Introduction. In order to develop strategies to prevent delay in diagnosis, it is important to gain knowledge of symptoms and healthcare-seeking processes in the population. This paper describes a combined survey and register-based study with (1) focus on development of a questionnaire concerning experience of symptoms and subsequent consequences and (2) feasibility of the study. Methods. The study is a nationwide cohort study of 100 000 individuals randomly selected from the Danish general population. A comprehensive questionnaire concerning experience of symptoms and subsequent consequences was developed. The methodological framework for the development included defining the domains to be measured, identification of previous items, scales and questionnaires in the literature, and pilot and field testing. Results. A total of five domains and 16 subdomains were defined covering the area of symptom experience, symptom characteristics, reaction in response to symptom experience, external factors, and personality characteristics with potential influence on the symptom experience. In total, 49 706 questionnaires were completed, yielding a response rate of 52.2%. Conclusion. We developed a comprehensive questionnaire used in a large combined survey and register-based study concerning experience of symptoms and subsequent consequences of symptom experiences. We succeeded in conducting a large survey providing the groundwork for The Danish Symptom Cohort. Symptom experiences among people in the general population are common. Studies have shown that over three quarters of adults have experienced a symptom within the past two weeks, and up to 15% have experienced an alarm symptom of one of the four most frequently occurring cancers within the preceding year .Symptom experiences are embedded in a complex interplay of biological, psychological, and cultural factors and may reflect a variety of interpretations of sensations, which are not necessarily expressions of underlying disease. Many people manage symptom experiences privately without consulting the healthcare system. Thus only some symptom experiences are presented to the healthcare system, a phenomenon referred to as the “symptom iceberg” , 4. FromSome of the factors which can affect the decision to seek healthcare are symptom characteristics, impact on daily activities, personal experience with or witnessing of symptoms and disease, health perceptions, and network and social context , 6–8. InProviding timely and effective healthcare in relation to serious diseases is an important task for the healthcare system. In order to develop strategies to prevent delayed diagnosis, it is important to gain knowledge of the symptoms occurring in the general population and knowledge about factors important for the healthcare-seeking process. The purpose of this paper is to describe the development of a comprehensive questionnaire concerning experience of symptoms, interpretation, and subsequent consequences of symptom experiences. The specific objectives are (1) conceptualization of “symptom experience” and “healthcare-seeking,” defining the domains to be measured, identification and inclusion of previously used and validated items, scales, and questionnaires, and development of single symptom items pilot and field testing of the comprehensive questionnaire and (2) the feasibility of the study.The study was designed as a nationwide cohort study of 100 000 people randomly selected from the general population and with baseline data collected in a web-based survey. All Danish citizens are registered in the Danish Civil Registration System (CRS) with a unique personal identification number enabling accurate linkage between national registers. In Denmark researchers are prohibited by law to contact persons who have declined to participate in research-related inquiries. These persons were excluded prior to sampling, based on information in the CRS. From the CRS, 100 000 adults aged 20 years or above were randomly selected and invited to participate in the survey. The individuals received a postal letter explaining the purpose of the study. In the letter a unique 12-digit login for a secure webpage was included.Due to the large sample size the study population was randomly divided into four equally sized groups. The groups were invited with two-week time intervals, except the first two groups who were invited with a four-week interval because of the holiday season. A reminder letter followed the initial invitational letter to nonrespondents after two weeks. After additional two weeks the nonrespondents were contacted by telephone and encouraged to participate. A private telemarketing company conducted the latter reminder procedure. In this procedure the participants were offered the opportunity to receive an e-mail with a direct link to the questionnaire.In order to prevent the exclusion of people with no access to a computer, tablet, or smartphone we offered the participants the opportunity of the survey being conducted as a telephone interview. A group of trained interviewers were assigned to conduct the telephone interviews. The interviewers were instructed to read the questions and prespecified options out loud, not contributing with their own interpretation of the questions. We drew lots for 10 iPads among all the respondents as gratuity for their efforts.The questionnaire was designed in the web-based online platform SurveyXact . To acceThe conceptual objective of the study was to measure the prevalence of symptom experience in the general population and the individual's interpretation of symptoms and subsequent healthcare-seeking behaviour. Data concerning self-reported experience of symptoms and subsequent consequences together with personal and social characteristics were collected using a comprehensive questionnaire. The questionnaire is based on standard rating scales, previously validated questionnaires, and ad hoc items.based on the objective, defining the constructs and conceptual framework, and exploring the literature on these concepts with the purpose of defining the domains to be measured;identification of previous items, scales, and questionnaires in the literature followed by item generation and item reduction;pilot testing with regard to content validity, relevance, acceptability, and feasibility;field testing within a pilot study on 500 randomly selected people from the general population testing data quality and floor and ceiling effects and assessing the distribution of the answers in the various categories. Besides field testing the pilot study was used to test study procedures, resources, time scale, and estimation of the recruitment rate.The methodological framework for developing the questionnaire included the following steps :based onThe first step in the process was to define the concepts of “symptom experience” and “healthcare-seeking behaviour.”The term symptom as presented in the discipline of medicine is influenced by a desire to predict underlying diseases and risks of negative effects on health. In medicine, it is common to distinguish between subjective health complaints (symptoms) and signs with the latter being objectively verifiable , whereas symptoms often refer to subjective complaints. The WONCA Dictionary of General/Family Practice defines a symptom as “any subjective evidence of a health problem as perceived by the patient” . The facCurrent literature on healthcare-seeking often presents a dichotomous approach: either you seek medical advice or you do not seek medical advice. In this study we wanted to approach healthcare-seeking behaviour in a multifactorial context . A groupThe Developing Process of the Questionnaire. The developing process involved several meetings in the group comprising the three different disciplines: psychology, anthropology, and medical science. The development of the domains as well as the item generation in each domain was based on the literature of symptoms and healthcare-seeking and related factors. Overall the discussion in the group concerned (1) reflections on which symptoms to include where the emphasis was on frequency and severity, (2) recall periods, and (3) operationalising the conceptual framework. Domains in the Questionnaire. Based on our conceptual framework, a core content of domains was developed to be included in the questionnaire. A total of five domains were identified The fourth domain concerns the potential influence of a number of selected factors on the symptom experience, for example, lifestyle, social network, the GP's and the surroundings' reactions to—and concern for—the person's health, and experience of illness in the immediate family and circle of friends.(v)The fifth domain considers the respondents' personality characteristics such as self-rated health, coping strategies, and their attitude towards risk taking.The remaining two domains were included in order to explore how various factors may influence symptom experience and healthcare-seeking.Domain 1: Symptom Experience. We created a large item bank with various predefined symptoms. In relation to the conceptual framework we aimed to include a variety of bodily symptom experiences. From a medical perspective some of these are categorized as alarm symptoms, but also a variety of symptoms that are frequently occurring and categorized as benign were included. The following subdomains were identified: (1) specific and nonspecific cancer alarm symptoms, (2) general, frequent symptoms, (3) abdominal symptom complexes, and (4) bodily distress syndrome.Re 1. For representativeness of symptoms that from a medical perspective are defined as indicating a serious disease, we selected a number of specific and nonspecific alarm symptoms covering the following areas: lung, gastrointestinal, gynaecological, and urogenital cancer. The symptoms were selected based on a review of literature, national and international cancer referral guidelines, and descriptions of cancer pathways –17.Re 2. We included a number of general symptoms based on the knowledge that cancer patients in addition to presenting a specific alarm symptom often also present vague and uncharacteristic symptoms , 18. TheRe 3. As an example of an organ-specific area, we chose abdominal symptoms, because abdominal symptoms are frequently occurring in the population, are often occurring in frequent healthcare-seekers, and are associated with a range of definable symptom-based conditions, for example, dyspepsia, gastroesophageal reflux disease, and irritable bowel syndrome. Further, there are symptoms which both occur in cancer referral pathways and in the functional abdominal symptom complexes. The selection of symptoms was based on the latest symptom-based consensus classification regarding dyspepsia and irritable bowel syndrome (the ROME III criteria) –21, whilRe 4. Symptoms not attributable to any medical diagnosis challenge the concept of diagnosis. Patients with symptom experiences from numerous organ systems and with a high symptom burden are referred to in a number of different ways in the literature, for example, unexplained medical disorders, psychosomatic disease, or somatisation. These symptoms are now assembled in one classification called bodily