Sequential Test Research Articles

Timed up and go demonstrates strong interrater agreement and criterion validity as a functional test in geriatric dogs.

To measure interobserver agreement for 4 functional tasks and their summed geriatric functional score (GFS) and correlate tasks and GFS with client-specific outcome measurements (CSOMs): Canine Brief Pain Inventory (CBPI) pain severity, CBPI pain interference, and Liverpool Osteoarthritis in Dogs. 89 geriatric dogs were recruited between April and September 2023 from staff, friends, and clients of the Cornell University College of Veterinary Medicine with a median age of 11.0 years and weight of 26.4 kg. Dogs underwent 4 sequential functional tests: timed up and go (TUG), cavallettis, figure 8s, and down to stands. Two observers independently scored each dog. The GFS was calculated based on the summed scores of the individual tests. Additional information collected included signalment, weight, measurements reflecting the comorbidities of aging (body condition score and muscle condition score), and CSOMs. Strong interrater agreement was found for all functional tests. The TUG in seconds (sTUG) and figure 8s demonstrated significant (P < .05) moderate to strong correlations to all CSOMs. The GFS showed similar significant correlations with all CSOMs except CBPI pain severity; however, when correlating individual tests to CSOMs, only figure 8s and TUG were significantly contributing to GFS results. Receiver operating characteristic curve analysis defined highly functional dogs as those completing the sTUG in under 3.83 seconds. The sTUG represented the best test for geriatric function given it was objective, reliable, correlated well to CSOMs, and could help identify highly functioning dogs. The sTUG appears to be the first practical and reliable functional test of canine geriatric mobility.

Economic modelling and optimisation of SPRT-based quality control schemes for individual observations

In many industrial processes, it may not be practical to obtain sample sizes larger than one due to various reasons. As a result, practitioners must rely on control charts based on individual observations for statistical process monitoring and control. The sequential probability ratio test (SPRT) chart is an appropriate solution for such situations. Existing literature predominantly delves into the statistical aspects of designing or optimising an SPRT chart, neglecting the economic and associated design aspects. However, past experience suggests that statistical design may not always be optimal from an economic perspective. This paper aims to bridge this research gap by proposing a two-stage Markov chain approach to develop an economic model for the optimal design of the SPRT chart with individual observations. Following the principles of economic-statistical designs, optimal parameters are determined by solving a mixed-integer non-linear programming problem that minimises the long-run cost per item while ensuring compliance with practical constraints. Through an extensive study, we find that the economic performance of the SPRT chart surpasses that of competing individual control charts in many cases. This indicates that the economic-statistical design of the SPRT chart can yield significant economic benefits while maintaining desirable statistical properties. Moreover, enhancements have been introduced to refine the optimal design of the SPRT chart, retaining excellent overall performance across a wide range of shifts. Finally, we provide two industrial examples to illustrate the effectiveness of the proposed SPRT chart.

Development, validation and application of single molecule molecular inversion probe based novel integrated genetic screening method for 29 common lysosomal storage disorders in India

BackgroundCurrent clinical diagnosis pathway for lysosomal storage disorders (LSDs) involves sequential biochemical enzymatic tests followed by DNA sequencing, which is iterative, has low diagnostic yield and is costly due to overlapping clinical presentations. Here, we describe a novel low-cost and high-throughput sequencing assay using single-molecule molecular inversion probes (smMIPs) to screen for causative single nucleotide variants (SNVs) and copy number variants (CNVs) in genes associated with 29 common LSDs in India.Results903 smMIPs were designed to target exon and exon–intron boundaries of targeted genes (n = 23; 53.7 kb of the human genome) and were equimolarly pooled to create a sequencing library. After extensive validation in a cohort of 50 patients, we screened 300 patients with either biochemical diagnosis (n = 187) or clinical suspicion (n = 113) of LSDs. A diagnostic yield of 83.4% was observed in patients with prior biochemical diagnosis of LSD. Furthermore, diagnostic yield of 73.9% (n = 54/73) was observed in patients with high clinical suspicion of LSD in contrast with 2.4% (n = 1/40) in patients with low clinical suspicion of LSD. In addition to detecting SNVs, the assay could detect single and multi-exon copy number variants with high confidence. Critically, Niemann-Pick disease type C and neuronal ceroid lipofuscinosis-6 diseases for which biochemical testing is unavailable, could be diagnosed using our assay. Lastly, we observed a non-inferior performance of the assay in DNA extracted from dried blood spots in comparison with whole blood.ConclusionWe developed a flexible and scalable assay to reliably detect genetic causes of 29 common LSDs in India. The assay consolidates the detection of multiple variant types in multiple sample types while having improved diagnostic yield at same or lower cost compared to current clinical paradigm.

