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Reactive oxygen species (ROS) play a crucial role in regulating numerous functions in organisms. Among the key regulators of ROS production are NADPH oxidases, primarily referred to as respiratory burst oxidase homologues (RBOHs). However, our understanding of whether and how pathogens directly target RBOHs has been limited. In this study, we revealed that the effector protein RipBJ, originating from the phytopathogenic bacterium Ralstonia solanacearum, was present in low- to medium-virulence strains but absent in high-virulence strains. Functional genetic assays demonstrated that the expression of ripBJ led to a reduction in bacterial infection. In the plant, RipBJ expression triggered plant cell death and the accumulation of H 2 O 2 , while also enhancing host defence against R. solanacearum by modulating multiple defence signalling pathways. Through protein interaction and functional studies, we demonstrated that RipBJ was associated with the plant's plasma membrane and interacted with the tomato RBOH known as SlWfi1, which contributed positively to RipBJ's effects on plants. Importantly, SlWfi1 expression was induced during the early stages following R. solanacearum infection and played a key role in defence against this bacterium. This research uncovers the plant RBOH as an interacting target of a pathogen's effector, providing valuable insights into the mechanisms of plant defence., (© 2024 John Wiley & Sons Ltd.)

Background: Relative deprivation is a critical mechanism for understanding how income inequality affects mental health. However, few studies have compared the effects of objective and subjective relative deprivation on health outcomes. This study compared how objective and subjective relative deprivation and their interaction relate to human flourishing measures, including health, happiness, life satisfaction, social relationships, and financial stability., Methods: This cross-sectional study analyzed data from 1592 adults in Taiwan. The objective and subjective relative deprivation were measured using the Yitzhaki Index and the Personal Relative Deprivation Scale-Revised (PRDS-R), respectively. We conducted least-squares regression models to investigate the associations between these relative deprivation measures and human flourishing outcomes., Results: The correlation between the Yitzhaki Index and PRDS-R was 0.16 (p < 0.001). After controlling for absolute income and covariates, the regression models showed that objective and subjective relative deprivation was negatively associated with all six human flourishing outcomes. Notably, subjective relative deprivation is strongly associated with outcomes than objective relative deprivation. Also, the Yitzhaki Index remained adversely associated with all human flourishing outcomes after accounting for the PRDS-R. Furthermore, the interaction between the Yitzhaki Index and PRDS-R was associated with additional risks to well-being, particularly affecting health, happiness, life satisfaction, and financial stability., Conclusion: Both objective and subjective relative deprivation were negatively associated with multiple dimensions of human flourishing. Policies aimed at addressing relative deprivation and reducing income inequality could contribute to higher levels of health, happiness, life satisfaction, social relationships, and economic stability., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 The Author(s).)

Long-term morphine use leads to tolerance and hyperalgesia in patients with chronic pain, with neuroinflammation playing a key role, but its underlying mechanisms remain elusive. This study determines that repeated intrathecal morphine injections increase double-stranded RNA (dsRNA) production in spinal neurons, due to downregulated adenosine deaminase RNA specific 1 (ADAR1) expression. Lentivirus-induced ADAR1 elevation decreases the high levels of intracellular dsRNA and attenuates morphine tolerance and hyperalgesia. dsRNA is released into cerebrospinal fluid via exosomes (Exos) after repeated morphine injections and is taken up by microglia for TLR3-TRIF-IL-6 signaling activation. Blocking Exos release with GW4869 or inhibition of TLR3 signaling mitigates neuroinflammation, preventing the development of morphine tolerance and hyperalgesia. Intrathecal injection of TLR3 inhibitor alone shows analgesic effects in neuropathic pain, and co-administration with morphine amplifies the analgesic efficacy of morphine. These findings demonstrate that targeting dsRNA-TLR3 signaling to mitigate neuroinflammation could be a promising treatment for morphine tolerance., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Introduction: Cholesteatoma is a rare disease characterized by the accumulation of keratinized squamous epithelial cells in the middle ear or mastoid cavity. Vertigo and facial palsy, which are rare complications, may indicate erosion into the semicircular canals or the fallopian canal., Patient Concerns: A 40-year-old woman presented to our clinic with progressive right-sided hearing loss over 5 years (primary concern). Approximately 10 years ago, the patient had developed acute right-sided facial weakness with no additional symptoms. A neurologist at another hospital had diagnosed her condition as Bell's palsy and treated it accordingly., Diagnosis: Adult-onset congenital cholesteatoma in the hypotympanum., Intervention: Combined endoscopic and microscopic removal of the cholesteatoma., Outcomes: Physical examination revealed slight improvement in right-sided peripheral facial palsy., Lesson: Routine eardrum examination is recommended for patients presenting with isolated peripheral facial palsy. If necessary, a patient should be referred to an otologist for further evaluation and treatment., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2024 the Author(s). Published by Wolters Kluwer Health, Inc.)

