The program comparisons suggest that, despite differing stringency levels they all identify a similar set of known and novel predictions. Comparisons between the first and second version of miRDeep suggest that the
stringency level of each of these programs may, in fact, be a result of the algorithm used to map the reads to the target. Different stringency levels are likely to affect the number of possible novel candidates for functional verification, causing selleck kinase inhibitor undue strain on resources and time. With that in mind, we propose that an intersection across multiple programs be taken, especially if considering novel candidates that will be targeted for additional analysis. Using this approach, we identify and performed Sapanisertib datasheet initial validation of 12 novel predictions in our in-house data with real-time
PCR, six of which have been previously unreported.”
“ObjectiveThe aim of this study was to document the association between pancreatic agenesis or hypoplasia and multicystic renal dysplasia related to transcription factor 2 (TCF2) or hepatocyte nuclear factor 1 beta mutations. MethodologyWe describe the phenotype of the pancreas and the kidneys from three fetuses heterozygous for a mutation of TCF2. CasesCase 1 had bilateral hyperechogenic, multicystic kidneys, bilateral clubfoot and pancreatic agenesis. Case 2 had two enlarged polycystic kidneys, anamnios and pancreatic agenesis. Case 3 had multicystic renal dysplasia, oligohydramnios and hypoplasia of the tail of the pancreas. ConclusionTCF2 mutations are frequently discovered in fetuses presenting with bilateral hyperechogenic kidneys. The association between pancreatic agenesis and a TCF2 mutation has not previously been reported. TCF2 deficiency in mice leads to pancreatic agenesis, suggesting that the gene is essential for pancreatic development. Our observations indicate the importance of visualizing the pancreas during ultrasound examinations if renal malformations are discovered. (c) 2013 John Wiley & Sons, Ltd.”
“The available research evidence pertaining to anogenital injury in victims of sexual violence
presents a very wide range of injury prevalence data. As such, it is extraordinarily challenging for health care practitioners involved in clinical forensic examination of victims of sexual violence to place their examination findings in to context. It is generally accepted that PD173074 mouse the broad range of existing injury prevalence data is reflective of heterogeneous research study methodologies and clinical practice techniques. Thus, health care practitioners should be encouraged to present their evidence in the context of the prevalence data that are most representative of their clinical practice. Presented herein is a simple categorization of existing prevalence data in accordance with national clinical practice guidelines. The range of anogenital injury prevalence is narrower when presented in this manner than when taken as a whole.
Rutaceae) and Fructus gardeniae (Gardenia jasminoide Ellis, Rubiaceae) in a weight ratio of 3:2:2:3.This formula was described by Wang Tao (in the Chinese Tang Dynasty) in his treatise ‘Wai Tai Mi Yao”. It has been used to treat inflammation, hypertension, gastrointestinal disorders, and liver and cerebrovascular diseases in the clinical practice of Traditional Chinese medicine, especially in treating inflammation for nearly two thousand years. However, the essential compounds in it have
not Cyclopamine cell line been identified, and the mechanisms remain to be addressed. To investigate the protective effects of HLJDT and its component group (HLJDT-CG) on collagen-induced arthritis in rats. Materials and methods: CIA was established in male Wistar rats with subcutaneous injection of type II bovine collagen at the base of the tail of animals. CIA rats were treated daily with oral administration of HLJDT aqueous extracts (270
mg/kg) or HLJDT-CG (40 mg/kg) once per day from day 6 to day 28. Rats in normal and vehicle control groups were given an equal volume of vehicle (0.9% saline) and 0.025 mg/kg Dexamethasone GSK2879552 datasheet was given to the Standard group at the same time. The protective effect of them were assessed by measuring arthritis index, swelling, the cytokines such as TNF-alpha, IFN-gamma and IL-17 in serum, type II collagen antibodies, splenocyte proliferation and so on. Results: The results demonstrated that treatment of CIA rat with either HLJDT aqueous extracts or HLJDT-CG not only ameliorated the symptoms of arthritis, prevented joint damage but also reduced the serum levels of TNF-alpha, IFN-gamma and IL-17 in CIA rats. Anti-CII antibodies showed the similar trend except that of IgGl. Furthermore,
HLJDT aqueous extracts and HLJDT-CG administration also suppressed CII-induced proliferative response of splenocytes. More importantly, HIJDT-CG exhibited similar pharmacological activities as HLJDT aqueous extracts in all aforementioned experiments. Conclusions: HLJDT aqueous extracts and HLJDT-CG could effectively ameliorate CII-induced arthritis and significantly suppress the immune response against CII with similar pharmacological efficacy. These findings suggest that Selleck Prexasertib HLJDT has therapeutic potential in RA treatment and HLJDT-CG can represent the effectivecomposite of HLJDT. (C) 2013 Published by Elsevier Ireland Ltd.”
