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In 2023, international rheumatology societies issued new classification criteria for antiphospholipid syndrome (APS). The criteria require scoring antiphospholipid antibody (aPL) titers as moderate or high using the traditional thresholds of 40U or 80U determined by \"standardized\" ELISA. With current popularity of non-standardized aPL assays (non-ELISA), we aimed to broaden the application of the criteria by estimating equivalent thresholds for them. Four types of aPLs (aCL/aβ2GPI-IgG/IgM) were measured using six reagents in 50 APS and 50 non-APS patients. By regression analysis of measurements between standardized ELISA and non-ELISA assays, thresholds equivalent to 10, 20, 40 and 80U were estimated for each assay. Data points below the detection limit of each assay were excluded from the regression. The diagnostic thresholds were also evaluated using \"specificity-based\" method described by the International Society on Thrombosis and Haemostasis (ISTH). This approach allegedly estimates diagnostic thresholds that attain predefined specificities of 0.975 and 0.995 in distinguishing APS from non-APS cases, respectively corresponding to moderate and high titers. The between-assay concordance of diagnostic classification using the estimated thresholds was calculated as kappa coefficient (κ). Using major-axis regression, thresholds equivalent to the traditional units (10 - 80U) were estimated for non-ELISA assays, which led to harmonized semi-quantitative classification with high κ values. Conversely, the specificity-based method yielded thresholds that dissociated from the traditional ones, particularly for IgG-isotype assays, resulting in lower κ values than regression-based method (P = 0.0039 - 0.0098). The regression-based conversion of diagnostic thresholds is practical in harmonizing diagnostic classification across major aPL assays. The specificity-based method may need adjusted predefined-specificities to estimate thresholds that are equivalent to the traditional thresholds.

Background Anticardiolipin antibodies (aCL) and anti‐β2‐glycoprotein I antibodies (aβ2GPI) are essential in diagnosing antiphospholipid syndrome (APS) according to the international APS guideline. Five commercial assays for aCL and aβ2GPI are available in Japan, but their test results are quite discordant. For harmonization of diagnosing APS, upper reference limit (URL) and diagnostic accuracy of each assay were evaluated and compared by testing common sets of specimens across all assays. Methods We evaluated two manual and three automated assays for aCL and aβ2GPI of IgG‐ and IgM classes. 99%URL (the upper limit of reference interval: as per guideline) together with 97.5%URL were determined by testing sera from 198 to 400 well‐defined healthy subjects. Both URLs were compared with the cutoff values, which were determined based on ROC analysis by testing 50 each of plasma specimens from patients with/without APS. Diagnostic accuracy was evaluated as area under curve (AUC) of the ROC curve. Results A variable degree of discrepancy between URLs and the cutoff values was observed, which was partly attributable to between‐year assay variability. 97.5%URLs were set lower and closer to the cutoff values than 99%URLs. For all assays, diagnostic accuracies of both aβ2GPI‐IgG and aCL‐IgG were generally high (AUC: 0.84−0.93); whereas those for IgM‐class assays were low (AUC: 0.57−0.67), implicating its utility is limited to rare IgG negative APS cases. Conclusion To ensure harmonized APS diagnosis, the diagnostic thresholds of the five assays were evaluated by common procedures. Contrary to the guideline, 97.5%URL is rather recommended for diagnosing APS, which showed a closer match to the cutoff value. Anticardiolipin antibodies (aCL) and anti‐β2‐glycoprotein I antibodies (aβ2GPI) are required for diagnosing antiphospholipid syndrome (APS). Five commercial assays for aCL and aβ2GPI of IgG/IgM classes are used in Japan, but test results are quite discordant. For harmonized diagnosis of APS, 99% upper reference limits were derived for each assay using sera from healthy subjects in common. Diagnostic performance was found comparable across all IgG class assays, but IgM class assays generally exhibited low diagnostic utility.

In “Hypothermia Reduces Toll-Like Receptor 3-Activated Microglial Interferon-β and Nitric Oxide Production,” there was an error in Figure 1. The unit for concentrations of IFN-β was pg/dL. Here, we provide the right form of Figure 1.

