A randomised comparison of two faecal immunochemical tests in population-based colorectal cancer screening.

OBJECTIVE: Colorectal cancer screening programmes are implemented worldwide; many are based on faecal immunochemical testing (FIT). The aim of this study was to evaluate two frequently used FITs on participation, usability, positivity rate and diagnostic yield in population-based FIT screening. DESIGN: Comparison of two FITs was performed in a fourth round population-based FIT-screening cohort. Randomly selected individuals aged 50-74 were invited for FIT screening and were randomly allocated to receive an OC -Sensor (Eiken, Japan) or faecal occult blood (FOB)-Gold (Sentinel, Italy) test (March-December 2014). A cut-off of 10 µg haemoglobin (Hb)/g faeces (ie, 50 ng Hb/mL buffer for OC-Sensor and 59 ng Hb for FOB-Gold) was used for both FITs. RESULTS: In total, 19 291 eligible invitees were included (median age 61, IQR 57-67; 48% males): 9669 invitees received OC-Sensor and 9622 FOB-Gold; both tests were returned by 63% of invitees (p=0.96). Tests were non-analysable in 0.7% of participants using OC-Sensor vs 2.0% using FOB-Gold (p<0.001). Positivity rate was 7.9% for OC-Sensor, and 6.5% for FOB-Gold (p=0.002). There was no significant difference in diagnostic yield of advanced neoplasia (1.4% for OC-Sensor vs 1.2% for FOB-Gold; p=0.15) or positive predictive value (PPV; 31% vs 32%; p=0.80). When comparing both tests at the same positivity rate instead of cut-off, they yielded similar PPV and detection rates. CONCLUSIONS: The OC-Sensor and FOB-Gold were equally acceptable to a screening population. However, FOB-Gold was prone to more non-analysable tests. Comparison between FIT brands is usually done at the same Hb stool concentration. Our findings imply that for a fair comparison on diagnostic yield between FIT's positivity rate rather than Hb concentration should be used. TRIAL REGISTRATION NUMBER: NTR5385; Results.

Participation, yield, and interval carcinomas in three rounds of biennial FIT-based colorectal cancer screening.

BACKGROUND: The effectiveness of colorectal cancer screening programs based on the fecal immunochemical test (FIT) is influenced by program adherence during consecutive screening rounds. We aimed to evaluate the participation rate, yield, and interval cancers in a third round of biennial CRC screening using FIT and to compare those with the first and the second screening round. METHODS: A total of 3566 average-risk individuals aged 50-75 years were invited to participate in a third round of biennial FIT-based CRC screening. All FIT positives were recommended to undergo colonoscopy. We merged our data with the national cancer registry in the Netherlands to identify all non-screen-detected cancers in our cohort. RESULTS: Of the invitees, 2142 (60%) returned the FIT in this third screening round, compared to 56% in the second round and 57% in the first round. Overall, 153 of the third-round participants (7.1%) had a positive FIT result, versus 7.9% in the second round and 8.1% in the first round (P=0.05). Of all FIT positives, 123 (80%) underwent colonoscopy. Within this group, 33 persons had advanced neoplasia. The predictive value of FIT positivity for advanced neoplasia was 27% (33/123), compared to 42% in the second round and 54% in the first round - a significant decline (P<0.01). CONCLUSION: In an FIT-based screening program, participation rates remained stable over consecutive biennial screening rounds, while the FIT positivity rate and positive predictive value for advanced neoplasia gradually declined. Cancers in non-participants are significantly more advanced in staging than cancers in participants in the first round of screening.

Enlargement of the endoplasmic reticulum membrane in Saccharomyces cerevisiae is not necessarily linked to the unfolded protein response via Ire1p.

Conditions that stress the endoplasmic reticulum (ER) in Saccharomyces cerevisiae can elicit a combination of an unfolded protein response (UPR) and an inositol response (IR). This results in increased synthesis of ER protein-folding factors and of enzymes participating in phospholipid biosynthesis. It was suggested that in cells grown on glucose or galactose medium, the UPR and the IR are linked and controlled by the ER stress sensor Ire1p. However, our studies suggest that during growth on oleate the IR is controlled both by an Ire1p-dependent pathway and by an Ire1p-independent pathway.

