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Summary: There are variations in individual eltrombopag concentrations that may impact efficacy and adverse drug reactions (ADRs) in paediatric immune thrombocytopenia (ITP). To solve this problem, we tailored the eltrombopag dosage refer to concentration, then followed up to assess concentration value in paediatric ITP. This is a single‐centre, prospective, observational study. The eltrombopag dosage was adjusted, and children were divided into three groups: the maintenance, discontinuation, and increase groups. Concentration and other data were compared to explore concentration value in guiding the individualized treatment of paediatric ITP. Thirty‐nine patients were enrolled, including 23 in the maintenance group, 3 in the discontinued group and 13 in the increase group. 3 patients discontinued eltrombopag due to ADRs, which was significantly higher than patients in the maintenance group (t = 3.606, p = 0.001). In all, 13 patients increased their dosage due to poor response, whose concentration and platelet count were significantly lower than patients in the maintenance group (t = 2.461, p = 0.019; t = 4.633, p < 0.001). Two months after the increase, the number of patients reaching CR and R respectively increased by 2 and 3, while the median platelet count was significantly raised (Z = −2.411, p = 0.016). Concentration could be used as a reference index for the individualized treatment of eltrombopag in paediatric ITP. [ABSTRACT FROM AUTHOR]

Summary: Chronic refractory primary immune thrombocytopenia (CRITP) is currently defined as refractory to multiple therapeutic of second‐line agents with or without splenectomy, faced with the threat of severe bleeding and challenging to obtain effective treatment. Although stable and effective drug therapy is needed, it is tough to find one. Daratumumab (Dara), an anti‐CD38 monoclonal antibody presented the target cloned plasma cells in multiple myeloma, has also been reported to be effective in refractory autoimmune cytopenia in some case or series reports and ongoing clinical trials for adult patients with CRITP. Here, we report the early and durable response of Dara combination with avatrombopag in three CRITP patients (2 male and 1 female aged 12, 5 and 7 years, respectively) in our centre, with a follow‐up period of more than 25 weeks. Before Dara, the duration of immune thrombocytopenia was 9, 1.4 and 4 years, respectively, a baseline platelet count of 4, 6, 9 × 109/L, the bleeding score was all above level 2 and the number of previous drugs was >3. The time to response (R: Plt ≥30 × 109/L with at least a twofold increase in the baseline count) of Dara was on Day 45, 6 and 4 and achieved complete response (CR: Plt ≥100 × 109/L) on Day 51, 6 and 8, the sustained response (SR: Plt >30 × 109/L following Dara at ≥75% of the platelet count assessment at follow‐up end‐point since the patient achieved response) was 48, 175 and 204 days with the follow‐up time of 39.1, 25.9 and 29.7 weeks. The bleeding score decreased from grade 3 to grade 0 during follow‐up. No significant treatment‐related adverse events were found during follow‐up. Dara combination with avatrombopag may be a safe and efficacious therapy for children with CRITP, but it needs to be further explored. [ABSTRACT FROM AUTHOR]

Importance: It remained unclear that the efficacy comparison between low‐dose immune tolerance induction (LD‐ITI) incorporating immunosuppressants (IS) when severe hemophilia A (SHA) patients had inhibitor‐titer ≥200 Bethesda Units (BU)/mL (LD‐ITI‐IS200 regimen) and LD‐ITI combining with IS when SHA patients had inhibitor‐titer ≥40 BU/mL (LD‐ITI‐IS40 regimen). Objective: To compare the efficacy of the LD‐ITI‐IS200 regimen with that of the LD‐ITI‐IS40 regimen for SHA patients with high‐titer inhibitors. Methods: A prospective cohort study on patients receiving LD‐ITI‐IS200 compared to those receiving LD‐ITI‐IS40 from January 2021 to December 2023. Both received LD‐ITI [FVIII 50 IU/kg every other day]. IS (rituximab + prednisone) was added when peak inhibitor tier ≥200 BU/mL in the LD‐ITI‐IS200 regimen and ≥40 BU/mL in the LD‐ITI‐IS40 regimen. Success is defined as a negative inhibitor plus FVIII recovery ≥66% of the expected. Results: We enrolled 30 patients on LD‐ITI‐IS200 and 64 patients on LD‐ITI‐IS40, with similar baseline clinical characteristics. A lower IS‐use rate was discovered in the LD‐ITI‐IS200 regimen compared to the LD‐ITI‐IS40 regimen (30.0% vs. 62.5%). The two regimens (LD‐ITI‐IS200 vs. LD‐ITI‐IS40) had similar success rate (70.0% vs. 79.7%), median time to success (9.4 vs. 10.6 months), and annualized bleeding rate during ITI (3.7 vs. 2.8). The cost to success was lower for LD‐ITI‐IS200 than for LD‐ITI‐IS40 (2107 vs. 3256 US Dollar/kg). Among patients with peak inhibitor‐titer 40–199 BU/mL, 10 non‐IS‐using (on LD‐ITI‐IS200 regimen) and 28 IS‐using (on LD‐ITI‐IS40 regimen) had similar success rates (70.0% vs. 78.6%) and time to success (9.0 vs. 8.8 months). Interpretation: In LD‐ITI, IS are not necessary for inhibitor titer <200 BU/mL. [ABSTRACT FROM AUTHOR]

