Cost-Effectiveness Analysis of Imaging Modalities for Breast Cancer Surveillance Among BRCA1/2 Mutation Carriers: A Systematic Review

BackgroundBRCA1/2 mutation carriers are suggested with regular breast cancer surveillance screening strategies using mammography with supplementary MRI as an adjunct tool in Western countries. From a cost-effectiveness perspective, however, the benefits of screening modalities remain controversial among different mutated genes and screening schedules.MethodsWe searched the MEDLINE/PubMed, Embase, Cochrane Library, Scopus, and Web of Science databases to collect and compare the results of different cost-effectiveness analyses. A simulated model was used to predict the impact of screening strategies in the target group on cost, life-year gained, quality-adjusted life years, and incremental cost-effectiveness ratio (ICER).ResultsNine cost-effectiveness studies were included. Combined mammography and MRI strategy is cost-effective in BRCA1 mutation carriers for the middle-aged group (age 35 to 54). BRCA2 mutation carriers are less likely to benefit from adjunct MRI screening, which implies that mammography alone would be sufficient from a cost-effectiveness perspective, regardless of dense breast cancer.ConclusionsPrecision screening strategies among BRCA1/2 mutation carriers should be conducted according to the acceptable ICER, i.e., a combination of mammography and MRI for BRCA1 mutation carriers and mammography alone for BRCA2 mutation carriers.Systematic Review RegistrationPROSPERO, identifier CRD42020205471.

Comparative accuracy of cervical cancer screening strategies in healthy asymptomatic women: a systematic review and network meta-analysis

To compare all available accuracy data on screening strategies for identifying cervical intraepithelial neoplasia grade ≥ 2 in healthy asymptomatic women, we performed a systematic review and network meta-analysis. MEDLINE and EMBASE were searched up to October 2020 for paired-design studies of cytology and testing for high-risk genotypes of human papillomavirus (hrHPV). The methods used included a duplicate assessment of eligibility, double extraction of quantitative data, validity assessment, random-effects network meta-analysis of test accuracy, and GRADE rating. Twenty-seven prospective studies (185,269 subjects) were included. The combination of cytology (atypical squamous cells of undetermined significance or higher grades) and hrHPV testing (excepting genotyping for HPV 16 or 18 [HPV16/18]) with the either-positive criterion (OR rule) was the most sensitive/least specific, whereas the same combination with the both-positive criterion (AND rule) was the most specific/least sensitive. Compared with standalone cytology, non-HPV16/18 hrHPV assays were more sensitive/less specific. Two algorithms proposed for primary cytological testing or primary hrHPV testing were ranked in the middle as more sensitive/less specific than standalone cytology and the AND rule combinations but more specific/less sensitive than standalone hrHPV testing and the OR rule combination. Further research is needed to assess these results in population-relevant outcomes at the program level.

Evaluation of Virtual Screening Strategies for the Identification of γ-Secretase Inhibitors and Modulators

γ-Secretase is an intramembrane aspartyl protease that is important in regulating normal cell physiology via cleavage of over 100 transmembrane proteins, including Amyloid Precursor Protein (APP) and Notch family receptors. However, aberrant proteolysis of substrates has implications in the progression of disease pathologies, including Alzheimer’s disease (AD), cancers, and skin disorders. While several γ-secretase inhibitors have been identified, there has been toxicity observed in clinical trials associated with non-selective enzyme inhibition. To address this, γ-secretase modulators have been identified and pursued as more selective agents. Recent structural evidence has provided an insight into how γ-secretase inhibitors and modulators are recognized by γ-secretase, providing a platform for rational drug design targeting this protease. In this study, docking- and pharmacophore-based screening approaches were evaluated for their ability to identify, from libraries of known inhibitors and modulators with decoys with similar physicochemical properties, γ-secretase inhibitors and modulators. Using these libraries, we defined strategies for identifying both γ-secretase inhibitors and modulators incorporating an initial pharmacophore-based screen followed by a docking-based screen, with each strategy employing distinct γ-secretase structures. Furthermore, known γ-secretase inhibitors and modulators were able to be identified from an external set of bioactive molecules following application of the derived screening strategies. The approaches described herein will inform the discovery of novel small molecules targeting γ-secretase.