distress syndrome (BDS). Items already identified to classify BDS were included .Based on the subdomains, we created items asking whether people had experienced one or more of the predefined symptoms within the preceding four weeks.Domain 2: Symptom Experience Characteristics. In the second domain we wanted to explore the time point for each symptom experience, concerns in relation to the symptom experience, and impact on activities of daily living.People are more likely to seek healthcare if symptoms are perceived as severe or incapacitating . The perDomain 3: Reactions in Response to Symptom Experience. Studies have shown that use of and access to social network, for example, telling and interacting with others when experiencing symptoms or asking for advice, influences healthcare-seeking [-seeking . Viewed -seeking . The use-seeking . In combStudies have shown that people often experience one or more barriers to seek healthcare. The respondents were asked to decide on four of the most common considerations in relation to healthcare-seeking . MoreoveDomain 4: Selected Factors with Potential Influence on the Symptom Experience and Healthcare-Seeking. The fourth domain was developed based on the hypothesis that the symptom experience and healthcare-seeking behaviour may be influenced by a number of external factors. We therefore included items from existing questionnaires on lifestyle factors, for example, smoking and alcohol consumption, and items about general contact to the social network as well as the GP's and social network's expressed concern for the respondent's health. Moreover, we included items exploring experience of illness in the immediate family and circle of friends [ friends .Domain 5: Personality Characteristics in relation to Symptom Experience and Healthcare-Seeking. One of the aims of the study is to examine possible associations between personality facets, symptom experiences, and healthcare-seeking behaviour, respectively. Risk-taking attitudes as well as dispositional coping strategies have shown to be associated with various types of health-related behaviours in different patient populations [ulations –35. In tulations .On the last page of the questionnaire we added a commentary box encouraging respondents to add additional comments and to report any comprehension problems in the questionnaire.The aim of the pilot testing was to test the content validity, that is, relevance, acceptability, and feasibility. Before conducting the first test, the questionnaire was discussed by a multidisciplinary expert panel comprising a psychologist, an anthropologist, a biostatistician, two GPs, and five medical doctors. Further, the questionnaire was sent out to a group of 25 persons from an academic setting  and was further discussed in this academic setting. This resulted in both alterations in the order of the items and clarification of introductory captions to each of the domains.The pilot testing was conducted in two stages, the first with seven women and four men aged 22–61 years who were observed as they completed the questionnaire. The people participating in the pilot testing were recruited at a train station outside a public library. Trained interviewers asked the participants to read each item and answer it while thinking out loud, highlighting problems, and expressing their attitude to the question.The second round of pilot testing included 11 new participants, four men and seven women, with an age range of 20–78 years.A pilot study was conducted among 500 Danish adults aged at least 20 years and randomly selected using the CRS. We used the electronic platform SurveyXact and offered the possibility of completing the questionnaire by a telephone interview. Field testing of the questionnaire was incorporated in the pilot study. We assessed the mean and standard deviation of each item, median, and extent of floor and ceiling effects.The Regional Scientific Ethics Committee for Southern Denmark evaluated the project and concluded that the project was not notifiable and could be implemented without the permission from The Regional Scientific Ethical Committee for Southern Denmark according to Danish law. The participants in the study were clearly informed that there would be no clinical follow-up and that they should contact their own GP in case of concern or worry. The project has been approved by the Danish Data Protection Agency .A conceptual framework with regard to symptom experience and healthcare-seeking was developed. The final questionnaire consisted of five domains with 16 subdomains. Field testing of the questionnaire was performed in a pilot study on 500 people resulting in alterations in formulations of questions and introductory captions.A pilot study was conducted as a part of the feasibility assessment. In the pilot study a total of 182 of the 500 subjects completed the questionnaire, yielding a response rate of 36.4%. The final questionnaire was adjusted in light of the pilot and field testing. Changes primarily consisted of alterations in formulations of questions and introductory captions.The response rate of 36.4% in the pilot study resulted in the hiring of a telemarketing company to perform reminder phone calls. The pilot study also provided an estimate on how many telephone interviews as well as incoming calls with questions from the respondents would be expected.Of the 100 000 randomly selected subjects, 4 474 (4.7%) were not eligible because they had either died, could not be reached due to unknown address, were suffering from severe illnesses (including dementia), had language problems, or had moved abroad. Information on severe illness and subjects who had moved abroad was obtained through contact with family or relatives in the reminder procedure. Of the 95 253 (95.3%) eligible subjects, 49 706 subjects completed the questionnaire, yielding an overall response rate of 52.2% . The medThe pilot study provided information with regard to the logistics resulting in the division of the study into four waves.Well-known medical symptoms and bodily sensations including cancer alarm symptoms formed the base of the questionnaire. The survey was based on a limited number of predefined symptoms, leaving some respondents in a situation where they could not express all their symptoms. Instead, we opted to gather a more comprehensive analysis of the impact of the symptom on functioning and how the respondent's social network is utilized with respect to the symptom. To allow respondents to elaborate on their symptom experience in their own words and to learn more about the respondents' understanding of symptoms, we added a commentary box encouraging respondents to add additional comments, creating a possibility of evaluating the comprehension of the questionnaire.In designing the questionnaire we included anthropological, psychological, and medical paradigms. To our knowledge no previous surveys on symptoms have used a similar multiperspective approach. Using this approach, we believe that symptom experiences in the general population can be analysed in a more nuanced way and with greater precision. In an attempt to minimise recall bias, we chose to ask about symptoms experienced within the last four weeks.The large sample of 100 000 subjects with 49 706 completed baseline questionnaires makes it possible to estimate prevalence of, for example, cancer alarm symptoms and of some rarer conditions with good statistical precision.The subjects invited to participate in the study were randomly selected using the Danish Civil Registration System, which reduces the risk of selection bias. The response rate in the study (52.2%) was slightly lower than in previous Danish population-based surveys . This coA minority of the respondents (2.4%) responded to the questionnaire via telephone interview. It is possible that data from the interviews are different from the data derived from the online version. The difference was sought minimised by using trained interviewers who were instructed only to read the questions out loud and ask the respondent to choose between the available answers. The interviewers were explicitly instructed not to engage in the interpretation of the questions with the respondent. However, the fact that the telephone respondents were not able to see the questions and answers themselves and reflect on the answers in private might have affected their answers. The respondents who participated by telephone interview were mainly women in the older age groups. Obtained data may differ between self-administered questionnaires and telephone interviews. It is, however, not possible to determine whether differences would be caused by selection due to variations in age, sex, health status, or socioeconomic position or whether the differences would be due to the answering method.We succeeded in conducting a large survey providing the groundwork for The Danish Symptom Cohort. Conducting the study in four waves solved the logistic challenges in terms of making it possible to handle both incoming calls with questions and conducting telephone interviews. The use of a telephone reminder procedure was implemented due to the poor response rate in the pilot study. The increase in the response rate of 8.5 percentage points from the reminder letter to the telephone reminder was a result in line with what we had expected. A similar procedure may well be applied in other large population-based studies.To explore possible selection bias linkage to register data allows us to compare respondents and nonrespondents with regard to sex, age, socioeconomic status, and healthcare utilisations. Moreover, we are able to compare early and late respondents based on available information on the distribution date of the questionnaire and on the date the questionnaire was filled in.Early diagnosis and prompt treatment are generally presumed to be a key to a better prognosis of most illnesses. To improve early diagnosis it is important to gain knowledge about which symptoms, groups of symptoms, and related factors lead to healthcare-seeking. Information from this study will provide important knowledge on symptom experiences as well as on relationships between specific symptom experiences and, respectively, personal characteristics, subsequent healthcare-seeking, and the patient's interaction with the healthcare system. This large cohort of individuals will be followed for a number of years with complete follow-up on development of diseases by linkage with register data on socioeconomic status, health care utilisation, and hospital based diagnosis. By gaining this knowledge it will be possible for healthcare providers to form better and more precise referral pathways and hereby minimising delay in diagnosis.We developed a comprehensive questionnaire consisting of five domains with 16 subdomains covering the area of symptom experience, symptom characteristics, reaction in response to symptom experience, external factors, and personality characteristics with potential influence on the symptom experience. We succeeded in conducting a large survey providing the groundwork for The Danish Symptom Cohort. With 49 706 having completed the questionnaire, an overall response rate of 52.2% was achieved.


