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Abstract: To evaluate the potential of using surficial shell accumulations for paleoenvironmental studies, an extensive time series of individually dated specimens of the marine infaunal bivalve mollusk Semele casali was assembled using amino acid racemization (AAR) ratios (n=270) calibrated against radiocarbon ages (n=32). The shells were collected from surface sediments at multiple sites across a sediment-starved shelf in the shallow sub-tropical São Paulo Bight (São Paulo State, Brazil). The resulting 14C-calibrated AAR time series, one of the largest AAR datasets compiled to date, ranges from modern to 10,307calyr BP, is right skewed, and represents a remarkably complete time series: the completeness of the Holocene record is 66% at 250-yr binning resolution and 81% at 500-yr binning resolution. Extensive time-averaging is observed for all sites across the sampled bathymetric range indicating long water depth-invariant survival of carbonate shells at the sediment surface with low net sedimentation rates. Benthic organisms collected from active depositional surfaces can provide multi-millennial time series of biomineral records and serve as a source of geochemical proxy data for reconstructing environmental and climatic trends throughout the Holocene at centennial resolution. Surface sediments can contain time-rich shell accumulations that record the entire Holocene, not just the present. [Copyright &y& Elsevier]

The interpretations of the Wallace site offered by Huffman and Earley are invalid. The site is not Upper Republican in affiliation, the structural remains in it do not support the interpretations made, and the proposed correspondences to Pawnee cosmology are based on unjustified assumptions. [ABSTRACT FROM AUTHOR]

Background: Population-, assay-, and trimester-specific reference intervals for thyroid function tests are necessary to assess thyroid status accurately and manage thyroid disease throughout pregnancy. This study's objective was to verify if the manufacturer's recommended trimester-specific reference intervals for thyroid tests and the American Thyroid Association's recommended total thyroxine (TT4) pregnancy reference intervals were verifiable and appropriate for use in the authors' multicultural population. Methods: Blood samples were obtained from the following sources: stored frozen surplus blood from women undergoing routine aneuploidy screening (first- and second-trimester samples, n = 274), women participating in an observational cohort study (second- and third-trimester samples, n = 135), and blood collected from women presenting for assessment to the labor and delivery ward (third-trimester samples, n = 35). Exclusions included thyroid medication or disease and positive thyroid peroxidase antibodies (anti-TPO). Samples were analyzed for thyrotropin (TSH), free T4 (fT4), free triiodothyronine (fT3), TT4, and anti-TPO using the Roche Cobas 8000 Modular e602 electrochemiluminescence immunoassay. Results: Nine percent of the aneuploidy screening samples were excluded prior to thyroid testing due to maternal use of thyroid medication. Six percent of analyzed samples were excluded: 5.9% with positive anti-TPO and one with a TSH >10 mIU/L. The manufacturer's recommended trimester-specific reference intervals for TSH were not verified by described standardized methods. Therefore, 95th percentile reference intervals were determined using a minimum number of samples. Reference intervals for TSH and fT4 were as follows: 9–12 weeks, 0.18–2.99 mIU/L and 11–19.2 pmol/L; second trimester, 0.11–3.98 mIU/L and 10.5–18.2 pmol/L; and third trimester, 0.48–4.71 mIU/L and 9.0–16.1 pmol/L, respectively. The TT4 reference interval after 19 weeks' gestation was 77–186 nmol/L. Conclusions: This study provides a simple approach to verify or establish trimester-specific thyroid function reference intervals in local populations. The TT4 reference interval was lower than the interval proposed by the American Thyroid Association, suggesting the need for further study of TT4 in pregnancy and reliance on locally established fT4 reference intervals after 19 weeks, especially when there are no equivalent reference intervals for TT4. [ABSTRACT FROM AUTHOR]

Objectives: Two identical, phase 3, randomized, double-blind, placebo-controlled trials evaluated the efficacy and safety of plecanatide in patients with irritable bowel syndrome with constipation (IBS-C).Methods: Adults meeting Rome III criteria for IBS-C were randomized (1:1:1) to placebo or plecanatide (3 or 6 mg) for 12 weeks. The primary efficacy end point was the percentage of overall responders (patients reporting ≥30% reduction from baseline in worst abdominal pain plus an increase of ≥1 complete spontaneous bowel movement (CSBM)/week from baseline in the same week for ≥6 of 12 treatment weeks). Safety was assessed by adverse events (AEs).Results: Overall, 2189 individuals were randomized across the two studies and 1879 completed the studies. Demographic and baseline characteristics were similar across treatment groups and between studies. The percentage of overall responders in Study 1 was 30.2% and 29.5% for plecanatide 3 and 6 mg, respectively, vs. 17.8% placebo (P < 0.001 for each dose vs. placebo), and in Study 2 was 21.5% (P = 0.009) and 24.0% (P < 0.001) for plecanatide 3 and 6 mg, respectively, compared to 14.2% for placebo. The percentage of sustained efficacy responders (overall responders plus weekly responders for ≥2 of last 4 weeks of the 12-week treatment period) was significantly greater for both doses of plecanatide vs. placebo across both studies. All secondary end points (stool frequency/consistency, straining, abdominal symptoms) showed statistically significant improvements compared with placebo. The most common AE was diarrhea (3 mg, 4.3%; 6 mg, 4.0%; placebo, 1.0%). Discontinuation due to diarrhea was infrequent (3 mg, 1.2%; 6 mg, 1.4%; placebo, 0).Conclusions: Plecanatide significantly improved both abdominal pain and constipation symptoms of IBS-C with minimal associated side effects and high levels of tolerability. [ABSTRACT FROM AUTHOR]

