预测重度溃疡性结肠炎患者需手术治疗的临床指标

目的探讨预测重度溃疡性结肠炎(ulcerative cditis,UC)患者对静脉激素治疗的反应及需手术治疗的临床指征。方法回顾性分析重度UC 62例,根据患者最终是否接受结肠切除手术分为手术组(24例)和非手术组(38例)。收集患者入院第1天和激素治疗第3天的临床资料,利用单因素回归分析法,找出重度UC需手术治疗的危险因素,并比较4种预测指数(Oxford指数、Swedish指数、Edinburgh指数、Seo指数)的准确性。结果 (1)手术组与非手术组激素治疗第3天的大便次数、C-反应蛋白(CRP)、白蛋白、粪便钙卫蛋白水平比较,差异有统计学意义(P0.05);两组间肠外营养、抗生素及中药灌肠3项治疗比较,差异有统计学意义(P0.05)。(2)Oxford指数敏感度65.5%,特异度91.4%;Swedish指数敏感度58.6%,特异度85.7%;Edinburgh指数敏感度41.4%,特异度94.3%;Seo指数敏感度34.5%,特异度94.7%。Oxford指数与Swedish指数预测手术的准确性相当(k=0.874,P=0.000),且明显优于Edinburgh指数和Seo指数(P=0.032,0.028)。结论上述7项预测因子及2项指数均可作为重度UC患者激素治疗无效和转换手术的预测手段。     

CT监视下定向硬通道技术治疗老年高血压脑出血的疗效分析

目的探讨CT监视下定向硬通道技术及开颅手术治疗3～5级老年高血压脑出血（HICH）患者的疗效差别。方法回顾性分析我科治疗的94例老年HICH患者,按手术方式分开颅手术组（50例）及微创手术组（44例）,比较两组患者死亡率及重度残疾率的差别。结果开颅手术组死亡率为44%,微创手术组死亡率为32%,两组无显著统计学差异（P〉0.05）;应用ADL分级法评价患者预后,Ⅳ级及V级植物生存状态为重度残疾,开颅手术组重度残疾率为50%,微创手术组重度残疾率为23%,两者有显著的统计学差异（P〈0.05）。结论 CT监视下定向硬通道技术是简便、有效的方法,可改善3～5级老年高血压脑出血患者的预后。     

非手术与手术治疗肝硬化并脾功能亢进患者肝功能损害的对比观察

目的对比观察非手术与手术治疗肝硬化并脾功能亢进患者肝功能损害的临床疗效和安全性。方法将58例肝硬化并脾功能亢进患者分为非手术组（34例）和手术组（24例）。并对两组患者治疗前后临床表现、肝功能[丙氨酸氨基转移酶（ALT）、天门冬氨酸氨基转移酶（AST）、总胆红素（TBil）、直接胆红素（DBil）]和不良反应进行比较,探讨非手术与手术治疗肝硬化脾功能亢进患者肝功能损害的疗效和安全性。结果两组治疗后1周和2周时,ALT和AST均显著降低（P〈0．01,P〈0．05）;与非手术组比较,手术组治疗后1周和2周时,ALT、AST降低显著优于非手术组（P〈0．01,P〈0．05）。两种治疗方法均能改善患者的临床症状,缓解并发症,且手术治疗较非手术治疗不良反应少。结论手术和非手术治疗均能显著改善肝硬化并脾功能亢进患者肝功能损害,且手术治疗改善肝功能疗效显著,不良反应较少,安全性较好。     

GFAP和COX-2在中重度活动期溃疡性结肠炎活检标本中的表达及其临床意义

背景：研究发现肠神经胶质细胞（EGC）和环氧合酶-2（COX-2）参与了肠道炎症的发生、发展过程。目的：探讨神经胶质细胞特异性标记物胶质纤维酸性蛋白（GFAP）和COX-2在中重度活动期溃疡性结肠炎（UC）病变部位活检标本中的表达及其临床意义。方法：中重度活动期UC、腹泻型肠易激综合征（IBS-D）和正常对照者各30例纳入研究,以免疫组化方法检测活检标本中的GFAP、COX-2表达。结果：UC组GFAP强阳性表达率和免疫组化评分均低于IBS-D组和正常对照组,其中中度UC显著高于重度UC（P〈0.05）;UC组COX-2强阳性表达率和免疫组化评分均高于IBS-D组和正常对照组,其中中度UC显著低于重度UC（P〈0.05）。UC病变累及广泛结肠者COX-2强阳性表达率显著高于病变仅累及部分肠段者（P〈0.05）,GFAP表达与UC病变范围无关。结论：活动期UC GFAP表达强度降低,COX-2表达强度增高,两者均与UC严重程度相关。     

