While the incidence of type 1 diabetes continues to rise by 3% each year, the ability to prevent this disease remains elusive. Hybrid closed loop devices, artificial pancreas systems, and continuous glucose monitoring technology have helped to ease the daily burden for many people living with type 1 diabetes. However, the artificial pancreas is not a cure; more research is needed to achieve our ultimate goal of preventing type 1 diabetes. The preceding decades have generated a wealth of information regarding the natural history of pre-type 1 diabetes. Islet autoimmunity in the form of multiple autoantibodies is known to be highly predictive of progression to disease. Staging systems have been devised to better characterize pre-type 1, direct mechanistic understanding of disease, and guide the design of prevention studies. However, there are no evidence-based recommendations for practitioners caring for autoantibody patients other than to encourage enrollment in research studies. Close monitoring of high-risk patients in natural history studies markedly reduces diabetic ketoacidosis rates at diagnosis and research participation is critical to finding a means of preventing type 1 diabetes. The discovery of an effective preventative strategy for type 1 diabetes will justify universal risk screening for all children. As is the case for type 2 diabetes, the incidence and prevalence of type 1 diabetes is increasing annually. It is estimated that more than 542,000 children worldwide have type 1 diabetes. With the diagnosis of type 1 diabetes rising by 2–3% per year, 86,000 children are expected to developed type 1 diabetes each year  at onset in those followed prospectively –8. TheseTo prevent type 1 diabetes, our understanding of the natural history of pre-type 1 diabetes and the mechanisms culminating in the autoimmune destruction of beta cells must continue to advance. Large international cohorts have been studied from birth in both relatives of patients with type 1 diabetes and more recently in the general population who are at high genetic risk. These studies have selected infants based on high-risk human leukocyte antigen (HLA) alleles, most commonly HLA-DR3/4, DQB1*0201/DQB1*0302. Monozygotic twins have a lifetime 50–70% risk of developing type 1 diabetes . In the The forethought to initiate long-term natural history studies greatly increased our knowledge of islet autoimmunity, the precursor of clinical disease. Large birth cohorts including Germany’s BABYDIAB (started in 1989), Finland’s Diabetes Prediction and Prevention , and Colorado’s Diabetes Autoimmunity Study in the Young  demonstrated a peak in islet autoimmunity development within the first 2–5 years of life and more rapid disease progression in those who developed autoantibodies in these early years compared to later childhood and adulthood , 14. IAACombining data derived from the aforementioned DIPP, DAISY, and, BABYDIAB birth cohort studies, Ziegler et al. demonstrated the risk of progression to type 1 diabetes based on the age of appearance of autoimmunity and number of autoantibodies. This young cohort of genetically high-risk children with one autoantibody had a 10-year risk of progression to diabetes of 14.5%. Children with two or more autoantibodies were at markedly increased risk of progression to type 1 diabetes at 5-year (43.5%), 10-year (69.7%), and 15-year (84.2%) follow-up. Sixty percent of children with multiple autoantibodies progressed to diabetes (median age of 6.1 years) compared to 10% of children with a single autoantibody (median age 5.2 years) Figure .per se, often occurs years before the onset of symptoms. Thus, pre-type 1 diabetes is a unique physiologic state where autoimmunity is present and progression to metabolic derangement and clinical onset can be predicted especially in younger children and adolescents. As such, the ADA, JDRF, and Endocrine Society released a joint position statement for the staging of pre-type 1 diabetes  and the Type 1 Diabetes TrialNet Pathway to Prevention  studies have allowed us to further characterize the time period before diagnosis. Although the actual diagnosis of diabetes has traditionally been based on American Diabetes Association (ADA) criteria , it is cs Figure . Stage 1Why is this distinction important? The overall goal of all those who care for children and adults with type 1 diabetes is to cure the disease (obviously preventing its recurrence) as well as prevention of the disease in those at risk and destined to subsequently develop clinical onset. Participants screened and followed as part of natural history studies whether enrolled in prevention trials or not have a decreased incidence of DKA at diagnosis compared to those screened but not followed and those not screened –8. WhileUnderstanding the likelihood of progression to disease in different groups is crucial. In prevention studies, a clinical endpoint, such as type 1 diabetes, can take years to reach and result in lengthy, expensive clinical trials. Limiting enrollees to those already in stage 2 may see endpoints reached more rapidly. That said, curtailing studies to those with advanced autoimmunity limit those available to enroll and can slow recruitment. Additionally, non-interventional, mechanistic-focused studies in stage 1 and 2 subjects can be designed to further our understanding of the etiopathogenesis of disease. The classification of pre-type 1 diabetes provides a uniform way in which researchers and clinicians can converse while promoting more individualized medical management . ClinicaBiomarkers, if validated, would be useful in understanding the natural history of the disease, heterogeneity, and as well as in clinical trials to shorten studies. C-peptide preservation is well studied as a metabolic endpoint in intervention trials. Samples collected during OGTT can be used as absolute values (fasting and peak C-peptide) or as part of a multivariable equation such as Index60 derived from a proportional hazards regression model as predictors of progression to type 1 diabetes –29. MarkOur knowledge of rates of progression, risk factors and the heterogeneity of the disease has been greatly advanced by these studies. Recently, it has been proposed that stage 1 and 2 could also be referred to by the terminology autoimmune beta cell disorder (ABCD), though this is new and may be controversial nomenclature –32. SemaThe cost of population screening and the parental anxiety associated with early monitoring for a disease must also be kept in mind . ParentaA practical approach to the management of islet autoantibody positivity starts with how islet autoantibody positivity is determined. This may occur through (1) testing of islet autoantibodies in patients found to have a mildly elevated blood glucose found incidentally (not meeting criteria for diabetes), (2) hyperglycemia detected during an acute illness that resolves but in whom autoantibody testing was done, (3) screening in the setting of multiple other autoimmune conditions, (4) screening of family members of probands diagnosed with clinical type 1 diabetes as part of a research study, or (5) population screening (only in the context of research). After confirmation of either one or more islet autoantibodies (specific autoantibody assays mentioned previously), the patient should be counseled if possible  and referred to centers participating in available research studies . If the patient does not qualify for any trials or does not wish to participate in a trial or research follow-up, the primary care provider, endocrinologist, or diabetologist should consider performing a hemoglobin A1c (HbA1c) and/or random/fasting/post-prandial blood glucose self-monitoring. An OGTT may be done to detect early clinical diabetes (Stage 3).Initiation of insulin is not recommended in the pre-type 1 phase. Initiation of insulin early in disease was previously thought to provide for beta cell rest and recovery even without severe metabolic derangement or markedly elevated HbA1c. More recent studies, such as the DPT-1, have shown that this is not the case, and others looking at intensive insulin therapy initiated shortly after diabetes diagnosis fail to show increased preservation of C-peptide compared to conventional treatment , 38. ManPrevention trials may have multiple endpoints and the populations treated may differ. Those found to be genetically at risk for developing islet autoimmunity are targeted with primary prevention strategies that are typically of low risk. Secondary prevention studies aim to slow down or halt the destruction of beta cells in those who have islet autoantibodies. Multiple approaches have been used with limited success to date Table . These iAntigen therapy was established with the hope of inducing peripheral tolerance by exposure of the naïve immune system to an antigen found in the target organ (beta cell) or through induction of anergy of already present autoreactive T cells , 43. Thead hoc analysis of a subgroup—those with positive ICA, elevated IAA titers (≥80 nU/mL), and normal glucose tolerance—a projected delay of 4.8 years in onset was observed. An even greater delay was observed in those with higher IAA levels (>300 nU/mL). The protective effect continued even after the end of the study (Insulin was first targeted as an autoantigen in the late 1980s starting in the non-obese diabetic (NOD) mouse model. In the early 1990s, two insulin-based therapies were conducted in the DPT-1 network. In separate studies, oral insulin and intravenous/subcutaneous insulin were administered to those of intermediate and high-risk, respectively. No difference was seen except in an he study . The larhe study . Furtherhe study .®), in the Diabetes Prevention—Immune Tolerance (DIAPREV-IT) study, has shown increases in GADA titers but no delayed onset of disease (Glutamic acid decarboxylase (GAD), another islet autoantigen, as a vaccination in the new onset and prevention time period has failed to provide preservation of beta cell function and effective delay in type 1 diabetes onset, respectively . The use disease . The add disease .In addition to the oral insulin and GAD-alum studies mentioned above there are other ongoing antigen-based prevention (and intervention) trials including those using multiple peptide mixtures from known islet autoantigens with the aim of inducing immunological tolerance to beta cells . More reA cellular therapy approach seeking the promotion of tolerizing Treg cells using autologous cord blood is underway in Australia (The CoRD Study). This open label pilot study is recruiting multiple islet autoantibody-positive first-degree relatives. Simultaneously, the DIAPREVI-IT2 and the INIT II studies mentioned above have built off their predecessors and are looking to add new therapies or enlarge the group studied.Once efficacy, safety, and feasibility (and hopefully mechanism) is demonstrated in new-onset type 1 diabetes patients receiving immune and other therapies they should be moved into the prevention arena. Due to the number of potential therapeutic targets—both immune and non-immune—multi-agent (cocktail) therapy targeting multiple aspects of this disease is likely to be needed. The timing of initiation and duration of treatment are also important areas of study.Type 1 Diabetes TrialNet has recently expanded to other therapeutics that have been approved and tested safe in other conditions and populations. One is the use of methyldopa to inhibit the communication between antigen presenting cells through MHC Class II signaling in susceptible HLA-DQ8 haplotypes. This focused, small mechanistic study will enroll participants with HLA-DQ8, 1 or more autoantibodies and stage 1 or stage 2 disease. Second, hydroxychloroquine, after its success in rheumatoid arthritis, will be tested in stage 1 individuals. The rationale for this therapeutic, historically used to treat malaria, includes modulation of T cells and interleukins, specifically reductions in Th17 cells in the NOD mouse model of type 1 diabetes. Hydroxychloroquine also has been shown to improve glucose metabolism and insulin sensitivity in type 2 diabetes .In Germany, the Fr1da study, performing general population screening for islet autoantibodies, will also be conducting the Fr1da Insulin Intervention looking at oral insulin in multiple autoantibody-positive subjects enrolled in the natural history study and progression to dysglycemia. This study serves many important purposes, mainly, the feasibility of population screening and seamless enrollment into a prevention study.Many exciting trials will finish enrollment and follow-up in the next couple of years. As is the challenge with prevention trials, waiting for a clinical endpoint is costly and