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Abstract Background Idiopathic pulmonary fibrosis (IPF) is a special kind of chronic interstitial lung disease with insidious onset. Previous studies have revealed that mutations in ZCCHC8 may lead to IPF. The aim of this study is to explore the ZCCHC8 mutations in Chinese IPF patients. Methods Here, we enrolled 124 patients with interstitial lung disease from 2017 to 2023 in our hospital. Whole exome sequencing and Sanger sequencing were employed to explore the genetic lesions of these patients. Results Among these 124 patients, a novel mutation (NM_017612: c.1228 C > G/p.P410A) of Zinc Finger CCHC-Type Containing 8 (ZCCHC8)was identified in a family with IPF and chronic obstructive lung disease. As a component of the nuclear exosome-targeting complex that regulates the turnover of human telomerase RNA, ZCCHC8 mutations have been reported may lead to IPF in European population and American population. Functional study confirmed that the novel mutation can disrupt the nucleocytoplasmic localization of ZCCHC8, which further decreased the expression of DKC1 and RTEL1, and finally reduced the length of telomere and led to IPF and related disorders. Conclusions We may first report the ZCCHC8 mutation in Asian population with IPF. Our study broadens the mutation, phenotype, and population spectrum of ZCCHC8 deficiency.

Abstract Dental calculus severely affects the oral health of humans and animal pets. Calculus deposition affects the gingival appearance and causes inflammation. Failure to remove dental calculus from the dentition results in oral diseases such as periodontitis. Apart from adversely affecting oral health, some systemic diseases are closely related to dental calculus deposition. Hence, identifying the mechanisms of dental calculus formation helps protect oral and systemic health. A plethora of biological and physicochemical factors contribute to the physiological equilibrium in the oral cavity. Bacteria are an important part of the equation. Calculus formation commences when the bacterial equilibrium is broken. Bacteria accumulate locally and form biofilms on the tooth surface. The bacteria promote increases in local calcium and phosphorus concentrations, which triggers biomineralization and the development of dental calculus. Current treatments only help to relieve the symptoms caused by calculus deposition. These symptoms are prone to relapse if calculus removal is not under control. There is a need for a treatment regime that combines short-term and long-term goals in addressing calculus formation. The present review introduces the mechanisms of dental calculus formation, influencing factors, and the relationship between dental calculus and several systemic diseases. This is followed by the presentation of a conceptual solution for improving existing treatment strategies and minimizing recurrence.

Abstract We study the mass spectra of hidden-charm tetraquark systems with quantum numbers (I G )J P = (1+)1+ (and their I = 1 2 $$ \frac{1}{2} $$ partners) using QCD sum rules. The analysis incorporates the complete next-to-leading order (NLO) contribution to the perturbative QCD part of the operator product expansions, with particular attention to operator mixing effects due to renormalization group evolution. We find that both the parametric dependence and the perturbative convergence are significantly improved for the two mixed operators J 1 , 5 Mixed $$ {J}_{1,5}^{\textrm{Mixed}} $$ and J 2 , 6 Mixed $$ {J}_{2,6}^{\textrm{Mixed}} $$ , compared with those for the unmixed meson-meson or diquark-antidiquark type ones. For the d ¯ c c ¯ u $$ \overline{d}c\overline{c}u $$ system, the masses of J 1 , 5 Mixed $$ {J}_{1,5}^{\textrm{Mixed}} $$ and J 2 , 6 Mixed $$ {J}_{2,6}^{\textrm{Mixed}} $$ are determined to be 3.89 − 0.12 + 0.18 $$ {3.89}_{-0.12}^{+0.18} $$ GeV and 4.03 − 0.07 + 0.06 $$ {4.03}_{-0.07}^{+0.06} $$ GeV, respectively, closely matching those of Z c (3900) and Z c (4020). Similarly, for the s ¯ c c ¯ u $$ \overline{s}c\overline{c}u $$ states, the masses of J 1 , 5 Mixed $$ {J}_{1,5}^{\textrm{Mixed}} $$ and J 2 , 6 Mixed $$ {J}_{2,6}^{\textrm{Mixed}} $$ are found to be 4.02 − 0.09 + 0.17 $$ {4.02}_{-0.09}^{+0.17} $$ GeV and 4.21 − 0.07 + 0.08 $$ {4.21}_{-0.07}^{+0.08} $$ GeV, respectively, in close proximity to Z cs (3985)/Z cs (4000) and Z cs (4220), consistent with the expectation that they are the partners of Z c (3900) and Z c (4020). Our results highlight the crucial role of operator mixing, an inevitable effect in a complete NLO calculation, in achieving a robust phenomenological description for the tetraquark system.

Abstract We present an analytic calculation of the one-loop correction to the double-real emission contribution to the zero-jettiness soft function at N3LO in QCD, accounting for both gluon-gluon and quark-antiquark soft final-state partons. We explain all the relevant steps of the computation including the reduction of phase-space integrals to master integrals in the presence of Heaviside functions, and the methods we employed to compute them.

Abstract Background The global dementia prevalence is surging, necessitating research into contributing factors. We aimed to investigate the association between metabolic syndrome (MetS), its components, serum uric acid (SUA) levels, and dementia risk. Methods Our prospective study comprised 466,788 participants without pre-existing MetS from the UK Biobank. We confirmed dementia diagnoses based on the ICD-10 criteria (F00-03). To evaluate the dementia risk concerning MetS, its components, and SUA levels, we applied Cox proportional hazards models, while adjusting for demographic factors. Results Over a median follow-up of 12.7 years, we identified 6845 dementia cases. Individuals with MetS had a 25% higher risk of all-cause dementia (hazard ratio [HR] = 1.25, 95% confidence interval [CI] = 1.19–1.31). The risk increased with the number of MetS components including central obesity, dyslipidemia for high-density lipoprotein (HDL) cholesterol, hypertension, hyperglycemia, and dyslipidemia for triglycerides. Particularly for those with all five components (HR = 1.76, 95% CI = 1.51–2.04). Dyslipidemia for HDL cholesterol, hypertension, hyperglycemia, and dyslipidemia for triglycerides were independently associated with elevated dementia risk (p < 0.01). MetS was further linked to an increased risk of all-cause dementia (11%) and vascular dementia (VD, 50%) among individuals with SUA levels exceeding 400 μmol/L (all-cause dementia: HR = 1.11, 95% CI = 1.02–1.21; VD: HR = 1.50, 95% CI = 1.28–1.77). Conclusions Our study provides robust evidence supporting the association between MetS, its components, and dementia risk. These findings emphasize the importance of considering MetS and SUA levels in assessing dementia risk, offering valuable insights for prevention and management strategies.