Adaptive two-stage seamless sequential design for clinical trials

ABSTRACT We propose an adaptive sequential testing procedure for the selection and testing of multiple treatment options, such as dose/regimen, different drugs, sub-populations, endpoints, or a mixture of them in a seamlessly combined phase II/III trial. The selection is to be made at the end of phase 2 stage. Unlike in many of the published literature, the selection rule is not required to be to “select the best”, and does not need to be pre-specified, which provides flexibility and allows the trial investigators to use any efficacy and safety information/criteria, or surrogate or intermediate endpoint to make the selection. Sample size and power calculations are provided. The calculations have been confirmed to be accurate by simulations. Interim analysis can be performed after the selection, sample size can be modified if the observed efficacy deviates from the assumed. Inference after the trial, including p-value, median unbiased point estimate and confidence intervals, are provided. By applying a dominance theorem, the procedure can be applied to normal, binary, Poisson, negative binomial distributed endpoints and time-to-event endpoints, and a mixture of these distributions (in trials involving endpoint selection).

Sequential fusion‐based defense strategy against sophisticated Byzantine attacks in cognitive IoT networks

Sequential fusion‐based defense strategy against sophisticated Byzantine attacks in cognitive <scp>IoT</scp> networks

Abstract PO4-14-10: Circulating Tumor DNA as a Biomarker for ADCs in Metastatic Breast Cancer

Abstract Background: Breast cancer is a complex disease characterized by heterogeneity, and the analysis of circulating tumor DNA (ctDNA) holds promise for capturing this heterogeneity. Recently, ctDNA testing has been employed in clinical practice to guide targeted therapies for metastatic breast cancer, particularly in cases of hormone receptor-positive disease with mutations in PIK3CA and ESR1. This approach becomes necessary when traditional tumor biopsies are inadequate for next-generation sequencing (NGS) testing or fail to capture the full extent of the cancer's heterogeneity. Moreover, the utilization of antibody-drug conjugates (ADC) in addressing tumor heterogeneity continues to expand. However, there has been no biomarker, outside of HER2 protein expression, to predict ADC response. In this project, we test the hypothesis that ctDNA can be utilized as a biomarker to predict response to novel therapies such as ADCs. Methods: We analyzed a subset of patients from the Dallas Metastatic Breast Cancer Study comprised of patients with metastatic breast cancer (n= 109) who underwent ctDNA testing using the Tempus xF liquid biopsy ctDNA sequencing panel. This panel detects 105-genes that are known oncogenic drivers and resistance mutations. The data was collected from a single academic medical center between the initial year of ctDNA collection in 2019 and 2023. Results: Among these patients, 85 (77.9%) had hormone receptor-positive disease, 13 (11.9%) had triple-negative breast cancer, and 11 (10.0%) had HER2-positive disease (including 3 (2.75%) patients with triple-positive disease). Only 22 of these patients had tissue biopsies that underwent NGS testing. Analysis of all patients revealed that the most common gene alteration was PIK3CA, which was identified in 70 patients. Specifically, the most frequently observed alteration was PIK3CA p.545K, found in 25 patients. Table 1 further details the frequency of each gene in this subset of patients. Among the patients, 34 out of 109 (31%) received an ADC, while only 8 out of 109 (7%) received immunotherapy. Patients with CDKN2A achieved the longest progression-free survival (PFS) on an ADC, with a median PFS of 7 months, whereas patients carrying mutations in TP53, PIK3R1, PIK3CA, PTEN, NF1, BRAF, RHOA, FGFR4, KRAS, TERT, GATA3, HNF1A, FB1, STOP had median PFSs of 2 months or less. Table 2 provides additional information on the response of patients with specific mutations to ADCs. Notably, only one patient received sequential ctDNA testing, and in that case, there was a gain of TP53 p.N239S following sacituzumab govitecan administration compared to the baseline ctDNA test, followed by a gain of PIK3CA p.P449_L455del after trastuzumab deruxtecan administration. Conclusions: As we observe changes in subtypes following treatment progression, researchers are actively seeking biomarkers to better characterize real-time changes in tumor biology that can predict response and resistance to treatments. Further studies are needed to identify additional genes present in ctDNA that can provide mechanistic insights into why certain patients respond favorably to ADCs while others do not. We are currently enrolling patients for a prospective study that aims to assess baseline ctDNA levels and monitor changes in variant allele frequency following treatment with ADCs and immunotherapy. Table 2 Median PFS on ADC by Gene Citation Format: Hannah Chang, Isabela Anawate, Alyssa Low, Shao-Po Huang, Julia Maues, Christine Hodgdon, Isaac Chan. Circulating Tumor DNA as a Biomarker for ADCs in Metastatic Breast Cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-14-10.

