Parallel Comparison Research Articles

The Impact of COVID-19 on the Insurance Industry

This study investigated the impact of COVID-19 on the insurance industry by studying the case of Ghana from March to June 2020. With a parallel comparison to previous pandemics such as SARS-CoV, H1N1 and MERS, we developed outlines for simulating the impact of the pandemic on the insurance industry. The study used qualitative and quantitative interviews to estimate the impact of the pandemic. Presently, the trend is an economic recession with decreasing profits but increasing claims. Due to the cancellation of travels, events and other economic losses, the Ghanaian insurance industry witnessed a loss currently estimated at GH Ȼ112 million. Our comparison and forecast predicts a normalization of economic indicators from January 2021. In the meantime, while the pandemic persists, insurers should adapt to working from remote locations, train and equip staff to work under social distancing regulations, enhance cybersecurity protocols and simplify claims/premium processing using e-payment channels. It will require the collaboration of the Ghana Ministry of Health, Banking Sector, Police Department, Customs Excise and Preventive Service, other relevant Ministries and the international community to bring the pandemic to a stop.

DNA methylation modulates allograft survival and acute rejection after renal transplantation by regulating the mTOR pathway

Acute rejection (AR) can lead to allograft dysfunction following renal transplantation, despite immunosuppressive treatments. Accumulating evidence points out a role for epigenetic modification in immune responses. However, the mechanism and contribution of DNA methylation in allograft survival remain unclear. In this study, we followed up patients who successively experienced end‐stage renal disease, renal transplantation with allograft function or dysfunction, and hemodialysis. Peripheral blood mononuclear cells were collected at different time points for analysis of the DNA methylation. Epigenetic modifier analysis was also performed to explore its effect of methylation in a mouse model of AR. Compared with the allograft‐stable cohort, patients who experienced AR‐induced allograft dysfunction demonstrated more changes in methylation patterns. Pathway analysis revealed that the hypermethylated areas in the allograft dysfunction group were associated with genes related to the mechanistic target of rapamycin (mTOR) signaling pathway. Moreover, in the mouse AR model, treatment with the DNA methyltransferase inhibitor—decitabine regulated the Th1/2/17/regulatory T cell (Treg cell) immune response via its demethylating role in the suppressing the activity of the mTOR pathway, which ultimately ameliorated renal allograft‐related inflammatory injuries. These results revealed that changes in methylation accompany AR‐induced allograft dysfunction after renal transplantation. Epigenetics may provide new insights into predicting and improving allograft survival.

Parallel comparison and combining effect of radiomic and emerging genomic data for prognostic stratification of non-small cell lung carcinoma patients.

BackgroundA single institution retrospective analysis of 124 non‐small cell lung carcinoma (NSCLC) patients was performed to identify whether disease‐free survival (DFS) achieves incremental values when radiomic and genomic data are combined with clinical information.MethodsUsing the least absolute shrinkage and selection operator (LASSO) Cox regression method, radiomic and genetic features were reduced in number for selection of the most useful prognostic feature. We created four models using only baseline clinical data, clinical data with selected genetic features, clinical data with selected radiomic features, and clinical data with selected genetic and radiomic features together. Multivariate Cox proportional hazards analysis was performed to determine predictors of DFS. Receiver operating characteristic (ROC) calculation was made to compare the discriminative performance for DFS prediction by four constructed models at the five‐year time point.ResultsOn precontrast scan, improved discrimination performance was obtained in a merging of selected radiomics and genetics (AUC = 0.8638), compared with clinical data only (AUC = 0.7990), selected genetic features (AUC = 0.8497), and selected radiomic features (AUC = 0.8355). On post‐contrast scan, discrimination performance was improved (AUC = 0.8672) compared with the clinical variables (AUC = 0.7913), and selected genetic features (AUC = 0.8376) and selected radiomic features (AUC = 0.8399) were considered.ConclusionsThe combination of selected radiomic and genomic features improved stratification of NSCLC patients upon survival. Thus, integrating clinicopathologic model with radiomic and genomic features may lead to improved prognostic accuracy compared to conventional clinicopathological data alone.Key pointsSignificant findings of the studyReceiver operating characteristic (ROC) calculation was made to compare the discriminative performance for disease‐free survival (DFS). The discriminative performance for DFS was better when combining radiomic and genetic features compared to clinical data only, selected genetic features, and selected radiomic features.What this study addsThe combination of selected radiomic and genomic features improved stratification of NSCLC patients upon survival. Thus, integrating a clinicopathological model with radiomic and genomic features may lead to improved prognostic accuracy compared to conventional clinicopathological data alone.