Ovarian aging is a complex process characterized by a decline in oocyte quantity and quality, directly impacting fertility and overall well-being. Recent researches have identified mitochondria as pivotal players in the aging of ovaries, influencing various hallmarks and pathways governing this intricate process. In this review, we discuss the multifaceted role of mitochondria in determining ovarian fate, and outline the pivotal mechanisms through which mitochondria contribute to ovarian aging. Specifically, we emphasize the potential of targeting mitochondrial dysfunction through innovative therapeutic approaches, including antioxidants, metabolic improvement, biogenesis promotion, mitophagy enhancement, mitochondrial transfer, and traditional Chinese medicine. These strategies hold promise as effective means to mitigate age-related fertility decline and preserve ovarian health. Drawing insights from advanced researches in the field, this review provides a deeper understanding of the intricate interplay between mitochondrial function and ovarian aging, offering valuable perspectives for the development of novel therapeutic interventions aimed at preserving fertility and enhancing overall reproductive health.

This study proposes an integrated approach to developing a Microservice, Cloud Computing, and Software as a Service (SaaS)-based Real-Time Storm Sewer Simulation System (MBSS). The MBSS combined the Storm Water Management Model (SWMM) microservice running on the EC2 Amazon Web Services (AWS) cloud platform and an Internet of Things (IoT) monitoring device to prevent disasters in smart cities. The Python language and Docker container were used to develop the MBSS and Web API of the SWMM microservice. The IoT comprised a pressure water level meter, an Arduino, and a Raspberry Pi. After laboratory channel testing, the simulated and IoT-monitored water levels under different flow rates indicate that the simulated water level in MBSS was such as that monitored by the IoT. These findings suggest that MBSS is feasible and can be further used as a reference for smart urban early warning systems. The MBSS can be applied in on-site stormwater sewers during heavy rain, with the goal of issuing early warnings and reducing disaster damage. The use case can be the process by which the SWMM model parameters will be optimized based on the water level data from IoT monitoring devices in stormwater sewer systems. The predicted rainfall will then be used by the SWMM microservices of MBSS to simulate the water levels at all manholes. The status of the water levels will finally be applied to early warning.

Abstract Background Enhancer dysregulation is one of the important features for cancer cells. Enhancers enriched with H3K4me3 have been implicated to play important roles in cancer. However, their detailed features and regulatory mechanisms have not been well characterized. Results Here, we profile the landscape of H3K4me3-enriched enhancers (m3Es) in 43 pairs of colorectal cancer (CRC) samples. M3Es are widely distributed in CRC and averagely possess around 10% of total active enhancers. We identify 1322 gain variant m3Es and 367 lost variant m3Es in CRC. The target genes of the gain m3Es are enriched in immune response pathways. We experimentally prove that repression of CBX8 and RPS6KA5 m3Es inhibits target gene expression in CRC. Furthermore, we find histone methyltransferase MLL1 is responsible for depositing H3K4me3 on the identified Vm3Es. We demonstrate that the transcription factor AP1/JUN interacts with MLL1 and regulates m3E activity. Application of a small chemical inhibitor for MLL1 activity, OICR-9429, represses target gene expression of the identified Vm3Es, enhances anti-tumor immunity and inhibits CRC growth in an animal model. Conclusions Taken together, our study illustrates the genome-wide landscape and the regulatory mechanisms of m3Es in CRC, and reveals potential novel strategies for cancer treatment.

Owing to the limitation of a large genome size (~13 Gb), the genetic and gene mapping studies on faba bean (Vicia faba L.) are lagging far behind those for other legumes. In this study, we selected three purified faba bean lines (Yundou 8137, H0003712, and H000572) as parents and constructed two F2 populations. These two F2 populations, namely 167 F2 plants in Pop1 (Yundou 8137×H0003712) and 204 F2 plants in Pop2 (H000572×Yundou 8137), were genotyped using a targeted next-generation sequencing (TNGS) genotyping platform, and two high-density single nucleotide polymorphisms (SNP) genetic linkage maps of faba bean were constructed. The map constructed from Pop1 contained 5 103 SNPs with a length of 1 333.31 cM and an average marker density of 0.26 cM. The map constructed from Pop2 contained 1 904 SNPs with a greater length of 1 610.61 cM. In these two F2 populations, QTL mapping identified 98 QTLs for 14 agronomic traits related to the flowers, pods, plant types and grains. The two maps were then merged into an integrated genetic linkage map containing 6 895 SNPs, with a length of 3 324.48 cM. These results not only lay the foundation for fine mapping and map-based cloning of related genes, but can also accelerate the molecular marker-assisted breeding of faba bean.

Most elderly persons suffer from chronic diseases. To treat chronic diseases, good medication adherence and refilling medication as physicians’ advice are key points of pharmaceutical therapy. However, the literature revealed that only limited studies have focused on the medication adherence of the elderly in rural communities. This study evaluated the adherence to medication and the degree of refilling prescriptions as physician’s advice by the Adherence to Refills and Medications Scale (ARMS) and evaluated the factors associated with poor adherence to medication. This cross-sectional study focused on the medication use of the elderly population in rural areas in western Taiwan and analyzed related personal and social factors which influence the behaviors of pharmaceutical therapy. In conclusion, most of the elderly who lived in rural areas in western Taiwan have poor adherence (ARMS score over 12) to medication and a poor degree of refilling prescriptions as per physicians’ advice. Moreover, age ≥75 years and low urbanization were significantly associated with poor adherence. Future research is warranted to assess the effect of the interventions to improve medication adherence on chronic disease control, disability, and mortality.

