Research investigating Whiplash Associated Disorder (WAD) has largely focused on the cervical spine yet symptoms can be widespread. Thoracic spine pain prevalence is reported ~66%; perhaps unsurprising given the forceful stretch/eccentric loading of posterior structures of the spine, and the thoracic spine’s contribution to neck mobility/function. Approximately 50% WAD patients develop chronic pain and disability resulting in high levels of societal and healthcare costs. It is time to look beyond the cervical spine to fully understand anatomical dysfunction in WAD and provide new directions for clinical practice and research.To evaluate the scope and nature of dysfunction in the thoracic region in patients with WAD.CRD42015026983) and published protocol. All forms of observational study were included. A sensitive topic-based search strategy was designed from inception to 1/06/16. Databases, grey literature and registers were searched using a study population terms and key words derived from scoping search. Two reviewers independently searched information sources, assessed studies for inclusion, extracted data and assessed risk of bias. A third reviewer checked for consistency and clarity. Extracted data included summary data: sample size and characteristics, outcomes, and timescales to reflect disorder state. Risk of bias was assessed using the Newcastle-Ottawa Scale. Data were tabulated to allow enabling a semi-qualitative comparison and grouped by outcome across studies. Strength of the overall body of evidence was assessed using a modified GRADE.A systematic review and data synthesis was conducted according to a pre-defined, registered  which were conducted across a range of countries were included. Few authors responded to requests for further data (5 of 9 contacted). Results were reported in the context of overall quality and were presented for measures of pain or dysfunction and presented, where possible, according to WAD severity and time point post injury. Key findings include: 1) high prevalence of thoracic pain (>60%); higher for those with more severe presentations and in the acute stage, 2) low prevalence of chest pain (<22%), 3) evidence of thoracic outlet syndrome, with some association to and involvement of the brachial plexus, 4) muscle dysfunction in the form of heightened activity of the sternocleidomastoid or delayed onset of action of the serratus anterior, 5) high prevalence of myofascial pain and trigger points in the scalene muscles, sternocleidomastoid and mid/lower fibres of trapezius muscle (48–65%), and 6) inconclusive evidence of altered thoracic posture or mobility.Considerable evidence supports thoracic pain and dysfunction in patients with WAD, involving primarily nerves and muscles. Notwithstanding the low/very low level of evidence from this review, our findings do support a more extensive clinical evaluation of patients presenting with WAD. Additional high quality research is required to further characterise dysfunction across other structures in the thoracic region, including but not limited to the thoracic spine (mobility and posture) and thoracic muscles . In turn this may inform the design of clinical trials targeting such dysfunction. The cumulative incidence of patients seeking healthcare post-whiplash from a road traffic accident has increased over the last 30 years to an annual incidence of between 3 and 6/1000 inhabitants in North America and Western Europe . The sevWhilst research has identified risk factors for poor prognosis , 5, and Although current research into WAD has focused on the primary complaint of neck pain , symptomWith reduced cervical mobility being characteristic of chronic WAD and evidence that the thoracic spine contributes up to 33% and 21% of the movement occurring during neck flexion and rotation respectively  perhaps Nevertheless, a systematic review of the current evidence has never been conducted to examine the scope and nature of dysfunction/impairment in the thoracic spine region following whiplash injury and in WAD. Knowledge of such dysfunction may be used to inform clinical practice and examination of patients with WAD, but also future clinical trials of novel interventions targeting thoracic impairments in WAD.The primary objective is to evaluate the scope and nature of dysfunction in the thoracic spine region in patients with WAD. A secondary objective is to explore the scope and nature of such changes based on severity using the Quebec Task Force classification (I-III) and stage post injury (acute/sub-acute less than 3 months or chronic 3+ months). Thirdly, we wish to make evidence based recommendations for clinical practice and future research.PRISMA)  included: ‘whiplash’, ‘whiplash associated disorder’, ‘WAD’, ‘whiplash injury’, ‘motor vehicle accident OR collision’, ‘road traffic accident’, ‘cervical strain’ and ‘thoracic spine’, ‘dorsal spine’, ‘mid-spine’, ‘thoracic injuries’, limiting to adults >19 years and diagnosis to achieve the best balance of sensitivity and specificity. An example a search from Medline is included Two reviewers  independently searched information sources and assessed identified studies for inclusion, facilitated by grading each eligibility criterion as eligible/not eligible/might be eligible . Full teUsing a standardised form, the two reviewers extracted data independently . A furthData were extracted from each study, including: study design, sample characteristics including age, gender, severity of WAD using the QTF Classification if reported, time point post injury and patient reported or performance based measures of thoracic dysfunction.Risk of bias for each included study was independently assessed by the same initial reviewers. The third reviewer mediated in situations of disagreement. All tools and processes were piloted prior to use. Risk of bias was only assessed for cohort and case-control studies using the Newcastle-Ottawa Scale ; that inSummary measures of patient reported or performance based measures of thoracic dysfunction are presented in the form of prevalence data and confidence intervals where provided, for thoracic pain, chest pain, thoracic outlet syndrome (TOS), myofascial pain and trigger points, dysfunction involving the brachial plexus, thoracic spine posture or mobility. Results are presented where possible, according to severity (QTF) and stage of WAD i.e. acute/sub-acute (< 3 months) or chronic (> 3 months).In accordance with the protocol  meta-anaupgraded where a large dose response was evident, or the effects could not be accounted for by bias [very low’ where concerns were identified from the body of studies relating to precision, consistency, directness, precision or potentially other additional domains relating to strength of association e.g. magnitude of effect [Quality of evidence, including risk of bias across studies was evaluated using GRADE  for indi by bias . Likewisf effect .A total of 38 studies met the eligibility criteria, including 19 cohort studies, 16 case control studies and 3 single case studies/reports. The process of selection is detailed in etc. An overview of the types of dysfunction is provided in Study characteristics are detailed in Agreement of risk of bias following discussion was excellent with studies ranging considerably in quality from 1/9 to 7/9. Key methodological flaws included poor definition of cases, representativeness of cases, lack of non-exposed cohort, lack of blinding, controlling for risk factors beyond age and gender and clarity of follow up time point in cohort studies. There were many instances where information was missing and email requests for additional data or clarification was unforthcoming, resulting in ratings being ‘unclear’. See From this review we identified evidence of the following dysfunction,: thoracic spine pain in acute/sub-acute/chronic WAD ranging from minor injuries to more severe (WADIII) presentations , 58, 62;Synthesis of findings from cohort and case control studies across outcomes of dysfunction are provided in Tables Despite the very low quality of included studies, there is evidence of thoracic spine pain in a sub-acute WAD population n = 11,576) [,576 11,, 52, 60,etc.), time points post injury, sample heterogeneity and the overall methodological low quality of research. This may also be a related to the focus of this review, being to those with mild to moderate presentations of WAD where studies including WADIV or fractures were excluded.Prevalence of chest pain in acute/sub-acute was reported to range 0.0–19% , 17, 52,Evidence of thoracic postural dysfunction is inconclusive given conflicting findings from a small number of studies of low methodological quality evidence where postural assessment was not a primary focus , 61. FutThere is a notable gap in the evidence exploring thoracic and chest mobility in WAD, with just two studies (n = 54) of very low quality suggesting a trend for reduced chest mobility (p>0.05) and flexion hypomobility at the cervico-thoracic junction in women. In terms of thoracic mobility, evidence from one study (n = 7)  suggestsFive studies found, a prevalence of 31–74+% , 47, 51 Acute/sub-acute WADNotwithstanding that evidence is drawn principally from one research group, there is evidence of thoracic dysfunction in relation to the brachial plexus provocation test (BPPT) in WADI-III. From the research by Sterling et al , 57, 59,Chronic WADFor participants with CWADII and/or III, evidence indicates dysfunction detected during the BPPT, with pain levels and restriction in elbow extension almost double those found in asymptomatic controls , 55. FurThere are limited and very variable findings of thoracic muscle dysfunction (activation) in WAD with studies investigating a relatively small number of muscles: sternocleidomastoid , 49, 56;Myofascial trigger points are highly prevalent in WAD with estimates ranging between 48–64% , 37, 40.This is the first methodologically rigorous systematic review investigating thoracic dysfunction in whiplash associated disorders. From a comprehensive search, 38 studies were included and evaluated as part of the review. Many studies were at risk of bias, primarily due to poor reporting with most studies published prior to the introduction of the STROBE reporting guidelines for observational