Error budget calculations in laboratory medicine: linking the concepts of biological variation and allowable medical errors.

BACKGROUND: Random, systematic and sporadic errors, which unfortunately are not uncommon in laboratory medicine, can have a considerable impact on the well being of patients. Although somewhat difficult to attain, our main goal should be to prevent all possible errors. A good insight on error-prone steps in the laboratory process is essential to achieving a structured system for error reduction. METHODS: Here, the process of laboratory medicine is divided into phases, and for each phase, an error frequency is presented. While error frequencies in the laboratory (pre-analytical to post-analytical) have been reported elsewhere, we also include them in the present paper. In order to investigate error frequencies in the pre-pre- and post-post-analytical phases, clinicians were asked to carefully answer questions concerning their ordering strategies for laboratory investigation and their interpretation of results. RESULTS: In the present study, the overall error rate in laboratory medicine was found to be 20.0%. The error percentages in the pre-pre- and post-post-analytical phase were about 12.0% and 5.0%, respectively. This indicates that, also on the clinical side, error reduction is desirable, especially in the requesting of laboratory investigation. Error reduction can be achieved through process redesigning by, for example, applying the Hazard Analysis and Critical Control Points approach. The error budget that clinicians might spend, based upon critical differences, is 26.9%. For the same test set and production circumstances, the overall biological variation is 7.9%. Clinicians thus take the error rates into account in their practical, daily use, and the ultimate achievable in laboratory medicine is biological variation. CONCLUSIONS: Several currently available software applications can aid error reduction in clinical chemistry. Both laboratory consultants and the use of information and communication technology are essential tools in optimizing the efficiency of laboratory medicine.

Reference range determination for whole-blood platelet aggregation using the Multiplate analyzer.

OBJECTIVES: To develop reference ranges for platelet aggregation using the Multiplate analyzer (Roche Diagnostics, Mannheim, Germany) in blood anticoagulated with sodium citrate (Na-citrate), lithium heparin (Li-heparin), or hirudin. METHODS: The study was performed at three sites on consented, healthy adults (n = 193) not taking antiplatelet medication. Platelet aggregation was evaluated in response to adenosine-5'-diphosphate, arachidonic acid, collagen, thrombin receptor activating peptide, ristocetin, and adenosine-5'-diphosphate combined with prostaglandin E1. Precision testing was conducted using healthy donors and donors taking aspirin. RESULTS: Whole-blood platelet aggregation showed anticoagulant-dependent differences in platelet responses to all agonists. Samples collected in Na-citrate demonstrated the lowest responses to all agonists. The highest responses were obtained using Li-heparin. Precision testing revealed high variability in platelet aggregation at lower agonist doses, regardless of anticoagulant. Highest platelet response variations occurred in response to arachidonic acid in blood anticoagulated with hirudin from participants taking aspirin. CONCLUSIONS: These data demonstrate the importance of establishing locally relevant reference ranges.

The influence of aspirin dose and glycemic control on platelet inhibition in patients with type 2 diabetes mellitus.

BACKGROUND: Low-dose aspirin seems to offer no benefit in the primary prevention of cardiovascular disease in type 2 diabetes mellitus (DM2). The anti-platelet effect may be diminished by poor glycemic control or inadequate dosing of aspirin. OBJECTIVES: To study the effects of both glycemic control and increasing aspirin dose on platelet response to aspirin in DM2 patients and matched controls. PATIENTS/METHODS: Platelet effects of increasing doses of aspirin (30, 100 and 300 mg daily) were prospectively assessed in 94 DM2 patients and 25 matched controls by measuring thromboxane levels in urine (11-dhTxB2) and platelet aggregation using VerifyNow(®) and light transmission aggregometry (LTA). DM2 patients were stratified for glycemic control (hemoglobin-A1c [HbA1c] ≤ 53, 53-69, ≥ 69 mmol mol(-1)). RESULTS: At baseline, median 11-dhTxB2 excretion was higher in the poorly controlled patients (77 ng mmol(-1)), and the moderately controlled (84 ng mmol(-1)) compared with the well-controlled patients (64 ng mmol(-1)) and controls (53 ng mmol(-1)), P < 0.01. Next, 30 mg of aspirin reduced 11-dhTxB2 excretion to 31, 29 and 24 ng mmol(-1) in the poorly, moderately and well-controlled patients, respectively, and to 19 ng mmol(-1) in controls, P < 0.001. VerifyNow(®) and LTA were also incompletely suppressed in DM2 patients using 30 mg of aspirin, but 100 mg resulted in similar platelet suppression in all groups, with no additional effect of 300 mg. CONCLUSIONS: DM2 patients with inadequate glycemic control (HbA1c > 53 mmol mol(-1)) have higher baseline platelet activity and incomplete suppression of platelet activity with 30 mg of aspirin. However, 100 mg of aspirin leads to optimal inhibition irrespective of glycemic control, and 300 mg does not further improve platelet suppression.

