In academic research contexts, eHealth interventions for caregivers of people with dementia have shown ample evidence of effectiveness. However, they are rarely implemented in practice, and much can be learned from their counterparts  that are already being used in practice.This study aims to examine a sample of case studies of eHealth interventions to support informal caregivers of people with dementia that are currently used in the Netherlands; to investigate what strategies are used to ensure the desirability, feasibility, viability, and sustainability of the interventions; and to apply the lessons learned from this practical, commercial implementation perspective to academically developed eHealth interventions for caregivers of people with dementia.In step 1, experts (N=483) in the fields of dementia and eHealth were contacted and asked to recommend interventions that met the following criteria: delivered via the internet; suitable for informal caregivers of people with dementia; accessible in the Netherlands, either in Dutch or in English; and used in practice. The contacted experts were academics working on dementia and psychosocial innovations, industry professionals from eHealth software companies, clinicians, patient organizations, and people with dementia and their caregivers. In step 2, contact persons from the suggested eHealth interventions participated in a semistructured telephone interview. The results were analyzed using a multiple case study methodology.In total, the response rate was 7.5% (36/483), and 21 eHealth interventions for caregivers of people with dementia were recommended. Furthermore, 43% (9/21) of the interventions met all 4 criteria and were included in the sample for the case study analysis. Of these 9 interventions, 4 were found to have developed sustainable business models and 5 were implemented in a more exploratory manner and relied on research grants to varying extents, although some had also developed preliminary business models.These findings suggest that the desirability, feasibility, and viability of eHealth interventions for caregivers of people with dementia are linked to their integration into larger structures, their ownership and support of content internally, their development of information and communication technology services externally, and their offer of fixed, low pricing. The origin of the case studies was also important, as eHealth interventions that had originated in an academic research context less reliably found their way to sustainable implementation. In addition, careful selection of digital transformation strategies, more intersectoral cooperation, and more funding for implementation and business modeling research are recommended to help future developers bring eHealth interventions for caregivers of people with dementia into practice. A recent systematic review  showed tThe Lancet on the impact of COVID-19 on people with dementia and their caregivers advised care professionals to organize psychoeducation, self-management, and consultations for dementia caregivers on the web [In general, eHealth has many potential benefits compared with more traditional face-to-face interventions: it is relatively easy to implement on a larger scale; it has the potential to reach users from various socioeconomic and demographic backgrounds; and it can include extensive personalization, instant delivery, and real-time feedback ,20. Ther the web . A surve the web .Unfortunately, the implementation of eHealth is often fragmented and short lived and lacks sufficient vision and strategy . In addiA useful framework to explore the factors that contribute to the  sustainability of nonacademic interventions is the Business Model Canvas . The BusThis study aims to explore how lessons learned from interventions currently being used in practice could aid the implementation of evidence-based interventions for informal caregivers of people with dementia. To accomplish this, this study had 3 aims: (1) to examine a sample of case studies of eHealth interventions to support informal caregivers of people with dementia that are currently used in the Netherlands; (2) to investigate what strategies are used to ensure the desirability, feasibility, viability, and sustainability of the interventions; and (3) to formulate lessons learned to facilitate the implementation of future eHealth interventions.First, to acquire a sample of eHealth interventions to support caregivers of people with dementia that are being used in practice, experts (N=483) in the fields of eHealth, dementia, and caregiving were contacted via email.The experts were asked to provide the names of interventions that met the following 4 inclusion criteria: eHealth intervention (1) delivered via the internet; (2) suitable for informal caregivers of people with dementia, (3) available in the Netherlands, either in Dutch or in English; and (4) used in practice. The aim was to receive recommendations for between 5 and 10 interventions that met all criteria, as this would achieve data saturation but still be a small enough number to analyze in depth. The suggested interventions were not meant to serve as an exhaustive overview of all available eHealth interventions for caregivers of people with dementia in the Netherlands. Rather, they are a sample of this type of intervention, which was defined using a systematic approach.After receiving these recommendations, the researchers reached out to the interventions’ contact people with an invitation to participate in a telephone interview about their experiences with their intervention’s implementation. This study used a multiple case study methodology for the analysis. This methodology was chosen for its ability to qualitatively explore complex phenomena within their contexts and explore differences within, as well as between, cases . The focFirst, emails with an invitation to provide examples of interventions meeting the 4 inclusion criteria were sent to a diverse sample of experts. Experts (n=330) in the academic field were approached via the INTERDEM mailing list. INTERDEM is an international research network that focuses on psychological care for dementia. Second, 4 emails were sent to experts in the industry , 10 emails were sent to representatives from dementia and caregiver patient organizations, and 4 emails were sent to clinicians in the field of dementia care (3 psychologists and 1 psychiatrist). Regarding the significant difference in the number of emails sent per subsample, the possibility of approaching researchers via the INTERDEM network (consisting of 330 mailing list contacts) was associated with a much lower response rate, as it was a general mailing instead of a targeted personal mailing. Third, 15 dementia caregivers were asked to provide examples of interventions that met the 4 inclusion criteria during a dementia client panel meeting at Maastricht University. The caregivers were part of the Maastricht University’s dementia client panel. Finally, a notice was placed on the social media channels  of the Nederlandse Vereniging voor Neuropsychologie , which was clicked on 120 times across channels, according to NVN.Results section provides more details on intervention inclusion).First, emails with an invitation to provide examples of interventions that met the 4 inclusion criteria were sent to a diverse sample of experts (N=483). Each of these experts was known to the research team through their own professional networks. Each email was sent once. A total of 15 dementia caregivers were asked face-to-face to provide examples during a dementia client panel meeting at Maastricht University. The notice on the NVN was placed once.Results section).Once interventions were identified, the providers of these interventions were interviewed over the telephone. For the 9 included case studies, interview data were collected using the interview guide in explanation building [The data were analyzed using a qualitative, multiple case study methodology . HLC conbuilding , where tThe second phase involved comparing cases with each other to identify common and differential characteristics. To do this, the interview transcripts were analyzed across cases by assigning codes  to respondents’ replies that provided more information on these topics. This guided an explanation of which characteristics could contribute to intervention desirability, feasibility, and viability across cases.In the third phase, the results of this initial analysis were discussed with HLC, LMMB, HJT, MG, and MEDV in a consensus meeting, where differences in interpretation were resolved and external validity was supported. In particular, the authors discussed the value propositions  of the included cases; their common characteristics in terms of desirability, feasibility, and viability; and their respective implementation phases and business models. Finally, a member check   served tmember check was conducted. Through this member check, all participants (including the participants involved in case studies 5 and 8) approved (in writing) the information in the transcripts being used in this study (with the exception of the names of case studies 5 and 8).This study did not fall under the scope of the Medical Research Involving Human Subjects Act. Therefore, ethical approval by Maastricht University’s institutional review board was not required. The respondents were verbally informed of the purpose of the study before the interview and gave their consent to the interview being audio recorded and analyzed anonymously. However, it was not possible to guarantee total anonymity because the interventions themselves were discussed by name. Therefore, it was requested that names of interventions not be used for case studies 5 and 8. The participants consented to this, and a The first section provides an overview of all the interventions suggested by the contacted experts and describes the included case studies. In the second section, the following characteristics of the included case studies are examined: (1) desirability, feasibility, and viability of the interventions; (2) findings on the sustainability of their business models; and (3) lessons learned from the respondents.A total of 36 responses were received , resulting in a response rate of 7.5% (36/483). Although this response rate is rather low, it was deemed well suited for the described purpose of gathering a limited, nonexhaustive sample of cases to be analyzed in depth by multiple case study methodology. A total of 21 interventions were