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Fecal concentrations of pyruvate kinase isoform M2 (M2-PK) and calprotectin (FC) serve as biomarkers of inflammation of gastrointestinal mucosa. The value of M2-PK in discriminating between patients with viral and bacterial acute diarrhea (AD) is currently unknown. We analyzed M2-PK and FC concentrations in fifty hospitalized children with AD (29 of which were caused by rotavirus and 21 by Salmonella enteritidis) as well as 32 healthy subjects. There was no difference in the areas under the receiver operating characteristic curves plotted for the two tests in differentiating rotaviral from bacterial AD. The sensitivity and specificity of M2-PK at optimal cut-off (20 U/g) were 75.9% and 71.4%, respectively. M2-PK and FC had similar values in distinguishing between children with AD caused by rotavirus and Salmonella enteritidis. The performance of both tests in hospitalized patients did not meet the needs of everyday clinical practice. Moreover, no advantage of fecal tests over the measurement of CRP was documented.

Advances in understanding the biology of cancer, as well as advances in diagnostic technologies, such as the advent of affordable high-resolution DNA sequencing, have had a major impact on the approach to identification of specific alterations in a given patient's cancer that could be used as a basis for treatment selection, and hence the development of companion diagnostics. Although there are now several examples of successful development of companion diagnostics that allow identification of patients who will achieve the greatest benefit from a new therapeutic, the path to coapproval of a diagnostic test along with a new therapeutic is complex and often inefficient. This review and the accompanying articles examine the current state of companion diagnostic development in the United States and Europe from academic, industry, regulatory, and economic perspectives. See all articles in this CCR Focus section, "The Precision Medicine Conundrum: Approaches to Companion Diagnostic Co-development.", (©2014 AACR.)

Context: The College of American Pathologists surveys are the largest laboratory peer comparison programs in the world. These programs allow laboratories to regularly evaluate their performance and improve the accuracy of the patient test results they provide. Proficiency testing is offered twice a year to laboratories performing microsatellite instability testing. These surveys are designed to emulate clinical practice, and some surveys have more challenging cases to encourage the refinement of laboratory practices., Objective: This report summarizes the results and trends in microsatellite instability proficiency testing from participating laboratories from the inception of the program in 2005 through 2012., Design: We compiled and analyzed data for 16 surveys of microsatellite instability proficiency testing during 2005 to 2012., Results: The number of laboratories participating in the microsatellite instability survey has more than doubled from 42 to 104 during the 8 years analyzed. An average of 95.4% of the laboratories correctly classified each of the survey test samples from the 2005A through 2012B proficiency challenges. In the 2011B survey, a lower percentage of laboratories (78.4%) correctly classified the specimen, possibly because of overlooking subtle changes of microsatellite instability and/or failing to enrich the tumor content of the specimen to meet the limit of detection of their assay., Conclusions: In general, laboratories performed well in microsatellite instability testing. This testing will continue to be important in screening patients with colorectal and other cancers for Lynch syndrome and guiding the management of patients with sporadic colorectal cancer.

Since 2006, the US Food and Drug Administration, Congress, and other policymakers have explored the appropriate way to guarantee the clinical and analytical validity of laboratory-developed tests. In the past, the Association for Molecular Pathology has publicly urged the Food and Drug Administration to exercise caution in implementing regulatory changes that could potentially hinder innovation or interfere with the practice of medicine. In 2012, the Association for Molecular Pathology Professional Relations Committee chose to develop this paper with the goal of outlining the best methods for ensuring appropriate oversight and validation of molecular diagnostic procedures. At the conclusion of this process, the workgroup reaffirmed the Association's previous position that the Centers for Medicare and Medicaid Services Clinical Laboratory Improvement Amendments program can provide the appropriate level of oversight for the vast majority of diagnostic tests., (Copyright © 2014 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.)