This study proposes a deep neural network (DNN)-based downscaling model incorporating kernel principal component analysis (KPCA) to investigate the precipitation uncertainty influenced by typhoons in Taiwan, which has a complex island topography. The best tracking data of tropical cyclones from the Joint Typhoon Warning Center (JTWC) are utilized to calculate typhoon and non-typhoon precipitation. KPCA is applied to extract nonlinear features of the BCC-CSM1-1 (Beijing Climate Center Climate System Model version 1.1) and CanESM2 (second-generation Canadian Earth System Model) GCM models. The length of the data used in the two GCM models span from January 1950 to December 2005 (historical data) and from January 2006 to December 2099 (scenario out data). The rainfall data are collected from the weather stations in Taichung and Hualien (cities of Taiwan) operated by the Central Weather Administration (CWA), Taiwan. The period of rainfall data in Taichung and in Hualien spans from January 1950 to December 2005. The proposed model is constructed with features extracted from the GCMs and historical monthly precipitation from Taichung and Hualien. The model we have built is used to estimate monthly precipitation and uncertainty in both Taichung and Hualien for future scenarios (rcp 4.5 and 8.5) of the GCMs. The results suggest that, in Taichung and Hualien, the summer precipitation is mostly within the normal range. The rainfall in the long term (January 2071 to December 2080) for both Taichung and Hualien typically fall between 100 mm and 200 mm. In the long term, the dry season (January to April, November, and December) precipitation for Taichung and that in the wet season (May to October) for Hualien are less and more affected by typhoons, respectively. The dry season precipitation is more affected by typhoons in Taichung than Hualien. In both Taichung and Hualien, the long-term probability of rainfall exceeding the historical average in the dry season is higher than that in the wet season.

Abstract We study the mass spectra of Q ¯ Q Q ¯ Q $$ \overline{Q}Q\overline{Q}Q $$ (Q = c, b) systems in QCD sum rules with the complete next-to-leading order (NLO) contribution to the perturbative QCD part of the correlation functions. Instead of meson-meson or diquark-antidiquark currents, we use diagonalized currents under operator renormalization. We find that differing from conventional mesons q ¯ q $$ \overline{q}q $$ and baryons qqq, a unique feature of the multiquark systems like Q ¯ Q Q ¯ Q $$ \overline{Q}Q\overline{Q}Q $$ is the operator mixing or color configuration mixing induced by NLO corrections, which is crucial to understand the color structure of the states. Our numerical results show that the NLO corrections are very important for the Q ¯ Q Q ¯ Q $$ \overline{Q}Q\overline{Q}Q $$ system, because they not only give significant contributions but also reduce the scheme and scale dependence and make Borel platform more distinct, especially for the b ¯ b b ¯ b $$ \overline{b}b\overline{b}b $$ in the MS ¯ $$ \overline{\textrm{MS}} $$ scheme. We use currents that have good perturbation convergence in our phenomenological analysis. With the MS ¯ $$ \overline{\textrm{MS}} $$ scheme, we get three J PC = 0++ states, with masses 6.35 − 0.17 + 0.20 $$ {6.35}_{-0.17}^{+0.20} $$ GeV, 6.56 − 0.20 + 0.18 $$ {6.56}_{-0.20}^{+0.18} $$ GeV and 6.95 − 0.35 + 0.21 $$ {6.95}_{-0.35}^{+0.21} $$ GeV, respectively. The first two seem to agree with the broad structure around 6.2 ~ 6.8 GeV measured by the LHCb collaboration in the J/ψJ/ψ spectrum, and the third seems to agree with the narrow resonance X(6900). For the 2++ states we find one with mass 7.03 − 0.26 + 0.22 $$ {7.03}_{-0.26}^{+0.22} $$ GeV, which is also close to that of X(6900), and another one around 7.25 − 0.35 + 0.21 $$ {7.25}_{-0.35}^{+0.21} $$ GeV, which has good scale dependence but slightly large scheme dependence.

Under the tide led by artificial intelligence, the application of deep learning methods in underwater target recognition has gained increasing attention. However, obtaining underwater sample data from actual scientific research is extremely difficult because of environmental constraints, time, cost, and other factors. An insufficient number of samples leads to poor training effects in deep learning models. Generative adversarial networks(GAN), a new artificial intelligence technology, have a wide range of applications in data enhancement, image generation, and other fields. However, the traditional GAN model is unsuitable for underwater echo samples and cannot be used directly for sample data generation. Therefore, this study proposed an underwater echo signal generation method based on an improved GAN for a small sample to address the problem of insufficient underwater target data. Combining the characteristics of the echo signal, the study designed and built a convolution unit-based GAN model. Furthermore, an echo signal generation simulation experiment was carried out using the pool experimental test data. Finally, the effectiveness of the generated signal was verified at the level of the signal waveform and amplitude probability distribution. The experimental results show that the improved GAN model proposed in this study is suitable for generating highly realistic original echo signals in the case of small samples, which provides a new idea for the active detection and recognition of underwater targets.

Abstract Abnormality of enhancer regulation has emerged as one of the critical features for cancer cells. KDM5C is a histone H3K4 demethylase and frequently mutated in several types of cancer. It is critical for H3K4me3 and activity of enhancers, but its regulatory mechanisms remain elusive. Here, we identify TRIM11 as one ubiquitin E3 ligase for KDM5C. TRIM11 interacts with KDM5C, catalyzes K48-linked ubiquitin chain on KDM5C, and promotes KDM5C degradation through proteasome. TRIM11 deficiency in an animal model represses the growth of breast tumor and stabilizes KDM5C. In breast cancer patient tissues, TRIM11 is highly expressed and KDM5C is lower expressed, and their expression is negatively correlated. Mechanistically, TRIM11 regulates the enhancer activity of genes involved in cell migration and immune response by targeting KDM5C. TRIM11 and KDM5C regulate MCAM expression and cell migration through targeting H3K4me3 on MCAM enhancer. Taken together, our study reveals novel mechanisms for enhancer regulation during breast cancer tumorigenesis and development.

