Effects of 3-nitrooxypropanol (3-NOP, Bovaer®10) and whole cottonseed on milk production and enteric methane emissions from dairy cows under Swiss management conditions.

The objective of this study was to determine the potential effect and interaction of 3- nitrooxypropanol (3-NOP; Bovaer®) and whole cottonseed (WCS) on lactational performance, and enteric methane (CH4) emission of dairy cows. A total of 16 multiparous cows, including 8 Holstein Friesian (HF) and 8 Brown Swiss (BS) [224 ± 36 d in milk, 26 ± 3.7 kg milk yield], were used in a split-plot design, where the main plot was the breed of cows. Within each subplot, cows were randomly assigned to a treatment sequence in a replicated 4 × 4 Latin Square design with 2 × 2 factorial arrangements of treatments with 4, 24-d periods. The experimental treatments were: 1) Control (basal TMR), 2) 3-NOP (60 mg/kg TMR DM), 3) WCS (5% TMR DM), and 4) 3-NOP + WCS. The treatment diets were balanced for ether extract, crude protein, and NDF contents (4%, 16%, and 43% of TMR DM, respectively). The basal diets were fed twice daily at 0800 and 1800 h. Dry matter intake (DMI) and milk yield were measured daily, and enteric gas emissions were measured (using the GreenFeed system) during the last 3 d of each 24-d experimental period when animals were housed in tie stalls. There was no difference in DMI on treatment level, whereas the WCS treatment increased ECM yield and milk fat yield. There was no interaction of 3-NOP and WCS for any of the enteric gas emission parameters, but 3-NOP decreased CH4 production (g/d), CH4 yield (g/kg DMI), and CH4 intensity (g/kg ECM) by 13, 14 and 13%, respectively. Further, an unexpected interaction of breed by 3-NOP was observed for different enteric CH4 emission metrics: HF cows had a greater CH4 mitigation effect compared with BS cows for CH4 production (g/d; 18 vs. 8%), CH4 intensity (g/kg MY; 19% vs. 3%) and CH4 intensity (g/kg ECM; 19 vs. 4%). Hydrogen production was increased by 2.85 folds in HF and 1.53 folds in BS cows receiving 3-NOP. Further, there was a 3-NOP ' Time interaction for both breeds. In BS cows, 3-NOP tended to reduce CH4 production by 18% at around 4 h after morning feeding but no effect was observed at other time points. In HF cows, the greatest mitigation effect of 3-NOP (29.6%) was observed immediately after morning feeding and it persisted at around 23% to 26% for 10 h until the second feed provision, and 3 h thereafter, in the evening. In conclusion, supplementing 3-NOP at 60 mg/kg DM to a high fiber diet resulted in 18 to 19% reduction in enteric CH4 emission in Swiss Holstein Friesian cows. The lower response to 3-NOP by BS cows was unexpected and has not been observed in other studies. These results should be interpreted with caution due to low number of cows per breed. Lastly, supplementing WCS at 5% of DM improved ECM and milk fat yield but did not enhance CH4 inhibition effect of 3-NOP of dairy cows.

Brassica napus BnaA09.MYB52 enhances seed coat mucilage accumulation and tolerance to osmotic stress during seed germination in Arabidopsis thaliana.

Seed coat mucilage plays an important role in promoting seed germination under adversity. Previous studies have shown that Arabidopsis thaliana MYB52 (AtMYB52) can positively regulate seed coat mucilage accumulation. However, the role of Brassica napus MYB52 (BnaMYB52) in accumulation of seed coat mucilage and tolerance to osmotic stress during seed germination remains largely unknown. We cloned the BnaA09.MYB52 coding domain sequence from B. napus cv ZS11, identified its conserved protein domains and elucidated its relationship with homologues from a range of plant species. Transgenic plants overexpressing BnaA09.MYB52 in the A. thaliana myb52-1 mutant were generated through Agrobacterium-mediated transformation and used to assess the possible roles of BnaA09.MYB52 in accumulation of seed coat mucilage and tolerance to osmotic stress during seed germination. Subcellular localization and transcriptional activity assays demonstrated that BnaA09.MYB52 functions as a transcription factor. RT-qPCR results indicate that BnaA09.MYB52 is predominantly expressed in roots and developing seeds of B. napus cv ZS11. Introduction of BnaA09.MYB52 into myb52-1 restored thinner seed coat mucilage in this mutant to levels in the wild type. Consistently, expression levels of three key genes participating in mucilage formation in developing seeds of myb52-1 were also restored to wild type levels by overexpressing BnaA09.MYB52. Furthermore, BnaA09.MYB52 was induced by osmotic stress during seed germination in B. napus, and ectopic expression of BnaA09.MYB52 successfully corrected sensitivity of the myb52-1 mutant to osmotic stress during seed germination. These findings enhance our understanding of the functions of BnaA09.MYB52 and provide a novel strategy for future B. napus breeding.

