In practice, online health communities have passed the adoption stage and reached the diffusion phase of development. In this phase, patients equipped with knowledge regarding the issues involved in health care are capable of switching between different communities to maximize their online health community activities. Online health communities employ doctors to answer patient questions, and high quality online health communities are more likely to be acknowledged by patients. Therefore, the factors that motivate patients to maintain ongoing relationships with online health communities must be addressed. However, this has received limited scholarly attention.The purpose of this study was to identify the factors that drive patients to continue their use of online health communities where doctor-patient communication occurs. This was achieved by integrating the information system success model with online health community features.A Web spider was used to download and extract data from one of the most authoritative Chinese online health communities in which communication occurs between doctors and patients. The time span analyzed in this study was from January 2017 to March 2017. A sample of 469 valid anonymous patients with 9667 posts was obtained . A combination of Web mining and structural equation modeling was then conducted to test the research hypotheses.R2=0.88). These variables explain 87.6% of the variance in perceived usefulness of online health communities; (2) similarly, patient satisfaction was found to be significantly determined by the three variables listed above (R2=0.69). These variables explain 69.3% of the variance seen in patient satisfaction; (3) continuance use (dependent variable) is significantly influenced by perceived usefulness and patient satisfaction (R2=0.93). That is, the combined effects of perceived usefulness and patient satisfaction explain 93.4% of the variance seen in continuance use; and (4) unexpectedly, individual literacy had no influence on perceived usefulness and satisfaction of patients using online health communities.The results show that the research framework for integrating the information system success model and online health community features contributes to our understanding of the factors that drive patients' relationships with online health communities. The primary findings are as follows: (1) perceived usefulness is found to be significantly determined by three exogenous variables (ie, social support, information quality, and service quality; First, this study contributes to the existing literature on the continuance use of online health communities using an empirical approach. Second, an appropriate metric was developed to assess constructs related to the proposed research model. Additionally, a Web spider enabled us to acquire objective data relatively easily and frequently, thereby overcoming a major limitation of survey techniques. Research indicates that online health communities (OHCs) have become major sources of health information for the general public and have dramatically changed health information seeking and exchange . IndividIn practice, OHCs have passed the adoption stage to reach the diffusion phase of development. In this phase, patients equipped with knowledge regarding health care issues are capable of switching between different communities to maximize their OHC activities. OHCs employ doctors to answer patient questions, and high quality OHCs are more likely to be acknowledged by patients. Therefore, one important question that must be addressed is: what factors drive patients to maintain ongoing relationships with OHCs in which communication occurs between doctors and patients? However, this important question has received limited scholarly attention .The goal of this study was to examine the factors that drive patients to perpetuate ongoing relationships with OHCs in which communication occurs between doctors and patients, by integrating the information system success model (ISSM) and OHC features. Methodologically, the study uses a combination of Web mining and structural equation modeling (SEM)  to analyAn OHC is a group of individuals who interact in health and wellness-related virtual communities to seek information, assistance, emotional support, and communication opportunities . Many beAs a critical indicator of information system (IS) success, continuance use is essential for realizing the value of IS within organizations . TherefoThe validity of the ISSM in various contexts, which has been demonstrated through a variety of empirical studies, indicates that ISSM are well accepted by IS scholars and useful for practitioners . So, it In summary, the aim of this study was to develop a research model integrating the ISSM and OHC features to study which factors drive patients to maintain ongoing relationships with OHCs in which communication occurs between doctors and patients. The proposed model identifies several attributes as predictors of a patient’s OHC continuance use. The relationships between the constructs are depicted in the conceptual model demonstrated in Although the current use of OHCs is extensive and their possible benefit for the public is substantial, website limitations prevent patients from exploiting the full potential of OHCs. Problems associated with retrieving information from OHCs tend to involve language, literacy, education, technology, and cultural barriers .The relationship between individual literacy and perceived usefulness is of interest to many scholars . Three tInformation literacy is defined as a set of skills that are necessary to identify, access, evaluate, and use information effectively . It is ii  could be evaluated by the average text length of each post  is the text length of the jth post pij by patient i and n is the total number of posts by patient i during a certain time interval.Thus, the information literacy of a patient pij of patient i as a negative, neutral, or positive emotion  is the jth post pij by patient i, length(pij) is the text length of the jth post pij by patient i,s is number of sentences in the jth post pij by patient i, and t is sentiment expression terms in sentences, pos is part of t in sentence s, pol polarity of t in sentence s, and ntusd, pol) is the NTUSD intensity value for term t based on its sentence part pos and polarity pol. The media literacy of patient i  could be calculated as the average sentiment of each post  could then be calculated as the average number of medical terms in each post  is the number of medical terms in the jth post pij by patient i, and n is the total number of posts by patient i during a certain time interval.Health literacy has been defined as the ability to read, comprehend, and act upon health information . The numGenerally, individual literacy is directly related to the ability to communicate with others  and to eThe social support aspect is used to assess whether patients can benefit from social relationships in the OHC context . Social Three types of social support   are exami  could be calculated as the average number of doctors who replied to each post by the patient  is the total number of doctors who replied to the jth post pij by patient i, and n is the total number of posts by patient i during a certain time interval.Companionship support gives someone a sense of social belonging, through the presence of companions to engage in shared social activities . Companii  could be calculated as the average number of best answers provided by doctors to each post by the patient  is the total number of best answers provided by doctors to the jth post pij by patient i, and n is the total number of posts by patient i during a certain time interval.Informational support refers to advice, guidance, suggestions, or useful information provided to someone. Informational support in OHCs involves a doctor-patient interaction where the former assists latter with managing particular questions and uncertainties regarding a given situation in a highly supportive manner . The numi  could be calculated as the average reply sentiment of the doctors to each post  is the reply sentiment of the doctors to the jth post pij by patient i, and n is the total number of posts by patient i during a certain time interval.Patients in an OHC are influenced by the emotional support they receive and the quality of information and companionship they are provided . InteracThe social support of OHCs is credited with many positive health outcomes such as increased immune system strength and reduced stress and depression . Here, wInformation quality in OHCs refers to content issues and includes the completeness, accuracy, format, and currency aspects of the information . Three ti  could be calculated as the average title of the doctors who replied to each post  is the academic title of the kth doctors who replied to the jth post pij by patient i, num(drpij) is the total number of doctors who replied to the jth post pij by patient i, and n is the total number of posts by patient i during a certain time interval. A scale of 1 to 5 was used to normalize the job titles .Information reliability is, literally, the extent to which an individual can rely on the source of the information . The offi replied to by doctors and the expertise tag of each replying doctor. Then, the information relevancy to patient i  could be calculated as the average number of the relevancy degree  divided by tag(pij) is the number of the relevancy degree of the kth doctors who replied to the jth post pij by patient i, num(drpij) is the total number of doctors who replied to the jth post pij by patient i, and n is the total number of posts by patient i during a certain time interval.Information relevancy in OHCs means that information is applicable and helpful for health-related goals of patients . Thus, wi could be calculated as the average number of medical terms in the replies of doctors to each post  is the number of medical terms in the replies of kth doctors who answered the jth post pij by patient i, num(drpij) is the total number of doctors who replied to the jth post pij by patient i, and n is the total number of posts by patient i during a certain time interval.Information consistency in OHCs denotes that information is always presented in the same format and is in line with previous information . The numAs a necessary measure of success, OHC information quality is a highly vital factor that affects the patient’s online behavior. This factor indicates the importance of quality online information and references ; and infOHC service quality is defined by the feelings of patients regarding the level of service while browsing and interacting within the community . Three ti  could be measured as the average time taken for the first reply to be posted to the jth post [t(rpij)−t(pij)] as shown in i is n during a certain time interval.Service responsiveness in OHCs refers to the willingness of doctors to help patients with prompt service. Thus, service responsiveness  of doctoi  could be evaluated by the average text length of replies to each post [length(rpij) is the text length of replies to the jth post pij by patient i, and n is the total number of posts by patient i during a certain time interval.Service effort is defined in OHCs as the amount of time and energy the doctor invests in replying to patients . Thus, sach post , as showi  could be evaluated by the average number of patients to whom doctors have replied  is the total number of patients to whom the kth doctor replied, in which the kth doctor is the one who replied to jth post pij by patient i, num(drpij) is the total number of doctors who replied to the jth post pij by patient i, and n is the total number of posts by patient i during a