Pediatric tibial fractures have been described internationally as mainly caused by fall during leisure activities and organized sports and showing a higher incidence in boys. Still, most studies are single center studies or have a small sample size. This study aimed to analyze sex and age distribution, seasonal variation, injury mechanisms and treatment of pediatric tibial fractures based on the nationwide Swedish Fracture Register (SFR).All tibial fractures in patients < 16 years at injury and registered in 2015–2019 were extracted from the SFR. We analyzed patient characteristics such as sex and age, injury mechanism, fracture location and treatment.The study cohort consisted of 5828 pediatric tibial fractures in 5719 patients. Median age of the patients was 7 years and 58% were boys. Shaft fractures were most common, followed by the distal and proximal tibia. The lowest incidence was observed during autumn. The most common cause of injury was fall mostly involving winter sports, stumbles and fall from play equipment. Play/free time and sports were the most common activities, common places of injury were sports facility and home. 1% were open fractures. 78% were treated non-surgically. Screw fixation was performed in 52% of surgically treated fractures, predominantly in the distal segment.Injury mechanism differs between age groups; play/free time injuries are common in younger children compared with sport activities in older children. Most patients are treated non-surgically. Open fractures are rare. Information on injury patterns is useful working preventively, for example safety work in playgrounds. Internationally, tibial fractures account for about 15% of the long-bone fractures in children and adolescents , 3 durinInternational studies are often single center studies with smaller study groups or focus on specific types of tibia fractures showing variations in the overall fracture risk and fractures of the tibia . The exiWhat are common population characteristics, fracture locations and injury mechanisms for pediatric tibial fractures in Sweden?Is there a seasonal variation in the incidence of tibial fractures in Sweden?What is the most common treatment strategy in Sweden?Which type of treating physician mainly treats pediatric tibial fractures when surgical treatment is chosen?This study aimed to answer the following research questions:This is an observational study on the epidemiology of pediatric tibial fractures in Sweden. The study is based on data extracted from the Swedish Fracture Register (SFR). The SFR is a nationwide quality register established in 2011 where treating physicians register all fractures and accompanied information such as injury mechanism, patient characteristics (age and sex) and performed treatment. Patients with a fracture are individually registered through the SFR’s online platform after secure login . TogetheAll patients < 16 years at injury with a registered tibial fracture (ICD code S82.10/11/20/21/30/31) sustained between January 1 2015 and December 31 2019, including refractures. Refractures are defined as fracture with the same ICD-code and fracture site that occurred at least 7 days after the primary registered fracture.This study analyzes sex, age, fracture localization , injury mechanism , injury type (high or low energy trauma), open or closed fracture, injury season, performed primary treatment and level of treating physician.The patients were divided in age groups, 0–3, 4–6, 7–9, 10–12 and 13–15 years, which has been used in previous epidemiologic fracture studies .In the SFR, fractures are classified both according to the AO-classification system and according to fracture localization/skeletal segment; proximal, diaphyseal (shaft) or distal. We have chosen to report our results divided by skeletal segment.Injury cause variables were divided in fall, transport accidents, exposure to living forces, exposures to mechanical forces and other. Subgroup variables with a frequency < 100 fractures were combined. The combined group “other fall” included fall from bed, tree, chair, building, cliff, ladder, wheelchair, scaffolding, diving, jumping or falling from height and fall when carried or supported. Under transport accidents, “other transport accident” included pedestrian, horse riding, tricycle, car, watercraft, funicular, bus, “other vehicle” and unspecified. Under living forces, “other living forces” were a combination of being hit or bitten by another person, squeezed by crowd, bitten by animal and other living forces. Under mechanical forces, “other mechanical forces” were a combination of being squeezed between objects, exposed to thrown or falling object, other objects and other machine. Lastly, “other” causes include stress fracture, spontaneous fracture, abuse, intentional self-destructive action, exposure to natural forces and other factors, primary tumor and other accident.Injury activity variables were divided in play/free time, sports and other specified. The activity group “other specified” was variables with low frequencies and include work, other and rest/hygiene/meal.Place variables were divided in sports facility, home, school/hospital/public premises and other specified. “Other specified” places include street, road, institutional housing, store area/service area, industrial area/construction and agricultural area.Regarding seasonal variation, months were divided in seasons; winter (Dec–Feb), spring (Mar–May), summer (Jun–Aug) and fall (Sep–Nov).Treatment is registered as surgical or non-surgical where surgical treatment includes all treatments under anesthesia. The surgical treatment is further specified in screw fixation, K-wire, intramedullary nail, external fixation, plate fixation, fixation with bio implant, extraction of implant, other fracture fixation/combined method and other surgery. Type of surgery method is also divided into primary, secondary, tertiary treatment.U tests as most of these were nonparametric. The level of significance was set at p < 0.05 in all analyses. Multivariable logistic regression models were used to calculate the risks for fracture location and surgery as the dependent variable in relation to age, sex and season of fracture occurrence and reported as Odds ratio (OR) with 95% confident interval (CI). The statistical analyses were calculated in R software (R version 4.0.5 (2021–03-31). The tables were created with IBM SPSS statistics (version 28.0.1.0).Continuous data were described using means, medians, ranges, and standard deviations, as appropriate, and differences between observed and expected counts of categorical data were investigated by the Chi-square test and Bonferroni post-hoc test. Continuous variables were analyzed using the Mann–Whitney Ethical approval from the Swedish Ethical Review Authority was obtained before the start of this study (D-nr 2019-04282).n = 109; 2%). Median age was 7 years  and 58% of all fractures occurred in boys (n = 3404). Girls were statistically significantly younger at fracture than boys, median age in girls 6 years , in boys 8 years . The age and sex distribution shows two incidence peaks around 2 and 13 years. A larger proportion of boys were seen in the oldest age group (74%) compared to the youngest (54%)  with simple falls as the most common cause of injury in all age groups. Winter sport activities  were the most common reasons for falling. Fall from play equipment and stumbles were most common causes of injury for the youngest age group Table . Sport aTransport accidents accounted for 11% of all injury causes. Transport accidents were more frequent in the oldest age group (Table The most common activity when sustaining a fracture was play and free time (43%) followed by sports (23%). Unspecified or missing data accounted for 33.3%. Play and free time decreased with higher age, whereas sports increased with age Table . Play/frSports facility was the most common place at time of injury (28%) followed by home (23%), school/hospital/public premises (8.4%) and street/road (1.7%). 37.7% were registered as other specified, unspecified or missing. The child’s own home was the most common place in younger ages and decreased with higher age while sports facility increased.Low energy trauma accounted for 74% of the fractures, 9% were high energy trauma. 17% were unknown or not applicable due to injury mechanism. High energy trauma frequency increased with age, 4% high energy trauma in the youngest age group, 11% in the middle age group and 19% in the oldest age group. 66% of all patients with high energy trauma were male. For low energy trauma, 57% of all patients were male. High energy trauma accounted for 10% of all distal fractures (202/2092), 9% of all shaft fractures (225/2586) and 8% of all proximal fractures (89/1150).n = 24), meaning high energy trauma with adequate soft tissue coverage. Remaining open fractures were Gustilo-Anderson type I (n = 7), type II (n = 15), type IIIb (n = 2), type IIIc (n = 3) or unknown (n = 12).1.1% of tibial fractures were open (63/5828). 1.8% of shaft fractures (47/2586) and 0.8% of distal tibia fractures (16/2092) were open. No proximal fractures were open. Gustilo-Anderson type IIIa was the most common open fracture type . Proximal tibia fractures showed no statistically significant seasonal variation. There was no seasonal variation in fracture frequency between sexes. The youngest age group had most fractures during summer and spring  were treated non-surgically of these, 77% were isolated tibia fractures. 19% were treated surgically of these, 48% were isolated tibia fractures and 3% had missing information on the treatment choice. When studying treatment options, the risk for surgery increased with increasing age , female sex , and two-bone engagement (tibia and fibula)  . Of these 288 fractures, 11% were proximal, 36% shaft fractures and 53% distal tibial fractures. For the remaining fractures receiving surgical treatment, screw fixation was most common (52%) followed by K-wire/cerclage fixation (14%) and intramedullary nail (14%). Divided in fracture locations, most distal fractures were treated with screw fixation (70%) followed by K-wire (16%). Most surgically treated shaft fractures were treated with intramedullary nail (66%) followed by external fixation (17%). For proximal fractures, most surgically treated fractures were treated with screw fixation (51%) followed by K-wire (17%). Screw fixation was the most common surgical treatment type in proximal and distal fractures, while intramedullary nail was most common in shaft fractures  in different European sites by Lyons et al. found lower fracture rates in the Scandinavian pediatric population . This diThis is to our knowledge the first nationwide population-based study on tibial fractures in children in Sweden based on data from SFR. The greatest strength of this study is the size of study population, with 5828 fractures included and the national design. However, as many register studies there are some sources of possible errors. At the start of the pediatric registration in 2015 36 of 54 orthopedic departments were active in the SFR. This increased to 49 at the end of 2019 (91% coverage). This stepwise introduction of the SFR makes it impossible to report on incidence rates with this study design. Completeness of the registrations is controlled annually by comparison with the National Patient Register. Completeness of pediatric tibia fractures was 42% in 2019 which is probably an underestimation as described by Bergdahl et al.  and haveThe fractures do not always have all variables registered, resulting in groups of “missing” or “unspecified.” Registrations are time-consuming and unspecified fracture causes or locations are probably partly due to human factors, for example if the treating physician forgot to ask or register when meeting the patient. Comparing the distribution of missing data we found no sex-differences, but more missing data were found in younger ages up to 8 years compared to 9 years and older. A slightly bigger proportion of missing data was seen for shaft fractures compared to proximal and distal fractures. A few more distal fractures had missing data on place of injury.Another limitation of this study is the risk of reporting bias. One hospital accounted for 17% of all fractures in the register, which is a large proportion of fractures for 1 out of 20 units. The county with the most fractures registered coincides with the clinic from which the Swedish fracture register originates . The SFRWith the risk of reporting bias in mind, further research is encouraged focused on how the possible reporting bias affect the results. An observational study comparing statistics in the National Patient Register in Sweden with the SFR could for example display how the unregistered fractures are distributed and if they contribute to a different result.This study provides epidemiological data on tibial fractures in children in Sweden. Characteristics and injury mechanisms vary depending on age. The younger child is often injured at home during play and free time because of a fall from play equipment or stumble, resulting in a shaft fracture. Adolescents are injured while participating in sports or because of a transport accident, resulting in a distal fracture. Seasonal variation differs from international studies, being more common in spring and winter in Sweden. Overall, male sex and fall at home or at sports facilities are predominant and fractures are mostly treated non-surgically. High-energy trauma and open fractures are rare. There are different areas where incidence peaks are observed, where preventive work could be of use. For example, safety work in ski slopes and playgrounds, and improving protective equipment in sports.