溃疡性结肠炎患者心理特征的研究

目的研究溃疡性结肠炎患者的心理特征。方法对确诊的溃疡性结肠炎患者（65例中,男34例,女31例）进行心理学评分,并与对照组（健康志愿者60例）进行比较;同时比较男性与女性UC患者之间的心理学评分差异,以及比较轻度、中度、重度UC患者之间的心理评分差异。心理学评分采用症状自评量表（SCL-90）、抑郁自评量表（SDS）、焦虑自评量表（SAS）以及状态-特质焦虑问卷（STAI）。结果SCL-90评分显示：UC患者的躯体化、强迫、人际关系、抑郁、焦虑、偏执等因子评分和总症状分均显著高于对照组（P〈0.05）。敌对及精神症状评分与对照组比较无显著性差异（P〉0.05）。抑郁自评分（SDS）、焦虑自评分（SAS）、状态焦虑评分（SAI）和特质焦虑评分（TAI）UC患者均显著高于对照组（P〈0.05）。而女性UC患者上述评分稍高于男性患者,但两者差异没有显著性（P〉0.05）。重度UC患者上述评分显著高于轻度、中度UC患者（P〈0.05）。中度UC患者评分高于轻度患者,但两者差异没有显著性（P〉0.05）。结论UC患者主要心理特征是抑郁和焦虑。重度UC患者心理异常较中、轻度更为明显。男女患者之间心理异常无明显差异。     

溃疡性结肠炎患者血清TNF-α、IL-8的检测及意义

目的探讨TNF-α、IL-8在溃疡性结肠炎（UC）发病中的作用及临床意义。方法采用ELISA法测定38例活动期（病情为轻度12例、中度15例、重度11例）、22例缓解期UC患者（观察组）及20例查体健康者（对照组）血清TNF-α及IL-8水平。结果观察组活动期患者TNF-α和IL-8水平均显著高于缓解期和对照组（P均〈0．05）,缓解期患者显著高于对照组（P〈0．05）。轻、中、重度患者血清TNF-α和IL-8水平逐渐升高（P〈0．05）。结论TNF-α和IL-8参与了UC的炎症过程;血浆TNF-α和IL-8水平可作为判断UC患者病变严重程度和复发的重要指标。     

溃疡性结肠炎患者血小板α颗粒膜蛋白和血小板平均容积检测及临床意义

目的 探讨血小板α颗粒膜蛋白（GMP-140）和血小板平均容积（MPV）在溃疡性结肠炎（UC）发生发展中的作用。方法 检测67例UC患者（观察组）及30例健康人（对照组）血清GMP-140水平和MPV,分析两者与UC病情的相关性。结果 观察组GMP-140水平明显高于对照组（P〈0．05）,活动期患者明显高于缓解期患者（P〈0．05）;观察组MPV明显低于对照组（P〈0．05）,活动期患者明显低于缓解期患者（P〈0．05）;UC病情为重度、中度患者GMP-140水平明显高于轻度者（P〈0．05）、重度者明显高于中度者（P〈0．05）;重度、中度患者MPV明显低于轻度组（P〈0．05）、重度者明显低于中度者（P〈0．05）。结论 GMP-140和MPV可反映UC的病情活动性及严重程度。     

黄芩汤颗粒剂联合美沙拉秦对溃疡性结肠炎的临床疗效研究

[目的]观察黄芩汤颗粒剂对溃疡性结肠炎（UC）患者IL-10、IL-6和TNF-α表达的影响以及临床疗效。[方法]收集河北省遵化市人民医院2011年1月-2015年3月消化科诊治的UC患者68例,随机分为常规治疗对照组和黄芩汤颗粒剂治疗观察组。IL-10、IL-6、TNF-α表达的检测使用ELISA法。[结果]IL-10、IL-6、TNF-α表达水平治疗前在观察组和对照组差异无统计学意义（P〉0.05）,治疗后2组均出现IL-10显著升高（P0.05）,治疗后上述损伤检出率2组均出现显著减低（P〈0.05和P〈0.01）,但观察组的检出率显著低于对照组（P〈0.05）。观察组治疗有效率为91.2%显著优于对照组的76.5%（P〈0.05）。[结论]黄芩汤颗粒剂可以显著升高UC患者IL-10表达,抑制炎症反应,临床疗效显著,值得临床借鉴采用。     