“Phylogenetic studies have suggested that the HIV-1 epidemic in the Americas is mainly dominated by HIV subtype B. However, countries of South America and the Caribbean have recently reported changes in their circulating HIV-1 genetic profiles. The aim of this study was to characterize the molecular profile of the HIV-1 epidemic in Panama by the analysis of 655 polymerase gene (pol) sequences that were obtained from HIV-infected Panamanians diagnosed between 1987 and 2013.
\n\nConclusion: Here we demonstrated the synergism FG-4592 mw between the pyrethroid flumethrin and the neonicotinoid imidacloprid, both provided in therapeutically relevant doses by a slow release collar matrix system over 8 months. This collar is therefore a convenient and safe tool for a long-term protection against ectoparasites.”
“Healthcare associated pneumonia (HCAP) is a different entity from community-acquired pneumonia and nosocomial pneumonia. There exist several risk factors that lead to it. Different features, severity and pathogens are described and there is controversy about the initial empirical treatment. The aim of this work was to analyze
the etiology, clinical characteristics and evolution of the HCAP. It is a prospective and observational study that includes 60 patients; 32 had previous hospitalization during the last 90 days, 9 were under hemodialysis, 12 residents in nursing homes and 7 received outpatient intravenous therapy. The mean age was 63 years and the severity index was high. The most frequent comorbidities were cardiac. The radiological compromise was more than one lobe in 42% of cases and 18% had pleural effusion. Germ isolation was obtained in 30% of patients where the most isolated germ was Streptococcus pneumoniae (9 cases). There was only one case of multidrug-resistance. The mean length hospital stay was 11 days, six patients had complications and mortality was 5%. Complications
but not mortality were significantly higher in the group of patients on hemodialysis (p value AS1842856 = 0.011 and 0.056 respectively). The antibiotic-resistance found do not justify a change in the antibiotic treatment commonly used for community acquired pneumonia.”
“Background Headache is a common symptom during space travel, both isolated PF-03084014 ic50 and as part of space motion syndrome. Head-down-tilted bed rest (HDTBR) studies are used to simulate outer space microgravity on Earth, and allow
countermeasure interventions such as artificial gravity and training protocols, aimed at restoring microgravity-induced physiological changes. Objectives The objectives of this article are to assess headache incidence and characteristics during HDTBR, and to evaluate the effects of countermeasures. Methods In a randomized cross-over design by the European Space Agency (ESA), 22 healthy male subjects, without primary headache history, underwent three periods of -6-degree HDTBR. In two of these episodes countermeasure protocols were added, with either centrifugation or aerobic exercise training protocols. Headache occurrence and characteristics were daily assessed using a specially designed questionnaire. Results In total 14/22 (63.6%) subjects reported a headache during 1 of the three HDTBR periods, in 12/14 (85.7%) non-specific, and two of 14 (14.4%) migraine. The occurrence of headache did not differ between HDTBR with and without countermeasures: 12/22 (54.5%) subjects vs. eight of 22 (36.4%) subjects; p=0.20; 13/109 (11.9%) headache days vs.
Seventy-six accessions belonging to four B. napus groups were screened for resistance to two X. campestris pv. campestris races (1 and 4). The strain of race I used in this study was more virulent on the tested materials than the strain of race 4. No race-specific resistance was found to race 1. Most cultivars were susceptible except Russian kale, from the pabularia group, which showed some resistant plants and some other accessions with some partially resistant plants. High levels of race-specific
resistance to race 4 were found in the pabularia group, and great variability within accessions was identified. Three improved cultivars (Ragged Jack kale, Friese Gele, and Valle del Oro) and four landraces (Russian kale, MBG-BRS0037, MBG-BRS0041, and MBG-BRS0131) showed plants INCB024360 mouse with some degree of resistance to both races, which may indicate that race-nonspecific
resistance is involved. These accessions could be directly used in breeding programs, either as improved cultivars or as donors of race-specific resistance to other Brassica cultivars.”
