To determine whether sirolimus, a mechanistic target of rapamycin (mTOR) inhibitor, reduces epileptic seizures associated with focal cortical dysplasia (FCD) type II.Sixteen patients (aged 6–57 years) with FCD type II received sirolimus at an initial dose of 1 or 2 mg/day based on body weight (FCDS‐01). In 15 patients, the dose was adjusted to achieve target trough ranges of 5–15 ng/mL, followed by a 12‐week maintenance therapy period. The primary endpoint was a lower focal seizure frequency during the maintenance therapy period. Further, we also conducted a prospective cohort study (RES‐FCD) in which 60 patients with FCD type II were included as an external control group.The focal seizure frequency reduced by 25% in all patients during the maintenance therapy period and by a median value of 17%, 28%, and 23% during the 1–4‐, 5–8‐, and 9–12‐week periods. The response rate was 33%. The focal seizure frequency in the external control group reduced by 0.5%. However, the background characteristics of external and sirolimus‐treated groups differed. Adverse events were consistent with those of mTOR inhibitors reported previously. The blood KL‐6 level was elevated over time.The reduction of focal seizures did not meet the predetermined level of statistical significance. The safety profile of the drug was tolerable. The potential for a reduction of focal seizures over time merit further investigations. Fewer than 20% of patients with focal cortical dysplasia (FCD) have transient responsiveness to pharmacotherapy,MTOR) and other genes correlated with the mTOR signaling pathway, such as AKT3 and PIK3CA, have been identified in the pathological brain tissues of patients with FCD type IIa or IIb.MTOR is the most frequent causative gene for FCD IIa or IIb and the second common causative gene for hemimegalencephaly . An independent data and safety monitoring board reviewed the trial progress. Written informed consent was obtained from all patients or their legal guardians prior to study enrollment. Able patients under 16 years provided consent. This study was registered at the University Hospital Medical Information Network Clinical Trial Registry (UMIN000033504).Patients with a body weight of <40 and ≥40 kg received oral sirolimus as a tablet at an initial dose of 1 and 2 mg/day, respectively, once a day. The dose was adjusted to achieve the target blood trough levels (range: 5–15 ng/mL) during the 8–24‐week titration period (dose‐adjustment phase). If the concentrations were <5 ng/mL, the daily sirolimus dosage was increased by 1 mg every 2 weeks until the 8th week, and then every 4 weeks until the 24th week. From the time when the trough concentration reached the target range, or after 24 weeks if the trough concentration did not reach the target range, 12‐week maintenance therapy was started. The participants visited the hospitals at 4, 8, and 12 weeks during the maintenance therapy period. No further adjustments were made during this period unless medication‐related adverse events required treatment, discontinuation, or dosage adjustment to half of the current dose.The primary endpoint was a reduced frequency of focal seizures , which is a main seizure type in patients with FCD, per 28 days during the maintenance therapy period. Patients or their guardians recorded data in a seizure diary throughout the study. The secondary endpoints were changes in the frequency of generalized seizures, epileptic spasms, and status epilepticus; response rate, which is the percentage of patients showing a ≥50% reduction in the frequency of focal seizure during the maintenance therapy period; proportion of patients who are free from focal seizure during the maintenance therapy period; decreased incidence and response rates of focal seizures at 4, 8, and 12 weeks in the maintenance therapy period; and adverse events. During the study, adverse events were recorded and categorized based on the Common Terminology Criteria for Adverse Events version 4.03. All investigators completed the Columbia‐Suicide Severity Rating Scale trainingWe performed an exploratory investigation of the pharmacokinetics of sirolimus, correlation between combination drugs and pharmacokinetics of sirolimus, degree of decrease in seizure frequency using FCD registration data as the external control group, and changes in blood KL‐6 level, which is a chemical marker for pneumonitis (reference range: <500 U/mL),The sample size was 15, which was based on the feasibility of the study. The study was registered within the given period even if the sample size exceeded 15. To ensure efficacy, two analysis sets were used: full analysis set (FAS) and per protocol set (PPS). FAS was the main analysis set, and it comprised patients who were enrolled and treated with the drug. However, patients who had serious protocol violations, such as the absence of FCDS type II diagnosis or informed consent, and who were not eligible and without any data about seizure