Burden and Trends of IBD in 5 Asian Countries From 1990 to 2019: A Comparison With the United States and the United Kingdom.

BACKGROUND: IBD is becoming a global health challenge, with substantial variations in incidence and death rates between Eastern and Western countries. OBJECTIVE: This study aimed to investigate the burden and trends of IBD in 5 Asian countries, the United States, and the United Kingdom. DESIGN: This was a cross-sectional study. SETTING: Data were obtained from Global Burden of Disease 2019 Study. PATIENTS: Patients with IBD were included. MAIN OUTCOME MEASURES: Incidence, death, and age-standardized rates of IBD were measured. RESULTS: The age-standardized incidence and rates of death from IBD gradually decreased worldwide from 1990 to 2019. The age-standardized incidence rate in the United States decreased from 1990 to 2000 and then increased gradually from 2000 to 2019; the age-standardized incidence rates in the United Kingdom, Mongolia, and China increased gradually from 1990 to 2019, whereas in the Democratic People's Republic of Korea, it decreased from 1990 to 1995 and increased gradually from 1995 to 2019. The age-standardized death rate in the Republic of Korea exhibited a rising trend until 1995, fell significantly up to 2015, and then stabilized from 2015 to 2019. The age-standardized death rate in the United States showed a rising trend until 2007, and then decreased gradually from 2007 to 2019, whereas the rate in the United Kingdom showed a rising trend until 2010 and decreased from 2010 to 2019. The age-standardized death rates in China, Mongolia, the Democratic People's Republic of Korea, and Japan decreased gradually from 1990 to 2019. The age-standardized incidence and death rates in the United States and United Kingdom in recent decades were higher than those in the 5 Asian countries. The peak age-standardized incidence rates in the 7 countries were among people of 20 to 60 years of age. The age-standardized death rates in all 7 countries exhibited rising trends with increasing age, with older individuals, particularly those aged ≥70 years, accounting for the most deaths. LIMITATIONS: Limitations of this study include data from different countries with different quality and accuracy. CONCLUSIONS: There have been large variations in the burdens and trends of IBD between 5 Asian countries, the United States, and the United Kingdom during the past 3 decades. These findings may help policymakers to make better public decisions and allocate appropriate resources. See Video Abstract at http://links.lww.com/DCR/B996 . CARGA Y TENDENCIAS DE LA ENFERMEDAD INFLAMATORIA INTESTINAL EN CINCO PASES ASITICOS DESDE HASTA UNA COMPARACIN CON LOS ESTADOS UNIDOS Y EL REINO UNIDO: ANTECEDENTES:La enfermedad inflamatoria intestinal se está convirtiendo en un desafío en la salud mundial, con variaciones sustanciales en las tasas de incidencia y mortalidad entre los países orientales y occidentales.OBJETIVO:Investigar la carga y las tendencias de la enfermedad inflamatoria intestinal en cinco países asiáticos, EE. UU. y el Reino Unido.DISEÑO:Estudio transversal.ESCENARIO:Estudio de carga global de morbilidad 2019.PACIENTES:Enfermedad inflamatoria intestinal.PRINCIPALES MEDIDAS DE RESULTADO:Incidencia, muerte y tasas estandarizadas por edad de enfermedad inflamatoria intestinal.RESULTADOS:Las tasas de incidencia y muerte estandarizadas por edad de la enfermedad inflamatoria intestinal disminuyeron gradualmente en todo el mundo desde 1990 hasta 2019. La tasa de incidencia estandarizada por edad en los EE. UU. disminuyó de 1990 a 2000 y luego aumentó gradualmente de 2000 a 2019, las tasas en el Reino Unido, Mongolia y China aumentaron gradualmente de 1990 a 2019, mientras que la tasa en la República Popular Democrática de Corea disminuyó de 1990 a 1995 y aumentó gradualmente de 1990 a 2019. La tasa de mortalidad estandarizada por edad en la República de Corea exhibió un tendencia ascendente hasta 1995, cayó significativamente hasta 2015 y luego se estabilizó de 2015 a 2019. La tasa de mortalidad estandarizada por edad en los EE. UU. mostró una tendencia ascendente hasta 2007 y luego disminuyó gradualmente de 2007 a 2019, mientras que la tasa en el Reino Unido mostró una tendencia ascendente hasta 2010 y disminuyó de 2010 a 2019. Las tasas de mortalidad estandarizadas por edad en China, Mongolia, la República Popular Democrática de Corea y Japón disminuyeron gradualmente de 1990 a 2019. La tasa de incidencia estandarizada por edad y mortalidad en los EE. UU. y el Reino Unido en la última década fueron más altas que las de los cinco países asiáticos. Las tasas máximas de incidencia estandarizadas por edad en los siete países se dieron entre personas de 20 a 60 años. Las tasas de mortalidad estandarizadas por edad en los siete países exhibieron tendencias crecientes con el aumento de la edad, y las personas mayores, en particular las de ≥70 años, representaron la mayoría de las muertes.LIMITACIONES:Datos de diferentes países con diferente calidad y precisión.CONCLUSIONES:Ha habido grandes variaciones en las cargas y tendencias de la enfermedad inflamatoria intestinal entre cinco países asiáticos, EE. UU. y el Reino Unido durante las últimas tres décadas. Estos hallazgos pueden ayudar a los formuladores de políticas a tomar mejores decisiones públicas y asignar los recursos apropiados. Consulte Video Resumen en http://links.lww.com/DCR/B996 . (Traducción- Dr. Francisco M. Abarca-Rendon ).