nominated to be part of the sample. Some experts suggested multiple interventions, whereas others did not suggest any interventions. Overall, 11 interventions were excluded based on the 4 criteria described earlier. A final intervention was excluded because nobody could be contacted for the interview, resulting in insufficient data for a case study analysis. In total, 9 interventions met all 4 criteria and could be contacted for interviews, resulting in their inclusion as case studies. The interventions included as case studies were targeted at informal caregivers of people with dementia. However, many case studies have also decided to target formal care by developing aspects of their platforms for health care professionals:Well you notice that there is a lot of demand from health care professionals. So people say “Gosh, we find this interesting” and recommend it to their clients, to know what is going on and what they are getting, before they give advice about which modules exist. It should be used that way. That the caregiver can initiate, but also the health care professional, and they both have need of that knowledge.Respondent case study 5Interestingly, even in blended interventions where the guidance of a health care professional is necessary, the eHealth platform was not targeted at these care professionals. In all cases, there remained a primary focus on the needs of informal caregivers. Next, a common characteristic was the overall relatively low pricing of eHealth . The eHeI think an advantage of our situation at the university is that we have a national network of meeting centres. There are already 160 of them in the Netherlands, which come together once a year, where we inform them about all kinds of interesting developments for them, also the STAR course.Respondent STARThis integration significantly increased the visibility of the case study and provided a supportive structure. All case studies mentioned the time and effort needed to keep eHealth content relevant and up-to-date as a significant but necessary drain on resources. Finally, many case studies have emphasized the importance of creating a community around the eHealth intervention. These communities were places where caregivers could contact each other and share experiences about the eHealth intervention and dementia caregiving in general. These communities sometimes took place on a designated forum on the intervention website or via social media channels, such as a closed Facebook group.Most of the cases were developed by groups with specific expertise in dementia and caregiving. Most of the studied cases chose to develop the content themselves (and hence owned this content) while hiring an external party to help build and maintain the web-based platform. Often, it was the expertise party who ran a helpdesk and support service for users, forwarding technical questions to the hired software party. In this case, these support tasks were either part of a research position at a university or on a volunteer basis. Most of the studied cases were limited in terms of marketing. In general, their aim seemed to be to sustain eHealth rather than scale it up:So when regions report that this sounds good, they also want this, then we start. But we do not actively search for regions where we can implement OZOverbindzorg. We do not think that is societally appropriate. So no, they come to ask us.Respondent OZOverbindzorgThis is because none of the cases aimed to make a profit. Payment was mentioned as a barrier multiple times, with respondents warning that setting up a secure payment system takes considerable time and effort and that their older demographic is not always comfortable with solutions such as PayPal.subscription packages of services. They did this in terms of both content and volume. Other case studies (such as Thinkability) offered their eHealth interventions on the web for a fixed price, after which the buyer had access to the service indefinitely. Indeed, in this sample, Thinkability is the only intervention whose cost structure was centered around direct download from the internet by the caregiver, without mediation by an existing health care system. STAR eLearning and the case study 6 modules are also available for the caregiver to access without a health care organization, although these modules are at least partly integrated into existing dementia care systems, such as dementia meeting centers and a care organization, respectively. Finally, some cases, such as Carenzorgt and DementieNL (and Myinlife), made no revenue but instead increased the attractiveness of a larger health care platform or organization:In total, 4 different types of viability strategies were observed in 9 cases. Most interventions  opted to vary their prices for different We mainly make software for health care institutions, especially in elderly care and disabled care and a bit in mental health care. Nine years ago, we thought it was important to involve the client’s family in the process. This also helps health care professionals do better. So we said, we will make this platform. We think it’s important for the entire infrastructure that we have this and offer it for free.Respondent CarenzorgtFinally, other case studies (such as DementieNL and Myinlife) existed to supply information and services at no cost to caregivers and were financed in large part through sponsorships.It was clear that although all the case studies were included because of their use in practice, the levels of use varied strongly. During the interviews, respondents from each case study were asked to formulate recommendations for future eHealth developers based on their experiences in bringing eHealth for dementia caregivers into practice. Make use of an innovation consortium by involving health care providers, financers, users, and technical developers in every phase of developmentProvide a good fit with the intervention’s implementation contextEnsure long-lasting marketingStart implementing and learning, rather than waiting and perfecting designs. In other words, start small and develop the interventions further based on user feedbackBigger implementation budgets are crucialCommercial collaboration is a big help Health insurer collaboration is beneficial to sustainable implementation through its potential to determine priorities and develop relevant and sustainable interventionsInvolve users in the whole process as much as possible, for example, through co-design and cocreationThis study identified a sample of 9 case studies on the implementation, use, and development of eHealth interventions for caregivers of people with dementia that are currently used in practice in the Netherlands. The main findings from interviews with representatives of these interventions showed that 4 cases were found to have developed sustainable business models . Overall, 5 cases were implemented in a more exploratory manner and relied on research grants to varying extents, although some had also developed preliminary business models. These findings have led to the following recommendations for the design, the implementing team, and the suggested implementation strategies of a core business model to help achieve the long-term implementation of eHealth interventions for caregivers of people with dementia.First, the design of the proposed core business model is based on the desirability, feasibility, and viability characteristics of the case studies. The first key element of this design concerns its desirability, specifically by incorporating eHealth interventions into larger, pre-existing health care contexts. The case study interview respondents mentioned that the fit of the interventions with existing organizational goals and contexts was an important part of intervention desirability, separately from any financial considerations. This is in line with previous studies on the implementation of eHealth interventions in other populations -37. IndeThe second key element of the proposed design concerns the similarities in the feasibility characteristics of the interventions. The case studies tend to supply the dementia-specific content and helpdesk of the eHealth internally, whereas ICT and software services are outsourced to an external party that does not own the content. In other words, the execution of these ICT-related key activities is shifted to key partners. Previous research has discussed the frequent outsourcing of services in ICT  and emphFinally, the third key element of the proposed core model’s design pertains to its viability. A prevalent, sustainable cost structure is a fixed price for access to the intervention’s information or services, which is paid by health care organizations. Another viable option for sustainability is integration into a larger platform that sponsors the eHealth intervention, so no cost is charged from the caregiver. Again, it is clear that when considering the viability of these business models, viewing the intervention within its health care context can facilitate its sustainable implementation . This peNext, the main finding of this study concerns the question of who is implementing these interventions. In this study, case studies that did not originate in an academic research context more successfully achieved sustainable implementation, compared with the case studies that originated in an academic research context. There is a noticeable absence of eHealth interventions that originated as research projects in the identified, sustainable financing models used in practice. Indeed, most academic interventions are constrained by expiring funding , and intIn addition, more traditional research methods such as randomized controlled trials are not time efficient or resource efficient and can impede researchers from reaching this implementation stage . The usefreemium business models [Finally, an important question is, “Which strategies can help bring the proposed core business model into practice, and keep it in practice?” Here, it may be useful to gain inspiration from business. For instance, digital transformation strategies are a key part of bringing business models into practice by coordinating and prioritizing the many different aspects of digital transformation . Previous models . A freems models . Communifreemium business model in this sample, community creation was an important part of many of the included case studies, even more so among those grouped in the sustainable implementation category. Future research could test the proposed core model for