Remote ischemic preconditioning for cardioprotection in elective inpatient abdominal surgery - a randomized controlled trial.

BACKGROUND: Perioperative myocardial injury (PMI) is common in elective inpatient abdominal surgery and correlates with mortality risk. Simple measures for reducing PMI in this cohort are needed. This study evaluated whether remote ischemic preconditioning (RIPC) could reduce PMI in elective inpatient abdominal surgery. METHODS: This was a double-blind, sham-controlled trial with 1:1 parallel randomization. PMI was defined as any post-operative serum troponin T (hs-TNT) > 14 ng/L. Eighty-four participants were randomized to receiving RIPC (5 min of upper arm ischemia followed by 5 min reperfusion, for three cycles) or a sham-treatment immediately prior to surgery. The primary outcome was mean peak post-operative troponin in patients with PMI, and secondary outcomes included mean hs-TnT at individual timepoints, post-operative hs-TnT area under the curve (AUC), cardiovascular events and mortality. Predictors of PMI were also collected. Follow up was to 1 year. RESULTS: PMI was observed in 21% of participants. RIPC did not significantly influence the mean peak post-operative hs-TnT concentration in these patients (RIPC 25.65 ng/L [SD 9.33], sham-RIPC 23.91 [SD 13.2], mean difference 1.73 ng/L, 95% confidence interval - 9.7 to 13.1 ng/L, P = 0.753). The treatment did not influence any secondary outcome with the pre-determined definition of PMI. Redefining PMI as > 5 ng/L in line with recent data revealed a non-significant lower incidence in the RIPC cohort (68% vs 81%, P = 0.211), and significantly lower early hs-TnT release (12 h time-point, RIPC 5.5 ng/L [SD 5.5] vs sham 9.1 ng/L [SD 8.2], P = 0.03). CONCLUSIONS: RIPC did not at reduce the incidence or severity of PMI in these general surgical patients using pre-determined definitions. PMI is nonetheless common and effective cardioprotective strategies are required. TRIAL REGISTRATION: This trial was registered with Clinicaltrials.gov, NCT01850927 , 5th July 2013.

Where have all the trisomies gone?

Providing reliable prenatal screening performance estimates is critical for patient counseling and policy-making. Women who choose prenatal screening for aneuploidy are likely to be concerned not only with the common aneuploidies but with all causes of intellectual disability and serious birth defects. Sequential prenatal screening (combined serum and ultrasound testing) for aneuploidy detection commonly is offered as a primary screening test. Among women identified as screen positive, cell-free (cf)DNA has been added recently as a secondary, noninvasive screening option, before the consideration of invasive diagnostic testing (eg, amniocentesis and karyotype). With the anticipation of lower costs in the future, cfDNA might be an alternative to sequential screening in the general population. Sequential and cfDNA tests are both noninvasive, and both identify common aneuploidies. Screening via cfDNA detects more common chromosome abnormalities (eg, trisomy 21, sex trisomies). Sequential screening can identify other aneuploidies (eg, triploidy), as well as chromosome abnormalities associated with fetal structural abnormalities. When the advantages and disadvantages of routine sequential screening with routine cfDNA screening are compared, one important measure is the proportion and severity of chromosome abnormalities identified. When reporting these detection rates, authors need to carefully consider the impact of multiple well-described biases. For women to make informed choices in situations of this type, determining reliable comparative performance estimates is crucial.

Modeling risk for severe adverse outcomes using angiogenic factor measurements in women with suspected preterm preeclampsia.

INTRODUCTION: Preeclampsia (PE) is a pregnancy-specific syndrome associated with adverse maternal and fetal outcomes. Patient-specific risks based on angiogenic factors might better categorize those who might have a severe adverse outcome. METHODS: Women evaluated for suspected PE at a tertiary hospital (2009-2012) had pregnancy outcomes categorized as 'referent' or 'severe', based solely on maternal/fetal findings. Outcomes that may have been influenced by a PE diagnosis were considered 'unclassified'. Soluble fms-like tyrosine kinase (sFlt1) and placental growth factor (PlGF) were subjected to bivariate discriminant modeling, allowing patient-specific risks to be assigned for severe outcomes. RESULTS: Three hundred twenty-eight singleton pregnancies presented at ≤34.0 weeks' gestation. sFlt1 and PlGF levels were adjusted for gestational age. Risks above 5 : 1 (10-fold over background) occurred in 77% of severe (95% CI 66 to 87%) and 0.7% of referent (95% CI <0.1 to 3.8%) outcomes. Positive likelihood ratios for the modeling and validation datasets were 19 (95% CI 6.2-58) and 15 (95% CI 5.8-40) fold, respectively. CONCLUSIONS: This validated model assigns patient-specific risks of any severe outcome among women attending PE triage. In practice, women with high risks would receive close surveillance with the added potential for reducing unnecessary preterm deliveries among remaining women. © 2015 The Authors. Prenatal Diagnosis published by John Wiley & Sons Ltd.

