Chronic hepatitis C is a major public health burden. With new interferon-free direct-acting agents , elimination of HCV seems feasible for the first time. However, as HCV infection often remains undiagnosed, screening is crucial for improving health outcomes of HCV-patients. Our aim was to assess the long-term cost-effectiveness of a nationwide screening strategy in Germany.We used a Markov cohort model to simulate disease progression and examine long-term population outcomes, HCV associated costs and cost-effectiveness of HCV screening. The model divides the total population into three subpopulations: general population (GEP), people who inject drugs (PWID) and HIV-infected men who have sex with men (MSM), with total infection numbers being highest in GEP, but new infections occurring only in PWIDs and MSM. The model compares four alternative screening strategies  differing in participation and treatment rates.Total number of HCV-infected patients declined from 275,000 in 2015 to between 125,000 (no screening) and 14,000  in 2040. Similarly, lost quality adjusted life years (QALYs) were 320,000 QALYs lower, while costs were 2.4 billion EUR higher in total screening compared to no screening. While incremental cost-effectiveness ratio (ICER) increased sharply in GEP and MSM with more comprehensive strategies , ICER decreased in PWIDs .Screening is key to have an efficient decline of the HCV-infected population in Germany. Recommendation for an overall population screening is to screen the total PWID subpopulation, and to apply less comprehensive advanced screening for MSM and GEP. Chronic hepatitis C is a global public health burden. More than 185 million people have been infected with the hepatitis C virus (HCV) worldwide and approximately 350,000 patients die each year from HCV-related diseases . Data frThe historical dual therapy with pegylated interferon and ribavirin was the standard of care for more than a decade until first generation protease inhibitors telaprevir and boceprevir were approved for the treatment of patients with HCV genotype 1 in 2011. In 2014 the treatment of HCV has significantly improved with the introduction of the first all-oral direct-acting antiviral drug (sofosbuvir). Other direct acting antivirals (DAAs) simeprevir, daclatasvir, sofosbuvir/ledipasvir, ombitasvir/paritaprevir/ritonavir plus dasabuvir, elbasvir/grazoprevir, and pangenotypic effective combinations sofosbuvir/velpatasvir, sofosbuvir/velpatasvir/voxilaprevir, and glecaprevir/pibrentasvir subsequently followed, ultimately leading to interferon-free strategies. Meanwhile DAAs achieve sustained viral response (SVR) rates of > 98%, show minimal adverse effects and shorten treatment duration considerably [Thus, for the first time elimination of hepatitis C virus seems feasible. As HCV infection often remains undiagnosed, screening and early diagnosis are crucial for improving health outcomes of HCV patients. The World Health Organization pursues the ambitious target to eliminate HCV until 2030 . HoweverThe aim of the present study was to analyze the impact of different nationwide screening strategies  on the long-term development of HCV prevalence, liver-related mortality, quality-adjusted life years (QALYs), and healthcare costs, and to identify the most cost-effective screening strategy . We used Germany as an example for high income countries.We applied a sequential, multi-cohort, health-state transition (Markov) model to examine population outcomes and cost-effectiveness of HCV screening over a 25-year time horizon from 2015 to 2040). In contrast to the WHO target to eliminate HCV until 2030, the time horizon of this model is enhanced to 2040 as elimination of HCV until 2030 seems to be unrealistic given the lack of a nationwide organized strategy to eliminate HCV. Further, we want to illustrate the development of the HCV induced burden on the long term if no activities are implemented. Model structure and assumptions are summarized in Fig. 5 to 2040The model considers three distinct subpopulations as main target groups for HCV screening: general population (GEP), people who inject drugs (PWID) and HIV-infected men who have sex with men (MSM). The subpopulations differ in the transmission of the HCV infection.The GEP population  includes persons with increased risks for HCV infection, like immigrants from Mediterranean or East European countries, recipients of HCV infected blood transfusions prior to 1992 when universal blood product screening was introduced , 11 or hIn the PWID population HCV infection is transmitted via common use of injecting equipment. The PWID population consists of two subgroups: PWIDs in community who regularly inject drugs (PWID-C) and (former) PWIDs undergoing substitution therapy (PWID-S). Screening measures are easier implemented in PWID-S as they are in regular contact with the healthcare system, while PWID-C should be approached by the community . At model start about 90% of assumed annual new infections (4300 in 2015)  are suppHCV infection in MSM is transmitted via sexual contacts. The MSM subpopulation is a small group within the HCV-infected population (3700), but represents about 10% of all incident cases and faces an increasing prevalence rate over the last years (assumed to be about 7% at model start) , 15. SimThe model reflects the natural course of the HCV infection see Fig. . InfecteTreatment of HCV-infected patients is performed with most advanced DAAs, as being used in German clinical practice. Non-cirrhotic patients (F0-F2) who achieve sustained viral response (SVR) are considered cured and their liver damage is assumed to resolve. If re-infected, patients re-enter the infected population with an undamaged liver. Patients with failed treatment remain infected and their liver disease continues to progress. In patients with Metavir score F3+ liver damage is assumed to remain and continues to progress, even if SVR is achieved, though more slowly than in patients with active HCV infection .All model parameters are based on published literature  no screening, (2) basic screening, (3) advanced screening and (4) total screening which differ by the number of detected (and treated) HCV-infected persons. Screening approaches (and percentage of diagnosed and treated patients) differ between GEP, PWID and MSM subpopulations. Maximum HCV treatment capacity is supposed to be 25,000 patients per annum  . All treThe no screening scenario represents the current situation in Germany. At model start, the total number of new diagnoses is about 4900 . If no sIn the GEP subpopulation, basic screening is applied to persons who participate in check-up 35+, a biannual free of charge medical check-up in Germany for people with age above 35 years. In basic screening a three-stage test is applied: 1) risk-based questionnaire and ALT test , (2) anti-HCV test  and (3) HCV-RNA test . 48% of all eligible persons (about 45 million) participate in check-up 35+ , 53% of  risk-basAdvanced screening differs from basic screening as follows: the risk-based screening in the GEP population is expanded to the total general population aged 16+ years  with a supposed 80% participation rate . In the PWID subpopulation screening is broadened to PWID-C (assuming 40% participation rate among PWID-C and 80% among PWID-S and MSM). Extra costs for social workers approaching PWID-C individuals are considered.The total-screening scenario assumes that the entire population is screened and all HCV-infected persons are treated in the subsequent years after diagnosis. A two-stage screening test for all individuals is applied. Increasing costs for including individuals into the screening program (similar to the advanced screening scenario) are considered.Depending on cost-effectiveness results derived from the screening model the optimal screening strategy might differ between subpopulations. Thus, an overall optimum might combine e.g. basic screening in general population, advanced screening in PWIDs and total screening in MSM (or other combinations).To analyze long-term effectiveness and cost-effectiveness we calculate long-term development of HCV prevalence, liver-related mortality and lost quality-adjusted life years (QALYs) (due to HCV-infection and compared to non-infected persons) and derive incremental cost-effectiveness ratios (ICERs) for the screening strategies analyzed.Health state utilities reflect the quality of life of HCV-infected patients in each health state on a scale from 1  to 0 (death). Information is derived from German studies which used EuroQoL-5D for determination of quality of life in HCV infected and non-infected persons , 25. If “cost-effective” has to be set. In Germany there is no official cost-effectiveness threshold and cost-effectiveness plays a minor role in the decision if health services are implemented. For this analysis we selected a fictive threshold of 20,000 EUR per QALY which is based on the official cost-effectiveness threshold of 20,000 GBP per QALY in the UK [When conducting cost-effectiveness analyses a threshold at which health services could be regarded as n the UK .Cost data include screening, treatment and indirect cost. Screening costs comprise costs for the (two-stage or three-stage) test and time expenditures for approaching and including specific target groups (as PWID-C). Screening cost data are derived from the German uniform physicians’ fee scale in the statutory health insurance scheme. Costs of treating hepatitis C include antiviral treatment associated costs  and costs of disease progression . Pharmaceutical treatment costs vary between different treatment options. Since the introduction of first DAAs prices have significantly decreased. We assumed average treatment costs of 34,000 EUR reflecting recent costs developments , 28. An The study is conducted from a societal perspective. All cost data are reported in 2015 euros. An annual discount-rate of 3% is used for costs and QALYs , and treatment numbers by ±5000 (to