Aims: Accurate assessment of inflammatory bowel disease (IBD) activity is the cornerstone of effective therapy. Fecal M2 isoform of pyruvate kinase (M2-PK) and fecal calprotectin (FC) are noninvasive markers of mucosal inflammation in IBD. The aim of this study was to compare performance of M2-PK and FC in assessment of pediatric ulcerative colitis (UC) and Crohn's disease (CD) severity and activity., Materials and Methods: 121 patients with IBD, including 75 with UC and 46 with CD were recruited. Control group consisted of 35 healthy children (HS). Patients were assigned to groups depending on disease severity and activity. M2-PK and calprotectin concentration were determined in stool samples using ELISA. Areas under receiver operating characteristic curves (AUC) for FC and M2-PK with cut-off level at which M2-PK specificity was matching FC specificity were calculated and compared., Results: Performance of M2-PK at identifying patients with IBD, UC and CD among HS was inferior to FC. The differences in AUC were respectively: -0.10 (95% confidence interval [CI] [-0.13-(-0.06)], p<0.0001), -0.14 (95% CI [-0.19-(-0.09)], p<0.0001) and -0.03 (95% CI [-0.05-(-0.001)], p<0.02). M2-PK was inferior to FC in discriminating patients with mild UC from those with HS (AUC difference -0.23, 95% CI [-0.31-(-0.15)], p<0.0001)., Conclusions: FC reflects pediatric IBD severity and activity better than M2-PK. This difference is particularly pronounced when identifying patients with mild UC and UC in remission.

Three-dimensional imaging of the mucosa of the lower lip and labial minor salivary glands is demonstrated in vivo using swept source optical coherence tomography (OCT) system at 1310 nm with modified interface. Volumetric data sets of the inner surface of the lower lip covering ~230 mm(2) field are obtained from patients with Sjögren's syndrome and a control group. OCT enables high-resolution visualization of mucosal architecture using cross-sectional images as well as en-face projection images. Comprehensive morphometry of the labial minor salivary glands is performed, and statistical significance is assessed. Statistically significant differences in morphometric parameters are found when subgroups of patients with Sjögren's syndrome are analyzed.

Introduction: Heart failure (HF) in the elderly is frequently associated with limited therapeutic options and may cause severe complications. Unfortunately, these patients are often excluded from clinical trials., Objectives: The aim of the study was to determine the relationship between HF, coexisting diseases, and use of medications in patients of advanced age living in nursing homes., Patients and Methods: The study group included 79 women and 21 men between 65 and 102 years of age living in 2 nursing homes. Information about the health status of patients was gathered from history and medical records. We conducted a physical examination and, in eligible cases, also an orthostatic test. Comorbidity was assessed using the age‑adjusted Charlson comorbidity index (ACCI)., Results: The prevalence of HF was 26%. The number of chronic diseases coexisting with HF was remarkably higher than the number of diseases among patients without HF (median, 6 [0-11] vs. 3 [0-8]; P <0.0001). The ACCI was also higher in the HF group compared with patients without HF (median, 7 [5-12] vs. 5.5 [2-9]; P <0.0001). Patients with HF took significantly more medications, although HF was treated according to the current guidelines in less than half of the cases., Conclusions: Our data revealed that HF is associated with significant morbidity and polypharmacy. There is a need for further research that would guide therapy of HF in elderly patients with limited life expectancy and multiple comorbidities as inhabitants of nursing homes. Nonetheless, the current treatment of nursing home patients with HF seems to be suboptimal.

Biliary tract cancers (gallbladder cancer, intra- and extra-hepatic cholangiocarcinoma, and selected periampullary cancers) accounted for 12,760 new cases of cancer in the USA in 2010. These tumors have a dismal prognosis with most patients presenting with advanced disease. Early, accurate diagnosis is essential, both for potential cure where possible and for optimal palliative therapy in all others. This review examines the currently available and emerging technologies for diagnosis and treatment of this group of diseases., (Copyright © 2012 Wiley Periodicals, Inc.)

