Expert systems for clinical pathology reporting

* Conventional automated interpretative reporting systems use standard or "canned" comments for patient reports. These are result-specific and do not generally refer to the patient context. * Laboratory information systems (LIS) are limited in their application of patient-specific content of reporting. * Patient-specific interpretation requires extensive cross-referencing to other information contained in the LIS such as previous test results, other related tests, and clinical notes, both current and previous. * Expert systems have the potential to improve reporting quality by enabling patient-specific reporting in clinical laboratories.     

A statistical framework for the interpretation of mtDNA mixtures: forensic and medical applications

Background

Mitochondrial DNA (mtDNA) variation is commonly analyzed in a wide range of different biomedical applications. Cases where more than one individual contribute to a stain genotyped from some biological material give rise to a mixture. Most forensic mixture cases are analyzed using autosomal markers. In rape cases, Y-chromosome markers typically add useful information. However, there are important cases where autosomal and Y-chromosome markers fail to provide useful profiles. In some instances, usually involving small amounts or degraded DNA, mtDNA may be the only useful genetic evidence available. Mitochondrial DNA mixtures also arise in studies dealing with the role of mtDNA variation in tumorigenesis. Such mixtures may be generated by the tumor, but they could also originate in vitro due to inadvertent contamination or a sample mix-up.

Methods/Principal Findings

We present the statistical methods needed for mixture interpretation and emphasize the modifications required for the more well-known methods based on conventional markers to generalize to mtDNA mixtures. Two scenarios are considered. Firstly, only categorical mtDNA data is assumed available, that is, the variants contributing to the mixture. Secondly, quantitative data (peak heights or areas) on the allelic variants are also accessible. In cases where quantitative information is available in addition to allele designation, it is possible to extract more precise information by using regression models. More precisely, using quantitative information may lead to a unique solution in cases where the qualitative approach points to several possibilities. Importantly, these methods also apply to clinical cases where contamination is a potential alternative explanation for the data.

Conclusions/Significance

We argue that clinical and forensic scientists should give greater consideration to mtDNA for mixture interpretation. The results and examples show that the analysis of mtDNA mixtures contributes substantially to forensic casework and may also clarify erroneous claims made in clinical genetics regarding tumorigenesis.     

Two-step impression for atrophic mandibular ridge

BACKGROUND: The clinical difficulties encountered while treating edentulous patients with atrophic mandibular ridges are legion. Capturing tissue details while making an impression of a resorbed mandibular ridge poses a great clinical challenge. Extending the denture bases adequately to cover all of the available supporting tissues is one of the prime requisite. Surgical approach is necessary only when the patient is incapable of wearing a conventional denture. This article describes a technique of making an impression of an atrophic mandibular ridge by the use of monophase and light-bodied impression material where surgical options such as implants, vestibuloplasty or ridge augmentation may not be feasible. This procedure results in improved stability and retention of the denture base.     

Wildlife trade products available to U.S. military personnel serving abroad

Military personnel and affiliates have significant buying power that can influence demand for wildlife products. Purchase and transport of certain wildlife products violates United States laws, military regulations, and national country laws where the items were purchased. We surveyed military bazaars (n = 4) in Kabul, Afghanistan from June 2007 to March 2009 to observe which species were available to soldiers. In June 2008, we conducted a pilot survey of U.S. Army personnel (n = 371) stationed at Fort Drum, New York, USA, who had been deployed or stationed overseas including in Afghanistan and Iraq. Soldiers reported skins of wild felids and gray wolf Canis lupus as most commonly observed wildlife products available for sale in Afghanistan. Forty percent of respondents said they had either purchased or seen other members of the military purchase or use wildlife products. The U.S. military was willing to assist in curtailing supply and demand for wildlife products in order to protect soldiers from unknowingly breaking the law and to conserve wildlife in the countries where they serve. Regular, focused training of military personnel should be considered an important step to reducing trade in wildlife products by addressing both demand and market supply.     