Efficacy and Safety of CD28- or 4-1BB-Based CD19 CAR-T Cells in B Cell Acute Lymphoblastic Leukemia

CD19-directed chimeric antigen receptor-T (CAR-T) cells with a 4-1BB or CD28 co-stimulatory domain have shown impressive antitumor activity against relapsed or refractory B cell acute lymphoblastic leukemia (r/r B-ALL). However, a parallel comparison of their performances in r/r B-ALL therapy has not been sufficiently reported. Here, we manufactured 4-1BB- and CD28-based CD19 CAR-T cells using the same process technology and evaluated their efficacy and safety in r/r B-ALL therapy based on pre-clinical and exploratory clinical investigations. In B-ALL-bearing mice, a similar antitumor effect and CAR-T kinetics in peripheral blood were observed at the CAR-T dose of 1 × 107/mouse. However, when the dose was decreased to 1 × 106/mouse, 4-1BB CAR-T cells were more potent in eradicating tumor cells and showed longer persistence than CD28 CAR-T cells. Retrospective analysis of an exploratory clinical study that used 4-1BB- or CD28-based CAR-T cells to treat r/r B-ALL was performed. Compared with CD28 CAR-T cells, 4-1BB CAR-T cells resulted in higher antitumor efficacy and less severe adverse events. This study demonstrated that the performance of 4-1BB CAR-T cells was superior to that of CD28 CAR-T cells in suppressing CD19+ B-ALL, at least under our manufacturing process.

Fuller-Rylenes: Paving the Way for Promising Acceptors

The hybridization of different acceptors remains a fertile ground awaiting exploration, to fully promote the properties of both components. The concept of this work is to exploit a new form of fuller-rylene hybrids as promising acceptors by integrating planar rylene dye and spherical fullerene for boosting the power conversion efficiency. The synthesis of the fuller-rylenes via a straightforward synthetic strategy by one-pot Pd-catalyzed cyclization can be scaled-up. Specifically, our strategy allows the supplements and enhancement of absorption in the visible region, much wider structural and electronic variations by installing R1 groups as well as decorating R2 on the perylene core at will, and good processability without compromising the superior characteristics of fullerene. Thus, bay-decorated fuller-rylene S-Fuller-PMI revealed a ground-breaking efficiency as high as 8.01%, even outperforming [6,6]-phenyl-C61-butyric acid methyl ester (PC61BM) as a parallel comparison (7.09%). Our exploration paves a new way for the design of high-efficiency acceptors, which are promising alternatives to PC61BM in photovoltaic devices.

Premature infant skin barrier maturation: status at full-term corrected age.

To evaluate the effects of gestational age (GA) and postnatal age on skin barrier integrity by comparing premature infants at full-term corrected age with infants born at term. Parallel comparison of chest skin in 36 premature infants with 39 full-term infants using daily measures of transepidermal water loss (TEWL), skin pH, erythema and rash, over 2 weeks. Chest skin pH was significantly lower for premature infants, indicating that acid mantle formation had occurred in the premature versus full-term infants. Chest TEWL was significantly higher for premature versus full-term infants over 2 weeks, suggesting that even 7-8 weeks after birth, skin integrity is poorer in premature infants. Skin barrier properties of premature infants at adjusted full-term age differ from full-term infants, suggesting that epidermal barrier development depends on GA and time from birth. These maturational differences may influence premature infant response to topical agents.

