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Disease Activity Score-28 (DAS28) with erythrocyte sedimentation rate (DAS28ESR), DAS28 with C-reactive protein (DAS28CRP), and simplified disease activity index (SDAI) are widely used to assess disease activity as low, moderate, or high or in remission in patients with rheumatoid arthritis (RA). However, these indicators can generate inconsistent results, influencing treatment decisions and limiting comparisons across studies. We aimed to establish equations for conversion from DAS28ESR and DAS28CRP to SDAI.We conducted a retrospective study, including 933 outpatients who were simultaneously assessed using DAS28ESR, DAS28CRP, and SDAI. The patients were divided into a training set (70%) and a validation set (30%). We developed equations to convert DAS28ESR and DAS28CRP values into SDAI values by bisquare-weighted robust regression to obtain SDAI-DAS28ESR and SDAI-DAS28CRP. In addition to using kappa values to assess consistency, differences in disease activity classification between SDAI-DAS28ESR and SDAI-DAS28CRP were examined by the Stuart-Maxwell test and the Bowker test.Two quadratic equations were developed as follows: SDAI-DAS28ESR = 1.168 × (DAS28ESR)^SDAI-DAS28ESR and SDAI-DAS28CRP are interchangeable with the SDAI on the group level, which will facilitate comparisons among studies. In addition, the equations improved consistency between indicators. Key Points • There is disagreement in assessing disease activity in patients with rheumatoid arthritis between Disease Activity Score-28 (DAS28) with erythrocyte sedimentation rate (DAS28ESR), DAS28 with C-reactive protein (DAS28CRP), and simplified disease activity index (SDAI). • We developed and validated two quadratic equations to convert DAS28ESR and DAS28CRP into SDAI. We found there was no longer significant difference in disease activity between indicators after applying the equations. • This work may allow comparisons across studies which use different indicators.

Since gaining approval for the treatment of chronic lymphocytic leukemia (CLL), the BCL-2 inhibitor venetoclax has transformed the treatment of this and other blood-related cancers. Reflecting the large and hydrophobic BH3-binding groove within BCL-2, venetoclax has significantly higher molecular weight and lipophilicity than most orally administered drugs, along with negligible water solubility. Although a technology-enabled formulation successfully achieves oral absorption in humans, venetoclax tablets have limited drug loading and therefore can present a substantial pill burden for patients in high-dose indications. We therefore generated a phosphate prodrug (3, ABBV-167) that confers significantly increased water solubility to venetoclax and, upon oral administration to healthy volunteers either as a solution or high drug-load immediate release tablet, extensively converts to the parent drug. Additionally, ABBV-167 demonstrated a lower food effect with respect to venetoclax tablets. These data indicate that beyond-rule-of-5 molecules can be successfully delivered to humans via a solubility-enhancing prodrug moiety to afford robust exposures of the parent drug following oral dosing.

1. Measured pKa values of ABBV-167 (Table S1. Ionization constants of ABBV-167) 2. Preparation of ABBV-167 on large scale (Scheme S1: Synopsis of GMP synthesis of ABBV-167) 3. Preparation of clinical ABBV-167 drug supply 4. Animal pharmacokinetics (Table S2. Single dose pharmacokinetics of prodrug 3 and parent venetoclax in mouse and dog after IV dosing of prodrug 3. Table S3. Single dose pharmacokinetics of 3 after oral dosing in mouse and dog. Table S4. Single dose pharmacokinetics of parent venetoclax in mouse and dog after oral dosing of 3.) 5. Clinical study (Study design, Pharmacokinetic and statistical analysis, Safety and tolerability assessments, Clinical pharmacokinetic results, Table S5. Effect of prodrug and food on venetoclax bioavailability, Safety results) 6. Crystallography methods (Protein preparation. BCL-2 ABBV-167 complex crystallization. X-ray structure determination. Table S6. Diffraction data collection and refinement statistics for BCL-2 in complex with ABBV-167 (PDB code 7LHB))

