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Background: A small portion of patients are diagnosed with early gastric cancer (EGC) and undergo endoscopic submucosal dissection (ESD) at a young age. However, their clinical outcomes are rarely known. Aim: We investigated to identify the feasibility and clinical outcomes of ESD for EGC focusing on young patients. Methods: We analyzed the clinical characteristics and outscomes of patients who had undergone ESD for the treatment of EGC at < 50 years of age. We enrolled patients who had been diagnosed with EGC and had undergone ESD between 2006 and 2020. We divided them by age as follows: ≤ 50 and > 50 years into the young age (YA) and other age (OA) groups, respectively. Results: Altogether, 1681 patients underwent ESD for EGC (YA group: 124 [7.4%], OA group: 1557 [92.6%]). The YA group had less severe atrophy and more undifferentiated (37.1% vs. 13.9%, P < 0.001) and diffuse type (25% vs. 7.7%, P < 0.001) histology. The curative resection rate was not significantly different between the groups. However, among 1075 patients who had achieved curative resection and had been followed-up for > 12 months, the YA group had a lower incidence of MGN (5.2% vs. 17.5%, P = 0.004) and MGC (2.6% vs. 10.9%, P = 0.019) than those exhibited by the OA group. The YA group was a significant negative predictor of MGN (odds ratio [OR]: 2.983, 95% confidence interval [CI] 1.060–8.393, P = 0.038), and marginally negative predictor in MGC (OR: 3.909, 95% CI: 0.939–16.281, P = 0.061). Conclusion: ESD is a favorable and effective therapeutic modality for EGC patients aged < 50 years, once curative resection is achieved. [ABSTRACT FROM AUTHOR]

Recently, non-pharmacological treatments are gaining increasing importance for improving the quality of life in patients with chronic obstructive pulmonary disease (COPD). This pilot study aimed to evaluate the feasibility of conducting extensive research on Chuna manual therapy (CMT). This study investigated the effectiveness and safety of CMT adjuvant to Western medicine (WM) in patients with COPD. Forty patients with COPD were randomized into two groups in a 1:1 ratio: experimental (CMT plus WM) and control (WM only) groups. The CMT intervention was administered once a week for eight weeks. The primary outcome measured was the 6-min walk distance (6MWD). Secondary outcomes measured were: forced expiratory volume in 1 s (FEV1), forced vital capacity (FVC), assessments using the modified Medical Research Council (mMRC) scale and Visual Analog Scale (VAS) for dyspnea, the COPD Assessment Test (CAT), St. George's Respiratory Questionnaire (SGRQ), and the EuroQoL five-dimensional questionnaire (EQ-5D). The mean differences in FEV1 (L) between Weeks 1 and 8 were statistically significant between the groups (p = 0.039). Additionally, the experimental group showed improved 6MWD, mMRC, VAS for dyspnea, CAT, SGRQ (total), and EQ-VAS scores than the control group. However, the differences between the two groups were not statistically significant. No adverse events were observed during this trial. CMT has the potential to alleviate symptoms, improve quality of life, and delay the decline in lung function in patients with COPD. The results of this pilot study could lead to large-scale clinical trials in the future. [ABSTRACT FROM AUTHOR]

This study aimed to verify, for the first time, the need for Good Pharmacy Practice (GPP) regulations as guidelines to provide pharmaceutical care services in community pharmacies in Korea. Statistical analyses were performed with demographic characteristics, institutional factors, and diversity factors of 3 pharmaceutical care services as independent variables and the favorability of GPP implementation as a dependent variable. In assessing the diversity of methods of providing pharmaceutical care services as an indicator of willingness to provide these services, this study understood such diversity as an innovative behavior that represents the efforts and willingness of pharmacists to provide better services. The results of descriptive statistics showed that most pharmacists in community pharmacy recognize that guidelines are necessary to provide better pharmaceutical care services. The statistical correlation analysis results confirmed that a greater need for guidelines was strongly related to higher GPP favorability. The institutional factors had the greatest influence on GPP favorability, rather than diversity factors of pharmaceutical care services, ultimately with the Korean perspectives to equate the GPP with the guidelines for pharmaceutical care services. Our study confirmed that it is a wish and a policy task of community pharmacists in Korea to enact GPP as soon as possible. [ABSTRACT FROM AUTHOR]