Objectives: The primary aim was to determine the prevalence of gastrointestinal diseases in patients with chronic rhinosinusitis (CRS), utilizing the National Health Insurance Research Database (NHIRD) in Taiwan. Several studies have supported the existence of distinct immune patterns between the Asian and Western populations in CRS patients. Through the population-based case-control study, we could compare the differences between various regions and provide further treatment strategies for subsequent studies in Asian CRS patients. The secondary aim was to assess whether different types of CRS influence the correlation with specific GI diseases. Understanding how different phenotypes or endotypes of CRS may relate to distinct GI disease patterns could provide valuable insights into the underlying mechanisms and potential shared pathways between these conditions. Methods: We use the NHIRD in Taiwan. Newly diagnosed patients with CRS were selected between January 1, 2001 and December 31, 2017 as the case group, and the controls were defined as individuals without a history of CRS. Patients with CRS were divided into two groups: with nasal polyps and without nasal polyps. We also separated GI tract diseases into four groups based on their different pathophysiologies. Results: This study included 356,245 participants (CRS: 71,249 and control: 284,996). The results showed that CRS was significantly associated with some specific GI tract diseases, including acute/chronic hepatitis B, gastroesophageal reflux disease (GERD) with/without esophagitis, achalasia of cardia, peptic/gastrojejunal ulcer, Crohn's disease, and ulcerative colitis. In addition, when CRS was subcategorized into chronic rhinosinusitis with nasal polyps (CRSwNP) and chronic rhinosinusitis without nasal polyps (CRSsNP), GERD with esophagitis and peptic ulcer were significantly associated with CRSsNP. Conclusions: A significant association between CRS and premorbid GI tract diseases has been identified. Remarkably, GERD with esophagitis and peptic ulcer were significantly associated with CRSsNP. The underlying mechanisms require further investigation and may lead to new treatments for CRS. Researchers can further investigate the mechanisms by referring to our classification method to determine the implications for diagnosis and treatment., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Perovskite nanocrystals (PeNCs) are known for their use in numerous optoelectronic applications. Surface ligands are critical for passivating surface defects to enhance the charge transport and photoluminescence quantum yields of the PeNCs. Herein, we investigated the dual functional abilities of bulky cyclic organic ammonium cations as surface-passivating agents and charge scavengers to overcome the lability and insulating nature of conventional long-chain type oleyl amine and oleic acid ligands. Here, red-emitting hybrid PeNCs of the composition Cs x FA (1-x) PbBr y I (3-y) are chosen as the standard (Std) sample, where cyclohexylammonium (CHA), phenylethylammonium (PEA) and (trifuluoromethyl)benzylamonium (TFB) cations were chosen as the bifunctional surface-passivating ligands. Photoluminescence decay dynamics showed that the chosen cyclic ligands could successfully eliminate the shallow defect-mediated decay process. Further, femtosecond transient absorption spectral (TAS) studies uncovered the rapidly decaying non-radiative pathways; i.e., charge extraction (trapping) by the surface ligands. The charge extraction rates of the bulky cyclic organic ammonium cations were shown to depend on their acid dissociation constant (pKa) values and actinic excitation energies. Excitation wavelength-dependent TAS studies indicate that the exciton trapping rate is slower than the carrier trapping rate of these surface ligands.