IGF-1和MMP-9检测在溃疡性结肠炎的临床应用价值研究

[目的]检测溃疡性结肠炎（UC）患者胰岛素样生长因子-1（IGF-1）和基质金属蛋白酶-9（MMP-9）表达变化,并探讨其相关的临床意义。[方法]收集2013年2月-2015年8月我院消化内科诊治的溃疡性结肠炎患者54例,另取同期我院健康体检者40例作为正常对照。ELISA法检测IGF-1和MMP-9表达。[结果]对照组IGF-1表达为（113.64±32.52）ng/ml,显著高于UC组的（68.57±21.38）ng/ml（P〈0.05）。对照组MMP-9表达为（16.15±3.23）ng/ml,显著低于UC组的（24.36±5.74）ng/ml（P〈0.05）。缓解期患者IGF-1表达为（90.52±28.18）ng/ml,显著高于活动期患者的（45.32±17.52）ng/ml（P〈0.05）。缓解期患者MMP-9表达为（18.09±3.07）ng/ml,显著低于活动期患者的（33.42±4.72）ng/ml（P〈0.05）。内镜活动性分级Ⅰ、Ⅱ、Ⅲ级溃疡性结肠炎患者之间IGF-1和MMP-9表达存在显著性差异（P〈0.05）。其中IGF-1表达Ⅰ级患者高于Ⅱ级患者（P〈0.05）,Ⅱ级患者又高于Ⅲ级患者（P〈0.05）;其中MMP-9表达Ⅰ级患者低于Ⅱ级患者（P〈0.05）,Ⅱ级患者又低于Ⅲ级患者（P〈0.05）。[结论]IGF-1和MMP-9异常表达可能在溃疡性结肠炎发病机制中发挥着重要作用,检测二者有可能作为评价溃疡性结肠炎患者病情活动性及严重程度的指标。     

溃疡性结肠炎患者血清IL-6、IL-8、TNF-α水平变化及意义

目的观察溃疡性结肠炎（UC）患者血清IL-6、IL-8、TNF-α水平变化,并探讨其意义。方法 UC患者60例（UC组）,对照组30例。采用ELISA法检测两组血清IL-6、IL-8、TNF-α。结果 UC组血清IL-6、IL-8、TNF-α水平明显高于对照组（P均〈0.05）;重度UC患者血清IL-6、IL-8、TNF-α水平高于轻中度、中度高于轻度（P均〈0.05）。结论 UC患者血清IL-6、IL-8、TNF-α水平升高,检测血清IL-6、IL-8、TNF-α有助于UC病情的判断。     

炎症性肠病858例临床分析

目的总结分析炎症性肠病（IBD）的临床特点,探讨诊治策略。方法对1998年1月至2009年7月354例炎症性肠病住院患者和2003年1月至2009年7月504例炎症性肠病门诊患者资料进行回顾性分析。结果本组资料显示我院近12年来IBD发病呈逐年上升趋势,溃疡性结肠炎（UC）明显多于克罗恩病（CD）。本组IBD患者中男女之比为1.28∶1。IBD平均发病年龄（41.07±16.07）岁。UC发病高峰年龄为30～49岁,CD发病高峰年龄为20～39岁。本组住院患者中UC和CD两组民族构成比较无统计学差异。肠镜检查中UC以直肠和乙状结肠病变为主,CD以回盲部及回肠末端病变为主。本组患者IBD病理组织学检出率为41.5%,UC误诊率为17.0%,CD误诊率为25.0%。治疗以氨基水杨酸类及类固醇激素为主。结论炎症性肠发病数呈逐年上升趋势;IBD诊断主要依靠内镜及病理。IBD呈慢性复发性发作过程,应长期维持治疗。     

Treatment cost of ulcerative colitis: Is apheresis with Adacolumn® cost-effective?

