In LF, the soil moisture increased significantly (p < 0.05), and its value can reach 47.85 ± 1.93%, which is consistent with the change of soil porosity. With the recovery process, soil nutrients gradually accumulated. Except for total phosphorus (TP), there was obvious surface enrichment of soil nutrients. Soil organic carbon (15.43 ± 2.28 g/kg), total nitrogen (1.08 ± 0.12 g/kg), and total phosphorus (0.43 ± 0.03 g/kg) in LF were significantly higher than those in EF (p < 0.05). The soil available nutrients, that is, soil available phosphorus and available potassium decreased significantly in LF (p < 0.05). In LF, more canopy interception weakened the P limitation caused by atmospheric acid deposition, so that the soil C:P (37.68 ± 4.76) and N:P (2.49 ± 0.24) in LF were significantly lower than those in EF (p < 0.05). Affected by TP and moisture, microbial biomass C and microbial biomass N increased significantly in LF, and the mean values were 830.34 ± 30.34 mg/kg and 46.60 ± 2.27 mg/kg, respectively. Further analysis showed that total soil porosity (TSP) and TP  contributed the most to the final soil quality index (SQI). With the forest restoration, the SQI gradually increased, especially in LF the value of SQI was up to 0.84, which was significantly higher than that in EF and MF (p < 0.05). This result is of great significance to understanding the process of restoration of subtropical forests and improving the management scheme of subtropical secondary forests.Vegetation succession can change the function and quality of the soil. Exploring the changes in soil properties during secondary forest restoration is of great significance to promote forest restoration and improve the ecological service function of subtropical ecosystems in South China. In this study, we chose three typical forests in subtropical China as restoration sequences, broadleaf–conifer mixed forest (EF), broad-leaved forest (MF), and old-growth forest (LF), to study the changes in soil physico-chemical and biological properties and the changes of soil comprehensive quality during the secondary succession of subtropical forest. The results showed that the soil physical structure was optimized with the progress of forest succession. The soil bulk density decreased gradually with the progress of forest restoration, which was significantly affected by soil organic carbon ( Forests are universally known to be one of the most important terrestrial ecosystems in terms of the diverse ecological functions they serve, including carbon sequestration, biodiversity conservation, water, soil conservation and cleaning the air, etc. . A serioForest restoration has been documented to be accompanied by changes in the species’ structure and soil evolution . Over thPedosphere is an active interface in the biogeochemical cycle of forest ecosystems, and its physical, chemical, and microbial characteristics can indicate the process of soil formation, soil development, and fertility along forest succession . Soil quXinfengjiang National Forest Park is located in Guangdong Province, China, and it includes forest types in different succession stages. Due to extensive deforestation in the 1950s, most of the stands in the study site are now secondary forests . In 1984The study area is located in the Xinfengjiang National Forest Park , China, with a total area of 4479.47 hectares. The region has a subtropical monsoon climate, with a forest coverage rate of 78%. The vegetation types are mainly an evergreen broad-leaved forest, an evergreen coniferous forest, and a broadleaf–conifer mixed forest. The average temperature is 21.2°C and the annual average precipitation is about 1,420 mm, mainly from April to September, and the average relative humidity is about 76%. Bedrocks are classified as granite, basalt, and sandshale. Soils are classified as yellow and red earth, mostly medium loam and heavy loam .Pinus massoniana and Cunninghamia lanceolata. The broad-leaved forest was partially logged before conservation, and the dominant tree species are Castanopsis chinensis, Schefflera octophylla, and Itea chinensis. The old-growth forest is relatively close to the central area and has not been disturbed much in the past, so it can be regarded as a well-developed forest in the later stage of succession. Its dominant tree species are Schima superba, Cinnamomum porrectum, and Machilus thunbergii.In 2014, six plots were permanently set up in the study area, of which two duplicate plots were established for each stand type . Each pl3 stainless steel cylinders from each soil layer. The disturbed soil samples were collected using a soil drill with a diameter of 3.5 cm from five points, at the four corners and the center of each quadrat, and then the samples from the five points in each layer were fully mixed making up the composite samples (the weight of each composite sample was about 1 kg). The fresh soil samples from every 30 cm were stored in a 4°C refrigerator for the determination of soil microbial biomass C (MBC) and microbial biomass N (MBN).In every plot, three randomly repeated small quadrats were set up with an area of 10 m × 10 m. We dug two holes about 1.3 m × 1 m in size for collecting soil samples in each quadrat. Soil samples were taken at 0–25 cm, 25–50 cm, 50–75 cm, and 75–100 cm layers for the determination of the soil’s physical and chemical properties. The soil microbial biomass was determined using the samples taken at 0–30 cm, 30–60 cm, and 60–90 cm layers. Soil sampling was conducted once during the rainy season and dry season, respectively, a total of 66 samples were collected  each time for each stand. Three duplicate undisturbed soil cores were collected with 100 cm3 (m0). After sampling, we weighed the cylindrical soil auger with the contained fresh soil sample (m1). We then soaked the cylindrical metal core with the undisturbed soil in water for 12–14 h and weighed it thereafter (m2). The specific calculation formula used is as follows:The bulk density (BD), soil water content (SWC), and porosity were determined using the undisturbed soil sample cores using Kopecky’s cylinder method . We firsSWC is water content of soil (%); md is the dry soil weight (g); MWHC is the maximum water holding capacity (%).where Plant roots, debris, and gravels were removed before the analysis of the mixed soil, and the soil samples from every 25 cm were screened through a 2-mm mesh for available phosphorus (AP) and available potassium (AK); through a 1-mm mesh for soil alkaline hydrolysis nitrogen (AN); and through a 0.25-mm mesh for soil organic matter (SOM), total nitrogen (TN) and total phosphorus TP; . The SOMWe selected a soil quality index (SQI) to comprehensively represent all the indicators we had measured to evaluate the overall soil quality. It has been widely used under the condition of minimum data sets (MDS), which enables researchers to select the most representative soil indicators and reduce data redundancy . The estr < 0.7, all indexes were selected into MDS; if the correlation r > 0.7, the high factor load index with the largest sum of correlation coefficients was selected into MDS  reached by the function, x is the value of the indicator, 0x is the mean value of each soil indicator, and b is the value of the equation’s slope (b) of −2.5 was set for “more is better” and 2.5 was set for “less is better” curve, respectively  was performed on the experimental data and the normality of the data was judged. One-way ANOVA was used to compare the differences in soil properties between different vegetation types and soil depths. When the ANOVA results were significant according to the F value (p < 0.05), Duncan’s test was performed to compare the mean differences of soil variables. All sample mean values and standard errors in this study were processed and analyzed by Microsoft Excel 2010  and IBM SPSS Statistics 22.0 , and the data results were plotted using Origin 2021 .Before statistical data analysis, the Kolmogorov–Smirnov test (3) > MF (1.28 ± 0.03 g/cm3) > LF (1.16 ± 0.03 g/cm3). The TSP decreased with increasing soil depth gradually in EF and MF, while the change in TSP was not significant between layers in LF. When averaged across the 0–100 cm depth, the TSP value was significantly decreased in the order LF (52.36 ± 0.85%) > MF (45.53 ± 1.17%) > EF (42.41 ± 0.85%). In this study, soil porosity in three forests consisted mainly of capillary porosity. As forest restoration continued, the CP increased significantly from 33.63 ± 0.93% (EF) to 48.77 ± 0.99% (LF). When averaged across the 0–100 cm depth, the NCP in EF (8.79 ± 0.72%) was significantly higher than that in MF (4.61 ± 0.48%) and LF (3.60 ± 0.54%). The MWHC was regarded as the amount of water held by the soil when all its pores are filled with water. In each forest, the MWHC gradually decreased with increasing soil depth. When averaged across the 0–100 cm depth, the MWHC (47.85 ± 1.93%) in LF was significantly higher than that in other forests .As shown in As shown in As shown in As shown in As shown in p < 0.05) and SOC . MWHC was mainly affected by TSP  and SOC . The SOC was closely related to TN  and AN . The physical properties of soil also have a certain impact on the stoichiometric characteristics. The NCP was positively correlated with C:P  and N:P . As for soil microbial biomass C and N, the TP was positively correlated with MBC and MBN, and the correlation coefficients were 0.96 and 0.94, respectively (p < 0.01). While the content of AK was negatively correlated with MBC and MBN, and the correlation coefficients were −0.73 and −0.69, respectively (p < 0.05).A comprehensive index, that is, SQI was established to evaluate the change in soil properties. Based on the principal component analysis and the correlation between various properties, a soil quality index equation was constructed. The principal component analysis showed that values of the first two PCs were all ≥1 and explained 94.22% of the total variance. TSP, TP, and MWHC in the first principal component (PC1) are high-weight indicators . MWHC hap < 0.05), that is, LF (0.84) > MF (0.72) > EF  were species-dependent, which could be explained by the “complementary” or “mass” effects related to plant diversity in forest ecosystems . Han et Soil stoichiometry is the core of C, N, and P biogeochemistry , which rAlong the soil vertical profile in this study, the stoichiometric ratio in the surface layer of different forests was higher than that in other soil layers. Subtropical China is one of the regions with the highest level of nitrogen deposition in the world . The incSoil microbial biomass carbon (MBC) and microbial biomass nitrogen (MBN) are the main components of soil microbial biomass, and their subtle changes affect the turnover of the soil organic matter and nutrients . In thisSoil microbial biomass is very sensitive to changes in soil environmental factors . Hu et aBased on the basic properties of soil, a comprehensive index (SQI) was constructed to reflect the changes in soil under forest restoration, which is of great significance to evaluate sustainable land use and effective management . In thisOur findings show that secondary forest restoration in southern China significantly affected soil physico-chemical and microbiological properties. As forest restoration proceeded, soil properties, that is, BD, porosity, and water holding capacity were significantly improved. The soil structure especially the topsoil was also optimized to a great extent. Total soil nutrients and soil microbial biomass gradually increased, while the amounts of the available nutrients, that is, AP and AK showed a downward trend. In addition to TP, there was a significant surface enrichment of forest soil nutrients. The SQI, which integrated physico-chemical and microbiological properties, demonstrated that higher soil quality was mainly affected by soil porosity and total phosphorus in this area. The SQI as a forest restoration evaluation method proved to be effective in revealing the local factors that require more attention for sustainable and scientific forestry management. The present study provides new evidence that soil properties improved during the restoration of a secondary subtropical forest, and is of great significance for evaluating the function and improving the management scheme of subtropical forests in South China.The datasets generated and analyzed during the current study are available from the corresponding authors on reasonable request.XZ, PL, and YF: data processing and writing. WZ: conceptualization and data collection. BN: language correction. FL, QZ, CQ, and XG: site maintenance and data collection. XL: experimental design and review. All authors contributed to the article and approved the submitted version.This work was supported by the Forestry Science and Technology Innovation Project of Guangdong Province, China (2021KJCX003 and 2022KJCX015) and Operation Subsidy Program of Technology Innovation Platform of National Forestry and Grassland Administration (2021132084 and 2021132085).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