time-consuming. Large numbers of patients need to be screened and well-powered studies require large numbers of participants, which limit the number of studies able to be performed. Other clinically relevant endpoints are being explored and small, brief studies are being designed to test mechanistic outcomes.We have gained incredible knowledge and understanding of the natural history of type 1 diabetes thanks to the international natural history and birth cohort studies described in this review. The presence of increased genetic risk (HLA) and multiple autoantibodies currently provides the most reliable means of predicting type 1 diabetes. However, additional clinical, metabolic, and genetic factors can be assessed to fine-tune that risk. While whole population screening for HLA risk or islet autoimmunity is not yet justified, several groups continue to create networks that will be poised to provide this screening as soon as meaningful prevention is identified. We await the results of several prevention clinical trials and other innovations as we labor to develop a sustainable method of preventing the complex autoimmune process that leads to type 1 diabetes.www.trialnet.org). Through this connection, individuals can decide if enrollment in a prevention clinical trial and/or natural history study is feasible as this is the best way to advance the field of prevention research.As we identify more patients with islet autoimmunity, we must contemplate how to best care for them. All individuals found to have 1 or more islet autoantibodies should, ideally, be referred to contact a type 1 diabetes clinical research center which can be reached through type 1 diabetes supporting agencies, including the JDRF, ADA, NIDDK, and the Type 1 Diabetes TrialNet. Specifically, TrialNet has more than 200 clinical and affiliate centers across the US and worldwide (Because of these efforts, a growing number of children are diagnosed with type 1 diabetes prior to the onset of clinical symptoms. There remain no firm guidelines for the follow-up and monitoring of individuals with 1 or more autoantibodies in the general community. Anecdotal evidence is provided and case studies emanating from birth cohorts like TEDDY will help to clarify management options that will undoubtedly vary based on institutional and country-specific preferences. The DPT-1, the Type 1 Diabetes TrialNet international clinical trial collaboration, the SEARCH for Diabetes in Youth Study, Fr1DA, and others will continue to provide valuable information with regards to the potential for population-based screening and the management of patients diagnosed with early type 1 diabetes.In closing, whether it be through targeted screening of relatives for autoantibodies or population-based screening for high-risk HLA, we must continue to study the natural history of type 1 diabetes and identify patients with beta cell autoimmunity. We feel that primary care providers and subspecialists alike must continue to work together to identify these patients and encourage them to participate in research. Only through these concerted efforts will we move closer to our ultimate goal of preventing and reversing type 1 diabetes.DAS conceptualized this proposal and reviewed/edited the manuscript, LMJ reviewed the current literature and wrote the manuscript, MJH reviewed/edited the manuscript. All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.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.


This study aimed to assess the impacts of heat waves during the summer of 2015 on mortality in the Czech Republic and to compare them with those of heat waves back to the previous record-breaking summer of 1994. We analyzed daily natural-cause mortality across the country’s entire population. A mortality baseline was determined using generalized additive models adjusted for long-term trends, seasonal and weekly cycles, and identified heat waves. Mortality deviations from the baseline were calculated to quantify excess mortality during heat waves, defined as periods of at least three consecutive days with mean daily temperature higher than the 95th percentile of annual distribution. The summer of 2015 was record-breaking in the total duration of heat waves as well as their total heat load. Consequently, the impact of the major heat wave in 2015 on the increase in excess mortality relative to the baseline was greater than during the previous record-breaking heat wave in 1994 (265% vs. 240%). Excess mortality was comparable among the younger age group (0–64 years) and the elderly (65+ years) in the 1994 major heat wave while it was significantly larger among the elderly in 2015. The results suggest that the total heat load of a heat wave needs to be considered when assessing its impact on mortality, as the cumulative excess heat factor explains the magnitude of excess mortality during a heat wave better than other characteristics such as duration or average daily mean temperature during the heat wave. Comparison of the mortality impacts of the 2015 and 1994 major heat waves suggests that the recently reported decline in overall heat-related mortality in Central Europe has abated and simple extrapolation of the trend would lead to biased conclusions even for the near future. Further research is needed toward understanding the additional mitigation measures required to prevent heat-related mortality in the Czech Republic and elsewhere. Many studies have documented seasonal and meteorological effects on human mortality in various geographical areas ,2,3. In As a result of climate change, increased heat-related mortality is projected in the future ,14,15. MPhysiological (acclimatization), behavioural , and technological  adaptations have been often hypothesized as the reasons for declining vulnerability to extreme temperatures ,24,25,26In 1994, Central Europe experienced its hottest summer since at least the 1950s . An exceSeveral studies have evaluated mean effects of hot spells on mortality  and morbDaily natural-cause mortality ) was analysed in the Czech Republic during 1994–2015 . The data were collected and processed by the Czech Statistical Office and the Institute of Health Information and Statistics of the Czech Republic. The data were stratified by gender and age into four subgroups—a total of 2,253,788 deaths were recorded in the national registry during the examined period, out of which 1,110,755 were males, 1,143,033 females, 486,789 younger than 65 years (0–64 years), and 1,766,999 deceased were 65 years and older (65+ years). As the demographic structure of the population has shifted toward a higher proportion of the elderly during the examined period see , we calcDaily air temperature was calculated as the mean from 12 high-quality meteorological stations operated by the Czech Hydrometeorological Institute, representing the spatial population distribution in the Czech Republic , and useTo select only those heat waves affecting the majority of the area, we used one temperature time series calculated from the 12 stations distributed across the whole area. Heat waves are defined as periods of at least 3 days with daily mean temperature (Tmean) reaching or exceeding the 95th percentile (21.2 °C) of the annual distribution (estimated from data over 1994–2015), with at least 1 day exceeding the 98th percentile (23.2 °C). Although there is no universally accepted heat wave definition in public health studies, the 95th percentile of temperature distribution is generally understood as a threshold of a heat wave according to the WHO and WMO Guidance on Warning-System Development . The seci denotes daily mean temperature on day i, T95 represents the 95th percentile of daily mean temperature, EHIsigi is defined as the exceedance of the previous three-day mean temperature (starting on day i) above T95, and EHIaccli on day i is calculated as the difference between the three-day mean temperature and a mean of the prior 30 days. It should be noted that we slightly modified the original Nairn and Fawcett’s (2015) equations by calculating the three-day mean temperature over days i to i − 2 instead of days i to i + 2, since human mortality on day i can be affected by thermal conditions on day i or previous days, but not on upcoming days. Consequently, daily EHF was calculated using Equation (3):Koppe and Jendritzky  pointed Finally, values of EHIsig, EHIaccl, and EHF on all days of a heat wave were summed, in order to evaluate its total heat load.E(M) is the predicted daily mortality, α is the model intercept, time is a variable to account for long-term trends and seasonality, n(y) is the number of years in the time series, s represents thin plate smoothing spline [factor variables define categorical variables for days of week (dow) and heat-wave days (hwd). A smoothing spline with six degrees of freedom (df) per year  was applied after sensitivity tests evaluated by a combination of procedures, including partial autocorrelation plots, models’ unbiased risk estimator criterion [df used was also in accordance with an estimate (137 df) made via generalized cross-validation using the “bruto” function in the “mda” R package . The hwd variable reaches values 0/1, where 1 is used for the heat wave days. The coefficient of the hwd variable was subtracted from the model-predicted baseline on heat-wave days and therefore the excess mortality during the heat waves was calculated with respect to the baseline adjusted for the effect of heat waves [To assess the mortality increase during heat waves, daily baseline for natural-cause mortality was determined using generalized additive models (“mgcv” package in R (version 2.15.2) ). Specifg spline , and facriterion , percenton 0.4-9 ) accordion 0.4-9 . The weeat waves .Daily numbers of deaths per standardized 10 million inhabitants and their relative deviations from the mortality baseline  are shown in Characteristics of heat waves such as average daily mean temperature (average Tmean), intensity (EHIsig), duration, and timing within a year have been documented as important factors modifying the eventual impact on mortality ,36. UsinAlthough heat waves are defined by the temperature thresholds presented above, the actual periods of heat stress are likely to be slightly longer  and the total effect of a heat wave may be slightly greater than that of the identified heat wave period. On the other hand, the effect of a short-term mortality displacement (harvesting) after the end of a heat wave may substantially reduce the net effect of a heat wave on excess mortality ,83. To ep = 0.05) different from the mortality baseline in 40 events (see t-test at p = 0.05) different between women and men , it was significantly larger in the elderly (65+ years) than the younger (0–64 years) age group .A total of 49 heat waves were identified between 1994 and 2015 in the Czech Republic, with maximum of four heat waves per year . Althougents see . The mea2015 was the record-breaking year during the examined period regarding the total duration of heat waves (36 days) as well as their cumulative excess heat factor —were remarkable not only because of their meteorological characteristics, but also due to their impact on excess mortality, which was substantially larger than during any other heat wave (p = 0.05) among the elderly in 2015_3 .The two persistent heat waves—1994_4 and 2015_3  was the third longest heat wave during the examined period (11 days) and avgTmean was equal to 1994_4 (24.1 °C), its impact on ∑RMD (93%) ranked as the 11th largest among all heat waves. Similarly, the longest heat wave in 2003 had a relatively small impact on mortality (∑RMD = 60%), despite its 10-day duration . In both cases, the values of ∑EHF  were much lower than during the major heat waves (1994_4 and 2015_3). On the contrary, other heat waves, such as 1994_1, 2007_1 , 2013_1,2 = 0.75). The ∑RMD of a heat wave depended more strongly on ∑EHF than other indicators of heat wave intensity such as average  and maximum daily mean temperature  during a heat wave, as well as its duration (R2 = 0.59). The above presented results highlight the importance of considering the total heat load of a heat wave when evaluating its impact on human health. This finding was also supported by the linear regression analysis performed among all 49 heat waves. As shown in Generally, the order of heat waves with the largest impact on mortality was maintained also if the mortality displacement effect during the extended heat wave period (EHP) was considered . The netWe analyzed effects of heat waves on natural-cause mortality in the Czech Republic during summer 2015 and compared them with the effects of previous heat waves back to 1994. Two major heat waves, occurring on 22 July–8 August 1994 