Nowadays, there is an increased tendency for researches to focus on accelerating methods for tooth movement due to the huge demand for adults for a shorter orthodontic treatment time. Unfortunately, long orthodontic treatment time poses several disadvantages like higher predisposition to caries, gingival recession, and root resorption. This increases the demand to find the best method to increase tooth movement with the least possible disadvantages. The purpose of this study is to view the successful approaches in tooth movement and to highlight the newest technique in tooth movement. A total of 74 articles were reviewed in tooth movement and related discipline from 1959 to 2013. There is a high amount of researches done on the biological method for tooth movement; unfortunately, the majority of them were done on animals. Cytokine, PTH, vitamin D, and RANKL/RANK/OPG show promising results; on the other hand, relaxin does not accelerate tooth movement, but increases the tooth mobility. Low-level laser therapy has shown positive outcome, but further investigation should be done for the best energy and duration to achieve the highest success rate. Surgical approach has the most predictable outcomes but with limited application due to its aggressiveness. Piezocision technique is considered one of the best surgical approaches because it poses good periodontal tissue response and excellent aesthetic outcome. Due to the advantages and disadvantages of each approach, further investigations should be done to determine the best method to accelerate tooth movement. Orthodontics has been developing greatly in achieving the desired results both clinically and technically. This is especially so by using new technologies, like stimulation software that can assist in treatment planning and translational products. In addition, continuous modification of wires and brackets as a result of the biomechanical efficiencies in orthodontics has greatly improved. However, these biomechanical systems may have reached their limit and there is a need to develop new methods to accelerate teeth movement.Today, it is still very challenging to reduce the duration of orthodontic treatments. It is one of the common deterents that faces orthodontist and causes irritation among adults plus increasing risks of caries, gingival recession, and root resorption.A number of attempts have been made to create different approaches both preclinically and clinically in order to achieve quicker results, but still there are a lot of uncertainties and unanswered questions towards most of these techniques. Most attempts can broadly be categorized into biological, physical, biomechanical, and surgical approaches. Before going into details of these attempts, we need to understand the basics of orthodontic tooth movements and the factors that initiate inhibition and delayed tooth movement.Orthodontic tooth movement occurs in the presence of a mechanical stimuli sequenced by remodeling of the alveolar bone and periodontal ligament (PDL). Bone remodeling is a process of both bone resorption on the pressure site and bone formation on the tension site . OrthodoThere are three phases of tooth movement: the initial phase, which is characterized by rapid movement after the application of force; followed by a lag period, where little or no movement, and the last phase, where gradual or sudden increase of movement occurs .The early phase of tooth movement involves acute inflammatory responses characterized by leucocytes migrating out of blood capillaries and producing cytokines, which stimulates the excretion of prostaglandins and growth factors . The acuExperiments have been done using these molecules exogenously to enhance tooth movement both in animal experiments and humans. Example of these molecules are prostaglandin E (PGE), cytokines that include lymphocytes and monocytes-derived factors, receptor activator of nuclear factor kappa B ligand (RANKL), and macrophage colony-stimulating factor (MCSF) –9 Table.Table 1High concentration of cytokines such as interleukins IL-1, IL-2, IL-3 IL-6, IL-8, and tumor necrosis factor alpha (TNF) were found to play a major role in bone remodeling; moreover, interleukin-1 (IL-1) stimulates osteoclast function through its receptor on osteoclasts .Other cytokines which are also involved in the acceleration of tooth movement are RANKL, which is a membrane-bound protein on the osteoblasts that bind to the RANK on the osteoclasts and causes osteoclastogenesis –25. On tAlso a correlation was found among RANK, OPG, and root resorption during orthodontic teeth movement, and patients with root resorption produced a large amount of RANKL in the compressed site , 29.In vivo and in vitro experiments were conducted to show clearly the relation between PGs, applied forces, and the acceleration of tooth movement. Yamasaki [Prostaglandins (PGs) are inflammatory mediator and a paracrine hormone that acts on nearby cells; it stimulates bone resorption by increasing directly the number of osteoclasts. Yamasaki , 11 was Yamasaki  have shoYamasaki .Furthermore, chemically produced PGE2 has been studied in human trials with split-mouth experiments in the first premolar extraction cases. In these experiments the rate of distal retraction of canines was 1.6-fold faster than the control side .Vitamin D3 has also attracted the attention of some scientist to its role in the acceleration of tooth movement; 1,25 dihydroxycholecalciferol is a hormonal form of vitamin D and plays an important role in calcium homeostasis with calcitonin and parathyroid hormone (PTH).Another set of investigators  has madePTH has been shown to accelerate orthodontic tooth movement on rats, which was studied by continuous infusion of PTH (1 to 10 μg/100 g of body weight/day) implantation in the dorsocervical region, and the molars were moved 2- to 3-fold faster mesially by orthodontic coil spring .Some studies have shown that locally injected PTH induces local bone resorption, and it is more advantageous to give PTH locally rather than systemically . The devin vitro studies were also performed to test the PDL mechanical strength and tooth mobility using tissue from additional 20 rats that had previously received the same relaxin treatment for several days [Relaxin effect has also been investigated. Relaxin is a hormone that helps during childbirth by widening of the pubic ligaments in females and is suggested to be present in cranial suture and PDL . The rolral days .The remodeling of PDL by relaxin might reduce the rate of relapse after orthodontic treatment as suggested by others . RecentlAnother approach in accelerating tooth movement is by using device-assisted therapy Table . This teThe concept of using physical approaches came from the idea that applying orthodontic forces causes bone bending (bone bending theory) and bioelectrical potential develops. The concave site will be negatively charged attracting osteoblasts and the convex site will be positively charged attracting osteoclasts as detected by Zengo  in his mThe bioelectrical potential is created when there is application of discontinuous forces, which leads to the idea of trying cyclic forces and vibrations. It has been found that applying vibrations for different duration per day accelerated tooth movements between 15% and 30% in animal experiments , 44.We have also used this concept by using the cyclical force device with patients and achieved 2 to 3 mm/month of tooth movement. The vibration rate was 20 to 30 Hz and used for 20 min/day . FurtherAnother approach is to use direct electric current. This technique was tested only on animals by applying direct current to the anode at the pressure sites and cathode at the tension sites (by 7 V), thus, generating local responses and acceleration of bone remodeling as shown by group of investigators . Their sPhotobiomodulation or low-level laser therapy (LLLT) is one of the most promising approaches today. Laser has a biostimulatory effect on bone regeneration, which has been shown in the midpalatal suture during rapid palatal expansion , and alsAnimal experiments have shown that low-level laser can accelerate tooth movement. Furthermore, clinical trial attempts were made in which different intensities of laser were used and different results were obtained , 42. LowThe surgical technique has been documented in many case reports. It is a clinically effective technique used for adult patients, where duration of orthodontic treatment may be critical in selected groups of patients. The PDL and alveolar bone remodeling are the important parameters in tooth movement, and bone turnover is known to increase after bone grafting, fracture, and osteotomy.Several surgical approaches that have been tried in order to accelerate tooth movement were interseptal alveolar surgery, osteotomy, corticotomy, and Piezocision technique Table .Table 3Interseptal alveolar surgery or distraction osteogenesis is divided into distraction of PDL or distraction of the dentoalveolar bone; example of both is the rapid canine distraction. The concept of distraction osteogenesis came from the early studies  of limb In the rapid canine distraction of PDL, the interseptal bone distal to the canine is undermined surgically at the same time of extraction of the first premolars, thus, this will reduce the resistance on the pressure site. In this concept the compact bone is replaced by the woven bone, and tooth movement is easier and quicker due to reduced resistance of the bone . It was In this technique the interseptal bone is undermined 1 to 1.5 mm in thickness distal to the canine after the extraction of the first premolar, and the socket is deepened by a round bur to the length of the canine. The retraction of the canine is done by the activation of an intraoral device directly after the surgery. It has been shown that it took 3 weeks to achieve 6 to 7 mm of full retraction of the canine to the socket of the extracted first premolars .Rapid canine distraction of the dentoalveolar bone is done by the same principle of the distraction of PDL, with the addition of more dissection and osteotomies performed at the vestibule as shown in –57, 63.In all the studies done, both techniques accelerated tooth movement with no evidence of significant root resorption, ankylosis, and root fracture. However, there were contradictory results regarding of the electrical vitality test of the retracted canines. Liou  reportedOsteotomy and corticotomy are also surgical techniques that have been clinically used for many years. Osteotomy is when a segment of the bone is cut into the medullary bone and is separated and then moved as a unit as shown in , 67.Corticotomy is one of the surgical procedures that is commonly used in which only the cortical bone is cut and perforated but not the medullary bone, suggesting that this will reduce the resistance of the cortical bone and accelerate tooth movements. It was first tried in orthodontics by Kole , where tIn 2001 Wilcko  reportedThis technique is reported to have postoperative stability and improved retention as shown in , but morOne of the latest techniques in accelerating tooth movement is the Piezocision technique. Dibart  was amonThe administration of exogenous biological molecules to accelerate tooth movement during orthodontic treatments has been intensively tested on animal experiments. However, clinical trials on humans are limited since they must be administered occasionally by local injections that can be painful and cause discomfort to the patients avoiding systemic applications, plus their side effect was not tested for long periods of time. However, administration of certain molecules has shown promising results; for example, cytokine, PTH, vitamin D, and RANKL/RANK/OPG system play an important role in bone remodeling and tooth movement. Human relaxin does not accelerate tooth movement in rats, but increases tooth mobility by decreasing the organization and mechanical strength of the PDL. However, a lot of these mechanisms are not fully understood and the dose-dependent mechanisms should also be further investigated.In the physical approach, the low level laser therapy is the most promising method; however, contradictory results were shown. This is due to the different energies, duration, and experimental design. Furthermore, most of these experiments were done in only few weeks, which is a very short time to notice any side effects.The surgical approach is the most clinically used and most tested with known predictions and stable results. However, it is invasive, aggressive, and costly, and patients are not open to the ideas involving surgery unless it is the only option that is needed to have a good occlusion. Piezocision technique is one of the newest techniques in accelerating tooth movement, and it has good clinical outcome and is considered the least invasive in the surgical approach.In general, all these techniques had draw backs and uncertainties that made them not commonly used clinically. However, there has been a rapid increase in the interest levels of product companies to enhance the effects of biology in orthodontics. These new approaches have the potential to be the next frontier for orthodontics and its resources.


