Point-of-care antigen-detecting rapid diagnostic tests (RDTs) to detect Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) represent a scalable tool for surveillance of active SARS-CoV-2 infections in the population. Data on the performance of these tests in real-world community settings are paramount to guide their implementation to combat the COVID-19 pandemic. We evaluated the performance characteristics of the CareStart COVID-19 Antigen test (CareStart) in a community testing site in Holyoke, Massachusetts. We compared CareStart to a SARS-CoV-2 reverse transcriptase quantitative polymerase chain reaction (RT-qPCR) reference, both using anterior nasal swab samples. We calculated the sensitivity, specificity, and the expected positive and negative predictive values at different SARS-CoV-2 prevalence estimates. We performed 666 total tests on 591 unique individuals. 573 (86%) were asymptomatic. There were 52 positive tests by RT-qPCR. The sensitivity of CareStart was 49.0%  34.8–63.4) and specificity was 99.5% (95% CI 98.5–99.9). Among positive RT-qPCR tests, the median cycle threshold (Ct) was significantly lower in samples that tested positive on CareStart. Using a Ct ≤ 30 as a benchmark for positivity increased the sensitivity of the test to 64.9% (95% CI 47.5–79.8). Our study shows that CareStart has a high specificity and moderate sensitivity. The utility of RDTs, such as CareStart, in mass implementation should prioritize use cases in which a higher specificity is more important, such as triage tests to rule-in active infections in community surveillance programs. In addition to preventive measures such as social distancing, mask wearing, and vaccination, pillars of pandemic control rely on tools to rapidly identify cases and monitor transmission3. Molecular testing methods based on reverse transcription quantitative polymerase chain reactions (RT-qPCR) remain the backbone of many testing programs globally4. However, RT-qPCR-based testing is heavily influenced by supply chain restrictions, need for trained personnel and central laboratories, and relatively long turnaround times, particularly in resource-constrained settings5. Therefore, it is still challenging to scale up RT-qPCR tests for population surveillance and the timely detection of the large proportion of asymptomatic SARS-CoV-2-infected carriers6. Rapid detection of SARS-CoV-2 infected individuals allows for faster clinical intervention and implementation of public health measures such as isolation and contact-tracing, to prevent forward transmission7.The Coronavirus disease 2019 (COVID-19) pandemic caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is the most significant infectious disease pandemic in the last century8. Furthermore, decentralized access to RT-qPCR testing remains sparse in resource-constrained communities9. The low cost of antigen-detecting RDTs, short turnaround times and ease of use make them excellent candidates to increase their accessibility for large-scale implementation in varied community settings10.Rapid antigen-detecting diagnostic tests (RDTs) for COVID-19, many of which can yield actionable results in turnaround times often below 20 min, require little laboratory capacity, and can be performed easily by non-laboratory personnel11. Many of the antigen-detecting RDTs received Emergency Use Authorization (EUA) approvals by the Food and Drug Administration (FDA)12. Indeed, over the last year, rapid diagnostic tests have become more widely used for the diagnosis of COVID-19 in diverse settings outside the hospital, including at-home testing. However, evaluations to receive EUA were performed by demonstrating accuracy in symptomatic individuals only13. This narrow indication for antigen-detecting RDTs raises their limited utility in detecting SARS-CoV-2 infection in asymptomatic carriers. In fact, several independent evaluations demonstrate the decreased sensitivity of antigen-detecting RDTs in asymptomatic RT-qPCR positive individuals compared to those with symptoms17. In the United States, studies thus far have focused on 3 RDTs: Quidel Sofia18, BD Veritor19 and Abbott BinaxNOW20. On March 31st, 2021, the FDA also authorized these tests for home use, raising concerns about misinterpretation of false negative results21. Therefore, evidence to establish their performance characteristics to guide their implementation in real-world settings is even more urgent now.Since the pandemic’s onset, several antigen-detecting RDTs have been developed for the detection of SARS-CoV-217. We evaluated CareStart in asymptomatic and mildly symptomatic individuals presenting for routine testing at one of the ‘Stop the Spread’ free community testing sites in Holyoke, Massachusetts22. Public health messaging for testing at these community testing sites targeted asymptomatic individuals. We evaluate the sensitivity, specificity, and positive (PPV) and negative predictive values (NPV) as a function of different prevalence scenarios.In this study, we evaluated the Access Bio CareStart COVID-19 RDT (CareStart), a chromatographic antigen-detecting lateral flow immunoassay that received EUA by the FDA on October 8th, 202022. The testing site opened three days a week. Individuals who presented to the site during testing hours were approached by our research staff who explained the nature of the study, risks, benefits, and answered any questions before inviting individuals to participate in the study. Informed verbal consent, in lieu of written consent, was obtained and documented by the research staff from participants standing in testing lines to collect a second anterior nasal swab as well as from guardians of minors below 18 years of age, from whom verbal assent was also obtained. The participants were treated in accordance with Good Clinical Practice guidelines and the Declaration of Helsinki. The study protocol was approved by the Partners Institutional Review Board (Protocol ID: 2020P003892).This was a prospective evaluation using convenience sampling of asymptomatic and mildly symptomatic individuals presenting for routine testing for COVID-19. The study was performed between January 6 and February 26, 2021, at the Holyoke “Stop the Spread” walk-up testing site, a free Massachusetts public testing program, which targets asymptomatic individuals23: cough, sore throat, chills, shortness of breath, fever, muscle aches or soreness, nausea, vomiting or diarrhea, decreased sense of smell or taste, loss of appetite, general weakness or fatigue, or headaches. The survey also captured prior COVID-19 testing and potential exposures. Each test was assigned a unique anonymous ID. Data collected was inputted into a secure Research Electronic Data Capture (REDCap) database on encrypted tablets. We used the demographic information and specimen numbers to match the RDTs result with the RT-qPCR data collected at the Broad Institute Clinical Research Sequencing Platform (CRSP) as performed in other studies24.After enrollment in the study, our study staff implemented an intake questionnaire capturing information on participant demographics, presence or absence of symptoms based on case definitions from the Council for State and Territorial Epidemiologistshttps://sites.broadinstitute.org/safe-for-school/result-code-information. Briefly, the assay is a multiplexed RT-qPCR assay, which runs up to 40 cycles. The assay targets the N1 and N2 genes, using the CDC primers, with an RNase P (RP) gene as an internal control gene for test validity25. Any cycle threshold (Ct) value for either N1 or N2 below 40 is considered a positive result, which is how we define SARS-CoV-2-positive individuals to benchmark the performance of the CareStart RDT.The sample was collected at the city testing site by personnel who had received a brief training on performance of the RDT but were not trained health care providers or diagnostic specialists. We used dry anterior nasal (AN) swabs: Puritan 6″ Sterile Standard Foam Swab with Polystyrene Handle . Both anterior nares were swabbed 2 times (5 rotations in each nostril), once for RT-qPCR testing and once for the RDT sample. For practical reasons, the swabs for RT-qPCR and RDT were not always collected in the same order. Both samples were placed inside closed test tubes. The RT-qPCR sample was transported to the Broad Institute at the Massachusetts Institute of Technology. The second anterior nasal swab sample was transported to a nearby testing station and the RDT was performed within an hour of sample collection. The RT-qPCR testing results were interpreted according to the publicly available rubric for the Broad Institute COVID-19 testing program: 26, took pictures of the tests, read the result as positive or negative, and captured into the electronic data entry forms. Participants with a positive RDT were contacted by phone per request from the Department of Public Health within a twenty-four-hour period, informed of their result, and advised to isolate until they received their RT-qPCR result.The CareStart device came with instructions for use and diagrams. The study staff received a one-hour training prior to the study and practiced the RDT on positive and negative control samples provided in the kit. One operator performed the test at a workstation following the CareStart manufacturer’s instructions for use (IFU)17.The gold standard reference used was the SARS-CoV-2 RT-qPCR laboratory developed test through the Broad Institute CRSP, which is approved by the FDA under EUA. The test provides two cycle threshold (Ct) values, one for the nucleocapsid (N2) gene, and one for an internal positive control RNaseP gene. We compared the sensitivity of CareStart against both the qualitative binary RT-qPCR results and the Ct values of the N2 gene amplification reaction, as previously describedU test. 95% Pearson-Clopper confidence intervals (CI) were calculated for sensitivity and specificity estimates. Since RDTs have been reported to have high accuracy among symptomatic individuals17, we also tested whether presence of symptoms would increase the sensitivity of the CareStart RDT. Statistical analyses were conducted using R V3.6.0 (R Core Team 2020).We calculated sensitivity, specificity, PPV and NPV of the RDT from 2 × 2 contingency tables using RT-qPCR as the gold standard reference. Sensitivity and specificity were further stratified and compared by presence of symptoms and quantitative Ct values. Median Ct values were compared using the non-parametric unpaired Mann–Whitney We performed 666 CareStart RDTs from participants who provided verbal consent at the walk-up testing site. Of these, 4 tests were excluded because test vial caps were malformed and the operator was unable to load the RDT, resulting in 662 tests included for analysis. The 662 tests performed were comprised of 588 unique participants. Tables . 