BCVA was significantly improved in both subgroups of closed PIMH . Minimum linear diameter (MLD) was closely related to the closure rate ; p = 0.03). MLD = 650 μm seemed like a cut-off point for closure rate . In conclusion, we demonstrated that extended ILM peeling combined with SiO or air tamponade is effective in PIMH treatment. Moreover, though not statistically significant herein, the anatomic closure rate was better for silicone-operated eyes than for air-operated eyes. MLD is the best predictor of PIMH closure; MLD ≤ 650 μm could achieve a significantly higher closure rate.Persistent idiopathic macular hole (PIMH), the occurrence of idiopathic macular holes that have failed to close after standard pars plana vitrectomy (PPV) with internal limiting membrane (ILM) peeling, has become a global health threat to the aging population. Because postoperative anatomic closure or restoration of visual acuity is more difficult to achieve in PIMH, surgical approaches that would yield the best outcomes remain to be elucidated. On paper, extended ILM peeling combined with silicone oil (SiO) tamponade is believed to be a feasible option for excellent macular hole closure. However, no studies on this combined treatment for PIMH is compared with simple air tamponade have been conducted. Thus, in this retrospective case series, we used spectral-domain optical coherence tomography (SD-OCT) and other technologies to investigate real-world evidence for the anatomical and functional outcomes of revisional PPV with either SiO or air tamponade for failed primary idiopathic macular hole surgery. We included the records of 76 patients with PIMH who had SD-OCT examinations and best-corrected visual acuity (BCVA). Regression analysis was performed to find factors affecting PIMH fracture closure. Seventy-six participants were allocated to a SiO group  or an air group . Anatomical success was achieved in 18 (85.7%) and 40 (72.7%) eyes in the SiO and air groups, respectively ( HoweTo increase the closure rate of PIMH, clinical researchers have focused more on completely relieving residual traction and prolonging effective tamponade to stimulate glial cell proliferation . Therefo2.PIMH refers to the occurrence of iMH that have failed to close after standard pars plana vitrectomy (PPV) with ILM peeling. All patients underwent small-gauge (25–27 gauge) PPV with retrobulbar anesthesia, which was performed by experienced ophthalmologist, under monitored anesthetic care. Patients were allocated to either the SiO or air group at the discretion of the treating surgeon. Normally, by clinical experience, patients with a poor degree of adaptability, monophthalmia, or a planned flight were advised to undergo SiO tamponade.2.1.This study was approved by the Institutional Review Board of Zhongshan Ophthalmic Center, which is affiliated with Sun Yat-sen University , and was performed in accordance with the World Medical Association’s Declaration of Helsinki. All extracted patient data were anonymized for analysis.2.2.The inclusion criteria were the availability of high-quality spectral-domain-optical coherence tomography  images pre-and postoperation and the presence of PIMH, as determined by SD-OCT.The exclusion criteria were as follows: (1) presence of anamnestic data of previous eye trauma, (2) high myopia , (3) rhegmatogenous retinal detachment with macular hole, (4) history of fundus disease, (5) low-quality SD-OCT image, which was defined as an image with no diameter measurement, (6) postoperative follow-up shorter than 4 months, (7) absence of comprehensive presurgery examination, and (8) glaucoma or other concurrent vision-limiting eye conditions were excluded.2.3.Baseline patient demographics include age, sex, ocular characteristics, mean preoperative minimum linear diameter (MLD) of the PIMH, and lens status . All patThe primary outcome was anatomical success defined on OCT. We noted all available OCT examination data at the following time intervals: prior to revision surgery, post-revision surgery, and finally, at the most recent follow-up visit. According to the Manchester large macular hole study in which iMH size was the linear width across the narrowest point of the hole, we defined large PIMH as PIMH with a MLD of larger than 650 μm, and those in the 400–650 μm quartile were graded as medium PIMH . We measUsing OCT images, we measured MLD, base diameter (BD), and height (H) to describe the anatomical characters of PIMHs . Hole clSecondary outcomes included functional BCVA and significant gain in BCVA. Snellen visual acuities were converted to the log of the minimum angle of resolution (logMAR) units for statistical analysis, and non-numeric values were changed as follows: count fingers = 1.7 Log MAR, hand movement = 2.0 LogMAR (20/2000 Snellen), light perception = 2.3 LogMAR, and no light perception = 3.0 LogMAR (20/20000 Snellen) . Signifi2.4.® Vision System; Alcon Laboratories, Fort Worth, TX, United States). In the SiO group, standard three-port PPV, followed by enlargement of the ILM peeling with adjunctive 0.125% indocyanine green staining, was performed by the same surgeon. Indocyanine green staining was performed to elucidate the extent of the original ILM peel. Care was taken as 25-gauge or 27-gauge forceps were used to ascertain the presence of residual perifoveal ILM or other additional membranes that required peeling. The fluid-air exchange was then repeated, with drainage of the preretinal fluid over the optic disc. Air was exchanged for SiO of 5,000 centistoke viscosity. Patients were instructed to maintain a face-down or prone position for 2 weeks postoperatively. Approximately 6 months after the surgery, the SiO was removed through a machine-independent method using a short infusion tube connected to a 10-mL syringe. Residual droplets of SiO were removed by using a flute needle to capture small oil bubbles in the vitreous cavity . All continuous variables conformed to the normal distribution and were expressed as descriptive statistics, including total numbers, means, standard deviations, and percentages. Descriptive statistics were used to calculate demographic data. Means with standard deviation were presented where relevant. Paired 3.3.1.We enrolled 76 patients (21 patients [21 eyes] who underwent extended ILM peeling with SiO tamponade and 55 patients [55 eyes] who underwent extended ILM peeling and air tamponade) from January 2016 to June 2022 at Zhongshan Ophthalmic Center. Average age, sex ratios, ocular characteristics, duration between the iMH and PIMH surgeries, and base lens status were balanced between the two groups. The clinical characteristics of the patients at baseline are shown in 3.2.In the SiO group, a total of 18 eyes of 21 patients (85.7%) achieved anatomical closure , with 16p = 0.002).We found that for all cases of MLD ≤650 μm, extended ILM peeling and SiO tamponade could produce stable anatomical closure success (100%). Further, when the MLD of PIMH was >650 μm, the success rate reduced notably 60.0%, . For bot3.3.p = 0.038 and p < 0.001), and the mean postoperative BCVA improved in the closed subgroup  (p = 0.03).Previous studies have documented that the time between iMH surgery and PIMH surgery influences the anatomical closure rate . We also = 0.54) . UnivariAnother structural feature of PIMH we studied based on OCT findings was the elevated edge of the PIMH at baseline . We note3.5.Overall, 19 eyes (90.5%) were phakic at baseline, with the remaining eyes having a history of cataract extraction, including intraocular lens implantation. Of the patients with phakic eyes, 16 patients (88.9%) underwent advanced cataract extraction, and a majority (93.8%) underwent SiO removal combined with cataract extraction within 1 year of the repeat surgery (mean 6.2 ± 1.3 months). One patient developed high intraocular pressure after SiO tamponade, which resolved after pharmacotherapy. No other adverse events, such as SiO emulsification or cystoid macular edema, were observed during the follow-up. Two patients in the SiO group experienced subretinal fluid accumulation during the follow-up period, but at the end of the follow-up period, the fluid level had decreased and visual acuity had improved in both patients. In the air group, one patient experienced retinal detachment 9 months after PIMH surgery. The details of three patients that did not achieve anatomical closure success are listed in 4.Failure of the primary surgery and persistent iMH is the most common complication of iMH surgery. Successful secondary closure of iMH is probably influenced by multiple factors. Several factors have been linked to the failure of primary iMH surgery, including residual traction from ILM, poor patient compliance with proper positioning, and size of iMH > 400 μm. Whether the choice of intraocular gas or SiO as a surgical tamponade in the second iMH surgery affects surgical success is unclear.We found notable facts: live retinal tissue studies have suggested that the retina is soft and actively mechanoresponsive, approximately 100 times more compliant than soft silicone rubber , 20. BroThe anatomic closure rate in our SiO group was 85.7%, similar to recently reported results in the literature. Conversely, the anatomic closure rate in our air group was 72.7%, which was worse than in a previous study , 23. We In our series, among all cases of anatomical closure, most cases of PIMH were associated with closure on the postoperation first day . Thus, we can hypothesize that SiO supplies strong tension for aggregating hole margins, and using SiO of 5.000 centistokes of viscosity may elucidate this phenomenon. Because closure detection is via OCT, we could not verify the closure rate in the air tamponade group on the postoperation first day. Therefore, closure speed could not be compared between the two groups.p = 0.010) at the final examination  at baseline was significantly improved to 0.65 logMAR  for the publication of any potentially identifiable images or data included in this article.YS: conceptualization. YS and LW: data curation. LF: formal analysis. LF and XH: methodology. YL: project administration. YS, YL, and DF: resources. DF: visualisation. YS: writing – original draft. YW, TZ, and SZ: writing – review & editing. All authors contributed to the article and approved the submitted version.This study was supported by grants Shenzhen Science and Technology Program (KCXFZ20211020163813019) and the Sanming Project of Medicine in Shenzhen (SZSM202011015).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.


