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Background: Concerns have been raised about the long-term performance of aortic stent grafts for the treatment of abdominal aortic aneurysms, in particular, unibody stent grafts (eg, Endologix AFX AAA stent grafts). Only limited data sets are available to evaluate the long-term risks related to these devices. The SAFE-AAA Study (Comparison of Unibody and Non-Unibody Endografts for Abdominal Aortic Aneurysm Repair in Medicare Beneficiaries Study) was designed with the Food and Drug Administration to provide a longitudinal assessment of the safety of unibody aortic stent grafts among Medicare beneficiaries. Methods: The SAFE-AAA Study was a prespecified, retrospective cohort study evaluating whether unibody aortic stent grafts are noninferior to non-unibody aortic stent grafts with respect to the composite primary outcome of aortic reintervention, rupture, and mortality. Procedures were evaluated from August 1, 2011, through December 31, 2017. The primary end point was evaluated through December 31, 2019. Inverse probability weighting was used to account for imbalances in observed characteristics. Sensitivity analyses were used to evaluate the effect of unmeasured confounding, including assessment of the falsification end points heart failure, stroke, and pneumonia. A prespecified subgroup included patients treated from February 22, 2016, through December 31, 2017, corresponding to the market release of the most contemporary unibody aortic stent grafts (Endologix AFX2 AAA stent graft). Results: Of 87 163 patients who underwent aortic stent grafting at 2146 US hospitals, 11 903 (13.7%) received a unibody device. The average age of the total cohort was 77.0±6.7 years, 21.1% were female, 93.5% were White, 90.8% had hypertension, and 35.8% used tobacco. The primary end point occurred in 73.4% of unibody device-treated patients versus 65.0% of non-unibody device–treated patients (hazard ratio, 1.19 [95% CI, 1.15–1.22]; noninferior P value of 1.00; median follow-up, 3.4 years). Falsification end points were negligibly different between groups. In the subgroup treated with contemporary unibody aortic stent grafts, the cumulative incidence of the primary end point occurred in 37.5% of unibody device–treated patients and 32.7% of non-unibody device–treated patients (hazard ratio, 1.06 [95% CI, 0.98–1.14]). Conclusions: In the SAFE-AAA Study, unibody aortic stent grafts failed to meet noninferiority compared with non-unibody aortic stent grafts with respect to aortic reintervention, rupture, and mortality. These data support the urgency of instituting a prospective longitudinal surveillance program for monitoring safety events related to aortic stent grafts.

Administrative claims for aortic stenosis (AS) regurgitation may be useful, but their accuracy and ability to identify individuals at risk for valve-related outcomes have not been well characterized.Using echocardiographic (transthoracic echocardiogram [TTE]) reports linked to US Medicare claims, 2017 to 2018, the performance of candidateOf those included in the derivation (N=5497, mean age 74.4±11.0 years, 49.7% female), any AS or aortic regurgitation was present in 24% and 38.8%, respectively. The sensitivity and specificity ofAmong US Medicare beneficiaries receiving a TTE

Background: Medicare Advantage plans now provide health insurance coverage to >24 million older adults in the United States, and enrollment is increasing among individuals with cardiovascular disease (CVD). Whether Medicare Advantage enrollment is associated with similar health care access, acute care utilization, and financial strain for adults with CVD compared with traditional Medicare is unknown. Methods: We performed a cross-sectional study of Medicare beneficiaries 65 years or older with CVD using the 2019 National Health Interview Survey. We fit multivariable logistic regression models to examine the association of Medicare program type (Medicare Advantage versus traditional Medicare) with measures of health care access, acute care utilization, and affordability. Results: The weighted population included 11 013 437 Medicare beneficiaries, of whom 3 922 104 (35.6%) were enrolled in Medicare Advantage, and 7 091 334 (64.4%) were enrolled in traditional Medicare. Medicare Advantage and traditional Medicare enrollees were similar with respect to age, sex, racial/ethnic distribution, and household income; however, Medicare Advantage beneficiaries were more likely to live in an urban setting (82.7% versus 76.0%; P =0.01) and to be college educated (24.2% versus 19.0%; P =0.01). Medicare Advantage beneficiaries were more likely to have a usual source of care (93.5% versus 88.9%; OR, 1.99 [95% CI, 1.33–2.98)]; however, there were no other differences in health care access or utilization. Medicare Advantage beneficiaries were more likely to have problems paying medical bills (16.5% versus 11.6%; OR, 1.68 [1.17–2.40]) and to worry about paying medical bills (40.1% versus 33.8%; OR, 1.37 [1.07–1.76]) compared with those enrolled in traditional Medicare. Conclusions: Adults with CVD in Medicare Advantage were more likely to experience financial strain related to their medical bills compared with those in traditional Medicare. As enrollment in Medicare Advantage grows, policy efforts should focus on ensuring care is affordable for patients with CVD.

Opioid use disorder (OUD) is a chronic disease requiring long-term treatment and is associated with opioid overdose and increased risk of mortality. However, existing randomized clinical trials focused on short-term treatment engagement and detoxification rather than overdose or mortality risk due to limited follow-up time and ethical considerations. We used a hypothetical trial framework to conduct a retrospective cohort study to assess the effectiveness of time-varying buprenorphine-naloxone on opioid overdose and death. We identified 58,835 insured adult patients with OUD diagnosis in the US, 2010–2017. We fit a marginal structural model using inverse probability weighting methods to account for measured baseline and time-varying confounders, as well as selection bias due to possibly differential loss-to-follow-up. We found that receipt of buprenorphine-naloxone was associated with reduced risk of opioid overdose (hazard ratio (HR) = 0.66, 95% confidence interval (CI): 0.49, 0.91), death (HR = 0.24, 95% CI: 0.08, 0.75), and overdose or death (HR = 0.58, 95% CI: 0.40, 0.84). The E-value for death was 7.8, which was larger than the upper 95% CI of the association between each measured baseline variable and all-cause death, which implies that the unmeasured confounding itself may not explain away the estimated effect of treatment on the endpoint of all-cause mortality.

