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The International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) adopted Guideline M10 entitled "Bioanalytical Method Validation and Study Sample Analysis" in May 2022. In October 2023, approximately one year after the adoption of the ICH M10 guideline, a "Hot Topic" session was held during the AAPS PharmSci 360 meeting to discuss the implementation of the guideline. The session focused on items the bioanalytical community felt were challenging to implement or ambiguous within the guideline. These topics included cross-validation, parallelism, comparative bioavailability studies, combination drug stability, endogenous analyte bioanalysis, and dilution QCs. In addition, the regulatory perspective on the guideline was presented. This report provides a summary of the Hot Topic session.

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Rapid detection of SARS-CoV-2 is essential for clinical management in the emergency department during the COVID-19 pandemic. We evaluated the clinical performance of the recently developed cartridge-based rapid RT-PCR assay (STANDARD M10 SARS-CoV-2) in patients visiting the emergency department from July 2022 to January 2023, which was when the Omicron BA.5 sublineage was predominant in Korea. A total of 534 specimens were subjected to the STANDARD M10 and standard RT-PCR (Allplex SARS-CoV-2) assays. The overall, positive, and negative percent agreements between these two assays were 99.6%, 100%, and 99.6%, respectively. The results showed that compared with the established RT-PCR assay, the STANDARD M10 SARS-CoV-2 assay is a reliable and useful tool for SARS-CoV-2 detection during the study period. The new rapid RT-PCR will expand the diversity in rapid diagnostics and can help resolve the global imbalance associated with the supply of diagnostic resources.

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A test statistic for nonlinearity of a given heavy-tailed time series process is constructed, based on the sub-sample stability of Gini-based sample autocorrelations. The finite-sample performance of the proposed test is evaluated in a Monte Carlo study and compared to a similar test based on the sub-sample stability of a heavy-tailed analogue of the conventional sample autocorrelation function. In terms of size and power properties, the quality of our test outperforms a nonlinearity test for heavy-tailed time series processes proposed by [S.I. Resnick and E. Van den Berg, A test for nonlinearity of time series with infinite variance, Extremes 3 (2000), pp. 145-172.]. A nonlinear Pareto-type autoregressive process and a nonlinear Pareto-type moving average process are used as alternative specifications when comparing the power of the proposed test statistic. The efficacy of the test is illustrated via the analysis of a heavy-tailed actuarial data set and two time series of Ethernet traffic.

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In this article, we introduce a Gegenbauer autoregressive tempered fractionally integrated moving average process. We work on the spectral density and autocovariance function for the introduced process. The parameter estimation is done using the empirical spectral density with the help of the nonlinear least square technique and the Whittle likelihood estimation technique. The performance of the proposed estimation techniques is assessed on simulated data. Further, the introduced process is shown to better model the real-world data in comparison to other time series models.

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This study compared the performance of two commercial molecular assays, the STANDARD M10 Clostridioides difficile assay (M10) and the Xpert C. difficile assay (Xpert), for detecting toxigenic C. difficile in stool specimens. A total of 487 consecutive stool specimens submitted for routine C. difficile testing between June and November 2023 were included. Following routine testing using C. DIFF QUIK CHEK COMPLETE (QCC), M10 and Xpert were tested in parallel, alongside toxigenic culture (reference standard). Additionally, two-step algorithms, using QCC on the first step and either M10 or Xpert on the second step, were assessed. Both M10 and Xpert demonstrated a sensitivity and negative predictive value (NPV) of 100%. M10 exhibited significantly higher specificity and positive predictive value (PPV; 91.9% and 64.2%, respectively) than Xpert (90.3% and 59.8%, respectively). Both two-step algorithms showed a sensitivity and NPV of 98.4% and 99.8%, respectively. The specificity and PPV of the two-step algorithm using M10 (95.2% and 75.0%, respectively) were slightly higher than those of the one using Xpert (94.8% and 73.2%, respectively), without statistical significance. Receiver operating characteristic curve analysis, assessing the predictive ability of cycle threshold (Ct) values for the detection of free toxin, exhibited an area under the curve of 0.825 for M10 and 0.843 for Xpert. This indicates the utility of Ct values as predictors for the detection of free toxin in both assays. In conclusion, M10 proves to be an effective diagnostic tool with performance comparable to Xpert, whether utilized independently or as part of a two-step algorithm.