studies. Notwithstanding the low quality of the evidence, there is unequivocal evidence of thoracic dysfunction in WAD.Although there is a high prevalence of acute and chronic pain experienced in the thoracic spine region following injury, distinguishing the interplay of pain mechanisms is however challenging. Whilst we know peripheral and central sensitisation begin immediately following injury , it is pWith limited very low quality evidence and relative to the cervical spine, there is a paucity of research investigating thoracic posture and mobility in WAD , 48, 61.etc. [Although this review suggests a relatively high prevalence of thoracic outlet syndrome, the quality of evidence is very low and derived from relatively older studies, including two studies from the same group of authors , 36. Whietc. . Future There is considerable evidence of brachial plexus dysfunction in both acute/sub-acute and chronic WAD from research investigating the brachial plexus provocation test. Although coming from a relatively small group of researchers, the evidence supports further investigation. Future research could usefully consider the relationship of brachial plexus dysfunction to other musculoskeletal changes in the cervical and thoracic spine following a whiplash injury, but also approaches to managing this; a notable gap within the whiplash management evidence , 10, 66.There is unequivocal evidence of altered function of muscles following whiplash injury , howeverThis review has identified that myofascial trigger points are highly prevalent in WAD , 37, 40,This review provides unequivocal evidence of thoracic dysfunction in WAD, albeit from evidence of low/very low quality. The findings do support a more extensive clinical evaluation of patients following a whiplash injury and the need for more methodologically robust observational studies to further characterise thoracic dysfunction in WAD across stages of the condition and levels of severity. Knowledge and understanding of thoracic dysfunction, where anatomical and biomechanical relationships with the cervical spine exist, offers novel directions for research into management of this disabling condition.etc. targeting the cervical spine [Research into WAD management has been, and continues to be primarily focused on managing cervical spine dysfunction, with interventions such as manual therapy, exercise al spine , and taral spine . With inal spine  it is peetc.[Whilst exercise as part of multimodal packages of care is recommended in the management of acute and chronic WAD , 68, theetc.. The autetc., 10 and etc. further It has not until recent years that the thoracic spine, coined the ‘Cinderella’ of the spine , has staThis review is rigorous and original, with a design and focus on the thoracic spine region using a pre-defined rigorous and published protocol with subject and methodological experts contributing to the evaluation. The key limitation of the review is lack of high quality evidence and compounding this was that few authors responded to requests for additional information or data.This first and rigorous systematic review found considerable evidence of thoracic pain and dysfunction in patients at all stages following whiplash injury. Notwithstanding the low/very low level of evidence, our findings do support a more extensive clinical evaluation of patients presenting with WAD. Key findings include 1) a high prevalence of thoracic spine pain, with the highest levels of pain immediately following injury and in more severe presentations 2) evidence of muscle dysfunction (delayed onset or heightened levels of activity) in a limited number of muscles 3) evidence of thoracic outlet syndrome and brachial plexus involvement 4) inconclusive/limited evidence of postural changes and effect on thoracic spinal mobility. Additional high quality research is required to further characterise dysfunction across other structures in the thoracic region, including but not limited to the thoracic spine (mobility and posture) and thoracic muscles . In turn this may inform the design of clinical trials targeting such dysfunction.S1 Table(DOC)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S3 Table(DOCX)Click here for additional data file.


A cross-sectional study was conducted among rural residents in Zhejiang province, China. Information was collected from 659 participants using a structured questionnaire. Univariate analysis and multivariable analysis were used to analyze the data. Participants were most concerned about property damage, followed by their health and life. Television, short message service (SMS), relatives and friends were the most common information sources. Most people had not been educated with disaster prevention measures. The complementary log–log (CLL) model showed that understanding typhoon warning signal, preparation time, risk perception of health damage and life threat, and fears of typhoon were independent predictors of adoption of coping behaviors. We found that: 1. Residents’ risk perception of health and life threat caused by typhoon is inadequate; 2. There is a gap between residents’ cognition or knowledge and behavior in rural areas; 3. The government should further make strategies to develop educational activities, in order to eliminate the gap and improve the ability of preparing for typhoon among rural residents. Typhoons are considered to be extremely devastating natural hazards worldwide. There are seven to eight typhoons on average landing on the coastline areas of southeastern China each year, which makes China one of the countries that were hit most frequently by typhoons ,2. BetweStudies have reported that the impact of typhoon disaster depends on the intensity and strengths of the typhoon, which is also linked with the precautionary concerns and knowledge of local residents . Lack ofKnowledge of the public’s awareness about risks from natural disaster is of vital importance to effective risk communication strategies ,13. In rPrevious studies have indicated that residents’ awareness and coping behaviors of typhoon disaster was related to their socio-demographic characteristics, especially educational status and economic conditions ,19. RuraIt has been reported that among rural residents, the KAP-gap (knowledge–attitudes–practice gap) hampers their ability to takes valid adaptive measures . People Among the southeastern regions of China, Zhejiang province is one of the very high-risk provinces most frequently affected by typhoons . Super TA cross-sectional study was conducted in July 2015, 10 days after the typhoon “Chan-hom” landing on the southeast coastal area of Zhejiang. Ninghai, one of the counties affected by “Chan-hom” was selected as study site. Ninghai is a county with multiple typhoons every year and has contingency plans for typhoon disasters. Cluster sampling was used to choose three villages in Ninghai. The population of the three villages ranged from 1400 to 1900 and the maximum distance between these villages and coastlines is no more than 10 km. We calculated the sample size for this study according to the formula of survey sample size calculation , as wellThe targeted study population was local residents of the three villages. The criteria for the participants to be included were: (1) local resident or had lived in the village for at least one year; (2) in the village during the typhoon; and (3) 15 to 74 years old. All eligible residents were invited to participate in the study. Migrant workers, people with mental diseases, and unconscious persons were not included.A structured questionnaire was developed after a review of the literature in combination with consultations with local CDC experts who are familiar with the situation of local residents and typhoon. The questionnaire collected the following information: (1) demographic characteristics, such as gender, age, race, educational level, occupation and marital status; (2) source of typhoon warning information and risk perceptions of typhoon ; (3) attitude towards typhoon disaster prevention; (4) knowledge and individual behaviors to cope with typhoon disasters, including a question about awareness of typhoon warning signal; (5) disaster insurance and government’s measures on evacuation.Interviewers were trained staff at the local Centers for Disease Control (CDC) and graduate students from Shandong University, who were familiar with field interviews and received training before the survey. A quality control person was assigned to each of the seven groups of interviewers. All information was collected by face-to-face interviews at participants’ homes. Thirty-three people refused to participate in our study. The main reason being the perception of receiving no benefit from the study and/or a waste of their time. A total of 683 participants were interviewed with a response rate of 95.4%. There were 24 (3.5%) questionnaires having too much missing information and errors, which were excluded before being entered into the computers. We included 659 valid questionnaires in our analysis.p < 0.15) from the univariate analysis were then analyzed by complementary log–log (CLL) regression for the reason that the Yes/No responses of dependent variable were asymmetrically distributed [Data were entered into Epidata version 3.1. Statistical analysis was conducted with the Statistical Package for Social Sciences (SPSS) version 21. Descriptive statistics were used to describe respondents’ demographic characteristics as well as their perceptions, attitudes and behaviors. Chi square or Fisher’s exact texts were used to test for the relationships between demographic variables and other categorical variables. The mean and standard deviation (SD) was used to describe the score of risk perception. Factors with significant associations  of Public Health at Shandong University has reviewed and approved the proposed use of human subjects in this survey (No. 20120501). Written informed consent was obtained from each participant  after they were informed that their participation was voluntary and their refusal to participate would have no negative consequences. All data were kept anonymous and confidential throughout the study.The mean age of participants was 48.9 years with a standard deviation (SD) of 14.0 years. The majority of respondents was in their middle age or older  and currently married (87.4%). As the study was conducted in coastal rural villages, almost all the respondents (98.8%) had a rural household registration and most participants were farmers (71.0%). Over half of the participants (55.1%) had primary and lower level of education including 30.1% were illiterate, 40.2% had secondary education, only 4.7% had post-secondary education or higher. The majority (88.4%) of the illiterate group was over 50 years old. There was no significant relation between adopting behaviors and gender, age, education, or marital status. 