external validity and investigate the effectiveness of community creation as part of a digital implementation strategy to increase the sustainability of eHealth interventions for caregivers of people with dementia. Here too, alternative, flexible research designs offer possibilities for comparing and evaluating innovative implementation strategies [Although there was no clear example of a rategies . Figure This study helps alleviate a significant problem in the field of eHealth interventions for caregivers of people with dementia: a lack of information on financially viable, long-term implementation trajectories. By taking an intersectoral perspective and learning from interventions already being used in practice, this research is broader than most studies, which are often limited to studying interventions developed in an academic research context. This approach made use of a systematic method to select interventions for case studies based on expert opinion and predefined criteria. Finally, it is important to note the timeliness of this study. It is fair to say that in the context of the COVID-19 pandemic, there is a greater need than ever to provide caregivers of people with dementia with good web-based support options. The findings of this study provide concrete implementation lessons to aid eHealth developers who wish to implement and scale up eHealth interventions to support caregivers of people with dementia at a distance.This study has several limitations. First, there is a possibility of selection bias, as the definition of this sample required responses from the authors’ own dementia and eHealth networks. As a result, the first possible bias is toward experts from academia, who are overrepresented in this sample. Second, there is likely a higher than average degree of sample familiarity with the authors’ own interventions, Partner in Balance and Myinlife, as the contacted experts belong to the same networks (such as INTERDEM) and are often exposed to other members’ research. Moreover, the authors acknowledge the potential bias in reporting the results concerning Myinlife and Partner in Balance, as they were involved in their development and evaluation. Third, it is likely that more interventions originating from the Southern Netherlands were included (as this is where the authors’ research group is based), whereas interventions from elsewhere in the Netherlands remained underrepresented. A second limitation concerns the potential self-report bias of the included case study respondents to emphasize positive aspects of their own interventions and minimize difficulties in the responses about their learned lessons. A final limitation concerns the fact that this study did not guarantee respondents’ total anonymity; because interventions would be referred to by name , the intervention could conceivably be linked to one of a few possible intervention respondents. This was discussed before the interview and agreed to by the respondents, who also provided a member check, approving the interview transcript. This lack of total anonymity could have impeded respondents from discussing more sensitive implementation topics candidly, out of fear of  repercussions from collaborators. Another possible consequence of this lack of anonymity is that the eHealth contact persons might not have wanted to share important details of their business plans to remain competitive.Case studies that did not originate from an academic research context seemed to achieve more sustainability, whereas case studies from academic research contexts experienced barriers to financial independence from research grants. Examining the common and differential characteristics of these case studies resulted in the proposal of a core business model for eHealth interventions for caregivers of people with dementia, derived from a sample of case studies currently being used in practice. This proposed core business model suggests increasing desirability, feasibility, and viability by integrating into larger structures; owning and supporting content internally while developing ICT services externally; and offering fixed, low-level pricing. Together with the origin of the case studies, these elements contributed to the sustainability of case studies. Finally, targeted digital transformation strategies, more intersectoral cooperation, and more financial incentives for research on sustainable business models are recommended to help future developers bring eHealth interventions for caregivers of people with dementia into practice.


Coronavirus disease 2019 (COVID-19) pandemic continues to spread across the world. Specimens of blood, body fluids and excreta received in the department of pathology undoubtedly increased the risk of infection, especially in some hospitals that are short of professional protection capability. Here we provided a new simple way for the sputum cytology test during the COVID-19 pandemic.Sputum samples from 30 patients with lung cancer were collected and divided into two groups, including the control group and the experimental group. Samples of the control group were processed in the biological safety cabinet, while the experimental group was put into the sealed specimen bag directly and pretreated with 75% medical alcohol. Then the cell morphology and tumor cell identification were analyzed by cell smears and liquid-based cell staining. The expression of cell antigens was determined by immunohistochemical staining.Our result showed that both sputum samples in two groups exhibited complete cell structure and clear morphology according to the cell smear and liquid-based cell staining. In addition, the immunohistochemical result showed that cell antigens, including cytokeratin (CK), leukocyte common antigen (LCA), and thyroid transcription factor-1 (TTF1), were specifically expressed in the cell membrane, cytoplasm, and nucleus, respectively. The tumor cells were distributed diffusely, and cell antigens were located accurately after pretreatment with 75% medical alcohol and were consistent with that of the control group.Using 75% medical alcohol to pretreat sputum specimens has no obvious impact on cell morphology and antigens expression. Our study provided a new method for the sputum cytology test with no direct contact so as to protect medical staff against the virus during COVID-19 outbreak. Coronavirus disease 2019 (COVID-19) was first detected in China in December 2019, and declared as a pandemic by the WHO on March 11, 2020 . During The experimental materials are the sealed specimen bag, rubber band, and 75% medical alcohol. Initially, 30 ml of alcohol was injected into the sealed bag and the sealed bag was tilted so that the alcohol can flow to the corner of one side of the bag. Then the corner of the bag was fastened with a rubber band .Sputum samples were collected from 30 patients with lung cancer in the respiratory department of the Ninth People's Hospital affiliated with the Shanghai Jiaotong University, School of Medicine from February to July in 2020. Two copies of each sample were collected from one patient, one of the samples act as the control group and another was the experimental group. Samples of the control group were placed into a biosafety box and sent to the laboratory. All the next steps were performed in the biosafety cabinet. Samples of the experimental group were directly put into a sealed specimen bag and treated with 75% medical alcohol, then were processed to the next step the same as the control group.Samples of the control group were conducted according to the routine cytology experiment procedure. All the processes were performed in the biosafety cabinet for cytology staining and immunohistochemistry. The process of the experimental group was done as follows:Sputum samples were placed into a specimen box and transferred to the specimen bag. After adding 75% of medical alcohol, the corner of the bag was fastened with a rubber band and the specimen bag was sealed .The specimen box was opened inside the sealed bag. Then to cut the rubber band and squeeze the bottom of the specimen bag, so that the alcohol could flow into the specimen box. Close the lid of the specimen box and keep it stand for 20 min so that the virus and bacteria can be inactivated by the alcohol . A totalCytological staining was done as previously reported. Briefly, cytological specimens were placed in a 15 ml centrifuge tube and centrifuged at 2,500 rpm for 5 min. After that, part of the precipitate was collected to perform a cell smear, while the rest was collected for liquid-based staining by using a liquid-based cell preservation solution.After centrifugation, samples were wrapped with sponge paper and put into a dehydrator for dehydration. After dehydration, samples were soaked into the wax and cut into slices. Then slices were baked for 1 h and repaired with pH 9.0 ethylenediaminetetraacetic acid (EDTA) for 20 min. After that slices were incubated with primary antibody against CK , LCA)  orTTF1  at room temperature for 1 h. The color reaction was then made with DAB staining.The used specimen box was put into a sealed bag and re-sealed. Then it was disposed of as medical waste.The cell smears and liquid-based cell staining results showed that the structure of tumor cells and other kinds of cells in two groups are intact with clear nuclei and a clean background . The numImmunohistochemical results showed that the expression of cell antigens is complete, and the localization of cell antigens is clear and accurate. Cell antigens, such as CK and LCA, was expressed on the membrane and cytoplasm, respectively , and TTFvia droplet particles arising through sneezing and coughing action of an infected person, COVID-19 Diagnosis and Treatment Protocol , released by the National Health Commission (NHC) on 19 February 2020 pointed out the possibility of virus transmission through aerosols when prolonged exposure to high concentrations of aerosols in a relatively closed environment  that was further declared as a pandemic owing to rapid spread to different parts of the world . Althougironment .During COVID-19 pandemic, pathological specimens, such as sputum and lavage fluid, from the department of respiratory and emergency may be at risk of infecting medical staff. Thus, sputtering and aerosol transmission are very likely to occur if specimens are processed routinely. At present, pathology departments in some middle- and small-scale hospitals are still suffering from a lack of a simple and efficient way to process the cytological