Immunotherapy has shown clinical benefit in patients with non-small-cell lung cancer (NSCLC). Due to the limited response of monotherapy, combining immune checkpoint inhibitors (ICIs) and chemotherapy is considered a treatment option for advanced NSCLC. However, the mechanism of combined therapy and the potential patient population that could benefit from combined therapy remain undetermined. Here, we developed an NSCLC model based on the published quantitative systems pharmacology (QSP)-immuno-oncology platform by making necessary adjustments. After calibration and validation, the established QSP model could adequately characterise the biological mechanisms of action of the triple combination of atezolizumab, nab-paclitaxel, and carboplatin in patients with NSCLC, and identify predictive biomarkers for precision dosing. The established model could efficiently characterise the objective response rate and duration of response of the IMpower131 trial, reproducing the efficacy of alternative dosing. Furthermore, CD8+ and CD4+ T cell densities in tumours were found to be significantly related to the response status. This significant extension of the QSP model not only broadens its applicability but also more accurately reflects real-world clinical settings. Importantly, it positions the model as a critical foundation for model-informed drug development and the customisation of treatment plans, especially in the context of combining single-agent ICIs with platinum-doublet chemotherapy.

Ship wake detection is an effective method for undersea vehicles to detect and track surface ships. However, traditional wake detection methods based on time-domain features are limited by subjective experience and complex varying marine environments with certain limitations in the intelligent detection of ship wakes. Aiming at the problem of insufficient accuracy and efficiency of traditional wake detection methods in complex environments, this study introduces a deep learning theory to improve the independent learning and adaptive capabilities of the model. Subsequently, a novel ship wake detection method based on transfer learning and time-frequency analysis is proposed, considering the difficulty of obtaining ship wake samples. First, in this method, the time-frequency domain characteristics of the wake signal are extracted using short-time Fourier transform. Then, through the strategy of parameter freezing and fine-tuning, transfer learning based on a pre-trained convolutional neural network is completed. Finally, the effective detection of ship wakes using a small sample dataset is realized. Combining the wake detection experiment with actual measured data, the results show that, when compared with the traditional wake detection method, the correct rate of the wake detection method based on time-frequency analysis and transfer learning is increased by approximately 10%, with the highest reaching 97.49%. It combines the characteristics of a low time cost, low sample demand, and high recognition performance.

Abstract Background Inflammation is a potential risk factor of mental disturbance. FKBP5 that encodes FK506-binding protein 51 (FKBP51), a negative cochaperone of glucocorticoid receptor (GR), is a stress-inducible gene and has been linked to psychiatric disorders. Yet, the role of FKBP51 in the inflammatory stress-associated mental disturbance remained unclear. Methods Fkbp5-deficient (Fkbp5-KO) mice were used to study inflammatory stress by a single intraperitoneal injection of lipopolysaccharide (LPS). The anxiety-like behaviors, neuroimaging, immunofluorescence staining, immunohistochemistry, protein and mRNA expression analysis of inflammation- and neurotransmission-related mediators were evaluated. A dexamethasone drinking model was also applied to examine the effect of Fkbp5-KO in glucocorticoid-induced stress. Results LPS administration induced FKBP51 elevation in the liver and hippocampus accompanied with transient sickness. Notably, Fkbp5-KO but not wild-type (WT) mice showed anxiety-like behaviors 7 days after LPS injection (LPS-D7). LPS challenge rapidly increased peripheral and central immune responses and hippocampal microglial activation followed by a delayed GR upregulation on LPS-D7, and these effects were attenuated in Fkbp5-KO mice. Whole-brain [18F]-FEPPA neuroimaging, which target translocator protein (TSPO) to indicate neuroinflammation, showed that Fkbp5-KO reduced LPS-induced neuroinflammation in various brain regions including hippocampus. Interestingly, LPS elevated glutamic acid decarboxylase 65 (GAD65), the membrane-associated GABA-synthesizing enzyme, in the hippocampus of WT but not Fkbp5-KO mice on LPS-D7. This FKBP51-dependent GAD65 upregulation was observed in the ventral hippocampal CA1 accompanied by the reduction of c-Fos-indicated neuronal activity, whereas both GAD65 and neuronal activity were reduced in dorsal CA1 in a FKBP51-independent manner. GC-induced anxiety was also examined, which was attenuated in Fkbp5-KO and hippocampal GAD65 expression was unaffected. Conclusions These results suggest that FKBP51/FKBP5 is involved in the systemic inflammation-induced neuroinflammation and hippocampal GR activation, which may contribute to the enhancement of GAD65 expression for GABA synthesis in the ventral hippocampus, thereby facilitating resilience to inflammation-induced anxiety.

Abstract We compute the non-factorisable O $$ \mathcal{O} $$ ( α s 2 $$ {\alpha}_s^2 $$ ) corrections to t-channel single-top quark production at the LHC. These peculiar corrections arise because of interactions between the heavy- and the light-quark lines and appear for the very first time at next-to-next-to-leading order in perturbative QCD. We find that the non-factorisable corrections change the single-top production cross section and the relevant kinematic distributions in this process by about half a percent.