Interpretation of skeletal variations for human risk assessment: delayed ossification and wavy ribs

Delayed (or incomplete) ossification of developing fetal bones and wavy ribs are some of the most common skeletal variations encountered in regulatory guideline developmental toxicity studies. Although they tend to be regarded as minor effects, they can be quite sensitive and consequently may influence the study lowest-observed-adverse-effect levels (LOAELs), and thus, impact classification, labeling, and risk assessment. In this study, we review the underlying mechanisms of these skeletal variations, evaluate different scenarios in which they have been observed, offer guidance for their interpretation, and comment on their use for risk assessment. Both minor delays in ossification and wavy ribs seem to be readily repairable via postnatal skeletal remodeling, are not mechanistically linked to malformation, and often are seen in the presence of maternal or fetal toxicity. As such, these minor variations would not generally be considered adverse in and of themselves but should be interpreted in the context of other maternal and fetal findings, information available on normal skeletogenesis patterns, mode of action of the test agent, and historical control incidence using a weight of evidence approach.     

Analysis of Your Professional Liability Insurance Policy

The most important lessons for the physician to learn in regard to his professional liability insurance coverage are the following:1. The physician should carefully read his professional liability policy and should secure the educated aid of his attorney and his insurance broker, if they are conversant with this field.2. He should particularly read the definition of coverage and carefully survey the exclusion clauses which may deny him coverage under certain circumstances.3. If the physician is in partnership or in a group, he should be certain that he has contingent partnership coverage.4. The physician should accept coverage only from an insurance carrier of sufficient size and stability that he can be sure his coverage will be guaranteed for “latent liability” claims as the years go along—certainly for his lifetime.5. The insurance carrier offering the professional liability policy should be prepared to offer coverages up to at least $100,000/$300,000.6. The physician should be assured that the insurance carrier has claims-handling personnel and legal counsel who are experienced and expert in the professional liability field and who are locally available for service.7. The physician is best protected by a local or state group program, next best by a national group program, and last, by individual coverage.8. The physician should look with suspicion on a cancellation clause in which his policy may be summarily cancelled on brief notice.9. The physician should not buy professional liability insurance on the basis of price alone; adequacy of coverage and service and a good insurance company for his protection should be the deciding factors.     

Refugee species: which historic baseline should inform conservation planning?

Understanding species' historical ranges can provide important information for conservation planning in the face of environmental change. Cromsigt et al. (this issue) comment on our recent European bison (Bison bonasus) range reconstruction, suggesting that bison were already 8000 years ago a refugee species (i.e. restricted to marginal habitat due to past human pressure) and that species distribution models (SDM) are generally of limited use for refugee species conservation. While we welcome this discussion, we find no evidence for the claim that human pressure prior to 8000 BP determined where bison occurred. More importantly, as human pressure is generally high and increasing, attempts to restore species across their former range may fail where the factors that relegated species into refugee status are still at play or where their optimal habitat has vanished. Identifying areas where human pressure is low and where refugee species have persisted over the last millennia is crucial, and SDM based on historical data are important for doing so. Refugee species suffer from the shifting baseline syndrome, but careful reality checks are needed and all available data should be considered before determining the baseline that should inform conservation planning.     

Structural biology of the aldo-keto reductase family of enzymes: catalysis and cofactor binding

The aldo-keto reductases (AKR) comprise a large family of oxidoreductases with importance to both health and industrial applications. The redox chemistry of the AKRs is dependent on NAD(P)H as a cofactor. Despite a wealth of structural and biochemical data relating to the interaction of AKRs with specific inhibitors, much less is known regarding the interactions with cofactor or substrate. In particular, while many X-ray structures are available for AKR/inhibitor complexes, they are only a few examples where apo- and holo- forms can be directly compared. Thus, while the role of the cofactor in the redox chemistry is generally understood, the details of the structural dynamics associated with cofactor binding are less clear. Likewise, the structural details of both cofactor and substrate specificity are limited. In this review, we focus on details of the structural biology and molecular dynamics associated with catalysis, cofactor, and substrate binding as elucidated for those AKRs for which apo- and holo- structures are available. Understanding such dynamics may identify a new direction in the design of specific inhibitors.     