Probabilistic microsimulation to examine the cost-effectiveness of hospital admission screening strategies for carbapenemase-producing enterobacteriaceae (CPE) in the United Kingdom

Background Antimicrobial resistance has been recognised as a global threat with carbapenemase- producing-Enterobacteriaceae (CPE) as a prime example. CPE has similarities to COVID-19 where asymptomatic patients may be colonised representing a source for onward transmission. There are limited treatment options for CPE infection leading to poor outcomes and increased costs. Admission screening can prevent cross-transmission by pre-emptively isolating colonised patients. Objective We assess the relative cost-effectiveness of screening programmes compared with no- screening. Methods A microsimulation parameterised with NHS Scotland date was used to model scenarios of the prevalence of CPE colonised patients on admission. Screening strategies were (a) two-step screening involving a clinical risk assessment (CRA) checklist followed by microbiological testing of high-risk patients; and (b) universal screening. Strategies were considered with either culture or polymerase chain reaction (PCR) tests. All costs were reported in 2019 UK pounds with a healthcare system perspective. Results In the low prevalence scenario, no screening had the highest probability of cost-effectiveness. Among screening strategies, the two CRA screening options were the most likely to be cost-effective. Screening was more likely to be cost-effective than no screening in the prevalence of 1 CPE colonised in 500 admitted patients or more. There was substantial uncertainty with the probabilities rarely exceeding 40% and similar results between strategies. Screening reduced non-isolated bed-days and CPE colonisation. The cost of screening was low in relation to total costs. Conclusion The specificity of the CRA checklist was the parameter with the highest impact on the cost-effectiveness. Further primary data collection is needed to build models with less uncertainty in the parameters.

Understanding the Pattern of Oropharyngeal Cancers from North-East Romanian Patients

Background: Human papilloma virus (HPV) is acknowledged as a risk factor for oropharyngeal squamous cellular cancers (OPSCC), of which the dominant types are tonsillar (TSCC) and base of tongue cancer (BOTSCC). Objective: To assess the role of HPV in selected OPSCC cases, from Romanian patients by sensitive and complementary molecular assays. Material and Methods: Fifty-four formalin fixed paraffin embedded (FFPE) OPSCC samples were analyzed for HPV DNA by a PCR-based bead-based multiplex-assay. Thirty-four samples were tested for HPV RNA and for overexpression of p16INK4a by immunohistochemistry. Twenty samples were evaluated by Competitive Allele-Specific Taqman PCR (CAST-PCR) for fibroblast growth factor receptor 3 protein (FGFR3) status. Results: A total of 33.3% (18/54) OPSCC samples were positive for HPV DNA. HPV16 was the most frequent type (30%, 16/54); followed by HPV18 (3.7%, 2/54); and 1 sample (1.8%) was positive for both HPV16 and 18. HPV18 E6*I was detected in a HPV18 DNA-positive oropharynx tumor. Four samples positive for HPV16 were also positive for p16INK4a. All the tested samples were negative for FGFR3. Conclusions: The increased HPV16 prevalence is in line with similar studies and is a new confirmation that HPV16 is the most prevalent type in our country; supporting the potential benefit of prophylactic vaccines. Overall, there is no concordance between DNA and any of the two other analytes that are considered being markers of HPV-driven cancers. There is a need to explore novel screening strategies that could be broadly used in the clinical routine to initiate preventive measures.

Commercially-available heart rate monitor repurposed into a 9-gram standalone device for automatic arrhythmia detection with snapshot electrocardiographic capability: a pilot validation.

Background: The usefulness of opportunistic arrhythmia screening strategies, using an electrocardiogram (ECG) or other methods for random snapshot assessments is limited by the unexpected and occasional nature of arrhythmias, leading to a high rate of missed-diagnosis. We have previously validated a cardiac monitoring system for AF detection pairing simple consumer-grade Bluetooth low-energy (BLE) heart rate (HR) sensors with a smartphone application (RITMIA, Heart Sentinel srl, Italy). In the current study we test a significant upgrade to the abovementioned system, thanks to the technical capability of new HR sensors to run algorithms on the sensor itself and to acquire (and store on-board) single-lead ECG strips, if asked to do so. Methods and Results We have reprogrammed a HR monitor intended for sports use (Movensense HR+) to run our proprietary RITMIA algorithm code in real-time, based on RR analysis, so that if any type of arrhythmia is detected it triggers a brief retrospective recording of a single-lead ECG, providing tracings of the specific arrhythmia for later consultation. We report the initial data on the behavior, feasibility and high diagnostic accuracy of this ultra-low weight customized device for standalone automatic arrhythmia detection and ECG recording, when several types of arrhythmias were simulated, under different baseline conditions. Conclusions This customized device was capable to detect all types of simulated arrhythmias and correctly triggered an visually interpretable ECG tracing. Future human studies are needed to address real-life accuracy of this device.