Clear guidance on fetal growth assessment is important because of the strong links between growth restriction or macrosomia and adverse perinatal outcome in order to reduce associated morbidity and mortality. Fetal growth curves are extensively adopted to track fetal sizes from the early phases of pregnancy up to delivery. In the literature, a large variety of reference charts are reported but they are mostly up to five decades old. Furthermore, they do not address several variables and factors , which are very important for a correct evaluation of the fetal well-being. Therefore, currently adopted fetal growth charts are inadequate to support the melting pot of ethnic groups and lifestyles of our society. Customized fetal growth charts are needed to provide an accurate fetal assessment and to avoid unnecessary obstetric interventions at the time of delivery. Starting from the development of a growth chart purposely built for a specific population, in the paper, authors quantify and analyse the impact of the adoption of wrong growth charts on fetal diagnoses. These results come from a preliminary evaluation of a new open service developed to produce personalized growth charts for specific ethnicity, lifestyle, and other parameters. In current clinical medicine, data coming from medical records and analysis are often used to document diagnostic issue, giving the opportunity of a systematic data meta-analysis to improve patient care and to develop new health-assessment techniques.Correct assessment of gestational age and fetal growth is essential for optimal obstetric management. For this purpose, ultrasound obstetric scans in pregnancy are routinely used to track fetal growth and to assess fetal health.Fetal size charts are used to compare the size of a fetus  with reference data and to compare it on two or more different circumstances.This can be performed using look-up tables or charts, but, as it is easier to identify any deviation from normal by plotting measurements on charts, the use of charts is recommended and the clinical evidence supports their efficacy.The detection of a potential abnormal growth by means of intrauterine fetal parameters during pregnancy was proposed by serial US scans by Lubchenco , Usher aFetal growth charts are compared to statistical data  so that clinicians may detect fetal growth associated to fetal intrauterine anomalies .Numerous studies have been conducted to derive reference charts for fetal size. Many, however, have a suboptimal design, using a hospital-based population or having an inappropriate sample size.The proliferation of further studies on specific subgroups of patients –12 and tAs a consequence in clinical practice, generic charts are preferred to specific ones or to more complex approaches based on suitable mathematic models , becauseMoreover, the World Health Organization (WHO) standards are still commonly based on generic reference charts; they do not differentiate by ethnic origin and are not subject to frequent update, so they are unsuitable to assess the biometric parameters in several cases of practical interest.To preserve the feasibility of the approach without losing diagnostic power, some authors proposed the adoption of purposely developed software tools  allowing us to create customized growth charts , 14, basMedical literature clearly showed its main drawbacks: (A) the number of patients considered in the studies (some thousandth) is low with respect to the total number of newborn per year (about 160 Millions in 2013) in the world; (B) patients considered in the studies are not representative of the variety of anthropometrical factors due to ethnicity, familial aspects, and other relevant internal and external factors; (C) the commonly used growth curves are up to five decades old; they are not updated for the current population and they are not suitable to investigate temporal trends and dynamic aspects in fetal growth curves.Nevertheless, fetal growth is influenced by a variety of factors, racial, social, and economic among others, as well as specific medical conditions that may preexist or that may develop during pregnancy.Hence, it is not surprising that fetal biometric parameters show high degree of variation in evaluated population from country to country and from area to area, within the same country. Beyond ethnicity, many other factors affect fetal growth including fetus gender, physiological and pathological variables, maternal height and weight, drug or tobacco exposure, genetic syndromes, congenital anomalies, and placental failure –18.In this context, it is necessary to have personalized charts for fetal growth in order to provide an accurate fetal assessment and to make the presence of false positive and false negative potentially avoidable.The adoption of wrong reference curves on specific fetuses could cause an incorrect evaluation of fetal biometric parameters, identifying for example cases known in literature as Small for Gestational Age (SGA) or Large for Gestational Age (LGA). So, using personalized growth curves would result in a considerable decline in the rate of a false-positive diagnosis of SGA/LGA.In this scenario, authors quantify and analyse the impact of the adoption of such wrong growth charts on fetal diagnoses. As initial results, authors show how much different are values and boundaries of certain biometric parameters according to ethnicity. Salentinian population  has been analysed and its samples have been compared with the reference curves adopted for Italian  and EuroThese preliminary results have been obtained by adopting a new “online service” in charge to develop personalized growth charts, which take into account differences due to ethnicity, lifestyle, familial aspects, and other parameters.The study includes a population of about 500 Italian women undergoing ultrasound examination between the 11th and 41th weeks of gestation, between November 2012 and September 2013.All pregnant women were enrolled in a previously defined area, southeast of Italy, in the Vito Fazzi Hospital, Italy, and Departments of Obstetrics and Gynecology assessed the investigation.Gestational age was established by using US imaging during the first visit, at study enrolment. All patients received written and oral information about the study, and they signed the informed consent.Before enrolment, authors defined, in the setup study, the inclusion and exclusion criteria Inclusion criteria were: singleton pregnancies, known first day of the Last Menstrual Period (LMP), regular cycle (lasting 28 ±  4 days) The date of the LMP was confirmed with the pregnant woman at the first obstetric visit, and additional information on regularity and duration of the cycle was collected during visit. Cases with low birth weight, preterm delivery, or other prenatal complications were not excluded from analysis. Gestational age was based on the last menstrual period and in all cases adjusted according to the CRL measured in the first trimester ultrasound.Pregnant women were excluded from analysis if they joined the study after the 24th week of pregnancy, because reliable dating of pregnancy is more difficult as pregnancy proceeds. Bidimensional (2D) US scans were conducted either with a Logic 7 Pro US system , an IU 22 xMATRIX US system , or a Voluson 730 US system  equipped with a 3.8–5.2 MHz transabdominal transducer by resident clinicians well-trained in obstetric US. All machines had a standard US setting of Doppler and grey scale, provided by companies. Measurements of the biparietal diameter (BPD) and head circumference (HC) were obtained from a transverse axial plane of the fetal head showing a central midline echo broken in the anterior third by the cavum of septum pellucidi and demonstrating the anterior and posterior horns of the lateral ventricle. The BPD was measured from the outer margin of the proximal skull to the inner margin of the distal skull. The HC was measured fitting a computer-generated ellipse to include the outer edges of the calvarial margins of the fetal skull. The abdominal circumference (AC) was measured fitting a computer-generated ellipse through a transverse section of the fetal abdomen at the level of the stomach and bifurcation of the main portal vein into its right and