Search

Yen-Ching Lin,1,* Chia-Hsuin Chang,1– 3,* Wei-Ju Su,4,5 Chin-Hui Yang,4 Jann-Tay Wang1,2 1Department of Medicine, College of Medicine, National Taiwan University, Taipei, Taiwan; 2Department of Internal Medicine, National Taiwan University Hospital, Taipei, Taiwan; 3Institute of Epidemiology and Preventive Medicine, College of Public Health, National Taiwan University, Taipei, Taiwan; 4Centers for Disease Control, Ministry of Health and Welfare, Taipei, Taiwan; 5Department of Pediatrics, National Taiwan University Hospital, Taipei, Taiwan*These authors contributed equally to this workCorrespondence: Chia-Hsuin Chang, Department of Internal Medicine, National Taiwan University Hospital, 7, Chung-Shan South Road, Taipei, 100, Taiwan, Tel +886-2-23123456, Fax +886-2-2392-0456, Email chiahsuin@yahoo.comPurpose: Early studies showed that the risks of mRNA vaccine-associated myocarditis and pericarditis are low but with substantial variation across studies. Study characteristics, ethnicity, vaccine types, dose intervals, and SARS-CoV-2 infection prevalence may influence the rates of myocarditis and pericarditis after mRNA vaccination in population-based studies.Methods: We comprehensively searched MEDLINE for relevant articles published before November 30, 2022. We also searched the websites of health authorities in several countries for unpublished surveillance data on myocarditis and pericarditis after mRNA vaccination. The outcome of interest was the incidence of myocarditis and pericarditis developed after mRNA vaccination for COVID-19.Results: A total of 17 studies form 10 countries were included for review. We noted that considerable heterogeneity in study characteristics, including surveillance method, case definition, and observation period, may partially be responsible for the widely varied reported rates. Studies from countries that adopted active surveillance reported higher rates than those using passive surveillance. Compared to BNT162b2 vaccine, mRNA-1273 may have a higher risk of myocarditis only in young men after the second dose. Our comparison of sex-, age-, vaccine type-, and dose-specific rates of myocarditis across countries did not support the hypothesis that individuals with recent SARS-CoV-2 infection and young Asian males were at higher risk. We also could not find sufficient evidence to conclude whether extending the between-dose interval could reduce myocarditis incidence following mRNA vaccination.Conclusion: Differences in the study characteristics must be fully considered when comparing the risks of mRNA vaccine-related myocarditis and pericarditis in different countries.Keywords: COVID-19, mRNA vaccine, myocarditis, population-based study, surveillance data

Meng-Chang Yang,1,&ast; Peng Li,1,&ast; Wen-Jie Su,1 Rong Jiang,1 Jia Deng,1 Ru-Rong Wang,2 Chao-Li Huang3 1Department of Anesthesiology, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, People’s Republic of China; 2Department of Anesthesiology, West China Hospital, Sichuan University, Chengdu, People’s Republic of China; 3Department of Internal Medicine, Eastern Hospital, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, Chengdu, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Ru-Rong WangDepartment of Anesthesiology, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of ChinaTel +86 18140049936Fax +86 28-87393632Email wangrurong@scu.edu.cnChao-Li HuangDepartment of Internal Medicine, Eastern Hospital, Sichuan Provincial People’s Hospital, University of Electronic Science and Technology of China, No. 585, Damian, Honghe North Road, Longquanyi District, Chengdu, People’s Republic of ChinaTel +86 13350855681Fax +86 28-87775681Email chaoli_huang@126.comPurpose: Several randomized clinical trials (RCTs) investigated the effects of the manual placental removal on hemorrhage or other hemorrhage-related complications compared with the spontaneous placental removal during cesarean section (CS), while the results remained controversial and were inconsistent. The purpose of this meta-analysis was to quantify the pooled effects of the methods of placental removal on hemorrhage during CS.Patients and Methods: A systematic literature search was conducted using PubMed, EMBASE, Web of Science, and Google Scholar. Heterogeneity was tested by I2 statistics and Q-statistic. The random-effects model or fixed-effects model were used to calculate the pooled effect for the included studies according to heterogeneity. And the term of standardized mean difference (SMD) with 95% confidence intervals (CI) was pooled and estimated the effects across all studies.Results: A total of nine RCTs were included in this meta-analysis. Compared with spontaneous group, manual placental removal increased the amount of hemorrhage (SMD = 0.53, 95% CI [0.12, 0.94]; Z = 2.54, P = 0.011) and increased the risk of endometritis (OR = 1.84, 95% CI [1.31, 2.58]; Z = 3.52, P < 0.0001). In contrast, there was no significant difference concerning the operating time (SMD = − 0.30, 95% CI [− 0.85, 0.24]; Z = 1.09, P = 0.276), the length of hospital stays (SMD = 0.11, 95% CI [− 0.08, 0.30]; Z = 1.11, P = 0.265), and blood transfusion requirement (OR = 1.36, 95% CI [0.91, 2.04]; Z = 1.52, P = 0.129), respectively.Conclusion: Comparing with spontaneous placental removal, manual placental removal appeared to be less positive effect during CS. Because of the limitations of this meta-analysis, more high-quality RCTs are needed to confirm our findings.Keywords: cesarean section, manual placental removal, spontaneous placenta removal, hemorrhage, meta-analysis

(See the editorial commentary by Schwarz, on page 702.) Background. Raising concerns about the waning immunity of cohorts receiving hepatitis B virus (HBV) vaccination in infancy persuaded us to identify the changing incidence of acute hepatitis B (AHB) in children and young adults. Methods. Data on AHB surveillance through the National Notifiable Disease Surveillance System from July 2001 to June 2009 were collected and described. Cases were divided into 2 cohorts according to their birth year: before or after the universal newborn HBV vaccination program. Age-specific incidence was compared for the 2 birth cohorts with diagnosis at age 15-24 years. Results. In total, 2226 patients with AHB were identified. AHB rates varied by age; the highest rates occurred among unvaccinated individuals aged 25-39 years (2.33/100 000). Due to breakthrough HBV infection from mother-to-infant transmission, vaccinated infants (0.78/100 000) had higher rates than those aged 1-14 years (0.04/100 000), who had the lowest rates. The incidence in vaccinated birth cohorts was significantly lower than in unvaccinated birth cohorts among patients 15-24 years old, with an adjusted-relative risk of 0.42. Conclusions. Implementation of universal-at-birth HBV immunization programs has effectively reduced the occurrence of AHB among adolescents and young adults in Taiwan for >25 years, making infants and the 25-39-year-old cohort additional targets for preventing AHB. [ABSTRACT FROM AUTHOR]

Background: Previous studies on congenital heart diseases (CHD) associated with dextrocardia were based on selective patient databases and did not reflect the full spectrum of dextrocardia in the general population. Additionally, these studies had complex classification and presentation. Nor did these studies elaborate on the distribution of the associated CHD's complexity, the various segmental connections, and associated CHD among the four visceroatrial situs., Methods: We retrospectively reviewed the medical records of 211 children with primary dextrocardia. We used a segmental approach to diagnose CHD. We then analyzed and compared the distribution of the above-mentioned issues among the four visceroatrial situs., Results: Dextrocardia occurred most commonly with situs inversus (52.6%), followed by situs solitus (28.4%), asplenia (17.1%), and polysplenia (1.9%). Although some patients had a structurally normal heart (22.7%) or they were associated with simple CHD (17.5%), most patients had complex CHD (59.7%) consisting of a single ventricle (34.6%) or conotruncal anomaly (25.1%) (double-outlet right ventricle [7.6%], corrected transposition of the great arteries [6.2%], complete transposition of the great arteries [5.7%], tetralogy of Fallot [4.7%], etc.). Situs inversus or polysplenia had a higher prevalence of a structurally normal heart or associated with simple CHD, two patent atrioventricular (AV) valves connections, and biventricular AV connections. Situs solitus or asplenia had a higher prevalence of associated complex CHD, common AV valve connection, univentricular AV connection, pulmonary outflow tract obstruction, and anomalous pulmonary venous drainage., Conclusion: Our study finds that situs inversus is the most common visceroatrial situs in dextrocardia. Although some patients had a structurally normal heart or were associated with simple CHD, most patients have associated complex CHD consisting of a single ventricle or conotruncal anomaly. Dextrocardia is associated with a higher incidence of complex CHD in situs solitus and asplenia groups than in situs inversus and polysplenia groups., (Copyright © 2024 Taiwan Pediatric Association. Published by Elsevier B.V. All rights reserved.)