Background The World Health Organization and the American and Canadian Diabetes Associations approved HbA1c > 6.5% as diagnostic for type 2 diabetes mellitus (T2DM). Hb variants and/or their chemically modified species can interfere with HbA1c measurements. We recently described a patient with Hb Wayne trait who was misdiagnosed with T2DM based on falsely elevated HbA1c. Hb Wayne is a clinically silent variant that exists as two isoforms: Hb Wayne I (Asn 139) and Hb Wayne II (Asp 139). Methods Hemoglobinopathy investigation was performed by HPLC (Bio-Rad VARIANT-II), alkaline and acid electrophoresis (Sebia Hydrasis2), capillary zone electrophoresis (Sebia CAPILLARYS2™) and DNA sequencing. HbA1c was measured by five methods. Results Hb Wayne eluted as two small fractions with retention times of 1.0 and 1.46 min on the HPLC (Bio-Rad VARIANT-II). Alkaline gel and capillary electrophoresis showed two small bands migrating faster than HbA. Hb Wayne generated spuriously high results on the Bio-Rad VARIANT-II Turbo 2.0, no results on the Tosoh G8, and did not interfere with either the Sebia CAPILLARYS2™ or immunoassays from Roche (tinaquant) and Siemens (Bayer DCA2000 +). Based on the Hb Wayne HPLC profile of 3 patients, an algorithm was developed to facilitate its detection, which identified 9 additional patients with Hb Wayne trait. Conclusions We characterize Hb Wayne by chromatographic and electrophoretic techniques and show the effect of Hb Wayne on five common HbA1c methodologies. We developed a quality assurance tool to assist in detecting Hb Wayne trait during HbA1c analysis on the Bio-Rad VARIANT-II™ Turbo 2.0. [ABSTRACT FROM AUTHOR]

Abstract: Background: Carbamylated hemoglobin (carbHb) is reported to interfere with measurement and interpretation of HbA1c in diabetic patients with chronic renal failure (CRF). There is also concern that HbA1c may give low results in these patients due to shortened erythrocyte survival. Methods: We evaluated the effect of carbHb on HbA1c measurements and compared HbA1c with glycated albumin (GA) in patients with and without renal disease to test if CRF causes clinically significant bias in HbA1c results by using 11 assay methods. Subjects included those with and without renal failure and diabetes. Each subject''s estimated glomerular filtration rate (eGFR) was used to determine the presence and degree of the renal disease. A multiple regression model was used to determine if the relationship between HbA1c results obtained from each test method and the comparative method was significantly (p<0.05) affected by eGFR. These methods were further evaluated for clinical significance by using the difference between the eGRF quartiles of >7% at 6 or 9% HbA1c. The relationship between HbA1c and glycated albumin (GA) in patients with and without renal failure was also compared. Results: Some methods showed small but statistically significant effects of eGFR; none of these differences were clinically significant. If GA is assumed to better reflect glycemic control, then HbA1c was approximately 1.5% HbA1c lower in patients with renal failure. Conclusions: Although most methods can measure HbA1c accurately in patients with renal failure, healthcare providers must interpret these test results cautiously in these patients due to the propensity for shortened erythrocyte survival in renal failure. [Copyright &y& Elsevier]

The article discusses a study which examined the trends in nephrologist visits and health care resource use before and following estimated glomerular filtration rate (GFR) reporting. The study included 1,135,968 patients with chronic kidney disease (CKD), who were followed in Alberta from May 15, 2003 to March 14, 2007. Study researchers found no association between estimated GFR reporting and the rate of first nephrologist visit or the use of angiotensin-converting enzyme inhibitors/angiotensin II receptor blockers. They concluded that estimated GFR reporting is linked to first nephrologist visits among patients with severe kidney dysfunction and those with comorbidities.

Abstract: Osteoporosis is the most common cause of fragility fractures. Bone remodelling is essential for repairing damaged areas within bone to preserve bone strength and for assisting in mineral homeostases. In young adults, bone remodelling is usually balanced with approximately as much bone replaced as is removed during each remodelling cycle. However, when remodelling becomes accelerated in combination with an imbalance that favours bone resorption over formation, such as during menopause, precipitous losses in bone mass occur. Bone turnover markers (BTMs) measure the rate of bone remodelling allowing for a dynamic assessment of skeletal status and hold promise in identifying those at highest risk of rapid bone loss and subsequent fracture. Further, the use of BTMs to monitor individuals administered osteoporosis therapy is attractive as monitoring anti-fracture efficacy with bone mineral density has significant limitations. This review details remodelling biology, pre-analytical and analytical sources of variability for BTMs, describes the most commonly used resorption and formation markers, and offers some guidelines for their use and interpretation in the laboratory and the clinic. [Copyright &y& Elsevier]