specimen without destruction of cell morphology. What is more, some middle- and small-scale hospitals were not even equipped with professional negative pressure laboratories and biosafety cabinets, which may cause cross-infection among medical staff during the process of handling pathological specimens. In addition, it is very likely to trigger contact infection by aerosol if specimen boxes containing samples are opened directly.As the cytological examination of sputum and lavage fluid is the major way to diagnose respiratory diseases, we first propose a new and economic way to process the specimens efficiently. In this study, we used a sealed bag to keep the sputum sample in a closed space, and then pretreated it with 75% medical alcohol to sterilize the sample, to protect the technician and other staff against the virus. The sealed pathological specimen bag has good corrosion resistance and fastness, and is not easy to be damaged during operation. The rubber band was used to prevent the alcohol from shaking in the bag. The seal strip was used to isolate the virus that may exist after the sample box was opened. As the 75% medical alcohol can cause protein coagulation, which may affect the sputum cytology test. In this study, we verified that the cell morphology and cell antigens expression are not affected after medical alcohol pretreatment by using cell smears, liquid-based cell staining, and immunohistochemical staining. Thus we conclude that this method has the advantage of being low cost and easy to operate, it is worth popularizing and applying in pathology departments, especially hospitals in backward areas.This study provided a new method for technicians to test samples that may contain pathogenic bacteria or viruses without direct contact to protect medical staff against viruses during COVID-19 outbreak.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author/s.The studies involving human participants were reviewed and approved by ethics committee on human research at Shanghai Jiaotong University, School of Medicine, Shanghai Ninth People's Hospital. The patients/participants provided written informed consent to participate in this study.JC and XW wrote the manuscript and contributed equally to this work. LL, TJ, and YR conduct experimental research, organize experimental data into manuscripts, and supervised the findings of this work. All authors contributed to the article and approved the submitted version.This study was supported by the Sponsored by Shanghai Sailing Program (No. 19YF1427600) and the National Nature Science Foundation of China (No. 81900438).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Depopulation accompanied by population aging is a major public health concern in Japan. Although adequate allocation of mental healthcare resources is needed, there have been few studies on the impact of population change on the supply–demand balance for mental illness in Japan. The aim of this study is to predict psychiatrists' distribution for patients with mental illness via a utilization-based approach.We set patients with schizophrenia, mood disorders, vascular dementia or Alzheimer’s disease as study subjects and conducted analyses for 2015, 2025, 2035, and 2045 across all prefectures. Moreover, we evaluated the regional maldistribution of demand and supply by calculating the number of psychiatrists per patient, Gini coefficients (GC), and Herfindahl–Hirschman Index (HHI).The mean number of psychiatrists per patient for patients with schizophrenia, mood disorders, vascular dementia, and Alzheimer’s disease in 2025, 2035, and 2045 was significantly lower than in 2015. For all of the abovementioned diseases, both the GC and HHI will increase until 2045.If psychiatrists are allocated at the current population-to-psychiatrist ratio, the shortage of psychiatrists will continue to worsen in the future. To overcome this inequity, policy makers should make plans to shift responsibilities from psychiatrists to other mental health workers and to ensure the adequate geographical allocation of healthcare resources. The increasing number of patients with mood disorders and Alzheimer's disease has increased the demand for psychiatrists in Japan . In 2013s by disease, changes in population structure could lead to different utilization patterns of healthcare services for each mental illness. Although adequate allocation of mental healthcare resources is needed, there have been few studies concerning the impact of population change on the supply–demand balance with respect to mental illness in Japan.Healthcare systems in Japan are facing the problems of depopulation accompanied by population aging. Based on 2015 national census data, the National Institute of Population and Social Security Research (IPSS) predicted that the Japanese population will decrease from 127 to 106 million by 2045 . In the In this study, we employed a utilization-based approach in which current or target rates of healthcare system utilization are multiplied by future population estimates to estimate the demand of mental illness. This approach has been widely used in Organisation for Economic Co-operation and Development (OECD) member countries , 5. TherThe aim of this study is to predict psychiatrists' distribution for patients with mental illness and to predict the future healthcare supply–demand balance. The projections of the availability of human resources in the mental healthcare system could support policy decision-making. To the best of our knowledge, this study is the first report on the projection of psychiatrists’ distribution for patients with mental illness in Japan.Data on the number of psychiatrists per prefecture were obtained from the 2016 Survey of Physicians, Dentists, and Pharmacists (SPDP) on the MHLW website . In addiTo project the number of future psychiatrists, we assumed that the psychiatrist-to-population ratio in Japan would be constant from 2015 to 2045. Although the current distribution of psychiatrists in Japan is not adequate, we assumed that attractiveness of urban areas to psychiatrists would not change . We calcIn a utilization-based approach, future demand is calculated by multiplying the future population by the utilization rate for each disease. First, we obtained the utilization rate for each disease, by age and sex, as variables from the 2017 Patient Survey. Population by age and sex in the future was based on population projections from 2015 to 2045. We then multiplied these variables for estimates of the future number of patients as the criterion for demand in each prefecture. For each disease, we calculated the number of psychiatrists per patient in Japan.We employed the Gini coefficient (GC) as an indicator of the distribution of psychiatrists to aid in the evaluation of inequity in human resources by prefecture. In this study, Lorenz curves are drawn by plotting the cumulative proportion of psychiatrists on the vertical axis and the cumulative proportion of the estimated number of patients on the horizontal axis in ascending order by psychiatrists per patient across all prefectures. After that, we calculated the GCs based on the Lorenz curves. The GC is traditionally used to analyze the distribution of income and wealth and has a theoretical range from 0 (perfect evenness) to 1 (maximum possible unevenness). It provides a standardized value to reflect the relative unevenness of a distribution. In this study, higher values of the GC indicated higher levels of human resource (psychiatrists) inequality experienced by patients with mental illnesses among prefectures.The Herfindahl–Hirschman Index (HHI), which has been widely used to evaluate mergers and acquisitions, was adopted as an indicator of patient concentration. In this study, the HHI for each disease is calculated as the sum of squared patient shares (percentages) across all prefectures. It approaches zero when a market is occupied by a large number of competitors of relatively equal size and reaches its maximum of 10,000 points when there is a market monopoly. The HHI was interpreted as the concentration of patients with mental illness to estimate future demand transfer. In this study, higher values of the HHI indicated higher concentrations of patients with mental illnesses among prefectures.In Tables p < 0.05 was considered significant. The data analysis was performed using R for Windows, Version 3.6.3  [Because the Shapiro–Wilk test did not confirm the normality of the data distribution, the Wilcoxon Signed-Ranks Test with the Bonferroni correction was employed for comparisons between 2015 and other time points. A value of Austria) .Table The GC and HHI for each mental illness are shown in Figs. In this study, we predicted psychiatrists’ distribution for patients with mental illness in Japan. On the supply side, the mean numbers of psychiatrists in 2025, 2035, and 2045 are significantly lower than those in 2015. On the demand side, in line with depopulation, the mean numbers of patients with schizophrenia and mood disorders are significantly lower than those in 2015. However, regarding vascular dementia and Alzheimer’s disease, the mean numbers of patients with these diseases at the abovementioned three time points are significantly higher than those in 2015. For all of the abovementioned diseases, the HHI will consistently increase from 2015 to 2045. Regarding the supply–demand balance, the mean number of psychiatrists per patient for patients with schizophrenia, mood disorders, vascular dementia, and Alzheimer’s disease at the abovementioned three time points is significantly lower than in 2015. For all of the abovementioned diseases, the GC will consistently increase from 2015 to 2045.In Japan, the shortage of physicians, including psychiatrists, has recently become a serious public health issue , 13. SevOur results indicate that the change in disease structure with the increase in patients with dementia and decrease in those with schizophrenia and mood disorders will continue until 2045. Unlike the overall trend, the predicted number of patients with schizophrenia or mood disorders had not decreased in Okinawa and Tokyo by 2045. The high birth rate of Okinawa, and the migration of young people to Tokyo, might explain these predictions. The mean number of psychiatrists per patient with mental illness, especially dementia, is predicted to decrease in the same period. The maldistribution of psychiatrists will worsen in the future. To overcome this inequity, policy makers should make plans for not