certain time interval i.Service empathy in the OHC means that the doctors provide individualized attention to the patients . The aveService quality at OHCs differs from the traditionally studied service quality in IS research, which focuses on the services of organizations . OHCs noThis study proposes that service quality influences the perceived usefulness and patient satisfaction of OHCs, which, in turn, influences continuance use. Thus, the following hypotheses are proposed:On the basis of its definition as capable of being used advantageously, perceived usefulness is explained as the degree to which a person believes that using a particular system would enhance his or her job performance . The perA patient post can be followed by replies from doctors, and then be followed by additional questions from the patient. The feedback provided through this back-and-forth dialogue adds to the perceived usefulness of patients ,52. Thusi  could be calculated as the average sentiment of additional questions to each post  is the sentiment of each additional question of the jth post pij by patient i, and n is the total number of posts by patient i during a certain time interval.As indicators of whether or not motives are satisfied in OHCs, emotions in additional questions show how patients feel about replies from doctors. Thus, emotions in patient feedback i  could be calculated as the average ratio of length to number of additional questions to each post  is the total number of additional questions of the jth post pij by patient i, length(fpij) the text length of additional questions of the jth post pij by patient i and, n is the total number of posts by patient i during a certain time interval.The patient feedback effort in OHCs is the amount of time and energy the patient invests in feedback to doctors. The patients can signal their perceived usefulness by feedback efforts. Thus, the feedback effort of patient i  could be evaluated by the average time taken before posting the first additional question following a post −t(pij) is the time interval until the first additional question to the jth post pij by patient i, and n is the total number of posts by patient i during a certain time interval.Feedback time in OHCs is the total amount of time it takes for patients to respond to replies from doctors. Thus, the feedback time of patient A system high in perceived usefulness is one that a user believes offers a positive use-performance relationship . SeveralIn the OHC context, patient satisfaction describes the feelings, attitudes, and expectations of patients who perceive that they have received good services from an OHC and are likely to revisit. Since the 1980s, user satisfaction has received considerable attention in the IS literature and remains a focus of considerable research interest . The quaPatients can express opinions to doctors conveniently and easily in OHCs; thus, their satisfactions can be broadly recognized by the total number of public thank-you letters, online votes, and virtual gifts to doctors. Therefore, three types of patient satisfaction are identified in this study .i  could be evaluated by the average number of thank-you letters received by doctors who replied to a post  is the total number of thank-you letters for the kth doctor who replied to the jth post pij by patient i, num(drpij) is the total number of doctors who replied to jth post pij by patient i, and n is the total number of posts by patient i during a certain time interval.Thank-you letters are written by patients to doctors to express appreciation in OHCs. Thus, satisfaction via thank-you letters of patient i  could be evaluated by the average number of online votes to doctors who replied to posts  is the total number of online votes for the kth doctor who replied to the jth post pij by patient i, num(drpij) is the total number of doctors who replied to the jth post pij by patient i, and n is the total number of posts by patient i during a certain time interval.Online votes show praise given by patients to doctors in OHCs. Thus, satisfaction via online votes of patient i  could be evaluated by the average number of virtual gifts given to doctors who replied to posts  is the total number of virtual gifts for the kth doctor who replied to the jth post pij by patient i, num(drpij) is the total number of doctors who replied to the jth post pij by patient i, and n is the total number of posts by patient i during a certain time interval.Virtual gifts are sent to doctors by patients in OHCs. Thus, satisfaction via virtual gifts of patient As DeLone and McLean  suggest,Typically, continuance use illustrates patients’ behavior to continue using OHCs ,59. Thusi  could be calculated as the time span from registration to the present  could be calculated as n posts during t(pij)−t(pi1) as shown in i is n during a certain time interval.The posting frequency of patient The objective of this study was to understand the factors that drive patients to maintain ongoing relationship with OHCs in which communication occurs between doctors and patients. Although survey instruments are often used in such circumstances, data are difficult to obtain, and data availability and sample size problems may occur. Therefore, this study collected objective data directly from OHCs by using a Web spider.To test our hypotheses, we captured data from a Chinese OHC (the club.xywy website). This OHC is one of the most authoritative forums in China that connects individuals with health problems with doctors who can help them solve these problems.In this study, Locoy Spider  was employed to download and extract data. This software is freely available and can be downloaded from the Locoy website. The time span analyzed in our study was from January 2017 to March 2017. We preprocessed the data according to the following rules: (1) delete records with no doctor’s reply; (2) delete records not in accordance with the required format; and (3) delete records with advertisements. Finally, 469 valid anonymous patients with 9667 posts were obtained, which is equal to 469 respondents in survey research. First, we examined the fitness and construct validity of the proposed measurement model by assessing reliability, convergent validity, and discriminant validity. Then, we examined the structural model to investigate the strength and direction of the relationships among the theoretical constructs.The reliability of all multi-item constructs should exhibit a Cronbach alpha larger than .70. Convergent validity should meet the following criterion: the indicator’s estimated coefficient should be significant with respect to its posited underlying construct factor.The measurement scales were evaluated using three criteria: all item-factor loadings (k) should be significant and exceed 0.7, the composite reliability (CR) for each construct should exceed 0.7, and the average variance extracted (AVE) for each construct should be larger than 0.5 . Table 3To test discriminant validity, the average variance shared between a construct and its measures should be larger than the variance shared by the construct and all other constructs in the model . The corThe structural model was tested to assess how well the model represented the data. We evaluated the following indices : the chiR2) indicate how well the data support the hypothesized model.The purpose of the analysis was to determine which factors and how these factors affect the continuance use. SEM using partial least squares (PLS) was applied to test the hypothesized model. Use of SEM is commonly justified in the social sciences because of its ability to impute relationships between unobserved constructs (latent variables) from observable variables, and PLS is a latent SEM technique that uses a component-based approach to estimation . These tR2=0.88). These variables explain 87.6% of the variance seen in perceived usefulness; (2) similarly, patient satisfaction is found to be significantly determined by social support, information quality, and service quality (R2=0.69). These variables explain 69.3% of the variance seen in patient satisfaction; and (3) the dependent variable (continuance use) is significantly determined by perceived usefulness and patient satisfaction (R2=0.93). That is, the combined effects of perceived usefulness and patient satisfaction explain 93.4% of the variance in continuance use.A summary of the hypothesis test results of the standardized path coefficients and path significances is provided in Unexpectedly, two hypotheses (hypothesis 1 and hypothesis 2), that were supported in previous empirical research, were not supported by our data. The results indicate that individual literacy has no influence on perceived usefulness and patient satisfaction. There are two plausible reasons for this result. First, this may be because nearly 75.7% (355/469) of the sample are older than 30 years, and they seek health information on behalf of others, such as their parents or children. Second, although individual literacy provides the ability to use an OHC, perceived usefulness and patient satisfaction depend on the functionality and characteristics of OHCs. From this perspective, the results are logical.Social support, information quality, and service quality exert significant direct effects on perceived usefulness and patient satisfaction. Thus, hypothesis 3 to 8 were supported. Generally, social support is an important component of OHCs. In terms of the main effects of social support on perceived usefulness and patient satisfaction, our findings agree with previous research results . BecauseComplementing the findings of prior studies , perceivOverall, these results suggest that increasing social support, informational quality, and service quality may improve the perceived usefulness and patient satisfaction of OHCs, which in turn fosters continuance use within OHCs.The results show that the research framework for integrating the ISSM and OHC features contributes to our understanding of the roles certain constructs play in motivating patients to revisit OHCs. Social support, information quality, and service quality exert significant direct effects on perceived usefulness and patient satisfaction. Regarding the influences of perceived usefulness and patient satisfaction, both have significant effects on continuance use of OHC patients. In addition, the effects of social support, information quality, and service quality on patient satisfaction are mediated by perceived usefulness. Overall, these results suggest that increasing social support, informational quality, and service quality may improve the perceived usefulness and patient satisfaction of OHCs, which could in turn positively influence the continuance use of OHC patients. Unexpectedly, individual literacy has no influence on perceived usefulness and satisfaction of OHC patients.Although the results of this study are promising, several limitations must be considered. First, the data analyzed in the study were collected from an OHC in China, in which communications are between patients and doctors. It is unclear whether the results of this study can be generalized to all OHCs, due to the limited number of Chinese OHCs. Therefore, future research should include additional OHCs. Second, this study used cross-sectional data to examine the critical factors that influence patient continuance use of OHCs, which may not fully capture OHC evolution. Future research may conduct longitudinal designs to better understand OHC success.Despite these limitations, this study has several important implications for future OHC research and interventions. First, Web-tracking techniques can provide more detailed and accurate information on patient behavior patterns, and in turn contribute to improving our