Assessment of Clinical Research Outcomes for Personalizing Nicotinamide Riboside Dosing

Abstract Objectives Introduction: Nicotinamide riboside (NR), is a NAD + precursor that is commercially available as a nutritional supplement. NAD + levels have been shown to decline in older adults, thus NR has been identified as a healthy aging nutritional supplement. Clinical and preclinical studies have demonstrated the safety and efficacy of NR supplementation at various doses, however individual responsiveness have been minimally reported. As individuals differ in multiple parameters that may result in variations in response to supplementation, dosing personalization may be a key to NR supplement effectiveness. Objective: Determine if published data of clinical NR supplementation can be used to personalize NR dosing. Methods A meta-analysis of published clinical trials of NR supplementation was conducted. Included studies were limited to those that were exclusive to NR supplementation with multiple doses for at least one week. The assessment compared NR dosing, study population demographics, changes in NAD levels, adverse effects, and study outcomes. Results A total of 11 publications report clinical results from NR supplementation demonstrated in 9 clinical trials (4 RCT), however only five of the studies met our criteria. Most of the studies have been conducted in both males and females with an average age of 45–65 years, with various BMIs. Dosing ranged from 100 mg/day to 2000 mg/day, for a duration of 9 days to 3 months, with no major adverse events reported. When measured, NAD + levels were shown to increase by as much as 139% with 1000 mg/day of NR for 56 days. Measurements for changes in NAD + lacked standardization in collection, analysis, and reporting, thus parallel comparisons could not be made. Additionally, studies did not separate NR responses based upon gender, age, BMI, and health status, preventing personalization of the available data. Conclusions To effectively personalize NR dosing, standardization of NAD + analyses and clinical outcomes is gravely needed. Future use of phenotypic flexibility approaches may be beneficial in demonstrating the clinical benefits of NR supplementation. Lastly, it is recommended that future studies include heterogenous response study outcomes to identify responders/non-responders to various endpoints following NR supplementation. Funding Sources None.

Solution-Phase DNA-Compatible Pictet-Spengler Reaction Aided by Machine Learning Building Block Filtering.

SummaryThe application of machine learning toward DNA encoded library (DEL) technology is lacking despite obvious synergy between these two advancing technologies. Herein, a machine learning algorithm has been developed that predicts the conversion rate for the DNA-compatible reaction of a building block with a model DNA-conjugate. We exemplify the value of this technique with a challenging reaction, the Pictet-Spengler, where acidic conditions are normally required to achieve the desired cyclization between tryptophan and aldehydes to provide tryptolines. This is the first demonstration of using a machine learning algorithm to cull potential building blocks prior to their purchase and testing for DNA-encoded library synthesis. Importantly, this allows for a challenging reaction, with an otherwise very low building block pass rate in the test reaction, to still be used in DEL synthesis. Furthermore, because our protocol is solution phase it is directly applicable to standard plate-based DEL synthesis.

Characterization of Postprandial Effects on CSF Metabolomics: A Pilot Study with Parallel Comparison to Plasma.

Cerebrospinal fluid (CSF) metabolites reflect biochemical diffusion/export from the brain and possibly serve as biomarkers related to brain disease severity, pathophysiology, and therapeutic efficacy/toxicity. Metabolomic studies using blood matrices have demonstrated interindividual and preanalytical variation of blood metabolites, whereas those of CSF metabolites remain unclear. In this study, we aimed to delineate the postprandial effects on CSF metabolites because fasting of patients with brain-related disorders is challenging. We collected pre- and postprandial (1.5, 3, and 6 h) plasma and CSF from nine healthy subjects. Using a mass-spectrometry-based global metabolomics approach, 150 and 130 hydrophilic metabolites and 263 and 340 lipids were detected in CSF and plasma, respectively. Principal component analysis of CSF hydrophilic metabolites and lipids primarily classified individual subjects at any time point, suggesting that the postprandial effects had a lower impact than interindividual variations on CSF metabolites. Individually, less than 10% of the CSF metabolites were putatively altered by postprandial effects (with either significant differences or over 2-fold changes, but not both) at any time point. Thus, global CSF metabolite levels are not directly associated with food intake, and except for several putatively altered CSF metabolites, postprandial effects are not a major concern when applying CSF metabolomics to screen biomarkers.

