Development of a clinical prediction model for recurrence and mortality outcomes after Clostridioides difficile infection using a machine learning approach.

OBJECTIVES: Clostridioides difficile infection (CDI) is associated with a large burden of morbidity and mortality worldwide. Previous studies have developed models for predicting recurrence and mortality following CDI, but no machine learning predictive models have been developed specifically using data from Japanese patients. METHODS: Using a database of records from acute care hospitals in Japan, we extracted records from January 2012 to September 2016 (plus a 60-day lookback window). A total of 19,159 patients were included. We used a machine learning approach, XGBoost, and compared it to a traditional unregularized logistic regression model. The first 80% of the dataset (by patient index date) was used to optimize model hyperparameters and train the final models, and evaluation was performed on the remaining 20%. We measured model performance by the area under the receiver operator curve and assessed feature importance using Shapley additive explanations. RESULTS: Performance was similar between the machine learning approach and the classical logistic regression model. Logistic regression performed slightly better than XGBoost for predicting mortality. CONCLUSION: XGBoost performed slightly better than logistic regression for predicting recurrence, but it was not competitive with existing published models. Despite this, a future machine learning-based application provided in a bedside setting at low cost might be a clinically useful tool.

Incidence of and risk factors for recurrent Clostridioidesdifficile infection in Japan using a claims database: A retrospective cohort study.

This retrospective cohort study aimed to determine the incidence rates of and risk factors for recurrent Clostridioides difficile infection (rCDI) in Japan using a claims database. Inpatients of any age with ≥1 record of C. difficile infection (CDI) during the study period (January 2012-September 2016) were analyzed. We estimated the incidence rate of health care onset, health care facility associated (HO-HCFA) primary CDI and HO-HCFA rCDI for each of the first to fifth recurrences. Risk factors for the first recurrence were investigated using a univariate, and subsequently, a multivariable Cox regression model. The incidence rates (95% confidence interval [CI]) of CDI and HO-HCFA CDI were 2.43 (2.40-2.46) and 1.26 (1.24-1.28) cases per 10,000 inpatient-days, respectively. Among the 11,287 inpatients with ≥1 HO-HCFA CDI, 1424 patients had ≥1 recurrent episode (12.6% [95% CI 12.0-13.2]). The rCDI incidence rates consistently increased, with the number of recurrences ranging from 29.2 to 181.8 cases per 10,000 inpatient-days. The multivariable analysis revealed five risk factors (hazard ratio [95% CI]): age ≥65 years (vs. <65 years; 65-74 years, 1.275 [1.048-1.551]; 75-79 years, 1.612 [1.315-1.975]; ≥80 years, 2.110 [1.776-2.507]); cephalosporin use both before (vs. without cephalosporin; 1.241 [1.098-1.402]) and during the primary CDI (vs. without cephalosporin; 1.137 [1.011-1.279]); higher number of comorbidities (vs. ≤10 comorbidities; 11-14 comorbidities: 1.336 [1.131-1.580]; 15-20 comorbidities: 1.433 [1.219-1.685]; ≥21 comorbidities: 1.310 [1.099-1.561]); and gastrointestinal surgery (vs. without surgery; 0.823 [0.701-0.965]). In conclusion, CDI recurred in some Japanese patients, and the incidence rates increased with the number of recurrences. Special care is needed in patients aged ≥65 years, those with a higher number (>10) of comorbidities, and those who have received cephalosporin before or during the primary CDI.

Switch rates, time-to-switch, and switch patterns of antiretroviral therapy in people living with human immunodeficiency virus in Japan, in a hospital-claim database.

