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Sui-Yi Xu,1,* Hui-Juan Li,2,* Shun Li,2 Qian-Qian Ren,1 Jian-Lin Liang,1 Chang-Xin Li1 1Department of Neurology, Headache Center, The First Hospital of Shanxi Medical University, Taiyuan, People’s Republic of China; 2Center for Medical Genetics & Hunan Key Laboratory of Medical Genetics, School of Life Sciences, Central South University, Changsha, People’s Republic of China*These authors contributed equally to this workCorrespondence: Chang-Xin Li, Department of Neurology, The First Hospital of Shanxi Medical University, Jiefangnan 85 Road, Taiyuan, Shanxi Province, 030001, People’s Republic of China, Tel +86 15103513579, Email lichangxin0351@sina.comAbstract: High temperature requirement serine peptidase A1 (HTRA1) related cerebral small vessel disease (CSVD) includes both symptomatic heterozygous HTRA1 variant carrier and cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL) patients. Presently, most reported symptomatic heterozygous HTRA1 variant carrier cases are sporadic family reports with a lack of specific characteristics. Additionally, the molecular mechanism of heterozygous HTRA1 gene variants is unclear. We conducted this review to collect symptomatic carriers of heterozygous HTRA1 gene variants reported as of 2022, analyzed all pathogenicity according to American College of Medical Genetics and Genomics (ACMG) variant classification, and summarized the cases with pathogenic and likely pathogenic HTRA1 variants gender characteristics, age of onset, geographical distribution, initial symptoms, clinical manifestations, imaging signs, HTRA1 gene variant information and to speculate its underlying pathogenic mechanisms. In this review, we summarized the following characteristics of pathogenic and likely pathogenic symptomatic HTRA1 variant carriers: to date, the majority of reported symptomatic HTRA1 carriers are in European and Asian countries, particularly in China which was found to have the highest number of reported cases. The age of first onset is mostly concentrated in the fourth and fifth decades. The heterozygous HTRA1 gene variants were mostly missense variants. The two variant sites, 166– 182 aa and 274– 302 aa, were the most concentrated. Clinicians need to pay attention to de novo data and functional data, which may affect the pathogenicity analysis. The decrease in HtrA1 protease activity is currently the most important explanation for the genetic pathogenesis.Keywords: stroke, HTRA1 gene, ACMG criteria, heterozygous variant, symptomatic carrier

Ge-Di Zhang,1,* Xi-Xi Liu,2,* Jia-Lang Liang,3 Qi-Ming Hu4 1Department of Endocrinology, Yuncheng Hospital of Traditional Chinese Medicine, Yuncheng, 274700, People’s Republic of China; 2Department of Endocrinology, Yichun Hospital of Traditional Chinese Medicine, Yichun, 336000, People’s Republic of China; 3Department of Endocrinology, Guangdong Integrated Traditional Chinese and Western Medicine Hospital, Foshan, 528000, People’s Republic of China; 4Department of Endocrinology, Affiliated Hospital of Jiangxi University of Traditional Chinese Medicine, Nanchang, 330000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Qi-Ming HuDepartment of Endocrinology, Affiliated Hospital of Jiangxi University of Traditional Chinese Medicine, No. 445 of Bayidadao Street, Donghu District, Nanchang, 330000, People’s Republic of ChinaTel +86 79107702803Email huqimingqw_as@163.comObjective: This study aimed to summarize the distribution pattern of traditional Chinese medicine (TCM) syndromes in patients with type 2 diabetes mellitus (T2DM).Methods: The frequency, characteristics and distribution of all TCM syndromes of 549 patients with T2DM were analyzed.Results: The average age of T2DM onset was higher in women than in men (ie, men experienced earlier onset). The distribution of TCM syndromes, in order of frequency, was as follows: damp-heat trapping spleen (including spleen deficiency and dampness, damp heat due to spleen deficiency, and qi weakness due to spleen deficiency) (58.29%), qi-yin deficiency (16.03%), deficiency of yin and excessive heat (12.93%), blood stasis in collaterals (9.41%), and yin-yang deficiency (3.21%). The physical intensity of patients’ occupational activity was mainly light (49.6%), followed by heavy (31.4%) and moderate (19.0%).Conclusion: Damp-heat trapping spleen is the most common TCM syndrome in patients with T2DM, with damp heat due to spleen deficiency the most significant subtype. This syndrome tends to occur in people over the age of 60 and those undertaking too much or too little physical activity in their occupational activities. The traditional “three more and one less” symptoms do not adequately describe the clinical symptoms of T2DM.Keywords: type 2 diabetes, TCM syndrome differentiation, damp heat due to spleen deficiency, epidemiology, clinical symptoms