Introduction: Lubiprostone capsules are approved for managing three different chronic constipation conditions. A "sprinkle" formulation may facilitate use in individuals with difficulty swallowing capsules. Our objective was to evaluate the bioequivalence, pharmacokinetics (PK), and bioavailability of lubiprostone sprinkles vs lubiprostone capsules, compared with placebo., Methods: A 1-week randomized, placebo-controlled, double-blinded, bioequivalence study (study 302) and a single-dose PK and bioavailability crossover study (study 304) were conducted. In study 302, 522 subjects with chronic constipation were randomized to lubiprostone sprinkle 24 μg twice daily (BID), lubiprostone capsule 24 μg BID, or placebo. The primary efficacy endpoint was observed spontaneous bowel movement (SBM) counts (equivalence defined as showing the 90% confidence interval [CI] of the "between-group SBM ratio" to be contained within 0.8-1.25). Study 304 included two cohorts of healthy volunteers randomized to a single 48-μg lubiprostone dose, sprinkle, or capsule (n = 35) or to a single 48-μg sprinkle dose, in fed or fasted state (n = 14)., Results: Both lubiprostone formulations significantly improved SBM count (sprinkle, 4.82 ± 3.66, P = 0.002; capsule, 5.74 ± 3.79, P < 0.0001) vs placebo (3.68 ± 2.16), but equivalent efficacy was not demonstrated, with a 90% CI for the SBM count ratio of 0.69-0.95. Quantifiable PK data on lubiprostone were limited; however, overall exposure to the M3 metabolite was approximately 44% higher with sprinkles vs capsules under fasted conditions (geometric mean ratio 1.441 [90% CI, 1.166, 1.782]), and exposure with the sprinkle formulation was 11% lower in the fed state vs the fasted state (geometric mean ratio 0.888 [90% CI, 0.675, 1.168]). Both formulations were generally well tolerated., Conclusion: Despite the significant improvement in SBM counts vs placebo, the sprinkle formulation did not demonstrate bioequivalence to the capsule formulation in either pharmacodynamic or PK key parameters., Trial Registration: Study 302: ClinicalTrials.gov identifier, NCT03097861; https://www.clinicaltrials.gov/ct2/show/NCT03097861 ; Study 304: ClinicalTrials.gov identifier, NCT03010631; https://www.clinicaltrials.gov/ct2/show/NCT03010631 .

Introduction: Gastric emptying scintigraphy (GES) or wireless motility capsules (WMCs) can evaluate upper gastrointestinal symptoms in suspected gastroparesis; WMC tests can also investigate lower gut symptoms. We aimed to determine whether these tests impact treatment plans and needs for additional diagnostic evaluation., Methods: In a prospective, multicenter study, 150 patients with gastroparesis symptoms simultaneously underwent GES and WMC testing. Based on these results, investigators devised management plans to recommend changes in medications, diet, and surgical therapies and order additional diagnostic tests., Results: Treatment changes were recommended more often based on the WMC vs GES results (68% vs 48%) (P < 0.0001). Ordering of additional test(s) was eliminated more often with WMC vs GES (71% vs 31%) (P < 0.0001). Prokinetics (P = 0.0007) and laxatives (P < 0.0001) were recommended more often based on the WMC vs GES results. Recommendations for prokinetics and gastroparesis diets were higher and neuromodulators lower in subjects with delayed emptying on both tests (all P ≤ 0.0006). Laxatives and additional motility tests were ordered more frequently for delayed compared with normal WMC colonic transit (P ≤ 0.02). Multiple motility tests were ordered more often on the basis of GES vs WMC findings (P ≤ 0.004). Antidumping diets and transit slowing medications were more commonly recommended for rapid WMC gastric emptying (P ≤ 0.03)., Discussion: WMC transit results promote medication changes and eliminate additional diagnostic testing more often than GES because of greater detection of delayed gastric emptying and profiling the entire gastrointestinal tract in patients with gastroparesis symptoms., Translational Impact: Gastric scintigraphy and WMCs have differential impact on management decisions in suspected gastroparesis.

Diagnosing streptococcal pharyngitis in children on the basis of clinical appearance and throat culture is complicated by high colonisation rates and by the ability of other pathogens to cause clinically similar disease. To characterise the epidemiology of Lancefield Group A, C and G β-haemolytic streptococcus (GAS, GCS and GGS, respectively) in children, we conducted a 2-year prospective study of 307 school children between 7 and 11 years old. GGS and GAS were commonly identified organisms both for silent streptococcal colonisation and symptomatic sore throat, while GCS was uncommonly found. Streptococcal culture positivity at the time of clinical pharyngitis was estimated to reflect true streptococcal pharyngitis in only 26% of instances, with the frequency varying from 54% for children rarely colonised to 1% for children frequently colonised. Numerous GAS emm types were identified, including several types previously associated with severe pharyngitis (e.g. emm types 1, 3 and 28). No severe complications were seen in any child. These data suggest that the clinical diagnosis of streptococcal pharyngitis is likely to remain difficult and that treatment decisions will remain clouded by uncertainty. There remains a need for organism-specific rapid point-of-care streptococcal diagnostic tests and tests that can distinguish between streptococcal colonisation and disease.