BACKGROUND: Regardless of chronic treatment with antiretroviral therapy (ART), the switching rate for ART regarding anchor drugs has not been articulated in real-world clinical-settings in Japan. We assessed switch rates and time-to-switch of ART regimens according to anchor drug classes (integrase strand transfer inhibitors (INSTI), non-nucleoside reverse transcriptase inhibitors (NNRTI) and protease inhibitors (PI)) and common switching patterns of anchor drug classes in people living with human immunodeficiency virus (HIV) (PLWH) from 2008 to 2016. METHODS: This retrospective, observational study used data of 1694 PLWH drawn from a large-scale medical claims database. The median time-to-switch and switch rates of anchor drug class were estimated by Kaplan-Meier analysis. To estimate 95% confidence intervals for switch rates and median days, the Brookmeyer and Crowley method and Greenwood method were used respectively. The switching patterns were summarized based on the time of switching. The switch rates were compared between two anchor drug classes for each year using log-rank tests. RESULTS: We focused our results on 2011-2016 (n = 1613), during which most ART prescriptions were observed. A total of 268 patients switched anchor drug class from the first to a second regimen. The switch rate constantly increased over four years for NNRTIs (17.8-45.2%) and PIs (16.2-47.6%), with median time-to-switch of 1507 and 1567 days, respectively, while INSTI maintained a low switch rate (2.3-7.6%), precluding median-days calculation. The majority originally treated with NNRTI and PI switched to INSTI regardless of the switching timing after starting the first regimen (< 1 year: 91.7 and 97.5%, respectively, and ≥ 1 year: 100.0 and 97.5%, respectively). The risk of switching anchor drug classes was lower for INSTI than for other anchor drug classes in the first regimen even after adjusting for potential confounding factors. CONCLUSIONS: Patients with an ART regimen including INSTI as an anchor drug class maintained a low switch rate for long durations. The major switching strategies of anchor drug class for secondary treatment were from NNRTI or PI to INSTI. These results suggest that INSTI may be a durable anchor drug class for PLWH on ART although there are limitations inherent to the database.

Greater burden of chronic comorbidities and co-medications among people living with HIV versus people without HIV in Japan: A hospital claims database study.

OBJECTIVE: This study examined the prevalence of chronic comorbidities and the use of co-medications among people living with HIV (PLWH) on antiretrovirals in Japan, compared with age-matched controls without HIV. METHODS: This was an observational, retrospective, cross-sectional study using a hospital claims database of Japanese hospitals with advanced medical capabilities (i.e., advanced treatment hospitals, general hospitals, acute care hospitals). We extracted data for PLWH aged ≥18 years with a prescription record of antiretrovirals between January 2010 and December 2015, and for age-, sex-, and hospital-matched people without HIV. For each group, chronic comorbidities (diabetes, hypertension, lipid disorders, vascular diseases, chronic kidney failure, cancers, psychiatric disorders, osteoporosis, and hepatitis B/C co-infection), and co-medications were examined by age group. RESULTS: We analyzed data for 1445 PLWH and 14,450 people without HIV. The proportion of patients with multiple comorbidities was much greater among PLWH than controls of the same age group. Lipid disorders and diabetes were more prevalent in PLWH than controls (31.6% vs. 10.3% and 26.8% vs. 13.2%, respectively), both of which were more common in PLWH at earlier ages. Cancer was present in 8.1% of PLWH and 8.9% of controls. A greater proportion of PLWH used multiple co-medications other than antiretrovirals at earlier ages than controls. CONCLUSION: PLWH taking antiretrovirals in Japan had a greater burden of comorbidities and co-medications with increasing age than people without HIV. In addition to appropriate management of comorbidities, medication reconciliation according to patients' co-medication profiles is important for successful management of this patient population.

Comorbidities and co-medications in populations with and without chronic hepatitis C virus infection in Japan between 2015 and 2016.

BACKGROUND: Direct-acting anti-viral agents have improved the treatment of chronic hepatitis C virus (HCV) infection, but this treatment is challenging for patients using co-medications because of potential drug-drug interactions. This study aimed to examine the comorbidities and co-medications of Japanese chronic HCV patients by age group, compared with a non-HCV patient population. METHODS: This was a retrospective observational study using a hospital-based medical claims database. We extracted data of patients with chronic HCV aged ≥18 years, and age-, sex-, and hospital-matched patients without HCV, for the period from January 2015 to November 2016, and then examined chronic comorbidities, long-term co-medications, and medications prescribed at least once during the study period. RESULTS: We analysed data from 128,967 chronic HCV patients and 515,868 non-HCV patients. The median age was 70 years, and 51.0% of patients were male. More chronic HCV patients than non-HCV patients (70.5% vs. 47.1%) had at least one comorbidity, and older patients had more comorbidities than younger patients. The most common comorbidities in chronic HCV patients were diseases of oesophagus, stomach and duodenum (41.7%), followed by hypertensive diseases (31.4%). Chronic HCV patients used co-medications more commonly than non-HCV patients, and older patients used more co-medications. The most common long-term co-medications in chronic HCV patients were proton pump inhibitors (14.0%), which were prescribed to 31.9% of chronic HCV patients at least once during the study period. CONCLUSIONS: Patients with chronic HCV in Japan had more comorbidities than patients without chronic HCV regardless of age. Particularly older patients, who constitute the majority of the HCV patient population in Japan, commonly had multiple comorbidities and used co-medications. To optimise HCV treatment, physicians need to know the exact medication profiles of patients and take appropriate action to manage drug-drug interactions.