Summary: Avatrombopag (AVA) is a novel thrombopoietin receptor agonist (TPO‐RA) that has been recently approved as a second‐line therapy for immune thrombocytopenia (ITP) in adults; however, its safety and efficacy data in children are lacking. Here, we demonstrated the efficacy and safety of AVA as second‐line therapy in children with ITP. A multicentre, retrospective, observational study was conducted in children with persistent or chronic ITP who did not respond to or relapsed from previous treatment and were treated with AVA for at least 12 weeks between August 2020 and December 2022. The outcomes were the responses (defined as achieving a platelet count ≥30 × 109/L, twofold increase in platelet count from baseline and absence of bleeding), including rapid response within 4 weeks, sustained response at weeks 12 and 24, bleeding control and adverse events (AEs). Thirty‐four (18 males) patients with a mean age of 6.3 (range: 1.9–15.3) years were enrolled. The median number of previous treatment types was four (range: 1–6), and 41.2% patients switched from other TPO‐RAs. Within 4 weeks, overall response (OR) was achieved in 79.4% patients and complete response (CR, defined as a platelet count ≥100 × 109/L and the absence of bleeding) in 67.7% patients with a median response time of 7 (range: 1–27) days. At 12 weeks, OR was achieved in 88.2%, CR in 76.5% and sustained response in 44% of patients. At 24 weeks, 22/34 (64.7%) patients who achieved a response and were followed up for 24 weeks were evaluated; 12/22 (54.55%) achieved a sustained response. During AVA therapy, median platelet counts increased by week 1 and were maintained throughout the treatment period. The proportion of patients with grade 1–3 bleeding decreased from 52.95% at baseline to 2.94% at 12 weeks, while concomitant ITP medications decreased from 36.47% at baseline to 8.82% at 12 weeks, with only 9 (26.47%) patients receiving rescue therapy 23 times within 12 weeks. There were 61.8% patients with 59 AEs: 29.8% with Common Terminology Criteria for Adverse Events grade 1 and the rest with grade 2. These findings show that AVA could achieve a rapid and sustained response in children with persistent or chronic ITP as a second‐line treatment, with good clinical bleeding control and reduction of concomitant ITP therapy, without significant AEs. [ABSTRACT FROM AUTHOR]

Summary: We have previously confirmed the efficacy and safety of eltrombopag (ELT) in children with chronic immune thrombocytopenia (cITP). However, data on both long‐term exposure and early use of TPO‐RAs are lacking, so further 'field‐practice' evidence on treatment is required. Here, we report the long‐term follow‐up results (between September 2018 and June 2023) of our previous study. The main objective of this study was to retrospectively review our large institutional experience with ITP patients previously enrolled in our paediatric cITP study. We had more than 3 years of follow‐up by June 2023 for treatment patterns and outcomes. A total of 65 patients (28 males) were enrolled, with a median age at ELT initiation of 6.34 (range 1.65, 14.13) years and a follow‐up of 47.07 (36.00, 57.00) months, with 40.36 (10.53, 56.83) months of ELT therapy at the time of analysis. In total, 29.23% (19/65) of patients discontinued ELT due to stable response, and 18.46% (12/65) of patients switched to other ITP therapies due to loss of response (LOR) after 19.13 (14.53, 26.37) months. Of the 19 patients who discontinued ELT due to a stable response, 24.62% (16/65) achieved a 12 m sustained response off‐treatment (SRoT); the last recorded platelet count ranged from 56 to 166 × 109/L (median 107 × 109/L); and 4.62% (3/65) patients relapsed at 5, 6 and 9 months after discontinuation. Of the 12 patients who LOR to ELT after 19.13 (14.53, 26.37) months of therapy, four switched to avatrombopag, three switched to hetrombopag, two switched to traditional Chinese medicine (TCM), one underwent splenectomy and two received additional prednisolone under ELT treatment. Thirty‐four patients who tapered and maintained a durable response. The patients with LOR and the patients with tapering were compared; the platelet count at the start of ELT is lower, and the time to response is longer in the patients with LOR. The platelet count at the start of ELT and the time to response may be the predictive factors for LOR during ELT treatment. We report more than 3 years of long‐term clinical data on children with cITP using ELT. These data do not raise any new safety concerns regarding the long‐term use of ELT in children with cITP. [ABSTRACT FROM AUTHOR]