Depression is a significant mental health issue with extensive economic implications, and recent studies suggest it may be transmitted between individuals. However, the mechanisms of this contagion remain unclear, and the social buffering effect has been understudied. This research employs three rodent models, including stress crossover, cohabitation-induced, and non-contact induced depression contagion models, to explore these mechanisms. Here, we report that that naive mice cohabiting with depressed mice showed increased corticosterone levels and depressive behaviors, unlike those with stressed mice, who did not exhibit these changes and even mitigated desperation in stressed mice. Non-contact cohabitation did not produce significant behavioral differences, but exposure to bedding from depressed mice reduced sucrose preference in naive mice. This study introduces reliable models of depression contagion, suggesting it operates independently of stress transmission. The interplay between depression contagion and social buffering may vary in different contexts. These findings provide new insights into the mechanisms of depression contagion and potential strategies for preventing depressive disorders., (© 2024. The Author(s).)

Background: Evaluation of the impact of a hepatitis B virus (HBV) prevention program that incorporates maternal antiviral prophylaxis on mother-to-child transmission (MTCT) is limited using real-world data., Methods: We analyzed data on maternal HBV screening, neonatal immunization, and post-vaccination serologic testing (PVST) for hepatitis B surface antigen (HBsAg) among at-risk infants born to HBV carrier mothers from the National Immunization Information System during 2008-2022. Through linkage with the National Health Insurance Database, information on maternal antiviral therapy was obtained. Multivariate logistic regression was performed to explore MTCT risk in relation to infant-mother characteristics and prevention strategies., Results: In total, 2 460 218 deliveries with maternal HBV status were screened. Between 2008 and 2022, the annual HBsAg and hepatitis B e antigen (HBeAg) seropositivity rates among native pregnant women decreased from 12.2% to 2.6% and from 2.7% to 0.4%, respectively (P for both trends < .0001). Among the 22 859 at-risk infants who underwent PVST, the MTCT rates differed between infants born to HBsAg-positive/HBeAg-negative and HBeAg-positive mothers (0.75% and 6.33%, respectively; P < .001). MTCT risk increased with maternal HBeAg positivity (odds ratio [OR], 9.29; 95% confidence interval [CI], 6.79-12.73) and decreased with maternal antiviral prophylaxis (OR, 0.28; 95% CI, .16-.49). For infants with maternal HBeAg positivity, MTCT risk was associated with mothers born in the immunization era (OR, 1.40; 95% CI, 1.17-1.67)., Conclusions: MTCT was related to maternal HBeAg positivity and effectively prevented by maternal prophylaxis in the immunized population. At-risk infants born to maternal vaccinated cohorts might possibly pose further risk., Competing Interests: Potential conflicts of interest . The authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest., (© The Author(s) 2024. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Introduction: To investigate whether the methylation of circulating cell-free DNA (cfDNA) differentiates active tuberculosis (TB) from latent TB infection (LTBI)., Methods: Patients with pulmonary TB, contacts with LTBI, and healthy controls were enrolled (2018-2021). Plasma cfDNA was extracted, and using a 5-methylcytosine (5mC) DNA ELISA kit, the global methylation of cfDNA (5mC-cfDNA) was measured., Results: 59 TB, 63 LTBI, 39 healthy controls were included. The 5mC-cfDNA level was higher in TB (6.4 %) than LTBI (4.1 %) and healthy controls (4.9 %) (both p<0.05). Independent TB factors were 5mC-cfDNA ≥6.6 % and CRP ≥0.32 mg/dL (adjusted odds ratio (aOR) 4.594 [95 % CI:1.628-12.965], p=0.004 and 5.338 [1.659-17.176], p=0.005). Having one or both factors increased TB odds 8- and 16-fold (aOR 8.688 [3.229-23.378], p <0.001 and 16.080 [3.092-83.632], p =0.001)., Conclusion: The global cfDNA methylation level was higher in TB than contacts without TB and helped differentiate patients with TB from contacts with LTBI., Competing Interests: Declaration of competing interest The authors declare to have no conflict of interest directly or indirectly related to the manuscript contents., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Objective: To compare the accuracy of intraocular lens (IOL) power calculations using total keratometry (TK) versus standard keratometry (K) in post-corneal refractive surgery cataract patients. Methods: This retrospective case series study included 30 patients (36 eyes) with a history of laser corneal refractive surgery who underwent cataract extraction and IOL implantation at Qingdao Eye Hospital, Affiliated to Shandong First Medical University, from September 2022 to December 2023. The cohort comprised 16 males and 14 females, with an average age of (53.6±8.1) years. IOL power was calculated using the K-based Haigis-L and Barrett True-K formulas, as well as the TK-based Haigis and Barrett Universal Ⅱ formulas. Postoperative objective refraction was performed to obtain the actual refractive status of the operated eyes. The refractive prediction error (RPE) was defined as the difference between the actual spherical equivalent and the predicted refraction. The absolute value of the RPE was taken as the refractive absolute error (RAE). Differences in errors calculated by the four formulas were compared. Results: TK showed good consistency with K, with TK being on average 0.50 D lower than K. Analysis of variance revealed statistically significant differences in RPE among the four formulas ( P <0.001). The RPE for the TK-based Haigis formula was (0.17±0.09) D, and for the Barrett Universal Ⅱ formula, it was (0.21±0.11) D, both significantly better than the K-based Haigis-L formula (-0.61±0.12) D and Barrett True-K formula (-0.57±0.11) D (all P <0.001). The percentage of eyes with postoperative RPE<±1.00 D was higher for the TK-based Haigis (92%, 33 eyes) and Barrett Universal Ⅱ (86%, 31 eyes) formulas compared to the TK-based Barrett True-K (75%, 27 eyes) and Haigis-L formulas (67%, 24 eyes), with statistically significant differences ( P <0.05). Conclusions: Compared with K, TK improves the accuracy of IOL power calculation in post-corneal refractive surgery patients. Both the TK-based Barrett Universal Ⅱ and Haigis formulas demonstrate high accuracy.

