Antibody Status and Incidence of SARS-CoV-2 Infection in Health Care Workers.

BACKGROUND: The relationship between the presence of antibodies to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and the risk of subsequent reinfection remains unclear. METHODS: We investigated the incidence of SARS-CoV-2 infection confirmed by polymerase chain reaction (PCR) in seropositive and seronegative health care workers attending testing of asymptomatic and symptomatic staff at Oxford University Hospitals in the United Kingdom. Baseline antibody status was determined by anti-spike (primary analysis) and anti-nucleocapsid IgG assays, and staff members were followed for up to 31 weeks. We estimated the relative incidence of PCR-positive test results and new symptomatic infection according to antibody status, adjusting for age, participant-reported gender, and changes in incidence over time. RESULTS: A total of 12,541 health care workers participated and had anti-spike IgG measured; 11,364 were followed up after negative antibody results and 1265 after positive results, including 88 in whom seroconversion occurred during follow-up. A total of 223 anti-spike-seronegative health care workers had a positive PCR test (1.09 per 10,000 days at risk), 100 during screening while they were asymptomatic and 123 while symptomatic, whereas 2 anti-spike-seropositive health care workers had a positive PCR test (0.13 per 10,000 days at risk), and both workers were asymptomatic when tested (adjusted incidence rate ratio, 0.11; 95% confidence interval, 0.03 to 0.44; P = 0.002). There were no symptomatic infections in workers with anti-spike antibodies. Rate ratios were similar when the anti-nucleocapsid IgG assay was used alone or in combination with the anti-spike IgG assay to determine baseline status. CONCLUSIONS: The presence of anti-spike or anti-nucleocapsid IgG antibodies was associated with a substantially reduced risk of SARS-CoV-2 reinfection in the ensuing 6 months. (Funded by the U.K. Government Department of Health and Social Care and others.).

The ratio of soluble fms-like tyrosine kinase 1 to placental growth factor predicts time to delivery and mode of birth in patients with suspected preeclampsia- a secondary analysis of the INSPIRE trial.

BACKGROUND: The ratio of soluble fms-like tyrosine kinase 1 to placental growth factor (sFLT1/PLGF) is a useful biomarker for preeclampsia. Since it is a measure of placental dysfunction, it could also be a predictor of clinical deterioration and fetal tolerance to intrapartum stress. OBJECTIVES: We tested the hypothesis that sFLT1/PLGF ratio predicts time to delivery. Secondary objectives were to examine associations between the sFLT1/PLGF ratio and mode of birth, fetal distress, need for labor induction and birthweight z-score. STUDY DESIGN: Secondary analysis of the INSPIRE trial, a randomized interventional study on prediction of preeclampsia/eclampsia in which women with suspected preeclampsia were recruited and their blood sFLT1/PLGF ratio was assessed. We stratified participants into three groups according to the ratio result: category 1 (sFLT1/PLGF≤38); category 2 (sFLT1/PLGF>38 and <85); and category 3 (sFLT1/PLGF≥85). We modelled time from sFLT1/PLGF determination to delivery using Kaplan-Meier curves and compared the three ratio categories adjusting for gestational age at sFLT1/PLGF determination and trial arm with Cox Regression. The association between ratio category and mode of delivery, induction of labour and fetal distress was assessed using a multivariable logistic regression adjusting for gestational age at sampling and trial arm. The association between birthweight z-score and sFLT1/PLGF ratio was evaluated using multiple linear regression. Subgroup analysis was conducted in women with no preeclampsia and spontaneous onset of labor; women with preeclampsia; and participants in the non-reveal arm. RESULTS: Higher ratio categories were associated with a shorter latency from sFLT1/PLGF determination to delivery (37 vs 13 vs 10 days for ratios categories 1-3 respectively), hazards ratio for category 3 ratio of 5.64 (95%CI 4.06-7.84, p<0.001). A sFLT/PlGF ratio≥85 had specificity of 92.7%(95%CI 89.0-95.1%) and sensitivity of 54.72% (95% CI, 41.3-69.5) for prediction of preeclampsia indicated delivery within 2 weeks. A ratio category 3 was also associated with decreased odds of spontaneous vaginal delivery (OR 0.47, 95%CI 0.25-0.89); an almost six fold increased risk of emergency cesarean section (OR 5.89, 95%CI 3.05-11.21); and a three-fold increased risk for intrapartum fetal distress requiring operative delivery or cesarean section (OR 3.04, 95%CI 1.53-6.05) when compared to patients with ratios≤38. Higher ratio categories were also associated with higher odds of induction of labor when compared to ratios category 1 (category 2, OR 2.20, 95%CI 1.02-4.76; category 3, OR 6.0, 95%CI 2.01-17.93); and lower median birthweight z-score. Within subgroups of women a)without preeclampsia and with spontaneous onset of labor and b)women with preeclampsia, the log ratio was significantly higher in patients requiring intervention for fetal distress or failure to progress compared to those who delivered vaginaly without intervention. In the subset of women with no preeclampsia and spontaneous onset of labour, those who required intervention for fetal distress or failure to progress had a significantly higher log ratio than those who delivered vaginaly without needing intervention. CONCLUSION: The sFLT1/PLGF ratio might be helpful in risk-stratification of patients who present with suspected preeclampsia regarding clinical deterioration, intrapartum fetal distress and mode of birth (including the need for intervention in labour).

