Factors for the onset of and the exacerbation of tuberculosis. 6. Recent socio-medical characteristics of tuberculosis and their perspectives in Japan

In the late 1970s the decline of TB incidence rate has begun to slow down among both elderly population and younger one. This phenomenon mostly owed the reactivation of dormant M. tuberculosis infection among the elderly people and small TB outbreaks in the younger generation. The micro-epidemics among adolescent and young adults have been reported since 1980. The latest data showed the TB incidence in 1997 was 33.9 per 100,000 population, increased from 33.7 per 100,000 in 1996. To explain the situation above, several sociomedical factors were discussed as follow: (1) Age distribution of TB: The highest peak of newly registered TB patients shifted to the elder age cohorts and was the age group between 65 and 74 years in 1997, contrasting small peaks observed in 20-29 years age group remained unchanged. (2) Characteristics of infection route: Overall incidence rates of smear positive TB cases slightly increased in 1980s and leveled off thereafter. However, the number of smear positive cases among persons elder than 70 years old sharply increased, 1,779, 3,744, 5,728, in 1977, 1987 and 1997, respectively. Several papers showed that about one quarter of TB patients was diagnosed as TB while being treated for diseases other than TB. This may have contributed to the current TB infection. (3) Delay in case-finding: Patient's delay in symptomatic smear positive cases, especially among male patients in 30-54 age group, has been increased during last 10 years. This may also contribute to the current TB issue to the younger people. (4) TB problems in the cities: TB incidence rate in a certain area of some big cities was much higher than the other areas and the regional difference became magnificent due to serial socioeconomic problems of vulnerable population there. (5) Notification of TB: One study using mailed questionnaires showed that only 76 percent of medical doctors knew the TB notification system under the TB control law. It concluded that contact tracing would become more important issue in case-finding and the 100 percent of TB notification in medical institutions would be indispensable.     

现代结核病控制模式的实施效果分析

目的　探索和建立一种适合湖南省乃至全国国情的现代结核病控制模式,实现结核病的高发现率和高治愈率。方法 结合实际,根据结核病控制的组织机构、筹资机制、病人发现、治疗管理、药品供应、健康促进、业务培训、激励政策、督导管理、科学研究、国际合作和监控评价等工作,制定出相应的实施方法和管理办法与措施。结果 (1)实现了肺结核病人的高发现率。新涂阳病人登记率从1992年的1.71/10万逐年上升到2005年的47.97/10万;病人发现率从1992年的2.9%逐年上升到2005年的81.4%。(2)获得了结核病人的高治疗率。1992—2005年,全省涂阳病人治愈率为90.5%;治疗成功率为93.8%。(3)取得了显著的社会效益。1992—2005年,全省已治愈涂阳肺结核病人273104例,减少了136550人因结核病死亡,使5462000～8193000健康人免遭结核病的感染。全省总投入直接成本为1.64亿元;产生的直接效益为1.91亿元。家庭的成本直接5.22亿元,产生的家庭直接效益为12.30亿元。(4)结核病疫情获得了有效的控制:①肺结核病涂阳患病率由1990年的179/10万下降至2000年的107/10万,下降了40.4%。②复治涂阳病人比例逐年降低,从1992年的64.9%降到2005年的8.2%。③患病年龄向老年推移。2005年0～14岁组人群的患病人数的构成比与1993年相比下降了80.0%;平均患病年龄由1993年的41.9岁,推移至2005年的44.3岁。结论 湖南省逐步建立和完善了政府承诺、机构建设、病人发现、治疗管理、药品供应、健康促进、业务培训、激励政策、督导管理、科学研究、国际合作和监控评价共12个要素组成的现代结核病控制模式,是实现结核病人高发现率与高治愈率,有效控制结核病流行的有效方法与措施。     

Incidence of tuberculosis in Korean patients with rheumatoid arthritis (RA): effects of RA itself and of tumor necrosis factor blockers

