Defining the risk threshold for risk reducing salpingo-oophorectomy for ovarian cancer prevention in low risk postmenopausal women.

OBJECTIVE: To define risk thresholds for cost-effectiveness of risk-reducing salpingo-oophorectomy (RRSO) for ovarian cancer (OC) prevention in low/intermediate risk postmenopausal women. METHODS: A decision-analytic model compares lifetime costs-&-effects of offering 'RRSO' with 'no RRSO' to postmenopausal women ≥50years for different lifetime OC-risk thresholds: 2%, 4%, 5%, 6%, 8% and 10%. Well established data from the literature are used to estimate total costs, effects in terms of Quality-Adjusted-Life-Years(QALYs), cancer incidence, incremental cost-effectiveness ratio(ICER) and impact. Costs are reported at 2012 prices; costs/outcomes discounted at 3.5%. Deterministic/probabilistic sensitivity analysis (PSA) evaluate model uncertainty. RESULTS: RRSO does not save QALYs and is not cost-effective at the 2% general population lifetime OC-risk. At 4% OC-risk RRSO saves QALYs but is not cost-effective. At risk thresholds ≥5%, RRSO saves more life-years and QALYs and is highly cost-effective. The ICERs for OC-risk levels 5%, 6%, 8% and 10% are £15,247, £9958, £4584, and £1864 respectively. The gain in life-years from RRSO equates to 29.2, 40.1, 62.1 and 80.3days at risk thresholds of 5%, 6%, 8% and 10% respectively. The results are not sensitive to treatment costs of RRSO/OC/cardiovascular events but are sensitive to utility-scores for RRSO. On PSA, 67%, 80%, 84%, 91% and 94% of simulations at risk thresholds of 4%, 5%, 6%, 8% and 10% respectively are cost-effective for RRSO. CONCLUSION: RRSO is highly cost-effective in postmenopausal women aged >50 with ≥5% lifetime OC-risk and increases life-expectancy by ≥29.2days. The results could have significant clinical implications given the improvements in risk prediction and falling costs of genotyping.The study is not funded by any charity or grant

Towards an API Marketplace for an e-Invoicing Ecosystem

Driven by a large number of very diverse and fast-evolving regulations, the adoption of e-invoicing is creating many challenges for solution providers, such as dealing with compliance requirements, cross-border issues, heterogeneity of standards and constant changes. Existing solutions do not represent a cost-effective and vendor-independent alternative to existing legacy systems, ERPs and databases. The proposed solution is based on leveraging cloud computing concepts, Software-as-a-Service concept, API economy, and Business Process Modelling (BPM) concepts. It allows solution providers to choose SaaS components and customise their offerings according to customers needs. Given an ecosystem of APIs available via a marketplace, it becomes possible to rapidly compose and build new applications via BPM technologies. The paper describes an implementation of this concept realised using several e-invoicing APIs being composed using the WASP workflow system. Some preliminary results regarding the feasibility of the proposed approach in a simple buyer-seller scenario are discussed

Cost-effectiveness of unselected multigene germline and somatic genetic testing for epithelial ovarian cancer