2 = 14.087, p < 0.001) and illiterate  preferred to house-to-house notification, while people who were less than 50 years old  and educated  preferred SMS. The average time that respondents were informed with typhoon warning information in advance was 2.8 days , with a range from one to five days.Television media was the most commonly mentioned way (83.5%) to get information before a typhoon, followed by short message service (SMS) (32.7%), and relatives/friends (27.8%). As for the most favorable way, people were inclined to television media (76.8%), SMS (43.9%) and house-to-house notification (36.0%) . There w2 = 31.293, p < 0.001), so were people over 50 years old .Most participants (74.9%) claimed that they knew how to prepare for the typhoon disaster, with the leading measures including: shutting the doors and windows (93.0%), keeping a watchful eye on typhoon warning (54.8%), preparing emergency articles include foods and drugs (54.0%), leaving the dangerous area (53.0%), keeping away from low-lying areas (48.2%), and checking the electrical circuit facilities (44.3%). Most participants knew that shutting the doors and windows could reduce losses, however, the awareness rate of other measures was not high, and the highest rate was 54.8%. The awareness rate of typhoon warning signal among our respondents was only 11.9%. As for coping behaviors taken, 82.9% participants claimed that they adopted measures before and during typhoon. However, this claim was inconsistent with the responses to the questions about the specific adoptive measures taken, only 434 (65.9%) stopped all outdoor activities, 289 (43.9%) repaired and reinforced their house, 277 (42.0%) stored foods and water. Of the participants, 17.1% did not adopt measures at all for the following reasons: (1) Did not know how to adopt measures; (2) Unnecessary to adopt measures; (3) No time to adopt measures. Among those respondents who adopted coping behaviors during typhoon, 94.4% thought it effective. The majority (73.3%) of the participants did not purchase disaster insurance, especially property insurance and agricultural meteorological disasters insurance , mainly In the univariate analysis, understanding typhoon warning signal, preparation time, perception of property damage, perception of health and life damage, fears of typhoon and attention were found to be significant factors (at 0.15 level) that affected the adaptation of coping behaviors. The factors were then included in the CLL model in the multivariable analysis. The results showed that knowing about the typhoon warning signal, preparation time, perception of health and life damage, and fears of typhoon were significant predictors of the adoption of coping behaviors while perception of property damage and attention were not statistically significant. Respondents with a better awareness of the typhoon warning signal , more days informed before typhoon , and higher fear of typhoon  were found to be more likely to adopt coping behaviors .In this study, we investigated the risk perception, attitude, knowledge, and behaviors related to typhoon among vulnerable residents in Zhejiang province which will be useful in preparing for future catastrophic events. Our results show that respondents had a high-risk perception of property damage, while the risk perception of health damage and life threat caused by typhoon was not enough. Majority of participants did not receive any formal education about typhoon disaster prevention prior. This could be a factor in lack of appropriate actual coping behavior. Although the majority. Although majority of them claimed they paid attention to typhoon disaster prevention and knew how to adopt measures, the actual coping behavior before and during typhoon was inadequate refer to .In our study, most residents identified television as the main ways to get information before typhoon (83.5%), the result was similar with previous studies in China ,28, FlorWith regard to the risk perception before typhoons, participants in our study showed a high concern on property damage, while an insufficient concern on health damage and life threat regardless of residents' gender, age or educational level. This result was similar with the previous study in New Jersey which indicated that the greatest concerns of residents before the typhoon was possessions and property damage, while during and after the disaster, their major concerns were personal health . In our Our results showed that there was no difference between residents’ risk perception, coping behaviors and their socio-demographic characteristics which is inconsistent with previous studies ,18. The Residents have paid great attention to typhoon disaster prevention, and most residents claimed that they knew how to prepare for a typhoon event. However, from our findings, their knowledge about adaptation measures was still inadequate. Most participants thought that shutting the doors and windows could reduce losses, but there were a significant proportion of participants who did not think the other measures such as keeping a watchful eye on typhoon warning, preparing emergency articles including foods and drugs, leaving the dangerous areas, keeping away from low-lying areas could work. The awareness rate of some critical issue like typhoon warning signals was low. The majority of participants claimed that they adopted coping behaviors before and during typhoon. However, only a fraction of participants actually responded when specific measures were asked. There was a gap between what they claimed and what they did. In our study, the result manifested that most residents received no typhoon preventive education, and the majority of the respondents expressed that they were willing to take part in the educational course. Previous study also suggested that compared with persons with general preparedness knowledge, persons with new knowledge and updated information were more likely to respond to typhoon effectively . As a reZhejiang is one of the most economically developed coastal provinces, the insurance industry in Zhejiang province has made a great contribution in the insurance indemnity of relief work. Ningbo city had been also developed as a comprehensive insurance pilot area a few years ago ,37. HoweOur study found that residents with more preparation time, a higher risk perception of health damage and life threat were more likely to take measures, so did people who were scared of typhoons. In addition, our study also found that residents with a clear understanding of typhoon warning signals would be more likely to adopt measures than others. Although residents may get information from TV to know the intensity and arrival time of typhoon to take responses, a better understanding of the typhoon warning signals also contributes people to adopt effectively coping measures to some extent, especially when there is blackout caused by a typhoon. While previous studies suggested that the perception of a high risk of injury is important in individual’s evacuation decision making in the face of disaster ,39, thisIn general, residents in costal rural areas have a high risk perception of property damage while that of health damage and life threat need to be improved. Most people thought they were aware of how to adopt measures to reduce losses, they were in fact still less knowledgeable and their coping behaviors were inadequate. This indicates an urgent need for appropriate targeted strategies and a necessity to develop educational and other suitable information activities to eliminate the gap. Public anti-disaster capacity building is linked with a strong awareness of disaster prevention. Only when residents have fully realized the influences and harmfulness from typhoons are they able to take the corresponding preventive measures seriously. Our findings will be useful for developing strategies to make adaptations to minimize the health and property loss.Our study has some limitations. First, our survey was conducted 10 days after the typhoon, people’s attitude and risk perception may change slightly before and after the landfall of the typhoon, and the difference could not be compared. Typhoon may improve the perception and awareness to some extent. During our investigation, we tried to use objective indicators as many as possible in questionnaires and explicitly asked participants face-to-face about their attitude and perception before typhoon to control this bias. Secondly, there were many young farmers going out for work, and over half of the participants were older than 50, thus the results might not represent the situation in total population. However, migrant workers are also a common phenomenon in rural areas in China, thus we believe that our participants are a representative sample of those who stay in the village and the results can still provide implications of how rural communities might cope with typhoons.Based on our findings, the rural residents in Zhejiang Province had a high attention on typhoon disaster prevention and a high-risk perception of property damage, while paying less attention to the risk perception of health and life risks. Most residents knew some measures to reduce losses, however the actual coping behaviors were inadequate. There was a gap between residents’ cognition or knowledge and behavior. Only a fraction of the participants received specialized education before. The popularizing rate of disaster insurance was pretty low. The government should further make strategies including educational activities, to eliminate the knowledge and behavior gap, improve typhoon preparedness, actively promote and expand the coverage of disaster insurance to rural residents.