BackgroundSince 2011, Taiwan’s National Health Insurance Administration (NHIA) issued a regulation on the reimbursement to anti-osteoporosis medications (AOMs). This study aimed to evaluate the impact of this regulation in reimbursement on the utilization of AOMs, clinical outcomes and associated medical expenditures of patients with incident hip fractures. MethodsBy using the National Health Insurance Research Database (NHIRD), patients with incident hip fracture from 2006 to 2015 were identified as our study cohort. Patients younger than 50 years old or prescribed with AOMs within one year prior to incident fracture were excluded. Outcomes of interest were quarterly estimates of the proportion of patients who received bone mineral density (BMD) examination, who were prescribed AOMs, as well as who encountered subsequent osteoporotic fracture-related visits and associated medical expenditures. Particularly, age- and gender-specific estimates were reported. An interrupted time series study design with segmented regression model was used to quantitatively explore the impact of the changes of the reimbursement criteria on the level (immediate) and trend (long-term) changes of these outcomes. ResultsOur study enrolled 118 493 patients with incident hip fracture with those patients aged older than 80 years old accounting for the largest proportion. A significantly decreased trend of AOMs prescription rates was observed immediately post regulation except for female aged between 65 and 80, while the long-term pattern showed no significant difference. However, the percentage of patients encountered subsequent osteoporotic fracture-related visit was not statistically different between pre- and post-regulation periods. Noteworthy, the policy regulation was associated with an increasing trend of osteoporotic fracture associated medical expenditures, especially for patients older than 80 years old. ConclusionThe regulation on the reimbursement for AOMs decreased the prescribing rate of AOMs immediately although the effect did not sustain thereafter. However, higher subsequent osteoporotic fracture-related medical expenditures were introduced, especially among those very old population.

Abstract We discuss peculiarities that arise in the computation of real-emission contributions to observables that contain Heaviside functions. A prominent example of such a case is the zero-jettiness soft function in SCET, whose calculation at next-to-next-to-next-to-leading order in perturbative QCD is an interesting problem. Since the zero-jettiness soft function distinguishes between emissions into different hemispheres, its definition involves θ-functions of light-cone components of emitted soft partons. This prevents a direct use of multi-loop methods, based on reverse unitarity, for computing the zero-jettiness soft function in high orders of perturbation theory. We propose a way to bypass this problem and illustrate its effectiveness by computing various non-trivial contributions to the zero-jettiness soft function at NNLO and N3LO in perturbative QCD.

Background: Osteoporosis increases the fracture and mortality risk of patients and has a higher disease burden than some cancers. Therefore, global concerns regarding the prevention and treatment of osteoporosis have been raised. However, fast-aging Taiwan lacks national epidemiological data on osteoporosis in recent years. We aimed to establish and update epidemiological data on osteoporosis by analyzing national data from 2008 to 2019. Methods: We estimated the prevalence and incidence of osteoporosis in patients aged ≥50 years based on claims data from Taiwan's National Health Insurance database from 2008 to 2019. We also analyzed the key parameters of fracture care (anti-osteoporosis medication use, bone mineral density examination rate, and length of hospital stay) to understand the secular trend of management and related clinical outcomes (imminent refracture rate and mortality). Results: The number of prevalent osteoporosis increased from 2008 to 2015 and remained constant until 2019; however, the age-standardized prevalence and incidence rates declined from 2008 to 2019 (3.77%–2.91% and 2.08%–1.02%, respectively). The overall incidence rates of hip and spine fractures decreased significantly by 34% and 27%, respectively. For patients with hip and spine fractures, the immanent refracture rates were 8.5% and 12.9% and the 1-year mortality rate remained stable at approximately 15% and 6%, respectively. Conclusion: The age-standardized prevalence and incidence rates decreased remarkably from 2008 to 2019, while the number of prevalent osteoporosis remained steady. Patients with hip fractures encountered a high 1-year mortality rate, while the risk of imminent refracture was notable for patients with spine fractures.

Background: Previous epidemiological researchers have used various algorithms to identify a second hip fracture; however, there has been no validation of these algorithms to date. This study aimed to verify existing algorithms for identifying second hip fracture under the International Classification of Diseases diagnostic coding systems. Furthermore, we examined the validity of two newly proposed algorithms that integrated the concept of periprosthetic fractures and laterality of the ICD-10 coding system. Methods: Claims data of patients hospitalized for hip fracture from National Taiwan University Hospitals between 2007 and 2020 were retrieved. Hip fracture was confirmed by 2 orthopaedic surgeons with medical records and imaging data as gold standards. The validity of 9 existing and 2 newly proposed algorithms for identifying second hip fracture was evaluated. Results: The positive predictive value (PPV) range between 84% and 90% in existing algorithms for identifying second hip fractures. Noteworthy, the longer time interval for discrimination resulted in slightly increased PPV (from 87% to 90%), while decreased sensitivity noticeably (from 87% to 72%). When considering the information about periprosthetic fracture, the PPV increased to 91% without diminished sensitivity. The PPV of the newly proposed ICD-10-specific algorithm was 100%. Conclusion: Algorithms integrated clinical insights of periprosthetic fractures and laterality concept of ICD-10 coding system provided satisfactory validity and help precisely define second hip fracture in future database research.

Background: Adherence to anti-osteoporosis medications (AOMs) is crucial. National Health Insurance (NHI) in Taiwan has its own rules of reimbursement rule for AOMs. The midterm adherence remained inconclusive. Here we investigated the adherence according to the initially used AOMs, for three consecutive years. Methods: The nationwide cohort study from 2008 to 2018, based on Taiwan's National Health Insurance Research Database, included 336,229 patients. Their adherence, indicated by medication possession ratio (MPR), to the initial AOMs was investigated yearly for three consecutive years. The overall MPRs (OMPR), including the switched AOMs, were also calculated in the first year. The Sankey diagram further visualized the patient flows toward different adherence according to the initial AOMs. Results: The OMPR in the first year improved if the patients used AOMs with longer dosing intervals. 100%, 68.9%, 40.7%, and 34.0% of the patients started the treatment with zoledronate, denosumab, alendronate, and raloxifene, respectively, had OMPR ≥75% in the first year. In the 3rd year, only 20.89%, 24.13%, and 12.83% of the patients continuously treated with zoledronate, denosumab, and alendronate, respectively, had MPR ≥75%. From the Sankey diagram, we also observed that patients who had poor adherence at one year were inclined to have poor adherence or discontinue antiosteoporosis treatment in the next year. Conclusion: The initial AOMs and the observed adherence may provide clues for optimizing patient treatment. The real-world adherence in Taiwan was far from satisfactory in our study.

