Clinical relevance of cytomegalovirus viraemia(*,†)

Using new sensitive quantitative polymerase chain reaction (PCR) assays, cytomegalovirus (CMV) DNA is often detectable in the plasma of immunosuppressed patients. We investigated the prognostic value of a positive CMV DNA test for the development of CMV end-organ disease, other AIDS-defining events and mortality.

Clinical relevance of coronary angiography at the time of percutaneous closure of a patent foramen ovale

BACKGROUND: The value of incidental coronary angiography during percutaneous shunt closure to screen for asymptomatic coronary artery disease (CAD) is unknown. METHODS: On the occasion of percutaneous closure of patent foramen ovale (PFO), incidental coronary angiography routinely offered to men >40 and women >50 years, or younger patients with particular risk patterns, was performed in 575 patients (64% men, mean age 55 +/- 10 years, mean 1.5 +/- 1.1 cardiovascular risk factors) without overt history, signs, or symptoms of CAD. RESULTS: CAD was found in 164 patients (29%); 53 (9%) had >or=50% diameter stenoses. Thirty patients (5%) had one-vessel, 13 (2%) two-vessel, and 10 (2%) three-vessel disease. Patients with CAD (n = 164) were older (60 +/- 9 vs. 53 +/- 10 years; P < 0.0001), more frequently male (76% vs. 59%; P = 0.0002), and had a higher body mass index (26.5 +/- 4.0 vs. 25.4 +/- 4.6; P = 0.006) and more cardiovascular risk factors (2.0 +/- 1.1 vs. 1.2 +/- 1.0; P < 0.0001). There were six procedural complications (1%). Two were unequivocally related to coronary angiography: one minor stroke (diplopia), and one iatrogenic dissection of the right coronary ostium requiring stenting. Furthermore, four arteriovenous fistulae at the puncture site requiring elective surgical closure were possibly related to coronary angiography. Forty-five patients (8% of total) underwent percutaneous (n = 43) or surgical (n = 2) revascularization. CONCLUSIONS: In selected asymptomatic patients referred for percutaneous PFO closure, incidental coronary angiography discloses a rather high prevalence of clinically unsuspected CAD. These findings are relevant not only for timely revascularization but also for maintenance of long-term antiplatelet therapy beyond the few months recommended after PFO closure.

Evaluation of the diagnostic value of serologic microagglutination testing and a polymerase chain reaction assay for diagnosis of acute leptospirosis in dogs in a referral center.

OBJECTIVE To determine the diagnostic value of a serologic microagglutination test (MAT) and a PCR assay on urine and blood for the diagnosis of leptospirosis in dogs with acute kidney injury (AKI). DESIGN Cross-sectional study. Animals-76 dogs with AKI in a referral hospital (2008 to 2009). PROCEDURES Dogs' leptospirosis status was defined with a paired serologic MAT against a panel of 11 Leptospira serovars as leptospirosis-associated (n = 30) or nonleptospirosis-associated AKI (12). In 34 dogs, convalescent serologic testing was not possible, and leptospirosis status was classified as undetermined. The diagnostic value of the MAT single acute or convalescent blood sample was determined in dogs in which leptospirosis status could be classified. The diagnostic value of a commercially available genus-specific PCR assay was evaluated by use of 36 blood samples and 20 urine samples. RESULTS Serologic acute testing of an acute blood sample had a specificity of 100% (95% CI, 76% to 100%), a sensitivity of 50% (33% to 67%), and an accuracy of 64% (49% to 77%). Serologic testing of a convalescent blood sample had a specificity of 92% (65% to 99%), a sensitivity of 100% (87% to 100%), and an accuracy of 98% (88% to 100%). Results of the Leptospira PCR assay were negative for all samples from dogs for which leptospirosis status could be classified. CONCLUSIONS AND CLINICAL RELEVANCE Serologic MAT results were highly accurate for diagnosis of leptospirosis in dogs, despite a low sensitivity for early diagnosis. In this referral setting of dogs pretreated with antimicrobials, testing of blood and urine samples with a commercially available genus-specific PCR assay did not improve early diagnosis.

Magmatic–hydrothermal molybdenum isotope fractionation and its relevance to the igneous crustal signature

We analysed the Mo isotope composition of a comprehensive series of molybdenite samples from the porphyry- type Questa deposit (NM, USA), as well as one rhyolite and one granite sample, directly associated with the Mo mineralization. The δ98Mo of the molybdenites ranges between −0.48‰ and +0.40‰, with a median at −0.05‰. The median Mo isotope composition increases from early magmatic (−0.29‰) to hydrothermal (−0.05‰) breccia mineralization (median bulk breccia = −0.17‰) to late stockwork veining (+0.22‰). Moreover, variations of up to 0.34‰ are found between different molybdenite crystals within an individual hand specimen. The rhyolite sample with 0.12 μg g−1 Mo has δ98Mo = −0.57‰ and is lighter than all molybde- nites from the Questa deposit, interpreted to represent the igneous leftover after aqueous ore fluid exsolution. We recognize three Mo isotope fractionation processes that occur between about 700 and 350 °C, affecting the Mo iso- tope composition of magmatic–hydrothermal molybdenites. Δ1Mo: Minerals preferentially incorporate light Mo isotopes during progressive fractional crystallization in subvolcanic magma reservoirs, leaving behind a melt enriched in heavy Mo isotopes. Δ2Mo: Magmatic–hydrothermal fluids preferentially incorporate heavy Mo iso- topes upon fluid exsolution. Δ3Mo: Light Mo isotopes get preferentially incorporated in molybdenite during crys- tallization from an aqueous fluid, leaving behind a hydrothermal fluid that gets heavier with progressive molybdenite crystallization. The sum of all three fractionation processes produces molybdenites that record heavier δ98Mo compositions than their source magmas. This implies that the mean δ98Mo of molybdenites published so far (~0.4‰) likely represents a maximum value for the Mo isotope composition of Phanerozoic igneous upper crust.

