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After fertilization, rapid changes of the Caenorhabditis elegans cytoskeleton occur in the transition from meiosis to mitosis, requiring precise regulation. The MEI-1/MEI-2 katanin microtubule-severing complex is essential for meiotic spindle formation but must be quickly inactivated to allow for proper formation of the mitotic spindle. MEI-1/MEI-2 inactivation is dependent on multiple redundant pathways. The primary pathway employs the MEL-26 substrate adaptor for the CUL-3/cullin-based E3 ubiquitin ligase, which targets MEI-1 for proteosomal degradation. Here, we used quantitative antibody staining to measure MEI-1 levels to determine how other genes implicated in MEI-1 regulation act relative to CUL-3/MEL-26 The anaphase-promoting complex/cyclosome, APC/C, the DYRK (Dual-specificity tyrosine-regulated kinase), MBK-2, and the CUL-2-based E3 ubiquitin ligase act together to degrade MEI-1, in parallel to MEL-26/CUL-3 CUL-2 is known to keep MEL-26 low during meiosis, so CUL-2 apparently changes its target from MEL-26 in meiosis to MEI-1 in mitosis. RFL-1, an activator of cullin E3 ubiquitin ligases, activates CUL-2 but not CUL-3 for MEI-1 elimination. HECD-1 (HECT/Homologous to the E6AP carboxyl terminus domain) E3 ligase acts as a MEI-1 activator in meiosis but functions as an inhibitor during mitosis, without affecting levels of MEI-1 or MEI-2 Our results highlight the multiple layers of MEI-1 regulation that are required during the switch from the meiotic to mitotic modes of cell division., (Copyright © 2016 Beard et al.)

Background: Left atrial appendage closure (LAAC) and nonwarfarin oral anticoagulants (NOACs) have emerged as safe and effective alternatives to warfarin for stroke prophylaxis in patients with nonvalvular atrial fibrillation (AF)., Objectives: This analysis assessed the cost-effectiveness of warfarin, NOACs, and LAAC with the Watchman device (Boston Scientific, Marlborough, Massachusetts) for stroke risk reduction in patients with nonvalvular AF at multiple time points over a lifetime horizon., Methods: A Markov model was developed to assess the cost-effectiveness of LAAC, NOACs, and warfarin from the perspective of the Centers for Medicare & Medicaid Services over a lifetime (20-year) horizon. Patients were 70 years of age and at moderate risk for stroke and bleeding. Clinical event rates, stroke outcomes, and quality of life information were drawn predominantly from PROTECT AF (Watchman Left Atrial Appendage System for Embolic Protection in Patients with Atrial Fibrillation) 4-year data and meta-analyses of warfarin and NOACs. Costs for stroke risk reduction therapies, treatment of associated acute events, and long-term care following disabling stroke were presented in 2015 U.S. dollars., Results: Relative to warfarin, LAAC was cost-effective at 7 years ($42,994/quality-adjusted life-years [QALY]), and NOACs were cost-effective at 16 years ($48,446/QALY). LAAC was dominant over NOACs by year 5 and warfarin by year 10. At 10 years, LAAC provided more QALYs than warfarin and NOACs (5.855 vs. 5.601 vs. 5.751, respectively). In sensitivity analyses, LAAC remained cost-effective relative to warfarin ($41,470/QALY at 11 years) and NOACs ($21,964/QALY at 10 years), even if procedure costs were doubled., Conclusions: Both NOACs and LAAC with the Watchman device were cost-effective relative to warfarin, but LAAC was also found to be cost-effective and to offer better value relative to NOACs. The results of this analysis should be considered when formulating policy and practice guidelines for stroke prevention in AF., (Copyright © 2015 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Second-generation atypical antipsychotics such as clozapine, olanzapine, risperidone, quetiapine, ziprasidone, amisulpride and ariprazole offer the potential to reduce the significant health care resource demands in the treatment of schizophrenia through improved levels of initial clinical response and reduced levels of long-term acute relapse. However, the optimal sequencing of these drugs remains unclear. To consider this issue from a health economic viewpoint a decision model approach was used comparing healthcare costs and clinical outcomes when treating patients with alternative sequences of atypical antipsychotic treatment. Treated patients were assumed to be in a current acute episode with at least a 10-year history of disease and to be naive to previous atypical treatments. Treatment strategies were based on either first-line olanzapine or risperidone with switching to the alternative drug as second-line treatment following an inadequate clinical response to first-line drug therapy. Clinical response data were derived from a pivotal published comparative study of both olanzapine and risperidone. Published data on the long-term use of antipsychotic drugs where used wherever possible to populate the model for relapse rates during the maintenance phase. Health care resource data were defined for Germany based on expert clinical opinion. A treatment strategy of first-line olanzapine was shown to be cost saving over a 1-year period, with additional clinical benefits in the form of avoided relapses. The model suggests that over the first year of treatment a strategy of first-line olanzapine is associated with lower risk of additional relapse (0.33 fewer acute relapses per 100 patients per year) and with cost savings (euro 35,306 per 100 patients per year). There is a need for longer term direct in-trial comparisons of atypical antipsychotics to confirm these indicative results.