“Introduction: The aim of this study was to investigate the value of placental growth factor (PLGF), soluble fms-like tyrosine kinase-1 (sFlt-1) and sFlt-1/PLGF ratio, in predicting symptomatic preeclampsia (PE). Methods: A prospective longitudinal study was carried out on 71 high risk preeclamptic women cohort. All of them had normal blood pressure level (<= 140/90 mmHg) at the time of enrolment, 26.8 +/- 1.5 weeks. Maternal blood was collected and plasma was stored in a freezer at -80 degrees C. PE was defined according to the National High Blood Pressure Sapanisertib inhibitor Education
Program Working Group Criteria. Accuracy of angiogenic factors in predicting PE was evaluated using Receiver-operating characteristics. Results: Maternal plasma concentrations of PLGF and sFlt-1 were able to predict PE (0.90, p < 001; 0.78, p = 0.003, area under the curve, respectively) but the sFlt-1/PLGF ratio presented the best prediction potential over the others (0.95, area under the curve, p < 0.001). Conclusion: selleck compound All angiogenesis factors were effective biomarkers in predicting PE during the second trimester, before the clinical onset of PE.”
“The optimal route for delivery of preterm breech-presenting fetuses remains a clinical dilemma. Available data from the literature are largely based on retrospective cohort studies, and randomised controlled trials are considered impossible to conduct. Consistently however, large population-based surveys have shown that planned caesarean sections for these fetuses were associated with better neonatal outcomes compared with those following vaginal delivery. Nevertheless, the increased surgical risks for the mother having caesarean delivery of an early preterm breech fetus must be balanced with the probable neonatal survival benefits.
014). Increases in the odds of not being employed post-injury were associated with not being employed pre-injury, having lower levels of education pre-injury,
etiologies due to violence or falls, increased PTA, an associated spinal cord injury, lower FIM motor scores, and greater lengths of stay in rehabilitation.\n\nConclusions: The first year post-TBI is critical for recovery and gainful employment, particularly for Hispanic individuals. Early identification of factors influencing successful gainful employment and expeditious implementation of services to ameliorate these issues are paramount in improving employment outcomes for Hispanic individuals with TBI.”
“BACKGROUND: In liposarcoma (LS), tumor-grade, histopathologic subtype, size, Domatinostat and completeness of
resection are important 10058-F4 prognostic factors. METHODS: We analyzed 80 patients with LS in an unselected patient sample concerning local recurrence, metastases, and survival in relation to clinicopathological characteristics and treatment. RESULTS: The five-year event-free rate was 82%. The strongest predictive prognostic factor was tumor grading. There was a significant influence of age over 60 showing a worse prognosis. Within 5 years after diagnosis, metastases were diagnosed in 13.1% (95% CI from 2.9% to 22.2%). The mean interval from first diagnosis to metastases was 27 months (0 to 63 months). Local recurrence occurred just in patients, who were not primary treated in a tumor-center and first resection was inadequate (five LS G II and one LS G I). CONCLUSIONS: Prognosis of LS is good if surgical treatment
is adequate and resection performed with clear margins. Patients with suspected LS should be referred to specialized tumor-centers.”
“The hormone glucagon-like peptide-1 (GLP-1) is released from the gut in response to food intake. It acts as ZD1839 chemical structure a satiety signal, leading to reduced food intake, and also as a regulator of gastric emptying. Furthermore, GLP-1 functions as an incretin hormone, stimulating insulin release and inhibiting glucagon secretion from the pancreas in response to food ingestion. Evidence suggests that the action or effect of GLP-1 may be impaired in obese subjects, even in those with normal glucose tolerance. GLP-1 impairment may help explain the increased gastric emptying and decreased satiety signalling seen in obesity. Incretin impairment, probably associated with reduced insulinotropic potency of GLP-1, is also characteristic of type 2 diabetes (T2D). Therefore, it is possible that incretin impairment may contribute to the pathophysiological bridge between obesity and T2D. This review summarises current knowledge about the pathophysiology and consequences of GLP-1 and incretin impairment in obesity, and examines the evidence for an incretin-related link between obesity and T2D.
