Association of Nutritional Risk With Gait Function and Activities of Daily Living in Older Adult Patients With Hip Fractures.

OBJECTIVE: To investigate the association of nutritional risk with gait function and activities of daily living (ADLs) in older adult patients with hip fractures. METHODS: The retrospective data of older adult patients diagnosed with hip fractures who visited the recovery-phase rehabilitation ward between January 2019 and December 2022 were reviewed. Nutritional risk was evaluated using the Geriatric Nutritional Risk Index; gait function and ADLs were assessed using the modified Harris Hip Score subitem and Functional Independence Measure, respectively. Multivariate linear regression and path analysis with structural equation modeling were used to examine the factors associated with ADLs and the associations among the study variables. RESULTS: This study included 206 participants (172 females and 34 males; mean age, 85.0±7.3 years). In the multivariate analysis, gait function (ß=0.488, p<0.001), cognitive function (ß=0.430, p<0.001), and surgery (ß=-0.143, p<0.001) were identified as independent factors. Pathway analysis revealed that nutritional risk was not directly correlated with ADLs but was directly associated with gait and cognitive functions. Gait and cognitive functions, in turn, were directly related to ADLs. CONCLUSION: Nutritional risk was found to be associated with ADLs through an intermediary of gait and cognitive functions.

In situ/In vivo Optical Microspectroscopy to Probe the Emergence of Morphology.

Morphology governs function. Yet, understanding and controlling the emergence of morphology at the molecular level remains challenging. The difficulty in studying the early stage of morphology formation is due to its stochastic nature both spatially and temporally occurring at the nanoscale. This nature has been particularly detrimental for the application of optical spectroscopy. To overcome this problem, we have been developing new in situ/in vivo optical spectroscopy tools, which are label-free and non-invasive. This account highlights several examples of how optical spectroscopy can become an important tool in studying the birth of morphology.

Changes in walking speed 6 months after discharge may be more sensitive to subsequent prognosis than handgrip strength in patients hospitalized for heart failure.

BACKGROUND: Despite the prognostic importance of walking speed (WS) and handgrip strength (HGS) in patients with heart failure (HF), no study has reported the prognostic impact of changes in these parameters. This study aimed to examine the association between changes after discharge and the subsequent prognosis. METHODS: This study included 881 elderly patients hospitalized for HF. WS and HGS were measured at discharge and 6 months after discharge. Based on the presence of slowness (WS <0.98 m/s) or weakness (HGS <30.0 kg for men and < 17.5 kg for women) at both points, patients were divided into four groups (WS: A = -/-, B = -/+, C = +/-, D = +/+; HGS: E = -/-, F = -/+, G = +/-, H = +/+). The study endpoint was a composite of all-cause mortality and HF rehospitalization during the 18 months after 6 months of discharge. The Cox proportional hazards model was used to assess the association between the groups and study outcomes. RESULTS: Stratified by the WS change patterns, groups B and D showed higher risk of the study outcomes than group A [B: hazard ratio 2.34, 95% confidence interval (CI) 1.29-4.28; D: 2.38, 1.67-3.39], whereas group C was not. When stratified by the HGS change in patterns, only group H was associated with a worse prognosis (HR; 1.85, 95%CI; 1.31-2.60). CONCLUSION: Changes in WS were related to HF prognosis, suggesting that changes in WS may be more sensitive to further risk stratification than changes in HGS.

Questionnaire-based scoring system for screening moderate-to-vigorous physical activity in middle-aged Japanese workers.

OBJECTIVES: Currently available questionnaires have limited ability to measure physical activity (PA) using accelerometers as a gold standard. This study aimed to develop a PA questionnaire for middle-aged Japanese workers and propose a PA scoring system for predicting low moderate-to-vigorous PA (MVPA). METHODS: A total of 428 participants (median age 49 years; 75.8% men) participated in a 7-day PA measurement using an accelerometer and a questionnaire. The association between questionnaire responses and low MVPA (<150 min/wk) was assessed by logistic regression analysis. A score was assigned to each response based on the correlation coefficients of the multivariate model. The ability of the sum score to predict low MVPA was assessed using the area under the receiver operating characteristic curve (AUC). RESULTS: Five questionnaire items were used for measuring PA scores (range: 0-50; higher scores indicated a higher probability of low MVPA). The AUC was 0.741 (95% CI, 0.689-0.792), and the sensitivity and specificity at the optimal cut-off value were 66.7% and 68.2%, respectively. This predictive ability was slightly increased by body mass index (AUC 0.745 [95% CI, 0.693-0.796]; sensitivity 69.9%; specificity 66.9%). These predictive values were greater than those of conventional questionnaires used in health checkups in Japan (P < .05). CONCLUSIONS: This questionnaire-based PA scoring system showed moderate accuracy in predicting low MVPA. It is useful for screening physically inactive workers and promoting PA.