[Clinical effects of early rehabilitation treatment after repair surgery of skin and soft tissue defects accompanied by extensor tendon injury on the back of hand].

Objective: To explore the clinical effects of early rehabilitation treatment after repair surgery of skin and soft tissue defects accompanied by extensor tendon injury on the back of hand. Methods: This study was a retrospective non-randomized controlled study. From February 2015 to February 2023, 24 patients (15 males and 9 females, aged 12-55 years) with skin and soft tissue defects accompanied by extensor tendon injury on the back of hand, who met the inclusion criteria and were repaired with flap transplantation and tendon grafting or tendon anastomosis, were admitted to the First Affiliated Hospital of Air Force Medical University. According to different intervention time for postoperative rehabilitation treatment of patients, the patients were divided into conventional rehabilitation group and early rehabilitation group, with 12 cases in each group. Patients in early rehabilitation group received rehabilitation treatment immediately after surgery under the rehabilitation guidance of specialized rehabilitation physicians based on the characteristics of different postoperative periods. Patients in conventional rehabilitation group began rehabilitation treatment from the third week after surgery, and their rehabilitation treatment was the same as that of patients in early rehabilitation group from the second week after surgery. The patients in 2 groups were treated in the hospital until the sixth week after surgery. The occurrence of flap vascular crisis and tendon rupture were observed within 6 weeks after surgery. After 6 weeks of surgery, the manual muscle test was used to measure the pinching force between the index finger and thumb, lateral pinching force, three-point pinching force, and grip force of the affected hand; the total action motion method was used to evaluate the finger joint range of motion of the affected hand, and the excellent and good ratio was calculated; the Carroll upper extremity function test was used to score and rate the function of the affected hand. Results: Within 6 weeks after surgery, only 1 patient in conventional rehabilitation group suffered from venous crisis, and the flap survived after the second surgical exploration and anastomosis of blood vessels; there was no occurrence of tendon rupture in patients of 2 groups. After 6 weeks of surgery, there were no statistically significant differences in pinching force between the index finger and thumb, lateral pinching force, three-point pinching force, or grip force of the affected hand between the two groups of patients (P>0.05); the excellent and good ratio of the finger joint range of motion of the affected hand of patients in early rehabilitation group was 11/12, which was higher than 7/12 in conventional rehabilitation group, but there was no statistically significant difference (P>0.05); the affected hand function score of patients in early rehabilitation group was 90±6, which was significantly higher than 83±8 in conventional rehabilitation group (t=2.41, P<0.05); the function rating of the affected hand of patients in early rehabilitation group was obviously better than that in conventional rehabilitation group (Z=2.04, P<0.05). Conclusions: Early rehabilitation treatment for patients with skin and soft tissue defects accompanied by extensor tendon injury on the back of hand after repair surgery can improve hand function, but it would not increase surgery related complications, which is worthy of clinical promotion and application.

Genome sequencing and molecular networking analysis of the wild fungus Anthostomella pinea reveal its ability to produce a diverse range of secondary metabolites.