Fat grafting is increasingly used as an adjuvant surgery to blepharoplasty to refill the volume loss of an aged face and promote cellular regeneration. Complications, such as hematoma, infection, seroma, and palpable mass, may occur. We collected the patients that underwent lower blepharoplasty combined with fat graft to evaluate the incidence of oil cyst formation in the lower eyelid and to identify risk factors.A retrospective review was performed of all patients who underwent lower or total blepharoplasty combined with fat graft at the authors' institution between January 2018 and June 2020. Complication rates were observed, and associations between preoperative variables and outcomes were assessed.A total of 119 patients were included in the series (all bilateral, 238 eyelids). The average patient age was 54.88 ± 11.94 years, and the average grafted fat was 1.88 ± 1.0 mL. On a per-eyelid basis for all patients, the complication rate of oil cyst formation was 6.72% (16 of 238 eyelids). The occurrence of oil cyst formation was associated with hypertension (P = 0.012; adjusted odds ratio, 9.27; 95% confidence interval, 1.62-52.99) and diabetes mellitus (P = 0.005; adjusted odds ratio, 14.02; 95% confidence interval, 2.22-88.45), but not associated with anticoagulants use (P = 0.931), age (P = 0.784), sex (P = 0.317), or fat volume (P = 0.215). The mean interval between the fat graft procedure and oil cyst noted was 236.5 ± 118.9 days.Oil cyst in lower eyelid can be defined as a palpable, firm, and persistent subcutaneous cystic lesion found postoperatively in any size during physical examination. The complication rate of oil cyst formation occurring after lower blepharoplasty with autologous fat grafting is 6.72%. Hypertension and diabetes mellitus maybe are risk factors of oil cyst formation. Steroid injection, needle capsulotomy, liposuction, and excision are safe and effective treatments. Reduce surgical trauma by diminishing anterior lamina trauma and capsulopalpebral fascia repair might decrease the complication rate of oil cyst formation.Transconjunctival lower blepharoplasty with fat graft or 2-stage surgery may be a choice to prevent oil cyst formation.

PEFTs have excellent classical spinning properties as compared to PET and have potential applications in hydrophobic nanofibrous films.

The synthesis and optimization of chitosan-based inorganic/organic composites have gained growing interest in the last years. In the current study, genipin crosslinked hydroxyapatite/Chitosan (HA/CHI) composite rods (GCHR), which had been prepared and reported in our prevenient studies, were further evaluated via their formation of layer-by-layer structure, cross-linking degree and so on. The cross-linking degree in the range of 28.73∼43.32% was moderate for the in situ periodic precipitation and the formation of homogeneous HA/CHI/Genipin composite rods. In this range the composite rods could obtain a complex structure combined with layer-by-layer structure and radial spokes structure. Benifiting from the special structure, the rods can obtain superior mechanical properties and become fresh device for internal fixation of fracture. Mouse bone marrow mesenchymal stem cells (mBMSCs) were co-cultured with extract of the GCHR100 rods to evaluate the cytocompatibility of the composite. The results showed that the leachate of the GCHR100 rods significantly up-regulated osteogenesis-related genes like ALP, Runx2 and OCN after 7 days compared with control (P< 0.05).

This paper presents a systematic review and meta-analysis of 26 randomized controlled trials (RCTs) involving 1721 patients to assess the effects of hydrolyzed collagen (HC) supplementation on skin hydration and elasticity. The results showed that HC supplementation significantly improved skin hydration (test for overall effect: Z = 4.94, p < 0.00001) and elasticity (test for overall effect: Z = 4.49, p < 0.00001) compared to the placebo group. Subgroup analyses demonstrated that the effects of HC supplementation on skin hydration varied based on the source of collagen and the duration of supplementation. However, there were no significant differences in the effects of different sources (p = 0.21) of collagen or corresponding measurements (p = 0.06) on skin elasticity. The study also identified several biases in the included RCTs. Overall, the findings suggest that HC supplementation can have positive effects on skin health, but further large-scale randomized control trials are necessary to confirm these findings.