Abstract PO2-06-04: Prospective study on eribulin efficacy in advanced and metastatic breast cancer: changes in TGF-β compared to other standard chemotherapy agents (KBCSG-TR 2018, POTENTIAL)

Abstract Introduction Eribulin (E) has been demonstrated to improve overall survival (OS) compared to standard chemotherapies in pivotal phase III clinical trials (studies 301 and 305), although there was no difference in progression-free survival. These findings suggest that E might have a mechanism for OS improvement different from the common anti-tumor effect. Several studies reported that E inhibits epithelial-mesenchymal transition and the suppression of TGF-β plays a central role. Data on the relationship between the E-induced serial change in TGF-β and the improvement in OS remains insufficient. Therefore, we conducted this prospective observational study of patients treated with E while undergoing sequential TGF-β testing. This study also enrolled patients who received chemotherapy other than E as a control. Methods Patients with HER2-negative recurrent/metastatic breast cancer (MBC) were prospectively enrolled from 23 breast cancer centers in Japan, if they had not previously used E, had received two or fewer prior chemotherapy regimens, and were scheduled to start either E, capecitabine, S-1 or paclitaxel (± bevacizumab) between September 2020 and February 2022. The target sample sizes were 150 and 50 patients scheduled to receive E (Cohort E) and other drugs (Cohort Others), respectively. We collected blood samples for TGF-β testing at baseline, at two or three weeks (week 2/3), and at four or five weeks (week 4/5) from the beginning. The observation period was until February 2023. The primary endpoint was to evaluate the relationship between changes in TGF-β and clinical response, including OS and time to treatment failure (TTF). Results A total of 202 of the 203 enrolled patients were included in the analysis (1 patient declined consent). The median age was 60.0 (interquartile range, 52.0-69.0) years and ECOG performance status was 0 or 1 in all patients. Among 152 patients in Cohort E and 50 patients in Cohort Others, 37 patients (24.3%) and 12 patients (24.0%) had hormonal receptor-negative breast cancer, and 29 patients (19.1%) and 30 patients (60.0%) had no prior chemotherapy for MBC, respectively. Visceral metastasis totaled 115 (75.7%) in Cohort E and 46 (92.0%) in Cohort Others. In OS analysis of 199 patients, the median OS was 24.5 months (95% CI, 17.3-NA) for no prior chemotherapy, and 17.7 months for one or two prior chemotherapy (median follow-up 14.5 months). In Cohort E and Cohort Others, 139 and 45 patients, respectively, had paired samples for TGF-β testing at baseline and week 2/3. The proportion of patients with a percent change at week 2/3 from baseline in TGF-β (ΔTGF-β) of less than zero (decreased TGF-β) was 46.8% in Cohort E and 33.3% in Cohort Others, indicating a 13.4% (-2.6% – 29.5%) higher trend in Cohort E. Based on the time-dependent receiver operating characteristic (ROC) curves at 6 months for TTF, the threshold of ΔTGF-β was determined to be 27%. For the low ΔTGF-β group (&amp;lt; 27%) and the high ΔTGF-β group (≥27%), OS rates at median follow-up (14.5 months) were 70.6% and 54.3% (p=0.085) in Cohort E and 68.9% and 58.2% (p=0.585) in Cohort Others, respectively, suggesting a relationship between low ΔTGF-β and a favorable prognosis only in Cohort E. Conclusions The current study showed the trend in the higher frequency of decreased TGF-β, as well as the important relationship between decreased TGF-β and a favorable prognosis in patients treated with E compared with those receiving other chemotherapies. As the next step, further biomarker analyses including cytokines and chemokines, and immunological analyses are planned. Citation Format: Takahiro Nakayama, Tersuhiro Yoshinami, Fumie Fujisawa, Minako Nishio, Takashi Yamanaka, Toshinari Yamashita, Chiya Oshiro, Ayaka Izui, Nobumoto Tomioka, Hideki Maeda, Masafumi Shimoda, Kenzo Shimazu, Michiko Tsuneizumi, Ryoichi Matsunuma, Hiroko Bando, Aya Ueda, Hiroyuki Yasojima, Kumiko Okada, Kenichi Inoue, Yuichiro Kai, Katsuhide Yoshidome, Hidetoshi Kawaguchi, Masayuki Nagahashi, Kazuteru Oshima, Shinichiro Kashiwagi, Tsutomu Iwasa, Kanae Taruno, Shigeru Tsuyuki, Fumine Tsukamoto, Takashi Morimoto, Nobuyoshi Kittaka, Toru Higuchi, Yoichi Naito, Ryotaro Saita, Hiroyoshi Nishikawa, Daisuke Sugiyama, Yasuo Miyoshi, Yohei Uchida, Tomomi Yamada, Norikazu Masuda. Prospective study on eribulin efficacy in advanced and metastatic breast cancer: changes in TGF-β compared to other standard chemotherapy agents (KBCSG-TR 2018, POTENTIAL) [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO2-06-04.