Problem/Condition: Since 1971, CDC, the U.S. Environmental Protection Agency (EPA), and the Council of State and Territorial Epidemiologists have maintained a collaborative Waterborne Disease and Outbreaks Surveillance System for collecting and reporting data related to occurrences and causes of waterborne disease and outbreaks (WBDOs). This surveillance system is the primary source of data concerning the scope and effects of WBDOs in the United States.Reporting Period: Data presented summarize 36 WBDOs that occurred during January 2003--December 2004 and nine previously unreported WBDOs that occurred during 1982--2002.Description of System: The surveillance system includes data on WBDOs associated with drinking water, water not intended for drinking (excluding recreational water), and water of unknown intent. Public health departments in the states, territories, localities, and Freely Associated States (i.e., the Republic of the Marshall Islands, the Federated States of Micronesia, and the Republic of Palau, formerly parts of the U.S.-administered Trust Territory of the Pacific Islands) are primarily responsible for detecting and investigating WBDOs and voluntarily reporting them to CDC by using a standard form.Results: During 2003--2004, a total of 36 WBDOs were reported by 19 states; 30 were associated with drinking water, three were associated with water not intended for drinking, and three were associated with water of unknown intent. The 30 drinking water-associated WBDOs caused illness among an estimated 2,760 persons and were linked to four deaths. Etiologic agents were identified in 25 (83.3%) of these WBDOs: 17 (68.0%) involved pathogens (i.e., 13 bacterial, one parasitic, one viral, one mixed bacterial/parasitic, and one mixed bacterial/parasitic/viral), and eight (32.0%) involved chemical/toxin poisonings. Gastroenteritis represented 67.7% of the illness related to drinking water-associated WBDOs; acute respiratory illness represented 25.8%, and dermatitis represented 6.5%.The classification of deficiencies contributing to WBDOs has been revised to reflect the categories of concerns associated with contamination at or in the source water, treatment facility, or distribution system (SWTD) that are under the jurisdiction of water utilities, versus those at points not under the jurisdiction of a water utility or at the point of water use (NWU/POU), which includes commercially bottled water. A total of 33 deficiencies were cited in the 30 WBDOs associated with drinking water: 17 (51.5%) NWU/POU, 14 (42.4%) SWTD, and two (6.1%) unknown. The most frequently cited NWU/POU deficiencies involved Legionella spp. in the drinking water system (n = eight [47.1%]). The most frequently cited SWTD deficiencies were associated with distribution system contamination (n = six [42.9%]). Contaminated ground water was a contributing factor in seven times as many WBDOs (n = seven) as contaminated surface water (n = one).Interpretation: Approximately half (51.5%) of the drinking water deficiencies occurred outside the jurisdiction of a water utility in situations not currently regulated by EPA. The majority of the WBDOs in which deficiencies were not regulated by EPA were associated with Legionella spp. or chemicals/toxins. Problems in the distribution system were the most commonly identified deficiencies under the jurisdiction of a water utility, underscoring the importance of preventing contamination after water treatment. The substantial proportion of WBDOs involving contaminated ground water provides support for the Ground Water Rule (finalized in October 2006), which specifies when corrective action is required for public ground water systems.Public Health Actions: CDC and EPA use surveillance data to identify the types of water systems, deficiencies, and etiologic agents associated with WBDOs and to evaluate the adequacy of current technologies and practices for providing safe drinking water. Surveillance data also are used to establish research priorities, which can lead to improved water-quality regulation development. The growing proportion of drinking water deficiencies that are not addressed by current EPA rules emphasizes the need to address risk factors for water contamination in the distribution system and at points not under the jurisdiction of water utilities. [ABSTRACT FROM AUTHOR]