High flow nasal cannula (HFNC) has significantly success in treating acute respiratory distress while HFNC failure dramatically increases mortality and morbidity.To describe factors associated with failure of HFNC use in children.We performed a retrospective observational study using demographic and laboratory findings. We compared clinical and laboratory variables in both successful and failed HFNC groups. The correlations between factors and HFNC failure were constructed by binary logistic regression analysis.p = 0.005), HFNC use with maximum FiO2 > 0.6 (p = 0.021), lobar infiltration on chest X‐ray (p = 0.012), the reduction of heart rate, and respiratory rate <20% after 1 h of HFNC use .Between August 2016 and May 2018, 250 children receiving HFNC  were enrolled. Pneumonia was the most common cause of respiratory distress, and the median length of stay (LOS) in hospital was 11 days. HFNC failure was found 16.4% while HFNC complication was 4.8% including epistaxis, pressure sore, and gastric distension. Based on multivariable logistic regression analysis, factors associated with HFNC failure were children with congenital heart disease comorbidity (2 > 0.6, lobar infiltration on chest X‐ray should be closely monitored. Heart rate and respiratory rate are important parameters in addition to clinical assessment for evaluating HFNC failure in children.HFNC is feasible to use for children with respiratory distress; however, patients with congenital heart disease, using HFNC with FiO 2 > 0.6, having lobar infiltration on chest X‐ray and unimproved vital signs after HFNC use are factors associated with failure of using HFNC in children.HFNC seems to be well tolerated in children with respiratory distress; however, children with congenital heart disease, using HFNC with FiO BiPAPbi‐level positive airway pressureBWbody weightCAPcommunity‐acquired pneumoniaCBCcomplete blood countCPAPcontinuous positive airway pressure2FiOfraction of inspired oxygenGAgestational ageHFNChigh flow nasal cannulaIQRinterquartile rangekgkilogramsLOSlength of stayLPMliters per minuteNIVnon‐invasive ventilationORodds ratio2pCOpartial pressure of carbon dioxidePICUpediatric intensive care unitPRISM IIIPediatric Risk of Modified III scoresRRrelative riskSLEsystemic lupus erythematosus2SpOoxygen saturation12).High flow nasal cannula (HFNC) is extensively used as an important non‐invasive respiratory support.Recent studies have demonstrated that the HFNC failure rate ranges from 6.0 to 24.4%1.1The first objective of our study was identifying factors associated with HFNC failure in children. The second objective was to characterize the complications from HFNC use.22.1This was a single‐center, retrospective chart review of children using HFNC in a tertiary care hospital in pediatric intensive care (PICU) and outside PICU between August 2016 and May 2018 at Pediatric Department, Faculty of Medicine, Chiang Mai University hospital, Chiang Mai, Thailand. A retrospective review was approved by the Institutional Review Board at the Research Ethics Committee, Faculty of Medicine, Chiang Mai University hospital (Study code: PED‐2561‐05570), with a waiver of informed consent granted.2.22, duration, outcome, and complication of HFNC use were recorded. HFNCs are available in both pediatric general ward and PICU setting. HFNC initiation and monitoring in this study were based on Figure Inclusion criteria was pediatric patients aged 1 month to 15 years of age who used HFNC at Chiang Mai University Hospital. Exclusion criteria was the pediatric patient who were on tracheostomy. The patient data including age, sex, date of admission and discharge from hospital, history of prematurity , history of intubation, underlying diseases, diagnosis, length of stay (LOS) in hospital, place where HFNC used, infiltration pattern on chest X‐ray, initial vital signs, and vital signs after HFNC use were collected. HFNC data including maximum total flow, FiO2.32 started at 0.6 and titrated as needed to achieve target oxygen saturation (SpO2); and set temperature at 34–37°C and was adjusted to the patient performance. After using HFNC, vital signs , clinical status, work of breathing, chest X‐ray, and blood gas were monitored. HFNC use was discontinued when patients needed more respiratory support such as intubation or NIV. In the other hand, if the patients improved from their respiratory distress, HFNC weaning protocol would be considered.HFNC therapy in our institution uses the GGM HF‐2900 Humidoflo® HFT system . Enrollment for HFNC management was based on the decision of physicians following HFNC recommendations. The HFNC guidelines follow the Pediatric HFNC guideline at the Pediatric Pulmonary and Critical Care Division, Chiang Mai University Hospital Figure . Regardi2.4t tests, and skewed continuous variables were compared using Mann–Whitney U test. Categorical data were evaluated by chi‐square test or Fisher's exact test. A p value less than 0.05 indicated statistical significance. The correlations between factors and HFNC failure were constructed by logistic regression analysis.Data analysis was carried out using IBM SPSS 23.0. The demographic data were evaluated by descriptive statistics. Normally distributed continuous variables were compared using Student's 33.1n = 131), while the failure of HFNC use following with intubation was 16.4% (n = 41). The median of intubation time was 26 h (IQR: 0–144). The median of maximum total flow rate and FiO2 used in both successful and failed groups were 1 L/min/kg (IQR: 1–2), 1.8 L/min/kg (IQR:1–2), FiO2 0.6 (IQR:0.6–0.6), and 0.6 (IQR:0.6–0.7), respectively. The median LOS in hospital was 11 days  while the median duration of HFNC use was 48 h . On chest X‐ray, we found perihilar infiltration in 139 patients (55.6%), interstitial infiltration in 44 patients (17.6%), hyperinflation with atelectasis in 43 patients (17.2%), and lobar infiltration in 24 patients (9.6%). Most patients used HFNC without complication (95.2%); however, the complications from HFNC such as gastric distension in 7 patients (2.8%), nose pressure sore in 4 patients (1.6%), and epistaxis in 1 patient (0.4%) occurred.Two hundred and fifty pediatric patients using HFNC due to respiratory distress were admitted between August 1, 2016, and May 31, 2018. Table p = 0.041) and history of preterm  compared with the other group. More than half of both groups had a diagnosis of pneumonia. The second most common diagnosis in the HFNC success group was acute bronchiolitis while the other group had congestive heart failure. Most patients in the HFNC group had no underlying disease while nearly one‐third of the comorbidities of patients in the HFNC failure group had congenital heart disease comorbidity. Both patients in HFNC success and failure groups used HFNC at pediatric ward . Moreover, baseline characteristics including maximum FiO2, duration of HFNC use, lobar infiltration on chest X‐ray, and LOS in hospital were different between the HFNC success and failure group with statistical significance. However, our study found that there were no statistical differences between groups in terms of sex, body weight (BW), history of intubation, initial heart rate, initial respiratory rate, maximum total flow rate, complete blood count (CBC), electrolyte, and complications.The comparison of baseline characteristic of patients between HFNC success and failure groups was shown in Table 3.2p = 0.005), using HFNC with maximum FiO2 > 0.6 , presence of lobar infiltration on chest X‐ray , and reduction of heart rate and respiratory rate less than 20% after HFNC use for 1 h  were dramatically associated with HFNC failure , HFNC use with maximum FiO2 > 0.6 (p = 0.021), lobar infiltration on chest X‐ray (p = 0.012), and the reduction of heart rate and respiratory rate less than 20% after 1 h HFNC use  were associated with increasing HFNC failure. However, our finding found no differences of HFNC failure rate in younger children than 2 years of age, preterm, using HFNC at ward or PICU, initial heart rate, and respiratory rate. Comparing with other studies, Better et al. retrospectively examined patients using HFNC outside PICU concluding that higher FiO2 requirement , diagnosis less likely to be bronchiolitis , history of intubation (p = 0.046), and cardiac comorbidities (p = 0.026) are related with HFNC failure.2/FiO2 ratio <264 and higher FiO2 requirement are associative predictors of HFNC failure.p < 0.001), pCO2 before and after HFNC use (p < 0.001) and (p < 0.001), respectively, and higher Pediatric Risk of Modified III scores (PRISM III) (p < 0.001).Based on the multivariable logistic regression analysis, we found that the presence of congenital heart comorbidity ,p = 0.358).2 adjusted following clinical signs and symptoms bring about effective respiratory support. Higher FiO2 requirement is another factor associated with HFNC failure, which were found in Betters2 could predict HFNC failure . Patients having more severity of disease or progression of disease require higher oxygen requirement or higher respiratory support such as invasive ventilation.2 might be a substantial predictor for HFNC failure.For the HFNC setting, we found a maximum FiO2 by HFNC.Children with congenital heart disease comorbidity and lobar infiltration on chest X‐ray both revealed significant values in the logistical regression analysis, and may demonstrate significance in the setting of more patients. Children with congenital heart disease may present with increased work of breathing and hypoxia which might be concealed by positive airway pressure and high FiOAlthough initial heart rate and respiratory rate were not associated with HFNC failure in our study, the reduction of heart rate and respiratory rate less than 20% after 1 h HFNC use were associated with increasing HFNC failure significantly. This emphasizes that vital signs including heart rate and respiratory rate are important parameters in addition to clinical assessment for evaluating HFNC failure in children especially in the first hour after HFNC initiation.p = 0.015)This study shows the LOS in hospital was 11 days, however, with multifactorial issues impacting the duration, namely, clinical signs and symptoms of patients, progression of disease, cause of respiratory distress, other comorbidities, and different physician management. We illustrated that the failure group had less duration of HFNC use than the success group with statistical significance, which was similar to Betters et al. study . The requirement of informed consents was waived by the Ethics Committee of the Faculty of Medicine, Chiang Mai University, Thailand.Figure S1: HFNC initiation and monitoring in Pediatric Department, Chiang Mai University hospitalClick here for additional data file.


