Dihydropyrimidinase and β-ureidopropionase gene variation and severe fluoropyrimidine-related toxicity

AIMS To assess the association of DPYS and UPB1 genetic variation, encoding the catabolic enzymes downstream of dihydropyrimidine dehydrogenase, with early-onset toxicity from fluoropyrimidine-based chemotherapy. PATIENTS & METHODS The coding and exon-flanking regions of both genes were sequenced in a discovery subset (164 patients). Candidate variants were genotyped in the full cohort of 514 patients. RESULTS & CONCLUSIONS Novel rare deleterious variants in DPYS (c.253C > T and c.1217G > A) were detected once each in toxicity cases and may explain the occurrence of severe toxicity in individual patients, and associations of common variants in DPYS (c.1-1T > C: padjusted = 0.003; OR = 2.53; 95% CI: 1.39-4.62, and c.265-58T > C: padjusted = 0.039; OR = 0.61; 95% CI: 0.38-0.97) with 5-fluorouracil toxicity were replicated.

Validation of the Valve Academic Research Consortium Bleeding Definition in Patients With Severe Aortic Stenosis Undergoing Transcatheter Aortic Valve Implantation.

BACKGROUND The Valve Academic Research Consortium (VARC) has proposed a standardized definition of bleeding in patients undergoing transcatheter aortic valve interventions (TAVI). The VARC bleeding definition has not been validated or compared to other established bleeding definitions so far. Thus, we aimed to investigate the impact of bleeding and compare the predictivity of VARC bleeding events with established bleeding definitions. METHODS AND RESULTS Between August 2007 and April 2012, 489 consecutive patients with severe aortic stenosis were included into the Bern-TAVI-Registry. Every bleeding complication was adjudicated according to the definitions of VARC, BARC, TIMI, and GUSTO. Periprocedural blood loss was added to the definition of VARC, providing a modified VARC definition. A total of 152 bleeding events were observed during the index hospitalization. Bleeding severity according to VARC was associated with a gradual increase in mortality, which was comparable to the BARC, TIMI, GUSTO, and the modified VARC classifications. The predictive precision of a multivariable model for mortality at 30 days was significantly improved by adding the most serious bleeding of VARC (area under the curve [AUC], 0.773; 95% confidence interval [CI], 0.706 to 0.839), BARC (AUC, 0.776; 95% CI, 0.694 to 0.857), TIMI (AUC, 0.768; 95% CI, 0.692 to 0.844), and GUSTO (AUC, 0.791; 95% CI, 0.714 to 0.869), with the modified VARC definition resulting in the best predictivity (AUC, 0.814; 95% CI, 0.759 to 0.870). CONCLUSIONS The VARC bleeding definition offers a severity stratification that is associated with a gradual increase in mortality and prognostic information comparable to established bleeding definitions. Adding the information of periprocedural blood loss to VARC may increase the sensitivity and the predictive power of this classification.

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.

Plant regeneration directs changes in grassland composition after extreme drought: a 13-year study in southern Switzerland

1. The cover of plant species was recorded annually from 1988 to 2000 in nine spatially replicated plots in a species-rich, semi-natural meadow at Negrentino (southern Alps). This period showed large climatic variation and included the centennial maximum and minimum frequency of days with ≥ 10 mm of rain. 2. Changes in species composition were compared between three 4-year intervals characterized by increasingly dry weather (1988–91), a preceding extreme drought (1992–95), and increasingly wet weather (1997–2000). Redundancy analysis and anova with repeated spatial replicates were used to find trends in vegetation data across time. 3. Recruitment capacity, the potential for fast clonal growth and seasonal expansion rate were determined for abundant taxa and tested in general linear models (GLM) as predictors for rates of change in relative cover of species across the climatically defined 4-year intervals. 4. Relative cover of the major growth forms present, graminoids and forbs, changed more in the period following extreme drought than at other times. Recruitment capacity was the only predictor of species’ rates of change. 5. Following perturbation, re-colonization was the primary driver of vegetation dynamics. The dominant grasses, which lacked high recruitment from seed, therefore decreased in relative abundance. This effect persisted until the end of the study and may represent a lasting response to an extreme climatic event.