Although autologous fat grafting is a feasible surgical technique to improve facial deformity in patients with localized scleroderma, its success is limited by the low graft retention induced by the local inflammatory environment. This study investigated the potential effect of adipose-derived stem cells (ASCs) on skin fibrosis and fat retention in a localized scleroderma mouse model.BALB/C nude mice that were induced by bleomycin to establish a localized scleroderma model were divided randomly into five groups: blank control; fat grafting; and low, moderate, and high doses of ASC-assisted fat grafting. The backs of the mice were subcutaneously injected with phosphate-buffered saline or fat, or fat with low, moderate, and high doses of ASCs (1 × 10 5 /mL, 5 × 10 5 /mL, and 25 × 10 5 /mL, respectively). The skin fibrosis and fat retention were analyzed after 1 month or 3 months, respectively.Compared to the disease model group, the fat-grafting group, and the low- and moderate-dose ASC-enriched groups, the high-dose ASCs significantly attenuated skin fibrosis, inhibited the production of type III collagen and transforming growth factor-β1, increased fat graft retention, enhanced the expression of angiogenesis-related cytokines and angiogenesis, and increased the expression of adipogenesis-related cytokines.The results demonstrated that high-dose ASCs attenuated skin fibrosis and improved fat retention in a localized scleroderma model by reducing inflammation and by promoting angiogenesis and adipogenesis. The authors further demonstrated that ASCs enhanced adipogenesis through the AKT/ERK signaling pathway.Fat grafting has been used to treat localized scleroderma patients but with low fat retention. In this study, ASC attenuated skin fibrosis and improved fat retention in the localized scleroderma model, providing evidence for cell therapy in future application of localized scleroderma treatment.

Background Epithelium-mesenchymal interactions are involved in odontogenic processes. Previous studies have focused on the intracellular signalling regulatory network in tooth development, but the functions of extracellular regulatory molecules have remained unclear. This study aims to explore the gene profile of extracellular proteoglycans and their glycosaminoglycan chains potentially involved in dental epithelium-mesenchymal interactions using high-throughput sequencing to provide new understanding of early odontogenesis. Results Whole transcriptome profiles of the mouse dental epithelium and mesenchyme were investigated by RNA sequencing (RNA-seq). A total of 1,281 and 1,582 differentially expressed genes were identified between the dental epithelium and mesenchyme at E11.5 and E13.5, respectively. Enrichment analysis showed that extracellular regions and ECM-receptor interactions were significantly enriched at both E11.5 and E13.5. Polymerase chain reaction analysis confirmed that the extracellular proteoglycan family exhibited distinct changes during epithelium-mesenchymal interactions. Most proteoglycans showed higher transcript levels in the dental mesenchyme, whereas only a few were upregulated in the epithelium at both stages. In addition, 9 proteoglycans showed dynamic expression changes between these two tissue compartments. Gpc4, Sdc2, Spock2, Dcn and Lum were expressed at higher levels in the dental epithelium at E11.5, whereas their expression was significantly higher in the dental mesenchyme at E13.5, which coincides with the odontogenic potential shift. Moreover, the glycosaminoglycan biosynthetic enzymes Ext1, Hs3st1/5, Hs6st2/3, Ndst3 and Sulf1 also exhibited early upregulation in the epithelium but showed markedly higher expression in the mesenchyme after the odontogenic potential shift. Conclusion This study reveals the dynamic expression profile of extracellular proteoglycans and their biosynthetic enzymes during the dental epithelium–mesenchymal interaction. This study offers new insight into the roles of extracellular proteoglycans and their distinct sulfation underlying early odontogenesis.

Fig. S1: BTK mutations detected in cDNA in five FL BTK mutant cases. Fig. S2:BTK mutations destabilize the mutant BTK proteins. Fig. S3:BTK mutations do not influence PLCγ2-1217 phosphorylation in reconstituted lymphoma cell lines. Fig. S4:BTK mutations do not influence PLCγ2-759 phosphorylation in reconstituted lymphoma cell lines Fig. S5:Preserved PLCγ2-1217 phosphorylation in OCI-LY7 BTK-/- BLK-/- cells. Fig. S6:PLCγ2-1217 or PLCγ2-759 phosphorylation in OCI-LY7 BTK-/- BLK-/- or SUDHL4 BTK-/- BLK-/- cells treated with kinase inhibitors. Fig. S7:BTK mutations enhance anti-IgM induced AKT308 phosphorylation Fig. S8: Acute inhibition of BTK by ibrutinib or acalabrutinib does not augment anti-Ig induced AKT phosphorylation Fig. S9: The proteolysis targeting chimera (PROTAC)-mediated degradation of BTK protein results in augmentation of sIG-crosslinking induced AKT phosphorylation. Fig. S10:Primary human FL B cells have augmented AKT phosphorylation following surface IgM crosslinking: Fig. S11: The augmented phosphorylation of AKT by BTK mutants following anti-Ig treatment is abolished by pre-treatment with a PI3KÎ' inhibitor (CAL101) Fig. S12: Effects of BTK mutations on ibrutinib sensitivities in HBL1 and TMD8 cell lines

Supplementary Figure and Table legends

Results from IP-mass spec of HA-BTK WT and two HA-BTK mutants and a control (BTK-/- reconstituted with empty vector FG9) and embedded VENN diagram