BACKGROUND: Filamentous fungi are prolific producers of bioactive molecules and enzymes with important applications in industry. Yet, the vast majority of fungal species remain undiscovered or uncharacterized. Here we focus our attention to a wild fungal isolate that we identified as Anthostomella pinea. The fungus belongs to a complex polyphyletic genus in the family of Xylariaceae, which is known to comprise endophytic and pathogenic fungi that produce a plethora of interesting secondary metabolites. Despite that, Anthostomella is largely understudied and only two species have been fully sequenced and characterized at a genomic level. RESULTS: In this work, we used long-read sequencing to obtain the complete 53.7 Mb genome sequence including the full mitochondrial DNA. We performed extensive structural and functional annotation of coding sequences, including genes encoding enzymes with potential applications in biotechnology. Among others, we found that the genome of A. pinea encodes 91 biosynthetic gene clusters, more than 600 CAZymes, and 164 P450s. Furthermore, untargeted metabolomics and molecular networking analysis of the cultivation extracts revealed a rich secondary metabolism, and in particular an abundance of sesquiterpenoids and sesquiterpene lactones. We also identified the polyketide antibiotic xanthoepocin, to which we attribute the anti-Gram-positive effect of the extracts that we observed in antibacterial plate assays. CONCLUSIONS: Taken together, our results provide a first glimpse into the potential of Anthstomella pinea to provide new bioactive molecules and biocatalysts and will facilitate future research into these valuable metabolites.

Vegetation-fire feedbacks increase subtropical wildfire risk in scrubland and reduce it in forests.

Climate dictates wildfire activity around the world. But East and Southeast Asia are an apparent exception as fire-activity variation there is unrelated to climatic variables. In subtropical China, fire activity decreased by 80% between 2003 and 2020 amid increased fire risks globally. Here, we assessed the fire regime, vegetation structure, fuel flammability and their interactions across subtropical Hubei, China. We show that tree basal area (TBA) and fuel flammability explained 60% of fire-frequency variance. Fire frequency and fuel flammability, in turn, explained 90% of TBA variance. These results reveal a novel system of scrubland-forest stabilized by vegetation-fire feedbacks. Frequent fires promote the persistence of derelict scrubland through positive vegetation-fire feedbacks; in forest, vegetation-fire feedbacks are negative and suppress fire. Thus, we attribute the decrease in wildfire activity to reforestation programs that concurrently increase forest coverage and foster negative vegetation-fire feedbacks that suppress wildfire.

Exhalomics as a noninvasive method for assessing rumen fermentation in dairy cows: Can exhaled-breath metabolomics replace rumen sampling?

Previously, we used secondary electrospray ionization-mass spectrometry (SESI-MS) to investigate the diurnal patterns and signal intensities of exhaled (EX) volatile fatty acids (VFA) of dairy cows. The current study aimed to validate the potential of an exhalomics approach for evaluating rumen fermentation. The experiment was conducted in a switchback design, with 3 periods of 9 d each, including 7 d for adaptation and 2 d for sampling. Four rumen-cannulated original Swiss Brown (Braunvieh) cows were randomly assigned to 1 of 2 diet sequences (ABA or BAB): (A) low starch (LS; 6.31% starch on a dry matter basis) and (B) high starch (HS; 16.2% starch on a dry matter basis). Feeding was once per day at 0830 h. Exhalome (with the GreenFeed System), and rumen samples were collected 8 times to represent every 3 h of a day, and EX-VFA and ruminal (RM)-VFA were analyzed using SESI-MS and HPLC, respectively. Furthermore, the VFA concentration in the gas phase (HR-VFA) was predicted based on RM-VFA and Henry's Law (HR) constants. No interactions were identified between the types of diets (HS vs. LS) and the measurement methods on daily average VFA profiles (RM vs. EX or HR vs. EX), suggesting a consistent performance among the methods. Additionally, when the 3-h interval VFA data from HS and LS diets were analyzed separately, no interactions were observed between methods and time of day, indicating that the relative daily pattern of VFA molar proportions was similar regardless of the VFA measurement method used. The results revealed that the levels of acetate sharply increased immediately after feeding, trailed by an increase in the acetate:propionate ratio and a steady increase for propionate (2 h after feeding the HS diet, 4 h for LS), and butyrate. This change was more pronounced for the HS diet than the LS diet. However, there was no overall diet effect on the VFA molar proportions, although the measurement methods affected the molar proportions. Furthermore, we observed a strong positive correlation between the levels of RM and EX acetate for both diets (HS: r = 0.84; LS: r = 0.85), RM and EX propionate (r = 0.74), and RM and EX acetate:propionate ratio (r = 0.80). Both EX-VFA and RM-VFA exhibited similar responses to feeding and dietary treatments, suggesting that EX-VFA could serve as a useful proxy for characterizing RM-VFA molar proportions to evaluate rumen fermentation. Similar relationships were observed between RM-VFA and HR-VFA. In conclusion, this study underscores the potential of exhalomics as a reliable approach for assessing rumen fermentation. Moving forward, research should further explore the depth of exhalomics in ruminant studies to provide a comprehensive insight into rumen fermentation metabolites, especially across diverse dietary conditions.

