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Objective: To retrospectively evaluate complications reported in dogs and cats with a closed suction subcutaneous drain that were either managed completely in hospital (Group ND) or discharged home for ongoing outpatient care (Group D)., Animals: 101 client-owned animals involving 94 dogs and 7 cats with a subcutaneous closed suction drain placed during a surgical procedure., Procedures: Electronic medical records (January 2014 to December 2022) were reviewed. Signalment, reason for drain placement, surgical procedure, location and duration of drain placement, drain discharge status, antimicrobial usage, culture and sensitivity results, and intraoperative and postoperative complications were recorded. Associations among variables were evaluated., Results: There were 77 animals in Group D and 24 animals in Group ND. Majority (n = 21/26) of complications were classified as minor and were all from Group D. Length of hospitalization in Group D (1 day) was significantly shorter than Group ND (3.25 days). Duration of drain placement was significantly longer in Group D (5.6 days) than Group ND (3.1 days). There were no associations between drain location, drain duration, or surgical site contamination with risk of complications., Clinical Relevance: There is a higher risk of complications associated with discharging an animal from hospital (37%) with a subcutaneous closed suction drain than removing it prior to discharge (4%). These complications, however, were primarily minor and easily managed. Discharging an otherwise stable animal to home with a subcutaneous closed suction drain may be feasible to decrease duration of hospitalization, cost to the owner, and stress for the animal.

Background: A 2D fluoroscopy/3D model-based registration with statistical shape modeling (SSM)-reconstructed subject-specific bone models will help reduce radiation exposure for 3D kinematic measurements of the knee using clinical alternating bi-plane fluoroscopy systems. The current study aimed to develop such an approach and evaluate in vivo its accuracy and identify the effects of the accuracy of SSM models on the kinematic measurements., Methods: An alternating interpolation-based model tracking (AIMT) approach with SSM-reconstructed subject-specific bone models was used for measuring 3D knee kinematics from dynamic alternating bi-plane fluoroscopy images. A two-phase optimization scheme was used to reconstruct subject-specific knee models from a CT-based SSM database of 60 knees using one, two, or three pairs of fluoroscopy images. Using the CT-reconstructed model as a benchmark, the performance of the AIMT with SSM-reconstructed models in measuring bone and joint kinematics during dynamic activity was evaluated in terms of mean target registration errors (mmTRE) for registered bone poses and the mean absolute differences (MAD) for each motion component of the joint poses., Results: The mmTRE of the femur and tibia for one image pair were significantly greater than those for two and three image pairs without significant differences between two and three image pairs. The MAD was 1.16 to 1.22° for rotations and 1.18 to 1.22 mm for translations using one image pair. The corresponding values for two and three image pairs were 0.75 to 0.89° and 0.75 to 0.79 mm; and 0.57 to 0.79° and 0.6 to 0.69 mm, respectively. The MAD values for one image pair were significantly greater than those for two and three image pairs without significant differences between two and three image pairs., Conclusions: An AIMT approach with SSM-reconstructed models was developed, enabling the registration of interleaved fluoroscopy images and SSM-reconstructed models from more than one asynchronous fluoroscopy image pair. This new approach had sub-millimeter and sub-degree measurement accuracy when using more than one image pair, comparable to the accuracy of CT-based methods. This approach will be helpful for future kinematic measurements of the knee with reduced radiation exposure using 3D fluoroscopy with clinically alternating bi-plane fluoroscopy systems., Competing Interests: The authors declare there are no competing interests., (©2023 Lu et al.)

Cooperation among teams or individuals of healthcare professionals (HCPs) is one of the crucial factors towards patients' survival outcome. However, it is challenging to uncover and understand such factors in the complex Multiteam System (MTS) communication networks representing daily HCP cooperation. In this paper, we present a study on MTS communication networks constructed with real-world cancer patients' Electronic Health Record (EHR) access logs. We adopt a visual analytics workflow to extract associations between semantic characteristics of MTS communication networks and the patients' survival outcomes. The workflow consists of a neural network learning phase to classify the data based on the chosen input and output attributes, a dimensionality reduction and optimization phase to produce a simplified set of results for examination, and finally an interpreting phase conducted by the user through an interactive visualization interface. We provide the insights found using this workflow with two case studies and an expert interview.

STAT6 (signal transducer and activator of transcription 6) is a transcription factor that plays a central role in the pathophysiology of allergic inflammation. We have identified 16 patients from 10 families spanning three continents with a profound phenotype of early-life onset allergic immune dysregulation, widespread treatment-resistant atopic dermatitis, hypereosinophilia with esosinophilic gastrointestinal disease, asthma, elevated serum IgE, IgE-mediated food allergies, and anaphylaxis. The cases were either sporadic (seven kindreds) or followed an autosomal dominant inheritance pattern (three kindreds). All patients carried monoallelic rare variants in STAT6 and functional studies established their gain-of-function (GOF) phenotype with sustained STAT6 phosphorylation, increased STAT6 target gene expression, and TH2 skewing. Precision treatment with the anti-IL-4Rα antibody, dupilumab, was highly effective improving both clinical manifestations and immunological biomarkers. This study identifies heterozygous GOF variants in STAT6 as a novel autosomal dominant allergic disorder. We anticipate that our discovery of multiple kindreds with germline STAT6 GOF variants will facilitate the recognition of more affected individuals and the full definition of this new primary atopic disorder., (© 2023 Sharma et al.)

Lateral ankle instability (LAI) compromises the normal kinematics of the ankle, affecting activities of daily living. In vitro kinematics of ankles with LAI during single-plane motions are available, but the active control stability of these motions remains unclear. The current study measured the 3D ankle kinematics during unresisted single-plane motion tests using a bi-plane fluoroscope with a CT model-based 2D/3D registration method in 12 patients with LAI and 14 healthy peers. The coupling of the kinematic components at the talocrural and subtalar joints was quantified by the path difference between the forward and return paths of the coupled motion. Significantly increased path differences were found in the subtalar dorsiflexion/plantarflexion and inversion/eversion components during internal/external rotation tests (p < 0.05). During inversion/eversion, significantly reduced tibiocalcaneal ranges of motion and the path differences in the talocrural and subtalar dorsiflexion/plantarflexion components were noted (p < 0.05). The current results suggest that chronic LAI had compromised control stability at the subtalar joint during internal/external rotation tests and a conservative motion control strategy with significantly reduced ranges of motion to maintain good control of out-of-plane motion components in response to direct challenges of the anterior talofibular ligament during inversion/eversion tests. The current results also suggest that, compared to kinematic patterns of individual components, the path difference of the coupled motion may serve as a better measure of the motion control stability of the ankle in differentiating LAI from healthy controls., (© 2022 Orthopaedic Research Society. Published by Wiley Periodicals LLC.)