Background and Aims: Hepatitis B virus (HBV) vaccination programs in Taiwan are one of the earliest programs in the world and have largely reduced the prevalence of HBV infection. We aimed to demonstrate the vaccination efficacy after 35 years and identify gaps toward HBV elimination., Methods: A total of 4717 individuals aged 1-60 years were recruited from four administrative regions based on the proportion of population distribution. Serum levels of hepatitis B surface antigen (HBsAg), hepatitis B surface antibody (anti-HBs), and hepatitis B core antibody (anti-HBc) levels were assessed. HBV viral load, genotypes and HBsAg 'ɑ' determinant variants were evaluated if indicated., Results: After 35 years of vaccination, the overall seropositivity rates for HBsAg and anti-HBc in Taiwan were 4.05% and 21.3%, respectively. The vaccinated birth cohorts exhibited significantly lower seropositivity rates for both markers compared to the unvaccinated birth cohorts (HBsAg: 0.64% vs. 9.78%; anti-HBc: 2.1% vs. 53.55%, respectively; p < 0.0001). Maternal transmission was identified as the main route of HBV infection in breakthrough cases. Additionally, increased prevalences of genotype C and HBsAg escape mutants were observed., Conclusion: The 35-year universal HBV vaccination program effectively reduced the burden of HBV infection, but complete eradication of HBV infection has not yet been achieved. In addition to immunization, comprehensive screening and antiviral therapy for infected individuals, especially for pregnant women, are crucial strategies to eliminate HBV., (© 2024 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Background: Conjunctival prolapse (CP) is an uncommon but challenging condition following maximal levator resection (MLR) and other extensive periorbital procedures. MLR extending beyond the Whitnall's ligament is frequently performed to address severe blepharoptosis with poor levator function (LF). Patients with CP may encounter symptoms such as ocular discomfort, tearing, vision impairment, persistent conjunctival chemosis, lagophthalmos, or exposure keratopathy. Typically, surgical intervention becomes necessary if conservative measures prove to be ineffective; nevertheless, there is no consensus regarding the optimal treatment approach., Objectives: This study aimed to propose a simple sutureless direct excision method and explore the surgical advancements in CP correction through a systematic review., Methods: Patients with recurrent CP after MLR who underwent sutureless direct excision of the conjunctiva using loupe magnifiers at a tertiary hospital were included in this study. The clinical evolution and surgical results were recorded. PubMed, MEDLINE, EMBASE, and Web of Science databases were queried following The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) protocol., Results: The comprehensive analysis of 1858 articles identified 88 patients from 24 studies, highlighting that blepharoptosis surgery is predominantly associated with CP (36.6%). Surgically treated CP showed a higher resolution rate compared to those managed conservatively (54.8% vs. 45.2%; p = 0.034). No relapse was observed in patients treated with sutureless direct excision of CP in long-term follow-up., Conclusion: We proposed a simple sutureless direct excision technique that offers a straightforward and efficient approach in treating CP, which is particularly suitable for cases requiring excision lengths >16 mm during MLR. Furthermore, stitch removal can be obviated after surgery., (Copyright © 2024 British Association of Plastic, Reconstructive and Aesthetic Surgeons. Published by Elsevier Ltd. All rights reserved.)

The PD-1/PD-L1 pathway plays a pivotal role in T cell activity and is involved in the pathophysiology of Mycobacterium tuberculosis (MTB) infection. DNA methylation is a mechanism that modulates PD-L1 expression in cancer cells. However, its effect on PD-L1 expression in macrophages after MTB infection remains unknown. We prospectively enrolled patients with active tuberculosis (TB) and non-TB subjects. The expression of PD-L1 and methylation-related genes in peripheral blood mononuclear cells (PBMCs) were investigated and their correlation with disease severity and treatment outcomes were examined. PD-L1 promoter methylation status was evaluated using bisulfite sequencing. Immunohistochemistry (IHC) and immunofluorescence (IF) staining were used to visualize PD-L1- and TET-1-expressing cells in lung tissues from patients with TB and in macrophage cell lines with MTB-related stimulation. In total, 80 patients with active TB and 40 non-TB subjects were enrolled in the analysis. Patients with active TB had significantly higher expression of PD-L1 , DNMT3b , TET1 , TET2 , and lower expression of DNMT1 , compared to that in the non-TB subjects. The expression of PD-L1 and TET-1 was significantly associated with 1-month smear and culture non-conversion. IHC and IF staining demonstrated the co-localization of PD-L1- and TET-1-expressing macrophages in patients with pulmonary TB and in human macrophage cell lines after MTB-related stimulation. DNMT inhibition and TET-1 knockdown in human macrophages increased and decreased PD-L1 expression, respectively. Overall, PD-L1 expression is increased in patients with active TB and is correlated with treatment outcomes. DNA methylation is involved in modulating PD-L1 expression in human macrophages., Competing Interests: The authors of this article declare that they do not have any conflict of interest.

Competing Interests: Declaration of competing interest The authors have no conflict of interest to declare.

We propose a scheme for realizing nonreciprocal microwave photon routing with two cascaded magnon-cavity coupled systems, which work around the exceptional points of a parity-time (PT)-symmetric Hamiltonian. An almost perfect nonreciprocal transmission can be achieved with a broad bandwidth, where the transmission for a forward-propagating photon can be flexibly controlled with the backpropagating photon being isolated. The transmission or isolated direction can be reversed via simply controlling the magnetic field direction applied to the magnons. The isolation bandwidth is improved by almost three times in comparison with the device based on a single PT-symmetric system. Moreover, the effect of intrinsic cavity loss and added thermal noises is considered, confirming the experimental feasibility of the nonreciprocal device and potential applications in quantum information processing.

The role of the aryl hydrocarbon receptor (AhR) in regulating oxidative stress and immune responses has been increasingly recognized. However, its involvement in depression and the underlying mechanisms remain poorly understood. This study aimed to investigate the effect of 6-formylindolo[3,2-b]carbazole (FICZ), an endogenous AhR ligand, on a lipopolysaccharide (LPS)-induced depression model and the underlying mechanism. After being treated with FICZ (50 mg/kg), male C57BL/6J mice received intraperitoneal injection of LPS and underwent behavioral tests 24 h later. The levels of inflammatory cytokines, including IL-1β, IL-6, and TNF-α, were measured in the hippocampus and serum using enzyme-linked immunosorbent assay (ELISA). The expression levels of CYP1A1, AhR and NLRP3 were analyzed using qPCR and Western blot. The results showed that, compared with control group, LPS alone significantly down-regulated the expression levels of CYP1A1 mRNA and AhR protein in the hippocampus of mice, reduced glucose preference, prolonged immobility time in forced swimming test, increased IL-6 and IL-1β levels in the hippocampus, increased serum IL-1β level, and up-regulated NLRP3 mRNA and protein expression levels in mouse hippocampus, while FICZ significantly reversed the aforementioned effects of LPS. These findings suggest that AhR activation attenuates the inflammatory response associated with depression and modulates the expression of NLRP3. The present study provides novel insights into the role of AhR in the development of depression, and presents AhR as a potential therapeutic target for the treatment of depression.

Aims: Enhancing life satisfaction is vital for adults with congenital heart disease (ACHD). Life satisfaction potentially correlates with a health-promoting lifestyle and grit. However, the mediating role of grit-a trait marked by perseverance and long-term goal-oriented passion-between a health-promoting lifestyle and life satisfaction in ACHD remains unverified. This study aimed to examine the relationships between health-promoting lifestyle, grit, and life satisfaction in full-time employed ACHD and to confirm the mediating role of grit., Methods and Results: A total of 181 full-time employed ACHD aged 20-59 years with patient-reported New York Heart Association classes I-IV were recruited from two medical centres in northern Taiwan. Participants completed questionnaires, including the short version of the Chinese Health-Promoting Lifestyle Profile Scale, Grit-10 Scale, and Satisfaction with Life Scale between February and December 2022. Data analysis employed the Hayes PROCESS macro. Health-promoting lifestyle, grit, and life satisfaction were discovered to be positively correlated. Overall grit score was a partial mediator between a health-promoting lifestyle and life satisfaction, accounting for 20% of the total variation. Of the grit domains, perseverance served as a partial mediator between a health-promoting lifestyle and life satisfaction, accounting for 32% of the total variation, whereas passion had a nonsignificant mediation effect., Conclusion: A health-promoting lifestyle boosts ACHD individuals' life satisfaction through grit, particularly perseverance. Integrating grit into such a lifestyle could benefit from comprehending support systems and influential factors aiding grit development for enhanced life satisfaction., Competing Interests: Conflict of interest: The authors declare no potential conflicts of interest, real or perceived., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Society of Cardiology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Competing Interests: Declaration of competing interest The authors have no conflict of interest to declare.