after drug administration were excluded from the FAS. Meanwhile, the PPS comprised patients from the FAS who had no serious protocol violation, met the provision of the clinical trial practice plan, and could be evaluated for efficacy according to the protocol. As for the reduction rate of focal seizures, the Wilcoxon one‐sample signed‐rank test was used to evaluate the null hypothesis against a median of 0. Moreover, the log‐transformed incidence of focal seizures, ratio of the maintenance therapy period to baseline, and 90% confidence interval (CI) were calculated. The response rate and proportion of patients who experienced focal seizure resolution and their 90% CI were examined. In addition, the frequency of focal seizures at baseline and at 4, 8, and 12 weeks was evaluated via a regression analysis with time as a fixed effect and the patient as a random effect, which was based on a negative binomial distribution with the response variable as the frequency of seizures (times/28 days) and the log‐transformed observation period as the offset variable. To examine differences in characteristics between the external control and sirolimus‐treated groups, the Fisher's exact test and Wilcoxon rank‐sum test were used. The propensity score of the groups (sirolimus‐treated/control) based on each characteristic was assessed. For the subgroup analysis, we calculated the rate of reduction of focal seizure frequency in patients who did and did not undergo surgery. In addition, changes from baseline in KL‐6 were assessed using the one‐sample Wilcoxon test. All statistical analyses were conducted using the SAS version 9.4 .n = 13). However, they were included in the safety analysis. Table n = 16). The patient's mean age was 16.7 ± 12.1 years (mean ± standard deviation [SD]), and the median age was 13 years. In addition, 13 patients underwent neurosurgery; six and seven of these patients were classified as FCD type IIa and FCD type IIb, respectively. Three patients who did not undergo neurosurgery presented with FCD type II, which were classified according to brain MRI findings. Patient 11 who had a pathogenic variant of MTOR (NM_004958:c.4448G>A:p.Cys1483Tyr) with a variant allele frequency of 4% in the surgically resected brain tissue atypically experienced her first seizure at 53 years of age. Focal seizure types were classified as focal awareness seizure (n = 7), focal impaired awareness seizure (n = 12), and focal to bilateral tonic–clonic seizure (n = 4). The daily dose during the maintenance therapy period was 2 or 4 mg (Table Sixteen patients (aged 7–57 years) were screened, and none dropped out during the baseline phase. One patient Patient 13) dropped out during the dose‐adjustment phase due to the use of prohibited drugs  for status epilepticus, which had occurred repeatedly before administration of sirolimus. This patient had no data on seizure frequency during the maintenance therapy period; thus, the data were eliminated from the efficacy analysis in FAS. Further, two more patients were excluded from the FAS due to non‐compliance and use of prohibited drugs . The estimated frequency of focal seizures per 28 days were 32.3 (90% CI: 14.8–70.7) at baseline, 23.0 (90% CI: 10.5–50.3) at 1–4 week, 17.4 (90% CI: 7.9–38.2) at 5–8 week, and 19.4 (90% CI: 8.8–42.5) at 9–12 week . Similar results were observed in the PPS. The median frequency of focal seizures per 28 days at baseline and during the maintenance therapy period were 22.0  and 18.2 , respectively, in the PPS. The median reduction rate of focal seizure frequency per 28 days during the maintenance therapy period was 25% . The response rate was 33% . One patient (Patient 16) was free from seizure during the maintenance therapy period . The frequency of generalized seizures per 28 days (mean ± SD) at baseline and during the maintenance therapy period were 5.9 ± 15.69 (range: 0–47) and 2.5 ± 9.3 (range: 0–36), respectively. None of the patients showed epileptic spasms or status epilepticus at baseline or during the maintenance therapy period.The median frequency of focal seizures per 28 days at baseline and the maintenance therapy period in the FAS were 24.0 (range: 4.0–1122.0) and 18.2 (range: 0–867.4), respectively. The median reduction rate of focal seizure frequency per 28 days during the maintenance therapy period was 25% (range: −89% to 100%), which was not a substantial change (p < 0.15) affected age and frequency of focal seizures, epileptic spasms, sensory disturbance, and surgical intervention. The propensity score based on age, age at disease onset, baseline frequency of focal seizures, and surgery differed between the external control and sirolimus‐treated groups (median [interquartile range] of 0.02 [0.01–0.16] and 0.67 [0.32–0.77]). Because comparability could not be guaranteed, we did not estimate the difference in the reduction rate of focal seizure frequency between the two groups. However, the median reduction rates for