Objectives: To assess current treatment‐related outcomes for children with severe and moderate haemophilia A (cHA) in China. Methods: This cross‐section Patient Report Outcome (PRO) report collected PRO data of severe and moderate cHAs registered in the 'Hemophilia Home Care Center' database (http://web.bjxueyou.cn) between January 2021 and November 2022. Data included records of bleeding, activities, and concentrates consumption. All patients had a confirmed diagnosis of moderate or severe haemophilia A (FVIII: C ≤ 5%) and were < 18 years old. Results: Among 1038 analysable cases, 9.6% of children with inhibitors had a higher rate of intracranial haemorrhage, dropout school rate, and higher FVIII consumption than children without inhibitors. Among 100 children with inhibitors, 36 patients were treated without immune tolerance induction (ITI), 14 patients with irregular treatment and 50 patients received ITI. Children with ITI had a lower ABR (2.4 (0,6.6) vs. 13.4 (9.5, 26.6), p<.001) and AJBR (0 (0, 3.1) vs. 8.9 (1.6, 19.3), p <.001) compared to those without ITI. Among 938 children without inhibitors, 28.5% received on‐demand treatment and 71.5% received prophylaxis. Of 528 children with 1343.8 (1050.4, 2922.9)IU/kg/year median FVIII consumption, 43.0% received low‐dose, 43.2% received intermediate‐dose, and 13.8% received high‐dose regimen; these children with prophylaxis had a lower ABR (3.1 (0, 10.7) vs. 12.8 (2.4, 45.5), p <.001), AJBR (0.5 (0, 3.9) vs. 3.0 (0, 12.0), p <.001) and disability rate (9.0% vs.18.5%, p =.032) compared to children who received on‐demand treatment. Conclusion: The high rate of drop‐out of school and disability still present a huge gap to meet the needs in China. It is necessary to improve the level of medical accessibility and medicine affordability and strengthen the patient/parent's education in China. [ABSTRACT FROM AUTHOR]

Summary: The thrombopoietin receptor agonists (TPO‐RA) were recommended for primary immune thrombocytopenia (ITP) during the pandemic of COVID‐19. However, the incidence of thrombocytosis and thrombosis was sporadically reported in the chronic immune thrombocytopenia (CITP) patients receiving TPO‐RA during the COVID‐19 infection. With the local prevalence of COVID‐19 in December 2022 in the Beijing area, we got more powerful evidence about the change in platelet (Plt) counts associated with COVID‐19 infection. A single‐centre observational cohort study was performed from the beginning of December 2022 to the end of February 2023 to enrol CITP children treated with TPO‐RA alone as the second‐line treatment and suffering from the COVID‐19 infection in December 2022. The Plt counts before, during and after COVID‐19 infection were collected. In total, 67 (34 males and 33 females) patients with 8.10 (2.15, 15.70) years of age were enrolled. Sixty‐three patients who had responded to the TPO‐RA showed a transient increase in Plt counts after the infection of COVID‐19. The time of starting to increase was on Day 3 (2, 7), and to the peak level on Day 14 (7, 19) of infection with the peak Plt count was 289 (88, 1974) × 109/L. With at least 2 months observation period from COVID‐19 infection, the Plt counts of 100% (63/63) patients declined to the baseline on Day 25 (14, 41). The phenomenon of transient increase in Plt counts has been shown in the CITP children who responded to TPO‐RA when suffering from COVID‐19 infection. [ABSTRACT FROM AUTHOR]

Summary: Eltrombopag (ELT) is effective and safe in adult persistent/chronic immune thrombocytopenia (p/cITP); a proportion could achieve a sustained response off treatment (SRoT); however, data on children are lacking. We attempted to analyse SRoT of ELT in children with p/cITP in this study. A multicentre retrospective observational study was performed in November 2022 for children with p/cITP who used ELT alone for >2 months between January 2017 and November 2021. Clinical data of pre‐, during and post‐ELT were collected. SRoT was defined as maintaining a platelet count of ≥30 × 109/L without rescue therapy for at least 6 months off ELT. There were 143 patients enrolled; 69.2% (99/143) achieved an overall response of 43.3% and 25.9% achieved complete response (CR) and response (R). Among the 35 patients analysed from whom ELT was withdrawn, 71.4% (25/35) showed SRoT after discontinuing ELT without additional ITP therapy, with a median follow‐up of 0.94 (range, 0.53–3.8) years, equal to 17.5% (25/143) in all patients treated with ELT. Compared with the patients with relapse (n = 10), the SRoT patients (n = 25) had a higher rate of CR (80% [20/25] vs. 40% [4/10]), shorter interval time from initiation to taper (6.4 months vs. 9.4 months), longer time from taper to withdrawal (1.1 years vs. 0.3 years) and a longer duration of ELT treatment (1.6 years vs. 0.5 years) with p < 0.05. Patients who achieved CR could attain SRoT more easily (p = 0.02). ELT had a response in 69.2% of children with p/cITP and 17.5% of them attained SRoT with good tolerance. The patients who achieved CR and began ELT treatment as early as possible, with a longer treatment duration and slower tapering, had a higher probability of SRoT. [ABSTRACT FROM AUTHOR]