Psychometric Evaluation of the Affect Regulation Checklist: Clinical and Community Samples, Parent-Reports and Youth Self-Reports.

The Affect Regulation Checklist (ARC) was designed to capture affect dysregulation, suppression, and reflection. Importantly, affect dysregulation has been established as a transdiagnostic mechanism underpinning many forms of psychopathology. We tested the ARC psychometric properties across clinical and community samples and through both parent-report and youth self-report information. Clinical sample: Participants included parents (n = 814; Mage = 43.86) and their child (n = 608; Mage = 13.98). Community sample: Participants included independent samples of parents (n = 578; Mage = 45.12) and youth (n = 809; Mage = 15.67). Exploratory structural equation modeling supported a three-factor structure across samples and informants. Dysregulation was positively associated with all forms of psychopathology. In general, suppression was positively associated with many forms of psychopathology, and reflection was negatively associated with externalizing problems and positively associated with internalizing problems.

An Observational Cohort Study on the Incidence of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Infection and B.1.1.7 Variant Infection in Healthcare Workers by Antibody and Vaccination Status.

BACKGROUND: Natural and vaccine-induced immunity will play a key role in controlling the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic. SARS-CoV-2 variants have the potential to evade natural and vaccine-induced immunity. METHODS: In a longitudinal cohort study of healthcare workers (HCWs) in Oxfordshire, United Kingdom, we investigated the protection from symptomatic and asymptomatic polymerase chain reaction (PCR)-confirmed SARS-CoV-2 infection conferred by vaccination (Pfizer-BioNTech BNT162b2, Oxford-AstraZeneca ChAdOx1 nCOV-19) and prior infection (determined using anti-spike antibody status), using Poisson regression adjusted for age, sex, temporal changes in incidence and role. We estimated protection conferred after 1 versus 2 vaccinations and from infections with the B.1.1.7 variant identified using whole genome sequencing. RESULTS: In total, 13 109 HCWs participated; 8285 received the Pfizer-BioNTech vaccine (1407 two doses), and 2738 the Oxford-AstraZeneca vaccine (49 two doses). Compared to unvaccinated seronegative HCWs, natural immunity and 2 vaccination doses provided similar protection against symptomatic infection: no HCW vaccinated twice had symptomatic infection, and incidence was 98% lower in seropositive HCWs (adjusted incidence rate ratio 0.02 [95% confidence interval {CI} < .01-.18]). Two vaccine doses or seropositivity reduced the incidence of any PCR-positive result with or without symptoms by 90% (0.10 [95% CI .02-.38]) and 85% (0.15 [95% CI .08-.26]), respectively. Single-dose vaccination reduced the incidence of symptomatic infection by 67% (0.33 [95% CI .21-.52]) and any PCR-positive result by 64% (0.36 [95% CI .26-.50]). There was no evidence of differences in immunity induced by natural infection and vaccination for infections with S-gene target failure and B.1.1.7. CONCLUSIONS: Natural infection resulting in detectable anti-spike antibodies and 2 vaccine doses both provide robust protection against SARS-CoV-2 infection, including against the B.1.1.7 variant.

Combining faecal immunochemical testing with blood test results for colorectal cancer risk stratification: a consecutive cohort of 16,604 patients presenting to primary care.

