Specifying the ovarian cancer risk threshold of 'premenopausal risk-reducing salpingo-oophorectomy' for ovarian cancer prevention: a cost-effectiveness analysis

BACKGROUND: Risk-reducing salpingo-oophorectomy (RRSO) is the most effective intervention to prevent ovarian cancer (OC). It is only available to high-risk women with >10% lifetime OC risk. This threshold has not been formally tested for cost-effectiveness. OBJECTIVE: To specify the OC risk thresholds for RRSO being cost-effective for preventing OC in premenopausal women. METHODS: The costs as well as effects of surgical prevention ('RRSO') were compared over a lifetime with 'no RRSO' using a decision analysis model. RRSO was undertaken in premenopausal women >40 years. The model was evaluated at lifetime OC risk levels: 2%, 4%, 5%, 6%, 8% and 10%. Costs and outcomes are discounted at 3.5%. Uncertainty in the model was assessed using both deterministic sensitivity analysis and probabilistic sensitivity analysis (PSA). Outcomes included in the analyses were OC, breast cancer (BC) and additional deaths from coronary heart disease. Total costs and effects were estimated in terms of quality-adjusted life-years (QALYs); incidence of OC and BC; as well as incremental cost-effectiveness ratio (ICER). DATA SOURCES: Published literature, Nurses Health Study, British National Formulary, Cancer Research UK, National Institute for Health and Care Excellence guidelines and National Health Service reference costs. The time horizon is lifetime and perspective: payer. RESULTS: Premenopausal RRSO is cost-effective at 4% OC risk (life expectancy gained=42.7 days, ICER=£19 536/QALY) with benefits largely driven by reduction in BC risk. RRSO remains cost-effective at >8.2% OC risk without hormone replacement therapy (ICER=£29 071/QALY, life expectancy gained=21.8 days) or 6%if BC risk reduction=0 (ICER=£27 212/QALY, life expectancy gained=35.3 days). Sensitivity analysis indicated results are not impacted much by costs of surgical prevention or treatment of OC/ BC or cardiovascular disease. However, results were sensitive to RRSO utility scores. Additionally, 37%, 61%, 74%, 84%, 96% and 99.5% simulations on PSA are cost-effective for RRSO at the 2%, 4%, 5%, 6%, 8% and 10% levels of OC risk, respectively. CONCLUSIONS: Premenopausal RRSO appears to be extremely cost-effective at ≥4% lifetime OC risk, with ≥42.7 days gain in life expectancy if compliance with hormone replacement therapy is high. Current guidelines should be re-evaluated to reduce the RRSO OC risk threshold to benefit a number of at-risk women who presently cannot access risk-reducing surgery

Specifying the ovarian cancer risk threshold of "premenopausal risk-reducing salpingo-oophorectomy' for ovarian cancer prevention: a cost-effectiveness analysis

BACKGROUND: Risk-reducing salpingo-oophorectomy (RRSO) is the most effective intervention to prevent ovarian cancer (OC). It is only available to high-risk women with >10% lifetime OC risk. This threshold has not been formally tested for cost-effectiveness. OBJECTIVE: To specify the OC risk thresholds for RRSO being cost-effective for preventing OC in premenopausal women. METHODS: The costs as well as effects of surgical prevention ('RRSO') were compared over a lifetime with 'no RRSO' using a decision analysis model. RRSO was undertaken in premenopausal women >40 years. The model was evaluated at lifetime OC risk levels: 2%, 4%, 5%, 6%, 8% and 10%. Costs and outcomes are discounted at 3.5%. Uncertainty in the model was assessed using both deterministic sensitivity analysis and probabilistic sensitivity analysis (PSA). Outcomes included in the analyses were OC, breast cancer (BC) and additional deaths from coronary heart disease. Total costs and effects were estimated in terms of quality-adjusted life-years (QALYs); incidence of OC and BC; as well as incremental cost-effectiveness ratio (ICER). DATA SOURCES: Published literature, Nurses Health Study, British National Formulary, Cancer Research UK, National Institute for Health and Care Excellence guidelines and National Health Service reference costs. The time horizon is lifetime and perspective: payer. RESULTS: Premenopausal RRSO is cost-effective at 4% OC risk (life expectancy gained=42.7 days, ICER=£19 536/QALY) with benefits largely driven by reduction in BC risk. RRSO remains cost-effective at >8.2% OC risk without hormone replacement therapy (ICER=£29 071/QALY, life expectancy gained=21.8 days) or 6%if BC risk reduction=0 (ICER=£27 212/QALY, life expectancy gained=35.3 days). Sensitivity analysis indicated results are not impacted much by costs of surgical prevention or treatment of OC/ BC or cardiovascular disease. However, results were sensitive to RRSO utility scores. Additionally, 37%, 61%, 74%, 84%, 96% and 99.5% simulations on PSA are cost-effective for RRSO at the 2%, 4%, 5%, 6%, 8% and 10% levels of OC risk, respectively. CONCLUSIONS: Premenopausal RRSO appears to be extremely cost-effective at ≥4% lifetime OC risk, with ≥42.7 days gain in life expectancy if compliance with hormone replacement therapy is high. Current guidelines should be re-evaluated to reduce the RRSO OC risk threshold to benefit a number of at-risk women who presently cannot access risk-reducing surgery