Background. Allergic rhinitis (AR) is a common disease, and conventional medications are often insufficient for treatment. Bojungikgi-tang (BJIGT) is an herbal medicine widely used in traditional medicine and has anti-inflammatory and immunoregulatory effects. We hypothesize that BJIGT would improve nasal symptoms in patients with persistent AR (PAR). Methods. This is a randomized, double-blind, placebo-controlled, phase II trial. A total of 105 patients, identified with perennial allergens, with a history of PAR and a mean total nasal symptom score (TNSS) ≥ 5 during the run-in period will be recruited from Daejeon Korean Medicine Hospital. Participants will be randomly assigned to a high-dose BJIGT group, standard-dose BJIGT group, or control group (placebo) in a 1 : 1 : 1 allocation ratio after a week run-in period. The treatment medication will be taken three times per day for 4 weeks. The primary outcome measure is the mean change in the TNSS before and after medication. The secondary outcome measures include the Korean Allergic Rhinitis-Specific Quality of Life Questionnaire, total IgE and eosinophil count, overall assessment of AR, pattern identification questionnaire for AR, and Sasang constitution. Discussion. The aim of this study is to investigate the efficacy and safety of BJIGT in the treatment of PAR and to determine the suitable dosage of BJIGT. Therefore, we planned a randomized, controlled, phase II trial of two different doses of BJIGT compared with placebo, and the results of this study are expected to provide evidence for the use of BJIGT as a treatment of PAR. Trial Registration. The National Clinical Trial Registry Clinical Research Information Service, CRIS, KCT0006616, https://cris.nih.go.kr/cris/search/detailSearch.do/20706. [ABSTRACT FROM AUTHOR]

Individuals with Rett syndrome suffer from severely impaired cognitive and motor performance. Current movement-related therapeutic programs often include traditional physical therapy activities and assisted treadmill walking routines for those individuals who are ambulatory. However, there are no quantitative reports of kinematic gait parameters obtained during treadmill walking. The purpose of this research was to characterize the kinematic patterns of the lower limbs during treadmill walking as speed was slowly increased. Seventeen independently ambulatory females diagnosed with a methyl-CpG-binding protein 2 gene mutation walked on a motorized treadmill while joint kinematics were obtained by a camera-based motion capture system and analysis software. Stride times progressively decreased as treadmill speeds increased. There were significant main effects of speed on sagittal knee and hip ranges of motion and hip velocity. There were large joint asymmetries and variance values relative to other ambulatory patient populations, although variance values decreased as walking speed increased. The results indicate that individuals with Rett syndrome can adapt their kinematic gait patterns in response to increasing treadmill speed, but only within a narrow range of speeds. We suggest that treadmill training for ambulatory individuals with Rett syndrome may promote improved walking kinematics and possibly provide overall health benefits. Walking is an activity that can counter the negative impacts of the sedentary lifestyle of many individuals with disabilities, including those individuals with Rett syndrome. Documentation of the lower limb kinematic patterns displayed during walking by ambulatory females with Rett syndrome can be used by clinicians to evaluate their patients' gait performance in response to therapeutic and pharmacological interventions designed to promote walking. The ability to adapt to increases in treadmill speed suggests that a training program of treadmill walking may be effective in promoting improved gait performance in individuals with Rett syndrome. [ABSTRACT FROM AUTHOR]

Adults with type 2 diabetes (T2D) experience decline in cognitive function compared with controls. Cognitive function is a major component in the performance of daily activities that involve motor components. The aim of this project was to evaluate working memory cognitive deficits and sensorimotor deficits in adults with T2D versus healthy participants. Ten community-dwelling persons with T2D and 10 age- and sex-matched healthy controls were recruited. Cognitive function, tactile function, motor function, and health state measures were evaluated. Reduced cognitive function, tactile function, and motor function were exhibited in the T2D group. Cognitive and motor functions remained impaired versus controls during tasks with both cognitive and motor components (dual tasks). Health state measures were found to covary with measures of interest. The conclusions of this article are as follows: (a) systemic deficits beyond tactile dysfunction contribute to reduced hand/finger function in T2D, and (b) participants with T2D demonstrate impairments in working memory, tactile function, and motor function. [ABSTRACT FROM AUTHOR]