Temozolomide (TMZ) resistance presents a significant challenge in the treatment of gliomas. Although lysine demethylase 4A (KDM4A) has been implicated in various cancer-related processes, its role in TMZ resistance remains unclear. This study aims to elucidate the contribution of KDM4A to TMZ resistance in glioma cells and its potential implications for glioma prognosis. We assessed the expression of KDM4A in glioma cells (T98G and U251MG) using qRT-PCR and Western blot assays. To explore the role of KDM4A in TMZ resistance, we transfected siRNA targeting KDM4A into drug-resistant glioma cells. Cell viability was assessed using the CCK-8 assay and the TMZ IC50 value was determined. ChIP assays were conducted to investigate KDM4A, H3K9me3, and H3K36me3 enrichment on the promoters of ROCK2 and HUWE1. Co-immunoprecipitation confirmed the interaction between HUWE1 and ROCK2, and we examined the levels of ROCK2 ubiquitination following MG132 treatment. Notably, T98G cells exhibited greater resistance to TMZ than U251MG cells, and KDM4A displayed high expression in T98G cells. Inhibiting KDM4A resulted in decreased cell viability and a reduction in the TMZ IC50 value. Mechanistically, KDM4A promoted ROCK2 transcription by modulating H3K9me3 levels. Moreover, disruption of the interaction between HUWE1 and ROCK2 led to reduced ROCK2 ubiquitination. Inhibition of HUWE1 or overexpression of ROCK2 counteracted the sensitization effect of si-KDM4A on TMZ responsiveness in T98G cells. Our findings highlight KDM4A's role in enhancing TMZ resistance in glioma cells by modulating ROCK2 and HUWE1 transcription and expression through H3K9me3 and H3K36me3 removal., (© 2023 The Authors. The Kaohsiung Journal of Medical Sciences published by John Wiley & Sons Australia, Ltd on behalf of Kaohsiung Medical University.)

Training Deep Neural Networks (DNNs) with adversarial examples often results in poor generalization to test-time adversarial data. This paper investigates this issue, known as adversarially robust generalization, through the lens of Rademacher complexity. Building upon the studies by Khim and Loh (2018); Yin et al. (2019), numerous works have been dedicated to this problem, yet achieving a satisfactory bound remains an elusive goal. Existing works on DNNs either apply to a surrogate loss instead of the robust loss or yield bounds that are notably looser compared to their standard counterparts. In the latter case, the bounds have a higher dependency on the width m of the DNNs or the dimension d of the data, with an extra factor of at least 𝒪 ( m ) or 𝒪 ( d ) . This paper presents upper bounds for adversarial Rademacher complexity of DNNs that match the best-known upper bounds in standard settings, as established in the work of Bartlett et al. (2017), with the dependency on width and dimension being 𝒪 ( ln ( d m ) ) . The central challenge addressed is calculating the covering number of adversarial function classes. We aim to construct a new cover that possesses two properties: 1) compatibility with adversarial examples, and 2) precision comparable to covers used in standard settings. To this end, we introduce a new variant of covering number called the uniform covering number , specifically designed and proven to reconcile these two properties. Consequently, our method effectively bridges the gap between Rademacher complexity in robust and standard generalization.

Background: Abundant evidence suggests that inflammatory cytokines contribute to the symptoms of major depressive disorder (MDD) by altering neurotransmission, neuroplasticity, and neuroendocrine processes. Given the unsatisfactory response and remission of monoaminergic antidepressants, anti-inflammatory therapy is proposed as a feasible way to augment the antidepressant effect. Recently, there have been emerging studies investigating the efficiency and efficacy of anti-inflammatory agents in the treatment of MDD and depressive symptoms comorbid with somatic diseases., Methods: In this narrative review, prospective clinical trials focusing on anti-inflammatory treatment for depression have been comprehensively searched and screened. Based on the included studies, we summarize the rationale for the anti-inflammatory therapy of depression and discuss the utilities and confusions regarding the anti-inflammatory strategy for MDD., Results: This review included over 45 eligible trials. For ease of discussion, we have grouped them into six categories based on their mechanism of action, and added some other anti-inflammatory modalities, including Chinese herbal medicine and non-drug therapy. Pooled results suggest that anti-inflammatory therapy is effective in improving depressive symptoms, whether used as monotherapy or add-on therapy. However, there remain confusions in the application of anti-inflammatory therapy for MDD., Conclusion: Based on current clinical evidence, anti-inflammatory therapy is a promisingly effective treatment for depression. This study proposes a novel strategy for clinical diagnosis, disease classification, personalized treatment, and prognostic prediction of depression. Inflammatory biomarkers are recommended to be assessed at the first admission of MDD patients, and anti-inflammatory therapy are recommended to be included in the clinical practice guidelines for diagnosis and treatment. Those patients with high levels of baseline inflammation (e.g., CRP > 3 mg/L) may benefit from adjunctive anti-inflammatory therapy., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Objectives: Determining a diagnosis for non- Tuberculous mycobacterium (NTM)-lung disease (LD) remains difficult. The value of circulating cell-free DNA (cfDNA) secreted from microbes has been established in the detection of pathogens in septic patients. However, it is unknown whether NTM-derived cfDNA is detectable in plasma from patients with NTM-LD and whether this is associated with the disease status of NTM-LD, especially in patients with Mycobacterium avium complex (MAC)-LD., Materials and Methods: In this pilot study, from 2018 to 2019, we enrolled adult patients with MAC-LD at Taipei Veterans General Hospital in Taiwan for the detection of circulating cfDNA. We performed cfDNA extraction from plasma, next-generation sequencing (NGS) for nonhuman cfDNA, and sequence matching to a microbial database and then assessed the association between pathogen cfDNA and MAC-LD., Results: Two (40%) plasma samples from MAC-LD patients had detectable MAC-specific cfDNA, namely one instance of DNA polymerase III alpha subunit and one instance of ATP-binding cassette transporters permease. The plasma samples from the three other MAC-LD cases and the one tuberculosis control were negative for either NTM-derived cfDNA or tuberculosis-related cfDNA. In addition to MAC-specific cfDNA, Ralstonia solanacearum , Staphylococcus aureus , and Pasteurella multocida were the most observed bacteria in our patients. The two patients with MAC-cfDNA positivity yielded higher radiographic scores ( P = 0.076) and presented a higher number of nonhuman reads than those without MAC-cfDNA positivity ( P = 0.083)., Conclusion: Using NGS method, we demonstrated MAC-cfDNA was detectable in patients with MAC-LD. Further large-scale research is warranted to assess the clinical value of detecting MAC-specific cfDNA in MAC-LD patients., Competing Interests: There are no conflicts of interest., (Copyright: © 2023 Tzu Chi Medical Journal.)

While deep learning has enabled significant advances in many areas of science, its black-box nature hinders architecture design for future artificial intelligence applications and interpretation for high-stakes decision-makings. We addressed this issue by studying the fundamental question of how deep neural networks process data in the intermediate layers. Our finding is a simple and quantitative law that governs how deep neural networks separate data according to class membership throughout all layers for classification. This law shows that each layer improves data separation at a constant geometric rate, and its emergence is observed in a collection of network architectures and datasets during training. This law offers practical guidelines for designing architectures, improving model robustness and out-of-sample performance, as well as interpreting the predictions.

Competing Interests: Declaration of competing interest The authors have no conflict of interest to declare.