Biliary tract cancers (gallbladder cancer, intra- and extra-hepatic cholangiocarcinoma and selected periampullary cancers) accounted for 12,760 new cases of cancer in the USA in 2010. These tumors have a dismal prognosis with most patients presenting with advanced disease. Early, accurate diagnosis is essential, both for potential cure where possible and for optimal palliative therapy in all others. This review examines the currently available and emerging technologies for diagnosis and treatment of this group of diseases., (Copyright © 2012 Wiley Periodicals, Inc.)

Frailty syndrome (FS) and cognitive impairment are associated with an increased risk of falls, disability, hospitalization and death. We investigated prognostic meaning of FS and cognitive impairment in persons ≥ 65 years, living in 2 nursing homes. Information about the health status of patients was gathered from history, medical documentation, test assessing FS, according to the Canadian Study of Health and Aging-Clinical Frailty Scale (CSHA-CFS) and the Mini-Mental State Examination (MMSE). The study group included 66 women and 20 men, between 66 and 101 years of age (mean ± S.D.=83.8 ± 8.3 years). The frequency of severe frailty (CSHA-CFS=7) among the elderly living in nursing homes was 34.9%, while severe cognitive impairment (MMSE<18) was present in 55.8%. Residents with severe FS and MMSE<18 consisted 33.7% of examined and 50.0% of those who died during 12-month follow-up, p<0.05. Individuals with severe FS and severe cognitive impairment (n=29) as compared to all other patients, were significantly less probable (59% vs. 79%, p=0.03) to survive one year. Neither frailty, nor dementia, nor severe FS or cognitive impairment when considered separately was associated with higher mortality rate. The risk assessment in severely disabled geriatric patients is best performed with measures of functional and cognitive function considered jointly, but not separately., (Copyright © 2011. Published by Elsevier Ireland Ltd.)

Loss-of-function defects in DNA mismatch repair (MMR), which manifest as high levels of microsatellite instability (MSI), occur in approximately 15% of all colorectal carcinomas (CRCs). This molecular subset of CRC characterizes patients with better stage-specific prognoses who experience no benefit from 5-fluorouracil chemotherapy. Most MMR-deficient (dMMR) CRCs are sporadic, but 15% to 20% are due to inherited predisposition (Lynch syndrome). High penetrance of CRCs in germline MMR gene mutation carriers emphasizes the importance of accurate diagnosis of Lynch syndrome carriers. Family-based (Amsterdam), patient/family-based (Bethesda), morphology-based, microsatellite-based, and IHC-based screening criteria do not individually detect all germline mutation carriers. These limitations support the use of multiple concurrent tests and the screening of all patients with newly diagnosed CRC. This approach is resource intensive but would increase detection of inherited and de novo germline mutations to guide family screening. Although CRC prognosis and prediction of 5-fluorouracil response are similar in both the Lynch and sporadic dMMR subgroups, these subgroups differ significantly with regard to the implications for family members. We recommend that new CRCs should be classified into sporadic MMR-proficient, sporadic dMMR, or Lynch dMMR subgroups. The concurrent use of MSI testing, MMR protein IHC, and BRAF c.1799T>A mutation analysis would detect almost all dMMR CRCs, would classify 94% of all new CRCs into these MMR subgroups, and would guide secondary molecular testing of the remainder., (Copyright © 2012 American Society for Investigative Pathology and the Association for Molecular Pathology. Published by Elsevier Inc. All rights reserved.)