Characteristics of 2-drug regimen users living with HIV-1 in a real-world setting: A large-scale medical claim database analysis in Japan.

BACKGROUND: Regimen simplification to 2-drug antiretroviral therapy (2-ART) may address potential tolerability issues, increase adherence, and reduce toxicity and potential drug-drug-interactions among people living with HIV-1 (PLWH). However, real-world treatment patterns and characteristics of 2-ART users are unclear. METHODS: This retrospective observational cohort study employed a large-scale medical claim database of Japanese hospitals to extract data on 4,293 PLWH aged ≥18 years with diagnosis of HIV and treated with any ART regimens between April 2008 and April 2019. A 2-ART cohort was compared with a 3-drug antiretroviral therapy (3-ART) cohort in terms of population characteristics, comorbid conditions, and treatment patterns. Treatment switching rates were calculated for each cohort followed by sensitivity analysis to confirm the robustness of the findings. RESULTS: There were 94 individuals identified in the 2-ART cohort. Compared to the standard 3-ART cohort (n = 3,993), the 2-ART cohort was older (median age 53 [IQR 44-64] vs 42 years [IQR 35-50]), with a lower proportion of males (87.2% vs 93.8%), higher Charlson Comorbidity Index (CCI) (median score 6 [IQR 5-8] vs 5 [IQR 4-6]), more co-medications (median 6 [IQR 4-11] vs 3 [IQR 2-7]), and a higher percentage of AIDS-defining conditions (66.0% vs 42.8%). The most common 2-ART were protease inhibitor (PI) + integrase strand transfer inhibitor (INSTI) and non-nucleoside reverse transcriptase inhibitor (NNRTI) + INSTI (33.0% and 31.9%, respectively). Overall, most of the regimens were nucleoside reverse transcriptase inhibitor (NRTI)-sparing (71.3%), with a decreasing trend over time (76.2% to 70.2%). ART regimen switch occurred more often in the 2-ART cohort than in the 3-ART cohort (33.0% vs 21.2%). CONCLUSION: The profiles of individuals on 2-ART in Japan were demonstrated to be complex. Most were treated with NRTI-sparing regimens which may reflect an effort to reduce treatment-related toxicities.

The complete supraannular concept: in vivo hemodynamics of bovine and porcine aortic bioprostheses.

BACKGROUND: Complete supraannular placement of an aortic bioprosthesis is one approach to optimize the hemodynamic result of an aortic valve replacement. It is achieved with the combination of a special valve design and the supraannular sewing technique with noneverted mattress sutures. We evaluated 5 bioprostheses designed for complete supraannular placement to assess potential hemodynamic differences caused by factors (eg, valve material) other than implantation position. METHODS AND RESULTS: In 336 patients (mean age, 72.0+/-7.1 years; 143 women), hemodynamics including mean pressure gradients, effective orifice areas, and indices and incidence of patient-prosthesis mismatch were evaluated 6 months after surgery. Annulus diameter was measured during surgery. Patients received the Carpentier Edwards Perimount Magna (Magna, n=169), the Medtronic Mosaic (Mosaic, n=46), the Mosaic Ultra (Ultra, n=17), the SJM Epic Supra (Epic, n=46), and the Sorin Soprano (Soprano, n=58). For small annulus sizes (<23 mm), the mean pressure gradients of the Magna (11.82+/-4.8 mm Hg) were significantly lower than the Mosaic (16.04+/-6.1 mm Hg) and the Ultra (22.0+/-4.1 mm Hg), and the Soprano (13.3+/-5.2 mm Hg) was hemodynamically superior to the Ultra. For medium (23 to 24 mm) and large (>24 mm) annulus sizes, the mean pressure gradients of the Magna were lower than the Epic (10.0+/-3.5 mm Hg versus 14.9+/-6.4 mm Hg; 9.9+/-4.0 mm Hg versus 18.6+/-12.7 mm Hg). Furthermore, in patients with large annulus size, the mean pressure gradients of the Soprano (11.4+/-3.8 mm Hg) were lower compared with the Epic (18.5+/-12.7 mm Hg). Severe patient-prosthesis mismatch was observed more frequently in patients with the Mosaic (12/46; 26.1%) and the Ultra (3/17; 17.6%) prostheses. CONCLUSIONS: Complete supraannular placement cannot prevent high pressure gradients or patient-prosthesis mismatch thoroughly, but the choice of a bovine prosthesis can optimize hemodynamic performance.