P064: Hot days make for long stays: the impact of extreme heat events on emergency department lengths of stay and volumes in two Canadian community hospitals

Introduction: The average temperature in Canada has risen 1.7°C between 1948-2016, increasing the frequency, severity and duration of extreme heat events. These events can exacerbate underlying health conditions, bringing patients to emergency departments (EDs). There is limited data associating sustained heat events to Canadian ED volumes and performance. This retrospective analysis assessed the impact of humidex and temperature on ED volume and length of stay (LOS). Methods: LOS is an indicator of ED overcrowding and system performance. The authors compared median and maximum LOS (hours) and patient volumes in both ambulatory and stretcher ED sections of two community hospitals (NDH, VH) in Montreal, QC to humidex and temperature during the summers of 2016-2018. Data were analyzed with one-way ANOVA and post hoc means analysis with Fisher LSD tests of a priori determined thresholds of mean three-day maximum humidex and temperature preceding ED presentation. Results: The mean maximum humidex and temperature values for the 2016-2018 summers in Montreal, QC were 30.4 and 26.1°C, respectively (n = 276 days). Elevated mean three-day maximum humidex was associated with increased ED volumes (F[3,88] = 4.2,p = 0.008) and median LOS (F[3,88] = 7.7,p = 0.0001) in the NDH. Mean three-day maximum humidex was associated with ED volumes (F[3,272) = 2.9,p = 0.03) but not with median and maximum LOS (p > 0.05) in the VH. Parallel comparisons with mean three-day maximum temperature similarly showed an association with increased ED volumes (F[3,88] = 5.0,p = 0.003) and increased duration of median LOS (F[3,88] = 3.5,p = 0.02) in the NDH. Mean three-day maximum temperature was associated with increased ED volumes (F[3,272] = 3.3,p = 0.02) but not with median and maximum LOS (p > 0.05) in the VH. Conclusion: Warming climates are associated with an increased number of ED presentations and longer median ED LOS. As heat events disproportionately impacted NDH, future investigations need to determine why these two hospitals were affected differently. This study provides local evidence that climate change can disrupt emergency services by increasing the demand for and delaying timely care. This is the first study that the authors are aware of that demonstrates these findings. Hospitals need to be climate ready. Heat waves often happen during times when summer bed closures and vacations already impact system capacity. EDs should dynamically adapt to meet community needs during periods of extreme heat.

A metabolic labeling method detects m6A transcriptome-wide at single base resolution.

Transcriptome-wide mapping of N6-methyladenosine (m6A) at base resolution remains an issue, impeding our understanding of m6A roles at the nucleotide level. Here, we report a metabolic labeling method to detect mRNA m6A transcriptome-wide at base resolution, called 'm6A-label-seq'. Human and mouse cells could be fed with a methionine analog, Se-allyl-L-selenohomocysteine, which substitutes the methyl group on the enzyme cofactor SAM with the allyl. Cellular RNAs could therefore be metabolically modified with N6-allyladenosine (a6A) at supposed m6A-generating adenosine sites. We pinpointed the mRNA a6A locations based on iodination-induced misincorporation at the opposite site in complementary DNA during reverse transcription. We identified a few thousand mRNA m6A sites in human HeLa, HEK293T and mouse H2.35 cells, carried out a parallel comparison of m6A-label-seq with available m6A sequencing methods, and validated selected sites by an orthogonal method. This method offers advantages in detecting clustered m6A sites and holds promise to locate nuclear nascent RNA m6A modifications.

A large-scale systematic framework of Chinese snakes based on a unified multilocus marker system

Snakes are one of the most diverse groups of terrestrial vertebrates, with approximately 3500 extant species. A robust phylogeny and taxonomy of snakes is crucial for us to know, study and protect them. For a large group such as snakes, broad-scale phylogenetic reconstructions largely rely on data integration. Increasing the compatibility of the data from different researches is thus important, which can be facilitated by standardization of the loci used in systematic analyses. In this study, we proposed a unified multilocus marker system for snake systematics by conflating 5 mitochondrial markers, 19 vertebrate-universal nuclear protein coding (NPC) markers and 72 snake-specific noncoding intron markers. This marker system is an addition to the large squamate conserved locus set (SqCL) for studies preferring a medium-scale data set. We applied this marker system to over 440 snake samples and constructed the currently most comprehensive systematic framework of the snakes in China. Robust snake phylogenetic relationships were recovered at both deep and shallow evolutionary depths, demonstrating the usefulness of this multilocus marker system. Discordance was revealed by a parallel comparison between the snake tree based on the multilocus marker system and that based on only the mitochondrial loci, highlighting the necessity of using multiple types of markers to better understand the snake evolutionary histories. The divergence times of different snake groups were estimated with the nuclear data set. Our comprehensive snake tree not only confirms many important nodes inferred in previous studies but also contributes new insights into many snake phylogenetic relationships. Suggestions are made for the current Chinese snake taxonomy.