One hundred and twenty‐two (27%) received carfilzomib‐based treatment in line 2, 133 (30%) in line 3, 90 (20%) in line 4, and 100 (23%) in line 5 or higher. Carfilzomib was dosed weekly in 40% of patients and twice weekly in 60%. The overall response rate of the entire cohort was 57.7%, with 33.6% of patients achieving very good partial response or better. Median progression‐free survival for the overall cohort was 6.3 months with overall survival 19.7 months. This study provides a benchmark for carfilzomib‐based regimens in the real world, demonstrating that these regimens are effective in treating patients with relapsed MM.Carfilzomib is an active and commonly used treatment in patients with multiple myeloma (MM). Using the Canadian Myeloma Research Group Database, we performed a retrospective observational study of patients treated with carfilzomib for relapse of MM in a real‐world setting in Canada between years 2007 and 2020. A total of 445 patients were included in this study: the doublet (Kd/p,  In the Carfilzomib is a second‐generation PI that irreversibly binds the proteasome. It differs in its structure (tetrapeptide epoxyketone) as compared to the first‐generation PI bortezomib (dipeptide boronate) . CarfilzCarfilzomib was initially approved in Canada based on the results of two pivotal phase III randomized controlled trials. In 2015, Stewart et al.  publisheThree additional carfilzomib‐based triplets have been studied. The CANDOR trial studied the combination of daratumumab, carfilzomib, and dexamethasone (DKd) versus Kd, with DKd having a PFS of 28.6 months compared to 15.2 months for Kd . Lastly,There are ongoing studies being conducted with carfilzomib in the front‐line and relapsed setting in both transplant ineligible as well as patients with smoldering myeloma and in many different quadruplet regimens , 20. CarThere is limited real‐world data with carfilzomib‐based treatments. These data are important in understanding the overall clinical benefits as most real‐world patients would have been excluded from clinical trials due to stringent enrolment criteria , with anGiven the discordance between clinical trial and available real‐world evidence, there is a need to understand the real‐world‐treatment patterns and outcomes of patients treated with regimens containing carfilzomib in RRMM.2We conducted a retrospective observational study using the Canadian Myeloma Research Group Database (CMRG‐DB). This project was approved by the Ottawa Hospital Research Ethics Board in keeping with the CMRG‐DB governance structure. Data were collected from the CMRG‐DB, which is a prospectively maintained web‐based centralized disease‐specific database of over 7000 patients with MM at 15 Canadian institutions, including legacy data from 2007. Local research ethics boards at every contributing site approve entry of patient data into the CMRG‐DB and all patients are consented for research studies. For this analysis, patients were identified that initiated their carfilzomib treatment between July 1, 2009 and December 31, 2020.n ≤ 7).Patients were included if they had a diagnosis of MM and were treated with carfilzomib after at least one prior line of therapy. As the CMRG‐DB is a retrospective database on unselected MM patients, some previously enrolled into clinical trials were included in the analysis for this study. Patients were grouped as follows: (1) carfilzomib monotherapy or in combination with corticosteroids (Kd/p), (2) carfilzomib in combination with lenalidomide and dexamethasone (KRd), (3) carfilzomib in combination with cyclophosphamide and dexamethasone (KCd), and (4) carfilzomib in combination with pomalidomide and corticosteroids (KPd/p). Other combinations were not included in the analysis due to insufficient sample size , overall response rates (ORR) by International Myeloma Working Group criteria, PFS and OS of patients treated with carfilzomib and reasons for treatment discontinuation.PFS is defined as the length of time between the date of first dose of carfilzomib‐based treatment and the earliest date of disease progression or death due to any cause. OS is defined as the length of time between the date of first dose of carfilzomib‐based therapy and death due to any cause.2.1Descriptive statistics were used to report standard baseline characteristics at diagnosis of all MM patients in the CMRG‐DB. Categorical variables were summarized with counts and percentages. Continuous variables were summarized with means, standard deviations, medians, and/or ranges as appropriate.p < 0.05 were considered to indicate a statistically significant result.Time to event analyses were used to assess the PFS and OS curves that were constructed according to the Kaplan–Meier method and the impact of covariates of interest was assessed using the log‐rank test. The summary from Kaplan–Meier analyses included the median and 95% confidence interval of the estimates for each time‐to‐event outcome analyzed. Statistical analyses were performed using R core team 2020 (R‐4.1.1), Vienna, Austria, and RStudio team 2019 (RStudio‐1.4.1717), Boston, MA, USA for Windows. All tests were two‐sided, 33.1t, or t).Five hundred and sixteen unique patients were treated with carfilzomib in the CMRG‐DB, of which 445 were identified meeting study criteria Figure . Baselin3.2Treatment details by line of therapy are shown in Table The most commonly used regimens at first relapse were KRd, Kd/p, and KCd used in 58.2%, 20.1%, and 18.9%, respectively. At second relapse, Kd/p became most commonly used at 51.1%, followed by KCd (23.3%), KRd (15.0%), and KPd/p (10.5%). Kd/p was again the dominant regimen used in fourth line (60%) and fifth or higher lines (71%), followed by KCd (22.2% in fourth line and 14.0% in fifth or higher lines) and KPd/p (12.2% in fourth line and 12.0% in fifth or higher lines).Figure In the overall cohort, 249 (56.0%) of evaluable patients were treated with twice weekly dosing and 168 (37.8%) were dosed weekly (Table 3.3Details of response rates by line and regimen are displayed in Figure Details of PFS and OS by line and regimen are provided in Table Forty‐seven patients received carfilzomib‐based therapy specifically when progressing on lenalidomide maintenance post‐ASCT. Seventeen patients received KRd and had an ORR of 92% with median PFS 19.3 months, whereas the 11 patients treated with KCd in this setting had ORR of 73% and median PFS 6.0 months and the 19 patients treated with Kd/P had an ORR of 50% and median PFS 11.2 months.3.4At the time of the analysis, 414 out of 445 patients had discontinued therapy, while 31 remained on treatment without evidence of progression. Reasons for discontinuation are presented in Table 4In this retrospective observational study, we utilized the CMRG‐DB to describe our real‐world experience in Canada with carfilzomib‐based combinations for the treatment of relapsed MM. The results provide insight into which combinations are being used in clinical practice, as well as a benchmark of expected efficacy results for our patients. While our results support the use of carfilzomib in triplet combinations and earlier in the disease course for maximizing outcomes, they also support the use of carfilzomib throughout the disease trajectory, with reasonable response rates and outcomes seen even in patients treated in line 5 and beyond.Outside of the context of clinical trials and as displayed in Figure In our study, the responses and efficacy observed were less than what has been demonstrated in prospective RCTs, but similar to what has been reported in other real‐world series. For example, the ASPIRE trial showed an ORR of 87%  with PFSOur study importantly demonstrates that carfilzomib‐based treatments are currently used across many lines of therapy in RRMM, with one‐quarter of Canadian patients who receive carfilzomib doing so in line 5 or higher. Even so, response rates of >50% are maintained among this heavily pre‐treated group, with meaningful PFS and OS outcomes for this selected group of patients. This has been described in other studies, with KCd‐treated patients after median six prior lines showing ORR of 52% and OS 11.9 months in a real‐world analysis . These rOur study has several limitations. We were not able to capture some variables that are not uniformly collected outside of clinical trials and could impact efficacy results in a real‐world setting, including baseline performance status and frailty assessments. In addition, we were unable to describe subsequent post‐carfilzomib treatments in a meaningful fashion, as the heterogeneity of post‐carfilzomib combinations in multiply relapsed was vast, including more than 12 agents in more than 40 unique combinations. Lastly, at the time of this manuscript, carfilzomib is not reimbursed in combination with anti‐CD38 MAbs, though they have received regulatory approvals, which is an important component of modern MM therapy and will require follow‐up in the future to evaluate those outcomes.In summary, the results of our retrospective CMRG‐DB study provide a benchmark for outcomes with carfilzomib‐based regimens in the real world, demonstrating that these regimens are effective in treating patients with RRMM, with the KRd and KCd combinations used in earlier lines of therapy affording the best outcomes. An improved understanding of the reasons underlying the differences in effectiveness between our results and those reported in clinical trials, including patient factors and the availability of other potent treatments, might lead to improved clinical decision‐making in the future and translate into better real‐world outcomes. Further studies are required to elucidate strategies for optimizing carfilzomib use in the real world and closing the efficacy‐effectiveness gap.Arleigh McCurdy, Alissa Visram, Martha Louzada, Christopher