Cognitive decline assessed using a brief screening test and cardiovascular and non-cardiovascular events in older patients with heart failure.

BACKGROUND: Although cognitive decline is recognized as a prognostic factor of heart failure (HF), the association of cognitive decline with specific clinical outcomes in patients with HF remains unclear. AIM: This study examines the relationship between cognitive decline using a brief test and cardiovascular and non-cardiovascular events in older patients with HF. METHODS: This study included 146 hospitalised patients with HF (median age, 77 years; male, 56.8%). Cognitive decline was defined as a score of ≤ 9 points on the Rapid Dementia Screening Test at the time of discharge. RESULTS: Cumulative incidence of cardiovascular events after discharge was twofold higher in patients with cognitive decline (Model 1 adjusted for basic characteristics, hazard ratio (HR) = 2.01, 95% confidence interval (CI): 0.94-4.31; Model 2 adjusted for potential confounders, HR = 2.30, 95% CI: 1.07-4.97). The association between cognitive decline and non-cardiovascular events decreased after adjusting for potential confounders. CONCLUSION: The results of this study emphasize the clinical utility of cognitive assessment for risk stratification of worsening cardiovascular conditions, including HF.

Association between outpatient cardiac rehabilitation and all-cause mortality after cardiovascular surgery: A propensity score-matched analysis.

Objectives: Cardiac rehabilitation (CR) is a class I recommendation in the treatment guidelines for cardiovascular disease; however, its postoperative prognostic effects after surgery are not fully understood. Therefore, this study aimed to examine the effect of multidisciplinary outpatient CR on postdischarge all-cause mortality in patients who underwent cardiovascular surgery. Methods: This retrospective cohort study included consecutive patients who underwent elective cardiovascular surgery between April 2015 and March 2021. Patients were categorized into CR and non-CR groups. The primary outcome measure was all-cause mortality. Propensity score-matching analysis was performed to minimize selection bias and differences in clinical characteristics. The propensity score for each patient was produced using logistic regression analysis, with the CR group and the subsequent 27 variables as the dependent and independent variables, respectively. Results: In our cohort (n = 1095), 51 patients (4.7%) died during the follow-up period (mean, 1042 days). The CR group had a significantly lower mortality rate than the non-CR group (hazard ratio, 0.45; 95% CI, 0.21-0.95; P = .036). After propensity score matching adjusted for confounders, the association between CR and reduced risk of all-cause mortality remained (hazard ratio, 0.35; 95% CI, 0.14-0.85; P = .02). Conclusions: Postdischarge multidisciplinary outpatient CR in patients who underwent cardiovascular surgery was associated with a substantial survival benefit, which persisted after adjusting for variables, including age, operative factors, physical and cognitive functions, and nutritional status.

Prognostic impact of nutrition measures in patients with heart failure varies with coexisting physical frailty.

AIMS: Malnutrition is prevalent among patients with heart failure (HF); however, the effects of coexisting malnutrition and frailty on prognosis are unknown. This study examines the impact of malnutrition and frailty on the prognosis of patients with HF. METHODS AND RESULTS: We examined 1617 patients with HF aged 65 years or older (age: 78.6 ± 7.4; 44% female) from a Japanese multicentre prospective cohort study. The nutritional status was evaluated using the Geriatric Nutritional Risk Index (GNRI), Controlling Nutritional Status (CONUT), and Mini Nutritional Assessment Short Form on discharge. Frailty was assessed using the criteria determined in a previous study on patients with HF. The prognostic impact of each nutrition measure on the risk of composite all-cause mortality and cardiac readmissions within 2 years of hospital discharge was assessed using Kaplan-Meier survival curves and Cox proportional hazards model analysis for non-frail and frail groups. Over 2324.2 person-years of follow-up, 88 patients died and 448 patients experienced readmission due to HF. In the non-frail group, poor nutritional status assessed using the GNRI and CONUT was associated with an increased hazard ratio (HR) of composite outcomes in the crude model; however, adjustment for potential confounders diminished the association. In the frail group, all three nutritional indicators were associated with the cumulative incidence of the study outcome (log-rank test, P < 0.05). In multivariate analysis, only the CONUT score was associated with an increased HR even after adjustment for confounders. CONCLUSIONS: The CONUT score predicted a poor prognosis in HF patients with coexisting physical frailty, highlighting the potential clinical benefit of nutritional assessment based on biochemical data for further risk stratification.