assess the impact of expanding or downsizing treatment capacities). Variation of utilities was according to 95% confidence interval, and discount rates were set at 0 and 5%. Furthermore, we examined the impact of substantial treatment price reductions .Figure Similarly, the (cumulated) number of premature (HCV-related) death is decreasing with more comprehensive screening approaches  and the (discounted) total number of lost QALYs (compared to non-infection) is decreasing as well   GEP, 29%  PWID, and 1.4% (or 3700) MSM. Depending on the screening strategy, the development of infection numbers differs between subgroups  is reduced with more comprehensive screening strategies in all subgroups Fig. . The larTransition to more comprehensive screening strategies is resulting in ICERs as shown in Table Though GEP, PWID and MSM subgroups are disjunct according to subpopulation definition, they are interconnected via the fixed annual treatment capacity  (i.e. an increase in treatment numbers in one subpopulation induces a decrease in at least one other subgroup). Thus, efficiency of a mixed strategy derived from the cost-effective scenarios in subgroups  needs to be verified.As shown in Table In sensitivity analyses, we identified the parameters with major impact on costs per QALY results for comparing (a) mixed screening versus advanced screening and (b) total screening versus mixed screening. As shown in Fig. The aim of the present study was to analyze different screening strategies to eliminate hepatitis C virus infection in Germany until 2040 using a model that is different from all other existing models to our knowledge. Thus we applied a comprehensive approach targeting the complete German HCV-infected population. In fact, we considered all relevant target groups. GEP included the total population (except for PWIDs and MSM), in particular blood recipients before 1992, healthcare workers, and immigrants . Advanced screening is expanded to the general population 16+ at risk (assuming an 80% screening rate), while total screening includes the complete general population (with or without increased risk for HCV infection).In the PWID subpopulation, basic screening is focusing on PWIDs undergoing substitution therapy, and advanced screening is, in addition, addressing PWIDs in community (with both strategies assuming participation rates of 40 to 80%), while total screening includes the total PWID subpopulation. In MSM, screening strategies just differ in the participation rate (with screening participation rates between 50 and 100%).To address the burden of disease, GEP and PWIDs are the most relevant subgroups , while PWIDs and MSM are the main target groups for long-term elimination of HCV infections .Infection numbers are decreasing with all screening strategies . During the same period, the percentage of GEP population among HCV infected population is decreasing from 70% in 2015 to between 36% (in the no screening scenario) and 11%  in 2040, while the percentage of PWIDs is increasing from 29% to about 62% in 2040 (showing only little variation between screening strategies ranging between 59 and 65%), and the percentage of MSM is increasing from 1.4% to between 5.4% (in no screening) and 27% . Thus, the aggregate percentage of PWIDs and MSM among the infected population increases from 30% in 2015 to between 64 and 89% in 2040, emphasizing the importance of tackling new infections for long-term elimination.Assuming a threshold of 20,000 EUR per QALY, incremental cost-effectiveness analyses in subgroups suggest that advanced screening is efficient in GEP and MSM, while total screening is cost-effective in PWIDs. In GEP and MSM, incremental cost-effectiveness ratio is increasing with intensified screening efforts, amounting to 15,000 and 13,000 EUR per QALY for advanced compared to basic screening, respectively . In contrast, ICER is decreasing with intensified screening efforts in the PWID subpopulation .The subgroup cost-effectiveness results are confirmed by the mixed strategy  The mixed strategy proved to be efficient . Thus, based on ICER efficiency criteria, recommendations for an overall population screening imply to focus on the risk-based screening in GEP, while in PWIDs the entire subpopulation should be tackled (and in MSM a high percentage of the subpopulation).Though, acknowledging that it is difficult to realize the full potential of total screening, the cost-effectiveness results support efforts to include as many PWIDs as possible. In particular, total screening in PWIDs would still be cost-effective , if social worker expenditures to include PWIDs into the screening program are expanded to about 330 h (or 43 working days) per PWID in community.As PWIDs and MSM play a crucial role for long-term elimination (via tackling transmission), a reasonable strategy might even be to restrict HCV treatment to PWIDs and MSM in the first periods of the screen and treat program (as treatment capacities are supposed to be limited). Treatment of the general population would follow when there are free capacities .Several studies , 41 explStudies on screening in the general population compare birth cohorts screening to either no screening or risk-based screening (which often corresponds to the status quo). There are several recent studies (from the period 2012–2017) conducted in various countries across Europe , 45, NorComparisons of birth cohort screening versus no screening show mixed results with incremental cost-effectiveness ratios ranging from 6000 USD to 65,000 USD per QALY gained , 49–52. Analyses of birth cohort screening versus risk-based screening are only conducted in US studies –48, 51, Besides, there are only a few studies considering the new interferon-free DAAs , 52, 53.Studies on screening PWIDs are from Europe –59 or thUnlike the screening literature, our study provides a uniform analysis framework for assessing screening strategies aiming at elimination HCV infections in a nationwide approach. The framework allows considering interactions between subgroup screening decisions, examining target-specific screening approaches and deriving an optimal overall screening strategy.In general, our findings are supported by the literature: Cost-effectiveness ratios of screening seem to be lower in PWIDs compared to the general population . Moreover, the literature shows that strategies to approach PWIDs in community might be cost-effective.While the literature on screening the general population shows mixed cost-effectiveness results, it is an efficient strategy according to our model. Moreover, in contrast to findings of the US literature, risk-based screening is recommended in our model as cost-effective in the general population (compared to birth cohort screening) which might be partially due to lower prevalence rates in the German general population (born 1945 to 1965).There are some limitations that have to be considered when interpreting study results. SVR-rates are based on the results from different clinical trials. Trials often overestimate efficacy data due to selected trials participants and increased health care professionals’ attention. However, recent analyses in real-life settings show comparable SVR-rates in clinical practice , 64. FurA general problem in modelling the long-term effects of screening programs is the availability and reliability of data. Extensive literature analyses have been performed to determine the best available data. Moreover, sensitivity analyses suggest that the impact of most parameters might not be critical to the cost-effectiveness assessment. However, e.g. expanding treatment capacities  might affect cost-effectiveness assessment (thus including more patients into the screening program and subsequent treatment might be recommended).Screening participation rates are also critical to the model results. We mapped variations of participation rates in the definition of the screening scenarios . Basic screening is modelled as a conservative scenario resting on published participation rates from Germany . Participation rates in advanced screening are assumed to be feasible, while participation rates in total screening are hypothetical showing the potential of screening. However, in both scenarios higher costs to include patients into the screening program are considered.At last, we restricted the number of defined patient groups to GEP, PWIDs, and MSM, while assuming that e.g. healthcare workers and migrants (two subgroups often considered in the literature) are included in the general population. In fact, these subgroups are included in our risk-based screening approach in the GEP subpopulation (which is performed in basic and advanced screening) and thus show a higher detection rate than the “rest” of the general population reflecting their higher infection risk . Nevertheless, specific screening strategies for healthcare workers and/or migrants could have been added to our screening model .Screening is the key to an efficient decline of the HCV-infected population in Germany. Recommendation for an overall population screening is to screen the total PWID subpopulation, and to apply less comprehensive advanced screening for MSM and GEP. With new interferon-free DAAs, elimination of HCV infection in Germany seems to be feasible and cost-effective. If treatment costs decreased to 20,000 EUR per patient, even overall total screening might be a cost-effective option. This scenario is conceivable as price-reduced generics of sofosbuvir/velpatasvir and ledipasvir/sofosbuvir have been launched in the US market and might spill over to Europe soon. Critical is the participation rate of PWIDs in community as this target group is difficult to approach. Our calculations show that high resource inputs for approaching might be an efficient investment to exploit the potential of PWIDs willing to participate in the screening program.Additional file 1: Table S1. Model inputs. Table S2. Parameters of the different screening strategies.