[Clinical research of multisystem inflammatory syndrome in children].

Objective: To analyze the clinical characteristics of children with multisystem inflammatory syndrome (MIS-C) associated with SARS-CoV-2 in China, and to improve the understanding of MIS-C among pediatricians. Methods: Case series study.Collect the clinical characteristics, auxiliary examinations, treatment decisions, and prognosis of 64 patients with MIS-C from 9 hospitals in China from December 2022 to June 2023. Results: Among the 64 MIS-C patients, 36 were boys and 28 were girls, with an onset age being 2.8 (0.3, 14.0) years. All patients suffered from fever, elevated inflammatory indicators, and multiple system involvement. Forty-three patients (67%) were involved in more than 3 systems simultaneously, including skin mucosa 60 cases (94%), blood system 52 cases (89%), circulatory system 54 cases (84%), digestive system 48 cases (75%), and nervous system 24 cases (37%). Common mucocutaneous lesions included rash 54 cases (84%) and conjunctival congestion and (or) lip flushing 45 cases (70%). Hematological abnormalities consisted of coagulation dysfunction 48 cases (75%), thrombocytopenia 9 cases (14%), and lymphopenia 8 cases (13%). Cardiovascular lesions mainly affected cardiac function, of which 11 patients (17%) were accompanied by hypotension or shock, and 7 patients (12%) had coronary artery dilatation.Thirty-six patients (56%) had gastrointestinal symptoms, 23 patients (36%) had neurological symptoms. Forty-five patients (70%) received the initial treatment of intravenous immunoglobulin in combination with glucocorticoids, 5 patients (8%) received the methylprednisolone pulse therapy and 2 patients (3%) treated with biological agents, 7 patients with coronary artery dilation all returned to normal within 6 months. Conclusions: MIS-C patients are mainly characterized by fever, high inflammatory response, and multiple organ damage. The preferred initial treatment is intravenous immunoglobulin combined with glucocorticoids. All patients have a good prognosis.

Relationship between 1-, 3-, and 6-Month Gingival Bleeding Outcomes.

INTRODUCTION: Results from systematic reviews and meta-analyses show generally consistent antigingivitis effects between 3- and 6-mo observation time points with twice-daily use of stannous fluoride (SnF2) dentifrice. However, the relationship between 1-, 3-, and 6-mo gingivitis responses has not been investigated. METHODS: This pooled analysis was conducted to understand the relationship of 1-, 3-, and 6-mo gingival bleeding outcomes. Number of bleeding sites, derived from Löe-Silness Gingival Index (LSGI) or Gingival Bleeding Index, was identified as the primary end point of the analysis for the biological and clinical relevance. Randomized, double-blinded, controlled clinical studies meeting the following predefined selection criteria were identified: 1) published and unpublished gingivitis clinical trials conducted from 1995 to 2022 comparing efficacy of 0.454% SnF2 dentifrices to negative controls (sodium fluoride or sodium monofluorophosphate dentifrice) and 2) studies with a 3-mo assessment and at least a 1- or 6-mo assessment. RESULTS: The search resulted in ten 6-mo and fourteen 3-mo studies meeting selection criteria. A mixed-effects model was performed on the pooled data to assess gingival bleeding outcomes across time. The bleeding efficacy significantly increased between months 1 and 3 (P < 0.0001) and plateaued between months 3 and 6 (P = 0.007), supporting the fact that bleeding reduction relative to control established by 1 mo will increase and be maintained through 3 and 6 mo (R2 = 0.857). In addition, gingival bleeding and gingivitis efficacy, as measured by LSGI, were found to be highly correlated (R2 = 0.874). CONCLUSION: A clear relationship has been demonstrated between 1-, 3-, and 6-mo gingival bleeding outcomes in gingivitis clinical studies comparing SnF2 dentifrice to negative control dentifrice. These findings have important implications to the dental practice and scientific research as antigingivitis efficacy evaluations can be observed as early as 1 mo and are consistent with those seen at 3 or 6 mo. KNOWLEDGE TRANSFER STATEMENT: Outcomes from this investigation indicate that the clinical evaluation of antigingivitis efficacy at 1 mo is predictive of that at 3 and 6 mo, supporting studies of 1-mo duration as a viable method of knowledge acquisition. This more efficient, expedited research design has positive implications for patient care, clinical practice guidelines, protocols, and policies.