The purpose of this study was to examine whether loneliness mediates the relationship between social engagement and depressive symptoms and to determine how age moderates the mediation effect. Data for this study came from the survey with community‐dwelling adults aged 18 and older in South Korea, from March to April 2017. The total of 1,017 respondents were drawn from three age groups (18–44, 45–64, or 65 and older). The mediating effect of loneliness was tested between each of three social engagement‐related variables (family network, friend network, and perceived community support) and depressive symptoms. The results showed age differences in mediation: the effect was most pronounced in the relationship of family network with loneliness for the older group, whereas the size of friend network significantly predicted loneliness for younger adults. Both younger and older groups felt less lonely when they had a higher level of perceived community support; the middle age group remained uninfluenced by the mediation effects. Our findings confirm that loneliness is one of the mechanisms by which social engagement exerts its effect on depressive symptoms. As the Korean society embraces its growing proportions of older adults, the results of the study provide implications for adaptive strategies for changing social engagement need and mental health associated with ageing. [ABSTRACT FROM AUTHOR]

Objectives:As the opposite end of the continuum from social integration, social isolation may put individuals at a greater risk of poor mental health. Conceptualizing living alone as an objective and structural indicator of social isolation and loneliness as subjective perceptions of social isolation, the present study hypothesized that the relation between living alone and depressive symptoms would be mediated by the feelings of loneliness. Using older Korean Americans as the target population, the mediation model was examined in consideration of the contextual factors such as demographics (age, gender, education, perceived income, and length of stay in the USA), health (chronic conditions and functional disability), and general social integration (size of social network and community social cohesion). Method:Date were drawn from surveys with 209 older Korean Americans in Central Texas (Mage= 69.6, SD = 7.5). Multivariate regression models of depressive symptoms were entered in the following order: (1) demographics, (2) health, (3) living alone, (4) social network/community social cohesion, and (5) loneliness. The mediation effect of loneliness in the relationship between living alone and depressive symptoms was separately examined using the bootstrapping method. Results:Loneliness was found to mediate the relation between living alone and depressive symptoms (indirect effect = 1.03, 95% CI = .05–2.08). Conclusion:The results suggest that subjective perceptions of loneliness may explain the mechanism through which objective social isolation presents risks for depressive symptoms in older Korean Americans. [ABSTRACT FROM AUTHOR]

Scrotal hyperthermia leads to oxidative stress and apoptosis in spermatogenic cells, which subsequently causes male infertility. In this study, we examined the effects of β-carotene and/or curcumin on heat-stress- (HS-) induced testicular injuries in mice. ICR male mice (8 weeks old) were consecutively treated with β-carotene (10 mg/kg) and/or curcumin (20 mg/kg) orally once a day for 14 days and then subjected to single exposure with scrotal HS at 43°C for 15 min on day 7. HS induced a significant reduction in testicular weight, appearance of multinucleated giant cells, and desquamation of germ cells in destructive seminiferous tubules, as well as degenerative Leydig cells. Moreover, HS reduced the superoxide dismutase (SOD) activity and mRNA levels of mitochondrial SOD, phospholipid hydroperoxide glutathione peroxidase, B-cell lymphoma-extra-large, and 3β-hydroxysteroid dehydrogenase, with increases in lipid peroxidation levels and mRNA levels of BCL2-associated X protein and caspase-3 relative to those of the control group. However, these changes were significantly recovered by combined treatment with β-carotene and curcumin after HS. These findings indicate that the combined treatment with β-carotene and curcumin might be a valuable protective agent to ameliorate hyperthermic spermatogenic disorders via its potent antioxidative, antiapoptotic, and androgen synthetic effects. [ABSTRACT FROM AUTHOR]