Dirofilaria species infect dogs: D. immitis and D. repens. While D. immitis has a worldwide distribution, D. repens is currently found only in Europe, Asia, and Africa. Adult D. repens are located in subcutaneous tissues of natural hosts where they survive for long periods of time. First-stage larvae, microfilariae, circulate in the peripheral bloodstream, where they are taken up by the mosquito intermediate hosts. Infected mosquitoes then transmit infective third-stage (L3) larvae to new hosts through the blood meal. In dogs, most infections are asymptomatic, although cutaneous disorders such as pruritus, dermal swelling, subcutaneous nodules, and ocular conjunctivitis can be observed. Currently, two factors have increased the concerns about this parasitic infection 1) its spread throughout the European countries and to other continents and its prevalence in dog populations, where in some cases it has overcome D. immitis; and 2) its zoonotic potential, which is much greater than that of D. immitis.Two main D. immitis. Furthermore, the absence of clinical signs in the majority of canine infections and the difficulty in diagnosing the infection, due to the lack of serologic tests and thus the reliance on the identification of microfilariae and differentiation from D. immitis to confirm the presence of the parasite, favor the further spread of this species. Finally, among the macrocyclic lactones currently used to prevent heartworm infection, only moxidectin has been found to be fully effective against the infective larvae transmitted by mosquitoes and partially effective (efficacy 96%) against adult D. repens in experimental studies.Different hypotheses can be put forward to explain these concerns. First, climate change has allowed more favorable conditions for survival of culicid vectors. Second, accidental hosts such as humans may have a less efficient immune reaction against a parasite that is located in subcutaneous tissues, and thus less exposed to the host’s immune response than, for instance, Dirofilaria repens infection is much more difficult than D. immitis to diagnose and control in the reservoir population (microfilaremic dogs). In addition, lack of familiarity with D. repens infection could lead to lack of vigilance underestimation for this parasite. The number of human cases in Europe and Asia is currently a serious public health concern. Medical doctors and veterinarians must collaborate closely for better control and surveillance of D. repens infection. Dirofilaria (Noctiella) repens and D. immitis. D. repens is endemic in many countries of the Old World but has not yet been found in the Americas  survival . Interessurvival survival . In mostsurvival . Occasiosurvival . Allergireported . In thesD. repens infection as they frequently have microfilariae in the peripheral blood. Since the early 1900s, canine D. repens infection has been reported as endemic in central and southern Italy and in other southern European countries, such as France, Greece, and the former Yugoslavia [D. repens infection. The introduction of the Pet Travel Scheme in 2000 allowed easier movement of companion animals throughout the European Union [Aedes albopictus) and other competent vector species such as Ae. koreicus [D. repens prevalence is higher than D. immitis: for example, in Romania, where the heartworm prevalence ranges 02% to 2% and the D. repens prevalence range is from 7% to 20% [Infected dogs are the main reservoir of goslavia . Severalan Union . Rising koreicus . Currentkoreicus –19. It i% to 20% .D. immitis and D. repens. Comparing the data of zoonotic infections caused by D. immitis in the United States and Japan with that observed in Europe in recent years, however, the figures are surprisingly different. Approximately 110 human cases of D. immitis have been reported in the US in the last 50 years [D. repens, more than 3500 human cases were reported in Europe from 1977 to 2016 [D. repens have such a high zoonotic potential in comparison with D. immitis?Humans can be accidental hosts for both 50 years , 24 and 50 years , while i50 years –28. It i to 2016 –32. Furt to 2016 –35. The D. immitis strain in the Americas than in Europe, although recently genetic differences have been observed in worms from human ocular infections both in the Americas and Europe [Dirofilaria [D. repens, while a clear genetic difference has been found among D. repens–like worms from Asia (India and Thailand) and between the Asian and the European samples, the genetic variability within the European samples is rather low [Currently, there is no evidence indicating the existence of a more virulent d Europe , 37, sugofilaria . Concernther low .D. immitis and D. repens, however, are able to grow in the same mosquito species and at the same temperature and humidity under laboratory conditions. In addition, both species have the same developmental time from the microfilarial stage to the infective larva [D. repens larvae have been identified in Anopheles maculipennis and Aedes vexans from Slovakia and Austria [D. immitis and D. repens in Culex pipiens from Germany and Italy [D. immitis [One hypothesis to justify such a difference in the zoonotic potential between the two species could be a consequence of an unidentified factor related to the vector. Both ve larva , 17. Rec Austria , 41 and nd Italy , 43. The immitis . TherefoD. repens infective larvae are transmitted by an infected mosquito, in most cases the parasite is found in subcutaneous nodules or in the ocular conjunctiva, apparently near the points of infected mosquito bites [D. immitis larvae that migrate within deep tissues where they could be killed by the immune system of the host [In humans, once to bites , althougto bites –46. In mto bites , 47. We the host .D. repens infections are subclinical or the clinical signs are nonspecific, and most infections go undiagnosed. Furthermore, while several antigen test kits with high sensitivity and specificity are available for the serologic diagnosis of heartworm infection, no serologic test is available for D. repens. This also makes the diagnosis of occult infections, despite clinical suspicion, nearly impossible [D. repens and D. immitis [Dirofilaria species [Dirofilaria infections, but this is the only method of D. repens diagnosis. Many veterinarians, however, are not familiar with the Knott test, which allows for visualization and identification of microfilariae, particularly those in areas where the parasite has only been recently introduced.Most canine possible . It is n immitis  is due t immitis  may incr species . ExaminaD. immitis patent infections  was assessed in several experimental laboratory studies and in field studies [D. repens has been evaluated only for the oral ivermectin formulation at 6 μg/kg and 12 μg/kg [D. repens microfilariae; only moxidectin has been approved as a microfilaricidal agent and it must be administered in four monthly doses [The efficacy of the macrocyclic lactones (ML) currently used to prevent  studies  and all  studies . No repo12 μg/kg  and both12 μg/kg , 55. Bot12 μg/kg . Furtherly doses .D. repens, the efficacy of melarsomine dihydrochloride currently used against D. immitis patent infections is doubtful. There is only one report of an effective treatment obtained with melarsomine plus doramectin in a dog naturally infected with D. repens [Against the adult stages of . repens , but the. repens .D. immitis infective larvae is 3 μg/kg vs 6 μg/kg of ivermectin [D. repens larval stages and adult worms reside in the subcutaneous tissues, which are rich in fat and connective tissue.There are several reasons that might explain the difference in efficacy between avermectins and milbemycins. Moxidectin is more lipophilic in nature than ivermectin and it is stored in the fat, which may act as a drug reservoir. Compared with ivermectin, moxidectin has a higher distribution volume and a longer half-life elimination. This may facilitate its distribution from the bloodstream to different tissues and longer residence time for the drug in the body , 59. FurTherefore, the higher lipophilic nature of moxidectin is probably the reason for the full efficacy observed in the studies. Furthermore, P-glycoprotein (P-gp) is a membrane protein belonging to the superfamily of the ATP-binding cassette (ABC) transporters and exerts a potent action vs drug disposition. Moxidectin toxicity depends to a lesser extent on P-gp activity compared with ivermectin (moxidectin seems to be a weaker substrate inhibitor of P-gp than ivermectin ). This mD. repens infection is much more difficult than D. immitis to diagnose and control in the reservoir population (microfilaremic dogs). If the spread of D. repens continues, it is certainly possible that it could be introduced in the United States by translocation of infected dogs. In addition, while veterinarians and pet owners are aware of D. immitis infection [D. repens infection could lead to lack of vigilance underestimation for this parasite.For all the reasons discussed in this article, nfection , lack ofD. repens is not merely a reflection of the more “visible” clinical signs in humans, eg, subcutaneous nodules and conjunctival and subconjunctival infections, which are easier to diagnose than D. immitis lung infections. Nonetheless, medical doctors and veterinarians must collaborate closely for better control and surveillance of D. repens infection. In the Ukraine, reporting cases of dirofilariosis has been mandatory since 1975, and the disease was included in the national surveillance system for notifiable diseases [D. repens infections can be found in the ESCCAP Guideline 5 [The number of human cases in Europe and Asia is currently a serious public health concern. On the other hand, we cannot exclude the possibility that the high zoonotic impact of diseases . Guidelideline 5 .