Background: A gluten-free diet is the only means to manage coeliac disease, a permanent immune intolerance to gluten. We developed a therapeutic vaccine, Nexvax2, designed to treat coeliac disease. Nexvax2 is an adjuvant-free mix of three peptides that include immunodominant epitopes for gluten-specific CD4-positive T cells. The vaccine is intended to engage and render gluten-specific CD4-positive T cells unresponsive to further antigenic stimulation. We assessed the safety and pharmacodynamics of the vaccine in patients with coeliac disease on a gluten-free diet., Methods: We did two randomised, double-blind, placebo-controlled, phase 1 studies at 12 community sites in Australia, New Zealand, and the USA, in HLA-DQ2·5-positive patients aged 18-70 years who had coeliac disease and were on a gluten-free diet. In the screening period for ascending dose cohorts, participants were randomly assigned (1:1) by central randomisation with a simple block method to a double-blind crossover, placebo-controlled oral gluten challenge. Participants with a negative interferon γ release assay to Nexvax2 peptides after the screening oral gluten challenge were discontinued before dosing. For the biopsy cohorts, the screening period included an endoscopy, and participants with duodenal histology who had a Marsh score of greater than 1 were discontinued before dosing. Participants were subsequently randomly assigned to either Nexvax2 or placebo in ascending dose cohorts (2:1) and in biopsy cohorts (1:1) by central randomisation with a simple block method. In the three-dose study, participants received either Nexvax2 60 μg, 90 μg, or 150 μg weekly, or placebo over 15 days; in a fourth biopsy cohort, patients received either Nexvax2 at the maximum tolerated dose (MTD) or placebo. In the 16-dose study, participants received Nexvax2 150 μg or 300 μg or placebo twice weekly over 53 days; in a third biopsy cohort, patients also received either Nexvax2 at the MTD or placebo. In the 4-week post-treatment period, ascending dose cohorts underwent a further double-blind crossover, placebo-controlled oral gluten challenge, which had a fixed sequence, and biopsy cohorts had a gastroscopy with duodenal biopsies and quantitative histology within 2 weeks without oral gluten challenge. Participants, investigators, and study staff were masked to the treatment assignment, except for the study pharmacist. The primary endpoint was the number and percentage of adverse events in the treatment period in an intention-to-treat analysis. Both trials were completed and closed before data analysis. Trials were registered with the Australian New Zealand Clinical Trials Registry, numbers ACTRN12612000355875 and ACTRN12613001331729., Findings: Participants were enrolled from Nov 28, 2012, to Aug 14, 2014, in the three-dose study, and from Aug 3, 2012, to Sept 10, 2013, in the 16-dose study. Overall, 62 (57%) of 108 participants were randomly assigned after oral gluten challenge and 20 (71%) of 28 participants were randomly assigned after endoscopy. In the three-dose study, nine participants were randomly allocated to Nexvax2 60 μg and three to placebo (first cohort), nine were allocated to Nexvax2 90 μg and four to placebo (second cohort), eight were allocated to Nexvax2 150 μg and four to placebo (third cohort), and three were allocated to Nexvax2 150 μg and three to placebo (biopsy cohort). In the 16-dose study, eight participants were randomly allocated to Nexvax2 150 μg and four to placebo (first cohort), ten were allocated to Nexvax2 300 μg and three to placebo (second cohort), and seven were allocated to Nexvax2 150 μg and seven to placebo (biopsy cohort). The MTD for Nexvax2 was 150 μg because of transient, acute gastrointestinal adverse events with onset 2-5 h after initial doses of the vaccine, similar to those caused by gluten ingestion. In the ascending dose cohorts in the three-dose study, six (55%) of 11 placebo recipients, five (56%) of nine who received Nexvax2 60 μg, seven (78%) of nine who received Nexvax2 90 μg, and five (63%) of eight who received Nexvax2 150 μg had at least one treatment-emergent adverse event, as did all three (100%) placebo recipients and one (33%) of three Nexvax2 150 μg recipients in the biopsy cohort. In the ascending dose cohorts of the 16-dose study, five (71%) of seven placebo-treated participants, six (75%) of eight who received Nexvax2 150 μg, and all ten (100%) who received Nexvax2 300 μg had at least one treatment-emergent adverse event, as did six (86%) of seven placebo recipients and five (71%) of seven Nexvax2 150 μg recipients in the biopsy cohort. Vomiting, nausea, and headache were the only treatment-emergent adverse events that occurred in at least 5% of participants in either study. Among participants given the MTD, eight gastrointestinal treatment-emergent adverse events occurred in four (50%) of eight participants in the third cohort and none (0%) of three participants in the biopsy cohort in the three-dose study, and five events occurred in five (63%) of eight participants in the first cohort and three events in two (29%) of seven participants in the biopsy cohort of the 16-dose study. Median villous height to crypt depth ratio in distal duodenal biopsies was not significantly different between those who received the vaccine at the MTD on either schedule and those who received placebo. Of the participants who completed the post-treatment oral gluten challenge per protocol, interferon γ release assay to Nexvax2 peptides was negative (responders to treatment) in two (22%) of nine placebo-treated participants in the three-dose study versus two (33%) of six who received Nexvax2 60 μg, five (63%) of eight who received Nexvax2 90 μg, and six (100%) of six who received Nexvax2 150 μg (p=0·007); in the 16-dose study, none (0%) of five placebo-treated participants had a negative assay versus six (75%) of eight who received Nexvax2 150 μg (p=0·021)., Interpretation: The MTD of Nexvax2 was 150 μg for twice weekly intradermal administration over 8 weeks, which modified immune responsiveness to Nexvax2 peptides without deterioration in duodenal histology. The gastrointestinal symptoms that followed the first intradermal administration of the vaccine resembled those associated with oral gluten challenge. These findings support continued clinical development of this potential therapeutic vaccine for coeliac disease., Funding: ImmusanT., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Background: HbA1c is used in the diagnosis and monitoring of diabetes mellitus (DM). Interference from hemoglobin variants is a well-described phenomenon, particularly with HPLC-based methods. While immunoassays may generate more reliable HbA1c results in the presence of some variants, these methods are susceptible to negative interference from high concentrations of HbF. We report a case where an accurate HbA1c result could not be obtained by any available method due to the presence of a compound hemoglobinopathy., Methods: HbA1c was measured by HPLC, immunoassay, and capillary electrophoresis. Hemoglobinopathy investigation consisted of a CBC, hemoglobin fractionation by HPLC and electrophoresis, and molecular analysis., Results: HbA1c analysis by HPLC and capillary electrophoresis gave no result. Analysis by immunoassay yielded HbA1c results of 5.9% (Siemens DCA 2000+) and 5.1% (Roche Integra), which were inconsistent with other markers of glycemic control. Hemoglobinopathy investigation showed HbC with the hereditary persistence of fetal hemoglobin-2 Ghana deletion., Conclusion: Reliable HbA1c results may be unobtainable in the presence of some hemoglobinopathies. HPLC and capillary electrophoresis alerted the laboratory to the presence of an unusual hemoglobinopathy. Immunoassays generated falsely low results without warning, which could lead to missed diagnoses and under treatment of patients with DM., (Copyright © 2016 Elsevier B.V. All rights reserved.)