and 3–15 August 2015, respectively, were exceptional in both the climatological extremity and their impact on excess mortality. Although the excess mortality (deaths per standardized 10 million inhabitants) was higher in 1994, the increase in mortality relative to the baseline in a given year was larger in 2015. These findings suggest that the health response to the major heat-stress events has not improved significantly during the examined period and that the total heat load of a heat wave, given by its intensity, duration, and temperature change with respect to the previous conditions, constitutes one of the main factors affecting the magnitude of the mortality increase.Studies reporting significant decrease in heat-related mortality over time have mostly assessed temporal changes in relative risk of increased mortality per unit of temperature increase, aggregating all days above a certain threshold ,24. ThisOn the other hand, while the summer of 2003 (June–August) was the second warmest in the Czech Republic during the examined period (according to mean temperature), temperature increases during heat waves were generally small compared to the non-heat wave conditions, thus resulting in low cumulative excess heat factor of the heat waves in 2003. Therefore, despite its length comparable to the 2015 major heat wave, the total heat load of the August 2003 heat wave was substantially lower. The importance of the total heat load of a heat wave  in tDespite the declared importance of the total heat load in the final impact of a heat wave on excess mortality, heat waves with comparable ∑EHF in our study had in some cases substantially different impact on ∑RMD. These variations were related mainly to different conditions preceding the heat waves. For example, while in 2007 a mild summer without obvious temperature extremes prevailed in Central Europe prior to the heat wave with the third largest ∑RMD during the examined period, a comparably intense heat wave in 2010 (2010_3) had a weaker impact on excess mortality as it was preceded by two other heat waves earlier in the season. On the other hand, the cumulative excess mortality during both heat waves was comparable when the extended heat wave periods (EHPs) including the harvesting effect were considered. This finding emphasizes limitations of the regression analyses of associations between ∑RMD and heat wave characteristics, assuming that all heat-related excess deaths occurred only during the identified heat waves. On the other hand, it is also not very likely that all excess deaths that occurred during EHPs were associated to the heat stress. Although we attempted to estimate mortality displacement during individual EHPs, the resulting values have to be perceived very carefully, since quantifying the real proportion of deaths that would have occurred regardless of the heat wave is still not a completely resolved issue ,83.In addition, the study did not take into account other potential confounding variables or effect modifiers, such as air pollution  and mortIn addition to meteorological factors, demographic changes over time may significantly modify the effect of heat. Age-standardization of mortality is commonly applied in epidemiological studies in order to adjust the time series for changes in population structure over time and space . Due to Significant decreases in heat-related mortality risk during recent decades have been observed also in the U.S.  and otheTogether with the favourable socioeconomic development over recent decades, the demographic structure of the population has shifted toward a higher proportion of the elderly during the same period. While in 1994, 13% of the Czech population was older than 65 years of age, this figure was already 18% in 2015 . Our resHeat-and-health warning systems (HHWSs) have been often presented as an effective tool of heat-related mortality alleviation ,41,91. RThe Czech Republic does not so far have an HHWS based on temperature–health relationships and including steps to follow after an alert’s issuance . As demoFor better understanding of associations between weather events and human health when developing an effective HHWS, the WMO/WHO guideline  recommenImpacts of heat waves in summer of 2015 on natural-cause mortality in the Czech Republic were evaluated and compared with those of previous heat waves back to the record-breaking summer of 1994. The summer 2015 exceeded the 1994 one in both the intensity of heat waves and magnitude of heat-related mortality. Despite the smaller excess mortality associated with the major heat wave in 2015 in comparison to 1994, the relative increase from the baseline was larger in 2015. The effect of the major 2015 heat wave was more pronounced in particular due to stronger impact on excess mortality among the elderly (65+ years) than the younger age group (0–64 years) in 2015 compared to 1994. The results suggest that the cumulative excess heat factor of a heat wave, considered as a function of absolute temperature anomaly during a heat wave, heat wave duration, and temperature increase relative to the previous conditions, explains better the magnitude of excess mortality during a heat wave than other characteristics such as duration and average daily mean temperature during the heat wave alone. Further research is needed to improve the effectiveness of measures to prevent heat-related mortality while considering changes in the intensity, duration, and frequency of heat waves due to ongoing climate change as well as changes in the demographic, epidemiological, and socioeconomic structure of the population over space and time. The comparison of mortality impacts of the 2015 and 1994 major heat waves suggests that the recently reported decline in overall heat-related mortality in Central Europe has abated and a simple extrapolation of the trend would lead to biased conclusions even for the near future.


Patients often seek other patients’ experiences with the disease. The Internet provides a wide range of opportunities to share and learn about other people’s health and illness experiences via blogs or patient-initiated online discussion groups. There also exists a range of medical information devices that include experiential patient information. However, there are serious concerns about the use of such experiential information because narratives of others may be powerful and pervasive tools that may hinder informed decision making. The international research network DIPEx  aims to provide scientifically based online information on people’s experiences with health and illness to fulfill patients’ needs for experiential information, while ensuring that the presented information includes a wide variety of possible experiences.The aim is to evaluate the colorectal cancer module of the German DIPEx website krankheitserfahrungen.de with regard to self-efficacy for coping with cancer and patient competence.In 2015, a Web-based randomized controlled trial was conducted using a two-group between-subjects design and repeated measures. The study sample consisted of individuals who had been diagnosed with colorectal cancer within the past 3 years or who had metastasis or recurrent disease. Outcome measures included self-efficacy for coping with cancer and patient competence. Participants were randomly assigned to either an intervention group that had immediate access to the colorectal cancer module for 2 weeks or to a waiting list control group. Outcome criteria were measured at baseline before randomization and at 2 weeks and 6 weeksThe study randomized 212 persons. On average, participants were 54 (SD 11.1) years old, 58.8% (124/211) were female, and 73.6% (156/212) had read or heard stories of other patients online before entering the study, thus excluding any influence of the colorectal cancer module on krankheitserfahrungen.de. No intervention effects were found at 2 and 6 weeks after baseline.The results of this study do not support the hypothesis that the website studied may increase self-efficacy for coping with cancer or patient competencies such as self-regulation or managing emotional distress. Possible explanations may involve characteristics of the website itself, its use by participants, or methodological reasons. Future studies aimed at evaluating potential effects of websites providing patient experiences on the basis of methodological principles such as those of DIPEx might profit from extending the range of outcome measures, from including additional measures of website usage behavior and users’ motivation, and from expanding concepts, such as patient competency to include items that more directly reflect patients’ perceived effects of using such a website.Clinicaltrials.gov NCT02157454; https://clinicaltrials.gov/ct2/show/NCT02157454 (Archived by WebCite at http://www.webcitation.org/6syrvwXxi) Activating patients to become partners in their care has been a priority in health policy in many Western countries over the past years . IncreasAlthough medical information on diseases, treatments, and outcomes that is based on available quality criteria -19 repreAgainst this background, this study asks whether a website that provides experiential information on living with colorectal cancer based on scientifically rigorous data collection and analysis positively influences self-efficacy for coping with cancer -15 and pThe study used a randomized two-group between-subjects design with repeated measures; participants were randomly assigned either to an intervention group that had immediate access to the colorectal cancer module for 2 weeks or to a waiting list control group that was given access to the module after completion of the study 6 weeks after randomization. Coping self-efficacy served as the primary outcome; patient competencies constituted the secondary outcome. Outcome criteria were measured in both groups at baseline before randomization and at 2 weeks (time 1). At 6 weeks after baseline (time 2), follow-up measures were taken to test for the short-term stability of the intervention. The trial was conducted before the website became available to the general public.The study protocol was approved by the Charité Universitätsmedizin Berlin ethics committee (EA4/053/12) and was registered . This trial is reported according to the Consolidated Standards of Reporting Trials (CONSORT) statement and the CONSORT-EHEALTH extension.The intervention of the study consisted of a website providing information of experiences by men and women diagnosed with colorectal cancer. The website is a section (module) of a German website krankheitserfahrungen.de, which aims to provide scientifically collected and analyzed experiences of health and illness to patients, health care providers, and the wider public. The project team DIPEx Germany that runs the website is a member of the international research network DIPEx  . The webThe content of the modules of the DIPEx website can be accessed via thematic pages  or by interviewed persons (person pages). The person pages can be searched applying a filter  for ease of navigation. These features of the website are positively viewed by users -39. In pd (between-group mean difference divided by SD) [d=.20-.49). Based on these premises, a sample size of n=205 participants per group was deemed necessary.In determining the necessary sample size for the trial, it was assumed that given a standard deviation of 18 ,41, a did by SD) , this liPotential participants were considered eligible if they were German-speaking, 18 years of age or older, and had either been diagnosed with colorectal cancer within the past 3 years before enrollment or—independent of time since diagnosis—had metastasized colorectal cancer and/or a relapse of the disease, and who consented to participate online on the study website. Potential participants who indicated on the survey that the time since their diagnosis was more than 3 years and who indicated that they had no recurrence or metastases were excluded from the study.A wide range of recruitment strategies was used. Many major websites related to colorectal cancer, such as felix-burda-stiftung.de and lebensblicke.de, were informed about the study and provided a link to the study website. Information on the study was posted regularly on a colorectal cancer Facebook group and on online colorectal cancer discussion groups. The study was presented in-person to support groups, in rehabilitation clinics, and to hospital staff for them to aid in recruitment. Some colorectal cancer centers also informed their patients about the study. Finally, the project was presented at information events for patients at hospitals and cancer meetings. Recruitment started in June 2014 and ended in August 2015.Study