the external control and sirolimus‐treated groups were 0.5% and 25%, respectively. In the subgroup analysis of patients who did and did not undergo surgery, the median rate of reduction of focal seizure frequency for the external control and sirolimus‐treated groups were 0% (n = 19) and 25% (n = 13) in patients who underwent surgery and 5% (n = 41) and 10% (n = 2) in patients who did not undergo surgery, respectively.Figure n = 16, range: 129–501) at baseline, and it increased to 185 , 243 , and 243  at week 4 of the dose‐adjustment phase, just before the maintenance therapy period and at week 12 of the maintenance therapy period, respectively  was comparable to that of everolimus, another mTOR inhibitor, for treatment‐resistant seizures in patients with TSC.The average trough level of sirolimus was relatively lower than the anticipated value during the maintenance therapy period. There was no difference in terms of trough levels between five responders (5.2 ± 1.6 ng/mL) and 10 nonresponders (4.9 ± 2.1 ng/mL). Everolimus had a dose or blood level‐dependent effect against seizure in patients with TSC, with a response rate of 28.2% for a low‐trough level (3–7 ng/mL) and 40.0% for a high‐trough level (8–15 ng/mL).We included an FCD cohort (RES‐FCD) and collected clinical information from 60 patients who were included in the control group. The two groups differed in terms of background characteristics, thereby affecting the prognosis of seizures and comorbidities.All patients developed adverse events during the study period. The safety profile of this study was consistent with that of previous studies of patients treated with sirolimus or everolimus.MTOR are most commonly associated with FCD type II.MTOR or other MTOR‐related genes respond more efficiently to sirolimus than those with condition not related to elevated mTOR function. Mutation analysis of brain tissue, which should ideally be performed prior to sirolimus treatment, is not always possible. FCD is mainly caused by a somatic mosaic mutation with low‐frequency mutant allele, which requires deep sequencing for detection, and samples of pathological brain tissues are needed for examination. In terms of practical use, the diagnosis of FCD type II would be a minimum requirement for selecting patients eligible for sirolimus.Only one patient underwent mutation analysis. Somatic activating mutations in Most patients with FCD experience their first seizure within the first 5 years.The current study has several limitations. That is, a placebo group was not included. The background characteristics of external control and sirolimus‐treated groups, including the proportion of patients with pathology‐proven FCD type II, differed. Moreover, the number of participants were limited, and the trial duration was relatively short. In total, 12 patients, including two from the preceding proof‐of‐concept study (manuscript submitted), received continuous sirolimus treatment in the extension trial. However, further investigations must be performed to confirm the efficacy and safety of short‐ and long‐term treatment with sirolimus.In conclusion, the reduction of focal seizures did not meet the predetermined level of statistical significance. The safety profile of the drug was tolerable. The potential for a reduction of focal seizures over time merit further investigations in large and long‐term trials.M. K. contributed to the conception of the study; M. K., A. Kada, J. T., and A. M. S. contributed to the design of the study; M. K. and A. Kada contributed to the analysis of data and drafting the text or preparing figures; A. Kada contributed to statistical analysis; H. S., J. T., E. N., Y. T., and T. A. contributed to enrollment of the patient and collection and analysis of clinical data; A. Kakita contributed to neuropathological diagnosis; N. M. and A. F. contributed to molecular analysis; A. M. S. contributed to the management of data; Y. I. contributed to the design of the external cohort study.Y. T. received academic donation from Eisai. A. Kada, who is a member of the independent data monitoring committee of clinical trials, received personal fees from Bayer Yakuhin, Ltd. outside the submitted work. The other authors have no conflict of interest to disclose.ktmthr@gmail.com.De‐identified individual participant data (including data dictionaries) in addition to study protocols, statistical analyses, and informed consent forms will be made available upon publication to researchers who provide a methodologically sound proposal for the use of data. Proposals should be submitted to Table S1. Distribution of the causative genes in patients with each type of focal cortical dysplasia or hemimegalencephaly.Click here for additional data file.Table S2. Previous trials for epileptic seizures treated with mTOR inhibitors.Click here for additional data file.Table S3. All adverse events reported in patients receiving sirolimus.Click here for additional data file.