Clinical outcomes and revascularization strategies in patients with low-flow, low-gradient severe aortic valve stenosis according to the assigned treatment modality

OBJECTIVES This study compared clinical outcomes and revascularization strategies among patients presenting with low ejection fraction, low-gradient (LEF-LG) severe aortic stenosis (AS) according to the assigned treatment modality. BACKGROUND The optimal treatment modality for patients with LEF-LG severe AS and concomitant coronary artery disease (CAD) requiring revascularization is unknown. METHODS Of 1,551 patients, 204 with LEF-LG severe AS (aortic valve area <1.0 cm(2), ejection fraction <50%, and mean gradient <40 mm Hg) were allocated to medical therapy (MT) (n = 44), surgical aortic valve replacement (SAVR) (n = 52), or transcatheter aortic valve replacement (TAVR) (n = 108). CAD complexity was assessed using the SYNTAX score (SS) in 187 of 204 patients (92%). The primary endpoint was mortality at 1 year. RESULTS LEF-LG severe AS patients undergoing SAVR were more likely to undergo complete revascularization (17 of 52, 35%) compared with TAVR (8 of 108, 8%) and MT (0 of 44, 0%) patients (p < 0.001). Compared with MT, both SAVR (adjusted hazard ratio [adj HR]: 0.16; 95% confidence interval [CI]: 0.07 to 0.38; p < 0.001) and TAVR (adj HR: 0.30; 95% CI: 0.18 to 0.52; p < 0.001) improved survival at 1 year. In TAVR and SAVR patients, CAD severity was associated with higher rates of cardiovascular death (no CAD: 12.2% vs. low SS [0 to 22], 15.3% vs. high SS [>22], 31.5%; p = 0.037) at 1 year. Compared with no CAD/complete revascularization, TAVR and SAVR patients undergoing incomplete revascularization had significantly higher 1-year cardiovascular death rates (adj HR: 2.80; 95% CI: 1.07 to 7.36; p = 0.037). CONCLUSIONS Among LEF-LG severe AS patients, SAVR and TAVR improved survival compared with MT. CAD severity was associated with worse outcomes and incomplete revascularization predicted 1-year cardiovascular mortality among TAVR and SAVR patients.

Transcarotid aortic valve-in-valve implantation for degenerated stentless aortic root conduits with severe regurgitation: a case series

OBJECTIVES Transcatheter aortic valve implantation (TAVI) is routinely performed via the transfemoral and the transapical route. Subclavian and direct aortic access are described alternatives for TAVI. Recently, the transcarotid approach has been shown to be feasible among patients with limited vascular access and severe native aortic valve stenosis. We aim to investigate the feasibility of transcatheter aortic valve-in-valve implantation via the transcarotid access in patients with severe aortic regurgitation due to degenerated stentless Shelhigh conduits using the 29 mm Medtronic CoreValve bioprosthesis. METHODS Three patients with complex vascular anatomy undergoing transcatheter valve-in-valve implantation via the transcarotid route were enrolled in the study. The procedure was performed under general anaesthesia using surgical cut-down to facilitate vascular access. Immediate procedural results as well as echocardiographic and clinical outcomes after 30 days and 6 months of the follow-up were recorded and analysed. RESULTS All three patients underwent unproblematic TAVI and experienced dramatic improvement of symptoms. Mean transvalvular gradient was 3, 6 and 11 mmHg, respectively. Effective orifice area ranged between 1.7 and 2.2 cm(2). Only mild paravalvular regurgitation was detected by echocardiography after 30 days of the follow-up. CONCLUSIONS The transcarotid approach can be safely performed for valve-in-valve procedures using the Medtronic CoreValve in patients with limited vascular access. It enables accurate positioning and implantation of the prosthesis.

Millennial to orbital-scale variations of drought intensity in the Eastern Mediterranean

Millennial to orbital-scale rainfall changes in the Mediterranean region and corresponding variations in vegetation patterns were the result of large-scale atmospheric reorganizations. In spite of recent efforts to reconstruct this variability using a range of proxy archives, the underlying physical mechanisms have remained elusive. Through the analysis of a new high-resolution sedimentary section from Lake Van (Turkey) along with climate modeling experiments, we identify massive droughts in the Eastern Med- iterranean for the past four glacial cycles, which have a pervasive link with known intervals of enhanced North Atlantic glacial iceberg calving, weaker Atlantic Meridional Overturning Circulation and Dansgaard-Oeschger cold conditions. On orbital timescales, the topographic effect of large Northern Hemisphere ice sheets and periods with minimum insolation seasonality further exacerbated drought intensities by suppressing both summer and winter precipitation.

Outbreak of severe foot rot associated with benign Dichelobacter nodosus in an Alpine ibex colony in the Swiss Prealps.

An outbreak of foot rot occurred in the ibex colony "Vanil Noir" in Switzerland from May to December 2014. This article describes field observations and the analyses carried out on the limbs of 3 animals submitted for postmortem examination. Disease signs observed in the field included lameness, poor body condition and overgrown hooves. Macroscopic examination of selected limbs revealed severe lesions in all of them, including interdigital inflammation with ulceration and malodorous exudation. Histological changes were consistent with chronic laminitis with bone resorption, which was not detected at radiographical examination. Grocott-positive organisms compatible with Dichelobacternodosus were detected in the lesions. Samples collected from the lesions were positive by polymerase chain reaction for benign D. nodosus, which is typically associated with only mild lesions in domestic sheep. Whether D. nodosus is endemic in the colony or had previously been transmitted from sympatric domestic livestock is unclear. The unusual warm and humid weather conditions in 2014 may well have contributed to the outbreak.