Tomato root transcriptome response to a nitrogen-enriched soil patch.

BACKGROUND: Nitrogen (N), the primary limiting factor for plant growth and yield in agriculture, has a patchy distribution in soils due to fertilizer application or decomposing organic matter. Studies in solution culture over-simplify the complex soil environment where microbial competition and spatial and temporal heterogeneity challenge roots' ability to acquire adequate amounts of nutrients required for plant growth. In this study, various ammonium treatments (as 15N) were applied to a discrete volume of soil containing tomato (Solanum lycopersicum) roots to simulate encounters with a localized enriched patch of soil. Transcriptome analysis was used to identify genes differentially expressed in roots 53 hrs after treatment. RESULTS: The ammonium treatments resulted in significantly higher concentrations of both ammonium and nitrate in the patch soil. The plant roots and shoots exhibited increased levels of 15N over time, indicating a sustained response to the enriched environment. Root transcriptome analysis identified 585 genes differentially regulated 53 hrs after the treatments. Nitrogen metabolism and cell growth genes were induced by the high ammonium (65 mug NH4+-N g-1 soil), while stress response genes were repressed. The complex regulation of specific transporters following the ammonium pulse reflects a simultaneous and synergistic response to rapidly changing concentrations of both forms of inorganic N in the soil patch. Transcriptional analysis of the phosphate transporters demonstrates cross-talk between N and phosphate uptake pathways and suggests that roots increase phosphate uptake via the arbuscular mycorrhizal symbiosis in response to N. CONCLUSION: This work enhances our understanding of root function by providing a snapshot of the response of the tomato root transcriptome to a pulse of ammonium in a complex soil environment. This response includes an important role for the mycorrhizal symbiosis in the utilization of an N patch.

Effects of Culture Conditions (Microplate and Solvent) on in vitro Antifungal Activity of Caspofungin Against Candida Species.

Effects of the type of microplates and solvent for preparation of caspofungin (CPFG) on antifungal susceptibility testing of CPFG against clinical isolates of Candida albicans, Candida glabrata, and Candida krusei (20 strains each) by broth microdilution method according to the Clinical and Laboratory Standards Institute were evaluated. When CPFG was dissolved in water, MICs against the three Candida species decreased 3.1-6.0-fold in surface-untreated microplates compared to those in treated microplates. When CPFG was dissolved in dimethyl sulfoxide, MICs against the three Candida species decreased 1.3-2.5-fold in surface-untreated microplates compared to those in treated microplates. Differences in MICs according to the type of solvent did not exceed the difference for one dilution interval (0.5-2-fold MIC ratio) regardless of whether the microplate surface was treated or not. These findings suggest that differences in CPFG MICs may depend mainly on the type of surface treatment of assay microplates.

Hemodynamic characterization of the Sorin Mitroflow pericardial bioprosthesis at rest and exercise.