left branches. The femur length (FL) was measured in a longitudinal scan where the whole femural diaphysis was seen almost parallel to the transducer and measured from the greater trochanter to the lateral condyle. In the third trimester, particular care was taken not to include the epiphysis.Each interval of gestational age was centred on a week, so that from 13 weeks and 4 days up to 14 weeks and 3 days has been considered as 14th week.http://www.r-project.org).Statistical analysis has been performed using appropriate packages of R Software , mean is the mean, and SD is the standard deviation of the mean of the fetal measurements for each gestational age.Assuming that, at each gestational age, the measurement of interest has a Gaussian distribution with a mean and a standard deviation (SD) and that, in general, both vary smoothly with gestational age, a centile curve has been calculated using the well-known formula:The mean has been estimated by the fitted values from an appropriate polynomial regression curve of the measurement of interest on gestational age.Several curve-fitting and smoothing techniques have been tested for the mean estimation of the different biometric parameters and the goodness of fit for each regression model has been carefully assessed. The polynomial model that better satisfies the experimental data is the cubic one, since it better fulfils the fractional polynomial and the logarithmic transformations.The adopted equation isGenerally, if the scaled absolute residuals appear to show no trend with gestational age, the SD is estimated as the standard deviation of the unscaled residuals (measurements minus the estimated mean curve). If there is a trend, then polynomial regression analysis is needed to estimate an appropriate curve in the same way of the mean.For BPD, HC, and AC biometric parameters, the residuals were regressed on gestational ages by using a linear model in the form ofFull biometric measurements  were obtained for about 500 fetuses.Data analysis showed that neither the use of fractional polynomials  nor the logarithmic transformation improved the fitting of the curves. Therefore, the data were kept in their original scale. The best-fitted regression model to describe the relationships between HC, AC, BPD, and FL and gestational age was a cubic one, whereas other studies proved that a simple quadratic model fitted BPD and FL .Models fitting the SD were straight lines for BPD, HC, and AC and quadratic line for FL.R2 index  but the value of R2 alone is not the only factor that we have considered in choosing the best model. Other factors we have considered include the validity and the effectiveness of the model.To choose the best fitting model, we have taken into consideration primarily the There will be an improvement in fit as higher-order terms are added, but because these terms are not theoretically justified, the improvement will be sample-specific.Unless the sample is very small, the fits of higher-order polynomials are unlikely to be very different from those of a quadratic over the main part of the data range.R2 for the quadratic specification of BPD parameter is 0.98081 and for the cubic and quartic curves it is 0.98229 and 0.98242, relatively small improvements.Consider that, for example, the Further, the cubic and quartic curves both exhibit implausible strange twists at the extremities Figures  and 2.The scatter of absolute residuals from the regression for estimation of the standard deviation of femur length as a function of gestational age is shown in R2 index for the mean and the standard deviation, are illustrated in The corresponding regression equations, with the respective The relevant centile , representing, respectively, the HC, the BPD, the A,C and the FL, are reported in Tables In order to validate the system, authors have performed an initial technical test with a growth curve simulator able to respect the mean and the standard deviation that characterize the Gaussian distribution for a specific patient age. The generated data allowed authors to prove the correctness of the elaboration of the fetal growth curves model.After this preliminary analysis, authors have performed a test on the field considering about 500 US pictures related to Italian women undergoing ultrasound examination between the 11th and 41th weeks of gestation at Vito Fazzi Hospital, Lecce, between November 2012 and September 2013. Measurements of biparietal diameter (BPD), head circumference (HC), abdominal circumference (AC), and femur length (FL) were obtained during the clinical practice.The obtained curves were then compared with those developed by Giorlandino et al.  as referThe AC and HC biometric parameters seem to follow more or less the same Italian and European trend according to the gestational age. In fact, no significant differences were observed in the values measured during the different growth stages. Considering the BPD and the FL parameters, instead, they present a little variability.As shown in Figures This variability may be better presented by means of scatterplot of Salentinian samples overlapped with the centile curves to verify the amount and the density of the samples that are outside the considered range.Considering the Italian reference centile curves depicted in Samples above the 95th centile are traditionally used to define large for gestational age (LGA), and the usage of such Italian reference curves on a Salentinian fetus could lead to misdiagnosis.To examine in a quick way one or more sets of data graphically, box plots can be used. They can be useful to indicate the degree of dispersion (spread) and skewness in the data and to identify outliers. Each plot depicts the five-number summaries for each biometric parameter, namely, the minimum and maximum values, the upper (Q3) and lower (Q1) quartiles, and the median.The variability present in the FL parameter can be also observed in this kind of graph, which considers more population groups.As can be seen in This variability has to be medically investigated since it can be due to several reasons: equipment or measurement errors, genetic variability of the analysed population, racial factors, and so on.In any case, the measured variability is useful to demonstrate the effectiveness of the proposed approach.http://www.fpgt.unisalento.it/FPGT/Projects/scientificFoundations.php.The complete set of curves obtained from the mentioned dataset and the complete description of the mathematical procedure adopted for the analysis are published and described at In order to quantify the impact of the adoption of wrong growth charts on fetal diagnoses, authors have analysed the samples' trend for each biometric parameter and have then compared it with the Italian and European standard.Authors found significant differences between Salentinian FL growth plots and those reported by Giorlandino et al.  for ItalFrom Tables The fetal growth assessment is a relevant problem, since it concerns about 160 ML of newborns per year. The population reshuffling and the increased mobility of families push for a new assessment approach based on dynamic and individualized fetal growth curves.The importance of the growth curves is proven by the fact that they are commonly used in neonatal units today. They serve as standard references to classify neonates as SGA, LGA, and AGA. In order to evaluate the applicability of these standards to current patients, we compared data accumulated in our research data system to determine whether our patients were categorized appropriately.Our findings require that we should carefully reexamine the appropriateness of continued use of currently adopted reference growth curves to classify neonates SGA, LGA, and AGA.In fact, considering, for example, the femur length parameter, Salentinian fetuses present bigger values with respect to those of Italy  and Europe .This is a preliminary approach, which does not represent the development and publication of new reference curves for Salentinian population but rather represents the introduction of a new method to construct the fetal growth curves which has to take into consideration several information about ethnicity, foods, lifestyle, drugs assumption, and other internal or external factors influencing growth.