Stoned

The stoned proteins, stoned A (STNA) and stoned B (STNB), are essential for normal vesicle trafficking in Drosophila melanogaster neurons, and deletion of the stoned locus is lethal. Although there is a growing body of research aimed at defining the roles of these proteins, particularly for STNB where homologues have now been identified in all multicellular species, their functions and mechanisms of action are not yet established. The two proteins are structurally unrelated, consistent with two distinct cellular functions. The evidence suggests a critical requirement for stoned proteins in recycling/regulation or specification of a competent synaptic vesicle pool. As stoned proteins may be specific to a particular pathway of endocytosis, studies of their function are likely to be valuable in distinguishing between the different mechanisms of membrane retrieval and their respective contributions to synaptic vesicle recycling, a subject of considerable scientific debate. In this review, we examine the published literature on stoned and comment on the available data, conclusions from these analyses and how they may relate to alternative models of vesicle cycling.     

Clinicians'' requirements for chemical sensors for in vivo monitoring: a multinational survey.

We report on a survey of senior clinicians in 11 countries which asked about what they see as the main areas where in vivo chemical sensors will be most useful in medicine, and about what their operating characteristics should be. This information may help those designing such sensors to match available and new technologies to clinical needs.     

Genetic polymorphism of alpha 2HS-glycoprotein.

A genetic polymorphism of the human serum glycoprotein, alpha 2HS-glycoprotein, can be recognized using isoelectric focusing in polyacrylamide, followed by silver-stain immunofixation. In a North American Caucasian population, two common alleles and one rare allele have been recognized, with frequencies as follows: AHSG*1: .6419, AHSG*2: .3535, and AHSG*3: .0046; polymorphism information content (PIC): .36. A black population from various islands of the Caribbean has the two most common alleles, plus a variant (B) not found in the white population. Allele frequencies in the blacks were: AHSG*1: .6901, AHSG*2: .2606, AHSG*B: .0493; PIC: .396. Family studies confirmed the allele designations. Alleles in both populations were in Hardy-Weinberg equilibrium. This polymorphism will be useful as a marker on chromosome 3q and for forensic studies. The serum concentration associated with AHSG*1 may be somewhat greater than that associated with AHSG*2. Differences between the allele products remained after removal of sialic acid from the glycoprotein with neuraminidase. The silver-stain immunofixation technique used for this polymorphism has wide application for the study of polymorphisms where the protein is present in low concentration or where only low titer antiserum is available.     

Analysis of stable states in global savannas – a response to Staver and Hansen

Staver & Hansen (2015, Global Ecology and Biogeography, doi: 10.1111/geb.12285) comment on our recent paper (Hanan et al., Global Ecology and Biogeography, 2014, 23 , 259–263) in which we argue that classification and regression tree methods used with remote sensing data to predict tree cover may bias inference of bifurcations in savanna vegetation communities. While we agree with several of their comments, we remain unconvinced that a remote sensing product based on an inherently discontinuous statistical approach can, or should, be used to test for discontinuities.     