BACKGROUND: Faecal immunochemical tests (FITs) are used to triage primary care patients with symptoms that could be caused by colorectal cancer for referral to colonoscopy. The aim of this study was to determine whether combining FIT with routine blood test results could improve the performance of FIT in the primary care setting. METHODS: Results of all consecutive FITs requested by primary care providers between March 2017 and December 2020 were retrieved from the Oxford University Hospitals NHS Foundation Trust. Demographic factors (age, sex), reason for referral, and results of blood tests within 90 days were also retrieved. Patients were followed up for incident colorectal cancer in linked hospital records. The sensitivity, specificity, positive and negative predictive values of FIT alone, FIT paired with blood test results, and several multivariable FIT models, were compared. RESULTS: One hundred thirty-nine colorectal cancers were diagnosed (0.8%). Sensitivity and specificity of FIT alone at a threshold of 10 µg Hb/g were 92.1 and 91.5% respectively. Compared to FIT alone, blood test results did not improve the performance of FIT. Pairing blood test results with FIT increased specificity but decreased sensitivity. Multivariable models including blood tests performed similarly to FIT alone. CONCLUSIONS: FIT is a highly sensitive tool for identifying higher risk individuals presenting to primary care with lower risk symptoms. Combining blood test results with FIT does not appear to lead to better discrimination for colorectal cancer than using FIT alone.

The potential for utilising in-hospital glucose measurements to detect individuals at high risk of previously undiagnosed diabetes: Retrospective cohort study.

BACKGROUND: Many people with undiagnosed diabetes have hyperglycaemia when admitted to hospital. Inpatient hyperglycaemia can be an indication of diabetes mellitus but can also indicate a stress response. This study reports the extent to which an in-hospital maximum observed random glucose measurement is an indicator of the need for in-hospital (or subsequent) HbA1c measurement to look for undiagnosed diabetes. METHODS: Blood glucose, HbA1c, age and sex were collected for all adults following admission to a UK NHS trust hospital from 1 January 2019 to 31 December 2020. We restricted the analysis to those participants who were registered with a GP practice that uses the trust laboratory and who had at least some tests requested by those practices since 2008. We stratified individuals according to their maximum in-hospital glucose measurement and report the number of these with HbA1c measurement ≥48 mmol/mol (6.5%) prior to the index admission, and during and after admission. We calculated an estimated proportion of individuals in each blood glucose stratum without a follow-up HbA1c who could have undiagnosed diabetes. RESULTS: In toal, 764,241 glucose measurements were recorded for 81,763 individuals who were admitted to the Oxford University Hospitals Trust. The median (Q1, Q3) age was 70 (56, 81) years, and 53% were males. Of the population, 70.7% of individuals declared themselves to be of White ethnicity, 3.1% of Asian background, and 1.1% of Black background, with 23.1% unstated. Of those individuals, 22,375 (27.4%) had no previous HbA1c measurement recorded. A total of 1689 individuals had a diabetes-range HbA1c during or after their hospital admission (2.5%) while we estimate an additional 1496 (2.2%) may have undiagnosed diabetes, with the greatest proportion of these having an in-hospital glucose of ≥15 mmol/L. We estimate that the number needed to detect a possible new case of diabetes falls from 16 (in-hospital glucose 8 mmol/L to <9 mmol/L) to 4 (14 mmol/L to <15 mmol/L). CONCLUSION: The number of people who need to be tested to identify an individual who may have diabetes decreases as a testing threshold based on maximum in-hospital glucose concentration increases. Among those with hyperglycaemia and no previous HbA1c measurement in the diabetes range, there appears to be a lack of subsequent HbA1c measurement. This work identifies the potential for integrating the testing and follow-up of people, with apparently unrecognised hospital hyperglycaemia across primary and secondary care.

How should we interpret lactate in labour? A reference study.