Developing new clinical practice guidelines (CPGs) can be time-consuming and expensive. A more efficient approach could be to adopt, adapt or contextualise recommendations from existing good quality CPGs so that the resultant guidance is tailored to the local context.‘adopt’ this (parent) clinical practice guidelines, and implement the recommendations in their entirety, without any changes, in your setting? If so, then no further work is required. However this situation is rare. What is more likely, is that even if recommendations from the parent clinical practice guidelines can be adopted, how they are implemented needs to address local issues. Thus you may need to ‘contextualise’ the guidance, by addressing implementation issues such as local workforce, training, health systems, equipment and/or access to services. Generally this means that additional information is required (Practice/Context Points) to support effective implementation of the clinical practice guidelines recommendations. In some cases, you may need to ‘adapt’ the guidance, where you will make changes to the recommendations so that care is relevant to your local environments. This may involve additional work to search for local research, or obtain local consensus, regarding how best to adapt recommendations. For example, adaptation might reflect substituting one drug for another . There is lack of standardisation of clinical practice guidelines terminology, leading clinical practice guideline activities often being poorly conceptualised or reported. We provide an approach that would help improve efficiency and standardisation of clinical practice guidelines activities.The first steps are to search for international CPGs that have a similar purpose, end-users and patients to your situation. The second step is to critically appraise the methodological quality of the CPGs to ensure that your guidance is based on credible evidence. Then the decisions begin. Can you simply  The volume of literature available to support the construction of new (de novo) evidence-based clinical practice guidelines (CPGs) was recently highlighted by Schünemann et al. in a recent comprehensive international review of the content of 35 guideline development manuals . This voHowever international CPG repositories are generally freely available via the internet –11 and aDe novo CPG development (‘from scratch’) is usually an expensive and time-consuming business, requiring dedicated teams of methodologists and experts , who search, critique and debate the usefulness and relevance of the body of evidence which could provide relevant clinical guidance. Consequently, the financial, human resource and opportunity costs of de novo CPG development are often outside budgets of low-to-middle income countries (LMICs). Moreover, the disease burden in these countries is often higher than in middle-to-high income countries, and thus a focus on evidence-based disease management is often even more urgent, to minimise wastage and ensure optimal care for optimal cost . Thus inThis paper proposes ways to consider the need for de novo CPG development when already available good quality CPGs might be sourced from elsewhere, and modified to provide guidance appropriate for local contexts.In a paper we recently published, we proposed a CPG classification system [the ‘South African Guidline Evaluation (SAGE) Clinical Practice Guideline Development Framework’] that has a base of transparent evidence synthesis processes (tier one); layered with clinical contexts (tier two); which in turn supports end-products tailored specifically for different contexts, users and purposes (tier three)—classified as ‘evidence-based summary recommendations’, ‘patient management tools’, or ‘protocols’.The evidence base forms the foundation of all forms of clinical guidance. Without this tier, there is little to support the credibility of recommendations in terms of ‘what the evidence says’. Producing the evidence base is usually the domain of methodologists, who establish what literature is available to answer clinical questions in the CPG, and how believable the evidence is. The GRADE group produced a widely-used set of instructions to classify the strength of the underlying evidence for CPG recommendations [very strong  to the very weak ] , 18. To Evidence derived from experts is not always dependable. While expert opinion is an essential element in the Evidence-based Medicine model proposed by Sackett et al. , it needThe second CPG tier we proposed requires expert input, as this layer is essential in determining relevance and applicability of research evidence to local contexts. Local contexts deal with a range of issues that are often not addressed or reported in the body of research, such as local systems, and operational issues such as funding and funding priorities, historical health service delivery, health priorities, health workforce type, training, mobility and availability, how decisions are made, available human and infrastructure resources, burden of disease, and patient need. In a CPG team, determining the second layer of CPGs is usually the domain of lead clinicians, managers, policy-makers, funders and end-users . However, there is little in the CPG literature regarding how to comprehensively address the relevance and applicability of evidence, to local contexts. FORM is one of the few tools that provides guidance when considering the contexts of recommendations, regarding applicability to end-users and patients, and relevance to local healthcare environments . This seThis is the least well explored in the literature, and it refers to the way that guidance is presented to address end-user needs . How recommendations are presented has a significant impact on evidence-uptake and compliance , 22.Adopt, Contextualise or Adapt CPGs, using an existing high quality evidence base from international guidelines developed in other countries for the same target patient population and the same end-users. CPG groups should rather not focus on recreating Tier 1 in the CPG development framework [Considering the cost, time and human resource implications of de novo CPG development, we suggest that CPG groups should consider alternatives to de novo development activities. To assist CPG groups particularly in LMICs to be effective and efficient, we propose an approach to ramework , but insAdopting refers to something being accepted and put into use without any change [e.g. a suitcase borrowed and being used as it is  be changed (depending on whether the guidelines questions remain relevant in the new setting), and adaptation may occur within the Tier2 process, to revise the way recommendations are worded or presented in Tier 3. Not adapting may mean that the CPG recommendations may be rendered useless in a new setting. The analogy of the suitcase ‘chair’ is provided  for a condition may be readily adopted, whilst recommendations for management  may require contextualisation and/or adaptation to be actionable locally.Research into CPGs has escalated over the last 15–20 years, with a concomitant increase in theories and methods . Terminothe systematic approach to considering the use and/or modification of a guideline developed in one cultural or organizational setting for application in a different context. Adaptation can be considered as an alternative to de novo guideline development …….Best known research into transferring CPGs from one setting to another is the work of the ADAPTE Collaboration, which reported 24 steps in adapting CPG recommendations from one setting to another process , 7. ThisThe adaptation process…….has been designed to ensure that the final recommendations address specific health questions relevant to the context of use, and address the needs, priorities, legislation, policies and resources in the target setting without undermining the validity of the target recommendations’ (Adaptation Resource Kit 2009 p9) [2009 p9) . We beli2009 p9) . PARM re2009 p9) . This wo2009 p9) .Table 2AThe differences between the ADAPTE framework and the PARM group’s processes are outlined in Table CPGs are integral to the delivery of best practice care. The work required to develop and update the evidence base underpinning CPGs needs to be ongoing, to ensure currency of the evidence base underpinning recommendations. However the utility, applicability and relevance of recommendations to local settings requires significant investment from local experts and opinion leaders . Clear d


Post-deinstitutionalisation, mental health supported accommodation services have been implemented widely. The available research evidence is heterogeneous in nature and resistant to synthesis attempts, leaving researchers and policy makers with no clear summary what works and for whom. In this context, we undertook a comprehensive systematic review of quantitative studies in order to synthesise the current evidence on mental health and psychosocial outcomes for individuals residing in mental health supported accommodation services.Using a combination of electronic database searches, hand searches, forward-backward snowballing and article recommendations from an expert panel, 115 papers were identified for review. Data extraction and quality assessments were conducted, and 33 articles were excluded due to low quality, leaving 82 papers in the final review. Variation in terminology and service characteristics made the comparison of service models unfeasible. As such, findings were presented according to the following sub-groups: ‘Homeless’, ‘Deinstitutionalisation’ and ‘General Severe Mental Illness (SMI)’.Results were mixed, reflecting the heterogeneity of the supported accommodation literature, in terms of research quality, experimental design, population, service types and outcomes assessed. There is some evidence that supported accommodation is effective across a range of psychosocial outcomes. The most robust evidence supports the effectiveness of the permanent supported accommodation model for homeless SMI in generating improvements in housing retention and stability, and appropriate use of clinical services over time, and for other forms of supported accommodation for deinstitutionalised populations in reducing hospitalisation rates and improving appropriate service use. The evidence base for general SMI populations is less developed, and requires further research.A lack of high-quality experimental studies, definitional inconsistency and poor reporting continue to stymie our ability to identify effective supported accommodation models and practices. The authors recommend improved reporting standards and the prioritisation of experimental studies that compare outcomes across different service models.The online version of this article (10.1186/s12888-018-1725-8) contains supplementary material, which is available to authorized users. These studies are unique, not only for their population-focus but also for the type of supported accommodation examined; the bulk of the ‘homeless’ papers examined the permanent supported housing approach which aims to support homeless individuals to achieve housing stability or permanent accommodation, as well providing support with mental health issues. Specifically, this approach “ollowed”  (p.2). In = 16), followed by RCTs (n = 8), quasi-experimental studies (n = 6), and a single case control study (n = 1)  . ParadoxIn total, six homeless supported accommodation service studies examined the association between the supported accommodation and substance use .Across the seven studies , with a smaller number of quasi-experimental (n = 2) and a single case-control (n = 1) and randomised controlled trial (n = 1) . Importantly, as opposed to the deinstitutionalisation group, they will generally not present with the clinical, social and behavioural impairments associated with long-term hospitalisation.n = 19) [n = 4) [n = 18), with one quasi-experimental (n = 1) and one matched case control study (n = 1)  –91, 96,  [n = 4) –95. HoweFor this group of papers, service types ranged from intensive congregate residential care settings, with 24 h staffing , 93, 95,Twelve papers, including two high quality , 94 and Nine papers assessed changes in symptoms over time . These findings are in line with the conclusions of a recent review of HF [The strongest evidence for supported accommodation comes from research with homeless mentally ill populations and the permanent supported housing model. Studies in this area demonstrate consistent evidence for improvements in housing retention and stability, and appropriate use of clinical services over time. There is also some indication that this form of support for this group is associated with improvements in symptoms, QoL and social functioning, but this evidence is inconsistent. The majority of studies reviewed found no change in substance use over time. As stated by Tsermberis , “Housinew of HF .Although the permanent supported housing approach has been shown to be effective in some domains, the intervention specifically targets mentally ill homeless populations, and the characteristics of the studied cohorts make generalising to other mental health populations