BACKGROUND: Scarce data are available in Europe on the cost of treatment for ulcerative colitis (UC). AIM: To assess the cost of illness of moderate-to-severe UC in two scenarios: traditional treatment versus alternative treatment incorporating granulocyte, monocyte adsorption - apheresis (GMA-Apheresis; Adacolumn). To determine the relative cost-effectiveness of both options in steroid-dependent patients. METHODS: One-year cost-of-illness and cost-effectiveness analysis from the third-payer perspective using a decision tree model was carried out. Probabilities of each event were derived from the literature and an expert panel. Direct medical costs were obtained from official sources (euro2004). Effectiveness was measured by the proportion of patients achieving clinical remission. RESULTS: The average annual cost per patient treated with traditional treatment was estimated to be euro6740; with GMA-Apheresis, the cost was estimated to be euro6959. In steroid-dependent patients, the average annual cost was euro6059 and euro11,436, respectively. The proportion of patients achieving clinical remission with GMA-Apheresis was 22.5% higher. As second- and third-line therapy, a new course of corticosteroids and surgery was avoided in 18.5 and 4% of patients, respectively. CONCLUSIONS: Incorporating GMA-Apheresis (Adacolumn) in the therapeutic management of moderate-to-severe UC patients is cost-effective and implies savings related to the reduction of adverse effects derived from corticosteroid use and to the decreased number of surgical interventions.     

Cytomegalovirus infection in severe ulcerative colitis patients undergoing continuous intravenous cyclosporine treatment in Japan

AIM： TO investigate active cytomegalovirus （CMV） infection following the cydosporine A （CyA） treatment of steroid-refractory ulcerative colitis （UC）. METHODS： Twenty-three patients with severe UC not responding to steroid therapy （male 14, and female 9） enrolled at Nagoya University Hospital from 1999 to 2005. They received continuous intravenous infusion of CyA （average 4 mg/kg per day） for 1 mo. Serum and colonic biopsy samples were collected before CyA treatment and 4 d, 10 d, 20 d, and 30 d after treatment. Patients were evaluated for CMV by using serology （IgM antibody by ELISA）, quantitative real-time PCR for CMV DNA, and histopathological assessment of hematoxylin and eosin （HE）-stained colonic biopsies. CMV infection was indicated by positive results in any test. RESULTS： No patients had active CMV infection before CyA treatment. Eighteen of 23 UC patients treated with CyA were infected with active CMV （IgM antibody in 16/23 patients, 69.6%; CMV DNA in 18/23 patients, 78.2%; and inclusion bodies in 4/23 patients, 17.3%）. There was no difference in the active CMV-infection rate between males and females. Active CMV infection was observed after approximately 8 d of CyA treatment, leading to an exacerbation of colitis. Fifteen of these 18 patients with active CMV infection （83.3%） required surgical treatment because of severe deteriorating colitis. Treatment with ganciclovir rendered surgery avoidable in three patients. CONCLUSION： Our results suggest that active CMV infection in severe UC patients treated with CyA is associated with poor outcome. Further, ganciclovir is useful for treatment of CMV-associated UC after immunosuppressive therapy.     

Antineutrophil cytoplasmic antibodies in sera from colectomised ulcerative colitis patients and its relation to the presence of pouchitis.

BACKGROUND: Few studies have evaluated the influence of colectomy on antineutrophil cytoplasmic antibody (ANCA) positivity in ulcerative colitis (UC). In small series of patients it has been suggested that ANCA positivity in UC might be predictive for development of pouchitis after colectomy. AIMS: To assess the prevalence of ANCA in UC patients treated by colectomy and a Brooke's ileostomy (UC-BI) or ileal pouch anal anastomosis (UC-IPAA), and the relation between the presence of ANCA, the type of surgery, and the presence of pouchitis. SUBJECTS: 63 UC patients treated by colectomy (32 with UC-BI and 31 with UC-IPAA), 54 UC, and 24 controls. METHODS: Samples were obtained at least two years after colectomy. ANCA were detected by indirect immunofluorescent assay. RESULTS: There were no differences between patients with (36.3%) or without pouchitis (35.0%) and between patients with UC (55%), UC-BI (40.6%), and UC-IPAA (35.4%). However, ANCA prevalence significantly decreases in the whole group of operated patients (38.0%) compared with non-operated UC (p = 0.044). CONCLUSIONS: The prevalence of ANCA in operated patients was significantly lower than in non-operated UC, suggesting that it might be related either to the presence of inflamed or diseased tissue. ANCA persistence is not related to the surgical procedure and it should not be used as a marker for predicting the development of pouchitis.     