BACKGROUND AND AIM OF THE STUDY: Although the long-term clinical outcome after aortic valve replacement (AVR) with the Sorin Mitroflow pericardial bioprosthesis has been well described, few data are available with regards to hemodynamic performance. On the basis of its specialized design, with the pericardium mounted on the outside of the stent, the Mitroflow valve is considered to provide optimal opening and orifice areas. METHODS: Between February 2006 and April 2007, a total of 127 patients (66 females, 61 males; mean age 77.6 +/- 5.2 years) underwent AVR with the Mitroflow valve at the authors' institution. Echocardiography was performed at discharge in 91 patients, while a six-month follow up examination was conducted in 78 (including ergometer hemodynamics in 25 cases). RESULTS: The mean systolic pressure gradient (MPG) ranged from 19.7 +/- 3.3 mmHg (size 19 valve) to 12.4 +/- 2.4 mmHg (size 27 valve), and the mean effective orifice area (EOA) from 0.96 +/- 0.0 cm2 (size 19 valve) to 2.36 +/- 0.4 cm2 (size 27 valve). The incidence of mild-to-moderate and severe prosthesis-patient mismatch (PPM) was 33% and 10% at the six-month follow up. During exercise (25 W-100 W), the MPG increased from 17.1 +/- 3.6 mmHg to 23.6 mmHg in valve sizes 19 to 21, and from 12.2 +/- 3.6 mmHg to 15.9 +/- 2.5 mmHg in valve sizes 23 to 27. The effective orifice fraction (EOF = EOA/annulus area) was 38 +/- 7%. CONCLUSION: The Mitroflow valve exhibits an adequate MPG and EOA, as might be expected for a pericardial bioprosthesis. Of note, the gradient increase during exercise was low, especially for the larger valve sizes. Due to its special design, the Mitroflow prosthesis shows a large opening, as demonstrated by the high EOF. These data relating to the EOA of all prosthesis sizes may help surgeons to select the minimum prosthesis size in order to prevent PPM.

Long-term tolerability and effectiveness of raltegravir in Japanese patients: Results from post-marketing surveillance.

Antiretroviral agents are approved in Japan based on non-clinical and clinical data reported from overseas. Neither the long-term tolerability nor the effectiveness of raltegravir or other integrase strand transfer inhibitors in Japan is known. This study reports on the long-term tolerability and effectiveness of raltegravir in Japanese clinical practice using data collected through approximately 9 years of post-marketing surveillance. This observational survey used data on human immunodeficiency virus (HIV) infected patients initiated treatment with raltegravir between 2008 and 2017 in the HIV-related drug (HRD) cooperative survey to assess the safety and effectiveness of raltegravir in real world clinical practice. There were totally 1,303 patients prescribed raltegravir across 30 institutions; 1,293 patients and 1,178 patients were included for the safety and effectiveness analyses, respectively. The overall risk of adverse drug reaction was 17.25%, with abnormal hepatic function and hyperlipidaemia (<1.5%) having the highest proportion. Median HIV-1 RNA viral loads rapidly decreased below 40 copies/mL after 3 months of raltegravir use in treatment-naïve patients, and consistently sustained below 40 copies/mL after the start of raltegravir use in treatment-experienced patients. Among the patients who were treated for 7 years, 92.00% (95% CI: 73.97-99.02) maintained HIV-1 RNA viral load below 50 copies/mL. Additionally, CD4+ cell counts exceeded >500 cells/µL in treatment-naïve and treatment-experienced patients after 3 years and 4 years of treatment, respectively. In Japanese HIV patients, long-term treatment with raltegravir is well-tolerated and effective at viral suppression as measured by HIV-1 RNA levels and subsequent change in CD4+ cell counts. Such benefits can be expected for not only treatment-naïve but also treatment-experienced patients.

Hemodynamic performance of the new St. Jude Medical Epic Supra porcine bioprosthesis in comparison to the Medtronic Mosaic on the basis of patient annulus diameter.

BACKGROUND AND AIM OF THE STUDY: The St. Jude Medical Epic Supra (ES) valve is a new porcine bioprosthesis designed for complete supra-annular implantation. To date, no in-vivo data regarding the hemodynamic and clinical performance of this valve are available. The study aim was to compare the hemodynamic performance of the ES valve with the completely supra-annular Medtronic Mosaic (MM) porcine valve. METHODS: Between July 2000 and April 2006, 83 patients (39 males, 44 females) underwent aortic valve replacement with either the ES (n = 44) or MM (n = 39) bioprosthesis. Hemodynamic performance was evaluated echocardiographically at six months postoperatively. Comparison between the valves was performed by dividing the patient groups according to their intraoperatively measured tissue annulus diameter rather than the labeled valve size. RESULTS: The internal diameter and sewing ring diameter differed in ES and MM valves with the same labeled size. For example, in valves labeled '23' the internal diameter/sewing ring diameters were 21.5 and 29.3 mm in the ES valve versus 20.5 and 30 mm in the MM. The mean pressure gradients (MPG) for patients with ES or MM valves were 15.5 +/- 4.5 or 14.8 +/- 5.1 mmHg for annulus diameter < or =22 mm, 14.6 +/- 6.4 or 13.9 +/- 3.6 for annulus diameter 23-24 mm, and 15.3 +/- 3.8 or 13.4 +/- 4.2 mmHg for annulus diameter > or =25 mm. No significant differences were identified in the hemodynamic data, including MPG, effective orifice area (EOA) and effective orifice area index (EOAI). The incidence of moderate or severe patient-prosthesis mismatch (PPM) was 40% (n = 18) and 5% (n = 1) in patients with ES valves, and 26% (n = 10) or 23% (n = 9) in patients with MM valves (p = 0.01). In patients with an annulus size < or =22 mm, severe PPM occurred in 29% (n =5) of patients with MM valves but in none of those with ES valves. CONCLUSION: The hemodynamic performance of the ES valve was comparable to that of the well-established MM valve. The incidence of severe PPM was lower in patients with ES valves than MM valves, presumably due to the somewhat larger EOA values in patients with a small aortic annulus (<25 mm).