A comprehensive understanding of the integrative nature of the molecular network in thrombosis would be very helpful to develop multicomponent and multitarget antithrombosis drugs for use in traditional Chinese medicine (TCM). This paper attempts to comprehensively map the molecular network in thrombosis by combining platelet signaling, the coagulation cascade, and natural clot dissolution systems and to analyze the topological characteristics of the network, including the centralities of nodes, network modules, and network robustness. The results in this research advance understanding of functions of proteins in the thrombosis network and provide a reference for predicting potential therapeutic antithrombotic targets and evaluating their influence on the network. Thromboembolic disorders are a major cause of death and disability and affect millions worldwide. Thrombosis can occur in either the arterial or the venous circulation and results in different clinical symptoms, such as pulmonary emboli, deep vein thrombosis, strokes, and heart attacks.While antithrombotic drugs, including anticoagulants, antiplatelet drugs, and thrombolytic drugs, have been widely used for the prevention and treatment of arterial and venous thrombosis, new targets, more effective agents against existing targets, as well as new therapeutic strategies still need to be developed for overcoming resistance to current drugs, suppressing the stimulus in platelet activation, and regulating the anticoagulation effect more conveniently .Traditional Chinese medicine (TCM), especially HuoXueHuaYu Chinese medicines, has long been used to treat thrombosis. The significant efficacy of TCM in treating thrombosis has been reported in the literature and in recent pharmacological experiments –4. Thus,Moreover, several studies have been so far conducted to evaluate the efficacy of different compounds against platelet aggregation, exhibit formula-target relations, and develop model to predict coagulation response –10. HoweOn the other hand, the rapid progress of bioinformatics and systems biology has provided not only a systems-level understanding of biological processes and disease complexity but also an efficient and promising approach, such as network analysis, for integrative drug development , 11. CseIn this context, this research attempts to comprehensively map the thrombosis molecular network and analyze topological characteristics of the network from several perspectives, including the centralities of nodes, network modules, and network robustness. This research is of significance to improve the understanding of molecular functions in the thrombosis network and further predict potential targets for the treatment of thrombosis by evaluating their influence on the network. Homo sapiens . Th. Thp(k) l system .Hubs with a high degree of centrality occupy a critical position in a network, although they house only a small number of all the nodes in a network. If hubs are attacked, the integrity of the network deteriorates more rapidly than nonhubs, which makes hubs attractive drug targets . Thus, iOn average, the targets of FDA-approved drugs tend to have more connections than most peripheral nodes but do not cover all the hubs . Hub conDifferent centrality measures indicate different importance of nodes in the network. Nodes with high betweenness centrality indicate their particular targeting potential for antithrombosis due to their bottleneck positions in the thrombosis network. It should be noted that 16 out of 27 hubs also have high betweenness centrality. Moreover, high degree and betweenness centralities exhibit essential topological significance in thrombosis network by serving as network hubs and bridges.On the other hand, a substantial number of key proteins in Nodes with overlapping function are key determinants of network cooperation. Overlapping nodes occupy specific network positions and can provide more subtle regulation. As shown in We compared the average degree, betweenness centrality, and closeness centrality of multifunctional proteins with those of the nonmultifunctional proteins shown in To facilitate the interpretation of the complex relationships in the thrombosis system, the modular structure of the system was explored. We marked eight modules positioned in the largest component in In module 1, GPIb-IX-V and vWF not only were important components of platelet adhesion but also strongly associated with the classic coagulation cascade by factor XI and factor VIII . In addiOtherwise, modular hubs which are not network hubs should also be emphasized in view of their local influence on some specific functions. For example, phosphorylated phospholipase C gamma 2 (p-PLCG2), as a hub of module 6, and kininogen and prekallikrein as hubs in the kallikrein-kinin system have been demonstrated by previous studies to show the potential as antithrombotic targets –43. AnotRobustness is an intrinsic property of networks. It refers to the ability of a network to continue functioning in the face of various perturbations. The action of drugs can be perceived as a disease network perturbation modulating disordered network towards a functional state , 46. DruDue to advances in the theoretical understanding of network structure, it is possible to quantitatively describe a network with graph concepts. As the degree distribution of the thrombosis network conforms to power law, and the network is relatively scale free , it is lf = 0.1), the size of the largest component S remained the dominating position under random failure but fell apart to moderate size obviously when hubs or bridges were attacked , S ≈ 0.2, and the network experienced catastrophic fragmentation. As shown in an earlier study, the fragmentation would break off continuously but less severely when larger fraction than 0.1 of nodes was removed [As shown in attacked . When on removed .s〉 of the isolated components increased slowly indicated that increasing failure level led to the isolation of single nodes, not large components (s〉 for the small f. Similar threshold of 〈s〉 was detected in attack mode, where the main component broke into small pieces and also led to the size of fragments peaks. As we continued to remove nodes, the isolated components became deflated, leading to a descending 〈s〉. The aforementioned behavior provides evidence that the thrombosis network shows topological stability against random failures but that it fragments in response to attacks on a small number of nodes. Obviously, bridge attacks are more sensitive than attacks on hubs, and hub attacks cause more serious fragmentation of the network. These observations of the global influence of network attacks could provide clues for seeking fragile targets and designing multitarget therapeutic strategies against thrombosis.The fact that the average size 〈mponents . In the Network analysis has the advantage of providing system-level perspectives on complex issues. Topological analysis can help to extract valuable information hiding in large-scale and complex experimental data. In summary, on the foundation of evidence-based data, we constructed an integrated thrombosis network composed of platelet signaling, the coagulation cascade, and the natural clot dissolution system and conducted various network topological analyses. The degree distribution followed a power law, and the network was relatively scale free. With this in mind, local topology analysis was conducted to identify central nodes that could be putative drug targets. The results showed that targets can also be predicted from their modular position by modularity analysis. The analysis of the robustness of the thrombosis network demonstrated that it was highly resistant to random failure but sensitive to hub and bridge attacks. Such studies can elucidate the function of proteins in thrombosis network, help discover new targets for the treatment of thrombus using TCM, and contribute to the development of new targets of TCM and multitarget strategies.Network analysis seems to provide a valuable prediction of therapeutic targets, but it is still insufficient to validate the effectiveness of targets. Further pharmaceutical experiments are necessary for eventual validation of network results. Network approach can serve as a valuable complement to the experimental efforts, while a combination between simulated and experimental studies is of great significance for effective drug discovery in future.


Bioinformatics is now a critical skill in many research and commercial environments as biological data are increasing in both size and complexity. South African researchers recognized this need in the mid-1990s and responded by working with the government as well as international bodies to develop initiatives to build bioinformatics capacity in the country. Significant injections of support from these bodies provided a springboard for the establishment of computational biology units at multiple universities throughout the country, which took on teaching, basic research and support roles. Several challenges were encountered, for example with unreliability of funding, lack of skills, and lack of infrastructure. However, the bioinformatics community worked together to overcome these, and South Africa is now arguably the leading country in bioinformatics on the African continent. Here we discuss how the discipline developed in the country, highlighting the challenges, successes, and lessons learnt. The fields of bioinformatics and computational biology have grown in importance as drivers of research in the life sciences as evidenced by the increasing number of journals and international conferences dedicated to these fields. The need for skills in these areas has grown accordingly in South Africa, as researchers are more frequently awarded grants for projects generating large-scale biological data. Local scientists are generating large and varied datasets including next-generation sequencing , proteomic data, and other data, coupled with rich phenotypic datasets, especially large patient and surveillance cohorts. These research groups seldom have embedded data analysts, so they turn to bioinformatics groups for support. Fortunately, there are well-established bioinformatics and computational biology groups at many of the universities in South Africa, reflecting the significant resources committed to bioinformatics development in the country since the 1990s. In this article, we outline the growth of bioinformatics in South Africa, highlighting the challenges as well as the impact of government support on the development of the field. Where relevant, we also describe lessons learnt.South Africa is a middle-income country , with significant social inequality. While there are resources to develop new scientific fields, demands on government to meet immediate social needs makes neither organic growth nor strategic investment a given. Following the Second World War, state policy and government funding built a strong South African tradition of scientific research. Despite areas of great strength and international leadership, however, there were many neglected areas, policy challenges, and a fragmented science and innovation landscape across both the public and private sector  and "south africa"–"working in partnership with the European Bioinformatics Institute" and “.ac.za”, where “subject area” was [“bioinformatics” or “computational biology”], “chemistry,” “cardiology,” “geology,” “microbiology”. Patents and citations were excluded. We chose to simplify the search and use the broad terms bioinformatics and computational biology, as it is challenging to identify all bioinformatics publications by journal or topic alone. We therefore included the other subjects to demonstrate the relative differences in impact using broad subject terms. It is evident that the number of bioinformatics-related publications in South Africa has increased substantially since 2001, with a sharper rise than other subjects over the same time period.Bioinformatics in South Africa started with a single group at one South African university, but developed rapidly through the injection of funds from the DST via the NBN initiative. The NBN provided a springboard for the development of bioinformatics skills in postgraduate students and bench scientists, and these new initiatives are ensuring a continuation of this momentum. Since then, the Bio-Innovation Unit of the DST has invested in several key bioinformatics-based initiatives, including, the BFG program; the BSP; and the SAHGP. They have contributed to a significant increase in bioinformatics outputs including trained postgraduate students, research publications see , patentsSome of the key achievements of the South African bioinformatics community lie in training, research, and infrastructural capacity development. The universities have collectively trained 130 Masters and 60 PhD students in bioinformatics, many of which have gone on to academic positions or placements in prestigious institutes abroad, including Harvard and the EBI. Bioinformatics courses in South Africa are increasingly being taught by exclusively local trainers, many of whom are frequently invited to give training courses in Africa and abroad. Several groups have contributed to or developed resources used by the international scientific community, one example being the HIV drug resistance database. The strength and international recognition of the community is reflected in the participation of South African academics in key positions in international societies, such as ISCB and ASBCB, partnerships with international research groups in successful funding proposals, and the increase in publications in international bioinformatics journals. One of the highlights, though, is the NIH award for H3ABioNet, which is one of the largest single awards to an African institution.Throughout the history of the development of bioinformatics in SA, many lessons have been learnt, some of which are described above. The take-home message is that commitment to bioinformatics capacity development by the government has been key to the success of many of the bioinformatics units in the country. The step-up provided by the NBN enabled groups in multiple universities to hire dedicated bioinformatics staff members in an environment where universities were not forthcoming in creating new positions. In some cases, the success of the groups convinced the institution of the importance of bioinformatics and the need to support it. The establishment of these bioinformatics units also facilitated the procurement of further funding from the NRF as well as international funding agencies, thus increasing outputs and enabling these units to become internationally competitive in the field.