Rationale: Cardiovascular diseases, such as myocardial infarction (MI), are the leading causes of death worldwide. Reperfusion therapy is the common standard treatment for MI. However, myocardial ischemia/reperfusion (I/R) causes cardiomyocyte injury, including apoptosis and fibrosis. We aimed to investigate the effects of conditioned medium from adipose-derived stem cells (ADSC-CM) on apoptosis and fibrosis in I/R-treated hearts and hypoxia/reoxygenation (H/R)-treated cardiomyocytes and the underlying mechanisms. Methods: ADSC-CM was collected from ADSCs. The effects of intramuscular injection of ADSC-CM on cardiac function, cardiac apoptosis, and fibrosis examined by echocardiography, Evans blue/TTC staining, TUNEL assay, and Masson's trichrome staining in I/R-treated mice. We also examined the effects of ADSC-CM on apoptosis and fibrosis in H/R-treated H9c2 cells by annexin V/PI flow cytometry, TUNEL assay, and immunocytochemistry. Results: ADSC-CM treatment significantly reduced heart damage and fibrosis of I/R-treated mice and H/R-treated cardiomyocytes. In addition, the expression of apoptosis-related proteins, such as p53 upregulated modulator of apoptosis (PUMA), p-p53 and B-cell lymphoma 2 (BCL2), as well as the fibrosis-related proteins ETS-1, fibronectin and collagen 3, were significantly reduced by ADSC-CM treatment. Moreover, we demonstrated that ADSC-CM contains a large amount of miR-221/222, which can target and regulate PUMA or ETS-1 protein levels. Furthermore, the knockdown of PUMA and ETS-1 decreased the induction of apoptosis and fibrosis, respectively. MiR-221/222 overexpression achieved similar results. We also observed that cardiac I/R markedly increased apoptosis and fibrosis in miR-221/222 knockout (KO) mice, while ADSC-CM decreased these effects. The increased phosphorylation of p38 and NF‐κB not only mediated myocardial apoptosis through the PUMA/p53/BCL2 pathway but also regulated fibrosis through the ETS-1/fibronectin/collagen 3 pathway. Conclusions: Overall, our results show that ADSC-CM attenuates cardiac apoptosis and fibrosis by reducing PUMA and ETS-1 expression, respectively. The protective effect is mediated via the miR-221/222/p38/NF-κB pathway.

The present study aims to investigate relative clause production in Chinese and English from a cognitivefunction approach that explores underlying cognitive, semantic, and discourse-pragmatic factors operative in discourse processing. With this approach we are able to account for both general and specific distributional patterns of RCs between the two languages on the one hand and between speech and writing on the other, using narrative data elicited from native speakers of both languages.

Biomedical engineering (BME) (biomedical materials track) is a typical field of interdisciplinary integration. Its specialty education simultaneously undertakes the duo reformation responsibilities for the new engineering education and the new medical education due to its unique strengths in interdisciplinary nature, comprehensive scope of knowledge, and status of being on the cutting edge of technology. We made an analysis, in this paper, of the opportunities and challenges faced by BME (biomedical materials track) specialty education on the basis of the trends and frontiers of development in biomedical materials in the world. From the perspective of new requirements raised by major national strategies and industrial development for the qualifications and competence of professionals specializing in biomedical materials, thorough reflections were made on the specialized education of BME (biomedical materials track) under the background of the new engineering education and the new medical education. Furthermore, we proposed herein to reconstruct the specialized core knowledge system according to the main line of the reactions and the responses between the biomedical materials and human bodies at different levels and set up a series of courses of biomedical materials science centered on Materiobiology as the core. We also proposed to establish a diversified integrated reform model of the training system incorporating production, learning, research and application for highly competent BME (biomedical materials track) professionals. This paper attempts to contribute to the solution of the major issue of how to train the innovative talents and leaders who will pioneer a new round of diagnosis and treatment technology revolution and the development of the medical device industry.

Background Bowen's disease (BD) is a persistent, progressive intraepidermal carcinoma. BD usually occurs in areas exposed to sunlight. Involvement of the dorsum of the hand is not rare, but that of the palmar aspect is very unusual. Only a few cases have been reported in the literature. Case summary Here, we report the case of a 48-year-old male patient who presented with a history of persistent local erythema lasting for 2 years on the thenar eminence of the left palm. Initially diagnosed as hand eczema, the condition did not improve with intermittent treatment with anti-allergy medications or topical glucocorticoid ointments, among other approaches. Then, the area of erythema gradually enlarged and was accompanied by mild itching. For a definite diagnosis and treatment, the patient came to our hospital. Dermoscopic examination revealed BD, and histopathological examination confirmed the diagnosis. We performed partial resection of the skin lesion followed by photodynamic therapy. No recurrence was observed at the 6-mo follow-up. Conclusion For all atypical palmar lesions, early dermoscopy and/or skin biopsy are needed to avoid missed diagnosis or misdiagnosis.

This study proposes a new approach to analyse the effects of an overlap term on the calculation of the overall Gini coefficient and estimates China’s Gini ratios since the adoption of the economic reform and open-door policies. A decomposition of the Chinese Gini coefficient for 1978–2010 reveals that the key factor contributing to income inequalities is the income disparity between rural and urban inhabitants. We further investigate the features of this income inequality between rural and urban areas and employ statistical approaches to evaluate the effects of urbanisation and rural-to-urban average income on nationwide income inequality. The results show that accelerating the pace of urbanisation is mainly responsible for decreasing China’s income disparity. Drawing on these results, we conclude with suggestions for related policies.