Background Alagille syndrome ( AGS) is a multisystem autosomal dominant disorder that affects the liver, heart, eyes, face, bone, and other organs. AGS is caused by mutations in one of two genes, JAG1 or NOTCH2. We evaluated clinical features, outcomes, and the presence of JAG1 and NOTCH2 mutations in Korean children with AGS. Methods Between January 1997 and December 2013, 19 children were diagnosed with AGS at Asan Medical Center, Seoul, Korea. Their clinical features, outcomes, and JAG1 and NOTCH2 mutation status were retrospectively analyzed. Results The prevalence of clinical features in the 19 patients was as follows: dysmorphic facial features, 100% ( n = 19); liver symptoms, 89% ( n = 17); cardiac symptoms, 95% ( n = 18); ophthalmologic symptoms, 67% ( n = 10); skeletal deformities, 47% ( n = 9); and renal symptoms, 21% ( n = 4). JAG1 mutations were identified in 14 patients. The 13 different JAG1 mutations, seven of which were novel, included four deletions, three insertions, two missense mutations, three nonsense mutations, and one indel mutation. No NOTCH2 mutations were found. Two patients who received liver transplantation due to liver failure were still alive. Two patients died of comorbidities related to AGS: one of cardiac failure and one of hepatic failure. Conclusion This study describes the clinical characteristics of 19 Korean AGS patients with seven novel JAG1 mutations. Neonatal cholestatic jaundice was the most common initial presenting symptom; thus the presence of neonatal cholestasis warrants screening for syndromic features of AGS. Complex heart anomalies and progressive liver dysfunction resulted in significant morbidity and mortality in AGS. [ABSTRACT FROM AUTHOR]

In this study, we found that alpha-pinene (α-pinene) exhibits anti-inflammatory activity through the suppression of mitogen-activated protein kinases (MAPKs) and the nuclear factor-kappa B (NF-κB) pathway in mouse peritoneal macrophages. α-Pinene is found in the oils of many coniferous trees and rosemary. We investigated the inhibitory effects of α-Pinene on inflammatory responses induced by lipopolysaccharide (LPS) using mouse peritoneal macrophages. α-Pinene significantly decreased the LPS-induced production of interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α), and nitric oxide (NO). α-Pinene also inhibited inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) expressions in LPS-stimulated macrophages. Additionally, the activations of MAPKs and NF-κB were attenuated by means of α-pinene treatment. These results indicate that α-pinene has an anti-inflammatory effect and that it is a potential candidate as a new drug to treat various inflammatory diseases. [ABSTRACT FROM AUTHOR]

Objective: Idiopathic chronic fatigue (ICF), defined as medically unexplained chronic fatigue, is common these days. To date, there is no definite cure for ICF, and alternative therapies are being investigated. Oriental medicine music therapy (OMMT), a novel music therapy that occurs through an active behavioral process, has been applied to various chronic diseases, including ICF. In the present study, we aimed to evaluate the effect of OMMT on ICF. Design: Randomized controlled trial of OMMT compared with the waitlist control (6 sessions each) during a 2-week period. Participants: Thirty participants who had had ICF for at least 6 months before the experiments were recruited. Outcome measures: We evaluated fatigue severity scale (FSS), visual analog scale (VAS) for overall fatigue, revised Chalder fatigue scale (RCFS), World Health Organization quality of life scale abbreviated version (WHOQOL-BREF), Buzhongyiqi-Tang questionnaire (BZTQ), and salivary cortisol level at baseline (week 0) and at the end of the study (week 2) in the two groups. Results: FSS, VAS, and RCFS scores were significantly lower, and WHOQOL-BREF scores were significantly higher in the OMMT group than in the waitlist group ( p=0.006, p=0.004, p=0.002, and p=0.002, respectively). In contrast, salivary cortisol level and BZTQ scores were not significantly different between the OMMT group and the waitlist group. Conclusions: The present study suggests that OMMT may be an alternative treatment for ICF. Based on this result, further studies including possible mechanisms are needed. [ABSTRACT FROM AUTHOR]

Objectives: Abdominal examination (AE) is the evaluation of the status of illness by examining the abdominal region in traditional Korean medicine (TKM). Although AE is currently considered an important diagnostic method in TKM, owing to its clinical usage, no studies have been conducted to objectively assess its accuracy and develop standards. Design: Twelve healthy subjects and 21 patients with functional dyspepsia have participated in this study. The patients were classified into epigastric discomfort group ( n=11) and epigastric discomfort with tenderness group ( n=10) according to the clinical diagnosis by AE. After evaluating the subjective epigastric discomfort in all subjects, two independent clinicians measured the pressure pain threshold (PPT) two times at an acupoint (CV 14) using an algometer. We then assessed the interrater and intrarater reliability of the PPT measurements and evaluated the validity (sensitivity and specificity) via a receiver operating characteristic plot and optimal cutoff value. Results: The results of the interrater reliability test showed a very strong correlation (correlation coefficient range: 0.82-0.91). The results of intrarater reliability test also showed a higher than average correlation (intraclass correlation coefficient: 0.58-0.70). The optimal cutoff value of PPT in the epigastric area was 1.8 kg/cm2 with 100% sensitivity and 54.54% specificity. Conclusions: PPT measurements in the epigastric area with an algometer demonstrated high reliability and validity for AE, which makes this approach potentially useful in clinical applications as a new quantitative measurement in TKM. [ABSTRACT FROM AUTHOR]