Magnetite particles accelerate methanogenic degradation of highly concentrated acetic acid in anaerobic digestion process

The anaerobic digestion (AD) process has become significant for its capability to convert organic wastewater into biogas, a valuable energy source. Excessive acetic acid accumulation in the anaerobic digester can inhibit methanogens, ultimately leading to the deterioration of process performance. Herein, the effect of magnetite particles (MP) as an enhancer on the methanogenic degradation of highly-concentrated acetate (6 g COD/L) was examined through long-term sequential AD batch tests. Bioreactors with (AM) and without (AO) MP were compared. AO experienced inhibition and its methane production rate (qm) converged to 0.45 L CH4/g VSS/d after 10 sequential batches (AO10, the 10th batch in a series of the sequential batch tests conducted using bioreactors without MP addition). In contrast, AM achieved 3–425% higher qm through the sequential batches, indicating that MP could counteract the inhibition caused by the highly-concentrated acetate. MP addition to inhibited bioreactors (AO10) successfully restored them, achieving qm of 1.53 L CH4/g VSS/d, 3.4 times increase from AO10 after 8 days lag time, validating its potential as a recovery strategy for inhibited digesters with acetate accumulation. AM exhibited higher microbial populations (1.8–3.8 times) and intracellular activity (9.3 times) compared to AO. MP enriched Methanosaeta, Peptoclostridium, Paraclostridium, OPB41, and genes related to direct interspecies electron transfer and acetate oxidation, potentially driving the improvement of qm through MP-mediated methanogenesis. These findings demonstrated the potential of MP supplementation as an effective strategy to accelerate acetate-utilizing methanogenesis and restore an inhibited anaerobic digester with high acetate accumulation.

Trend Behavior of Malaysia Consumer Price Index: Evidence from National Database (2003–2022)

The Consumer Price Index (CPI) is a general indicator used to measure price changes over time. The Malaysia CPI is published using a base year of 2010. This study aimed to identify the significant trend behavior in the Malaysia CPI series for the period 2003–2022. The main question of the paper is whether there exists any difference in trends between the main and overall CPI variables? If so, is the difference significant? If so, how strong or weak is the magnitude of its trend? This is analyzed empirically through five statistical analysis methods involving the serial correlation analysis, Mann–Kendall test, Mann–Kendall sequential test, Sen’s-T test, and Sen’s estimator. Overall, we conclude that there is a significant upward trend for 11 of the 13 variables, while two variables, which are Transportation and Communication, showed no significant monotonic trend. The results of this study provide insight into a better understanding of the behavioral trends of the CPI in Malaysia. This study can help policymakers to understand the importance of increasing expenditure into certain sectors in order to have better production and with this implementation, the trend of inflation rate can be better understood.