understanding of OHC communication mechanisms . The modFirst, our insights support a reconsideration of the impact of individual literacy on perceived usefulness and patient satisfaction. Because individual literacy does not contribute to perceived usefulness and patient satisfaction, practitioners should invest substantial effort in promoting continuous activity, as patients may seek health information on behalf of others. Because social support  contribuSecond, our findings have implications for practitioners concerned with constructing sustainable OHCs that are active and supportive. By showing that perceived usefulness mediates the influence of social support, information quality, and service quality on patient satisfaction and, in turn, on continuance use of OHCs, we emphasize the importance of useful OHC information resources. Therefore, entities responsible for information-resource allocation should use the powerful role that online collectives can play .The goal of this study was to examine the factors that drive patients to maintain ongoing relationships with OHCs in which communication occurs between doctors and patients. First, this study contributes to the literature by identifying which factors and how these factors influence patient continuance use. Moreover, the measures for the constructs in the proposed model have intuitive explanations and display good performance.Second, we developed an appropriate metric for constructs in the proposed model. In addition, a Web spider to collect data enabled us to acquire objective data frequently and with relative ease, thereby overcoming a major limitation of survey-based techniques. For example, if a questionnaire alone had been used, we could not control for all variables or claim causal effects regarding sentiment change . Thus, t


Background and objective: Background and objective: Drug repurposing has been considered a cost-effective and reduced-risk strategy for developing new drugs. Little is known and documented regarding the efficiency of repurposing strategies in drug development. The objective of this article is to assess the extent and meaning of this process in the CNS area.Methods: In order to identify repurposed drugs that target the CNS, an extensive search was performed. For each identified case, its initial and target indication, development status and the type of repurposing strategy  was recorded.Results: One hundred and eighteen source products were identified. They were repurposed (mainly repositioned) 203 times with 81 products repurposed once and 38 products repurposed twice or more. The highest number of source drugs originated from the CNS area. Alzheimer’s disease was targeted most often. Half of the new indications were approved. Regarding repurposing within the CNS area, epilepsy, schizophrenia and depression were the richest sources of repurposed drugs.Conclusions: Repurposing drugs into CNS is an efficient and very active drug development method, exemplified by the considerable number of new indications that have been found via this strategy, with approximately half of the target indications currently under development. Drug repurposing pertains to the development of new therapeutic uses or new formulations for a known drug, or the combination of two or more known drugs that were previously used separately. These drug development strategies are known as drug repositioning, drug reformulation and drug combination, respectively. Within drug repurposing, the two most frequent strategies are drug repositioning and drug reformulation.Traditionally, drug repurposing has been considered a cost-effective and reduced-risk strategy for developing new drugs, and extending the patent protection period for existing products.,3 HoweveCNS seems to be a critical area for drug repurposing. The undeAlthough it can be stated that drug repurposing has become a common drug development strategy in the last decade  – corresAs such, it is of relevance to evaluate what exact role drug repurposing has played for the already approved CNS drugs, and to understand what potential it can have for future development in this area.The objective of this article was to quantitatively assess the extent of repurposing within the CNS area. We aimed to identify drugs that underwent, or are undergoing, the repurposing process, and to find their initial and target indication, as well as their development status.In order to identify and gather information on repurposed drugs that target the CNS, a comprehensive literature review was performed. Various complementary sources were searched up to January 2016.A comprehensive literature search through MEDLINE  and EMBASE databases was conducted. The detailed search strategy is described in the Supplementary Material. The retrieved titles and abstracts were screened. Abstracts that appeared to report on particular cases of drug repurposing were included for further full text analysis. References of each publication were checked for additional sources.The websites of pharmaceutical companies involved in repurposing/reformulation of drugs, as well as the websites of all initiatives undertaken to promote and develop repurposing/reformulation, were reviewed .In addition, the following databases were screened: MedTrack, Google, websites of regulatory agencies (European Medicines Agency [EMA] and the FDA), ClinicalTrials.gov. These databases were used to identify new cases of repurposing, as well as to obtain missing information, for example initial or target indication of previously identified cases. Depending on the information missing, key words included initial or target indication or formulation, followed by the name of the repurposed drug.in vivo, in vitro, animal) data were excluded.Publications and other sources that reported on any cases of drugs repurposed to the CNS area were included. No restrictions on type, date or geographical scope of the publications were applied. Publications that reported on cases which failed in development or had only preclinical , as well as by the type of repurposing strategy .Cases were analysed according to their development status (approved vs. in development), type of repurposing (reformulation vs. repositioning vs. both) as well as the number of repurposing episodes (one vs. two vs. three or more). In addition, cases were grouped according to initial therapeutic area and target therapeutic indication. Separate analysis using initial therapeutic indications  was performed for drugs that were repurposed within the CNS.In total, 172 information sources were included in the analysis. There were 65 publications, 39 ClinicalTrials.gov links, 30 Medtrack Reports, 24 regulatory and medical research agency materials  with 80 products repurposed once, 16 products repurposed twice and 22 products repurposed three times or more. The details of all identified cases are listed in the Supplementary Material. Among products repurposed multiple times, over two thirds (68%) came from the CNS area. Half of the new indications (102 cases) were approved. The majority of approved cases (80%) originated from the CNS area, while the majority (61%) of cases in development originated from areas outside the CNS. Most of the cases were repositioned (171), while only 16 were reformulated, and 16 were reformulated and repositioned at the same time. All results are presented in As shown in Among new therapeutic indications, Alzheimer’s disease was targeted most often (22 cases), followed by substance dependence , bipolar disorder, depression, neuropathy/neuralgia, multiple sclerosis and schizophrenia, with 10 and more cases each .Figure 2Regarding repurposing within the CNS area, epilepsy, schizophrenia and depression were the richest sources of repurposed drugs with 10 and more products each, targeting 27, 30 and 20 new indications respectively .Figure 3We have been able to identify 118 source products targeting 203 new indications.When analysing approved cases it can be seen that the majority of source products  originated from the CNS area. In contrast, amongst products in development, the proportion of CNS source products is much lower . For approved products, the high prevalence of CNS-origin drugs may be related to serendipity and a history of clinical experience-driven development within the therapy area. On the other hand, amongst products in development, the increase in the share of ex-CNS drugs repositioned into the area may be related to pharmacology knowledge gained in recent decades, allowing the discovery of new targets for existing products and new aspects of disease pathophysiology outside of the CNS field. However, it is unknown whether this shift in the origin of repurposed drugs means that repurposing in the CNS area is currently adopting a greater range of products to incorporate more non-CNS source drugs, or if the success ratio for approval is higher for drugs sourced within CNS, compared with drugs repurposed from outside the CNS area. Further research will be necessary to track the success rate in terms of regulatory approval for products in development retrieved from our research, and to shed light on whether the regulatory approval rates are indeed higher when products repositioned into CNS are sourced within the same area.It is noteworthy that about one third of the source products have been repurposed more than once (i.e. have two or more indications approved or in development). This indicates that multiple repurposing for the same source product is not uncommon in the CNS area. Interestingly, the source drugs that underwent multiple repurposing episodes mostly originated from therapeutic areas within CNS (56% of source products repurposed twice and 77% of source products repurposed three times or more). This is not unexpected, as many diseases of the CNS share part of the known pathophysiology  and many CNS diseases associate with comorbidities that also affect the CNS. This could also be explained by the fact that most pharmacological agents acting on the CNS target symptoms, which are often common to multiple diseases. For example, there are symptoms that overlap between bipolar disorder, schizophrenia and depression. It is also well known that deep brain stimulation therapy used to alleviate Parkinson’s disease may induce transient acute depression which resolves after adjustment of the electrode position.,21 This When evaluating repurposing into CNS by initial therapeutic area, irrespective of the stage of development, the majority of drugs are repurposed from one CNS indication to another (60% of the indications retrieved), with endocrine, metabolic and genetic disorders, cardiovascular diseases and oncology being the ex-CNS therapeutic areas with the highest frequency of repurposing into CNS. From the cardiovascular drugs repurposed into CNS, with the exception of cilostazol and indobufen, all drugs were initially used as antihypertensives, antiarrhythmics, or both. Despite this common background in terms of cardiovascular effect, there is not a single overlap between the target indications (13 distinct indications), which range from psychiatric to neurological disorders, including neurodegenerative disorders such as Parkinson’s or Alzheimer’s disease. This heterogeneity in terms of target CNS indications for products originating from the cardiovascular area may be explained by the fact that, albeit they have a similar clinical effect within the cardiovascular system, those drugs have different mechanisms of action . Indeed those receptors are also present in the CNS and may be involved in CNS disorders. As such, it is not surprising that when repurposed into CNS, those drugs have distinct therapeutic effects compared with their original indication.In terms of target indications, the