OBJECTIVE: To elucidate the incidence rate and relative risk of tuberculosis (TB) in patients with rheumatoid arthritis (RA) and in patients with RA treated with tumor-necrosis-factor (TNF) blockers in Korea. METHODS: Using data from the Korean National Tuberculosis Association (KNTA) as a control and data from a single-center cohort of patients with RA, we conducted an evaluation of 1285 patients with RA not exposed to TNF blockers and reviewed medical records of 90 and 103 patients with RA treated with infliximab and etanercept, respectively, between 2001 and 2005. RESULTS: The mean incidence rate of TB, reported by the KNTA, was 67.2 per 100,000 person years (PY) from 2001 to 2004. In the TNF-blocker-na?ve RA cohort, 9 cases of TB developed during 3497 PY of followup (257 per 100,000). In the infliximab-treated RA group, 2 cases of TB developed during 78.17 PY of followup (2558 per 100,000 PY), and there was no case of TB during 73.67 PY of followup in the etanercept-treated RA group. The risk of TB was higher in RA patients not treated with TNF blockers (sex- and age-adjusted risk ratio 8.9; 95% confidence interval 4.6-17.2), and in those treated with infliximab (sex- and age-adjusted risk ratio, 30.1; 95% confidence interval, 7.4-122.3) compared with the general Korean population. CONCLUSION: The risk of TB infection is 8.9-fold higher in Korean patients with RA and 30.1-fold higher in RA patients treated with infliximab, compared with the general Korean population.     

烟台市行政干预措施对提高肺结核发现率的效果分析

目的　总结实施综合干预措施对提高肺结核患者发现率的影响。方法 强化行政与技术措施干预,广泛深入地宣教,落实归口管理,结合主动发现及考核、评价、奖惩等综合干预措施,并对干预前后进行调查、统计、对比。结果 综合医疗机构的肺结核及疑似肺结核病人转诊率由干预前1993年的53.2%上升至干预后2001年的98.6%;活动性肺结核患者发现(新登记)率由干预前1993年的1755/10万上升至干预后2001年的3038/10万;涂阳肺结核患者发现(新登记)率由干预前1993年的607/10万上升至干预后2001年的1794/10万(χ²=57.73,P<0.001),有非常显著性差异。采取干预措施后的8年(1994-2001年)新登记的涂阳病人,比干预前的8年(1986-1993年)增加了12.78%(7097/3186)。结论 烟台市对肺结核患者发现实施综合干预措施,并规范疫情登记、转诊、报告工作,有效提高了肺结核患者发现(新登记)率。     

DOTS in Osaka City]

The tuberculosis (TB) incidence rate and the smear positive TB incident rate in Osaka City were 107.7 and 34.7 per 100,000 respectively in 1999, which were approximately 3 times higher than the national average. The TB mortality rate in Osaka City was 6.9 per 100,000 in 1999, which was highest in Japan. The TB incidence in the "AIRIN" area, where about 20% TB patients are homeless, shows highest rate of above 1,000/100,000. The treatment defaulter rate in Osaka City is about 10% against the average rate of 4% in Japan. A new strategic plan to intensify TB control is now being prepared by Osaka City government. A goal has been set up to make the TB incidence half in ten years. The plans consists of 4 points of "DOTS", "early detection of patient", "education and campaign", and "cohort analysis of treatment outcome". "DOTS" is being expanded in Osaka City. DOT is applied not only to the special group of homeless patients but also to the patients in the hospitals and in the community. Further systematic development of "DOTS" is necessary to achieve the goal.     

高州市实施结核病控制项目十年效果评价

目的　高州市实施结核病控制项目的评价。方法　因症就诊胸透筛选痰检确诊病人 ,按统一化疗方案治疗 ,实行全程督导管理。结果　 10年间共接诊可疑肺结核症状者 2 0 12 4人 ,可疑者检痰率为 37.77% ,发现活动性肺结核 5 10 8例 ,其中涂阳肺结核、新发涂阳肺结核分别为 3971和 3317例。涂阳登记率由 13/ 10万提高到 33/10万 ;初治涂阳治愈率达 97.71%、复治涂阳治愈率达 84 .10 %。结论　 10年来结核病控制水平全面提高 ,是实施DOTS现代结核病控制策略的结果。     