Zm00001d026568 and Zm00001d026569 were highly associated with SNP 2376873-7-G and encoded pentatricopeptide repeat-containing protein and chloroplastic palmitoyl-acyl carrier protein thioesterase, respectively. As expected, higher expression levels of these two genes are associated with higher chlorophyll contents. These results provide a certain experimental basis for discovering the candidate genes of chlorophyll content and finally provide new insights for cultivating high-yield and excellent maize suitable for planting environment.Chlorophyll is an essential component that captures light energy to drive photosynthesis. Chlorophyll content can affect photosynthetic activity and thus yield. Therefore, mining candidate genes of chlorophyll content will help increase maize production. Here, we performed a genome-wide association study (GWAS) on chlorophyll content and its dynamic changes in 378 maize inbred lines with extensive natural variation. Our phenotypic assessment showed that chlorophyll content and its dynamic changes were natural variations with a moderate genetic level of 0.66/0.67. A total of 19 single-nucleotide polymorphisms (SNPs) were found associated with 76 candidate genes, of which one SNP, 2376873-7-G, co-localized in chlorophyll content and area under the chlorophyll content curve (AUCCC).  Zea mays L.) is an important source used for animal feed and bioenergy and has become the top crop produced in China, with production estimated up to 272.6 million tons (MT) in 2021 . High yield based on photosynthesis has always been the focus topic in crop breeding [Maize  of chlorophyll content in leaves of different populations of various crops from different angles and have made considerable progress ,17,18,19to aging . HoweverZmVPP1, and transgenic maize with enhanced ZmVPP1 expression exhibited improved drought tolerance. Sun et al. [As a research tool, GWAS have become a common way to study natural variation and inheritance of important agronomic traits in various plants . Maize hn et al.  identifin et al.  used GWAIn this study, 378 maize inbred lines and 96,726 SNPs were used for the GWAS of the chlorophyll content in two environments. The purpose of this study is to identify candidate genes of chlorophyll content. Our findings provide new insights for mining candidate genes of leaf chlorophyll content.An association panel comprising 378 diverse maize inbred lines from the northeast of China, temperate region in the United States and the International Maize and Wheat Improvement Center (CIMMYT), Mexico, were used for GWAS. All materials were kept in the College of Bioscience and Biotechnology, Shenyang Agricultural University.n is the number of assessment times, γ is the meter reading, i is the ith rating date, and t is time (in days).The 378 inbred lines were grown in Fushun City, Liaoning Province, China  in May 2017 (17FS) and Ledong city, Hainan Province, China  in November 2017 (17LD). The field experiment was designed as random blocks with 2 replicates. Fifteen plants were planted in a 2.5 m long row with 0.6 m row distance, and the planting density was approximately 45,000 plants/ha. The inbred lines were labeled before pollination for standard field management. Chlorophyll content was measured using a portable chlorophyll meter , which was non-destructive, fast and cheap. SPAD-502 readings were taken from five plants per plot on five dates at a 5 d interval starting 0 d after silking. There were three measurements in the middle of the ear leaf for each plant, and the average value was used for the statistical analysis. AUCCC was calculated based on SPAD-502 readings on all measure dates. Larger AUCCC values represent higher chlorophyll content, and lower AUCCC values represent lower chlorophyll content. The formula used to calculate AUCCC was modified from the AUCCC formula :AUCCC = l + rk(l) + fi + (fe)il + εlikyijk = μ+e, where yijk was the phenotypic value of the attenuation rate ijk in this test, μ denoted the average value of attenuation rate, el was the influence of two environments, rk(l) was the repeated effect in the environment, fl was the genetic effect of the ith family, (fe)il was the interaction between genetic and environmental effects, and εlik was a random error.The “PROC MIXED” program in SAS software was used to analyze the variance heritability of the phenotypic values at the two places. The mixed linear model (MLM) was used for the analysis, and the model 2 = σg2/(σg2 + σge2/e + σε2/re)h [2h represents the generalized heritability of the trait, 2σg is the genetic variance of the trait, 2σge represents the variance of the interaction between genetic and environmental effects, 2σε denotes the residual error, and e and r denote the number of environments and the number of repetitions of the trait in each environment. The total phenotype of the two trials was predicted and expressed by the best linear unbiased prediction (BLUP) value so as to minimize the environmental impact.The generalized heritability formula is:  σε2/re) , where hp value was calculated as 1/n , and we obtained p < 1.03 × 10−5 as significant nodes.The 96,726 SNPs (MAF ≥ 0.05) were used to conduct GWAS by combining the data from two genotyping platforms (RNA-seq and SNP array). The mixed linear model (MLM) calculation method was used to analyze the association of chlorophyll content in R 4.0.3, where population structure and kinship were fitted to control false positives ,33. We u2 < 0.2). The physical locations of significant SNPs were determined using the B73 RefGen v4 database. The annotated genes were searched within the 100 kb region around (50 kb upstream and 50 kb downstream) the detected significant SNP and were identified based on functional domains. The function of annotation genes referred to the MaizeGDB (https://maizegdb.org/), NCBI (https://www.ncbi.nlm.nih.gov/gene) and the homologous genes of Arabidopsis.The most significant SNP was selected to represent the locus associated with chlorophyll content in the same LD block  method [ZmTubulin1 (Zm00001d033850) was used as an internal control for data normalization. All data were measured in three independent biological replicates. The primers are listed in The SNP allele effect was analyzed using R 4.0.3, and leaves of 6 varieties  were selected during maize V4 stage. A leaf segment of 2 cm in length was excised from the middle of the fourth leaf and stored at −80 °C. The RNAprep Pure Plant Kit was used to extract the RNA (TIANGEN). cDNA was synthesized from 2 μg of total RNA using the FastKing RT Kit (TIANGEN). RT-qPCR reactions were performed using a Bio-Rad  real-time PCR system using the SuperReal PreMix Plue (SYBR Green) (TIANGEN). Transcript levels were analyzed using the comparative CT  were calculated between chlorophyll content of ear leaf and 10 agronomic traits, including hundred kernel weight (HKW), flowering time (FT), ear rows number (ERN), kernel number per row (KNR), ear length (EL), ear perimeter (EP), kernel length (KL), kernel width (KW), kernel thickness (KT) and kernel area (KA). As shown in p < 1.03 × 10−5 , chloroplastic palmitoyl-acyl carrier protein thioesterase and UDP-D-galacturonate, respectively , gradually increased after pollinating. AAP belongs to the amino acid/auxin permease family, which is involved in transportation of the principal nitrogen assimilates amino acid [AAP2 gene was mutated in Arabidopsis thaliana, the mutant leaf had more chlorophyll content than the wild-type plant [Zm00001d003403 expression in maize. These results are in line with previous reports.Expression of ino acid ,40. Whenpe plant . The leaZm00001d026568 and Zm00001d026569 genes were associated with the same SNP 2376873-7-G. The relative expressions of Zm00001d026568 and Zm00001d026569 were higher in the genotypes carrying the SNP A allele  families in plants that is involved in biotic/abiotic stress, compound storage and plant growth and development [A total of 76 candidate genes were identified for the chlorophyll content and the dynamic changes of chlorophyll content according to the position of significantly associated SNPs. In addition, Li et al. , which ielopment ,74,75,76elopment ,78. Palmelopment . Fatty aelopment ,81. Leafelopment ,83. TherZm00001d026563, Zm00001d026569, Zm00001d026568 or this SNP may help to regulate chlorophyll content in maize breeding. Taken together, the discovery of candidate genes provides help for further analyzing the molecular regulatory network of chlorophyll content on maize ear leaves. The identification of SNP will promote marker-assisted selection in maize molecular breeding.To explore the potential roles of candidate genes in regulating chlorophyll content, we performed expression profiling analysis on RNA-seq data from different tissues at 0, 6, 12, 18, 24, and 30 days after pollination. The expressions of AP2/EREBP transcription factor 40 and chloroplast palmitoyl carrier protein thioesterase in leaves were low, and the expressions were moderately high on the 6th day after pollination. These results indicate that they have direct or indirect effects on chlorophyll content. Thus, selection of Zm00001d026568 and Zm00001d026569 contained significant SNP and encoded pentatricopeptide repeat-containing protein and chloroplastic palmitoyl-acyl carrier protein thioesterase, respectively. They were found to be highly expressed in lines with the A allele as determined by RT-qPCR. These candidate genes provide valuable resources for further study of the molecular network regulating chlorophyll content in maize. In addition, the prediction of SNPs with chlorophyll content may help devise effective breeding plans and selection strategies to improve maize yield.In this study, we discovered candidate genes of natural variation in maize ear chlorophyll content by GWAS. Chlorophyll content appeared to be of moderate heritability and showed extensive variation in the association panel, indicating that chlorophyll content is a quantitative trait suitable for GWAS. GWAS showed that the natural changes regulating chlorophyll content had manymicro effect loci. We found 19 SNPs containing 76 candidate genes that may participate in leaf senescence, photosynthesis, and plant developmental processes. One of the SNPs was co-localized in AUCCC and chlorophyll content that was associated with five genes.


