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Background: The comorbidity of asthma and allergic rhinitis is remarkably high, but not much is known about the effects of this combined condition on the quality of life. We aimed to evaluate the factors associated with asthma exacerbations and the effect of the exacerbations on the quality of life (QOL) through a one-year, large-scale, observational study in Japanese patients with asthma and rhinitis. Methods: A case survey by attending physicians and a patient survey was conducted at each assessment timepoint over a period of one year. Patients were divided into two groups according to the presence or absence of asthmatic attacks after enrollment and were matched using propensity scores to evaluate the factors associated with asthma exacerbations and the effect of the exacerbation on QOL. Results: Potential factors associated with asthma exacerbations included high body mass index value, low forced expiratory flow 75% of forced vital capacity (FEF75%), severe rhinitis as determined based on ARIA (Allergic Rhinitis and its Impact on Asthma). Although patients with asthma exacerbations had significantly impaired quality of life at baseline as evidenced by the economic aspects, in addition to physical, mental, and social activities, no further reduction with the attacks was observed. Conclusions: This study suggested that higher body mass index (BMI) and severe asthma as well as severe rhinitis were factors associated with asthma exacerbations. Although patients with asthma exacerbations had impaired QOL, attacks caused no further reduction. Keywords: Allergic rhinitis, Asthma, Asthma exacerbation, Observational study, Quality of life (QOL)

We report the rare case of a 72-year-old man with double cancers (gastric adenocarcinoma and Hodgkin’s lymphoma) with collision between gastric adenocarcinoma and Hodgkin’s lymphoma. Abdominal computed tomography showed increased wall thickness in the fundus region of the stomach and multiple lymph node swellings in the lesser curvature, periceliac and left cardial regions. Upper gastrointestinal endoscopy showed an ulcer approximately 5 cm in diameter with a malignant appearance in the fundus region of the stomach. On histopathologic examination, two completely different tumors were recognized in the stomach. One tumor was a poorly differentiated adenocarcinoma characterized by poorly developed tubular structures associated with prominent lymphoid infiltration of the stroma. The other tumor was found to have proliferated in the wall of the stomach, with diffuse granulomatous lesions and bordering the adenocarcinoma. Large atypical lymphoid cells with prominent nucleoli and enlarged mononuclei or multinuclei were seen in the latter tumor. Hodgkin’s lymphoma was also found in the swollen lesser curvature lymph nodes. As a result, gastric adenocarcinoma and metastasis of Hodgkin’s lymphoma were collided in the stomach. In conclusion, this case might be helpful in exploring the occurrence mechanism of tumor collision between lymphoma and carcinoma.

Tulobuterol patch (Hokunalin™ Tape), which contains a β2-adrenergic agonist, is the first bronchodilator to be available as a transdermal patch. This drug delivery system ensures that the time at which the peak drug concentration in the blood is reached coincides with the morning dip in respiratory function. The use of the patch also prevents excessive increase in blood drug concentrations, thereby reducing the incidence of systemic adverse reactions. Since 1998, when it was first approved in Japan and worldwide, the tulobuterol patch has been used widely in the treatment of bronchial asthma and chronic obstructive pulmonary disease (COPD), and evidence collected since it was approved has confirmed its clinical efficacy and safety. Because the patch is easy to use and requires only once-daily application, treatment adherence of patients using the patch is good. In this article, we discuss the rationale behind the development of the tulobuterol patch, evaluate data on its clinical efficacy and safety in the treatment of asthma and COPD, and examine the treatment adherence in individuals using the patch.

Background: Psychological stress has a recognized association with asthma symptoms. Using a murine model of allergic asthma, we recently demonstrated the involvement of μ-opioid receptors (MORs) in the central nervous system in the stress-induced exacerbation of airway inflammation. However, the involvement of MORs on neurons and immunological alterations in the stress asthma model remain unclear. Methods: MOR-knockout (MORKO) mice that express MORs only on noradrenergic and adrenergic neurons (MORKO/Tg mice) were produced and characterized for stress responses. Sensitized mice inhaled antigen and were then subjected to restraint stress. After a second antigen inhalation, bronchoalveolar lavage cells were counted. Before the second inhalation, bronchial lymph node (BLN) cells and splenocytes from stressed and non-stressed mice were cultured with antigen, and cytokine levels and the proportions of T cell subsets were measured. Results: Stress-induced worsening of allergic airway inflammation was observed in wild-type and MORKO/Tg mice but not MORKO mice. In wild-type stressed mice, IFN-γ/IL-4 ratios in cell culture supernatants and the proportion of regulatory T cells in BLN cell populations were significantly lower than those in non-stressed mice. These differences in BLN cells were not observed between the stressed and non-stressed MORKO mice. Restraint stress had no effect on cytokine production or T cell subsets in splenocytes. Conclusions: Restraint stress aggravated allergic airway inflammation in association with alterations in local immunity characterized by greater Th2-associated cytokine production and a reduced development of regulatory T cells, mediated by MORs.