To describe the oral health profile of individuals who had undergone gastric bypass surgery (GBP) or sleeve gastrectomy (SG) to generate hypotheses for further studies.Fourteen individuals treated with GBP or SG surgery ≥ 2 years ago and with observed and/or perceived oral problems were recruited to a case series. The documentation included clinical and radiographic examinations, biomedical sampling, and self‐reported diet and questionnaires. The results are presented descriptively.Results: The age range was 31 to 66 years and all had a BMI > 25 (range 25.4–44.7). Only four participants were fully dentate. Eleven out of 14 individuals exhibited severe decay. A majority had poor oral hygiene and high bacterial counts. The flow rates of unstimulated saliva were extremely low and hyposalivation was present in ten of the fourteen cases. Most perceived several oral health problems, such as chewing difficulty and tooth hypersensitivity.Individuals who had undergone GBP or SG surgery had poor clinically diagnosed oral health and perceived oral health problems. Longitudinal studies are needed to monitor the patients' oral health, from before bariatric surgery to long‐term postoperatively. The cor2 WHO, . Obesity2 WHO,  however,2 WHO, .2 or a BMI≥35 kg/m2 in presence of obesity‐related comorbidities f.i. diabetes or hypertension  and nutritional deficiencies . However, the long‐term adverse effects are not fully elucidated  approved the study and all participants provided written consent.2.1Recruitment took place through a network of dental practitioners and health care professionals, such as physicians, dieticians and nurses in the western part of Sweden, who in their work identified patients with oral health problems after bariatric surgery. This selection generated a kind of convenience sample.The participants filled out a 4‐day food record prior to the dental visit. They were instructed to eat according to their normal everyday meal patterns while keeping a detailed record during four consecutive days (three weekdays and one weekend day). Instructions were also given to express the quantities using common household measures and kitchen scales, and to provide detailed descriptions of the food items, portion sizes and type of meals. The food records were analyzed by a registered dietician (SB) using the software Dietist Net Pro® and the National Food Composition Tables version 20171215. Meal frequencies and total daily energy intake were calculated and the distribution of the nutrient content was analyzed.At the dental visit, the participants first filled in a questionnaire. Oral health habits were represented by tooth brushing , interdental cleaning , frequency of dental appointments during the last 5 years , and the reason for the last dental visit . Possible oral problems included tooth hypersensitivity, acid reflux episodes and vomiting episodes . The participants rated their chewing ability . Their Oral Health‐Related Quality of Life (OHRQoL) was assessed using the Oral Health Impact Profile (OHIP‐14) Slade, . The res2).A medical history was recorded in connection with the dental examination. Height (cm) and weight (kg) wearing light clothes were registered and Body Mass Index (BMI) was calculated (kg/m®). Total bacterial count, total streptococci count, streptococcus mutans (SM) and lactobacilli, all per colony‐forming unit (CFU)/ml of stimulated saliva were analyzed at the laboratory of the Department of Cariology, Institute of Odontology, University of Gothenburg, Sweden. Salivary electrolytes were analyzed at the Clinical Chemistry laboratory, Sahlgrenska University Hospital, Gothenburg, Sweden  of the stimulated saliva was determined chairside . The third molars were excluded from all examinations.Dental caries was registered by visual and radiographic examination. Visual assessments of all tooth surfaces  were made according to the International Caries Assessment System II (ICDAS)  visible dental plaque, 0/1; (b) gingivitis, bleeding on probing, (0/1) and (c) probing pocket depths : healthy (<3.5 mm) or pathological (≥ 3.5 mm) Löe, .2.2SDs and minimum‐maximum scores.Data management and analyses were carried out using SPSS version 25. Results are presented with descriptive statistics including mean values, 3A total of 14 subjects were examined, with an age range of 31–66 years. Six participants were younger than 40 years, five were between 40 and 59 years old and three were 60 years or older. Two were males. All participants had a BMI > 25 (range 25.4–44.7) at the time of the clinical examination. They had undergone bariatric surgery 2–19 years ago (mean 13 years) Table . Six of The number of remaining teeth ranged between 16 and 28 (mean 24), with only four participants being fully dentate. The proportion of clinically registered dental caries of any stage, ICDAS codes 1‐6, on the total number of examined surfaces in all participants was 26% (not in tables). Two‐thirds of all lesions were categorized as initial non‐cavitated caries (ICDAS 1‐2).SD 0.6, median 1.1), while the mean unstimulated secretion rate was 0.08 ml/min . Four participants did not produce any unstimulated saliva. The majority (n = 12) had a medium or high salivary buffer capacity. The total bacterial count (206–3206) and the total number of streptococci (2.96–666) in the saliva were considerable. Four participants had a count of SM in the span 100,000–1,000,000 CFU/ml and six participants had ≥1,000,000 CFU/ml. Lactobacilli were present in the saliva from all participants, with half of them having a count of ≥100,000. As can be seen in Table Dental caries and periodontal status, for all 14 participants separately, are presented in Table ount 206–206 and tThe outcomes in patient‐reported variables are displayed in Table A majority reported regular dental visits and tooth brushing twice daily. However, nine participants reported some difficulty chewing, and six noted problems with tooth hypersensitivity daily or several times a week. Slightly fewer (five participants) reported reflux problems but only one (participant 3) had frequent vomiting episodes (not in tables). All participants reported an impact on their OHRQoL, with a mean OHIP score of 22 with a wide range (1–44).4The overall picture from this case series was that the participants had poor oral health. They all showed manifestations of oral disease; that is, dental caries and/or periodontal disease at different stages. The salient findings were the frequent occurrence of hyposalivation and the large amounts of microbiota. The participants also perceived many impacts on their oral health. The results indicate that post‐bariatric individuals are a vulnerable group that may require special attention provided by the