Comorbidities and the use of comedications in people living with HIV on antiretroviral therapy in Japan: a cross-sectional study using a hospital claims database.

OBJECTIVES: To investigate the prevalence of chronic comorbidities and the use of comedications in people living with HIV (PLWH) and on antiretrovirals in Japan, by using a hospital claims database. DESIGN: Observational, retrospective, cross-sectional study. SETTING: A hospital claims database of Japanese hospitals that have advanced medical treatment capabilities (ie, advanced treatment hospitals, general hospitals, acute care hospitals), which include those providing acute and chronic care (excluding nursing homes or hospices). PARTICIPANTS: A total of 1445 PLWH aged ≥18 years and with a prescription record of antiretrovirals between January 2010 and December 2015 were identified from the database. OUTCOME MEASURES: The number and types of chronic comorbidities, as well as the number and types of comedications, in different age groups of the PLWH. RESULTS: The median (range) age of patients was 45 (18-90) years, and 90.4% were men. Of the 1445 patients, 972 (67.3%) had at least one chronic comorbidity. Common chronic comorbidities included lipid disorders (31.6%), diabetes (26.8%), hypertension (18.2%) and hepatitis B/C coinfection (18.2%). Patients in the older age groups had greater numbers of chronic comorbidities. The most common chronic comorbidities in the older age groups were hypertension, diabetes and lipid disorders. The majority of patients used at least one comedication, and those in the older age groups used greater numbers of comedications. The most common therapeutic category of comedication included antacids, antiflatulents and antiulcerants (31.7%). Of 151 malignancies reported in 117 patients, 84 were AIDS-defining cancers and 67 were non-AIDS-defining cancers. CONCLUSIONS: Chronic comorbidities and comedications were common among PLWH in Japan taking antiretrovirals; particularly among older patients, who more frequently used comedications. This suggests the need for giving special attention to the appropriate management of this patient population.

Hemodynamic evaluation of the Sorin Soprano bioprosthesis in the completely supra-annular aortic position.

BACKGROUND AND AIM OF THE STUDY: The study aim was to evaluate the clinical and hemodynamic performance of the Sorin Soprano bioprosthesis in the aortic position. METHODS: Rest and stress echocardiography were performed at six months after surgery in 57 patients who underwent aortic valve replacement with the stented Soprano bioprosthesis. The exercise protocol included workloads of 25, 50, 75 and 100 W, each of 2 min duration. RESULTS: Thirty-day mortality was 1.8% (n = 1). Due to malperfusion of the coronary arteries, two Soprano prostheses had to be replaced by a different prosthesis, and one patient received coronary artery bypass grafts. One patient developed bacterial endocarditis of his prosthesis at seven months postoperatively and died as a result of a fulminant sepsis. There were no other prosthesis-related adverse events. Mean pressure gradients (MPG) ranged from 7.8 to 15.9 mmHg, effective orifice areas (EOA) from 1.25 to 2.98 cm2, EOA index (EOAI) from 0.79 to 1.43 cm2/m2, and EOA fraction from 34 to 45%. Stress echocardiography showed no significant increase in MPG up to 50 W, and MPGs did not exceed 35 mmHg at 75 and 100 W. CONCLUSION: Initial hemodynamic results showed low MPGs during rest and exercise. The EOAI was large due to completely supra-annular placement of the Soprano valve. The difficulty of complete supraannular placement is that the prosthesis is positioned relatively high, especially in narrow aortic roots, and this may handicap coronary artery perfusion. Patient selection with suitable aortic root anatomy is crucial to achieve the benefit of completely supra-annular implantation without coronary ostium deterioration.