Objective: To investigate the allocation of nursing human resources in burn centers in China. Methods: A cross-sectional survey was conducted. Using a self-designed questionnaire, a survey was carried out from January to March 2022 to investigate the January to December 2021 status of 39 burn centers in China that met the inclusion criteria based on six strategic regions and other regions, including the hospital grade and the region, the number of nurses and opening beds in the burn centers and burn intensive care units (BICUs), the age, working seniority in burn specialty, educational background, professional title, personnel employment, and turnover of nurses and training of newly recruited nurses in the burn centers. Results: This survey covered 30 provinces, municipalities, and autonomous regions in China (excluding Hong Kong Special Administrative Region, Macao Special Administrative Region, and Taiwan region of China). A total of 39 questionnaires were collected, all of which were valid. The 39 burn centers were located in 38 tertiary A hospitals and 1 tertiary B hospital, with 26 burn centers in strategic areas. The nurse/bed ratio of burn centers in the Greater Bay Area of Guangdong, Hong Kong, and Macao was the highest, while the nurse/bed ratio of burn centers in border ethnic minority area was the lowest. Except for the Chengdu-Chongqing Economic Circle, BICUs had been set up in burn centers in other regions. Among the 39 burn centers, the percentage of nurses aged 25 to 34 years was 51.21% (738/1 441), the percentage of nurses worked in burn specialty for less than 5 years was 31.16% (449/1 441), the percentage of nurses with bachelor's degree was 69.74% (1 005/1 441), and the percentage of nurses with nursing professional title was 44.14% (636/1 441), which were the highest. There were significant differences in the employment of nurses, the percentage of permanent nurses in burn centers in the collaborative development zone of Beijing-Tianjin-Hebei was 82.48% (113/137), while the percentage of permanent nurses in burn centers in important military strategic area was only 9.42% (34/361); the turnover rate of nurses was 9.03% (143/1 584), among which the turnover rate of nurses was 18.14% (80/441) in burn centers in important military strategic area. The training for newly recruited nurses in 39 burn centers was mainly based on the guidance of senior nurses and the pre-job education+specialist training. Conclusions: The burn nursing human resources in strategic areas in China are seriously insufficient and unevenly distributed, with unstable nurse team and lack of standardized specialist training. In particular, the nursing human resources in BICUs need to be equipped and supplemented urgently.

The fatty acid ethyl ester (FAEE) content of olive oil is an important indicator of its quality. At present, the international standard method used to detect FAEEs in olive oil is silica gel (Si) column chromatography-gas chromatography (GC); however, this technique presents a number of disadvantages, including complex operation, long analysis times, and high reagent consumption. In this study, a method based on Si solid phase extraction (SPE)-GC was established to determine four FAEEs in olive oil, namely, ethyl palmitate, ethyl linoleate, ethyl oleate, and ethyl stearate. First, the effects of the carrier gas were investigated, and He gas was ultimately selected as the carrier gas. Next, several internal standards were screened, and ethyl heptadecenoate ( cis -10) was determined as the optimal internal standard. The SPE conditions were also optimized, and the effects of different brands of Si SPE columns on the recoveries of analytes were compared. Finally, a pretreatment method in which 0.05 g of olive oil was extracted with n -hexane and purified through a Si SPE column (1 g/6 mL) was developed. A sample could be processed within approximately 2 h using a total reagent volume of about 23 mL. Validation of the optimized method revealed that the four FAEEs have good linearities within the range of 0.1-5.0 mg/L (coefficients of determination ( R 2 )>0.999). The limits of detection (LODs) of the method were within 0.78-1.11 mg/kg, and its limits of quantification (LOQs) were in the range of 2.35-3.33 mg/kg. The recoveries ranged from 93.8% to 104.0% at all spiked levels tested (4, 8, and 20 mg/kg), and the relative standard deviations were 2.2%-7.6%. Fifteen olive oil samples were tested using the established method, and the total FAEEs of three extra-virgin olive oil samples were found to exceed 35 mg/kg. Compared with the international standard method, the proposed method has the advantages of simpler pretreatment process, shorter operation time, lower reagent consumption and detection cost, high precision, and good accuracy. The findings provide an effective theoretical and practical reference for improving olive oil detection standards.

β-thalassemia is caused by mutations that reduce β-globin production, causing globin chain imbalance, ineffective erythropoiesis, and consequent anemia. Increased fetal hemoglobin (HbF) levels can ameliorate the severity of β-thalassemia by compensating for the globin chain imbalance. Careful clinical observations paired with population studies and advances in human genetics have enabled the discovery of major regulators of HbF switching (i.e. BCL11A, ZBTB7A) and led to pharmacological and genetic therapies for treating β-thalassemia patients. Recent functional screens using genome editing and other emerging tools have identified many new HbF regulators, which may improve therapeutic HbF induction in the future., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background: Venomous snakebites induce tissue destruction and secondary infection; however, the optimal timing of surgical intervention for these complications remains unknown. This study assessed the clinical predictors of early surgical intervention in patients with snakebites., Methods: This retrospective study included 63 patients (45 men and 18 women) with venomous snakebites. In addition to the snake species, the demographics, affected body parts, clinical characteristics, and ultrasound findings of the patients in the surgical (32 patients) and nonsurgical (31 patients) groups were analyzed and compared., Results: A higher incidence of acute compartment syndrome, local ecchymosis, skin necrosis, bullae, blisters, and fever was found in the surgical group than in the nonsurgical group, and ultrasound findings of the absence of Doppler flow were more frequently noted in the surgical group than in the nonsurgical group. After adjustment using a multivariate logistic regression model, only advanced age, Naja atra bite, local ecchymosis, and bulla or blister formation remained significant factors for surgical intervention. Furthermore, comparison of the outcomes of patients who received early (≤ 24 h) and late (> 24 h) surgical intervention revealed that the duration of continuous negative pressure wound therapy (6 vs. 15 days; P = 0.006), duration of hospital stay (13 vs. 26 days; P = 0.002), and duration of outpatient follow-up (15 vs. 36 days; P < 0.001) were significantly lower in patients who received early surgical intervention. The final reconstructive surgery was simple among the patients who received surgical intervention within 24 h of being bitten (P = 0.028)., Conclusion: In patients with snakebites, advanced age, high-risk clinical manifestations (e.g., local ecchymosis and bulla or blister formation), and Naja atra envenomation are predictors of surgical intervention within 24 h., (© 2023. The Author(s).)

Autoimmune diseases such as ankylosing spondylitis (AS) can be driven by emerging neoantigens that disrupt immune tolerance. Here, we developed a workflow to profile posttranslational modifications involved in neoantigen formation. Using mass spectrometry, we identified a panel of cysteine residues differentially modified by carboxyethylation that required 3-hydroxypropionic acid to generate neoantigens in patients with AS. The lysosomal degradation of integrin αIIb [ITGA2B (CD41)] carboxyethylated at Cys96 (ITGA2B-ceC96) generated carboxyethylated peptides that were presented by HLA-DRB1*04 to stimulate CD4 + T cell responses and induce autoantibody production. Immunization of HLA-DR4 transgenic mice with the ITGA2B-ceC96 peptide promoted colitis and vertebral bone erosion. Thus, metabolite-induced cysteine carboxyethylation can give rise to pathogenic neoantigens that lead to autoreactive CD4 + T cell responses and autoantibody production in autoimmune diseases.