Background: Although investigations of the drug aerosols generated from inhaled corticosteroid (ICS) preparations and combined drug preparations provide basic information about inhalation therapy, many clinicians have one-sided data about the precision of drug aerosols from the manufacturer. The present study was conducted to analyze and compare the performances of dry powder inhaler (DPI) devices of ICS and combined drug preparations. Methods: The particle size of individual aerosols was measured according to the time-of-flight principle in terms of their aerodynamic diameter by using the aerodynamic particle sizer spectrometer Model 3321. Percent aerosolization was measured using only stage #0 and backup filters of the Andersen non-viable sampler model AN-200. Results: The particle size distribution of aerosols generated from a Turbuhaler™ and Twisthaler™ showed a mono-modal distribution of less than 5 ^m. In contrast, Diskus™ showed a polydisperse distribution, ranging from 0.5 to 20 ^m. The percentages of DPI preparations converted into aerosols with a particle size less than 11 ^m at a suction flow rate of 28.3 L/min were 5.7-6.2% for Diskus, 37.5-47.0% for Turbuhaler, and 19.8% for Twisthaler. At a suction flow rate of 60 L/min, the conversion percentages for DPI preparations into aerosols with a particle size less than 7.6 ^m were 5.9-7.5%, 78.2-86.7%, and 43.5%, respectively. Conclusions: Because in vitro differences in the aerosolization among different DPI devices containing ICS and combined drug preparations were observed, prescribers of these preparations should consider whether the patients will benefit more from the treatment of the central airways versus the peripheral airways.

Background: Bronchial asthma (BA) and allergic rhinitis (AR) are thought to share a common pathogenesis. However, reports concerning the comorbidity of the two diseases in a large-scaled population are rare in Japan. In the present study, we performed an analysis on the two diseases using questionnaires that addressed the diagnosis, symptoms and period of occurrence in more than 10,000 patients with BA or AR. Methods: Patients with BA (adult: n = 2,781, childhood: n = 3,283) and AR (n = 3,945) were enrolled in the present study during the 3 months from August 1, 2006 to October 31, 2006. Results: Sixty one percent of the patients with adult BA showed symptoms of AR. Among them, 68% of the patients were diagnosed with AR. Among the patients with childhood BA, 68% showed AR symptoms and 60% were diagnosed with AR. On the other hand, 49% of AR patients showed BA symptoms and 35% of them were diagnosed with BA. The symptoms of both BA and AR in the BA and AR patients were frequent in two seasons, March and April, and September and October. In addition, BA and AR symptoms often co-occurred in the patients with BA and AR. Conclusions: Comorbidity of BA and AR was high in both populations of BA and AR. The symptoms of both BA and AR co-occurred on both a daily and seasonal basis. These results suggested that BA and AR share a common immuno-pathogenesis in the airway and need to be treated as a single airway disease.

Background: Although procaterol is used clinically as a β2-adrenergic receptor agonist to relax airway smooth muscle, it has not yet been clarified whether procaterol has inotropic effects on respiratory muscles. Methods: Three intervention groups were investigated: a procaterol inhalation only group; a procaterol inhalation plus endotoxin injection group (in vivo); and a procaterol incubation group (in vitro). The diaphragm muscle in all groups was dissected and measurements of its contractile properties were performed. Results: The effects of procaterol inhalation shifted the force-frequency curves upward at 30 minutes after inhalation, and inhibited the decline of force-frequency curves due to endotoxin injection in vivo. In vitro administration of procaterol resulted in an increase in the force-frequency curves in a dose-dependent manner. Conclusions: It can be concluded that procaterol has an inotropic effect on the diaphragmatic muscles taken from normal animals as well as on the diaphragm muscles in a septic animal model.