Recently, results from the CLARA childhood asthma cohort suggested an implication of IL-37 for human asthma pathogenesis. This study aimed to investigate the effects of IL-37 on allergic airway inflammation in a mouse model of experimental asthma. Methods: Peripheral blood mononuclear cells (PBMCs) of children were cultured for 48 h (anti-CD3/anti-CD28 stimulation Galardin inhibitor or unstimulated), and IL-37
concentrations in supernatants were determined. Wild-type, IL-18R alpha-deficient ((-/-)), and SIGIRR(-/-) C57BL/6 mice were sensitized to ovalbumin (OVA) and challenged with OVA aerosol to induce acute experimental asthma, and IL-37 was applied intranasally prior to each OVA challenge. Airway hyper-responsiveness (AHR), airway inflammation, cytokine levels in broncho-alveolar lavage fluid, Selleck 3 MA and mucus production were determined. Results: IL-37 production of human PBMCs was significantly lower in allergic asthmatics vs healthy children. In wild-type mice, intranasal administration of IL-37 ablated allergic airway inflammation as well as cytokine production and subsequently diminished the hallmarks of experimental asthma including mucus hyperproduction and AHR. In contrast, local application of IL-37 produced none of these effects in mice lacking either IL18R alpha or SIGIRR/IL-1R8. Conclusions: This study demonstrates that IL-37 is able to ablate
a TH2 cell-directed allergic inflammatory response and the hallmarks of experimental asthma in mice, suggesting that IL-37 may be critical for asthma pathogenesis. Furthermore, these data suggest a mode of action of IL-37 that involves IL18R alpha as well as the orphan receptor SIGIRR/IL-1R8.”
“Octopamine and 5-hydrroxytryptamine (5-HT) have been
known to mediate cellular immune responses, such as hemocytic phagocytosis and nodule formation, during bacterial invasion in some insects. In addition, eicosanoids also mediate these cellular immune reactions in various insects, resulting in. clearing the bacteria circulating Selleck BMS-777607 in the hemolymph. This study investigated a hypothesis on signal cross-talk between both types of immune mediators in the beet armyworm, Spodoptera exigua, which had been observed in the effect of eicosanoids on mediating the cellular immune responses. In response to bacterial infection, octopamine or 5-HT markedly enhanced both hemocytic phagocytosis and nodule formal,ion in S. exigua larvae. Their specific antagonists, phentolamine (an octopamine antagonist) or ketanserin (a 5-HT antagonist) suppressed both cellular immune responses of S. exigua. These effects of biogenic monoamines on the immune mediation were expressed through eicosanoids because the inhibitory effects of both antagonists were rescued by the addition of arachidonic acid (a precursor of eicosanoid biosynthesis).
“Background: In spite of the increasing use of robot-assisted radical prostatectomy (RALP) worldwide, no level 1
evidence-based benefit favouring RALP versus pure laparoscopic approaches has been demonstrated in extraperitoneal laparoscopic procedures.\n\nObjective: To compare the operative, functional, and oncologic Selleckchem LDK378 outcomes between pure laparoscopic radical prostatectomy (LRP) and RALP.\n\nDesign, setting, and participants: From 2001 to 2011, 2386 extraperitoneal LRPs were performed consecutively in cases of localised prostate cancers.\n\nIntervention: A total of 1377 LRPs and 1009 RALPs were performed using an extraperitoneal approach.\n\nOutcome measurements and statistical analysis: Patient demographics, surgical
parameters, pathologic features, and functional outcomes were collected into a prospective database and compared between LRP and RALP. Biochemical recurrence-free survival was tested using the Kaplan-Meier method. Mean follow-up was 39 and 15.4 mo in the LRP and RALP groups, respectively.\n\nResults and limitations: Shorter durations of operative time and of hospital stay were reported in the RALP group compared with the LRP group (p < 0.001) even beyond the 100 first cases. Mean blood loss was significantly lower in the RALP group (p < 0.001). The overall rate and the severity of the complications did not differ between the two groups. LDC000067 in vitro In pT2 disease, lower rates of positive margins were reported in the RALP group (p = 0.030; odds ratio [OR]: 0.396) in multivariable analyses. The surgical approach did not affect the continence
recovery. Robot assistance was independently predictive for potency recovery (p = 0.045; OR: 5.9). Survival analyses showed an equal Dinaciclib oncologic control between the two groups. Limitations were the lack of randomisation and the short-term follow-up.\n\nConclusions: Robotic assistance using an extraperitoneal approach offers better results than pure laparoscopy in terms of operative time, blood loss, and hospital stay. The robotic approach independently improves the potency recovery but not the continence recovery. When strict indications of nerve-sparing techniques are respected, RALP gives better results than LRP in terms of surgical margins in pathologically organ-confined disease. Longer follow-up is justified to reach conclusions on oncologic outcomes. (C) 2012 European Association of Urology. Published by Elsevier B.V. All rights reserved.”