dental team and continuous dental care.Many of the subjects had a lower number of retained teeth, more caries and fillings than similar age groups in the general Swedish population  exhibited hyposalivation for unstimulated saliva (Nauntofte, Tenovuo, & Lagerlöf, Another salient finding were the high bacterial counts in saliva. Especially the SM count mirrors the intake of carbohydrates and sucrose (Beighton, Adamson, & Rugg‐Gunn, The self‐reports revealed various ailments, such as tooth hypersensitivity, chewing difficulties and reflux, in line with an earlier study (Taghat, Werling, & Östberg, The design for this study—a case series—infers no generalizable results, which is an obvious limitation of the study. Our aim was however to generate hypotheses for further longitudinal studies which can be considered achieved. Especially the frequent hyposalivation and high numbers of microbiota needs further investigation. The lack of information about the subjects' pre‐operative dental status is a disadvantage and no causation can be claimed due to the study design. The elapsed time after surgery varied among subjects which is another limitation however gained insight into possible long‐term effects of bariatric surgery on oral health.The multidisciplinary recruitment in both general and dental health care likely provided a diversity of subjects. The uneven distribution by gender mirrors the larger number of women than men who undergo bariatric surgery (Guerra, Jean, Chiu, & Johnson, In conclusion, individuals who had undergone GBP or SG surgery had poor clinically diagnosed oral health and perceived many oral health problems. Longitudinal studies are needed to monitor bariatric patients' oral health, from before bariatric surgery to long‐term postoperatively.The authors have no conflicts of interest to disclose.Negin Taghat: conceptualization, formal analyses, writing: original draft and final version of manuscript, funding acquisition.Karin Mossberg: methodology—medical aspects, writing—review and editing.Peter Lingström: methodology—dental aspects, resources, writing—review and editing.Sofia Björkman and Anna Lehrkinder: analyses, writing—review and editing.Malin Werling: conceptualization, writing—review and editing.Anna‐Lena Östberg: conceptualization, methodology, data curation, formal analyses, funding acquisition, supervision, writing: original draft and final version of manuscript.Table S1. ICDAS coding rationaleClick here for additional data file.


Micro‐ and macroparasites are a leading cause of mortality for humans, animals, and plants, and there is great need to understand their origins, transmission dynamics, and impacts. Disease ecology formed as an interdisciplinary field in the 1970s to fill this need and has recently rapidly grown in size and influence. Because interdisciplinary fields integrate diverse scientific expertise and training experiences, understanding their composition and research priorities is often difficult. Here, for the first time, we quantify the composition and educational experiences of a subset of disease ecology practitioners and identify topical trends in published research. We combined a large survey of self‐declared disease ecologists with a literature synthesis involving machine‐learning topic detection of over 18,500 disease ecology research articles. The number of graduate degrees earned by disease ecology practitioners has grown dramatically since the early 2000s. Similar to other science fields, we show that practitioners in disease ecology have diversified in the last decade in terms of gender identity and institution, with weaker diversification in race and ethnicity. Topic detection analysis revealed how the frequency of publications on certain topics has declined , increased , remained relatively common , or have consistently remained relatively infrequent . Other topics, such as climate change, superspreading, emerging infectious diseases, and network analyses, have recently come to prominence. This study helps identify the major themes of disease ecology and demonstrates how publication frequency corresponds to emergent health and environmental threats. More broadly, our approach provides a framework to examine the composition and publication trends of other major research fields that cross traditional disciplinary boundaries. Here, we describe the composition and research trends in the growing field of disease ecology using a large survey and powerful literature synthesis. Disease ecology practitioners are more diverse in terms of gender, but less so in terms of race and ethnicity and country of research. Research trends have followed global disease events , with some foci increasing in publication frequency , some decreasing , and some remaining stable and prominent . Finally, articles with fewer than four citations were removed as a form of quality control.The final literature search was conducted in Web of Science for the years 1975 to 2018. Each article had to meet specific criteria using Boolean filters, including a focus on studying a pathogen or parasite, host infections , and individual‐level or higher‐order dynamics . The full list of search terms is provided in the Appendix κ = 0.84). Within false‐positive papers, there was no association between topical and temporal trends  independently evaluated the same 100 randomly selected articles and classified them as “disease ecology” or “outside the field.” Papers that fell outside the field predominantly described pathogenesis, bacterial communities, or genetics/genomics Figure . Within‐To evaluate false negatives, we cross‐validated our corpus using our survey data. Specifically, we assessed whether articles that were identified by at least two survey participants as influential were present in our corpus. We calculated the proportion of papers that were included in our corpus out of the list of such articles, with the requirement that at least 70% of papers had to be included. Of the influential articles identified by survey participants (written ≥2 times) restricted to journals used in building the corpus, approximately 71% (50/70) were present in the corpus. The “most influential” articles had a higher probability of being included: the corpus included 85% of articles written four or more times, 75% of articles written three times, and 63% of articles written twice. We adjusted the search and exclusion terms twice using the workflow described in Figure 2.3i) and words per topic (j) were the only parameters imposed on the literature analysis. To select appropriate values for i and j, we ran topic detection for a range of values and combinations of i and j and assessed outputs. If i was too small or too large, we were unable to detect temporal variation in that topic. If j was too small or too large, the topics were not clearly defined. For example, a topic with only five words may not be interpretable; similarly, a topic with 30 words may be too broad to assign meaning. We used i = 15 and j = 15, so our corpus was analyzed for 15 topics with 15 words each. A “topic” therefore describes the frequency of co‐occurring words or phrases in the literature corpus; topics could span any number of interests, methods, taxa, or set of words/phrases that emerged from the literature or are of interest to researchers.We conducted topic detection on the validated corpus using non‐negative matrix factorization. Topic clusters represent a set of co‐occurring words that can be used to define an area of research. The number of topic clusters  at the zero‐year lag.We used K‐means clustering from the Appendix . To ensu R Wood, . The pro33.1n = 348; categorized as: ≤25, 26–30, 31–35, 36–40, 41–50, 51–60, >60). 