Background: Osteoporosis is a common metabolic bone disease that benefits from many newly developed anti-osteoporosis medications (AOMs). Reimbursement policies need to allocate medical budgets properly based on evidence-based data. This study aimed to investigate the 11-year secular trend, focusing on older age and males in this adjustment wave of the National Health Insurance reimbursement. Methods: We adopted a nationwide cohort from Taiwan's National Health Insurance Research Database (NHIRD). Patients undergoing newly initiated AOMs from 2008 to 2018 were included. The AOMs in this study included denosumab, zoledronate, ibandronate, alendronate, raloxifene, and risedronate. Patients

Background: The Bureau of National Health Insurance in Taiwan implemented a new reimbursement scheme incorporating bone mineral density (BMD) criteria on Jan. 1, 2011. This study aimed to investigate a real-life 11-year secular trend of adherence in new AOMs users and evaluated the change of adherence to AOMs therapy in different urbanization areas after reimbursement criteria were restrained. Methods: We used Taiwan's National Health Insurance Research Database to identify new AOMs users as our study population. The AOMs in this study included denosumab, zoledronate, ibandronate, alendronate, raloxifene, and risedronate. The first prescription date of AOMs was defined as the cohort entry date. The adherence rates within one year after initiation were assessed. Results: High adherence (≥75%) in the first year increased markedly after the new reimbursement scheme in 2011, changing from 31.8% in 2008, and 41.7% in 2011 to 54.2% in 2018. On the other hand, low adherence (

Background: Real-world cost and effectiveness analyses of the anti-osteoporosis medications (AOM) using a nationwide database in Asia were limited. The aim of this study was to evaluate the cost and effectiveness of AOMs therapy under the reimbursement of National Health Insurance in Taiwan. Methods: Using Taiwan's National Health Insurance Research Database, patients who had hospitalization due to incident hip fractures with related operation between 2008 and 2017 were identified as our study population. Patients who initiated AOMs within 1 year post incident hip fracture were matched with those did not according to the propensity score. The direct medical cost and subsequent fracture within three years were estimated. Statistically significant differences of risk for subsequent fracture between the AOM and non-AOM groups were estimated using the COX proportional hazards model. All costs were presented as New Taiwan Dollars (NTD). Results: There were 27,357 new hip fracture patients who initiated AOMs, and 76% of them were women with a mean age of 77.7 years. Among patients ages ≥70 who encountered hip fractures, those who initiated AOMs experienced fewer non-vertebral fractures (HR = 1.07 (1.02–1.13), p = 0.0114 for those ages 70–79 years old; HR = 1.11 (1.06–1.17), p

The gamma-ray burst GRB 221009A, known as the “brightest of all time,” is the closest energetic burst detected so far, with an energy of E _γ _,iso ∼ 10 ^55 erg. This study aims to assess its compatibility with known GRB energy and luminosity distributions. Our analysis indicates that the energy/luminosity function of GRBs is consistent across various redshift intervals, and that the inclusion of GRB 221009A does not significantly impact the function at low redshifts. Additionally, our evaluation of the best-fitting result of the entire GRB sample suggests that the expected number of GRBs with energy greater than 10 ^55 erg at a low redshift is 0.2, so that the emergence of GRB 221009A is consistent with expected energy/luminosity functions within ∼2 σ Poisson fluctuation error, still adhering to the principles of small number statistics. Furthermore, we find that GRB 221009A and other energetic bursts, defined as E _γ _,iso ≳ 10 ^54 erg, exhibit no significant differences in terms of distributions of T _90 , minimum timescale, Amati relation, E _γ _,iso – E _X,iso relation, L _γ _,iso –Γ _0 relation, E _γ _,iso –Γ _0 relation, L _γ _,iso – E _p,i –Γ _0 relation, and host galaxy properties, compared to normal long GRBs. This suggests that energetic GRBs (including GRB 221009A) and other long GRBs likely have similar progenitor systems and undergo similar energy dissipation and radiation processes. The generation of energetic GRBs may be due to more extreme central engine properties or, more likely, a rarer viewing configuration of a quasi-universal structured jet.

Active enhancers are still understudied in colorectal cancers (CRC). Here the authors analyse active enhancers in CRC patients using genomics, transcriptomics, and epigenomics, identifying and validating variant super-enhancer loci as well as KLF3 as a relevant transcription factor.

Abstract We compute the non-factorisable contribution to the two-loop helicity amplitude for t-channel single-top production, the last missing piece of the two-loop virtual corrections to this process. Our calculation employs analytic reduction to master integrals and the auxiliary mass flow method for their fast numerical evaluation. We study the impact of these corrections on basic observables that are measured experimentally in the single-top production process.

Owing to condensed development processes, expanding evidence and differences in healthcare system characteristics, many COVID-19 guidelines differ in their quality and treatment recommendations, which has consequences for clinical practice. This review aimed to identify COVID-19 treatment guidelines, assess their quality and summarise their recommendations. Guidelines were identified for five therapies most commonly used among inpatients with COVID-19 (remdesivir, dexamethasone, tocilizumab, baricitinib and casirivimab/imdevimab) from 11 countries. Guideline quality was assessed using the Appraisal of Guidelines for Research and Evaluation II (AGREE-II) tool. Full details of recommendations and supporting evidence were analysed for high-quality guidelines, defined as those scoring ≥50% in Domain 3 (Rigour of Development) of AGREE-II. Overall, guidelines differed substantially in their quality and, even among high-quality guidelines using the same evidence, recommendations regarding specific therapeutics varied. Potential reasons for this heterogeneity, including the availability and consistency of clinical data, visibility of trial end-points and context-specific factors, are discussed.