60 partp < 0.0001) .To determine the accuracy of the CareStart RDT, we calculated the concordance between the RDT and RT-qPCR Table . Thirty-1) Table . Due to 1) Table A,B. In a1) Table C,D. Sens27. The Ct values of samples recorded as negative using the CareStart RDT were significantly higher than positive counterparts  than what was reported in the FDA package insert (87.2%), which was restricted to 39 symptomatic individuals within 5 days of symptom onset32, had a clear impact on the sensitivity of the CareStart RDT. Concordant results showed lower Ct values whereas discordant results had higher Ct values. Consistent with this, the CareStart RDT sensitivity improved with a RT-qPCR positivity Ct cut-off of < 30. These data suggest that the CareStart RDT positivity suggested a state of higher viral load, which correlates with infectivity of cells in vitro33 and likely transmissibility. The viral load at the time of testing depends on multiple factors including host vaccination status, host immunity, viral variants and replication kinetics, local epidemic curves, and the method and quality of sample collection. For example34, individuals vaccinated with the Pfizer/BioNtech BNT162b2 vaccine with breakthrough SARS-CoV-2 infections have been reported to show higher Ct values post-vaccination than unvaccinated counterparts, which correlates with lower viral loads35, suggesting that vaccinated individuals with breakthrough SARS-CoV-2 infections would be more difficult to detect by antigen-detecting RDT with similar performance characteristics to CareStart. Further studies are needed to evaluate the performance characteristics of CareStart and other RDTs in these different scenarios.The RT-qPCR cycle threshold (Ct), a proxy for lower viral load, as reported in other evaluations27. Samples from these recently infected individuals had low Ct values, and were thus more likely to transmit the virus33. Though our data is underpowered to evaluate performance characteristics in the setting of repeat testing, this limited sample supports the usefulness of serial rapid antigen testing in detecting recent infections and guiding the implementation of containment measures36. This is supported by studies with other RDTs, for example, a study showing that daily testing increased the sensitivity of Quidel SARS Sofia antigen fluorescent immunoassay (FIA)37. The public health benefits of serial testing with RDTs should be studied further.Although our sample of repeat testers was limited, it suggested that individuals who recently converted from negative to positive RT-qPCR test, i.e. recently acquired SARS-CoV-2 infection, were easily detectable by the CareStart RDT. Recently infected individuals have been shown to be more contagious20. Second, it remains possible that we overestimated the sensitivity of the CareStart rapid test by using anterior nare swabs instead of nasopharyngeal swab samples for the qPCR reference, which may be a slightly less sensitive gold-standard compared than nasopharyngeal swabs39. Third, since rapid testing in the USA has primarily transitioned from community-based testing to over the counter direct-to-consumer testing40, it is important to develop tools to facilitate the interpretation of the positive predictive value of a test with low or moderate sensitivity. We previously published a tool to facilitate the interpretation of serological lateral flow assays, that translates the test accuracy and community prevalence into a PPV: https://covid.omics.kitchen/41, which can be applied to rapid tests. Overall, the high specificity of the test increases its utility as a rule-in triage test, since false positive results are unlikely, but it is important to emphasize that false negatives are still likely. Finally, the study was conducted in Jan-Feb 2021, when the major lineage in New England, USA were predominantly the Wuhan or alpha variants42. Hence, it is unclear if the CareStart RDT is less sensitive for detecting the subsequent delta or Omicron variants and sub-lineages. Finally, the study was conducted at the time when vaccination against SARS-CoV-2 was low, which may affect the generalizability of these findings. Further studies are needed to evaluate the performance characteristics of this and other SARS-CoV-2 RDTs in these different scenarios.This study has several limitations. First, we had limited control over or ability to monitor the order by which the two bilateral nasal swabs were collected because of embedding the study in a ‘real world’ testing program. It is possible that performing the PCR swab first may decrease the available viral load for the antigen test. However, a recent evaluation of the Abbott BinaxNOW suggested that the order of swabs had little impact on the test resultIn conclusion, RDTs such as CareStart, can support SARS-CoV-2 testing efforts in minimally symptomatic or asymptomatic individuals. However, the impact of the limited sensitivity of these tests on their positive predictive values warrants caution. The moderate sensitivity of these tests means that some potentially infectious individuals may be classified as SARS-CoV-2-negative. Therefore, implementing RDTs for travel, home testing, or to guide re-openings of schools and workplaces should be interpreted with caution and the utility of RDTs in each of these use cases should be carefully evaluated. Furthermore, implementation studies to analyze their usefulness and acceptability by both users and providers are necessary.Supplementary Information.


An increasing number of patients with cancer are being treated with immune checkpoint inhibitors. Consequently, the incidence of immune checkpoint inhibitor-related myocarditis has been increasing. Nonetheless, the diagnostic criteria for the immune checkpoint inhibitor-related myocarditis have not been sufficiently established. Therefore, the real-world incidence or prevalence of immune checkpoint inhibitor-related myocardial damage remains unknown. This was a single-center cohort study that included 100 patients admitted for immune checkpoint inhibitor therapy for any type of cancer. The patients underwent monthly measurement of cardiac troponin I and N-terminal pro-brain natriuretic peptide levels with electrocardiography. Additionally, echocardiography was performed every 3 months. Our protocol was continued until 6 months after the initiation of immune checkpoint inhibitors. We defined immune checkpoint inhibitor-related myocardial damage as an increase in cardiac troponin I levels by >0.026 ng/mL and/or a decrease in the left ventricular ejection fraction by >10% to <53% on echocardiography. The mean patient age was 64 years; 71% were men. The most commonly used immune checkpoint inhibitor was nivolumab (47%), followed by pembrolizumab (29%). Overall, 5% of patients received combination therapy. Among 100 patients, 10 (10%) were diagnosed with immune checkpoint inhibitor-related myocardial damage. Among them, five patients underwent endomyocardial biopsy. Of these patients, four were histopathologically observed to have lymphocyte infiltration in their myocardium. In conclusion, serial cardiac troponin I measurement during immune checkpoint inhibitor treatment could help detect early-phase myocardial damage. The prevalence of myocardial damage was much higher than previously expected. The prognosis of various cancers has improved owing to the development of novel anticancer drugs categorized as immune checkpoint inhibitors (ICIs) . RecentlThe study protocol and consent forms were approved by the local ethics committee of Osaka International Cancer Institute . All patients provided written informed consent prior to their inclusion in the prospective study.In this prospective cohort study, we comprehensively screened consecutive patients with any type of cancer scheduled for admittance to our hospital with the help of a medical clerk between March 2020 and September 2020 to initiate ICI treatment based on the clinical state. As the present study involved all the clinical departments in our institute, it was challenging to collect enough samples prospectively. Therefore, as a pilot study, we set the sample size at approximately 100 patients. Overall, 107 patients who provided informed consent were enrolled in this study. Among them, we excluded five patients who dropped out of the study by their requests and two patients who had missing data for cardiac troponin I (cTnI) during the follow-up period. Among the remaining patients, we included three patients who missed undergoing either electrocardiography or echocardiography once during follow-up because they did not have any signs of myocarditis. Finally, 100 patients were enrolled in this study. Case numbers are detailed in all figures and tables.The enrolled patients underwent measurements for the cTnI and N-terminal pro-brain natriuretic peptide (NT-proBNP) levels and electrocardiography before ICI therapy initiation, and they were observed on follow-up once a month. Echocardiography was performed once before ICI therapy initiation and subsequently every 3 months. Patients were observed on follow-up for 6 months after ICI therapy initiation. The permissive error was 1 week for the first month, 2 weeks for the second and third months, 3 weeks for the fourth month, 4 weeks for the fifth month, and 6 weeks for the sixth month, depending on the clinical course of each patient receiving ICI. Patients were observed during follow-up until the sixth month, even if ICI therapy was discontinued for any reason. However, follow-up was discontinued when patients died or stopped treatment to transition to palliative care or the best supportive care. Therefore, cancer prognosis, especially for less than 6 months, could be potentially biased. Echocardiography data were obtained using an IE 33 imaging device . Left ventricular ejection fraction (LVEF) was measured using the modified Simpson method. Global longitudinal strain (GLS) was assessed using QLAB15 (Philips). For patients who were clinically suspected of having ICI-related myocarditis, cardiac magnetic resonance (CMR) imaging  and/or endomyocardial biopsy (EMB) was performed if medical conditions were suitable.We defined “ICI-related myocardial damage” as an increase in the cTnI levels and/or a decrease in the LVEF. The cut-off value for cTnI was set at >0.026 ng/mL in accordance with the manufacturer’s reference . The other definition was a decrease in the LVEF by >10% to <53% on echocardiography , 7–10. FBuffered formalin-fixed and paraffin-embedded (FFPE) tissues obtained from endomyocardial biopsies were subjected to immunohistochemistry staining. FFPE tissues were cut into 4-μm-thick sections and stained with hematoxylin, eosin, and Masson’s trichrome stains for morphological observation. The immunohistochemical study was performed using primary antibodies against CD3  for T lymphocytes, CD4  for helper T lymphocytes, CD8  for cytotoxic T lymphocytes, and CD68  for macrophages. In addition, a commercially available tenascin-C antibody  was also used. We used BOND-III automated immunohistochemical staining system . After immunostaining, CD3-, CD8-, and CD68-positive cells were counted by two pathologists in a high-power field in the most intensively lymphocyte-infiltrated area. Each sample was classified using the grading system reported by Palaskas et al. .Overall, 100 patients were included, and their data were analyzed . PatientBased on our definition, we determined that ICI-related myocardial damage occurred in 10% (10/100) of our population, and the prevalence was 0.014 cases per person-month. We performed EMB in five patients with ICI-related myocardial damage. As a result, 4% of cases (4/100) were histopathologically diagnosed with myocardial inflammation. We identified 10 patients showing an increase in the cTnI levels and/or a decrease in the LVEF Tables  and 3. WIn the present study, a total of four patients had a history of Adriamycin treatment , and theAccording to the results, the prevalence of ICI-related myocarditis was assessed to be 7% as per the ESC criteria , we observed various gene expression patterns in each patient in both the myocardial-damaged group and the control group , and the expression was relatively higher than that in other control individuals; however, each patient with myocardial damage had a completely different gene expression pattern. Furthermore, in the representative genes shown in S3 Fig in In fact, five possible pathophysiological mechanisms of irAEs have been reported . Among tThere has been an increasing evidence supporting immunosuppression therapy for fatal fulminant myocarditis or definite myocarditis , 13, 26.Our study had some limitations. First, as the present study had a small number of samples, we could not statistically analyze the risk factors or prognosis. For the diagnosis of ICI-related myocardial damage, we included approximately the half of patients who could have EMB and CMR because of the clinical or social situation. In addition, the follow-up period had been set as 6 months; late-onset myocarditis could have been observed after the follow-up period. Furthermore, in the present study, the effects of concomitant chemotherapy and/or TKI/VEGFI in addition to ICI were not thoroughly assessed.Serial cTnI measurement during cancer treatment with ICIs could aid in the detection of low-grade myocarditis or early-phase myocardial damage. The prevalence of myocardial damage was much higher than expected in previous studies. For most patients, the increase in the cTnI levels was attenuated by the discontinuation of ICI therapy. Although it is essential to recognize that the increase in cTnI levels could reflect the beginning of ICI-related myocardial damage, it is more important to treat patients through close cooperation between oncologists and cardio-oncologists.S1 File(DOCX)Click here for additional data file.