Although recurrent event data analysis is a rapidly evolving area of research, rigorous studies on estimation of the effects of intermittently observed time-varying covariates on the risk of recurrent events have been lacking. Existing methods for analyzing recurrent event data usually require that the covariate processes are observed throughout the entire follow-up period. However, covariates are often observed periodically rather than continuously. We propose a novel semiparametric estimator for the regression parameters in the popular proportional rate model. The proposed estimator is based on an estimated score function where we kernel smooth the mean covariate process. We show that the proposed semiparametric estimator is asymptotically unbiased, normally distributed, and derives the asymptotic variance. Simulation studies are conducted to compare the performance of the proposed estimator and the simple methods carrying forward the last covariates. The different methods are applied to an observational study designed to assess the effect of group A streptococcus on pharyngitis among school children in India. Copyright © 2016 John Wiley & Sons, Ltd., (Copyright © 2016 John Wiley & Sons, Ltd.)

Background: There is limited information about the effects of instituting CLSI Document C56A recommended workflows for the automated detection of hemolysis, lipemia and icterus (HIL) in different clinical laboratories and patient populations. We describe a process to develop and tailor automated reporting rules that are appropriate for the local laboratory population., Methods: Automated decision algorithms were generated and applied to 2 high volume labs serving community and hospital populations. Proposed rules were applied to the datasets offline to predict the outcomes, and then were further optimized prior to implementation., Results: Introduction of automated serum indices decreased HIL flagging compared to manual flagging. Hemolysis flagging was the greatest in all 3 patient populations, and was successfully reduced for LD, CK and AST by optimized rules that incorporated both the H-index result and the analyte result. Changes in flagging rates were also patient population specific, particularly for icterus which was a problem in hospitalized populations but not in the community. Overall, concordance between manual and automated flagging methods was very low in both laboratories., Conclusions: We demonstrate that flagging algorithms may not be universally transferable due to lab specific and population specific factors and demonstrate the benefits of local, a priori testing of algorithms prior to implementation., (Copyright © 2015 Elsevier B.V. All rights reserved.)

During the first decade of the twentieth century, the German bacteriologist Fred Neufeld, later Director of the Robert Koch-Institute in Berlin, first described the differentiation of pneumococci into serotypes on the basis of type-specific antisera. This finding was essential for subsequent research at the Rockefeller Institute of Medical Research (RIMR) in New York, and elsewhere, aiming for the conquest of human pneumococcal pneumonia, including antiserum therapy, the discovery that the type-specific antigens were carbohydrates, and the development of effective multivalent pneumococcal polysaccharide vaccines. Moreover, on the basis of pneumococcal serotypes Fred Griffith, in 1928 in London, discovered pneumococcal transformation, and Oswald T. Avery and coworkers, in 1944 at RIMR, identified DNA as the transforming substance. This sequence of events, leading to today's knowledge that genes consist of DNA, was initiated by a farsighted move of Simon Flexner, first Director of the RIMR, who asked Neufeld to send his pneumococcal typing strains, thus setting the stage for pneumococcal research at RIMR. Here, we describe Fred Neufeld's contributions in this development, which have remained largely unknown.

Background: Carbamylated hemoglobin (carbHb) is reported to interfere with measurement and interpretation of HbA(1c) in diabetic patients with chronic renal failure (CRF). There is also concern that HbA1c may give low results in these patients due to shortened erythrocyte survival., Methods: We evaluated the effect of carbHb on HbA(1c) measurements and compared HbA(1c) with glycated albumin (GA) in patients with and without renal disease to test if CRF causes clinically significant bias in HbA(1c) results by using 11 assay methods. Subjects included those with and without renal failure and diabetes. Each subject's estimated glomerular filtration rate (eGFR) was used to determine the presence and degree of the renal disease. A multiple regression model was used to determine if the relationship between HbA(1c) results obtained from each test method and the comparative method was significantly (p<0.05) affected by eGFR. These methods were further evaluated for clinical significance by using the difference between the eGRF quartiles of >7% at 6 or 9% HbA(1c). The relationship between HbA(1c) and glycated albumin (GA) in patients with and without renal failure was also compared., Results: Some methods showed small but statistically significant effects of eGFR; none of these differences were clinically significant. If GA is assumed to better reflect glycemic control, then HbA(1c) was approximately 1.5% HbA(1c) lower in patients with renal failure., Conclusions: Although most methods can measure HbA(1c) accurately in patients with renal failure, healthcare providers must interpret these test results cautiously in these patients due to the propensity for shortened erythrocyte survival in renal failure., (Copyright © 2013 Elsevier B.V. All rights reserved.)