OBJECTIVE: To investigate maternal lactate concentrations in labour and the puerperium. DESIGN: Reference study. SETTING: Tertiary obstetric unit. POPULATION: 1279 pregnant women with good perinatal outcomes at term. METHODS: Electronic patient records were searched for women who had lactate measured on the day of delivery or in the following 24 hours, but who were subsequently found to have a very low likelihood of sepsis, based on their outcomes. MAIN OUTCOME MEASURES: The normative distribution of lactate and C-reactive protein (CRP), differences according to the mode of birth, and the proportion of results above the commonly used cut-offs (≥2 and ≥4 mmol/l). RESULTS: Lactate varied between 0.4-5.4 mmol/l (median 1.8 mmol/l, interquartile range [IQR] 1.3-2.5). It was higher in women who had vaginal deliveries than caesarean sections (median 1.9 vs. 1.6 mmol/l, pdiff  < 0.001), demonstrating the association with labour (particularly active pushing in the second stage). In contrast, CRP was more elevated in women who had caesarean sections (median 71.8 mg/l) than those who had vaginal deliveries (33.4 mg/l, pdiff  < 0.001). In total, 40.8% had a lactate ≥2 mmol/l, but 95.3% were <4 mmol/l. CONCLUSIONS: Lactate in labour and the puerperium is commonly elevated above the levels expected in healthy pregnant or non-pregnant women. There is a paucity of evidence to support using lactate or CRP to make decisions about antibiotics around the time of delivery but, as lactate is rarely higher than 4 mmol/l, this upper limit may still represent a useful severity marker for the investigation and management of sepsis in labour.

Intravenous iron to treat anaemia following critical care: a multicentre feasibility randomised trial.

BACKGROUND: Anaemia is common and associated with poor outcomes in survivors of critical illness. However, the optimal treatment strategy is unclear. METHODS: We conducted a multicentre, feasibility RCT to compare either a single dose of ferric carboxymaltose 1000 mg i.v. or usual care in patients being discharged from the ICU with moderate or severe anaemia (haemoglobin ≤100 g L-1). We collected data on feasibility (recruitment, randomisation, follow-up), biological efficacy, and clinical outcomes. RESULTS: Ninety-eight participants were randomly allocated (49 in each arm). The overall recruitment rate was 34% with 6.5 participants recruited on average per month. Forty-seven of 49 (96%) participants received the intervention. Patient-reported outcome measures were available for 79/93 (85%) survivors at 90 days. Intravenous iron resulted in a higher mean (standard deviation [sd]) haemoglobin at 28 days (119.8 [13.3] vs 106.7 [14.9] g L-1) and 90 days (130.5 [15.1] vs 122.7 [17.3] g L-1), adjusted mean difference (10.98 g L-1; 95% confidence interval [CI], 4.96-17.01; P<0.001) over 90 days after randomisation. Infection rates were similar in both groups. Hospital readmissions at 90 days post-ICU discharge were lower in the i.v. iron group (7/40 vs 15/39; risk ratio=0.46; 95% CI, 0.21-0.99; P=0.037). The median (inter-quartile range) post-ICU hospital stay was shorter in the i.v. iron group but did not reach statistical significance (5.0 [3.0-13.0] vs 9.0 [5.0-16.0] days, P=0.15). CONCLUSION: A large, multicentre RCT of i.v. iron to treat anaemia in survivors of critical illness appears feasible and is necessary to determine the effects on patient-centred outcomes. CLINICAL TRIAL REGISTRATION: ISRCTN13721808 (www.isrctn.com).

The Duration, Dynamics, and Determinants of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Antibody Responses in Individual Healthcare Workers.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immunoglobulin G (IgG) antibody measurements can be used to estimate the proportion of a population exposed or infected and may be informative about the risk of future infection. Previous estimates of the duration of antibody responses vary. METHODS: We present 6 months of data from a longitudinal seroprevalence study of 3276 UK healthcare workers (HCWs). Serial measurements of SARS-CoV-2 anti-nucleocapsid and anti-spike IgG were obtained. Interval censored survival analysis was used to investigate the duration of detectable responses. Additionally, Bayesian mixed linear models were used to investigate anti-nucleocapsid waning. RESULTS: Anti-spike IgG levels remained stably detected after a positive result, for example, in 94% (95% credibility interval [CrI] 91-96%) of HCWs at 180 days. Anti-nucleocapsid IgG levels rose to a peak at 24 (95% CrI 19-31) days post first polymerase chain reaction (PCR)-positive test, before beginning to fall. Considering 452 anti-nucleocapsid seropositive HCWs over a median of 121 days from their maximum positive IgG titer, the mean estimated antibody half-life was 85 (95% CrI 81-90) days. Higher maximum observed anti-nucleocapsid titers were associated with longer estimated antibody half-lives. Increasing age, Asian ethnicity, and prior self-reported symptoms were independently associated with higher maximum anti-nucleocapsid levels and increasing age and a positive PCR test undertaken for symptoms with longer anti-nucleocapsid half-lives. CONCLUSIONS: SARS-CoV-2 anti-nucleocapsid antibodies wane within months and fall faster in younger adults and those without symptoms. However, anti-spike IgG remains stably detected. Ongoing longitudinal studies are required to track the long-term duration of antibody levels and their association with immunity to SARS-CoV-2 reinfection.