2008 - 2012 年四川省盐边县肺结核流行病学分析

目的掌握四川省盐边县2008—2012年肺结核流行情况,为今后防治肺结核流行提供科学依据。方法采用描述流行病学方法对盐边县的肺结核病发病率、地区分布、人群分布、职业分布、时间分布等内容进行统计分析。结果2008—2012年盐边县发现活动性肺结核病例558例,其中痰检结核菌阳性（涂阳）肺结核病例249例,痰检结核菌阴性（涂阴）肺结核病例309例;年平均发病率53．77／10万,以2008年发病率最高64．53／10万,其次2009年55．29／10万,以后呈逐年平稳下降趋势;25-45岁发病293例,占总发病数的52．5％。男女性别比为1．26：1。全县16个乡镇均有发病,病例主分布在格萨拉乡、渔门镇和永兴镇,分别占总病人数的31．2％、21．7％和18．6％等。结论2008—2012年盐边县肺结核发病呈逐年下降趋势,以青壮年男性为主。     

武汉市青山区2005-2012年肺结核控制情况分析

目的 了解武汉市青山区2005-2012年结核病控制工作情况,为全区2011-2015年结核病防治规划的实施提供依据。 方法 统计分析武汉市青山区8年的结核病资料、手工季度和年度报表及《中国结核病控制信息系统》数据资料,率的比较采用χ²检验。 结果 2005-2012年青山区登记活动性肺结核患者2848例,其中男2100例,女748例。男性活动性肺结核、新涂阳肺结核、复治涂阳肺结核和涂阴肺结核患者分别为女性患者的2.8倍（2100/748）、3.3倍（949/289）、5.3倍（159/30）和2.3倍（992/429）。初治涂阳和复治涂阳患者均以65～岁组老人为主,共计263例和52例,初治涂阳前三位从高到低依次为65～岁（263例）、45～岁（239例）、55～岁（159例）;而涂阴则由高到低前三位依次为25～岁（268例）、15～岁（259例）、35～岁（242例）;活动性肺结核职业分布上,离退休人员最多（711例),工人和家政家务及待业人员居第二位(647例)和第三位(489例)。年平均登记率分别为：活动性肺结核78.6/10万,初治涂阳34.2/10万,复治涂阳5.2/10万,涂阴39.2/10万;962例涂阳患者治愈,2008年及以后治愈率达90%及以上。因症就诊患者1073例,结核病防治机构因症就诊的活动性肺结核和涂阳肺结核患者由2005年的41.0%(133/324)和52.6%(70/133）下降到2012年的11.9%（40/336）和47.5%（19/40）;非结核病专科医院查出1477例活动性肺结核和722例涂阳肺结核患者。 结论 武汉市青山区登记活动性肺结核患者男性多于女性,老年离退休患者居多,肺结核患者登记率不高,结核病防治机构因症就诊率下降。     

滨州市2001～2010年肺结核发病情况及DOTS策略实施的效果

目的了解滨州市《规划》实施情况,评价DOTS策略的执行效果。方法通过对2001年～2010年登记管理的病人,以病人登记本、月报、季报和年报为来源,进行患病登记率、流行特征、DOTS策略执行情况进行分析。结果 2001年～2010年登记患病率为35.65/10万,新涂阳登记率24.39/10万;治愈率为92.07%;避免63 164人感染结核菌,避免5 667人发病。结论滨州市积极推行现代结核病控制策略,结核病人的发现率和治愈率显著提高。     

南海市实施结核病控制项目效果分析

目的　评价南海市实施世界银行贷款结核病控制项目的成效。方法 因症就诊胸透筛选、痰检确诊病人,按统一化疗方案治疗,实行全程督导管理。结果 10年间共接诊可疑肺结核症状者19569人,可疑者检查率平均为0.2%,发现活动性肺结核4286例,其中涂阳2558例,涂阳病人占活动性病人59.7%,涂阳登记率从14.07/10万提高到35.66/10万;初复治涂阳比例1:0.14,初治涂阳治愈率94.3%;复治涂阳治愈率82.2%。结论 10年来结核病控制水平整体提高,是实施DOTS现代结核病控制策略的结果。     

Rising incidence of low-trauma fractures of the calcaneus and foot among Finnish older adults