only the adequate geographical allocation of healthcare resources, but also the shifting of responsibilities from psychiatrists to other mental health workers. The use of information and communication technologies (ICTs) for the delivery of health services to rural communities and improved productivity of psychiatrists with more effective interventions would also ameriolate the inequity.Several limitations of this study should be acknowledged. First, our study focuses on the number of psychiatrists as the supply side of the mental healthcare system. However, human resources in the healthcare system consist of not only psychiatrists but also nurses and other health care professionals. Furthermore, the accessibility, number and performance of medical facilities are also important factors for the supply side of the system. Analysis of supply and demand in view of these various factors is important for carrying out a more detailed analysis that will be useful for supporting policy formulation. Increasing data collection on relevant values will minimize the limitations in this area. Second, we estimated the number of psychiatrists using population projections until 2045 and psychiatrists' distribution in 2015. Our results indicate that the shortage of psychiatrists will continue to worsen if psychiatrists are allocated at the current population-to-psychiatrist ratio. However, the age distribution, retirement patterns, and future supply of psychiatrists could affect the future number of psychiatrists. Further updating research is needed to predict the number of psychiatrists for forecasting the supply–demand balance accurately. Third, our results are limited by the fact that the utilization-based approach is based on several assumptions, as with other modeling methods. The utilization-based approach could result in an over-estimation of the demand, particularly in service areas open to supply-induced demand (for instance private psychiatry services) or areas where best practices are poorly implemented. The assumption of this approach is that patients’ behavior will not change during the forecast period. Several factors, such as innovations in preventive medicine, screening and treatment, changes in medical care preferences, and changes in the capacity of the population to pay for services, could affect the behaviors of patients with mental illness. Although this analysis is based on a fixed value for the utilization rate, future research with newer rates would enable us to provide more accurate results.In conclusion, this study forecasts the psychiatrists' distribution for patients with mental illness to analyze the healthcare supply–demand balance based on a utilization-based approach. While the number of patients with schizophrenia or mood disorders in each prefecture, excluding Tokyo and Okinawa, will decrease by 2045, the number with Alzheimer's disease or vascular dementia in all prefectures is projected to increase. For the four mental illness estimated considered, the difference between prefectures in the minimum and maximum number of psychiatrists per patient were approximately 2-folds or more in 2015. As long as psychiatrists are allocated at the current population-to-psychiatrist ratio, the shortage of psychiatrists will continue to worsen in the future. To overcome this inequity, it is necessary to discuss incentives for medical services in rural area, or mandatory requirement of practice in rural areas for psychiatrists who become board-certified psychiatrist. Although this analysis is based on a fixed value for the utilization rate, future research with frequent model updating would yield more accurate results.


This paper aims to investigate the impact of environmental regulations on trade patterns, in terms of trade in environmental goods listed in Asia-Pacific Economic Cooperation (APEC) and Organization for Economic Co-operation and Development (OECD). Environmental goods are defined here as those that enable sustainable growth and reduce pollution from human activity. For this reason, issues on environmental goods can be put at the forefront to analyze the linkage between environmental regulations and trade flows in the perspective of international institutions. Within the framework of a gravity model, panel data on 112 exporter countries and 53 importer countries is used at a bilateral level over the period of 1989–2013 to gain an understanding of this trade-environmental regulation nexus. This paper proxies the environmental policies by employing the z-score, which includes three comprehensive environmental indicators. The findings indicate that the strict environmental policies impede the trade, and this effect is greater in terms of the environmental goods listed in APEC compared to the ones listed in OECD. Finally, although these stringent environmental regulations reduce the trade flows, they can help to foster the demand for environmentally-friendly products. The considerable volume of production and transportation generated by trade activities has given rise to a number of global environmental problems: primarily, climate change and pollution. In an attempt to cut emissions and make production greener, the World Trade Organization (WTO) Doha Ministerial Declaration brought the importance of environmental goods and services to the forefront of a global negotiation. The concept of environmental goods is aimed at bringing about sustainable growth and reducing the pollution caused by human activity. Besides engaging in a global cooperation, countries should also take a proactive response by implementing environmental regulations.Several issues can be addressed concerning the trade-environment nexus  denotes the natural logarithm;where Exports_Similarijt is exports of similar goods, which are the products that share the same HS4 commodity code with environmental goods. Hereafter, we refer to this type of goods as similar goods .Exports_EGijt is exports of environmental goods. Trade flows are from origin i to destination j in year t in current US dollars;zscoreERit, zscoreERjt are the proxy for environmental policy based on several variables in year t for origin i and destination j, respectively;GDPit, GDPjt denotes GDP level from origin i to destination j;Yit, Yjt are country i and trading partner j's GDP per capita in US dollars in year t;RTAijt is a dummy variable for regional trade agreements that takes a value of 1 if the origin i has a regional trade agreement relationship with destination j and 0 otherwise. DISij represents the geographical distance between origin i and destination j;CONij is a dummy variable that takes a value of 1 if the origin i and destination j are contiguous, and 0 otherwise;ComCurrencyijt is a dummy variable for a common currency that takes a value of 1 if the origin i and destination j share the same currency, and 0 otherwise;ComReliijt is a dummy variable that takes a value of 1 if the origin country i and destination country j have the same religious background, and 0 otherwise;Normal_Tariffijt is the average tariff for similar goods between the origin i and destination j;EG_Tariffijt is the average tariff for environmental goods between the origin i and destination j;EnvirProijt reports the number of clauses relating to environmental provisions in the trade agreement between the origin i and destination j.Remotenessit, Remotenessjt are the indicators used to control for multilateral resistance terms.ij denotes the fixed effects for each country pair, origin i and destination j; σt is a time dummy; εijtis the error term.γER_zscore) consists of three indicators: the number of environmental laws, law and order, and renewable energy consumption.The dataset used for the model above covers 112 exporting countries and 53 importing countries of environmental goods from both the APEC and OECD lists of environmental goods from 1989 to 2013, at the macro level. The z-score that is used to proxy environmental regulations (LawNum) is sourced from the ECOLEX platform jointly operated by the Food and Agriculture Organization (FAO), the International Union for Conservation of Nature (IUCN), and the United Nations Environment Program (UNEP). This database includes the laws, treaties, regulations, etc., in several areas related to the environment and sustainable development. Nunez-Rocha and Turcu  in each country. This score is based on both the strength and impartiality of the legal system and the awareness of the citizens. For the third component, renewable energy consumption  is taken from the World Bank dataset.For the second component, we use a variable from the International Country Risk Guide (ICRG) rating dataset, namely, we use the law and order score to proxy the legal system (EG) and similar goods (Similar) in US dollars are drawn from the BACI database. In addition, GDP (GDP in the regression), GDP per capita (Y in the regression), and the presence of a regional trade agreement (RTA in the regression) are gravity variables drawn from CEPII. Data on tariffs are from the World Integrated Trade Solution (WITS), and they are computed as the average for both environmental goods EG_tariff and similar goods . In addition, data on environmental provision (EnvirPro) are taken from the global preferential trade agreements database (World Bank). The data description is provided in Environmental goods are those from the APEC list of 54 goods  for the case of environmental goods on the OECD list. The elasticity of coefficients shows a higher impact than the ones on the APEC list. The results for environmental goods that are listed by the OECD are basically the same as the ones by the APEC in column (2). This finding reinforces the fact that stringent environmental regulations do not help a country trade more in environmental goods. This can be explained by the fact that strict policies on the environment will trigger local demand for environmentally-friendly commodities; thus, countries reduce their exports in order to supply the local market. However, this issue lies beyond the scope of this paper, since we do not have data on production activity.In regard to the gravity variables, they show the coefficients have the expected signs and are generally statistically significant. Although GDP does not always show a positive impact on these types of products, in most cases GDP per capita shows a positive sign for both origin and destination countries. This finding indicates a higher demand for environmental goods and similar goods in countries with high income