Economics and laboratory efficiency of atrial fibrillation ablation.

PURPOSE OF REVIEW: Atrial fibrillation is a growing public health problem and is associated with an increased risk of comorbidities with enormous socioeconomic implications. This review article focuses on fiscal burden of atrial fibrillation on the healthcare system and economic value of atrial fibrillation ablations brought to the patient and the payers by improvement in outcomes and reduction in treatment costs. RECENT FINDINGS: This article summarizes the recently published studies evaluating the economic impact of atrial fibrillation treatment. Catheter ablation have shown to be the most successful strategy for treatment of defibrillation. However, repeat ablation is associated with higher costs, over and above any subsequent procedural costs, compared with a single ablation procedure for atrial fibrillation. Cryoballoon ablation has been shown to have fewer repeat ablations than radiofrequency ablations, which resulted in overall cost reduction. Improvement in laboratory efficiency, better utilization of laboratory resources and same-day discharge strategy can lead to further healthcare savings and increase in value to all stakeholders. SUMMARY: The value of healthcare delivery for patient with atrial fibrillation can be improved by advancement in technology that demonstrates cost reduction to the health system and outcomes improvements. Implementation of tactics that decrease cost and improve outcomes can alleviate some of the financial strain on healthcare systems, which is of extreme importance in the current climate.

Same-day discharge after cryoballoon ablation of atrial fibrillation: A multicenter experience.

BACKGROUND: It is common practice to observe patients during an overnight stay (ONS) following a catheter ablation procedure for the treatment of atrial fibrillation (AF). OBJECTIVES: To investigate the safety and economic impact of a same-day discharge (SDD) protocol after cryoballoon ablation for treatment of AF in high-volume, geographically diverse US hospitals. METHODS: We retrospectively reviewed 2374 consecutive patients (1119 SDD and 1180 ONS) who underwent cryoballoon ablation for AF at three US centers. Baseline characteristics, acute procedure-related complications, and longer-term evaluations of safety were recorded during routine clinical follow-up. The mean cost of an ONS was used in a one-way sensitivity analysis to evaluate yearly cost savings as a function of the percentage of SDD cases per year. RESULTS: The SDD and ONS cohorts were predominately male (69% vs. 67%; p = .3), but SDD patients were younger (64 ± 11 vs. 66 ± 10; p < .0001) with lower body mass index (30 ± 6 vs. 31 ± 61; p < .0001) and CHA2 DS2 -VASc scores (1.4 ± 1.0 vs. 2.2 ± 1.4; p < .0002). There was no difference between SDD and ONS in the 30-day total complication rate (n = 15 [1.26%] versus n = 24 [2.03%]; p = .136, respectively). The most common complication was hematoma in both the SDD (n = 8; 0.67%) and ONS (n = 11; 0.93%) cohorts. Sensitivity analysis demonstrated that when 50% of every 100 patients treated were discharged the same day, hospital cost savings ranged from $45 825 to $83 813 per year across US hospitals. CONCLUSIONS: SDD following cryoballoon ablation for AF appears to be safe and is associated with cost savings across different US hospitals.

Improving Procedural Skill Confidence in Pediatric Residents: A Longitudinal Simulation-Based Workshop Curriculum.

Introduction: Exit surveys among our pediatric residency graduates found 50% were not confident performing required procedures. While procedural competency poses many curricular challenges, simulation is an effective educational modality many programs have adopted, though often only through onetime workshops limited to single procedures, clinical settings, or levels of training. We sought to develop a comprehensive, recurring, yearlong, simulation-based curriculum covering many important pediatric procedures. Methods: We created a longitudinal curriculum of recurring monthly workshops using both low- and high-fidelity simulators, highlighting 17 pediatric procedures. Comprehensive facilitator guides contained equipment lists, instructions, competency checklists, and quizzes for each workshop. Correlation between attendance and confidence was assessed for skills in which residents attended two or more workshops on the same skill. ACGME exit surveys compared graduates' confidence regarding procedural skills before and after curriculum implementation. Results: On exit surveys, graduates who agreed or strongly agreed to feeling comfortable with the procedures in our curriculum improved from 50% to 66% after 2 years, and those who disagreed or strongly disagreed decreased from 40% to 22%. A positive correlation existed between repeated workshop attendance and confidence in many procedures (R2 range, .60-.99). Discussion: Longitudinal simulation is an effective educational modality that increases learner confidence in performing procedures. Our curriculum addresses adult learners' need for repetition and can be adopted by other programs to improve graduates' confidence. The curriculum's sustainability is underscored by use of cost-reducing low-fidelity simulators and comprehensive guides that allow any instructor to conduct the workshop.