An association between HIV infection and cervical cancer, a major public health issue worldwide, has been reported. The aim of this study was to estimate the prevalence of human papillomavirus (HPV) infection and the distribution of HPV genotypes in HIV-infected women living in French Antilles and Guiana and to determine HIV-related characteristics associated with HPV infection. This cross-sectional study included 439 HIV-infected women who were followed between January 2011 and May 2014. Variables related to HIV infections were collected, and cervical samples were analysed to determine HPV genotypes. The median age of the population was 46 years. Estimated prevalence of HPV and high-risk (HR)-HPV infection were 50.1% IC95 [45.4–54.7] and 42% IC95 [37.3–46.6], respectively. HR-HPV 16, 52, 53 or intermediate risk-HPV-68 were found in 25% to 30% of the HPV-infected patients. Gynaecological screening revealed abnormal cervical smear in 24% and 42% of HR-HPV-negative and HPV-positive women, respectively (p = 0.003). Approximately 90% of women were on antiretroviral therapy (ART). Demographic characteristics associated with a higher prevalence of HPV infection included alcohol consumption. Regarding HIV-related characteristics, current therapy on ART, its duration, and undetectable plasma concentrations of RNA-HIV1 were associated with a lower risk of HPV infection. Infection rate with HR-HPV was higher than what is commonly reported in HIV-negative women worldwide and was more likely in women with incomplete HIV suppression. These results highlight the need for supporting adherence to ART, cervical cytology, HPV testing and HPV vaccination. Cervical cancer is a major health issue worldwide. In 2012, 528,000 new cases were estimated and approximately 270,000 women died from cervical cancer . Most HPHPV genotypes have been classified according to their oncogenic potential . In the The overall prevalence of HPV infection varies greatly among populations, with a worldwide heterogeneity dependent on behaviours and economic levels . BecauseThe aim of this study was to estimate the prevalence of HPV infection and the distribution of HPV genotypes in HIV-infected women in French Antilles and French Guiana where HPV infection is highly prevalent compared with other countries worldwide  or with rd 2011 and May 2nd 2014 in four hospitals in the French Antilles  and French Guiana  at the time of their annual visits scheduled for gynaecological follow-up. All patients included in the study gave informed consent for HPV testing and cervical-uterine smear. Because screening of the patients was made in the context of their routine follow up for HIV infection, oral non-opposition was considered for sample collection. Written consent was given for the inclusion of data in the French national HIV Nadis database. The study was approved by the Comité de Protection des Personnes (CPP) Sud-Ouest et Outre Mer III ethics committee. ClinicalTrials.gov identifier NCT01226368.This was a cross-sectional study of the HPV genotype’s prevalence in a collection of biological samples and its associated de-identified data. Women were followed between January 3Patients’ inclusion criteria were to be at least 18 years old, to be followed for HIV1 or HIV2 infection in one of the participating centres and to have an indication for cervical-uterine smear analysis for routine screening in the context of HIV infection follow-up, or any cervical-uterine pathology. Exclusion criteria included a history of total hysterectomy and the impossibility of obtaining smear samples.Variables recorded were demographic characteristics, alcohol and drug consumption, history of HIV infection  and medical history . Regarding HIV infection, CD4 counts at the beginning of the study, CD4 nadir, HIV1-RNA load and status regarding past and current antiretroviral therapy, if any, were collected. Macroscopic examination of the cervix with acetic acid or lugol’s iodine was reported.Cervical samples were taken using the ThinPrep-PreservCyt solution kits (Hologic). Samples were then sent to the pathology laboratory of Martinique University hospital for a centralized assessment and, after processing for cytological study (Hologic), to the virology laboratory. The detection and genotyping of HPV-DNA was performed using the Papillocheck kit (Greiner-Bio-one) after DNA extraction on EasyMag (Biomérieux). This kit allows the identification of HPV genotypes including HR or group 1  intermediate risk or group 2  and LR or group 3  genotypes. Abnormal cervical smear analysis identified atypical squamous cells of unknown significance (ASCUS), low-grade (LSIL) or high-grade (HSIL) squamous intraepithelial lesions according to the 2014 Bethesda classification ), with no significant difference between Antilles and Guiana centres . The distribution of HPV genotypes revealed that 63.6% of HPV were HR-HPV  with the predominance of HPV 16, 52, and intermediate risk-HPV 68 found in 25% to 30% of HPV-infected patients . HPV 18 Regarding patients’ demographics and behaviours, alcohol consumption was significantly associated with HPV infection . A high The durations of HIV infection were similar in patients with positive or negative HPV detection, as were the proportions of patients having experienced AIDS (approximately 25%). However, being currently on ART, the duration on ART and undetectable plasma concentrations of HIV1-RNA were significantly associated with a lower risk of HPV infection. There was a negative correlation between low CD4 counts and HR-HPV infection, but that did not reach statistical significance. A significant inverse relationship between mean CD4 counts and HPV was found when considering HPV irrespective of HR or LR type .This study reports the prevalence and genotypes of HPV in HIV-infected women living in the French Antilles and Guiana. HPV infection was found in half of the study population, which mainly corresponded to HR-HPV. These results are in agreement with those reporting that HR-HPV was present in about 50% of HIV-infected women living in Tanzania  or in BrThe estimated rate of HPV infection was also higher than that reported in HIV-negative women living in the same area. A study conducted in the French Caribbean island of Guadeloupe showed a prevalence of HR-HPV of 36% among healthy women , and twoIn the present study, one third of cervical smears showed abnormal cytology, which is far greater than in HIV-negative women in French Guiana where the proportion is 10% and is already considered high . For HSIA meta-analysis based on 21 studies including HIV-infected African women with invasive cervical cancer (ICC) showed that HPV16, found to be highly prevalent in the present study, was the most frequently detected type (42.5%), followed by HPV18, HPV45, and HPV35 . The preThe burden of HPV-related cancers can then be expected to increase in HIV-seropositive patients, and both American and European guidelines recommend pap test for cervical cancer screening for all HIV-positive women older than 21 years of age or within one year after initiation of sexual activity ,41. In H3 and with a protective effect of ART on HIV-associated malignancies in compliant women [The present study did not find any association between HPV positive status and the time since HIV diagnosis. However, HPV infection was statistically associated with the absence of ART and with characteristics such as low CD4 counts or nadir CD4 known to be associated with a lack of ART efficacy or a poor compliance. These data are consistent with those reported in the cross-sectional hospital-based study involving HIV-infected women in Tanzania , showingnt women . A meta-nt women . One of nt women . Taken tThe main limitation of the study is the lack of a control HIV-negative group, which did not allow a direct assessment of the impact of the HIV infection on the prevalence and characterisation of HPV infection. It cannot be excluded that the ethnicity of populations was different dependent on the HIV status and that the higher prevalence of HPV infection in HIV-infected women may be due to a greater genetic susceptibility. However, while an ethnic influence may be addressed, the interpretation is expected to be poorly biased when considering women living in the same area. Finally, one may not exclude that visual inspection or cervical cytology may be result in cervical disease misclassification. However, cervical samples have been taken by gynaecologists and have been sent to one pathology laboratory for a centralized assessment, which limit biases on interpretation.In summary, this prospective cross-sectional study shows that in the population of the French Antilles and Guiana, half of the HIV-infected women are co-infected with HR-HPV, which corresponds to a higher prevalence than that reported in populations not infected with HIV. The detection of HPV was independent from the time of HIV diagnosis but was positively associated with low CD4 levels, which is in agreement with the correlation between HPV persistence and the host immune status. Such a correlation should cause physicians to be particularly cautious regarding treatment compliance and when considering a modification of ART regimen, whatever the reason. Finally, the high prevalence of infections with various types of HR-HPV in HIV-infected women and the associated risks for cancer support a close cervical screening programme coupled with HPV testing. Regarding vaccination-based prevention, the newly approved nonavalent vaccine including HPV-52 should be preferred.S1 Dataset(XLSX)Click here for additional data file.


This study examined the feasibility and acceptability of an exergaming program that utilized custom exergames, and compared it to a traditional physical exercise (control) program in older adults at risk for falls. A quasi-experimental study was conducted in older adults who lived in senior living communities. Participants enrolled in either program offered twice weekly for 8 weeks based on their residential site. Thirty-five participants enrolled in the study (mean age 77±7y) and 29 (82%) completed the follow-up assessment . Overall attendance was 73% , and 22 participants returned their program satisfaction form. There were no significant between-group differences in ratings of overall quality, enjoyment, instructors, peers, and facility of their assigned exercise programs. The exergaming intervention was well received and perceived as enjoyable. This study demonstrates that an 8-week exergaming intervention is feasible and acceptable for older adults at risk for falls.


Fibrous dysplasia (FD) is a benign bone tumor due to developmental failure in the process of primitive bone remodeling to mature lamellar bone. The most common locations of monostotic FD of the extremity bones are the proximal femur, tibia, humerus and the radius. FD in the calcaneus is extremely rare and usually manifests clinically as a single bone lesion. Moreover, no research has reported on multiple lesions in calcaneal FD.We report a 21-year-old man presented to our institution with pain upon walking for 2 months.We diagnosed the patient with multiple calcaneal FD through histologic examination of the excised biopsy that revealed cellular, spindly stroma and woven bone without osteoblastic rimming resembling Chinese charactersPlain X-ray, computed tomography, magnetic resonance imaging and histologic examination. An excisional biopsy with extended curettage and bone grafting with allogenous bone and autogenous bone marrow aspirate concentrate were performed.No complications developed after surgery and during serial follow-ups at 3, 6 and 12 months. At a postoperative 12-month follow-up, a plain radiogram showed a well-consolidated bone graft in the lesions.Calcaneal FD is rare disease entity. This case can help guide clinical decision-making in the future. Thus, we provide the first case study on multiple calcaneal FD that can help guide clinical decision-making in the future.FD in the calcaneus is extremely rare and usually manifests as a single lesion in the bone. An extensive English literature search revealed only 3 published case reports on this topic.1.1The patient signed informed consent for the publication of this case report and any accompanying images. Ethical approval of this study was waived by the ethics committee of Chonbuk National University Hospital because it was a case report.2A 21-year-old man presented to our institution with pain upon walking for 2 months. No mass was palpated. There was no trauma and past medical history. On physical exam, there was no swelling or pain of the lateral aspect of the right ankle and hindfoot. The patient exhibited a full range of motion of his right ankle during the physical exam. A plain radiogram showed an ill-defined osteoblastic lesion around the subtalar joint in the body of the calcaneus measuring 2.5 cm × 3.0 cm  scan showed 5 round-shaped lesions , 3 were located in the upper  and 2 were in the lower medial calcaneus, which showed a sclerotic and osteoblastic lesion under the subtalar joint with a cystic round hole in the calcaneal body. Cortical involvement was developed in the lateral-upper lesion , tibia (15%), humerus (5%) and the radius (5%). However, the present case showed multiple (5) lesions in the calcaneus. Monostotic FD is known to enlarge in proportion to skeletal growth. Moreover, monostotic FD usually manifests as a single large bone lesion in a long bone, such as the proximal femur, tibia, humerus and radius but the present case showed 5 bone lesions in a short bone, the calcaneus. We believe this phenomenon resulted from the arrest of bone remodeling at different times in the 5 lesions in the calcaneus. The different arrest times in the calcaneus made a boundary between the normal lamellar bone and pathologic woven bone area, unlike previously reported cases that showed enlargement in the same area.–5The most common presentation of monostotic FD is a single-bone lesion without any other disturbance. This present case did not show a typical radiolucent ground glass matrix and showed multiple lesions with high signal intensity on T2-weighted image. We provisionally diagnosed the patient with multiple bone tumors, not FD, which needed to be biopsied.The common radiologic findings of FD bone lesions generally manifest as cystic, sclerotic or mixed. A typical FD lesion in the axial skeleton appears as an area of radiolucent ground glass matrix, which is usually smooth and homogeneous, not centrally located within the medullary bone. Additionally, FD lesions show sharply demarcated borders and intermediate-to-low signal intensity on T1-weighted image and intermediate-to-high intensity on T2-weighted images. These fibrous tissues expand from the medullary cavity to the cortical bone. The strangely-shaped trabeculae have been likened to “alphabet soup” or “Chinese characters.” The histological findings in this case are consistent with typical FD.The histopathologic hallmark of FD is fibrous tissue and immature, spindle-shaped, fibroblast-like cells within the bone marrow.–8 The choice of grafts, whether allografts or autografts, is controversial. Leet et al concluded that there was no difference in resorption rates between allografts and autografts. They reported that the resorption rate was high, especially at younger ages and in patients with polyostotic disease. The present case was well treated with an allogenous bone graft and autogenous bone marrow aspirate without resorption at the 1-year postoperative follow-up.Treatment of FD is indicated when it becomes symptomatic or there is a risk of fracture. This patient experienced pain on walking for 2 months that was unresponsive to pain killers. The provisional diagnosis was multiple bone tumors based on the CT and MRI images. An excisional biopsy and bone graft were considered to further evaluate the bone defect. Curettage and bone grafting, with or without bone internal fixation, are generally accepted as the treatment of choice in the majority of cases.Conceptualization: Kwang-Bok Lee.Data curation: Gun-Joo Park, Kwang-Bok Lee.Formal analysis: Jong-Hyun Ko, Kwang-Bok Lee.Funding acquisition: Kwang-Bok Lee.Investigation: Jong-Hyun Ko.Methodology: Gun-Joo Park, Kwang-Bok Lee.Software: Gun-Joo Park.Supervision: Kwang-Bok Lee.Writing – original draft: Jong-Hyun Ko.Writing – review & editing: Kwang-Bok Lee.