Stringent thresholds in SARS-CoV-2 IgG assays lead to under-detection of mild infections.

BACKGROUND: Thresholds for SARS-CoV-2 antibody assays have typically been determined using samples from symptomatic, often hospitalised, patients. In this setting the sensitivity and specificity of the best performing assays can both exceed 98%. However, antibody assay performance following mild infection is less clear. METHODS: We assessed quantitative IgG responses in a cohort of healthcare workers in Oxford, UK, with a high pre-test probability of Covid-19, in particular the 991/11,475(8.6%) who reported loss of smell/taste. We use anosmia/ageusia and other risk factors as probes for Covid-19 infection potentially undiagnosed by immunoassays by investigating their relationship with antibody readings either side of assay thresholds. RESULTS: The proportion of healthcare workers reporting anosmia/ageusia increased at antibody readings below diagnostic thresholds using an in-house ELISA (n = 9324) and the Abbott Architect chemiluminescent microparticle immunoassay (CMIA; n = 11,324): 426/906 (47%) reported anosmia/ageusia with a positive ELISA, 59/449 (13.1%) with high-negative and 326/7969 (4.1%) with low-negative readings. Similarly, by CMIA, 518/1093 (47.4%) with a positive result reported anosmia/ageusia, 106/686 (15.5%) with a high-negative and 358/9563 (3.7%) with a low-negative result. Adjusting for the proportion of staff reporting anosmia/ageusia suggests the sensitivity of both assays in mild infection is lower than previously reported: Oxford ELISA 89.8% (95%CI 86.6-92.8%) and Abbott CMIA 79.3% (75.9-82.7%). CONCLUSION: Following mild SARS-CoV-2 infection 10-30% of individuals may have negative immunoassay results. While lowered diagnostic thresholds may result in unacceptable specificity, our findings have implications for epidemiological analyses and result interpretation in individuals with a high pre-test probability. Samples from mild PCR-confirmed infections should be included in SARS-CoV-2 immunoassay evaluations.

SARS-CoV-2 antibody prevalence, titres and neutralising activity in an antenatal cohort, United Kingdom, 14 April to 15 June 2020.

SARS-CoV-2 IgG screening of 1,000 antenatal serum samples in the Oxford area, United Kingdom, between 14 April and 15 June 2020, yielded a 5.3% seroprevalence, mirroring contemporaneous regional data. Among the 53 positive samples, 39 showed in vitro neutralisation activity, correlating with IgG titre (Pearson's correlation p<0.0001). While SARS-CoV-2 seroprevalence in pregnancy cohorts could potentially inform population surveillance, clinical correlates of infection and immunity in pregnancy, and antenatal epidemiology evolution over time need further study.

Filling a Niche in "Ligand Space" with Bulky, Electron-Poor Phosphorus(III) Alkoxides.

The chemistry of phosphorus(III) ligands, which are of key importance in coordination chemistry, organometallic chemistry and catalysis, is dominated by relatively electron-rich species. Many of the electron-poor PIII ligands that are readily available have relatively small steric profiles. As such, there is a significant gap in "ligand space" where more sterically bulky, electron-poor PIII ligands are needed. This contribution discusses the coordination chemistry, steric and electronic properties of PIII ligands bearing highly fluorinated alkoxide groups of the general form PRn (ORF )3-n , where R=Ph, RF =C(H)(CF3 )2 and C(CF3 )3 ; n=1-3. These ligands are simple to synthesize and a range of experimental and theoretical methods suggest that their steric and electronic properties can be "tuned" by modification of their substituents, making them excellent candidates for large, electron-poor ligands.

Trends in Cancer Antigen 125 testing 2003-2014: A primary care population-based cohort study using laboratory data.