Evolution of the Conceptual Foundations of Russian Scientific Diplomacy 1996-2016

The process of changing the conceptual foundations of Russian scientific diplomacy as an instrument of foreign policy and one of the forms of international scientific and technical cooperation over a twenty-year time span, the chronological boundaries of which are determined by the adoption of key strategic documents in this area, is examined. Based on the analysis of the regulatory framework, a sample of doctrinal sources related to the international aspects of the state scientific policy has been compiled. Through their analysis and parallel comparison with the Foreign Policy Concepts of the Russian Federation of 1993, 2000, 2008, 2013 and 2016, key transformations of the perception and vision of scientific diplomacy by decision-makers in the field are identified. Based on the results of the systematization of guidelines and value orientations reflected in the relevant political and determining documents, the periodization of the formation of scientific diplomacy was carried out with the identification of two stages. The first (1996 - mid-2000s) is characterized by a transition from a liberal paradigm to a realistic one, a certain politicization, and national interests at the forefront. The second stage (mid-2000s - 2016) is characterized by a reorientation to the economic dimension of international scientific and technical cooperation with a clear formation of scientific diplomacy as a concept in its modern form. It is shown that this evolution proceeded relatively smoothly in line with the objective changes in the international situation, Russia's position on the world stage, as well as adjustments to its foreign policy. Along with this, the role of E. M. Primakov as one of the ideological founders of modern Russian scientific diplomacy was identified and outlined.

A Learning-Enhanced Two-Pair Spatiotemporal Reflectance Fusion Model for GF-2 and GF-1 WFV Satellite Data.

Since requirements of related applications for time series remotely-sensed images with high spatial resolution have been hard to be satisfied under current observation conditions of satellite sensors, it is key to reconstruct high-resolution images at specified dates. As an effective data reconstruction technique, spatiotemporal fusion can be used to generate time series land surface parameters with a clear geophysical significance. In this study, an improved fusion model based on the Sparse Representation-Based Spatiotemporal Reflectance Fusion Model (SPSTFM) is developed and assessed with reflectance data from Gaofen-2 Multi-Spectral (GF-2 MS) and Gaofen-1 Wide-Field-View (GF-1 WFV). By introducing a spatially enhanced training method to dictionary training and sparse coding processes, the developed fusion framework is expected to promote the description of high-resolution and low-resolution overcomplete dictionaries. Assessment indices including Average Absolute Deviation (AAD), Root-Mean-Square Error (RMSE), Peak Signal to Noise Ratio (PSNR), Correlation Coefficient (CC), spectral angle mapper (SAM), structure similarity (SSIM) and Erreur Relative Global Adimensionnelle de Synthèse (ERGAS) are then used to test employed fusion methods for a parallel comparison. The experimental results show that more accurate prediction of GF-2 MS reflectance than that from the SPSTFM can be obtained and furthermore comparable with popular two-pair based reflectance fusion models like the Spatial and Temporal Adaptive Fusion Model (STARFM) and the Enhanced-STARFM (ESTARFM).

Development and characterization of mammary intraductal (MIND) spontaneous metastasis models for triple-negative breast cancer in syngeneic mice

Triple-negative breast cancer (TNBC) has a more aggressive phenotype and higher metastasis and recurrence rates than other breast cancer subtypes. TNBC currently lacks a transplantation model that is suitable for clinical simulations of the tumor microenvironment. Intraductal injection of tumor cells into the mammary duct could mimic the occurrence and development of breast cancer. Herein, we injected 4T1 cells into the mammary ducts of BALB/C mice to build a preclinical model of TNBC and optimized the related construction method to observe the occurrence and spontaneous metastasis of tumors. We compared the effects of different cell numbers on tumorigenesis rates, times to tumorigenesis, and metastases to determine the optimal number of cells for modelling. We demonstrated that 4T1-MIND model mice injected with 20,000 cells revealed a suitable tumor formation rate and time, thus indicating a potential treatment time window after distant metastasis. We also injected 20,000 cells directly into the breast fat pad or breast duct for parallel comparison. The results still showed that the 4T1-MIND model provides sufficient treatment time for lung metastases in mice and that it is a more reliable model for early tumor development. The 4T1-MIND model requires continuous improvement and optimization. A suitable and optimized model for translational research and studies on the microenvironment in TNBC should be developed.