Catastrophic antiphospholipid syndrome mimicking a malignant pancreatic tumour--a case report.

The catastrophic antiphospholipid syndrome is characterised by rapid onset thromboses, often resistant to conventional anticoagulant treatment, and resulting in life threatening multiple organ dysfunction. The diagnosis of catastrophic antiphospholipid syndrome may be difficult, predominantly due to its frequently atypical presentation. We report a case of a 35-year-old female who presented with a pancreatic tumour and extensive thromboses. Following a storm of ischemic events due to thrombotic occlusions in spite of therapeutic heparin dose, the suspicion of catastrophic antiphospholipid syndrome emerged. The patient was successfully treated with anticoagulants, immunoglobulins, plasmapheresis and rituximab. The present report shows that the use of the diluted Russell's viper venom time can be helpful in providing additional information on the lupus anticoagulants antibody status, allowing careful monitoring of lupus anticoagulants conversion and hence response to therapy.

Human short-chain L-3-hydroxyacyl-CoA dehydrogenase: cloning and characterization of the coding sequence.

The cDNA encompassing the complete coding sequence of human liver short-chain L-3-hydroxyacyl-CoA dehydrogenase (SCHAD) was isolated and characterized. Screening of a cDNA library combined with rapid amplification of 5' cDNA ends resulted in a SCHAD cDNA sequence of 1877 bp. It encodes a protein of 314 amino acids with a calculated molecular weight of 34.3 kDA containing a mitochondrial import signal peptide of 12 amino acids and 302 amino acids of mature SCHAD protein. The deduced amino acid sequence of the mature protein shows a 92 percent identity with SCHAD from pig heart. Northern blot analysis reveals SCHAD mRNA to be expressed in liver, kidney, pancreas, heart and skeletal muscle. The human SCHAD gene was mapped by fluorescence in situ hybridization to chromosome 4q22-26.

Structural organization of the human short-chain L-3-hydroxyacyl-CoA dehydrogenase gene.

The third step in the mitochondrial beta-oxidation spiral of short-chain fatty acids is catalyzed by short-chain L-3-hydroxyacyl-CoA dehydrogenase (HADHSC; EC 1.1.1.35). We have determined the structural organization of the human HADHSC gene by sequencing of cloned genomic amplification products, obtained using HADHSC-specific cDNA-based primers, as well as by direct sequencing of an isolated PAC clone containing the HADHSC gene. Upon comparison with the HADHSC cDNA sequence, HADHSC was shown to encompass at least eight exons, ranging in size from 73 to 158 bp, and 7 introns. The total HADHSC gene spans approximately 49 kb. The HADHSC 5'-flanking region was characterized with an AluI plasmid library constructed from a partially AluI-digested PAC clone containing the human HADHSC gene. Several typical promoter elements such as a CAAT-box, Sp1, AP1, and AP2 sites were found, while a TATA-box was apparently absent. Among other putative regulatory elements, a NRRE-1 site was identified. By radiation hybrid panel, assisted fine-mapping HADHSC was linked to marker AFM070TH5, corresponding to Chromosome (Chr) 4q22-26, and a putative HADHSC pseudogene was linked to marker D15S1324, located at Chr 15q17-21. Knowledge of the genomic organization and 5'-flanking region of HADHSC will enable genomic mutation analysis of patients suspected of HADHSC deficiency, as well as facilitate the investigation into the transcriptional regulation of short-chain fatty acid oxidizing gene products in general and HADHSC expression in particular.