External validation of the Oakland Score to assess safe hospital discharge among adult patients with acute lower gastrointestinal bleeding in a single New Zealand Centre.

BACKGROUND: Acute lower gastrointestinal bleeding (LGIB) is a common reason for hospital admission. However, the majority resolve spontaneously and only a minority require inpatient intervention. We aimed to describe the epidemiology and aetiology of acute LGIB admissions in our institution. We also aimed to validate the Oakland Score, which can identify patients at low risk of adverse outcome from LGIB, in our population and determine the proportion who could have safely avoided admission. METHODS: Using the prospective, validated Otago Clinical Audit database (DIVA), we searched for adult patients admitted to Dunedin Hospital with a primary diagnosis of LGIB between January 2013 and December 2020. We retrieved data to calculate the Oakland Score and details of inpatient treatment from the electronic patient record. We excluded patients admitted electively, admissions related to inflammatory bowel disease, and those with upper gastrointestinal bleeding. RESULTS: We identified 761 patients of which 501 met inclusion criteria (56% male, median age 76 years, 82% NZ European). Overall, 72% were managed with observation or diagnostic endoscopy, 32% received blood products, and 7% required haemostatic intervention to control bleeding. The area under the receiver operating characteristic curve for the Oakland Score was 0.85 (95% CI, 0.81-0.89). A cut-off score of ≤10 predicted a 95% probability of safely avoiding admission. This equates to saving 30 bed-days annually. CONCLUSION: The majority of patients admitted with LGIB are managed conservatively. The Oakland Score could be used as a stratification tool to safely reduce the admission rate.

Improving the efficiency and relevance of evidence-based recommendations in the era of whole-genome sequencing: an EGAPP methods update.

To provide an update on recent revisions to Evaluation of Genomic Applications in Practice and Prevention (EGAPP) methods designed to improve efficiency, and an assessment of the implications of whole genome sequencing for evidence-based recommendation development. Improvements to the EGAPP approach include automated searches for horizon scanning, a quantitative ranking process for topic prioritization, and the development of a staged evidence review and evaluation process. The staged process entails (i) triaging tests with minimal evidence of clinical validity, (ii) using and updating existing reviews, (iii) evaluating clinical validity prior to analytic validity or clinical utility, (iv) using decision modeling to assess potential clinical utility when direct evidence is not available. EGAPP experience to date suggests the following approaches will be critical for the development of evidence based recommendations in the whole genome sequencing era: (i) use of triage approaches and frameworks to improve efficiency, (ii) development of evidence thresholds that consider the value of further research, (iii) incorporation of patient preferences, and (iv) engagement of diverse stakeholders. The rapid advances in genomics present a significant challenge to traditional evidence based medicine, but also an opportunity for innovative approaches to recommendation development.

The impact of maternal plasma DNA fetal fraction on next generation sequencing tests for common fetal aneuploidies.

Maternal plasma contains circulating cell-free DNA fragments originating from both the mother and the placenta. The proportion derived from the placenta is known as the fetal fraction. When measured between 10 and 20 gestational weeks, the average fetal fraction in the maternal plasma is 10% to 15% but can range from under 3% to over 30%. Screening performance using next-generation sequencing of circulating cell-free DNA is better with increasing fetal fraction and, generally, samples whose values are less than 3% or 4% are unsuitable. Three examples of the clinical impact of fetal fraction are discussed. First, the distribution of test results for Down syndrome pregnancies improves as fetal fraction increases, and this can be exploited in reporting patient results. Second, the strongest factor associated with fetal fraction is maternal weight; the false negative rate and rate of low fetal fractions are highest for women with high maternal weights. Third, in a mosaic, the degree of mosaicism will impact the performance of the test because it will reduce the effective fetal fraction. By understanding these aspects of the role of fetal fraction in maternal plasma DNA testing for aneuploidy, we can better appreciate the power and the limitations of this impressive new methodology.