[Research advances on application of pancreatic stone protein in the early diagnosis of sepsis].

Sepsis is a severe life-threatening syndrome characterized by an abnormal host response to infection that can rapidly evolve into septic shock and multiple organ failure. Treatment of sepsis depends on early identification and diagnosis as well as adequate and timely anti-infection and multi-organ functional support. In recent years, pancreatic stone protein has been widely studied as a new biomarker for sepsis. Existing evidence shows that compared with the commonly used inflammatory markers in clinical practice, pancreatic stone protein has higher sensitivity and specificity in the diagnosis of sepsis. It enables the early diagnosis of sepsis and assessment of the severity of septic patients to a certain extent. This article reviews the characteristics, biological functions, diagnostic features, and clinical application of pancreatic stone protein.

[Clinical experience of free superficial temporal fascia flap/anterolateral femoral fascial flap combined with skin grafting in repairing deep tissue defects of special parts of extremities].

The deep tissue defects of extremities are prone to cause the exposure of tendons, blood vessels, nerves, and bones, which are commonly repaired with free flaps in clinical practice. However, for special parts such as fingers, toes, posterior ankles, anterior tibias, and dorsum of feet, the appearances are usually bulky after being repaired with free flaps and need lipectomy operations, which bring great physiological, psychological, and economic burden to patients. As the fascia flap is soft and thin with reliable blood supply and strong anti-infection ability, the free fascia flap combined with skin grafting offers some advantages in repairing the above-mentioned wounds. However, its clinical application is severely limited due to the complexity of surgical operation and the difficulty in observing blood supply after operation. In recent years, our team has carried out a lot of work and accumulated rich experience in repairing deep tissue defects of special parts of extremities with free superficial temporal fascia flap/anterolateral femoral fascial flap combined with skin grafting. From the clinical perspective, this paper mainly introduces the anatomy and harvesting method of free superficial temporal fascia flap/anterolateral femoral fascial flap, as well as the advantages, difficulties, and precautions of clinical application, for reference of peers.

[Curative effects of medial plantar free flap in reconstructing electric burn wound and scar contracture in the palm].

Objective: To explore the curative effects of medial plantar free flap in reconstructing electric burn wound and scar contracture in the palm. Methods: A retrospective observational study was conducted. From January 2020 to January 2023, 6 patients with electric burn wounds or scar contracture in the palm who met the inclusion criteria were admitted to the First Affiliated Hospital of Air Force Medical University, including 5 males and 1 female, aged 35 to 55 years. The wound area was 5.0 cm×3.0 cm-8.0 cm×7.0 cm after the debridement of electric burn wounds or resection of scar in the palm. The medial plantar free flap anastomosed with cutaneous nerve was used for wound reconstruction, with flap area of 5.5 cm×3.5 cm-8.5 cm×7.5 cm. The wound in the donor site was repaired with transplantation of abdominal full-thickness skin graft. After surgery, the survival of flaps and skin grafts were observed, the shape and texture of flap and the recovery of donor site of flap were observed, and the holding function of the affected hand was assessed. At the last follow-up, the two-point discrimination distance of flap was measured, the sensory recovery of flap was evaluated with the trial standard for the evaluation of the functions of the upper limbs of the Hand Surgery Society of the Chinese Medical Association, and the function recovery of flap was evaluated by post-surgery flap function evaluation scale. Results: After surgery, 5 flaps survived well, while the distal part of 1 flap was partially necrotic, which was repaired by medium-thickness skin graft from lateral thigh after debridement. All the skin grafts at the donor sites survived well. During follow-up of 3 to 24 months, the flap was not bloated, the texture and color were good, the match with the surrounding tissue was high, with no obvious scar contracture occurred at the donor site. The affected hand had good holding function. At the last follow-up, the two-point discrimination distance of flap was 6-8 mm, the flap sensation recovery was as follows: 5 flaps recovered to grade S3+, 1 flap recovered to grade S3, and the functional evaluation of flaps was excellent in 5 cases and good in 1 case. The patients basically returned to normal life and work. Conclusions: The medial plantar free flap with cutaneous nerve anastomosis has many advantages, such as high matching degree of appearance, good sensory recovery, and holding function of the affected hand. It is an ideal choice for the reconstruction of the electric burn wound and scar contracture in the palm.