Background : Parallel panel germline and somatic genetic testing of all patients with ovarian cancer (OC) can identify more pathogenic variants (PVs) that would benefit from PARP inhibitor (PARPi) therapy, and allow for precision prevention in unaffected relatives with PVs. In this study, we estimate the cost-effectiveness and population impact of parallel panel germline and somatic BRCA testing of all patients with OC incorporating PARPi therapy in the United Kingdom and the United States compared with clinical criteria/family history (FH)–based germline BRCA testing. We also evaluate the cost-effectiveness of multigene panel germline testing alone. Methods: Microsimulation cost-effectiveness modeling using data from 2,391 (UK: n=1,483; US: n=908) unselected, population-based patients with OC was used to compare lifetime costs and effects of panel germline and somatic BRCA testing of all OC cases (with PARPi therapy) (strategy A) versus clinical criteria/FH-based germline BRCA testing (strategy B). Unaffected relatives with germline BRCA1/BRCA2/RAD51C/RAD51D/BRIP1 PVs identified through cascade testing underwent appropriate OC and breast cancer (BC) risk-reduction interventions. We also compared the cost-effectiveness of multigene panel germline testing alone (without PARPi therapy) versus strategy B. Unaffected relatives with PVs could undergo risk-reducing interventions. Lifetime horizon with payer/societal perspectives, along with probabilistic/one-way sensitivity analyses, are presented. Incremental cost-effectiveness ratio (ICER) and incremental cost per quality-adjusted life year (QALY) gained were compared with £30,000/QALY (UK) and $100,000/QALY (US) thresholds. OC incidence, BC incidence, and prevented deaths were estimated. Results: Compared with clinical criteria/FH-based BRCA testing, BRCA1/BRCA2/RAD51C/RAD51D/BRIP1 germline testing and BRCA1/BRCA2 somatic testing of all patients with OC incorporating PARPi therapy had a UK ICER of £51,175/QALY (payer perspective) and £50,202/QALY (societal perspective) and a US ICER of$175,232/QALY (payer perspective) and $174,667/QALY (societal perspective), above UK/NICE and US cost-effectiveness thresholds in the base case. However, strategy A becomes cost-effective if PARPi costs decrease by 45$68,808/QALY and societal-perspective ICERs of £6,923/QALY or $65,786/QALY. One year’s testing could prevent 209 UK BC/OC cases and 192 deaths, and 560 US BC/OC cases and 460 deaths. Conclusions: Unselected panel germline and somatic BRCA testing can become cost-effective, with a 45% to 46% reduction in PARPi costs. Regarding germline testing, unselected panel germline testing is highly cost-effective and should replace BRCA testing alone

Cost-Effectiveness of Genetic Testing for All Women Diagnosed with Breast Cancer in China

Unselected multigene testing for all women with breast cancer (BC) identifies more cancer susceptibility gene (CSG) carriers who can benefit from precision prevention compared with family history (FH)/clinical-criteria-based guidelines. Very little CSG testing is undertaken in middle-income countries such as China, and its cost-effectiveness remains unaddressed. We aimed to estimate cost-effectiveness and population impact of multigene testing for all Chinese BC patients. Data from 8085 unselected BC patients recruited to a Peking University Cancer Hospital study were used for microsimulation modeling, comparing three strategies in the Chinese setting: all BC women undergo BRCA1/BRCA2/PALB2 genetic testing, only BC women fulfilling FH/clinical criteria undergo BRCA testing, and no genetic testing. Prophylactic mastectomy and salpingo-oophorectomy would be adopted where appropriate. Societal and payer perspectives with a lifetime horizon along with sensitivity analyses were presented. Incremental cost-effectiveness ratio (ICER): incremental cost per quality-adjusted life-year (QALY) gained is compared to the USD 10,260/QALY (one-times GDP per capita) willingness-to-pay threshold. BC incidence, ovarian cancer (OC) incidence, and related deaths were also estimated. FH/clinical-criteria-based BRCA testing was ruled out on the principle of extensive dominance. Compared with no genetic testing, multigene testing for all BC patients had an ICER = USD 4506/QALY (societal perspective) and USD 7266/QALY (payer perspective), well below our threshold. Probabilistic sensitivity analysis showed unselected multigene testing remained cost-effective for 94.2%/86.6% of simulations from the societal and payer perspectives. One year's unselected multigene testing could prevent 7868 BC/OC cases and 5164 BC/OC deaths in China. Therefore, unselected multigene testing is extremely cost-effective and should be offered to all Chinese women with BC

Cost-Effectiveness of Risk-Reducing Surgery for Breast and Ovarian Cancer Prevention: A Systematic Review