BACKGROUND: Although various low-trauma fractures among older adults are said to be a major public health concern in contemporary societies with aging populations, reliable epidemiologic information on their secular trends is scarce. METHODS: We assessed the current trend in the number and incidence (per 100,000 persons) of low-trauma fractures of the calcaneus and foot of older adults in Finland, a European Union country with a well-defined white population of 5.2 million, by taking into account all persons 50 years old or older who were admitted to Finnish hospitals for primary treatment of such injury in 1970-2005. RESULTS: The number and raw incidence of low-trauma fractures of the calcaneus and foot among Finns 50 years old or older rose considerably between the years 1970 and 2005, from 64 (number) and 5.6 (incidence) in 1970 to 294 and 15.2 in 2005. For the study period, the age-adjusted incidence of fracture was higher in men than women and showed a clear increase in both sexes in 1970-2005, from 7.3 to 17.4 in men (138% increase), and from 4.3 to 12.5 in women (191% increase). A similar finding was observed in the age-specific incidences. Assuming that the observed increase in the age-specific fracture incidence continues in the 50-year-old or older group and the size of this population increases as predicted, the annual number of low-trauma fractures of the calcaneus and foot in this population will be two times higher in the year 2030 (approximately 550 fractures annually) than it was during 2001-2005. CONCLUSIONS: In Finnish persons aged 50 years or older, the number of low-trauma fractures of the calcaneus and foot has risen considerably in 1970-2005 with a rate that cannot be explained merely by demographic changes. Further studies are needed to explore the exact reasons for the rise and possibilities for fracture prevention.     

Analysis of factors related to the high incidence of tuberculosis in the city of Wakayama--analysis according to age groups, and sputum test results

Over the last 20 years, the decrease in the incidence of Tuberculosis (TB) in Japan has slowed down. As of 1999, the incidence rate was 34.6 per 100,000 population in Japan, which was higher than that of the other developed countries, and the incidence rate in the city of Wakayama, one of the prefectural capital cities in Japan, during the same period was 42.9 per 100,000 population. We investigated the causes of this high incidence rate of TB in Wakayama City according to the analysis by age groups and sputum test results when patients are newly registered. Comparing our data during the period from 1.1.1998 to 12.31.1999 with data during the same period in the whole country and the rest of Wakayama Pref., the following results were obtained. Observing by age-groups, the incidence of TB in Wakayama City as well as in the rest of Wakayama Pref. and in the whole country was highest in the age-group above 70 years of age, though the rate of Wakayama City was significantly higher (146.2 per 100,000 population) than that in the rest of Wakayama Pref. (98.5 per 100,000 population) and that in the whole country (90.3 per 100,000 population). Furthermore, the incidence rate of cases diagnosed as TB without bacteriological proof in Wakayama City (57.1 per 100,000 population) was significantly higher than that of the whole country (33.7 per 100,000 population). Therefore, we concluded that one of the causes of high incidence of TB in Wakayama City was due to inappropriate method of diagnosing TB. More extensive use of sputum examination and strict evaluation of cases without bacteriological proof are desirable to increase the accuracy of TB diagnosis in Wakayama City.     

2008—2012年日本结核病流行病学分析

目的 分析日本结核病发病变化情况,为我国结核病防治提供参考. 方法 从日本厚生劳动省官网获取2008—2012 年日本结核病疫情资料,采用描述性流行病学方法对数据进行分析. 结果 2008—2012 年日本新登记结核病患者合计 116 155 例,年均罹患率为 18.2/10 万 ;年龄越大发病人数越多,但外国人主要集中在 20~49 岁.其中痰涂片阳性患者合计 45 394 例,年均罹患率为 7.1/10 万.因结核病死亡 10 784 例,年均病死率为 1.7/10 万;其中,因肺结核病死亡 9573 例,年均病死率为 1.5/10 万.结核集体感染事件发生 222 起,涉及 298 个场所.每年新登记潜伏性结核感染者与结核病患者例数比为 0.2:1~0.4:1.结论 日本在结核病防治过程中取得了显著成果,但人口老龄化、境外输入病例增加以及结核集体感染事件多发等问题的出现影响了结核病发病和死亡,防治过程中遇到的新问题须引起我们的重视.     