troublesome. First, many of the samples used in these studies have relatively low rates of serious psychiatric illness. In the current review, we utilised a > 50% with psychiatric diagnosis cut-off point to ensure we included appropriate studies. However, even with this approach, it remains difficult to confidently apply the synthesised findings to other groups of people with mental health problems. Second, the presence of long term homelessness amongst the target population conflates the findings when considering the applicability to general SMI populations. It remains difficult to establish whether positive changes in psychosocial outcomes are attributable to intervention components that impact on homelessness (such as housing), or mental health (such as medication management) or both. Third, participants in the permanent supported housing studies typically present with higher rates of drug and alcohol use than comparable, non-homeless samples. There is danger that, due to the large and growing evidence base for these services, policy makers will attempt a wholesale import of the permanent supported housing model for use with psychiatric populations, without a reliable evidence base.Research on outcomes in supported accommodation for deinstitutionalised populations provided good evidence for improvement or non-deterioration in psychiatric symptoms, social functioning and rates of rehospitalisation. There was limited evidence for improvement in QoL and employment. Notably, a number of studies highlighted a consistent association between more restrictive settings and poorer outcomes, across psychiatric, social and QoL outcomes, for this group. Although, these findings are somewhat inconsistent, the threshold of ‘success’ for this population is radically different than for other groups. Due to the severity of clinical presentations and duration of institutionalised care, most researchers and clinicians consider the absence of deterioration as indicative of successful transition to community care. Indeed, one of the greatest challenges of the deinstitutionalisation process was to address the chronic psychiatric, social and behavioural difficulties of patients, while simultaneously maintaining their tenure in the community . SupportIn reality, the deinstitutionalisation ‘story’ has already been told; in most European and north American countries, the deinstitutionalisation process commenced the late 1980s and early 1990s and, as such, the majority of the studies cited in this review are old, or report on longer-term follow-ups. It is generally accepted that community based settings are more humane and offer a better QoL than long term hospitalisation . This isThe reviewed papers in this group presented less clear evidence between supported accommodation and psychosocial outcomes for general SMI populations. While there was a trend toward reductions in rates of hospitalisation over time, the evidence was mixed with regards to symptoms, social functioning and QoL, with studies variously demonstrating improvement, no-change, or deterioration in these outcomes over time. These findings may reflect the heterogeneous nature of the literature.This sub-group had the fewest number of studies overall, the fewest number of high-quality papers and the largest number of omitted low-quality studies, yet this population is growing rapidly, reflecting the broad adoption of the supported accommodation model, current approaches to community-based rehabilitation and the rejection of long-term hospitalisation as a form of treatment.. This observation highlights an urgent need for increased research in this area. As mentioned above, there is a genuine danger that due to the growing evidence base, the HF model is applied to this group despite the problems in generalising the research findings.The current review had a number of strengths. We applied a thorough search strategy, utilising a broad date range, and included a range of psychosocial outcomes and a variety of quantitative designs beyond RCTs. These methodological decisions enabled us to be comprehensive in our review and confident in capturing all key outcome studies.As the reviewed studies relate to supported accommodation only, it must be acknowledged that, by examining the outcomes in relation to subgroups, broader findings related to these groups may have been overlooked. For example, many of the Team for the Assessment of Psychiatric Services (TAPS) studies, and other programmes of research investigating outcomes for deinstitutionalised groups, were not included in this review as they did not explicitly consider supported housing, however data from these studies would have expanded and contextualised the reported findings as they relate to the deinstitutionalisation sub-group. The population-based conclusions, therefore, must be considered strictly in relation to supported accommodation.As we were unable to examine differences in outcomes across models, the current review cannot comment on their relative merits in relation to outcomes. As described, there is a large variation in housing models; within each of the population sub-groups considered above, service models ranged from independent tenancies with outreach support to high-staffed, congregate residential settings. Inevitably, the characteristics of a service, such as the physical structure, staffing arrangements, levels of support, recovery focus, and discharge and move-on policies, will impact on service user outcomes, possibly beyond the influence of population characteristics. As a result, this review is limited in its ability to fully consider the effectiveness of mental health supported accommodation services.By comparing services from different national contexts, we aimed to enhance our understanding of the critical components of these interventions and how contextual factors impact outcomes. However, due to the aforementioned variation in service models (evident even within countries), it was difficult to discern the impact of national level factors, such as legislation, funding barriers or statutory responsibilities. The international focus of this review makes it challenging to provide any specific recommendations for local policy makers and commissioners. A more targeted study, focusing on one country or region, would be better suited for this purpose. In line with the recovery approach, however, it is likely that any high-quality supported accommodation provision will comprise of a range of accommodation options, with the delivery of flexible, personalised support.Finally, as we have considered evidence from non-RCT designs, the data presented herein, even from studies rated as ‘high quality’, should be interpreted with caution.In the absence of evidence of their relative efficacy, decisions on the provision of alternative forms of accommodation and continued support for people with mental illness can only be based on a combination of professional judgement, patient preference and availability” (p.6).The mixed results of this study highlight the heterogeneity of the supported accommodation literature, in terms of research quality, experimental design, population, service types and outcomes assessed. There is some evidence that supported accommodation is effective across a range of psychosocial outcomes, with the most robust evidence showing the effectiveness of the HF model for homeless SMI and for other forms of supported accommodation for deinstitutionalised populations in reducing hospitalisation rates and improving appropriate service use. The evidence base for general SMI populations is less developed, and requires further research. Unfortunately, these broad observations reinforce the conclusions of Chilvers and colleagues  in theirThe intention of the current review was to compare and contrast the effectiveness of various models of supported accommodation, across a range of psychosocial outcomes. However, as noted, this attempt was stymied by the large variation in service models, the lack of definitional consistency and, at times, poor reporting practices in the literature. In order to make assertions regarding the effectiveness of various models of supported accommodation, it is clear that a simple method of service categorisation, based on current reporting practices, is required. A taxonomy that can be applied retrospectively to existing research, and utilised in future studies, would allow effective synthesis of outcome data, facilitate an examination of efficacy and effectiveness, and strengthen follow-up/replication studies . While sMental health supported accommodation services are widely implemented, however, currently we have no clear research base articulating what works and for whom. There is a clear need for high quality effectiveness research, improved reporting standards and consistent and meaningful descriptions of supported accommodation services in the literature. Researchers must prioritise experimental studies that compare outcomes across different service models. These developments should inform and improve mental health commissioning and service development decisions in the future.Additional file 1:Final Search Strategy. The search strategy used for the systematic review, organised according to database. (DOCX 28 kb)Additional file 2:Summary table: All included studies. Summary of extracted data from all studies included in the final synthesis. (DOCX 60 kb)


Bile acids (BAs) are important regulatory factors of life activities, which are involved in the regulation of glucose, lipid and energy metabolisms, and closely associated with intestinal hormones, microbiotas and energy balance. BAs abnormalities easily lead to inflammation and metabolic diseases, in turn, the progress of diseases could influence characteristics of BAs. Therefore, accurate detection of BAs contents is of great significance to disease prevention, diagnosis and treatment. At present, the most widely used enzymatic method in clinical practice is applicable to the detection of total bile acid (TBA). In laboratory research, different types of BAs can be accurately separated and quantified by liquid chromatography-mass spectrometry (LC-MS). The metabolic profiling of BAs based on detection technologies can completely and accurately monitor their types and contents, playing a crucial role in disease prevention, diagnosis and treatment. We herein reviewed the main detection technologies of BAs and the application of metabolic profiling in related diseases in recent years. Bile acids (BAs) are a kind of cholanic acids synthesized from cholesterol in the liver . They arAs important regulatory factors of life activities, the disorders of in vivo processes and regulation of BAs easily lead to inflammation, metabolic diseases and other symptoms. In turn, liver and intestinal diseases are often accompanied by systemic cycling disorders of BAs , 4, so tThe metabolic profiling of BAs (MPBA) is quantification of BAs and their metabolites based on the theory of metabolomics. It is a modern analytical strategy that guides and assists the diagnosis of BAs metabolic pathway changes, which can reveal their synthesis and the entire metabolic process comprehensively, thoroughly and systematically. MPBA changes can characterize those in the contents of various BAs in different physiological or pathological environments, thereby being an important evidence for disease diagnosis and treatment. With continuous improvement of BAs detection technologies, MPBA has been