Influenza virus subtyping has emerged as a critical tool in the diagnosis of influenza. Antiviral resistance is present in the majority of seasonal H1N1 influenza A infections, with association of viral strain type and antiviral resistance. Influenza A virus subtypes can be reliably distinguished by examining conserved sequences in the matrix protein gene. We describe our experience with an assay for influenza A subtyping based on matrix gene sequences. Viral RNA was prepared from nasopharyngeal swab samples, and real-time RT-PCR detection of influenza A and B was performed using a laboratory developed analyte-specific reagent-based assay that targets a conserved region of the influenza A matrix protein gene. FluA-positive samples were analyzed using a second RT-PCR assay targeting the matrix protein gene to distinguish seasonal influenza subtypes based on differential melting of fluorescence resonance energy transfer probes. The novel H1N1 influenza strain responsible for the 2009 pandemic showed a melting profile distinct from that of seasonal H1N1 or H3N2 and compatible with the predicted melting temperature based on the published novel H1N1 matrix gene sequence. Validation by comparison with the Centers for Disease Control and Prevention real-time RT-PCR for swine influenza A (novel H1N1) test showed this assay to be both rapid and reliable (>99% sensitive and specific) in the identification of the novel H1N1 influenza A virus strain.

The following report represents guidelines for competency-based fellowship training in Molecular Genetic Pathology (MGP) developed by the Association for Molecular Pathology Training and Education Committee and Directors of MGP Programs in the United States. The goals of the effort were to describe each of the Accreditation Council for Graduate Medical Education competencies as they apply to MGP fellowship training, provide a summary of goals and objectives, and recommend assessment tools. These guidelines are particularly pertinent to MGP training, which is a relatively new specialty that operates within a rapidly changing scientific and technological arena. It is hoped that this document will provide additional material for directors of existing MGP programs to consider for improvement of program objectives and enhancement of evaluation tools already in place. In addition, the guidelines should provide a valuable framework for the development of new MGP programs.

Background: Considerable interest has been focused on the design of the glenoid component used in total shoulder arthroplasty in order to reduce the risk of loosening. One design-related feature that has attracted attention is whether to use pegged or keeled cemented glenoid components. The main purpose of this study was to compare the fixation of cemented keeled glenoid components with that of cemented in-line pegged glenoid components., Methods: In a prospective randomized study, we compared the stability of cemented, all-polyethylene, keeled glenoid components and cemented, all-polyethylene, in-line three-pegged glenoid components by radiostereometric analysis. Twenty-seven shoulders in twenty-five patients with osteoarthritis (twenty-two shoulders had primary and five shoulders had secondary osteoarthritis) were included. There were sixteen women and nine men, and the mean age was sixty-four years. Radiostereometric analysis and conventional radiographs were carried out at five days, at four months, and at one and two years postoperatively., Results: The mean Constant and Murley score preoperatively and two years postoperatively was 25 and 70, respectively, for shoulders with the keeled glenoid component and 22 and 70 for the shoulders with a pegged component. No significant difference was detected between groups with regard to the average micromigration of the glenoid components at any of the time points. The average translation was <1 mm, while the median value was <0.3 mm at two years, with no significant difference between the different axes. In five shoulders (three with the keeled component and two with the pegged component), translation at two years was >1 mm. In fourteen shoulders (eight with the keeled and six with the pegged component), the rotation around one or several axes was >2 degrees . We were not able to detect any specific pattern with regard to movement for either type of component nor were we able to detect any difference between the two types of components in the way they migrated, if migration occurred., Conclusions: Cemented all-polyethylene keeled or in-line three-pegged glenoid components appear to have similar stability during the first two years after surgery. Studies with a longer follow-up period are needed to relate these findings to long-term clinical and radiographic outcomes.