[Best evidence summary of prevention strategies for pressure injury in adult hospitalized burn patients].

Objective: To summarize the best evidence of prevention strategies for pressure injury in adult hospitalized burn patients. Methods: A bibliometric approach was used. Systematic searches were carried out to retrieve the published evidence of prevention strategies for pressure injury in adult hospitalized burn patients in the official websites of relevant academic organizations such as International Society for Burn injury, American Burn Association, and Japanese Dermatology Association, National Pressure Injury Advisory Panel, European Pressure Injury Advisory Panel, Pan Pacific Pressure Injury Alliance International Guidelines Website, foreign language databases such as UpToDate, BMJ Best Practice, MedSci, Joanna Briggs Institute Evidence-Based Practice Database, Cochrane Library, Web of Science, Embase, and PubMed, and Chinese databases such as China Biology Medicine disc, China National Knowledge Infrastructure, Wanfang Database, and China Clinical Guidelines Library. The literature types include clinical decision-making, evidence summary, guidelines, systematic review, and expert consensus. The search time was till February 21st, 2023. Two researchers independently screened the literature and evaluated the quality, and other researchers extracted and graded the evidence according to the topic. Results: A total of 10 papers were included, including 6 evidence summaries, 3 guidelines, and 1 expert consensus, all with high literature quality. After extracting evidence and classifying, 27 pieces of best evidences were summarized from three aspects, including prevention training and supervision, risk assessment, and prevention measures of pressure injury. Conclusions: A total of 27 pieces of best evidences of prevention strategies for pressure injury in adult hospitalized burn patients were summarized from 3 aspects. Medical workers can follow the best evidence and give personalized prevention strategies according to the specific condition of adult hospitalized burn patients to reduce the incidence of pressure injury.

[Analysis of the clinical characteristics and therapeutic effect of refractory juvenile dermatomyositis to tofacitinib].

Objective: To elucidate the clinical features of patients with refractory juvenile dermatomyositis (JDM), and to explore the efficacy and safety of tofacitinib in the treatment of refractory JDM. Methods: A total of 75 JDM patients admitted to the Department of Rheumatology and Immunology in Shenzhen Children's Hospital from January 2012 to January 2021 were retrospectively analyzed, and to analyze the clinical manifestations, efficacy and safety of tofacitinib in the treatment of refractory JDM. Patients were divided into refractory group with using of glucocorticoids in combination with two or more anti-rheumatic drugs for treatment, and the presence of disease activity or steroid dependence after a one-year follow-up. The non-refractory group is defined as clinical symptoms disappeared, laboratory indicators were normal, and clinical remission was achieved after initial treatment, and the clinical manifestations and laboratory indexes of the two groups were compared. The Mann-Whitney U test, Fisher's precision probability test was used for intergroup comparison. Binary Logistic multivariate regression analysis was used to identify risk factors for refractory JDM. Results: Among the 75 children with JDM, 41 were males and 34 were females with a age of onset of 5.3 (2.3, 7.8) years. The refractory group consisted of 27 cases with a age of onset of 4.4 (1.5, 6.8) years, while the non-refractory group consisted of 48 cases with a age of onset of 5.9 (2.5, 8.0) years. Compared with 48 cases in the non-refractory group, the proportion of interstitial lesions and calcinosis in the refractory group was higher than that in the non-refractory group (6 cases (22%) vs. 2 cases (4%), 8 cases (30%) vs. 4 cases (8%), both P<0.05). Binary Logistic regression analysis showed that observation group were more likely to be associated with to interstitial lung disease (OR=6.57, 95%CI 1.22-35.31, P=0.028) and calcinosis (OR=4.63, 95%CI 1.24-17.25, P=0.022). Among the 27 patients in the refractory group, 22 cases were treated with tofacitinib, after treatment with tofacitinib, 15 of 19 cases (86%) children with rashes showed improvement, and 6 cases (27%) with myositis evaluation table score less than 48 score both were improved, 3 of 6 cases (27%) had calcinosis were relieved, and 2 cases (9%) had glucocorticoid-dependence children were successfully weaned off. During the tofacitinib treatment, there was no increase in recurrent infection, blood lipids, liver enzymes, and creatinine were all normal in the 22 cases. Conclusions: Children with JDM with calcinosis and interstitial lung disease are more likely to develop refractory JDM. Tofacitinib is safe and effective for refractory JDM.