Face-to-face brief interventions for problem drinking are effective, but they have found limited implementation in routine care and the community. Internet-based interventions could overcome this treatment gap. We investigated effectiveness and moderators of treatment outcomes in internet-based interventions for adult problem drinking (iAIs).p < 0.001) and a higher rate of TR . Persons above age 55 showed higher TR than their younger counterparts . Drinking profiles were not significantly associated with treatment outcomes. Human-supported interventions were superior to fully automated ones on both outcome measures . Participants treated in iAIs based on personalised normative feedback (PNF) alone were significantly less likely to sustain low-risk drinking at follow-up than those in iAIs based on integrated therapeutic principles . The use of waitlist control in RCTs was associated with significantly better treatment outcomes than the use of other types of control . The overall quality of the RCTs was high; a major limitation included high study dropout (43%). Sensitivity analyses confirmed the robustness of our primary analyses.Systematic searches were performed in medical and psychological databases to 31 December 2016. A one-stage individual patient data meta-analysis (IPDMA) was conducted with a linear mixed model complete-case approach, using baseline and first follow-up data. The primary outcome measure was mean weekly alcohol consumption in standard units . Secondary outcome was treatment response (TR), defined as less than 14/21 SUs for women/men weekly. Putative participant, intervention, and study moderators were included. Robustness was verified in three sensitivity analyses: a two-stage IPDMA, a one-stage IPDMA using multiple imputation, and a missing-not-at-random (MNAR) analysis. We obtained baseline data for 14,198 adult participants . Their baseline mean weekly alcohol consumption was 38.1 SUs (SD = 26.9). Most were regular problem drinkers  and 19.9%  were binge-only drinkers. About one third were heavy drinkers, meaning that women/men consumed, respectively, more than 35/50 SUs of alcohol at baseline . Post-intervention data were available for 8,095 participants. Compared with controls, iAI participants showed a greater mean weekly decrease at follow-up of 5.02 SUs . This is, to our knowledge, the first study to identify moderators at the participant, intervention, and study design levels that are associated with treatment outcomes in internet-based interventions for adult problem drinking.Our IPDMA included 14,198 adults at baseline from 19 randomised controlled trials who exhibited various profiles of problem drinking. We obtained posttreatment data for 8,095 participants.Our results show that internet-based alcohol interventions in both community and healthcare populations are effective in reducing mean weekly alcohol consumption and in achieving adherence to low-risk drinking limits.We did not find differences in impact related to drinking profiles, meaning that people exceeding risk limits to a smaller or a larger degree benefited from the interventions, as did binge-only drinkers. Human-guided interventions showed a stronger impact on treatment outcome than fully automated ones, but waitlist design controls may inflate outcomes.The health gains of internet-based alcohol interventions could be substantial, because such programmes can reach high numbers of problem drinkers by virtue of their swift entry procedures and their easy scalability.Future research should seek to identify categories of people for whom such interventions work best, to analyse how the interventions work and to determine what delivery contexts are most favourable. It should explore which patient populations could benefit most from referral to unguided forms and which would be more amenable to guidance by GPs or other professionals. Global estimations continue to show increasing physical and psychological morbidity, all-cause and specific-cause mortality, and social harm deriving from all types of alcohol misuse. Usually, a positive and linear association is seen between increased consumption and related health risks . A numbeBrief alcohol interventions (BAIs) in primary care and community settings have been found clinically and cost-effective, with effect sizes in the small to moderate range, for reducing both hazardous drinking  and harmful drinking  . TogetheInternet-based alcohol interventions (iAIs) may overcome some of these problems by virtue of their low-threshold accessibility, their high scalability, and their acceptability to problem drinkers, as was recently echoed by McCambridge and Saitz . Major aAll this notwithstanding, various uncertainties still surround the evidence base for iAIs. First of all, still little is known about whether women and older people derive benefits comparable to those seen for male and younger problem drinkers. Such knowledge is important in view of the rising prevalence rates of problem drinking among women and the elderly and their underrepresentation in many intervention studies . SecondlThe few moderator analyses conducted to date had a common limitation: they were statistically underpowered to properly address such questions . To overPsycINFO, Science Citation Index Expanded, Social Sciences Citation Index, Arts and Humanities Citation Index, CINAHL, PubMed, and EMBASE were searched up to 31 December 2016. All papers retrieved were evaluated by independent assessors   were eligible if they (1) studied people aged ≥18 with quantifiable levels of alcohol consumption that exceeded recommendations for low-risk drinking; (2) compared an iAI with a control condition ; (3) studied an iAI based on therapeutic principles such as PNF, BSC, CBT, MI, or combinations thereof; and (4) studied either an unguided or a guided intervention or both. RCTs in populations of students or pregnant women were excluded. Primary authors of identified trials were asked to provide their raw RCT data for a set of pre-identified variables : (1) adequate random sequence allocation, (2) concealment of allocation to the different conditions, (3) blinding of participants and therapists to the study condition, (4) blinding of assessors to outcomes, and (5) handling of missing data .The primary outcome was mean weekly alcohol consumption, expressed in standard units. As RCTs differ in the quantification of alcohol in beverages, based on national custom (ranging from 8 to 14 grams of ethanol per unit ), we recTreatment response (TR) was defined as an alcohol consumption level below 14/21 SUs per week for females/males at the first post-intervention follow-up.The following participant-level putative moderators were tested: gender ; age (below 55/above 55); education , employment (yes/no), and partner relationship (yes/no). Two dimensions of problem drinking were explored: regular drinking  as contrasted with binge-only drinking ; and heavy drinking  as contrasted with non-heavy drinking . Intervention-level putative moderators were therapeutic guidance (human-guided versus unguided interventions), intensity (single versus multiple sessions), therapeutic orientation (PNF-only versus integrated therapeutic principles), and intervention setting . A study design moderator, type of control, was also included .Replications of individual study outcomes based on the raw data in comparison with the published results led to only one correction to the published tables . We nextN = 14,198) but ignoring missing post-intervention outcomes. This analysis implicitly assumes that the missing data are missing at random (MAR) rather than missing completely at random (MCAR), allowing missingness of post-intervention scores to depend on the pre-intervention score.To deal with missing baseline alcohol data, we used mean imputation to estimate scores . We subsb), which refer to the overall effect of the intervention on posttreatment drinking behaviour in terms of comparative SU levels.To evaluate the effect of iAIs using an LMM, we regressed the post-intervention weekly SU level on the iAI intervention indicator, the baseline weekly SU level, and the comparison indicators , assuming random effects (both intercepts and intervention slopes) for those comparisons and equal residual variances across trials. The estimates of the iAIs’ effects are presented as unstandardised regression coefficients  was similarly used. TR at follow-up (yes/no) was the dichotomous dependent variable, and all fixed and random effects were identical to those in the LMM for the continuous primary outcome, except that fixed intercepts were removed for reasons of identification (convergence), resulting in a model with random intercepts (and slopes). We calculated odds ratios (ORs), representing the probability that an outcome will occur given a particular exposure as compared with the probability in the absence of that exposure . TR was We subsequently tested whether participant, intervention, or study design characteristics moderated the effect of iAIs on either the primary or the secondary outcome or both. However, participant-level characteristics and study- and intervention-level characteristics were analysed differently. For participant-level characteristics, within-study and across-study interaction effects had to be separated to avoid ecological bias , whilst In the one-stage approach, we added a second sensitivity analysis to compare our results against those of a procedure applying multiple imputation to include all participants . This analysis was conducted on the request of one of the reviewers. The multiple imputation procedure used chained equations to impute missing alcohol consumption scores—both before and after the intervention—together with missing values of the participant-level putative moderators. The ITT analysis employed logistic regression models for the dichotomous variables and predicted-mean matching for the continuous variables, with study indicators and intervention indicators (fully interacted) included as covariates. This second sensitivity analysis tested the main intervention effect and the moderator effects of all participant-level and study-level moderators on the primary outcome variable.In the two-stage approach, we employed a third sensitivity analysis that evaluated the MAR assumption on the missing data mechanism, thereby answering an additional question of one of the reviewers. This additional, missing-not-at-random (MNAR) analysis is part of the ITT strategy suggested by White and colleagues ; it inclI2 statistic using the two-stage approach as well. This indicator is expressed as a percentage: an I2 value of 0% is interpreted as no heterogeneity, 25% as low, 50% as moderate, and 75% as high heterogeneity [I2 using the noncentral chi-squared–based approach within the heterogeneity module for Stata [To examine heterogeneity, we calculated the ogeneity . We calcor Stata ,33. All The potential differences in treatment outcomes between the trials included and those that could not be included in preparing our IPDMA were assessed with a conventional meta-analysis  [n = 4, cutoff ≥4 or ≥5) [n = 12 trials), from healthcare settings (n = 4), or from work settings (n = 3). Eight trials employed a minimal-intervention control design, six trials applied assessment-only control, and five included a waitlist-control comparator. Eleven trials estimated the effects of multiple-session iAIs, seven studied single-session iAIs, and one study included both types. Twelve investigated effects of therapeutically integrated iAIs and seven studied PNF-only interventions. Most comparisons (n = 19) involved unguided iAIs; eight involved human-guided interventions. The first post-intervention assessment occurred in most trials (n = 15) between 1 and 3 months after treatment, in three trials at 6 months, and in one study at 12 months. A total of N = 14,198 participants was included, out of the 17,545 participants in the 24 identified trials (a 79.77% inclusion rate).toff ≥8)  or AUDIT4 or ≥5)  as inclu4 or ≥5) . Particin = 9 trials) was 15.0 (SD = 6.8), indicating hazardous or harmful alcohol use [n = 678) scored above 20, indicating a risk of alcohol dependence. Missing SU scores at baseline were virtually nil (0.4%). Missing data at the first post-intervention assessment for the primary outcome were considerable (43%), predominantly resulting from study dropout, which was not entirely random: participants under age 55 and those with baseline heavy-drinking profiles dropped out significantly more than others.Of the total of 14,198 enrolled participants, 8,095 provided post-intervention outcome data . For two trials , we had estimated the mean weekly SUs on the basis of the first two questions of the AUDIT-C; removal of those trials likewise only slightly altered the result .The overall difference in mean weekly alcohol reduction was significant and in favour of the iAI condition , which remained after removal of the outliers .iAI participants also had a significantly greater likelihood of TR than controls . Additional sensitivity analyses maintained this difference. In the first analysis we included only men and women who were exceeding 14 SUs of alcohol at baseline and found a moderator effect of b = 2.36  for female gender. In the second analysis we included males and females who were exceeding 21 SUs at baseline, resulting in a very similar difference of b = 2.52 . A comparable result emerged for higher- versus lesser-educated participants . Participants above age 55 were significantly more likely to show TR than younger participants . No other participant-level moderators were identified for the primary or the secondary outcome.Both men and women treated in iAIs decreased their mean weekly SU levels to a greater degree than controls, but women did so less than men  and guided iAIs  were significantly more effective in reducing mean weekly SUs as compared with controls. Guided interventions were significantly more effective than unguided ones . Similar significant differences in favour of guided iAIs were seen in terms of TR . Guided interventions positively moderated TR likelihood in comparison to unguided ones . PNF-only interventions showed a significantly lower likelihood of TR than iAIs based on integrated therapeutic principles . Intervention settings significantly moderated alcohol consumption outcomes for healthcare patients  and for community populations  but not for work populations. Similar significant results were evident for TR .Both unguided . Only the guided iAIs in WLC designs differed significantly from those in otherwise-controlled trials . iAI intervention participants in WLC trials were also significantly more likely to show favourable TR  than those in other trials; significant differences were maintained for both unguided and guided iAIs with WLC designs as compared to other control .Treatment participants in waitlist-controlled (WLC) trials significantly reduced their mean weekly alcohol consumption by greater amounts in comparison to controls than those treated in otherwise-controlled trials , as was the case for assessment-only interventions. The contrast between PNF versus integrated iAIs became nonsignificant, as was the case for the contrast between unguided iAIs with WLCs versus other types of control conditions. Thus, in some cases these made our moderator analysis appear more conservative, while in some other cases the MI was more conservative.The third sensitivity analysis concerned the MAR assumption that is commonly used to deal with missing outcome data. All three of our sensitivity analyses confirmed the results of our main analysis for the overall effect and for most of the moderating effects of participant-, intervention-, and study-level characteristics for the primary and secondary outcomes. This appears to verify the robustness of our findings  and for the secondary outcome as well . It could be partly explained by the identified outliers, as it dropped from high to moderate for the primary outcome  and from high to small for the secondary outcome  after removal of the outliers from the analyses . No significant difference in effect size was observed between the included and non-included RCTs in the IPDMA in terms of the primary outcome (SU reduction).The conventional meta-analysis  was based on our search up to 31 December 2016 and included additional data from two RCTs published in 2017 . It revep < 0.05), but there was no publication bias observed on the basis of Duval and Tweedie’s trim-and-fill procedure (random-effects model). We could not conduct a conventional meta-analysis for our secondary outcome, as only a limited number of studies reported on it. In There were indications of publication bias, based on a visual inspection of the funnel plot see  and EggeThis study found that participants treated in iAIs showed a higher mean weekly decrease of 5.02 SUs of alcohol consumption and a greater likelihood of favourable TR (OR 2.20) than controls. Women decreased their mean weekly alcohol consumption significantly less than men (around 2 SUs). Our sensitivity analysis confirmed our assumption that this difference was not an artefact of the higher cutoff thresholds for men than for women at study inclusion  . More hiGuided iAIs yielded significantly better results than unguided ones for both treatment outcomes. iAIs based solely on PNF showed a lower likelihood of TR than iAIs based on integrated therapeutic principles. Waitlist control moderated both types of treatment outcomes, with iAIs in WLC studies showing significantly better outcomes in terms of both SU reduction and TR than those in otherwise-controlled studies. It thus appears that iAI treatment outcomes could have been overestimated in studies in which WLC groups were applied as comparators. One possible explanation for such higher effect sizes in WLC studies would be that problem drinkers allocated to waiting lists might delay their alcohol reduction because they anticipate treatment soon. In contrast, people in other types of control groups might have already found alternative support by the time of the follow-up assessment, thus potentially reducing their alcohol consumption more than WLC controls. By the same token, such tendencies could deflate effect sizes in non-WLC studies .The overall greater reduction of 5.02 SUs of alcohol consumption seen here in iAI treatment participants as compared with controls was higher than the 2.2 SUs we found in our earlier, conventional meta-analysis . One potTo the best of our knowledge, this is the first IPDMA to test the impact of iAIs and their moderators on treatment outcomes with adequate statistical power. The included RCTs had a low overall risk of methodological bias. Our results appear robust after comparison with our two-stage IPDMA results, as well as with those from our multiple imputation analysis and those from our conventional meta-analysis. The ANCOVA model that underlies our IPDMA implicitly relies on the MAR assumption, allowing dropout, which was 43% in our study, to depend on baseline consumption level. Although it cannot be ruled out that dropout was actually attributable to characteristics not included in the model, our MNAR sensitivity analysis suggested that the estimate of the overall effect would be reasonably stable against moderate deviations from the MAR assumption. The generalisability of our results to people in real-life settings might be hampered by poor assessment of ethnicity and by the focus on studies from high-income countries. In addition, only a small number of studies addressed effects of iAIs administered in care settings other than the community . Another limitation is that all studies applied self-reported alcohol consumption measures, which is possibly a source of social desirability bias . We alsoBoth men and women from different age groups and with different drinking profiles, including heavy drinking and binge-only drinking, can benefit from iAIs, and in particular from the therapeutically integrated ones as opposed to PNF-only interventions. Participants in iAIs reduced their mean alcohol consumption from 38.1 to 32.9 SUs per week, and they had a substantially higher probability of posttreatment adherence to low-risk drinking recommendations. The fact that heavy drinkers decreased their alcohol consumption by amounts similar to those of non-heavy drinkers has favourable implications, as the health impact of a given reduction is greater at higher levels of alcohol consumption . DespiteIn view of the constraints experienced with face-to-face BAIs in primary care settings, future studies should also explore various types of brief interventions, in order to gauge how problem drinkers in such settings can best be targeted. Those could be either face-to-face BAIs or iAIs, and the latter could be guided by general practitioners (GPs) or other professionals. For some patient populations, referral to unguided forms could be more beneficial . More prS1 PRISMA guidelines checklist(DOCX)Click here for additional data file.S1 Data(DOCX)Click here for additional data file.S2 DataRCT, randomised controlled trial.(DOC)Click here for additional data file.S3 Data(DOCX)Click here for additional data file.S4 Data(XLSX)Click here for additional data file.S1 TextMNAR, missing-not-at-random.(DOCX)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S3 Table(DOCX)Click here for additional data file.S1 Fig(TIF)Click here for additional data file.