Our aim was to determine the efficacy of four-week probiotic supplementation on gastrointestinal health. The secondary objectives were to assess probiotic effects on immune reaction, as well as weight control and metabolic health.We conducted two randomized sub-trials, respectively, among subjects who were diagnosed with functional constipation (FC) or functional diarrhea (FDr) according to the Rome IV criteria. In each sub-trial, 70 eligible Chinese adults were randomized to receive a multi-strain probiotic combination or a placebo. Gastrointestinal symptoms, defecation habits, stool characteristics, blood and fecal biochemistry markers, anthropometrics measures, stress-associated responses, and intestinal flora changes were assessed at baseline and after probiotics intervention.p < 0.0001). Their mean weekly stool frequency increased from 3.3 times to 6.2 times; immune response and inflammation markers improved with increases in serum IgA, IFN-γ and fecal sIgA, and decrease in hsCRP; most components of lipid profile were significantly ameliorated, with increases in HDL-C and reductions in TC and TG; body weight, body mass index and basal metabolic rate decreased following probiotics consumption. For FDr participants, probiotics consumption markedly reduced overall gastrointestinal symptom scores (p < 0.0001); decreased stool frequency by 3 times per week; increased IgA, IFN-γ, sIgA concentrations, while lowered hsCRP and IL-4 levels. Both FC and FDr participants had improvement in the scores of defecation habits, anxiety or depression, and perceived stress. Probiotics supplementation promoted the production of all three major short-chain fatty acids. No changes were observed in LDL-C, IgG, IgM, IL-8, IL-10 and motilin.Four weeks of probiotic supplementation reduced overall gastrointestinal symptoms scores in FC participants (Supplementation with the probiotic formula over a four-week period could help relieving gastrointestinal symptoms, improving satisfaction with defecation habits, emotional state and immune response, and ameliorating dysbacteriosis in participants with FC or FDr. It also had beneficial effects on lipid metabolism and weight control for FC participants. Both FC and FDr exclude those that meet irritable bowel syndrome (IBS) criteria, although abdominal pain and/or bloating may be present . Deviati2 . Subjects were followed for another week after the end of the intervention (the washout period) to assess the persist of the probiotic effect. The research practices of this study were in accordance with the Declaration of Helsinki. The Institutional Review Board of Shanghai Nutrition Society reviewed and approved this study. All subjects provided written informed consent prior to enrollment.2. We excluded subjects who were under treatment for GI symptoms; lactose intolerant; currently suffering from organic diseases that might affect intestinal function, such as prior GI resection, colon or rectal cancer, inflammatory bowel disease, diabetes, hyperthyroidism or hypothyroidism, Hirschsprung disease, scleroderma, anorexia nervosa; on diet, doing excessive workout, taking weight control drugs or drugs that can affect their appetite in the past 3 months; having history or clinically diagnosed with any diseases that may affect efficacy evaluation of the study product, including GI disorders, liver, kidney, endocrine, blood, respiratory and cardiovascular diseases; currently or have been overusing alcohol, drugs or supplements which may cause intestinal dysfunction or affect efficacy evaluation of the study product; frequently using drugs that may affect GI function or the immune system; used laxatives or other supplements to improve digestive function within 2 weeks before study entry; used dairy products or other products that contains prebiotics or probiotics within 10 days before study entry; pregnant or breast-feeding women. Subjects were required to avoid the consumption of other fermented milk, yogurt and supplements containing probiotic or prebiotic, and to maintain their usual diet and daily physical exercise habits.Eligible subjects included males and females aged 18–65 years, self-reported history of constipation or diarrhea symptoms, and fulfilled the Rome IV criteria for FC or FDr . To inve2.2.10 colony forming units of six probiotic strains: Lactobacillus (L) acidophilus NCFM, Bifidobacterium (B) lactis HN019, B. lactis Bl-04, B. lactis B420, Lactobacillus (L) plantarum Lp-115 and Lacticaseibacillus (L) paracasei Lpc-37, with addition of prebiotics. The placebo contained only maltodextrin and the appearance was the same as the probiotic product. Each participant orally received the products directly or with warm water half an hour after meal, twice daily, for a period of 4 weeks.The active probiotic combination under study was supplied by WONDERLAB®  as a fine white powder (2 g) packed in sealed bottle. The product contained 4 × 102.3.The primary outcome was a GI symptom score assessed via the Intestinal Health Evaluation Form . At the Evaluations of defecation habits in the past week were recorded on the Defecation Evaluation Form . It gathWeekly stool frequency was recorded. Stool characteristics were evaluated using the Bristol Stool Form Scale . The BriBody weight, height, body mass index (BMI), waist and hip circumference, body fat percentage and basal metabolic rate (BMR) were measured using InBody bioelectrical body composition analyzing device . Blood samples were drawn between 8 to 10 a.m. following an overnight fast of at least 12 h to quantify biomarkers of lipid concentrations, systemic inflammation, immune response and GI motility. The biomarkers measured include total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), high-sensitivity C-reactive protein (hsCRP), immunoglobulin A (IgA), immunoglobulin G (IgG), and immunoglobulin M (IgM), interleukin-4, -8 and -10 , interferon-γ (IFN-γ) and motilin (MTL). Fecal secretory immunoglobulin A (sIgA) and short-chain fatty acids (SCFAs) and were also assessed as these are sensitive markers for inflammation in the GI tract.Participants completed the Hospital Anxiety and Depression (HAD) questionnaire and the Perceived Stress Scale (PSS) questionnaire to investigate the effects of the study formula on anxiety, depression, and perceived stress. The Chinese language versions were used in all cases. The HAD is a self-assessment scale for measuring states of anxiety and depression . The queThe scores for GI symptoms, intestinal health and satisfaction with defecation habits were measured at baseline and at the end of each week during the study (week 1 to week 5). The InBody test, blood and fecal laboratory tests, HAD and PSS scales were assessed at baseline and the end of the intervention (week 4).Participants were instructed to record their daily food and beverage intake during the 3 days before the baseline, the last 3 days before the end of the intervention and the last 3 days of the washout period according to the food models and scales provided. The portion sizes were converted to grams or milliliters and summarized by food categories. Physical activity in the past week of the baseline, in the last week of the intervention period and in the washout week were assessed using a continuous measure for metabolic equivalent of task (MET-minutes) derived using the algorithms provided by the Guidelines for Data Processing and Analysis of the International Physical Activity Questionnaire (IPAQ) . These dGut microbial diversity was monitored using 16 s rRNA sequencing  of the s2.4.Demographic and baseline characteristics were summarized by study group. Continuous outcome variables are reported as means ± SD or median (quartiles), and categorical outcomes are reported as frequency (%). Prior to testing, distributional assumptions for the outcomes were assessed and transformations or nonparametric versions of the tests were used if deemed necessary. The differences between study groups were evaluated using analysis of (co)variance for normal distributed outcomes. Analyses of post-intervention data were adjusted for baseline measurements. For non-normal data, group differences were analyzed using Kruskal Wallis test. The differences between baseline and post-intervention outcomes within each study group were evaluated using paired t-test for normal distributed continuous outcomes and Wilcoxon signed ranks test for non-normal or ordinal outcomes. A mixed model was used to assess repeated measured outcomes. The number and percent of adverse events (AEs) and serious adverse events (SAEs) were summarized. All analyses were conducted for enrolled participants who consumed at least one dose of the study product. The significance level for the statistical tests was set at 0.05. Statistical analyses were performed using SAS software version 9.4 .3.A total of 140 subjects participated in this study, with 70 in the each of the two sub-trails. Of all enrolled subjects, mean age was 45.7 years  and 28.6% were men . All sub3.1.p = 0.0001 and 0.0003, respectively, p < 0.0001). After the intervention ended for a week, the symptoms scores of the probiotic groups remained significantly lower compared to that of the baseline and that of the CGs.The GI symptoms scores of both the FC  and the FDr  subjects significantly decreased since the second week of probiotics consumption and were both significantly lower than that of the CGs  since the second week of probiotics consumption. The score further reduced as the intervention continued and was significantly lower than that of the CG since week 2. The mean score remained at the same level as the intervention ended for 1 week .For subjects with FDr, the overall score reduced significantly from baseline and was significantly lower than that of the CG after 4 weeks of probiotics consumption. At the end of the washout period, the mean score slightly increased but was still significantly lower than that of the baseline and the CG. The change of scores from week 4 to week 5 was not significant in the probiotics group.3.3.After 2 weeks of probiotics supplementation, significant improvement in the satisfaction with defecation habit (indicated by decreased score) was observed among subjects with FC and those with FDr as well. Subjects’ satisfaction score reduced further as taking the probiotics product for two more weeks. By the end of the washout period, the satisfaction scores of the probiotics group in both the FC and the FDr sub-trials were significantly lower than their own baseline scores, and also showed no significant change compared to that at the end of the intervention. The differences in the satisfactions scores between the probiotics group and the CG were significant from week 2 to week 5 in both sub-trials .3.4.Subjects with FC had an average stool frequency of 3.3 ± SD 1.4 times per week at baseline. Their stool frequency increased significantly after 2 weeks of probiotics consumption and continued to improve in the following 2 weeks. By the end of probiotics intervention, the average stool frequency reached 6.2 ± 1.5 times per week. At the end of the washout period, their stool frequency maintained at about 6 times per week. In the meantime, significant improvement was observed in Bristol scores of stool characteristics. The average stool consistency of the probiotics group changed from lumpy and sausage like  at baseline to normal consistency of type 3 or type 4 since the second week of probiotics consumption. Moreover, their stool color become significantly lighter compared to that at baseline since week 2. The probiotics group had significantly higher weekly stool frequency, less dry and lighter colored stool than that of the CG from week 2 to week 5 of the study .In the FDr sub-trial, subjects experienced multiple times of defecation in 1 day at baseline. Their weekly stool frequency decreased gradually following probiotics consumption. At week 2, stool frequency of the probiotics group was 11.0 ± 4.1 times per week, which was significantly lower than that at baseline (12.7 ± 4.0 times) and that of the CG (13.3 ± 3.7 times). The mean stool frequency reduced to 9.8 ± 4.7 times per week by the end of the probiotics intervention and remained similar after 1 week of washout. Stool consistency and stool color also improved after probiotics consumption. Bristol score of stool consistency reduced significantly from 5.4 ± 0.5 at baseline to 4.9 ± 1.1 at week 2, and then to 4.2 ± 0.8 at the end of the intervention. The score of stool color increased significantly from baseline since the second week of probiotics consumption, indicating that the stool color became darker. The differences in stool frequency, Bristol scores of stool consistency and stool color between the probiotics group and the CG were significant from week 2 to week 5 .3.5.p = 0.001) and PSS score (p = 0.013) significantly decreased from baseline to end of the intervention and were significantly lower than that of the CG, indicating a significant effect of the probiotic formula in reducing anxiety, depression and perceived stress. After 1 week of washout, both scores of the probiotics group remained at similar level and were significantly lower than the baseline scores and that of the CG  and PSS score (p = 0.002) at the end of the intervention compared to that at baseline and the CG , TG (p < 0.0001) and hsCRP (p < 0.0001) after 4 weeks of probiotics consumption. Besides, probiotic consumption resulted in significant increases in serum HDL-C (p = 0.005), IgA (p = 0.0004), IFN-γ (p = 0.0003), as well as fecal concentrations of sIgA (p < 0.0001), acetic acid (p < 0.0001), propanoic acid (p < 0.0001) and butyric acid (p < 0.0001). The difference between the probiotics group and the CG was significant in the above-mentioned biomarkers. There was no significant change in LDL-C, IgG, IgM, IL-4, IL-8, IL-10, and motilin levels  and IL-4 (p = 0.009), as well as significant higher levels of IgA (p = 0.0003), IFN-γ (p < 0.0001), fecal sIgA (p = 0.0002), acetic acid (p < 0.0001), propanoic acid (p < 0.0001) and butyric acid (p < 0.0001) were observed following 4 weeks of probiotics consumption. The probiotics group distinguished itself from the CG in the above-mentioned biomarkers post study intervention.Among FDr subjects, significant lower levels of hsCRP . The probiotics group also showed a 0.7 cm and 0.6 cm reduction in waist and hip circumference  compared to the baseline (Mean body weight decreased by 2.2 kg and BMI by 0.8 kg/mbaseline .3.8.p = 0.001) and in Lactobacillus of 1.6% (p > 0.05) with 4 weeks of probiotics supplementation vs. 0.9% and 0.5% in the control group, respectively (p = 0.06) compared to baseline remained for Bifidobacterium at one week after the end of probiotics supplementation, while the abundance of Lactobacillus was 1.6% (p > 0.05) higher than the baseline level.We detected a back-transformed mean increase of ASV relative abundance in Bifidobacterium of 4.5% (ectively . There wThe 20 most abundant ASVs in the FC and FDr probiotics groups are presented in 3.9.p = 0.595). No serious adverse events occurred during the study.There were a total of 15 (10.7%) AEs during the study, among which 7 (10.0%) in the probiotics group and 8 11.4%) in the CG. The AEs reported included otitis media , traumat% in the 4.FC and FDr are two common type of FBDs that can affect men and women of all ages. Various GI symptoms are involved with FC or FDr and may have a significant impact on health and quality of life. The digestive tract contains billions of bacteria from more than 400 different species, both harmful and beneficial, that play an important role in promoting a healthy digestive system by stimulating immune responses and controlling pathogenic mechanisms . RecentlB. lactis Bi-04, L. acidophilus NCFM, B. lactis HN019 and L. plantarum Lp-115 have been shown to enhance immunity in different age groups  in FC participants with low stool frequency , the probiotics formula showed beneficial effect in weight control and lipid metabolism. Significantly increased SCFAs and reduced waist circumference in overweight and obese adults following the supplementation of probiotics together with a dietary fiber have been documented by another study  Consulting Co., Ltd., which is the company hired by Shenzhen Precision Health to conduct the study.The authors declare that this study received funding from Shenzhen Precision Health Food Technology Co., Ltd. The funder had the following involvement in the study: study design, interpretation of data, the writing of this article and the decision to submit it for publication.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.