Background: During 1978 and 1979, we initiated a prospective multicenter study to evaluate the results of nonoperative treatment of primary anterior shoulder dislocation. In the current report, we present the outcome after twenty-five years., Methods: Two hundred and fifty-five patients (257 shoulders) with an age of twelve to forty years who had a primary anterior shoulder dislocation were managed with immobilization (achieved by tying the arm to the torso with use of a bandage) or without immobilization. All 227 living patients (229 shoulders) completed the follow-up questionnaire, and 214 patients completed the Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire., Results: Ninety-nine (43%) of 229 shoulders had not redislocated, and seventeen (7%) redislocated once. Thirty-three recurrent dislocations had become stable over time (14.4%), and eighteen were considered to be still recurrent (7.9%). Sixty-two shoulders (27%) had undergone surgery for the treatment of recurrent instability. Immobilization after the primary dislocation did not change the prognosis. Only two of twenty-four shoulders with a fracture of the greater tuberosity at the time of the primary dislocation redislocated (p < 0.001). When shoulders with a fracture of the greater tuberosity were excluded, forty-four (38%) of 115 shoulders in patients who had been twelve to twenty-five years of age at the time of the original dislocation and sixteen (18%) of ninety shoulders in patients who had been twenty-six to forty years of age had undergone surgical stabilization. At twenty-five years, fourteen (23%) of sixty-two shoulders that had undergone surgical stabilization were in patients who subsequently had a contralateral dislocation, compared with seven (7%) of ninety-nine shoulders in patients in whom the index dislocation had been classified as solitary (p = 0.01). Gender and athletic activity did not appear to affect the redislocation rate; however, women had worse DASH scores than men did (p = 0.006)., Conclusions: After twenty-five years, half of the primary anterior shoulder dislocations that had been treated nonoperatively in patients with an age of twelve to twenty-five years had not recurred or had become stable over time.

Context: Molecular pathology is a rapidly growing area of laboratory medicine in which DNA and RNA are analyzed. The recent introduction of array technology has added another layer of complexity involving massive parallel analysis of multiple genes, transcripts, or proteins., Objective: As molecular technologies are increasingly implemented in clinical settings, it is important to bring uniformity to the way that test results are reported., Data Sources: The College of American Pathologists Molecular Pathology Resource Committee members summarize elements that are already common to virtually all molecular pathology reports, as set forth in the College of American Pathologists checklists used in the laboratory accreditation process. Consensus recommendations are proposed to improve report format and content, and areas of controversy are discussed. Resources are cited that promote use of proper gene nomenclature and that describe methods for reporting mutations, translocations, microsatellite instability, and other genetic alterations related to inherited disease, cancer, identity testing, microbiology, and pharmacogenetics., Conclusions: These resources and recommendations provide a framework for composing patient reports to convey molecular test results and their clinical significance to members of the health care team.

Context: The diagnosis of B-cell lymphoid malignancy can frequently be substantiated by detecting clonal immunoglobulin heavy chain (IGH) gene rearrangements, which is typically done by polymerase chain reaction (PCR) amplification and/or Southern blot analysis., Objective: To characterize current laboratory practice for the assessment of IGH rearrangements and to identify opportunities for improvement., Design: The data from the Molecular Oncology Proficiency Survey distributed to participating laboratories by the Molecular Pathology Committee of the College of American Pathologists from 1998 through 2003 were analyzed., Results: Thirty-nine proficiency survey specimens (29 positive and 10 negative for clonal IGH rearrangements) were distributed. For Southern blot analysis, 944 results were reported, with a successful response rate of 95%. For PCR detection, 2349 results were reported, with a successful response rate of 72%. A higher rate of successful responses by PCR was achieved using framework 3 primers in combination with other frameworks (82%) compared with framework 3 primers only (76%) and when fresh/frozen (72%) compared with paraffin-embedded (65%) tissues were analyzed., Conclusions: The performance of the participating laboratories was very good, by both Southern blot and PCR analysis. As expected, Southern blot analysis consistently detects a higher proportion of IGH rearrangements than PCR analysis. Further improvement and standardization of the IGH PCR assay is important if it is to replace Southern blot analysis as the standard method. Participation in this survey is a valuable tool for assessing laboratory performance and it directs our attention to areas where we may improve laboratory practice.