Background: The incidence of classic radiation-induced liver disease (cRILD) has been significantly reduced. However, non-classic radiation-induced liver disease (ncRILD) remains a major concern following radiotherapy in patients with hepatocellular carcinoma (HCC). This study evaluated the incidence of ncRILD following intensity-modulated radiotherapy (IMRT) for Child-Pugh grade B (CP-B) patients with locally advanced HCC and established a nomogram for predicting ncRILD probability., Methods: Seventy-five CP-B patients with locally advanced HCC treated with IMRT between September 2014 and July 2021 were included. The max tumor size was 8.39 cm ± 5.06, and the median prescribed dose was 53.24 Gy ± 7.26. Treatment-related hepatotoxicity was evaluated within three months of completing IMRT. A nomogram model was formulated to predict the probability of ncRILD, using univariate and multivariate analysis., Results: Among CP-B patients with locally advanced HCC, ncRILD occurred in 17 (22.7%) patients. Two patients (2.7%) exhibited a transaminase elevation of ≥ G3, fourteen (18.7%) exhibited a Child-Pugh score increase of ≥ 2, and one (1.3%) demonstrated both a transaminase elevation of ≥ G3 and a Child-Pugh score increase of ≥ 2. No cRILD cases were observed. A mean dose to the normal liver of ≥ 15.1 Gy was used as the cutoff for ncRILD. Multivariate analysis revealed that the prothrombin time before IMRT, tumour number, and mean dose to the normal liver were independent risk factors for ncRILD. The nomogram established on the basis of these risk factors displayed exceptional predictive performance (AUC = 0.800, 95% CI 0.674-0.926)., Conclusions: The incidence of ncRILD following IMRT for CP-B patients with locally advanced HCC was acceptable. A nomogram based on prothrombin time before IMRT, tumour number, and mean dose to the normal liver accurately predicted the probability of ncRILD in these patients., (© 2023. The Author(s).)

Competing Interests: The authors declare no conflict of interest.

Objectives: To investigate the changes and significance of type 2 innate lymphoid cells (ILC2), interleukin-33 (IL-33), interleukin-25 (IL-25), thymic stromal lymphopoietin (TSLP), interleukin-5 (IL-5), and interleukin-13 (IL-13) in peripheral blood of preterm infants with bronchopulmonary dysplasia (BPD)., Methods: A total of 76 preterm infants with a gestational age of <32 weeks and a length of hospital stay of ≥14 days who were admitted to the Department of Pediatrics of the Affiliated Hospital of Jiangsu University from September 2020 to December 2021 were enrolled. According to the diagnostic criteria for BPD, they were divided into a BPD group with 30 infants and a non-BPD group with 46 infants. The two groups were compared in terms of the percentage of ILC2 and the levels of IL-33, IL-25, TSLP, IL-5, and IL-13 in peripheral blood on days 1, 7, and 14 after birth., Results: The BPD group had significantly lower birth weight and gestational age than the non-BPD group ( P <0.05). On days 7 and 14 after birth, the BPD group had significantly higher levels of ILC2, IL-33, TSLP, and IL-5 than the non-BPD group ( P <0.05), and these indices had an area under the curve of >0.7 in predicting the devolpment of BPD ( P <0.05). Multivariate logistic regression analysis showed that after adjusting for gestational age and birth weight, peripheral blood IL-33, TSLP and IL-5 on days 7 and 14 after birth were closely related to the devolpment of BPD ( P <0.05)., Conclusions: Early innate immune activation and upregulated expression of related factors may be observed in preterm infants with BPD. ILC2, IL-33, TSLP, and IL-5 may be used as biological indicators for early diagnosis of BPD.

Monolayer biphenylene is a new two-dimensional (2D) carbon allotrope, which has been experimentally synthesized and theoretically predicted to show superconductivity. In this work, we investigate functionalized biphenylene with the adsorption of Li. The superconducting critical temperature ( T c ) can be pushed from 0.59 K up to 3.91 K after Li adsorption. Our calculations confirm that the adsorption pushes the peak showing a high electronic density of states closer to the Fermi level, which usually leads to a larger T c . Furthermore, the application of biaxial tensile strain can soften phonons and further enhance the T c up to 15.86 K in Li-deposited biphenylene. Interestingly, a pair of type-II Dirac cones below the Fermi level has been observed, expanding the range of Dirac materials. It suggests that monolayer biphenylene deposited with Li may be a material with potential applications and improves the understanding of Dirac-type superconductors.

Purpose: To investigate the generalizability of transfer learning (TL) of automated tumor segmentation from cervical cancers toward a universal model for cervical and uterine malignancies in diffusion-weighted magnetic resonance imaging (DWI)., Methods: In this retrospective multicenter study, we analyzed pelvic DWI data from 169 and 320 patients with cervical and uterine malignancies and divided them into the training (144 and 256) and testing (25 and 64) datasets, respectively. A pretrained model was established using DeepLab V3 + from the cervical cancer dataset, followed by TL experiments adjusting the training data sizes and fine-tuning layers. The model performance was evaluated using the dice similarity coefficient (DSC)., Results: In predicting tumor segmentation for all cervical and uterine malignancies, TL models improved the DSCs from the pretrained cervical model (DSC 0.43) when adding 5, 13, 26, and 51 uterine cases for training (DSC improved from 0.57, 0.62, 0.68, 0.70, p < 0.001). Following the crossover at adding 128 cases (DSC 0.71), the model trained by combining data from adding all the 256 patients exhibited the highest DSCs for the combined cervical and uterine datasets (DSC 0.81) and cervical only dataset (DSC 0.91)., Conclusions: TL may improve the generalizability of automated tumor segmentation of DWI from a specific cancer type toward multiple types of uterine malignancies especially in limited case numbers., (© 2023. The Author(s).)

Interferon regulatory factor 4 (IRF4) is a transcription factor (TF) and key regulator of immune cell development and function. We report a recurrent heterozygous mutation in IRF4, p.T95R, causing an autosomal dominant combined immunodeficiency (CID) in seven patients from six unrelated families. The patients exhibited profound susceptibility to opportunistic infections, notably Pneumocystis jirovecii , and presented with agammaglobulinemia. Patients' B cells showed impaired maturation, decreased immunoglobulin isotype switching, and defective plasma cell differentiation, whereas their T cells contained reduced T H 17 and T FH populations and exhibited decreased cytokine production. A knock-in mouse model of heterozygous T95R showed a severe defect in antibody production both at the steady state and after immunization with different types of antigens, consistent with the CID observed in these patients. The IRF4 T95R variant maps to the TF's DNA binding domain, alters its canonical DNA binding specificities, and results in a simultaneous multimorphic combination of loss, gain, and new functions for IRF4. IRF4 T95R behaved as a gain-of-function hypermorph by binding to DNA with higher affinity than IRF4 WT . Despite this increased affinity for DNA, the transcriptional activity on IRF4 canonical genes was reduced, showcasing a hypomorphic activity of IRF4 T95R . Simultaneously, IRF4 T95R functions as a neomorph by binding to noncanonical DNA sites to alter the gene expression profile, including the transcription of genes exclusively induced by IRF4 T95R but not by IRF4 WT . This previously undescribed multimorphic IRF4 pathophysiology disrupts normal lymphocyte biology, causing human disease.

Stroke, a neurological emergency, is a leading cause of death and disability in adults worldwide. In acute or rehabilitative stages, stroke survivors sustain variable neurological recovery with long-term disabilities. The influence of post-stroke nutritional status on long-term survival has not been confirmed. Using the United States National Health and Nutrition Examination Survey data (2001−2010), we conducted a matched-cohort analysis (929 and 1858 participants in stroke and non-stroke groups, respectively) to investigate the influence of nutritional elements on post-stroke survival. With significantly lower nutrient consumption, the mortality risk was 2.2 times higher in stroke patients compared to non-stroke patients (Kaplan−Meier method with Cox proportional hazards model: adjusted hazard ratio, 2.208; 95% confidence interval: 1.887−2.583; p < 0.001). For several nutritional elements, the lower consumption group had significantly shorter survival than the higher consumption stroke subgroup; moreover, stroke patients with the highest 25% nutritional intake for each nutritional element, except moisture and total fat, had significantly shorter survival than non-stroke patients with the lowest 25% nutrition. Malnutrition is highly prevalent in stroke patients and is associated with high mortality rates. The dynamic change in energy requirements throughout the disease course necessitates dietary adjustment to ensure adequate nutritional intake.