Sustained intra-cartilage delivery of interleukin-1 receptor antagonist using cationic peptide and protein-based carriers.

OBJECTIVE: Blocking the interleukin-1 (IL-1) catabolic cascade following joint trauma can be achieved using its receptor antagonist, IL-1Ra. However, its clinical translation for osteoarthritis therapy has been unsuccessful due to its rapid joint clearance and lack of targeting and penetration into deep cartilage layers at therapeutic concentrations. Here, we target the high negative charge of cartilage aggrecan-glycosaminoglycans (GAGs) by attaching cationic carriers to IL-1Ra. IL-1Ra was conjugated to the cartilage targeting glycoprotein, Avidin, and a short length optimally charged cationic peptide carrier (CPC+14). It is hypothesized that electro-diffusive transport and binding properties of IL-1Ra-Avidin and IL-1Ra-CPC+14 will create intra-cartilage depots of IL-1Ra, resulting in long-term suppression of IL-1 catabolism with only a single administration. DESIGN: IL-1Ra was conjugated to Avidin or CPC+14 using site specific maleimide linkers, and confirmed using gel electrophoresis, high-performance liquid chromatography (HPLC), and mass spectrometry. Intra-cartilage transport and retention of conjugates was compared with native IL-1Ra. Attenuation of IL-1 catabolic signaling with one-time dose of IL-1Ra-CPC+14 and IL-1Ra-Avidin was assessed over 16 days using IL-1α challenged bovine cartilage and compared with unmodified IL-1Ra. RESULTS: Positively charged IL-1Ra penetrated through the full-thickness of cartilage, creating a drug depot. A single dose of unmodified IL-1Ra was not sufficient to attenuate IL-1-induced cartilage deterioration over 16 days. However, when delivered using Avidin, and to a greater extent CPC+14, IL-1Ra significantly suppressed cytokine induced GAG loss and nitrite release while improving cell metabolism and viability. CONCLUSION: Charge-based cartilage targeting drug delivery systems hold promise as they can enable long-term therapeutic benefit with only a single dose.

Multiomics approach to profiling Sertoli cell maturation during development of the spermatogonial stem cell niche.

Spermatogonial stem cells (SSCs) are the basis of spermatogenesis, a complex process supported by a specialized microenvironment, called the SSC niche. Postnatal development of SSCs is characterized by distinct metabolic transitions from prepubertal to adult stages. An understanding of the niche factors that regulate these maturational events is critical for the clinical application of SSCs in fertility preservation. To investigate the niche maturation events that take place during SSC maturation, we combined different '-omics' technologies. Serial single cell RNA sequencing analysis revealed changes in the transcriptomes indicative of niche maturation that was initiated at 11 years of age in humans and at 8 weeks of age in pigs, as evident by Monocle analysis of Sertoli cells and peritubular myoid cell (PMC) development in humans and Sertoli cell analysis in pigs. Morphological niche maturation was associated with lipid droplet accumulation, a characteristic that was conserved between species. Lipidomic profiling revealed an increase in triglycerides and a decrease in sphingolipids with Sertoli cell maturation in the pig model. Quantitative (phospho-) proteomics analysis detected the activation of distinct pathways with porcine Sertoli cell maturation. We show here that the main aspects of niche maturation coincide with the morphological maturation of SSCs, which is followed by their metabolic maturation. The main aspects are also conserved between the species and can be predicted by changes in the niche lipidome. Overall, this knowledge is pivotal to establishing cell/tissue-based biomarkers that could gauge stem cell maturation to facilitate laboratory techniques that allow for SSC transplantation for restoration of fertility.