BackgroundThis retrospective study compared positron emission tomography (PET)/computed tomography (CT) and CT in the treatment of extracranial oligometastatic non-small-cell lung cancer (NSCLC) and explored the impact of thorax radiotherapy (TRT) on patient survival.MethodsWe reviewed the medical records of Chinese patients with stage IV extracranial oligometastatic NSCLC who underwent PET/CT or CT at two centers. Propensity score matching (PSM) was used to control differences in patient characteristics between the maintenance chemotherapy alone and TRT plus maintenance chemotherapy groups.ResultsWe analyzed 192 eligible patients. The median survival time was better in patients who received PET/CT than in those who only received CT (n = 192, 16 months vs. 6 months, p

Background: Lithium is an effective medication approved for the treatment of bipolar disorder (BD). It has a narrow therapeutic index (TI) and requires therapeutic drug monitoring. This study aimed to conduct a population pharmacokinetics (PPK) analysis of lithium and investigate the appropriateness of the dosing regimen according to different patient characteristics.Methods: A total of 476 lithium concentrations from 268 patients with bipolar disorder were analyzed using nonlinear mixed-effects modeling. Monte Carlo simulations were employed to investigate the influence of covariates, such as weight, creatinine clearance, and daily doses of lithium concentrations, and to determine the individualized dosing regimens for patients.Results: Lithium PK was described by a one-compartment model with first-order absorption and elimination processes. The typical estimated apparent clearance was 0.909 L/h−1 with 16.4% between-subject variability in the 62 kg patients with 116 ml/min creatinine clearance and 600 mg daily doses. To achieve a target trough concentration (0.4–0.8 mmol/L) in the maintenance phase, the regimen of 500 mg than 750 mg daily dose was recommended for patients with renal insufficiency and weighing 100 kg.Conclusion: A PPK model for lithium was developed to determine the influence of patient characteristics on lithium pharmacokinetics. Weight, creatinine clearance, and total daily dose of lithium can affect the drug’s clearance. These results demonstrate the nonlinear renal excretion of lithium; hence, dosage adjustments are recommended for patients with renal insufficiency.

Abstract We compute the top quark contribution to the two-loop amplitude for on-shell Z boson pair production in gluon fusion, gg → ZZ. Exact dependence on the top quark mass is retained. For each phase space point the integral reduction is performed numerically and the master integrals are evaluated using the auxiliary mass flow method, allowing fast computation of the amplitude with very high precision.

Background: Therapeutic drug monitoring (TDM) is recommended during treatment with valproic acid (VPA), as is the measurement of free VPA concentration (MfVPA). However, MfVPA is unavailable in many institutions. Based on the highly protein-bound characteristics of VPA, an albumin-adjusted formula has been proposed to predict free VPA concentration (PfVPA). Nevertheless, the factors affecting the accuracy of this formula remain unknown, as does the concordance between MfVPA and PfVPA. Methods: Adult patients receiving VPA and undergoing TDM were enrolled. Free and total serum concentration (TVPA) were categorized as subtherapeutic, therapeutic, or supratherapeutic based on the reference range of 5–15 and 50–100 μg/mL, respectively. Concordance was defined as MfVPA and PfVPA, or MfVPA and TVPA, falling within the same category. Multivariate logistic regression with generalized estimating equation was adopted to identify factors affecting concordance, and the receiver operating characteristic curve was applied to determine the cutoff values of predictors. Results: A total of 98 data points from 51 participants were included for analysis. The concordance of MfVPA and PfVPA, and MfVPA and TVPA, was 72% and 44%, respectively. Blood urea nitrogen (BUN) (0.97 [0.95–0.99], P = 0.01) and TVPA (0.97 [0.95–0.99], P = 0.02) had a significant influence on the concordance of MfVPA and PfVPA. The cutoff values of TVPA and BUN for the accuracy of the albumin-adjusted formula were 56.4 μg/mL and 51.05 mg/dL, respectively. Conclusion: If MfVPA is not available, the albumin-adjusted formula should be applied before VPA dosage adjustment when TVPA is

Abstract MLL3 is a histone H3K4 methyltransferase that is frequently mutated in cancer, but the underlying molecular mechanisms remain elusive. Here, we found that MLL3 depletion by CRISPR/sgRNA significantly enhanced cell migration, but did not elevate the proliferation rate of cancer cells. Through RNA-Seq and ChIP-Seq approaches, we identified TNS3 as the potential target gene for MLL3. MLL3 depletion caused downregulation of H3K4me1 and H3K27ac on an enhancer ~ 7 kb ahead of TNS3. 3C assay indicated the identified enhancer interacts with TNS3 promoter and repression of enhancer activity by dCas9-KRAB system impaired TNS3 expression. Exogenous expression of TNS3 in MLL3 deficient cells completely blocked the enhanced cell migration phenotype. Taken together, our study revealed a novel mechanism for MLL3 in suppressing cancer, which may provide novel targets for diagnosis or drug development.

A new cleaning agent for silicon contamination in the wafer dicing process was formulated in this research. Ammonium bifluoride was introduced as the main ingredient in the formula, and MSA and sulfuric acid were added as the solvent and buffer solution against metal corrosion. It was confirmed that the new formula cleaning agent could be used in the cleaning of silicon contamination from dicing. Silicon contamination is common in the wafer dicing process and consists of silicon powder and relevant metal particles during cutting, all of which are mixed with some adhesive residues. These contaminating particles on the IC surface are exposed to cleaning agents. However, while it is imperative to clean the wafer, the exposed surface is also vulnerable to damage from the solution. This further complicates the procedure because there is currently no ideal cleaning agent for the process. Our proposed formula hopefully provides an ideal chemical for use in wafer cleaning (SC-1, SC-2, BOE), since it uses a less toxic compound, ammonium bifluoride, which yielded good results during our experiments.

Abstract Background Metabolic acidosis is a major complication of critical illness. However, its current epidemiology and its treatment with sodium bicarbonate given to correct metabolic acidosis in the ICU are poorly understood. Method This was an international retrospective observational study in 18 ICUs in Australia, Japan, and Taiwan. Adult patients were consecutively screened, and those with early metabolic acidosis (pH

Abstract We compute the contribution of third generation quarks (t, b) to the two-loop amplitude for on-shell W boson pair production in gluon fusion gg → WW. We present plots for the amplitude across partonic phase space as well as reference values for two kinematic points. The master integrals are efficiently evaluated by numerically solving a system of ordinary differential equations.