Differentiating Mild Cognitive Impairment (MCI) from dementia and estimating the risk of MCI-to-dementia conversion (MDC) are challenging tasks. Thus, objective tools are mandatory to get early diagnosis and prognosis. About that, there is a growing interest on the role of cerebellum-cerebrum connectivity (CCC). The aim of this study was to differentiate patients with an early diagnosis of dementia and MCI depending on the effects of a transcranial magnetic stimulation protocol (intermittent theta-burst stimulation -iTBS) delivered on the cerebellum able to modify cortico-cortical connectivity. Indeed, the risk of MDC is related to the response to iTBS, being higher in non-responder individuals. All patients with MCI, but eight (labelled as MCI-), showed preserved iTBS aftereffect. Contrariwise, none of the patients with dementia showed iTBS aftereffects. None of the patients showed EEG aftereffects following a sham TBS protocol. Five among the MCI- patients converted to dementia at 6-month follow-up. Our data suggest that cerebellar stimulation by means of iTBS may support the differential diagnosis between MCI and dementia and potentially identify the individuals with MCI who may be at risk of MDC. These findings may help clinicians to adopt a better prevention/follow-up strategy in such patients. Dementia is a clinical syndrome encompassing progressive cognitive impairment  that leads to difficulties in activities of daily living up to total dependence. Alzheimer’s disease, vascular dementia, mixed dementia, and dementia with Lewy bodies are the most common types . DementiSome EEG features  have been tested for their usefulness in differentiating dementia and MCI at the prodromal stage ,5. It haNew objective markers are consequently necessary to early differentiate MCI and dementia and identify the patients at risk of MDC. Given that the paraclinical assessment in resting condition is not necessarily either conclusive or informative, perturbing brain connectivity, e.g., by using non-invasive neurostimulation, may allow the clinician to identify changes in connectivity that could be undetectable during the resting condition, or possibly misinterpreted during the administration of cognitive tasks ,29,30,31To date, a few studies employing fMRI and EEG/MEG explored cerebellum-cerebrum connectivity (CCC) to provide an early dementia/MCI diagnosis ,51,52,53A useful approach to assess in vivo the deterioration of CCC at rest, may consist in the analysis of the effects of non-invasive cerebellar stimulation on brain network connectivity measured using EEG. It is indeed well-known that cerebellar transcranial magnetic and electric stimulation, including theta-burst stimulation (TBS), largely affect brain connectivity ,63,64,65We enrolled 25 patients with MCI  and 24 with probable dementia  between March 2018 and January 2019. The clinical diagnosis was achieved according to the available international diagnostic guidelines ,74,75,760). Then, an iTBS paradigm was applied on the lateral cerebellum. iTBS aftereffects onto EEG functional connectivity were thus recorded after 10 min from protocol end (T1)  . This ti2 MagStim for iTBS provision.TMS was carried out using a figure of eight coil (90 mm wing diameter) wired to a MagStim stimulator  for TMS basic measures  and a RapidFirst, we determined the so-called hotspot, i.e., the point over M1 where the coil with the handle pointing backwards and laterally induced a posterior-to-anterior directed electrical current in the brain that consistently evoked the largest MEP with the steepest initial slope in the relaxed first dorsal interosseous muscle (FDI) of the right hand. Then, we determined the RMT and AMT of M1 by using single-pulse TMS stimuli with the coil positioned over the M1 hotspot. These measures were used to set up iTBS protocol. Specifically, RMT was defined as the minimum intensity that evoked a peak-to-peak MEP of 50 µV in at least 5 out of 10 consecutive trials in the relaxed FDI muscle. AMT was defined as the minimum intensity that elicited a reproducible MEP of at least 200 μV in the tonically contracting FDI muscle in at least 5 out of 10 consecutive trials. Participants maintained a force level of approximately 10–15% of maximum force during measurements of the active MT.To carry on iTBS, the abovementioned figure of eight coil was centered over the lateral cerebellum , positioned tangentially to the scalp, with the handle pointing superiorly . The ordEEG was recorded for at least 10 min while the subjects were sitting in a comfortable recliner chair in resting state in a quiet and mild-lighted room, with the eyes closed, before (T0) and 10 min after the end of iTBS administration (T1). To the purpose of an easy clinical application of the paradigm, we used a standard headset with 19 Ag-AgCl disk electrodes  placed according to 10-20-International System. The ground was put on the forehead, the reference on both mastoids. Eye movements and blinks were detected by an EOG . Data were acquired using a Brain-Quick System , sampled at 512 Hz, and filtered at a 0.3/70 Hz band-width (with 50 Hz notch). Skin-electrode impedance was always below 5 kOhm. Data were stored on a personal computer for offline analysis through a free license of EEGLAB toolbox. EEG artifacts were identified and removed by using visual inspection and ICA. Artifact-free EEG was thus segmented into 2 s epochs , thus obtaining 300 ± 50 epochs at each time T. Standardized LORETA (sLORETA) was thus used to analyze the cortical distribution of current source density. Computations were made using the Montreal Neurological Institute template (MNI152) template restricted to cortical gray matter  according to the probabilistic Talairach atlas ,78,79. AFunctional connectivity was analyzed between cortical regions of interest (ROIs) determined according to a voxel-wise approach. Because there are still no clear rules for determining ROIs, in this study sLORETA defined the MNI coordinates of the cortical voxels underlying the 19 electrode sites to create the ROIs, in keeping with previous works ,83. ThesOne may be concerned on the fact that the use of a canonical template and canonical electrode positions for the calculation of the forward model for connectivity in brain may lead to weak connectivity data. However, it has been shown that there is no systematic bias or inconsistency between template and native MRI co-registration of brain electric signals for the analysis of functional connectivity, even in small samples .The data analysis aimed at measuring changes in the intrinsic connectivity in the source-reconstructed EEG obtained above as a result of iTBS neuromodulation . Specifically, we investigated how a single session of iTBS changed cortico-cortical coherence (Coh) during resting-state following iTBS application. To this end, we estimated ROI-wise Coh in each frequency range and for post-pre iTBS differences in resting state EEG ,87,88,89The imaginary part of coherency  ,87,88,89Multivariate statistical analysis was used to compare the so-obtained post-pre iTBS functional connectivity arrays by employing the Partial Least Squares (PLS). This data-driven approach easily identifies the changes in intrinsic connectivity induced by any intervention . The simple contrast between pre- and post-iTBS aftereffects on iCoh  represented the independent variable. The pre-iTBS iCoh represented the dependent variable ,87,88,89p < 0.05). We thus elaborated the group-level PLS by averaging iCoh for post-pre iTBS contrast, thus yielding iCoh values as a function of group × frequency × voxel. Then, the contrasted  iCoh values were averaged across subjects, yielding grand-average group-level functional connectivity array as a function of frequency × voxel combinations. Therefore, we generated surrogate data using permutation testing ,91. We rt-tests to assess whether the EEG phase difference and the Hurst component of iCoh values were significantly different between pre- and post-iTBS [f (f is the frequency). In our case, it estimated the phase direction of functional connectivity among pairs of ROIs as influenced by cerebellar stimulation [As post-hoc analysis, we compared the average iCoh values between pre- and post-iTBS to identify the direction of the changes. About that, we employed paired ost-iTBS ,88,89,92mulation ,94. In or). The correlations between clinical  and electrophysiological measures  were tested using a Pearson correlation  in differentiating patients with MCI at the individual level  by using the likelihood ratio (LR). This analysis provides a summary of how many times more (or less) likely patients with a disease  are to have a particular result  than patients without the disease . In other words, LR can be used to calculate the probability of disease  for each individual . Last, the receiver operating characteristics (ROC) analysis was used to assess the relative predictive power of specific iTBS-induced modulations in connectivity to predict MDC at six months. We calculated the area under the curves (AUC) and the sensitivities and specificities for MDC using a ROC Analysis Calculator ,97.All patients well tolerated the experimental procedure, reporting no adverse events. Cerebellar iTBS modulated different cortico-cortical connectivity patterns in the majority of patients with MCI, namely MCS+. Specifically, iTBS caused significant variations in resting-state functional connectivity  , as reflt-tests to compare post-pre iTBS resting-state connectivity changes, between left somatosensory association cortex (BA5) and left (p = 0.002) and right sensorimotor areas (BA2/4) (p < 0.001), and between BA5L and left (p < 0.001) and right supplementary motor area (BA8) (p < 0.001) (p = 0.001), and left and right BA47    . On the ctively) . Other ciTBS significantly affected high-alpha and low-beta (11–20 Hz) PSD within BA5L-BA2/4L, BA5L-BA2/4R, and BA5R-BA8R, and the theta and low-alpha (5–8 Hz) PSD within BA5L-BA2/4L and BA5R-BA8R A,B. The All post-TBS phase spectra increased significantly within the networks and frequency ranges mentioned afore . In addir = −0.496, p = 0.001)  A. Among = 0.001) B. We thuThe relevance of specific detrimental patterns of connectivity within distinct frequency bands was confirmed by LR analysis, which disclosed that the preservation of iTBS-induced changes in BA5-BA8 theta and low-alpha connectivity was of significant utility to differentiate MCI patients at individual level . In factAll the participants were clinically re-assessed six months after the end of the experimental protocol. All the patients with dementia, MCI+, and three with MCI- (two naMCI and one aMCI) remained substantially stable at the neuropsychological tests, whereas the other five patients with MCI- (four aMCI and one naMCI) converted to dementia. ROC analysis showed that a clear prediction of MDC  was obtained with the lack of BA5-BA8 theta and alpha connectivity changes after iTBS application . Group cTo the best of our knowledge, this is the first study using PLS investigating the changes