This study explored factors contributing to older adults’ self-perceptions about their own aging in assisted living (AL) communities. Data analysis was completed based on interviews with 150 older residents from 17 AL communities. Multiple regression analyses found that functional disability and hearing impairment negatively affected attitudes toward personal aging among AL residents, and satisfaction with social support positively influenced attitudes. Health perception mediated attitudes toward personal aging. Findings suggest the importance of social workers helping older AL residents recognize social support as a means of promoting their positive self-regard. [ABSTRACT FROM AUTHOR]

The objectives of this study were (1) to develop an empirical typology of physical health risks in racially and ethnically diverse older adults and (2) to examine whether the impact of social resources on depressive symptoms differs across the identified health risk groups (low, moderate, and high risks). The data source was the Survey of Older Floridians, a statewide survey of older adults aged 65 and older (n = 1,432). Latent profile analysis with multiple indicators of physical health (chronic conditions, functional disability, and self-rated health) was used to identify three health risk groups (low, moderate, and high risks). The direct and interactive effects of the health risk group membership and social resources (social support and religious service attendance) on depressive symptoms were found. Of particular interest was that the positive impact of social support was most pronounced in the moderate health risk group. [ABSTRACT FROM PUBLISHER]

This study focuses on the identification of multiple latent trajectories of pain intensity, and it examines how religiousness is related to different classes of pain trajectory. Participants were 720 community-dwelling older adults who were interviewed at four time points over a 3-year period. Overall, intensity of pain decreased over 3 years. Analysis using latent growth mixture modeling (GMM) identified three classes of pain: (1) increasing (n = 47); (2) consistently unchanging (n = 292); and (3) decreasing (n = 381). Higher levels of intrinsic religiousness (IR) at baseline were associated with higher levels of pain at baseline, although it attenuated the slope of pain trajectories in the increasing pain group. Higher service attendance at baseline was associated with a higher probability of being in the decreasing pain group. The increasing pain group and the consistently unchanging group reported more negative physical and mental health outcomes than the decreasing pain group. [ABSTRACT FROM PUBLISHER]

The purpose of this study was to develop empirically based typologies of religiousness/spirituality (R/S) and to determine whether the typologies were related to health and well-being. The study used a nationally representative sample of adults ( N = 1,431). Using latent profile analysis, typologies were derived based on religious service attendance, prayer, positive religious coping, and daily spiritual experiences. Multivariate statistical tests were used to examine cluster differences in health and well-being. A four-class model was identified: highly religious, moderately religious, somewhat religious, and minimally religious or non-religious. The four classes were distinctively different in psychological well-being, in that the highly religious class was most likely to be happy and satisfied with finances and least likely to be psychologically distressed. [ABSTRACT FROM AUTHOR]

The present study examined how self-rated health was influenced by sociodemographic characteristics, physical health indicators, and sociocultural resources among four racial/ethnic groups of older adults. The data source was the Survey of Older Floridians, a statewide sample of Whites (n = 503), African Americans (n = 360), Cubans (n = 328), and non-Cuban Hispanics (n = 241) who were age 65 and older. Hierarchical regression models of self-rated health were estimated to explore the direct effects of the predictor variables as well as their interactive roles in each racial/ethnic group. Compared to Whites, racial/ethnic minority older adults rated their health more poorly. Although physical health indicators were significant predictors of self-rated health across all groups, the authors found group-specific predictors and interactions. Findings show similarities and differences in predictors of self-rated health across diverse racial/ethnic groups and suggest the importance of understanding group-specific factors in efforts to improve older adults’ perceived and actual health. [ABSTRACT FROM PUBLISHER]