Background: Tulobuterol tape is the first long-acting transdermal preparation of a p2-agonist designed to release tulobuterol in an optimal fashion over a 24-hour period. We investigated the additive effect of tulobuterol tape in adult asthma patients treated with inhaled corticosteroids. Methods: A randomized, double-blind, double-dummy, parallel-group, multicenter trial was conducted. Male and female patients with a diagnosis of asthma requiring inhaled short-acting β2-agonists despite treatment with inhaled corticosteroids took tulobuterol tape (1 mg or 2 mg) and corresponding placebo tapes for 4 weeks. Results: Mean morning peak expiratory flows (PEF) in the 1 and 2 mg/day groups were significantly increased from the baseline value by 23.8 and 35.9 L/min at week 4, respectively. The increase in mean morning PEF in the 2 mg/day group was significantly higher than that in the 1 mg/day group. The mean evening PEF was significantly increased in both treatment groups compared with baseline values. Although the increase in mean evening PEF in the 2 mg/day group was greater than that in the 1 mg/day group, the difference between groups was statistically significant only at week 1. The safety profiles of the two treatments were similar. Conclusions: In patients with persistent asthma who require inhaled short-acting β2-agonists while receiving inhaled corticosteroids, transdermal tulobuterol significantly improved PEF in a dose-dependent manner, i.e., greater effect with 2 mg than with 1 mg per day.

Although the efficacy of cysteinyl leukotriene receptor antagonists in asthma therapy has been established through controlled clinical trials, there are no data concerning the effectiveness of their use in clinical practice, in which there is no rigid selection based on specific inclusion and exclusion criteria. The aim of the present study was to evaluate the effectiveness of pranlukast in clinical practice. More than 2500 outpatients with mild to severe persistent asthma answered an input questionnaire, which consisted of 33 items assessing asthma symptoms in terms of six activities of daily living during the previous 2 weeks. Of these patients, 1138 received treatment with pranlukast and answered the same questionnaire 4–6 weeks after the start of treatment. In 923 of these 1138 patients, we examined the impact of concomitantly used inhaled steroids, β2-adrenergic agonists or sustained-release theophylline on the effectiveness of pranlukast treatment. One hundred and sixty-seven control patients completed the questionnaire twice but did not receive pranlukast treatment. We found a significant decrease in the number of asthma symptoms reported among both the 1138 patients treated with pranlukast and the 167 control patients. However, the magnitude of the decrease in symptoms was significantly (P < 0.001) greater with pranlukast treatment. Moreover, pranlukast was equally efficacious in the presence and absence of concomitantly used inhaled steroids, β2-adrenergic agonists or sustained-release theophylline. In conclusion, pranlukast was shown to have clinical effectiveness in the treatment of mild to severe persistent asthma symptoms.

The intrusion of airborne allergens into airways elicits eosinophilic inflammation, as represented by bronchial asthma. It has been shown that excessive amounts of allergen in murine trachea lead to an unexpected evasion of deleterious eosinophilic inflammation by inducing T cell tolerance. In the present study, the mechanisms of tracheal high-dose tolerance are examined with regard to accessory cell functions and the effects of pro-inflammatory cytokines on tolerance. Antigen-induced tracheal eosinophilia was suppressed on instillation of high doses of antigen into the trachea, while concurrent instillation of granulocyte-macrophage colony stimulating factor (GM-CSF) with the antigen restored the diminished responses. The restoration of eosinophilic infiltration by GM-CSF occurred in parallel with an increase in interleukin (IL)-4 production by CD4+ T cells from the mediastinal lymph nodes. This was found to reflect the empowerment of antigen-presenting cells by GM-CSF, because the impaired ability of Ia+ cells from the tolerant mice to stimulate IL-4-producing T cells is restored by GM-CSF administration. The prevention of tolerance by up-regulating accessory cell functions is a feature unique to GM-CSF, because another pro-inflammatory cytokine, IL-iβ, failed to empower antigen-presenting cells. Thus, besides the induction of transforming growth factor-β-secreting CD4+ T cells, high-dose tolerance in the trachea includes an impairment of the accessory cell functions that support IL-4 production from T cells, which was reversed by GM-CSF. This report is the first demonstration that GM-CSF breaks the T cell tolerance of IL-4-producing T helper cells.