Introduction:PRKCG mutations have been implicated in the pathogenesis of spinocerebellar ataxia type 14 (SCA14), which is a rare autosomal dominant disease marked by cerebellar degeneration, dysarthria, and nystagmus. Until now, there has never been a report of patients with mutations of c.1232G>C worldwide.Case description: We report a case of a 30-year-old Chinese man with episodic dystaxia, speech disorder, and cognitive impairment; however, his father exclusively exhibited a speech disorder regardless of the same mutation. Whole-exome sequencing revealed a heterozygous c.1232G>C (p.G411A) variant of PRKCG.Conclusion: This case presents an extended genotype and phenotype of SCA14, and emphasizes the importance of gene sequencing in patients with spinocerebellar ataxia. PRKCG variants encoding protein kinase C γ (PKCγ) (PRKCG (PRKCG in a Chinese family to extend the genotype and phenotype of SCA14. Our results emphasize the importance of detecting PRKCG mutations in patients with episodic ataxia.Spinocerebellar ataxia type 14 (SCA14) [OMIM: 605361]  Rossi e is an auγ (PKCγ) . Althoug)   suffered from episodic ataxia for 3 years and was hospitalized for hypokalemia in the Endocrinology Department, Dushu Lake Hospital Affiliated with Soochow University on 6 July 2022. The patient was experiencing fatigue and limb weakness after heavy sweating in hot weather. He had experienced a speech disorder and cognitive impairment since birth and his speech was characterized as slow and slurred. A neurological examination revealed that his gait was ataxic and his tandem gait was impaired. The tendon reflexes were normal, and Hoffman and Babinski’s signs were negative. No axial myoclonus or tremors had been observed during the past 30 years. There was a requirement for assistance while transferring (activities of daily living score: 95). After admission, a complete examination revealed that the Renin–angiotensin–aldosterone system was normal. The potassium level in the 24 h urine sample was 64.58 mmoL/L , and the calcium level was 0.59 mmoL/L . Because the patient suffered from headaches, a right-sided parietooccipital tumorectomy was performed in 2009, and the postoperative pathology suggested an arteriovenous malformation. The postoperative magnetic resonance imaging (MRI) and computerized tomography (CT) scans  suggestePRKCG c.1232G>C (p.G411A) (PRKCG mutation was classified under “uncertain significance” on the basis of the evidence framework of PM2 and BP4. The PRKCG sequence (NM_002739) was obtained from the National Center for Biotechnology Information (NCBI) (https://www.ncbi.nlm.nih.gov/). The three-dimensional model of PRKCG protein was obtained from the AlphaFold Protein Structure Database . The three-dimensional models of the wild-type and p.G411A (c.1232G>C) mutant proteins were generated by PyMOL 2.5, a protein three-dimensional structure visualization software  , 3. The software .PRKCG with no mutations in KCNA1 or CACNA1A, which are commonly observed in episodic ataxia. Based on the genotype and phenotype, it was concluded that repeated falls were caused by ataxia rather than hypokalemia. Moreover, during previous episodic ataxia, the patient did not undergo strenuous exercise or exhibit a loss of appetite, vomiting, diarrhea, and other causes of low potassium levels. Additionally, no relationship between SCA14 and hypokalemia was reported. The absence of ataxia and cognitive dysfunction in the patient’s father, who had the same genotype, may be explained by the decreased penetrance of the disorder , which is a member of the serine/threonine enzyme family, plays a vital role in cell growth and signal transduction, and is highly expressed in Purkinje cells . PRKCG consists of two domains, namely, the regulatory domain and the catalytic domain. The regulatory domain consists of the C1 and C2 regions. The majority of the mutations discovered in the C1 region are missense variants (Until now, many mutation sites have been reported  Schmitz Figure  in PRKCGvariants . Variantvariants  because variants , which ivariants  with PKCMany patients diagnosed with SCA14 display progressive cerebellar syndrome, which is rarely associated with severe disabilities . DysarthWe reported on this family of Chinese origin with episodic ataxia, speech disorders, and cognitive impairment with an extended genetic profile and clinical features of SCA14, and emphasize the importance of gene sequencing in patients with episodic ataxia regardless of the absence of classic dysmetria and nystagmus and also independent of familial history.


Background Several randomized clinical trials (RCTs) have shown that dual orexin receptor antagonists (DORAs) are effective in the treatment of chronic insomnia. However, the superiority of one particular DORA over the others remains unclear.Objective To perform a network meta-analysis to evaluate the efficacy of different DORAs in patients with chronic insomnia.Methods The Medline, Embase, and Cochrane Central databases were searched for RCTs that compared DORA with placebo in patients ≥ 18 years of age with a diagnosis of insomnia disorder. We pooled outcomes for wake time after sleep onset (WASO), latency to persistent sleep (LPS), total sleep time (TST), and adverse events (AEs).Results We included 10 RCTs with 7,806 patients, 4,849 of whom received DORAs as the intervention. Overall, we found that DORAs were associated with the improvement of all analyzed efficacy outcomes. Concerning TST, an apparent dose-dependent pattern was noticed, with higher doses relating to a longer TST. Lemborexant 10mg provided the largest reduction in WASO (at month 1) in minutes , followed by suvorexant 20/15mg , which also appeared to provide the largest decrease in long-term WASO . The most frequent AEs were somnolence, nasopharyngitis, and headache, with rates of up to 14.8%.Conclusion Our results suggest that DORAs are associated with greater efficacy when compared with placebo in the treatment of insomnia, a complex 24-hour sleep disorder. Additionally, dosing might play an important role in the management of chronic insomnia. Insomnia, which is defined as difficulty in sleep induction or maintenance along with daytime manifestations, is the most prevalent sleep disorder.Approximately 30% to 50% of adults experience short-term insomnia, and up to 10% meet the criteria for chronic insomnia, with a higher prevalence in older individuals.In this context, dual orexin receptor antagonists (DORAs) emerged over a decade agoOver the last years, several clinical trials were developed to assess the safety and efficacy of DORAs in both adults and elderly individuals, including suvorexant,Inclusion in the present meta-analysis was restricted to studies that met all of the following criteria: (1) randomized controlled trials (RCTs), (2) comparing DORAs with placebo or DORAs with placebo and zolpidem, (3) enrolling patients ≥ 18 years of age diagnosed with insomnia disorder according to DSM-4 or -5, (4) and reporting at least one of the outcomes of interest. We excluded studies with (1) crossover design, (2) overlapping patient populations, and (3) studies that used selective orexin receptor antagonists (SORAs) as the intervention.Of note, most studies included compared DORAs with placebo, whereas some of themInsomniaORsleep initiation and maintenance disorders) AND . Previous systematic reviews, meta-analyses, as well as the references of the selected studies were also manually screened for any additional applicable studies. Two investigators (FFB and RBR) independently screened the search results using the Mendeley  reference manager software and performed data extraction using the Microsoft Excel  software. Discrepancies were solved by the senior author (JPMT). The study protocol was registered in the International Prospective Register of Systematic ReviewsWe systematically searched the Medline, Embase, and Cochrane Central Register databases for RCTs published in English from inception to May 2022. The following search strategy was used: , latency to persistent sleep (LPS), total sleep time (TST), and the most frequent adverse events (AEs). Depending on the protocol of each clinical trial, the mentioned outcomes could be presented as subjective measures, objective measures, or both. When both measures were available, objective measures were the preferred choice. Subjective (s) outcomes included sWASO and sTST, derived from electronic sleep diary entries made by patients. Polysomnography was performed for the objective outcomes.Quality assessment and risk of bias were evaluated using the Cochrane Risk of Bias Assessment tool, version 2 . Two independent authors (RBR and GBN) completed the risk of bias analyses according to five domains: randomization process, deviations from intended interventions, missing outcome data, measurement of outcome, and selection of reported results. The risk of bias was stratified into low risk of bias, high risk of bias, and some concerns. Disagreements were solved by the senior author (JPMT). Certainty of evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach based on each efficacy outcome included in the present study .2) statistic, and values > 50% were considered representative of substantial heterogeneity. Random-effects models were used, and all analyses were performed using the “netmeta” R package . The R software  was used to perform statistical analysis.The present systematic review and meta-analysis followed the Cochrane Collaboration and the Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) statement guidelines.The initial literature search yielded 1,704 results . A totaA total of 4,849 patients received a DORA as the intervention. Suvorexant was used in 1,844 patients, daridorexant, in 1,475, lemborexant, in 1,166, and almorexant, in 364 subjects. The follow-up ranged from 2 weeks to 12 months, and the drug doses ranged from 5 mg (lemborexant and daridorexant) to 200 mg . Specifically, the doses of suvorexant ranged from 15 mg to 40 mg. The high doses (of 30 mg and 40 mg) included in these studies are not currently approved. In contrast, for daridorexant, the doses ranged from 5 mg to 50 mg. The lower doses (of 5 mg and 10 mg) are non-therapeutic, and not approved either. The main characteristics of the included studies are reported inFour network meta-analyses were conducted for 3 efficacy outcomes: (1) WASO month 1 and WASO ≥ 3 months, (2) LPS, and (3) TST.p = 0.13), zolpidem 10 mg (p = 0.08), almorexant 100 mg (p = 0.33), almorexant 200 mg (p = 0.16), and lower doses of daridorexant: 5 mg (p = 0.68), and 10 mg (p = 0.88). Lemborexant and suvorexant had the largest reductions in WASO in minutes. Lemborexant 10 mg and 5 mg had very similar results (SMD =  -25.40 and -24.00 respectively), despite using a double dose. For daridorexant, the highest dose (of 50 mg) showed a greater effect . I2statistic tests revealed very high heterogeneity among the studies .A total of six studies2statistic tests also revealed very high heterogeneity .Four studies2 = 56.5% [95%CI = 4.2%–80.2%]) using I2statistic.Four studies2statistic tests revealed low heterogeneity .Five studies The most frequent AEs were somnolence, nasopharyngitis, and headache , with iOverall, the studies were found to be of high quality. Only one study