Background: Abundant evidence suggests that the prevalence and risk of depression in people with diabetes is high. However, the pathogenesis of diabetes-related depression remains unclear. Since neuroinflammation is associated with the pathophysiology of diabetic complications and depression, this study aims to elucidate the neuroimmune mechanism of diabetes-related depression., Methods: Male C57BL/6 mice were injected with streptozotocin to establish a diabetes model. After screening, diabetic mice were treated with the NLRP3 inhibitor MCC950. Then, metabolic indicators and depression-like behaviors were evaluated in these mice, as well as their central and peripheral inflammation. To explore the mechanism of high glucose-induced microglial NLRP3 inflammasome activation, we performed in vitro studies focusing on its canonical upstream signal I (TLR4/MyD88/NF-κB) and signal II (ROS/PKR/P 2 X 7 R/TXNIP)., Results: Diabetic mice exhibited depression-like behaviors and activation of NLRP3 inflammasome in hippocampus. In vitro high-glucose (50 mM) environment primed microglial NLRP3 inflammasome by promoting NF-κB phosphorylation in a TLR4/MyD88-independent manner. Subsequently, high glucose activated the NLRP3 inflammasome via enhancing intracellular ROS accumulation, upregulating P 2 X 7 R, as well as promoting PKR phosphorylation and TXNIP expression, thereby facilitating the production and secretion of IL-1β. Inhibition of NLRP3 with MCC950 significantly restored hyperglycemia-induced depression-like behavior and reversed the increase in IL-1β levels in the hippocampus and serum., Conclusion: The activation of NLRP3 inflammasome, probably mainly in hippocampal microglia, mediates the development of depression-like behaviors in STZ-induced diabetic mice. Targeting the microglial inflammasome is a feasible strategy for the treatment of diabetes-related depression., Competing Interests: Declaration of Competing Interest None., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Mycobacterium avium complex lung disease (MAC-LD) preferentially occurs in postmenopausal women and may have immune exhaustion involving the programmed cell death 1 (PD-1) pathway. It is still unknown whether sex-specific associations between susceptibility to MAC-LD and programmed cell death 1 gene (PDCD1) polymorphisms exist., Methods: Adult patients with MAC-LD (n = 152) and controls (n = 167) were included at 2 medical centers in Taiwan. Five single-nucleotide polymorphisms in PDCD1 genes were genotyped, and their associations with MAC-LD and soluble PD-1 protein were analyzed, especially in sex subgroups., Results: PDCD1 rs2227982 polymorphism was associated with increased risk of MAC-LD in women (adjusted odds ratio for AA vs AG vs GG, 2.205 [95% confidence interval, 1.108-4.389]; P = .02), and the rs10204525 TT genotype was associated with low risk in men (TT vs TC and CC, 0.396 [.176-.890]; P = .02). Compared with men with rs10204525 TT, women with rs2227982 AG and with AA had 2.7- and 5.0-fold increased risks, respectively. Soluble PD-1 levels were lower in the female subgroup with rs2227982 AG and AA than in the remainder (median level [interquartile range], 46.7 [33.7-71.5] pg/mL vs 66.2 [48.6-101.5] pg/mL; P < .001)., Conclusions: PDCD1 genetic polymorphisms were associated with the risk of MAC-LD in a sex-specific pattern, possibly through regulation of PD-1 expression., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

The harvesting efficiency of a cantilevered piezoelectric energy harvester is limited by its uneven strain distribution. Moreover, a cantilevered harvester requires a large workspace due to the large displacement of its free end. To address these issues, a novel piezoelectric energy harvester based on an extended simply supported beam is proposed. The proposed design features a simply supported piezoelectric main beam with an extended beam attached to its roller end and a tip mass to reduce the resonant frequency. The theoretical model of the proposed piezoelectric energy harvester is developed based on the Euler-Bernoulli beam theory. The model has been experimentally validated through the fabrication of a prototype. The extended beam and tip mass are adjusted to see their influence on the performance of the harvester. The resonant frequency can be maintained by shortening the extended beam and increasing the tip mass simultaneously. A shorter extend beam leads to a more even strain distribution in the piezoelectric layer, resulting in an enhanced output voltage. Moreover, the simulation results show that a torsional spring is installed on the roller joint which greatly influences the voltage output. The strain distribution becomes more even when proper compressive preload is applied on the main beam. Experiments have shown that the proposed design enhances the output power by 86% and reduces tip displacement by 63.2% compared to a traditional cantilevered harvester.

Background: An extended interval between the two primary doses may reduce the risk of myocarditis/pericarditis after COVID-19 mRNA vaccination. Taiwan has implemented a two-dose regimen with a 12-week interval for adolescents. Here we present nationwide data of myocarditis/pericarditis following COVID-19 vaccinations., Methods: Data on adverse events of myocarditis/pericarditis were from the Taiwan Vaccine Adverse Events Reporting System between March 22, 2021, and February 9, 2022. The reporting rates according to sex, age, and vaccine type were calculated. We investigated the rates among young individuals under different two-dose intervals and among those who received two doses of different vaccines., Results: Among 204 cases who met the case definition of myocarditis/pericarditis, 75 cases occurred after the first dose and 129 after the second. The rate of myocarditis/pericarditis after COVID-19 vaccination varied across sex and age groups and was highest after the second dose in males aged 12-17 years (126.79 cases per million vaccinees) for the BNT162b2 vaccine and in males aged 18-24 years (93.84 cases per million vaccinees) for the mRNA-1273 vaccine. The data did not suggest an association between longer between-dose interval and lower rate of myocarditis/pericarditis among males and females aged 18-24 or 25-29 years who received two doses of the BNT162b2 or mRNA-1273 vaccine. Rates of myocarditis/pericarditis in males and females aged 18-49 years after receiving ChAdOx1-S - mRNA-1273 vaccination was significantly higher than after ChAdOx1-S - ChAdOx1-S vaccination., Conclusions: Myocarditis and pericarditis are rare following mRNA vaccination, with higher risk occurring in young males after the second dose., Competing Interests: Conflict of interest disclosure None reported., (Copyright © 2023. Published by Elsevier B.V.)

Background: Numerous studies have found that inhibiting the expression of NLRP3 inflammasome can significantly improve depressive-like behaviors in mice, but the research on its effect on cognitive decline in depression and its mechanism is still lacking. This study aimed to elucidate the role of NLRP3 inflammasome in cognitive decline in depression and explore the common neuro-immunological mechanisms of depression and Alzheimer's disease (AD)., Methods: Male C57BL/6 mice were subjected to chronic unpredictable mild stress (CUMS) for 5 weeks, treatment group was administered with the NLRP3 inhibitor MCC950 (10 mg/kg, i.p.), fluoxetine served as positive control. Then, the mice were assessed for cognitive behaviors and depression-like behaviors, and changes of microglia and neurons in hippocampus and levels of Aβ metabolic pathway and tau protein were measured. To explore the mechanism of NLRP3 activation on neurons, we performed in vitro studies using BV2 microglia and mouse primary neurons. Furthermore, we focused on the role of NLRP3 inflammasome in the function of neurons and the expression of AD pathological indicators., Results: CUMS induced depressive-like behaviors and cognitive decline in mice, which could be reversed by inhibiting NLRP3 inflammasome. MCC950, a specific NLRP3 inhibitor, alleviated CUMS-induced neuron injury and AD-like pathological changes, including the abnormal expression of Aβ metabolic pathway and the hyper-phosphorylation of tau protein. LPS (1 μg/mL) + ATP (1 mM) treatment activated the expression of NLRP3 inflammasome and IL-1β in vitro. In vitro experiment also proved that inhibiting the expression of NLRP3 inflammasome in microglia can restore the Aβ metabolic pathway to normal, decrease neuronal tau protein phosphorylation and protect neurons., Conclusions: Inhibition of NLRP3 inflammasome effectively alleviated CUMS-induced depressive-like behaviors and cognitive decline in mice, and inhibited the activation of AD physiological indicators., (© 2023. The Author(s).)