Bronchial asthma (BA) is characterized by infiltration of the respiratory tracts by eosinophils. A wide variety of adhesion molecules is involved in the binding of eosinophils to the vascular endothelium and their subsequent transmigration from the circulation to the airways, while little is known about CD44 expression on eosinophils. In the present study we introduce a novel staining combination with which surface markers on eosinophils can be analyzed without purification prior to staining and examined whether the expression of CD44 on peripheral blood eosinophils could be monitored as a marker of the control of BA. Staining of eosinophils with anti-CD16 and anti-VLA-4 monoclonal antibodies enabled us to delineate eosinophils as VLA-4highCDl6- cells from other leukocyte populations in the whole blood. CD44 was constitutively expressed on resting eosinophils and expression increased following cytokine-mediated activation. In all BA patients examined, CD44high eosinophils were enriched in sputum relative to peripheral blood, indicating that eosinophils in sputum were more activated than those in the blood. By comparing the extent of CD44 expression on blood eosinophils from poorly controlled and well-controlled asthma patients, we unexpectedly found that the density of CD44 expression is lower on blood eosinophils from the poorly controlled group. Thus, the extent of CD44 expression on blood eosinophils defined as VLA- 4highCD16- cells is a novel marker indicative of the management of BA.

The purpose of this study was to evaluate the effect of newly developed selective phosphodiesterase (PDE) inhibitors, KF19514 (type l/IV) and cilostazol (type III), and theophylline on the secretions of tumor necrosis factor a (TNFα) and interleukin-1β (IL-1 β) from human peripheral monocytes stimulated by lipopolysaccha- ride (LPS). Human blood monocytes were incubated with LPS in the absence or presence of KF19514, cilostazol or theophylline. TNFα and IL-1in the cell- free supernatants were measured with enzyme-linked immunosorbent assay. KF19514 showed significant inhibition on the release of TNFα (% inhibition ± SEM was 82.8 ± 7.4% at 1 nmol/L) and IL-1 β (34.4 ± 7.5% at 10 (μmol/L). In addition, KF19514 inhibited the expression of TNFa mRNA. Cilostazol inhibited the release of TNFa significantly (60.2 ± 8.9% at 30 μmol/L) but not IL-1 β. Theophylline inhibited slightly but significantly the release of TNFa at a therapeutic concentration (1 7.4 ± 5.1% at 100 μmol/L). These results suggest that theophylline may not only have a bronchodilating action but also an anti-inflammatory property in the treatment of bronchial asthma, and that KF19514 may have an anti-inflammatory action on at least the transcriptional level.

To study the function and mechanism of eosinophils via the low affinity IgE receptor (FceRII), we examined the production of 02 metabolites by measuring the luminol-dependent chemiluminescence (LDCL) response and the generation of cysteinyl leukotrienes. Eosinophils obtained from guinea pig peritoneal fluid sensitized with horse serum were purified. Luminol-dependent chemiluminescence was induced by stimulation with monoclonal anti-CD23 antibody, but not by mouse serum (controls). The mean (±SEM) value of LDCL was 20.6±1.3X103 c.p.m. This reaction consisted of an initial rapid phase and a propagation phase and ended within lOmin. Guinea pig eosinophils were histochemically stained with monoclonal anti-CD23 antibody. The major product generated in the LDCL response was superoxide, as determined by the measurement of superoxide by cytochrome c reduction and the complete inhibitory effect of superoxide dismutase on the LDCL response. Pretreatment with either pertussis toxin or cholera toxin inhibited the LDCL reaction. Depletion of bivalent ions by EDTA inhibited this response and the protein kinase C inhibitor D-sphingosin inhibited both 1-oleoyl-2-acetyl-glycerol-induced and FcϵRII-mediated LDCL. These findings suggest that the NADPH-protein kinase C pathway may be involved in the FceRII-mediated LDCL response in guinea pig eosinophils.