Pitx3 controls multiple aspects of lens development.

The transcription factor Pitx3 is critical for lens formation. Deletions in the promoter of this gene cause abnormal lens development in the aphakia (ak) mouse mutant, which has only rudimentary lenses. In this study, we investigated the role of Pitx3 in lens development and differentiation. We found that reduced expression of Pitx3 leads to changes in the proliferation, differentiation and survival of lens cells. The genetic interactions between Pitx3 and Foxe3 were investigated, as these two transcription factors are expressed at the same time in lens development and their absence has similar consequences for lens development. We found no evidence that these two genes genetically interact. In general, our study shows that the abnormal phenotype of the ak lenses is not due to just one molecular pathway, rather in the absence of Pitx3 expression multiple aspects of lens development are disrupted.

7-(4-Chloro-phen-yl)-9-phenyl-7H-pyrrolo[3,2-e]tetra-zolo[1,5-c]pyrimidine.

In the title compound, C(18)H(11)ClN(6), the pyrrole, pyrimidine and tetra-zole rings form a nearly planar fused trihetrocyclic system with an r.m.s. deviation of 0.0387 (13) Å, to which the 4-chloro-phenyl group and the phenyl group are substituted at the 7 and 9 positions, respectively. The dihedral angles between the pyrrole ring and the 4-chloro-phenyl and phenyl rings are 32.1 (4) and 7.87 (7)°, respectively. In the crystal, weak inter-molecular C-H⋯N and C-H⋯Cl hydrogen bonds link the mol-ecules into a layer parallel to the (001) plane. The layers are further connected by π-π stacking inter-actions [centroid-centroid distances: 3.8413 (8) and 3.5352 (8) Å]. Intra-molecular C-H⋯N hydrogen bonds are also present.

12-(4-Methoxy-phen-yl)-10-phenyl-3,4,5,6,8,10-hexa-azatricyclo-[7.3.0.0]dodeca-1(9),2,4,7,11-penta-ene.

In the title compound, C(19)H(14)N(6)O, the fused 12-membered tetra-zolo/pyrimidine/pyrrole ring system is almost planar (r.m.s. deviation = 0.013 Å). The 4-methoxy-phenyl and phenyl substituents on the pyrrole ring are both twisted with respect to the fused-ring system [dihedral angles = 25.39 (18) and 36.42 (18)°, respectively]. Intra-molecular C-H⋯N inter-actions occur. In the crystal, mol-ecules pack into layers in the ac plane and these are connected along the b axis via C-H⋯π and π-π [centroid-centroid separation = 3.608 (3) Å] inter-actions.

12-(4-Chloro-phen-yl)-7-methyl-10-phenyl-3,4,5,6,8,10-hexa-aza-tricyclo-[7.3.0.0]dodeca-1(9),2,4,7,11-penta-ene.

The 12 non-H atoms defining the triple-fused-ring system in the title compound, C(19)H(13)ClN(6), are almost coplanar (r.m.s. deviation = 0.023 Å). The chloro-substituted ring is almost effectively coplanar with the central atoms [dihedral angle = 6.74 (13)°], but the N-bound benzene ring is not [dihedral angle = 54.38 (13)°]. In the crystal, supra-molecular chains along the a axis sustained by C-H⋯π and π-π [centroid-centroid distance between N(4)C and C(4)N five-membered rings = 3.484 (2) Å] stacking occur. A very long C-Cl⋯π contact is also seen.

7-(4-Bromo-phen-yl)-9-phenyl-7H-pyrrolo[3,2-e]tetra-zolo[1,5-c]pyrimidine.

In the title compound, C(18)H(11)BrN(6), the phenyl ring is almost coplanar [dihedral angle 7.2 (1)°] with the planar (r.m.s. deviation 0.039 Å) tricyclic ring system while the 4-bromo-phenyl ring makes a dihedral angle of 33.98 (6)° with the ring system. Weak inter-molecular C-H⋯N and C-H⋯Br hydrogen-bonding inter-actions and π-π stacking [centroid-centroid distances = 3.7971 (17) and 3.5599 (16) Å] stabilize the crystal packing. A comparison of the structure to a MOPAC PM3 geometry optimization calculation in vacuo supports these observations.