Summary: Electrical fires caused by leakage, short circuit, overload, and other electrical failures occur frequently in residential areas, and failure to find and locate the fault location in time is the main reason for the evolution of circuit fault into electrical fire, especially in the ancient buildings with aging circuit facilities. Different from modern large‐scale buildings, ancient architectural complex is composed of a large number of scattered low buildings with inconsistent facility specifications and simple structure, so it does not have the conditions to deploy unified electrical lines and establish traditional large‐scale circuit monitoring system. In this study, we design an electrical fire monitoring IoT (EFM‐IoT) framework, which can realize early fire warning by monitoring the residual current of appliances and is easy to deploy in ancient buildings. EFM‐IoT adopts the data cleaning mechanism based on report form to filter redundant data, reducing computing and storage pressure in the cloud. Moreover, we analyze the energy consumption in the process of residual current and temperature data flow, and explore an effective energy‐saving mechanism for transmission. EFM‐IoT has been successfully applied in Chinese historical and cultural street—Pingjiang Road of Suzhou. Extensive evaluation and analysis results demonstrate that EFM‐IoT can effectively alleviate the data traffic and load in the cloud and reduce the response time of early warning. [ABSTRACT FROM AUTHOR]

Introduction: As standard care of severe haemophilia A (SHA), prophylaxis should be individualised. Aim: This study aimed to investigate the effectiveness of this new‐proposed individualised prophylaxis protocol. Methods: Boys with SHA were enrolled and followed a PK‐guided, trough‐level escalating protocol of prophylaxis after a six‐month observational period. In the next 2 years, clinical assessments including joint bleeds, ultrasound (US) scores and Haemophilia Joint Health Score (HJHS) in both sides of ankles, knees and elbows were conducted every 6 months as a scoring system, which determined whether the trough level's escalation. Adjustment of dosing regimen was based on WAPPS‐Hemo. Results: Fifty‐eight SHA boys were finally analysed. Their age and bodyweight were 5.3(2.8,6.9) years and 21.5(16,25) kg. During the study, 47 escalations were conducted. At study exit, the patient number and proportion of different trough level groups were: < 1 IU/dl, 17.2% (10/58); 1–3 IU/dl, 53.5% (31/58); 3–5 IU/dl, 15.5% (9/58); > 5 IU/dl, 13.8% (8/58). Significantly reduced annualised bleeding rate [4(0,8) to 0(0,2), p <.0001] and annualised joint bleeding rate [2(0,4) to 0(0,.25), p <.0001] was observed at study exit as well as the continuous trend of increased zero bleeding proportion (ZBP) (27.6%–69.0%) and zero joint bleeding proportion (46.5%–81.3%). Besides, 85% (6/7) of the target joints vanished. Statistical improvements of US scores (p =.04) and HJHS (p =.02) were also reported at study exit. Conclusion: Our results showed the effectiveness of our protocol based on individualised target trough level and emphasise the importance of personalised prophylaxis. [ABSTRACT FROM AUTHOR]

Introduction: Development of haemophilia B inhibitors (HBI) results in the ineffectiveness of FIX replacement therapy. Inhibitor eradication by immune tolerance induction (ITI) is therefore necessary. In HBI, ITI even at high FIX dose is less effective and has a higher risk of severe complications. Aim: To characterize clinical features and outcome of ITI on HBI. Methods: This retrospective study was conducted in Haemophilia Paediatric Comprehensive Care Centre of China. We used low‐dose ITI (25–50 FIX IU/kg/three‐times‐weekly to every‐other‐day) with domestic prothrombin complex concentrate (PCC), combined with two successive immunosuppressive (IS) regimens. Results: Sixteen HBI children, representing 5.7% of all and 14.4% of our severe registered HB patients, were enroled. Seven cases reported allergic reactions (ARs) proximal to inhibitor development. The historic peak inhibitor titre was median 54.2 (range 4.7–512) BU, and 15 (93.8%) had high‐titre inhibitors. Twelve patients adherent to ITI were analysable. Of the nine ITI patients who received rituximab/prednisone (IS Regimen‐1), four achieved tolerization in 1.4–43.3 months. Two subsequently relapsed but re‐tolerized after a second course of IS Regimen‐1. During ITI, the median treated bleed was.39/month (82.7% reduction from before ITI), and the incidence of AR and nephrotic syndrome (NS) complications was each at 22% (2/9). Three ITI patients received modified 'Beutel' protocol (IS Regimen‐2) using multiple‐IS‐drugs, and two had rapid tolerization (.8 and 1.8 months). Conclusions: Inhibitor eradication could be achieved by low‐dose ITI protocol using PCC combined with IS. Larger studies are needed to confirm if ITI with IS Regimen‐2 is more effective with less complications. [ABSTRACT FROM AUTHOR]