Evidence points to the indispensable function of alveolar macrophages (AMs) in normal lung development and tissue homeostasis. However, the importance of AMs in bronchopulmonary dysplasia (BPD) has not been elucidated. Here, we identified a significant role of abnormal AM proliferation and polarization in alveolar dysplasia during BPD, which is closely related to the activation of the IL-33-ST2 pathway. Compared with the control BPD group, AMs depletion partially abolished the epithelialmesenchymal transition process of AECII and alleviated pulmonary differentiation arrest. In addition, IL-33 or ST2 knockdown has protective effects against lung injury after hyperoxia, which is associated with reduced AM polarization and proliferation. The protective effect disappeared following reconstitution of AMs in injured IL-33 knockdown mice, and the differentiation of lung epithelium was blocked again. In conclusion, the IL-33-ST2 pathway regulates AECII transdifferentiation by targeting AMs proliferation and polarization in BPD, which shows a novel strategy for manipulating the IL-33-ST2-AMs axis for the diagnosis and intervention of BPD., (© 2022 The Authors. Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Health literacy is the ability to understand, process, and obtain health information and make suitable decisions about health care [3]. Traditionally, text has been the main medium for delivering health information. However, virtual assistants are gaining popularity in this digital era; and people increasingly rely on audio and smart speakers for health information. We aim to identify audio/text features that contribute to the difficulty of the information delivered over audio. We are creating a health-related audio corpus. We selected text snippets and calculated seven text features. Then, we converted the text snippets to audio snippets. In a pilot study with Amazon Mechanical Turk (AMT) workers, we measured the perceived and actual difficulty of the audio using the response of multiple choice and free recall questions. We collected demographic information as well as bias about doctors' gender, task preference, and health information preference. Thirteen workers completed thirty audio snippets and related questions. We found a strong correlation between text features lexical chain, and the dependent variables, and multiple choice response, percentage of matching word, percentage of similar word, cosine similarity, and time taken (in seconds). In addition, doctors were generally perceived to be more competent than warm. How warm workers perceive male doctors correlated significantly with perceived difficulty.

Sex steroid hormones influence olfactory-mediated social behaviors, and it is generally hypothesized that these effects result from circulating hormones and/or neurosteroids synthesized in the brain. However, it is unclear whether sex steroid hormones are synthesized in the olfactory epithelium or the olfactory bulb, and if they can modulate the activity of the olfactory sensory neurons. Here, we review important discoveries related to the metabolism of sex steroids in the mouse olfactory epithelium and olfactory bulb, along with potential areas of future research. We summarize current knowledge regarding the expression, neuroanatomical distribution, and biological activity of the steroidogenic enzymes, sex steroid receptors, and proteins that are important to the metabolism of these hormones and reflect on their potential to influence early olfactory processing. We also review evidence related to the effects of sex steroid hormones on the development and activity of olfactory sensory neurons. By better understanding how these hormones are metabolized and how they act both at the periphery and olfactory bulb level, we can better appreciate the complexity of the olfactory system and discover potential similarities and differences in early olfactory processing between sexes., (© 2022. The Author(s).)

Theoretically and experimentally, MXenes consisting of Mo and C have aroused much interest due to superconductivity in their films and even monolayer forms. Here, based on first-principles calculations, we systematically calculate the electronic structure, phonon dispersion, and electron-phonon coupling (EPC) of monolayer Mo 2 C (both T- and H-phases), Mo 3 C 2 , and Mo 3 C 3 . The results show that H-Mo x C y ( x = 2 or 3, y = 1-3) always have lower total energies than their corresponding T phase and other configurations. All these two-dimensional (2D) molybdenum carbides are metals and some of them display weak phonon-mediated superconductivity at different superconducting transition temperatures ( T c ). The Mo 4d-orbitals play a critical role in their electronic properties and the Mo atomic vibrations play a dominant role in their low-frequency phonons, EPC, and superconductivity. By comparison, we find that increasing the Mo content can enhance the EPC and T c . Besides, we further explore the impact of strain engineering on their superconducting related physical quantities. With increasing biaxial stretching, the phonon dispersions are gradually softened to form some soft modes, which can trigger some peaks of α 2 F ( ω ) in the low-frequency region and evidently increase the EPC λ . The T c of H-Mo 2 C can be increased up to 11.79 K. Upon further biaxial stretching, charge density waves may appear in T-Mo 2 C, H-Mo 3 C 2 , and H-Mo 3 C 3 .

Introduction: Mild cognitive impairment (MCI) is considered a transitional stage between soundness of mind and dementia, often involving problems with memory, which may lead to abnormal postural control and altered end-point control when dealing with neuromechanical challenges during obstacle-crossing. The study aimed to identify the end-point control and angular kinematics of the pelvis-leg apparatus while crossing obstacles for both leading and trailing limbs., Methods: 12 patients with MCI (age: 66.7 ± 4.2 y/o; height: 161.3 ± 7.3 cm; mass: 62.0 ± 13.6 kg) and 12 healthy adults (age: 67.7 ± 2.9 y/o; height: 159.3 ± 6.1 cm; mass: 61.2 ± 12.0 kg) each walked and crossed obstacles of three different heights (10, 20, and 30% of leg length). Angular motions of the pelvis and lower limbs and toe-obstacle clearances during leading- and trailing-limb crossings were calculated. Two-way analyses of variance were used to study between-subject (group) and within-subject (obstacle height) effects on the variables. Whenever a height effect was found, a polynomial test was used to determine the trend. A significance level of α = 0.05 was set for all tests., Results: Patients with MCI significantly increased pelvic anterior tilt, hip abduction, and knee adduction in the swing limb during leading-limb crossing when compared to controls ( p  < 0.05). During trailing-limb crossing, the MCI group showed significantly decreased pelvic posterior tilt, as well as ankle dorsiflexion in the trailing swing limb ( p  < 0.05)., Conclusion: Patients with MCI adopt altered kinematic strategies for successful obstacle-crossing. The patients were able to maintain normal leading and trailing toe-obstacle clearances for all tested obstacle heights with a specific kinematic strategy, namely increased pelvic anterior tilt, swing hip abduction, and knee adduction during leading-limb crossing, and decreased pelvic posterior tilt and swing ankle dorsiflexion during trailing-limb crossing. The current results suggest that regular monitoring of obstacle-crossing kinematics for reduced toe-obstacle clearance or any signs of changes in crossing strategy may be helpful for early detection of compromised obstacle-crossing ability in patients with single-domain amnestic MCI. Further studies using a motor/cognitive dual-task approach on the kinematic strategies adopted by multiple-domain MCI will be needed for a complete picture of the functional adaptations in such a patient group., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Lu, Kuan, Wu, Lu, Tsai, Chen and Lu.)