Safety of Ancestral Monovalent BNT162b2, mRNA-1273, and NVX-CoV2373 COVID-19 Vaccines in US Children Aged 6 Months to 17 Years

Active monitoring of health outcomes after COVID-19 vaccination provides early detection of rare outcomes that may not be identified in prelicensure trials. To conduct near-real-time monitoring of health outcomes after COVID-19 vaccination in the US pediatric population. This cohort study evaluated 21 prespecified health outcomes after exposure before early 2023 to BNT162b2, mRNA-1273, or NVX-CoV2373 ancestral monovalent COVID-19 vaccines in children aged 6 months to 17 years by applying a near-real-time monitoring framework using health care data from 3 commercial claims databases in the US (Optum [through April 2023], Carelon Research [through March 2023], and CVS Health [through February 2023]). Increased rates of each outcome after vaccination were compared with annual historical rates from January 1 to December 31, 2019, and January 1 to December 31, 2020, as well as between April 1 and December 31, 2020. Receipt of an ancestral monovalent BNT162b2, mRNA-1273, or NVX-CoV2373 COVID-19 vaccine dose identified through administrative claims data linked with Immunization Information Systems data. Twenty-one prespecified health outcomes, of which 15 underwent sequential testing and 6 were only monitored descriptively due to lack of historical rates. Among 4 102 016 vaccinated enrollees aged 6 months to 17 years, 2 058 142 (50.2%) were male and 3 901 370 (95.1%) lived in an urban area. Thirteen of 15 sequentially tested outcomes did not meet the threshold for a statistical signal. Statistical signals were detected for myocarditis or pericarditis after BNT162b2 vaccination in children aged 12 to 17 years and seizure after vaccination with BNT162b2 and mRNA-1273 in children aged 2 to 4 or 5 years. However, in post hoc sensitivity analyses, a statistical signal for seizure was observed only after mRNA-1273 when 2019 background rates were selected; no statistical signal was observed when 2022 rates were selected. In this cohort study of pediatric enrollees across 3 commercial health insurance databases, statistical signals detected for myocarditis or pericarditis after BNT162b2 (ages 12-17 years) were consistent with previous reports, and seizures after BNT162b2 (ages 2-4 years) and mRNA-1273 vaccinations (ages 2-5 years) should be further investigated in a robust epidemiologic study with confounding adjustment. The US Food and Drug Administration concludes that the known and potential benefits of COVID-19 vaccination outweigh the known and potential risks of COVID-19 infection.

Variable selection using data splitting and projection for principal fitted component models in high dimension

Sufficient dimension reduction (SDR) is such an effective way to detect nonlinear relationship between response variable and covariates by reducing the dimensionality of covariates without information loss. The principal fitted component (PFC) model is a way to implement SDR using some class of basis functions, however the PFC model is not efficient when there are many irrelevant or noisy covariates. There have been a few studies on the selection of variables in the PFC model via penalized regression or sequential likelihood ratio test. A novel variable selection technique in the PFC model has been proposed by incorporating a recent development in multiple testing such as mirror statistics and random data splitting. It is highlighted how we construct a mirror statistic in the PFC model using the idea of projection of coefficients to the other space generated from data splitting. The proposed method is superior to some existing methods in terms of false discovery rate (FDR) control and applicability to high-dimensional cases. In particular, the proposed method outperforms other methods as the number of covariates tends to be getting larger, which would be appealing in high dimensional data analysis. Simulation studies and analyses of real data sets have been conducted to show the finite sample performance and the gain that it yields compared to existing methods.

Detection of Emergent Anomalous Structure in Functional Data

Motivated by an example arising from digital networks, we propose a novel approach for detecting the emergence of anomalies in functional data. In contrast to classical functional data approaches, which detect anomalies in completely observed curves, the proposed approach seeks to identify anomalies sequentially as each point on the curve is received. The new method, the Functional Anomaly Sequential Test (FAST), captures the common profile of the curves using Principal Differential Analysis and uses a form of CUSUM test to monitor a new functional observation as it emerges. Various theoretical properties of the procedure are derived. The performance of FAST is then assessed on both simulated and telecommunications data.

Expanding Access to Noninvasive Prenatal Diagnosis for Monogenic Conditions to Consanguineous Families.