High flow nasal oxygen versus conventional oxygen therapy in gastrointestinal endoscopy with conscious sedation: Systematic review and meta-analysis with trial sequential analysis.

OBJECTIVES: Although conventional oxygen therapy (COT) is widely used, hypoxemia frequently occurs in gastrointestinal endoscopy with conscious sedation and can lead to life-threatening consequences. High flow nasal oxygen (HFNO) has been applied to improve oxygenation in clinical entities. However, its efficacy to prevent hypoxemia in gastrointestinal endoscopy with conscious sedation has not been evaluated. METHODS: We searched databases to identify randomized controlled trials that compared the efficacy of HFNO with COT in gastrointestinal endoscopy with conscious sedation. The primary outcome was hypoxemia. Meta-analyses with trial sequential analysis were performed using a random-effects model. RESULTS: Eight trials with 3212 patients were included. Compared with COT, HFNO significantly reduced the risk of hypoxemia (eight trials; 3212 patients; risk ratio 0.30; 95% confidence interval [CI] 0.13-0.70). Trial sequential analysis showed that the cumulative Z curve did not cross the monitoring or futility boundaries, nor reach the required information size line, indicating that more trials are needed to reach a definitive conclusion. Subgroup analyses indicated the superiority of HFNO over COT with respect to hypoxemia in patients at low risk and high risk. HFNO further improved the lowest oxygen saturation (four trials; 459 patients; mean difference 2.30, 95% CI 0.84-3.77). CONCLUSIONS: Compared with COT, HFNO can reduce the risk of hypoxemia and improve the lowest oxygen saturation in gastrointestinal endoscopy with conscious sedation. However, the results should be interpreted with caution due to substantial heterogeneity and limited evidence. Further studies are needed to verify the preliminary findings.

The feasibility of laparoscopic TSME preserving the left colic artery and superior rectal artery for upper rectal cancer.

BACKGROUND: Laparoscopic tumor-specific mesorectal excision (TSME) preserving the left colic artery and superior rectal artery is still a technically challenging procedure. We conducted this study to demonstrate the feasibility of this procedure for upper rectal cancer. METHODS: A total of 184 patients with upper rectal cancer were retrospectively analyzed in our cancer center between April 2010 and April 2017. These patients were treated with either laparoscopic TSME (n = 46) or laparoscopic total mesorectal excision (TME) (n = 138). In the TSME group, the left colonic artery and superior rectal artery were preserved while they were not in the TME group. RESULTS: The operation time in the TSME group was longer than that in the TME group (218.56 ± 35.85 min vs. 201.13 ± 42.65 min, P = 0.004). Furthermore, the number of resected lymph nodes in the TSME group was greater than that in the TME group (19.43 ± 9.46 vs. 18.03 ± 7.43, P = 0.024). The blood loss between the TSME and TME groups was not significant. No mortality occurred in either the TSME or TME groups. One patient in the TME group underwent conversion to laparotomy. The total postoperative complication rates in the TSME and TME groups were 8.7% and 17.4%, respectively. There was no difference in severe complications between the two groups (anastomotic leakage and stenosis). CONCLUSIONS: Laparoscopic TSME preserving the left colic artery and superior rectal artery can be safely conducted for upper rectal cancer.