To understand Cancer Antigen 125 (CA125) testing in primary care in relation to a national guideline, we conducted a retrospective observational study including CA125 data from a well-defined region in the UK, from 2003 to 2014. 51,033 CA125 tests from 30,737 women were stratified by month and year of testing, location of test request and patient age. Absolute numbers and rates of testing, rates and proportions of positive and negative tests, and frequencies of single and repeat tests were calculated. Negative binomial and logistic regression were used to test the effect of the guideline's introduction. Primary care testing spiked in the three months following the release of the guideline. However, there was no difference in the increase in testing observed across age groups. The proportion of positive tests decreased over time despite both the rates of positive and negative tests increasing. Retesting and repeat testing were associated with the initial CA125 value with no significant difference between women whose first test was 30-35 and >35 IU/L. Large studies using linked data are required to investigate the impact of increasing CA125 testing on onward intervention and patient outcomes. CA125 guidelines should be refined to avoid over-investigation in low risk age-groups.

Do lipid microemboli induce acute kidney injury during cardiopulmonary bypass?

BACKGROUND: Acute kidney injury (AKI) following cardiopulmonary bypass affects 5% of patients, representing significant postoperative morbidity and mortality. Animal models have shown an increased uptake of lipid microemboli (LME) into the renal vasculature, potentially indicating ischaemic causation. This study tested a new lipid filtration system (RemoweLL) against a conventional system with no lipid-depleting capacity to determine the efficacy of the filtration system and its effects on renal function. METHODS: Thirty consecutive patients underwent coronary artery bypass graft surgery using either the RemoweLL filtration system (15 patients) or a conventional cardiopulmonary bypass circuit (15 patients). Renal function was assessed using cystatin C concentrations as a surrogate marker of glomerular injury, as well as perioperative glomerular filtration rate (GFR) and serum creatinine concentrations. Patients were defined as having acute renal injury if there was an increase in absolute serum creatinine ⩾3 mg/dL (26.4 µmol/L) or 1.5-fold increase from baseline as categorised using the AKIN criteria. RESULTS: Postoperative differences in LME count between the two groups were highly significant [p<0.001]. Analysis of peak cystatin C concentrations showed significantly lower levels in the LME filtration group on the 2nd postoperative morning [p=0.04]. Two-factor ANOVA revealed a trend towards interaction, but this failed to reach significance [p=0.06]. There were no differences throughout the study period in serum creatinine or GFR [p>0.05]. There were no differences in any of the serum or urinary electrolytes. CONCLUSIONS: This study has shown a trend towards improved cystatin C removal with LME filtration; with significantly lower peak concentrations, although no further evidence of renoprotection could be demonstrated. Further research is warranted to establish possible renal benefits of LME filtration in patients undergoing cardiac surgery.

Point-of-care testing of electrolytes and calcium using blood gas analysers: it is time we trusted the results.

BACKGROUND: Point-of-care testing allows rapid analysis of samples to facilitate prompt clinical decisions. Electrolyte and calcium abnormalities are common in acutely ill patients and can be associated with life-threatening consequences. There is uncertainty whether clinical decisions can be based on the results obtained from blood gas analysers or if laboratory results should be awaited. OBJECTIVES: To assess the agreement between sodium, potassium and calcium results from blood gas and laboratory mainstream analysers in a tertiary centre, with a network consisting of one referral and two peripheral hospitals, consisting of three networked clinical biochemistry laboratories. METHOD: Using the laboratory information management system database and over 11 000 paired samples in three hospital sites, the results of sodium, potassium and ionised calcium on blood gas analysers were studied over a 5-year period and compared with the corresponding laboratory results from the same patients booked in the laboratory within 1 h. RESULTS: The Pearson's linear correlation coefficient between laboratory and blood gas results for sodium, potassium and calcium were 0.92, 0.84 and 0.78, respectively. Deming regression analysis showed a slope of 1.04 and an intercept of -5.7 for sodium, slope of 0.93 and an intercept of 0.22 for potassium and a slope of 1.23 with an intercept of -0.55 for calcium. With some strict statistical assumptions, percentages of results lying outside the least significant difference were 9%, 26.7% and 20.8% for sodium, potassium and calcium, respectively. CONCLUSIONS: Most clinicians wait for the laboratory confirmation of results generated by blood gas analysers. In a large retrospective study we have shown that there is sufficient agreement between the results obtained from the blood gas and laboratory analysers to enable prompt clinical decisions to be made.

Blood CEA levels for detecting recurrent colorectal cancer.