On-site wastewater treatment systems (OWTS) are widely used in Western Australia (WA) to treat and dispose of household wastewater in areas where centralized sewerage systems are unavailable. Septic tanks, aerobic treatment units (ATUs), and composting toilets with greywater systems are among the most well established and commonly used OWTS. However, there are concerns that some OWTS installed in WA are either performing below expected standards or failing. Poorly performing OWTS are often attributed to inadequate installation, inadequate maintenance, poor public awareness, insufficient local authority resources, ongoing wastewater management issues, or inadequate adoption of standards, procedures, and guidelines. This paper is to review the installations and failures of OWTS in WA. Recommendations to the Department of Health Western Australia (DOHWA) and Local Government (LG) in regard to management strategies and institutional arrangements of OWTS are also highlighted. Septic tanks, aerobic treatment units (ATUs), and composting toilets with greywater treatment are among the more commonly used OWTS in Australia and elsewhere . In the the OWTS . Nutrienthe OWTS . Salmonella or viruses such as rotavirus or protozoa (namely Giardia),gastroenteritis from bacteria such asbacterial dysentery, Salmonella,typhoid fever frompolio from enterovirus,infectious hepatitis (hepatitis A) causing liver disease,skin infections from viruses, bacteria, and fungi.Undoubtedly, poorly performing or failing OWTS have economic impacts on the owners and pose environmental impacts due to nutrients that may disrupt ecosystem balance. Furthermore, poorly performed or failed OWTS can contribute to eutrophication of sensitive water bodies and create algae blooms. Failing OWTS are one of the main causes of streams, lakes, rivers, wetlands, and groundwater contamination due to the release of nutrients and pathogens into the environment . VariousPooling off effluent creates a nuisance by emitting offensive odours thus affecting the amenity of an area. Spray irrigation of untreated greywater or septic tank effluent can result in aerosol transmission of diseases causing organisms. Irrigation of effluent or greywater water onto food crops can cause diseases such as gastroenteritis or serious life-threatening diseases. Contact with lawn areas recently irrigated with untreated wastewater may also result in skin infections or gastroenteritis via direct or indirect ingestion of organisms .Swimming in water contaminated with effluent may result in skin, ear, and eye infections or gastroenteritis. Similarly, consuming shellfish from effluent contaminated water may result in diseases such as hepatitis A . methemoglobinemia in children [Most of the public health impacts of poorly performing OWTS are related to pathogens. However the main chemical hazard of poorly performing OWTS is nitrate. Elevated nitrogen levels in drinking water supplies impacted by wastewater contamination may result in irregular haemoglobin levels orchildren .Poor performance or failures of OWTS are often associated with systems not situated and constructed correctly. In particular, areas with low permeability soils and/or high water tables present the greatest challenge in WA. Failure of many onsite systems is generally not due to inherent flaws in system technology but rather due to inappropriate sitting and construction design or their operation and management . Other clack of area on the properties for the treatment and disposal of wastewater,undersized or inadequate wastewater treatment units or absorption trenches,poor maintenance, such as failure to desludge septic tanks,a change in occupancy from occasional to permanent,inappropriate location of absorption trenches, that is, in areas that are poorly drained, subject to flooding or high seasonal water table,poor knowledge of operation and maintenance procedures by homeowners/occupiers.The following causes have been identified as the major reasons for OWTS failure :lack of There is an increasing concern with the cumulative environmental impacts and local public health risk of failing or inadequately designed OWTS in unsewered areas . Therefo Health  Regulations 1974 is required to be lodged to the Local Government (LG) in the first instance. If it is intended that the proposed OWTS will handle less than 540 L/day of wastewater and the building to be serviced is a single dwelling, the LG will process the application. If the wastewater volume generated is greater than 540 L/day and the building being serviced is not a single dwelling, the LG will assess the application, prepare a local government report, and forward the application to the DOHWA for approval. The DOHWA is also responsible for the approval of apparatus for sewage treatment within the state and it provides technical information to assist LGs and the community.In areas where reticulated sewerage is not available, on-site disposal of wastewater is required. An application to Construct or Install an Apparatus for the Treatment of Sewage in accordance with the Health Act 1911 (WA). Sewage in the act includes sewage from faecal waste, urine from toilets, and water from shower, bath, laundry, and kitchen. It necessitates the collection, treatment, and disposal of sewage and greywater to ensure public health safety [h safety . Health  Regulations 1974. The regulations specifically cover construction, installation, and operation of sewage systems. Applications for the installation of OWTS are only approved in the cases where sewer connections are not available [vailable . Code of Practice for the Reuse of Greywater in WA. This Code of Practice supports the long-term reuse of greywater in both sewered and unsewered areas in WA. DOHWA assesses and approves applications when multiple dwellings or commercial premises intend to use greywater for “in-house” end-uses, premises to reuse greywater via spray irrigation, or premises to reuse greywater via subsoil irrigation that produce more than 5,000 L of greywater daily [er daily . Code of Practice for the Design, Manufacture, Installation, and Operation of Aerobic Treatment Units (ATUs). This Code of Practice is published under the provisions of the Health Act 1911 (WA) and to be used simultaneously with the Health  Regulations 1974. It provides guidance on the design, construction, installation, and operation of ATU to serve single dwellings [wellings . Code of Practice for Product Approval of On-Site Wastewater Systems in WA. The Code of Practice specifies the conditions necessary for on-site wastewater systems (OWS) manufacturers who wish to sell their systems to the public or to use the systems for treating and disposing sewage. Applicants are required to demonstrate that the OWS comply with relevant Australian Standards and other regulations through documentations submitted to the DOHWA [he DOHWA . The DOHWA Is Currently Adopting Standards Australia and Standards New Zealand (AS/NZS) 1547:2000 On-Site Domestic Wastewater Management (AS/NZS 1547.2012). This standard is performance based and it guides system design based on site and soil assessment, with the aim of achieving sustainable performance. The DOHWA is currently preparing the Code of Practice for On-Site Wastewater Management with endorsement of AS/NZS 1547. It is expected that this Code of Practice will supersede the current codes and regulations. Government Sewerage Policies. The policies encourage all new developments and subdivisions in WA to connect to reticulated sewerage as the most efficient, socially equitable, and safe method of wastewater disposal [disposal . Howeverdisposal , 18.These legislations and guidelines for OWTS in unsewered areas in WA are listed and briefly described below.This paper aims to review the installations and failures of OWTS in WA from 1997 to 2011. Recommendations to the DOHWA and local government in regard to the administration of OWTS are also presented.A literature review related to OWTS legislation, standards, and approval process was undertaken. Following on from this, data on the numbers of OWTS installed in WA was collected from two sources: centralised DOHWA Data Management System and data provided by LG from their own data systems.As explained above, the LG is responsible for the approval of OWTS producing less than 540 L/day of wastewater while nondomestic and commercial OWTS producing more than 540 L/day are referred to the DOHWA for approval. Inspections of installed OWTS are the responsibility of the LG Environmental Health Officer (EHO). The EHO is required to inspect the OWTS and ensure that installation complies with the approval and conditions issued either by LG or by DOHWA.The DOHWA database collected the following information: applicant's details, date of application, dwelling address and purpose, type of apparatus installed, and date of inspection. The database was created in 1997 and in order to match the information with the DOHWA database, data from 1997 onwards was requested to LG. Data related to the numbers of OWTS approved by LG was obtained via emails that were distributed in August 2012 to 140 LGs across WA. There were 140 LGs across WA at the time the information was requested [At the end of the analysed period in 2011, the DOHWA conducted a survey to gather data from various LGs in WA on the primary causes of OWTS failures. The survey in the form of Microsoft Excel 2007 spreadsheet was sent out to 140 LGs across WA. The information collected in the survey included the type of OWTS and the reasons for system failures. Data was then examined, manually screened, and validated to remove any noncompliance. Follow-up interviews via phone calls were conducted to correct any errors in the data.Overall, 28 LGs (out of 140) provided data on the numbers of OWTS installations . The numBased on the data collected from the DOHWA database from 1997 to 2011, the DOHWA approved over 3,700 OWTS applications, with an average of 247 applications annually. 