Identification of a metastatic lung adenocarcinoma of the palate mucosa through genetic and histopathological analysis: a rare case report and literature review.

BACKGROUND: Cancers of unknown primary origin (CUPs) are reported to be the 3-4th most common causes of cancer death. Recent years have seen advances in mutational analysis and genomics profiling. These advances could improve accuracy of diagnosis of CUPs and might improve the prognosis of patients with CUPs. CASE PRESENTATION: A 76-year old male with an adenocarcinoma of unknown primary origin in the lung presented with another tumor of the palate mucosa. The tumor cells in the pleural effusion were all negative for immunohistochemical markers (TTF-1 and Napsin A) and lung-specific oncogenic driver alterations (EGFR mutation and ALK translocation). The tumor of the palate mucosa was likewise identified as an adenocarcinoma, and the cells showed cytological similarities with the tumor cells in the pleural effusion; TTF-1, Napsin A, EGFR mutation and ALK translocation were all negative. This result suggested that origins of the tumors of the palate mucosa and in the lung were the same, even though the origin had not yet been determined. Next, we addressed whether the tumor of the palate mucosa was a primary tumor or not. Secretory carcinoma (SC), which is a common type of minor salivary gland tumor (MSGT), was suspected; however, mammaglobin was negative and ETV6-NTRK3 (EN) fusion was not observed. Other MSGTs were excluded based on histological and immunohistochemical findings. Furthermore, an additional examination demonstrated an oncogenic KRAS mutation at codon 12 (p.G12D) in both palate tumor and in pleural effusion. KRAS mutation is known to exist in one-third of lung adenocarcinomas (LUADs), but quite rare in MSGTs. The possibility of metastasis from other organs was considered unlikely from the results of endoscopic and imaging studies. This result indicated that the primary site of the CUP was indeed the lung, and that the tumor of the palate mucosa was a metastasis of the LUAD. CONCLUSIONS: A tumor of the palate mucosa that showed diagnostic difficulties was determined to be a metastatic LUAD by genomic alterations and histopathological findings.

Secretory carcinoma - impact of translocation and gene fusions on salivary gland tumor.

Secretory carcinoma (SC), previously described as mammary analogue secretory carcinoma (MASC), is a recently described salivary gland tumor which morphologically resembles mammary secretory carcinoma. The first description of SC/MASC, reported by Skálová et al. in 2010, was as a rare salivary carcinoma imitating secretory carcinoma of the breast. SC/MASC is a unique salivary gland tumor with morphological overlap with acinic cell carcinoma (AciCC), mucoepidermoid carcinoma (MEC), and adenocarcinoma not otherwise specified (ADC-NOS). SC/MASC shares similar clinicopathological features with AciCC. As a critical difference between SC/MASC and AciCC, SC/MASC characteristically has the chromosomal translocation t(12;15)(p13;q25) which leads to a fusion gene between the ETV6 gene on chromosome 12 and the NTRK3 gene on chromosome 15. This genetic background is an important differential diagnostic finding for excluding other salivary gland tumors and may be a critical factor determining the prognosis for patients with SC/MASC. Research in recent years has provided a large body of new data on SC/MASC and suggests the possibility that the ETV6-NTRK3 translocation could be a therapeutic target. Here, we review the morphological and clinicopathological features of SC/MASC and discuss new directions for therapy.

High-risk oral leukoplakia is associated with aberrant promoter methylation of multiple genes.