Abstract Aims The objective of this study was to estimate the nationwide annual incidence, healthcare utilization, and mortality among hospitalized heart failure (HF) patients in Taiwan. Methods and results People aged 20 years or older and having been newly admitted for HF between 2010 and 2015 were identified from Taiwan's National Health Insurance Research Database. For 124 816 patients with incident HF hospitalizations between 2010 and 2012, we further analysed their treatment patterns, healthcare utilizations, and mortality during index hospitalization and within 3 years following discharge from the index hospitalization. The age‐stratified incidences were declined by 10–20% in people aged 55 years or older, but increased by ~4% among people younger than 44 years old between 2010 and 2015. For all incident hospitalized HF patients, the percentages of patients visiting the emergency room, were rehospitalized, and treated with guideline‐directed medical therapy were highest in the first year. Approximately two‐thirds of subsequent hospitalizations were due to non‐HF and non‐cardiovascular causes. The all‐cause mortality rate during index hospitalization was 8.5%, whereas the mortality rates at 30 days, 90 days, 180 days, 1 year, 2 years, and 3 years following discharge were 3.5%, 8.9%, 14.4%, 22.5%, 33.9%, and 42.8%, respectively, for those surviving index HF hospitalization. Non‐cardiovascular disease‐related deaths accounted for nearly 60% of all deaths. Conclusions Our study reveals that, in contemporary Taiwan, the >10% annual mortality following the first year of hospitalization, 30% deaths occurring outside the hospital, and 60% non‐cardiovascular‐related deaths, along with the decreasing use of guideline‐directed medical therapy, highlight sectors requiring more attention.

Elephant grass (Pennisetum purpureum) is a fast-growing and low-nutrient demand plant that is widely used as a forage grass and potential energy crop in tropical and subtropical regions of Asia, Africa, and the United States. Transgenic tobacco with the PpCCoAOMT gene from Pennisetum purpureum produces high lignin content that is associated with drought tolerance in relation to lower accumulation of reactive oxygen species (ROS), along with higher antioxidant enzyme activities and osmotic adjustment. In this study, transgenic tobacco plants revealed no obvious cost to plant growth when expressing the PpCCoAOMT gene. Metabolomic studies demonstrated that tobacco plants tolerant to drought stress accumulated flavonoids under normal and drought conditions, which likely explains the observed tolerance phenotype in wild-type tobacco. Our results suggest that plants overexpressing PpCCoAOMT were better able to cope with water deficit than were wild-type controls; metabolic flux was redirected within primary and specialized metabolism to induce metabolites related to defense to drought stress. These results could help to develop drought-resistant plants for agriculture in the future.

IntroductionAmnestic mild cognitive impairment (MCI) can be classified as either early MCI (EMCI) or late MCI (LMCI) according to the severity of memory impairment. The aim of this study was to compare the prognosis and clinical course between EMCI and LMCI.MethodsBetween January 2009 and December 2017, a total of 418 patients with MCI and 146 subjects with normal cognition were recruited from a memory clinic. All the patients received at least two series of neuropsychological evaluations each year and were categorized as either EMCI or LMCI according to Alzheimer's Disease Neuroimaging Initiative 2 (ADNI2) criteria.ResultsIn total, our study included 161 patients with EMCI, 258 with LMCI, and 146 subjects with normal cognition as controls (NCs). The mean follow-up duration was 3.55 ± 2.18 years (range: 1–9). In a first-year follow-up assessment, 54 cases (32.8%) of EMCI and 16 (5%) of LMCI showed a normal cognitive status. There was no significant difference between the first year EMCI reverter and NCs in terms of dementia-free survival and further cognitive decline. However, first-year LMCI reverters still had a higher risk of cognitive decline during the following evaluations. Until the last follow-up, annual dementia conversion rates were 1.74, 4.33, and 18.6% in the NC, EMCI, and LMCI groups, respectively. The EMCI and LMCI groups showed a higher rate of progression to dementia (log-rank test, p < 0.001) than normal subjects. Compared with NCs, patients in the LMCI group showed a significantly faster annual decline in global cognition [annual rate of change for the mini-mental status examination (MMSE) score: −1.035, p < 0.001]) and all cognitive domains, while those in the EMCI group showed a faster rate of decline in global cognitive function (annual rate of change for the MMSE score: −0.299, p = 0.001).ConclusionIt is important to arrange follow-up visits for patients with MCI, even in the EMCI stage. One-year short-term follow-up may provide clues about the progression of cognitive function and help to identify relatively low-risk EMCI subjects.

Objective: There has been no previous study on the interaction between neonatal hyperbilirubinemia and NSAID use in breastfeeding mothers. This study aimed to investigate whether postpartum analgesics (with NSAIDs) can affect neonatal hyperbilirubinaemia. Materials and methods: Mothers who gave birth between January 2017 and December 2017 were included. Those who were not exclusively breastfeeding, gave premature birth, who underwent caesarean section, or whose infants had abnormalities such as an imperforated anus, diaphragmatic hernia, or ovarian tumour were excluded. Mothers were divided into 2 groups based on the analgesics received postpartum: acetaminophen and NSAID (non-steroidal anti-inflammatory drug; flurbiprofen) users. Multivariable logistic regression was adopted to estimate the risk of hyperbilirubinaemia with the use of different kinds of painkillers. Results: In total, 1153 mothers were reviewed. After applying the exclusion criteria, 480 mothers were finally included in the analyses. Among them, 348 (72.67%) and 132 (27.33%) mothers received acetaminophen and flurbiprofen, respectively. Seven (2.01%) and 1 (0.76%) newborn had hyperbilirubinaemia among the acetaminophen and flurbiprofen users, respectively. Hyperbilirubinaemia risk of infants whose mothers were flurbiprofen users was not significantly different from that of infants whose mothers were acetaminophen users (adjusted odd ratio = 0.50, 95% confidence interval = 0.06–4.50, p-value = 0.4552). Conclusions: Breastfeeding mothers receiving flurbiprofen do not have increased risk of neonatal hyperbilirubinaemia.