Sandra Fischer

Handheld Computing in Medicine

Handheld computers have become a valuable and popular tool in various fields of medicine. A systematic review of articles was undertaken to summarize the current literature regarding the use of handheld devices in medicine. A variety of articles were identified, and relevant information for various medical fields was summarized. The literature search covered general information about handheld devices, the use of these devices to access medical literature, electronic pharmacopoeias, patient tracking, medical education, research, business management, e-prescribing, patient confidentiality, and costs as well as specialty-specific uses for personal digital assistants (PDAs). The authors concluded that only a small number of articles provide evidence-based information about the use of PDAs in medicine. The majority of articles provide descriptive information, which is nevertheless of value. This article aims to increase the awareness among physicians about the potential roles for handheld computers in medicine and to encourage the further evaluation of their use.

Canadian survey of the use of sedatives, analgesics, and neuromuscular blocking agents in critically ill patients.

Objectives:To characterize the perceived utilization of sedative, analgesic, and neuromuscular blocking agents, the use of sedation scales, algorithms, and daily sedative interruption in mechanically ventilated adults, and to define clinical factors that influence these practices. Design:Cross-sectional mail survey. Participants:Canadian critical care practitioners. Measurements and Main Results:A total of 273 of 448 eligible physicians (60%) responded. Respondents were well distributed with regard to age, years of practice, specialist certification, size of intensive care unit and hospital, and location of practice. Twenty-nine percent responded that a protocol/care pathway/guideline for the use of sedatives or analgesics is currently in use in their intensive care unit. Daily interruption of continuous infusions of sedatives or analgesics is practiced by 40% of intensivists. A sedation scoring system is used by 49% of respondents. Of these, 67% use the Ramsay scale, 10% use the Sedation-Agitation Scale, 9% use the Glasgow Coma Scale, and 8% use the Motor Activity Assessment Scale. Only 3.7% of intensivists use a delirium scoring system in their intensive care units. Only 22% of respondents currently have a protocol for the use of neuromuscular blocking agents in their intensive care unit, and 84% of respondents use peripheral nerve stimulation for monitoring. In patients receiving neuromuscular blocking agents for >24 hrs, 63.7% of respondents discontinue the neuromuscular blocking agent daily. Intensivists working in university-affiliated hospitals are more likely to employ a sedation protocol and scale (p < .0001), as are intensivists working in larger intensive care units (≥15 beds, p < .01). Intensivists with anesthesiology training (and no formal critical care training) are more likely to use a protocol and sedation scale, and critical care–trained intensivists are more likely to use daily interruption. Younger physicians (<40 yrs) are more likely to practice daily interruption (p = .0092). Conclusions:There is significant variation in critical care sedation, analgesia, and neuromuscular blockade practice. Given the potential effect of practices regarding these medications on patient outcome, future research and educational efforts related to evidence-based protocols for the use of these agents in mechanically ventilated patients might be worthwhile.

Intestinal microbiota in patients with nonalcoholic fatty liver disease

Despite evidence that the intestinal microbiota (IM) is involved in the pathogenesis of obesity, the IM composition of patients with nonalcoholic fatty liver disease (NAFLD) has not been well characterized. This prospective, cross‐sectional study was aimed at identifying differences in IM between adults with biopsy‐proven NAFLD (simple steatosis [SS] or nonalcoholic steatohepatitis [NASH]) and living liver donors as healthy controls (HC). Fifty subjects were included: 11 SS, 22 NASH, and 17 HC. One stool sample was collected from each participant. Quantitative real‐time polymerase chain reaction was used to measure total bacterial counts, Bacteroides/Prevotella (herein referred to as Bacteroidetes), Clostridium leptum, C. coccoides, bifidobacteria, Escherichia coli and Archaea in stool. Clinical and laboratory data, food records, and activity logs were collected. Patients with NASH had a lower percentage of Bacteroidetes (Bacteroidetes to total bacteria counts) compared to both SS and HC (P = 0.006) and higher fecal C. coccoides compared to those with SS (P = 0.04). There were no differences in the remaining microorganisms. As body mass index (BMI) and dietary fat intake differed between the groups (P < 0.05), we performed linear regression adjusting for these variables. The difference in C. coccoides was no longer significant after adjusting for BMI and fat intake. However, there continued to be a significant association between the presence of NASH and lower percentage Bacteroidetes even after adjusting for these variables (P = 0.002; 95% confidence interval = −0.06 to −0.02).