Background Therapeutic hypothermia protects neurons after severe brain injury. Activated microglia produce several neurotoxic factors, such as pro-inflammatory cytokines and nitric oxide (NO), during neuron destruction. Hence, suppression of microglial release of these factors is thought to contribute partly to the neuroprotective effects of hypothermia. After brain insults, adenosine triphosphate (ATP) is released from injured cells and activates microglia. Here, we examined the acute effects of temperature on ATP-activated microglial production of inflammatory factors, and the possible involvement of p 38 mitogen-activated protein kinase ( p 38) underlying such effects. Methods Microglia were cultured with ATP at 33, 37, and 39°C, or with ATP in the presence of a p 38 inhibitor, SB203580, at 37°C. Cytokine and NO levels, and p 38 activation were measured. Results Compared to 37°C, TNF-α was reduced at 33°C and augmented at 39°C for 1.5 h. IL-6 was reduced at 33°C for 6 h. NO was reduced at 33°C, but augmented at 39°C for 6 h. p 38 was reduced at 33°C for 1 min. SB203580 inhibited ATP-induced TNF-α, IL-6, and NO production. Conclusion Lowering temperature rapidly reduced p 38 activation and the subsequent p 38-regulated production of pro-inflammatory cytokines and NO in ATP-activated microglia, suggesting that attenuation of early phase inflammatory responses via suppression of p 38 in microglia is one possible neuroprotective mechanism of therapeutic hypothermia. Temperature elevation increased TNF-α and NO production in these cells. These temperature-dependent changes imply that monitoring of TNF-α and NO in the cerebrospinal fluid during the early phase might be useful as biomarkers for responses to therapeutic hypothermia and hyperthermia.

BackgroundIn 2023, international rheumatology societies issued new classification criteria for antiphospholipid syndrome (APS). The criteria require scoring antiphospholipid antibody (aPL) titers as moderate or high using the traditional thresholds of 40U or 80U determined by \"standardized\" ELISA. With current popularity of non-standardized aPL assays (non-ELISA), we aimed to broaden the application of the criteria by estimating equivalent thresholds for them.MethodsFour types of aPLs (aCL/aβ2GPI-IgG/IgM) were measured using six reagents in 50 APS and 50 non-APS patients. By regression analysis of measurements between standardized ELISA and non-ELISA assays, thresholds equivalent to 10, 20, 40 and 80U were estimated for each assay. Data points below the detection limit of each assay were excluded from the regression. The diagnostic thresholds were also evaluated using \"specificity-based\" method described by the International Society on Thrombosis and Haemostasis (ISTH). This approach allegedly estimates diagnostic thresholds that attain predefined specificities of 0.975 and 0.995 in distinguishing APS from non-APS cases, respectively corresponding to moderate and high titers. The between-assay concordance of diagnostic classification using the estimated thresholds was calculated as kappa coefficient (κ).ResultsUsing major-axis regression, thresholds equivalent to the traditional units (10 - 80U) were estimated for non-ELISA assays, which led to harmonized semi-quantitative classification with high κ values. Conversely, the specificity-based method yielded thresholds that dissociated from the traditional ones, particularly for IgG-isotype assays, resulting in lower κ values than regression-based method (P = 0.0039 - 0.0098).ConclusionThe regression-based conversion of diagnostic thresholds is practical in harmonizing diagnostic classification across major aPL assays. The specificity-based method may need adjusted predefined-specificities to estimate thresholds that are equivalent to the traditional thresholds.