participants had to enroll themselves through the study website, which also provided detailed information about the study. If participants then chose to enroll, this was considered as giving consent because they had previously been informed. After enrollment, participants were first asked to complete the baseline measures and were then randomized.Online data collection at the three measurement points required patients to complete validated questionnaire measures of self-efficacy for coping with cancer, patient competence, depression, social support, health-related quality of life, and medical information received . In addiSelf-efficacy for coping with cancer may be defined as a patient’s confidence in his or her ability to perform coping behaviors in the context of cancer . As the Following Giesler and Weis , patientThe competencies measured at baseline and weeks 2 and 6 were “self-regulation” , “managing distressing emotions” , “dealing explicitly with the threat posed to life by cancer” (being able to confront the idea that one might die), and “(low) avoidance” (ability not to engage in ruminating thoughts and avoidance behaviors) . ProblemTo allow a more comprehensive characterization of the participants, depression, social support, quality of life, and satisfaction with information received on the condition and its treatment were measured. Depression was measured at baseline using the two-item Patient Health Questionnaire (PHQ-2) ,45. AlsoData analysis was performed using IBM SPSS versions 23 and 24. Baseline differences between the intervention and the waiting list group were analyzed by means of chi-square statistics for categorical variables or one-way analyses of variance (ANOVAs) in the case of continuous variables based on all participants with nonmissing data for a given variable. Effect sizes were estimated by computing phi coefficients or eta squared. Following Cohen , these m231,997=27,222.8 (P>.99). The effect sizes of the predictors in the regression models are reported as beta weights for which the minima and maxima across the analyzed imputed datasets will be given. Following Cohen [For testing the hypothesized intervention effect on the primary and secondary outcomes, we preformed separate regression analyses of the postintervention (week 2) and follow-up (week 6) scores with the intervention dummy coded  and the respective pretest scores as an additional predictor, which is equivalent to a traditional analysis of covariance. These analyses were based on all randomized participants, using multiple imputation of missing values at baseline and at 2 and 6 weeks. We ran 10 multiple imputations with the full information maximum likelihood method when data were missing in single items or scales. Multiple imputation creates multiple datasets, in which the missing observations are imputed, using a stochastic algorithm that estimates values based on given information and creates different imputed values in each dataset. Statistics are performed separately for these datasets and coefficients are combined after having finished the analyses . The assng Cohen , values The sample consisted of 212 randomized participants who completed the baseline survey. The mean age of participants was 54.1 (SD 11.1) years and 58.8% (124/211) were female. Approximately 73.6% (156/212) of the study sample had read or heard stories and experiences of other patients online before that were unrelated to the intervention provided in the study. Most participants were recruited via the Internet , 33 (15.6%) were referred to the website by their physician, 25 (11.8%) were recruited via flyers, 8 (3.8%) had been informed by friends, and 23 (10.8%) provided no information about their recruitment path.As shown in On average, participants in the intervention group visited the intervention website for mean 42.21  minutes in total. The mean number of sessions at the site was 3.43 . A mean 40.15  clicks across all sessions suggests that the intervention participants accessed a moderately large number of subpages.F values not shown, for mean values see This randomized controlled trial investigated the effects of a website presenting systematically collected and organized patients’ experiences of living with colorectal cancer on self-efficacy for coping with the disease and on patient competencies such as coping with emotional distress or dealing with the life threatening nature of cancer . ParticiIn what follows, we will briefly discuss possible explanations for each of these observations. Insofar as these explanations involve factors relating to characteristics of the new website module itself or to its use by participants, they will primarily be discussed in the section comparing these results to prior work. In contrast, explanations that involve methodological factors will be discussed in the limitations section. Considering these factors in more detail may help improve the design of future studies that aim at evaluating websites providing patient narratives on living with  cancer. This appears especially important if one shares the conviction that such narratives contain elements that are relevant for empowering cancer patients and helping them develop their coping competencies and coping self-efficacy.Regarding the slight, but significant, decrease of self-efficacy for coping with cancer and three patient competence scales across time observed in this study, a possible explanation may lie in assuming the operation of a response shift . In the A major limitation of this study may be that its participants were much younger on average  than patients with colorectal cancer in Germany in general (mean 71 years) . AlthougAnother important limitation may be the fact that far fewer participants could be recruited for the study than suggested by the initial determination of the necessary sample size. This inevitably reduced the power of the trial to detect a treatment effect, if it in fact existed. It would certainly have been preferable to extend the recruitment phase of the study. Unfortunately, this was not possible because of the timeline of the study and the intention to make the newly constructed website available to the public in due time. Nevertheless, achieving the targeted sample size would by no means have guaranteed to establish the hypothesized effect.Traditional face-to-face psychoeducational interventions in cancer patients have been shown to yield small-to-medium positive effects on distress and quality of life, although problems with study quality and heterogeneity have to be acknowledged -59. InteRegarding self-efficacy for coping with cancer and patient competence, this study found that having access to a new website presenting illness narratives of colorectal cancer patients that have been systematically collected on a scientific basis has no effect compared to a control condition. Possible explanations of this finding may be seen in specific features of the website itself and in features of patients’ on-site usage behavior that might operate as a moderator of online intervention effects on coping self-efficacy and patient competence and other patient-reported outcomes. As a consequence, it may be of importance to analyze patients’ usage behavior in more detail in future research. Furthermore, future research should extend the range of outcome criteria and include measures that more directly reflect patients’ perceived effects of using such a website.


Rationale (hypothesis): IgG4-related disease (IgG4-RD) is a pathological entity recently recognized by the medical world that can affect any organ or system. However, there is insufficient data about this disease in medical literature.Aim (objective): A more extensive clarification of the IgG4 molecule, the diversified aspects of IgG4-related disease, and the response of this disease to treatment, will provide a crucial understanding of the immune system and other diseases now known to be associated with IgG4.Methods and results: The MEDLINE online medical database was used, and, after a comprehensive review of medical articles regarding IgG4-RD, published after 2003, using the search words “IgG4- related disease” and “IgG4 molecule”, we have described the clinical, pathological and therapeutic features of IgG4-RD, as well as the presence of the IgG4 molecule in the evolution, diagnosis and management of this syndrome. We characterized the potential disease mechanisms and discussed early observations related to treatment.Discussion: Given the response to immunosuppressive therapy, it is hypothesized that IgG4-related disease is most likely an autoimmune disease. Therefore, IgG4-related disease is a fibro-inflammatory condition that can affect any organ and can lead to the formation of pseudotumoral lesions requiring differential diagnosis with various malignancies. Positive diagnostic criteria are histopathological and require at least two features out of the following three: dense limphoplasmocitary infiltrate, storiform fibrosis, obliterative phlebitis. Damage can be done to a single organ or to multiple tissues or systems that are involved in a synchronous or metachronous way. The clinical expression of the disease varies depending on the organs involved. The histopathological examination is considered the gold standard in obtaining a diagnosis, and the observed morphopathological changes are similar regardless of the affected organ. From this perspective, IgG4-related disease may be compared to sarcoidosis, another multisystemic disease with similar morphopathological changes in any sample of tissue that is involved. The histological criteria are: diffuse lymphoplasmacytic infiltrate, numerous IgG4 positive plasma cells in the examined tissue, storiform fibrosis (resembling the spokes of a cartwheel), eosinophils in mild to moderate quantities, obliterative phlebitis, and pseudotumoral lesions that tend to form in the affected organs [2]. Though initially considered that markedly elevated serum IgG4 levels were essential for diagnosis, it is known now that up to 30% of the patients may have a normal serum concentration despite the histopathological criteria supporting a positive diagnosis [3]. However, many aspects of the disease remain unclear.IgG4-related disease (IgG4-RD) is a pathological entity recently recognized by the medical world that can affect any organ or system. The basics of this condition have begun to be constructed since 2003, when patients with autoimmune pancreatitis have also been observed to have extrapancreatic manifestations [4].Epidemiology of the disease is insufficiently described, but some demographic peculiarities stand out. Most patients are males over 50 years of age with a male/ female ratio of 3/ 1. Here, what should be noted is the discrepancy with other classic autoimmune diseases such as Sjogren's syndrome, systemic lupus erythematosus, primary biliary cirrhosis, which are predominantly found in females. The incidence and prevalence of the disease are not known, because only studies of autoimmune pancreatitis were conducted mainly in Japan. The prevalence is 0.8 cases/ 100,000 inhabitants/ year, accounting for 6% of the total cases of chronic pancreatitis [5]. Therefore, over time, more and more diseases have been included in the spectrum of IgG4-related disease. Considered a variant of Sjogren's syndrome, Mikulicz syndrome consists in the swelling of the submandibular, lacrimal and parotid glands, and is now reclassified as being IgG4-related sialadenitis/ dacryoadenitis [6]. Kuttner tumor is an increase in the volume of submandibular glands in the context of a lithiasis or an infectious etiology, while bilateral damage to the submandibular glands in the absence of a precise etiology should be regarded as pertaining to IgG4-RD [7]. Also, Riedel thyroiditis is now a small part of the many diseases included in the IgG4-RD family. In the initial stages of the disease, the diagnosis is effortless based on classical histopathological criteria, but as the disease progresses and fibrotic tissue replaces the parenchyma, it is troublesome to obtain a definite diagnosis [8]. The affliction of the thoracic aorta in ~10% of the cases is found in IgG4-RD in the form of a chronic sclerosing aorta. The abdominal aorta , pancreas - type 1 autoimmune pancreatitis, biliary tract  may also be involved. Ocular and periorbital tissue may be affected, but the reported frequency appears to be very low due to refraining from performing a biopsy. Eosinophilic angiocentric fibrosis causes pseudotumoral lesions of the eye or upper respiratory tract.Type 1 autoimmune pancreatitis (AIP) is associated with an increased serum IgG4 level and it was the first disease included in the broad spectrum of IgG4- related disease. The