The resistance of Helicobacter pylori to antimicrobials, known to be increasing in many countries, is an important factor compromising the efficacy of eradication therapy. Therefore, our study aimed at analysing the current susceptibility status of H. pylori in Poland. A total of 337 H. pylori isolates were cultured from children (N=179) and adults (N=158) from various regions of the country from January 2001 to December 2004. All strains were susceptible to amoxicillin and tetracycline. The overall resistance to clarithromycin (CL) was 28%, but there were significant differences between the centres (ranging from 0% to 33%) and between child and adult isolates (28% versus 15%, respectively; P=0.01) for primary a resistance. Altogether, 46% of H. pylori isolates were resistant to metronidazole (MTZ) and 20% of isolates were simultaneously resistant to CL and MTZ.

Background: Nonoperative treatment is preferred for clavicular fractures irrespective of fracture and patient characteristics. However, recent studies indicate that long term results are not as favourable as previously considered., Methods: We have identified predictive risk factors associated with demographic and baseline data on clavicular fractures. In particular, the following symptoms were investigated: pain at rest, pain during activity, cosmetic defects, reduction in strength, paresthesia and nonunion until 6 months after injury. We followed 222 patients with a radiographically verified fracture of the clavicle, and who were at least 15 years of age, for 6 months., Results: Nonunion occurred in 15 patients (7%). 93 patients (42%) still had sequelae at 6 months. Displacement of more than one bone width was the strongest radiographic risk factor for symptoms and sequelae. Both radiographic projections used in this study (0 degree and 45 degrees tilted view) provided important information. A comminute fracture and higher age were associated with an increased risk of symptoms remaining at 6 months. Shortening was not predictive of functional outcome; nor was the site of the fracture in the clavicle., Interpretation: The risk for persistent symptoms following nonoperative treatment of clavicular fractures was far higher than expected. Based on these findings it seems reasonable to explore the possibly use of alternative treatment options including surgery for certain clavicular fracture types.

The aim of this long-term, prospective study was to identify risk factors associated with the outcome of clavicular fractures. During 1989 through 1991, 245 patients aged 15 years or older with a radiographically verified fracture of the clavicle were included. Clinical and radiographic examinations were standardized. Of the 208 patients seen at the 9- to 10-year follow-up, 112 (54%) had recovered completely whereas 96 (46%) still had sequelae. Nonunion occurred in 15 patients (7%). No bony contact was the strongest radiographic predictor for sequelae. Comminuted fractures with transverse fragments had a significantly increased risk for remaining symptoms, as did older patients, whereas there was no significant difference between sexes. Fracture location and shortening did not predict outcome except for cosmetic defects. Angulation of the fracture had no effect on cosmetic defects. Patients with predictive risk factors, such as fractures with no bony contact or displacement, especially if comminuted, and also elderly patients with fractures should be considered for more active treatment options.

A retrospective study was done to assess long-term results after surgery with the Eden-Hybbinette technique for unidirectional anterior glenohumeral instability. Between 1962 and 1976, 118 patients (119 shoulders) were treated. Eighty-seven patients answered a questionnaire. Of 119 shoulders, 77 were examined clinically and 74 radiographically a mean of 29 years after surgery. Forty-two were lost to follow-up. For 74% of shoulders, patients were satisfied, and for 26%, patients had some remaining discomfort. The most common reason for discomfort was persistent instability. The recurrence rate was 20%, although only 8 patients required reoperation. The mean time from surgery until redislocation was 15 months (range, 1-60 months). The mean Rowe shoulder score was 84 +/- 15 (range, 45-100), with 48 of 77 shoulders rated as excellent, 16 of 77 as good, 9 of 77 as fair, and 4 of 77 as poor. The Constant-Murley score averaged 85 +/- 14 (range, 20-100). Glenohumeral arthrosis was seen in 35 of 74 shoulders (47%). There was no significant difference between those with arthrosis and those without as far as age at first dislocation, age at surgery, or follow-up. Shoulders with arthrosis had a tendency to have reduced external rotation (P =.056) when compared with shoulders without radiologic changes. This study showed that most patients were satisfied with their shoulders. There was a high rate of radiologic arthrosis, but in most patients it caused limited restriction of movement as the only symptom.