Policymakers require robust cost-effectiveness evidence of risk-reducing-surgery (RRS) for decision making on resource allocation for breast cancer (BC)/ovarian cancer (OC)/endometrial cancer (EC) prevention. We aimed to summarise published data on the cost-effectiveness of risk-reducing mastectomy (RRM)/risk-reducing salpingo-oophorectomy (RRSO)/risk-reducing early salpingectomy and delayed oophorectomy (RRESDO) for BC/OC prevention in intermediate/high-risk populations; hysterectomy and bilateral salpingo-oophorectomy (BSO) in Lynch syndrome women; and opportunistic bilateral salpingectomy (OBS) for OC prevention in baseline-risk populations. Major databases were searched until December 2021 following a prospective protocol (PROSPERO-CRD42022338008). Data were qualitatively synthesised following a PICO framework. Twenty two studies were included, with a reporting quality varying from 53.6% to 82.1% of the items scored in the CHEERS checklist. The incremental cost-effectiveness ratio/incremental cost-utility ratio and cost thresholds were inflated and converted to US$2020, using the original currency consumer price index (CPI) and purchasing power parities (PPP), for comparison. Eight studies concluded that RRM and/or RRSO were cost-effective compared to surveillance/no surgery for BRCA1/2, while RRESDO was cost-effective compared to RRSO in one study. Three studies found that hysterectomy with BSO was cost-effective compared to surveillance in Lynch syndrome women. Two studies showed that RRSO was also cost-effective at ≥4%/≥5% lifetime OC risk for pre-/post-menopausal women, respectively. Seven studies demonstrated the cost-effectiveness of OBS at hysterectomy (n = 4), laparoscopic sterilisation (n = 4) or caesarean section (n = 2). This systematic review confirms that RRS is cost-effective, while the results are context-specific, given the diversity in the target populations, health systems and model assumptions, and sensitive to the disutility, age and uptake rates associated with RRS. Additionally, RRESDO/OBS were sensitive to the uncertainty concerning the effect sizes in terms of the OC-risk reduction and long-term health impact. Our findings are relevant for policymakers/service providers and the design of future research studies

Quality of life after risk-reducing surgery for breast and ovarian cancer prevention: a systematic review and meta-analysis.

OBJECTIVE: This study aimed to assess the impact of risk-reducing surgery for breast cancer and ovarian cancer prevention on quality of life. We considered risk-reducing mastectomy, risk-reducing salpingo-oophorectomy, and risk-reducing early salpingectomy and delayed oophorectomy. DATA SOURCES: We followed a prospective protocol (International Prospective Register of Systematic Reviews: CRD42022319782) and searched MEDLINE, Embase, PubMed, and Cochrane Library from inception to February 2023. STUDY ELIGIBILITY CRITERIA: We followed a PICOS (population, intervention, comparison, outcome, and study design) framework. The population included women at increased risk of breast cancer or ovarian cancer. We focused on studies reporting quality of life outcomes (health-related quality of life, sexual function, menopause symptoms, body image, cancer-related distress or worry, anxiety, or depression) after risk-reducing surgery, including risk-reducing mastectomy for breast cancer and risk-reducing salpingo-oophorectomy or risk-reducing early salpingectomy and delayed oophorectomy for ovarian cancer. METHODS: We used the Methodological Index for Non-Randomized Studies (MINORS) for study appraisal. Qualitative synthesis and fixed-effects meta-analysis were performed. RESULTS: A total of 34 studies were included (risk-reducing mastectomy: 16 studies; risk-reducing salpingo-oophorectomy: 19 studies; risk-reducing early salpingectomy and delayed oophorectomy: 2 studies). Health-related quality of life was unchanged or improved in 13 of 15 studies after risk-reducing mastectomy (N=986) and 10 of 16 studies after risk-reducing salpingo-oophorectomy (N=1617), despite short-term deficits (N=96 after risk-reducing mastectomy and N=459 after risk-reducing salpingo-oophorectomy). Sexual function (using the Sexual Activity Questionnaire) was affected in 13 of 16 studies (N=1400) after risk-reducing salpingo-oophorectomy in terms of decreased sexual pleasure (-1.21 [-1.53 to -0.89]; N=3070) and increased sexual discomfort (1.12 [0.93-1.31]; N=1400). Hormone replacement therapy after premenopausal risk-reducing salpingo-oophorectomy was associated with an increase (1.16 [0.17-2.15]; N=291) in sexual pleasure and a decrease (-1.20 [-1.75 to -0.65]; N=157) in sexual discomfort. Sexual function was affected in 4 of 13 studies (N=147) after risk-reducing mastectomy, but stable in 9 of 13 studies (N=799). Body image was unaffected in 7 of 13 studies (N=605) after risk-reducing mastectomy, whereas 6 of 13 studies (N=391) reported worsening. Increased menopause symptoms were reported in 12 of 13 studies (N=1759) after risk-reducing salpingo-oophorectomy with a reduction (-1.96 [-2.81 to -1.10]; N=1745) in the Functional Assessment of Cancer Therapy - Endocrine Symptoms. Cancer-related distress was unchanged or decreased in 5 of 5 studies after risk-reducing mastectomy (N=365) and 8 of 10 studies after risk-reducing salpingo-oophorectomy (N=1223). Risk-reducing early salpingectomy and delayed oophorectomy (2 studies, N=413) led to better sexual function and menopause-specific quality of life. CONCLUSION: Risk-reducing surgery may be associated with quality of life outcomes. Risk-reducing mastectomy and risk-reducing salpingo-oophorectomy reduce cancer-related distress, and do not affect health-related quality of life. Women and clinicians should be aware of body image problems after risk-reducing mastectomy, and of sexual dysfunction and menopause symptoms after risk-reducing salpingo-oophorectomy. Risk-reducing early salpingectomy and delayed oophorectomy may be a promising alternative to mitigate quality of life-related risks of risk-reducing salpingo-oophorectomy