As motor disorders are increasingly recognized as part of the clinical spectrum, the current study aimed to describe motor phenotypes caused by genetic FTD, quantify their temporal association, and investigate their regional association with brain atrophy.Frontotemporal dementia (FTD) is a highly heritable disorder. The majority of genetic cases are caused by autosomal dominant pathogenic variants in the chromosome 9 open reading frame 72 , 143 GRN (112 presymptomatic), and 57 MAPT (43 presymptomatic) pathogenic variant carriers. Principal component analysis revealed 5 motor clusters, which we call progressive supranuclear palsy (PSP)-like, bulbar amyotrophic lateral sclerosis (ALS)-like, mixed/ALS-like, Parkinson disease (PD) like, and corticobasal syndrome–like motor phenotypes. There was no significant group difference in the frequency of signs of different motor phenotypes. However, mixed/ALS-like motor signs were most frequent, followed by PD-like motor signs. Although the PSP-like phenotype was associated with mesencephalic atrophy, the mixed/ALS-like phenotype was associated with motor cortex and corticospinal tract atrophy. The PD-like phenotype was associated with widespread cortical and subcortical atrophy. Estimated time to onset, genetic group and their interaction influenced motor signs. In c9orf72 pathogenic variant carriers, motor signs could be detected up to 25 years before expected symptom onset.A total of 322 pathogenic variant carriers were included in the analysis: 122 These results indicate the presence of multiple natural clusters of motor signs in genetic FTD, each correlated with specific atrophy patterns. Their motor severity depends on time and the affected gene. These clinicogenetic associations can guide diagnostic evaluations and the design of clinical trials for new disease-modifying and preventive treatments. The associated clinical syndromes classically affect personality and social behavior or language.8-10Because of the clinical heterogeneity, a precise knowledge of clinical presentations correlated with genetic subgroups is essential to guide diagnostic workup and assist decisions regarding genetic testing. It will also become increasingly important as disease-modifying drug trials are underway in each of the 3 genetic FTD groups.11 Parkinson disease (PD), progressive supranuclear palsy (PSP), or corticobasal syndrome (CBS).13 We propose that the anatomic distribution of pathologic brain changes determines the clinical phenotype. This distribution can be defined in terms of brain regions14 or functionally in terms of degeneration of the first and second motor neuron and basal ganglia.15 The identification of motor structure-function relationships in sporadic FTD is hindered by uncertainty of the molecular pathology. This challenge is addressed by the analysis of genetic FTD.Patients can also present with a wide range of motor signs, including those commonly associated with amyotrophic lateral sclerosis (ALS),14 or in the form of case reports or case series.16 Longitudinal data on motor phenotypes are lacking. We aimed to describe motor phenotypes in genetic FTD, from the Genetic Frontotemporal dementia Initiative (GENFI). We examined motor sign occurrence in the course of the disease, including the presymptomatic phase, and tested whether structural brain changes are associated with particular motor phenotypes.Although there is a wide literature covering behavioral and linguistic features in FTD, detailed phenotypic characterization of motor disorders is mostly in sporadic casesThe study was performed according to the Declaration of Helsinki (1991). Ethical approval for conduction of the study has been obtained at the coordinating site at University College London and all participating centers. Written informed consent was obtained from every participant.genfi.org.uk/) and enrolls participants who are known carriers of a pathogenic variant in c9orf72, GRN, or MAPT or are at risk of carrying a pathogenic variant because a first-degree relative was a known carrier. A pathogenic c9orf72 expansion was defined as more than 30 repeats. Participants were genotyped at their local site. All eligible and interested participants were enrolled. A total of 322 pathogenic variant carriers, including 122 c9orf72 (79 presymptomatic), 143 GRN (112 presymptomatic), and 57 MAPT pathogenic variant carriers (43 presymptomatic) were included in the analysis. Baseline visit data were used.To assess motor findings in genetic FTD, we used Data Freeze 3 from the GENFI multicenter cohort study, gathered between January 30, 2012, and January 31, 2017. The GENFI consists of research centers across Europe and Canada  was defined as the difference between the participants' current age and the mean age at onset within the participants' family.links.lww.com/WNL/C158). For motor signs affecting different limbs, the score of the most severely affected limb was used. To assess limb motor asymmetry, laterality indices (LIs) defined as the difference of left and right were calculated. For motor signs scoring 4 extremities, the mean of side differences was calculated. To assess overall asymmetry, the amount of the sum of all LIs was used.The presence and severity of the following signs was assessed: supranuclear gaze palsy, impaired eyelid function, facial weakness, bulbar palsy, pseudobulbar palsy, neck weakness, neck rigidity, respiratory muscle weakness, myoclonus, rest tremor, postural tremor, dystonia, chorea, bradykinesia, rigidity, limb apraxia, alien limb phenomenon, cortical sensory loss, limb fasciculations, spasticity, limb weakness, hyperreflexia, ataxia, arising from chair, sitting down, and postural instability. Severity of signs was scored as follows: score 0 = no impairment, score 0.5 = very mild impairment, score 1 = mild impairment, score 2 = moderate impairment, and score 3 = severe impairment . Acquisition protocols were synchronized across scanners and sites to achieve the best possible match.18 in MATLAB . Images were segmented into probability maps of gray matter, white matter, and CSF, nonlinearly transformed using DARTEL19 to create a study specific template for white and gray matter and normalized to the Montreal Neurological Institute space with Jacobian modulation. Spatial smoothing was applied using a full width at half maximum 6-mm Gaussian kernel. An estimate of total intracranial volume for each subject was computed by summing the 3 tissue class volumes.20Voxel-based morphometry was performed using the Statistical Parametric Mapping toolbox (SPM12)p < 0.05.Data were analyzed using IBM SPSS Statistics for Windows . Nondichotomized mean scores of demographic data were compared via the Kruskal-Wallis test and post hoc Bonferroni-corrected Mann-Whitney test. Chi-square analysis was used to check for significant differences in sex. Standard statistical significance level was set at To identify groups of similar clinical variables, our set of motor scores as well as overall LI were subjected to a principal component analysis (PCA) with varimax rotation. Variables with factor loadings below 0.4 were eliminated from the analysis and the PCA run anew. Components were labeled post hoc according to the pattern of signs. No a priori assumptions regarding the clustering of motor signs were applied. To visualize the similarity of variables assigned to a specific component during PCA, multidimensional scaling (MDS) was performed. Furthermore, to visualize possible gene clustering between phenotype clusters, a between-cases MDS was performed. For each group, the variance in each dimension was calculated, and a Levene test was performed to assess possible inequality of variances.To test for differences of motor signs depending on the affected gene, we calculated for each participant a sum score from the variables of each component. As overall LI has a different scale than the other variables, it was analyzed separately. Sum scores were compared via Kruskal-Wallis and post hoc Bonferroni-corrected Mann-Whitney tests between groups.To assess the proportion of the predominant phenotype of patients with motor signs depending on the affected gene, cases were assigned to the component with the highest PCA-based sum score. In addition, the frequency of signs of different components was determined for each group. Chi-square analysis was used to check for significant differences in frequency of signs.p < 0.001, cluster threshold k = 20 voxel).We assessed for each component the association between the sum scores and the patterns of atrophy using linear regression models. Data of patients with a sum score of 0 were excluded. The estimate of total intracranial volume was included as a covariate. Probability maps of gray matter and white matter were analyzed separately. T-maps were merged for visualization purposes. Images of the association between the sum scores of component 5 and cross-sectional atrophy patterns were partly flipped according to the expected atrophy pattern. The hemisphere with the expected atrophy  was arranged to the left. Absolute threshold masking was set at 0.1 to prevent interference by nonbrain voxels  models17 Fixed effect variables included EYO, genetic group, and sex, along with interactions between genetic group and EYO. Nonlinear time dependence was expected, so a second-order contribution of EYO, including an interaction with genetic group, was added to the model. Higher-order contributions and logarithmic transformations were tested with no significant improvement of the model.We tested several models including random intercepts per family and site.2 test to the model, to estimate the relationship between the fixed variables and the sum scores. Afterward, the 3-way empirical significance was estimated from a Monte-Carlo sampling of the models for each sum score22 every 5 years in the EYO range from −25 to +10 to identify each sign's degree of differentiation. As indicator of the point in time at which motor signs of each component and genetic group start to increase, the time at which the lower 95% CI crosses zero on the x-axis was used. These analyses were performed using R 3.6.3.We applied a type II Wald χData will be shared according to the GENFI data sharing agreement, after review by the GENFI data access committee with final approval granted by the GENFI steering committee.MAPT pathogenic variant carriers were younger compared with the other groups. The proportion of presymptomatic participants was lower in c9orf72 compared with GRN pathogenic variant carriers. Groups did not differ in terms of education, sex, and EYO.23Demographics of the study sample are provided in 2 (351) 7,662.23, p < 0.001) and the Kaiser-Meyer-Olkin Measure of Sampling Adequacy (KMO = 0.766) indicated that variables were suitable for PCA with varimax rotation, which revealed the presence of 7 components with eigenvalues above 1. As 2 of these components contained only 2 variables, these were excluded from the analysis, leaving a 5-component solution explaining 67.3% of variance. The motor sign chorea was excluded as its factor loadings were below 0.4.Both the Bartlett test .Respiratory muscle weakness, neck weakness, bulbar palsy, facial weakness, and myoclonus: we call this the bulbar ALS-like motor phenotype (bulbar ALS-MP).Spasticity, limb weakness, limb fasciculations, arising from chair, bradykinesia, sitting down, postural instability, and hyperreflexia: we call this the mixed/ALS-like motor phenotype (mixed/ALS-MP), as this phenotype contains both nonspecific motor signs like bradykinesia and typical ALS features like spasticity, limb weakness, fasciculations, and hyperreflexia.Rest tremor, postural tremor, overall LI, and rigidity: we call this the PD-like motor phenotype (PD-MP).Cortical sensory loss, limb apraxia, and alien limb phenomenon: we call this the CBS-like motor phenotype (CBS-MP).The variables group in the components as follows (details in p = 0.039) with highest variances in c9orf72 pathogenic variant carriers. No