Unveiling the Configurational Landscape of Carbamate: Paving the Way for Designing Functional Sequence-Defined Polymers.

Carbamate is an emerging class of a polymer backbone for constructing sequence-defined, abiotic polymers. It is expected that new functional materials can be de novo designed by controlling the primary polycarbamate sequence. While amino acids have been actively studied as building blocks for protein folding and peptide self-assembly, carbamates have not been widely investigated from this perspective. Here, we combined infrared (IR), vibrational circular dichroism (VCD), and nuclear magnetic resonance (NMR) spectroscopy with density functional theory (DFT) calculations to understand the conformation of carbamate monomer units in a nonpolar, aprotic environment (chloroform). Compared with amino acid building blocks, carbamates are more rigid, presumably due to the extended delocalization of π-electrons on the backbones. Cis configurations of the amide bond can be energetically stable in carbamates, whereas peptides often assume trans configurations at low energies. This study lays an essential foundation for future developments of carbamate-based sequence-defined polymer material design.

Toward time resolved dynamic light scattering microscopy: Retrieving particle size distributions at high temporal resolutions.

Dynamic light scattering (DLS) is a widely applied technique in multiple scientific and industrial fields for the size characterization of nanoscale objects in solution. While DLS is typically applied to characterize systems under static conditions, the emerging interest in using DLS on temporally evolving systems stimulates the latent need to improve the time resolution of measurements. Herein, we present a DLS microscopy setup (micro-DLS) that can accurately characterize the size of particles from autocorrelation functions built from sub-100 ms time windows, several orders of magnitude faster than previously reported. The system first registers the arrival time of the scattered photons using a time-correlated single photon counting module, which allows the construction of the autocorrelation function for size characterization based on a time window of freely chosen position and width. The setup could characterize both monomodal (60 or 220 nm polystyrene particles; PS) and multimodal size distributions (e.g., mixture of 20 nm LUDOX and 80 nm PS) with high accuracy in a sub-100 ms time window. Notably, the width of the size distribution became narrower as a shorter time window was used. This was attributed to the ability of the system to resolve the sub-ensemble of the broad size distribution, as the broad distribution could be reconstructed by accumulating the distribution obtained by consecutive 80 ms time windows. A DLS system with high temporal resolution will accelerate the expansion of its application toward systems that evolve as a function of time beyond its conventional use on static systems.

Physical Frailty and Use of Guideline-Recommended Drugs in Patients With Heart Failure and Reduced Ejection Fraction.

BACKGROUND Guideline-recommended therapies that improve prognosis remain underused in clinical practice. Physical frailty may lead to underprescription of life-saving therapy. We aimed to investigate the association between physical frailty and the use of evidence-based pharmacological therapy for heart failure with reduced ejection fraction and the impact of this on prognosis. METHODS AND RESULTS The FLAGSHIP (Multicentre Prospective Cohort Study to Develop Frailty-Based Prognostic Criteria for Heart Failure Patients) included patients hospitalized for acute heart failure, and data on physical frailty were collected prospectively. We analyzed 1041 patients with heart failure with reduced ejection fraction (aged 70 years; 73% male) and divided them by physical frailty categories using grip strength, walking speed, Self-Efficacy for Walking-7 score, and Performance Measures for Activities of Daily Living-8 score: categories I (n=371; least frail), II (n=275), III (n=224), and IV (n=171). Overall prescription rates of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers, ß-blockers, and mineralocorticoid receptor antagonists were 69.7%, 87.8%, and 51.9%, respectively. The proportion of patients receiving all 3 drugs decreased as physical frailty increased (in category I patients, 40.2%; IV patients, 23.4%; P for trend<0.001). In adjusted analyses, the severity of physical frailty was an independent predictor for nonuse of angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (odds ratio [OR], 1.23 [95% CI, 1.05-1.43] per 1 category increase) and ß-blockers (OR, 1.32 [95% CI, 1.06-1.64]), but not mineralocorticoid receptor antagonists (OR, 0.97 [95% CI, 0.84-1.12]). Patients receiving 0 to 1 drug had a higher risk of the composite outcome of all-cause death or heart failure rehospitalization than those treated with 3 drugs in physical frailty categories I and II (hazard ratio [HR], 1.80 [95% CI, 1.08-2.98]) and III and IV (HR, 1.53 [95% CI, 1.01-2.32]) in the multivariate Cox proportional hazard model. CONCLUSIONS Prescription of guideline-recommended therapy decreased as severity of physical frailty increased in heart failure with reduced ejection fraction. Underprescription of guideline-recommended therapy may contribute to the poor prognosis associated with physical frailty.