endocrine, metabolic and genetic drugs repurposed into CNS have all been, apart from one new indication of insulin, repurposed within neurological disorders. The same is observed for the oncology drugs repurposed into CNS, with the exception of tamoxifene, which was repositioned into bipolar disorder and ondansetron repositioned into substance dependence.Regarding drugs repurposed within CNS, the most common source indications are epilepsy, depression, schizophrenia and Parkinson’s disease, in total accounting for nearly three quarters (74%) of the cases repositioned within CNS. This result is not unexpected, as those indications are among the most prevalent diseases, each with numerous treatment alternatives; however, there is still very limited knowledge regarding the aetiology and/or pathophysiology of these diseases.Our research for cases of drug repurposing in the CNS area had the objective to be as extensive and wide as possible, so that a thorough analysis of drug repurposing in CNS could be made possible for the first time. Although we were able to collect both approved and in-development drug repurposing cases in the CNS area, it is expected that more cases may exist that have not been captured even through systematic research, as they may not have been communicated for multiple reasons, including risk of intellectual propriety challenges. Nevertheless, the sheer quantity of products and the number of indications retrieved for drug repurposing in CNS through our research can be considered almost exhaustive, and is sufficient to conclude that drug repurposing is an important development strategy within this currently under-served therapeutic area.It has to be noted that, as we wanted to identify cases that have meaningful impact on treatment and bring substantial benefit to patients, we excluded minor reformulations that did not lead to changes in the route of administration. We think that inclusion of minor reformulations would lead to identification of many meaningless cases, and would blur the real picture of the pathways for repurposing in the CNS area.Drug repurposing is an efficient drug development strategy that could be valuable in promoting development efforts in the CNS area, either by producing historic databases of failed drug repurposing cases that can clear the way for alternative research, or by making potential target databases more readily available, so that they can be used for future research and development. Additionally, given the huge unmet need in this therapeutic area, it would be important to consider the role and regulation of market access evaluations in the availability or restriction to patients of medicines issued by repurposing, in order to incentivise value-added drug repurposing in CNS.The importance of repurposing was recently recognised by the European Commission, which raised the discussion on this topic and constituted the Commission Expert Group on Safe and Timely Access to Medicines for Patients (‘STAMP’). STAMP aims at recognizing the importance of comprehensive investigation of different opportunities that a molecule could bring to patients, with faster development times, and at reduced costs and risk for pharmaceutical companies.Several initiatives focusing on promoting drug repurposing and based on public, private and academic partnership have also been established. In the UK in 2011, the Medical Research Council established a partnership with AstraZeneca to give academic researchers access to clinical and preclinical compounds for potential repurposing. In FrancIn the research conducted, we were able to find 203 target indications in the CNS area, where drugs were developed through repurposing (mainly repositioning) from 118 source products. This means that drug repurposing in CNS is a relevant and currently very active drug development method, exemplified by the considerable number of new indications that have been found via this strategy, with approximately half of the target indications currently under development.Public policies that support and encourage the development of new CNS therapies may prove critical to bringing new therapeutic options to the market for a currently very poorly serviced population. Developing incentives for manufacturers to systematically explore repurposing may significantly help to address the high unmet need amongst patients suffering from CNS disorders.Click here for additional data file.


The Black Church has long been purported as being strongly influential in the lives of Blacks in America. Recent U.S. census data trends highlight a “reverse migration” pattern where Blacks are moving back to the South from larger metropolitan areas in other U.S. geographical regions. This migration pattern parallels the increasing HIV/AIDS prevalence among Blacks in the Deep South. This paper reviews both the historical and current migration patterns among Blacks, as well as the current HIV/AIDS epidemic among Blacks in the Deep South. Thereafter, the authors discuss an existing framework for increasing HIV/AIDS prevention capacity through a conceptual connection of migration, religion and sexual health. The authors use case studies to support the proposed framework. It is hoped that the framework could be used to address HIV/AIDS health disparities and other chronic diseases affecting Blacks in America. Recent migration trends suggest a “reversal” where Blacks are moving back to the Deep South. These more recent migration trends mirror current demographic changes in HIV/AIDS prevalence where increased risk has shifted from large urban settings in the Northeastern and Western U.S. to the urban and rural communities in the Deep South. Additional HIV/AIDS demographic changes include a shift from being a mainly White male disease to a one largely affecting both Black males and females During the 20Although the influential role of religion in Black culture is well represented in the literature, its interconnection with migration and sexual health, particularly among those with HIV/AIDS has not been well documented. The goal of this article is to examine the influence of recent migration patterns and religion among Blacks, as well as utilizing this relationship to develop a framework for prevention strategies in sexual health including HIV/AIDS. Specifically, the authors of this paper will provide: 1) an overview of historical and current migration patterns of U.S. Blacks and their sociological implications; 2) an overview of the current HIV/AIDS epidemic among Blacks in the Deep South; and 3) give a description of a framework that connects migration, religion, and sexual health for building HIV/AIDS prevention capacity in Blacks in the Deep South using case studies to support the framework. It is hoped that the paper will not only provide a platform for strategies designed to mitigate HIV/AIDS health disparities, but also provide a model for building prevention capacity for other health disparities in the Deep South.2.th century. Moreover, the 1920s drop in cotton's price further hampered the economic viability of being a sharecropper in the Southern U.S. agrarian economy, which increased the attractiveness of Midwestern and Northern U.S. industries looking to hire new employees. These previously discussed pattern of events and policies led to significant migration movements of Blacks from the South to other U.S. regions After slavery through the signing of the Emancipation Proclamation and Post-Reconstruction period of American history, there was evidence that more than 90% of Blacks lived in the South The Promised Land, Nicholas Lemann wrote “in all, between 1910 and 1970, about 6.5 million Blacks migrated to the northern U.S. The Black Migration was one of the largest and most rapid mass internal movements of people in history-perhaps the greatest not caused by the immediate threat of execution or starvation. In sheer numbers it outranks the migration of any other ethnic group-Italians or Irish or Jews or Poles-to this country” In his book, Since the 1970s, the demographic shift initiated at the start of World War I has reversed, with large groups of Blacks moving from large urban Midwestern and Northern cities like New York, Chicago and Detroit back to areas of the U.S. Deep South The reasons for the population reversal may largely be related to factors associated with the first large Black migration. More specifically, the lower cost of living and increased job opportunities in the South, combined with the economic decline of manufacturing industries like the U.S. car industry in Detroit might make the southern U.S. region more attractive to Blacks despite its racially oppressive history For some reverse migrators, the move back to the U.S. southern region may be related to the perception of the political and structured environment being “safer” now compared to the post-emancipation and civil rights era. For others, the move back to their ancestral roots may stem from the desire to be closer to family because of parental illness, land inheritance, or and the increased sense of community often attached to the Southern culture. Recent research suggests that Blacks following homeplace ties to the South may be declining in the movement, since Blacks born outside of the South now have a greater rate of migration to the South than those originally born in the South 3.th and early 21st centuries, the demographic profile of the HIV/AIDS epidemic has shifted from a largely White gay male disease to a predominately Black male and female disease. HIV and AIDS rates are concerning illnesses in Black communities, threatening the health, well-being, and potential of Black men and women across the U. S. While prevention efforts have helped to maintain stability in the overall level of HIV infections, Blacks continue to face the most severe burden of HIV and AIDS of all racial/ethnic groups in the nation. Compared with other races and ethnicities, Blacks account for a higher proportion of HIV infections at all stages of the illness-from new infections to AIDS deaths. Blacks also accounted for an estimated 44% of all new HIV infections among adults and adolescents (aged 13 years or older) in 2010, despite representing only 12% to 14% of the U.S. population. Moreover, Black men accounted for 70% of all new infections among Blacks and have a rate of infection that is six and a half times higher than that of white men. The majority of new HIV infections are in men who have sex with men (MSM); new infections among young (ages 13–29) MSM increased by 48% from 2006-2009. For women, the racial disparity is even greater. The estimated prevalence rate of new HIV infections for Black women  was 20 times as high as the rate for white women, and almost five times as high as that of Latinas. HIV was also the ninth leading cause of death for all Blacks at the end of 2008 and the third leading cause of death for all Blacks aged 35–44 At the same time that reverse migration patterns among Blacks in U.S. are occurring during the late 204.In addition to ethnic/racial shifts, there have been geographic and population changes over the course of the HIV/AIDS epidemic. In the early stages of the HIV/AIDS epidemic (circa 1980s), the epidemic predominately affected gay White men living in large metropolitan cities form the Northeast and West regions of the U.S. th highest HIV infection rate in the country and the eighth highest AIDS related death rate The state of Alabama reflects these ethnic/racial as well as geographic and population changes in the HIV/AIDS epidemic. In Alabama, Blacks account for 69% of new cases, yet they comprise only 26% of the state's population Factors related to understanding the dynamics of the HIV/AIDS epidemic, particularly in the rural Deep South include: lack of access to screening and healthcare, racism, lack of trust and suspicion, religious beliefs, homophobia, and poverty 5.Scholars have long recognized the Black Church as one of the most important institutions found in the Black community, because of the absence of interference from Whites in the religious activities and expressions of Blacks after slavery. This social institution historically addressed and met the economic, social and political needs of the Black community In addition to its social role, there is evidence that the Black Church has influenced the sexuality and sexual health of its members. Historically, the Black Church has encouraged sexual silence for men and women alike. This silence is rooted in the history of early colonization of the United States, during a time when Black women were viewed as hypersexual. This mythology surrounding women in slavery was suggested to be a barrier to seeing their humanity Documented in the contemporary literature is again the encouragement of abstinence and married, heterosexual relationships. In addition, homosexuality is discouraged, as Frederick and Douglas note that homophobic messages conveyed through the Black Church are widespread, with homosexuality viewed as a sin. Pertinent to the topic of this manuscript, some Black church members view HIV as a “punishment from God” due to the fact that homosexuality perceived as immoral For example, these interpretations, on one hand, may have increased the odds of inclusion among sexual minorities. For instance, Frederick notes in her ethnography of married and single Black women's membership at Black churches in rural North Carolina that while messages of homophobia are received and imbedded into personal beliefs, these Black women interviewed regularly interacted socially with homosexual minorities. These women who participated regularly in the Black Church had difficulty adopting homophobic attitudes that apply to gay and bisexual family and friends as ordained by the Black Church. Participants instead viewed those in their social networks as a whole person and not merely their sexual preferences On the other hand, these personal interpretations may have also led to increased high risk behaviors among Black church members. Valera and Taylor present a complex example of sexual behaviors of men who attend church and increase HIV risk of Black women. More specifically they describe nine married men associated with the Black Church who identified themselves as heterosexual, but also engaged in same-sex activity within the past six months of their interviews. Some participants served in leadership positions at the churches they attended. When asked how they reconcile their sexual behavior to include both their wives and secret male partners, participants noted that the Black Church's framework that encourages members to “Hate the Sin but not the Sinner” made it possible for men engaging in same-sex relationships to continue attending church. They believed that God would forgive them for their behavior, and noted that their spiritual relationship was personal, hence encouraging greater secrecy of their private sexual relationships In addition, Frederick highlights the increased risk related to sexual silence among Black women attending Black Churches. While single women were aware of the Biblical teachings regarding abstinence, they revealed that they used their personal experience and faith to make decisions regarding their sexuality, whether they were married or not. Furthermore, the church's teaching on abstinence appears to have minimal influence on the likelihood of these single women engaging in sexual activity While sexual silence has led to different outcomes as just illustrated, there is a need to overcome these barriers to engage in the HIV epidemic. Because of the HIV epidemic, these conversations are imperative to have in both Black Churches and local communities 6.Black migration has had a mixed relationship with Black churches and spirituality. The Great Migration, like other historical events affecting the Black community, was a source for Black religiosity to provide cultural, social, financial, and organizational tools to help Blacks engage in politics and community action Black ministers also worked to connect new migrants with resources during the Great Migration Research on religion in the Black reverse migration is less developed. Stack discusses a migrant who moves to the South in part because of a spiritual experience in her church in Brooklyn, New York Religious beliefs rooted in Southern Black communities influence health beliefs and health behaviors in this community. For example, some rural Southern Blacks believe that God is the ultimate cause of all illness and misfortune, which appears to be a sign of increased external locus of control. Counterintuitive to what one may believe, individuals “who violate the moral codes of the community or who indulge in improper or “sinful” behavior” 7.Because of the emerging and shifting demographics of HIV/AIDS in the U.S. over the last three decades, characterization of the epidemic in the rural Deep South is relatively new and limited. However, one of this manuscript's authors developed a theoretical framework for preventing HIV/AIDS in the rural South Blacks based on experiential HIV prevention activities 7.1.In order to illustrate the interconnection between HIV prevention using the SFD Prevention framework and knowledge regarding reverse migration, the Black church, and sexual health in Black communities, we present the following two cases in the Deep South. The first case involves findings from interviews with eight Black Baptist pastors in rural Alabama about their current HIV/AIDS prevention activities within their churches and their own personal interests in HIV prevention activities. The second case highlights activities of two AIDS Service Organizations that conduct faith-based prevention activities and have moved their services to the Deep South in order to accommodate changes in the HIV/AIDS epidemic.7.1.1.The first study was conducted by this manuscript's first author to assess potential barriers of HIV/AIDS prevention among Black Baptist Pastors with their congregations in rural Alabama. All Pastors were members of the New Era Progressive Baptist Conference, which has 110 member congregations. A total of eight Black pastors were interviewed in a one-to-two hour semi-structured interview. In-depth interviews were audiotaped and transcribed in order to conduct constant comparative analysis. Open coding was used to identify key concepts and categories for summarization and analysis of data. All interviews were conducted by the research team in the offices or homes of the participants. Informed consent was obtained by all participants before the start of the interview. Demographic information of each Pastor was also collected.All eight of the Pastors interviewed were Black, male, and married. Seventy-five percent of the participants (6/8) were over the age of 50. One of the participants was a college graduate with some graduate school and half (4/8) attended some college. All men served as pastors of churches considered rural as designated by the U.S. rural-urban commuting area codes Initially, the proposed study sought to explore potential barriers for rural Black pastors to conduct HIV prevention activities in their congregations and communities including disinterest in presenting this information to church members. However as the study unfolded, the researchers realized that because most of the study participants were indeed either participating or very interested in participating in HIV prevention activities, we needed to expand beyond looking at barriers to HIV prevention activities to begin to look at what positive influencers might encourage a Pastor to become involved in HIV/AIDS prevention. One of the most interesting positive influencers that we captured from this study was that several of the participants were reverse migrators. Although all participants were born and raised in Alabama, several had moved away to other geographical areas of the country, often larger metropolitan areas, and eventually moved back home. Reports of reverse migration to suburban and rural Deep South have not been extensively reported in the literature, especially as it relates to HIV/AIDS prevention  may be more willing to engage in HIV prevention than non-migrators who live in the Deep South. The reasons for this are unknown. The authors theorize that reverse migrators may have the advantage of greater access to HIV/AIDS information, AIDS service organizations, AIDS advocacy, and HIV/AIDS treatment and prevention activities which might make them more prepared to engage in HIV/AIDS prevention activities. Additionally, there may be increased access of reverse migrators with persons who are openly living with the disease. For example, many of the pastors were influenced to get involved because they personally knew someone affected by the disease.Ironically, the linkage of reverse migration and HIV/AIDS in this group of pastors also seemed to correspond to data from other studies by this manuscript's first author where “reverse migrators living with HIV/AIDS (RMLWHA)” often came back to the Deep South because of their desire to be close to family. For example, focus groups conducted with older infected persons over the age of 50 revealed that several of the participants were “reverse migrators” who often moved back home to the rural South from larger cities like Atlanta, New York, Washington D.C. and Los Angeles in order to be closer to family for support We also noticed that often these RMLWHA were often more knowledgeable about their disease than non-migrators, which empowered them to maximize management of their disease as copartners with their health care providers and act as peer leaders for others infected. Additionally, they appeared to be more open about their diagnosis in order to disclose to a larger network of friends, family, and the larger community. Many were active in support groups, and peer network groups, and community-based HIV/AIDS prevention activities where they often took leadership roles. Additional studies for reverse migrators in both pastors and PLWHA are needed to test these theories within the framework.The second case study illustrates the shifting of faith based organizational capacity around HIV prevention from places like New York City where there was an initial need for addressing the HIV epidemic to places in the South like Virginia, where the need for HIV capacity building is emerging. In many ways, these faith-based organizations are “reverse migrators” in shifting initial needs around the epidemic, to move to where the need is now greatest. The use of both groups of reverse migrators as well as shifting or migrating organizational capacity where it is needed could be powerful in building the capacity of African American communities to prevent HIV/AIDS, particularly in the rural Deep South.This paper presents a theoretical framework and data, which loosely correlates the timing of the increasing HIV epidemic in the rural South, reverse migration and the importance of faith-based approaches in HIV prevention. This review paper appears to be one of the first of its kind to make these correlations. Because the relationships are not directly measured, preliminary and qualitative in nature, this is a limitation. Despite this limitation, we believe that because HIV/AIDS continues to increase in rural Blacks in the Deep South, studies which can further investigate the interrelationships between all of these factors in building capacity to address the epidemic in Blacks in the rural Deep South needs to be further explored.