消费者视角下用户评论对公众再生水消费意愿的影响机制——来自眼动实验的证据

再生水回用是解决水资源紧缺的有效途径,对缓解区域水资源紧缺和促进环境保护有重要的意义。公众作为再生水的直接使用者,其对再生水的态度是再生水回用项目实施的关键环节。再生水作为一种再生资源产品,价格是消费者使用再生水必须支付的货币成本,用户评论是消费者了解再生水,评估再生水质量的最直接途径。为了更加清晰的辨明价格、用户评论对公众再生水使用意愿的影响机制,以消费者为视角,模拟再生水购买场景,以刺激-机体-反应模型为理论框架,采用3(实验分组：高价格、中价格和低价格)×2(评论分类：质量评论和环境评论)的眼动追踪实验,探究公众再生水购买决策过程中的行为机理,并进一步分析不同价格下公众再生水使用行为的差异。研究结果表明：(1)公众再生水使用意愿在中价格组最高,低价格组次之,高价格组最低。(2)公众决策过程中,不论是再生水质量评价,还是环境评价,均偏向于注视消极评论内容。在低价格组中,公众对评论内容的关注程度最高,高价格组最低,中价格组中,公众更关心再生水对环境的影响。(3)消费过程中,公众对评论内容的关注会影响消费情绪从而影响再生水使用意愿。(4)再生水价格在公众消费决策过程中发挥重要的调节作用...     

Brain Magnetic Resonance in the Diagnostic Evaluation of Mitochondrial Encephalopathies

Brain MR imaging techniques are important ancillary tests in the diagnosis of a suspected mitochondrial encephalopathy since they provide details on brain structural and metabolic abnormalities. This is particularly true in children where non-specific neurologic symptoms are common, biochemical findings can be marginal and genetic defects may be not discovered. MR imaging modalities include conventional, or structural, imaging (MRI) and functional, or ultrastructural, imaging (spectroscopy, MRS; diffusion, DWI-ADC; perfusion, DSCI––ASL). Among them MRI and MRS are the main tools for diagnosis and work up of MD, and this review will focus mainly on them. The MRI findings of MD are very heterogeneous, as they depend on the metabolic brain defects, age of the patient, stage and severity of the disease. No correlation has been found between genetic defects and neuroimaging picture; however, some relationships between MR findings and clinical phenotypes may be identified. Different combinations of MRI signal abnormalities are often encountered but the most common findings may be summarized into three main MR patterns: (i) non-specific; (ii) specific; (iii) leukodystrophic-like. Regarding the functional MR techniques, only proton MRS plays an important role in demonstrating an oxidative metabolism impairment in the brain since it can show the accumulation of lactate, present as a doublet peak at 1.33 ppm. Assessment of lactate should be always performed on brain tissue and on the ventricular cerebral spinal fluid. As for MRI, metabolic MRS abnormalities can be of different types, and two distinct patterns can be recognized: non-specific and specific. The specific metabolic profiles, although not frequent to find, are highly pathognomonic of MD. The un-specific metabolic profiles add value to structural images in allowing to define the lesion load and to monitor the response to therapy trials.     

Preventive therapies: weighing the pros and cons.

The author comments on three issues raised by Dr. Kenneth G. Marshall in his series on the benefits and harms of preventive therapies, which begins in this issue on page 1493. First, because the method by which the results of clinical trials are presented markedly affects the perception of those results some measure of absolute benefit and harm must be used when the results of clinical trials are presented. Second, there is increasing interest in decision aids as a means of helping patients to understand evidence and make therapeutic choices. It is important that these aids undergo rigorous testing before they are adopted for common use. Third, evidence-based clinical practice guidelines are a welcome resource for busy clinicians. However, physicians and patients should bear in mind that interpretations of the available evidence can vary, leading to different conclusions about the appropriateness of preventive therapies.     