P. Venner, Esther Masih‐Khan, and Donna Reece designed research, performed research, collected, analyzed, interpreted data, and wrote the manuscript. Moustafa Kardjadj performed statistical analysis and interpreted data. All authors contributed to data collection, interpreted data, and reviewed the manuscript.Arleigh McCurdy: honoraria—BMS, Janssen, Amgen, Takeda, Sanofi, and GSK. Martha Louzada: honoraria—Janssen, BMS, Amgen, and Pfizer. Christopher P. Venner: honoraria—Janssen, Amgen, and Takeda; research funding—BMS and Amgen. Victor H. Jimenez‐Zepeda: honoraria—Janssen, Takeda, Merck, and BMS. Richard LeBlanc: membership on an entity's Board of Directors or advisory committees—BMS Canada, Janssen Inc., Amgen Canada, Takeda Canada, and Sanofi Canada. Michael Sebag: membership on an entity's Board of Directors or advisory committees—Janssen Inc., Amgen Canada, Takeda Canada, and BMS Canada. Kevin Song: research funding—BMS; honoraria—BMS, Janssen, Amgen, and Takeda. Darrell White: honoraria—Amgen, Antengene, BMS, Janssen, Karyopharm, Sanofi, and Takeda. Hira Mian: honoraria—BMS, Janssen, Amgen, Takeda, Sanofi, and GSK; awards—HHS Research Early Career Award from Hamilton Health Sciences Foundation; research funding—Janssen. Rami Kotb: research funding—Merck and Sanofi; ownership/share holder—Karyopharm; honoraria—BMS, Janssen, Takeda, Amgen, Sanofi, and Merck. Donna Reece: research funding—Otsuka, BMS, Janssen, Takeda, Merck, BMS, and Millennium; consultancy—BMS, Janssen, Amgen, Karyopharm, and Takeda; honoraria—BMS, Janssen, Amgen, Takeda, Sanofi, and GSK. All remaining authors have declared no financial or perceived conflicts of interest.The approval for this review was obtained from the Ottawa Hospital Research Ethics Board, Ottawa, Canada.All patients whose data are reported to the CMRG Database by participating centers have provided informed consent for use of their information for research purposes.


Early prediction for short-term prognosis is essential for the management of hepatitis B virus (HBV)-related acute-on-chronic liver failure (ACLF). In this study, we aim to establish a noninvasive model for predicting the 90-day mortality in patients with HBV–ACLF received glucocorticoid therapy.Two hundred and eighty patients with HBV–ACLF were enrolled from July 2010 to June 2022. All patients received routine medicine treatment and 204 of them received additional glucocorticoid treatment. Then, the patients who received glucocorticoid treatment were randomly divided into a training cohort and a validation cohort. An early prediction model for 90-day mortality of HBV–ACLF was established in the training cohort and then validated in the validation cohort.P < 0.01). In the training cohort, a noninvasive model was generated with hepatic encephalopathy grade, INR, total bilirubin, age and SIRS status, which was named HITAS score. It showed significantly better predictive value for 90-day mortality of HBV–ACLF than MELD score and Child–Turcotte–Pugh score in both the training cohort and validation cohort. Using the Kaplan–Meier analysis with cutoff points of 2.5 and 3.47, the HITAS score can classify HBV–ACLF patients into different groups with low, intermediate and high risk of death after glucocorticoid therapy.HBV–ACLF patients received glucocorticoid treatment showed significantly better survival that those not (We proposed a HITAS score, which was an early prediction model for the prognosis of HBV–ACLF. It might be used to identify HBV–ACLF patients with favorable responses to glucocorticoid treatment. Acute-on-chronic liver failure (ACLF) is a life-threatening clinical syndrome and occurs during an acute insult in the patients with chronic liver diseases, which is manifested as jaundice, coagulopathy, ascites as well as encephalopathy . In AsiaImmunologic imbalance plays a vital role in the pathogenesis of HBV–ACLF. In patients with HBV–ACLF, liver injury is mainly induced by cytotoxic T-lymphocyte mediated damage in HBV-infected hepatocytes . GlucocoIn previous studies, several efforts have been made to find out indicators for predicting the treatment efficacy of glucocorticoids in patients with ACLF. A previous study found that patients responding best to glucocorticoids treatment were those with a lower MELD score and hepatic encephalopathy (HE) grade but extremely high alanine aminotransferase (ALT) levels . Zhao etIn this study, we attempt to establish a noninvasive model for predicting the 90-day mortality in patients with HBV–ACLF received glucocorticoid therapy. The parameters that constructed the model should be easily obtained at most medical facilities. Meanwhile, the model should be able to stratify the death risks of HBV–ACLF patients received glucocorticoid treatment and find out the patients that are suitable to be treated with glucocorticoids.A total of 280 HBV–ACLF patients were enrolled from July 2010 to June 2022, at Qilu Hospital of Shandong University. HBV–ACLF was diagnosed according to the consensus recommendations of APASL: (1) the presence of serum hepatitis B surface antigen (HBsAg) for at least 6 months; (2) progressive jaundice ; (3) coagulopathy (INR ≥ 1.5 or prothrombin activity < 40%)  + 3.78 × loge[TBIL (mg/dl)] + 11.2 × loge(INR) + 6.43 ×  [herwise) .The start date of follow-up was the date of the diagnosis of HBV–ACLF. All the patients were followed up for 90 days and the outcomes  were recorded. The survival time was calculated from the date of the diagnosis to the date of death or the end of 90-day follow-up.t test and Mann–Whitney U test were used to compare quantitative variables. Chi-square test was used to compare categorical variables. In the training cohort, univariate cox proportional hazards regression analysis was performed to determine the association of demographic, biochemical, clinical parameters with 90-day mortality. Then, the variables with a P value of < 0.05 in the univariate regression analyses were introduced into a forward conditional stepwise cox proportional hazards regression to identify independent predictors. The conditional probabilities for stepwise entry and removal of a factor were 0.05 and 0.10, respectively. A prognostic index (PI = b1 × 1 + b2 × 2… + bnxn) was calculated.Quantitative variables were expressed as median . Categorical variables were expressed as number (percentage). The data were analyzed using SPSS 16.0 statistical software . Student’s P < 0.05 was considered to be statistically significant.The area under the receiver operating characteristic curve (AUC) was used to determine the predictive value of the prognostic index, MELD score and CTP score for 90-day mortality of HBV–ACLF. Sensitivity and specificity were used to identify the diagnostic accuracy. Survival curves were drawn with the Kaplan–Meier method and the statistical significances were determined by log-rank test. All statistical analyses were two sided. From July 2010 to June 2022, 361 patients with HBV–ACLF were screened at Qilu Hospital of Shandong University. Twenty-one patients with HBV–ACLF were excluded for co-infected with HAV, HCV or HEV. Nineteen patients were excluded for alcoholic hepatitis and 12 for autoimmune hepatitis. Twenty-three patients were excluded for hepatocellular carcinoma and 6 for incomplete clinical data. Finally, 280 patients were enrolled, among which 204 patients received additional glucocorticoid treatment . In the glucocorticoid treatment group, 3 patients in the training cohort and 4 patients in the validation cohort received liver transplantation (P = 0.17).In this study, there were 7 patients in the glucocorticoid treatment group and 5 patients in the routine treatment group received liver transplantation. No significant difference was observed between them (P = 0.19). Meanwhile, all the patients in this study received antiviral drugs. In the routine treatment group, 1 patient received lamivudine (LAM), 7 patients received adefovir dipivoxil (ADV), 30 patients received entecavir (ETV), 28 patients received tenofovir disoproxil fumarate (TDF) and 10 patients received tenofovir alafenamide fumarate (TAF). In the glucocorticoid treatment group, 4 patients received LAM, 19 patients received ADV, 89 patients received ETV, 65 patients received TDF and 27 patients received TAF. No significant difference was observed of the antiviral treatment strategy between the two groups (P = 0.94).In this study, there were 66 (32.35%) patients in the glucocorticoid treatment group and 31 (40.79%) patients in the routine treatment group received artificial liver support (Table Baseline characteristics of the patients received glucocorticoid treatment are shown in Table P = 0.01). The mean survival time was 66.39  days in the patients received additional glucocorticoid treatment and 55.53  days in those not. Patients received additional glucocorticoid treatment showed significantly better survival that those not , which was significantly lower than that of patients in the routine treatment group  and routine treatment group  before treatment , 60 days  and 90 days  after treatment .The incidence of newly onset infection in the glucocorticoid treatment group was 31.37% (64/204), which was higher than that in the routine treatment group . However, no significant difference was observed between them (P = 0.71). The incidence of HRS was 7.84% (16/204) in the glucocorticoid treatment group, whereas 10.53% (8/76) in the routine treatment group (P = 0.48). The incidence of electrolyte disturbance was 42.16% (86/204) in the glucocorticoid treatment group, whereas 39.47% (30/76) in the routine treatment group (P = 0.69).The incidence of UGIH was 9.31% (19/204) in the glucocorticoid treatment group, whereas 7.89% (6/76) in the routine treatment group (P = 0.002), TBIL (P < 0.001), ALB (P = 0.018), INR (P = 0.038), Cr (P = 0.013), HGB (P = 