Background and Objectives: Despite reporting estimated GFR (eGFR), use of evidence-based interventions in CKD remains suboptimal. This study sought to determine the effect of an enhanced eGFR laboratory prompt containing specific management recommendations, compared with standard eGFR reporting in CKD., Design, Setting, Participants, & Measurements: A cluster randomized trial of a standard or enhanced eGFR laboratory prompt was performed in 93 primary care practices in Alberta, Canada. Although all adult patients with CKD (eGFR <60 ml/min per 1.73 m(2)) were included, medication data were only available for elderly patients (aged ≥66 years). The primary outcome, the proportion of patients with diabetes or proteinuria receiving an angiotensin converting enzyme inhibitor (ACEi) or angiotensin receptor blocker (ARB), was assessed in elderly CKD patients., Results: There were 5444 elderly CKD patients with diabetes or proteinuria who were eligible for primary outcome assessment, irrespective of baseline ACEi/ARB use. ACEi/ARB use in the subsequent year was 77.1% and 76.9% in the standard and enhanced prompt groups, respectively. In the subgroup of elderly patients with an eGFR <30 ml/min per 1.73 m(2), ACEi/ARB use was higher in the enhanced prompt group. Among 22,092 CKD patients, there was no difference in the likelihood of a composite clinical outcome (death, ESRD, doubling of serum creatinine, or hospitalization for myocardial infarction, heart failure, or stroke) over a median of 2.1 years., Conclusions: In elderly patients with CKD and an indication for ACEi/ARB, an enhanced laboratory prompt did not increase use of these medications.

Introduction: The study objective was to determine the accuracy of answers to clinical questions by emergency medicine (EM) residents conducting Internet searches by using Google. Emergency physicians commonly turn to outside resources to answer clinical questions that arise in the emergency department (ED). Internet access in the ED has supplanted textbooks for references because it is perceived as being more up to date. Although Google is the most widely used general Internet search engine, it is not medically oriented and merely provides links to other sources. Users must judge the reliability of the information obtained on the links. We frequently observed EM faculty and residents using Google rather than medicine-specific databases to seek answers to clinical questions., Methods: Two EM faculties developed a clinically oriented test for residents to take without the use of any outside aid. They were instructed to answer each question only if they were confident enough of their answer to implement it in a patient-care situation. Questions marked as unsure or answered incorrectly were used to construct a second test for each subject. On the second test, they were instructed to use Google as a resource to find links that contained answers., Results: Thirty-three residents participated. The means for the initial test were 32% correct, 28% incorrect, and 40% unsure. On the Google test, the mean for correct answers was 59%; 33% of answers were incorrect and 8% were unsure., Conclusion: EM residents' ability to answer clinical questions correctly by using Web sites from Google searches was poor. More concerning was that unsure answers decreased, whereas incorrect answers increased. The Internet appears to have given the residents a false sense of security in their answers. Innovations, such as Internet access in the ED, should be studied carefully before being accepted as reliable tools for teaching clinical decision making.

The high concentration of molecular oxygen in Earth's atmosphere is arguably the most conspicuous and geologically important signature of life. Earth's early atmosphere lacked oxygen; accumulation began after the evolution of oxygenic photosynthesis in cyanobacteria around 3.0-2.5 billion years ago (Gya). Concentrations of oxygen have since varied, first reaching near-modern values ~600 million years ago (Mya). These fluctuations have been hypothesized to constrain many biological patterns, among them the evolution of body size. Here, we review the state of knowledge relating oxygen availability to body size. Laboratory studies increasingly illuminate the mechanisms by which organisms can adapt physiologically to the variation in oxygen availability, but the extent to which these findings can be extrapolated to evolutionary timescales remains poorly understood. Experiments confirm that animal size is limited by experimental hypoxia, but show that plant vegetative growth is enhanced due to reduced photorespiration at lower O(2):CO(2). Field studies of size distributions across extant higher taxa and individual species in the modern provide qualitative support for a correlation between animal and protist size and oxygen availability, but few allow prediction of maximum or mean size from oxygen concentrations in unstudied regions. There is qualitative support for a link between oxygen availability and body size from the fossil record of protists and animals, but there have been few quantitative analyses confirming or refuting this impression. As oxygen transport limits the thickness or volume-to-surface area ratio-rather than mass or volume-predictions of maximum possible size cannot be constructed simply from metabolic rate and oxygen availability. Thus, it remains difficult to confirm that the largest representatives of fossil or living taxa are limited by oxygen transport rather than other factors. Despite the challenges of integrating findings from experiments on model organisms, comparative observations across living species, and fossil specimens spanning millions to billions of years, numerous tractable avenues of research could greatly improve quantitative constraints on the role of oxygen in the macroevolutionary history of organismal size.