Health education interventions to promote early presentation and referral for women with symptoms of endometrial cancer.

Diagnosis of endometrial (womb) cancer is normally made at an early stage, as most women with the disease experience abnormal vaginal bleeding, which prompts them to seek medical advice. However, delays in presentation and referral can result in delay in diagnosis and management, which can lead to unfavourable treatment outcomes. This is particularly a problem for pre- and peri-menopausal women. Providing educational information to women and healthcare providers regarding symptoms relating to endometrial cancer may raise awareness of the disease and reduce delayed treatment. To assess the effectiveness of health education interventions targeting healthcare providers, or individuals, or both, to promote early presentation and referral for women with endometrial cancer symptoms. We searched CENTRAL, MEDLINE and Embase. We also searched registers of clinical trials, abstracts of scientific meetings and reference lists of review articles. We planned to include randomised controlled trials (RCTs), both individually randomised and cluster-RCTs. In the absence of RCTs we planned to include well-designed non-randomised studies (NRS) with a parallel comparison assessing the benefits of any type of health education interventions. Two review authors independently evaluated whether potentially relevant studies met the inclusion criteria for the review, but none were found. A comprehensive search of the literature yielded the following results: CENTRAL (1022 references), MEDLINE (2874 references), and Embase (2820 references). After de-duplication, we screened titles and abstracts of 4880 references and excluded 4864 that did not meet the review inclusion criteria. Of the 16 references that potentially met the review inclusion, we excluded all 16 reports after reviewing the full texts. We did not identify any ongoing trials. There is currently an absence of evidence to indicate the effectiveness of health education interventions involving healthcare providers or individuals or both to promote early presentation and referral for women with endometrial cancer symptoms. High-quality RCTs are needed to assess whether health education interventions enhance early presentation and referral. If health education interventions can be shown to reduce treatment delays in endometrial cancer, further studies would be required to determine which interventions are most effective.

Understanding the effects of climate warming on streamflow and active groundwater storage in an alpine catchment: the upper Lhasa River

Abstract. Climate warming is changing streamflow regimes and groundwater storage in cold alpine regions. In this study, the Yangbajain headwater catchment in the Lhasa River basin is adopted as the study area to assess streamflow changes and active groundwater storage in response to climate warming. The results show that both annual streamflow and the mean air temperature increase significantly at respective rates of about 12.30 mm per decade and 0.28 ∘C per decade from 1979 to 2013 in the study area. The results of gray relational analysis indicate that the air temperature acts as a primary factor for the increased streamflow. Due to climate warming, the total glacier volume has retreated by over 25 % during the past 50 years, and the areal extent of permafrost has degraded by 15.3 % over the last 20 years. Parallel comparisons with other subbasins in the Lhasa River basin indirectly reveal that the increased streamflow at the Yangbajain Station is mainly fed by the accelerated glacier retreat. Using baseflow recession analysis, we also find that the estimated groundwater storage that is comparable with the GRACE data increases significantly at rates of about 19.32 mm per decade during the abovementioned period. That is to say, as permafrost thaws, more spaces have been made available to accommodate the increasing meltwater. Finally, a large water imbalance (of more than 5.79×107 m3 a−1) between the melt-derived runoff and the actual increase in runoff as well as the groundwater storage is also observed. The results from this study suggest that the impacts of glacial retreat and permafrost degradation show compound behaviors on the storage–discharge mechanism due to climate warming, and that this fundamentally affects the water supply and the mechanisms of streamflow generation and change.