in resting state brain-wide functional connectivity after a single session of cerebellar iTBS. We found that the somatosensory association cortex, the sensorimotor areas, and the supplementary motor area showed significant functional connectivity changes after iTBS within theta, alpha, and beta frequency ranges in some patients with MCI . On the contrary, all patients with dementia and the others with MCI  lacked of iTBS aftereffects. There were no significant differences concerning the different subgroups . It is noteworthy that no effects were observed after sham-TBS, suggesting that connectivity changes were due to iTBS and not to other, confounding effects. As the main finding, cerebellar iTBS shaped the cortico-cortical functional connectivity (with their specific frequency ranges of oscillatory activity) among some of the brain areas that are crucial for sensorimotor integration processes, as indicated by PSD, iCoh, and PLS data analyses ,99. FurtMoreover, cerebellar iTBS aftereffects allowed to differentiate patients with dementia and MCI, and to identify the patients with MCI who may be at risk of MDC. Concerning the first issue, patients with dementia did not show any significant iTBS aftereffects contrary to the patients with MCI. In addition, overall electrophysiological aftereffects were independent from cognitive decline etiology , group categorization , the neuroradiological pattern, and the clinical-demographic features of the enrolled patients. This finding may somehow limit the extrapolation of the data to a real-world setting. However, it contemporary confirms the potential feasibility of our electrophysiological approach concerning differential diagnosis at a group level. More interestingly, concerning the second issue, our approach allowed a differential diagnosis at the individual level concerning patients with MCI. In fact, we identified eight patients with MCI who did not properly respond to iTBS . Notably, five among these patients converted into dementia at the six-month follow-up, depending on the degree of detrimental BA5-BA8 connectivity in the theta and alpha frequency range, regardless of their subgroup categorization (aMCI vs. naMCI). One may argue that patients with MCI- might be part of a normal variability in the general population, given that some healthy people do not even respond to any particular non-invasive stimulation paradigm. However, the fact that the patients who converted to dementia were those complaining of specific, distinctive connectivity feature, i.e., the failure in BA5-BA8 theta and alpha connectivity, makes unlikely the concern above. Indeed, such a connectivity failure is relevant to several behavioral and cognitive functions  ,103,104.To summarize, patients with a clinical diagnosis of MCI lacking of cerebellar neuromodulation-induced changes in cortico-cortical connectivity patterns (as found in patients with dementia) should be strictly followed, as they may be at an increased risk of MDC . HoweverOur study offers also some information regarding the mechanisms of CCC. It is known that the cerebellum can affect the excitability of several cortical areas. Non-invasive neuromodulation can be employed to investigate the contribution of specific cerebellar components and structures to CCC ,29,52,75We extended these findings by demonstrating extensive, top-down changes in brain-wide functional connectivity using PLS . The connectivity dynamics we described agree with previous studies showing that specific areas within the fronto-parietal network (including the associative complex and primary sensorimotor areas) receive cerebellar projections that are necessary to regulate the top-down information flow within the cortex ,112,113.Cortical oscillations arise from complex interactions among the thalamus, subcortical areas and the cerebral cortex, namely the thalamo-cortical system. This encompasses both intrinsic (depending on the interactions between specific intrinsic currents) and extrinsic (produced by the interplay of excitatory and inhibitory neurons) oscillatory mechanisms. The GABAergic neurons are attributed to regulate these complex interaction patterns with particular regard to frontoparietal and sensorimotor regions connections . In keepThere are some limitations to acknowledge. First, we enrolled a relatively small and heterogeneous sample. This somehow limits the extrapolation of the data to the real world, thus obviously implicating the necessity of larger and more homogeneous samples to confirm our promising findings. Second, we followed-up the patients for a relatively short period, so that the prognostic value of EEG signal analysis needs further confirmation. Third, one may be concerned on the fact that we mapped the electrodes on MNI brain template without taking into account the placement of the electrodes around individual brains. Indeed, the analysis and statistical approaches we used concerning ROI-wise functional connectivity assessment substantially reduces the biasing effect of different sources on the recorded signals, so that it was not mandatory to take into account the placement of the electrodes around individual brains ,115,116.Even though the usefulness of the EEG complex analysis we implemented in assessing the clinical progress and estimating prognosis needs to be substantiated more to have relevant implications in real clinical setting, we furnished an objective description of the degree of cognitive dysfunction by estimating connectivity failure. In fact, our study suggests that the degree of cognitive and behavioral impairment is correlated to the deregulation of connectivity among distinct cortical networks that are under cerebellar influence . Such degree of connectivity deregulation supports the differential diagnosis between patients with dementia and MCI and, among the latter, it might identify the patients who may be at risk of MDC, independently from etiology and subgroup categorization. Last, the knowledge of these electrophysiological patterns could be helpful to personalize rehabilitation strategies based on cognitive training and/or non-invasive neuromodulation approaches aimed at restoring large-scale cortico-cortical connections harnessing CCC.


Self-management support aims to give people with chronic disease confidence to actively manage their disease, in partnership with their healthcare provider. A meta-review can inform policy-makers and healthcare managers about the effectiveness of self-management support strategies for people with type 2 diabetes, and which interventions work best and for whom.A meta-review of systematic reviews of randomised controlled trials (RCTs) was performed adapting Cochrane methodology.Eight databases were searched for systematic reviews of RCTs from January 1993 to October 2016, with a pre-publication update in April 2017. Forward citation was performed on included reviews in Institute for Scientific Information (ISI) Proceedings. We extracted data and assessed quality with the Revised-Assessment of Multiple Systematic Reviews (R-AMSTAR).Glycaemic control as measured by glycated haemoglobin (HbA1c) was the primary outcome. Body mass Index, lipid profiles, blood pressure and quality of life scoring were secondary outcomes. Meta-analyses reporting HbA1c were summarised in meta-forest plots; other outcomes were synthesised narratively.41 systematic reviews incorporating data from 459 unique RCTs in diverse socio-economic and ethnic communities across 33 countries were included. R-AMSTAR quality score ranged from 20 to 42 (maximum 44). Apart from one outlier, the majority of reviews found an HbA1c improvement between 0.2% and 0.6% (2.2–6.5 mmol/mol) at 6 months post-intervention, but attenuated at 12 and 24 months. Impact on secondary outcomes was inconsistent and generally non-significant. Diverse self-management support strategies were employed; no single approach appeared optimally effective (or ineffective). Effective programmes tended to be multi-component and provide adequate contact time (>10 hours). Technology-facilitated self-management support showed a similar impact as traditional approaches (HbA1c MD −0.21% to −0.6%).Self-management interventions using a range of approaches improve short-term glycaemic control in people with type 2 diabetes including culturally diverse populations. These findings can inform researchers, policy-makers and healthcare professionals re-evaluating the provision of self-management support in routine care. Further research should consider implementation and sustainability. Meta-reviews provide a high-level overview of evidence ideal for informing policy and health service development, but fine-grained detail is lost as randomised controlled trials (RCTs) are synthesised into systematic reviews and then meta-reviews.A comprehensive search strategy in line with a predefined protocol was used to gather a large evidence base examining the impact of diverse self-management support interventions on different type 2 diabetes populations from 1993 to 2017.Individual RCTs may be included in multiple systematic reviews; this precludes meta-analysis and means that that some RCTs may be over-represented in our synthesis; we have identified and report this overlap.The research team encompassed public health, statistics, epidemiology, primary care and health psychology expertise, enabling a multi-disciplinary approach to interpretation.The burden of type 2 diabetes is a prominent global health challenge currently estimated to affect 415 million adults worldwideSupported self-management aims to give people with chronic disease confidence in taking an active role in all aspects of their disease management, and health behaviours,https://www.journalslibrary.nihr.ac.uk/programmes/hsdr/11101404/#/.We adapted Cochrane methodology to conduct a meta-review of systematic reviews of randomised control trials (RCTs) examining self-management support in people with type 2 diabetes.st January 1993)  search strategy) online . We sear10.1136/bmjopen-2018-024262.supp1Supplementary file 1Using a piloted form, data were extracted on: review rationale, review methodology, inclusion criteria, participant demographics and intervention details, outcomes and conclusions as synthesised by the review authors. Only data provided in systematic reviews were extracted; data were not extracted from individual RCTs within systematic reviews. Data extraction was undertaken  with a 10% check of extraction and quality assurance  and a 100% check of numerical data extracted . Methodological quality was assessed  using the R-AMSTAR tool (Revised - A MeaSurement Tool to Assess systematic Reviews)The primary outcome was HbA1c (or other measure of glycaemic control). Secondary outcomes included: other biomedical markers of disease (blood pressure (BP), lipid profile, weight and body mass index (BMI); quality-of-life; intermediate outcomes .In addition to the definition of self-management and self-management support that were used to select relevant studies , we alsoOur lay collaborator, people with