Cell-free fetal DNA exists within the maternal bloodstream during pregnancy and provides a means for noninvasive prenatal diagnosis (NIPD). Our accredited clinical service offers definitive NIPD for several autosomal recessive (AR) and X-linked conditions using relative haplotype dosage analysis (RHDO). RHDO involves next-generation sequencing (NGS) of thousands of common single nucleotide polymorphism (SNPs) surrounding the gene of interest in the parents and an affected or unaffected offspring to conduct haplotype phasing of the high- and low-risk alleles. NGS is carried out in parallel on the maternal cell-free DNA, and fetal inheritance is predicted using sensitive dosage calculations performed at sites where the parental genotypes differ. RHDO is not currently offered to consanguineous couples owing to the shared haplotype between parents. Here we test the expansion of RHDO for AR monogenic conditions to include consanguineous couples. The existing sequential probability ratio test analysis pipeline was modified to apply to SNPs where both parents are heterozygous for the same genotype. Quality control thresholds were developed using 33 nonconsanguineous cases. The performance of the adapted RHDO pipeline was tested on 8 consanguineous cases. The correct fetal genotype was predicted by our revised RHDO approach in all conclusive cases with known genotypes (n = 5). Haplotype block classification accuracies of 94.5% and 93.9% were obtained for the nonconsanguineous and consanguineous case cohorts, respectively. Our modified RHDO pipeline correctly predicts the genotype in fetuses from consanguineous families, allowing the potential to expand access to NIPD services for these families.

Opportunities of digital health technologies for rheumatology: from clinics to quality and research

Recent developments in digital health technologies are overwhelming, and their use in routine work is still difficult to anticipate. This narrative review summarizes the concept of consecutive cohorts in the literature, together with local research experiences in consecutive rheumatic outpatients. Digital health techniques have to reflect the clinicians’ needs, support real-life care of patients, and allow for the specific assessment of quality parameters fulfilling the Donabedian aspect of qualified health care, using quality indicators to improve health care and research. Rapidly growing observational cohorts will perform best to provide follow-up data as the basis for further development of healthcare approaches for rheumatic patients. The challenges of a selection bias, patients with limited disease expression, and chances of early detection of patients with rare diseases are addressed. For research purposes, sequential analyses with growing cohort size, comparative cross-sectional studies with sequential hypothesis testing and other prognostic, diagnostic, and therapeutic aspects of patient management can be performed. With the support of new technologies, young clinicians can easily approach such clinical topics, and learn about clinical data analyses. The use of quality standards as proposed in international recommendations for diagnostic issues and classification criteria, management recommendations, monitoring, and training issues can be supported by digital technologies. In conclusion, collaborative projects allow detailed clinical analyses of large cohorts, but local initiatives can prepare these co-operations, provide first local logistics and research experiences, and teach clinicians how to perform clinical research. Digital health technologies will strongly support these local initiatives.

Comparative analysis of videofluoroscopy and pulse oximetry for aspiration identification in patients with dysphagia after stroke and non-dysphagics

PurposeDysphagia is a prevalent symptom observed in acute stroke. Several bedside screening tests are employed for the early detection of dysphagia. Pulse oximetry emerges as a practical and supportive method to augment the existing techniques utilized during bedside swallowing assessments. Desaturation levels, as measured by pulse oximetry, are acknowledged as indicative of aspiration by certain screening tests. However, the predictive capability of pulse oximetry in determining aspiration remains a subject of controversy. The objective of this study was to compare aspiration and oxygen desaturation levels by time and aspiration severity in dysphagic patients compared to healthy controls. It also aimed to evaluate the accuracy of pulse oximetry by comparing it with VFSS findings in detecting aspiration in both liquid (IDDSI-0) and semi-solid (IDDSI-4) consistencies.Materials and methodsEighty subjects (40 healthy and 40 acute stroke patients) participated. Patients suspected of dysphagia underwent videofluoroscopy as part of the stroke unit’s routine procedure. Baseline SpO2 was measured before VFSS, and stabilized values were recorded. Sequential IDDSI-0 and IDDSI-4 barium tests were conducted with 5 ml boluses. Stabilized SPO2 values were recorded during swallowing and 3-min post-feeding. Patients with non-dysphagia received equal bolus monitoring. Changes in SPO2 during, before, and after swallowing were analyzed for each consistency in both groups.ResultsThe study revealed a statistically significant difference in SPO2 between patients with dysphagia and controls for IDDSI-4 and IDSSI-0. In IDDSI-4, 20% of patients experienced SpO2 decrease compared to 2.5% in control group (p = 0.013). For IDDSI-0, 35% of patients showed SpO2 decrease, while none in the control group did (p = 0.0001). Aspiration rates were 2.5% in IDDSI-4 and 57.5% in IDDSI-0. In IDDSI-0, SpO2 decrease significantly correlated with aspiration (p = 0.0001). In IDDSI-4, 20.5% had SpO2 decrease without aspiration, and showing no significant difference (p = 0.613). Penetration-Aspiration Scale scores had no significant association with SpO2 decrease (p = 0.602). Pulse oximetry in IDDSI-4 had limited sensitivity (0%) and positive predictive value, (0%) while in IDDSI-0, it demonstrated acceptable sensitivity (60.9%) and specificity (100%) with good discrimination capability (AUC = 0.83).ConclusionsA decrease in SPO2 may indicate potential aspiration but is insufficient alone for detection. This study proposes pulse oximetry as a valuable complementary tool in assessing dysphagia but emphasizes that aspiration cannot be reliably predicted based solely on SpO2 decrease.