Intra-articular kinetics of a cartilage targeting cationic PEGylated protein for applications in drug delivery.

OBJECTIVES: Cartilage targeting cationic glycoprotein Avidin was PEGylated to synthesize a multi-arm Avidin (mAv) nano-construct with high drug loading content. Here we investigate mAv biodistribution and kinetics over a 7-day period following intra-articular (IA) administration in rat knee joints. METHODS: Labeled mAv was injected into healthy rat knees, and joint tissues (articular cartilage, menisci, ligaments, tendons, fat pad) were harvested following sacrifice at 6 h, 1, 4 and 7 days. Its IA biodistribution and retention were measured using fluorescence microscopy. Tissue localization was compared in young vs old rats by immunohistochemistry. mAv chondrotoxicity and immune response were evaluated to determine safe carrier dose limits. RESULTS: mAv penetrated through the full thickness of rat cartilage and other joint tissues within 6 h, remaining detectable within most joint tissues over 7 days. Intra-tissue uptake correlated strongly with tissue GAG concentration, confirming the dominant role of electrostatic interactions between positively charged mAv and the negatively charged aggrecan proteoglycans. mAv was uptaken by chondrocytes and also penetrated the osteocyte lacuno-canalicular system of peri-articular bone in both young and old rats. mAv did not cause cytotoxicity at concentrations up to 300 µM but elicited a dose dependent immunogenic response. CONCLUSIONS: mAv's ability to target a variety of joint tissues, chondrocytes, and peri-articular osteocytes without sequestration in synovial fluid makes it a versatile carrier for delivering a wide range of drugs for treating a broad class of musculoskeletal diseases. Drugs can be conjugated using simple aqueous based avidin-biotin reaction, supporting its clinical prospects.

[Associations between different levels of blood pressure and risk of prediabetes].

Objective: To explore sex and rural-urban differences in the associations of different blood pressure levels with the risk of prediabetes. Methods: We used a multi-stage stratified cluster random sampling method to investigate 21 637 residents aged ≥18 years from 10 survey areas in Hubei province in 2020. The data on questionnaire, physical measurements, and laboratory indicators of the participants were collected. The associations of different blood pressure levels with risk of prediabetes by sex and regions were analyzed using multivariate logistic regressions after complex weighting. Results: A total of 16 111 subjects were included. The prevalence (95%CI) of prediabetes, impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and IFG complicated with IGT were 25.1% (14.4%-35.9%), 12.7% (3.2%-22.1%), 8.1% (6.3%-9.8%), and 4.4% (2.3%-6.5%), respectively. After multivariate adjustment, the risk of prediabetes, IFG, IGT, and IFG complicated with IGT increased with the increment of blood pressure (both P for trend <0.05). The positive dose-response relationships between blood pressure levels and risk of prediabetes were also significant among male, urban, and rural residents (both P for trend <0.05), and the interactions between sex and blood pressure showed significant associations for risk of prediabetes and IGT (both P for interaction <0.05). Conclusions: Higher blood pressure levels were associated with an increased risk of prediabetes. The association with prediabetes was stronger in males, but no significant difference was found between urban and rural residents. More distinctive and effective prevention and control strategies should be developed for different populations.

[Research progress of microvascular invasion in hepatocellular carcinoma].

Hepatocellular carcinoma (HCC) is a kind of highly aggressive tumor of the digestive system. Several studies have confirmed that microvascular invasion (MVI) is an independent risk factor for early recurrence and poor prognosis of HCC after surgery. Currently, pathological examination is the gold standard for diagnosing MVI. This paper summarizes concept, prognosis, preoperative prediction and treatment plan based on literature review of MVI in HCC.