Problem/Condition: Since 1971, CDC, the U.S. Environmental Protection Agency, and the Council of State and Territorial Epidemiologists have collaboratively maintained the Waterborne Disease and Outbreak Surveillance System for collecting and reporting waterborne disease and outbreak (WBDO)-related data. In 1978, WBDOs associated with recreational water (natural and treated water) were added. This system is the primary source of data regarding the scope and effects of WBDOs in the United States.Reporting Period: Data presented summarize WBDOs associated with recreational water that occurred during January 2003--December 2004 and one previously unreported outbreak from 2002.Description of the System: Public health departments in the states, territories, localities, and the Freely Associated States (i.e., the Republic of the Marshall Islands, the Federated States of Micronesia, and the Republic of Palau, formerly parts of the U.S.-administered Trust Territory of the Pacific Islands) have primary responsibility for detecting, investigating, and voluntarily reporting WBDOs to CDC. Although the surveillance system includes data for WBDOs associated with drinking water, recreational water, and water not intended for drinking, only cases and outbreaks associated with recreational water are summarized in this report.Results: During 2003--2004, a total 62 WBDOs associated with recreational water were reported by 26 states and Guam. Illness occurred in 2,698 persons, resulting in 58 hospitalizations and one death. The median outbreak size was 14 persons (range: 1--617 persons). Of the 62 WBDOs, 30 (48.4%) were outbreaks of gastroenteritis that resulted from infectious agents, chemicals, or toxins; 13 (21.0%) were outbreaks of dermatitis; and seven (11.3%) were outbreaks of acute respiratory illness (ARI). The remaining 12 WBDOs resulted in primary amebic meningoencephalitis (n = one), meningitis (n = one), leptospirosis (n = one), otitis externa (n = one), and mixed illnesses (n = eight). WBDOs associated with gastroenteritis resulted in 1,945 (72.1%) of 2,698 illnesses. Forty-three (69.4%) WBDOs occurred at treated water venues, resulting in 2,446 (90.7%) cases of illness. The etiologic agent was confirmed in 44 (71.0%) of the 62 WBDOs, suspected in 15 (24.2%), and unidentified in three (4.8%). Twenty (32.3%) WBDOs had a bacterial etiology; 15 (24.2%), parasitic; six (9.7%), viral; and three (4.8%), chemical or toxin. Among the 30 gastroenteritis outbreaks, Cryptosporidium was confirmed as the causal agent in 11 (36.7%), and all except one of these outbreaks occurred in treated water venues where Cryptosporidium caused 55.6% (10/18) of the gastroenteritis outbreaks.In this report, 142 Vibrio illnesses (reported to the Cholera and Other Vibrio Illness Surveillance System) that were associated with recreational water exposure were analyzed separately. The most commonly reported species were Vibrio vulnificus, V. alginolyticus, and V. parahaemolyticus. V. vulnificus illnesses associated with recreational water exposure had the highest Vibrio illness hospitalization (87.2%) and mortality (12.8%) rates.Interpretation: The number of WBDOs summarized in this report and the trends in recreational water-associated disease and outbreaks are consistent with previous years. Outbreaks, especially the largest ones, are most likely to be associated with summer months, treated water venues, and gastrointestinal illness. Approximately 60% of illnesses reported for 2003--2004 were associated with the seven largest outbreaks (>100 cases). Deficiencies leading to WBDOs included problems with water quality, venue design, usage, and maintenance.Public Health Actions: CDC uses WBDO surveillance data to 1) identify the etiologic agents, types of aquatic venues, water-treatment systems, and deficiencies associated with outbreaks; 2) evaluate the adequacy of efforts (i.e., regulations and public awareness activities) to provide safe recreational water; and 3) establish public health prevention priorities that might lead to improved regulations and prevention measures at the local, state, and federal levels. [ABSTRACT FROM AUTHOR]