Background/purpose: The signaling mechanisms for Porphyromonas gingivalis lipopolysaccharide (PgLPS)-induced inflammation in human dental pulp cells are not fully clarified. This in vitro study aimed to evaluate the involvement of phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) pathway in PgLPS-induced pulpal inflammation., Methods: Human dental pulp cells (HDPCs) were challenged with PgLPS with or without pretreatment and coincubation with a PI3K/Akt inhibitor (LY294002). The gene or protein levels of PI3K, Akt, interleukin (IL)-6, IL-8, alkaline phosphatase (ALP), osteocalcin and osteonectin were analyzed by reverse transcription polymerase chain reaction (PCR), real-time PCR, western blotting, and immunofluorescent staining. In addition, an enzyme-linked immunosorbent assay was used to analyze IL-6 and IL-8 levels in culture medium., Results: In response to 5 μg/ml PgLPS, IL-6, IL-8, and PI3K, but not Akt mRNA expression of HDPCs, was upregulated. IL-6, IL-8, PI3K, and p-Akt protein levels were stimulated by 10-50 μg/ml of PgLPS in HDPCs. PgLPS also induced IL-6 and IL-8 secretion at concentrations higher than 5 μg/ml. Pretreatment and co-incubation by LY294002 attenuated PgLPS-induced IL-6 and IL-8 mRNA expression in HDPCs. The mRNA expression of ALP, but not osteocalcin and osteonectin, was inhibited by higher concentrations of PgLPS in HDPCs., Conclusion: P. gingivalis contributes to pulpal inflammation in HDPCs by dysregulating PI3K/Akt signaling pathway to stimulate IL-6 and IL-8 mRNA/protein expression and secretion. These results are useful for understanding the pulpal inflammation and possible biomarkers of inflamed pulp diagnosis and treatment., Competing Interests: Declaration of competing interest The authors have no conflicts of interest relevant to this article., (Copyright © 2022 Formosan Medical Association. Published by Elsevier B.V. All rights reserved.)

Background: Castleman disease and lymphoma each have a distinct treatment plan; however, they share the same features on contrast-enhanced computed tomography., Methods: To assess the quantitative outcomes of Castleman disease versus lymphoma using contrast-enhanced computed tomography based on Hounsfield units (HU). We retrospectively reviewed eight patients with unicentric Castleman disease and 30 patients with lymphoma based on pathological diagnosis at China Medical University Hospital between 2015 and 2020. Preoperative computed tomography with contrast scans was reviewed, and the HU of each tumor were measured., Results: This study included eight patients with unicentric Castleman disease (four men and four women; mean age, 33 years) and 25 patients with lymphoma (11 men and 14 women; mean age, 53 years). There was no significant difference in heterogeneity between the two diseases (0.161 ± 0.052 vs 0.239 ± 0.063, p = 0.22); however, enhancement in Castleman disease was higher than that in lymphoma (126.40 ± 31.90 vs 74.19 ± 7.11, p < 0.001), providing a very good diagnostic tool (cutoff point at 88.5-91.3, sensitivity 0.86/specificity 0.88). Furthermore, we found a highly linear relationship in Castleman disease, which was not noted in lymphoma., Conclusion: The value of HU provides a good diagnostic tool for the differential diagnosis of Castleman disease versus lymphoma in the neck lymph nodes. Considering the linear relationship in Castleman disease, an increasingly accurate differential diagnosis can be made., Competing Interests: Conflicts of interest: The authors declare that they have no conflicts of interest related to the subject matter or materials discussed in this article., (Copyright © 2022, the Chinese Medical Association.)

Chronic otitis media (COM) has been considered as a localized disease, and its systemic impact is poorly understood. Whether COM-induced inflammation could be associated with systemic bone loss and hip fracture is unknown at present. Our study tried to determine the risk of hip fracture among COM patients. We selected the comparison individuals without the COM coding and paired the controls with COM patients by gender, age, and comorbidities (including osteoporosis) by about a one-to-two ratio. Our study showed that the incidence of hip fracture was 4.48 and 3.92 per 1000 person-years for comparison and COM cohorts respectively. The cumulative incidence of hip fracture is higher in the COM cohort (p < 0.001). After adjustment for gender, age, and comorbidities, the COM patients had a 1.11-fold (aHR = 1.11; 95% CI = 1.05−1.17) risk of hip fracture than the control subjects. Among COM patients, a history of hearing loss is associated with higher (aHR = 1.21; 95% CI = 1.20−1.42) fracture risk. Our study showed that COM patients, especially those with hearing loss, are susceptible to a higher risk for hip fracture.