Allergic reactions to FIX have been associated with nephrotic syndrome and poor ITI outcome.3 Both our cases did, with case 2 having allergic reactions simultaneously with inhibitor development. This is consistent with previous observations that NS development was closely related to a significant decline in inhibitor titre.2 Interestingly, the NS in case 2 was preceded by a second allergic reactions to the ITI regimen and in case 1 by a fluctuation of inhibitor titres during ITI-rituximab. Patients with haemophilia B (HB) may develop factor IX (FIX) inhibitors with a cumulative incidence of 10.2% following FIX replacement therapy by 500 exposure days.1 In 50-60% cases, occurrence of severe allergic reactions may precede or occur simultaneously with the inhibitor development.2 The propensity for FIX to induce allergic reactions (compared to FVIII) may be related to the extravascular distribution of the smaller FIX molecules.3 Immune tolerance induction (ITI) therapy to eradicate FIX inhibitors has a poor success rate of only 13-31%.2,4 There is also a risk of developing nephrotic syndrome (NS) in 17-33% cases. Nephrotic syndrome in two haemophilia B children with inhibitor under low-dose immune tolerance induction combined with rituximab-based immunosuppressant protocol. [Extracted from the article]

Interactions between proteinaceous matter and atmospheric oxidants can affect amino acids (AAs) bioavailability, the climate, and human health. However, atmospheric reactions of proteinaceous matter remain poorly understood. PM2.5 samples were collected during spring (2019) and winter (2020) sampling campaigns conducted in Nanchang, China. Concentrations of combined and free AAs, and the δ15N values of combined and free glycine (C‐Gly and F‐Gly) in PM2.5 samples were analyzed. Concentrations of TFAA under different O3 and NO2 levels, and correlations of specific FAA species with ambient O3 and NO2 concentrations suggest that the ability of O3 to release TFAA from proteinaceous matter is greater than that of NO2. Furthermore, O3 may trend to release neutral and hydrophilic FAA species, whereas NO2 tends to generate hydrophobic FAA species. With aerosol aging, the slope of the fitted line between [TFAA] and [TSAA] [O3 + NO2] increased, indicating that FAAs yield from protein degradation in PM2.5 was affected greatly by aerosol aging. The TCAAs concentration observed in spring was substantially higher than that in winter. Moreover, the δ15NF‐Gly and δ15NC‐Gly values in PM2.5 exhibited negative correlations with atmospheric O3 concentration. These results suggest that increased levels of proteinaceous matter in spring were derived from natural sources related to biological activities rather than biomass burning sources. Our study confirms that the reaction of degradation of proteinaceous matter to FAAs could be influenced by aerosol aging, which is a finding that enhances current understanding regarding atmospheric processes of aerosol proteinaceous matter under different ambient O3 and NO2 levels. Key Points: Ability of O3 to release TFAA from proteinaceous matter is greater than that of NO2O3 might trend to release neutral and hydrophilic free amino acids (FAA) species, whereas NO2 tends to generate hydrophobic FAA speciesYield of FAAs from the degradation of protein in PM2.5 samples was affected greatly by the degree of aerosol aging [ABSTRACT FROM AUTHOR]

A low-dose immune tolerance induction (ITI) protocol incorporating immunosuppressive agents in haemophilia A children with high-titre factor VIII inhibitor and poor-ITI prognostic risk These were all on good-ITI risk patients with inhibitor titre <10 BU at the initiation of ITI and historical peak inhibitor titre <200 BU. Nineteen haemophilia A inhibitor children with poor-ITI risk (historical peak inhibitor titre >=100 BU and/or inhibitor titre >=40 BU at ITI initiation) (Table 1) were enrolled from September 2016 through April 2019. Various ITI regimens achieved an overall success rates of 60%-80%.2,3 According to the UK guideline,4 low-dose ITI (50 IU/kg, every-other-day) was only suggested for using in patient with low-titre inhibitors (historical peak inhibitors <5 BU). [Extracted from the article]

Background: The traditional weight‐based dosing regimen can lead to under‐ or overdosage due to the interindividual variability of pharmacokinetic (PK) parameters. PK‐guided prophylaxis can be an optimized therapy choice. Aim: This study aimed to investigate the clinical outcomes of PK‐guided prophylaxis in 46 boys with severe haemophilia A. Methods: Forty‐six boys with severe haemophilia A were enrolled in Beijing Children's Hospital. The PK tests were performed using a five‐point assay. PK parameters were calculated using WinNonlin software. The dosing regimen and bleeding rates recorded during the observation period. The adjustment was based on PK evaluation, bleeding details, doctor's advice and patients' choice. Results: The half‐life time, in vivo recovery and clearance of Kovaltry were 14.34 ± 2.68 h, 1.78 ± 0.29 kg/dl and 3.38 ± 0.94 ml/kg/h, respectively. In 18 patients without any change in the dosing regimen, the trough level was 4.0 ± 2.41 IU/dl and the bleeding rates were similar after PK tests. For patients with a higher trough level after adjustment, higher dose and frequency were observed, as well as a higher trough level. Also, reduced annual bleeding rate (ABR), annual joint bleeding rate and annual spontaneous bleeding rate (ASBR) were found. In five patients with a reduced trough level, lower infusion frequency and weekly coagulation factor VIII (FVIII) consumption were observed, with no statistically significant difference in ABR and ASBR. Conclusion: PK‐guided prophylaxis can help haemophiliac patients improve quality of life by decreasing bleeds with appropriate FVIII consumption and reducing infusion frequency without increments in bleeds, thus optimizing haemophilia treatment. [ABSTRACT FROM AUTHOR]