significant group differences were detected in dimension 2.Of note, high scores on a certain component do not make a specific diagnosis, the names given are but a simplified label for a cluster of signs. MDS confirmed the grouping of variables as reasonable  . In addic9orf72 pathogenic variant carriers , χ2 analysis detected only significant group differences regarding the frequency of signs of the bulbar ALS-MP with highest frequency of signs in c9orf72 pathogenic variant carriers.When looking at the group of pathogenic variant carriers showing motor signs, no significant group differences could be detected regarding the frequency of signs of different motor phenotypes . This waGRN and MAPT pathogenic variant carriers. In contrast, in c9orf72 pathogenic variant carriers, signs of the PSP-MP (34.7%) occurred more frequently than signs of the CBS-MP (30.8%). The least common signs were those of the bulbar ALS-MP (7.7%–13.5%). This was the case in all genetic groups, regardless of whether the cohort of patients showing motor signs or the whole cohort was analyzed.Signs of the mixed/ALS-MP were most frequent across groups (63.3%–76.9%), followed by signs of the PD-MP (51.0%–61.5%). Signs of the CBS-MP  were slightly more frequent than signs of the PSP-MP  in c9orf72 pathogenic variant carriers, the most frequent predominant phenotype was the mixed/ALS-MP (44%), followed by signs of the PD-MP (33%) . Although 21.7% of c9orf72 pathogenic variant carriers with a predominant mixed/ALS-MP had confirmed motor neuron disease, in none of the patients with a GRN or MAPT pathogenic variant, motor neuron disease was diagnosed. The third most common predominant phenotype was the CBS-MP in all genetic groups, which was equally frequent in c9orf72 and GRN (≈15%) and slightly less frequent in MAPT pathogenic variant carriers (8%). In c9orf72 pathogenic variant carriers, the PSP-MP (4%) was slightly more frequent than the bulbar ALS-MP (2%). All c9orf72 pathogenic variant carriers with a predominant bulbar ALS-MP had confirmed motor neuron disease. None of the GRN pathogenic variant carriers showed a predominant bulbar ALS-MP, and no MAPT pathogenic variant carrier showed a predominant PSP-MP or mixed/ALS-MP.In MP (33%) , whereaslinks.lww.com/WNL/C158). Atrophy clusters correlating with sum scores of the bulbar ALS-MP were rather small and distributed over all lobes with a focus on the frontal and temporal lobe. For the mixed/ALS-MP, the clusters of white matter atrophy were mainly located in extranuclear and brain stem white matter as well as in subcortical white matter of the medial frontal and precentral gyrus. Clusters of gray matter atrophy were located in the precentral, medial frontal, and superior frontal gyrus , mixed/ALS-MP (p = 0.030), and PD-MP (p < 0.001) and a significant effect of genetic group on the sum scores of the mixed/ALS-MP (p < 0.001) and PD-MP (p = 0.016). The interaction of EYO and genetic group had a significant effect on the sum scores of the PD-MP (p = 0.027). None of the variables included in the model reached statistical significance when evaluating the sum scores of the bulbar ALS-MP and CBS-MP.The visual distribution of sum scores and overall laterality over EYO is depicted in c9orf72 and GRN pathogenic variant carriers, an increase of signs of the PSP-MP could be detected already shortly before estimated onset . The fact that motor disorders and parkinsonism are typically brought into connection with a MAPT pathogenic variant may be caused by the earlier discovery of MAPT pathogenic variants in people with PSP-like phenotypes,7 8 years earlier than GRN6 and 13 years earlier than c9orf72.5 Therefore, a higher number of papers reporting MAPT pathogenic variants may have skewed the perception of prevalence, leading to the impression that MAPT has a higher proportion of motor disorders.In previous reports, parkinsonism and Richardson syndrome have been described in association with MAPT pathogenic variants,c9orf72 compared with GRN pathogenic variant carriers is surprising as previous reports have described CBS to be most often associated with GRN pathogenic variants.28-30 This discrepancy may be due to the fact that most previous studies on motor disorders in genetic FTD have been case reports and case series that have focused on the predominance phenotype without describing accompanying low-grade signs. In fact, when looking solely at patients showing motor signs, GRN pathogenic variant carriers were similarly likely to show a predominant CBS-MP compared with c9orf72 pathogenic variant carriers.The more frequent occurrence of signs of the CBS-MP in c9orf72 pathogenic variant carriers31 and could rarely be detected in GRN and MAPT pathogenic variant carriers. None of the GRN and MAPT pathogenic variant carriers showing motor signs exhibited a predominant bulbar ALS-MP. The presence of manifest bulbar signs therefore effectively excludes the presence of GRN and MAPT pathogenic variants.Signs of a bulbar ALS-MP were most frequent in 32 the between-cases MDS performed demonstrates tightly overlapping phenotype clusters, albeit with higher variance in c9orf72 pathogenic variant carriers and a more consistent syndrome for GRN and MAPT. This is reflected by the higher frequency and greater severity of signs across all phenotype clusters in c9orf72 compared with GRN and MAPT pathogenic variant carriers. In agreement with the concept that the anatomy determines the phenotype,15 we were able to demonstrate strong clinicoanatomic correlations. This is reassuring about the validity of phenotype clusters defined by PCA. In agreement with previous studies on PSP-Richardson syndrome34 and PSP-like signs in sporadic FTD,14 the severity of the PSP-MP correlated with mesencephalic atrophy. The bulbar ALS-MP correlated with small areas of atrophy, mainly in the frontal and temporal lobe. This is consistent with previous studies reporting atrophy in frontotemporal regions, especially in patients additionally displaying behavioral or language signs,36 which was the case in all of our patients showing signs of the bulbar ALS-MP.Although the clinical phenotype is known to be highly heterogeneous across all pathogenic variants under investigation,37 As in previous reports on the FTD-ALS continuum, clusters of atrophy in further frontotemporal regions38 and the cerebellum were also detectable.40As expected, mixed/ALS-MP signs correlated with bilateral atrophy of the motor and premotor cortex and the corticospinal tracts including the internal capsule and brainstem.41-43 However, our cases carry FTD pathogenic variants associated with TDP-43 and tau-pathology, not alpha-synucleinopathy. Dual pathology can occur but is very unlikely to be common across the GENFI cohort sufficient to cause the correlations with atrophy. The absence of basal ganglia atrophy may reflect the different underlying molecular pathology of PD-like MP in genetic FTD vs PD. The data suggest that mild PD-like signs in genetic FTD are rather due to diffuse cortical and subcortical atrophy than profound degeneration of the basal ganglia.Surprisingly, there was only a small correlation of the PD-MP with basal ganglia atrophy but widespread cortical and subcortical correlates. Recent studies have demonstrated a similar widespread pattern of subtle bilateral cortical thinning involving frontal, parietal, temporal, and occipital lobes and extensive white matter damage already in early PD.Even when flipping images according to the expected clinical atrophy pattern, only small atrophy clusters correlated with the CBS-MP. These were in the parietal, temporal, and occipital lobes. Although the clinical presentation of CBS is typically asymmetric, the variable overall LI was assigned to the PD-MP, not the CBS-MP by PCA, which explains why atrophy clusters correlating with the CBS-MP are not asymmetrically distributed. The fact that the factor loading of the variable overall LI on the CBS-MP was comparatively low may, however, be due to the small number of participants showing motor signs of the CBS-MP (n = 33).45 and cerebral glucose metabolism46 differ depending on the underlying pathology. Although in patients with corticobasal degeneration, the premotor cortex, supplemental motor area, and insula are typically affected, those with TDP-43 pathology exhibit pronounced frontotemporal atrophy, and patients with CBS with underlying Alzheimer pathology show more posterior atrophy, in parietal and temporal lobes. Although small, the atrophy clusters detected in our cohort seem to correspond to the atrophy detected in CBS caused by Alzheimer pathology. However, it is also possible that a differing distribution of pathology depending on the affected genes could have led to a mutual cancellation of atrophy patterns in our pooled analysis.Previous studies in CBS have demonstrated that atrophy patterns17 We show the emergence of motor signs up to 25 years before expected onset. Furthermore, our results demonstrate that severity of signs depends on the affected gene and that its effect varies over time. Mixed/ALS-MP, PD-MP, and CBS-MP signs occurred earliest in c9orf72 pathogenic variant carriers, in agreement with the early detectable structural imaging findings47 and slow progress described in some c9orf72 patients.48-50 In contrast, in MAPT pathogenic variant carriers that have been typically described in association with motor disorders, motor signs occurred later. Although the severity of signs remained highest in c9orf72 pathogenic variant carriers, severity with GRN and MAPT pathogenic variant carriers converged over time.Previous studies in genetic FTD described changes in neuropsychological measures and structural imaging 5–10 years before expected onset.As the majority of participants are alive, no valid conclusion on the influence of motor signs on overall survival can be drawn. However, an effect of motor signs, especially of the bulbar and mixed/ALS-MP, seems likely and should be investigated in future studies.Besides the high number of patients with genetic FTD and the prospective evaluation of signs, the identification of natural clusters of motor signs by PCA represents a key strength of our study. Applying a data-driven approach allows for an objective analysis that does not follow classical clinical concepts and is not influenced by a priori assumptions.c9orf72 and GRN, such that EYO becomes a surrogate of age.A limitation of the current study that needs to be considered is the lack of a comparison to data from healthy controls. However, the primary aim was to compare motor disorders and their development over time between the genetic groups under investigation. We analyzed only cross-sectional differences between different genetic groups at different times from estimated onset. Whether the progression of signs, especially in the presymptomatic phase when subtle signs may be challenging to measure, is followed within individuals has to be shown in future longitudinal studies. Furthermore, a replication of phenotypes in another cohort would be of interest but is difficult to pursue due to the rarity of genetic FTD. Another limitation is the method used for estimation of estimated years to symptom onset. There is a significant correlation between an individual's age at onset and mean familial age at onset for MAPT pathogenic variants. This correlation is weak for Keeping these limitations in mind, our data reveal the presence of natural clusters of motor signs in genetic FTD. Their severity increases over time and depends on the affected gene. The emergence of motor signs occurs early in the presymptomatic period, up to 25 years before estimated onset. Motor phenotypes have distinctive anatomic correlates. Given the heterogeneity of signs and symptoms and phenotypic overlap, these clinicogenetic associations of motor phenotypes in genetic FTD will help clinicians in their diagnostic workup, assist in decision making regarding genetic testing, and the design of preventive and disease-modifying treatments.