Background: The purpose of the study was to examine both direct and interactive roles of race/ethnicity with patients' characteristics (age, gender, relationship with caregiver, diagnosis, referral source, and payment type) in predicting length of hospice care. Method: This study included a total of 16,323 patients 65 years of age and older ( Mage=81.4, SD=8.3) who were served by a hospice in central Florida during a four-year period, 2002-2006. Survival analyses were conducted using the Cox proportional hazards model to predict the length of hospice care and test the interaction effects of race/ethnicity. Results: The majority of subjects (83.5%) were white, 7.6% were African-American, and 8.9% were Hispanic. During the study period, 58.5% died. All patient characteristics were significantly associated with the length of hospice care ( p < .05). Overall, Hispanics had the longest hospice stay ( M=98.84 days), followed by African-Americans ( M=90.29) and whites ( M=88.20). With the exception of African-American women who were no more likely to stay longer under hospice care than African-American men, the women in this study stayed longer under hospice care than men did. Patients referred from long-term care (LTC) settings had shorter stays in hospice care compared to those referred by physicians in other settings. Additionally, African-Americans and Hispanics referred from LTC had significantly shorter hospice stays than those referred by primary physicians. Conclusion: In this limited sample of hospice patients, length of stay was longer for minority patients than white patients. [ABSTRACT FROM AUTHOR]

Nutmeg (seed of Myristica fragrans [MF]) is one of the most commonly used spices in the world and also a well-known herb for the treatment of various intestinal diseases, including colitis in traditional Korean medicine. The purpose of the current study was to investigate whether water extract of MF (MFE) can protect against dextran sulfate sodium (DSS) induced colitis in a mouse model. Colitis was induced by 5% DSS in balb/c mice. MFE (100, 300 or 1000 mg/kg) was orally administered to the mice twice a day for 7 days. Body weight, colon length, clinical score, and histological score were assessed to determine the effects on colitis. Proinflammatory cytokines (interferon- γ, tumor necrosis factor- α, interleukin [IL]-1 β, and IL-6) were measured to investigate the mechanisms of action. MFE dose dependently inhibited the colon shortening and histological damage to the colon. However, it did not prevent weight loss. MFE also inhibited proinflammatory cytokines. The current results suggest that MFE ameliorates DSS-induced colitis in mice by inhibiting inflammatory cytokines. Further investigation, including the exact mechanisms is needed. [ABSTRACT FROM AUTHOR]

Abstract: This study aims to observe the effects of gestational stage on the pharmacokinetics of puerarin after oral administration in rats. The pharmacokinetics of puerarin was studied in pregnant rats using a sensitive and reproducible high-performance liquid chromatography/ultraviolet method. The concentration–time curves in both normal and pregnant rats were fit into a two-compartment model. The results indicated that gestation influences the pharmacokinetics of puerarin at different levels, especially during the early stages of pregnancy. Furthermore, puerarin penetrates the placental barrier and maintains high concentrations in fetal rat plasma. Therefore, puerarin administration should be carefully considered in pregnant women. [Copyright &y& Elsevier]

Abstract: Ethnopharmacological relevance: In traditional Korean medicine, Bojanggunbi-tang (BGT), which consists of 16 herbs, is one of the most frequently used herbal prescriptions in South Korea for treating intestinal disorders such as colitis. Aim of the study: This study investigated whether BGT could show a protective action on 2 different mice models of experimental colitis induced by dextran sulfate sodium (DSS) and 2,4,6-trinitrobenzene sulfonic acid (TNBS), which have been popularly used as inflammatory bowel disease models. Materials and methods: Colitis was induced by DSS and TNBS in institute of cancer research mice. BGT at doses of 50, 150, or 450mg/kg were orally administered twice a day for 7d in the DSS model and for 3d in the TNBS model. The body weight of the mice was measured daily. Colon length and histological damages were assessed on day 7 in the DSS model and on day 3 in the TNBS model. Results: BGT showed protective effects in both types of experimental colitis. In the DSS model, BGT dose dependently inhibited weight loss, shortening of colon length, and histological damages of the colon. In the TNBS model, BGT inhibited shortening of colon length and improved the survival rate of mice; however, it did not inhibit weight loss. Conclusion: The current results indicate that BGT ameliorates both DSS- and TNBS-induced colitis in mice. Further investigations to unveil the exact mechanisms are needed. [Copyright &y& Elsevier]