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The 16th GCC Closed Forum was held in Orlando, FL, USA, on 23 June 2023. Representatives from international bioanalytical Contract Research Organizations were in attendance in order to discuss scientific and regulatory issues specific to bioanalysis. The issues discussed at the meeting included: IS response, flow cytometry, changes to the bioanalytical industry, NGS assays, biomarker assay for tissues, dPCR validation, immunogenicity harmonization and ICH M10 implementation. Conclusions and consensus from discussions of these topics are included in this article.

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We present a full Bayesian analysis of multiplicative double seasonal autoregressive (DSAR) models in a unified way, considering identification (best subset selection), estimation, and prediction problems. We assume that the DSAR model errors are normally distributed and introduce latent variables for the model lags, and then we embed the DSAR model in a hierarchical Bayes normal mixture structure. By employing the Bernoulli prior for each latent variable and the mixture normal and inverse gamma priors for the DSAR model coefficients and variance, respectively, we derive the full conditional posterior and predictive distributions in closed form. Using these derived conditional posterior and predictive distributions, we present the full Bayesian analysis of DSAR models by proposing the Gibbs sampling algorithm to approximate the posterior and predictive distributions and provide multi-step-ahead predictions. We evaluate the efficiency of the proposed full Bayesian analysis of DSAR models using an extensive simulation study, and we then apply our work to several real-world hourly electricity load time series datasets in 16 European countries.

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In this study, we firstly established and verified a method by ultra performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) for the analysis of vilazodone and its metabolite M10 in rat plasma, then this method was used to explore the pharmacokinetics of vilazodone and M10 present or absence of 80 mg/kg bergenin in rats. Protein precipitation with acetonitrile was used to prepare the samples in this research. The mobile phase for liquid chromatography was consisted of 0.1% formic acid aqueous solution and acetonitrile. Brexpiprazole was used as the internal standard (IS), and the multiple reaction monitoring (MRM) mode was used for detection. The verification items required by the US Food and Drug Administration (FDA) guidelines such as selectivity, sensitivity, linearity, stability, recovery and matrix effect of this method were all met the standards. Besides, rats were used to explore the drug-drug interaction between vilazodone and bergenin, which were divided into two groups, and separately gavaged with the same-volume of carboxymethyl cellulose sodium (CMC-Na) solution and 80 mg/kg bergenin, respectively. The results showed that bergenin significantly affected the metabolism of vilazodone. It suggested that there was a potential drug-drug interaction between bergenin and vilazodone in rats. In clinical application, we should pay attention to the dose of vilazodone when in combination with bergenin.

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In this paper, we consider the structural change in a class of discrete valued time series, where the true conditional distribution of the observations is assumed to be unknown. The conditional mean of the process depends on a parameter θ∗ which may change over time. We provide sufficient conditions for the consistency and the asymptotic normality of the Poisson quasi-maximum likelihood estimator (QMLE) of the model. We consider an epidemic change-point detection and propose a test statistic based on the QMLE of the parameter. Under the null hypothesis of a constant parameter (no change), the test statistic converges to a distribution obtained from increments of a Browninan bridge. The test statistic diverges to infinity under the epidemic alternative, which establishes that the proposed procedure is consistent in power. The effectiveness of the proposed procedure is illustrated by simulated and real data examples.

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BACKGROUND: Rapid and accurate detection of viral respiratory infections is important for infection control measures. This study compares the analytical and clinical performance of the Xpert® Xpress CoV-2/Flu/RSV plus test ("Xpert", Cepheid) and the STANDARD™ M10 Flu/RSV/SARS-CoV-2 test ("M10", SD Biosensor). Both tests are quadruplex RT-PCR assays for rapid diagnosis of SARS-CoV-2, influenza A/B and RSV. STUDY DESIGN: Analytical sensitivities were determined by limit of detection for SARS-CoV-2, influenza A, influenza B and RSV, respectively. Additionally, the clinical performance of the Xpert and the M10 tests was evaluated against standard-of-care RT-PCR by testing of 492 clinical specimens. RESULTS: The analytical sensitivities for Xpert versus M10 test was 10, 50, 50 and 300 versus 300, 200, 800 and 1500 copies/mL for SARS-CoV-2, influenza A, influenza B and RSV, respectively. Clinical sensitivity for the Xpert test was superior across all four pathogens compared to the M10 test. Xpert showed clinical sensitivity of 100 % in all Ct-ranges for all four pathogens whereas M10 showed clinical sensitivity of 100 % in the 25-30 Ct-range, 84-100 % in the 30-35 Ct-range and 47-67 % in the >35 Ct-range across the four pathogens. Translating into real-life clinical sensitivity, the Xpert would detect 100 % of all four pathogens, whereas M10 would detect 92.1, 92.4, 84.8 and 94.7 % for SARS-CoV-2, influenza A, influenza B and RSV. CONCLUSION: This study demonstrates improved analytical and clinical performance of Xpert Xpress CoV-2/Flu/RSV plus compared to STANDARD M10 Flu/RSV/SARS-CoV-2, which is important for ensuring accuracy of diagnosis at all stages of a respiratory infection.