The main aim of this study is to compare the incidence rate and severity of deep neck infection (DNI) in patients post-UPPP+ T (uvulopalatopharyngoplasty plus tonsillectomy) and without UPPP+ T. We utilized the data derived from the Longitudinal Health Insurance Database (LHID) of the National Health Insurance Research Database (NHIRD) in Taiwan from 1 January 2000 to 31 December 2012. Patients who had undergone combined UPPP and tonsillectomy were selected using National Health Insurance (NHI) surgical order. Patients with DNI were selected using International Classification of Diseases (ICD-9-CM) code. A logistic regression model was applied for risk analysis. There were 1574 patients in the UPPP+ T cohort, and 6,296 patients who did not undergo combined UPPP and tonsillectomy for the control group. Our analysis showed that patients with an obstructive sleep apnea syndrome (OSAS) history constitute 76.1% ( n = 1198) of the UPPP+ T cohort. Compared to the control group, there was no significantly increased incidence rate of DNI after UPPP+ T within 1-60 months. Patients undergoing combined UPPP and tonsillectomy had a lower intubation rate for DNI, with an adjusted odds ratio of 0.47 (95% CI = 0.32-0.69). The combined UPPP and tonsillectomy does not increase the risk of DNI within 1-60 months. Furthermore, combined UPPP and tonsillectomy can reduce the severity for DNI by decreasing the intubation rate and length of hospitalization.

Background Few studies have evaluated the prognostic significance of diameter-based carotid sonographic measurements for mortality. We investigated whether a reduction in diameter of different carotid anatomical segments is associated with cardiovascular and all-cause mortality in a hospital-based cohort with universal health care. Methods and Results We conducted a retrospective cohort study of 38 201 patients who underwent carotid duplex ultrasound at a medical center in Taiwan. Carotid sonographic parameters were the diameter reduction percentage in carotid bifurcation, the internal carotid artery, the common carotid artery, and the external carotid artery and the overall carotid atherosclerotic burden score, determined by summing the scores from all segments. The vital status was ascertained by linking data to National Death Registry until 2017. During a median follow-up of 4.2 years, 5644 participants died, with 1719 deaths attributable to cardiovascular diseases. The multivariable-adjusted hazard ratios (HRs; 95% CIs) for cardiovascular mortality were 1.33 (1.16‒1.53), 1.58 (1.361.84), and 1.89 (1.58, 2.26) for participants with 30% to <40%, 40% to <50%, and ≥50% reduction in carotid bifurcation diameter, respectively, compared with participants with <30% diameter reduction ( P for trend <0.001). The corresponding HRs (95% CIs) for all-cause mortality were 1.25 (1.16‒1.34), 1.42 (1.31‒1.54), and 1.60 (1.45‒1.77), respectively. Diameter reduction at other carotid sites and the carotid atherosclerotic burden score exhibited the same dose-response relationship. Conclusions This study suggests that reduction in carotid artery diameter, which can be determined through routinely available sonography, is an independent risk factor for all-cause and cardiovascular mortality.

Objective: Chronic osteomyelitis (COM) can induce systemic inflammation, and systemic inflammation may be associated with suicide tendency. However, no studies have investigated the correlation between COM and suicide tendency., Methods: The aim of this population-based study was to determine the epidemiology of fatal/non-fatal suicide among COM patients. Subjects with at least two outpatient visits or one course of inpatient care diagnosed with COM were recruited into a COM cohort. The control/COM subject ratio was approximately 4:1 matched by age, sex, major depression coding and index year (COM patients). Subjects with suicide attempts before COM diagnosis and subjects aged <20 years were excluded., Results: COM patients had 1.93 (95% confidence interval [CI]: 1.11-3.36) times the risk of fatal/non-fatal suicide as control subjects. Considering death as the competing event of fatal/non-fatal suicide, COM patients had 1.76 (95% CI: 1.03-3.01) times the risk of fatal/non-fatal suicide (competing risk regression model). The effect of COM on fatal/non-fatal suicide was more prominent among diabetic patients. COM severity also correlated with the risk of fatal/non-fatal suicide., Conclusions: More attention must be paid to suicide tendency among COM patients.