According to the GRADE analysis, the quality of the evidence was rated as moderate for WASO (month 1 and ≥ 3 months). The quality of the evidence for LPS and TST was considered high. The downgrade in the certainty of evidence was due to inconsistency, which was stated as very serious, serious, and not serious for WASO, LPS and TST respectively  with placebo and zolpidem. Our findings can be summarized as follows: (a) DORAs were associated with an improvement in all analyzed efficacy outcomes; (b) lemborexant and suvorexant resulted in the greatest reductions in WASO month 1; (c) suvorexant 20 mg/15 mg and 30 mg/40 mg, and Daridorexant 50 mg, the greatest reductions in WASO ≥ 3 months; (d) suvorexant 40 mg/30 mg and 20 mg/15 mg, and Daridorexant 50 mg and 25 mg presented significant reductions in LPS; (e) regarding TST, significant results were observed for all DORAs, with an apparent dose-dependent pattern; and (f) the most frequent AEs were mild, with incidence rates of up to 14.8%.Daridorexant is the most recent DORA, and it was first approved in early 2022. The recommended therapeutic doses include both 25-mg and 50-mg formulations.Regarding TST, an apparent dose-dependent pattern was noticed for each individual drug, with higher doses correlating with longer TST in minutes. Although dosing proved to be an important aspect of TST, it was not the case for other outcomes. For WASO and LPS, such a clear distinction was not observed. Overall, lemborexant 5 mg and 10 mg presented very similar results, despite dose differences. It is also important to note that although higher doses of suvorexant are effective and outperform lower doses (of 15 mg/20 mg) for some endpoints (LPS and TST), they are not currently approved due to safety concerns.Regarding the safety profile of DORAs, we observed predominantly mild AEs with low incidence rates . The most common AEs were somnolence, nasopharyngitis, and headache. According to a previous meta-analysis by Xue et al.,The present study has limitations. First, the absence of direct comparisons regarding different DORAs. The data extracted for efficacy outcomes from all trials incorporated were restricted to differences between DORA and placebo, or Zolpidem and placebo. In addition, the studies only included adult individuals with insomnia disorder and excluded patients with important comorbidities. Therefore, the results of the present meta-analysis might not apply to all patients.Finally, the tools to assess sleep parameters were heterogeneous. Most trials provided both subjective and objective outcome measures, as shown inDespite the known limitations, the present study has several strengths. It is the first to include two recently published trials on daridorexant,In conclusion, our results suggest that DORAs are a safe class of drugs associated with greater efficacy when compared with placebo in the treatment of insomnia, which is a complex sleep-wake disorder. The pharmacological treatment for insomnia is challenging, and it must address several aspects of the disease, including sleep variables and next-day functioning. When using a DORA, dosing may play an important role in sleep maintenance, and higher doses correlate with longer TSTs for each individual drug. Additional trials comparing two or more DORAs are needed.


To explore the clinicopathologic features and outcomes of IgAN patients who presented with fibrinoid necrosis (FN) lesions or not and the effect of immunosuppressive (IS) treatment in IgAN patients with FN lesions as well.This was a retrospective cohort study with 665 patients diagnosed with primary IgAN from January 2010 to December 2020 in Tianjin Medical University General Hospital and having detailed baseline and follow-up characteristics. Patients were divided into two groups depending on the appearance of FN lesions. Patients with FN lesions were recruited into Group FN1, while patients who were not found FN lesions in their renal biopsy specimens were recruited into Group FN0. Compare the differences between Group FN0 and Group FN1 in baseline clinicopathologic features, treatment solutions and follow-up data as well. To evaluate the impact of different fractions of FN lesions on baseline characteristics and prognosis of IgAN, we subdivided patients in Group FN1 into 3 groups depending on the FN lesions distribution, Mild Group: 0 < FN% < 1/16; Moderate Group: 1/16 < FN% < 1/10; Severe Group: FN% > 1/10. Furthermore, we compared the differences in baseline clinicopathologic features, treatment solutions and follow-up data among these three groups. Kidney endpoint event was defined as patients went into end-stage kidney disease (ESKD), which estimated glomerular filtration rate (eGFR) < 15 ml/min/1.73 m^2, regularly chronic dialysis over 6 months or received renal transplantation surgery. The kidney composite endpoint was defined by a ≥ 30% reduction in eGFR, double Scr increase than on-set, ESKD, chronic dialysis over 6 months or renal transplantation. Compare the survival from a composite endpoint rate in different groups by Kaplan-Meier survival curve. The univariate and multivariate Cox models were used to establish the basic model for renal outcomes in patients with FN lesions.(1) A total of 230 patients (34.59%) were found FN lesions in all participants. Patients with FN lesions suffered more severe hematuria than those without. On the hand of pathological characteristic, patients with FN lesions showed higher proportions of M1, E1, C1/C2 and T1/T2 lesions compared with those without FN lesions. (2) The 1-year, 3-year, and 5-year survival of the composite endpoint were lower in the FN1 group than FN0 group. (3) After adjusting for clinicopathological variables, the presence of FN lesions was a significantly independent risk factor for composite endpoint. By using multivariate Cox regression analyses, we also found when the fraction of FN lesions exceeded 10%, the risk of progression into composite endpoint increased 3.927 times.Fibrinoid necrosis of capillary loops is an independent risk factor of poor renal outcomes. More effective treatment should be considered for those who had FN lesions.The online version contains supplementary material available at 10.1186/s12882-023-03419-4. IgA nephropathy (IgAN) is the most common type of primary glomerulonephritis worldwide especially in Asia and remains a leading cause of chronic kidney disease (CKD). Approximately 30 to 40% IgAN patients will develop into renal failure within 20–25 years from on-set . Many stFibrinoid necrosis (FN) was defined as the fragmentation lesions in glomerular capillary characterized by the presence of fibrin-rich material around the capillaries. Over 6 to 15% IgAN biopsies would present FN lesions , 9. A reIn this study, we analyze the clinicopathologic features and outcomes of IgAN patients who presented with FN lesions or not. In addition, we assessed the effect of immunosuppressive therapy in IgAN patients with FN lesions as well.n = 8) were excluded in our study. Patients with less than 8 glomeruli in biopsy specimens (n = 47) were also excluded. Finally, a total of 665 patients with IgAN were included in this study for baseline and follow-up data analysis , mean arterial pressure (MAP), hemoglobin (Hb), serum albumin (Alb), serum creatinine (Scr), estimated glomerular filtration rate (eGFR), serum uric acid (UA), serum immunoglobulin A (IgA), proteinuria and hematuria were collected at the time of renal biopsy. MAP was defined as diastolic BP + 1/3 (systolic BP - diastolic BP). eGFR was calculated by the Chronic Kidney Epidemiology Collaboration (CKD-EPI) formula. The treatment solutions after renal biopsy were collected simultaneously. Renin-angiotensin system blocker (RASB) treatment was defined as the use of an angiotensin-converting enzyme inhibitor and/or angiotensin receptor blocker after renal biopsy. Immunosuppressive (IS) treatments referred to the use of glucocorticoid and/or immunosuppressive agents such as cyclophosphamide, mycophenolate mofetil, and cyclosporine regardless of dose. We recorded Scr, eGFR and proteinuria during follow-up.All renal biopsy specimens were obtained by percutaneous needle biopsy and processed routinely for immunofluorescence microscopy, light microscopy and electron microscopy. All sections were stained with hematoxylin and eosin (HE), periodic acid-Schiff (PAS), PAS together with silver methenamine (PASM) and Masson’s trichrome. The biopsy specimens were reviewed independently by two renal pathologists using the updated Oxford Classification criteria. M1 was defined by the presence of more than three cells in mesangial area on more than half the glomeruli. E1 was defined as the appearance of an increased number of cells within capillary lumina causing narrowing of the lumina. S1 was defined as the appearance of tuft adhesion and segmental sclerosis but not global sclerosis. T was scored according to the estimated percentage of interstitial fibrosis and tubular atrophy in the cortex: T0 (25% of cortex), T1 (26–50%), T2 (> 50%). C was scored according to the fractions of glomeruli with cellular or fibrocellular crescents: C0 (absence of crescents), C1 (< 25%), C2 (25%). Fibrinoid necrosis (FN) lesions were defined as a segmental destructive lesion of the glomerular capillary loop, with fibrin deposition within and around the capillaries. FN0 referred to the patients without FN lesions and FN1 referred to the patients with FN lesions. Similar to the MEST-C scores, we tried to make a FN score which would have to be categorical and on the basis of one or more cutoffs that are easily determined. We reported the biopsy findings with a number of glomeruli with FN lesions and a total number of glomeruli, and the fraction of glomeruli with FN lesions was also measured stepwise.The kidney composite endpoint was defined as the survival from a 30% reduction in eGFR, double Scr increase than on-set, end stage kidney disease , chronic dialysis over 6 months or renal transplantation.P values were 2-tailed, and values < 0.05 were considered statistically significant. Statistical analyses were carried out using SPSS  and the R software . Figures were produced by GraphPad Prism .Normally distributed variables are described as means ± SD and compared using Student’s t test or one-way analysis of variance (ANOVA), nonparametric variables are described as medians [interquartile ranges] and compared using the Mann-Whitney U test or Kruskal-Wallis test. Categorical variables are described as percentages and compared using the chi-squared test. Person correlation test was carried out to test the correlation between FN lesions and the number of glomeruli. Interobserver agreement was investigated by calculating the κ value. Kaplan-Meier survival curve was used among Group Mild/Moderate/Severe vs Group FN0 and Group FN1 vs FN0 to explore the effects on the prognosis of kidney disease. The univariate and multivariate Cox models were used to establish the basic model for renal outcomes in patients with FN lesions. All P < 0.001; 36.7 ± 4.9 g/L vs 37.6 ± 5.7 g/L, P = 0.040). While, there was no significant difference in baseline renal function and proteinuria between two groups.A total of 665 primary IgAN patients were enrolled in this study, and 230 of them had FN lesions. Initially, we tested the inter-rater reliability of FN lesions which showed a κ value of 0.73. Detailed clinical and pathological characteristics of IgAN patients with or without FN lesions were summarized in Table P < 0.05).On the hand of pathological characteristic, patients with FN lesions showed higher proportions of M1, E1, C1/C2 and T1/T2 lesions compared with those without FN lesions . The percentage of patients suffered from ESKD or composite endpoint showed no statistically significant in patients with or without FN lesions.The median length of follow-up was 44 months in the whole participants. The rate of renal function decline seems to be more slowly in FN1 groups than FN0 , obviously increase in excretion in proteinuria .Due to the differences in clinical and pathological characteristics between IgAN patients with or without FN lesions, we next tried to find the impact of different fractions of FN lesions on baseline characteristics. Firstly, we found there was less correlation between the number of glomeruli and number of FN lesions . We further evaluated the subsequent use of IS agents in different fraction of FN lesions. 