Purpose:On the basis of the recent discovery of mutations in Bruton tyrosine kinase (BTK) in follicular lymphoma, we studied their functional properties.Experimental Design:We identified novel somatic BTK mutations in 7% of a combined total of 139 follicular lymphoma and 11 transformed follicular lymphoma cases, none of which had received prior treatment with B-cell receptor (BCR) targeted drugs. We reconstituted wild-type (WT) and mutant BTK into various engineered lymphoma cell lines. We measured BCR-induced signal transduction events in engineered cell lines and primary human follicular lymphoma B cells.Results:We uncovered that all BTK mutants destabilized the BTK protein and some created BTK kinase-dead mutants. The phospholipase C gamma 2 (PLCγ2) is a substrate of BTK but the BTK mutants did not alter PLCγ2 phosphorylation. Instead, we discovered that BTK mutants induced an exaggerated AKT phosphorylation phenotype in anti-Ig-treated recombinant lymphoma cell lines. The short hairpin RNA–mediated knockdown of BTK expression in primary human nonmalignant lymph node–derived B cells resulted in strong anti-Ig-induced AKT activation, as did the degradation of BTK protein in cell lines using ibrutinib-based proteolysis targeting chimera. Finally, through analyses of primary human follicular lymphoma B cells carrying WT or mutant BTK, we detected elevated AKT phosphorylation following surface Ig crosslinking in all follicular lymphoma B cells, including all BTK-mutant follicular lymphoma. The augmented AKT phosphorylation following BCR crosslinking could be abrogated by pretreatment with a PI3Kδ inhibitor.Conclusions:Altogether, our data uncover novel unexpected properties of follicular lymphoma–associated BTK mutations with direct implications for targeted therapy development in follicular lymphoma.See related commentary by Afaghani and Taylor, p. 2123

Mutations and associated characteristics of 10 FL cases with BTK mutations

Modulation between optical and ferroelectric properties was realized in a lateral structured ferroelectric CuInP2S6 (CIPS)/semiconductor MoS2 van der Waals (vdW) heterojunction. The ferroelectric hysteresis loop area was modulated by the optical field. Two types of photodetection properties were realized in a device by changing the ON and OFF states of the ferroelectric layer. The device was used as a photodetector in the OFF state but not in the ON state. Higher tunnelling electroresistance (TER) (~1.4×104) in a lateral structured ferroelectric tunnelling junction was crucial, and it was analyzed and modulated by the barrier height and width of the ferroelectric CIPS/semiconductor MoS2 Schottky junction. The new parameter of the ferroelectric hysteresis loop area as a function of light intensity was introduced to analyze the relationship between the ferroelectric and photodetection properties. The proposed device has potential application as optoelectronic sensory cells in the biological nervous system or as a new type of photodetector.

Glioblastoma (GBM) is the most common aggressive malignant tumor in brain neuroepithelial tumors and remains incurable. A variety of treatment options are currently being explored to improve patient survival, including small molecule inhibitors, viral therapies, cancer vaccines, and monoclonal antibodies. Among them, the unique advantages of small molecule inhibitors have made them a focus of attention in the drug discovery of glioblastoma. Currently, the most used chemotherapeutic agents are small molecule inhibitors that target key dysregulated signaling pathways in glioblastoma, including receptor tyrosine kinase, PI3K/AKT/mTOR pathway, DNA damage response, TP53 and cell cycle inhibitors. This review analyzes the therapeutic benefit and clinical development of novel small molecule inhibitors discovered as promising anti-glioblastoma agents by the related targets of these major pathways. Meanwhile, the recent advances in temozolomide resistance and drug combination are also reviewed. In the last part, due to the constant clinical failure of targeted therapies, this paper reviewed the research progress of other therapeutic methods for glioblastoma, to provide patients and readers with a more comprehensive understanding of the treatment landscape of glioblastoma.

A constellation configuration performance evaluation method is proposed for the performance evaluation of the low-orbit large-scale communication satellite constellations. The practicality and feasibility analysis of the constellation configuration is mainly studied from the constellation coverage performance. Based on the consideration of the coverage performance of the LEO satellite constellation, four simulation models are established for the single coverage rate, observation elevation angle, number of visible satellites under different observation elevation angles, and coverage efficiency of the constellation. A population distribution density function is established according to the characteristics of population distribution to find the average minimum observation elevation angle and the average number of visible satellites under the population distribution. The evaluation method is applied to three typical low-orbit large-scale communication satellite constellations, Telesat, OneWeb, and Starlink, to derive the coverage performance index values of each constellation and to compare and analyze the characteristics of the three constellations. The results show that the evaluation method can evaluate the configuration performance of different types of LEO large-scale constellations and provide a basis and reference for the optimal design and evaluation of future LEO large-scale constellation configurations.

Compared with single-target drugs, multitarget drugs may improve the safety and efficacy of the treatment of multifactorial diseases. However, few multitarget drugs are on the market or in clinical trials currently, and multitarget small molecules account for the majority. Compared with multitarget small molecules, multitarget peptides have unique advantages and show good effects in a variety of diseases. This article discusses the design process of multitarget peptides in four aspects, including target combination, peptide selection, lead generation, and lead optimization. In addition, we analyzed in detail the research cases of multitarget peptides for several multifactorial diseases over years, aiming to reveal the trends and insights of the potential uses of multitarget peptides.

Desert wetland is a special ecological environment as water is fundamental to maintaining existence. The soil water of sandy wetland links surficial water and groundwater. This study Takes Habahu National Wetland Nature Reserve as the research area and the water movement characteristics of soil profile as the research purpose. According to the altitude and topographic characteristics, the main focus is monitoring soil moisture in different layers at specific sites. The results show that: (1) In the core area of sandy wetland, the water movement of the soil profile is slow with lower infiltration and evaporation; (2) On the slopes around the wetland, the surface water is recharged by rapid leakage along with the underlying impermeable layer after precipitation due to the sand coverage; (3) In the desert hinterland outside the wetland, the water rapidly infiltrates after precipitation and flows into different groundwater systems along the structural characteristics of the underlying stratum to supplement the nearby wetlands. Based on these characteristics, we put forward the unique viewpoints of environmental protection in sandy wetlands: (1) focus on the protection of surface organisms in the core area of sandy wetland to reduce evaporation and improvethe soil water-holding capacity; (2) Appropriate engineering and biological measures should be applied to the slope outside the core area to reduce surface evaporation and plant transpiration and improve the soil moisture; (3) In the periphery area of the wetland, infiltration should be promoted to ensure the source of water supply to wetlands, which would maintain the existence of wetlands and give full play to their ecological functions. In addition, this study analyzed the relationship between soil moisture and plant diversity of 35 species. 16 plants are considered to be suitable for planting in core area of sandy wetland and 9 plants for planting in the desert hinterland outside the wetland.