During advanced biological wastewater treatment, a huge amount of sludge is produced as a by-product of the treatment process. Hence, reuse and recovery of resources and energy from the sludge is a big technological challenge. The processing of sludge produced by Wastewater Treatment Plants (WWTPs) is massive, which takes up a big part of the overall operational costs. In this regard, anaerobic digestion (AD) of sewage sludge continues to be an attractive option to produce biogas that could contribute to the wastewater management cost reduction and foster the sustainability of those WWTPs. At the same time, AD reduces sludge amounts and that again contributes to the reduction of the sludge disposal costs. However, sludge volume minimization remains, a challenge thus improvement of dewatering efficiency is an inevitable part of WWTP operation. As a result, AD parameters could have significant impact on sludge properties. One of the most important operational parameters influencing the AD process is temperature. Consequently, the thermophilic and the mesophilic modes of sludge AD are compared for their pros and cons by many researchers. However, most comparisons are more focused on biogas yield, process speed and stability. Regarding the biogas yield, thermophilic sludge AD is preferred over the mesophilic one because of its faster biochemical reaction rate. Equally important but not studied sufficiently until now was the influence of temperature on the digestate quality, which is expressed mainly by the sludge dewateringability, and the reject water quality . In the field of comparison of thermophilic and mesophilic digestion process, few and often inconclusive research, unfortunately, has been published so far. Hence, recommendations for optimized technologies have not yet been done. The review presented provides a comparison of existing sludge AD technologies and the gaps that need to be filled so as to optimize the connection between the two systems. In addition, many other relevant AD process parameters, including sludge rheology, which need to be addressed, are also reviewed and presented. WWTPs are huge liquid waste management facilities for the existing and emerging cities worldwide. As a by-product of the WWTPs, a huge amount of primary and secondary sludge is being produced there and managing it is still a big challenge. For instance, in the European Union (EU) alone, about 30,000 tons of sludge dry mass are generated every day with an extra possible projection of a 10% increase by 2020 [Though landfilling and incineration are common practices for sludge management, recently their environmental and public opinion related impacts have triggered the need for better management alternatives. As a result, the reuse of sludge for land application and recovery of energy is getting more attention. In this regard, the anaerobic digestion (AD) of sewage sludge is favored for its advantages over other sludge management alternatives. These include recovery of clean energy (biogas), a reduction of 30% to 50% of sludge amounts, destruction of pathogens, removal of bad odor, and some others [The transport of sludge, the digester mixing energy requirement, digester heating energy, and energy for pumping sludge are the main issues in most cases. Hence, dewatering the water in the sludge is a necessary task in the WWTPs. The water in the sludge could exist in different forms; free, capillary, vicinal and chemically bound with the solid that is in suspension. Thus, the dewatering technology that could be preferred has to be able to remove those water forms in the sludge. Moreover, the water in the sludge has to be considered as a recoverable resource, as about 99% of the raw sludge is water by content . SeveralConcerning energy advantages, the thermophilic sludge AD is preferred to the mesophilic sludge AD ,6,7. ConThus, it is hypothesized in this review paper that temperature of the AD would have a consequence on the dewaterability of the sludge, the reject water quality and the foaming phenomena. Therefore, reviewing articles and comparing mesophilic and thermophilic sludge AD is important to identify such related gaps, in order to achieve process optimization. Afterwards, this review suggest the ways for optimization of sludge AD among biogas yield, dewater ability, and reject water quality, as it is an important issue in the forthcoming research.Conventionally, wastewater sludge is a by-product of the primary and secondary settling operations at the WWTPs. In that case, the conventional wastewater treatment process involves mainly three unit operations following screening and related preliminary treatments. The first of which is primary settling that is performed with the possible addition of coagulant chemicals to enhance the settling of the particles in the wastewater. By dosing coagulants, much of the solids are settled out, mainly the organic masses that are unstable, and such residues are useful inputs to AD plants . TherefoConsequently, the supernatant of the primary clarifier goes in to the activated sludge system unit where consortia of organisms, mainly bacteria and protozoa, degrade the organic substrates in to still nutrient rich effluent and biomass rich sludge known as the waste activated sludge (WAS). Obviously, there the strength of the waste and hence the extent of stabilization is evaluated and is expressed as the chemical oxygen demand (COD) of the wastewater. COD is thus an indirect expression for the strength of waste that is based on the amount of oxygen required to oxidize the organics.The WAS is then settled in a secondary clarifier. The secondary sludge settled in the secondary clarifier is partly recycled into the activated sludge process unit and partly goes to the sludge digestion unit. The supernatant that is still rich in nutrients and probably contains pathogens is followed by disinfection and nutrient removal based advanced processes. Those polishing unit processes help to comply with discharge limits. Generally, composition of sewage sludge is a function of the parent material and the subsequent treatments applied to it. The core compositions of typical sludge are organic compounds expressed in terms of the volatile solid (VS) or COD as stated earlier, suspended solids (SS) or dissolved solids (DS), and nitrogen and phosphorus. A: primary sludge, primary sludge with physical/chemical treatment or high pollution load;B1: biological sludge (low load);B2: biological sludge from clarified water (low and middle load);C: mixed sludge (mix of A and B2 types);D: digested sludge. The respective sludge composition is thus depicted in The sludge composition is classified into the following categories according to the report of the European Commission, 2001.In relation to wastewater sludge, various national and international rules are set to be met before discharge of the supernatant and the sludge into the natural environment from those conventional WWTPs. For example, the EU has regulation under the title of Urban Wastewater Treatment Directive 91/271/EEC, which sets the minimum levels prior to discharge to surface water that is assigned based on the population size. Especially, the nitrogen and phosphorus limits apply to sensitive areas, mainly to those of natural freshwater lakes. Similarly, there are rules with regard to pathogens, odours and stability of sludge. Thus, in an effort to optimize AD systems, the reject water quality needs to be considered from the point of view of meeting discharge limits.2S, and vulnerability to xenobiotic compounds are the most common process stability concerns with regard to AD in general where sludge AD is not exceptional. In that respect, optimization of AD temperature is subject to process stability as well.Process stability, the long start up period and the needed process time, mal-odorous nuisances mainly due to HProcess stability in AD is also partly a function of the type of substrate involved in the AD. Thus, the higher the degradability of the substrate used in the AD, the bigger the issue of process instability. With respect to sludge AD, biogas can be recovered from the raw sewage sludge directly, which is mostly difficult to manage, or from use of the WAS or a mixture of the two .Process stability in AD is attributed to different stages of degradation by the various organisms involved that may impact the thermophilic process differently from that of the mesophilic. As a system, AD consists of a series of microbiological processes that convert organic compounds to methane and carbon dioxide as well as hydrogen sulfide and water in the absence of oxygen. It reduces the VS by 35%–60%, depending on the operating conditions. As a complex and syntrophic microbiological process, AD mainly involves bacteria and archaea. The major syntrophic processes can be classified in to four stages: hydrolysis, acidogenesis, acetogenesis and methanogenesis, and these processes happen at the same time with different percentages of conversions . In mostIn most cases, the hydrolysis stage is process rate limiting, which splits polymers mainly into monomers and oligomers. The acidogenesis stage process is about the transformation of monomers into short and medium chain acids and alcohols. This stage is a concern due to the acidification of digesters that marks the need to monitor digesters to avoid process failures or stuck. Furthermore, the acetogenesis stage is the conversion of short and medium chain acids to hydrogen, carbon dioxide and acetate. Lastly, in the methanogenesis stage, the carbon dioxides, hydrogen and acetate are converted to methane and water. Methanosaetaconcelii, Methanobacteriumbeijingense and Methanosarcinaformcoccus, to mention a few [The conversion of acetate to methane is the major pathway in thermophilic AD. All of the processes take place under very low oxidation reduction potential with reference to hydrogen, and, hence, for the methanogenesis, the reduction potential goes down to −300 mV or it has to be less than −200 mV [on a few ,15. 2, which is an issue of concern with process stability. This process has to be in syntrophy with methanogens or sulfur reducers to proceed under standard conditions. Kaspar and Wuharmann clearly stated that hydrogen and acetate are inhibitors of microbial degradation of propionate and ethanol, hence the partial pressure of hydrogen and alkalinity have to be used as a monitoring parameters to sludge AD [These degradation processes are prone to be upset. Although the overall process in AD is exergonic (the change in Gibb’s free energy is negative), some steps such as propionate oxidation are sensitive to build-up of Hludge AD ,18. In complex waste mixtures like the sewage sludge, 30% of the electron flow occurs through oxidation of fatty acids. Thus, there is high production of the diatomic hydrogen, which has to be reduced by the responsible organisms in order for the process to proceed safely. −4 and 10−6 atmosphere for the system to operate efficiently, while for the oxidation of ethanol, its value should range between 10−1 and 10−6 [Propionate is the most produced intermediate in AD of organics. Propionate oxidation produces hydrogen molecule whose partial pressure has to be between 10and 10−6 . Appels and colleagues noted that process stability and control is more an issue for the thermophilic anaerobic reactors compared to the mesophilic ones. The reason for that is due to the increase of free ammonia in the system that inhibits the microorganisms therein. The amount of free ammonia in AD systems depends on the total ammonia, temperature and pH in the system. Free ammonia increases with pH and temperature. The resulting instability leads to an increase of volatile fatty acids (VFAs) that causes a decrease in pH and hence a decrease in free ammonia that the process remains to a certain extent self-regulating. However, the amount of methane production is reduced based on the ammonia level. 