Bronchiectasis is a common comorbidity in chronic obstructive pulmonary disease (COPD). There are limited data regarding the incidence of bronchiectasis in COPD. The purpose of the study was to use a nationwide database to evaluate the incidence of bronchiectasis in COPD in Taiwan. We used a cohort of 2,000,000 individuals followed from 2005 to 2018. Patients with COPD diagnosed between January 1, 2011, and December 31, 2017, were selected, and those with bronchiectasis before COPD were excluded. In total, 134,366 patients with COPD were enrolled, and propensity score matching was used to ensure homogeneity of baseline characteristics between the COPD and non-COPD groups. The incidence rate of bronchiectasis was higher in the COPD group than in the non-COPD group (87.83 vs 69.80 per 10,000 person-years). The adjusted hazard ratio (1.9; 95% confidence interval 1.75-2.05; P < 0.001) of bronchiectasis indicated that the risk of bronchiectasis was 1.9 times higher for patients with COPD than for patients without COPD. In the COPD group, the age-stratified incidence rates of bronchiectasis increased with age (55.01, 80.92, 101.52, and 105.23 for 40-49, 50-59, 60-69, and over 70 years, respectively). The incidence of bronchiectasis was higher in patients with COPD than in the general population, the risk of bronchiectasis increased with age in COPD, and post-tuberculosis status was an important risk factor for bronchiectasis., Competing Interests: Conflict of interest: Authors have no conflict of interest to declare., (© 2022 the author(s), published by De Gruyter.)

Musk was originally identified in male musk deer and other mammals to mark territories and attract females. In humans, musk compounds are widely used in perfumes and consumer products for their superior perceptual odor quality. 1 , 2 , 3 , 4 , 5 Strikingly diverse natural and synthetic chemicals have exhibited a similar "musky" odor, which has resulted in diverse models of musk odor perception and raises questions regarding the simplistic associations between chemical features and odor quality. Scientists' lack of understanding of this principle has hampered the design of a novel musk compound. Here, we functionally identified the odorant receptor, OR5A2, as a receptor for the musky odor of diverse musk compounds. First, we discovered that engineered OR5A2 with enhanced expression in heterologous cells is sensitive to and selective of musk compounds in all four structural classes. Second, the clarified functional variation of OR5A2 accounts for the reported association between genetic variation and perception in a musk compound. Finally, the revealed ligand selectivity of OR5A2 provides insight into developing a trained model to use machine learning-based virtual screening on candidates for a new musk compound. We propose that OR5A2 contributes to the long-sought gateway of sensing musk compounds and generating their unique odor quality., Competing Interests: Declaration of interests K.Y., J.D., and J.H. are employees of Kao Corporation. They have applied for patents related to cOR5A2. There are no products to declare. H.M. has received royalties from ChemCom, research grants from Givaudan, and consultant fees from Kao Corporation., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Transcription factors play important roles in the development of the intestinal epithelium and its ability to respond to endocrine, nutritional, and microbial signals. Hepatocyte nuclear factor 4 family nuclear receptors are liganded transcription factors that are critical for the development and function of multiple digestive organs in vertebrates, including the intestinal epithelium. Zebrafish have 3 hepatocyte nuclear factor 4 homologs, of which, hnf4a was previously shown to mediate intestinal responses to microbiota in zebrafish larvae. To discern the functions of other hepatocyte nuclear factor 4 family members in zebrafish development and intestinal function, we created and characterized mutations in hnf4g and hnf4b. We addressed the possibility of genetic redundancy amongst these factors by creating double and triple mutants which showed different rates of survival, including apparent early lethality in hnf4a; hnf4b double mutants and triple mutants. RNA sequencing performed on digestive tracts from single and double mutant larvae revealed extensive changes in intestinal gene expression in hnf4a mutants that were amplified in hnf4a; hnf4g mutants, but limited in hnf4g mutants. Changes in hnf4a and hnf4a; hnf4g mutants were reminiscent of those seen in mice including decreased expression of genes involved in intestinal function and increased expression of cell proliferation genes, and were validated using transgenic reporters and EdU labeling in the intestinal epithelium. Gnotobiotics combined with RNA sequencing also showed hnf4g has subtler roles than hnf4a in host responses to microbiota. Overall, phenotypic changes in hnf4a single mutants were strongly enhanced in hnf4a; hnf4g double mutants, suggesting a conserved partial genetic redundancy between hnf4a and hnf4g in the vertebrate intestine., (© The Author(s) 2022. Published by Oxford University Press on behalf of Genetics Society of America. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Objective: To investigate the current situation of self-perceived burden in patients with urostomy, analyze the correlation between self-perceived burden and quality of life, and explore the intermediary role of resilience and social support., Methods: The convenience sampling method was used to select 303 patients with urostomy of outpatient departments of the three tertiary hospitals in Yinchuan, Ningxia region, China, from April 1, 2020, to October 1, 2020, who then completed a survey questionnaire. The survey questionnaire contained a general data questionnaire and self-perceived burden scale, city of hope-quality of life-ostomy questionnaire, Connor-Davidson resilience scale, and social support rating scale., Results: Self-perceived burden was present among 89.8% patients with urostomy; the quality of life of patients with urostomy is low. The results showed that the self-perceived burden and quality of life, resilience, and social support are related in pairs; self-perceived burden was significantly negatively correlated with quality of life，resilience, and social support; there was a significant positive correlation between quality of life, resilience, and social support; resilience and social support were parallel mediators., Conclusions: Patients with urostomy had a heavy self-perceived burden and low quality of life. Reducing the self-perceived burden of patients with urostomy by improving the level of resilience and social support, could raise the level of quality of life. This study could provide empirical basis for nurses to take continuous nursing intervention measures in order to reduce the self-perceived burden of patients with urostomy and ultimately to improve the quality of life., Competing Interests: None of the authors has any potential financial conflicts of interest related to this manuscript., (Copyright © 2022 Yan Chang et al.)

Background: To investigate whether perceived attitudes of family and peers toward same-sex marriage (SSM) is a type of distal sexual minority stressor, as defined in minority stress theory, this cross-sectional study examined the associations of perceived attitudes of family and peers toward SSM with perceived sexual stigma from family and peers, internalized homonegativity, and mental health problems (e.g., depression, loneliness, anxiety) among gay and bisexual men in Taiwan., Methods: We recruited 400 gay and bisexual men and assessed their perceived attitudes of family and peers toward SSM; perceived sexual stigma from family and peers; internalized homonegativity; and severity of depression, loneliness, and anxiety., Results: Perceived attitudes of family and peers toward SSM (1) significantly correlated with various aspects of perceived sexual stigma from family and peers and (2) were significantly associated with internalized homonegativity, depression, loneliness, and anxiety., Conclusions: Perceived attitudes of family and peers toward SSM matched the characteristics of a distal sexual minority stressor, and as a new type of distal sexual minority stressor for lesbian, gay, and bisexual individuals, these perceived attitudes and related stress warrant greater attention from mental health professionals for the development of intervention programs., (© 2022. The Author(s).)