In recent years, the incidence of critical-size bone defects has significantly increased. Critical-size bone defects seriously affect patients’ motor functions and quality of life and increase the need for additional clinical treatments. Bone tissue engineering (BTE) has made great progress in repairing critical-size bone defects. As one of the main components of bone tissue engineering, stem cell-based therapy is considered a potential effective strategy to regenerate bone tissues. However, there are some disadvantages including phenotypic changes, immune rejection, potential tumorigenicity, low homing efficiency and cell survival rate that restrict its wider clinical applications. Evidence has shown that the positive biological effects of stem cells on tissue repair are largely mediated through paracrine action by nanostructured extracellular vesicles (EVs), which may overcome the limitations of traditional stem cell-based treatments. In addition to stem cell-derived extracellular vesicles, the potential therapeutic roles of nonstem cell-derived extracellular vesicles in critical-size bone defect repair have also attracted attention from scholars in recent years. Currently, the development of extracellular vesicles-mediated cell-free regenerative medicine is still in the preliminary stage, and the specific mechanisms remain elusive. Herein, the authors first review the research progress and possible mechanisms of extracellular vesicles combined with bone tissue engineering scaffolds to promote bone regeneration via bioactive molecules. Engineering modified extracellular vesicles is an emerging component of bone tissue engineering and its main progression and clinical applications will be discussed. Finally, future perspectives and challenges of developing extracellular vesicle-based regenerative medicine will be given. This review may provide a theoretical basis for the future development of extracellular vesicle-based biomedicine and provide clinical references for promoting the repair of critical-size bone defects.

Reduced sensitivity to chemotherapeutic drugs is almost inevitable in lung adenocarcinoma patients. Thus, understanding the relevant mechanisms is urgent. Positive cofactor 4 (PC4) was at first revealed to be a coactivator of basal transcription. Previous research has shown that PC4 participates in various cellular processes in normal and malignant cells. However, it is still unknown whether PC4 participates in altering the lung adenocarcinoma cell sensitivity to chemotherapy, and the relevant mechanisms remain to be explained. In this study, we discovered that PC4 was overexpressed in cisplatin-resistant lung adenocarcinoma cells. PC4 decreased cisplatin’s cytotoxic effects on lung adenocarcinoma in vivo and in vitro. Furthermore, PC4 positively correlated with SOX9 in multiple cancers. PC4 was an upstream regulator of SOX9 in lung adenocarcinoma. Furthermore, PC4 mediated lung adenocarcinoma cell sensitivity to the HIF-PH inhibitor DMOG and the mTOR inhibitor rapamycin, and PC4 mediated the synergistic effect of DMOG and cisplatin. Finally, PC4 destabilized HIF-1α upon cisplatin treatment. Our research showed that PC4 participates in mediating lung adenocarcinoma cell sensitivity to multiple drugs. Mechanistically, PC4 governs multiple downstream pathways associated with chemotherapy resistance, including the SOX9 and HIF-1α pathways. Thus, PC4 is a promising chemotherapeutic target in lung adenocarcinoma.

Leukemia is a common, multiple and dangerous blood disease, whose early diagnosis and treatment are very important. At present, the diagnosis of leukemia heavily relies on morphological examination of blood cell images by pathologists, which is tedious and time-consuming. Meanwhile, the diagnostic results are highly subjective, which may lead to misdiagnosis and missed diagnosis. To address the gap above, we proposed an improved Vision Transformer model for blood cell recognition. First, a faster R-CNN network was used to locate and extract individual blood cell slices from original images. Then, we split the single-cell image into multiple image patches and put them into the encoder layer for feature extraction. Based on the self-attention mechanism of the Transformer, we proposed a sparse attention module which could focus on the discriminative parts of blood cell images and improve the fine-grained feature representation ability of the model. Finally, a contrastive loss function was adopted to further increase the inter-class difference and intra-class consistency of the extracted features. Experimental results showed that the proposed module outperformed the other approaches and significantly improved the accuracy to 91.96% on the Munich single-cell morphological dataset of leukocytes, which is expected to provide a reference for physicians' clinical diagnosis.白血病是一种常见多发且较为凶险的血液疾病，其早期发现与治疗至关重要。目前白血病类型的诊断主要依靠病理医师对血细胞图像进行形态学检查，该过程枯燥、费时，且诊断结果有较强的主观性，易发生误诊与漏诊。针对上述问题，本文提出了一种基于改进Vision Transformer的血细胞图像识别方法。首先，使用快速区域卷积神经网络从图像中定位并裁剪出单个血细胞图像切片。然后，将单细胞图像划分为多个图像块并输入到编码层中进行特征提取。本文基于Transformer的自注意机制提出了稀疏注意力模块，该模块能够筛选出图像中的辨识性区域，进一步提升模型的细粒度特征表达能力。最后，本文采用对比损失函数，进一步增加分类特征的类内一致性与类间差异性。实验结果表明，本文模型在慕尼黑血细胞形态学数据集上的识别准确率为91.96%，有望为医师临床诊断提供参考依据。.