Constructing group sequential tests with data monitoring

Objective:Group sequential tests are procedures for repeatedly analysing accruing data, and aim to reduce test time by stopping data collection as soon as an effect is deemed statistically present or absent. Data monitoring, on the other hand, aims to control statistical power by repeatedly re-estimating sample variance from the accruing data, and then adjusting the sample size accordingly. The current work presents a numerical framework for combining group sequential tests with data monitoring, thus leveraging the best of both methods. Methods:The approach revolves around numerically convolving truncated probability density functions, which leads to numerically tracktable distributions for the sequential test statistic. This then allows conventional power analysis methodologies to be used during the data monitoring procedure, thus keeping the procedure relatively intuitive and transparent. The test operating characteristics of the procedure were evaluated extensively in simulations and in Auditory Brainstem Response data. Results:A good control over statistical power was observed, which was attributed to data monitoring. In some test conditions, however, data monitoring led to inflated type-I error rates and a reduced control over statistical power. This was attributed to sample variance estimation errors, and was largely overcome by initiating data monitoring after at least ∼40-90 samples had accrued and/or by leaving data blinded. Conclusion/Significance:When there is uncertainty regarding the effect size and/or the population variance, then group sequential tests with data monitoring may offer a solution, providing an efficient means to reach an unambiguous test outcome in terms of effect present/absent.

Conditioned pain modulation (CPM) paradigm type affects its sensitivity as a biomarker of fibromyalgia

Fibromyalgia (FM) is a widespread chronic pain syndrome, possibly associated with the presence of central dysfunction in descending pain inhibition pathways. Conditioned Pain Modulation (CPM) has been proposed as a biomarker of FM. Nonetheless, the wide variety of methods used to measure CPM has hampered robust conclusions being reached. To clarify the validity of CPM as a biomarker of FM, we tested two CPM paradigms (parallel and sequential) in a sample of 23 female patients and 23 healthy women by applying test (mechanical) stimuli and conditioning (pressure cuff) stimuli. We evaluated whether CPM indices could correctly classify patients and controls, and we also determined the correlations between the indices and clinical variables such as symptomatology, disease impact, depression, quality of life, pain intensity, pain interference, fatigue and numbness. In addition, we compared the clinical status of CPM responders (efficient pain inhibitory mechanism) and non-responders. We observed that only parallel CPM testing correctly classified about 70% of patients with FM. In addition, more than 80% of healthy participants were found to be responders, while the rate was about 50% in the FM patients. The sequential CPM test was not as sensitive, with a decrease of up to 40% in the response rate for both groups. On the other hand, we did not observe any correlation between CPM measures and clinical symptoms. In summary, our findings demonstrate the influence of the CPM paradigm used and confirm that CPM may be a useful marker to complement FM diagnosis. However, the findings also cast doubts on the sensitivity of CPM as a marker of pain severity in FM.

Emergence of ceftazidime-avibactam resistance in blaKPC-33-harbouring ST11 Klebsiella pneumoniae in paediatric patient