0.025), HE (P < 0.001), SIRS (P < 0.001) (Table P < 0.001), INR , TBIL , age  and SIRS  were identified to be independent predictors for 90-day mortality     Fig. A, the vaIn the training cohort, two cutoff points were chosen for HITAS score to predict the 90-day mortality in patients with HBV–ACLF received additional glucocorticoid treatment. A high cutoff point was chosen based on the ROC analysis of this model in the training cohort to provide a specificity of at least 85%. A low cutoff point was chosen to provide a sensitivity of at least 90% . FinallyUsing the cutoff points of 2.5 and 3.47, the HITAS score identified patients that have low (HITAS score ≤ 2.5), intermediate (2.5 < HITAS score ≤ 3.47), and high (HITAS score > 3.47) risks of death Table . In the P = 0.02) and CTP score . There was no significant difference between AUC of MELD score and CTP score (P = 0.50). In the validation cohort  and CTP score . No significant difference was found between AUC of MELD score and CTP score (P = 0.63). In the entire cohort  and CTP score . There was no significant difference between AUC of MELD score and CTP score (P = 0.40).In the training cohort Fig. A, the AUP < 0.01, respectively).After 90-day follow-up, the mortality was 55/136 40.44%) in the training cohort, 31/68 (45.59%) in the training cohort and 86/204 (42.16%) in the entire cohort. The mean survival time was 67.5  days in the training cohort, 64.16  days in the validation cohort and 66.39  days in the entire cohort. Then, we used Kaplan–Meier survival analyses to compare the survival probability in patients within the low-risk group, intermediate-risk group and high-risk group. As shown in Fig. 0.44% in Algorithm for the application of HITAS score to predict 90-day mortality of patients with HBV–ACLF received glucocorticoid treatment is presented in Fig. The short-term mortality of HBV–ACLF is extremely high. Until now, liver transplantation is still difficult to apply more widely in many countries due to the limitation of liver donors as well as the patients’ economic situation. Therefore, It is essential to develop more effective therapies for HBV–ACLF . In thisHBV induced liver failure is caused by an overwhelming immune response against HBV . GlucocoIn this study, HE was identified as an independent predictor for 90-day mortality in patients with HBV–ACLF received additional glucocorticoid treatment, which was consistent with several other studies. In a study performed by Romero-Gomez et al., HE was associated with a high mortality rate in a hospitalized cirrhotic patient and its presence added further to the mortality of patients with ACLF . In seveACLF is mainly manifested by jaundice and coagulopathy. TBIL and INR are important markers of hepatocellular necrosis. In this study, TBIL and INR were also included in the HITAS score. In a previous systematic review, a detailed analysis of 19 studies and 73 prognostic indicators also showed that TBIL, INR appeared to be promising candidates for predicting poor prognosis in patients with ACLF .SIRS and age were identified as independent risk factors in HITAS score. Glucocorticoids can suppress the host–immune response and promote the progression of severe infection. Therefore, it was reasonable that SIRS was associated with worse prognosis in patients with HBV–ACLF received additional glucocorticoid treatment. In a previous study, SIRS was found to be a major determinant of multiple organ failure and mortality in alcoholic hepatitis in the presence or absence of infections . Older pHITAS score is a model that can stratify the risks of death in patients with HBV–ACLF received glucocorticoid treatment. It may provide guidance for the clinical usage of glucocorticoids in HBV–ACLF. Meanwhile, the HITAS score was constructed by routine parameters  that could be easily obtained at admission. It is suitable to be applied in most medical facilities and allows a rapid identification of prognosis.However, this study also has several limitations. First, the HITAS score was constructed in a training group and then validated in an independent validation cohort. The sample size of the validation cohort was relatively small. Further validation of HITAS score in a large cohort and prospective multi-center study is essential prior to its clinical application. Second, we only obtained variables at admission to construct the model. The data collection at different time intervals might provide more valuable information. Thirdly, the study was performed in a Chinese population. Further validation is still needed prior to its application in other regions of the world.In conclusion, we constructed a non-invasive model to predict the 90-day mortality in patients with HBV–ACLF received glucocorticoid treatment. It can stratify the risks of death in patients with HBV–ACLF and might be used to identify HBV–ACLF patients with favorable responses to glucocorticoid treatment.


This study was conducted to examine the impact of sleep–wake problems on health-related quality of life of Japanese nursing college students. This cross-sectional study was conducted in 2019 on 150 third and fourth-year nursing college students from two locations in Japan. Insomnia severity was assessed using the Insomnia Severity Index (ISI) and health-related quality of life using the SF-8 questionnaire. The total sleep time (TST) was divided into 3 groups: < 6 h, 6–7 h (reference), and ≥ 7 h. The total ISI score was divided into 2 groups: ≥ 8 points and < 8 points (reference). Logistic regression analysis was performed to evaluate sleep–wake problems related to decline in mental health.The median mental health indicated in the SF-8 questionnaire was divided into two groups, and the factors causing decline in mental health were investigated. The odds ratios  for adjusted ISI ≥ 8 and TST on weekdays < 6 h was 6.51 (2.96–14.30) and 3.38 (1.40–8.17), respectively. Mental health status was significantly lower when ISI ≥ 8 and even lower when TST < 6 h.Insomnia and short sleep duration are associated with decreased mental health status in nursing college students. Many tended to lack sleep on weekdays. Sleep–wake problems identified while in university should be comprehensively dealt with. N = 4,531, average age 19.2 years) [N = 2,135, average age 22.2 years) [Sleep pattern among college students undergoes changes as part of their physiological development leading to adulthood. The power of slow-wave sleep decreases after puberty, around the age of 12 years . For a wIn addition to changes in physiological sleep–wake cycle, college students are exposed to changes in their living environment and habits associated with becoming a university student. As such, subjective deterioration in sleep quality is as high as 50–60% . This caThe prevalence of insomnia in college students has been reported to be 22.1–38.6% , 17, 18.Many reports have shown that sleep–wake problems in college students are associated with depressive symptoms. Poor sleep quality , 20, eveIn order to examine the impact of sleep–wake problems on health-related quality of life (HRQOL) of Japanese nursing college students, we evaluated the relationship between subjective sleep quality, severity of insomnia, chronotype, and HRQOL among third- and fourth-year students enrolled in nursing colleges.A total of 212 third-year students and 216 fourth-year students from 2 nursing colleges in Japan were invited to participate in the study. This survey was conducted from November to December 2019. The participants accessed the Google Form from the QR code in the manual using their smartphone and answered the questionnaire online. This study was reviewed by the author's belonging university and was carried out after obtaining permission (permission number: 19091203–2). The research plan was explained verbally using the instruction manual, and those from whom consent could be obtained were selected as the study participants.Regarding participants’ background, we surveyed their age, sex, living arrangement , exercise habits, drinking habits, smoking status , breakfast, night time meals after dinner until bedtime as well as use of mobile devices during bedtime. Habitual drinkers were defined as those who drink at least thrice a week. Those with exercise habits were defined as people who exercise at least twice a week. Based on the respondent’s answer to the question “Are you a morning or an evening person?” the participants were divided into four groups: 1. definite morning type, 2. moderate morning type, 3. moderate evening type, and 4. definite evening type. Subjective sleep quality, insomnia severity, and HRQOL was assessed using the questionnaire.Subjective sleep quality was assessed using the PSQI, which has 9 items. This questionnaire consists of seven subscales . Each subscale is scored based on a 4-point scale . The total score ranges from 0 to 21 points, with higher scores indicating more impaired sleep. The cutoff score, which indicates the pathological level, is 6 points . The percentage of those with ≥ 2 points on each subscale and the percentage of those with total scores of ≥ 6 points were calculated. In this study, we asked questions about bedtime, wake time, and sleep onset latency by dividing them into weekdays and weekends. The time in bed (TIB), total sleep time (TST), and sleep efficiency were calculated from the time and time information. The TST was divided into 3 groups of < 6 h, 6–7 h, and ≥ 7 h. Catch-up sleep was calculated from TST on weekends and weekdays: Catch-up sleep = Holiday TST – Weekday TST. The percentage of those who had catch-up sleep of ≥ 2 h was also calculated.The severity of insomnia was assessed using ISI, which has 7 items. The global score of this index ranges from 0 to 28 points, with higher scores indicating greater insomnia severity . The totHRQOL