As an allotrope of graphene, T-graphene was predicted to be an intrinsic two-dimensional (2D) superconductor with a superconducting critical temperature ( T c ) of about 20.8 K [Gu et al. , Chin. Phys. Lett. 36 , 097401 (2019)]. In this work, based on first-principles calculations, hole doping and biaxial tensile strain (BTS) are considered to modulate the electron-phonon coupling (EPC) and superconductivity of T-graphene. It is found that the EPC constant of T-graphene is 0.807 and the calculated critical temperature T c is 28.2 K at a doping level of 0.5 hole per unit cell (3.31 × 10 14 cm -2 ) and 12% BTS. Furthermore, when 0.8 hole per unit cell (5.43 × 10 14 cm -2 ) doping and 10% BTS are applied, the EPC constant is 0.939, and the T c can be boosted to 35.2 K, which is higher than those of the pristine T-graphene and many other 2D carbon-based superconductors.

What Is Known and Objective: Olanzapine is an atypical antipsychotic drug used for mental disorders. There are limited studies providing sufficient pharmacokinetic data, thus the variability of concentrations of olanzapine used in Chinese paediatric patients aged 10 to 17 years remains to be evaluated., Methods: Therapeutic drug monitoring data were collected from 151 paediatric patients aged 10 to 17 years who received olanzapine. The model was developed with a NONMEM software program. The final model validation and evaluation were assessed by bootstrap, diagnostic scatter plots, and normalized prediction distribution error (NPDE). Regimens of different dosages were simulated to reach the target concentration levels of 20 ng/ml, by using the final model with typical parameters., Results: The one-compartment model was considered the best fit for the data. Typical estimates of the absorption rate constant (Ka), apparent clearance (CL/F), and apparent distribution volume (V/F) in the final model were 0.142 h -1 , 15.4 L/h, and 322 L, respectively. Sex and concomitant valproate (VPA) were included as significant predictors of olanzapine clearance, which was described by the following equation: CL/F = 15.4 × (1 + 0.546 × SEX) × (1 + 0.264 × VPA). Results of Monte-Carlo simulation suggested that male paediatric patients with concomitant VPA were advised to take no less than 15 mg per day of olanzapine orally, and in female paediatric patients with concomitant VPA, a dosing regimen of 10 mg may be sufficient to achieve the therapeutic range of olanzapine., What Is New and Conclusion: Our results identified concomitant valproate and sex as significant covariates in olanzapine population pharmacokinetics. Our model may be a useful tool for recommending dosage adjustments for physicians. The pharmacokinetics of olanzapine in patients aged 10 to 17 years was generally similar to that of adults and the elderly., (© 2022 John Wiley & Sons Ltd.)

The discovery of humans with monogenic disorders has a rich history of generating new insights into biology. Here we report the first human identified with complete deficiency of nuclear factor of activated T cells 1 (NFAT1). NFAT1, encoded by NFATC2, mediates calcium-calcineurin signals that drive cell activation, proliferation, and survival. The patient is homozygous for a damaging germline NFATC2 variant (c.2023&#95;2026delTACC; p.Tyr675Thrfs∗18) and presented with joint contractures, osteochondromas, and recurrent B-cell lymphoma. Absence of NFAT1 protein in chondrocytes caused enrichment in prosurvival and inflammatory genes. Systematic single-cell-omic analyses in PBMCs revealed an environment that promotes lymphomagenesis with accumulation of naïve B cells (enriched for oncogenic signatures MYC and JAK1), exhausted CD4+ T cells, impaired T follicular helper cells, and aberrant CD8+ T cells. This work highlights the pleiotropic role of human NFAT1, will empower the diagnosis of additional patients with NFAT1 deficiency, and further defines the detrimental effects associated with long-term use of calcineurin inhibitors., (© 2022 by The American Society of Hematology.)

Nipa ( Nypa fruticans Wurmb.) is an important mangrove palm species, but it is understudied due to lack of information on genetic patterns within its distribution range. In this study, we identified 18 informative microsatellite markers to assess genetic variations among local populations in the Indo-West Pacific (IWP). Results showed population stratification based on high genetic differentiation (F ST = 0.22131) with the Mantel test indicating significance to isolation-by-distance. We found a pronounced differentiation between the west populations in Sri Lanka and east populations in Southeast Asia. The east populations around the South China Sea were more genetically similar than those along the Malacca Strait and Java Sea. These genetic clines were shaped by ocean circulations and seasonal monsoon reversals as plausible factors. The Malacca Strait was confirmed as both a genetic and a geographic barrier rather than a corridor according to the Monmonier plot. Simulations of directional migration indicated a statistically strong contemporary genetic connectivity from west to east where Sri Lankan immigrants were detected as far as central Philippines via long-distance dispersal. This is the first report on the recent migration patterns of nipa using microsatellites. Assignment of first-generation (F 0 ) immigrants suggested Mainland Southeast Asia as a melting pot due to the admixture associated with excess of homozygosity. The western populations were recent expansions that emerged in rapid succession based on a phylogram as supported by footprints of genetic drift based on bottleneck tests., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Mantiquilla, Shiao, Lu, Sridith, Sidique, Liyanage, Chu, Shih and Chiang.)

Alternaria alternata can resist high levels of reactive oxygen species (ROS). The protective roles of autophagy or autophagy-mediated degradation of peroxisomes (termed pexophagy) against oxidative stress remain unclear. The present study, using transmission electron microscopy and fluorescence microscopy coupled with a GFP-AaAtg8 proteolysis assay and an mCherry tagging assay with peroxisomal targeting tripeptides, demonstrated that hydrogen peroxide (H 2 O 2 ) and nitrogen depletion induced autophagy and pexophagy. Experimental evidence showed that H 2 O 2 triggered autophagy and the translocation of peroxisomes into the vacuoles. Mutational inactivation of the AaAtg8 gene in A. alternata led to autophagy impairment, resulting in the accumulation of peroxisomes, increased ROS sensitivity, and decreased virulence. Compared to the wild type, ΔAaAtg8 failed to detoxify ROS effectively, leading to ROS accumulation. Deleting AaAtg8 down-regulated the expression of genes encoding an NADPH oxidase and a Yap1 transcription factor, both involved in ROS resistance. Deleting AaAtg8 affected the development of conidia and appressorium-like structures. Deleting AaAtg8 also compromised the integrity of the cell wall. Reintroduction of a functional copy of AaAtg8 in the mutant completely restored all defective phenotypes. Although ΔAaAtg8 produced wild-type toxin levels in axenic culture, the mutant induced a lower level of H 2 O 2 and smaller necrotic lesions on citrus leaves. In addition to H 2 O 2 , nitrogen starvation triggered peroxisome turnover. We concluded that ΔAaAtg8 failed to degrade peroxisomes effectively, leading to the accumulation of peroxisomes and the reduction of the stress response. Autophagy-mediated peroxisome turnover could increase cell adaptability and survival under oxidative stress and starvation conditions., (© 2022 The Authors. Molecular Plant Pathology published by British Society for Plant Pathology and John Wiley & Sons Ltd.)