Carbapenem-resistant Klebsiella pneumoniae (CRKP) poses immense threats to the health of infected patients worldwide, especially children. This study reports the infection caused by CRKP in a paediatric intensive care unit (PICU) child and its drug-resistant mutation during the treatment. Twelve Klebsiella pneumoniae carbapenemase (KPC)-producing K. pneumoniae strains were isolated from the child. Broth microdilution method, plasmid transformation assay, and whole genome sequencing (WGS) were performed to investigate the antimicrobial susceptibility, resistance mechanisms, and genetic structural features of CRKPs. The results showed that 12 strains were highly resistant to most available antimicrobial agents. Among them, K. pneumoniae FD11 and K. pneumoniae FD12 were resistant to ceftazidime-avibactam (CZA, MIC >64 mg/L) and restored the carbapenem susceptibility (Imipenem, MIC =0.25 mg/L; Meropenem, MIC =2 mg/L). The patient improved after treatment with CZA in combination with aztreonam. Plasmid transformation assay demonstrated that the blaKPC-33-positive transformant increased MICs of CZA by at least 33-fold and 8-fold compared with the recipient Escherichia coli DH5α and blaKPC-2-positive transformants. WGS analysis revealed that all strains belonged to the ST11-KL64 type and showed highly homologous (3–26 single nucleotide polymorphisms [SNPs]). A single base mutation (G532T) of blaKPC-2 resulted in a tyrosine to aspartic acid substitution at Ambler amino acid position 179 (D179Y), which conferred CZA resistance in K. pneumoniae. This is the first report of a drug-resistant mutation evolving into blaKPC-33 during the treatment of blaKPC-2-positive CRKP in paediatric-infected patients. It advises clinicians that routine sequential antimicrobial susceptibility testing and KPC genotyping are critical during CZA therapy in children infected with CRKP.

Assessment of ulnar nerve tension directed towards understanding cubital tunnel syndrome

BackgroundUlnar nerve compression at the elbow is the second most common compressive neuropathy of the upper extremity. We hypothesize that tension on the ulnar nerve produced by elbow flexion and distraction contributes to this condition. We measured ulnar nerve tension generated during elbow flexion and proportional distraction to evaluate locations of soft tissue constraints to nerve translation. MethodsEight fresh-frozen upper limb specimens were tested. Each specimen included the proximal humeral shaft to the wrist. The ulnar nerve was dissected proximally and clamped to the humerus 8 ​cm proximal to the medial epicondyle. At 8 ​cm distal to the medial epicondyle, the ulnar nerve was dissected and clamped distally to a load cell that was mounted on a laboratory stand. A stage on the stand could be translated distally to apply load. Soft tissue was removed distal to the load cell clamp; all soft tissue from the load cell to the proximal humeral clamp was left intact.We measured the tension generated on the nerve throughout the full arc of elbow flexion with additional distal distractions of 0%, 2.5% and 5% of nerve length applied by distal translation of the stage on the lab stand. We then repeated these steps with the nerve unclamped proximally. We then excised 1 ​cm of soft tissue distally, clamped the nerve 7 ​cm distal to the medial epicondyle, and repeated the measurements. We continued this sequential dissection and testing until the nerve was clamped to the load cell 1 ​cm distal to the medial epicondyle. ResultsFlexion, distraction, and proximal clamping each increased nerve tension. Tension was greatest at 4, 5, and 6 ​cm distal to the medial epicondyle (p ​< ​0.01). ConclusionFlexion, distraction, and proximal clamping each increased ulnar nerve tension. The greatest ulnar nerve tension was recorded between 4 and 6 ​cm distal to the medial epicondyle.

The Effect of Paper Reading Versus Screen Reading on the Inferential Reading Performance among University ESL Learners

Contemporary ESL education focuses on screen-based reading, specifically in the context of university level learners. Also, a sudden shift from paper bound reading activities to screen-based tasks was inevitable in response to COVID-19 outbreak. In this regard, the case of inferential and advanced level reading among the young ESL learners of developing countries appears researchable because of the general low digital literacy of these learners. This study, therefore, aimed to investigate the effect of reading mode shift from paper to screen on the inferential comprehension performance among Pakistani ESL learners at university level. A total of 426 undergraduate learners were sampled from Bachelor of Science program in a well-known university in the city of Lahore, Pakistan. Inferential reading was conceptualized through Bloom’s higher order thinking skills, that is, Analyzing, Evaluating and Creating skills therefore the reading comprehension test was based on these skills. Adopting sequential test administration, first the paper-based reading test, and later the screen-based reading was given. The obtained data were analyzed using Rendell’s XCALIBRE and SPSS V. 26.0. The logit scale descriptives, learner ability (θ), and mean scores demonstrated that the learners performed significantly higher in the paper test as compared to screen test. Moreover, it was found that the effect of reading mode shift was larger in Creating skill. The findings may have significant implications for reading mode selection, enhancement of digital competence and effect of reading mode shift in developing countries with inadequate IT facilitation and digital literacy among ESL learners.