76.7% of participants (n = 408) considered at least half of their research to fall within disease ecology. Participants that considered ≥75% of their research to be disease ecology were concentrated from ages 26–40 and most self‐identified as women . More broadly, 56.1% of participants identified as women (n = 231), 42.5% as men (n = 175), 0.7% as non‐binary (n = 3), and 0.7% preferred not to say (n = 3). We report on participants that chose to disclose a gender identity for results regarding gender.A total of 413 self‐declared disease ecologists participated in the survey. The average respondent was 36.1 years old , and the oldest age category (>60 years) was 85.0% men (n = 20). Current positions held by survey participants were as follows: undergraduate student , master's student , PhD student , postdoctoral researcher , faculty , researcher , and other . Participants identifying as women comprised most of each academic position except Master's student and faculty (Table n = 3), as were participants who preferred not to provide a gender identity (n = 3).Most participants identifying as women were younger (age ≤35) than most participants identifying as men (age 26–50). The youngest age category (≤25 years) was 68.9% women (ty Table . In genety Table . Non‐binn = 382), 50.0% had completed their master's degree by 2018 (n = 206), and 73.3% had completed their PhD by 2018 (n = 302). 8.3% of participants had also earned an additional degree, most commonly as a Doctor of Veterinary Medicine (n = 18). Nearly half of participants had a PhD but not a master's degree . The total number of graduate degrees earned per year among disease ecology researchers has dramatically increased since the year 2000 . The least common areas included behavioral ecology, bioinformatics, field and laboratory techniques, movement ecology, virology, landscape ecology, and zoology.The most popular areas of research within disease ecology were ranked as: epidemiology, mathematical modeling, population ecology, wildlife ecology/management, parasitology, community ecology, and infectious disease evolution/life history  were most often published in Science (n = 17), Nature (n = 10), Trends in Ecology & Evolution (n = 9), Ecology Letters (n = 8), and Proceedings of the National Academy of Sciences (n = 6). Interestingly, however, Proceedings of the Royal Society ‐ Biology was ranked as the most influential journal by survey participants, followed by Ecology Letters, Proceedings of the National Academy of Sciences, Ecology, and Journal of Animal Ecology  those that emerged and were identifiable from the literature and (2) those that we deliberately searched for using key term searches. Of emergent topics, malaria and mosquito‐borne pathogens appeared most frequently in the topic clusters (3/15), followed by experimental infection trials (2/15). Other clear topics included HIV, influenza, vaccine research, and host–pathogen coevolution. Some topics were more ambiguous but still identifiable, such as wildlife pathogens, tick‐borne pathogens with rodent hosts, and serological analyses. Overall, we had high confidence assigning names to topic clusters emerging from the literature, indicating defined areas of research in the corpus , the dilution effect, superspreaders, network analysis, pathogens in rodents, pathogens in bats, chytrid fungus in amphibians, theoretical modeling, and field experiments Figure . As withρ = −0.89–0.88; Figure ρ = 0.88), superspreaders and the dilution effect (ρ = 0.85), EIDs and bats (ρ = 0.83), EIDs and the dilution effect (ρ = 0.83), EIDs and network analysis (ρ = 0.82), and superspreaders and bat pathogens (ρ = 0.80). Especially strong negative correlations were observed for EIDs and serology (ρ = −0.89), serology and the dilution effect (ρ = −0.87), serology and bat disease (ρ = −0.81), influenza and HIV (ρ = −0.77), climate change and HIV (ρ = −0.76), network analysis and serology (ρ = −0.70), influenza and rodent disease (ρ = −0.68), climate change and serology (ρ = −0.68), malaria and network analysis (ρ = −0.65), and malaria and rodent disease (ρ = −0.65).Frequencies of published topics displayed strong degrees of cross‐correlation, with both positive and negative covariation in annual trends  . Emergent topics were remarkably stable through time, with the exception of HIV and host–pathogen coevolution, which have, respectively, decreased and increased. The frequency of published research focusing on concepts  or approaches  rather than specific hosts or pathogens tended to rise more gradually and remain a notable proportion of the literature. Interestingly, self‐declared disease ecologists performed experimental, observational, and computational research equally Figure ; howeverAlthough our analysis of cross‐correlation between the topic frequency time series is associative, we observed several interesting relationships. The frequency of publications on bat disease, chytrid fungus, climate change, the dilution effect, superspreaders, and emerging infectious diseases all increased over time, suggesting a general increase in research on emergent disease risks to wildlife and humans in relation to anthropogenic change and heterogeneities in pathogen transmission ; Data curation (lead); Formal analysis (lead); Methodology ; Project administration (lead); Writing – original draft (lead). Daniel Becker: Conceptualization ; Formal analysis (supporting); Methodology ; Visualization ; Writing – review & editing . Laura Sampson: Conceptualization ; Data curation (supporting); Formal analysis ; Methodology ; Writing – review & editing (supporting). Kristian Forbes: Conceptualization ; Methodology ; Visualization (supporting); Writing – review & editing .Appendix S1Click here for additional data file.