Prognostic effects of cardiac rehabilitation in heart failure patients classified according to physical frailty: A propensity score-matched analysis of a nationwide prospective cohort study.

Background: Research regarding cardiac rehabilitation (CR) in the prognosis of heart failure (HF) patients and frailty remains lacking. Here, the effects of CR on the 2-year prognosis of HF patients were examined according to their frailty status. Methods: This multicenter prospective cohort study enrolled patients hospitalized for HF. Patients who underwent ≥1 session per 2 weeks of CR within 3 months after discharge were categorized in the CR group. Patients were divided in a non-frailty (≤8 points) and physical frailty group (≥9 points) based on their FLAGSHIP frailty score. The score is based on HF prognosis, with a higher score indicating worsened physical frailty. A propensity score-matched analysis was performed to compare survival rates between the two groups according to their physical frailty status. Endpoints included HF re-hospitalization and all-cause mortality during a 2-year follow-up period. Results: Of 2697 patients included in the analysis, 285 and 95 matched pairs were distributed in the non-frailty and physical frailty groups, respectively, after propensity-score matching. CR was associated with lower incidence of HF rehospitalization in both non-frailty (hazard ratio 0.65; 95% confidence interval 0.44-0.96; p = 0.032) and physical frailty (0.54; 0.32-0.90; p = 0.019) groups. CR was not associated with all-cause mortality in either group (log-rank test, p > 0.05). Conclusion: These findings suggest the effects of CR on reduced HF rehospitalization, regardless of physical frailty status.

Factors Associated With Changes in Objectively Measured Moderate to Vigorous Physical Activity in Patients After Percutaneous Coronary Intervention: A Prospective Cohort Study.

BACKGROUND: This study aimed to clarify factors affecting changes in moderate to vigorous physical activity (MVPA) in patients 1 to 3 months after undergoing percutaneous coronary intervention (PCI). METHODS: In this prospective cohort study, we enrolled patients aged <75 years who underwent PCI. MVPA was objectively measured using an accelerometer at 1 and 3 months after hospital discharge. Factors associated with increased MVPA (≥150 min/wk at 3 mo) were analyzed in participants with MVPA < 150 minutes per week at 1 month. Univariate and multivariate logistic regression analyses were performed to explore variables potentially associated with increasing MVPA, using MVPA ≥ 150 minutes per week at 3 months as the dependent variable. Factors associated with decreased MVPA (<150 min/wk at 3 mo) were also analyzed in participants with MVPA ≥ 150 minutes per week at 1 month. Logistic regression analysis was performed to explore factors of declining MVPA, using MVPA < 150 minutes per week at 3 months as the dependent variable. RESULTS: We analyzed 577 patients (median age 64 y, 13.5% female, and 20.6% acute coronary syndrome). Increased MVPA was significantly associated with participation in outpatient cardiac rehabilitation (odds ratio 3.67; 95% confidence interval, 1.22-11.0), left main trunk stenosis (13.0; 2.49-68.2), diabetes mellitus (0.42; 0.22-0.81), and hemoglobin (1.47, per 1 SD; 1.09-1.97). Decreased MVPA was significantly associated with depression (0.31; 0.14-0.74) and Self-Efficacy for Walking (0.92, per 1 point; 0.86-0.98). CONCLUSIONS: Identifying patient factors associated with changes in MVPA may provide insight into behavioral changes and help with individualized PA promotion.