Background: Administrative claims for aortic stenosis (AS) regurgitation may be useful, but their accuracy and ability to identify individuals at risk for valve-related outcomes have not been well characterized. Methods: Using echocardiographic (transthoracic echocardiogram [TTE]) reports linked to US Medicare claims, 2017 to 2018, the performance of candidate International Classification of Diseases, Tenth Revision claims to ascertain AS/aortic regurgitation was evaluated. The optimal performing algorithm was tested against outcomes at 1-year after TTE in a separate 100% sample of US Medicare claims, 2017 to 2019. Results: Of those included in the derivation (N=5497, mean age 74.4±11.0 years, 49.7% female), any AS or aortic regurgitation was present in 24% and 38.8%, respectively. The sensitivity and specificity of International Classification of Diseases, Tenth Revision code I35.0 for identification of any AS was 53.1% and 94.8%, respectively. Among those with an I35.0 code, 40.3% had severe AS. Claims were unable to distinguish disease severity (ie, severe versus nonsevere) or subtype (eg, bicuspid or rheumatic AS), and were insensitive and nonspecific for aortic regurgitation of any severity. Among all beneficiaries who received a TTE (N=4 033 844), adjusting for age, sex, and 27 comorbidities, those with an I35.0 code had a higher adjusted risk of all-cause mortality (adjusted hazard ratio, 1.33 [95% CI, 1.31–1.34]), heart failure hospitalization (adjusted hazard ratio, 1.37 [95% CI, 1.34–1.41]), and aortic valve replacement (adjusted hazard ratio, 34.96 [95% CI, 33.74–36.22]). Conclusions: Among US Medicare beneficiaries receiving a TTE, International Classification of Diseases, Tenth Revision claims, though identifying a population at significant greater risk of valve-related outcomes, failed to identify nearly half of individuals with AS and were unable to distinguish disease severity or subtype. These results argue against the widespread use of International Classification of Diseases, Tenth Revision claims to screen for patients with AS and suggests the need for improved coding algorithms and alternative systems to extract TTE data for quality improvement and hospital benchmarking.

Background The AHA Registry (American Heart Association COVID‐19 Cardiovascular Disease Registry) captures detailed information on hospitalized patients with COVID‐19. The registry, however, does not capture information on social determinants of health or long‐term outcomes. Here we describe the linkage of the AHA Registry with external data sources, including fee‐for‐service (FFS) Medicare claims, to fill these gaps and assess the representativeness of linked registry patients to the broader Medicare FFS population hospitalized with COVID‐19. Methods and Results We linked AHA Registry records of adults ≥65 years from March 2020 to September 2021 with Medicare FFS claims using a deterministic linkage algorithm and with the American Hospital Association Annual Survey, Rural Urban Commuting Area codes, and the Social Vulnerability Index using hospital and geographic identifiers. We compared linked individuals with unlinked FFS beneficiaries hospitalized with COVID‐19 to assess the representativeness of the AHA Registry. A total of 10 010 (47.0%) records in the AHA Registry were successfully linked to FFS Medicare claims. Linked and unlinked FFS beneficiaries were similar with respect to mean age (78.1 versus 77.9, absolute standardized difference [ASD] 0.03); female sex (48.3% versus 50.2%, ASD 0.04); Black race (15.1% versus 12.0%, ASD 0.09); dual‐eligibility status (26.1% versus 23.2%, ASD 0.07); and comorbidity burden. Linked patients were more likely to live in the northeastern United States (35.7% versus 18.2%, ASD 0.40) and urban/metropolitan areas (83.9% versus 76.8%, ASD 0.18). There were also differences in hospital‐level characteristics between cohorts. However, in‐hospital outcomes were similar (mortality, 23.3% versus 20.1%, ASD 0.08; home discharge, 45.5% versus 50.7%, ASD 0.10; skilled nursing facility discharge, 24.4% versus 22.2%, ASD 0.05). Conclusions Linkage of the AHA Registry with external data sources such as Medicare FFS claims creates a unique and generalizable resource to evaluate long‐term health outcomes after COVID‐19 hospitalization.

In patients with localized scleroderma (LoS), facial deformity induced by subcutaneous atrophy greatly reduces life quality. Autologous fat grafting (AFG) is used for volume restoration but with low‐fat retention due to various reasons. Adipose‐derived stem cells (ADSCs) have shown potential effects in improving fat retention. We aimed to compare the feasibility and efficacy of improving fat retention in LoS patients among the ADSCs‐assisted, the stromal vascular fraction (SVF)‐assisted and conventional AFG methods. A pilot study with a 6‐month follow‐up among 18 LoS patients was conducted. Participants were randomly assigned into three AFG groups: conventional group, SVF‐assisted group, and ADSCs‐assisted group. The SVF‐assisted group received SVF‐assisted AFG at the SVF:fat ratio of 1:1. The ADSCs‐assisted group received the mixture of ADSCs‐enriched fat graft supplemented with 5 × 105 ADSCs/mL fat. Volume retention was measured by magnetic resonance imaging, and clinical photographs were taken for outcome evaluation. At sixth‐month follow‐up, the fat retention of ADSCs‐assisted group was 49.83 ± 3.61%, significantly higher than 31.75 ± 1.73% of SVF‐assisted group (P = .0004), and 21.86 ± 1.68% of the conventional group (P, Adipose‐derived stem cells (ADSCs)‐assisted autologous fat grafting (AFG) significantly improved fat retention in localized scleroderma patients. This pilot study shows the potential advantage of ADSCs‐assisted AFG in the correction of facial atrophy of localized scleroderma patients. SVF, stromal vascular fraction.