Modeling extracellular fields for a three-dimensional network of cells using NEURON

Background: Computational modeling of biological cells usually ignores their extracellular fields, assuming them to be inconsequential. Though such an assumption might be justified in certain cases, it is debatable for networks of tightly packed cells, such as in the central nervous system and the syncytial tissues of cardiac and smooth muscle. New method: In the present work, we demonstrate a technique to couple the extracellular fields of individual cells within the NEURON simulation environment. The existing features of the simulator are extended by explicitly defining current balance equations, resulting in the coupling of the extracellular fields of adjacent cells. Results: With this technique, we achieved continuity of extracellular space for a network model, thereby allowing the exploration of extracellular interactions computationally. Using a three-dimensional network model, passive and active electrical properties were evaluated under varying levels of extracellular volumes. Simultaneous intracellular and extracellular recordings for synaptic and action potentials were analyzed, and the potential of ephaptic transmission towards functional coupling of cells was explored. Comparison with existing method(s): We have implemented a true bi-domain representation of a network of cells, with the extracellular domain being continuous throughout the entire model. This has hitherto not been achieved using NEURON, or other compartmental modeling platforms. Conclusions: We have demonstrated the coupling of the extracellular field of every cell in a threedimensional model to obtain a continuous uniform extracellulat" space. This technique provides a framework for the investigation of interactions in tightly packed networks of cells via their extracellular fields. (C) 2017 Elsevier B.V. All rights reserved

GABA and Glutamate Levels in Occlusal Splint-Wearing Males with Possible Bruxism

Objective The inhibitory neurotransmitter γ-aminobutyric acid (GABA) plays an important role in the pathophysiology of anxiety behavioural disorders such as panic disorder and post-traumatic stress disorder and is also implicated in the manifestation of tooth-grinding and clenching behaviours generally known as bruxism. In order to test whether the stress-related behaviours of tooth-grinding and clenching share similar underlying mechanisms involving GABA and other metabolites as do anxiety-related behavioural disorders, we performed a Magnetic Resonance Spectroscopy (MRS) study for accurate, in vivo metabolite quantification in anxiety-related brain regions. Design MRS was performed in the right hippocampus and right thalamus involved in the hypothalamic−pituitary−adrenal axis system, together with a motor planning region (dorsal anterior cingulate cortex/pre-supplementary motor area) and right dorsolateral prefrontal cortex (DLPFC). Eight occlusal splint-wearing men (OCS) with possible tooth-grinding and clenching behaviours and nine male controls (CON) with no such behaviour were studied. Results Repeated-measures ANOVA showed significant Group × Region interaction for GABA+ (p = 0.001) and glutamate (Glu) (p = 0.031). Between-group post hoc ANOVA showed significantly lower levels of GABA+ (p = 0.003) and higher levels of Glu (p = 0.002) in DLPFC of OCS subjects. These GABA+ and Glu group differences remained significant (GABA+, p = 0.049; Glu, p = 0.039) after the inclusion of anxiety as a covariate. Additionally, GABA and Glu levels in the DLPFC of all subjects were negatively related (Pearson's r = −0.75, p = 0.003). Conclusions These findings indicate that the oral behaviours of tooth-grinding and clenching, generally known as bruxism, may be associated with disturbances in brain GABAergic and glutamatergic systems