The tangerine pathotype of Alternaria alternata can withstand high-level reactive oxygen species (ROS). By analyzing loss- and gain-of-function mutants, this study demonstrated that a Cys2His2 zinc finger-containing transcription regulator, A. alternata Stress Response Regulator 1 (AaSRR1), plays a negative role in resistance to peroxides and singlet-oxygen-generating compounds. AaSRR1 plays no role in cellular susceptibility or resistance to superoxide-producing compounds. AaSRR1 also negatively regulates conidiogenesis, maintenance of cell wall and membrane integrities, and chitin biosynthesis. Some wild-type hyphae displayed necrosis after exposure to 30 mM H 2 O 2 , whereas AaSRR1 deficient mutant (ΔAaSRR1) hyphae had visible granules and vacuoles. sGFP-AaATG8 proteolysis assays revealed that H 2 O 2 and starvation could trigger autophagy formation in both wild type and ΔAaSRR1. Autophagy occurred at higher rates in ΔAaSRR1 than wild type under both conditions, particularly after H 2 O 2 treatments, indicating that autophagy might contribute to ROS resistance. Upon exposure to H 2 O 2 or under starvation, AaSRR1 was translocated into the nucleus, even though the expression of AaSRR1 was decreased. AaSRR1 is required for vegetative growth but is dispensable for fungal virulence as assayed on detached calamondin leaves. AaSRR1 suppressed the expression of the gene encoding a HOG1 mitogen-activated protein (MAP) kinase implicated in ROS resistance. Mutation of AaSRR1 increased catalase activity but decreased superoxide dismutase activity, leading to fewer ROS accumulation in the cytosol. Nevertheless, our results indicated that AaSRR1 is a transcription suppressor for ROS resistance. This study also revealed tradeoffs between stress responses and hyphal growth in A. alternata., (Copyright © 2022 Elsevier GmbH. All rights reserved.)

Background: Epidemiological studies suggest that advanced paternal age impact offspring health, but its impact on respiratory health is unclear. This study aimed to investigate the association of paternal age with lung function and fraction of exhaled nitric oxide (FeNO) in children., Methods: We analyzed data from 1330 single-born children (576 girls, 43.3%; mean age, 6.4 years), who participated in the Longitudinal Investigation of Global Health in Taiwanese Schoolchildren (LIGHTS) cohort and received measurements of lung function and FeNO at 6-year follow-up visits. Covariate-adjusted regression analyses were applied., Results: Every 5-year increase in paternal age at birth was associated with 0.51% decrease in FEV 1 /FVC ratio (95% CI - 0.86 to - 0.15; p = 0.005) and 19.86 mL/s decrease in FEF 75 (95% CI: - 34.07 to - 5.65; p = 0.006). Stratified analyses revealed that increasing paternal age at birth was associated with decreasing FEV 1 /FVC ratio and FEF 75 only among children with prenatal exposure to environmental tobacco smoke (ETS) or not being breastfed. Sensitivity analyses using paternal age as a categorical variable found decreasing FEV 1 /FVC ratio and FEF 75 in the groups of paternal age 35-39 and ≥ 40 years. There was no association of paternal age at birth with FeNO., Conclusion: Our findings provide novel evidence linking advanced paternal age at birth with decreasing lung function in children at school age. Children with prenatal exposure to ETS or not being breastfed are more vulnerable to the adverse effect of advanced paternal age on childhood lung function. Further studies are warranted to confirm this novel adverse effect of advanced paternal age., (© 2022. The Author(s).)

Yellow water lily ( Nuphar shimadai Hayata) is a critically endangered species in Taiwan. Here, we examined genetic structures of four extant populations, WP, GPa, GPb and GPn, using 39 simple sequence repeat (SSR) markers. Positive genetic correlation was observed within 50 m, beyond which no correlation was detected due to isolation by distance according to Mantel correlogram. This suggests a significant genetic structuring of the species. Besides, multilocus genotype (MLG) analysis revealed that GPa was a panmictic population and the species' putative center of origin. Genetic exchange was observed between GPa and GPb populations, which likely resulted from their geographic proximity. Nevertheless, there was a strong asymmetric migration detected from GPa to WP, but a recent genetic barrier prevented dispersal further northward (WP). Geneland estimated the best number of clusters as K = 2, where WP distinctly separated from the rest of the populations. In STRUCTURE output of K = 3, a third cluster was abundant only in WP. We suggest to consider GPn and WP as separate conservation units, being far from GPa. There is indeed a need to investigate these populations; as predicted, Ne = 1.6 to 3.0 is considered low and that may put the species at risk of extinction.

Objectives: To investigate the current status of antibiotic use in very low birth weight/extremely low birth weight infants in Jiangsu Province of China, and to provide a clinical basis for the quality and improvement of antibiotic management in the neonatal intensive care unit (NICU)., Methods: A retrospective analysis was performed on the data on general conditions and antibiotic use in the very low birth weight/extremely low birth weight infants who were admitted to 15 hospitals of Jiangsu Province from January 1, 2019 to December 31, 2020. A questionnaire containing 10 measures to reduce antibiotic use was designed to investigate the implementation of these intervention measures., Results: A total of 1 920 very low birth weight/extremely low birth weight infants were enrolled, among whom 1 846 (96.15%) were treated with antibiotic, and the median antibiotic use rate (AUR) was 50/100 patient-days. The AUR ranged from 24/100 to 100/100 patient-days in the 15 hospitals. After adjustment for the confounding factors including gestational age, birth weight, and neonatal critical score, the Poisson regression analysis showed that there was a significant difference in the adjusted AUR (aAUR) among the hospitals ( P< 0.01). The investigation results showed that among the 10 measures to reduce antibiotic use, 8 measures were implemented in less than 50% of these hospitals, and the number of intervention measures implemented was negatively correlated with aAUR ( r s =-0.564, P =0.029)., Conclusions: There is a high AUR among the very low birth weight/extremely low birth weight infants in the 15 hospitals of Jiangsu Province, with a significant difference among hospitals. The hospitals implementing a relatively few measures to reduce antibiotic use tend to have a high AUR. It is expected to reduce AUR in very low birth weight/extremely low birth weight infants by promoting the quality improvement of antibiotic use management in the NICU.

Paroxetine is one of the most potent selective serotonin reuptake inhibitors (SSRIs) approved for treating depression, panic disorder, and obsessive-compulsive disorder. There is evidence linking genetic polymorphisms and nonlinear metabolism to the Paroxetine's pharmacokinetic (PK) variability. The purpose of the present study was to develop a population PK (PPK) model of paroxetine in Chinese patients, which was used to define the paroxetine's PK parameters and quantify the effect of clinical and baseline demographic factors on these PK characteristics. The study included 184 inpatients with psychosis (103 females and 81 males), with a total of 372 serum concentrations of paroxetine for PPK analyses. The total daily dosage ranged from 20 to 75 mg. One compartment model could fit the PKs characterize of paroxetine. Covariate analysis revealed that dose, formulation, and sex had a significant effect on the PK parameters of paroxetine; however, there was no evident genetic influence of CYP2D6 enzymes on paroxetine concentrations in Chinese patients. The study determined that the population's apparent distribution volume (V/F) and apparent clearance (CL/F), respectively, were 8850 and 21.2 L/h. The CL/F decreased 1-2-fold for each 10 mg dose increase, whereas the different formulations caused a decrease in V/F of 66.6%. Sex was found to affect bioavailability (F), which decreased F by 47.5%. Females had higher F values than males. This PPK model described data from patients with psychosis who received paroxetine immediate-release tablets (IR-T) and/or sustained-release tablets (SR-T). Paroxetine trough concentrations and relative bioavailability were different between formulations and sex. The altered serum concentrations of paroxetine resulting from individual variants and additive effects need to be considered, to optimize the dosage regimen for individual patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Li, Huang, Xiao, Wang, Kong, Liu, Zhang, Yang, Huang, Ni, Lu, Zhang, Wen and Shang.)