Desert wetlands play a significant role in flood regulation, water purification, biodiversity maintenance, and regional ecological environment improvement. Vegetation is a key factor affecting wetland function and it is important to study the features of plant community and the driving forces of plant community succession. The Ningxia Habahu National Nature Reserve, a typical desert wetland ecosystem, was selected to study the features of wetland plant communities including plant density, biomass and frequency, and vegetation coverage, as well as the habitats, structural characteristics, species composition, dominant population structure, and other characteristics of different ecosystems. Data was collected using long-term fixed-point observation, sampling monitoring, and other methods. The results showed that the total plant density, total biomass, Magalef index and Shannon–Wiener index of the different desert wetlands in the reserve area were all relatively low, which was caused by the poor habitat and salinization of the arid environment. There was no significant difference between the root–shoot ratio of the wetland plants in the reserve area and that of the construct species of other ecosystems. The specific leaf area of the wetland plants was also not significantly different from that of the construct species of other ecosystems. Vegetation nitrogen-to-phosphorus (N/P) ratios were found to be the key driving force for the succession of plant community in the desert wetlands. These results not only provide underlying insights for the improvement of species diversity and ecological environment, but also provide a scientific basis for the sustainable protection and restoration of typical desert wetlands.

Pulmonary microbial diversity may be influenced by biotic or abiotic conditions (e.g., disease, smoking, invasive mechanical ventilation (MV), etc.). Specially, invasive MV may trigger structural and physiological changes in both tissue and microbiota of lung, due to gastric and oral microaspiration, altered body posture, high O2 inhalation-induced O2 toxicity in hypoxemic patients, impaired airway clearance and ventilator-induced lung injury (VILI), which in turn reduce the diversity of the pulmonary microbiota and may ultimately lead to poor prognosis. Furthermore, changes in (local) O2 concentration can reduce the diversity of the pulmonary microbiota by affecting the local immune microenvironment of lung. In conclusion, systematic literature studies have found that invasive MV reduces pulmonary microbiota diversity, and future rational regulation of pulmonary microbiota diversity by existing or novel clinical tools (e.g., lung probiotics, drugs) may improve the prognosis of invasive MV treatment and lead to more effective treatment of lung diseases with precision.

Treatment of oral squamous cell carcinoma remains a challenge due to a high incidence of treatment resistance, which is followed by tumor recrudescence and metastasis to the lymph nodes. Thus, it is important to explore novel inhibitors of OSCC. Here, we aimed to identify drugs that may cooperate with histone deacetylase inhibitors to reverse the EMT, inhibit EMT and cell migration and invasion, and contribute to therapeutic efficacy. We found that treatment with 4sc-202 potently reversed the EMT and thereby inhibited cell migration and invasion in vitro, in part by inducing expression of the FoxO1 tumor-suppressor gene. Furthermore, 4sc-202 also synergized with Ink-128 to inhibit tumor migration and invasion in vitro. Mechanistically, 4sc-202 induced FoxO1 expression, whereas Ink-128 promoted nuclear translocation of FoxO1. Our findings indicated that FoxO1 might reverse the EMT by interacting with Twist1 in OSCC. In conclusion, we identified an effective combination therapy involving class I histone deacetylase and mammalian target of rapamycin complex 1/2 inhibition that effectively blocked the EMT of tumor cells by upregulating FoxO1 expression to inhibit Twist1 transcription. These data have implications for developing new targets for early diagnosis and treatment of OSCC.

Soil total carbon (TC), phosphorus (P), and nitrogen (N) exports from the weathered granite slopes are greatly influenced by the complex hydrological processes and terrain factors. In this study, the coupling loss characteristics of N-P-C via runoff and sediment were studied with two soil tanks under simulated rainfalls. Three soils respectively derived from the tillage layer (T-soil), laterite layer (L-soil), and sand layer (S-soil) were employed to determine the interactions of hydrology and topography on N-P-C exports under three rainfall intensities (1.5, 2.0, and 2.5 mm/min). The erosion degree of different soils displayed an order of S-soil > L-soil > T-soil. The results showed that surface flow was the main runoff form for L- and T-soil, while underground flow was predominant for S-soil. There was a linear correlation between sediment and surface flow (R2 > 0.78). Surface flow was the dominant pathway of P loss via runoff with underground flow being an important supplementation, and the main P loss pattern switched between dissolved phosphorus (DP) and particle phosphorus (PP) during the experiment. However, P lost via eroded sediment accounted for more than 94% of the TP loss amount. N presented an opposite trend to P and was mainly lost via underground flow. The main N loss form in surface and underground flow was NO3--N. Underground flow was the predominant total nitrogen (TN) loss pathway for S- and L-soil, followed by sediment and surface flow. For T-soil, TN lost via runoff was much greater than that carried by eroded sediment. TC for S-soil was mainly lost via underground flow while that for L- and T-soil was mostly lost via surface flow. Both N-P loss loads in surface flow and P loss load in underground flow were positively correlated with TC loss load (p < 0.05), indicating that the presence of organic matter brings about more nutrient losses. These results expand our understanding of the combined effects of rainfall intensity and erosion degree on runoff and sediment yields as well as N-P-C losses from the bare weathered granite slopes of SE China.

Localized scleroderma (LoS) is an autoimmune connective tissue disorder leading to serious long-term aesthetic impairment on patients. Objective evaluation methods are badly needed to facilitate the evaluation of the surgical treatment on individual patients and clinical studies. To develop and assess the reliability and validity of Peking Union Medical College LoS facial aesthetic index (PUMC LoSFAI). Twelve experts devoted their time and resources in the development and validation. LoS patients in the stable phase were recruited. Reliability and validity was then assessed. LoS patients were evaluated by two plastic surgeons using PUMC LoSFAI and LoS skin damage index (LoSDI). The PUMC LoSFAI comprises 4 domains for the local assessment (surface area of lesion, dyspigmentation, skin thickness and soft tissue atrophy) and 3 domains for the overall assessment (facial symmetry, proportion and profile) to describe LoS facial aesthetic impairment. Face-Q was completed by patients at each visit. Thirty-two LoS patients had 96 visits, during which 138 lesions were assessed. PUMC LoSFAI and 7 domains demonstrated substantial to excellent inter- and intra-rater reliability (ICC 0.995, κw 0.72-0.91, r 0.85–0.99, respectively). Seven domains considered to be important to extremely important variables (mean rank 3.2–3.8) had high I-CVI (> 0.78) and S-CVI (0.93). PUMC LoSFAI correlated excellently with LoSDI (r = 0.933, P