Increased risk of tuberculosis in patients with rheumatoid arthritis

OBJECTIVE: To quantify the risk of tuberculosis (TB) in an unselected sample of patients with rheumatoid arthritis (RA) compared to the risk in the general population. METHODS: The incidence of TB in the general population of Spain was obtained from the National Network of Epidemiological Surveillance reports. The incidence of TB was ascertained from a cohort of 788 patients with RA selected randomly from the registries of 34 participating centers throughout Spain. A patient was considered a TB case only if information about disease symptoms, microorganism identification, and TB treatment were confirmed in the clinical records. The relative risk of TB in RA was calculated by dividing the standardized mean incidence of TB from 1990 to 2000 in the RA cohort by the mean incidence of TB in Spain during the same years. RESULTS: The mean incidence of TB in the general population of Spain from 1990 to 2000 was 23 cases per 100,000. Seven cases of TB were identified in the RA cohort, yielding a mean annual incidence (1990-2000) of 134/100,000 patients. The incidence risk ratio of pulmonary TB in patients with RA compared to the general population is 3.68 (95% CI 2.36-5.92). CONCLUSION: We found a 4-fold increased risk of TB infection in patients diagnosed with RA. These results might help to interpret the magnitude of the problem attributable to the introduction of new therapies in RA.     

广州市城区肺结核合并糖尿病流行病学特征分析

目的了解广州市城区肺结核合并糖尿病(TB-DM)流行病学情况,为制定相关的防治策略提供依据。方法统计分析广州市结核病防治所登记中心2004—2008年广州市越秀、荔湾、海珠、天河中心城区肺结核登记的资料。结果 2004—2008年广州市中心城区TB-DM患者1047例,占同期登记肺结核患者总数的比例5年平均6.2%,平均年登记率6.22/10万,5年间无明显的上升或下降趋势(P0.05)。男性TB-DM占肺结核登记人数中男性患者的构成比6.5%,女性构成比5.3%(P0.01)。TB-DM患者年龄19～91岁,中位年龄59岁,以中老年患者为主,40岁后两病并发率大幅上升。在TB-DM患者中,痰涂阳性者632例(60.4%)、涂阴415例(39.6%)、出现空洞527例(50.3%)。TB-DM患者的涂阳率和空洞率均高于无合并糖尿病的肺结核患者(P0.01)。患者的发现主要是因症就诊,占89.2%。结论 TB-DM发生率较高,以中老年发病为主,涂阳率和空洞率均较高,给结核病控制带来一定的困难,要加强这一人群的防治工作。     

Tuberculosis infection in patients with rheumatoid arthritis and the effect of infliximab therapy

OBJECTIVE: According to the Centers for Disease Control and Prevention, the 1999 and 2000 incidence rates for tuberculosis (TB) in the US population were 6.4 and 5.8, respectively, per 100,000 persons. Recently, reports of TB following infliximab administration have raised questions regarding the rate of TB in patients with rheumatoid arthritis (RA) generally and in those treated with infliximab in clinical practice. We undertook this study to determine the baseline rate of TB in RA prior to the introduction of infliximab and to determine the rate of TB among those currently receiving infliximab. METHODS: We surveyed patients with questionnaires, followed by detailed validation from medical records and physician reports. In study 1, we evaluated 10,782 RA patients in 1998-1999 prior to the widespread use of infliximab. In study 2, we evaluated 6,460 infliximab-treated patients in 2000-2002. RESULTS: In study 1, the lifetime rate of TB was 696 per 100,000 patients (95% confidence interval [95% CI] 547-872). Of these cases, 76.8% occurred prior to the onset of RA. During the period of prospective followup, 1 case of TB developed during 16,173 patient-years of followup, yielding a rate of 6.2 cases (95% CI 1.6-34.4) per 100,000 patients. In study 2, the TB incidence rate among infliximab-treated patients was 52.5 cases (95% CI 14.3-134.4) per 100,000 patient-years of exposure. Three of the 4 cases occurred in patients with a history of TB exposure, and no cases occurred in persons with recent TB skin tests or prophylaxis. CONCLUSION: The rate of TB is not increased in RA patients generally. Among infliximab-treated patients, the rate is 52.5 cases (95% CI 14.3-134.4) per 100,000 patient-years of exposure. A thorough medical history regarding TB, as well as tuberculin testing and radiographic examination (if indicated), should be an essential component of anti-tumor necrosis factor therapy.     