Cost-Effectiveness Of Atrial Fibrillation Screening Strategies: A Systematic Review

Objective: This study aims to analyze the cost-effectiveness of atrial fibrillation screening strategies.Design: Systematic review Setting: LiteraturePatient(s): Patients with atrial fibrillation.Intervention(s): To find related research and articles in this field, articles published in Iranian and international databases and based on inclusion and exclusion criteria were searched and reviewed. The quality-adjusted life-years (QALYs) were the main outcome used for measuring the effectiveness.­Main Outcome Measure(s): Incremental cost-effectiveness ratios (ICER) per gained or additional QALY, additional case detected, and avoided stroke.Result(s): Out of 3,360 studies found in the field of the present study, finally, fifteen studies were included in the research. The lowest ICER numerical value was 78.39 for AF screening using ECG for 65-85-year-old Japanese women. The highest value of this index is equal to 70864.31 for performing ECG monitoring for more than 60 days for Canadians over 80 years without AF history who have been referred to outpatient clinics. In two studies, the results were expressed with the Years of life gained (YLG) measure. Of course, in one study, the results were not reported with this measure and in one study, the results were reported with ICER. Conclusion(s): According to the results of all the studies analyzed, most of the studies acknowledged the cost-effectiveness of different AF screening strategies. However, studies that confirmed the cost-effectiveness of population-based screening were more than studies that confirmed the cost-effectiveness of other screening strategies.

Cost of providing cell-free DNA screening for Down syndrome in Finland using different strategies

Introduction A financial analysis is carried out to assess costs and benefits of providing cell-free DNA screening in Finland, using different strategies. Materials and methods Three cell-free DNA screening strategies are considered: Primary, all women; Secondary, those with positive Combined test; and Contingent, the 10–30% with the highest Combined test risks. Three costs are estimated: additional cost for 10,000 pregnancies compared with the Combined test; ‘marginal’ cost of avoiding a Down syndrome birth which occurs in a pregnancy that would have been false-negative using the Combined test; and marginal cost of preventing the iatrogenic loss of a non-Down syndrome birth which occurs in a pregnancy that would have been false-positive. Results Primary cell-free DNA will require additional funds of €250,000. The marginal cost per Down syndrome birth avoided is considerably less than the lifetime medical and indirect cost; the marginal cost per unaffected iatrogenic fetal loss prevented is higher than one benefit measure but lower than another. If the ultrasound component of the Combined test is retained, as would be in Finland, the additional funds required rise to €992,000. Secondary cell-free DNA is cost-saving as is a Contingent strategy with 10% selected but whilst when 20–30% costs rise they are much less than for the Primary strategy and are cost-beneficial. Conclusions When considering the place of cell-free DNA screening it is important to make explicit the additional and marginal costs of different screening strategies and the associated benefits. Under most assumptions the balance is favorable for Contingent screening.

Risk surveillance and mitigation: autoantibodies as triggers and inhibitors of severe reactions to SARS-CoV-2 infection

COVID-19 clinical presentation differs considerably between individuals, ranging from asymptomatic, mild/moderate and severe disease which in some cases are fatal or result in long-term effects. Identifying immune mechanisms behind severe disease development informs screening strategies to predict who are at greater risk of developing life-threatening complications. However, to date clear prognostic indicators of individual risk of severe or long COVID remain elusive. Autoantibodies recognize a range of self-antigens and upon antigen recognition and binding, important processes involved in inflammation, pathogen defence and coagulation are modified. Recent studies report a significantly higher prevalence of autoantibodies that target immunomodulatory proteins including cytokines, chemokines, complement components, and cell surface proteins in COVID-19 patients experiencing severe disease compared to those who experience mild or asymptomatic infections. Here we discuss the diverse impacts of autoantibodies on immune processes and associations with severe COVID-19 disease.