Challenges of modifying root traits in crops for agriculture.

Roots play an essential role in the acquisition of water and minerals from soils. Measuring crop root architecture and assaying for changes in function can be challenging, but examples have emerged showing that modifications to roots result in higher yield and increased stress tolerance. In this review, we focus mainly on the molecular genetic advances that have been made in altering root system architecture and function in crop plants, as well as phenotyping methods. The future for the modification of crop plant roots looks promising based on recent advances, but there are also important challenges ahead.

The Arabidopsis AP2/ERF transcription factor RAP2.11 modulates plant response to low-potassium conditions.

Plants respond to low-nutrient conditions through metabolic and morphology changes that increase their ability to survive and grow. The transcription factor RAP2.11 was identified as a component in the response to low potassium through regulation of the high-affinity K(+) uptake transporter AtHAK5 and other components of the low-potassium signal transduction pathway. RAP2.11 was identified through the activation tagging of Arabidopsis lines that contained a luciferase marker driven by the AtHAK5 promoter that is normally only induced by low potassium. This factor bound to a GCC-box of the AtHAK5 promoter in vitro and in vivo. Transcript profiling revealed that a large number of genes were up-regulated in roots by RAP2.11 overexpression. Many regulated genes were identified to be in functional categories that are important in low-K(+) signaling. These categories included ethylene signaling, reactive oxygen species production, and calcium signaling. Promoter regions of the up-regulated genes were enriched in the GCCGGC motif also contained in the AtHAK5 promoter. These results suggest that RAP2.11 regulates AtHAK5 expression under low-K(+) conditions and also contributes to a coordinated response to low-potassium conditions through the regulation of other genes in the low-K(+) signaling cascade.

A genome triplication associated with early diversification of the core eudicots.

BACKGROUND: Although it is agreed that a major polyploidy event, gamma, occurred within the eudicots, the phylogenetic placement of the event remains unclear. RESULTS: To determine when this polyploidization occurred relative to speciation events in angiosperm history, we employed a phylogenomic approach to investigate the timing of gene set duplications located on syntenic gamma blocks. We populated 769 putative gene families with large sets of homologs obtained from public transcriptomes of basal angiosperms, magnoliids, asterids, and more than 91.8 gigabases of new next-generation transcriptome sequences of non-grass monocots and basal eudicots. The overwhelming majority (95%) of well-resolved gamma duplications was placed before the separation of rosids and asterids and after the split of monocots and eudicots, providing strong evidence that the gamma polyploidy event occurred early in eudicot evolution. Further, the majority of gene duplications was placed after the divergence of the Ranunculales and core eudicots, indicating that the gamma appears to be restricted to core eudicots. Molecular dating estimates indicate that the duplication events were intensely concentrated around 117 million years ago. CONCLUSIONS: The rapid radiation of core eudicot lineages that gave rise to nearly 75% of angiosperm species appears to have occurred coincidentally or shortly following the gamma triplication event. Reconciliation of gene trees with a species phylogeny can elucidate the timing of major events in genome evolution, even when genome sequences are only available for a subset of species represented in the gene trees. Comprehensive transcriptome datasets are valuable complements to genome sequences for high-resolution phylogenomic analysis.

Early timing of surgical intervention in patients with Ebstein's anomaly predicts superior long-term outcome.