To confirm the clinical significance of NF-κB and JNK protein expression from experimentally identified candidates for predicting prognosis for patients with 5-FU treatment, we evaluated the protein expression of surgically removed specimens. A total of 79 specimens were obtained from 30 gastric and 49 colorectal cancer patients who underwent R0 resection followed by postoperative 5-FU based adjuvant chemotherapy. Immunohistochemical examinations of NF-κB and JNK on tissue microarrays (TMAs) revealed that significantly shorter time-to-relapse (TTR) in both NF-κB(+) and JNK(-) subgroups in both gastric (NF-κB(+), p = 0.0002, HR11.7. 95%CI3 3.2-43.4; JNK(-), p = 0.0302, HR4.4, 95%CI 1.2-16.6) and colon (NF-κB(+), p = 0.0038, HR36.9, 95%CI 3.2-426.0; JNK(-), p = 0.0098, HR3.2, 95%CI 1.3-7.7) cancers. These protein expression patterns also show strong discriminately power in gastric cancer patients for overall survival rate, suggesting a potential utility as prognostic or chemosensitivity markers. Baseline expression of these proteins using gastric cancer cell lines demonstrated the reciprocal patterns between NF-κB and JNK, while 5-FU exposure of these cell lines only induced NF-κB, suggesting that NF-κB plays a dominant role in the response to 5-FU. Subsequent siRNA experiments confirmed that gene knockdown of NF-κB increased 5-FU-specific sensitivity, whereas that of JNK did not affect the chemosensitivity. These results suggest that the expression of these proteins may aid in the decisions involved with adjuvant chemotherapy for gastrointestinal tract cancers.

Background The purpose of this study was to validate the prognostic effect and the frequency of mutations in the gene expressing epidermal growth factor receptor (EGFR) in lung adenocarcinoma of Japanese patients, on the basis of the new adenocarcinoma classification proposed by the International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society. Methods The new classification was used to reclassify 486 adenocarcinomas. The percentage of each histopathologic subtype and the predominant pattern were determined. EGFR mutation was also investigated. The relationship between these results and clinicopathologic backgrounds was investigated statistically. Results No patients with adenocarcinoma in situ or minimally invasive adenocarcinoma died within the follow-up periods, followed by patients with lepidic predominant. Patients with papillary or acinar predominant, or invasive mucinous adenocarcinoma, showed almost similar overall survival (OS). The patients with solid predominant and micropapillary predominant showed the worst OS. Multivariate analysis showed that the new classification was an independent predictor of OS. The frequency of EGFR mutation was adenocarcinoma in situ (62%), minimally invasive adenocarcinoma (60%), lepidic (77%), acinar (49%), papillary (50%), solid (28%), micropapillary (43%), and invasive mucinous adenocarcinoma (0%). Conclusions This new adenocarcinoma classification is a very useful predictive marker to plan and determine a therapeutic strategy for lung adenocarcinoma. [ABSTRACT FROM AUTHOR]

Methylation of normally unmethylated CpG-rich islands in or near the promoter region has been associated with transcriptional inactivation of tumor-suppressor and tumor-related genes in human cancers. However, so far, only a few studies have searched for DNA methylation in penile carcinoma (PC). On the other hand, human papillomavirus (HPV) has been reported to be associated with the pathogenesis of PC. To elucidate the methylation status of PC and HPV infection, the methylation status of eight genes (DAPK, FHIT, MGMT, p14, p16, RAR-beta, RASSF1A, and RUNX3), the incidences of the HPV status, and the expression of Fhit protein were examined in 25 PCs. The frequencies of methylation were: 28% for DAPK, 92% for FHIT, 20% for MGMT, 4% for p14, 24% for p16, 24% for RAR-beta, 12% for RASSF1A, and 44% for RUNX3. Negative expression of Fhit protein was observed in 22 of the 25 cancers (88%). Among those 22, 20 showed methylation of the FHIT gene. HPV-DNA was detected in three of the 25 cancers (12%). Methylation of FHIT gene was frequently found than HPV infection, therefore methylation of the FHIT gene is suggested to play an important role in the pathogenesis of penile squamous cell carcinoma. [ABSTRACT FROM AUTHOR]