Latinos living in rural South Texas have a higher prevalence of diabetes, but their access to diabetes self-management education and support (DSMES) is limited.We aimed to test the feasibility of a community health worker-led, mobile health -based DSMES intervention to reduce disparities in accessing DSMES in underserved rural Latino residents in South Texas.1c (HbA1c).This 12-week, single-arm, pre-post trial was delivered by trained community health workers to 15 adults with type 2 diabetes. The intervention consisted of digital diabetes education, self-monitoring, a cloud-based connected platform, and community health worker support. Feasibility was evaluated as retention, actual intervention use, program satisfaction, and barriers to implementation. We also explored the intervention’s effect on weight loss and hemoglobin AP=.001), while HbA1c level remained unchanged from baseline  to posttest .All 15 participants were Latino . The retention rate at posttest was 14 of 15 (93%). On average, the participants completed 37 of 42 (88%) digital diabetes education lessons with 8 participants completing all lessons. Participants spent 81/91 days (89%) step tracking, 71/91 days (78%) food logging, 43/91 days (47%) blood glucose self-monitoring, and 74/91 days (81%) weight self-monitoring. The level of program satisfaction was high. On average, participants lost 3.5 (SD 3.2) kg of body weight (A community health worker-led mHealth-based intervention was feasible and acceptable to improve access to DSMES services for Latino adults living in rural communities. Future randomized controlled trials are needed to test intervention efficacy on weight loss and glycemic control. Diabetes is a complex and costly disease that requires persons with diabetes to make daily self-care decisions to prevent the onset of complications . DiabeteSouth Texas has 38 counties, of which 25 are rural. Diabetes care disparities exist in rural South Texas for a variety of reasons. Rural persons with diabetes frequently lack adequate transportation and must travel long distances to clinics, impeding diabetes care and potentially impacting glycemic control ,5. MeanwMore than 80% of the South Texas population is Latino. Latinos face additional cultural barriers when it comes to diabetes care . The lacImproving access to DSMES for rural Latino population requires applying a multidimensional research lens. The National Institute on Minority Health and Health Disparities framework conceptualizes multiple domains of health determinants that affect minority health . AccordiCommunity health worker-led DSMES is a culturally-appropriate and cost-effective approach for improving access to DSMES services among rural and minority populations . CommuniIntegrating mobile health  technology is a promising approach to improve DSMES access in nonclinical settings and to improve health services provided by community health workers ,25. HealIn this paper, we report results of a feasibility study to evaluate retention, delivery, usage, and acceptability of an mHealth-based DSMES program led by trained community health workers for Latino persons with diabetes living in rural South Texas. The impact of the intervention on weight loss and glycemic control was also explored.This was a single-arm, pre-post, National Institutes of Health Stage 1B study to examine the feasibility of combining an mHealth-based intervention that relied on community health worker facilitation to improve access to DSMES in a resource-poor rural community . A 12-weParticipants were recruited through flyers posted at the Community Action Corporation of South Texas. Community health workers telephoned individuals who expressed interest in participation to assess their eligibility for enrollment. The inclusion criteria were as follows: (1) age ≥ 18 years, (2) a diagnosis of type 2 diabetes, (3) ability to read and write in English, (4) residency in Jim Wells County, (5) possession of a compatible smartphone with a data plan, and (6) readiness to make a lifestyle change. Participants were excluded if they were (1) on insulin treatment, (2) had a history of severe psychiatric disorder, (3) had difficulty in performing daily or regular activity, (4) had substance abuse issues, or (5) were planning a pregnancy or planning to breastfeed within the following 6 months. Participants gave verbal consent to participate. Prior to implementation of any study procedures, this project was reviewed by Office of the Institutional Review Board at the University of Texas Health Science Center at San Antonio and determined to be non-regulated research (HSC20190486N).Supporting behavior change is a key objective for DSMES programs . This stThis intervention adopted a unique “high-tech, high-touch” approach. We integrated self-monitoring data from multiple mHealth tools into a cloud-based platform so that (1) participants could increase self-efficacy for behavior change to improve health outcomes by reviewing data on the platform, (2) community health workers could access the platform and address participant barriers remotely, thereby promoting participant self-efficacy for behavior change and diabetes self-management, and (3) community health workers could obtain support from the research team for complex diabetes self-management cases and technological issues via video conferencing.The pilot DSMES intervention was delivered over a 12-week period by community health workers via mHealth. Once enrolled, participants received mHealth and one-on-one training from community health workers . To faciTo ensure fidelity of intervention delivery, all community health workers received a 1-day training session provided by a research staff member. The training covered a study description, diabetes self-management, data collection, and intervention delivery. During the intervention, the study team met with community health workers weekly to resolve problems they encountered, following the ECHO  model .Weekly digital diabetes education was delivered to increase the participants’ diabetes knowledge and skills. Building upon the Diabetes Prevention Program Group Lifestyle Balance Program, the curriculum was tailored to local needs. For example, we modified group-based activities to add individual-based aligned lessons with the AADE7 (American Association of Diabetes Educators-7) framework ; tailoreCollaborative goal setting between the community health workers and participants with diabetes was integral for DSMES . Each weData collected from the mHealth devices and apps was automatically synchronized and stored by the Connected Health Platform , an applOnce logged, the community health workers could see 7-day plots of diet, including macronutrient details, calorie intake, and water consumption; activity, including exercise type, steps, sleep, and weight; blood glucose; and weekly behavioral goals. The community health workers could also select a date range to view self-monitoring data trends and interactions by overlaying multiple sources, and they could track participants’ progress on goals, thereby enabling problem-solving strategies during behavioral follow-up sessions. The participants were also allowed access to the platform. Additionally, the platform served as a data storage tool from which the research team could download data from various mHealth sources.We addressed feasibility according to retention, actual intervention use, barriers to implementation, satisfaction, and preliminary health effects.Retention rate was the percentage of enrolled participants who completed posttest data collection.Actual use of digital education was quantified as the weekly number of days the lessons were accessed. Actual use of self-monitoring devices was operationalized as the weekly number of days with self-monitored weigh-ins, food logs, step counts, and blood glucose readings. All community health workers kept a log to record their contact with participants; data included call duration and issues addressed. We operationalized use of behavioral change strategies as the cumulative number of behavioral goals set during the study and reported the percentage of time during the week the participants accomplished these goals.The participants reported barriers to achieving behavioral goals during behavioral follow-up sessions; at posttest, they listed life events that affected diabetes self-care using the Recent Life Event Questionnaire .Satisfaction was measured using Customer Satisfaction Questionnaire short version (CSQ-8) . The CSQ1c with their doctor pre- and posttest. Weight was self-measured to 0.1 lb (0.045 kg) and represented as the mean of 2 measurements. To assess participants’ responses to the intervention, we plotted weekly changes in average daily steps and self-measured body weight.All participants checked HbAWe also measured changes in eHealth literacy and outcome expectations. The 14-item eHealth Literacy Toolkit assesses eHealth literacy as technology confidence, attitudes toward engaging with technology, and mobile technology familiarity . Items wAt baseline, participants completed surveys on demographic information, including age, sex, educational background, language spoken, marital status, diabetes history, medication history, and experience with mHealth.t test was used to determine intervention effects on weight loss, HbA1c, technology efficacy, and PTES score. All statistical procedures were performed using R software . The threshold for statistical significance was a 2-sided P value of .05.All descriptive statistics are reported as the mean (SD) for continuous variables and frequencies and relative frequencies for categorical variables. A 2-tailed paired 1c (for a retention rate of 93%). All participants attended the behavioral follow-up sessions at weeks 1, 2, 4, 6, and 10. Detailed demographic characteristics of the study participants are presented in All 15 participants completed the baseline assessment; 1 participant had missing data for posttest HbADigital education completion rates were high  with most  participants accessing all digital education modules and 8/15 (53%) completing all lessons. The participants accessed digital education modules multiple times during the week (2-5 times). There was a continual decline in the number of active users and average weekly logins as the study proceeded . The higDuring the 12-week (84-day) intervention, the mean percentage of days that the participants self-monitored steps, food, blood glucose, and weight were 89% (SD 21%), 78% (SD 21%), 47% (SD 13%), and 81% (SD 16%), respectively. Overall, the percentage of participants who used self-monitoring technologies daily did not change significantly during the study course .All participants set daily physical activity and diet goals with the community health workers and performed well in accomplishing these goals, as reported by the Connected Health Platform. Nearly one-third of the participants met their diet and physical activity goals on all days of the week. Most participants accomplished their daily dietary goals on more than half of the days of the week .On average, each participant made 16.73 (SD 8.0) calls to their community health worker, with each call lasting between 5 minutes