Effect of tobacco in human oral leukoplakia: a cytomorphometric analysis.

OBJECTIVES: Tobacco use is one of the most critical risk factors for different oral diseases. The aim of this study is to demonstrate the effect of tobacco on oral mucosa by cytomorphometric analysis of cells with the help of exfoliative cytology and to find out the improvement in diagnostic sensitivity of exfoliative cytology in the detection of dysplastic changes and early oral malignancy. METHODS: The nuclear area (NA) and cytoplasmic area (CA) of cells were measured within cytological smear obtained from leukoplakia lesions of buccal mucosa of 90 tobacco users, 30 smokers (TS), 30 chewers (TC) and 30 with combined habit of smoking and chewing (TSC) and from normal buccal mucosa of 30 non users (NU) of tobacco. Each habit group consisted of 30 tobacco users with oral leukoplakia lesion with mild epithelial dysplasia only. The 30 non-users of tobacco served as controls. The mean values of the CA and NA were obtained for each case, and the nuclear/cytoplasmic area (NA/CA) ratio was calculated. RESULTS: The results showed a statistically significant increase (P<0.001) in mean NA and a statistically significant decrease (P<0.001) in mean CA values of tobacco users with leukoplakia as compared to non-users, hence NA/CA ratio value was significantly higher in tobacco users with the lesion. CONCLUSION: The changes in cellular morphology caused by tobacco use can be visualized by use of exfoliative cytology with the help of cytomorphometric analysis. The evaluation of parameters (NA, CA and NA/CA ratio) may increase the sensitivity of exfoliative cytology for the early diagnosis of oral premalignant and malignant lesions.

Eye formation in the absence of retina.

Eye development is a complex process that involves the formation of the retina and the lens, collectively called the eyeball, as well as the formation of auxiliary eye structures such as the eyelid, lacrimal gland, cornea and conjunctiva. The developmental requirements for the formation of each individual structure are only partially understood. We have shown previously that the homeobox-containing gene Rx is a key component in eye formation, as retinal structures do not develop and retina-specific gene expression is not observed in Rx-deficient mice. In addition, Rx-/- embryos do not develop any lens structure, despite the fact that Rx is not expressed in the lens. This demonstrates that during normal mammalian development, retina-specific gene expression is necessary for lens formation. In this paper we show that lens formation can be restored in Rx-deficient embryos experimentally, by the elimination of beta-catenin expression in the head surface ectoderm. This suggests that beta-catenin is involved in lens specification either through Wnt signaling or through its function in cell adhesion. In contrast to lens formation, we demonstrate that the development of auxiliary eye structures does not depend on retina-specific gene expression or retinal morphogenesis. These results point to the existence of two separate developmental processes involved in the formation of the eye and its associated structures. One involved in the formation of the eyeball and the second involved in the formation of the auxiliary eye structures.

7-(4-Methoxy-phen-yl)-5-methyl-9-phenyl-7H-pyrrolo[2',3':4,5]pyrimido[1,6-d]tetrazole.

The title compound, C(20)H(16)N(6)O, is composed of a tetra-zolo ring and a 4-methoxy-phenyl and a benzene-substituted pyrrole ring at the 7 and 9 positions fused to a pyrimidine ring in a nearly planar fashion [maximum deviation of 0.018 (1) Šfor the fused ring system]. A methyl group at the 5 position is also in the plane of the hetero cyclic system. The dihedral angle between the mean planes of the benzene and 4-methoxy-phenyl rings is 40.4 (2)°. The dihedral angles between the mean planes of the pyrimidine and the benzene and 4-methoxy-phenyl rings are 15.6 (5)° and 52.6 (7)°, respectively. A weak intra-molecular C-H⋯N hydrogen bond inter-action, which forms an S(7) graph-set motif, helps to establish the relative conformations of the tetrazolo and benzene rings. In the crystal, weak inter-molecular C-H⋯O, C-H⋯π and π-π stacking inter-actions [centroid-centroid distances = 3.5270 (16), 3.5113 (16), 3.7275 (17) and 3.7866 (17) Å] link the mol-ecules into a two-dimensional array obliquely parallel to (101) and propagating along the b axis.