National survey on the secondary preventive measures for coronary artery disease among interventional cardiologists: a report from the Japanese Association of Cardiovascular Intervention and Therapeutics.

Insights from recent clinical trial testing revascularization strategies have interested interventional cardiologists in optimal medical therapy and secondary prevention modalities. As no large-scale survey has been recently conducted, this report presents the results of a nationwide survey on interventionists' concerns regarding secondary prevention after percutaneous coronary intervention (PCI) and discusses medical support system needs in Japan. A questionnaire to assess the status and challenges of secondary prevention interventions by interventional cardiologists during outpatient visits was supplied to Cardiovascular Interventional Technology (CVIT)-certificated hospitals. This was answered by representative cardiologists of each hospital and comprised three queries: (1) the necessity of outpatient cardiac rehabilitation to promote post-PCI lifestyle guidance; (2) the feasibility of providing lifestyle guidance; and (3) the barriers to lifestyle guidance, during outpatient visits. Questions 1 and 2 were answered using a 5-point Likert scale. Survey responses were received from 391 hospitals (54.9% of 712 CVIT-certificated facilities). For Question 1, 327 hospitals (84.1%) answered "agree", and 386 hospitals (98.7%) answered "agree" or "somewhat agree". For Question 2, 10% of hospitals answered "agree", and "agree" and "somewhat agree" amounted to less than 50%. For Question 3, 83.5% of the facilities answered lack of time as the major reason). The next reasons included an early reverse referral to family doctors after PCI, and a lack of managerial advantage (60% and 40% of the hospitals, respectively). In conclusion, interventionists are concerned about secondary prevention for their patients. The issues clarified in the survey will be important for developing next-generation secondary prevention systems.

Factors associated with postsurgical muscle weakness in patients who undergo thoracic aortic surgery: a retrospective cohort study.

OBJECTIVE: Aortic surgery is often performed in elderly patients, and these patients have a high risk of postsurgical muscle weakness. To reinforce purposeful postsurgical rehabilitation, we aimed to investigate the factors associated with postsurgical muscle weakness in patients who underwent thoracic aortic surgery. METHODS: This retrospective cohort study analyzed data of consecutive patients who underwent elective thoracic aortic surgery with cardiopulmonary bypass, and whose knee extensor isometric muscle strength (KEIS) were measured pre- and postoperatively at University Hospital between January 2012 and December 2018. The primary outcome was percent change in KEIS (% change in KEIS). Multivariate linear regression analysis was used to identify independent risk factors for % change in KEIS. RESULTS: Overall, 218 patients were included. Multivariate linear regression analysis showed that mechanical ventilation time, days from initial sitting to 100 m walking, and the number of exercises in the rehabilitation room were associated with % change in KEIS. CONCLUSIONS: This study may serve as a reference to stratify patients at risk of postsurgical muscle weakness. The preventive or alternative interventions in patients undergoing thoracic aortic surgery will be assessed in future studies.

Physical Frailty May Predict 2-Year Prognosis in Elderly Patients With Acute Myocardial Infarction　- A Report From the FLAGSHIP Study.

BACKGROUND: Elderly patients with acute myocardial infarction (AMI) are a high-risk population for heart failure (HF), but the association between physical frailty and worsening prognosis, including HF development, has not been documented extensively.Methods and Results: As part of the FLAGSHIP study, we enrolled 524 patients aged ≥70 years hospitalized for AMI and capable of walking at discharge. Physical frailty was assessed using the FLAGSHIP frailty score. The primary outcome was a composite outcome of all-cause death and HF rehospitalization within 2 years after discharge. The secondary outcome was all-cause death and HF rehospitalization. After adjusting for confounders, physical frailty showed a significant association with an increased risk of the composite outcome (hazard ratio [HR]=2.09, 95% confidence interval [CI]: 1.03-4.22, P=0.040). The risk of HF rehospitalization increased with physical frailty, but the association was not statistically significant (HR=2.14, 95% CI: 0.84-5.44, P=0.110). Physical frailty was not associated with an increased risk of all-cause death (HR=1.45, 95% CI: 0.49-4.26, P=0.501). CONCLUSIONS: The findings suggest that physical frailty assessment serves as a stratifying tool to identify high-risk populations for post-discharge clinical events among ambulant elderly patients with AMI.