Background: Kaposi's sarcoma (KS) is a highly disseminated angiogenic tumour of endothelial cells. Many deregulated miRNAs, including kshv-mir-k12-1-5p, have been identified in KS. kshv-mir-k12-1-5p plays important roles in KS. However, the underlying mechanism is not fully understood. The aim of this study was to investigate the exact functions of kshv-mir-k12-1-5p in KS cells. Materials and methods: The biological functions of kshv-mir-k12-1-5p were studied using CCK-8, apoptosis, migration and invasion assays. Bioinformatics software was used to identify the target gene (SOCS6) of kshv-mir-k12-1-5p. A dual luciferase assay, Western blot (WB) and quantitative real-time polymerase chain reaction (q-PCR) were performed to further verify the target gene. The underlying molecular mechanisms of kshv-mir-k12-1-5p in KS cells were also explored. Results: kshv-mir-k12-1-5p can promote the proliferation, migration and invasion of KS cells and inhibit cell apoptosis. Suppressor of cytokine signalling 6 (SOCS6) was identified as a direct target of kshv-mir-k12-1-5p, and kshv-mir-k12-1-5p can downregulate SOCS6 expression. In addition, knockdown of SOCS6 rescued the effects of kshv-mir-k12-1-5p inhibitor. Hence, a direct relationship between kshv-mir-k12-1-5p and SOCS6 was confirmed. Conclusions: kshv-mir-k12-1-5p promotes the malignant phenotype of KS cells by targeting SOCS6, suggesting that kshv-mir-k12-1-5p could be a potential therapeutic target for KS.

The process development of a new synthetic route leading to an efficient and robust synthetic process for venetoclax (1: the active pharmaceutical ingredient (API) in Venclexta) is described. The redesigned synthesis features a Buchwald-Hartwig amination to construct the core ester 23c in a convergent fashion by connecting two key building blocks (4c and 26), which is then followed by a uniquely effective saponification reaction of 23c using anhydrous hydroxide generated in situ to obtain 2. Finally, the coupling of the penultimate core acid 2 with sulfonamide 3 furnishes drug substance 1 with consistently high quality. The challenges and solutions for the key Pd-catalyzed C-N cross-coupling will also be discussed in detail. The improved synthesis overcomes many of the initial scale-up challenges and was accomplished in 46% overall yield from 3,3-dimethyldicyclohexanone (6), more than doubling the overall yield of the first generation route. The new process was successfully implemented for producing large quantities of 1 with99% area purity.

This paper presents an adaptive gain-scheduled backstepping control &#x0028 AGSBC &#x0029 scheme for the balance control of an underactuated mechanical power-line inspection &#x0028 PLI &#x0029 robotic system with two degrees of freedom and a single control input. First, a nonlinear dynamic model of the balance adjustment process of the PLI robot is constructed, and then the model is linearized at a nominal equilibrium point to overcome the computational infeasibility of the conventional backstepping technique. Second, to solve generalized stabilization control issue for underactuated systems with multiple equilibrium points, an equilibrium manifold linearized model is developed using a scheduling variable, and then a gain-scheduled backstepping control &#x0028 GSBC &#x0029 scheme for expanding the operational area of the controlled system is constructed. Finally, an adaptive mechanism is proposed to counteract the impact of external disturbances. The robust stability of the closed-loop system is ensured by Lyapunov theorem. Simulation results demonstrate the effectiveness and high performance of the proposed scheme compared with other control schemes.

We propose an extended BCS–Hubbard model and investigate its ground state phase diagram in an external magnetic field. By mapping the model onto a model of spinless fermions coupled with conserving Z 2 variables which are mimicked by pseudospins, the model is shown to be exactly solvable along the symmetric lines for an arbitrary on-site Hubbard interaction on the bipartite lattice. In the zero field limit, the ground states exhibit an antiferromagnetic order of pseudospins. In the large field limit, on the other hand, the pseudospins are fully polarized ordered. With the increase of the applied field, a first-order phase transition occurs between these kinds of phases when the on-site Coulomb interaction is less than a critical value U c. Above this critical U c, a novel intermediate phase emerges between the fully polarized and antiferromagnetic phases. The ground states in this phase are macroscopically degenerate, like in a spin ice, and the corresponding entropy scales linearly with the lattice size at zero temperature.