increasingly used in studies on metabolic, liver and intestinal diseases. We herein reviewed recent studies on the main detection technologies of BAs and the MPBA changes and applications in diseases.5-C27-hydroxysteroid dehydrogenase in microsomes. Catalyzed by CYP8B1, cholic acid (CA) is finally generated after a series of reactions. Without CYP8B1 metabolism, C4 is eventually metabolized into chenodeoxycholic acid (CDCA). CYP7A1 is the rate-limiting enzyme of this process, the expression of which is regulated by CA level through a negative feedback. In mice liver, most of CDCA is converted to α-muricholic acid (α-MCA) and β-MCA [BAs are synergistically produced by endogenous metabolic and symbiotic intestinal microbiotas. The process is associated with the catalytic oxidation of cholesterol in the liver and the transformation of intestinal microbiota. Catalytic enzymes are located in the cytoplasm, microsomes, mitochondria and peroxisomes successively. BAs are synthesized via two pathways. The classical pathway is initiated by cytochrome CYP7A1 on the hepatocyte endoplasmic reticulum, which catalyzes cholesterol into 7α-hydroxycholesterol, producing 7α-hydroxy-4-cholesten-3-one (C4) under the catalysis of 3β-hydroxy-Δnd β-MCA .CA and CDCA, once synthesized, mostly bind taurine or glycine rapidly to form conjugated BAs and then flow into the duodenum from the bile duct. In the intestinal tract, three main reactions are performed by the microbiota: 1) Deconjugation that hydrolyzes taurine and glycine groups on BAs; (2) epimerization; (3) dehydroxylation that acts on free primary BAs, relying on deconjugation as the prerequisite. As a result, primary conjugated BAs are converted into secondary free ones , 11, mai DeconjugBAs have similar structures, i.e. steroids containing carboxyl side chains to which glycine and taurine are usually bound. Human BAs are excreted with urine, mainly after sulfuric acid conjugation which usually occurs on C3-OH. The structures of common BAs are exhibited in Fig. BAs can reduce the surface tensions of both oil and water phases, and promote the absorption of fat and lipid-soluble vitamins. In addition, with endogenous signaling molecule-like effects, BAs can regulate FXR, pregnane X receptor (PXR), vitamin D receptor (VDR) and TGR5 to synergistically modulate the homeostasis of BAs and to participate in glucose, lipid, energy and drug metabolisms , 13.BAs are thus involved in the regulation of lipid, glucose and energy metabolisms. The activation of FXR and other nuclear receptors by BAs can inhibit fat synthesis in the liver, decrease very low density lipoprotein (VLDL), and reduce triglyceride (TG) levels  by supprBAs can also regulate drug metabolism and self-metabolism by activating nuclear receptors such as PXR, constitutive androstane receptor and VDR . For exaDiseases and metabolic abnormalities may alter the normal homeostasis of BAs, exhibiting proinflammatory activities. Known hydrophobic BAs, such as DCA and LCA, are strong proinflammatory factors. At over-high concentrations, they show cytotoxicity and lead to DNA damage and cell death, causing damage to the liver, intestinal tract and other tissues . AbnormaIn short, BAs play vital roles in life activities, which, when abnormally regulated, result in diseases, and their contents change correspondingly. Therefore, accurate detection of BAs is beneficial to the diagnosis, monitoring and treatment of diseases.Researchers have been devoted to BAs detection technologies for decades, which can mainly be classified into chromatographic and non-chromatographic methods. Chromatographic methods are mainly used for laboratory research, of which thin layer chromatography (TLC) and electrospray ionization (ESI)-MS are primarily applied to qualitative analysis. High performance liquid chromatography (HPLC), gas chromatography (GC)-MS and LC-MS are eligible for both qualitative and quantitative analyses, of which LC-MS is currently the mainstream strategy. These methods have high sensitivity and specificity, together with low detection limit, also with some shortcomings though Table . Non-chrWith simple operation, ESI-MS does not require sample derivatization and is applicable to the detection of unstable BAs, so it is often used for high-throughput analysis. Nowadays, ESI-MS often uses tandem MS (ESI-MS/MS) and low collision energy (< 100 eV). In this mode, structurally simple neutral or low-molecular-weight fragment ions are mainly produced, which can be used for the qualitative analysis of specific conjugated BAs. In the mode of low-energy collision-induced dissociation, Maekawa et al.  detected− ions of other substances in the matrix may interfere with the detection of target ones. These shortcomings render ESI-MS less commonly used for direct BAs detection, which is usually coupled with GC or LC (4.1.4 and 4.1.5).However, ESI-MS alone suffers from several disadvantages. For instance, competitive ionization restricts the detection limit; identical ion fragments produced by isomers cannot be directly distinguished based on ion channels ; free BAAt the end of the twentieth century, TLC was used for the qualitative analysis of BAs due to simplicity and low cost, without needing dissociation or derivatization of BAs with high polarity. Nevertheless, this method is not applicable to quantification. For example, a mixture of seven standard substances with different Rf values, including CDCA, DCA, CA, glycocholic acid (GCA), LCA, glycodeoxycholic acid (GDCA) and glycolithocholic acid (GLCA), can be qualitatively analyzed by two-dimensional TLC . MoreoveCalculus Bovis Sativus using nitrophenacyl bromide as the derivatization reagent at the wavelength of 263 nm. Kakiyama et al. [24BAs including CA, CDCA and DCA at the wavelength of 254 nm. HPLC can also be coupled with fluorescence detector to further raise the sensitivity and selectivity. For instance, rat liver BAs separated by HPLC were treated with the enzymatic method and quantified by using a fluorescence detector. As a result, more types of BAs could be detected, and the detection limit reached 0.02 nmol per 100 mg of liver tissue. However, the long detection time restricts its application currently [HPLC is the most widely used chromatographic separation technology, featuring high sensitivity and specificity. It is suitable for both qualitative and quantitative analyses of BAs. HPLC is generally coupled with UV detector, but BAs themselves have weak UV absorptions that can hardly be detected. Thus, proper sample pretreatment with derivatization is inevitable. Different derivatization methods give various detection wavelengths. For example, Shi et al.  detecteda et al.  performeurrently . AlthougCompared with HPLC, the new-generation ultrafast LC (UFLC) has shorter analysis time as well as higher sensitivity and peak capacity. Si et al.  establisIn early studies, BAs were mostly commonly quantified by GC and GC-MS. GC-MS outweighs other methods mainly in the efficient separation and detection of free BAs mixtures. Compared with LC and HPLC, the GC chromatographic column has a stronger separation ability, revealing more information about molecular structures. Early GC-MS detection was determined by the separation of conjugated and non-conjugated BAs and the conversion of non-conjugated BAs into nonpolar gaseous derivatives. This method can separate and quantify non-conjugated BAs, GCBAs, TCBAs and sulfated BAs.4I:dithioerythritol  using EI ion source and single ion monitoring (SIM), aiming to analyze the contents of seven common BAs in urine [The sample pretreatment process of GC-MS is complicated, with a different derivatization mechanism from that of HPLC. Since BAs themselves have high boiling points and can hardly be volatilized, it is often necessary to convert conjugated BAs into non-conjugated ones for derivatization. The selection of derivatization methods and reagents evidently affects the parameters and ion channels of GC-MS. Taking LCA, DCA, CDCA, HDCA, CA and UDCA as examples, Tsai et al.  evaluatein urine . Unlike 5-sterols and BAs in soil and geological sediment samples [GC-MS is applicable to both the detection of BAs in biological samples and the quantification of them in soil. For example, a Soxhlet extractor was used to extract stanols, △ samples , and a c2) as the mobile phase. SCCO2 has low viscosity, and high diffusivity and separation capability [Supercritical fluid chromatography (SFC), which incorporates the characteristics of GC and LC, can analyze hardly gasified nonvolatile samples. Meanwhile, this method is more efficient and takes shorter analysis time than LC, as a supplement to GC and LC accordingly. SFC uses supercritical carbon dioxide gas  coupled with MS is the mainstream method to simultaneously detect mixture of BAs, as it can improve the separation of isomers with the same ion fragments. When BAs are detected by LC-MS, aqueous and organic phases containing formic acid or ammonium acetate are often used as the mobile phases for gradient elution to increase the degree of separation. The elution times differ significantly because of different types of LC and BAs awaiting separation, and UPLC usually has shorter elution time and higher separation efficiency. Most studies conducted MS/MS with ESI ion source in the negative ion mode using MRM and SIM to increase the selectivity and sensitivity. LC-MS-based strategies have high accuracies, and their lower limits of quantification (LLOQ) usually reach down to 0.1 ng/mL, most of which are applicable to the detection of different species and samples. Compared with HPLC, LC-MS has higher specificity and shorter detection time, but phosphates should not be used as the mobile phase to prevent from damaging mass spectrometers. Compared with GC-MS and HPLC, LC-MS has quick sample prepared methods without requiring derivatization. Given the requirement of small sample amounts and automatic operation, it is suitable for analyzing samples on a large scale. Nowadays, LC-MS has become the mainstream detection method for BAs.The biological samples for BAs detection mainly include serum, plasma, bile, tissue homogenate, urine and feces, and adipose tissue in some cases. The preparation methods are selected according to sample characteristics, concentration of BAs and interfering substances, matrix effects, etc. When samples are pure and BAs concentrations are high, simple dilution can met the analysis requirement. However, extraction, adsorption and enrichment are in need in the case of complex sample compositions and low BAs concentration. The main purpose of sample treatment is to remove components like proteins, lipids and salts.In earlier studies, samples were often added a small amount of ammonium hydroxide or sodium hydroxide to attenuate the binding of proteins to BAs, thus facilitating extraction . NeverthSPE is one of the most selective and widely used methods for enriching and purifying BAs, which can also eliminate the impact of water-soluble salts in samples on mass spectrometer. Variations of conditions such as sample volume and solvent elution power all affect the extraction recovery. Nineteen types of BAs in piglet bile have been extracted by SPE, with the recoveries of 89.1–100.2%. Briefly, bile samples were diluted with pure water, mixed with internal standard and buffer, loaded onto a C18 solid phase extraction column that had been activated by methanol, and rinsed with water and methanol successively. The resulting extracting solution was evaporated