Expression of complement components coincides with early patterning and organogenesis in Xenopus laevis.

The complement system is the central component of innate immunity and an important player in the adaptive immunity of vertebrates. We analyzed the expression patterns of several key members of the complement cascade during Xenopus development. We found extensive expression of these molecules already during gastrula/early neurula stage. Remarkably, several genes also showed an organ-specific expression pattern during early organogenesis. Early expression is notable for two different expression patterns in the neuroectoderm. In one group, there is early strong neural plate and neural precursor expression. This is the case of properdin, C1qA, C3 and C9. The second pattern, seen with C1qR and C6, is noteworthy for its expression at the periphery of the neural plate, in the presumptive neural crest. Two genes stand out for their predominantly mesodermal expression. C3aR, the message for the cognate receptor for C3 in the complement cascade, is expressed at the same time as C3, but in a complementary, reciprocal pattern in the mesoderm. C1qA expression also predominates in somites, pronephros, visceral mesoderm and ventral blood islands. Finally, several genes are characterized by later expression in developing organs. C1qR displays a reticular pattern consistent with expression in the developing vasculature. The late expression of C1qA and C3bC4b is strongest in the pronephros. Finally, the expression of properdin in the hindbrain and in the developing lens are novel findings. The expression patterns of these molecules suggest that these components of the complement system may have in Xenopus a so far undefined developmental role.

Regulation and function of foxe3 during early zebrafish development.

In this article, we investigate the expression, regulation, and function of the zebrafish forkhead gene foxe3. In wild type embryos, foxe3 is first expressed in a crescent-shaped area at the anterior end of the prechordal plate, corresponding to the polster. At later stages, the hatching gland, the lens, and the anterior pituitary express this gene. Using morpholinos against the zinc finger Kruppel-like factor 4 (KLF4) we show that foxe3 is regulated differently in the polster and in the lens. In the absence of KLF4, expression of foxe3 in the polster is not activated, whereas in the lens placode the expression of KLF4 is not required for the transcription of foxe3. The expression of foxe3 is also regulated by the hedgehog and nodal signaling pathways. foxe3 expression is altered in the hedgehog pathway mutants iguana and you-too and the nodal pathway mutant cyclops. foxe3 function is necessary for the execution of lens-specific gene expression and lens morphogenesis, as the knockdown of foxe3 results in a loss of platelet-derived growth factor receptor alpha (pdgfralpha) expression and in the vacuolization of the lens.

N-(6-Meth-oxy-pyridin-2-yl)-1-(pyridin-2-ylmeth-yl)-1H-pyrazole-3-carboxamide: crystal structure and Hirshfeld surface analysis.

The title compound, C16H15N5O2, adopts the shape of the letter L with the dihedral angle between the outer pyridyl rings being 78.37 (5)°; the dihedral angles between the central pyrazolyl ring (r.m.s. deviation = 0.0023 Å) and the methyl-ene-bound pyridyl and methyoxypyridyl rings are 77.68 (5) and 7.84 (10)°, respectively. Intra-molecular amide-N-H⋯N(pyrazol-yl) and pyridyl-C-H⋯O(amide) inter-actions are evident and these preclude the participation of the amide-N-H and O atoms in inter-molecular inter-actions. The most notable feature of the mol-ecular packing is the formation of linear supra-molecular chains aligned along the b-axis direction mediated by weak carbonyl-C=O⋯π(triazol-yl) inter-actions. An analysis of the calculated Hirshfeld surfaces point to the importance of H⋯H (46.4%), C⋯H (22.4%), O⋯H (11.9%) and N⋯H (11.1%) contacts in the crystal.

Addition of vasopressin to norepinephrine as independent predictor of mortality in patients with refractory septic shock: an observational study.