Background: Osteoporosis and fragility fracture are the major complications after liver transplantation (LT). The aim of the study was to determine the incidence and risk factors of hip fracture after LT., Methods: We conducted a retrospective population-based cohort study, enrolling the patients receiving LT between January 1999 and December 2010. Control subjects were randomly matched to every recipient by age and sex by 1 : 10 ratios., Results: During the follow-up period, 17 recipients (0.77%) and 70 (0.32%) control subjects suffered from hip fractures. The incident rates (per 10000 person-years) were 21.49 for recipients and 7.52 for controls (adjusted hazard ratio = 2.71; 95% confidence interval = 1.21-6.05). The cumulative incidence of hip fracture was significantly higher among the recipients ( p < 0.0001). Among the recipients, the subjects aged >65 years at transplantation and with pretransplant steroid use are more susceptible to posttransplant hip fracture. Immunosuppressive agents did not significantly affect the risk of hip fracture among recipients., Conclusions: Liver transplantation is a risk factor for hip fractures. Aged >65 years at transplantation and pretransplant steroid use are risk factors for posttransplant hip fractures among the recipients., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2019 Yung-Cheng Chiu et al.)

FXYD proteins are the regulators of sodium-potassium ATPase (Na+/K+-ATPase, NKA). In teleosts, NKA is a primary driving force for the operation of many ion transport systems in the osmoregulatory organs (e.g. intestines). Hence, the purpose of this study was to determine the expression of FXYD proteins and NKA α-subunit in the intestines of two closely related medakas (Oryzias dancena and O. latipes), which came from different salinity habitats and have diverse osmoregulatory capabilities, to illustrate the association between NKA and FXYD proteins of two medaka species in response to salinity changes. The results showed that the fxyd12 mRNA was the most predominant in the intestines of both medakas. The association of FXYD12 and NKA in the intestines of the two medaka species was demonstrated via double immunofluorescent staining and co-immunoprecipitation. Upon salinity challenge, the localization of FXYD12 and NKA was similar in the intestines of the two medaka species. However, the expression profiles of intestinal FXYD12 and NKA (mRNA and protein levels), as well as NKA activity differed between the medakas. These results showed that FXYD12 may play a role in modulating NKA activity in the intestines of the two medakas following salinity changes in the maintenance of internal homeostasis. These findings contributed to knowledge of the expression and potential role of vertebrate FXYD12, the regulators of NKA, upon salinity challenge., Competing Interests: The authors have declared that no competing interests exist.

In this paper, the authors present a physical model developed to simulate accurate external ventricular drain (EVD) placement with realistic haptic and visual feedbacks to serve as a platform for complete procedural training. Insertion of an EVD via ventriculostomy is a common neurosurgical procedure used to monitor intracranial pressures and/or drain CSF. Currently, realistic training tools are scarce and mainly limited to virtual reality simulation systems. The use of 3D printing technology enables the development of realistic anatomical structures and customized design for physical simulators. In this study, the authors used the advantages of 3D printing to directly build the model geometry from stealth head CT scans and build a phantom brain mold based on 3D scans of a plastinated human brain. The resultant simulator provides realistic haptic feedback during a procedure, with visualization of catheter trajectory and fluid drainage. A multiinstitutional survey was also used to prove content validity of the simulator. With minor refinement, this simulator is expected to be a cost-effective tool for training neurosurgical residents in EVD placement.