Baseline Ductopenia and Treatment Response Predict Long-Term Histological Progression in Primary Biliary Cirrhosis

OBJECTIVES:Laboratory and pathological predictors of future histological progression in primary biliary cirrhosis (PBC) are needed for routine practice and clinical trials. We sought to develop clinically meaningful markers for those with predominantly early disease at risk of progressive liver damage.METHODS:Patients with PBC (n=69) with a follow-up liver biopsy performed approximately 10 years after initial histological diagnosis were identified and reviewed.RESULTS:Histological progression in the stage of fibrosis observed in paired liver biopsies from the same patient was associated with the absence of biochemical response to ursodeoxycholic acid (UDCA) at 2 years: alkaline phosphatase (ALP) >1.67 × ULN (upper limit of normal) (P=0.001, odds ratio (OR) 12.14, 95% confidence interval (CI) 2.69–54.74) when defined as an increase in one stage and ALP > 1.76 × ULN (P=0.03, OR 5.07, 95% CI 1.17–21.95) when defined as an increase in two stages. Ductopenia (>50% loss), as formally evaluated through blinded biopsy review of liver tissue obtained at initial diagnosis in a subset of 34 patients, predicted histological progression (P=0.012), along with biochemical response to UDCA (P=0.002). The presence of interface hepatitis in the same biopsies did not.CONCLUSIONS:Patients with PBC who fail to show a biochemical response to UDCA or who have ductopenia on baseline biopsy progress histologically during extended follow-up. Such patients may benefit from novel treatments, with our exploratory data providing a means of identifying these individuals early in their disease.

Identification of Driver Genes in Hepatocellular Carcinoma by Exome Sequencing

Genetic alterations in specific driver genes lead to disruption of cellular pathways and are critical events in the instigation and progression of hepatocellular carcinoma (HCC). As a prerequisite for individualized cancer treatment, we sought to characterize the landscape of recurrent somatic mutations in HCC. We performed whole‐exome sequencing on 87 HCCs and matched normal adjacent tissues to an average coverage of 59×. The overall mutation rate was roughly two mutations per Mb, with a median of 45 nonsynonymous mutations that altered the amino acid sequence (range, 2‐381). We found recurrent mutations in several genes with high transcript levels: TP53 (18%); CTNNB1 (10%); KEAP1 (8%); C16orf62 (8%); MLL4 (7%); and RAC2 (5%). Significantly affected gene families include the nucleotide‐binding domain and leucine‐rich repeat‐containing family, calcium channel subunits, and histone methyltransferases. In particular, the MLL family of methyltransferases for histone H3 lysine 4 were mutated in 20% of tumors. Conclusion: The NFE2L2‐KEAP1 and MLL pathways are recurrently mutated in multiple cohorts of HCC. (Hepatology 2013;58:1693–1702)

IgG4-related Sclerosing Disease: Autoimmune Pancreatitis and Extrapancreatic Manifestations

Autoimmune pancreatitis is the pancreatic manifestation of IgG4-related sclerosing disease, which recently was recognized as a distinct disease entity. Numerous extrapancreatic organs, such as the bile ducts, gallbladder, kidneys, retroperitoneum, thyroid, salivary glands, lung, mediastinum, lymph nodes, and prostate may be involved, either synchronously or metachronously. Most cases of autoimmune pancreatitis are associated with elevated serum IgG4 levels; extensive IgG4-positive plasma cells; and infiltration of lymphocytes into various organs, which leads to fibrosis. There are several established diagnostic criteria systems that are used to diagnose autoimmune pancreatitis and that rely on a combination of imaging findings of the pancreas and other organs, serologic findings, pancreatic histologic findings, and response to corticosteroid therapy. It is important to recognize multiorgan involvement of IgG4-related sclerosing disease and be familiar with its clinical and imaging features because it demonstrates a favorable response to treatment.

Cell-Type Specific Gene Expression Signature in Liver Underlies Response to Interferon Therapy in Chronic Hepatitis C Infection

BACKGROUND & AIMS Chronic hepatitis C virus (CHC) infection is treated with interferon/ribavirin, but only a subset of patients respond. Treatment nonresponders have marked pretreatment up-regulation of a subset of interferon stimulated genes (ISGs) in their livers, including ISG15. We here study how the nonresponder gene expression phenotype is influenced by clinical factors and uncover the cellular basis of the phenotype through ISG15 protein expression. METHODS Seventy-eight CHC patients undergoing treatment were classified by clinical (gender, viral genotype, viral load, treatment outcome) and histologic (inflammation, fibrosis) factors and subjected to gene expression profiling on their pretreatment liver biopsies. An analysis of variance model was used to study the influence of individual factors on gene expression. ISG15 immunohistochemistry was performed on a subset of 31 liver biopsy specimens. RESULTS One hundred twenty-three genes were differentially expressed in the 78 CHC livers when compared with 20 normal livers (P < .001; fold change, > or =1.5-fold). Of genes influenced by a single factor, genotype (1 vs 2/3) influenced more genes (17) than any other variable; when treatment outcome was included in the analysis, this became the predominant influence (24 genes), and the effect of genotype was diminished. Treatment response was linked to cell-specific activation patterns: ISG15 protein up-regulation was more pronounced in hepatocytes in treatment nonresponders but in Kuppfer cells in responders. CONCLUSIONS Genotype is a surrogate marker for the nonresponder phenotype. This phenotype manifests as differential gene expression and is driven by activation of different cell types: hepatocytes in treatment nonresponders and macrophages in treatment responders.