The dilemma of arranged marriages in people with epilepsy. An expert group appraisal

INTRODUCTION: Matrimony remains a challenging psychosocial problem confronting people with epilepsy (PWE). People with epilepsy are less likely to marry; however, their marital prospects are most seriously compromised in arranged marriages. AIMS: The aim of this study was to document marital prospects and outcomes in PWE going through arranged marriage and to propose optimal practices for counseling PWE contemplating arranged marriage. METHODS: A MEDLINE search and literature review were conducted, followed by a cross-disciplinary meeting of experts to generate consensus. RESULTS: People with epilepsy experience high levels of felt and enacted stigma in arranged marriages, but the repercussions are heavily biased against women. Hiding epilepsy is common during marital negotiations but may be associated with poor medication adherence, reduced physician visits, and poor marital outcome. Although divorce rates are generally insubstantial in PWE, divorce rates appear to be higher in PWE undergoing arranged marriages. In these marriages, hiding epilepsy during marital negotiations is a risk factor for divorce. CONCLUSIONS: In communities in which arranged marriages are common, physicians caring for PWE are best-equipped to counsel them about their marital prospects. Marital plans and aspirations should be discussed with the family of the person with epilepsy in a timely and proactive manner. The benefits of disclosing epilepsy during marital negotiations should be underscored

The Evolution of Compact Binary Star Systems

We review the formation and evolution of compact binary stars consisting of white dwarfs (WDs), neutron stars (NSs), and black holes (BHs). Binary NSs and BHs are thought to be the primary astrophysical sources of gravitational waves (GWs) within the frequency band of ground-based detectors, while compact binaries of WDs are important sources of GWs at lower frequencies to be covered by space interferometers (LISA). Major uncertainties in the current understanding of properties of NSs and BHs most relevant to the GW studies are discussed, including the treatment of the natal kicks which compact stellar remnants acquire during the core collapse of massive stars and the common envelope phase of binary evolution. We discuss the coalescence rates of binary NSs and BHs and prospects for their detections, the formation and evolution of binary WDs and their observational manifestations. Special attention is given to AM CVn-stars -- compact binaries in which the Roche lobe is filled by another WD or a low-mass partially degenerate helium-star, as these stars are thought to be the best LISA verification binary GW sources.Comment: 105 pages, 18 figure

Proteomic profiling of neuronal mitochondria reveals modulators of synaptic architecture