Abstract  Expression of hepatocyte nuclear factor-1beta (HNF-1beta) is significantly up-regulated in ovarian clear cell carcinoma (CCC). The mechanism of up-regulation, however, remains unclear. It has been recognized that hypomethylation of specific gene promoters is involved in aberrant gene expression in carcinogenesis. In the present study, ovarian CCCs were examined whether there was a correlation between the methylation and expression status of HNF-1beta, using combined bisulfite restriction analysis (COBRA), bisulfite-sequencing and immunocyto/histochemistry. In 2 CCC cell lines, hypomethylation of HNF-1beta CpG island strongly correlated with HNF-1beta expression, at both the mRNA and protein levels. In archival surgical specimens, 20 of 20 CCCs were immunohistochemically positive for HNF-1beta, whereas none of 20 serous adenocarcinomas (SAs) or 12 normal ovaries were positive for it. By COBRA, methylation of HNF-1beta CpG island was less frequently detected in CCCs (8 of 20, 40%) than SAs (18 of 20, 90%) or normal ovaries (12 of 12, 100%) (p HNF-1beta hypomethylation correlated with a high HNF-1beta immunostaining score in CCCs. These results strongly suggest that hypomethylation of the HNF-1beta CpG island participates in the HNF-1beta up-regulation in ovarian CCC. [ABSTRACT FROM AUTHOR]

Hepatoid adenocarcinoma of the stomach is a highly malignant neoplasm. Most gastric hepatoid adenocarcinomas coexist with tubular adenocarcinoma. However, the relationship between hepatoid adenocarcinoma and tubular adenocarcinoma is still unclear. In the present study, the characteristics of the coexistent tubular adenocarcinomas were determined by examining their profiles of mucin production. Subsequently, molecular pathological techniques were applied to determine the clonality of 15 mixed hepatoid and tubular adenocarcinomas of the stomach. Mucin analysis suggested that the coexistent tubular adenocarcinomas with hepatoid adenocarcinoma were of the intestinal type. The patterns of chromosome X inactivation were identical between the hepatoid adenocarcinoma component and tubular adenocarcinoma component in all of 3 informative female cases. Mutations in the p53 gene were found in 5 cases. The sequences were identical within both tumor components in all 5 cases. Microsatellite analysis indicated more than 3 common patterns of loss of heterozygosity in 8 cases. These observations strongly suggested that hepatoid adenocarcinomas were of identical origin to coexistent tubular adenocarcinomas. © 2003 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Although cutaneous squamous cell carcinomas (SCC) occur most frequently in sun-exposed areas of the skin, they can also arise in non-sun-exposed areas. Some risk factors for cutaneous SCC, such as ultraviolet (UV) light, are well known. However, the major factor for carcinogenesis may depend on the site of the tumor as well as the ethnicity of the patient. In this study we examined 41 Japanese cutaneous SCC cases, focusing on the area of appearance and the presence of genetic alteration, with 27 cases from sun-exposed areas, 10 from non-sun-exposed areas (excluding genital areas), and four from burn scars from sun-exposed areas. Squamous cell carcinomas arising in sun-exposed areas showed less frequent p53 gene mutations compared to SCC arising in non-sun-exposed areas. Ultraviolet light-specific mutations were found in only two cases of SCC from sun-exposed areas. Human papilloma virus (HPV) DNA was detected in two cases (7.4%) of the sun-exposed areas and none of the non-sun-exposed or scar areas. The frequency of loss of heterozygosity on D5S178 in non-sun-exposed SCC was significantly higher than in sun-exposed SCC. Furthermore, the incidence of fractional allelic loss (FAL) was significantly higher in non-sun-exposed SCC than in sun-exposed SCC. Our findings suggest that sun-exposed SCC in Japan may be relatively less involved with p53 mutation, and that non-sun-exposed SCC acquire more genetic alterations than sun-exposed SCC. [ABSTRACT FROM AUTHOR]

A number of tumor suppressor and tumor-related genes exhibit promoter hypermethylation with resultant gene silencing in human cancers. The frequencies of methylation differ among genes and genomic regions within CpG islands in different tissue types. Hypermethylation initially occurs at the edge of CpG islands and spreads to the transcription start site before ultimately shutting down gene expression. When the degree of methylation was quantitatively evaluated in neoplastic and non-neoplastic gastric epithelia using DNA microarray analysis, high-level methylation around the transcription start site appeared to be a tumor-specific phenomenon, although multiple tumor suppressor genes became increasingly methylated with patient age in non-neoplastic gastric epithelia. Quantitative analysis of DNA methylation is a promising method for both cancer diagnosis and risk assessment.