Application of Immunohistochemistry to Thyroid Neoplasms

CONTEXT Thyroid lesions with nodular architecture and follicular pattern of growth often pose difficulties in accurate diagnosis during the assessment of cytologic and histologic specimens. The diagnosis of follicular neoplasm on cytology or of follicular tumor of uncertain malignant potential on histology is likely to cause confusion among clinicians and delay effective management of these lesions. Occasionally, thyroid tumors represent unusual or metastatic lesions and their accurate diagnosis requires immunohistochemical confirmation. OBJECTIVE To review the literature on the applications of immunohistochemistry in the differential diagnosis of thyroid tumors. DATA SOURCES Relevant articles indexed in PubMed (National Library of Medicine) between 1976 and 2006. CONCLUSIONS Our review supports the use of ancillary techniques involving a panel of antibodies suitable for immunohistochemistry and molecular analysis in the assessment of thyroid nodules. These tools can improve diagnostic accuracy when combined with standard morphologic criteria.

Hepatic Cell–Type Specific Gene Expression Better Predicts HCV Treatment Outcome Than IL28B Genotype

BACKGROUND & AIMS Cell-type specific expression patterns of hepatic interferon-stimulated genes (ISGs) and single nucleotide polymorphisms (SNPs) near the IL28B gene are associated with response to interferon-based therapy in patients with chronic hepatitis C virus (HCV) infection. It is not known how the IL28B genotype influences the ISG expression pattern and which is a better predictor of treatment response. METHODS Patients at the Toronto Western Hospital Liver Centre with known outcome to interferon-based treatment for HCV infection were evaluated. Analysis included hepatic gene expression profile using complementary DNA microarrays, genotype at the IL28B SNP rs12979860, and immunostaining for human myxovirus A protein 1 (MxA) in hepatocytes and macrophages. RESULTS The level of ISG immunostaining in hepatic macrophages correlated inversely with that of hepatocytes and was strongly associated with treatment outcome. Gene expression profiles and the IL28B genotype were associated with treatment response, but only absence of MxA staining in macrophages accurately predicted nonresponse to treatment. The positive predictive value (PPV) of the IL28B genotype was 94% and the negative predictive value (NPV) was 51% (n = 209). For messenger RNA expression, the PPV was 94% and the NPV was 54% (n = 65). For detection of MxA in macrophages, the PPV was 60% and the NPV was 98% (n = 110). Of 53 patients with undetectable macrophage MxA staining, only one had a sustained virologic response. IL28B genotype was strongly associated with cell-type specific staining for MxA. There was a stepwise increase in macrophage staining and decrease in hepatocyte staining from the TT (lack of response) to CC SNP (associated with response) in IL28B. By logistic regression, after controlling for the presence of macrophage MxA staining, the IL28B genotype was no longer associated with treatment response. CONCLUSIONS The cell-type-specific expression pattern of ISGs varies among patients with different IL28B genotypes and is a strong predictor of response to interferon-based treatment.

Altered hepatic gene expression in nonalcoholic fatty liver disease is associated with lower hepatic n‐3 and n‐6 polyunsaturated fatty acids

In nonalcoholic fatty liver disease, hepatic gene expression and fatty acid (FA) composition have been reported independently, but a comprehensive gene expression profiling in relation to FA composition is lacking. The aim was to assess this relationship. In a cross‐sectional study, hepatic gene expression (Illumina Microarray) was first compared among 20 patients with simple steatosis (SS), 19 with nonalcoholic steatohepatitis (NASH), and 24 healthy controls. The FA composition in hepatic total lipids was compared between SS and NASH, and associations between gene expression and FAs were examined. Gene expression differed mainly between healthy controls and patients (SS and NASH), including genes related to unsaturated FA metabolism. Twenty‐two genes were differentially expressed between NASH and SS; most of them correlated with disease severity and related more to cancer progression than to lipid metabolism. Biologically active long‐chain polyunsaturated FAs (PUFAs; eicosapentaenoic acid + docosahexaenoic acid, arachidonic acid) in hepatic total lipids were lower in NASH than in SS. This may be related to overexpression of FADS1, FADS2, and PNPLA3. The degree and direction of correlations between PUFAs and gene expression were different among SS and NASH, which may suggest that low PUFA content in NASH modulates gene expression in a different way compared with SS or, alternatively, that gene expression influences PUFA content differently depending on disease severity (SS versus NASH). Conclusion: Well‐defined subjects with either healthy liver, SS, or NASH showed distinct hepatic gene expression profiles including genes involved in unsaturated FA metabolism. In patients with NASH, hepatic PUFAs were lower and associations with gene expression were different compared to SS. (Hepatology 2015;61:1565–1578)