“Heterozygous familial hypercholesterolemia (FH) is common but underdiagnosed, and typically undertreated. The molecular biology has been well understood for years, but public health efforts are essentially nonexistent in most countries, despite several outstanding examples in western Europe. Recent observational data suggest major benefit for even modest lipid intervention. The Make Early Diagnoses to Prevent Early Deaths (MEDPED) program seeks to identify and help patients with FH.
“Our previous study indicated that consuming (-)-epigallocatechin gallate (EGCG) before or after traumatic brain injury (TBI) eliminated free radical generation in rats, resulting in inhibition of neuronal degeneration and apoptotic death, and improvement of cognitive impairment. Here we investigated the
effects of administering EGCG at various times pre- and post-TBI on cerebral function and morphology. Wistar rats were divided into five groups and were allowed access to (1) normal drinking water, (2) EGCG pre-TBI, (3) EGCG pre- and post-TBI, (4) EGCG post-TBI, and (5) sham-operated selleck chemical group with access to normal drinking water. TBI was induced with a pneumatic controlled injury device at 10 weeks of age. Immunohistochemistry and lipid peroxidation studies revealed that at 1, 3, and 7 days post-TBI, the number of 8-Hydroxy-2′-deoxyguanosine-, 4-Hydroxy-2-nonenal- and single-stranded DNA (ssDNA)-positive cells, and levels of malondialdehyde around the damaged area were significantly decreased in all EGCG treatment groups compared with the water group (P < 0.05). Although there was a significant increase in the number of surviving neurons after TBI in each EGCG treatment group compared with the water group (P < 0.05), significant improvement of cognitive impairment
after TBI was only BAY 73-4506 order observed in the groups with continuous and post-TBI access to EGCG (P < 0.05). These results indicate that EGCG inhibits free radical-induced neuronal degeneration and apoptotic death around the area damaged by TBI. Importantly, continuous and post-TBI access to EGCG improved cerebral function following TBI. In summary, consumption of green tea may
be an effective therapy for TBI patients.”
“AIM: To investigate the association between epidermal growth factor (EGF) +61A/G polymorphism and susceptibility to gastric cancer, through a cross-sectional Selleckchem Pexidartinib study.\n\nMETHODS: Polymerase chain reaction resctriction fragment lenght polymorphism analyses were used to geno-type EGF +61 in 207 patients with gastric lesions (162 patients with gastric adenocarcinomas, 45 with atrophy or intestinal metaplasia) and 984 controls. All subjects were Caucasian.\n\nRESULTS: Genotype distribution was 23.5% for GG and 76.5% for GA/AA in the control group, 18.4% for GG and 68.6% for GA/AA in the entire group with gastric lesions and 17.9% for GG and 82.1% for GA/AA in the group with gastric adenocarcinoma. No statistically significant associations were found between EGF +61 variants and risk for developing gastric cancer [odds ratios (OR) = 1.41, 95% confidence intervals (CI): 0.90-2.21, P = 0.116]. However, the stratification of individuals by gender revealed that males carrying A alleles (EGF +61A/G or AA) had an increased risk for developing gastric cancer as compared to GG homozygous males (OR = 1.55, 95% CI: 1.05-2.28, P = 0.021).
“In order to support analysis of data from 3D-position-sensitive click here gamma-ray detectors, a software package, UMImaging, has been designed and implemented. UMImaging is designed to apply to a wide range of hardware configurations and analysis needs. Its framework centers around reconstruction methods that perform analysis including spectroscopy, imaging, and detection. These methods are supported by classes that supply events, describe geometry, set options, store and manipulate results, and interact with the user. The ability to bin and display highly multidimensional data is presented, drawing numerous examples from the analysis of data
from a CdZnTe array system. Parallel computing integrated into the structure of UMImaging is shown to provide almost a seven-fold speedup on a six-core computer with hyper-threading, and
the parallel implementation of iterative reconstruction is described. Design choices Panobinostat ic50 that make UMImaging platform independent and easily extendable are also discussed.”