Background We aimed to introduce our modifications by using eccentrically located muscular perforators to shorten the distance between the recipient vessels and the flap pedicle for overcoming the "short pedicle" drawback of the proximal lateral leg perforator (PLLP) flap. Patients and methods A retrospective review of 12 cases undergoing free PLLP flap for hand and foot regions reconstruction during 2010 and 2019. The mean age was 43.3 years. Most defects resulted from burn and trauma injuries. The dimensions of defects ranged from 8 × 1.5 cm2 to 12 × 6.5 cm2 . Muscular perforators were designed eccentrically 1-3 cm away from the central point of the flap to shorten the distance between the recipient vessels and the pedicle. The flap was designed to be 0.5-1 cm larger than the defect. Results The flap size ranged from 9 × 2 cm2 to 15 × 6 cm2 . All pedicles were long enough to ensure an appropriate anastomosis without tension. The post-operative course in all cases was uneventful. All flaps survived without complications. Primary repair of the donor sites was performed in all patients. Donor leg function was not hampered by flap harvesting. All patients were satisfied with the scar after at least 1 year of follow-up. Conclusion Based on our experience, selection of the eccentric locations of the musculo-cutaneous perforators were effective methods to overcome the short pedicle length of this flap type. Using our modifications, thin PLLP flaps can be used in foot and hand reconstruction with minimal donor site morbidity and a high success rate.

Since gaining approval for the treatment of chronic lymphocytic leukemia (CLL), the BCL-2 inhibitor venetoclax has transformed the treatment of this and other blood-related cancers. Reflecting the large and hydrophobic BH3-binding groove within BCL-2, venetoclax has significantly higher molecular weight and lipophilicity than most orally administered drugs, along with negligible water solubility. Although a technology-enabled formulation successfully achieves oral absorption in humans, venetoclax tablets have limited drug loading and therefore can present a substantial pill burden for patients in high-dose indications. We therefore generated a phosphate prodrug (3, ABBV-167) that confers significantly increased water solubility to venetoclax and, upon oral administration to healthy volunteers either as a solution or high drug-load immediate release tablet, extensively converts to the parent drug. Additionally, ABBV-167 demonstrated a lower food effect with respect to venetoclax tablets. These data indicate that beyond-rule-of-5 molecules can be successfully delivered to humans via a solubility-enhancing prodrug moiety to afford robust exposures of the parent drug following oral dosing.

Cardiovascular disease is a major health problem in industrialized and developing countries and is the leading cause of death and disability. Myocardial ischemia/reperfusion (I/R) causes cardiomyocyte damage such as apoptosis and hypertrophy. The purpose of this study was to investigate the effects of exosomes from adipose-derived stem cells (ADSC-Exo) on hearts from I/R mice and to explore the underlying mechanisms. ADSC-Exo significantly decreased I/R-induced cardiomyocyte apoptosis and hypertrophy, as detected by TdT-mediated dUTP nick end-labeling (TUNEL) and wheat germ agglutinin (WGA) staining, respectively. In addition, the expression of apoptosis-related proteins p-p53 and PUMA and hypertrophy-related proteins ETS-1 and ANP were significantly reduced in the cardiomyocytes of ADSC-Exo-treated I/R mice compared to those of control mice. Both PUMA and ETS-1 are reported to be target genes for miR-221/222. I/R operation significantly reduced miR-221/222 expression, while ADSC-Exo treatment increased miR-221/222 expression, as detected by RT-qPCR. We also observed that cardiac I/R operation markedly increased cell apoptosis and hypertrophy in miR-221/222 knockout (KO) mice, while ADSC-Exo reduced the effects of I/R operation. Furthermore, ADSC-Exo protected H9c2 cardiomyocytes from H2O2-induced damage by reducing apoptosis and hypertrophy in vitro. H2O2 treatment significantly reduced miR-221/222 expression, while ADSC-Exo treatment reversed this effect in H9c2 cells. ADSC-Exo treatment decreased H2O2-induced PUMA and ETS-1 expression. Compared with control treatment, I/R treatment significantly reduced p-AKT and increased p-p65, while ADSC-Exo and miR-221/222 mimics attenuated these effects. The AKT activator SC79 and p65 inhibitor Bay 11-7082 reduced H2O2-induced cell apoptosis and hypertrophy. Based on these findings, ADSC-Exo prevents cardiac I/R injury through the miR-221/miR-222/PUMA/ETS-1 pathway. Therefore, ADSC-Exo is an effective inhibitor of I/R-induced heart injury.