European experience with the second-generation Edwards SAPIEN XT transcatheter heart valve in patients with severe aortic stenosis: 1-year outcomes from the SOURCE XT Registry

OBJECTIVES The SOURCE XT Registry (Edwards SAPIEN XT Aortic Bioprosthesis Multi-Region Outcome Registry) assessed the use and clinical outcomes with the SAPIEN XT (Edwards Lifesciences, Irvine, California) valve in the real-world setting. BACKGROUND Transcatheter aortic valve replacement is an established treatment for high-risk/inoperable patients with severe aortic stenosis. The SAPIEN XT is a balloon-expandable valve with enhanced features allowing delivery via a lower profile sheath. METHODS The SOURCE XT Registry is a prospective, multicenter, post-approval study. Data from 2,688 patients at 99 sites were analyzed. The main outcome measures were all-cause mortality, stroke, major vascular complications, bleeding, and pacemaker implantations at 30-days and 1 year post-procedure. RESULTS The mean age was 81.4 ± 6.6 years, 42.3% were male, and the mean logistic EuroSCORE (European System for Cardiac Operative Risk Evaluation) was 20.4 ± 12.4%. Patients had a high burden of coronary disease (44.2%), diabetes (29.4%), renal insufficiency (28.9%), atrial fibrillation (25.6%), and peripheral vascular disease (21.2%). Survival was 93.7% at 30 days and 80.6% at 1 year. At 30-day follow-up, the stroke rate was 3.6%, the rate of major vascular complications was 6.5%, the rate of life-threatening bleeding was 5.5%, the rate of new pacemakers was 9.5%, and the rate of moderate/severe paravalvular leak was 5.5%. Multivariable analysis identified nontransfemoral approach (hazard ratio [HR]: 1.84; p < 0.0001), renal insufficiency (HR: 1.53; p < 0.0001), liver disease (HR: 1.67; p = 0.0453), moderate/severe tricuspid regurgitation (HR: 1.47; p = 0.0019), porcelain aorta (HR: 1.47; p = 0.0352), and atrial fibrillation (HR: 1.41; p = 0.0014), with the highest HRs for 1-year mortality. Major vascular complications and major/life-threatening bleeding were the most frequently seen complications associated with a significant increase in 1-year mortality. CONCLUSIONS The SOURCE XT Registry demonstrated appropriate use of the SAPIEN XT THV in the first year post-commercialization in Europe. The safety profile is sustained, and clinical benefits have been established in the real-world setting. (SOURCE XT Registry; NCT01238497).

Protrusio acetabuli: joint loading with severe pincer impingement and its theoretical implications for surgical therapy

Severe pincer impingement (acetabular protrusio) is an established cause of hip pain and osteoarthritis. The proposed underlying pathomechanism is a dynamic pathological contact of the prominent acetabular rim with the femoral head-neck junction. However, this cannot explain the classically described medial osteoarthritis in these hips. We therefore asked: (1) Does an overload exist in the medial aspect of the protrusio joint? and (2) What is the influence of three contemporary joint-preserving procedures on load distribution in protrusio hips? In vivo force and motion data for walking and standing to sitting were applied to six 3D finite element models (normal, dysplasia, protrusio, acetabular rim trimming, acetabular reorientation, and combined reorientation/rim trimming). Compared with dysplasia, the protrusio joint resulted in opposite patterns of von Mises stress and contact pressure during walking. In protrusio hips, we found an overload at the medial margin of the lunate surface (54% higher than normal). Isolated rim trimming further increased the medial overload (up to 28% higher than protrusio), whereas acetabular reorientation with/without rim trimming reduced stresses by up to 25%. Our results can be used as an adjunct for surgical decision making in the treatment of acetabular protrusio.

Severe postoperative wound healing disturbance in a patient with alpha-1-antitrypsin deficiency: the impact of augmentation therapy

Wound healing disturbance is a common complication following surgery, but the underlying cause sometimes remains elusive. A 50-year-old Caucasian male developed an initially misunderstood severe wound healing disturbance following colon and abdominal wall surgery. An untreated alpha-1-antitrypsin (AAT) deficiency in the patient's medical history, known since 20 years and clinically apparent as a mild to moderate chronic obstructive pulmonary disease, was eventually found to be at its origin. Further clinical work-up showed AAT serum levels below 30% of the lower reference value; phenotype testing showed a ZZ phenotype and a biopsy taken from the wound area showed the characteristic, disease-related histological pattern of necrotising panniculitits. Augmentation therapy with plasma AAT was initiated and within a few weeks, rapid and adequate would healing was observed. AAT deficiency is an uncommon but clinically significant, possible cause of wound healing disturbances. An augmentation therapy ought to be considered in affected patients during the perioperative period.