Background: Kovaltry (BAY81‐8973) is an unmodified full‐length factor VIII (FVIII) concentrate that enhances the pharmacokinetic (PK) profiles as compared to some other standard half‐life time FVIII concentrates. However, the PK of Kovaltry in haemophiliac patients aged <12 years has not been reported previously. Aim: To investigate the pharmacokinetics and clinical outcomes of Kovaltry in 35 paediatric patients aged <12 years. Methods: A total of 35 boys with severe haemophilia A were enrolled from August 2019 to May 2020 in Beijing Children's Hospital. After 72‐hour washout, PK tests were performed post‐infusion of 50 IU/kg Kovaltry in a five‐timepoint assay. WinNonlin software was used to generate individual PK parameters. The dose, frequency and bleeding details were collected within the first 6 months after switching to Kovaltry from other FVIII concentrates. Results: Compared to the blood group O, patients with blood group non‐O showed longer mean half‐life (t1/2) (p <.01), lower mean clearance (CL) (p =.01) and similar in vivo recovery (IVR) (p =.51). Higher von Willebrand factor antigen (VWF:Ag) level was correlated to longer t1/2 (p <.0001) and lower CL (p <.01). IVR was correlated to body mass index (BMI) (p <.0001). Patients with trough level >3 IU/dL demonstrated lower annual bleeding rate (ABR) (p <.01), annual joint bleeding rate (AJBR) (p <.01) and annual spontaneous bleeding rate (ASBR) (p <.01). Conclusion: This study firstly reported the PK profiles of Kovaltry in 35 paediatric patients <12 years old. The great inter‐individual variability of PK parameters was also confirmed in these patients. VWF:Ag and blood group were major influencing factors of t1/2 and CL of Kovaltry, while BMI was a vital predictor for IVR. Patients with high trough FVIII level in routine prophylaxis had reduced bleeding rates. [ABSTRACT FROM AUTHOR]

Importance: The use of factor VIII (FVIII) concentrates under pharmacokinetic (PK) guidance has become the main approach for treatment of hemophilia. However, limited PK research has been conducted in Chinese pediatric patients. Objective: To investigate the PK parameters of various FVIII concentrates in Chinese pediatric patients. Methods: Seventy‐nine patients were enrolled (28 treated with Kogenate FS®, 23 treated with Advate ®, and 28 treated with GreenMono™). All enrolled patients participated in single‐dose PK analysis after at least a 3‐day washout period. Blood samples were collected predose, as well as at 1 h, 9 h, 24 h, and 48 h after infusion; FVIII levels were measured using a one‐stage clotting assay. von Willebrand Factor Antigen (VWF:Ag) levels and blood types were also determined. PK parameters were evaluated by WAPPS‐Hemo. Results: Mean values of terminal elimination half‐life time (t1/2) for the Kogenate FS®, Advate®, and GreenMono™ FVIII groups were 12.24 h, 10.18 h, and 9.62 h; median clearance values were 4.16, 6.23, and 5.11 mL·kg−1·h−1; and median in vivo recovery values were 1.97, 1.55, and 1.61 IU/dL per IU/kg. Longer t1/2, higher in vivo recovery, and lower clearance were observed in patients with higher VWF:Ag level who were treated with recombinant concentrates. Interpretation: Chinese pediatric patients with hemophilia had FVIII PK characteristics similar to those previously observed in non‐Chinese children, including large variation among individuals. VWF:Ag level and FVIII brand were associated with differences in FVIII PK. Thus, PK‐guided dosing should be used to optimize individualized therapy in Chinese children. [ABSTRACT FROM AUTHOR]

Comparative pharmacokinetics of Kogenate FS and Kovaltry in 14 Chinese paediatric patients with haemophilia A: A single-centre study Although the CL of Kogenate FS and Kovaltry showed no statistical difference in our study, the CL of Kovaltry showed a decreasing trend when compared with Kogenate (3.35 vs 3.78 mL/kg/h). Keywords: factor VIII; haemophilia A; haemorrhage; paediatric patients; pharmacokinetics EN factor VIII haemophilia A haemorrhage paediatric patients pharmacokinetics e287 e290 4 03/23/21 20210301 NES 210301 Dear Editor, Haemophilia A is an X-linked inherited bleeding disease caused by a deficiency in the activity of coagulation factor VIII (FVIII). According to the World Federation of Hemophilia (WFH), the management of haemophilia A involves prophylaxis as standard of care, especially for patients with severe haemophilia A.1 However, significant interindividual variability is observed within the patients of haemophilia A in response to treatment. [Extracted from the article]