Rapid Genotyping of Alpha 1 Antitrypsin Deletion Mutation (PI*Mmalton) Using Bi-directional PCR Allele-specific Amplification

Alpha 1 antitrypsin deficiency (AATD) is a well recognized genetic risk factor for pulmonary disease and less common liver disease. The two most common deficiency alleles worldwide PI*S and PI*Z can be easily detected using several molecular methods. However, there are at least 30 other AATD variants, which are only detectable by alpha 1 antitrypsin (AAT) gene sequencing and, therefore, seem to be more under-recognized than the PI*S and PI*Z alleles. PI*Mmalton is the most frequent AATD variant in different regions of the Southern Mediterranean basin countries, where its prevalence seems to prevail over PI*S and PI*Z. In this work, we report the development of a simple PCR-based analysis designed for the detection of the PI*Mmalton deficiency alleles using two specific primers. A one-tube reaction enables the distinction between the different genotypes. This reliable, easy, fast, and low-cost technique might be useful for laboratories involved in the study of AATD-related diseases, especially those of the Southern Mediterranean basin area with modest budget or where sophisticated equipment is not available. This will allow larger targeted screening for PI*Mmalton in order to better understand this mutation epidemiology and its origin.     

Recommendations for Reporting and Flagging of Reference Limits on Pathology Reports

Surveys by the RCPA PITUS Project have shown significant variations in report rendering between Australasian Pathology Providers. The same project collected anecdotal evidence that this variation has led to the misunderstanding and misreading of results - a clinical safety issue. Recommendations are given for the rendering of reference limits on pathology reports, determination and rendering of result flags, and the documentation of sub-population partitions for reference intervals. These recommendations apply equally for paper or electronic reporting, but should not limit the use of novel techniques within electronic reports to convey additional meaning. PITUS Working Group 4 will publish draft recommendations for peer review and comment in relation to the above in the second half of 2014.     

Cost savings through use of the Internet: a case study

Introduction of a LIMS can bring immediate cost-savings and efficiency improvements to a Laboratory. However, peripheral problems can often prevent the full benefits from being realised. For example, in our case, reports generated on paper are subject to postal delays. They are also sent initially to an intermediary, for comments and recommendations to be added (this often means re-typing the report) causing a further delay. Within the Laboratory itself, telephone requests from clients for information on sample progress can consume a considerable amount of staff time. We have addressed both of these problems by use of the Internet. An e-mailing program takes ASCII reports produced from the LIMS and attaches them automatically to e-mail messages. Each can be configured to the specific requirements of the recipient (e.g., the use of encryption, digital signatures, and the document format). World-Wide-Web access to appropriate LIMS databases allows clients to determine progress of samples without involving Laboratory personnel. Read-only access is available to a limited sub-set of data determined by the LIMS manager. Both applications have been created in portable languages, in a way that is suitable for many different environments.     

Umbilical metastases: current viewpoint

BACKGROUND: Umbilical metastases from a malignant neoplasm, also termed Sister Mary Joseph's nodule, are not commonly reported in the English literature, and they have usually been considered as a sign of a poor prognosis for the patient. The present article reports on the current view point on umbilical metastasis besides discussing the epidemiology, clinical presentation, pathophysiology and treatment. METHOD: A search of Pubmed was carried out using the term 'umblic*' and 'metastases' or metastasis' revealed no references. Another search was made using the term "Sister Joseph's nodule" or sister Joseph nodule" that revealed 99 references. Of these there were 14 review articles, however when the search was limited to English language it yielded only 20 articles. Articles selected from these form the basis of this report along with cross references. RESULTS: The primary lesions usually arise from gastrointestinal or genitourinary tract malignancies and may be the presenting symptom or sign of a primary tumour in an unknown site. CONCLUSION: A careful evaluation of all umbilical lesions, including an early biopsy if appropriate, is recommended. Recent studies suggest an aggressive surgical approach combined with chemotherapy for such patients may improve survival.     

Modification of coevolved insect–plant interactions by an exotic plant pathogen

New Perspectives is intended to allow the communication of comments, viewpoints, and speculative interpretation of issues in ecology pertinent to entomology. Comments, viewpoints, or suggestions arising from published papers intended to fuel discussion and debate are also welcome. Contributions should be as concise as possible, normally not exceeding two thousand words. Formal research reports will not be acceptable, but summarised novel data, suitably supported by statistics, may be allowed.