BACKGROUND: Testing for carcino-embryonic antigen (CEA) in the blood is a recommended part of follow-up to detect recurrence of colorectal cancer following primary curative treatment. There is substantial clinical variation in the cut-off level applied to trigger further investigation. OBJECTIVES: To determine the diagnostic performance of different blood CEA levels in identifying people with colorectal cancer recurrence in order to inform clinical practice. SEARCH METHODS: We conducted all searches to January 29 2014. We applied no language limits to the searches, and translated non-English manuscripts. We searched for relevant reviews in the MEDLINE, EMBASE, MEDION and DARE databases. We searched for primary studies (including conference abstracts) in the Cochrane Central Register of Controlled Trials (CENTRAL), in MEDLINE, EMBASE, and the Science Citation Index & Conference Proceedings Citation Index - Science. We identified ongoing studies by searching WHO ICTRP and the ASCO meeting library. SELECTION CRITERIA: We included cross-sectional diagnostic test accuracy studies, cohort studies, and randomised controlled trials (RCTs) of post-resection colorectal cancer follow-up that compared CEA to a reference standard. We included studies only if we could extract 2 x 2 accuracy data. We excluded case-control studies, as the ratio of cases to controls is determined by the study design, making the data unsuitable for assessing test accuracy. DATA COLLECTION AND ANALYSIS: Two review authors (BDN, IP) assessed the quality of all articles independently, discussing any disagreements. Where we could not reach consensus, a third author (BS) acted as moderator. We assessed methodological quality against QUADAS-2 criteria. We extracted binary diagnostic accuracy data from all included studies as 2 x 2 tables. We conducted a bivariate meta-analysis. We used the xtmelogit command in Stata to produce the pooled estimates of sensitivity and specificity and we also produced hierarchical summary ROC plots. MAIN RESULTS: In the 52 included studies, sensitivity ranged from 41% to 97% and specificity from 52% to 100%. In the seven studies reporting the impact of applying a threshold of 2.5 µg/L, pooled sensitivity was 82% (95% confidence interval (CI) 78% to 86%) and pooled specificity 80% (95% CI 59% to 92%). In the 23 studies reporting the impact of applying a threshold of 5 µg/L, pooled sensitivity was 71% (95% CI 64% to 76%) and pooled specificity 88% (95% CI 84% to 92%). In the seven studies reporting the impact of applying a threshold of 10 µg/L, pooled sensitivity was 68% (95% CI 53% to 79%) and pooled specificity 97% (95% CI 90% to 99%). AUTHORS' CONCLUSIONS: CEA is insufficiently sensitive to be used alone, even with a low threshold. It is therefore essential to augment CEA monitoring with another diagnostic modality in order to avoid missed cases. Trying to improve sensitivity by adopting a low threshold is a poor strategy because of the high numbers of false alarms generated. We therefore recommend monitoring for colorectal cancer recurrence with more than one diagnostic modality but applying the highest CEA cut-off assessed (10 µg/L).

Comparative genomics of Ceriporiopsis subvermispora and Phanerochaete chrysosporium provide insight into selective ligninolysis.

Efficient lignin depolymerization is unique to the wood decay basidiomycetes, collectively referred to as white rot fungi. Phanerochaete chrysosporium simultaneously degrades lignin and cellulose, whereas the closely related species, Ceriporiopsis subvermispora, also depolymerizes lignin but may do so with relatively little cellulose degradation. To investigate the basis for selective ligninolysis, we conducted comparative genome analysis of C. subvermispora and P. chrysosporium. Genes encoding manganese peroxidase numbered 13 and five in C. subvermispora and P. chrysosporium, respectively. In addition, the C. subvermispora genome contains at least seven genes predicted to encode laccases, whereas the P. chrysosporium genome contains none. We also observed expansion of the number of C. subvermispora desaturase-encoding genes putatively involved in lipid metabolism. Microarray-based transcriptome analysis showed substantial up-regulation of several desaturase and MnP genes in wood-containing medium. MS identified MnP proteins in C. subvermispora culture filtrates, but none in P. chrysosporium cultures. These results support the importance of MnP and a lignin degradation mechanism whereby cleavage of the dominant nonphenolic structures is mediated by lipid peroxidation products. Two C. subvermispora genes were predicted to encode peroxidases structurally similar to P. chrysosporium lignin peroxidase and, following heterologous expression in Escherichia coli, the enzymes were shown to oxidize high redox potential substrates, but not Mn(2+). Apart from oxidative lignin degradation, we also examined cellulolytic and hemicellulolytic systems in both fungi. In summary, the C. subvermispora genetic inventory and expression patterns exhibit increased oxidoreductase potential and diminished cellulolytic capability relative to P. chrysosporium.