and 2.5 hours.Participants reported different types of barriers to completing the intervention activities. The most reported barriers were “motivation” for food logging, “time” for exercise self-monitoring, “technical” for weight self-monitoring, and “forgetfulness” for blood glucose self-monitoring.The COVID-19 pandemic appeared to affect diabetes control. Participants reported the following life events that affected diabetes control: “having relatives or close friends seriously ill, injured, or die” , “having immediate family be seriously ill, injured, or die” , and “having major financial difficulties” .Overall, the participants were satisfied with the intervention . The meaThe participants rated most digital education modules as “good.” The highest score was given to the “Healthy Eating” lesson and the lowest score was given to the lesson on “Motivation” .P=.001) from baseline to posttest (1c did not change significantly. We observed weekly improvement in weight loss and steps (Participants showed a significant reduction in body weight of 3.5 (SD 3.2) kg  and eHealth literacy by 37.57 from baseline to posttest,   .Latinos living in rural South Texas suffer high rates of diabetes, but their access to DSMES is poor. To address multidimensional access barriers, we designed an innovative DSMES intervention, combining the community health worker model and mHealth technologies. To our knowledge, this is the first published study to examine the combined impact of community health worker facilitation and mHealth in improving access to DSMES in a rural Latino population. Our findings demonstrate that an mHealth-based, community health worker-led approach is a feasible and acceptable means to augment DSMES services in South Texas. We found that mHealth facilitated community health worker engagement in delivering DSMES services. The intervention was well-received by the participants, as evidenced by their consistent use of mHealth and frequent participant-community health worker interaction. The participants reported a high level of satisfaction with the intervention. Moreover, we observed improvements in self-care behaviors and health outcomes. Taken together, this study suggests that our unique “high-tech, high-touch” solution has the potential to be tested for efficacy in larger randomized controlled trials.Our findings show that by using mHealth tools, community health workers can address the multidomain health determinants proposed by the National Institute on Minority Health and Health Disparities framework . For exaWe achieved a higher retention rate than previous diabetes self-management programs conducted in rural communities ,41 and oConsistent with other rural-based DSMES interventions, our sample reported high rates of satisfaction . We specLow health and eHealth literacy are major barriers to implementing mHealth in underserved communities . Our parThe high level of intervention acceptability could also be attributed to our integration of multiple personalization strategies . ConsidePoor integration of technology into health professionals’ workflow could increase their workload and discourage them from adopting mHealth interventions. Considering that community health workers are a valuable resource that can affect intervention scalability , we aime1c reduction after mHealth interventions in persons with diabetes, these studies were conducted in persons with diabetes with poor baseline HbA1c and had longer study durations [Consistent with previous DSMES programs in underserved communities, participants achieved 4.1% weight loss at 3 months. Participants also maintained good glycemic control at 3 months, similar to previous short-term mHealth-based DSMES interventions ,36. Whilurations . These fThis study was conducted during the COVID-19 pandemic. At the time of the study, Latinos represented 43.5% of confirmed COVID-19 deaths in Texas . MoreoveSeveral limitations need to be considered in interpreting our study findings. First, the duration was shorter than typical DSMES programs. Given that diabetes self-management requires long-term commitment, our study needs to be extended with a longer follow-up period. Second, the statistical findings of our study need to be interpreted with caution due to the small sample size. Third, we only included participants who had a digital data plan, which could limit the generalizability of our findings to rural Latinos with diabetes. Fourth, we only measured actual use of the intervention by the participants. Future studies should consider collecting data from community health workers to complement data from persons with diabetes to inform intervention scalability. Lastly, we did not collect data on recruitment, which could have provided valuable information on the potential reach of our program .Our findings suggest that a “high-tech, high-touch” approach holds promise to reduce DSMES access barriers faced by rural Latino residents of South Texas. We found that mHealth facilitated self-care and remote monitoring by participants with diabetes, interaction between community health workers and participants with diabetes, and enabled community health workers to actively contribute to providing DSMES services. In the future, our findings should be tested in a fully powered randomized controlled trial to examine the efficacy of our methods in improving access to quality DSMES and glycemic control in persons with diabetes living in resource-poor rural communities.


Immune system dysregulation plays a vital role in the pathogenesis of neurodegenerative diseases, even considered to be as important as classical pathological protein aggregation assumption. However, the associations of immune-mediated diseases with incident dementia are unclear and need to be clarified in prospective studies with a large population and long follow-up time.We investigated the relationship between any or individual immune-mediated diseases and incident dementia based on a prospective cohort UK Biobank. The risk for dementia was assessed with multivariable hazard ratio (HR) and 95% confidence interval (CI) after adjusting for various potential confounders using time-varying Cox proportional hazards regression. We also performed the subgroup Cox analysis stratified by time since immune-mediated diseases and gender. Causal mediation analyses with 1000 bootstrapped iterations were conducted to explore the mediation effects of peripheral immune cells on the associations of immune-mediated diseases with dementia.A total of 375,894 participants were included in the study, among which 5291 developed dementia during a median follow-up of 9.08 years. Immune-mediated diseases were associated with an increased risk of dementia , and the risk was highest between 1 and 2 years after immune-mediated diseases onset . Females who suffered from immune-mediated diseases were more prone to AD, while males were more susceptible to VD. Four of the individual immune-mediated diseases including type I diabetes mellitus , rheumatic fever or rheumatic heart diseases , multiple sclerosis , and necrotizing vasculopathies  were significantly related to higher dementia incidence. The relationship between immune-mediated diseases and dementia was partially mediated by peripheral immune cells including neutrophils and lymphocytes.In this large cohort study, immune-mediated diseases were proven to be significantly associated with an increased risk of incident dementia, especially for type I diabetes mellitus which was observed to be related to the higher incidence of all types of dementia. Our findings could provide new sights on dementia pathogenesis and intervention from the perspective of systemic immunology and immune-mediated diseases.The online version contains supplementary material available at 10.1186/s13195-022-01072-x. Aging accompanied neurodegeneration involving neuronal dysfunction and loss is critical in dementia pathogenesis. Since Alzheimer’s disease (AD) was first characterized by Alois Alzheimer in 1907, who found the hallmarks of extracellular plaques and intracellular neurofibrillary tangles, the mechanism studies of dementia in the past century mainly focused on protein aggregation such as amyloid β (Aβ), tau, α-synuclein, and transactive response DNA-binding protein 43 kDa (TDP-43) . In addiImmune-mediated diseases are systemic diseases of complex, multifactorial etiology in the context of immune system dysfunction as well, including but not limited to inflammatory bowel diseases, multiple sclerosis, type I diabetes, systemic lupus erythematosus, and rheumatoid arthritis , 12. TheTo fully unravel the associations of immune-mediated diseases with incident dementia, we investigated the risk for dementia in immune-mediated diseases patients compared to healthy controls based on a prospective cohort UK Biobank (UKB) taking advantage of long follow-up time and large population. Considering the critical role of peripheral immune cells in both immune-mediated diseases and dementia, we further performed the causal mediation analyses to explore the effects of peripheral neutrophils and lymphocytes on the associations of immune-mediated diseases with dementia.https://www.ukbiobank.ac.uk/). Environmental, genetic, disease status, and other clinical data were obtained from questionnaires, physical measures, sample assays, and linked electronic health data. Ethics approval for the UKB study was obtained from the North West Multicenter Research Ethical Committee. All participants provided written informed-consent paper at baseline. We restricted analyses to individuals with hospital inpatient data where the diagnosis information based on International Classification of Diseases (ICD)-10 codes were available to identify immune-mediated diseases patients. The control comparators were defined as the individuals with hospital inpatient data but none of the immune-mediated diseases was diagnosed. Prevalent dementia patients at baseline and those without traceable outcome data were excluded.The participants and data resources involved in this study were from a population-based prospective cohort UKB, under application number 19542. Between 2006 and 2010, over 500,000 participants aged 40–69 years were recruited in UKB with a comprehensive baseline assessment of health status at 22 centers throughout the UK . Follow-We identified immune-mediated diseases' status and diagnosis date by matching the corresponding ICD-10 codes  from hosIncident all-cause dementia (ACD), AD, and vascular dementia (VD) were ascertained and classified according to the ICD codes and Read codes (Supplementary Table Blood samples collected in ethylenediaminetetraacetic acid (EDTA) vacutainers of the UKB participants were analyzed at the UKB central laboratory within 24 h of blood draw. Differential leukocytes counts were acquired from the automated quantitative analyzer, the Beckman Coulter LH750 Hematology Analyzer. We extracted the blood count data of neutrophils and lymphocytes collected after immune-mediated diseases diagnosis and before dementia onset.ApoE-ε4, education, ethnicity, body mass index (BMI), socioeconomic status indicated by Townsend deprivation score, smoking, and alcohol consumption. The