BACKGROUND: Early detection of oral squamous cell carcinomas (OSCCs) is urgently needed to improve the prognosis and quality of life (QOL) of patients. Oral leukoplakias (OLs), known as the most common premalignant lesions in the oral cavity, often precede OSCCs. Especially, OLs with dysplasia are known to have a high risk of malignant transformation. Here, we searched for the promoter methylation characteristic of high-risk OLs. METHODS: To identify methylation-silenced genes, a combined analysis of methylated DNA immunoprecipitation (MeDIP) - CpG island (CGI) microarray analysis and expression microarray analysis after treatment with a demethylating agent was performed in two OSCC cell lines (Ca9-22 and HSC-2). The methylation statuses of each gene were examined by methylation-specific PCR. RESULTS: A total of 52 genes were identified as candidates for methylation-silenced genes in Ca9-22 or HSC-2. The promoter regions of 13 genes among the 15 genes randomly selected for further analysis were confirmed to be methylated in one or more of five cell lines. In OSCC tissues (n = 26), 8 of the 13 genes, TSPYL5, EGFLAM, CLDN11, NKX2-3, RBP4, CMTM3, TRPC4, and MAP6, were methylated. In OL tissues (n = 24), seven of the eight genes, except for EGFLAM, were found to be methylated in their promoter regions. There were significantly greater numbers of methylated genes in OLs with dysplasia than in those without dysplasia (p < 0.0001). CONCLUSIONS: OLs at high risk for malignant transformation were associated with aberrant promoter methylation of multiple genes.

Structure of a New Palatal Plate and the Artificial Tongue for Articulation Disorder in a Patient with Subtotal Glossectomy.

A palatal augmentation prosthesis (PAP) is used to facilitate improvement in the speech and swallowing functions of patients with tongue resection or tongue movement disorders. However, a PAP's effect is limited in cases where articulation disorder is severe due to wide glossectomy and/or segmental mandibulectomy. In this paper, we describe speech outcomes of a patient with an articulation disorder following glossectomy and segmental mandibulectomy. We used a palatal plate (PP) based on a PAP, along with an artificial tongue (KAT). Speech improvement was evaluated by a standardized speech intelligibility test consisting of 100 syllables. The speech intelligibility score was significantly higher when the patient wore both the PP and KAT than when he wore neither (p＝0.013). The conversational intelligibility score was significantly improved with the PP and KAT than without PP and KAT (p＝0.024). These results suggest that speech function can be improved in patients with hard tissue defects with segmental mandibulectomy using both a PP and a KAT. The nature of the design of the PP and that of the KAT will allow these prostheses to address a wide range of tissue defects.

Clinical application of the CpG island methylator phenotype to prognostic diagnosis in neuroblastomas.

Clinical applications of aberrant DNA methylation to cancer diagnostics and therapeutics are accelerating. Especially, the CpG island methylator phenotype (CIMP), simultaneous methylation of multiple genes, provides information that cannot be obtained by other diagnostic methods and therapeutic opportunities. CIMP is known to be associated with poor or good prognosis depending upon cancer types. We identified that CIMP in neuroblastomas (NBLs) is strongly associated with poor prognosis in Japanese NBL cases (hazard ratio (HR)=22). Almost all NBLs with MYCN amplification displayed CIMP, and even among NBLs without MYCN amplification, NBLs with CIMP had worse prognosis (HR=12). The prognostic power was faithfully reproduced in German NBL cases by the same methods, and also in Italian and Swedish NBL cases with different analytical methods. Mechanistically, methylation silencing of different sets of tumor-suppressor genes is involved in poor prognosis of NBLs with CIMP, and the presence of CIMP is most sensitively detected by methylation of the PCDHB family. For therapeutic purposes, a combination of 5-aza-2'-deoxycytidine, a DNA-demethylating drug, with 13-cis-retinoic acid, a differentiating drug, has been shown to be effective for NBLs in vitro, and further development of a better combination(s) is awaited. Now, epigenetic diagnosis and therapeutics are becoming or have become an important choice for cancer patients.

Putative Bidirectionality of Chronic Obstructive Pulmonary Disease and Periodontal Disease: A Review of the Literature.

The prevalence of chronic obstructive pulmonary disease (COPD) is increasing worldwide and is currently the third leading cause of death globally. The long-term inhalation of toxic substances, mainly cigarette smoke, deteriorates pulmonary function over time, resulting in the development of COPD in adulthood. Periodontal disease is an inflammatory condition that affects most adults and is caused by the bacteria within dental plaque. These bacteria dissolve the gums around the teeth and the bone that supports them, ultimately leading to tooth loss. Periodontal disease and COPD share common risk factors, such as aging and smoking. Other similarities include local chronic inflammation and links with the onset and progression of systemic diseases such as ischemic heart disease and diabetes mellitus. Understanding whether interventions for periodontal disease improve the disease trajectory of COPD (and vice versa) is important, given our rapidly aging society. This review focuses on the putative relationship between COPD and periodontal disease while exploring current evidence and future research directions.