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Current methods for clustering adult obesity prevalence by state focus on creating a single map of obesity prevalence for a given year in the United States. Comparing these maps for different years may limit our understanding of the progression of state and regional obesity prevalence over time for the purpose of developing targeted regional health policies. In this application note, we adopt the non-parametric Dynamic Time Warping method for clustering longitudinal time series of obesity prevalence by state. This method captures the lead and lag relationship between the time series as part of the temporal alignment, allowing us to produce a single map that captures the regional and temporal clusters of obesity prevalence from 1990 to 2019 in the United States. We identify six regions of obesity prevalence in the United States and forecast future estimates of obesity prevalence based on ARIMA models.

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According to several previous studies, neural network-based stock price predictors perform better for plunging patterns of stock prices than normal stock price patterns. Focusing on this issue, this study proposes a novel method that uses a neural network-based stock price predictor to predict the upward trend-reversal of the plunging market itself. To achieve more consistent prediction results for plunging patterns, newly designed input features are added to improve the performance of traditionally used neural network-based predictors. The statistics of the prediction scores for past plunging markets and analyzed, and the results are used to predict the upward trend-reversal in the plunging market that occurred during the test period. We demonstrate the superiority of the proposed method through the simulation results of 3-year trading on KOSDAQ, a representative stock market in South Korea.

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In emergency departments, rapid screening of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) was important for arranging limited isolation resources and patient care during the coronavirus disease 2019 (COVID-19) pandemic. STANDARD M10 SARS-CoV-2 (SD Biosensor) is a recently developed cartridge-based RT-PCR that provides a turnaround time of 1 h, which is shorter than that for conventional RT-PCR. This study evaluated the clinical performance of STANDARD M10 in patients visiting an emergency department. From March to June 2022, two specimens were collected from patients visiting an emergency department. Each specimen comprised one nasopharyngeal and one oropharyngeal swab. Respective specimens underwent rapid RT-PCR using STANDARD M10 and conventional RT-PCR using Allplex SARS-CoV-2 (Seegene). When discordant results occurred, specimens undergoing the STANDARD M10 were retested with the Allplex to exclude specimen variations. Retest results replaced initial results of the Allplex. Clinical performance of STANDARD M10 was compared with Allplex. The study enrolled 1971 patients. COVID-19 prevalence was 6.2% based on the Allplex. Compared with the Allplex, overall agreement, positive percent agreement, and negative percent agreement of STANDARD M10 were 99.5% (95% CI: 99.1%-99.8%), 95.9% (95% CI: 90.8%-98.3%), and 99.8% (95% CI: 99.4%-99.9%), respectively. Nine discordant results were all positive on droplet digital PCR, except for one specimen that was positive with STANDARD M10. The STANDARD M10 showed reliable diagnostic performance for detecting SARS-CoV-2 from patients visiting in emergency departments and is a useful tool in emergency healthcare systems because of its easy-to-use cartridge-based assay and short resulting time for detecting SARS-CoV-2.

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The 10th China Bioanalysis Forum annual conference was held in Suzhou between 9 and 11 June 2023. This year a full range of bioanalytical topics were discussed such as new technology and bioanalytical approaches for biotherapeutics and biomarkers, particularly in the areas of gene and cell therapy. Another research area covered extensively at the conference was drug metabolism, including new drug metabolism and pharmacokinetic methods; absorption, distribution, metabolism and excretion of new modality drugs, recent regulatory guidance such as human mass balance study and preclinical study of antibody-drug conjugates and case studies of drug metabolism support to newly approved drugs.