Endogenous fragments of p53 protein were identified in human cytomegalovirus (HCMV)‐infected human lung fibroblasts, particularly a 44‐kDa N‐terminal fragment [hereafter referred to as p53(ΔCp44)], generated via calpain cleavage. The fragment abundance increased in a biphasic manner, peaking at 6‐9 hours and 48 hours post infection. Treatment of LU cells with calpain inhibitors eliminated most detectable p53 fragments. In cell‐free experiments, exogenous m‐calpain cleavage generated p53(ΔCp44). Attempts to preserve p53 proteins by treating cells with the calpain inhibitor E64d for 6 hours before harvesting increased the sensitivity of p53 to calpain cleavage. p53 in mock‐infected cell lysates was much more sensitive to cleavage and degradation by exogenous calpain than that in HCMV‐infected cells. The proteasome inhibitor MG132 stabilized p53(ΔCp44), particularly in mock‐infected cells. p53(ΔCp44) appeared to be tightly associated with a chromatin‐rich fraction. The abundance of p53β was unchanged over a 96‐h time course and very similar in mock‐ and HCMV‐infected cells, making it unlikely that p53(ΔCp44) was p53β. The biological activities of this and other fragments lacking C‐terminal sequences are unknown, but deserve further investigation, given the association of p53(ΔCp44) with the chromatin‐rich (or buffer C insoluble) fraction in HCMV‐infected cells. [ABSTRACT FROM AUTHOR]

Importance: Tertiary prophylaxis using a low‐dose regimen is usually insufficient to prevent recurrent joint bleeding and deterioration in joint diseases in children with severe hemophilia A. Pharmacokinetic (PK) dosing is a useful approach to increase the precision and efficiency of prophylaxis. Objective: To explore the efficacy of PK‐tailored tertiary prophylaxis in children with severe hemophilia A. Methods: We implemented a PK‐tailored tertiary prophylaxis program for 15 boys with severe hemophilia A aged 5–16 years at Beijing Children's Hospital. Following PK testing and a 6‐month evaluation period (phase I), 15 patients were divided in two groups according to individual PK data and actual bleeding: (1) a PK‐tailored group [modified prophylaxis regimen according to PK data for the next 6 months (phase II); n = 8] and (2) a maintenance group (continued the original regimen for the next 6 months; n = 7). We compared the bleeding rate, infusion frequency, and factor VIII (FVIII) consumption between the two groups. Results: In the PK‐tailored group, the median annual joint bleeding rate was reduced from 7.8 in phase I to 1.4 in phase II, mean annual total factor consumption increased from 1619.0 IU/kg in phase I to 2401.9 IU/kg in phase II, and median infusion frequency for prophylaxis increased from 104 times/year in phase I to 156 times/year in phase II (P < 0.05). Although the FVIII consumption increased, it remained at approximately half of the standard method. Interpretation: PK‐tailored prophylaxis may represent a more efficient approach to individual prophylaxis in China, but further studies are required to verify this. [ABSTRACT FROM AUTHOR]

Summary: Dysregulation of plasma lipids is associated with age‐related cardiovascular diseases. L5, the most electronegative subfraction of chromatographically resolved low‐density lipoprotein (LDL), induces endothelial dysfunction, whereas the least electronegative subfraction, L1, does not. In this study, we examined the effects of L5 on endothelial senescence and its underlying mechanisms. C57B6/J mice were intravenously injected with L5 or L1 (2 mg kg−1 day−1) from human plasma. After 4 weeks, nuclear γH2AX deposition and senescence‐associated β‐galactosidase staining indicative of DNA damage and premature senescence, respectively, were increased in the aortic endothelium of L5‐treated but not L1‐treated mice. Similar to that, in Syrian hamsters with elevated serum L5 levels induced by a high‐fat diet, nuclear γH2AX deposition and senescence‐associated β‐galactosidase staining were increased in the aortic endothelium. This phenomenon was blocked in the presence of N‐acetyl‐cysteine (free‐radical scavenger) or caffeine (ATM blocker), as well as in lectin‐like oxidized LDL receptor‐1 (LOX‐1) knockout mice. In cultured human aortic endothelial cells, L5 augmented mitochondrial oxygen consumption and mitochondrial free‐radical production, which led to ATM activation, nuclear γH2AX deposition, Chk2 phosphorylation, and TP53 stabilization. L5 also decreased human telomerase reverse transcriptase (hTERT) protein levels and activity. Pharmacologic or genetic manipulation of the reactive oxygen species (ROS)/ATM/Chk2/TP53 pathway efficiently blocked L5‐induced endothelial senescence. In conclusion, L5 may promote mitochondrial free‐radical production and activate the DNA damage response to induce premature vascular endothelial senescence that leads to atherosclerosis. Novel therapeutic strategies that target L5‐induced endothelial senescence may be used to prevent and treat atherosclerotic vascular disease. [ABSTRACT FROM AUTHOR]

The energy supply for sensors in wireless sensor and actuator networks (WSANs) is usually limited, we therefore focus on how to design the adjacency weights for achieving second-order consensus with less communication energy consumption in a distributed way, and investigate this issue from both the viewpoints of the rate of convergence and the sparsity of the network. We also derived the conditions on the consensus control parameter and the updating period for the proposed consensus protocol to ensure the convergence. It is shown that, by removing some properly chosen links, the sparsity of the resulting network can produce a positive effect on the energy efficiency of WSANs. Finally, simulation results are presented to verify the effectiveness of the proposed algorithm. [ABSTRACT FROM AUTHOR]