The Link between Periodontal Disease and Asthma: How Do These Two Diseases Affect Each Other?

A growing body of evidence suggests that the effects of poor oral hygiene extend beyond the oral cavity and are associated with a variety of systemic diseases, including asthma. Asthma, which results in symptoms of cough, wheezing, and dyspnoea, and is characterized by airflow limitation with variability and (partial or complete) reversibility, is amongst the most prevalent respiratory diseases with approximately 262 million patients worldwide, and its prevalence and disease burden is on the increase. While asthma can occur at a young age, it can also develop later in life and affects a variety of age groups. Both of these diseases have a chronic course, and various researchers have suggested a link between the two. In this article, we aim to provide a literature review focusing on the association between the two diseases. The results demonstrate that medications (primarily, inhaler medicine), hypoxia induced by asthma, and the breathing behaviour of patients potentially trigger periodontal disease. In contrast, oral periodontopathogenic microorganisms and the inflammatory mediators produced by them may be involved in the onset and/or exacerbation of asthma. Common contributing factors, such as smoking, gastro-oesophageal reflux, and type-2 inflammation, should also be considered when evaluating the relationship between the two diseases.

A Comparative Study of Periodontal Health Status between International and Domestic University Students in Japan.

BACKGROUND: In our previous study, international university students showed a significantly higher dental caries morbidity rate than domestic students. On the other hand, the periodontal health status of international university students has not been clarified yet. In this study, we compared the periodontal health status of international and domestic university students in Japan. METHODS: We conducted a retrospective review of the clinical data of the university students that visited a dental clinic in the division for health service promotion at a university in Tokyo for screening between April 2017 and March 2019. Bleeding on probing (BOP), calculus deposition and probing pocket depth (PPD) were investigated. RESULTS: The records of 231 university students (79 international and 152 domestic university students) were analyzed; 84.8% of international students were from Asian countries (n = 67). The international university students showed a higher percentage of BOP than domestic students (49.4% and 34.2%, respectively: p < 0.05) and they showed more extensive calculus deposition (calculus grading score [CGS]) than domestic university students (1.68 and 1.43, respectively: p < 0.01), despite no significant difference in PPD. CONCLUSIONS: The current study shows that international university students have poorer periodontal health than domestic students in Japan, even though the result might include many uncertainties and possible biases. To prevent severe periodontitis in the future, regular checkups and thorough oral health care are essential for the university students, especially those from foreign countries.

Association between hospital surgical case volume and postoperative mortality in patients undergoing gastrectomy for gastric cancer: a systematic review and meta-analysis.

BACKGROUND: Postoperative mortality is an important indicator for evaluating surgical safety. Postoperative mortality is influenced by hospital volume; however, this association is not fully understood. This study aimed to investigate the volume-outcome association between the hospital surgical case volume for gastrectomies per year (hospital volume) and the risk of postoperative mortality in patients undergoing a gastrectomy for gastric cancer. METHODS: Studies assessing the association between hospital volume and the postoperative mortality in patients who underwent gastrectomy for gastric cancer were searched for eligibility. Odds ratios were pooled for the highest versus lowest categories of hospital volume using a random-effects model. The volume-outcome association between hospital volume and the risk of postoperative mortality was analyzed. The study protocol was registered with Prospective Register of Systematic Reviews (PROSPERO). RESULTS: Thirty studies including 586 993 participants were included. The risk of postgastrectomy mortality in patients with gastric cancer was 35% lower in hospitals with higher surgical case volumes than in their lower-volume counterparts (odds ratio: 0.65; 95% CI: 0.56-0.76; P <0.001). This relationship was consistent and robust in most subgroup analyses. Volume-outcome analysis found that the postgastrectomy mortality rate remained stable or was reduced after the hospital volume reached a plateau of 100 gastrectomy cases per year. CONCLUSIONS: The current findings suggest that a higher-volume hospital can reduce the risk of postgastrectomy mortality in patients with gastric cancer, and that greater than or equal to 100 gastrectomies for gastric cancer per year may be defined as a high hospital surgical case volume.

Identification and initial validation of maximal tumor area as a novel prognostic factor for overall and disease-free survival in patients with resectable colon cancer: a retrospective study.