DNA sequencing of maternal plasma reliably identifies trisomy 18 and trisomy 13 as well as Down syndrome: an international collaborative study.

PURPOSE: To determine whether maternal plasma cell-free DNA sequencing can effectively identify trisomy 18 and 13. METHODS: Sixty-two pregnancies with trisomy 18 and 12 with trisomy 13 were selected from a cohort of 4,664 pregnancies along with matched euploid controls (including 212 additional Down syndrome and matched controls already reported), and their samples tested using a laboratory-developed, next-generation sequencing test. Interpretation of the results for chromosome 18 and 13 included adjustment for CG content bias. RESULTS: Among the 99.1% of samples interpreted (1,971/1,988), observed trisomy 18 and 13 detection rates were 100% (59/59) and 91.7% (11/12) at false-positive rates of 0.28% and 0.97%, respectively. Among the 17 samples without an interpretation, three were trisomy 18. If z-score cutoffs for trisomy 18 and 13 were raised slightly, the overall false-positive rates for the three aneuploidies could be as low as 0.1% (2/1,688) at an overall detection rate of 98.9% (280/283) for common aneuploidies. An independent academic laboratory confirmed performance in a subset. CONCLUSION: Among high-risk pregnancies, sequencing circulating cell-free DNA detects nearly all cases of Down syndrome, trisomy 18, and trisomy 13, at a low false-positive rate. This can potentially reduce invasive diagnostic procedures and related fetal losses by 95%. Evidence supports clinical testing for these aneuploidies.

DNA sequencing of maternal plasma to identify Down syndrome and other trisomies in multiple gestations.

OBJECTIVE: Studies on prenatal testing for Down syndrome (trisomy 21), trisomy 18, and trisomy 13 by massively parallel shotgun sequencing (MPSS) of circulating cell free DNA have been, for the most part, limited to singleton pregnancies. If MPSS testing is offered clinically, it is important to know if these trisomies will also be identified in multiple pregnancies. METHOD: Among a cohort of 4664 high-risk pregnancies, maternal plasma samples were tested from 25 twin pregnancies (17 euploid, five discordant and two concordant for Down syndrome; one discordant for trisomy 13) and two euploid triplet pregnancies [Correction made here after initial online publication.]. Results were corrected for GC content bias. For each target chromosome (21, 18, and 13), z-scores of 3 or higher were considered consistent with trisomy. RESULTS: Seven twin pregnancies with Down syndrome, one with trisomy 13, and all 17 twin euploid pregnancies were correctly classified [detection rate 100%, 95% confidence interval (CI) 59%-100%, false positive rate 0%, 95% CI 0%-19.5%], as were the two triplet euploid pregnancies. CONCLUSION: Although study size is limited, the underlying biology combined with the present data provide evidence that MPSS testing can be reliably used as a secondary screening test for Down syndrome in women with high-risk twin gestations.

Lack of anti-TNF drugs levels in fistula tissue - a reason for nonresponse in Crohn's perianal fistulating disease?

INTRODUCTION: Anti-TNF therapy is recommended as treatment for patients with Crohn´s perianal fistulas. However, a significant proportion of patients have a sub-optimal response to anti-TNF therapy. Higher serum levels of anti-TNF agents have been associated with improved outcomes in perianal Crohn's disease. Currently, it is unknown whether anti-TNF agent levels can be detected in tissue from fistula tracts themselves and whether this is associated with response. AIMS AND METHODS: We undertook a pilot study to measure fistula tissue levels of anti-TNF medication (infliximab and adalimumab). We used a previously validated targeted proteomic technique, employing ultraperformance liquid chromatography-mass spectrometry, to detect/quantify anti-TNF drugs. Biopsies were obtained from fistula tracts of patients with Crohn's disease on maintenance treatment; with idiopathic (cryptoglandular) fistula tissues used as negative controls as well as positive controls (by spiking the latter tissues with anti-TNF drugs). RESULTS: Tissue was sampled from the fistula tracts of seven patients with Crohn's perianal disease (five patients were on adalimumab and two patients were on infliximab). The anti-TNF drugs, infliximab and adalimumab, were not detected in fistula samples from any of the Crohn's patients despite detection in 'spiked' positive control samples. CONCLUSION: Absence of detection of the anti-TNF drugs in fistula tissue raises the question on the role of tissue penetrance of anti-TNF drugs in response to therapy. Further work is required in a larger number of patients to validate the findings observed and investigate if any correlation exists between tissue and serum levels of anti-TNF and clinical outcome. SUMMARY: Predicting response in Crohn's fistula patients on biologic therapy is difficult with no reliable biomarkers. This pilot study uses targeted proteomics to investigate the potential role of tissue drug levels in acting as a biomarker of treatment response.