The value of susceptibility-weighted imaging (SWI) in patients with non-neonatal hypoxic-ischemic encephalopathy

OBJECTIVE In susceptibility-weighted imaging (SWI) in the normal brain, cortical veins appear hypointense due to paramagnetic properties of deoxy-hemoglobin. Global cerebral anoxia decreases cerebral oxygen metabolism, thereby increasing oxy-hemoglobin levels in cerebral veins. We hypothesized that a lower cerebral oxygen extraction fraction in comatose patients with non-neonatal hypoxic ischemic encephalopathy (IHE) produce a pattern of global rarefied or pseudo-diminished cortical veins due to higher oxy-hemoglobin. PURPOSE 1. To investigate the topographic relationship between susceptibility effects in cortical veins and related diffusion restrictions on diffusion-weighted imaging (DWI) in patients with IHE. 2. To relate imaging findings to patterns of altered resting activity on surface EEG. METHODS Twenty-three IHE patients underwent MRI. EEG patterns were used to classify the depth of coma. Regional vs. global susceptibility changes on SWI and patterns of DWI restrictions were compared with the depth of coma. RESULTS All patients exhibited areas of restricted cortical diffusion and SWI abnormalities. The dominant DWI restrictions encompassed widespread areas along the precuneus, frontal and parietal association cortices and basal ganglia. For SWI, nineteen patients had generalized bi-hemispherical patterns, the EEG patterns correlated with coma grades III to V. Four patients had focal decreases of deoxy-hemoglobin following DWI restrictions; associated with normal EEGs. CONCLUSION Focal patterns of diamagnetic effects on SWI according to relative decreases in deoxy-hemoglobin due to reduced metabolic demand are associated with normal EEG in IHE patients. Global patterns indicated increased depth of coma and widespread cortical damage. CLINICAL RELEVANCE The results indicate a potential diagnostic value of SWI in patients with IHE.

Clinical relevance of DPYD variants c.1679T>G, c.1236G>A/HapB3, and c.1601G>A as predictors of severe fluoropyrimidine-associated toxicity: a systematic review and meta-analysis of individual patient data

BACKGROUND The best-known cause of intolerance to fluoropyrimidines is dihydropyrimidine dehydrogenase (DPD) deficiency, which can result from deleterious polymorphisms in the gene encoding DPD (DPYD), including DPYD*2A and c.2846A>T. Three other variants-DPYD c.1679T>G, c.1236G>A/HapB3, and c.1601G>A-have been associated with DPD deficiency, but no definitive evidence for the clinical validity of these variants is available. The primary objective of this systematic review and meta-analysis was to assess the clinical validity of c.1679T>G, c.1236G>A/HapB3, and c.1601G>A as predictors of severe fluoropyrimidine-associated toxicity. METHODS We did a systematic review of the literature published before Dec 17, 2014, to identify cohort studies investigating associations between DPYD c.1679T>G, c.1236G>A/HapB3, and c.1601G>A and severe (grade ≥3) fluoropyrimidine-associated toxicity in patients treated with fluoropyrimidines (fluorouracil, capecitabine, or tegafur-uracil as single agents, in combination with other anticancer drugs, or with radiotherapy). Individual patient data were retrieved and analysed in a multivariable analysis to obtain an adjusted relative risk (RR). Effect estimates were pooled by use of a random-effects meta-analysis. The threshold for significance was set at a p value of less than 0·0167 (Bonferroni correction). FINDINGS 7365 patients from eight studies were included in the meta-analysis. DPYD c.1679T>G was significantly associated with fluoropyrimidine-associated toxicity (adjusted RR 4·40, 95% CI 2·08-9·30, p<0·0001), as was c.1236G>A/HapB3 (1·59, 1·29-1·97, p<0·0001). The association between c.1601G>A and fluoropyrimidine-associated toxicity was not significant (adjusted RR 1·52, 95% CI 0·86-2·70, p=0·15). Analysis of individual types of toxicity showed consistent associations of c.1679T>G and c.1236G>A/HapB3 with gastrointestinal toxicity (adjusted RR 5·72, 95% CI 1·40-23·33, p=0·015; and 2·04, 1·49-2·78, p<0·0001, respectively) and haematological toxicity (adjusted RR 9·76, 95% CI 3·03-31·48, p=0·00014; and 2·07, 1·17-3·68, p=0·013, respectively), but not with hand-foot syndrome. DPYD*2A and c.2846A>T were also significantly associated with severe fluoropyrimidine-associated toxicity (adjusted RR 2·85, 95% CI 1·75-4·62, p<0·0001; and 3·02, 2·22-4·10, p<0·0001, respectively). INTERPRETATION DPYD variants c.1679T>G and c.1236G>A/HapB3 are clinically relevant predictors of fluoropyrimidine-associated toxicity. Upfront screening for these variants, in addition to the established variants DPYD*2A and c.2846A>T, is recommended to improve the safety of patients with cancer treated with fluoropyrimidines. FUNDING None.

Expected Shortfall is jointly elicitable with Value at Risk - Implications for backtesting

In this note, we comment on the relevance of elicitability for backtesting risk measure estimates. In particular, we propose the use of Diebold-Mariano tests, and show how they can be implemented for Expected Shortfall (ES), based on the recent result of Fissler and Ziegel (2015) that ES is jointly elicitable with Value at Risk.