levels. The results for tariff report negative signs both for the case of similar goods and for environmental goods, indicating that tariffs impede trade in all cases. Furthermore, dummies such as for regional trade agreements and a common currency, have negative effects on trade. Surprisingly, environmental provisions show a negative impact on trade in environmental goods on the APEC list. Remoteness, which is the proxy used to control for the multilateral resistance terms, reports a positive sign and is statistically significant in all the estimations.Disparities in development levels compound the gaps in environmental policy between high-income (North) and low-income (South) countries. The latter group of countries is assumed to have laxer regulations, in terms of environmental protection. On the contrary, it is understood that high-income countries implement strict environmental policies. In a previous study, Cantore and Cheng  discuss The summary for different trade flows is shown in Table 3i in columns (1) and (3) indicate that more stringent environmental regulations in origin i (South) promote more trade in similar goods rather than in environmental goods to destination j (North). This may be due to the fact that countries in the North tend to import goods from those countries with high environmental standards, but not necessarily environmental goods. For South-South trade flows, which are represented in the fourth pair, strict environmental regulations in origin i trigger a less export supply for similar goods. Overall, the stringency of environmental regulations does not promote any trade in environmental goods, but this stringency has effects on the trade patterns of similar goods. In other words, the strict environmental policies do not change the trade relationship for the case of environmental goods, but they do have an effect on similar goods.Trade flows between the South and North are shown in the third pair. Positive coefficients for the environmental policies in origin Stringen) to reflect an increase in the proxy for environmental regulations, the z-score, increase in both origin and destination compared to the last period. This dummy takes a value of 1 if both origin and destination countries tighten their environmental regulations, and 0 otherwise. On the contrary, a lax dummy (Lax) is introduced to capture a loosening of regulations in both origin and destination.This subsection seeks to examine whether trade patterns are influenced by the introduction of stricter environmental regulations. On the contrary, what happens if the environmental regulations become laxer? To disentangle the answers to these questions, we create two dummies to capture changes in environmental regulations. We define first a stringent dummy  or laxer (Lax in the table).where The results for the case where both origin and destination countries implement stricter environmental regulations than the previous year are shown in Robustness checks are developed along two lines to provide a battery of tests for our results. The first one is to replace the z-score by using the law indicators directly, and the second one is to apply another methodology.Instead of employing the z-score as a proxy for environmental regulations as we do for the main results, we apply an interaction term of the score of law and order effectiveness for each country. The results are shown in Table A8 in the . The posAs a second robustness check, we apply a seemingly unrelated regression (SUR) estimation of the gravity model. This methodology allows us to efficiently estimate different regressions that have correlated residuals Zellner, .i show that they reduce exports of both environmental and similar goods. Also, in these results, the magnitude of the variables shows that the regulations have a stronger impact on trade in environmental goods than in similar goods.The results for the impact of environmental regulations on trade flows using the SUR estimation are reported in Tables A9, A10 in the  for bothThis paper analyzes the impact of environmental policies on trade patterns by comparing trade in environmental goods included in both the APEC and OECD lists and trade in similar goods. The data sample covers 112 exporters and 53 importers from 1989 to 2013. By employing the z-score as a comprehensive for proxy environmental regulations, we include three environmental indicators. A key finding is that strict environmental policies limit trade, which is in line with the previous literature (Jug and Mirza, This study complements existing researches into this trade-environment nexus by highlighting the impact of environmental regulations on the trade pattern, of both environmental goods and similar goods. By comparing the trade in two types of goods, we find that environmental regulations do not help countries to trade more and they even impede trade in environmental goods. We further analyze the link between environmental regulations and environmental goods from the perspective of South-North trade and North-North trade, and so forth. This helps us gain a more in-depth understanding of whether environmental regulations can impact trade relations. The results strongly suggest that stringent environmental policies do not influence the trade relationship for the case of environmental goods but they do so for similar goods. Concerning the changes in environmental regulations, our results indicate that trade in environmental goods is very sensitive to shift in environmental regulations. The trade flows tend to decline when the environmental policies in both origin and destination countries become stricter or laxer. Finally, we find that the stringency of environmental policies in the origin country has a considerably stronger impact on its exports.Based on this evidence, some policy implications can be highlighted. First of all, governments should pay more attention to the efficiency of environmental regulations. Indeed, strict environmental regulations reduce the trade value, but this stringency does tend to encourage more environmentally-friendly consumption and production. Furthermore, the negotiations between countries could focus on reducing tariff and non-tariff barriers to green trade. Last but not least, this paper does not include the shock of the current situation, such as the epidemic of covid-19. This epidemic changes the global situation from lifestyle of citizens' to international relationships of countries. On these grounds, future interesting research avenue could be on the impact of covid-19 on trade in environmental goods. Moreover, the impact of environmental regulations on global value chains can be also highlighted for future study.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.ZD collects the data, does the empirical analysis, and writes the manuscript. During the review of manuscript, ZD makes more contribution on reviewing and writing the manuscript. YZ designs the model, finishes the empirical analysis, reviews and writing the manuscript. During the review of manuscript, RZ helps to review the model and revisit the empirical analysis and data checking of the manuscript. All authors contributed to the article and approved the submitted version.ZD would like to thank the financial support received from National Social Science Fund of China, Project number: 20CFX054.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Background. Language disorder is the most frequent developmental disorder in childhood and it has a significant negative impact on children’s development. The goal of the present review was to systematically analyze the effectiveness of interventions in children with developmental language disorder (DLD) from an evidence-based perspective. Methods. We considered systematic reviews, meta-analyses of randomized controlled trials (RCTs), control group cohort studies on any type of intervention aimed at improving children’s skills in the phono-articulatory, phonological, semantic-lexical, and morpho-syntactic fields in preschool and primary school children (up to eight years of age) that were diagnosed with DLD. We identified 27 full-length studies, 26 RCT and one review. Results. Early intensive intervention in three- and four-year-old children has a positive effect on phonological expressive and receptive skills and acquisitions are maintained in the medium term. Less evidence is available on the treatment of expressive vocabulary (and no evidence on receptive vocabulary). Intervention on morphological and syntactic skills has effective results on expressive (but not receptive) skills; however, a number of inconsistent results have also been reported. Only one study reports a positive effect of treatment on inferential narrative skills. Limited evidence is also available on the treatment of meta-phonological skills. More studies investigated the effectiveness of interventions on general language skills, which now appears as a promising area of investigation, even though results are not all consistent. Conclusions. The effectiveness of interventions over expressive and receptive phonological skills, morpho-syntactic skills, as well as inferential skills in narrative context underscores the importance that these trainings be implemented in children with DLD. Language disorder is the most frequent developmental disorder in childhood ; howeverThese children have been called late talkers ,14. The DLD has been defined as a neurodevelopmental disorder that includes a set of variegated clinical pictures that are characterized by delay or disorder in one or more areas of language development in the absence of cognitive, sensory, motor, affective, and important socio-environmental deficiencies ,23. The The language difficulties of children with DLD often have severe consequences in pre-school and early primary school. In approximately 40 to 50% of cases, linguistic impairments lead to negative neuropsychological sequelae , particuThe breadth of these problems and their negative impact on a child’s development indicates the importance of an early identification of children who risk of exhibiting DLD or related problems, with the potential benefit of promoting interventions in an age group in which significant improvement is most likely to occur . EffectiTherefore, identifying effective interventions is a fundamental aim in clinical practice with children who have DLD. In fact, language intervention during development may not only have short-term outcomes on the language component treated, but also