DNA sequencing of maternal plasma to detect Down syndrome: an international clinical validation study.

PURPOSE: Prenatal screening for Down syndrome has improved, but the number of resulting invasive diagnostic procedures remains problematic. Measurement of circulating cell-free DNA in maternal plasma might offer improvement. METHODS: A blinded, nested case-control study was designed within a cohort of 4664 pregnancies at high risk for Down syndrome. Fetal karyotyping was compared with an internally validated, laboratory-developed test based on next-generation sequencing in 212 Down syndrome and 1484 matched euploid pregnancies. None had been previously tested. Primary testing occurred at a CLIA-certified commercial laboratory, with cross validation by a CLIA-certified university laboratory. RESULTS: Down syndrome detection rate was 98.6% (209/212), the false-positive rate was 0.20% (3/1471), and the testing failed in 13 pregnancies (0.8%); all were euploid. Before unblinding, the primary testing laboratory also reported multiple alternative interpretations. Adjusting chromosome 21 counts for guanine cytosine base content had the largest impact on improving performance. CONCLUSION: When applied to high-risk pregnancies, measuring maternal plasma DNA detects nearly all cases of Down syndrome at a very low false-positive rate. This method can substantially reduce the need for invasive diagnostic procedures and attendant procedure-related fetal losses. Although implementation issues need to be addressed, the evidence supports introducing this testing on a clinical basis.

The relationship between PTH and 25-hydroxy vitamin D early in pregnancy.

OBJECTIVE: Measure serum PTH and 25(OH)D in a cross-sectional sample of pregnant women at 11th through 13th weeks' gestation to examine vitamin D status and consider implications. DESIGN: Observational: we retrieved residual sera stored at -20 °C after routine first trimester Down's syndrome screening, distributed over 12 months. PATIENTS: 430 African American women and 586 Caucasian women. MEASUREMENTS: PTH and 25-hydroxy vitamin D [25(OH)D] immunoassays. RESULTS: PTH medians were: 1·33 pmol/l (African American women); 1·20 pmol/l (Caucasian women) (t = 0·43, P = 0·7). Concentrations were highest in winter and decreased significantly in spring, fall, and summer. There was a direct PTH/weight relationship in Caucasian (t = 3·12, P < 0·002), but not African American women (t = 1·34, P = 0·18). Median 25(OH)D concentrations were 47·5 nmol/l (African American women) and 65 nmol/l (Caucasian women) (t = 13·7, P < 0·001). Concentrations were lowest in winter and rose significantly in spring, fall, and summer. Reciprocal 25(OH)D/weight relationships existed for both racial groups (t =-4·31 P < 0·001; t = 4·54, P < 0·001, respectively). Among 68 Caucasian women who smoked, median PTH and 25(OH)D concentrations were somewhat lower (P = ns). In separate regression models with PTH and 25(OH)D [dependent variables] and season, weight and smoking [independent variables], the only qualifying interactive term was in the Caucasian PTH model (season*1/weight). A regression model applied to adjusted scatter plots of PTH vs 25(OH)D indicated a weak relationship. CONCLUSIONS: The PTH/25(OH)D relationship is weaker during early pregnancy than in non-pregnant adults, making it unreliable for estimating vitamin D sufficiency. A suitable reference point for sufficiency might be the maternal 25(OH)D level considered sufficient for adequate transfer to neonates.

Outcomes of interest in evidence-based evaluations of genetic tests.