under nitrogen and redissolved by methanol before analyzed by LC-MS/MS . Since SBiological samples barely containing interfering substances, such as plasma and serum, are often prepared by the protein precipitation method. This method mostly uses methanol or acetonitrile as the precipitant , 47. In In recent years, solid phase microextraction (SPME) has gradually been applied to the extraction and purification of BAs. SPME is suitable for a variety of biological matrices because of better sample purification and elimination of matrix effects, as well as one-step extraction and purification of detection substances . For exaCollectively, sample treatment is an important step in BAs detection process. The protein precipitation method, which is simple, rapid and low-cost while using small amounts of solvents, has been widely employed, especially for plasma and serum samples on a large scale. In contrast, biological tissue samples are commonly separated and extracted by SPE. This method plays key roles in reducing impurity interference and matrix effects, enriching low-content substances and raising detection sensitivity.With burgeoning development recently, LC-MS has been given first priority in the accurate detection of BAs in experimental studies. Currently, MPBA is mainly constructed based on LC-MS, and has been applied in medical and biological studies to detect BAs in the liver, intestinal tissues and body fluid of experimental animals together with in human blood, urine and feces , 52–56. Sulfated BAs is one of the BAs metabolic pathways in human urine, which have gradually been highlighted in recent years. Bathena et al.  desulfat4− fragments and PSDS and PADS based on (HSO4−)2 ones.Additionally, LC-MS has also been employed to study BAs in marine animals. Wang et al.  reported+ in the oxidation reaction of BAs. The reaction mechanisms are as followed.The enzymatic cycling reaction is a routine method for clinically detecting serum TBA. This method can quantify TBA indirectly by UV or fluorescence detection of NADH produced by NAD+ and genetically engineered 3α-HSD in an enzymatic reaction system at 37 °C. Serum TBA was quantified by measuring the absorbance changes of the product thio-NAD at 405/660 nm per minute, with the detection limit of 0.22 μM and without interference from bilirubin, hemoglobin, ascorbates or lactate dehydrogenase. Zhang et al. [Optimized strategies with simpler reactions and higher sensitivities have been established according to this method. Zhang et al.  added NAg et al.  improved24-steroids, while 3α-HSD can oxidize C3-OH of the C24-steroid structure specifically and reversibly. Therefore, this method no longer works if C3-OH is substituted with sulfuric acid or glucuronic acid group. Compared with GC-MS and LC-MS, the enzymatic method is not suitable for detecting low-content BAs owing to high limit of quantification.Although the 3α-HSD-based enzymatic cycling reaction can be carried out readily, there are still deficiencies, such as the failure to specifically distinguish an individual BA. Besides, BAs are C3-OH-substituted CELISA can detect certain BAs in plasma and in vitro samples specifically, simply and fast, which has been applied for over 30 years. Kobayashi et al.  detected1H NMR to simultaneously detect the concentrations of GCBAs, TCBAs, TBA and choline-phospholipids (choline-PLs) in human bile. GCBAs and TCBAs were quantified by the area of characteristic methylene (-CH2) peak, and TBA and choline-PLs were quantified with the areas of characteristic methyl (-CH3) and trimethylamine (-N+(CH3)3) peaks. Bile samples were derivatized by isotope-labeled TSP (3-(trimethylsilyl) propionic-2,2,3,3-d4 acid sodium salt), with TSP as the standard for quantification and chemical shift. To detect BAs by NMR, samples should be derivatized, so this technology is less commonly applied than the enzymatic method.As a less used method, NMR has mainly been applied to determine the total content of a certain type of BAs. Omkar et al.  establisMetabolic profiling, as a level of metabolomics research, can quantify a certain type of compounds with similar structures and properties as well as the characteristic metabolites in their metabolic pathways. It is a new method for systematic studies on the changes of metabolite spectra, which is suitable for analyzing various endogenous metabolic components in cells, tissues and other biological samples. Currently, this method is highlighted in disease diagnosis and treatment . MPBA, wBAs are endogenous metabolites, the metabolic profiles of which differ at different stages of physical development or under different physiological conditions. For example, types and contents of BAs vary in human with different ages , or thosAs endogenous signaling molecules, BAs can regulate the metabolic pathways and energy balances of lipids and saccharides in the liver and surrounding tissues. The liver, gallbladder and intestine synergistically participate in maintaining the homeostasis of BAs in human body, and only small amounts of BAs can enter the blood circulation in normal states. Liver or biliary tract diseases can cause metabolic disorders of BAs, leading to significant changes in the compositions and contents of serum BAs . Thus, iSugita et al.  comparedIntrahepatic cholestasis of pregnancy (ICP) is a severe pregnancy-specific disease that can be characterized by serum MPBA. The serum levels of TCA, GCA, taurochenodeoxycholic acid (TCDCA), GCDCA, tauroursodeoxycholic acid (TDCA) and TUDCA in pregnant women with severe ICP, especially the former two, increased compared with those of healthy volunteers and mild patients . AccordiAbnormal elevation of BAs also reflects drug hepatotoxicity . Guo et Yang et al. monitored the blood MPBA of cholestatic mice, and found that administration of Danning tablets corrected the abnormal levels of TCA, THDCA, TCDCA and TUDCA . Hence, The intestinal tract, as one of the main sites of BAs metabolism, is closely related with MPBA. Gastrointestinal diseases, such as gastric cancer, enteritis and diarrhea, can cause abnormal enterohepatic circulation of BAs and change the characteristics of MPBA. Therefore, analyzing MPBA as a whole is conducive to the diagnosis of gastrointestinal diseases. Recent studies have confirmed that DCA induced cell apoptosis and promoted the carcinomatous changes of gastric mucosal cells, eventually triggering gastric cancer . AccordiBAs accumulation in colon tissue causes cytotoxicity and inflammation thereafter, and the cytotoxicities of non-conjugated BAs are higher than those of conjugated ones. The blood TBA content of colitis mice is lower than that of normal ones, but the contents in colon tissues follow an opposite trend. Moreover, the concentrations of non-conjugated BAs increase in the intestinal tract of colitis mice .Intestinal diseases are closely associated with intestinal microorganisms which evidently interact with MPBA. Intestinal bacteria contribute to the conversion of primary BAs into secondary ones, which, when change, usually induce abnormalities in the contents of secondary BAs, conjugated ones in particular, thus altering the bile acid pool . FurtherBAs participate in not only the in vivo digestion and absorption of lipids, but also the regulation of energy metabolism balance via multiple signaling pathways. Obesity is caused by the imbalance of energy metabolism. Exogenous administration of BAs can activate TGR5 and facilitate the energy consumption of brown adipose tissue in mice, thereby preventing high-fat diet-induced obesity and type II diabetes mellitus . The bloGestational diabetes mellitus (GDM) is a manifestation of glucose intolerance during pregnancy. GDM women show severe dyslipidemia, centripetal obesity and insulin resistance, even suffering from postpartum type II diabetes mellitus as the disease progresses . As indiMPBA may also change during the treatment of metabolic diseases. Colesevelam, as a second-generation BAs chelator, is commonly combined with statins or antidiabetic drugs to control blood glucose. After treatment of type II mellitus diabetes with colesevelam, CA synthesis is enhanced, but the contents of CDCA and DCA drop. In the meantime, the total content of hydrophobic BAs decreases, and the TBA pool remains stable .There are significant differences between intracerebral and extracerebral BAs compositions and concentrations. Mano et al.  conducteHepatic encephalopathy (HE) is a brain dysfunction caused by metabolic disorders due to acute and chronic liver injuries . In a raAs signaling molecules that regulate lipid, glucose and energy metabolisms, BAs play important roles in many pathological and physiological activities. Accordingly, accurate monitoring of their contents is of great significance to both basic and clinical studies. Chromatographic technologies enable simultaneous qualitative and quantitative analyses, thus having become crucial strategies for BAs detection. With continuous development, the precision and sensitivity of chromatographic apparatuses have been gradually augmented, and a variety of BAs can now be separated and purified at ease. At present, both GC-MS and LC-MS can accurately separate and then quantify specific BAs. Regardless, since MS signals cannot distinguish BAs with conformational isomers, such as Tα-MCA, Tβ-MCA and Tω-MCA, these methods confront a bottleneck in complete separation. Furthermore, the process of sample treatment also markedly affects experimental results, such as attenuation of the matrix effect that is indispensable to the increase of precision and accuracy . Hence, The contents and compositions of different types of BAs vary largely during the progression of different diseases. Accordingly, researchers have endeavored to link MPBA with specific diseases, and to guide their diagnosis and treatment by monitoring the changes of BAs characteristics. Clinically, diseases are mainly diagnosed by detecting TBA in human serum, which is convenient, rapid and low-cost, with low specificity though . In cons


Background: Huntington disease (HD) is an inherited neuropsychiatric condition with progressive neurodegenerative changes, mainly affecting the striatum. Pathological processes within the striatum are likely to lead to alterations in dopamine and glutamate activity in frontostriatal circuitry, resulting in characteristic motor, behavioural and cognitive symptoms. Methods: We conducted a systematic literature search in order to identify and review randomised, double-blinded, placebo-controlled trials of anti-dopaminergic and anti-glutamatergic therapy in HD.Results: Ten studies satisfied our selection criteria. These studies investigated a range of agents which act to antagonise dopamine  or glutamate  transmission.Discussion: Although most agents showed efficacy in terms of amelioration of chorea, the available evidence did not allow us to identify a universally effective treatment. One difficulty associated with analysing the available evidence was a high prevalence of side effects, which prevented the full therapeutic potential of the medications from being adequately investigated. A further limitation is that many studies evaluated treatment effectiveness only in relation to patients' motor symptoms, even though behavioural and cognitive changes may negatively impact patients' quality of life. There is a clear need for further higher-level evidence addressing the effects of dopaminergic and glutamatergic agents on global functioning in HD.