medium- and long-term influences on the global development path. The links between oral language acquisition and written language learning are well-known; also important are the negative consequences on the quality of social integration and the emotional development of children with language disorder . At theThe international literature offers a wide range of rehabilitation interventions aimed at children with DLD. They not only reflect the wide variability in the expression of language disorder at different ages, but indicate the importance of establishing which rehabilitation intervention provides the best care for children with DLD. The goal of the present study was to systematically analyze the effectiveness of interventions on children with DLD from an evidence-based perspective. This effort is not new. In particular, Law et al.  carried Note that we focused on interventions on different aspects of language  and domains (comprehension and production) and did not analyze studies that were concerned with the improvement of pragmatic skills. Most of the interventions deal with language production, but a few investigate interventions aimed at reception/comprehension. Some of the approaches in the literature adopted techniques and protocols that aimed at single components , while other approaches aimed at a wider and “ecological” stimulation of different aspects of language production.The methods of administration depend, in part, on the approach, and can involve the intervention of specifically trained figures (speech and language therapists), educators, and teachers, or, increasingly, interventions mediated by parents with different training and supervision by clinicians. Another important aspect in evaluating the effectiveness of the interventions is the way the outcomes are evaluated. In fact, the tools that are used for diagnosis are often not very sensitive to change and the tools built ad hoc often only measure the skill being trained and do not allow for evaluating generalization to neighboring skills or other language domains.The location of the intervention also varies according to the different approaches. In addition to the interventions that were carried out in the clinical setting, many interventions are carried out at school or at home .The frequency and duration of the interventions also appear to be very variable. Generally, individual interventions are tested in short and relatively low-intensity cycles, on very specific targets, and with the frequent absence of follow-up evaluations. Group interventions are more rarely described .Another element of complexity for the “evidence-based” identification of the effectiveness of treatments is the variability that is linked to the characteristics of the language. Therefore, it is necessary to carefully consider the applicability of the treatments (often developed in an Anglo-Saxon context) to other languages and the possible influences of the characteristics of our language on the effectiveness of the treatment itself.Below, we report a systematic review (SR) of the studies on the effectiveness of intervention on children with DLD .A review of the literature was carried out as part of a Consensus Conference about the diagnosis and treatment of children with language disorder, which was held in Italy in November 2018 . This CoThe clinical question was formulated while using the PICO approach and the criteria for inclusion and exclusion of studies were established a priori see .speechbite.com; accessed on 30 December 2020), and PsycINFO (Ovid). In addition, we searched the clinical trials registers: ClinicalTrials.gov , World Health Organization International, and Clinical Trials Registry Platform  for ongoing or unpublished trials on December 2020.A systematic search of the literature published up until December 2020 was conducted through research on the following databases PubMed, Embase, Web of Science, The Cochrane Central Register of Controlled Trials , SpeechBITE , ‘no’ (clearly not done), or ‘not clear or not applicable’ category was assigned. The revisions were then classified, as follows:-random sequence generation (selection bias), which considers the risk that the allocation of subjects in the experimental and control groups may have occurred in a non-random way, indicating a possible problem in the selection of groups;-allocation concealment (selection bias), which evaluates the degree of protection against the risk that the trial operators are aware of the mechanism of random allocation of subjects;-the blinding of participants and personnel (performance bias), which considers the risk that the lack of blindness of trial objectives in participants and staff might alter performance , thus affecting the trial outcome;-blinding of outcome assessment (detection bias), which indicates the risk that persons evaluating the study’s outcome are aware of the group assignment to different forms of intervention, thus influencing the probability of capturing the effects of the intervention;-incomplete outcome data (attrition bias), which evaluates the possibility that the presence of missing data modifies the estimation of the effects of interventions. The reasons for attrition or exclusion were reported as well as whether missing data were balanced across groups or related to outcomes; and,-selective reporting (reporting bias), which indicates the possible risk that only a selection of variables is presented in the report, e.g., the tendency not presenting measures for which the results were not significant .For RCT studies, based on the criteria that were developed by the Cochrane Collaboration , the folFor each of the studies reviewed, an assessment of the possible presence of these bias risks is carried out. It is important to take the validity of the knowledge into account in order to assess the generalizability of the results of the included studies, i.e., the possible presence of a bias in the data, as well as transferability to clinical practice .External validity was evaluated based on the transferability of results to clinical practice. For each of the RCT studies examined, the setting in which the study was carried out as well as the language covered by the intervention were assessed and are reported in The characteristics of the included studies are presented in tables and summarized narratively. A meta-analysis of outcomes was not appropriate due to the heterogeneity of the data; however, narrative results are presented.Using the bibliographic research, we identified 3334 reports after removing duplicates; two independent reviewers excluded 3219 reports on the basis of title and abstract. Any doubtful cases were resolved by discussion with a second reviewer.We acquired 118 potentially relevant studies in full text, and we assessed their compliance with the a priori defined inclusion criteria. We identified 27 relevant studies ,86,87,88interventions compared to no treatment or later treatments;specific interventions with respect to general stimulation conditions ; and,interventions compared to other language therapy approaches .Law et al.   being treated.N = 264; SMD = 0.44, 95% CI: 0.01, 0.86) [N = 214; SMD = 0.67, 95%CI: 0.19, 1.16). Furthermore, the estimate was larger when only treatment lasting at least eight weeks was considered .Information regarding the effectiveness of interventions on phonological expressive skills in children with DLD comes from studies that were reviewed in the revision of Law et al. . In part1, 0.86) . The effFive studies investigated the effectiveness of interventions on phonological expressive skills in children with DLD. A brief description of these studies follows  was assigned to a combination of phonological awareness activities, phonological awareness program, auditory bombardment, and discrimination and listening tasks delivered with a tabletop or with an app running on a tablet. The results showed that both tabletop and tablet-based methods of delivery of a phonological intervention were effective in improving the speech of children. There was a significant improvement in PCC and in the percentage of phonemes correct from baseline (T1) to intervention (T3) for both groups, which was greater during the intervention period (between T2 and T3). Similar results were obtained for the percentage of correct vowel scores, with an improvement being noted at both baseline and intervention, but the increase after intervention was only significantly greater in the tablet group.Jesus et al., 2019  evaluateOverall, there is evidence that interventions aimed at expressive phonological skills produce appreciable results, even if it is not possible to specify which type of intervention is the most successful.Law et al.  showed nWe found one study that examined the effect of treatment over receptive phonological skills. Roden et al.  investigOverall, the evidence on the effect of intervention on receptive phonological skills is too limited to draw any conclusion. Yet, the positive effects that were reported by Roden et al.  suggest N = 82; SMD = 1.08, 95% CI: 0.61, 1.55), but not when compared with other cognitive therapies . A large intervention effect was also present when parental reports of vocabulary were used as dependent measures .Law et al.’s review  reportedN = 29) was able to learn new words through reading electronic storybooks without the support of adults and whether storybooks with video and audio effects were more or less advantageous when compared to electronic versions with static illustrations ; two stories that children had not heard during the intervention acted as a non-treatment control. The second experiment (N = 23) had a dual purpose, i.e., to confirm the results of the previous experiment and extend knowledge regarding learning new words in children with DLD by exploring two potential variables, i.e., phonological working memory and language skills. In the first experiment, better performance was obtained with “static” stories; this finding was also confirmed by the second experiment. Children with more severe DLD obtained less of an advantage from e-books when music and sounds were present (probably because they had difficulty in perceiving speech in noisy conditions).A cross-over RCT study  evaluateOverall, there is still limited evidence that targeted interventions on expressive vocabulary acquisition produce effective results. It seems important that these partial results be confirmed in future RCT investigations.No studies were identified that investigated the effectiveness