Genetic tests are increasingly available for use in traditional clinical practice settings and through direct-to-consumer marketing. The need for evidence-based information and guidance on their appropriate use has never been more apparent. The independent Working Group of the Evaluation of Genomic Applications in Practice and Prevention Initiative commissions evidence-based reviews and develops recommendations to inform decision making surrounding the implementation of genetic tests and other applications of genomic technologies into clinical practice. A critical component of this analysis involves the identification and appropriate weighting of relevant health outcomes from genetic testing. Impacts of testing on morbidity and mortality are central considerations although research to document such outcomes can be challenging to conduct. In considering the broader impacts of genetic tests on the individual, familial and societal levels, psychosocial outcomes often take on increasing importance, and their systematic evaluation is a challenge for traditional methods of evidence-based review. Incorporating these types of outcomes in evidence-based processes is possible, however, and necessary to extract balanced and complete (or as complete as available data will allow) information on potential benefits and on potential harms. The framework used by the Evaluation of Genomic Applications in Practice and Prevention Working Group in considering, categorizing, and weighting health-related outcomes as applied to genomic technologies is presented here.

Prevalence of steroid sulfatase deficiency in California according to race and ethnicity.

OBJECTIVE: Estimate steroid sulfatase deficiency (STSD) prevalence among California's racial/ethnic groups using data from a previous study focused on prenatal detection of Smith-Lemli-Opitz syndrome (SLOS). SLOS and STSD both have low maternal serum unconjugated estriol (uE3) levels. METHODS: Prevalence was estimated using three steps: listing clinically identified cases; modeling STSD frequency at three uE3 intervals using diagnostic urine steroid measurements; applying this model to determine frequency in pregnancies not providing urine. RESULTS: Overall, 2151 of 777 088 pregnancies (0.28%) were screen positive; 1379 of these were explained and excluded. Fifty-four cases were diagnosed clinically among 707 remaining pregnancies with a male fetus. Urine steroid testing identified 74 additional STSD cases: 66 (89.2%) at uE3 values < 0.15 MoM, 8 (10.8%) at 0.15-0.20 MoM, and 0 (0%) at > 0.20 MoM. Modeling estimated 107.5 STSD cases among 370 pregnancies without urine samples. In males, STSD prevalence was highest among non-Hispanic Whites (1:1230) compared to Hispanics (1:1620) and Asians (1:1790), but differences were not significant. No STSD pregnancies were found among 65 screen positive Black women. CONCLUSION: The overall prevalence estimate of 1:1500 males is consistent with published estimates and is reasonable for counseling, except among Black pregnancies where no reliable estimate could be made.

The Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Initiative: methods of the EGAPP Working Group.

The Evaluation of Genomic Applications in Practice and Prevention (EGAPP) Initiative, established by the National Office of Public Health Genomics at the Centers for Disease Control and Prevention, supports the development and implementation of a rigorous, evidence-based process for evaluating genetic tests and other genomic applications for clinical and public health practice in the United States. An independent, non-federal EGAPP Working Group (EWG), a multidisciplinary expert panel selects topics, oversees the systematic review of evidence, and makes recommendations based on that evidence. This article describes the EGAPP processes and details the specific methods and approaches used by the EWG.

Maternal urine and serum steroid measurements to identify steroid sulfatase deficiency (STSD) in second trimester pregnancies.

OBJECTIVE: To document the performance of second trimester maternal urine and serum steroid measurements for detecting fetal steroid sulfatase deficiency (STSD). METHODS: We studied detection rate and false positive rate (DR, FPR) of analytes in maternal urine [combinations of 16alpha-OH-dehydroepiandrosterone sulfate (16alpha-OH-DHEAS), 11beta-hydroxyandrosterone, total estriol] and serum [combinations of 16alpha-OH-DHEAS, 11beta-hydroxyandrosterone, total estriol, unconjugated estriol (uE3)]. Samples were obtained from pregnancies which were screen positive for Smith-Lemli-Opitz syndrome (SLOS). RESULTS: Among 1 079 301 pregnancies, 3083 (0.29%) were screen positive for SLOS. Urine and/or serum samples were available from 917 viable pregnancies with known gender. We assigned likelihood ratios (LRs) to steroid measurements from male fetuses with known STSD and unaffected female fetuses. An LR > or = 100 was present in urine from 84 of 86 STSD pregnancies (98% DR, 95% CI 92-99), along with 0 of 198 pregnancies with normal female fetuses (0.0% FPR, CI 0-1.9). LRs were > or = 100 in 4 of 129 female fetuses with major abnormalities (3% FPR). In maternal serum, steroid measurements performed less effectively, achieving a 71% DR for STSD at a 1.6% FPR. CONCLUSION: Maternal urine steroid measurements are effective for detecting STSD, including those with point mutations and those with full deletions.