Purpose Therapeutic hypothermia protects neurons following injury to the central nervous system (CNS). Microglia express toll-like receptors (TLRs) that play significant roles in pathological processes in sterile CNS injury. We have examined the effects of culture temperature on the TLR2-activated microglial production of cytokines and nitric oxide (NO), which are known to be associated with CNS damage, and the possible involvement of nuclear factor-κB (NF-κB) activation underlying such effects. Methods Rat microglia were cultured with a selective TLR2 agonist, Pam 3 CSK 4 , under hypothermic, normothermic, and hyperthermic conditions, and with Pam 3 CSK 4 in the presence of a NF-κB activation inhibitor at 37 °C. Cytokine and NO levels and NF-κB p65 activation were measured. Results The production of tumor necrosis factor-alpha (TNF-α), interleukin-10 (IL-10), and NO and the activation of NF-κB p65 were reduced by hypothermia, but augmented by hyperthermia at 3–6, 24–48, 48, and 0.5 h, post-treatment initiation, respectively. Pharmacological inhibition of NF-κB activation impaired the Pam 3 CSK 4 -induced TNF-α, IL-10, and NO production. Conclusions In TLR2-activated microglia, hypothermia reduced, while hyperthermia increased, the early activation of NF-κB and the subsequent NF-κB-mediated production of TNF-α, IL-10, and NO in a time-dependent manner, suggesting that attenuation of these factors via suppression of NF-κB in microglia is one possible neuroprotective mechanism of therapeutic hypothermia. Moreover, temperature-dependent changes in microglial TNF-α production during the early phase and IL-10 and NO production during the late phase indicate that these factors might be useful as clinical markers to monitor hypothermia-related neuronal protection and hyperthermia-related neuronal injury.

Therapeutic hypothermia protects neurons following injury to the central nervous system (CNS). Microglia express toll-like receptors (TLRs) that play significant roles in pathological processes in sterile CNS injury. We have examined the effects of culture temperature on the TLR2-activated microglial production of cytokines and nitric oxide (NO), which are known to be associated with CNS damage, and the possible involvement of nuclear factor-[kappa]B (NF-[kappa]B) activation underlying such effects. Rat microglia were cultured with a selective TLR2 agonist, Pam.sub.3CSK.sub.4, under hypothermic, normothermic, and hyperthermic conditions, and with Pam.sub.3CSK.sub.4 in the presence of a NF-[kappa]B activation inhibitor at 37 °C. Cytokine and NO levels and NF-[kappa]B p65 activation were measured. The production of tumor necrosis factor-alpha (TNF-[alpha]), interleukin-10 (IL-10), and NO and the activation of NF-[kappa]B p65 were reduced by hypothermia, but augmented by hyperthermia at 3-6, 24-48, 48, and 0.5 h, post-treatment initiation, respectively. Pharmacological inhibition of NF-[kappa]B activation impaired the Pam.sub.3CSK.sub.4-induced TNF-[alpha], IL-10, and NO production. In TLR2-activated microglia, hypothermia reduced, while hyperthermia increased, the early activation of NF-[kappa]B and the subsequent NF-[kappa]B-mediated production of TNF-[alpha], IL-10, and NO in a time-dependent manner, suggesting that attenuation of these factors via suppression of NF-[kappa]B in microglia is one possible neuroprotective mechanism of therapeutic hypothermia. Moreover, temperature-dependent changes in microglial TNF-[alpha] production during the early phase and IL-10 and NO production during the late phase indicate that these factors might be useful as clinical markers to monitor hypothermia-related neuronal protection and hyperthermia-related neuronal injury.

Gait speed in laboratory settings (in-laboratory gait speed) is one of the important indicators associated with the decline in functional abilities in older adulthood. Recently, it has become possible to measure gait speed during daily living (daily gait speed) using accelerometers. However, the relationship between these two gait speed parameters is unclear. This study aimed to compare in-laboratory gait speed, measured by a sheet-type pressure sensor, and daily gait speed, measured by an accelerometer, in healthy community-dwelling older adults. Participants were aged ≥60 years, residing in Takahama city, Aichi, Japan. To calculate daily gait speed, participants were instructed to wear a tri-axial accelerometer on their waist. A total of 1965 participants were included in the final analysis. The results showed a weak association ( r  = 0.333, p  < 0.001) between the two gait speed parameters. Furthermore, average daily gait speed was significantly lower than average in-laboratory gait speed. However, both gait speed parameters declined significantly with age. These results suggest that, in addition to in-laboratory gait speed, daily gait speed may be a helpful parameter for predicting decline in functional abilities.