of receptive vocabulary interventions in children with DLD.N = 233; SMD = 1.02, 95%CI: 0.04, 2.01) were excluded.Law et al.’s  review rEight studies investigated the effectiveness of interventions on morphological and syntactic expressive skills in children with DLD. A brief description of these studies follows , it appears to be necessary that these results be supported by RCT studies conducted in a variety of languages before definitive conclusions can be drawn on this issue.In Law et al.’s  study, tOne of the studies already described  investigThe information that is related to this area seems to be insufficient to draw any conclusions regarding the effectiveness of interventions aimed at improving receptive morphological and syntactic skills.Law et al.’s  review dOnly two RCT studies specifically evaluated the effectiveness of a narrative skill intervention. One was Maggiolo et al.’s study , which aN = 19) or phonological awareness control group (PA: N = 18). The mean comprehension scores prior to intervention were not significantly different for the two groups of children. When compared to the control PA group, the participants in the ICI group demonstrated a significant increase in the inferential comprehension scores from pre- to post-intervention, which was maintained over time. In addition, the ICI group scored significantly higher than the PA group for inferential comprehension on a post-intervention generalization measure. The results also demonstrated significant improvements at the individual level. No significant difference between the two groups for literal comprehension scores emerged at any assessment point.Dawes et al.’ study  aimed toThe available information is still limited, but both studies examined reported clear increases in the comprehension of causal and temporal links after the intervention. Therefore, it appears to be important that these findings be confirmed and substantiated in further research.The Law review  did not The study conducted by Hesketh et al.  evaluateHund-Reid and Schneider’s study  evaluateOverall, there is still limited information on the effectiveness of interventions on meta-phonological skills in children with DLD; however, the results of the two reviewed studies indicate this as a potentially interesting area of intervention. Further work is warranted, possibly also examining languages other than English.Law’s review found only one study that aimed at training general linguistic skills with overall non-significant results.Six of the RCTs included assessed the effectiveness of different interventions on language skills in general. A brief description of the individual studies follows.In Roberts and Kaiser’ study , the effWake et al.’s studies ,85 assesAt the five-year evaluation , signifiThe Wilcox et al.’s study  tested tTwo studies ,88 were In Cohen et al.’s study , seventySome of the studies on the effectiveness of different interventions on general language skills are now available, and they indicate this as a promising area of investigation. However, results appear to be mixed with several studies showing negative results.The main aim of the present review was to identify the most effective treatments to adopt for children with DLD. Because most of the studies aimed to verify the effectiveness of interventions for specific language skills, the analysis of the literature was organized according to the target language area. In this regard, the results of the new RCT studies that were identified after Law et al.’s  review pThe interventions aimed at phonological, lexical, morphological and syntactic expressive skills are those most studied, presumably because these verbal components are easily identifiable and during treatment can be isolated from other aspects of language. The proposed activities are limited to these specific skills and the changes obtained can be verified through standardized scales of measurement. In addition, children with DLD who have a language profile that is limited to these skills are the most numerous. They are easily identified by non-specialist healthcare staff, school staff, and caregivers, and therefore represent a high percentage of access and demand for care by specialist services.From the analysis of the studies included in this review, we can derive some general indications regarding the treatment of children with DLD. We have verified the effectiveness of intensive interventions based on the treatment with pairs of maximally contrasting phonemes, auditory discrimination, and phonological awareness. Regarding the phonological expressive component, a direct intervention, limited in time but intensive , which includes auditory discrimination activities and it is based on contrast in traits, can bring significant improvements ,64 that Additionally, with regard to morpho-syntax, some of the strategies can be considered effective, such as recast or reformulation of the child’s production by the adult in conversation . The samFurthermore, some of the studies have provided support for the effectiveness of treatments for meta-phonological and narrative skills ,80,81,82New studies have also emerged that investigate interventions that aimed at developing general communicative language competence. These interventions are carried out at home, are mediated by parents, and are under the supervision of the clinician ,84,85. TRelatively little evidence of the strategies or techniques aimed at improving receptive language skills has been identified. One possible interpretation of the lack of results could be related to the complexity of interventions that aimed at verbal comprehension, i.e., it is difficult to isolate the individual receptive skills and free them from more general skills, such as pragmatic skills or semantics, creating activities that aimed at specific receptive skills in the rehabilitation setting. In addition, although children with a disorder that also affects language comprehension have a more severe clinical picture than children with only expressive DLD and a worse prognosis, they are numerically fewer. Therefore, it may be difficult to find enough children for an RCT study. Finally, the intervention may be less (or not) effective, also because, in some cases, weaknesses or deficits in comprehension  are associated with weak  cognitive skills.Still, some recent studies have shown promising results. Regarding phonological skills, Roden et al.  demonstrWith respect to the other variables that are necessary to provide indications for treatment, such as the setting, frequency and duration of interventions, the way the results are evaluated, the age of the child, and the long-term effects of the intervention, the studies taken into consideration do not allow for us to draw firm conclusions. This is due to both the extreme heterogeneity across studies and the fact that these variables are often not described explicitly and exhaustively by the authors.The risk of bias was high in some studies and unclear in most studies , thus decreasing the certainty in results. The fact that several studies examined relatively small samples of children is also of note; this may be problematic, particularly in the case in which a more comprehensive linguistic deficit is present , which is typically associated with larger individual differences. These considerations indicate the importance and urgency that standards of RCT reporting will be improved in future research.Regarding the transferability of the results to different languages as compared to the one in which the intervention is delivered, it appears that the specificity of the phonological repertoire and of the morphological and syntactical rules always deserves a reflection on the implicit differences between languages. Thus, for some language levels, it is possible to generalize the results, while, for others, it is necessary to modify the verbal stimuli of the treatment by adapting them to the linguistic context while maintaining techniques and strategies.The reviewed evidence highlights the importance of carrying out timely assessments of linguistic  skills in pre-school children, so as to provide, if necessary, targeted treatment before the start of primary school, while considering the importance of these skills for future school learning.There seems to be two general problems in analyzing the literature on interventions on DLD. On one hand, there are many more studies available for expressive than receptive disorder. We have noted above that this, in turn, may be due to the asymmetry in targeted children between these two types of disturbances. Yet, there is a risk here to consider that the interventions on expressive disorder are more effective, simply because more studies were carried out. Only further research on receptive disorder will allow for us to reach more definite conclusions on this point. On the other hand, most reviewed studies concern English and research on other languages is scattered. Accordingly, there is a need for systematic research in a wide range of other languages, particularly in the areas (such as morpho-syntax) where linguistic differences are more marked.The present systematic review provides up-to-date information on the effectiveness of linguistic interventions for children with DLD. Evidence indicates that early intensive interventions in three to four-year old children are effective in the area of phonological expressive skills with acquisitions being maintained in the medium term. Some effectiveness of interventions over morpho-syntactic skills and, to some extent, on meta-phonological and narrative skills, was also detected. By contrast, there is fewer evidence that interventions on phonological receptive skills or receptive vocabulary are effective, but some recent studies raise the interest in further pursuing this area of research. A number of trainings aimed at general linguistic skills; the results are mixed, which makes it difficult to draw a definite conclusion, although there are indications that this may be a promising area of further investigation. Most research is carried out in English-speaking children, indicating the importance of studies in other languages.Overall, information on linguistic interventions is quite different, depending on the linguistic skills investigated, indicating the need of further RCT studies in this area. Nevertheless, the currently available information indicates the importance of implementing timely assessments of linguistic skills and, whenever appropriate, targeted treatment.