Background: The Alberta Kidney Disease Network is a collaborative nephrology research organization based on a central repository of laboratory and administrative data from the Canadian province of Alberta., Description: The laboratory data within the Alberta Kidney Disease Network can be used to define patient populations, such as individuals with chronic kidney disease (using serum creatinine measurements to estimate kidney function) or anemia (using hemoglobin measurements). The administrative data within the Alberta Kidney Disease Network can also be used to define cohorts with common medical conditions such as hypertension and diabetes. Linkage of data sources permits assessment of socio-demographic information, clinical variables including comorbidity, as well as ascertainment of relevant outcomes such as health service encounters and events, the occurrence of new specified clinical outcomes and mortality., Conclusion: The unique ability to combine laboratory and administrative data for a large geographically defined population provides a rich data source not only for research purposes but for policy development and to guide the delivery of health care. This research model based on computerized laboratory data could serve as a prototype for the study of other chronic conditions.

Objective: To determine if the addition of uterine artery (UA) Doppler pulsatility index (PI) at 18 and 22 weeks of gestation improves the predictive accuracy of low first trimester pregnancy associated plasma protein A (PAPP-A) in the detection of adverse obstetrical outcomes., Methods: This was a prospective interventional study. All women undergoing first trimester combined screening (FTS) at a single center, with a low maternal serum PAPP-A level (<0.4 MoM), were included. Patients underwent bilateral UA Doppler assessments at 18 and 22 weeks of gestation. A positive test was defined as a mean PI > 1.45. Primary outcomes were obtained from chart review, and logistic regression analysis was used to compare outcomes with positive and negative tests. Positive and negative predictive value, specificity and sensitivity were calculated., Results: Between January and October 2007, 5359 women completed FTS. Among the low PAPP-A group (n = 289), 18 week UA Doppler was a significant predictor of low birth weight (OR = 2.28, p = 0.04) while 22 week UA Doppler significantly predicted preterm birth (OR = 12.6, p = 0.001), small for gestational age (OR = 8.24, p = 0.001) and low birth weight (OR = 2.28, p = 0.04). Test characteristics suggested improved positive and negative predictive value for Doppler at 22 versus 18 weeks for these outcomes., Conclusions: UA Doppler at 22 weeks is a useful adjunct in patients with low PAPP-A. However, a negative Doppler does not rule out all adverse outcomes and clinical judgment is advised in the management of these patients.

The maximum size of organisms has increased enormously since the initial appearance of life >3.5 billion years ago (Gya), but the pattern and timing of this size increase is poorly known. Consequently, controls underlying the size spectrum of the global biota have been difficult to evaluate. Our period-level compilation of the largest known fossil organisms demonstrates that maximum size increased by 16 orders of magnitude since life first appeared in the fossil record. The great majority of the increase is accounted for by 2 discrete steps of approximately equal magnitude: the first in the middle of the Paleoproterozoic Era (approximately 1.9 Gya) and the second during the late Neoproterozoic and early Paleozoic eras (0.6-0.45 Gya). Each size step required a major innovation in organismal complexity--first the eukaryotic cell and later eukaryotic multicellularity. These size steps coincide with, or slightly postdate, increases in the concentration of atmospheric oxygen, suggesting latent evolutionary potential was realized soon after environmental limitations were removed.

Study Objective: Tape is the standard method for securing endotracheal tubes to prevent extubation. This study examines the force required to extubate endotracheal tubes from cadavers with either tape or one of 4 commercially available endotracheal tube holders., Methods: Newly deceased, unembalmed cadavers were intubated with standard tracheal intubation techniques. The endotracheal tube was secured with either tape or one of 4 commercially available endotracheal tube holders. The endotracheal tube was then connected to a force-measuring device and pulled until the cuff was removed from the trachea. The largest force recorded on the device was then marked as the "extubation force" for that trial., Results: When tape was used to secure the endotracheal tube, it required a significantly larger force to extubate than 3 of 4 off-the-shelf endotracheal tube holders. Only the Thomas Tube Holder secured the endotracheal tube better than tape., Conclusion: Although the Thomas Tube Holder had the greatest holding force in this study, tape was shown to be the least expensive and outperformed 3 other commercially available devices used to secure endotracheal tubes.

Objective: Alosetron is indicated for women with chronic, severe diarrhea-predominant IBS (d-IBS) who have not responded adequately to conventional therapy. Constipation is the most common adverse event with alosetron treatment. Multiple dosing regimens were assessed in a randomized, double-blind, placebo-controlled study (S3B30040) to determine efficacy, tolerability, and evaluate constipation rate., Methods: 705 women with severe d-IBS were randomized to placebo, alosetron 0.5 mg once daily, 1 mg once daily, or 1 mg twice daily for 12 wk. The primary end point was the proportion of week 12 responders (patients with moderate or substantial improvement in IBS symptoms) on the 7-point Likert Global Improvement Scale (GIS). Secondary end points were average rate of adequate relief of IBS pain and discomfort, and bowel symptom improvements., Results: The proportion of GIS responders at week 12 (primary time point) was significantly greater in all alosetron groups compared with placebo (54/176 [30.7%], 90/177 [50.8%], 84/175 [48%], and 76/177 [42.9%] for placebo, 0.5, 1 mg once daily, and 1 mg twice daily alosetron groups, respectively; P< or = 0.02). Results were similar for the average adequate relief rate (treatment effects > or =12%, P< or = 0.038). Bowel symptoms were improved in all alosetron groups. Constipation was the most common adverse event (9%, 16%, and 19% patients in the 0.5 mg, 1 mg once daily, and 1 mg twice daily groups, respectively). One event of intestinal obstruction and one of ischemic colitis occurred in the 0.5 mg group, and one event of fecal impaction occurred in the 1 mg twice-daily group. All were self-limited and resolved without sequelae., Conclusion: Alosetron 0.5 mg and 1 mg once daily as well as 1 mg twice daily are effective in providing global improvement in IBS symptoms, adequate relief of IBS pain and discomfort, and improvement in bowel symptoms in women with severe d-IBS. Lower dosing regimens resulted in a decreased constipation rate.