Utilizing the abundant and renewable solar energy to address the global energy shortage and water scarcity is promising. Great effort has been devoted to photothermal conversion for its typically full-spectrum utilization and high efficiency. Here, the coral-like micro/nanostructure was fabricated on an aluminum sheet by a facile laser direct writing technology. The nanocluster and microscale branches of corals endowed this black aluminum with broad-band plasmonic absorption and rapid heat transfer from the light absorption region to substrate. The black aluminum achieved ultrahigh solar absorbance of over 92.6% (>95.1% in the visible range) and excellent light heating ability (>90.6 °C under 1.0 sun). With good photothermal properties, this plasmonic absorber was used in a state-of-the-art eight-layer membrane distillation system, producing a water yield of up to 2.40 kg m-2 h-1 and a high solar conversion efficiency of 166.5% under 1-sun irradiation. Photothermal electricity was also achieved based on this system with a thermoelectric generator, with a water yield of 0.89 kg m-2 h-1 and a maximum electrical power output of 7.21 μW cm-2 under 1.0 sun. Considering the excellent performance of the plasmon-enhanced black aluminum, this work provides an alternative and feasible route toward high-efficient utilization of the solar energy.

Purpose: On the basis of the recent discovery of mutations in Bruton tyrosine kinase (BTK) in follicular lymphoma, we studied their functional properties. Experimental Design: We identified novel somatic BTK mutations in 7% of a combined total of 139 follicular lymphoma and 11 transformed follicular lymphoma cases, none of which had received prior treatment with B-cell receptor (BCR) targeted drugs. We reconstituted wild-type (WT) and mutant BTK into various engineered lymphoma cell lines. We measured BCR-induced signal transduction events in engineered cell lines and primary human follicular lymphoma B cells. Results: We uncovered that all BTK mutants destabilized the BTK protein and some created BTK kinase-dead mutants. The phospholipase C gamma 2 (PLCγ2) is a substrate of BTK but the BTK mutants did not alter PLCγ2 phosphorylation. Instead, we discovered that BTK mutants induced an exaggerated AKT phosphorylation phenotype in anti-Ig-treated recombinant lymphoma cell lines. The short hairpin RNA–mediated knockdown of BTK expression in primary human nonmalignant lymph node–derived B cells resulted in strong anti-Ig-induced AKT activation, as did the degradation of BTK protein in cell lines using ibrutinib-based proteolysis targeting chimera. Finally, through analyses of primary human follicular lymphoma B cells carrying WT or mutant BTK, we detected elevated AKT phosphorylation following surface Ig crosslinking in all follicular lymphoma B cells, including all BTK-mutant follicular lymphoma. The augmented AKT phosphorylation following BCR crosslinking could be abrogated by pretreatment with a PI3Kδ inhibitor. Conclusions: Altogether, our data uncover novel unexpected properties of follicular lymphoma–associated BTK mutations with direct implications for targeted therapy development in follicular lymphoma. See related commentary by Afaghani and Taylor, p. 2123

Cell sheets from bone marrow mesenchymal stem cells (BMSC) have been widely used in the field of bone tissue engineering, although their source remains a challenging issue. In this study, adipose-derived stem cells (ADSC) were induced to differentiate into osteoblasts, and the incorporation of coral scaffolds with ADSC sheets for bone formation at an ectopic site was also investigated. First, ADSC isolated from inguinal adipose tissue of New Zealand rabbits were cultured for two weeks without passaging under osteogenic induction, and the microstructures of cell sheets were analysed by histological and scanning electron microscope (EM) observation. In addition, the activity of alkaline phosphatase (ALP) and alizarin red staining was also measured to detect their osteogenic ability. Subsequently, ADSC were proved to be able to proliferate well when seeded on the coral scaffolds. Next, coral scaffolds were wrapped in cell sheets to prepare sheet-coral complexes, which were implanted into subcutaneous pockets in nude mice. At eight weeks after implantation, gross examination, microcomputed tomography (MicroCT), and histological analysis were investigated to assess new bone formation. MicroCT scanning and histological analysis showed that there was more highly dense tissue formed in the complex group than control group (p=0.0004). These results indicated that osteoblastic ADSC sheets could be used to construct engineered bone and the incorporation of coral scaffolds with ADSC sheets significantly improved bone formation, providing a newly approach for bone tissue engineering.

Bioactive scaffolds from synthetical polymers or decellularized cartilage matrices have been widely used in osteochondral regeneration. However, the risks of potential immunological reactions and the inevitable donor morbidity of these scaffolds have limited their practical applications. To address these issues, a biological extracellular matrix (ECM) scaffold derived from allogenic decellularized bone marrow mesenchymal stem cell (BMSC) sheets was established for osteochondral reconstruction. BMSCs were induced to form cell sheets. Three different concentrations of sodium dodecyl sulfate (SDS), namely, 0.5%, 1%, and 3%, were used to decellularize these BMSC sheets to prepare the ECM. Histological and microstructural observations were performed in vitro and then the ECM scaffolds were implanted into osteochondral defects in rabbits to evaluate the repair effect in vivo. Treatment with 0.5% SDS not only efficiently removed BMSCs but also successfully preserved the original structure and bioactive components of the ECM When compared with the 1% and 3% SDS groups, histological observations substantiated the superior repair effect of osteochondral defects, including the simultaneous regeneration of well-vascularized subchondral bone and avascular articular cartilage integrated with native tissues in the 0.5% SDS group. Moreover, RT-PCR indicated that ECM scaffolds could promote the osteogenic differentiation potential of BMSCs under osteogenic conditions while increasing the chondrogenic differentiation potential of BMSCs under chondrogenic conditions. Allogenic BMSC sheets decellularized with 0.5% SDS treatment increased the recruitment of BMSCs and significantly improved the regeneration of osteochondral defects in rabbits, thus providing a prospective approach for both articular cartilage and subchondral bone reconstruction with cell-free transplantation.