A patient who survived total colonic type ulcerative colitis complicated by toxic megacolon, disseminated intravascular coagulation, methicillin-resistant Staphylococcus aureus infection and bilateral femoral phlebothrombosis

We report a patient who survived total colonic type ulcerative colitis (UC) complicated by toxic megacolon (TM), disseminated intravascular coagulation (DIC), methicillin- resistant Staphylococcus aureus infection, and phlebothrombosis. A 69-year-old man was treated for about 4 months under the diagnosis of ischemic colitis at another hospital, and was transferred to our hospital. Based on endoscopic and pathological findings, we strongly suspected UC, and administered salazosulfapyridine and methylprednisolone, but TM and DIC developed, necessitating urgent subtotal colectomy. Despite his elderly age and the severe complications, he recovered and was discharged from our hospital about 4 months after admission. The mortality rate of UC complicated by TM and DIC in elderly patients is high, necessitating rapid initiation of high-dose steroid administration or surgical treatment. Received: May 6, 1998/Accepted: October 23, 1998     

Ethnic variations in ulcerative colitis: Experience of an international hospital in Thailand

AIM: To investigate the clinical characteristics, treatment, medication use, and treatment response in patients with ulcerative colitis(UC) across ethnic groups.METHODS: This study retrospectively analyzed medical records of all 268465 patients who visited the Bumrungrad International Digestive Disease Center during 2005-2010. The demographics, clinical characteristics, medication use, results of investigations, and medical and surgical management for patients with UC were evaluated. Evaluation included sigmoidoscopy and colonoscopy performed in compliance with the American Society of Gastrointestinal Endoscopy practice guidelines. Patient ethnicities were categorized into seven groups: Thai, Oriental, South Asian(SA), Middle Eastern(ME), Caucasian, African, and Hispanic. UC pathological severity was classified into inactive, mild, moderate, and severe. Associations between categorical variables were analyzed using the χ2 or Fischer's exact test. Associations between categorical and interval variables were analyzed usingStudent's t-test and/or analysis of covariance.RESULTS: UC was diagnosed in 371 of the 268465 patients: male 56.33%; ME 42%, Caucasian 23%, and Thai 19%. Annual incidence of UC was 82 cases per 100000 with wide ethnic variation, ranging from 29 to 206 cases per 100000 in Oriental and ME patients, respectively. Of the patients with UC, 16.71% had severe UC with highest incidence among the patients from ME(20.39%) and lowest among the Caucasian population(11.90%). ME had highest proportion of pancolitis(52.90%), followed by Caucasian(45.35%) and Asian(34.40%). Only 20.93% of Caucasian patients received steroid, compared with 26.40% and 27.10% of Asian and Middle Eastern, respectively(P = 0.732). Overall, 13.72% of UC patients did not respond to steroid therapy, with non-significantly higher proportions of non-responders among Asian and Middle Eastern patients(15.22% and 15.04%, respectively)(P = 0.781). On average, 5.93% underwent surgical management with ethnic variation, ranging from 0% in African to 18% in SA. Cancer was found in three(Thai, ME, and African) cases(0.82 institution-specific incidence).CONCLUSION: Incidence, symptom duration, pathological severity, clinical manifestations, medication use, treatment response, need for surgical consultation, and cancer incidence of patients with UC potentially vary by ethnicity.     

The production of interferon-γ-inducible protein 10 by granulocytes and monocytes is associated with ulcerative colitis disease activity