Prophylaxis-based antiviral treatment and intensive monitoring followed by pre-emptive antiviral treatment are both commonly used management strategies to reduce risk of cytomegalovirus (CMV) infection following renal transplantation. This study employed a decision-model approach using published efficacy data and information from a recent survey of French clinical practice to consider the relative costs and outcomes associated with CMV prevention strategies for high-risk patient groups. The cost per case of treating tissue invasive and symptomatic CMV disease was estimated at euro 15,431 and euro 10,852, respectively. In the highest infection-risk patient group (positive donor with no previous CMV history) prophylactic oral valaciclovir was shown to avoid the greatest number of CMV disease cases (35 cases per 100 transplanted patients) and reduced the overall CMV-related costs per transplanted patient by around 14% over a'wait-and-treat' baseline strategy. In contrast, intensive monitoring and preemptive treatment resulted in a much higher cost per transplanted patient. This analysis suggests that prophylactic treatment remains the most cost-effective approach to the management of CMV in renal-transplanted patients. Further comparative studies between prophylactic and pre-emptive treatment would be a valuable addition to the current evidence based on CMV prevention.

Objective: To analyze the cost-effectiveness of resection for liver metastases compared with standard nonsurgical cytotoxic treatment., Summary Background Data: The efficacy of hepatic resection for metastases from colorectal cancer has been debated, despite reported 5-year survival rates of 20% to 40%. Resection is confined to specialized centers and is not widely available, perhaps because of lack of appropriate expertise, resources, or awareness of its efficacy. The cost-effectiveness of resection is important from the perspective of managed care in the United States and for the commissioning of health services in the United Kingdom., Methods: A simple decision-based model was developed to evaluate the marginal costs and health benefits of hepatic resection. Estimates of resectability for liver metastases were taken from UK-reported case series data. The results of 100 hepatic resections conducted in Sheffield from 1997 to 1999 were used for the cost calculation of liver resection. Survival data from published series of resections were compiled to estimate the incremental cost per life-year gained (LYG) because of the short period of follow-up in the Sheffield series., Results: Hepatic resection for colorectal liver metastases provides an estimated marginal benefit of 1.6 life-years (undiscounted) at a marginal cost of 6,742 pound sterling++. If 17% of patients have only palliative resections, the overall cost per LYG is approximately 5,236 pound sterling (5,985 pound sterling with discounted benefits). If potential benefits are extended to include 20-year survival rates, these figures fall to approximately 1,821 pound sterling (2,793 pound sterling with discounted benefits). Further univariate sensitivity analysis of key model parameters showed the cost per LYG to be consistently less than 15,000 pound sterling., Conclusion: In this model, hepatic resection appears highly cost-effective compared with nonsurgical treatments for colorectal-related liver metastases.

Pertussis infection is associated with significant morbidity in younger children (<4 years), which can include pneumonia, seizures and encephalopathy. Around one in 250 cases of pertussis in infants under the age of 6 months lead to death or severe brain damage. In the United Kingdom the control of pertussis infection has been based on a three-dose schedule of combined diphtheria, tetanus, whole-cell pertussis vaccine (DTPw) during the first 4 months of life. Coverage rates for primary vaccination are currently at high levels of over 90 per cent and infection rates are relatively low (approximately 1.2 per 100,000). However, there are concerns over the potential under-reporting of pertussis and clear shifts in the age pattern of notified cases are evident, with surveillance data suggesting a possible upward trend in the absolute numbers of infections in those at most risk (i.e. infants <3 months old). The addition of childhood booster dose(s) of pertussis vaccine to the standard schedule has potential clinical benefits and may be cost-effective. Selective adult booster immunization may also have a role to play in controlling the circulation of pertussis.

As part of an NHS Executive Trent regional initiative we considered the role and cost-effectiveness of high dose chemotherapy in the treatment of relapsed Hodgkin's disease and non-Hodgkin's lymphoma. The key trials and case series show an additional patient benefit of 0.8-1.1 life years over standard chemotherapy. We estimate incremental cost per life year gained of 12 800 pound silver-17 600 pound silver, which reduces further if long-term benefits are considered. High dose chemotherapy in these conditions is both life-saving and cost-effective.