BACKGROUND: The tumor area may be a potential prognostic indicator. The present study aimed to determine and validate the prognostic value of tumor area in curable colon cancer. METHODS: This retrospective study included a training and validation cohorts of patients who underwent radical surgery for colon cancer. Independent prognostic factors for overall survival (OS) and disease-free survival (DFS) were identified using Cox proportional hazards regression models. The prognostic discrimination was evaluated using the integrated area under the receiver operating characteristic curves (iAUCs) for prognostic factors and models. The prognostic discrimination between tumor area and other individual factors was compared, along with the prognostic discrimination between the tumor-node-metastasis (TNM) staging system and other prognostic models. Two-sample Wilcoxon tests were carried out to identify significant differences between the two iAUCs. A two-sided P <0.05 was considered statistically significant. RESULTS: A total of 3051 colon cancer patients were included in the training cohort and 872 patients in the validation cohort. Tumor area, age, differentiation, T stage, and N stage were independent prognostic factors for both OS and DFS in the training cohort. Tumor area had a better OS and DFS prognostic discrimination characteristics than T stage, maximal tumor diameter, differentiation, tumor location, and number of retrieved lymph nodes. The novel prognostic model of T stage + N stage + tumor area (iAUC for OS, 0.714, P <0.001; iAUC for DFS, 0.694, P <0.001) showed a better prognostic discrimination than the TNM staging system (T stage + N stage; iAUC for OS, 0.664; iAUC for DFS, 0.658). Similar results were observed in an independent validation cohort. CONCLUSIONS: Tumor area was identified as an independent prognostic factor for both OS and DFS in curable colon cancer patients, and in cases with an adequate number of retrieved lymph nodes. The novel prognostic model of combining T stage, N stage, and tumor area may be an alternative to the current TNM staging system.

Systemic Disorders Closely Associated with Malocclusion in Late Adolescence: A Review and Perspective.

Oral diseases such as dental caries and periodontal disease are reported to be associated with various systemic diseases such as heart disease, respiratory disease, diabetes, rheumatism, and metabolic syndrome, thus increasing the importance of prevention and early treatment [...].

Surgical Strategies for Siewert Type II Esophagogastric Junction Carcinomas: A Randomized Controlled Trial.

Aim: To determine the ideal surgical approach for Siewert type II EGJ carcinomas. Methods: We conducted the randomized controlled trial (RCT) at Shanxi Cancer Hospital from January 2014 to August 2016. A total of 105 patients with T1-4N1-3M0 Siewert type II EGJ carcinomas were initially recruited. The final follow-up was up to June 30, 2019. Patients were randomized to undergo either a proximal gastrectomy plus jejunal interposition (PG+JI), proximal gastrectomy plus esophagogastrostomy (PG+EG), or total gastrectomy plus Roux-en-Y esophagojejunostomy (TG+RY). The primary endpoint was postoperative complications. Secondary endpoints were 5-year survival and recovery indexes. Results: Among 105 patients, 100 patients (95.2%; mean age, 56.2 years) with tumors <3cm in size underwent surgery: PG+JI (n=33) vs. PG+EG (n=33) and TG+RY (n=34); 91 patients completed the study. Among the groups, the PG+JI group had the longest reconstruction time: 34.11 ± 6.10 min vs. 21.97 ± 3.30 min (PG+EG) vs. 30.56 ± 4.26 min (TG+RY); p<0.001. There was no postoperative mortality. In the per-protocol analysis, the PG+JI group showed a decreased tendency in complication rate: 6.9% vs. 23.3% (PG+EG) vs. 18.8% (TG+RY), but there was no significant difference. For recovery indexes, the TG+RY group had the lowest values of the amount of single meal, weight loss, hemoglobin, albumin, pepsin, and gastrin among the three groups. There was no significant difference among the three groups in 5-year survival. Conclusions: Proximal gastrectomy is preferable for T1-4N1-3M0 Siewert type II EGJ carcinomas with tumors <3cm in size because of its better nutrition status under similar postoperative complication to total gastrectomy. Jejunal interposition can be recommended as a optional reconstruction approach after proximal gastrectomy. Clinical Trial Registration: https://www.chictr.org.cn/, identifier ChiCTR-IIR-16007733.

Oral Health in Japan: State-of-the-Art and Perspectives.

In the near future, Japan is entering a super-aging society that will be called the age of 100 years of life [...].