石家庄市实施世界银行贷款中国结核病控制项目效果分析

目的　分析石家庄市实施世界银行贷款中国结核病控制项目效果,为结核病控制可持续发展提供科学依据。方法 对 1991—2001年项目执行情况进行总结分析。结果 全市共接诊可疑肺结核病症状者 102396例,发现活动性肺结核病人 27149例,活动性肺结核新登记率由 1993年全面实施项目后的 21.0210万增加到 2001年的 39.9610万,涂阳登记率由 16.8510万提高到 29.7510万,新发涂阳治愈率达到 98.7%,复治涂阳治愈率达 94.4%。结论 石家庄市结控项目取得了满意效果。     

区域医疗卫生机构可疑肺结核转诊情况分析

目的　分析辖区医疗卫生机构可疑肺结核转诊的情况,探讨提高转诊率的措施。方法 根据深圳市罗湖区1995—2001年结核病控制项目登记本、表卡、转诊本(单)和逐年对各级医疗卫生机构抽查考核记录进行综合评价。结果 7年平均转诊到位率为89.4%,涂阳登记率由1995年14.3/10万,提高到2001年的30.7/10万,转诊的5941例发现活动性病人2132例占全部发现活动性病人的83.7%。结论 各级医疗卫生机构,尤其是综合医院是发现病人的主要来源,加强辖区综合医院转诊的管理,进一步规范转诊程序,从而提高转诊到位率。     

椒江区实施结核病防治规划（2001—2010年）中期效果

目的了解台州市椒江区实施《全国结核病防治规划（2001—2010年）》中期目标的达标情况。方法建立政府领导，有关部门配合，全社会参与的结核病防治体系。设立区结核病防治中心，建立区、街道（镇）、村三级防痨网。结果2001—2005年，结核病控制覆盖率100％；新发涂阳肺结核登记率11．22／10万-28．70／10万，新发涂阳发现率75．5％；累计涂阳595例，规划指标完成率119％；新发涂阳治愈率为76．92％-93．48％；专项经费41．29万元，到位率100％；专职人员到位率33．33％；医院转诊肺结核2229例，转诊率100％，2005年转诊到位率90％。结论该区已建立现代结核病防治体系；实现结核病防治规划中期目标：诊、治、管一体化服务是一种可行的有效结核病防治模式。     

Changing trends in the epidemiology and clinical outcome of acute upper gastrointestinal bleeding in a defined geographical area in Greece

AIM: Acute upper gastrointestinal bleeding (AUGIB) remains a common medical emergency and an important cause of morbidity and mortality. The aim of this study was to evaluate changes in clinico-epidemiologic characteristics of patients who presented with AUGIB during the last 10 years. METHODS: Data from all patients admitted with AUGIB in a defined geographical area in Greece from January 1 to December 31, 2005 (period B) were compared with retrospectively collected data from all patients admitted with AUGIB in the same area 10 years ago, from January 1 to December 31, 1995 (period A). The estimated incidence of AUGIB and peptic ulcer bleeding (PUB) in both periods was calculated using data from the population of this area according to the National Statistical Service. RESULTS: A reduction in the incidence of AUGIB from 162.9/100,000 population in 1995, to 108.3/100,000 population (rate ratio=0.49, confidence interval 95%=0.37-0.63) in 2005 and in the incidence of PUB from 104.8/100,000 population to 72.5/100,000 (rate ratio=0.49, confidence interval 95%=0.35-0.68) were, respectively, observed. This reduction was mainly due to the reduction in the incidence of duodenal ulcer bleeding (from 66.7 cases/100,000 to 35.5/100,000 population), whereas gastric ulcer bleeding incidence remained unchanged (33.1/100,000 vs. 34.4/100,000 cases). Mean age of patients increased from 59.4+/-17.1 years to 66.1+/-16.1, P<0.0001, and the patients' comorbidity. The percentage of NSAIDs' use remained stable (49.3% vs. 48.2%), whereas the use of oral anticoagulants and antiplatelets drugs increased significantly (from 2.2% to 6.8%, P=0.001 and from 1.2% to 10.8%, P<0.0001, respectively). Blood transfusion requirements per patient significantly decreased (from 2.5+/-2 to 2+/-2.4, P=0.009). The rate of rebleeding in PUB patients and emergency surgical hemostasis statistically decreased (from 12% to 5.9%, P=0.02 and from 5.9% to 3.1%, P=0.009, respectively). No significant difference in the overall mortality was observed (3.9% in 1995 vs. 6.5% in 2005). CONCLUSIONS: The incidence of AUGIB during the past 10 years significantly decreased, mainly due to the decline in the incidence of bleeding duodenal ulcers. Nowadays, patients are older with more comorbidities, but mortality remains unchanged.