Background/purpose: Data about volumetric remodeling of the provisional extension to induce complete attachment (PETTICOAT) technique on DeBakey type IIIb aortic dissection in acute and subacute phases were scarce. The proper timing to perform this technique to promote false lumen reduction was also unknown., Methods: Patients with DeBakey type IIIb aortic dissection who underwent the PETTICOAT technique between December 2005 and March 2017 were reviewed and divided into acute (treatment occurred ≦14 days after symptom onset) and subacute (15-90 days) groups. Remodeling parameters of the true and false lumens were analyzed. Receiver operating characteristic curve was used to deduce the timing of this technique., Results: In the 2-year follow-up, the acute group (N = 20) demonstrated significant true lumen expansion and false lumen regression in the thoracic, abdominal, and total aorta. However, the subacute group (N = 20) only showed significant shrinkage in the false lumen of the thoracic and total aorta. Using PETTICOAT technique within 36 days after the aortic event may result in better total false lumen reduction., Conclusion: For DeBakey type IIIb aortic dissection, more prominent true lumen expansion and false lumen reduction were noted when using the PETTICOAT technique in the acute phase. When performed within 36 days after symptoms onset, the PETTICOAT technique may potentiate better total false lumen regression., Competing Interests: Declaration of competing interest The authors have no conflicts of interest relevant to this article., (Copyright © 2022. Published by Elsevier B.V.)

We developed a bioinformatics-led substrate discovery workflow to expand the known substrate repertoire of MALT1. Our approach, termed GO-2-Substrates, integrates protein function information, including GO terms from known substrates, with protein sequences to rank substrate candidates by similarity. We applied GO-2-Substrates to MALT1, a paracaspase and master regulator of NF-κB signalling in adaptive immune responses. With only 12 known substrates, the evolutionarily conserved paracaspase functions and phenotypes of Malt1 -/- mice strongly implicate the existence of undiscovered substrates. We tested the ranked predictions from GO-2-Substrates of new MALT1 human substrates by co-expression of candidates transfected with the oncogenic constitutively active cIAP2-MALT1 fusion protein or CARD11/BCL10/MALT1 active signalosome. We identified seven new MALT1 substrates by the co-transfection screen: TANK, TAB3, CASP10, ZC3H12D, ZC3H12B, CILK1 and ILDR2. Using catalytically inactive cIAP2-MALT1 (Cys464Ala), a MALT1 inhibitor, MLT-748, and noncleavable P1-Arg to Ala mutant versions of each substrate in dual transfections, we validated the seven new substrates in vitro. We confirmed the cleavage of endogenous TANK and the RNase ZC3H12D in B cells by Western blotting and mining TAILS N -terminomics datasets, where we also uncovered evidence for these and 12 other candidate substrates by endogenous MALT1. Thus, protein function information improves substrate predictions. The new substrates and other high-ranked MALT1 candidate substrates should open new biological frontiers for further validation and exploration of the function of MALT1 within and beyond NF-κB regulation., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2022 The Author(s).)

Objective: To investigate the circumstances that lead to acute exacerbation readmission of elderly patients with chronic obstructive pulmonary disease (COPD) within 30 days and to explore the influencing factors of readmission using a structural equation model to provide evidence for medical staff so that effective intervention measures can be taken., Methods: The convenience sampling method was used to select 1120 elderly patients with COPD from the respiratory departments of thirteen general hospitals in the Ningxia region, China, from April 2019 to August 2020, who then completed a survey questionnaire. The survey questionnaire contained a general data questionnaire and the modified Medical Research Council, activities of daily living, geriatric depression scale and COPD assessment test scales., Results: The readmission rate of patients with COPD presenting with acute exacerbation within 30 days was determined to be 21.52%. Therefore, the modified model measures data accurately. The results showed that seasonal factors, family rehabilitation, age factors and overall health status were direct factors in the acute exacerbation readmission of patients with COPD within 30 days of hospital discharge. Smoking is not only a direct factor for acute exacerbation readmission within 30 days but also an indirect factor through disease status; disease status and chronic disease are not only direct factors for acute exacerbation readmission within 30 days but also indirect factors through the patient's overall health status., Conclusions: The rate of patients with COPD presenting with acute exacerbation within 30 days is high; while taking measures to prevent readmission based on influencing factors that directly impact admission rates, attention should also be paid to the interaction between these factors., (© 2022. The Author(s).)

Objectives: Systemic lupus erythematosus (SLE) is a female-dominated autoimmune disease that can occur at any age and has a diverse course. The clinical manifestation of this disease can vary depending on the patient's age at onset. The aim of this study was to characterise the comorbidities at the time of SLE diagnosis and after in different age groups., Methods: A total 1042 incident cases of SLE with a Catastrophic Illness Card in 2005 and 10,420 age- and sex-matched controls from the general population registered in the National Health Insurance Research Database in Taiwan were enrolled in the study. The risk of comorbidities before (adjusted odds ratio, [aOR]) and after (adjusted hazard ratio, [aHR]) of SLE was analysed. The burden of these SLE-associated comorbidities was weight by the Charlson comorbidity index (CCI). We used the cumulative incidence to evaluate the impact of comorbidities on different age onset groups., Results: In this study, musculoskeletal diseases had the highest positive association (aOR, 5.29; 95% confidence interval [CI]: 4.25-6.57) prior to the diagnosis of SLE and they were also the most common developing incident comorbidity after the diagnosis (HR, 13.7; 95% CI: 11.91-15.77). It only took less than 1 year for 50% of the late-onset SLE patients to develop any increase in CCI score. The developing comorbidities attributed to 16.3% all-cause mortality and they had the greatest impact on late-onset SLE patients, with 33.3% cumulative incidence to all-cause mortality. There is no difference in the incidence of infectious diseases across different age groups. The herpes zoster infection had the greatest cumulative incidence among the category of infection diseases in child-onset SLE patients., Conclusion: SLE patients had increased risks of multiple pre-existing comorbidities at diagnosis. The developed comorbidity after diagnosis could contribute to all-cause mortality. The herpes zoster infection is primarily an issue in child-onset SLE patients.

Epigenetic variation plays a significant role in normal development and human diseases including cancer, in part through post-translational modifications (PTMs) of histones. Identification and profiling of changes in histone PTMs, and in proteins regulating PTMs, are crucial to understanding diseases, and for discovery of epigenetic therapeutic agents. In this study, we have adapted and validated an antibody-based reverse phase protein array (RPPA) platform for profiling 20 histone PTMs and expression of 40 proteins that modify histones and other epigenomic regulators. The specificity of the RPPA assay for histone PTMs was validated with synthetic peptides corresponding to histone PTMs and by detection of histone PTM changes in response to inhibitors of histone modifier proteins in cell cultures. The useful application of the RPPA platform was demonstrated with two models: induction of pluripotent stem cells and a mouse mammary tumor progression model. Described here is a robust platform that includes a rapid microscale method for histone isolation and partially automated workflows for analysis of histone PTMs and histone modifiers that can be performed in a high-throughput manner with hundreds of samples. This RPPA platform has potential for translational applications through the discovery and validation of epigenetic states as therapeutic targets and biomarkers. SIGNIFICANCE: Our study has established an antibody-based reverse phase protein array platform for global profiling of a wide range of post-translational modifications of histones and histone modifier proteins. The high-throughput platform provides comprehensive analyses of epigenetics for biological research and disease studies and may serve as screening assay for diagnostic purpose or therapy development., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)