p values were further adjusted to control the false discovery rate (FDR) at 5% using the Benjamini–Hochberg procedure  when analyzing the associations of 20 individual immune-mediated diseases with dementia. In secondary analyses, we explored the effect of time since immune-mediated diseases on dementia. Time since immune-mediated diseases was split into overlapping periods . We also estimated the effect differences of immune-mediated diseases on dementia across sex groups at recruitment. To evaluate the potential reverse causation biases, we also performed the sensitivity analyses by excluding the participants with follow-up time less than 5 or 10 years as suggested in work conducted by Sipila et al. [Baseline characteristics of participants were summarized for those with and without incident dementia status as mean and standard deviation (SD) for continuous variables, number, and percentage for categorical variables. Longitudinal associations of immune-mediated diseases with incident dementia were examined with multivariable time-varying Cox proportional hazard regression models and presented with hazard ratio (HR) and 95% confidence interval (CI). Participants who died, withdrew from the study before the end of follow-up, or had not developed dementia by the end of follow-up  were censored. In the primary analysis, we performed the model unadjusted, then adjusted for age, sex, a et al. . Finallya et al.  with thep-value of less than 0.05 was considered to be statistically significant.All the above analyses were carried out using R version 4.0.2. A Among 502,493 participants at baseline in the UKB, 375,894 participants with HESIN ICD-10 data were eligible for Cox analysis after excluding 888 participants with prevalent dementia at baseline and 33,527 participants without follow-up data  and VD  while not associated with AD after multivariable adjustment for age, sex, education, Q values remained statistically significant for associations of type I diabetes mellitus with ACD, AD and VD, for multiple sclerosis with ACD, for rheumatic fever or rheumatic heart diseases and psoriasis with VD , rheumatic fever or rheumatic heart diseases , multiple sclerosis , and necrotizing vasculopathies   and lymphocytes with the proportion of mediation 1.55% (p = 0.024) respectively  of ascertaining ACD cases using the UK Biobank data is high, it is lower for AD and VD . Missed Our study suggests that immune-mediated diseases were associated with an increased risk of dementia with the risk varying according to type, sex, and timing since immune-mediated diseases. Peripheral immune cells neutrophils and lymphocytes partially mediated such associations. These findings support the importance of immune system dysregulation in dementia pathogenesis. Future studies are needed to confirm our findings in a larger cohort with a longer follow-up period, to improve our understanding of the underlined mechanisms between immune-mediated diseases and dementia, and to explore whether prevention and interventions of immune-mediated diseases reduce the risk of dementia in high-risk populations.Additional file 1: Supplementary Table 1. The list of immune-mediated diseases and their ICD-10 codes used in the study. Supplementary Table 2. The list of dementias and their codes used in the study. Supplementary Table 3. Baseline characteristics of UKB participants by immune-mediated diseases status. Supplementary Table 4. Risk for incident dementia according to the status of any immune-mediated diseases stratified by gender. Supplementary Table 5. Sensitivity analysis of the risk for incident dementia according to the status of any immune-mediated diseases. Supplementary Table 6. FDR adjusted risk for incident dementia according to the status of individual immune-mediated diseases. Supplementary Table 7. Sensitivity analysis of the risk for incident dementia according to the status of individual immune-mediated diseases. Supplementary Table 8. The interaction analyses between sex and peripheral immune cells in contributing to the dementia incidence. Supplementary Figure 1. Flowchart of the participants selection. Supplementary Figure 2. Peripheral immune cells mediation models of the relationship between individual immune-mediated diseases and dementia.


Among sarcomas, which are rare cancers, inflammatory myofibroblastic tumors are extremely rare. Unlike other subtypes, this is a largely oncogene-driven neoplasia, and early gene rearrangement identification is important for accurate advanced stage treatment. In this manuscript, we review the clinicopathologic characteristics of this ultra-rare entity, as well as the current treatment landscape, with a particular focus on opportunities provided by tyrosine kinase inhibitors (TKIs).An inflammatory myofibroblastic tumor (IMT) is a neoplasm composed of myofibroblastic and fibroblastic spindle cells accompanied by inflammatory cells, including lymphocytes and eosinophils. It is an ultra-rare tumor, the optimal management of which remains to be defined. Surgery is the treatment of choice for localized tumors. The treatment of advanced disease is not precisely defined. Chemotherapy regimens result in an overall response rate of approximately 50% based on retrospective data. The latest pathophysiological data highlight the role played by tyrosine kinase fusion genes in IMT proliferation. Anaplast lymphoma kinase (ALK) oncogenic activation mechanisms have been characterized in approximately 80% of IMTs. In this context, data regarding targeted therapies are most important. The aims of this article are to review the latest published data on the use of systematic therapy, particularly the use of molecular targeted therapy, and to publish an additional case of an IMT with Ran-binding protein 2 (RANPB2)-ALK fusion showing a long response to a tyrosine kinase inhibitor. Inflammatory myofibroblastic tumour (IMT) is an ultra-rare sarcoma that has been classified as a neoplastic disease of intermediate biological potential given the low risk of recurrence and metastatic potential . IMT usuKinase fusions play a critical role in the biology of many IMTs and have been reported in about 80% of these tumors . The scaIMTs can occur in any location, and the symptoms presented by patients depend primarily on the primary site of the IMT. The primary lesion occurs most commonly in the abdominal cavity , but there have been cases of primary lesions in the thorax, pelvis, limbs, skin, and even brain . At the The pathological diagnosis may be challenging. IMT often presents as a circumscribed nodular mass, but multinodular lesions have also been described . IMT hasThe etiology and pathogenesis of IMT are not fully understood. Several risk factors have been described, including smoking, minor trauma, and IgG4-related disease ,10. SomeALK gene rearrangements has greatly contributed to our understanding of this rare mesenchymal tumor. ALK is a receptor tyrosine kinase first identified as a component of the nucleophosmin (NPM)-ALK fusion oncoprotein aberrantly expressed in anaplastic large cell lymphoma (ALCL) [ALK rearrangement is far less common in adults than in children and young adults with IMT [In view of the variable phenotype, and the absence of an immuno-histochemical profile, the diagnosis of IMT has long been a diagnosis of exclusion, with a broad differential diagnosis, ranging from local inflammatory process and, idiopathic retroperitoneal fibrosis to inflammatory fibrosarcoma. The identification of recurrent a (ALCL) . Importawith IMT . A variawith IMT .ALK staining pattern and epithelioid or round cell morphology have been reported. Since its first description, it has been well demonstrated that epithelioid IMTs behave aggressively with rapid recurrence and evolution, compared to the remarkably indolent behavior of conventional IMTs [RANBP2)-ALK fusion, detected by reverse transcriptase polymerase chain reaction (RT-PCR) [Rare IMTs with a distinct nuclear membrane or perinuclear nal IMTs . In 2011nal IMTs ,18. To d(RT-PCR) .RANBP2-ALK dominated by epithelioid neoplastic cells also intrinsically reflects the heightened invasiveness of the tumor. However, it should be particularly noted that not all IMTs with epithelioid cell morphology carry the genetic alteration of RANBP2-ALK [The distinctive histology of IMT with NBP2-ALK . From a NBP2-ALK .Coffin et al. reported the pathological features of IMT do not correlate with tumor behavior, however, those of EIMS represent an exception .ALK rearrangement. A study using next-generation sequencing (NGS) from 9 patients that had tumors that were ALK-negative by immunohistochemistry (IHC) revealed that 6 of them harbored ALK, ROS1, and platelet-derived growth factor receptor beta (PDGFRB) fusion proteins, suggesting that IMT is a largely oncogene-driven neoplasia [Little is known about the pathogenesis of half of the IMT tumors that do not show eoplasia .ALK fusion partners. Most ALK gene partners provide a strong promoter and an oligomerization domain, resulting in oncogenic activation of the ALK kinase.In IMT, more than 10 different genes have been identified as ALK and ROS1-related fusions. They also demonstrated a link between genomics and clinical presentation, showing that most lung IMTs were positive for fusions (either ALK or ROS1).The study by Antenescu et al. applying RNA sequencing found that the majority of IMTs (85%) displayed kinase fusions . Their rIn 2021, Yamamoto and colleagues retrospectively studied 40 cases to elucidate the diagnostic utility of pan-Trk immunohistochemistry for IMTs . In 72.5The radiological presentation of IMTs is heterogeneous. IMTs can present as multiple masses in one anatomic region. The image may vary from an infiltrating lesion to a well-delineated lesion, with different proportions of inflammatory and fibrotic components in the mass. Variable attenuation can thus be noted on the CT scan, with persistent and delayed contrast uptake, in the fibrotic component of the IMT. MR imaging may show low signal intensity on T1-and T2-weighted images owing to fibrosis, along with restricted diffusion . BiologiSurgery remains the treatment of choice for localized tumors. According to the European Society for Medical Oncology (ESMO) guidelines, surgical management should be performed by a specifically trained surgeon in a sarcoma center . The staUp to one-quarter of surgically treated tumors recur . After cWhether IMT is a neoplastic or a reactive process had been a matter of controversy. In this context, some data exist regarding the use of corticosteroids.p = 0.046). The authors, therefore, conclude that glucocorticoids are especially recommended as a basic part of integrated therapy for ear, nose, and throat IMT. Another case report of a 48-year-old patient with inoperable maxillary sinus IMT with complete response after concomitant radiotherapy and prednisone have been published. In this context, combination of radiotherapy with steroids appears to be an effective alternative in non-operable maxillary IMT [In a study of 13 patients with IMT in the paranasal sinus or nasopharynx, of the ten patients for whom follow-up data were available, five received partial resection followed by various combinations