Comparison of cytokine and phosphoprotein profiles in idiopathic and Crohn's disease-related perianal fistula.

BACKGROUND: Perianal fistulae are either primary (idiopathic) or secondary [commonly associated with Crohn's disease, (CD)]. It is assumed, although not proven, that the pathophysiology differs. AIM: To systematically compare the clinical phenotypes, cytokine and phosphoprotein profiles of idiopathic and CD-related perianal fistulae. METHODS: Sixty-one patients undergoing surgery for perianal fistula were prospectively recruited (48 idiopathic, 13 CD) into a cohort study. Clinical data, including the Perineal Disease Activity Index (PDAI) and EQ-5D-5L were collected. Biopsies of the fistula tract, granulation tissue, internal opening mucosa and rectal mucosa were obtained at surgery. Concentrations of 30 cytokines and 39 phosphoproteins were measured in each biopsy using a magnetic bead multiplexing instrument and a chemiluminescent antibody array respectively. Over 12000 clinical and 23500 laboratory measurements were made. RESULTS: The PDAI was significantly higher (indicating more active disease) in the CD group with a mean difference of 2.40 (95%CI: 0.52-4.28, P = 0.01). Complex pathoanatomy was more prevalent in the CD group, namely more multiple fistulae, supralevator extensions, collections and rectal thickening. The IL-12p70 concentration at the internal opening specimen site was significantly higher (median difference 19.7 pg/mL, 99%CI: 0.2-40.4, P = 0.008) and the IL-1RA/IL-1ß ratio was significantly lower in the CD group at the internal opening specimen site (median difference 15.0, 99%CI = 0.4-50.5, P = 0.008). However in the remaining 27 cytokines and all 39 of the phosphoproteins across the four biopsy sites, no significant differences were found between the groups. CONCLUSION: CD-related perianal fistulae are more clinically severe and anatomically complex than idiopathic perianal fistulae. However, overall there are no major differences in cytokine and phosphoprotein profiles.

Maternal BMI, Peripheral Deiodinase Activity, and Plasma Glucose: Relationships Between White Women in the HAPO Study.

OBJECTIVES: Explore the maternal body mass index (BMI) relationship with peripheral deiodinase activity further. Examine associations between deiodinase activity, glucose, and C-peptide. Consider findings in the historical context of related existing literature. DESIGN: Identify fasting plasma samples and selected demographic, biophysical, and biochemical data from a subset of 600 randomly selected non-Hispanic white women recruited in the Hyperglycemia Adverse Pregnancy Outcomes (HAPO) study, all with glucose tolerance testing [545 samples sufficient to measure TSH, free T4 (fT4), and T3]. Exclude highest and lowest 1% TSH values (535 available for analysis). Assess deiodinase activity by using T3/fT4 ratios. Among women with and without gestational diabetes mellitus (GDM), compare thyroid measurements, C-peptide, and other selected data. Examine relationships independent of GDM status between BMI and thyroid hormones and between thyroid hormones and glucose and C-peptide. RESULTS: Levels of BMI, T3/fT4 ratio, and T3 were significantly higher among women with GDM (P = 0.01, 0.005, and 0.001, respectively). Irrespective of GDM status, maternal BMI was associated directly with both T3/fT4 ratio (r = 0.40, P < 0.001) and T3 (r = 0.34, P < 0.001) but inversely with fT4 (r = -0.21, P < 0.001). In turn, fasting thyroid hormone levels (most notably T3/fT4 ratio) were directly associated with maternal glucose [z score sum (fasting, 1, 2 hours); r = 0.24, P < 0.001] and with C-peptide [z score sum (fasting, 1 hour); r = 0.27, P < 0.001]. CONCLUSIONS: Higher BMI was associated with increased deiodinase activity, consistent with reports from elsewhere. Increased deiodinase activity, in turn, was associated with higher glucose. Deiodinase activity accounts for a small percentage of z score sum glucose.