This article discusses the factors that affect the possibility of the approval of same-sex marriage in China, or why China chose not to approve it even if the majority of other equally economically developed countries had done. The article focuses specifically on cultural and economic views. Due to the intrinsic taboo in Chinese society, meaning that one rarely discusses politics and/or homosexuality, there is currently a lack of studies investigating homosexuality and policies related to this topic. Therefore, this article sets up another bridge between same-sex marriage, homosexuality, and governmental policy in China, allowing the reader to reach beyond some Western-focused discussions on this topic. The data used in this article originates from statistics from large organizations, and NGOs, as well as official statistics from the Chinese government. For example, it includes data that demonstrate the lowering growth rate of the population in China and other data showing that over 57% of interviewees reported that society should not accept homosexuals. As the article argues, the root reason for the non-approval of same-sex marriage has its origins in the lack of population growth - which then extends to an economic crisis - and Chinese culture. After all, one can still find prejudice against homosexuals in the Chinese population, which influences the approval of policies such as same-sex marriage. This article provides a detailed discussion as well as evidence on the two reasons.

We proposed and experimentally demonstrated a low loss modified Bezier bend for silicon and silicon nitride photonic integrated circuits. Both simulation and experimental results confirm that the modified Bezier bend can effectively reduce the bend loss for silicon and silicon nitride platform. At a bend radius of 1 µm, the reduction of bend loss from 0.367 dB/90° of circular bend and 0.35 dB/90° of traditional Bezier bend to 0.117 dB/90° of modified Bezier bend for silicon platform was experimentally demonstrated. For a 12-µm radius silicon nitride bend, the bend loss reduction from 0.65 dB/90° of circular bend and 0.575 dB/90° of traditional Bezier bend to 0.32 dB/90° was achieved. The proposed modified Bezier bend design can also be applied to other material systems, such as InP, LN, GaAs, etc., to effectively reduce the bend waveguide loss.

Routinely-collected health data can be employed to emulate a target trial when randomized trial data are not available. Patients within provider-based clusters likely exert and share influence on each other’s treatment preferences and subsequent health outcomes and this is known as dissemination or spillover. Extending a framework to replicate an idealized two-stage randomized trial using routinely-collected health data, an evaluation of disseminated effects within provider-based clusters is possible. In this paper, we propose a novel application of causal inference methods for dissemination to retrospective cohort studies in administrative claims data and evaluate the impact of the normality of the random effects distribution for the cluster-level propensity score on estimation of the causal parameters. An extensive simulation study was conducted to study the robustness of the methods under different distributions of the random effects. We applied these methods to evaluate baseline prescription for medications for opioid use disorder among a cohort of patients diagnosed opioid use disorder and adjust for baseline confounders using information obtained from an administrative claims database. We discuss future research directions in this setting to better address unmeasured confounding in the presence of disseminated effects.

Background The formation of supernumerary teeth is an excellent model for studying the molecular mechanisms that control stem/progenitor cell homeostasis needed to generate a renewable source of replacement cells and tissues. Although multiple growth factors and transcriptional factors have been associated with supernumerary tooth formation, the regulatory inputs of extracellular matrix in this regenerative process remains poorly understood. Results In this study, we present evidence that disrupting glycosaminoglycans (GAGs) in the dental epithelium of mice by inactivating FAM20B, a xylose kinase essential for GAG assembly, leads to supernumerary tooth formation in a pattern reminiscent of replacement teeth. The dental epithelial GAGs confine murine tooth number by restricting the homeostasis of Sox2(+) dental epithelial stem/progenitor cells in a non-autonomous manner. FAM20B-catalyzed GAGs regulate the cell fate of dental lamina by restricting FGFR2b signaling at the initial stage of tooth development to maintain a subtle balance between the renewal and differentiation of Sox2(+) cells. At the later cap stage, WNT signaling functions as a relay cue to facilitate the supernumerary tooth formation. Conclusions The novel mechanism we have characterized through which GAGs control the tooth number in mice may also be more broadly relevant for potentiating signaling interactions in other tissues during development and tissue homeostasis.

Fabrication of membranes with high antifouling and self-cleaning ability is a long-term pursuit of research community. For this purpose, the current work proposed a strategy to use an external magnetic field to arrange the magnetic TiO2@Ni particles (MNPs) onto the polymeric polyether sulfone (PES) membrane surface. The characterization results clearly indicated that the MNPs were successfully embedded onto the membrane surface instead of uniformly distributing into the membrane bulk. Because of this superficial distribution, the prepared composite membrane exhibited a flux of 871.2 ± 2.9 L·m−2·h−1·bar−1, which was 5 times flux of the pristine PES membrane. Meanwhile, it remained a rejection of 95.85% bovine serum albumin (BSA), which was also better than that of the pristine PES membrane. The cycle filtration experiments verified that the composite membrane possessed promoted antifouling ability for filtrating BSA, yeast extract fermentation (YEF), ammonium alginate (SA) and humic acid (HA) solutions. The antifouling mechanism was analyzed by the total interaction energies (ΔGTotal), which were quantitatively evaluated by using the extended Derjaguin–Landau–Verwey–Overbeek (XDLVO) theory. Moreover, it was interestingly found that the composite membrane possessed a self-cleaning property under radiation of UV light and sunlight. The optimal membrane after self-cleaning presented flux recovery ratio (FRR) of 75.4%, 99.56%, 92.11% and 98.26% for BSA, YEF, SA and HA solutions, respectively. This work demonstrated a novel way to fabricate membranes with high antifouling and self-cleaning ability for water treatment.