3-N/L leads to inhibition of 50% of the methanogenesis at pH 7.6 under thermophilic conditions, and a total AD process inhibition can occur at a concentration of 10 g NH3-N/L. A VFA concentration of 2 g/L is also reported to inhibit cellulolytic hydrolysis, alarming that its concentration as acetic acid has to be kept lower than the inhibitory concentration level [In such a case, a free ammonia concentration in the range of 560–568 mg NHon level ,20. GeneRegarding the VFAs, the acids are diverse in ADs and have a joint effect on the bacteria and archaea working therein. Thus, the individual concentrations of those short as well as medium molecular sized acids do matter in the AD process stability with varying magnitude in impact. For example, an acetic acid concentration of 2400 mg/L and butyric concentration of 1800 mg/L do not have an inhibitive effect on methanogens. However, a propionic acid concentration of 900 mg/L resulted in a significant inhibition of the methanogens . This emRubia et al. stated in their review article that another issue of process stability of concern with the thermophilic digestion of sludge is related to the procedure in which the thermophilic inoculum is taken. As a result, the reviewers recommended that a fast increase in temperature to the target level with the gradual raising of the organic loading rate (OLR) can be an approach to this problem. Hence, the choice of an AD technology is linked to process stability. In a related fact, a limitation with a single-stage continuously stirred tank reactor (CSTR) process configuration technology is due to its little stability. This is why CSTRs are taking longer amounts of time to reach process equilibrium, or they could even fail to reach equilibrium as compared to the two-staged configuration . In most studies, comparison of mesophilic and thermophilic AD is geared towards the biochemical process speed and biogas yield. Some authors describe that the promising advantage of thermophilic sludge AD compared to mesophilic AD is better biogas and better digestate quality, though most findings are inconclusive. In addition, the kinetics of whole-sludge AD have been studied, and the results showed that the rate is faster in thermophilic AD than in mesophilic in general, which is ascribed to the temperature effect in speeding up the biochemical reaction rate ,10. −1, and an increase of process speed 1.5 times for each 10 °C of temperature rise is recorded. In a related recent study on WAS, the methane production is significantly improved (from 35.8% to 48.2%) in the thermophilic case compared to its mesophilic counterpart. Furthermore, the authors, Li et al, found out that the rate limiting stages of anaerobic process affected by temperature includes the acidogenesis in the mesophilic case in addition to the hydrolysis phase [Furthermore, the relative digestion kinetics of pure substances is investigated targeting the particular step that could be affected most by temperature variation during the AD process. In this regard, Ge et al. found out that the hydrolysis rate is the most temperature influenced stage that strongly followed the Arrhenius relationship, with activation energy of 31 ± 4 kJ·molis phase . Mesophilic AD has been widely in practice in most cases because of its lower process energy demand for reactor heating and its better stabilization. Conversely, thermophilic AD is preferred for its high biochemical reaction and low retention time in addition to stabilization. Moreover, the latter is more accepted for its conformity to discharge limits that are imposed by environmental regulatory authorities. For example, it meets the “class A” bio-solid product required by the United States Environmental Protection Agency (US EPA). Regarding advantages and disadvantages of mesophilic and thermophilic AD, The effect of thermal pretreatment on the WAS is also investigated for its influence in biogas yield and dewatering of the sludge that is digested under the two temperatures of AD. In a study by Gavala et al., in 2003, thermophilic sludge AD was found to be effective on organic matter removal and methane yield under shorter digestion time. According to these investigators, the pre-treatment of sludge showed a positive effect on the rate of methane production by both mesophilic and thermophilic ADs. The authors, however, reported that pretreatment of sludge at 70 °C showed a more positive effect with the secondary sludge digested at a mesophilic temperature that would be due to the improved hydrolysis of suspended solids. The latter fact is also affirmed by other researchers, where thermal pretreatment is known to improve biogas yield by 21% and 31% . According to Gavala et al., the improved stabilization and enhanced dewatering of sludge at a reasonable cost was mentioned as an advantage of thermal pretreatment; however, there are no detail provisions about it. These authors also underlined the effect of mixing primary sludge with secondary sludge to improve methane yield following the thermal pretreatment. Thus, there is an optimal mixing ratio corresponding to the methane yield in that regard.Furthermore, the desirable effect of thermal pretreatment on methane production rate can be linked to the microbial diversity and abundance. To support this, the study by Khemkhao et al., using a Polymerase Chain Reaction-Based Denaturing Gradient Gel Electrophoresis analysis, suggested the suitability of thermophilic temperature to a number of hydrolytic, acidogenic, and acetogenic bacteria, which is suggested as compared to mesophilic temperature .−3·d−1 to both mesophilic and thermophilic ADs. As a result, they found out that the particulate organic matter reduction, and hence sludge volume reduction by the thermophilic reactor, is superior compared to the mesophilic AD. In addition to that, there was a slight increase of biogas yield by the thermophilic reactor; however, a statistically significant difference in mean methane content was observed in favor of the mesophilic AD [In a study by Yong Zhi Chi et al., WAS is digested in a semi continuous stirred tank reactor at mesophilic and thermophilic temperatures. This comparative process is operated under the following conditions: 4% total solid (TS), 30 days of hydraulic retention time (HRT), and OLR set at 1.67 kg-COD mhilic AD . 4+ was seen by the thermophilic AD; from 0.42 mg/L for the mesophilic to 0.69 mg/L for the thermophilic. The latter thus raises an issue regarding the need for further treatment [As expected, the other recent full scale study by Cavinato et al. ,27 showereatment ,27.A more focused experimental study to compare the mesophilic and thermophilic with regard to quality and quantity of biogas was conducted by Amani and co-workers in 2011. The study is conducted in batch-AD using WAS as substrate. In addition to biogas, the solid reduction, COD reduction, as well as VFA production and the pH were assessed. According to this group, the thermophilic AD improved the dewaterability of sludge, but no detail was given on that. However, both digesters showed accumulation of propionate, a factor in process stability. For obvious reasons because of the time-temperature combination effect, the time required to remove pathogens took longer in the mesophilic case. The seemingly preferable advantage in the case of mesophilic AD is the slightly higher amount of volumetric methane production over the thermophilic AD, though the biogas quality did not show a difference. This study is, however, a direct opposite of what was reported within a year by Yong Zhi Chi et al. However, the slightly higher volumetric methane production in the former is obtained at a longer HRT, due to the relatively stable synthrophic process as well as possible biomass autolysis. Nevertheless, cell lysis is obviously faster for thermophilic AD as the substrate concentration declines faster with time in the system and is also favoured by the relatively higher temperature effect. Therefore, the single relatively high volume of methane cannot surpass the faster biochemical process, low volume of digester required, and attainment of the US EPA’s “class A” solid advantages of thermophilic AD. Rather, the most limiting disadvantages according to Amani and colleagues is the energy required to heat digesters, highly polluted supernatants, and process instability in thermophilic AD, where the latter is still contrary to a study by Cavinto et al. . In addi4+-N (mg/L) by the thermophilic digesters, as was the case in the earlier studies. The issue of dewaterability is not addressed here except in mentioning poor effluent quality and low dewaterability for the thermophilic digesters. This study still contradicts the report by Amani et al., but here they used a different substrate [With the advancement of WAS AD, a new technology called co-phasing that exchanges sludge between a spaced thermophilic and mesophilic digesters showed improved process stability and effluent quality as compared to the single stage mesophilic digesters. With the application of such technology, data on effluent quality showed increased NHubstrate ,28. NeveIn a study by Suhartini and co-workers, thermophilic and mesophilic AD of sugar beet pulp was compared by varying the OLR over a long retention time. They found out that digestate dewaterability was better for the thermophilic AD. They also explained that the higher the OLR, the worse the dewaterability . Thus, hA seemingly ‘attractive’ earlier study by Moen et al. showed that the significant difference between the mesophilic and thermophilic AD of sludge underlay in the solid retention time (SRT) required the same digestion results. The difference is significant between the 6th and 20th days of the SRT. The statistically significant difference in VS destruction was observed at the 15th day of the SRT. Similar studies have been made reporting that over 90% of the biogas is produced within the first 14 days, and suggests this HRT as ideal for a batch AD as well. However, such a suggestion without specification of the digestion conditions and parameters is not acceptable ,30. The Zabranska et al. also argued that the sudden increase in temperature created stress to the syntrophic conversion of acetate to methane that takes place at a faster rate than at lower temperatures. They also noted the relevance of thermophilic anaerobic systems in terms of lowering the demand for digester volume and sludge dewaterability, with no details about it. Regarding