Priority setting in scaled-up cancer screening in China: an systematic review of economic evaluation evidences

Objective: The existed economic evaluations of cancer screening in Chinese population are almost all single-cancer focused, evidence on parallel comparison among multiple cancers is lacking. Thus, the aim of this study was, from a priority setting perspective, to compare the cost-effectiveness of six common cancers(colorectal cancer, breast cancer, liver cancer, lung cancer, esophageal cancer and stomach cancer) to facilitate policy making in future scaled-up screening in populations in China. Methods: Partially based on our previous single-cancer systematic reviews (colorectal cancer, breast cancer, liver cancer, and lung cancer), evidence of economic evaluations of cancer screening in populations in mainland China were systematically updated and integrated. The main updates include: 1) Stomach cancer and esophageal cancer were newly added to the current analysis. 2) The literature searching was extended to 8 literature databases, including PubMed, EMbase, The Cochrane Library, Web of Science, CBM, CNKI, Wanfang Data, and VIP. 3) The period of publication year was updated to the recent 10 years: January 1, 2009 to December 31, 2018. 4) The study focused on populations in mainland China. Following the standard processes of literature searching, inclusion and exclusion from previous systematic reviews, the basic characteristics, evaluation indicators and main results of the included studies were extracted. All the costs were discounted to 2017 value using the by-year consumer price index of medical and health care residents in China and presented in the Chinese Yuan (CNY). The ratios of incremental cost-effectiveness ratio (ICER) to China's per capita GDP in 2017 were calculated (<1 means very cost-effective, 1-3 means cost-effective, >3 means not cost-effective). Given a specific indicator, the median value among all reported screening strategies for each cancer was calculated, based on which priority ranking was then conducted among all cancers when data available. Results: A total of 45 studies were included, 22 for breast cancer, 12 for colorectal cancer, 6 for stomach cancer, 4 for esophageal cancer (all conducted in high-risk areas), 1 for liver cancer and none for lung cancer (was not then considered for next ranking due to limited numbers of studies). When based on the indicator, the median ratio of cost per life-year saved to China's per capita GDP (reported in 12 studies), the lowest ratio (-0.015) was observed in esophageal cancer among 16 strategies of 2 studies (N=2, n=16), followed by 0.297 for colorectal cancer (N=3, n=12), 0.356 for stomach cancer (N=1, n=4) and 0.896 for breast cancer (N=6, n=52, P(75)=3.602). When based on another commonly used ICER indicator, the median ratio of cost per quality-adjusted life-year gained to China's per capita GDP (reported in 13 studies), the least cost was found in stomach cancer (0.495, N=3, n=8, P(75)=3.126), followed by esophageal cancer (0.960, N=1, n=4, P(75)=1.762) and breast cancer (2.056, N=9, n=64, P(75)=4.217). Data was not found for colorectal cancer. In addition, cost per cancer case detected was the most adopted indicator (32 studies). The median cost among all screening strategies for each cancer was 14 759 CNY for stomach cancer (N=5, n=7), 49 680 CNY for colorectal cancer (N=12, n=25) and 171 930 CNY for breast cancer (N=13, n=24), respectively. Data was not available for esophageal cancer and rare for precancer cases detected. Evidence related to cost per disability-adjusted life-year gained was not available. Conclusions: At China's national level and limited to the six cancers covered by the current study, the preliminary analysis suggests that stomach cancer and colorectal cancer were the most cost-effective target cancers and could be given priority in the future scaled-up screening in general populations. Esophageal cancer screening should be prioritized in high-risk areas. Breast cancer was also cost-effective in general but some of the intensive screening strategies were marginal. Data on liver cancer and lung cancer were too limited to conclude, and more well-designed studies and high-quality research evidence should be required. This priority ranking might be changed if other common cancers were involved analyses.

Parallel comparison of three methodologies for measuring functional C1-inhibitor in Hereditary angioedema patients

Hereditary angioedema (HAE) types I and II are characterized by functional C1 inhibitor (fC1-INH) deficiency which results in bradykinin overproduction. Sensitive, specific and robust methods to quantitate fC1-INH in human samples are required for diagnosing HAE and/or to measure pharmacodynamic activity of C1-INH drugs in clinical studies. To date, three methods have been reported in literature to measure fC1-INH: conventional chromogenic assay measuring residual C1-esterase activity, and immunoassays based on functional binding to either activated complement C1s or Factor XIIa/kallikrein.We used three qualified/validated fit-for purpose methods to quantitate fC1-INH in human plasma and to conduct a parallel comparison for diagnostic purposes and as a read-out for pharmacodynamic activity. Sensitivity and specificity were determined from the Receiver Operator Characteristics (ROC) curve analysis of the three fC1-INH methods through testing of fifty healthy control vs. HAE plasma samples. fC1-INH profile of fifteen HAE subjects, who underwent different treatment regimen in a cross-over Shire C1-INH clinical study, was analyzed in these three methods in parallel. A correlation analysis performed between these methods using data generated from clinical samples showed that profiles obtained from different fC1-INH methods matched for individual HAE subjects.Our findings suggest that functional binding immunoassay methods serve as reliable alternates for conventional chromogenic method to quantitate fC1-INH in human plasma samples with a better dynamic range of detection and ease of use. Of the two immunoassays used in this study, FXIIa-binding method gave better sensitivity, specificity, and correlation to the chromogenic method as a diagnostic method to distinguish HAE samples from healthy controls.