was evaluated using the SF-8 questionnaire, which has 11 items. Eight subscales , bodily pain, general health perception, vitality, social functioning, role limitations due to poor emotional health , and mental health) were scored based on the 2007 national standard values. The national standard value was set to 50 points, and the standard deviation was set to 10 points . Two sumρ. Fisher's exact test was used to test the independence of nominal variables. The significance probability was 0.05.Statistical processing was performed using R version 4.1.2 and EZR version 1.55 . The conTo clarify the factors related to sleep and wakefulness that affect the decrease in MCS of SF-8, logistic regression analysis was performed by dividing the subjects into two groups by the median MCS. A univariate analysis was performed to determine the odds ratio  adjusted for sex, year level, smoking habits, and habitual drinking from the following items that were significant in the univariate analysis: weekday sleep time , ≥ 7 h), and insomnia severity (ISI ≥ 8 vs. ISI < 8 (ref)).P < 0.001).Consent was obtained from 150 out of 428 students (35.0%). There were 142 women (94.7%) with a median age (IQR) of 22 (21–22) years. There were 72 (48%) participants with PSQI ≥ 6, all of whom were female. The definite evening type was 43 (28.7%) and the moderate evening type was 57 (38.0%). The number of people with ISI ≥ 8 or ISI ≥ 10 was 43 (28.7%) and 23 (15.3%), respectively. Twenty-seven (18.0%) had difficulty initiating sleep, difficulty maintaining sleep, or early-morning awakening. Late sleep and late waking-up tendencies were evident on weekends, and 60 (40%) of them slept for more than 2 h longer than weekdays on weekends , and factors that affected MCS decline were examined. When adjusted by sex, year level, smoking habits, and habitual drinking, ISI ≥ 8 and TST < 6 h on weekdays were significant related factors Table .Table 4LA survey of third and fourth-year students in nursing colleges revealed that insomnia and short sleep time were associated with mental health decline. The coexistence of insomnia and short sleep caused the most significant decrease in mental health. In general, insomnia patients with short sleep time of < 6 h are the insomnia subtype with the most problems . In thisMost study participants had longer sleep hours on weekends than weekdays, and about half of them slept ≥ 2 h longer on weekends. This catch-up sleep was not associated with a decrease in HRQOL. Catch-up sleep has been reported to be associated with good HRQOL in adults, decreased body mass index, low risk of metabolic syndrome, and low risk of depression –33. BaseProlonged sleep time for a longer period of time has been reported to reduce daytime sleepiness, improve mental symptoms, such as depressive symptoms; and improve the athletic performance of college athletes –36. FurtThis study needs to consider the following limitations. First, as parameters like sleep time are evaluated by subjective time, it would be desirable to conduct objective measurement. The aforementioned insomnia subtypes also reveal the problem of short sleep insomnia based on objective sleep time , 38–40. If insomnia is accompanied by short sleep duration, it is presumed to be a group that requires intervention, which may cause problems not only in schoolwork, but also in subsequent employment. If it is a relatively mild problem, it may be possible to address the issue by student education, including sleep hygiene guidance and self-care advice based on screening results. However, it is assumed that the group with insomnia and short sleep duration will require medical treatment because they are part of a more serious group, which requires consultation recommendations, among other measures. In insomniacs with short sleep duration, the above-mentioned prolongation of sleep duration may cause insomnia symptoms to manifest. They require an approach that includes cognitive-behavioral therapy for insomnia.Insomnia and short sleep duration were found to be associated with decreased mental health among nursing college students. Additionally, many students tended to lack sleep on weekdays. It is required to comprehensively address various sleep–wake problems identified while in university.


Upregulation of hepatic delta‐aminolevulinic acid synthase 1 with accumulation of potentially toxic heme precursors delta‐aminolevulinic acid and porphobilinogen is fundamental to the pathogenesis of acute hepatic porphyria. Aims: evaluate long‐term efficacy and safety of givosiran in acute hepatic porphyria.Interim analysis of ongoing ENVISION study (NCT03338816), after all active patients completed their Month 24 visit. Patients with acute hepatic porphyria (≥12 years) with recurrent attacks received givosiran (2.5 mg/kg monthly) (n = 48) or placebo (n = 46) for 6 months (double‐blind period); 93 received givosiran (2.5 mg or 1.25 mg/kg monthly) in the open‐label extension . Endpoints included annualized attack rate, urinary delta‐aminolevulinic acid and porphobilinogen levels, hemin use, daily worst pain, quality of life, and adverse events.Patients receiving continuous givosiran had sustained annualized attack rate reduction ; in placebo crossover patients, median annualized attack rate decreased from 10.7 to 1.4. Median annualized days of hemin use were 0.0 (double‐blind period) and 0.0 (open‐label extension) for continuous givosiran patients and reduced from 14.98 to 0.71 for placebo crossover patients. Long‐term givosiran led to sustained lowering of delta‐aminolevulinic acid and porphobilinogen and improvements in daily worst pain and quality of life. Safety findings were consistent with the double‐blind period.Long‐term givosiran has an acceptable safety profile and significantly benefits acute hepatic porphyria patients with recurrent attacks by reducing attack frequency, hemin use, and severity of daily worst pain while improving quality of life.  AARannualized attack rateAEadverse eventAHPacute hepatic porphyriaAIPacute intermittent porphyriaALAdelta‐aminolevulinic acidALAS1delta‐aminolevulinic acid synthase 1ALTalanine aminotransferaseCKDchronic kidney diseaseCrcreatinineDBdouble‐blindeGFRestimated glomerular filtration rateEQ‐5DEuroQOL‐5 DimensionEQ‐VASEuroQol‐visual analog scaleEVGFPExcellent, Very Good, Good, Fair, PoorGivogivosiranHCPhereditary coproporphyriaISRinjection‐site reactionIVintravenousMCSMental Component SummaryMedDRAMedical Dictionary for Regulatory ActivitiesmRNAmessenger RNAOLEopen‐label extensionPBGporphobilinogenPBOplaceboPCSPhysical Component SummaryPGICPatient Global Impression of ChangePPEQPorphyria Patient Experience QuestionnaireQMonce monthlyQOLquality of lifeSAEserious adverse eventSF‐12v212‐Item Short Form Health Survey Version 2SMQstandardized MedDRA queryULNupper limit of normalVPvariegate porphyriaAcute hepatic porphyria is a rare genetic disease that involves potentially life‐threatening acute attacks and, for some patients, persistent symptoms impacting their ability to perform daily activities. In this evaluation of information compiled from the ongoing ENVISION study, long‐term givosiran treatment benefited acute hepatic porphyria patients with repeated attacks by reducing the number of attacks, hemin use, and daily pain while improving quality of life. Long‐term givosiran use is safe and effective for patients with acute hepatic porphyria who experience repeated attacks.After a 6‐month double‐blind period, 93 patients with acute hepatic porphyria and recurrent attacks received givosiran in the 30‐month open‐label extension period ; data from the 24‐month interim analysis are reported here.Continuous givosiran patients had sustained annualized attack rate reduction; in placebo crossover patients, median annualized attack rate decreased from 10.7 (double‐blind period) to 1.4 (open‐label extension period).Long‐term givosiran treatment led to sustained lowering of delta‐aminolevulinic acid and porphobilinogen and improvements in daily worst pain and patient‐reported assessments of quality of life.Long‐term givosiran treatment was well tolerated.1Acute hepatic porphyria (AHP) is a family of four rare genetic diseases characterized by potentially life‐threatening acute attacks and, for some patients, chronic manifestations impacting daily functioning and quality of life (QOL).The most severe symptoms of AHP occur during acute neurovisceral attacks, which manifest most commonly as severe abdominal pain, nausea, vomiting, tachycardia, hypertension, hyponatraemia, mental status changes, muscle weakness, and change in urine colour to red/brown.Prior to the approval of givosiran, treatment options were limited, and disease management focused on avoidance of attack triggers and use of intravenous (IV) glucose or hemin for attacks.Givosiran is a subcutaneously administered RNA interference therapeutic approved for the treatment of AHP in adults ,Givosiran treatment for 6 months during the double‐blind period of the randomized, placebo‐controlled, phase 3 study in 94 patients with AHP and recurrent attacks (ENVISION) led to reductions in porphyria attack rate, hemin usage, ALA and PBG levels, and daily worst pain compared with placebo.22.1ENVISION (NCT03338816) is a 36‐month study evaluating the efficacy and safety of givosiran in patients with AHP: a 6‐month, double‐blind, randomized, placebo‐controlled period,Patients entering the 30‐month OLE received subcutaneous givosiran 2.5 or 1.25 mg/kg monthly through Month 12 Figure . The low2.2Medical Dictionary for Regulatory Activities Version 23.0.Efficacy assessments including AAR of composite porphyria attacks , annualized days of hemin use, and urinary levels of ALA and PBG were collected throughout the study. Patient‐reported outcomes included daily worst pain, fatigue, and nausea Figure ,33, 32.3This 