MALAT1 gene polymorphism was associated with cardiac and cerebrovascular diseases. However, the prognostic role of the MALAT1 polymorphism in major adverse cardiac and cerebrovascular events (MACCEs) remains unknown. Therefore, this study intends to explore the association between the MALAT1 rs3200401 polymorphism and MACCEs.Metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) participates in the occurrence and development of cardiovascular and cerebrovascular diseases such as stroke and coronary heart disease by regulating inflammatory reactions, programmed cell death, and other pathological processes. Previous studies revealed that the MALAT1 rs3200401 genotype. During the follow-up, MACCEs were recorded. Kaplan–Meier curves and univariate and multivariate Cox survival analyses were used to explore the correlation between MALAT1 gene polymorphisms and the occurrence of MACCEs.We enrolled 617 myocardial infarction (MI) patients and 1125 control participants who attended the First Affiliated Hospital of Xinjiang Medical University from January 2010 to 2018. SNPscan™ typing assays were used to detect the P = 0.047, MI patients 20.7% vs. 14.1%, P = 0.014) and CT + TT genotypes  were significantly higher in subjects with MACCEs than in subjects without MACCEs. However, in control participants, the frequencies of the T allele  and CT + TT genotypes  were not higher in subjects with MACCEs than in subjects without MACCEs. In addition, among the total participants and MI patients, the Kaplan–Meier curve analysis indicated that the subjects with rs3200401 CT + TT genotypes had a higher incidence of MACCEs than CC genotype carriers . Nevertheless, similar results were not observed in the control participants (P = 0.790). Multivariate Cox regression indicated that compared with patients with the CC genotype, patients with CT + TT genotypes had a 1.554-fold increase in MACCE risk .Among the total participants and MI patients, the frequencies of the T allele (total Participants 19.5% vs. 15.3%, MALAT1 rs3200401 CT + TT genotypes could be a risk factor for MACCEs in MI patients, suggesting that the MALAT1 gene may become a biomarker for poor prognosis in MI patients.The  Currently, with the aging of Chinese society and the development of urbanization, cardiac and cerebrovascular diseases, such as stroke, hypertension, and coronary heart disease, have become the leading killer diseases in China. Myocardial infarction (MI) is the main cause of mortality and disability among cardiac and cerebrovascular diseases. The death rate of MI increased by 3 times from 2010 to 2018 .In MI patients, compared with the nonMACCE group, patients in the MACCE group were older  and had lower levels of ApoA .For the control participants, compared with the nonMACCE group, subjects in the MACCE group were also older (59.76 ± 9.80 vs. 54.53 ± 9.96, P = 0.047, CT + TT genotypes, 37.4% vs. 28.1%, P = 0.013, Table Among the total participants, the MACCE group had higher frequencies of the rs3200401 T allele and CT + TT genotypes than the nonMACCE group (T allele, 19.5% vs. 15.3%, P = 0.014, CT + TT genotypes, 39.5% vs. 25.8%, P = 0.003, Table Similarly, in the MI patients, the MACCE group had higher frequencies of the rs3200401 T allele and CT + TT genotypes than the nonMACCE group (T allele, 20.7% vs. 14.1%, P = 0.860, CT + TT genotypes, 31.4% vs. 29.4%, P = 0.760, Table However, for the control participants, we did not observe a prominent difference in the distribution of the rs3200401 T allele or CT + TT genotypes between the MACCE group and the nonMACCE group (T allele, 16.7% vs. 16.0%, P = 0.381, Table P = 0.732, P = 0.076, Table P = 0.567, Table Among the MI patients carrying the CT + TT genotypes or the CC genotype, there was no significant difference in the number of lesion coronary arteries (P = 0.015, Fig. P = 0.001, Fig. P = 0.790, Fig. The Kaplan–Meier analysis revealed that among all participants and MI patients, the MACCE-free cumulative survival rate in the CT + TT genotype group was obviously lower than that in the CC genotype group (P = 0.031, Table Further, univariate Cox survival analysis was used to determine the risk factors for MACCEs among the total participants. The analysis showed that the rs3200401 CT + TT genotype, history of MI, male sex, age, diabetes, Gensini score, number of lesion coronary arteries, revascularization, admission