The 1918 influenza pandemic has shaped research and public health for nearly a century. In 1976, the specter of 1918 loomed large when a pandemic threatened the country again. Public health officials initiated a mass vaccination campaign, but the anticipated pandemic failed to occur. An examination of the available data in 1976 and the decision to vaccinate, as well as lessons learned from the HIV/AIDS epidemic in the early 1980s, may help shape an appropriate public health response to future threats from avian influenza or other infectious diseases.

Objective: To evaluate the effect of hemolysis on the measurement of cardiac troponin T (cTnT) using the Elecsys 2010 immunoanalyzer., Methods: cTnT concentrations were measured using the Elecsys 2010. Interference studies were conducted by mixing serum of known cTnT concentration with either hemolysates or serum to which purified hemoglobin (Hgb) had been added. Hemolysates were prepared by mechanical disruption. PROBIT analysis was conducted to determine the probability of a cTnT result of >0.1 microg/l being decreased to <0.1 microg/l due to hemoglobin interference., Results: Purified hemoglobin as well as serum-hemolysates mediated a concentration-dependent inhibition of cTnT determination with the Elecsys 2010. With every 1 g/l increase in hemoglobin, the probability of cTnT >0.1 is decreased by 2.5%., Conclusions: A concentration-dependent negative bias in the measurement of cTnT is associated with increasing hemoglobin concentrations in serum.

Microbes will evolve and the epidemics they cause will continue to occur in the future as they have in the past. Microbes emerge from the evolutionary stream as a result of genetic events and selective pressures that favor new over old. It is nature's way. Microbes and vectors swim in the evolutionary stream, and they swim much faster than humans. Bacteria reproduce every 30 minutes and, for them, a millennium is compressed into a fortnight. They are "fleet afoot," and the pace of research must keep up with them or they will overtake. Microbes were here on Earth 2 billion years before humans arrived, learning every trick of the trade for survival, and they are likely to be here 2 billion years after we depart. Current research on the rise and decline of epidemics is broadly based and includes evolutionary and population genetics of host-microbe relationships. Within this context, the 19th century pandemic of scarlet fever has been described. The possibility is raised that the GAS, which currently cause STSS, possess some of the virulence factors that caused pandemic scarlet fever. Furthermore, the GAS isolated during the recent outbreaks of ARF in certain locales in the United States have the virulence properties of the GAS frequently isolated in the first half of the 20th century. Finally, it is suggested that the strategy to confront emerging infectious diseases should be the study of infectious diseases from all points of view. They remain the greatest threats to our society.

Research on Group A streptococci (GAS) before 1950 paved the way for successful clinical trials to prevent acute rheumatic fever (ARF) by treating the prior streptococcal infection with penicillin. Prevention of ARF has led to almost complete disappearance of rheumatic heart disease in the industrialized world, but has yet to be accomplished in developing countries, where most of the world's populations reside. Twenty years of research beginning in 1918 by Lancefield and others delineated the modern classification of haemolytic streptococci and led to the recognition that only Group A is responsible for the pharyngitis that causes ARF. M-protein, identified as a major virulence factor, is a powerful inhibitor of phagocytosis, and antibodies to it promote type-specific phagocytosis and therefore type-specific immunity. Other virulent properties of GAS include a bulky capsule, as well as extracellular toxins such as streptolysins S and O and streptococcal proteinase. McCarty and others pursued the cell biology of GAS and identified the cellular localization of various antigenic components. The discovery of purified M-protein as a helical coiled-coiled fibrillar protein has sparked development of M-protein vaccine. US, UK, and Trinidad scientists described differences between streptococcal infections of the throat and skin and noted particularly that many of the GAS M-types that cause impetigo are less likely to cause pharyngitis. GAS impetigo may cause acute glomerulonephritis, but such infections do not result in ARF. The changing manifestations of disease over time and the evolution of microbes are common themes in medicine today. These themes are relevant to GAS pharyngitis and ARF, especially the decline in the incidence of severe ARF and the decrease in severity of GAS pharyngitis. Research on GAS bacteriophages led to the discovery of a relationship between lysogenic GAS and production of erythrogenic toxin and has broadened approaches to the molecular epidemiology of GAS virulence. The 21st century begins with determination of the complete genome sequence of M-1, M-18, and M-3 strains of GAS. These studies provide evidence for phage-encoded toxins, high-virulence phenotypes, and clone emergence. This research will reveal genetic processes at the molecular level that control the emergence and decline of streptococcal diseases in different places and times and the shifting patterns in clinical manifestations.