assumption that IgG4-RD is a multisystemic disease was raised from the fact that patients with autoimmune pancreatitis also express extrapancreatic manifestations. Fundamentally, IgG4-RD can affect any organ: the pancreas, bile ducts, eyes, salivary glands, lungs, heart, kidneys, skin, aorta, ganglia, meninges, prostate, breast, thyroid, retroperitoneal tissue, etc. [9]. In contrast, for pemphigus vulgaris or idiopathic membranous nephropathy, IgG4 triggers immune-mediated processes that lead to tissue destruction. The histopathological examination performed in these diseases differs substantially from the changes observed in IgG4. The main element is the lymphoplasmacytic infiltrate observed in most cases, with the acknowledgment that in advanced cases of retroperitoneal fibrosis or Riedel thyroiditis, extensive fibrosis virtually replaces the entire parenchyma, and typical changes that support the diagnosis of IgG4 are not found. Lymphocytes are especially CD4-positive T lymphocytes, and the B cells are confined to small cohesive lymphoid aggregates [10]. Eosinophils do not dominate the histopathological picture but justify the patient's allergic history. Many patients have a history of atopy, eczema, asthma, or chronic sinusitis. Besides the abundant cellularity of lymphocytes, plasmocytes and eosinophils, the storiform fibrosis is characterized by short, interlaced, curved collagen beads arranged in a matted and irregularly whorled pattern, which originate from a central point and radiate towards the periphery. Obliterative phlebitis is seen as veins with narrow lumens (sometimes completely stenotic) by the lymphoplasmacytic infiltrate; this process is always found in pancreatic and submandibular salivary glands, but less frequently in the lacrimal glands [2]. The differential diagnosis with a vasculitis is based on the absence of neutrophils, fibrinoid necrosis, or nuclear dust. Histopathological elements that make a diagnosis of IgG4-RD improbable are epithelioid cell granulomas, neutrophil infiltration, giant cells, and necrotic zones [11].Although it has a high concentration in the serum, IgG4 immunoglobulin does not appear to play a central role in the pathophysiology of the disease [12].Most of the plasmocytes are IgG4 positive, a change that can also be found in chronic inflammatory processes. This finding is insufficient to support the diagnosis and should be accompanied by other histopathological findings. A minimal percentage of IgG4-positive plasmocytes for diagnosis has not yet been established, but 30 plasmocytes per high-powered field or an IgG4: total IgG ratio of greater than 40% are suggestive for the diagnosis of IgG4-related disease. A lower cutoff point for IgG4-positive cells is accepted in patients with suggestive pathological findings [3]. For type 1 autoimmune pancreatitis, the sensitivity of serum IgG4 increases depending on the stage of the disease; it should be stated that some studies included patients with type 2 autoimmune pancreatitis with different characteristics at a microscopic level  [13]. No other serum markers have an established role in the diagnosis.Patients with IgG4-RD may have a polyclonal increase in immunoglobulins regarding the IgG4 subclass, a feature that can be useful in reinforcing the diagnosis but is not required to be present or self-sufficient for the diagnosis. A high serum concentration of IgG4 immunoglobulins is found in patients with multiple organ damage. A wrong diagnosis of IgG4-RD is commonly encountered because overestimation is given to the role of serum or tissue IgG4  .Patients with type 1 autoimmune pancreatitis have a clinical presentation similar to that of patients with pancreatic cancer: obstructive jaundice, weight loss, mild abdominal pain. Therefore, the diagnosis was obtained laparoscopically until recently, but with a better understanding of the IgG4-related disease concerning specific imaging changes  a high index of suspicion should be made. A differential diagnosis with primary sclerosing cholangitis is difficult based only on imaging studies and is based on histopathological changes [15].Patients with type 1 autoimmune pancreatitis can have liver damage that includes portal inflammation with or without perihepatitis, obstruction of large bile ducts, portal fibrosis, lobular hepatitis, canalicular cholestasis. The differential diagnosis of autoimmune hepatitis is based on autoantibodies . The gallbladder localization of the disease appears as acalculous cholecystitis, but the discovery is often made after the surgical removal, microscopic examination and staining for IgG4 . Other organs involved can be the pituitary gland, meninges, skin, prostate, pericardium, lymph nodes. Ganglia involvement can be isolated  or generalized; it is important to mention that a lymph node biopsy does not reveal storiform fibrosis commonly found in other locations, and a diagnosis of reactive follicular hyperplasia is usually made, as other diagnoses such as IgG4-RD are not considered. The frequency of localization in various organs is not fully known, as many lesions are asymptomatic such as cutaneous erythematous papular eruptions.The IgG4-related lung disease site comprises the following symptoms: cough, haemoptysis, shortness of breath, pleural effusion, chest pain. Interstitial pneumonia or pseudotumoral inflammatory lesions complete the clinical spectrum. Histologically and radiologically, four types of pulmonary patterns are described: nodular, bronchovascular, interstitial, round ground-glass opacities. Renal disease in IgG4 disease is difficult to distinguish from renal carcinoma. The microscopic examination reveals tubulointerstitial nephritis with diffuse or sometimes localized lymphoplasmacytic infiltration with associated interstitial fibrosis. Clinical features are hematuria, proteinuria, renal failure and other extrarenal manifestations in an overwhelming proportion of cases [17]. The molecule plays a pivotal role in the pathogenesis of diseases such as bullous pemphigus by interacting with desmoglein-1 [18]. Also, in podocytes, the interaction of IgG4 with M-type phospholipase A2 explains the appearance of idiopathic membranous glomerulonephritis. Thrombotic thrombocytopenic purpura is initiated by binding of IgG4 with ADAMTS13  [19]. The definitive role of IgG4 in the disease remains to be established, whether this subclass plays a central role in the pathogenesis of the disease, or is an epiphenomenon in other processes without a direct implication in the pathophysiology of the disease.The pathophysiology of the disease is complex and should start with the description of the IgG4 molecule. IgG4 has a concentration of less than 5% of total IgG immunoglobulins, being the subclass with the most stable interindividual concentration. IgG4 does not activate the classical complement pathway and plays a limited role in the immune process. The production is predominantly controlled by T helper type 2 lymphocytes through secretion of cytokines - interleukins 4 and 13 [20]. IgG4-RD is regarded as both an allergic as well as an autoimmune disorder.Is essential to distinguish IgG4-RD from a lymphoma. Type B lymphomas have a predominantly lymphocytic infiltrate of type B lymphocytes, unlike IgG4-RD where lymphocytes are predominantly T-type. Additional clonal studies are always required for a correct diagnosis. Inflammatory infiltrations adjacent to neoplastic processes are comprised of focal IgG4 positive plasmocytes aggregates, as opposed to their diffuse layout in IgG4-related disease. There is a similarity in the structure of human carbonic anhydrase type II and that secreted by Helicobacter pylori . Patients with autoimmune pancreatitis frequently have antibodies against Helicobacter pylori; thus, these antibodies directed against infectious agents may act as autoantibodies directed against various tissue structures in patients with a genetic predisposition [21].The role of type T and B-lymphocytes is still not fully understood. Finding a CD 4+ cytotoxic T cell remains the main objective in unveiling the main part of the pathophysiology, bearing in mind that these cells are found in the highest concentration within the lesions. This cell population secretes molecules such as interleukine-1, TGF-β or IFN-γ, which play a major role in the fibrosis that characterizes the late stages of the disease. As well, is important to mention that the CD4+ cytotoxic T cells have a molecule on their surface, called SLAMF7, not formerly labeled on T cells, only B cells . One study showed that the prozone effect led to false negative results of IgG4 concentration. The prozone effect is more common in those with active disease, and that is, precisely in patients in whom a correct and rapid diagnosis is crucial to begin the treatment. The concentration of IgG4 is measured by nephelometry; it is carried out by measuring the turbidity in a water sample by passing light through the sample being measured. The amount of light passing through is dependent on the level of aggregates formed by the interaction of the antibodies present in the reagent to the antigens (IgG4) present in the patient sample. If the antigen is present in the solution, the light scatter signal begins to decrease, a phenomenon known as the prozone effect. The prozone effect can be bypassed with the dilution of the sample as to obtain and maintain an antibody level greater than that of the antigen [23].There is contradictory information about a periodic monitoring of serum IgG4 levels to assess the response to treatment. Although there is a decrease in IgG4 concentration after the start of corticosteroid treatment, serum levels remain high in most patients . Only 30% of the cases with persistent elevated IgG4 levels had relapses. Also, 10% of the patients with normal IgG4 levels also experienced recurrences [24]. Other recommendations suggest the treatment should be stopped after 3 months [22]. Corticosteroid therapy is effective but relapses frequently occur. Methotrexate, azathioprine, or mycophenolate mofetil are other agents that can be used but have not been included in clinical trials to study their effectiveness. In patients with a recurrent or refractory disease, rituximab may be used with spectacular results. When rituximab is administered, there is a marked decrease in IgG4 level, with stable concentrations of the other immunoglobulin subclasses, and with clinical remission registered within a few weeks. The effect of rituximab is obtained by lowering the concentration of CD 20 positive B cells that differentiate into IgG4 producing plasmocytes [25]. Patients with longstanding disease, in whom extensive fibrosis has virtually replaced the parenchyma of the affected organ, have a lower rate of response to the glucocorticoid or rituximab treatment.Treatment should be instituted urgently when vital organs are affected, as the disease can evolve to severe organ dysfunction. Not all disorders require immediate treatment. Lymphadenopathy in the disease is often asymptomatic and may persist for decades without clinical consequences. Glucocorticoids are the first line of treatment. The starting dose should be 0.6 mg/ kg of prednisolone for 2-4 weeks, then adjusted to 5 mg/ day over a period of 3-6 months. The treatment can be continued for up to 3 years with a dose of 2.5-5 mg/ day [ Given the response to immunosuppressive therapy, it is hypothesized that IgG4-related disease is most likely an autoimmune disease. Therefore, the IgG4-related disease is a fibro-inflammatory condition that can affect any organ and can lead to the formation of pseudotumoral lesions requiring differential diagnosis with various malignancies. Positive diagnostic criteria are histopathological and require at least two features out of the following three: dense lymphoplasmacytic infiltrate, storiform fibrosis, obliterative phlebitis. IgG4 immunoglobulins weakly bind the complement and are considered to have anti-inflammatory properties. Various autoantibodies have been described in the disease, but their contribution to lesion progression remains to be established. The genetic substrate needs to be properly assessed by clinical studies as well as the possible role of bacteria in pathogenesis through human microbiota studies. Also, it is necessary to identify the target antigens of IgG4 as well as the role of fibroblasts and macrophages in the pathogenesis of the disease. A more thorough insight of the IgG4 immunoglobulin, the distinct aspects of the IgG4-related disease, and the response of this syndrome to treatment, especially B-cell reduction, may return critical understandings of the immune system and other conditions now known to be associated with IgG4.None declared.