of prednisone, radiation, and chemotherapy, while the other five received prednisone combined with chemotherapy and/or radiation without surgery . The corlary IMT .Systemic treatments are reserved for advanced, non-operable disease. Currently, there is no standard chemotherapy regimen established for advanced IMTs given the rarity of the disease and the lack of prospective data regarding the efficacy of chemotherapy. Efficacy of different chemotherapy regimens was studied in a recent retrospective case series analysis collecting data from 9 European sarcoma centers . Thirty-Therefore, the generation of data on new therapies are most important.ALK fusions in patients with non-small cell lung carcinoma (NSCLC) has facilitated the clinical development of ALK inhibitors, including crizotinib. Crizotinib is an oral small molecule inhibitor of ALK, MET, and ROS1. In 2011, it received accelerated approval by the United States Food and Drug Administration (FDA) for metastatic ALK-positive NSCLC based on a proof-of-concept phase I study [The discovery of  I study . In the  I study .Since 2010, crizotinib has been administrated at the time of disease relapse and treatment failure in patients with EIMS with varying effectiveness in several case reports ,37,38,39ALK and/or MET alterations [ALK-rearranged tumors, and 14% (1/7) ALK-negative patients had an objective response with crizotinib. In the ALK-positive group, two out of six patients showed complete response. Interestingly, a recent update analysis after a median follow-up of 50 months showed longer ORR up to 66.7% for ALK-positive patients due to the further reduction in tumor volume with long-term treatment [PIK3CA mutations (9% of cases) were associated with shorter progression-free survival in patients receiving crizotinib.In 2018, Schöffski et al. published the first prospective data for the IMT cohort as part of a phase II clinical trial (EORTC 90101 CREATE) of advanced tumors characterized by erations . In thisreatment . The 12-Several second and third-generation tyrosine kinase inhibitors with increased ALK selectivity, including ceritinib, alectinib, brigatinib, lorlatinib, and ensartinib, showed superior efficacy to crizotinib in both systemic and intracranial disease in ALK-positive NSCLC ,44. ReceALK fusions in IMT, other potential therapeutic agents can be considered. In the absence of large randomized studies, we must rely on published clinical cases, as well as choose treatments by analogy with the responses obtained in other cancers with the same genetic mutations. In-depth molecular characterization of archival IMT tissue from 24 patients enrolled in the CREATE trial revealed extensive molecular heterogeneity including DNA damage repair mechanisms (19/24), Wnt signaling (16/24), and cell-cycle and cell death pathway (13/24) [ATRX, FAT1, FCRL4, FOXO1, NUTM2B, PIK3CA, SMAD4, and TP53, no ROS1-rearranged tumor has been identified. In the CREATE trial, the patient who had the objective response in the ALK-negative cohort had an ETV6-NTRK3 fusion which may have made the IMT sensitive to crizotinib [Outside targeting  (13/24) ,48. AlthMDM2) gene amplification has also been detected in 27% of IMT cases, no data are available at this moment regarding the efficacy of MDM2 inhibitors alone or in combination with CDK4 inhibition [Although mouse double minute 2  with ROS1 expression [TGF-ROS1 fusion transcript in one of the cases. Histologically, both tumors showed a conventional morphology. It should be noted that neither case presents recurrence or metastasis.Another case concerning a 16-year-old patient with brain-metastatic chest wall IMT with a ublished . He was pression . Both tuALK rearrangements [TFG fusion partner) showed diffuse and dot-like cytoplasmic staining, whereas one tumor (with a YWHAE fusion partner) showed combined cytoplasmic and nuclear staining.In a study by Hornick et al. studying 30 cases of IMT, 21 tumors were positive for ngements . Among tTFG-ROS1 fusion. Crizotinib was then introduced with a partial response, excellent tolerance, and improvement of quality of life at 4 months. The second case described is that of a 14-year-old boy with an ALK-negative right lower lobe IMT for which NGS analysis revealed a TFG-ROS1 fusion [YWHAE1-ROS1 fusion rearrangement who responded to crizotinib [Four case report studies with ROS1 positive IMT treated with crizotinib have been reported: two of them were in pediatric patients ,56. In tizotinib .Vascular endothelial growth factor (VEGF) is highly expressed in the infiltrating inflammatory cells of IMT . In 2012Rarely, other oncogenes have been described in the context of IMT diagnosis. For example, the study by Antonescu et al. describes a case of rearranged during transfection (RET) gene rearrangement in a patient with pulmonary IMT, associated with a fatal outcome .ETV6-NTRK3 fusion gene have been reported [In addition, as reported above ALK-negative IMTs harboring the reported .ALK-negative IMTs [Other therapeutic strategies are being developed. For example, PD-L1 expression was noted in 80% of recurrent or metastatic tumors, and 88% of ive IMTs . Due to ive IMTs .POLE deletion does not influence the mutational profile in the analyzed cohort. No prospective data about the efficacy of ICI in IMT has been reported.High tumor mutational burden is an emerging predictive biomarker with relevance for tumor treatment with immune checkpoint inhibitors (ICI). The only available data are ad hoc analyses of the CREATE trial showing an average of 7 mutations per Mb suggesting an intermediate mutational burden in IMT . No assoRecently, rare reports on efficacy ICI in patients with sarcoma have been published. For example, partial response with single-agent nivolumab was seen in a 21-year-old woman with advanced IMT with PD1 positive, but negative PDL1 status . The antRANBP2-ALK, five RRBP1-ALK, one EML4-ALK, one VCL-ALK, and eighteen unknown ALK partners. Among these 58 cases, 19 patients were treated with TKIs, 17 of them with crizotinib in the first line. Among these seventeen patients, four benefited from a second-line TKI, among which, two benefited from a third-line TKI, among which, one benefited from a fourth-line TKI. In most cases, we do not have a follow-up, but we know that at least 22 patients died within one year.Among 58 cases reported on the Pubmed , 36 patiRANBP2 gene, located in chromosomal region 2q13, encodes a 358 kDa multi-domain nuclear pore protein. RANBP2 is a small GTP-binding protein of the RAS superfamily [RANPB2 and exon 20 of ALK. This ultimately leads to constitutive and ligand-independent autophosphorylation and activation of ALK. These studies suggest that the chimeric RANPB2-ALK gene may promote cell proliferation, which may be a potential mechanism for rapid growth and recurrence [The erfamily . RANBP2 currence ,84.RANBP2-ALK fusion gene demonstrated aggressive behavior. We reported a case of a 39-year-old female patient with abdominal EIMS with a RANBP2-ALK fusion where first-line treatment with alectinib has been initiated with a complete metabolic response ongoing after 6 months of treatment  is a protein participating in mitotic nuclear division and other microtubule-based processes. It is distributed along with microtubules in the cytoplasm and membranes. The most distinctive site for ALK staining was the cytoplasm under the membrane, which was consistent with the distribution of EML4 in the cell. EML4-ALK fusion occurs through a paracentric inversion within the short arm of chromosome 2, where EML4 and ALK genes are both located. Unfortunately, in the reported case, the patient died soon after diagnosis.In 2017, Jiang et al.  reportedVCL-ALK fusion [VCL–ALK fusion has been described in renal cell carcinomas, a single case of high-grade glioma and a subset of epithelioid fibrous histiocytoma. VCL (vinculin) encodes for an actin filament-binding protein involved in cell–matrix adhesion and cell–cell adhesion. It regulates E-cadherin expression on the cell surface and potentiates mechanosensing by the E-cadherin complex. The role of VCL in human malignancies has not been well demonstrated.In 2021, Chopra et al. reported the first case of EIMS with a K fusion . VCL–ALKThe case described is a case of a primary brain tumor in a 72-year-old patient, who was operated on and presented lung and bones metastases 3 months later. The patient was treated upfront with off-label alectinib, but no long follow-up was reported.ALK (G1269A) mutation has been described after 30 months of crizotinib in a young patient with pulmonary IMT. Therefore, ceritinib was administered as a second-line treatment leading to disease control for three months.Currently, there is no regulatory approved treatment for advanced IMT. Initial treatment by crizotinib as an off-label agent in ALK re-arranged IMT is highly recommended. Data for upfront use of new generation ALK inhibitors are sparse, and even crizotinib may be unavailable for patients in developing countries due to the high cost. The mechanism of acquired resistance to crizotinib in an ALK-positive IMT, and the management of drug resistance remain unanswered. From a future perspective, another question is at what point should ALK inhibitors be introduced? Given the aggressiveness of EIMS, is there any point in introducing adjuvant therapy after complete surgery, and if so, for how long? Furthermore, the use of ALK inhibitors in the neoadjuvant setting could be an excellent opportunity however, evaluating the benefit of adjuvant therapy is extremely challenging in such a rare disease. In the real world, patients tend to perform worse than clinical trial participants, limiting the ability to initiate and complete adjuvant therapy due to postoperative complications and decreased treatment tolerance. In addition, the neoadjuvant approach offers the unique opportunity to study radiological and adaptive responses of tumors to systemic therapy, which can be potentially used for prognostic purposes and to tailor adjuvant treatment strategies. At least one case of neo-adjuvant use of an ALK inhibitor has been described. In 2015, Rafee et al. reported a case in which an excellent response after 8 months of treatment with ALK inhibitor allowed for subsequent surgical management . This alIMT is a challenging disease and a perfect example of personalized medicine with the wide use of NGS. The best TKI strategy for ALK-positive IMTs is still yet to be determined. In addition to targeting ALK, more data are needed regarding the effectiveness of other TKIs, as well as regarding alternative treatment modalities such as chemotherapy and immunotherapy. Recently, long-term remission with rituximab for up to 19 months has been reported in a young, heavily pre-treated patient with lung IMT .The accumulation of further cases of IMTs is crucial. These data will not only allow for a better understanding of this rare tumor type but will also suggest rational targeted therapeutic strategies for existing TKIs, based on the genomic profile of the tumor.Considering the rarity of IMS, it is unlikely that we will get an answer to these questions soon, thus the inclusion of patients in clinical studies should always be encouraged.