Abstract Background Neurons are highly polarized cells consisting of three distinct functional domains: the cell body (and associated dendrites), the axon and the synapse. Previously, it was believed that the clinical phenotypes of neurodegenerative diseases were caused by the loss of entire neurons, however it has recently become apparent that these neuronal sub-compartments can degenerate independently, with synapses being particularly vulnerable to a broad range of stimuli. Whilst the properties governing the differential degenerative mechanisms remain unknown, mitochondria consistently appear in the literature, suggesting these somewhat promiscuous organelles may play a role in affecting synaptic stability. Synaptic and non-synaptic mitochondrial subpools are known to have different enzymatic properties (first demonstrated by Lai et al., 1977). However, the molecular basis underpinning these alterations, and their effects on morphology, has not been well documented. Methods The current study has employed electron microscopy, label-free proteomics and in silico analyses to characterize the morphological and biochemical properties of discrete sub-populations of mitochondria. The physiological relevance of these findings was confirmed in-vivo using a molecular genetic approach at the Drosophila neuromuscular junction. Results Here, we demonstrate that mitochondria at the synaptic terminal are indeed morphologically different to non-synaptic mitochondria, in both rodents and human patients. Furthermore, generation of proteomic profiles reveals distinct molecular fingerprints – highlighting that the properties of complex I may represent an important specialisation of synaptic mitochondria. Evidence also suggests that at least 30% of the mitochondrial enzymatic activity differences previously reported can be accounted for by protein abundance. Finally, we demonstrate that the molecular differences between discrete mitochondrial sub-populations are capable of selectively influencing synaptic morphology in-vivo. We offer several novel mitochondrial candidates that have the propensity to significantly alter the synaptic architecture in-vivo. Conclusions Our study demonstrates discrete proteomic profiles exist dependent upon mitochondrial subcellular localization and selective alteration of intrinsic mitochondrial proteins alters synaptic morphology in-vivo

MiR-34a Represses Numbl in Murine Neural Progenitor Cells and Antagonizes Neuronal Differentiation

MicroRNA (miRNA) function is required for normal animal development, in particular in differentiation pathways from stem cell and precursor populations. In neurogenesis, it is becoming increasingly appreciated that miRNAs act at many stages to ensure proper progression. In this study we examined the role of miR-34a in neural progenitor cells (NPC) derived from murine embryonic cortex. We found that over-expression of miR-34a in NPC significantly reduced the neuron yield upon in vitro induction of differentiation. MiR-34a has several predicted targets in the Notch pathway, which operates to balance progenitor self-renewal and differentiation during cortical neurogenesis. We tested several Notch pathway players for regulation by miR-34a in undifferentiated NPC, and found that mRNA and protein levels of Numbl, a negative regulator of Notch signaling, as well as two downstream pro-neural genes usually blocked by Notch signaling, NeuroD1 and Mash1, were diminished, while Notch1 and Cbf1 transcripts were enhanced by miR-34a over-expression. Using a luciferase reporter assay, we verified the Numbl 3′-UTR as a direct miR-34a target. Correspondingly, knock-down of endogenous miR-34a resulted in increased Numbl, NeuroD1 and Mash1, and reduced Notch1 transcript levels. Together these results implicate Numbl as a physiologically relevant target of miR-34a in NPC, allowing for enhanced Notch signaling and inhibition of neuronal differentiation. This work extends our understanding of miR-34a-mediated control of cell differentiation from cancer to mammalian nervous system development

A methodology to estimate the potential to move inpatient to one day surgery

BACKGROUND: The proportion of surgery performed as a day case varies greatly between countries. Low rates suggest a large growth potential in many countries. Measuring the potential development of one day surgery should be grounded on a comprehensive list of eligible procedures, based on a priori criteria, independent of local practices. We propose an algorithmic method, using only routinely available hospital data to identify surgical hospitalizations that could have been performed as one day treatment. METHODS: Moving inpatient surgery to one day surgery was considered feasible if at least one surgical intervention was eligible for one day surgery and if none of the following criteria were present: intervention or affection requiring an inpatient stay, patient transferred or died, and length of stay greater than four days. The eligibility of a procedure to be treated as a day case was mainly established on three a priori criteria: surgical access (endoscopic or not), the invasiveness of the procedure and the size of the operated organ. Few overrides of these criteria occurred when procedures were associated with risk of immediate complications, slow physiological recovery or pain treatment requiring hospital infrastructure. The algorithm was applied to a random sample of one million inpatient US stays and more than 600 thousand Swiss inpatient stays, in the year 2002. RESULTS: The validity of our method was demonstrated by the few discrepancies between the a priori criteria based list of eligible procedures, and a state list used for reimbursement purposes, the low proportion of hospitalizations eligible for one day care found in the US sample (4.9 versus 19.4% in the Swiss sample), and the distribution of the elective procedures found eligible in Swiss hospitals, well supported by the literature. There were large variations of the proportion of candidates for one day surgery among elective surgical hospitalizations between Swiss hospitals (3 to 45.3%). CONCLUSION: The proposed approach allows the monitoring of the proportion of inpatient stay candidates for one day surgery. It could be used for infrastructure planning, resources negotiation and the surveillance of appropriate resource utilization