Chronotropic incompetence (CI) has been proven to be an important factor in the diagnosis and management of cardiovascular diseases. In this paper, we extend the existing CI parameters and propose chronotropic competence indices (CCI) to describe the exercise response of the cardiopulmonary system. A cardiac chronotropic competence Test (3CT), dedicated to CCI measurement using a wearable device, is also presented. Preliminary clinical trials are presented for the validation of 3CT measurement accuracy, and to show the potential of CCI in the prevention and rehabilitation of cardiovascular diseases. The exercise response of the cardiopulmonary system is one of the most important basic physiological functions . CardiopThe exercise response of the cardiopulmonary system is one of the most important basic physiological functions. Cardiopulmonary exercise testing (CPET) is a well-supported assessment technique to delineate the physiologic system(s) underlying exercise responses. The major concept is to measure the cardiopulmonary system’s exercise limit, represented by maximum oxygen consumption. The addition of ventilatory gas exchange measurements during exercise testing provides a wide array of unique and clinically useful incremental information. However, the complex setup and protocol required and difficulties in testing certain groups of patients have limited the practical use of CPET among clinicians in US  as well In addition to the exercise testing, chronotropic incompetence  is another widely applied index in patients with cardiovascular disease. It is an independent predictor of major adverse cardiovascular events and overall mortality . CI paraIn order to physiologically validate the effectiveness of CI parameters in characterizing heart exercise response, two large-scale studies were conducted. Azarbal et al.  reportedHowever, although CI parameters such as maximum heart rate at peak exercise and heart rate reserve have shown some potential, there is a lack of consistent methodology for determining CI, since the current parameters depend on the exercise types and the status of the person. To overcome this problem, some ad-hoc methods have been proposed. For instance, Wilkoff et al.  proposedchronotropic rate, a newly defined metric. We also present a system for CCI measurement—cardiac chronotropic competence testing (3CT)—in To make the CI parameter a widely usable clinical index, in this article we propose a unified formal definition of CI parameters, which we call chronotropic competence indices (CCI) , by adapCI relies on heart rate response to exercise. Conceptually, this is consistent with oxygen consumption in measuring cardiopulmonary response to exercises. Based on the Fick equation ,(1)VO2mResting Heart Rate  disease . The norChronotropic Rate CR is similar to the “Exercise HR” in the EACPR/AHA Joint Scientific Statement , where iCR is an important parameter to provide personalized quantitative relation between HR and exercise intensity so that target heart rate (THR) can be used to prescribe exercise intensity in exercise training. However, a person’s CR may vary due to medication or rehab progress, and it is recommended to measure CR promptly or monitor CR changes in order to keep exercise prescription updated .Chronotropic Limit Maximal heart rate is usually obtained when reaching peak exercise, which is easily identified during CPET testing. In this case, the normal value of CL is 0.8–1.3. However, when CPET testing or peak exercise is not achievable, then CL normal values can be estimated from various types of exercise. For example, in a 6-min walking test, CL Heart Rate Recovery at 1 min after Exercise tatement  considerThere have been a number of clinical studies on the prognosis value of e et al.  examinedA device produced by SmartHealth Electronics Ltd. called cardiac chronotropic competence testing (3CT) was designed to measure CCI, as shown in A connector cable provides five electrodes resulting in three full-disclosure bipolar ECG channels. The digital sampling rate of the ECG signal is 250 frames per second, with an analog-to-digital (A/D) conversion of 12 bits, while the sampling rate for the 3D accelerometer and 3D gyroscope is 50 Hz. The collected ECG signals and activity signals are sent to the smart phone app via bluetooth. The smart phone app receives and processes ECG and activity signals, detects possible ECG abnormalities, derives heart rate, estimates walking step length, number of steps and walking speed, and calculates exercise intensity in terms of METs according to American College of Sports Medicine (ACSM) formula.With 3CT, the exercise test can be done by adapting a 6-min walking protocol, or on the treadmill or on leg cycle ergometry using a standard graded exercise protocol. The 6-min walking test protocol is adapted to a 1-6-1 testing protocol: the patient is required to stay at resting status for 1 min in order to properly obtain resting heart rate, blood pressure, and other measures. The smart phone app then gives instruction to the patient to start walking, and subsequently every minute a voice instruction to walk as quickly as possible if there is no ECG abnormality detected. The patient can know their walking speed and the distance they have covered from the app interface. After completing 6 min of walking, the patient is required to stop walking and stay at rest for at least 1 min. 3CT then measures the heart rate recovery Throughout the whole testing process, the smart phone app processes signals in real-time, gives testing instructions, and sends all data and testing information to the work station. At the work station, the clinician can observe all signals and status, and sends instructions to the smart phone app. At the end of testing, 3CT sends a report to the clinician for approval. The report consists of a form of CCI values as shown in Since the measurement accuracy of CCI by 3CT depends on its heart rate and walking speed measurement. A 3CT heart rate measurement validation trial has been conducted to compare 3CT equipment with the CPET machine manufactured by Care Fusion, Master Screen-CPET with software version 5.0. Subjects are required to wear ECG leads from both CPET and 3CT, and to walk on the CPET treadmill using the 3CT 1-6-1 minutes protocol. The walking speed during 6 min was 5–6 km per hour. In this setting, both 3CT and CPET ECG devices were under the same condition. The heart rate measurement accuracy of the ECG device depends on the noise level due to exercise.Walking distance measurement validation was done by the standard 6-min walking setting: the subject walked between two poles 100 feet apart for 6 min, and the walking distance displayed by 3CT was compared with manual marks on the ground.In accordance with the ethics policy of Jiangsu Provincial Hospital, 32 healthy volunteers aged between 50 and 65 were recruited, signed an informed consent, and participated in the validation test.x-axis is the mean of two distances, and the y-axis is the difference of the two distances. The systematic bias of 3CT against manual measurement was 0.94 meters; 95% of the difference in distances fell between −6.36 m and 8.21 m.3CT generates walking speed by estimating each step length based on 3D accelerometer and 3D gyroscope data, and accumulates all distances covered by steps. In the walking distance measurement validation test, each subject completed two 6 min walks; there were a total of 64 tests. The distance measurement accuracy was verified at the last cycle, where the subject stopped in between two cones placed at the beginning and end of the 30 m. A Bland–Altman plot was used to compare 3CT distances against manually measured distances. As in In the heart rate validation clinical trial, some subjects did not have experience using a treadmill, and this resulted in large ECG noise. The average heart rate has been considered by averaging over a time period. The reference CPET produces a heart rate by averaging over 15 s. If the acquired ECG signal is too noisy to produce a reasonable heart rate, the system assumes no heart rate change and the heart rate of the last 15 s interval is used for the current. On the contrary, 3CT produces a heart rate every 5 s. For the purpose of consistency, three 3CT heart rates were averaged to generate one heart rate. However, there is still an issue of time synchronization between reference CPET and 3CT when comparing heart rate. The heart rate mean error was calculated by averaging for the whole testing time for each subject and then for all 32 subjects. The mean error and deviation were 0.40 ± 1.43 bpm. The mean error and deviation of chronotropic rate (CR) produced by CPET and 3CT were 0.36 ± 1.32 bpm/MET.A clinical trial was designed to assess the effectiveness of digital rehabilitation delivered to home-based interventions on motor and non-motor outcomes after stroke. Before the intervention, all participants signed an informed consent approved by the institutional ethics policy review board of the Jiangsu Provincial Hospital. Sixty-one participants were recruited from the Nanjing metropolitan area. The main criteria for eligibility included a unilateral ischemic or hemorrhagic stroke within the previous 6 months, with some voluntary movement and preserved cognitive function. The main exclusion criteria were lack of independence before the stroke and antispasticity injection in the hemiparetic upper-extremity since stroke onset. Additional exclusion criteria were adopted to ensure that potential participants could successfully complete study-related interventions without the direct supervision of a therapist.After meeting inclusion criteria, participants completed baseline evaluation. All evaluations were completed by a physical therapist or occupational therapist. The baseline evaluation items included Mini-Mental State Examination (MMSE) , Health Each patient from both groups were evaluated at the beginning and after 3 months using both subjective/qualitative and objective/quantitative measures—namely, the International Classification of Functioning, Disability and Health (ICF), and chronotropic competence indices and 6 Minute Walking Test (6MWT) distance.Patients in the control group were given personalized rehab advice after the baseline test. There were no home rehab services for control group patients. Patients in the rehab group were equipped with a MicroSens rehab assistant, which consists of a rehab app on a smart phone and a wearable device. Based on the evaluation results, the physical therapist or occupational therapist designed a rehab prescription for each patient ,24, and There were 30 patients in the rehab group who completed the whole rehab process, and 31 patients in the control group. Here we mainly care about exercise capability improvement of stroke patients after 3 months of regular exercise training at home. For the purpose of the evaluation of exercise capabilities, we chose four activity-related parameters from ICF [t-test. In t-test shows that the rehab training group gained significantly in all four ICF measures  has been widely studied since 1970, and has been proven to be an important cardiovascular risk factor which is closely related to major cardiovascular diseases, and has great potential in clinical applications. Here we have proposed chronotropic competence indices (CCI) with the purpose of unifying the definition and clinical interpretation and provide the overall profile of heart rate response to exercise process. Cardiac chronotropic competence testing (3CT) is presented, which is dedicated to the measurement of CCI. By adapting a 6-min walking test protocol, the 6 MWT distance and CCI constitute a quantitative evaluation system for the cardiovascular system, especially exercise capabilities.We have also reported a clinical trial for the validation of 3CT, and a clinical trial on the use of CCI in cardiac rehabilitation applications. Both clinical trials are preliminary, and have shown the potentials of CCI and 3CT in cardiac exercise test and cardiac rehabilitations and prevention. The sound scientific basis and clear interpretations of CCI make it widely acceptable. 3CT is very easy to use, simple to maintain, and therefore has the potential to play an important role in the popularization of the cardiac exercise test. This will have a great impact in cardiovascular disease rehabilitation and prevention.Further studies are required to explore the physiological and pathological meanings of CCI. We are planning more clinical studies to investigate CCI applications in cardiac rehabilitation for coronary heart disease patients and heart failure patients.