effluent quality, Nges and Liu  found ouThe other point that Zabranska and colleagues as well as other research advises on is that the change in substrate loading as well as temperature elevation has to be very gradual in order to give time for bacteria to adapt themselves with the change in process variables of the system. This issue has been evidenced by the decline in biogas yield in the early stage of temperature phasing, as authors mentioned. However, some argue on the rapid increase of temperature and gradual increase of loading as an alternative in this regard ,30. The typical reject water compositions are summarized by Ocansey (2005) in an unpublished Master’s Thesis as shown in The key aspect of sludge quality and costs for sludge disposal is its dewaterability. The typical dewaterability of the conventional WWTP sludge increases from activated sludge through raw to stabilized sludge as expressed in %TS; 15–25, 20–30, and 25–35, consecutively (Jenicek P.: unpublished survey of the Czech WWTPs). Thus, the stabilized sludge is the highest in dewaterability. In relation to this sludge stabilization through AD is an existing and energy producing, among its other benefits, alternative regarding sludge management. Such dewatering processes are also dependent on the temperature of digestion. As stated earlier, dewatering the sludge is useful for many reasons. These include minimizing the sludge volume, lowering the sludge transport cost, energy saving of matters associated with sludge drying and incineration, and improving sludge handling and sludge stability. The stabilizing advantage with the sludge dewatering is via moisture limiting, and hence limiting the moisture based microbial activity and the bounds of the resulting associated nuisances. Further sludge dewatering minimizes the amount of additives in cases of necessary bulking . The low dewaterability of sludge incurs a cost of sludge management, which takes a share of 25%–50% of the overall cost of wastewater treatment . Thus, aSome articles published on this related aspect of sludge explain the poor settleability and dewaterability of anaerobic thermophilic sludge mainly due to high concentrations of dissolved COD. In addition, the thermophilic sludge has issues of excess ammonia in the reject water and related aspects but good sludge sanitary quality. The digestate is mainly a concern with regard to dewaterability and hydro-dynamicity that matter during pumping and transport of the sludge. Ge et al. mentioned in their study that thermophilic AD possesses better sludge quality in addition to improved gas yield . In an advanced AD processes, sludge undergoes a chain of mainly thermal treatments to enhance the degree of stabilization. In a study by Braguglia et al., thermal pretreatment before AD of sludge worsened the dewaterability of the sludge, though it produced improved solid destruction and better biogas yield. In a related comparative study on mesophilic and thermophilic sludge AD with thickening as pretreatment and under specified operational conditions, the sludge dewaterability was worse for the thermophilic case despite its superiority in sludge reduction efficiency ,34. It is important to remind readers that, in those reported studies, a comprehensive and comparative study on the effect of temperature of digestion on anaerobic sludge quality, without sludge pretreatment, is not performed. Moreover, those limited studies on sludge dewaterability show some level of disparity and are also inconclusive. Thus, the aim of this review is to suggest the importance of a comprehensive and comparative study on anaerobic sludge quality, with respect to temperature of digestion, and come up with a clear picture of the difference in dewaterability, reject water characteristics and foaming effect that will serve as inputs to optimize sludge management in the WWTPs.Sludge dewatering is not only limited to issues of volume minimization and subsequent liquor treatments. It is also important as sludge conditioning, which is a desired precondition for the subsequent other solids’ management, including odor removal, and in reducing the sludge putricibility. In an associated effort, various physicochemical approaches have been practiced to dewater sludge according to the US EPA. Those facts suggest that the thermal differential of AD would have an impact on the dewaterability of the sludge. Thus, if the effect of the temperature of sludge AD is found to be significant, it will have significant operational consequences. Unfortunately, most dewaterability related studies were not intended for comparison of mesophilic and thermophilic sludge ADs; rather, they are oriented to study the effect of physico-chemical and mechanical pretreatments on biodegradability and dewaterability as well as on sludge rheology. Among such studies, Liu et al. investigated the effect of sludge pretreatment with microwave-acid process, and they found improved sludge dewaterability with a capillary suction time (CST) . In a related study, sludge floc disintegration using an ultrasound showed a decrease in dewaterability due to the increase of fine particles and bound water. As a result, the CST increased fifteen times. The lower the CST, the better is the dewaterability. Whereas, in this same study, the use of ozone as a pretreatment resulted in a slight increase in CST. Thus, the authors suggest that the optimization of both the degree of disintegration and the HRT are necessary to improve the dewaterability after disintegration . It is a−1 TSS [EPS in the sludge is found to worsen the dewaterability of sludge after AD. With inoculation of selected microbes, Zhou et al. reduced the CST of sludge from 255.9 s to 25.45 s within 48 h in their work done in 2014. These EPSs are again impacted by the sludge composition, which is fed to digesters. Contrary to older papers from Zhou et al., the addition of glucose was found to increase the amount of EPSs produced, and it lowered the CST of sludge in an earlier study by Houghton and Stephenson. However, Houghton and Stephenson suggested an optimum level of EPS sought for better sludge dewaterability, with a value of 17.2 mg g−1 TSS . The use−1 TSS ,39.Since handling and management of sludge is a burdensome task for the existing and expanding WWTPs, it is highly demanded that cost effective dewatering alternatives are put in place as stated earlier in this document. The other most important sludge characteristics that need to be dealt also include physicochemical, sanitary and rheological aspects. These sludge properties affect the treatment of sludge, for example, by AD and the dewatering of sludge that are the principal processes in the WWTPs. Regarding rheological properties, anaerobically digested sludge is found to behave as a non-Newtonian fluid ,41. TherViscosity, the major variable affecting the rheological property of sewage sludge, which is determined by measuring the sludge sheer stress, is significantly impacted by disintegration (up to 60%) of the sludge before digestion. In a related fact, digestion has a consequence on the rheological property of sludge as well. Sludge treatment, including its fermentation, also brings a change in its properties as a result of the changes in its complex composition. Rheological properties are very important in optimizing operations like sludge pumping and mixing. The mixing, transport or pumping and heat exchange system design during sludge management largely depends on the rheological property of the sludge. The rheological properties and quality of sludge liquor are affected by temperature . VariousA more rigorous study by Wang et al. showed that hydrothermal treatment of sludge at an elevated temperature, with a threshold temperature of 120–150 °C, gave a further reduction of 19%–47% of the moisture content compared to the one made at room temperature with a residence time of 30 min. In this research, the moisture content of the cake was in correlation with surface charge and hydrophobicity. The hydrothermal treatment also exhibited an energy advantage compared to the thermal drying of sludge . The temperature of sludge treatment is also found to impact its hydrodynamic nature. This fact is studied by using the rheological property of the sludge following thermal treatment. However, other factors also matter in the fluidity of sludge, and the amount of the solid as one factor is worth mentioning here . The essence of mixing in a biological reactor is all about bringing contact between microbes and substrate, which is highly desired for the optimum microbial activity, like in the case of the ADs. In sludge AD, getting that contact is a huge challenge, especially when it comes in to WAS as a substrate, which is mainly composed of biomass suspension where filamentous bacteria are one such obstacle. The non-Newtonian nature of untreated sludge is attributed to its composition expressed as electrostatic and gel-like interactions, and the presence of EPSs, which withhold water and contribute to sludge viscosity. Thus, the sludge thermal treatments result in the breakdown of macromolecules and larger particles, which improves dissolution of particles that again enhance the fluidity of sludge and increase the degree of dewatering due to the restructuring of the particles and release of the bound water in the sludge.Due to the irreversible changes in composition of sludge at high temperatures mentioned above, it was proved that the higher the temperature, the more fluid the sludge. According to Urrea et al., if a temperature treatment of up to 200 °C is applied to sludge as a thermal treatment, the sludge starts behaving like a Newtonian fluid . Though various aspects of sludge AD have been studied under different conditions, an integrative and holistic approach must be applied with emphasis on operational temperature of digestion. Given the faster rate of sludge digestion and shorter SRT in the reactor, the use of thermophilic AD is often preferred over mesophilic AD. Thermophilic digestion is also capable of meeting the US EPA’s “class A” solid requirements in digested sludge. Nevertheless, the operational conditions during the use of the CSTRs are restrictive compared to the mesophilic AD. Though process stability issues favor mesophilic systems, in many cases, it is of less concern with regard to waste activated sludge AD. However, the digestate quality and reject water properties may clearly limit the thermophilic mode compared to mesophilic AD. Many studies in these regards are inconclusive and somehow contradictory. Furthermore, most studies done on the AD of sludge are not comprehensive enough in relation to the complete data about operational factors, and no clear decisive criterion is put in place to prefer one system over the other with respect to the two temperature categories—thermophilic and mesophilic. Thus, a comprehensive approach should encompass most, if not all, of the relevant process aspects or variables. Therefore, there is the need for a study on the optimization of the most important operational aspects such as that of biogas yield, sludge dewaterability, and the reject water quality for an informed choice between the two AD temperature systems.