2 had a total population of 11,950 in 2011, giving it a population density of 0.031 people per km2. On the other hand, City of Stirling had a total population of over 200,000 with a relatively smaller area of 105.2 km2, giving it a population density of 1,958 people per km2.The proportions of OWTS installed in WA regional areas are larger than in urban areas. However, the risks of contamination due to failed systems are higher in urban/metro areas due to the increased density of OWTS. Moreover, increasing population density increases the likelihood of release of contaminants such as nitrogen to the environment in OWTS failure . East PiData collected from 1997 to 2011 have revealed that conventional septic tanks account for 76.5% and 63.7% of all wastewater systems approved by LG and DOHWA, respectively. Due to its simplicity and affordable cost, septic system remains thus far the most common OWTS. This is despite the fact that ATU is becoming more prevalent. As evident from There were a total of 9% of OWTS categorized as “other” by LG. More than 80% of the “other” systems were simply described as other without any description or explanation, whereas the remaining 10% corresponds to 2% holding tanks, 4% greywater system, and 4% nutrient removal system. On the other hand, composting was the type described as “other” in the OWTS approved by DOHWA during the study period of 1997 to 2011.As mentioned in The most common reasons for OWTS failures in the survey include groundwater and surface water ingress, systems not installed properly, unsuitable soil type, and undersized systems. Several LGs also mentioned other factors that contributed to OWTS failures, including increase in wastewater volume, root invasion, illegal installation, unauthorised tampering, cross connection to stormwater disposal, undersized systems, and unauthorised materials . Septic systems remain a preferred option for onsite wastewater management in unsewered urban and rural regions of WA. However, the use of other types of OWTS such as ATU and composting toilets with greywater treatment has increased over the years . Given tAs significant amount of effluent is generated, OWTS have to be installed and monitored properly in order to prevent biological and nutrient contaminants from entering surface water and groundwater . ThroughCurrently, national and state guidelines are available to ensure adequate construction, installation, and management of OWTS in order to protect public health. However, the survey conducted in 2011 indicated that a number of OWTS are either performing poorly or failing with about 48% of OWTS failures in WA, which is due to groundwater and surface water ingress. Other reasons include incorrect system installation, unsuitable soil type, undersized system, increasing wastewater volume, hydrostatic pressure, high groundwater, root invasion, cross connection to stormwater disposal, and a small percentage of unauthorized tampering. Although technology is improving over time and some OWTS are capable of producing better effluent quality, the problems identified in the DOHWA survey are also reported elsewhere. As such, there is a need to assess site and soil conditions rather than relying solely on technology . FailingPopulation density and number of installed OWTS need to be addressed in more detail. Identifying and comparing areas with high OWTS installations in WA are necessary to ensure that effluents are not negatively impacting human or environmental health. In addition, it is essential to ensure that a fair and consistent approach to dealing with malfunctioning OWTS is taken by LGs under the guidance from the DOHWA.Inadequate management strategies and the lack of coordinate institutional arrangements in relation to OWTS have been previously reported in Australia . For insCollecting data of OWTS installations was conducted by the DOHWA via emails, relying on individual LG across WA to provide data on the number of OWTS installed during the study period. However, as previously mentioned, data regarding the number of approved OWTS applications by LG was only collected from 20% of the existing LGs in WA (28 out of 140). While responses were not expected from many of the metropolitan LGs as they have infill sewerage systems it is acknowledged that response was not received from some LGs with OWTS. A follow-up on the LG that failed to respond to the email sent out by the DOHWA staff enquiring about the numbers of OWTS approvals indicates inadequate number of staff to review the applications or lack of adequate records to respond to the survey. Among those who responded, however, several EHOs found it difficult to complete the task due to lack of simple and efficient methods to collate/retrieve the information.Records were not available, due to lack of general file, LG in remote locations, and lack of full time EHOs.Records were not easily retrieved as data stored in offsite storage.Information on OWTS was not recorded in the early years.For some LGs approval, inspection, and ongoing management for OWTS were conducted in a reactive way rather than on a proactive manner.EHOs do not have the time to collate information because OWTS are only one part of their several duties.Systems described as “other” were not explained or elaborated further.Several reasons for the lack of available data from LGs include the following.Lack of appropriate administration system to record OWTS approvals and installations is a significant drawback in the management of OWTS in WA. Without any feasible management strategies to assess and maintain the performance of OWTS in each region, the resulting environmental and public health risks associated with poor system performance would increase. Hence, there is a need to provide a generic approach for a standardized, common system that will allow each LG to record the number of OWTS applications that have been approved and to store information related to the approvals in a clear and standard record system. Furthermore, there is a need for a multigovernance approach that can address the importance of an effective and robust planning and development of sites. Government agencies need to understand their roles and responsibilities in the management of OWTS when assessing applications for land-use or other developments to ensure that all potential effects arising from such developments are considered prior to approvals. It is important that the site assessment for on-site wastewater management be carried out in the early stage of planning phase. This site assessment procedure should be applied at the rezoning or subdivision stages of the planning process. This will help to develop a management regime for OWTS that can minimize health risks and environmental impacts and enhance OWTS's long-term sustainability.It should provide a standard management tool to all LGs for record of OWTS including GPS location. Registration is the first step in complying with the regulatory requirement. Database should be able to record information on installation, operation, maintenance, and any other inspection requirements particularly for ATUs or systems achieving a secondary treated quality effluent.It should implement a soil absorption zone path length of at least 600 mm to reduce the potential for OWTS failure due to ground and surface water ingress.It should provide EHOs with on-site wastewater management training based on AS 1547 and current legislations as part of their professional development and an important measure of quality assurance for the industry, government, and general public.It should produce educational materials to owners of OWTS to facilitate the understanding of how OWTS work, how to identify signs of systems failures, and why inadequate maintenance can increase the system failures and the risk to humans and the environment.Based on the findings reported above, to improve water quality from OWTS, the DOHWA should do the following.They should implement a risk management program to minimise failures, to rapidly identify and to address failures when problems occur. It is considered that a tolerable rate of system failure is smaller than 5% annually.They should implement a planning strategy for OWTS in the early stage of any development to identify the resources that are required to ensure adequate OWTS performance.They should implement site inspection strategies that are predominantly risk based, taking account of sensitive receptors, and should be integrated with other regulatory inspections as appropriate.They should distribute educational materials produced by the DOHWA or LGs to owners of OWTS and provide advices to applicants on OWTS-related matters when required.They should update the register of installed OWTS in each LG jurisdiction and implement an inspection regime to identify legacy sites that will require remediation work. Inspection can initially be targeted at the highest risk areas or OWTS with previous history of failures and complaints.In the case of low-risk sites, a variety of nonroutine inspection strategies and in particular proxy , third party, engagement, and incentive strategies may be implemented. These strategies can involve working closely with home owners or stakeholders to ensure that those who are responsible for OWTS understand how to comply with the regulations and are encouraged to do so.They should embark on a series of activities to raise awareness and compliance related to the operation and maintenance of OWTS. Information campaigns may include the communication of international best practice to Water Services Australia (WSA) and specific local guidance to Nongovernment Organizations (NGOs) and homeowners.They should conduct follow-up site inspections of approved OWTS that focus specifically on operation and maintenance. Priority should be given to known areas of risk or environmental sensitive areas such as OWTS close to rivers and lakes. Inspections will vary in both type and frequency as the inspection program develops over time.As recommendations, the LGs should do the following.