For its fifth assessment report, the Intergovernmental Panel on Climate Change divided future scenario projections (2005–2100) into two groups: Socio-Economic Pathways (SSPs) and Representative Concentration Pathways (RCPs). Each SSP has country-level urban and rural population projections, while the RCPs are based on radiative forcing caused by greenhouse gases, aerosols and associated land-use change. In order for these projections to be applicable in earth system models, SSP and RCP population projections must be at the same spatial scale. Thus, a gridded population dataset that takes into account both RCP-based urban fractions and SSP-based population projection is needed. To support this need, an annual (2000–2100) high resolution (approximately 1km at the equator) gridded population dataset conforming to both RCPs (urban land use) and SSPs (population) country level scenario data were created. An Essay on the Principle of Population in 1798. Presently, the Population Division of the United Nations (UN) is one of several agencies or institutions that publish global population projections on a country-by-country basis at predefined intervals. The UN’s projections are published in a biennial report called the World Population Prospects (WPP) with the 2015 revision projecting a remarkable 270% increase in the African population between 2015 and 2100 4. Altogether, this will lead to a reallocation of population from rural to urban areas, and create strong incentives for landscape transformation.The size and future trend of the human population on Earth has been a topic of scientific enquiry at least since Thomas R. Malthus wrote et al.5 produced a smoothed continuous map-grid of total population at a global scale for the year 1994. This work was later labeled as the first version of the Gridded Population of the World (GPWv1) by the Center for International Earth Science Information Network (CIESIN). The fourth, and latest, version, GPWv4, was published in 2015  Fifth Assessment Report (AR5) framework which is based on gridded climate projection data.Population data has traditionally taken the form of estimates per administrative unit per unit time. The administrative units are often in the form of regional, national, or sub-national counts with temporal units at best at annual intervals but more commonly 5–10 years. From an analytical perspective this is troublesome. Since administrative units vary in size, shape, and usually are arbitrarily defined any study that uses administrative borders will obtain a very heterogeneous set of observations. Since the 1990s, there have been growing attempts to disaggregate population data into spatially explicit estimates distributed across a regular grid. Tobler, 015 ref.  and incl9 and Shared Socio-Economic Pathways (SSPs) population  urban fractions12 as a starting dataset. Distance to road and to population centers of gravity were used to allow each pixel to be ranked uniquely into urban or no-urban (see below). A complete list of the included data sources can be found in The method can be summarized as a distribution of country level SSP urban and rural population projections onto a 30 arc seconds grid conforming to the urban fraction grid at 30 arc minutes. For this we used the African population for year 2000 at 30 arc-second spatial resolution from the WorldPop Project13 further described in Hurtt et al.9 and the country-specific SSP population and urban fraction scenarios from the SSP database14. The urban fraction data is provided at a spatial resolution of 30 arc-minutes (0.5 degrees or approximately 50 kilometers at the equator) and represents annual projected global land use and land cover patterns until the year 2100. It is developed with a Global Land-use Model (GLM)15 which estimates future land use transitions and patterns within each 30 arc-minute grid cell using an accounting based method by considering a range of parameters 9. The five SSPs and four RCPs produce a set of 20 SSP-RCP scenario combinations that deliver a reasonable basis for future scenarios. However, some combination  are very unlikely to occur in the future16 (p<0.01). Consequently, we used the 15 most probable SSP-RCP combinations according to Engström et al.17.The population distribution for Africa was modeled to follow the RCP-specific urban fraction dataset12 was used as the starting point. The estimates of total number of people per grid cell across Africa are adjusted to match UN population division estimates. The national administrative boundaries dataset from GRUMPv1 (https://www.r-project.org/). To classify each 30 arc-second pixel within each 0.5 degree pixel as urban or non-urban based on their population value the inverse distance to roads and inverse distance to center of gravity (COG) were each rescaled to lie between 1.0·10−5 and 1.1·10−5 and added to the initial dataset  package SDMTools (https://cran.r-project.org/web/packages/SDMTools/). These operations are done to be able to more accurately classify pixels as urban or non-urban based on their unique population value and also to ensure that urban growth will be favored in proximity to population centers or roads. Our procedure requires ranking the pixels as non-urban or urban based on their population values. Hence a maximum of two arc-second pixels within each 30 arc-minute urban fraction grid cell were allowed to have the exact same value. This was achieved by addition of the rescaled inverse distance to road and COG, the result of that is from now on referred to as unique population dataset.The gridded population dataset for Africa for the year 2000 (ver. 3.020) from the WorldPop Project GRUMPv1 ,19 were  dataset . DistancThe unique population dataset for year 2000 is used together with the RCP specific urban fraction for year 2000 to create the urban mask . This iset al.17  and the scripts can be found on GitHub (https://github.com/niklasbokeolen/african_population/).The gridded population datasets were created using R3.3.0  in R 3.3.0 .The high resolution population projections for the RCP and SSP scenario combinations described here can be freely and publicly accessed at the DataGURU web site (Data citation 1) which also allows basic conversion/spatial and temporal cropping, thus enhancing the accessibility. The original data are stored as one geotiff (.tif) for each scenario combination and year with the datatype FLT4S and NA-value as -9999. They are in a longitude latitude projection with WGS84 as the datum and are created with the function writeRaster within the raster package  of 1.0.The technical validation of the dataset is performed by comparing the SSP 1 country populations with the gridded population dataset (for SSP1/RCP 4.5) aggregated to country levels. This is done for year 2005 since both SSP population projections and RCP land use projections do not deviate until after that year. Accordingly, we performed the technical validation on only one RCP–SSP combination. We show that all the population is accounted for and every country lies on the one to one line  with a c2>0.8) for most of the countries and administrative levels indicating that the spatial pattern is captured between the regions. This indicates that the method is well suited to capture the spatially pattern. However, due to considerable differences in the total population between GPWv4 and the SSP population data we do not expect the change to match perfectly for all regions.To further evaluate the created dataset we compared the 2000 to 2005 population change for the created gridded dataset with the change for UN (2015) adjusted Gridded Population of the World version 4 (GPWv4). This was done for a sample of six African countries  representing a wide variation in population density and spatial distribution. The population was aggregated to level 2 administrative regions within each country and only one SSP/RCP combination was used since the projections do not deviate until after year 2005. The result of the comparison to GPWv4 can be seen in −5 and 1.1·10−5 we argue that this will only have an effect for pixels that were equal in the initial WorldPop dataset. Pixels (30 arc-seconds) with unequal population values in the initial dataset will have a very low probability of being affected by this small addition based on the distance to road.We used a deterministic method to produce the gridded population projections which means that the level of uncertainty in the created dataset is originating from uncertainty in the input data . We woulHow to cite this article: Boke-Olén, N. et al. High-resolution African population projections from radiative forcing and socio-economic models, 2000 to 2100. Sci. Data 4:160130 doi: 10.1038/sdata.2016.130 (2017).Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.