“We study the nonlinear dynamics of spherical colloids under the influence of a pressure driven flow at vanishing Reynolds number. The colloids are confined between two parallel planar walls with a distance comparable to the particle diameter and they interact hydrodynamically via the solvent. We show that the bounded Poiseuille flow gives rise to new classes of trajectories resulting in cross-streamline migration. Two particles moving on these new trajectories exhibit either bound or unbound states. In the first case they oscillate on closed trajectories in the center-of-mass frame. In the second case, they exhibit cross-swapping trajectories in addition to swapping trajectories which were already observed in unbounded or bounded linear shear flow. The different classes of
trajectories occur depending on the initial positions of the two particles and their size. We present CYT387 supplier state diagrams in the lateral positions, where we categorize the trajectories and color code the oscillation frequencies of the bound states. Finally we discuss how the results on the two-particle system help to understand the stability of particle trains composed of several particles. (C) 2013 AIP Publishing LLC.”
“Oomycete genomes have yielded a large number of predicted effector proteins that collectively interfere with plant life in order to create a favourable environment for pathogen infection. Oomycetes secrete effectors that can be active in the host’s extracellular environment, for example inhibiting host defence enzymes, or inside host cells where they can interfere with plant processes, in particular suppression of defence. Two classes of effectors are known to be host-translocated: the RXLRs and Crinklers. Many effectors show defence-suppressive activity that is important for pathogen virulence.
5, P1(t) bigger than 0.99). Functional analysis associated the gene expression changes with lipid metabolism, transport, cell cycle and immune response. Most differentially expressed genes were in common to both treatments and
clustered together only at early time points (2-8 h). Complementary QRT-PCR studies in human HL1-1 and HepG2 cells treated with 50 mu M WY or DMSO for 1, 2, 4, 8, 12,24 or 48 h identified a minimal number of conserved orthologous responses (e.g., Pdk4, Adfp and Angptl4) while some genes (i.e., Bmf, a tumor suppressor) exhibited induction in human cells but repression PD0325901 mw in mice. These data suggest that PPs elicit species-specific PPAR alpha-mediated gene expression. (C) 2013 Elsevier Ltd. All rights reserved.”
“Fructose-1,6 -bisphosphatase (FBPase) is one of the key enzymes in Calvin circle and starch biosynthesis. In this study, the full-length of cpFBPase gene from Pyropia haitanensis was cloned by using rapid amplification of cDNA ends (RACE) technology The nucleotide sequence of PhcpFBPase consists of 1 400 bp, including a 5′ untranslated region (UTR) of 92 bp, a 3′ UTR of 69 bp, and an open reading frame (ORF) of 1 236 bp, which can be translated into a 412-amino-acid putative peptides with
a molecular weight of 44.3 kDa and a theoretical pI of 5.23. Multiple sequence alignment indicated that the protein belonged to the chloroplast FBPase enzyme. Phylogenetic analysis showed that the protein assembled with the cpFBPase of a thermal tolerant unicellular red micro-algae Galdieria sulphuraria. www.selleckchem.com/products/fosbretabulin-disodium-combretastatin-a-4-phosphate-disodium-ca4p-disodium.html Expression patterns analyzed by qRT-PCR revealed that the expression of PhcpFBPase gene in the thallus phage was 7-fold higher than in the conchocelis phage, which suggested the different mechanisms of inorganic carbon utilization among the different life phages of P. haitanensis. And the different response
modes of PhcpFBPase mRNA levels to high temperature and desiccation stress PD0332991 indicated that PhcpFBPase played an important role in responsing to abiotic stress.”
“CLL is extremely heterogeneous in its clinical course, with some patients living decades with no need for treatment whilst others have a rapidly aggressive clinical course. A major focus of research has been to try to identify those biological factors that influence this heterogeneity. The goal of therapy has been to maintain the best quality of life and treat only when patients become symptomatic from their disease. For the majority of patients this means following a “watch and wait” approach to determine the rate of progression of the disease and assess for development of symptoms. Any alteration to this approach will require identification of criteria that define patients sufficiently “high-risk” that they gain benefit by introduction of early therapy.