OBJECTIVE: To identify predictors of 28-day mortality among patients with refractory septic shock treated with norepinephrine with or without vasopressin. DESIGN: Prospective observational cohort study. SETTING: A 1,200-bed academic medical center. PATIENTS: One hundred thirty-seven patients with septic shock treated with norepinephrine with or without vasopressin. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The 28-day mortality rate was 37.2% (n = 51). By multivariate analysis, significant predictors of death were norepinephrine plus vasopressin administration (adjusted odds ratio [AOR], 13.96; 95% confidence interval [CI] 6.47, 30.08; p = 0.001), lack of goal-directed fluid administration during initial resuscitation (AOR 15.82; 95% CI 6.16, 40.61; p = 0.003), inappropriate initial antimicrobial therapy (AOR 8.95; 95% CI 2.93, 27.33; p = 0.05), and higher Acute Physiology and Chronic Health Evaluation (APACHE) II score (AOR 1.14; 95% CI 1.07, 1.21; p = 0.033). Patients who received norepinephrine plus vasopressin (n = 68) had a significantly higher mortality rate than patients managed with norepinephrine alone (n = 69) 28 days after the initiation of vasopressors (54.4% vs. 20.3%; p < 0.001). This finding was confirmed in patients matched optimally across treatment groups. CONCLUSIONS: Our study found an association between the use of norepinephrine plus vasopressin and 28-day mortality in refractory septic shock. In view of its known mechanism of action, vasopressin contributed to this excess mortality. Further recommendations regarding the use of vasopressin await the results of large randomized trials evaluating its efficacy and safety for septic shock.

Expression of FoxP2 during zebrafish development and in the adult brain.

Fox (forkhead) genes encode transcription factors that play important roles in the regulation of embryonic patterning as well as in tissue specific gene expression. Mutations in the human FOXP2 gene cause abnormal speech development. Here we report the structure and expression pattern of zebrafish FoxP2. In zebrafish, this gene is first expressed at the 20-somite stage in the presumptive telencephalon. At this stage there is a significant overlap of FoxP2 expression with the expression of the emx homeobox genes. However, in contrast to emx1, FoxP2 is not expressed in the pineal gland or in the pronephric duct. After 72 hours of development, the expression of zebrafish FoxP2 becomes more complex in the brain. The developing optic tectum becomes the major area of FoxP2 expression. In the adult brain, the highest concentrations of the FoxP2 transcript can be observed in the optic tectum. In the cerebellum, only the caudal lobes show high levels of Foxp2 expression. These regions correspond to the vestibulocerebellum of mammals. Several other regions of the brain also show high levels of Foxp2 expression.

Optimizing antibiotic treatment for ventilator-associated pneumonia.

Ventilator-associated pneumonia (VAP) is the most common infectious complication in patients receiving mechanical ventilation and accounts for exorbitant use of resources in the intensive care unit. Antimicrobial management of VAP incorporates an initial broad-spectrum, empiric regimen to ensure appropriate coverage with deescalation of therapy after 48-72 hours based on culture results and sensitivities. When VAP clinically responds to treatment, antimicrobials should be discontinued after 7-8 days to reduce overall antibiotic consumption and the selection pressure on flora observed in the intensive care unit and thus minimize the development and spread of antimicrobial resistance.

Regulation of vertebrate eye development by Rx genes.

The paired-like homeobox-containing gene Rx has a critical role in the eye development of several vertebrate species including Xenopus, mouse, chicken, medaka, zebrafish and human. Rx is initially expressed in the anterior neural region of developing embryos, and later in the retina and ventral hypothalamus. Abnormal regulation or function of Rx results in severe abnormalities of eye formation. Overexpression of Rx in Xenopus and zebrafish embryos leads to overproliferation of retinal cells. A targeted elimination of Rx in mice results in a lack of eye formation. Mutations in Rx genes are the cause of the mouse mutation eyeless (ey1), the medaka temperature sensitive mutation eyeless (el) and the zebrafish mutation chokh. In humans, mutations in Rx lead to anophthalmia. All of these studies indicate that Rx genes are key factors in vertebrate eye formation. Because these results cannot be easily reconciled with the most popular dogmas of the field, we offer our interpretation of eye development and evolution.

Management of severe sepsis: integration of multiple pharmacologic interventions.

Severe sepsis is an infection-induced process that often promotes organ dysfunction and death in up to 50% of afflicted patients. Clinical advances that improve patient survival include early goal-directed volume resuscitation, broad-spectrum empiric antimicrobial therapy with deescalation strategies, therapy with drotrecogin alfa (activated), glucocorticoid replacement in patients with adrenal insufficiency, and tight control of blood glucose levels. The challenge for critical care practitioners is to integrate the many pharmacologic and supportive interventions required for optimal care of these patients.