Abstract P6-08-13: Personalized and cost-effective detection of copy number variants by molecular-barcode next-generation sequencing and long-read nanopore sequencing

Abstract Background: Germline copy number variants (CNV) of hereditary breast and ovarian cancer genes are a known class of clinically significant mutations. However, failure to detect CNV is a known limitation of Sanger sequencing and conventional amplicon next-generation sequencing (NGS). Multiplex ligation-dependent probe amplification (MLPA), while robust for CNV detection, is labor-intensive, costly to scale up and has limited breakpoint resolution at exon level only. We evaluated the clinical utility of molecular-barcode NGS and long-read nanopore sequencing in our genetic testing algorithm, specifically on CNV detection and breakpoint characterization of probands and family members. Methods: Both molecular-barcode NGS (BRCA1, BRCA2, TP53, PTEN, PALB2 and CDH1) and MLPA (BRCA1 and BRCA2) were performed in parallel on 200 high-risk breast and/or ovarian cancer probands and 11 CNV positive controls. CNV calling from MLPA and NGS data was performed by Coffalyser.Net and a novel in-house bioinformatics algorithm BAMClipper-SE, respectively. Nanopore amplicon or whole-genome sequencing was attempted to map the exact breakpoint of CNV controls and any newly identified CNV positive probands (up to May 2019). Personalized breakpoint PCR test for specific CNVs was designed and validated on probands and subsequently applied to corresponding family members for carrier testing. Results: Molecular-barcode NGS was 100% sensitive in detecting all BRCA1/2 CNVs from 11 positive controls. A total of 4 BRCA1/2 CNVs were detected by NGS from the 200 probands and matched the corresponding MLPA results. In addition, a PALB2 CNV (exons 4-6 deletion) was also detected by NGS during the parallel comparison. Up to May 2019, a total of 22 probands with detectable CNV in BRCA1, BRCA2, PALB2 or CHEK2 were accrued. Exact CNV breakpoint at nucleotide resolution was identified from 20 probands by nanopore and Sanger sequencing (BRCA1 n=12, BRCA2 n=5, PALB2 n=2 and CHEK2 n=1). High-resolution breakpoint mapping was applicable to inform variant pathogenicity and to enable recurrent CNV identification. Personalized breakpoint PCR designed for the 20 probands were applied to 42 family members, of whom 16 were CNV carriers and 26 were non-carriers. Breakpoint PCR results and any available MLPA results of these family members were 100% concordant. Conclusion: Molecular-barcode NGS allows a streamlined workflow to detect both sequence mutations and CNVs. It proves to be a reliable and cost-effective replacement of BRCA1/2 MLPA in genetic testing algorithm of new probands. Simultaneously the NGS workflow expands CNV detection coverage to additional genes (e.g. PALB2) without costly scale-up of MLPA gene panels. Nanopore sequencing is a practical alternative to MLPA in orthogonal validation of newly detected CNV. The high-resolution breakpoint mapping transforms CNV carrier testing to a personalized, simple and cost-effective breakpoint PCR. Citation Format: Ava Kwong, Chun H Au, Dona N Ho, Elaine YL Wong, Yvonne Chung, Fian BF Law, Cecilia YS Ho, Jiawei Chen, Isabella W Cheuk, Vivian Y Shin, Tsun L Chan, Hextan YS Ngan, Edmond SK Ma. Personalized and cost-effective detection of copy number variants by molecular-barcode next-generation sequencing and long-read nanopore sequencing [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-08-13.