24‐month interim analysis was conducted using data with a cutoff date of June 24, 2020, when all active study patients had completed their Month 24 visit. Efficacy and patient‐reported outcomes were analysed according to whether patients received givosiran in the double‐blind period before receiving givosiran in the OLE (continuous givosiran group) or received placebo in the double‐blind period and crossed over to givosiran in the OLE (placebo crossover group). Analyses of efficacy outcomes were descriptive. Safety assessments were analysed in all patients who received at least one dose of givosiran; cumulative safety data from first dose of givosiran through June 24, 2020 were reported.33.1Of 94 patients enrolled in the double‐blind period, 89 had AIP, two had VP, one had HCP, and two had AHP without identified mutations. Of the 48 patients randomized to receive givosiran in the double‐blind period, 47 entered the OLE (continuous givosiran group). One patient with VP did not enter the OLE due to abnormal liver function tests and treatment discontinuation (discussed in Safety section). All 46 patients randomized to receive placebo in the double‐blind period entered the OLE and began givosiran treatment (placebo crossover group). In the OLE, 37 patients received givosiran 1.25 mg/kg monthly (n = 20 in the continuous givosiran group and n = 17 in the placebo crossover group), and 56 patients received givosiran 2.5 mg/kg monthly (n = 27 in the continuous givosiran group and n = 29 in the placebo crossover group). Of the 37 patients who initially received 1.25 mg/kg monthly in the OLE, 18 experienced inadequate disease control (n = 9 in the continuous givosiran group and n = 9 in the placebo crossover group) and received 2.5 mg/kg at or after the Month 13 visit. All patients remaining on the lower dose received 2.5 mg/kg following a subsequent protocol amendment  Figure . ContinuAt data cutoff, 10 patients had discontinued treatment and 7 patients had withdrawn from the study Figure ; overallAs of June 24, 2020, overall median exposure to givosiran was 22.2  months (1 month = 30.44 days), with a cumulative exposure of 164.0 person‐years. A total of 89, 87, 75, 28, and 2 patients received givosiran for ≥6, ≥12, ≥18, ≥24, and ≥30 months, respectively.3.23.2.1Long‐term treatment with givosiran led to sustained AAR reduction Figure . PatientLong‐term givosiran treatment was associated with a sustained reduction in hemin use Figure . In the 3.2.2Patients in the continuous givosiran group reported a further decrease in daily worst pain during the OLE . Placebo crossover patients also reported a decrease in daily worst pain in the OLE compared with the double‐blind period (median changes from baseline score of 3.50 in daily worst pain were +0.10 in the double‐blind period and −0.54 in the OLE). Decreases in the number of patients (67% vs 83%) and median proportion of days (5.7 vs 8.5) with opioid use were reported in the placebo crossover group during the OLE compared with the double‐blind period. No changes were observed in patient‐reported scores for fatigue and nausea.At Month 24, patients with long‐term treatment with givosiran showed further improvement in physical and mental health, as assessed by the SF‐12 Physical Component Summary (PCS), Mental Component Summary (MCS), and individual domain scores, all of which increased compared with Month 6 in both the continuous givosiran and placebo crossover groups  patients; the majority of events were mild or moderate in severity. Severe AEs were reported in 27 (29%) patients. The most frequently reported AEs (in ≥10% of patients) were injection‐site reaction (ISR), nausea, fatigue, nasopharyngitis, and headache  patients reported serious AEs (SAEs) during the study; SAEs reported in >1 patient were blood homocysteine increased, CKD, device breakage, pyrexia, and urinary tract infection  Table . Three pHepatic AEs were reported in 17 (18%) patients; all were mild or moderate in severity, the majority being serum aminotransferase elevations. A total of 10 patients (11%) had alanine aminotransferase (ALT) levels more than 3 times the upper limit of normal (ULN), of whom 3 patients (3%) had ALT levels more than 5 times ULN. One patient with ALT greater than 8 times the ULN, reported as an SAE of liver function test abnormal, discontinued treatment (due to a protocol‐defined stopping rule) and withdrew from the study at the end of the double‐blind period. The ALT elevations generally occurred approximately 3 to 6 months after givosiran was started, and then resolved subsequently Figure . No patiTwenty‐one patients (22%) reported renal AEs, which were mostly increased creatinine and/or decreased estimated glomerular filtration rate (eGFR); most events were mild or moderate in severity and none led to treatment discontinuation. Small decreases in eGFR observed early in therapy stabilized over Months 12 to 24 Figure . Some paISRs occurred in 37% of patients and 6% of the 2152 doses of givosiran given; all ISRs were mild or moderate in severity, and none led to discontinuation. The most common symptoms of ISRs included erythema, pruritus, rash, pain, and swelling at the injection site.On laboratory evaluation, there have been no notable changes in haematology parameters related to givosiran. Mean values for lipase and amylase have remained generally stable during the study; however, intermittent elevations of lipase and amylase have been observed in some patients. The proportion of patients with shifts in lipase and amylase were comparable between the placebo and givosiran groups during the double‐blind period, without any imbalances.4Disease burden is substantial and treatment options are limited for patients with AHP who experience recurrent attacks and chronic symptoms between attacks.Consistent with the results from the double‐blind period, this 24‐month interim analysis of the ENVISION study confirms that long‐term givosiran dosing leads to continuous and sustained reductions in AAR and hemin use, with 83% and 76% of patients being attack‐free , and 68% and 49% of patients, respectively, not requiring supplemental hemin. Lower opioid use occurred against a background of patient‐reported reduced daily worst pain (12‐month data). Long‐term givosiran dosing resulted in improvements in several patient‐reported outcomes, including physical functioning, activities of daily living, and overall health status assessment scores. The SF‐12 PCS score increased by 8.9 points in the continuous givosiran group and 10.0 points in placebo crossover patients in the OLE. In other chronic diseases, a ≥2‐ to 5‐point increase is considered a clinically meaningful improvement.During the OLE period, the protocol was amended to assess the efficacy and safety of a lower dose of givosiran (1.25 mg/kg). Results demonstrated a trend toward greater reductions in AAR, urinary ALA and PBG levels, and hemin use in placebo crossover patients treated with givosiran 2.5 mg/kg once monthly, compared with those treated with givosiran 1.25 mg/kg once monthly . Consistent with this observation, approximately half of the patients assigned to the 1.25 mg/kg dosing regimen (including those in the placebo crossover group and the continuous givosiran group) had inadequate disease control and required dose escalation to 2.5 mg/kg. Both dosing regimens had acceptable safety profiles. Thus, the recommended dosing regimen for givosiran is 2.5 mg/kg once monthly.2) at baseline. During treatment with givosiran, small (mostly reversible) decreases in eGFR were observed early in therapy and generally stabilized by Months 12 to 24. Renal function should be monitored during givosiran treatment, as clinically indicated.The key safety findings of this 24‐month interim analysis were consistent with those observed during the 6‐month double‐blind periodElevations of blood homocysteine have been reported in patients with AHP, with a correlation of higher levels in those with greater disease activity.The study is limited by the relatively small number of patients in the study population. However, the ongoing ENVISION study is the largest intervention study to date for this rare disease.The 24‐month data from this phase 3 study show that long‐term dosing with givosiran is well tolerated and provides sustained and continuous benefit to patients with AHP, as reflected by a durable reduction in frequency of attacks, hemin use to treat attacks, levels of toxic heme intermediates ALA and PBG, daily pain, and opioid use. Givosiran treatment was also associated with improvement in assessments of physical functioning and QOL.The study was approved by central and local institutional review boards or ethics committees and was conducted in accordance with Good Clinical Practice guidelines and the provisions of the Declaration of Helsinki.Dr Ventura reported receiving advisory board fees and lecture fees from Alnylam Pharmaceuticals and advisory board fees from Recordati Rare Diseases. Dr Bonkovsky reported receiving grant support and financial support, paid to Wake Forest University School of Medicine, from Alnylam Pharmaceuticals, Gilead Sciences, and Mitsubishi Tanabe, NA; consulting fees from Alnylam Pharmaceuticals, Disc Medicine, Eiger Biopharmaceuticals, Protagonist Therapeutics, and Recordati Rare Diseases. Dr Gouya reported receiving travel support and financial support from Alnylam Pharmaceuticals. Dr Aguilera‐Peiró reported receiving advisory board fees from Alnylam Pharmaceuticals. Dr Bissell reported receiving financial support, paid to University of California, San Francisco, from Alnylam Pharmaceuticals. Dr Stein reported receiving consulting fees, registration reimbursement, and financial support, paid to King's College Hospital, from Alnylam Pharmaceuticals. Dr Balwani reported receiving grant support, consulting