Background To clarify which types of cells produce interferon-γ-inducible protein 10 (IP-10) and whether IP-10 is associated with the development of ulcerative colitis (UC), we investigated IP-10 production in UC patients. Methods Serum IP-10 levels were measured using enzyme-linked immunosorbent assay in 29 patients with active and 21 with inactive UC and in 20 controls. The production of IP-10 by granulocytes and monocytes adsorbed to G-1 beads was examined. In 21 active UC patients treated with granulocyte and monocyte/macrophage adsorptive apheresis (GMA), serum IP-10 levels were measured before and after treatment. IP-10-positive cells in UC mucosa were also examined immunohistochemically using tissues obtained by surgical resection and colonoscopic biopsies. Results Serum IP-10 levels in active UC patients were significantly higher than those in inactive patients, although even in the latter the levels were increased compared with those in controls. IP-10 production by granulocytes and monocytes in active UC patients was significantly higher than that in controls. Furthermore, the number of IP-10-positive cells was elevated in the colonic mucosa of patients with active UC, and one of the main subpopulations of IP-10-positive cells was granulocytes. Serum IP-10 levels decreased following GMA treatment in responders, but not in nonresponders. Interestingly, serum IP-10 levels before GMA were higher in responders than in nonresponders. In parallel with the serum levels, IP-10-positive cells also decreased following GMA treatment. Conclusions Serum IP-10 levels reflected UC disease activity, and the source of IP-10 was granulocytes and monocytes. Furthermore, serum IP-10 levels may be a marker for the responsiveness of patients to GMA treatment.     

提高外科手术在溃疡性结肠炎治疗中的作用

溃疡性结肠炎(ulcerative colitis)是一种慢性、难治性疾病,我国溃疡性结肠炎的发病率近年呈上升趋势。约有20%～30%的溃疡性结肠炎患者需要接受外科手术治疗。适时、正确的手术治疗可以治愈溃疡性结肠炎,显著降低并发症与不良预后的发生率。然而我国对于溃疡性结肠炎的诊疗认知还存在一定的盲区,目前尚无规范性的炎症性肠病治疗体系和外科诊治指南,尚未在全国范围内开展溃疡性结肠炎的根治性手术—全结直肠切除回肠储袋肛管吻合术(IPAA术),国内炎症性肠病的手术比例不足5%。溃疡性结肠炎外科规范性治疗及外科技术发展水平远低于发达国家水平。因此,迫切需要提高各专业、各级医师对于溃疡性结肠炎诊治方案的知晓,制定IPAA手术技术规范,开展手术技术培训,弥补我国炎症性肠病诊治水平与发达国家的差距。     

重视溃疡性结肠炎的规范化外科治疗

我国溃疡性结肠炎(ulcerative colitis,UC)的发病率近20年来呈现快速上升趋势,但由于既往的低发病率以及结直肠外科亚专业化在我国的发展不足,国内对溃疡性结直肠炎的诊断治疗在相当程度上还存在一定盲区。与国外新的治疗理念相比,我国还存在诸多问题,如对内科治疗的过度依赖,对外科手术指征的过严把控,手术方式的选择上存在明显差异、对癌变的监控及早期处理严重不足等。因此迫切需要提高相关科室人员对UC诊断治疗标准的知晓,强化区域炎症性肠病(inflamatory bowel diseases,IBD)诊治中心的建设,大力推动UC诊治指南的宣传与应用,是提高我国UC治疗水平的关键。     

Treatment patterns for biologics in ulcerative colitis and Crohn’s disease: a Danish Nationwide Register Study from 2003 to 2015

Abstract

Background: The choice of treatment for Crohn’s disease (CD) and ulcerative colitis (UC) depends among other factors, disease severity. Patients with moderate-to-severe disease should be prescribed biologic response modifiers (biologics), according to guidelines. This study aims to explore the treatment patterns of patients diagnosed with CD and UC between 2003 and 2015 that were treated with biologics in Denmark between the years 2003 and 2016.

Methods: This national register study included patients diagnosed between 2003 and 2015, identified in the Danish National Patient Registry. Biologic therapies available during the study period were infliximab, adalimumab, vedolizumab and golimumab. The share of patients initiating and receiving biologic treatment in each year was estimated. Additionally, the time from IBD diagnosis to first biologic treatment and time between treatments was calculated.

Results: Among 10,302?CD patients and 22,144 UC patients, 28.5% of CD patients and 11.3% of UC patients received treatment with biologics during the study period, with an increasing trend in the number of patients initiating treatment with biologics each year. About 46% of CD patients and 45% of UC patients received their first biologic treatment within the first year after IBD diagnosis. About 57–68% of CD and UC patients received treatment with their second line biologic within 2 months of the last treatment of their first line.

Conclusions: The number of patients initiating biologic treatments after diagnosis increased throughout the study period. Most patients diagnosed with CD and UC are receiving biologic treatments relatively soon after their diagnosis.