Introduction: The ChAdOx1 nCoV-19 (ChAd), mRNA-1273 (m1273), MVC-COV1901 (MVC), and BNT162b2 (BNT) COVID-19 vaccines received authorization for emergency use in Taiwan beginning in February 2021. We investigated acute reactions to homologous primary COVID-19 vaccination series in adults aged ≥ 18 years., Methods: In this prospective observational study based on smartphone data (Taiwan V-Watch), we calculated the frequencies of self-reported local and systemic acute reactions within 7 days of a COVID-19 vaccination, and the health effects up to 3 weeks after each dose. Those who reported adverse reactions after both doses were assessed by the McNemar test., Results: During 22 March 2021-13 December 2021, 77,468 adults were enrolled; 59.0 % were female and 77.8 % were aged 18-49 years. For both doses of all four vaccines, the local and systemic reactions were minor in severity and highest on days 1 and 2 after vaccination, and declined markedly until day 7. For 65,367 participants who provided data after the first and second doses, systemic reactions were more frequent after dose 2 of the BNT and m1273 vaccines (McNemar tests: both p < 0.001), while local reactions were more frequent after dose 2 of the m1273 and MVC vaccines (both p < 0.001), compared with dose 1 of the homologous vaccine. Among the participants aged 18-49 years, the percentage who missed work on the day after vaccination was slightly higher among women (9.3 %) than among men (7.0 %)., Conclusions: Acute reactogenicity and impact of work absenteeism for the four COVID vaccines in the V-Watch survey were mild and of short duration., Competing Interests: Declaration of Competing Interest 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., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objectives: Suicide is the fourth leading cause of death for individuals aged 15-29 years, and early intervention on suicidal ideation and risk factors should be priortized. Brief mindfulness meditation (BMM) is convenient and cost-effective in improving physical and mental well-being, but less is known about its efficacy for suicidal ideation, stress and sleep quality. We investigated the effects of BMM on suicidal ideation, stress, and sleep quality for individuals with suicide risk., Methods: Sixty-four college students with high suicidal ideation (aged 18-30 years) were randomly allocated to either a BMM ( n  = 32) or control group ( n  = 32). The BMM was based on Anapanasati and core mindfulness concepts. Sixty participants completed all scheduled sessions including pretest, one month of intervention or waiting, and posttest. Suicidal ideation was measured with the Beck Scale for Suicidal Ideation. Stress was evaluated using the Perceived Stress Scale and salivary cortisol levels. Sleep was measured using the Pittsburgh Sleep Quality Index and actigraphy accompanied with 7-day sleep diaries., Results: Post-intervention, the BMM group showed significant decrease in suicidal ideation with a large effect size; the decrease showed a medium effect size in the control group. The BMM group, but not the control group, showed significant decrease in morning salivary cortisol and sleep latency, and improved sleep efficiency., Conclusions: BMM could help reduce suicidal ideation, stress, and sleep disturbance for individuals with high suicidal ideation and it may implicate effective suicide prevention strategy.

We study the enhanced sensing of optomechanically induced nonlinearity (OMIN) in a cavity-waveguide coupled system. The Hamiltonian of the system is anti-PT symmetric, with the two involved cavities being dissipatively coupled via the waveguide. The anti-PT symmetry may break down when a weak waveguide-mediated coherent coupling is introduced. However, we find a strong bistable response of the cavity intensity to the OMIN near the cavity resonance, benefiting from linewidth suppression caused by the vacuum induced coherence. The joint effect of optical bistability and the linewidth suppression is inaccessible by the anti-PT symmetric system involving only dissipative coupling. Due to that, the sensitivity measured by an enhancement factor is greatly enhanced by two orders of magnitude compared to that for the anti-PT symmetric model. Moreover, the enhancement factor shows resistance to a reasonably large cavity decay and robustness to fluctuations in the cavity-waveguide detuning. Based on the integrated optomechanical cavity-waveguide systems, the scheme can be used for sensing different physical quantities related to the single-photon coupling strength and has potential applications in high-precision measurements with systems involving Kerr-type nonlinearity.

The injection-molding process is a non-linear process, and the product quality and long-term production stability are affected by several factors. To stabilize the product quality effected by these factors, this research establishes a standard process parameter setup procedure and an adaptive process control system based on the data collected by a nozzle pressure sensor and a tie-bar strain gauge to achieve this goal. In this research, process parameters such as the V/P switchover point, injection speed, packing pressure, and clamping force are sequentially optimized based on the characteristics of the pressure profile. After the optimization process, this research defines the standard quality characteristics through the optimized process parameters and combines it with the adaptive process control system in order to achieve the purpose of automatic adjustment of the machine and maintain high-quality production. Finally, three different viscosity materials are used to verify the effectiveness of the optimization procedure and the adaptive process control system. With the system, the variation of product weight was reduced to 0.106%, 0.092%, and 0.079%, respectively.

Male patients with prolactinomas usually present with typical hyperprolactinemia symptoms, including sexual dysfunction and infertility. However, clinical factors related to sexual dysfunction and surgical outcomes in these patients remain unclear. This study aimed to investigate the outcomes of male patients with prolactinomas after transsphenoidal surgery and the risk factors affecting sexual dysfunction. This study was conducted on 58 male patients who underwent transsphenoidal surgery for prolactinomas between May 2014 and December 2020 at the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China. We evaluated the sexual function of patients before and after surgery through International Index of Erectile Function-5 scores, libido, and frequency of morning erection. Of the 58 patients, 48 (82.8%) patients had sexual intercourse preoperatively. Among those 48 patients, 41 (85.4%) patients presented with erectile dysfunction. The preoperative International Index of Erectile Function-5 scores in patients with macroprolactinomas were significantly higher than those in patients with giant prolactinomas (17.63 ± 0.91 vs 13.28 ± 1.43; P = 0.01). Postoperatively, the incidence of erectile dysfunction was 47.9%, which was significantly lower than that preoperatively (85.4%; P = 0.01). Twenty-eight (68.3%) patients demonstrated an improvement in erectile dysfunction. Tumor size and invasiveness were significantly correlated with the improvement of erectile dysfunction. Preoperative testosterone <2.3 ng ml -1 was an independent predictor of improvement in erectile dysfunction. In conclusion, our results indicated that tumor size and invasiveness were important factors affecting the improvement of sexual dysfunction in male patients with prolactinoma. The preoperative testosterone level was an independent predictor related to the improvement of erectile dysfunction., Competing Interests: None

A widely recognized difficulty in federated learning arises from the statistical heterogeneity among clients: local datasets often originate from distinct yet not entirely unrelated probability distributions, and personalization is, therefore, necessary to achieve optimal results from each individual's perspective. In this paper, we show how the excess risks of personalized federated learning using a smooth, strongly convex loss depend on data heterogeneity from a minimax point of view, with a focus on the FedAvg algorithm (McMahan et al., 2017) and pure local training (i.e., clients solve empirical risk minimization problems on their local datasets without any communication). Our main result reveals an approximate alternative between these two baseline algorithms for federated learning: the former algorithm is minimax rate optimal over a collection of instances when data heterogeneity is small, whereas the latter is minimax rate optimal when data heterogeneity is large, and the threshold is sharp up to a constant. As an implication, our results show that from a worst-case point of view, a dichotomous strategy that makes a choice between the two baseline algorithms is rate-optimal. Another implication is that the popular FedAvg following by local fine tuning strategy is also minimax optimal under additional regularity conditions. Our analysis relies on a new notion of algorithmic stability that takes into account the nature of federated learning.

Lung adenocarcinoma (LUAD) is the most common histological subtype of lung cancer. In the development and progression of LUAD, epigenetic aberration plays a crucial role. However, the function of RNA N6-methyladenosine (m 6 A) modifications in the LUAD progression is unknown. The m6A regulator modification patterns in 955 LUAD samples were analyzed comprehensively. Patterns were systematically correlated with the tumor microenvironment (TME) cell-infiltration characteristics. Using principal component analysis algorithms, the m6Ascore was generated to quantify m 6 A modification patterns in individual tumors. Then, their values for predicting prognoses and therapeutic response in LUAD patients were assessed. Three distinct m 6 A modification patterns in LUAD were identified. Among them, the prognosis of m6Acluster C was the best, while the prognosis of m 6 Acluster A was the worst. Interestingly, the characterization of TME cell infiltration and biological behavior differed among the three patterns. To evaluate m 6 A modification patterns within individual tumors, an m 6 Ascore signature was constructed. The results showed that the high m 6 Ascore group was associated with a better prognosis; tumor somatic mutations and tumor microenvironment differed significantly between the high- and low- m 6 Ascore groups. Furthermore, in the cohort with anti-CTLA-4 treatment alone, patients with a high m 6 Ascore had higher ICI scores, which indicated significant therapeutic advantage and clinical benefits., (© 2022. The Author(s).)