87.4% of patients with any fraction of FN lesions received IS treatment compared with 59.1% of patients without FN lesions. Stepwise examination of increasing fractions of glomeruli with FN lesions revealed a steady increase in the percentage of patients treated with immunosuppression agents . By contrast, patients showed no statistical significance on the survival of the composite kidney endpoint with or without FN lesions after IS treatment  reached composite kidney endpoint. The 1-year, 3-year, and 5-year survival of the composite endpoint were 91.8, 49.4, 20.2% in the FN group and 95.8, 64.8, 38.4% in the no-FN group , as well as Hb, Alb, eGFR, proteinuria, mesangial hypercellularity, endocapillary hypercellularity, tubular atrophy/interstitial fibrosis and crescents, were strongly associated with renal survival (Table P < 0.001).Univariate analyses followed by multivariate analyses were carried out to examine the predictive value of FN lesions for kidney outcome. Clinicopathological parameters were used in the univariate analyses: gender, baseline Hb and Alb, initial eGFR, proteinuria, hematuria, treatment modalities, MEST-C scores based on the updated Oxford classification and FN lesions. In univariate Cox analyses, FN lesions whatever fraction . As shown in Table P = 0.004).In order to further investigate the impact of immunosuppressive therapy on the prognosis of IgA nephropathy (IgAN) patients with concurrent FN lesions, a multivariable Cox regression analysis was performed on the population treated with immunosuppressive therapy. As shown in Table IgAN is a common complex disease with multiple factors involved in disease development and progression. As a rare phenomenon in IgAN, few studies reported the effect of FN lesions on the kidney function decline. In our study, 230 of 665 (34.59%) patients with IgAN were found fibrinoid necrosis lesions regardless of the fraction, of which 74% had a fraction of glomeruli with FN lesions less than 10%. We also found that there was little correlation of between the number of glomeruli and FN lesions, which differed from previous reported . FurtherFN is limited to small blood vessels including small arteries, arterioles, and glomeruli . FibrinoThe prognosis for patients with IgAN is frequently poor, with 25–30% of them developing progressive renal failure within 20–25 years after initial diagnosis and an estimated 1–2% of adults developing ESRD each year , 19. HowAs reported by D’Amico et al. Thirty Five out of 340 patients (10.3%) biopsied in the study showed active segmental necrotizing lesions . MoreoveSeveral limitations of this study should be acknowledged. First, this was a retrospective cohort study and the patients were all from a single hospital in China. Thus, the sample size and the strategy of treatment may not be uniform, which may lead to some bias. Second, some patients without detailed follow-up information were excluded in our study and the length of follow-up time may not be long enough. Finally, the number of patients who did not receive IS treatment is rare which means we could not explore the value separately. A multi-center prospective randomized controlled studied should be carried out to confirm these contradictory results in the future.In conclusion, we found fibrinoid necrosis of capillary loops is an independent risk factor of poor renal outcomes. More effective treatment should be considered for those who had FN lesions.Additional file 1: Supplemental Table 1. Multivariate effect of the presence of glomeruli with FN lesions on survival from combined event. Supplemental Table 2. Multivariate effect of the fraction of glomeruli with FN lesions on survival from combined event.


Hemispherical cerebral swelling or even encephalocele after head trauma is a common complication and has been well elucidated previously. However, few studies have focused on the secondary brain hemorrhage or edema occurring regionally but not hemispherically in the cerebral parenchyma just underneath the surgically evacuated hematoma during or at a very early stage post-surgery.In order to explore the characteristics, hemodynamic mechanisms, and optimized treatment of a novel peri-operative complication in patients with isolated acute epidural hematoma (EDH), clinical data of 157 patients with acute-isolated EDH who underwent surgical intervention were reviewed retrospectively. Risk factors including demographic characteristics, admission Glasgow Coma Score, preoperative hemorrhagic shock, anatomical location, and morphological parameters of epidural hematoma, as well as the extent and duration of cerebral herniation on physical examination and radiographic evaluation were considered.It suggested that secondary intracerebral hemorrhage or edema was determined in 12 of 157 patients within 6 h after surgical hematoma evacuation. It was featured by remarkable, regional hyperperfusion on the computed tomography (CT) perfusion images and associated with a relatively poor neurological prognosis. In addition to concurrent cerebral herniation, which was found to be a prerequisite for the development of this novel complication, multivariate logistic regression further showed four independent risk factors contributing to this type of secondary hyperperfusion injury: cerebral herniation that lasted longer than 2 h, hematomas that were located in the non-temporal region, hematomas that were thicker than 40 mm, and hematomas occurring in pediatric and elderly patients.Secondary brain hemorrhage or edema occurring within an early perioperative period of hematoma-evacuation craniotomy for acute-isolated EDH is a rarely described hyperperfusion injury. Because it plays an important prognostic influence on patients’ neurological recovery, optimized treatment should be given to block or reduce the consequent secondary brain injuries. Isolated acute epidural hematoma (EDH) is one of the most common intracranial injuries, accounting for 2.7–11% of all intracranial injury cases , 4. AmonThis retrospective study was based on patients admitted into our department between June 2009 and May 2020. The diagnosis was confirmed by the head trauma history, clinical presentations, and radiological findings. The inclusion criteria were as follows: (1) isolated supratentorial EDHs confirmed by computed tomography (CT); (2) patients with cerebral herniation; and (3) patients who underwent craniotomy or decompressive craniectomy. The exclusion criteria were as follows: (1) those with severe heart, lung, and other systemic diseases; (2) those with serious brain contusion and laceration, subdural hematoma, and primary brain stem injury; (3) those with infratentorial EDH or EDH straddling the transverse sinus; (4) those with secondary cerebral infarction; and (5) patients who had incomplete clinical data, including the 3-month follow-up. The research was reviewed and approved by the Institutional Review Board of the 909th Hospital, School of Medicine, Xiamen University.A head CT scan was performed for all patients after admission. Those who were suspected of having a risk of secondary brain injury would receive an additional CT angiography (CTA) and CT perfusion (CTP) examination. A craniotomy or a decompressive craniectomy was performed as soon as possible if necessary. Postsurgical management included intracranial pressure (ICP) monitoring, seizure prophylaxis, and nutritional support. Tracheal intubation and mechanical ventilation were adopted based on patients’ consciousness and arterial oxygen saturation.de novo low-dense lesions in the secondary hyperperfusion.Patients received regular CT examinations before and 1, 3, and 7 days after surgery. CT images were evaluated by two independent senior neuroradiologists with the assistance of clinical neurosurgeons. Diffusion-weighted imaging/apparent diffusion coefficient/magnetic resonance imaging (DWI/ADC-MRI) was applied to confirm if there were Patients were followed at 1 and 3 months after discharge with CT imaging and physical examinations. Thereafter, follow-ups were performed either by telephone interview or by outpatient examination at an interval of 6 months. Neurological outcome was evaluated by using the glasgow outcome scale (GOS) as follows: I, death; II, vegetative survival in a long-term coma; III, severe disability needing care providers; IV, mild disability, being able to take care of daily life; and V, good outcomes, with adults being able to work and study.t-test) or median and interquartile range . Categorical variables were analyzed by the Pearson χ2 or Fisher exact test. Parameters with a p-value of less than 0.2 in the univariate analysis were included in the multivariable logistic regression analysis. All the statistical analyses were performed with SPSS, and a p-value of less than 0.05 was considered to be statistically significant.Collected data included age, gender, and GCS score upon admission. Data distribution was evaluated by histogram and the Kolmogorov–Smirnov test. Continuous data were either expressed as mean ± standard deviation  male patients and 23 (14.65%) female patients, with a mean age of 35.20 ± 14.58 years. The injury mechanism included traffic accidents (120/157), assault injuries (19/157), and falling injuries (18/157). The hematoma was located in the temporal area in 89 (56.69%) cases, and in the non-temporal areas, it was seen in 68 (43.31%) cases. Preoperative unilateral pupil dilation was found in 127 (80.89%) cases and bilateral pupil dilation in 30 (19.11%) cases. The mean duration of brain herniation was 73.7 ± 36.6 min, and the mean GCS on admission was 7.30 ± 2.32 points.Diffusion-weighted/apparent diffusion coefficient magnetic resonance imaging (DWI/ADC-MRI) and CTP examinations were performed to clarify whether the secondary brain hemorrhage or edema was an ischemic lesion or hyperperfusion lesion. Among the 206 patients, 12 cases were found to have secondary hemorrhage or edema, confirmed with hyperperfusion by CTP , while ap = 0.011; Patients with hyperperfusion injury had significantly worse clinical outcomes compared to those with normal perfusion .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.


