces analyses ont permis d’identifier des items problématiques qui ont du être recatégorisés, lorsque possible, ou exclus des analyses subséquentes pour assurer une certaine qualité des données. La plupart des troupeaux étudiés utilisaient déjà la désinfection post-traite des trayons et le traitement universel des vaches au tarissement, mais beaucoup des pratiques recommandées n’étaient que peu utilisées. Ensuite, les facteurs de risque modifiables associés à l’incidence, à l’élimination et à la prévalence d’IIM à Staphylococcus aureus ont été investigués de manière longitudinale sur les 90 troupeaux sélectionnés. L’incidence d’IIM semblait être un déterminant plus important de la prévalence d’IIM du troupeau comparativement à l’élimination des IIM. Le port de gants durant la traite, la désinfection pré-traite des trayons, de même qu’une condition adéquate des bouts de trayons démontraient des associations désirables avec les différentes mesures d’IIM. Ces résultats viennent souligner l’importance des procédures de traite pour l’obtention d’une réduction à long-terme de la prévalence d’IIM. Finalement, les facteurs de risque modifiables associés à l’incidence, à l’élimination et à la prévalence d’IIM à staphylocoques coagulase-négatif (SCN) ont été étudiés de manière similaire. Cependant, afin de prendre en considération les limitations de la culture bactériologique du lait pour l’identification des IIM causées par ce groupe de pathogènes, une approche semi-Bayesienne à l’aide de modèles de variable à classe latente a été utilisée. Les estimés non-ajusté de l’incidence, de l’élimination, de la prévalence et des associations avec les expositions apparaissaient tous considérablement biaisés par les imperfections de la procédure diagnostique. Ce biais était en général vers la valeur nulle. Encore une fois, l’incidence d’IIM était le principal déterminant de la prévalence d’IIM des troupeaux. Les litières de sable et de produits du bois, de même que l’accès au pâturage étaient associés à une incidence et une prévalence plus basse de SCN.

L'évaluation systématique de la lombalgie selon les données probantes.

Les illustrations accompagnant le texte ont été dessinées par monsieur Mathieu Gagnon.

Diagnóstico imagiológico de cardiomiopatia hipertrófica

A hipertrofia cardíaca é uma alteração caracterizada pelo aumento do músculo cardíaco (miocárdio). Esta, pode ser primária e congénita, denominando-se cardiomiopatia hipertrófica felina (CMH) ou secundária a outra patologia, como no caso de estenoses valvulares, hipertiroidismo, entre outras. A CMH, é a cardiomiopatia mais frequente dos felinos e acredita-se que certas raças têm alguma predisposição genética. A sintomatologia é variável, podendo em alguns casos haver animais assintomáticos mesmo com casos avançados de doença. Outros sintomas como parésia dos membros posteriores devido a tromboembolismo aórtico, edema pulmonar e falha cardíaca congestiva são frequentemente encontrados. Quanto ao diagnóstico desta patologia, o método de eleição na prática clínica (in vivo) é o ecocardiograma, que vai detectar sobretudo uma hipertrofia da parede ventricular esquerda que quando comparada com valores pré-estabelecidos são suficientes para caracterizar uma hipertrofia, contudo não é específico para caracterizar a sua etiologia. Para uma hipertrofia cardíaca, ser denominada congénita/primária e portanto CMH, deve ser realizado um diagnóstico de exclusão para descartar as restantes patologias que podem causar esta alteração cardíaca (hipertiroidismo, hipertensão sistémica, estenose valvular). O modo-M e Doppler são fundamentais para um diagnóstico mais preciso.