Objectives: Human mitochondrial cell-free DNA (Mt-cfDNA) may serve as a useful biomarker for infectious processes. We investigated Mt-cfDNA dynamics in patients with pulmonary mycobacterial infections to determine if this novel biomarker could be used to differentiate disease states and severity., Methods: Patients with pulmonary tuberculosis (PTB), latent tuberculosis infection (LTBI), and nontuberculous mycobacterial-lung disease (NTM-LD) were enrolled at a tertiary care hospital in Taiwan between June 2018 and August 2021. Human Mt-cfDNA and nuclear-cfDNA (Nu-cfDNA) copy numbers were estimated by quantitative polymerase chain reaction. Variables associated with PTB and 2-month sputum culture-positivity, indicating poor treatment response, were assessed using logistic regression., Results: Among 97 patients with PTB, 64 with LTBI, and 51 with NTM-LD, Mt-cfDNA levels were higher in patients with PTB than in LTBI (p=0.001) or NTM-LD (p=0.006). In the Mycobacterium tuberculosis -infected population, Mt-cfDNA levels were highest in smear-positive PTB patients, followed by smear-negative PTB (p<0.001), and were lowest in LTBI persons (p=0.009). A Mt-cfDNA, but not Nu-cfDNA, level higher than the median helped differentiate culture-positive PTB from culture-negative PTB and LTBI (adjusted OR 2.430 [95% CI 1.139-5.186], p=0.022) and differentiate PTB from NTM-LD (adjusted OR 4.007 [1.382-12.031], p=0.011). Mt-cfDNA levels decreased after 2 months of treatment in PTB patients (p=0.010). A cutoff Mt-cfDNA level greater than 62.62 x 10 6 copies/μL-plasma was associated with a 10-fold risk of 2-month culture-positivity (adjusted OR 9.691 [1.046-89.813], p=0.046)., Conclusion: Elevated Mt-cfDNA levels were associated with PTB disease and failed sputum conversion at 2 months in PTB patients, and decreased after treatment., 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 Pan, Syed, Catanzaro, Ho, Shu, Tsai, Tseng, Feng, Chen, Su, Catanzaro and Rodwell.)

Transarterial chemoembolization (TACE) is the first-line treatment for unresectable intermediate-stage hepatocellular carcinoma (HCC). It is of high clinical significance to explore the synergistic effect of TACE with antiangiogenic inhibitors and the molecular mechanisms involved. This study determined that glucose, but not other analyzed nutrients, offered significant protection against cell death induced by sorafenib, as indicated by glucose deprivation sensitizing cells to sorafenib-induced cell death. Next, this synergistic effect was found to be specific to sorafenib, not to lenvatinib or the chemotherapeutic drugs cisplatin and doxorubicin. Mechanistically, sorafenib-induced mitophagy, as indicated by PINK1 accumulation, increased the phospho-poly-ubiquitination modification, accelerated mitochondrial membrane protein and mitochondrial DNA degradation, and increased the amount of mitochondrion-localized mKeima-Red engulfed by lysosomes. Among several E3 ubiquitin ligases tested, SIAH1 was found to be essential for inducing mitophagy; that is, SIAH1 silencing markedly repressed mitophagy and sensitized cells to sorafenib-induced death. Notably, the combined treatment of glucose restriction and sorafenib abolished ATP generation and mitophagy, which led to a high cell death rate. Oligomycin and antimycin, inhibitors of electron transport chain complexes, mimicked the synergistic effect of sorafenib with glucose restriction to promote cell death mediated via mitophagy inhibition. Finally, inhibition of the glucose transporter by canagliflozin (a clinically available drug used for type-II diabetes) effectively synergized with sorafenib to induce HCC cell death in vitro and to inhibit xenograft tumor growth in vivo. This study demonstrates that simultaneous treatment with sorafenib and glucose restriction is an effective approach to treat HCC, suggesting a promising combination strategy such as transarterial sorafenib-embolization (TASE) for the treatment of unresectable HCC., (© 2022. The Author(s).)

Objective: To analyze the clinicopathological features of IgG4-related diseases (RD) of retroperitoneum and the urinary and male reproductive system (IgG4-RUMR). Methods: A total of 11 IgG4-RUMR cases from January 2013 to March 2021 were retrospectively collected at Peking University Third Hospital and Shandong Provincial Hospital affiliated to Shandong First Medical University. The clinicopathologic features, laboratory and imaging findings were analyzed and scored according to the 2019 ACR/EULAR classification criteria for IgG4-RD. Results: The 11 patients (male:female is 9∶2; mean age 59 years, range from 44 to 83 years) were initially admitted to the Deparment of Urology/Kidney Transplantation (10 cases) and the Department of Oncology (1 case). All patients had urogenital disorders or imaging abnormalities. Three of the 11 patients had a history of IgG4-RD such as lacrimal gland engorgement, salivary gland engorgement and IgG4-associated pancreatitis. Abnormal retroperitoneal soft tissue and hydronephrosis were found in eight cases, while epididymal and spermatic cord masses were found in one case, simple renal mass in one case, and"benign prostatic hyperplasia"in one case. In the 10 patients tested for serum IgG4, the serum IgG4 level was 0.8-14.4 g/L. Histologically, all cases showed significant lymphoplasmacytic infiltration and storiform fibrosis, and some were accompanied by obliterative phlebitis. The number of IgG4 positive plasma cells was 12-155 per high-power field, and the IgG4/IgG ratio was 15%-77%. According to the 2019 ACR/EULAR IgG4-RD classification standard 11 cases scored 20-48 points, all of which met the diagnostic criteria of IgG4-RUMR. Therapeutically, the patient with a simple renal mass underwent partial nephrectomy. The patient with prostate lesion underwent transurethral resection of prostate and was initially diagnosed as nonspecific chronic prostatitis. Later, the patient was admitted again because of salivary gland swelling, and the pathologic diagnosis was amended. The patient with epididymal and spermatic cord masses participated in a clinical trial about retroperitoneal fibrosis. The remaining eight patients received symptomatic treatment such as adhesiolysis and stent placement. All the patients were subsequently treated with glucocorticoid/immunosuppressant and symptoms relieved. Conclusions: IgG4-RUMR is uncommon. In clinical practice, information from clinical, serologic, radiologic and pathologic evaluations must be integrated. IgG4-RUMR should be considered in the differential diagnosis of urinary and male reproductive diseases. The 2019 ACR/EULAR classification criteria for IgG4-RD, while relatively complex, are objective and practical in the diagnosis of IgG4-RUMR.

Background: In patients with nodular bronchiectatic (NB) nontuberculous mycobacterial lung disease (NTM-LD), risk factors for disease progression have not been clearly investigated. The roles of cavitary NB and soluble programmed death protein-1 (sPD-1), an immune-related biomarker, in the disease course of NB NTM-LD remain unknown., Methods: Patients with NB NTM-LD were enrolled from 2 medical centers in 2014-2020. We identified cavitary NB, measured sPD-1 levels, and analyzed factors associated with cavitary NB and predictors for disease progression of NB NTM-LD., Results: Of 120 cases of NB NTM-LD, 87 (72.5%) were caused by Mycobacterium avium complex. sPD-1 levels were lower in 13 (10.8%) patients with cavitary NB than in noncavitary patients (P = .020). Over 1.41 ± 1.43 years of follow-up, 12 (92.3%) patients in the cavitary and 66 (61.7%) in the noncavitary group developed disease progression (P = .032). In multivariable analysis, body mass index (BMI [kg/m2]; adjusted hazard ratio [aHR], .895 [95% confidence interval, .811-.988]), sputum smear grade (aHR, 1.247 [1.014-1.534]), cavitary NB (aHR, 2.008 [1.052-3.834]), and sPD-1 (per 10-pg/mL increase; aHR, .889 [.816-.967]) were predictive for disease progression. Notably, sPD-1 showed a dose-dependent association with disease progression (sPD-1 ≤23.5 pg/mL; aHR, 3.306 [1.664-6.567]; sPD-1: 23.6-53.7 pg/mL; aHR, 2.496 [1.390-4.483]) compared with the reference (sPD-1 >53.7 pg/mL)., Conclusions: Patients with NB NTM-LD and low sPD-1, low BMI, high smear grade, and cavitary NB were at high risk for disease progression. sPD-1 was low in patients with cavitary NB phenotype and dose-responsively associated with disease progression., Competing Interests: Potential conflicts of interest. The authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Replicability is a fundamental quality of scientific discoveries: we are interested in those signals that are detectable in different laboratories, different populations, across time etc. Unlike meta-analysis which accounts for experimental variability but does not guarantee replicability, testing a partial conjunction (PC) null aims specifically to identify the signals that are discovered in multiple studies. In many contemporary applications, for example, comparing multiple high-throughput genetic experiments, a large number M of PC nulls need to be tested simultaneously, calling for a multiple comparisons correction. However, standard multiple testing adjustments on the M PC p -values can be severely conservative, especially when M is large and the signals are sparse. We introduce AdaFilter, a new multiple testing procedure that increases power by adaptively filtering out unlikely candidates of PC nulls. We prove that AdaFilter can control FWER and FDR as long as data across studies are independent, and has much higher power than other existing methods. We illustrate the application of AdaFilter with three examples: microarray studies of Duchenne muscular dystrophy, single-cell RNA sequencing of T cells in lung cancer tumors and GWAS for metabolomics.