N6-methyladenine (6mA) is one of the most abundant types of DNA methylation, and plays an important role in bacteria; however, its roles in higher eukaryotes, such as plants, insects, and mammals, have been considered less important. Recent studies highlight that 6mA does indeed occur, and that it plays an important role in eukaryotes, such as worm, fly, and green algae, and thus the regulation of 6mA has emerged as a novel epigenetic mechanism in higher eukaryotes. Despite this intriguing development, a number of important issues regarding its biological roles are yet to be addressed. In this review, we focus on the 5mC and 6mA modifications in terms of their production, distribution, and the erasure of 6mA in higher eukaryotes including mammals. We perform an analysis of the potential functions of 6mA, hence widening understanding of this new epigenetic mark in higher eukaryotes, and suggesting future studies in this field. [ABSTRACT FROM AUTHOR]

Diamond-like carbon (DLC) films were deposited on Si substrates by pulsed unbalanced magnetron sputtering with different bias configurations: constant bias and step biasing. The structure, surface morphology, and mechanical properties of the DLC films were investigated by Raman spectroscopy, X-ray photoelectron spectroscopy, atomic force microscopy (AFM) and nanoindentation etc. It has been found that the sp3 content in the DLC films deposited with step biasing is less than that deposited under constant bias. AFM measurements show that the root-mean-square (RMS) surface roughness of the films deposited with step biasing is less than that deposited under constant bias; and the smaller step increase of bias, the lower the RMS roughness. Nanoindentation and residual stress tests indicate that step biasing with 20 min of time intervals and with 20 V of bias reduces the stress of DLC films from 5.8 to 3.5 GPa with little sacrifice of hardness from 13.3 to 12.5 GPa. The results above are useful for the practical application of DLC films. [ABSTRACT FROM AUTHOR]

Diepoxybutane (DEB) is the most potent active metabolite of the environmental chemical 1,3-butadiene (BD). BD is a known mutagen and human carcinogen and possesses multisystems organ toxicity. We previously reported the elevation of p53 in human TK6 lymphoblasts undergoing DEB-induced apoptosis. In this study, we have characterized the DEB-induced p53 accumulation and investigated the mechanisms by which DEB regulates this p53 accumulation. The elevation of p53 levels in DEB-exposed TK6 lymphoblasts and human embryonic lung (HEL) human fibroblasts was found to be largely due to the stabilization of the p53 protein. DEB increased the acetylation of p53 at lys-382, dramatically reduced complex formation between p53 and its regulator protein mdm2 and induced the phosphorylation of p53 at serines 15, 20, 37, 46, and 392 in human lymphoblasts. A dramatic increase in phosphorylation of p53 at serine 15 in correlation to total p53 levels was observed in DEB-exposed Ataxia Telangiectasia Mutated (ATM) proficient human lymphoblasts as compared to DEB-exposed ATM-deficient human lymphoblasts; this implicates the ATM kinase in the elevation of p53 levels in DEB-exposed cells. Collectively, these findings explain for the first time the mechanism by which p53 accumulates in DEB-exposed cells and contributes to the understanding of the molecular toxicity of DEB and BD. © 2009 Wiley Periodicals, Inc. J Biochem Mol Toxicol 23:373-386, 2009; Published online in Wiley InterScience (). DOI 10.1002/jbt.20300 [ABSTRACT FROM AUTHOR]

Th type 17 (Th17) cells have been identified as a proinflammatory T-cell subset. Here, we investigated the regulation of human Th17 cells by fetal BM-derived mesenchymal stem cells (FBM-MSC). We cocultured FBM-MSC with human PBMC or CD4 T cells from healthy donors. FBM-MSC significantly suppressed the proliferation of CD4 T cells stimulated by PHA and recombinant IL-2. Significantly higher levels of IL-17 were observed in FBM-MSC cocultured with either PBMC or CD4 T cells than that in PBMC cultured alone or CD4 T cells cultured alone. Flow cytometry analysis showed that the percentage of Th17 cells in coculture of FBM-MSC and CD4 T cells was significantly higher than that in CD4 T-cell cultured alone. FBM-MSC did not express IL-17 protein. Consistent with the augmentation of Th17 cells, significantly higher levels of IL-6 and IL-1 were observed in coculture of FBM-MSC and CD4 T cells than that in CD4 T-cell culture, while the levels of IL-23 were similar between FBM-MSC + PBMC coculture and PBMC alone, or FBM-MSC + CD4 T-cell and CD4 T-cell alone. The presence of FBM-MSC decreased the percentage of Th1 cells, but minimally affected the expansion of CD4CD25 T cells. In conclusion, our data demonstrate for the first time that FBM-MSC promote the expansion of Th17 cells and decrease IFN-γ-producing Th1 cells. These data suggest that IL-6 and IL-1, instead of IL-23, may be partly involved in the expansion of Th17 cells. [ABSTRACT FROM AUTHOR]