Association Between the Redox State of Human Serum Albumin and Exercise Capacity in Patients With Cardiac Disease.

The redox state of human serum albumin (HSA) is reported to be an oxidative stress biomarker; however, its clinical use in cardiac disease has not yet been examined. This study aimed to investigate the relation between the redox state of HSA and exercise capacity, which is a robust prognostic factor, in patients with cardiovascular disease. This cross-sectional study included outpatients with cardiac disease. Exercise capacity was assessed by peak oxygen consumption (peakVO2) measured using symptom-limited cardiopulmonary exercise testing. The high-performance liquid chromatography postcolumn bromocresol green method was used to part HSA into human nonmercaptalbumin (oxidized form) and human mercaptalbumin (HMA, reduced form). The fraction of human mercaptalbumin found in HSA (f[HMA]) was calculated as an indicator of the redox state of HSA. The association between peakVO2 and f(HMA) was examined using the Spearman correlation coefficient and multivariate linear regression analysis. A total of 70 patients were included (median age 76 years; 44 men; median peakVO2 15.5 ml/kg/min). The f(HMA) was positively correlated with peakVO2 (r = 0.38, p <0.01). Even after controlling for potential confounders, this association remained in the multivariate linear regression analysis (standardized beta = 0.24, p <0.05). We found a positive association between f(HMA) and peakVO2, independent of potential confounders in patients with cardiac disease, suggesting that f(HMA) may be a novel biomarker related to exercise capacity in cardiac disease. Longitudinal studies are required to further examine the prognostic capability of f(HMA), the responsiveness to clinical intervention, and the association between f(HMA) and cardiac disease.

Efficient Photoredox Cycles to Control Perylenediimide Self-Assembly.

Photoreduction of perylenediimide (PDI) derivatives has been widely studied for use in photocatalysis, hydrogen evolution, photo-responsive gels, and organic semiconductors. Upon light irradiation, the radical anion (PDI⋅- ) can readily be obtained, whereas further reduction to the dianion (PDI2- ) is rare. Here we show that full 2-electron photoreduction can be achieved using UVC light: 1) in anaerobic conditions by 'direct photoreduction' of PDI aggregates, or 2) by 'indirect photoreduction' in aerobic conditions due to acetone ketyl radicals. The latter strategy is also efficient for other dyes, such as naphthalenediimide (NDI) and methylviologen (MV2+ ). Efficient photoreduction on the minute time-scale using simple LED light in aerobic conditions is attractive for use in dissipative light-driven systems and materials.

Association between the Big Five personality traits and medication adherence in patients with cardiovascular disease: A cross-sectional study.

The correlation between personality traits and health outcomes of primary prevention has been examined. However, there is a lack of evidence on the association between the assessment of personality traits and medication adherence for secondary prevention of cardiovascular disease. Thus, this study aimed to explore the association between personality traits and medication adherence, including compliance to prescribed medications and attitudes toward taking medications among patients with cardiovascular disease. This cross-sectional study included patients hospitalized for cardiovascular disease. We assessed the Big Five personality traits (conscientiousness, neuroticism, openness, extraversion, and agreeableness) of each patient at discharge using the Ten-Item Personality Inventory. In addition, we evaluated four aspects of medication adherence using a 12-item version of the medication adherence scale: medication compliance, collaboration with health care providers, willingness to access and use information on medication, and acceptance to take medication. Logistic regression analysis was performed to assess the correlation between the level of each medication adherence domain and each personality trait. The data of 128 patients with cardiovascular disease were analyzed. Higher conscientiousness score was significantly associated with a high compliance score (odds ratio per 1 point increase, 1.90; 95% confidence interval, 1.30-2.79; p = 0.001), high collaboration score (1.90; 1.31-2.76; p = 0.001), and high willingness score (1.74; 1.19-2.54; p = 0.004) after adjustment for potential confounders. Other combinations of personality traits and medication adherence showed no statistically significant correlations in multivariate analyses. The findings of this study suggest that assessment of personality traits, especially conscientiousness, may facilitate patient-medical staff communication for the improvement of medication adherence in patients with cardiovascular disease.