fees, advisory board fees, and lecture fees from Alnylam Pharmaceuticals, advisory board fees from Recordati Rare Diseases, grant support and advisory board fees from Mitsubishi Tanabe, and advisory board fees from Alexion, Genzyme/Sanofi, and Takeda. In addition, Mount Sinai faculty are named Co‐Inventors with Alnylam on a patent related to the development of givosiran, the study drug. The Icahn School of Medicine at Mount Sinai receives payments related to this patent from Alnylam, and a portion of these payments are also distributed to faculty and other co‐inventors. Dr Anderson reported receiving grant support and consulting fees from Alnylam Pharmaceuticals, Recordati Rare Diseases, and Mitsubishi Tanabe, and consulting fees from Moderna Therapeutics. Dr Parker reported receiving financial support, paid to University of Utah, from Alnylam Pharmaceuticals. Dr Kuter reported receiving grant support and consulting fees from Actelion (Syntimmune), Agios, Alnylam Pharmaceuticals, Amgen, Argenx, Bristol Myers Squibb, Protalix, Rigel, and Takeda (Bioverativ), grant support from Kezar and Principia, and consulting fees from Caremark, Daiichi Sankyo, Dova, Kyowa‐Kirin, Merck Sharp Dohme, Momenta, Novartis, Pfizer, Platelet Disorder Support Association, Principia, Protalix, Sanofi, Genzyme, Shionogi, Shire, UCB, Up‐To‐Date, and Zafgen. Dr Monroy reported receiving advisory board fees from Alnylam Pharmaceuticals. Dr Oh reported lecture fees from Merck, Pfizer, and Genzyme. Dr Ritchie reported receiving consulting fees, paid to the University of Alberta from Alnylam, Takeda, CSL Behring, and BioCryst, and grant support from CSL Behring and OctaPharma. Drs. Ko, Hua, and Sweetser reported being employed by and owning stock and stock options in Alnylam Pharmaceuticals. Dr Sardh reported receiving grant support and personal fees, paid to Karolinska Institutet, from Alnylam Pharmaceuticals.All authors had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: Anderson, Balwani, Bissell, Bonkovsky, Gouya, Sardh. Acquisition, analysis, or interpretation of data: All authors. Drafting of the manuscript: Ko, Hua. Critical revision of the manuscript for important intellectual content: All authors. Statistical analysis: Hua. Supervision: Sardh, Ventura.Joseph Bloomer, MD , Daphne Vassiliou, MD, PhD , Elisabeth Minder, MD , John Phillips, PhD , David Rees, MD , Ashwani Singal, MD  and Bruce Wang, MD  also contributed to the design and concept of the study. Editorial assistance was provided by Jennifer LS Willoughby (PhD) of Alnylam Pharmaceuticals, Cambridge, MA, USA. Medical writing services were provided by Colette Szarka (MPhil) of Adelphi Communications Ltd, Macclesfield, UK, and by Michael Morren  of Peloton Advantage, LLC, an OPEN Health company, Parsippany, NJ, USA, in accordance with Good Publication Practice (GPP3) guidelines, and were funded by Alnylam Pharmaceuticals, Cambridge, MA, USA.ClinicalTrials.gov, NCT03338816.All patients provided written informed consent.Supplementary MaterialClick here for additional data file.


The literature provides some evidence of peripheral airways key role in the pathogenesis of asthma. However, the extent to which lung periphery including acinar zone contribute to asthma activity and control in pediatric population is unclear. Therefore, the aim of the study was to estimate peripheral airways involvement in children with asthma exacerbation and stable asthma simultaneously via different pulmonary function tests.n = 20) and stable asthma (n = 22) performed spirometry, body plethysmography, exhaled nitric oxide, impulse oscillometry (IOS), and multiple‐breath washout (MBW).Children with asthma exacerbation (Peripheral airway's function indexes were increased in children with asthma, particularly in group with asthma exacerbation when compared with stable asthma group. The prevalence of abnormal results was significantly higher in asthma exacerbation. All children with asthma exacerbation had conductive ventilation inhomogeneity; 76% had acinar ventilation inhomogeneity. According to IOS measurements, resistance and reactance were within normal range, but other IOS parameters were significantly higher in children with asthma exacerbation compared with stable asthma group. The 36% of children with acute asthma had air trapping.Significant involvement of peripheral airways was observed in children with asthma, particularly in asthma exacerbation, which determine lung periphery as important additional target for therapy and provide new insights into pathophysiological process of pediatric asthma. The stable asthmatic group was recruited from outpatient clinic, and the acute asthmatic group from patients admitted to the hospital because of exacerbation. The study involved only children who were able to perform lung function tests, whose parents/caregivers signed informed consent for participation.The asthma diagnosis and severity assessment were based on Global Initiative for Asthma (GINA) guidelines.The exclusion criteria included diagnosis of other chronic pulmonary disease, congenital lung malformation, history of prematurity, low birth weight, need for mechanical ventilation in neonatal period, or diagnosis of bronchopulmonary dysplasia. In those who underwent chest radiography, presence of consolidation or hilar adenopathy was considered as a reason for exclusion.Children were assigned to the stable asthma group if they had reported no exacerbations or changes in symptoms/medication use for at least 6 weeks before visit and they had ACT or cACT score of more than 20.Asthma exacerbation was defined as an acute or subacute episode of progressive worsening in symptoms .2.1All patients underwent pulmonary function tests including spirometry, body plethysmography, IOS, N2MBW test, and fractional exhaled nitric oxide (FeNO) measurement. All procedures were performed in agreement with the American Thoracic Society/European Respiratory Society (ATS/ERS) recommendations.Spirometry and IOS were performed using the Vyntus IOS , body plethysmography using the Master Screen Body (CareFusion), N2MBW using the Exhalyzer®DN2 MBW device , and FeNO with NOA 280i .The following parameters were recorded:Spirometry: forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), and forced expiratory volume in 1 s to forced vital capacity ratio (FEV1/FVC ratio).Body plethysmography: specific airway resistance (sReff), total lung capacity (TLC), RV, and RV/TLC ratio.IOS: resistance at 5 Hz (R5) and resistance at 20 Hz (R20), frequency dependence of resistance (R5–R20), reactance at 5 Hz (X5), area under the reactance curve (AX), and resonance frequency (Fres).N2MBW: lung clearance index (LCI) at 2.5% of the initial concentration of N2, conductive ventilation inhomogeneity (Scond), and acinar ventilation inhomogeneity (Sacin).z‐scores. The exceptions were FeNO, R5–R20, and AX, which were presented only as absolute values due to lack of the reference equations. Global Lung Function Initiative 2012 and Dencker and Berdel/Lechtenboerger reference values were used. For N2MBW, values provided by the manufacturer were applied. The abnormal results were defined as z‐score values outside of −1.65 to 1.65.All measured parameters were presented as 2.2Statistical analysis was performed with the Statistica 12 software package . Data are presented as median and interquartile range.U‐tests for interval variables and χ2 test was used to compare proportions. Possible relationships between different variables were evaluated using Spearman's rank correlation test. The two‐tailed significance level was set at p < 0.05.Because several lung function variables did not show normal distribution, non‐parametric tests were used. Comparison between groups and subgroups were performed using Mann–Whitney's 33.1Forty‐two children divided into two subgroups (20 with asthma exacerbation and 22 with stable asthma) aged 6–17 years (median 12.5 years) were included. Patients' characteristics are shown in Table 3.2z‐score) in stable versus exacerbation asthma group.In asthma exacerbation group, 70% of FEV1 were abnormal and in stable asthma group, the percentages were 9% Table . There wBody plethysmography showed significantly higher specific resistance in asthma exacerbation group Table . The abnz‐scores of Fres were significantly higher in asthma exacerbation group when compared with stable asthma group. However, the median z‐score of Fres, as well as median z‐scores of X5 and R5 were within normal range either in children with stable asthma or asthma exacerbation.There were also significantly increased some IOS variables reflecting peripheral airways function, that is, R5–R20, Fres, and AX  in patients with stable asthma. In contrast, all patients with asthma exacerbation had abnormal Scond values and vast majority (76%) of patients had abnormal Sacin values.All MBW parameters, that is, LCI, Scond, and Sacin, were abnormally increased in asthma exacerbation group Table . The medThe median of exhaled NO values in children with asthma exacerbation was higher than in children with stable asthma, but the difference did not reach statistical significance.3.3To see possible relationship between standard lung function tests  and those reflecting peripheral airway function (IOS and N2MBW), various parameters were correlated. Detailed information of the correlations found between lung function parameters are shown in Table 3.4r‐Spearman 0.39, p = 0.01) and with AX  and Scond with AX  in whole study group.There was a weak positive correlation of LCI with R5–R20 . Any associations with other N2MBW parameters and IOS measurements were not confirmed.Positive correlation between GINA scores and LCI was confirmed . The authors hereby confirm that all children and their caregivers gave their informed consent prior to their inclusion in the study.