Background: Differentiating between nontuberculous mycobacterial lung disease (NTM-LD) and pulmonary NTM colonization (NTM-Col) is difficult. Compared with healthy controls, patients with NTM-LD generally present immune tolerance along with increased expressions of T-cell immunoglobulin mucin domain-3 (TIM-3) and programmed cell death-1 (PD-1) on T lymphocytes. However, the role of soluble TIM-3 (sTIM-3) and soluble PD-1 (sPD-1) in differentiating NTM-LD from NTM colonization (NTM-Col) remains unclear., Methods: Patients with NTM-positive respiratory samples and controls were enrolled from 2016 to 2019. Patients were classified into NTM-Col and NTM-LD groups. Levels of sTIM-3, sPD-1, soluble PD-ligand-1 (sPD-L1), and TIM-3 expression were measured. Factors associated with NTM-LD were analyzed by logistical regression., Results: TIM-3 expression on CD4 + and CD8 + T lymphocytes were highest in NTM-LD group, followed by NTM-Col, and control (P=.017 and P=.011 for trend). sTIM-3 elevated in the NTM-Col group compared with the NTM-LD and control groups (856.3±518.7 vs. 595.3±352.6pg/mL, P=.009; vs. 437.0±267.4pg/mL, P<.001). Levels of soluble PD-1 and its ligand were similar among groups. Among the 79 NTM-positive patients, sTIM-3 was associated with NTM-LD (100-pg/mL increase, adjusted odds ratio (aOR) 0.658 [95% CI, 0.502-0.864], P=.003). Patients with ≥2 risk factors (sTIM-3≤530pg/mL, BMI≤22.5, and radiographic score ≥5) were 13 times more likely to exhibit NTM-LD than those without (aOR 13.234 [2.983-58.709], P=.001)., Conclusions: sTIM-3 was an independent factor for differentiating NTM-LD from NTM-Col, suggesting the immunologic role of sTIM-3 in NTM-LD pathogenesis. By assessing sTIM-3 levels and other risk factors, physicians may be able to identify NTM-LD cases in a simplified manner., (Copyright © 2022 SEPAR. Published by Elsevier España, S.L.U. All rights reserved.)

Scientific injection molding technologies involve the integration and collaboration of cyber-physical systems and smart manufacturing. In order to achieve adaptive process control and production optimization, injection molding systems with real-time sensing have gradually become the development- and application-trend of smart injection molding. At the same time, this technology is a highly non-linear process in which many factors affect the product quality during long-run fabrication processes. Therefore, in order to grasp changes in the characteristics of plastic materials and product quality monitoring, the injection process has become an important research topic. We installed sensors in the molding machine (injection barrel, nozzle, and mold-cavity) to collect the melting pressure and used different materials (semi-crystalline and amorphous polymer; the melting-fill-index (MFI) is unified to 14.5 ± 0.5 g/10 min) to explore the influences of melting pressure variation and its viscosity index on the quality characteristics of molded products. The experiment reveals that a combination of barrel, nozzle, and mold-cavity sensing on the melt-pressure trend-based injection process-control incorporated with viscosity index monitoring can confirm the weight and shrinkage variation of the injection product. At the same time, the pressure and viscosity index value measured and calculated during the melt-filling of two materials with similar MI resulted in significant variations in the amorphous polymer. This study showed the possibility of mastering and controlling the rheology (barrel position) and shrinkage properties of polymers and successful application in various product-quality monitoring platforms.

Diplopia is a common symptom after blowout fractures, with an incidence of 43.6%-83%. Although there is some consensus toward surgical correction, diplopia is not always resolved by surgery. Thus, there is a clinical dilemma for surgeons with regard to performing surgery at a specific time. This review aimed to create an algorithm to support accurate and effective decision-making., Methods: We reviewed articles published on PubMed during 2013-2020 regarding orbital fractures. Articles discussing surgical treatment for blowout fractures and diplopia were included. Five reviews, six prospective cohort studies, and 33 retrospective studies were identified. After reviewing and summarizing these articles, a step-by-step algorithm was created., Results: Most authors advise immediate surgery when a patient presents with either a positive oculocardiac reflex or a "trapdoor" fracture. Early surgical correction is recommended in children to prevent profound muscle damage. In other scenarios, most authors recommend performing surgery within 2 weeks. The algorithm begins with the aspect of motility, including muscle entrapment assessed by computed tomography or limited movement of the extraocular muscle. When there is no abnormality in motility, the algorithm continues to the aspect of position. Generally, an orbital floor defect of more than 50% or 2 cm 2 or an enophthalmos of more than 2 mm is indicated for surgery. However, diplopia may also gradually resolve after improvement of periorbital edema or swelling., Conclusion: We proposed a step-by-step approach to help surgeons make effective decisions concerning surgical correction for patients suffering from blowout fractures with diplopia at different time points., (Copyright © 2022 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of The American Society of Plastic Surgeons.)

Background: A regimen of once-weekly rifapentine plus isoniazid for 3 months (3HP) is an effective treatment for subjects with latent tuberculosis infection; however, no reliable biomarker exists for predicting systemic adverse reactions (SARs) to 3HP treatment., Methods: This prospective, multi-center study evaluated the plasma concentrations of soluble triggering receptors expressed on myeloid cells (sTREM)-1 and sTREM-2 in subjects undergoing 3HP treatment and examined the associations between these biomarkers and SARs., Results: This study enrolled 80 consecutive subjects receiving 3HP treatment, 25 of whom had SARs and 55 of whom did not. Subjects with SARs presented higher concentrations of sTREM-1 at baseline than those without SARs (240.1 ± 19.1 vs. 176.7 ± 9.4 pg/mL, P = 0.001). The area under the receiver operating characteristic curves revealed that day 1 plasma levels of sTREM-1 (0.708, 95% CI, 0.584-0.833, P = 0.003) and sTREM-2 (0.343, 95% CI, 0.227-0.459, P = 0.025) as well as the sTREM-1/sTREM-2 ratio (0.748, 95% CI, 0.638-0.858, P = 0.001) had modest discriminative power pertaining to the development of SARs. An sTREM-1 level exceeding the cut-off value (>187.4 pg/mL) (hazard ratio [HR], 6.15; 95% CI 1.67-22.70, P = 0.006) and a sTREM-2 below the cut-off value (<237.2 pg/mL) (HR, 4.46; 95% CI 1.41-14.1, P = 0.011) were independent predictors of SARs after controlling for other variables., Conclusions: Plasma sTREM-1 and sTREM-2 levels are useful biomarkers for predicting SARs during 3HP treatment., Clinical Trial Government: NCT04655794., 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 Wang, Feng, Shu, Lee, Chen, Wei, Lin, Huang, Su and Lin.)