OBJECTIVE: Various surgical valve repair and replacement techniques have been developed over the past decades for patients with Ebstein's anomaly. Determination of the appropriate moment for surgery, however, has not been elucidated clearly enough. METHODS: From 1976 to 2007, 130 patients (mean age 23.8+/-17.8 years, range: 1 month to 73.6 years) underwent surgery for Ebstein's anomaly at our centre. Four patients (3.0%), who underwent univentricular palliation, and four (3.0%), who only had an atrial septal defect closure, were excluded. In 110/122 (90.2%) patients, a primary tricuspid valve repair was feasible. Valve replacement was necessary in 12 (9.8%). Mean follow-up time was 10.5+/-9.1 years (94.3% complete, 1284 patient years). RESULTS: There were two (1.5%) hospital deaths. Overall survival was 87.2%+/-3.6%, 85.1%+/-4.1% and 81.2%+/-5.4% at 10, 20 and 25 years, respectively, without significant difference between the repair and replacement group (p=0.31). The New York Heart Association functional class >II (p=0.01) and cardiothoracic ratio >0.6 (p=0.02) were significant risk factors for mortality. Overall freedom from re-operation was 79.9+/-4.6%, 61.9+/-6.8% and 58.0+/-7.4% at 10, 20 and 25 years, respectively. Age0.6 (p=0.009) were significant risk factors for the need of a re-operation. CONCLUSIONS: Repair, as opposed to replacement, is feasible in the vast majority of patients presenting with Ebstein's anomaly with a low early mortality rate. Outcome, in terms of survival and freedom from re-operation in the long term is determined by the clinical state at the time of surgery. Therefore, timely operation is warranted before significant cardiomegaly develops and functional status deteriorates.

Impact of the indexed effective orifice area on mid-term cardiac-related mortality after aortic valve replacement.

BACKGROUND: There has been ongoing controversy as to whether prosthesis-patient mismatch (PPM, defined as indexed effective orifice area (EOAI) <0.85 m(2)/cm(2)) influences mortality after aortic valve replacement (AVR). In most studies, PPM is anticipated by reference tables based on mean EOAs as opposed to individual assessment. These reference values may not reflect the actual in vivo EOAI and hence, the presence or absence of PPM may be based on false assumptions. OBJECTIVE: To assess the impact of small prosthesis EOA on survival after aortic valve replacement AVR. METHODS: 645 patients had undergone an AVR between 2000 and 2007 entered the study. All patients underwent transthoracic echocardiography for determination of the actual EOAI within 6 months postoperatively. In order to predict time from surgery to death a proportional hazards model for competing risks (cardiac death vs death from other causes) was used. EOAI was entered as a continuous variable. RESULTS: PPM occurred in 40% of the patients. After a median follow-up of 2.35 years, 92.1% of the patients were alive. The final Cox regression model showed a significantly increased risk for cardiac death among patients with a smaller EOAI (HR=0.32, p=0.022). The effect of EOAI on the 2-5 year mortality risk was demonstrated by risk plots. CONCLUSIONS: In contrast to previous studies these EOAI values were obtained through postoperative echocardiography, substantially improving the accuracy of measurement, and the EOAI was modelled as a continuous variable. There was a significantly improved survival for larger EOAIs following AVR. Strategies to avoid PPM should become paramount during AVR.

Arabidopsis actin-depolymerizing factor AtADF4 mediates defense signal transduction triggered by the Pseudomonas syringae effector AvrPphB.

The actin cytoskeleton has been implicated in plant defenses against pathogenic fungi and oomycetes with limited, indirect evidence. To date, there are no reports linking actin with resistance against phytopathogenic bacteria. The dynamic behavior of actin filaments is regulated by a diverse array of actin-binding proteins, among which is the Actin-Depolymerizing Factor (ADF) family of proteins. Here, we demonstrate that actin dynamics play a role in the activation of gene-for-gene resistance in Arabidopsis (Arabidopsis thaliana) following inoculation with the phytopathogenic bacterium Pseudomonas syringae pv tomato. Using a reverse genetics approach, we explored the roles of Arabidopsis ADFs in plant defenses. AtADF4 was identified as being specifically required for resistance triggered by the effector AvrPphB but not AvrRpt2 or AvrB. Recombinant AtADF4 bound to monomeric actin (G-actin) with a marked preference for the ADP-loaded form and inhibited the rate of nucleotide exchange on G-actin, indicating that AtADF4 is a bona fide actin-depolymerizing factor. Exogenous application of the actin-disrupting agent cytochalasin D partially rescued the Atadf4 mutant in the AvrPphB-mediated hypersensitive response, demonstrating that AtADF4 mediates defense signaling through modification of the actin cytoskeleton. Unlike the mechanism by which the actin cytoskeleton confers resistance against fungi and oomycetes, AtADF4 is not involved in resistance against pathogen entry. Collectively, this study identifies AtADF4 as a novel component of the plant defense signaling pathway and provides strong evidence for actin dynamics as a primary component that orchestrates plant defenses against P. syringae.