long-term conditions, representatives of patient organisations as well as professional stakeholders  contributed to workshops throughout the PRISMS programme of reviews.The PRISMA diagram  details The 41 included systematic reviews encompassed RCTs from 33 countries: Argentina, Australia, Austria, Bahrain, Canada, China, Costa Rica, Croatia, Cuba, Denmark, Finland, Germany, Hong Kong, Iceland, India, Iran, Ireland, Israel, Italy, Japan, Mexico, New Zealand, South Korea, Spain, Sweden, Taiwan, Thailand, the Netherlands, Turkey, UK, USA, Vietnam and the West Indies. Year of publication ranged from 2001 to 2016, with the RCT publications ranging from 1981 to 2015 online . The majIntervention duration and follow-up duration were not always clearly defined. Where recorded, the average number of sessions ranged from 1 to 10 sessions, average contact time ranged from 30 min to 58 hours, over 6 weeks to 2 years online .15–18 21et al found publication bias but noted no change after sensitivity analysis, 12 identified possible publication bias18 26 27The quality of the reviews ranged from 20Thirty-five of 41 systematic reviews assessed glycaemic control, 24 of these presented meta-analyses of HbA1c data online . Follow-13–15 19 23 28–31 33 35–38 45 48 52 53All but one meta-analysisThe comparator group in the RCTs varied both within and between systematic reviews and ‘usual care’ was not always specified. Two reviews performed sub-set analyses based on the nature of the control intervention.et al  was one of two reviews showing an improvement in HbA1c that persisted at 24 months follow-up.Where follow-up times were differentiated in the systematic reviews, they are illustrated in 2) that was attenuated but still significant at 12 months.21 26Seven of eight meta-analyses found a non-significant decrease in BMI or weight.No statistically significant evidence of BP change was found in three meta-analyses.17 21 25 26 42 44Meta-analysis of lipid profiles showed non-significance,17 34Nine systematic reviews presented meta-analysis data of biomedical markersFour systematic reviews presented meta-analysis data for quality of life24Two studies performed meta-analysis of self-efficacy. These showed inconsistent18Health behaviour change outcomes encompassed diet, physical activity, self-measurement of blood glucose, recognition of complications, foot care and medication adherence behaviours. Three meta-analyses found a small but statistically significant improvement.43Self-management support interventions was coded into the 14 categories of the PRISMS taxonomy of self-management support21 29Generally, review authors concluded that intensity of the intervention influenced effectiveness. Five reviews identified that effective interventions provided moderate/high frequency of contacts,14 27Mode of delivery is an over-arching dimension of the PRISMS taxonomy. Diverse interventions were delivered by a broad range of professionals and lay people to groups, individuals, in person or remotely with varying durations and intensities. There were many permutations of delivery within and between systematic reviews, but with no clear evidence of an optimal mode of delivery or delivery provider online .We identified seven reviews reporting technology-facilitated self-management support.There were conflicting findings about the relative benefits of different forms of technological support, however, mobile app use (with/without an internet/multimedia approach) appeared to perform well.30 37The reviews encompassed interventions delivered to individuals with a broad range of demographic, cultural and clinical characteristics. People with poorer glycaemic control show greater benefit from self-management support than those whose control is already good.17 28 35 40 41 44 48 51 53Nine reviews looked at culturally ‘targeted’ interventions 17 19 24 25 29 40 45 55Culturally targeted interventions delivery used bilingual healthcare professional teams,et al, in the context of a Chinese ethnic majority, suggested that didactic group lectures might be more effective and culturally acceptable to Chinese populations than the ‘Western’ participatory self-management approaches.24 40The three reviews that focused on culturally tailored interventions concluded that tailoring should build on prior research or experience of the community and their characteristics.The one review that compared cultural tailoring to cultural targeting concluded that interventions were most beneficial when tailored, and when delivered using a range of options by multiple educators.24 29 45 55Targeted interventions can improve foot care behaviour in those at risk of foot ulceration,26The systematic reviews reported interventions carried out in a range of different settings: community,This meta-review synthesises evidence from 41 systematic reviews and 459 RCTs across 33 countries with diverse settings and healthcare systems. There is consistent evidence that supported self-management improves glycaemic control in people with type 2 diabetes with the effect attenuating over time. The impact on secondary outcomes , self-efficacy and self-management behaviours was generally non-significant. A wide variety of self-management support strategies were employed; most commonly information about the condition and its management; psychological strategies; lifestyle advice and support; and provision of social support. Improvement in HbA1c was demonstrated in diverse cultural groups, with interventions that were culturally, linguistically and socially appropriate. Effective interventions were delivered in a variety of settings, by a range of professionals and peer educators. Technology is increasingly being used and appears to be equally effective as traditional modes of delivery.Meta-reviews enable high-level over-arching summaries of evidence and are therefore ideal for informing health service policy, but an inherent limitation is the loss of fine detail.Data from commonly cited RCTs were included in several systematic reviews so that their findings will be presented in multiple meta-analyses; we recognised this by cataloguing the overlap in RCTs included in the systematic reviews  who were thus able to ensure fidelity to the original methodology. Title and abstract screening was carried out by one reviewer, increasing the risk of missing relevant papers. Structured training, and random duplicate checking (95% agreement) was undertaken to maintain quality. The multi-disciplinary team encompassed public health, statistics, epidemiology, primary care and health psychology expertise, and met regularly to discuss results and aid interpretation.Improvement in glycaemic control is a consistent and important finding. According to the UK Prospective Diabetes Study, each absolute 1% (11 mmol/mol) decrease in HbA1c is associated with reduction of 21% for any diabetes-related end point and 37% for microvascular complications. Therefore, an improvement between 0.25% and 0.5% (3 mmol/mol to 5 mmol/mol) (the the most common outcome in this meta-review) is modest, but clinically significantSelf-management did not consistently improve other physiological targets of diabetes care. This may be a consequence of a narrow focus on glycaemic control, inadequate intensity of interventions or limited ongoing reinforcement. Further research on strategies that might improve this broader range of outcomes is warranted.Implementation is challenging and only a minority of people with diabetes receive self-management support.It was not possible to definitively pinpoint the optimal composition, intensity or mode or delivery of supported self-management, though many studies concluded that effective programmes were multi-component and of adequate intensity (>10 hours). Attenuation of effect see , and theFlexibility is likely to be important,Echoing recommendations in other disease areas,Technology may be a promising mode of delivery, which, in our included reviews, seemed similarly effective to traditional approaches. Intuitively, they may be seen as offering convenient options for hard-to-reach groups such as economically active younger people or marginalised populations reluctant to attend multiple lengthy appointments or formal group self-management programmes. Self-monitoring and professional feedback  may offer other theoretical advantages. In the context of hypertension  qualitative evidence suggests that self-monitoring of physiological parameters can bridge the gap between a lay perspective (treating symptoms) and medical objective  promoting a collaborative approach to self-management.60Studies of self-management of type 2 diabetes are well-represented in the literature and findings are based on a mature and diverse database. Future RCTs should shift from establishing short-term effectiveness (reduced HbA1c) to exploring how to sustain self-management support in routine care. Longer term studies suggested attenuation of effect, but it is not clear whether this is the result of loss of effect of the intervention (implying the need for ongoing support) or the gradual increase of HbA1c over time making it more difficult to control.The shift in focus to implementation demands an understanding of the influence of context  and the development of locally adaptable implementation strategies promoting sustainable support for diabetes self-management. The PRISMS taxonomy of self-management support65Qualitative evidence suggests that self-management support needs to evolve over time. Initial support may need to focus on enabling people to accept the diagnosis; the optimal time to focus on lifestyle change may be when a person has made a conscious decision to take control over their condition.While tailoring to cultural groups was addressed by the included reviews, other groups were under-represented, for example, the frail elderly, people with multi-morbidity, people affected by substance misuse, disability and mental health problems. Self-management in populations with limited access to healthcare services either due to deprivation, rurality, geography, occupation, transiency or incarceration are contexts that could benefit from further exploration. The potential of technology as a mode of delivering supported self-management is an important research agenda. As in other disease areas,Self-management support, using a range of strategies, improves glycaemic control at least in the short term; the effect on other clinical indicators such as blood pressure is inconsistent. Tailored interventions enable targeted approaches that are culturally, socially and demographically sensitive to the individual and their community. Implementing an adaptable self-management programme offering tailored sustainable self-management support for individuals with type 2 diabetes, which is accessible throughout their diabetes journey will require a whole systems approach that involves active involvement of policy-makers, healthcare providers, patients and third sector organisations. Existing assets must be identified, and new services designed where gaps exist.