Background & Aims: Many companies provide genetic tests for obesity-related polymorphisms (nutrigenetics) and make dietary recommendations for weight loss that are based on the results. We performed a randomized controlled trial to determine whether more participants who followed a nutrigenetic-guided diet lost ≥5% of their body weight than participants on a standard balanced diet for 8 and 24 weeks., Methods: We performed a prospective study of 51 obese or overweight U.S. veterans on an established weight management program at the Veterans Administration San Diego Healthcare System (the MOVE! program). Participants were randomly assigned to groups placed on a nutrigenetic-guided diet (balanced, low-carbohydrate, low-fat, or Mediterranean; n = 30) or a standard balanced diet (n = 21). Nutrigenetic diets were selected on the basis of results from the Pathway FIT test., Results: There was no significant difference in the percentage of participants on the balanced diet vs the nutrigenetic-guided diet who lost 5% of their body weight at 8 weeks (35.0% ± 20.9% vs 26.9% ± 17.1%, respectively; P = .28) or at 24 weeks. Both groups had difficulty adhering to the diets. However, adherence to the nutrigenetic-guided diet correlated with weight loss (r = 0.74; P = 4.0 × 10(-5)), but not adherence to standard therapy (r = 0.34; P = .23). Participants who had low-risk polymorphisms for obesity lost more weight than all other participants at 8 weeks (5.0% vs 2.9%, respectively; P = .02) and had significantly greater reductions in body mass index (6.4% vs 3.6%, respectively; P = .03) and waist circumference (6.5% vs 2.6%, respectively; P = .02) at 24 weeks., Conclusions: In a prospective study, a nutrigenetic-based diet did not increase weight loss compared with a standard balanced diet. However, genetic features can identify individuals most likely to benefit from a balanced diet weight loss strategy; these findings require further investigation. ClinicalTrials.gov number: NCT01859403., (Copyright © 2015 AGA Institute. Published by Elsevier Inc. All rights reserved.)

Objective: The FAO has developed an approach for estimating the prevalence of undernourishment. Based on the FAO method Taiwan has a prevalence of undernourishment of 3.98%, which is higher than that of some developing countries. As this is not a true reflection of the status of undernourishment in our nation, the purpose of the present study was to modify the FAO methodology for Taiwan., Design: Two factors were considered in the modified version. As the minimum dietary energy requirement was the main factor contributing to the inflated prevalence in Taiwan, we adjusted for a lighter physical activity level, based on the average BMI of the Taiwanese population, and calculated a new minimum dietary energy requirement. We then fitted a second-order polynomial regression model for prediction of per capita dietary energy supply., Results: The adjusted minimum dietary energy requirement was reduced to 7648 kJ/d or 7765 kJ/d compared with the original value of 8054 kJ/d. This resulted in a decrease of the prevalence of undernourishment in Taiwan to 2.5% or 3.0%, which is much closer to that of other countries with the same level of economic development. The second-order polynomial regression model efficiently reduced the variation in dietary energy consumption and resulted in an undernourishment prevalence of less than 2.5%., Conclusions: This new adapted method is more appropriate for Taiwan. It is recommended that each country evaluates the appropriateness of the FAO approach for its population.

The p53 tumor suppressor gene is a 16-20-kb section of cellular DNA located on the short arm of human chromosome 17 at position 17 P 13.1. Allelic deletions and/or point mutations in p53 gene are now known to be associated with the development of carcinogenesis. A hallmark of p53 is that both alleles are generally altered during transformation, which usually represents a loss of heterozygosity (LOH). In this study 30 normal dental students and 22 oral cancer patients were collected from the affiliated hospital of Chung Shan Medical and Dental College, Taichung, Taiwan. Extractions of DNA from the buccal mucosa or cancer surface were sampled by cytology brush. The two polymorphic restriction sites exon 4 and intron 6 within the p53 gene were amplified with polymerase chain reactions followed by restriction fragment length polymorphism assay. In heterozygous individuals, 66% of oral cancers demonstrated loss of p53 gene heterozygosity at the exon 4 site, and 50% showed LOH at the intron 6 site. These results indicate that inactivation of p53 gene is associated with development and/or progression of oral cancer. The essential advantages of oral exfoliative cytology are the non-invasiveness, painlessness, rapidity, ease and cost-effectiveness of cell sampling and DNA extraction. Furthermore, this experimental assay might be useful for preliminary screening of carcinogenesis in human beings.

The chronic disease usually can not be cured well but controlling by the daily care activity, regular diagnosis and dosage under the physician's instructions. In this research, we propose a community medical care monitoring model for monitoring and managing the chronic patients of community through the WWW (World Wide Web) service network and/or telephone voice service network. It can collect more patients' physiological data measured at home or community health agent. Therefore, the chronic disease patients will be getting better cure from his doctor's diagnosis due to the patient's effort.