Human-perceived temperature (HPT) describes the joint effects of multiple climatic factors such as temperature and humidity. Extreme HPT events may reduce labor capacity and cause thermal discomfort and even mortality. These events are becoming more frequent and more intense under global warming, posing severe threats to human and natural systems worldwide, particularly in populated areas with intensive human activities, e.g., the North China Plain (NCP). Therefore, a fine-scale HPT dataset in both spatial and temporal dimensions is urgently needed. Here we construct a daily high-resolution (~1 km) human thermal index collection over NCP from 2003 to 2020 (HiTIC-NCP). This dataset contains 12 HPT indices and has high accuracy with averaged determination coefficient, mean absolute error, and root mean squared error of 0.987, 0.970 °C, and 1.292 °C, respectively. Moreover, it exhibits high spatiotemporal consistency with ground-level observations. The dataset provides a reference for human thermal environment and could facilitate studies such as natural hazards, regional climate change, and urban planning. They pose severe impacts on human society and the ecological systems10, putting more people at risk of extremely hot or cold12. For example, heatwave led to more than 70,000 deaths in Europe in 2003 and 55,000 deaths in Russia in 201014. Extreme cold events also pose a great threat to human health and often cause a higher proportion of deaths than extreme heat16.Under global warming, the frequency and intensity of extreme temperature events  are increasing in most parts of the world18. HPT is not only affected by air temperature but also by other meteorological variables . For instance, HPT would become higher on hot days with high humidity while becoming lower on cold days under the additional influence of wind22. Relevant studies revealed that discomfort HPT could impact human health, such as respiratory distress and reduced skin evaporation, and significantly increase the health risks and mortality in heat- and cold-exposed populations under the joint effects of multiple meteorological factors25. Li et al.26 showed that global HPT increases faster than the actual air temperature. Faster increases in HPT were also confirmed by regional studies28. However, previous studies mainly quantitated the human thermal environment and human heat exposure assessment based on meteorological station data and homogeneous climatic datasets32. These station-based or raster-based datasets have a coarse spatial resolution  and insufficient temporal resolution , which cannot meet the requirements of long time series, full regional coverage, and fine spatial scale studies28. A seamless dataset of HPT with high temporal frequency and spatial resolution is still lacking and sorely needed.Human-perceived temperature (HPT) has attracted much attention in recent years due to its close connection with human health18. Various HPT indices have been proposed to investigate human thermal stress previously. For example, the wet-bulb temperature (WBT), effective temperature (ET), and heat index (HI) have been widely used for quantitative assessment of human thermal environment research35. However, there is still a lack of unified evaluation standards or comprehensive datasets for assessing the human thermal environment and stress36. Therefore, it is imperative to develop a new collection with multiple indices for evaluating the thermal environment at a fine scale .A better understanding of the thermal environment helps prevent or mitigate heat/cold stress effectively39. In particular, the North China Plain (NCP), as one of the most populated and urbanized areas of the world, is suffering from severe thermal stress41. It is located in a typical East Asian monsoon region (113°E–121°E and 34°N–41°N)42, and spans eleven provincial units of China, including one of the regions with the most profound human activities in China, i.e., the Beijing-Tianjin-Hebei region43. NCP has a total population of 0.3 billion, which accounts for around one-fifth of the population of the country44. The population exposed to heatwaves in this area is up to 0.66 million persons/day during 1961–201545. By examining the long-term changes of major urbanization agglomerations in China, Wang et al.46 indicated that HPT in northern China grew faster than that in the south, particularly in NCP. Zhang et al.47 have generated a 1-km-resolution dataset of monthly human thermal index collection (HiTIC-Monthly) over China during 2003–2020. However, this monthly dataset is not capable of detecting extreme weather events such as heatwaves and cold spells, which are usually defined based on daily temperatures. The lack of a daily HPT dataset limits accurate heat stress-related studies in this region, and a multi-index dataset of human thermal stress at a daily scale over NCP is highly essential.Previous studies have projected that the morbidity and mortality induced by extreme temperatures may continue to rise, especially in populated AsiaTo fill the aforementioned research gap, this study aims to construct a high spatial resolution (1 km × 1 km) human thermal index collection at a daily scale over NCP from 2003 to 2020 . The 12 widely-used indices include Surface Air Temperature (SAT), indoor Apparent Temperature (ATin), outdoor shaded Apparent Temperature (ATout), Discomfort Index (DI), Effective Temperature (ET), Heat Index (HI), Humidex (HMI), Modified Discomfort Index (MDI), Net Effective Temperature (NET), Wet-Bulb Temperature (WBT), simplified Wet-Bulb Globe Temperature (sWBGT), and Wind Chill Temperature (WCT). Compared with our previous HiTIC-Monthly dataset, the current HiTIC-NCP dataset has improved the temporal resolution from a monthly to a daily scale. It also incorporates different predictors by including new variables such as daily precipitable water vapor, which reflect the high-frequency (day-to-day) fluctuations of atmospheric humidity that induces excessive heat stress as perceived by human body. This study is thus of great significance for regional climate change, urban planning, urban thermal environment, and public health research.et al.48 is used to produce 12 human thermal indices. The workflow of this study is shown in Fig. The data used in this study mainly include meteorological station observations and four gridded datasets. The Light Gradient Boosting Machine (LightGBM) algorithm proposed by Ke http://data.cma.cn). All station data have been strictly quality-controlled based on the method provided by Xu et al.49, including homogenizing climate data and processing outliers in the data series. The observational network includes 374 stations across NCP  LST dataset and the gap-filling algorithm51 to make it seamless at a global scale in 1 km grids from 2003 to 2020. The average root mean squared error (RMSE) of this LST dataset is 1.80–2.03 °C and 1.23–1.45 °C for daytime and nighttime temperatures, respectively. The daily mean LST was calculated by averaging the corresponding daytime and nighttime LSTs. In addition, population distribution and regional population density are demonstrated to affect regional temperature55, and we used a high-accuracy population density dataset provided by the WorldPop project team as a predictor56.LST is closely related to near-surface air temperature57 with a spatial resolution of 90 m was used in this study to extract slope and aspect. Compared with previous DEM data , the errors of MERIT DEM are significantly reduced, and the accuracy in the flat area has been effectively improved59. In addition, precipitation has been proven to affect air temperature and humidity61. Therefore, a global daily precipitable water vapor dataset with a spatial resolution of 1 km was used.The Multi-Error-Removed Improved-Terrain (MERIT) Digital Elevation Model (DEM)48. LightGBM consumes much less memory and improves training efficiency by more than 20 times while maintaining nearly the same accuracy48. Due to its superior degree of generalizability, extremely fast processing speed, and high accuracy, LightGBM has been widely applied in different fields 67. As shown in Fig. LightGBM is a gradient boosting decision tree (GBDT) based machine learning algorithm. Compared with other algorithms based on GBDT such as XGBoost and pGBRT, LightGBM has improved and optimized by the Gradient-based One-Side Sampling (GOSS) and Exclusive Feature Bundling (EFB) technologies, which allow LightGBM to better retain samples with large gradients without significantly altering the original data shape and focus more on undertrained samples68. Hyperparameter optimization configures the model by searching for various model hyperparameters and selecting a subset that achieves the best performance on the given dataset. The grid search-based hyperparameters tunning method was adopted in our study69.The accuracy of machine learning relies heavily on parameterization2), root mean absolute error (MAE), and RMSE. The R2, RMSE, and MAE values are computed as follows:N represents the number of data points, xp and xo are the ith prediction and observation values, respectively.Three statistical metrics were used to assess the performance of the training model, including the determination coefficient (R70. This dataset is stacked by year and each stack consists of daily images by day of the year in the NetCDF format. The unit of the dataset is 0.01 degree Celsius (°C), and the values are stored in an integer data type (Int16) to save storage space, and thus need to be divided by 100 to get the values in degree Celsius when in use. The geographic coordinate system of the dataset is World Geodetic System 1984 (WGS84) Coordinate System. The spatial distribution of the 12 human thermal indices on August 13, 2013, one of the severest heat stress days in the history of NCP, and January 3, 2008, when the sharpest snowstorm struck NCP, are shown as examples in Figs. The high spatial resolution (1 km) human thermal index collection at a daily scale from 2003 to 2020 over NCP (HiTIC-NCP) shows a high consistency between observations and predictions, and the product has respectable accuracies. HiTIC-NCP contains 216.rar files, with individual files decompressed into the NetCDF format. The dataset is available on the general-purpose repository Zenodo, at 10.5281/zenodo.75280012, MAE, and RMSE. All indices exhibit desirable performance, with the averaged R2, MAE, and RMSE being 0.987, 1.292 °C, and 0.970 °C, respectively. It demonstrates that the LightGBM model has good effectiveness in the prediction of human thermal indices at a daily scale. Figure We assessed the overall accuracy of 12 human thermal indices over NCP during 2003–2020 in terms of R2, MAE, and RMSE values of 12 predicted thermal indices during 2003–2020 are shown in Fig. 2 values range from 0.975 to 0.990, the MAE values are all smaller than 1.4 °C, and the RMSE values are smaller than 1.9 °C . WCT and NET exhibit the highest MAEs  and RMSEs . It is likely caused by the involvement of wind speed in the calculation of WCT and NET  are seen at most stations across NCP, especially in the central, southwestern, and northern parts. The R2 values of NET at most stations have relatively lower accuracies, likely caused by the inclusion of wind speed. Figures Figures 2, MAE, and RMSE values of 12 indices in individual years of 2003–2020. All R2 values of 12 indices in all years exhibit well performance . Annual averaged MAEs and RMSEs of all indices in nearly all years are less than 1.5 °C and 2.0 °C, respectively (Fig. Figure ely Fig. , demonst