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Simplices are used as building blocks to construct an interesting class of topological spaces called simplicial complexes, which exhibit remarkable symmetric properties. In this paper, we study the problems of inequalities for two simplices in the Euclidean space En. We establish some new inequalities for the vertex distances of two simplices and obtain some generalizations of the classical Neuberg-Pedoe inequality.

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In this paper, we investigate a reaction-diffusion model incorporating dynamic variables for nutrient, phytoplankton, and zooplankton. Moreover, we account for the impact of time delay in the growth of phytoplankton following nutrient uptake. Our theoretical analysis reveals that the time delay can trigger the emergence of persistent oscillations in the model via a Hopf bifurcation. We also analytically track the direction of Hopf bifurcation and the stability of the bifurcating periodic solutions. Our simulation results demonstrate stability switches occurring for the positive equilibrium with an increasing time lag. Furthermore, the model exhibits homogeneous periodic-2 and 3 solutions, as well as chaotic behaviour. These findings highlight that the presence of time delay in the phytoplankton growth can bring forth dynamical complexity to the nutrient-plankton system of aquatic habitats.

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The 14th Japan Bioanalysis Forum Symposium was held at Tower Hall Funabori, Japan from 1-3 March 2023. The conference theme, 'Bringing Together - the Expertise of Bioanalysis', aimed to enable people from various fields to gather, learn and collaborate together for the common goal of delivering medicines to patients faster. Approximately 360 participants from various fields, including pharmaceutical industries, contractors, academia and regulatory authorities, gathered at an in-person symposium which had an online participation option, for the first time in 4 years. The symposium offered a wide range of topics including ICH M10, new modalities, biomarkers, immunogenicity, electronization and patient-centric sampling. The latest research results were provided from domestic and overseas scientists. This report summarizes the major topics.

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A time-varying multivariate integer-valued autoregressive of order one (tvMINAR(1)) model is introduced for the non-stationary time series of correlated counts when under-reporting is likely present. A non-diagonal autoregression probability network is structured to preserve the cross-correlation of multivariate series, provide a necessary condition to ease model-fittings computations, and derive the full likelihood using the Viterbi algorithm. The motivating construction applies to fully under-reported counts that rely on a mixture presentation of the random thinning operator. Simulation studies are conducted to examine the proposed model, and the analysis of COVID-19 daily cases is accomplished to highlight its usefulness in applications. Finally, the comparison of models is presented using the posterior predictive checking method.

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Capturing asymmetry among time series is an important area of research as it provides a range of information regarding the behaviour and distribution of the underlying series, which in turn proves to be useful for prediction. Classically, this can be achieved by modeling the skewness of the underlying series, usually using the standard measure. We present here an improved measure of skewness for time series which are integrated by a certain order, which is easy to calculate and proves to be advantageous over the existing one. We complement our methodology by implementing it to represent the heavy asymmetry among the daily COVID-19 case counts of several countries.•Improved skewness measure proves to be better than the usual skewness measure for time series data•This new measure is applied on COVID-19 daily counts to capture the asymmetry appropriately.

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BACKGROUND: In Hymenoptera venom allergy serologically double-sensitized patients, it is often difficult to identify the culprit insect for venom immunotherapy (VIT). OBJECTIVES: To evaluate if basophil activation tests (BATs) performed not only with venom extracts but additionally with single component-resolved diagnostics could differentiate between sensitized and allergic individuals and how the test results influenced the physicians' decision regarding VIT. METHODS: BATs were performed with bee and wasp venom extracts and with single components (Api m 1, Api m 10, Ves v 1, and Ves v 5) in 31 serologically double-sensitized patients. RESULTS: In 28 finally included individuals, 9 BATs were positive and 4 negative for both venoms. Fourteen of 28 BATs showed positive results for wasp venom alone. Two of 10 BATs positive for bee venom were only positive to Api m 1 and 1 of 28 BATs only to Api m 10, but not for whole bee venom extract. Five of 23 BATs positive for wasp venom were only positive for Ves v 5 but negative for wasp venom extract and Ves v 1. Finally, VIT with both insect venoms was recommended in 4 of 28 individuals, with wasp venom alone in 21 of 28 patients and with bee venom alone in 1 of 28. In 2 cases no VIT was recommended. CONCLUSIONS: BATs with Ves v 5, followed by Api m 1 and Api m 10, were helpful for the decision for VIT with the clinically relevant insect in 8 of 28 (28.6%) patients. A BAT with components should therefore be additionally carried out in cases with equivocal results.

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