Bevacizumab, an anti-VEGF monoclonal antibody, has recently emerged as a new option for severe forms of hereditary hemorrhagic telangiectasia (HHT). Its utilization in this orphan disease has rapidly spread despite the lack of randomized trials and international guidelines. The objective of this study is to report the main clinical data  of HHT patients treated by intravenous bevacizumab in France.Retrospective observational study of HHT patients treated with bevacizumab for a severe form of the disease in the 14 centers of the French HHT network.Forty-six patients (median age: 68 years) were treated between March 2009 and May 2015. Ten patients were treated for high output cardiac failure, 20 patients for severe hemorrhages and 16 for both indications. The standard protocol (6 infusions of 5mg/kg every 2 weeks) was initially used in 89% of the cases but diverse strategies were subsequently applied. A clinical improvement was noted by the referent physician for 74% of the patients with a median effect’s duration of 6 months. Wound healing complications led to 2 amputations. Arthralgia/arthritis and arterial hypertension occurred in 5 patients each. One third of the patients were dead at the time of the final update, coherently with age and the poor prognosis of these highly symptomatic patients.Intravenous bevacizumab seems to provide a clinical benefice in severe HHT patients. Precautions concerning wound healing and vascular pathologies must be respected. Prospective double blinded versus placebo trials are needed. ENG, ALK1 and SMAD4) belonging to the BMP/SMAD signaling pathway. Data suggest that it results in an imbalanced state between pro- and anti-angiogenic factors, including a high level of Vascular Endothelial Growth Factor (VEGF), leading to dysregulation of the neo-angiogenesis [Hereditary Hemorrhagic Telangiectasia (HHT) is a worldwide vascular genopathy with an incidence rate estimated from 1/5000 to 1/8000. This autosomic dominant disorder is caused by the haplo-insufficiency of at least 3 genes , reducing the transfusion needs or the number of life-threatening hemorrhages by epistaxis or GI bleeding (Severe Hemorrhage (SH) group) or both (HCF+SH group). Standard protocol was considered as 6 administrations of 5 mg/kg of bevacizumab, each spaced by 14 days. Re-treatment’s procedure was defined by a new administration sequence in case of symptom recurrence after the end of the initial treatment. Maintenance therapy was defined by systematic and planned administrations after the initial treatment, independently from the intensity of HHT-related symptoms. To objectively assess the treatment efficacy, physicians were requested to detail, if available, NYHA class of dyspnea, cardiac index, hemoglobin level, transfusion frequency and epistaxis duration, before and after treatment. A global judgment of the clinical efficacy  was also systematically asked to the physician after having reviewed their files with patient’s statements, physical signs, laboratory results, imaging and associated treatment. A minimum period of three months after the first injection was required to establish this assessment. All clinically relevant events occurring after the first injection were considered as adverse events and registered, whatever the time interval between the treatment and the event. Exceptions were made for GI bleeding and epistaxis, considered as usual HHT hemorrhagic events.Once completed and returned, all the forms were reviewed by AG or SR. Complementary data were directly asked to the physician for clarification if required. In case of death, the main cause and the associated circumstances were discussed between the referent physician and AG or SR.The current status  of all included patients was updated between July and August, 2015.Patients and treatments characteristics are presented in tables. Quantitative variables are described with median, minimum and maximum values. Categorical variables are given in absolute number and percentage. Statistical comparisons between HCF, SH and HCF+SH groups were judged non pertinent given the objective and the size of the study. Potential predicting factors of efficacy were assessed by univariate models of logistic regression.https://doi.org/10.17026/dans-z7r-d74x. A p-value below 0.05 was considered as significant.A specific R script was built to generate all the statistical data (R version 3.1.2 (2014-10-31)) . This scPatients having medical care through the French HHT network give a written consent for epidemiological studies prior to be included in the national HHT database (CIROCO). This computerized database is registered and approved by the French National Committee for Information Technology and Freedom (CNIL).All patients were informed by their referent physician of the benefits and the risks potentially associated with bevacizumab and gave informed consent. In accordance to the French law (Loi française n° 2004–806 du 9 août 2004 relative à la politique de santé publique et ses décrets d’application), specific authorization by an ethic committee is not mandatory for a retrospective non-interventional protocol.Forty-six patients received intra-venous bevacizumab between March 2009 and May 2015. All of them were included in the study and analyzed. The median duration of the treatment was 106 days, corresponding to a total exposition of 51 patient-years.With a median age of 68 years and a well-balanced sex ratio , the cohort was characterized by a large majority of mutated ALK1 carriers (80%), with hepatic (89%) and digestive (63%) involvements. One patient had received a hepatic transplant for HHT-related disease 15 years before. The most common comorbidities were atrial fibrillation (24%) and arterial hypertension (22%). About one quarter (24%) of the patients had previously experienced at least one venous thrombo-embolic event and a similar proportion had a history of severe sepsis .The standard protocol was the most often used (89%) for initial treatment. A treatment continuation was decided for about the half of the cohort (54%) (re-treatment or maintenance therapy). Twelve patients were treated for more than one year. Four patients received bevacizumab injections during more than 4 years.Three patients underwent orthotopic liver transplantation after the bevacizumab treatment. They were 46, 53 and 63 years old, all treated for HCF and considered as improved by bevacizumab. One of them had experienced an adverse event (haemoperitoneum) leading to the discontinuation of the treatment. The time between the last injection of bevacizumab and the surgical procedure was 11, 15 and 17 months. No specific concerns were raised after the transplant procedure, especially concerning wound healing.Objective measures of efficacy after treatment  were very heterogeneous in terms of modalities and timing of evaluation. In some cases, data were missing. For these reasons, we were not able to adequately perform statistical analysis of the objective efficacy parameters. The clinical appreciation of efficacy by the referent physician was obtained for all cases. Improvement of the HHT-related symptoms was noted in 74% of the whole cohort. The median duration of efficacy was 6 months . In univariate, no patient characteristics were found to be significantly associated with bevacizumab efficacy. No improvement was observed in both cases of a twin’s pair, treated at an interval of 15 months.The most frequent adverse event was infections (22%) including 3 pneumonias, 1 bacteremia, 1 osteitis, 1 urinary tract infection, 1 epididymitis, 1 ophthalmic infection, 1 herpes zoster, 1 sepsis of undetermined origin. Arterial hypertension and rheumatologic symptoms were less frequent (11% each). Wound-healing complications occurred in 3 patients, 2 of them underwent leg amputation and the third developed of severe bedsores. Loss of efficacy under prolonged therapy (maintenance or re-treatment) was reported for 2 patients but no exacerbation of HHT-related symptoms was observed after treatment cessation. No case of proteinuria was notified. Fifteen (33%) patients died during the follow-up.Details on the death cases having occurred during the follow-up are reported in With an improvement of 74% of the whole cohort, our study strongly suggests a clinical benefit of bevacizumab for HHT patients. This result is only based on physicians’ judgments since the objective parameters of efficacy were unfortunately not exploitable . The overall assessment of an expert physician is considered as a reliable and relevant scoring system in many complex diseases. By example, the PGA  in lupus and the IGA  in atopic dermatitis are well-recognized scores based on this principle –10.Bevacizumab seems to be as effective in severe hemorrhage as in HCF. This is consistent with the central role of the VEGF dysregulation in HHT .Bevacizumab appears to have an only suspensive effect. All patients have experienced symptoms recurrence after the discontinuation of the treatment, but after a large range of time (1 to 20 months). The same phenomenon has recently been reported in the long term study of the patients included in the French open label trial  and is cWe observed that about one quarter of the patients did not exhibit a clinical improvement. This is higher than the 17% reported by Dupuis-Girod et al. in a prospective trial  but our Orthotopic liver transplant remains the only curative option in case of severe hepatic involvement. Three of our patients were treated by bevacizumab prior to the transplant procedure. No specific problems were reported but a long delay between the last injection and the surgery was respected. Bevacizumab seems to be able to improve the pre-transplant clinical status and could be a valuable option for frail candidates to surgery. It also involves a risk of missing the “transplant window” for patients under 65 years and the decision to treat with bevacizumab must be carefully considered in this context .The study was not designed to properly analyze the medico-economic impact of bevacizumab. Nevertheless, for the most highly responsive patients of the cohort, this treatment is an obvious cost-effective option given the reduction of overall hospital care costs related to acute hemorrhagic events and heart failure. This economic benefit has also been suggested by others studies ,18 and iOne important contribution of our study is to provide a global view of the adverse events associated with bevacizumab in this chronic and non-oncologic context.Blood pressure elevation has concerned 5 patients (11%). It is an expected side effect of bevacizumab and can be most of time easily managed . ArthralAmong the various adverse events reported here, the wound healing complications were highly problematic and have led to two cases of lower limb amputation. This process appears to be importantly disturbed by bevacizumab and special attention to skin wound and surgery should be kept in mind. In the oncologic context, it is recommended to stop bevacizumab 6 to 8 weeks before the surgery and to restart it at least 4 weeks after and only if the wound is totally healed . In the In this cohort, 33% of patients died during the follow up, essentially from usual HHT complications: end-stage heart failure, sepsis and cataclysmic hemorrhage. It has occurred either by unresponsive patients or after a long time after treatment cessation (up to 55 months). Mortality studies in HHT patients are scarce. In UK, diagnosis of HHT is associated with a 3-years reduction in median age at death . In contOur work suffers from limitations related to its retrospective, non-interventional and open design. The retrospective data collection and the diversity of participating centers have not allowed us to obtain standardized objective parameters for the efficacy assessment. Nevertheless, we think that our data honestly reflect the daily practice and provide valuable information to apprehend the risk/benefit ratio of this new drug. It constitutes a preliminary step to conducting a large, prospective, and randomized versus placebo trial, which is deeply needed.The lack of consensual modalities of bevacizumab use, especially for long term treatments, is another concern. It has generated a high level of heterogeneity in our data. Most of physicians have initially followed the "standard protocol" of 6 injections of 5mg/kg, by analogy with the oncological use and the prospective trial ,38 and cIn the field of rare diseases, therapeutic innovations are rare and challenging events. This multicenter retrospective study of 46 patients is, to our knowledge, the most important retrospective cohort of HHT patients treated by intra-venous bevacizumab. It supports a clinically pertinent therapeutic effect for highly symptomatic patients. Wound’s healing complications are a major limitation and should be considered as a contraindication. This collective experience leads us to provide some basic guidelines for the French “temporary use recommendations” of bevacizumab for HHT patients, summarized in S1 Table(DOCX)Click here for additional data file.