blood glucose, TG, HDL-C, and ApoA were all MACCE risk factors. The multivariate Cox regression analyses suggested that the CT + TT genotypes of rs3200401 were associated with a risk for MACCEs (HR: 1.441, 95% CI 1.035–2.084, P = 0.024, Table In addition, we studied the risk factors for MACCEs among MI patients with univariate Cox survival analysis. It indicated that the CT + TT genotypes of rs3200401, age, smoker, drinker, hypertension, Gensini score, number of lesion coronary arteries and TG were all risk factors for MACCE. After adjustment by multivariate Cox regression analyses, patients with the CT + TT genotypes of rs3200401 were associated with a higher risk of MACCEs than those carrying the CC genotype (HR: 1.554, 95% CI 1.060–2.277, MALAT1 gene polymorphism and MACCE and found that subjects carrying the CT + TT genotypes of rs3200401 were susceptible to MACCE, especially MI patients.In the present study, we investigated the relationship between the Human genome sequencing and the GENCODE project launched in 2003 have revealed that the minority of the human genome can be translated into proteins and that the majority of the genome is primarily transcribed to produce noncoding RNAs , proteinMALAT1 gene rs3200401 CT + TT genotypes were associated with better survival in patients with advanced lung adenocarcinoma [MALAT1 rs3200401 polymorphism and MACCEs occurring among MI patients and control participants and found the rs3200401 CT + TT genotypes were independent factors of MACCEs among MI patients. Nevine Fathy et al. reported that the CT + TT genotypes of rs3200401 were the independent predictors of cerebral ischemic stroke in Egypt [MALAT1 gene rs3200401 polymorphism may be a potential functional mutation that deserves further research and may be a genetic biomarker of MACCEs susceptibility among MI patients.Jian-Zhong Wang et al. first discovered that the arcinoma . In our in Egypt . Moreovein Egypt . Furtherin Egypt , we specin Egypt , and thein Egypt , while Hin Egypt . Taken tMALAT1 gene rs3200401 CT + TT genotypes and MACCE. However, we did not measure the level of lncRNA MALAT1 in plasma, resulting in the linkage between the expression of lncRNA MALAT1 in plasma and MACCE being undetected, which deserves further research.In the present study, there were several limitations. First, this was not a multicenter and large-sample study, which would provide less robust statistical estimations. Second, compared with the MACCE group, the participants were a little older than the participants in the nonMACCE group and it may leave the possibility that the predictive power of the MALAT1 gene rs3200401 polymorphism for MACCE could be influenced. After adjusting the confounders via multivariate Cox regression analyses, the MALAT1 gene rs3200401 CT + TT genotypes remained the risk factor for MACCEs in MI patients. However, age was not the risk factor for MACCEs so the age was not the confounder of MACCEs in this study which did not significantly influence the power of MALAT1 gene rs3200401 polymorphism for MACCEs. Third, we only analyzed the association between MALAT1 gene played an important role in the prognosis of MI patients and that the MALAT1 gene rs3200401 CT + TT genotypes are risk factors for the poor prognosis of MI patients, suggesting that the MALAT1 gene can be used as a biomarker susceptible to MACCE for MI patients. Further gene sequencing for individuals with traditional risk factors could help to identify whether they carry MALAT1 rs3200401 CT + TT genotypes, which may help clinicians distinguish high-risk MACCE patients with a history of MI. This is also the real purpose of precision medicine.In summary, these results indicated that the MALAT1 rs3200401 CT + TT genotypes could be a risk factor for MACCEs in MI patients, suggesting that the MALAT1 gene may become a biomarker for poor prognosis in MI patients.In conclusion, our study revealed that


AF progression phenotypes were defined as paroxysmal AF with/without low voltage areas (LVA) and persistent AF with/without LVA. While arginine, ADMA, and hArg were within reference limits for healthy controls, SDMA was higher in the AF cohort (0.57 ± 0.12 vs. 0.53 μmol/L (97.5th percentile in reference cohort)). SR restoration in AF patients resulted in normalization of SDMA concentrations . Patients with AF at the time of blood sampling had significantly lower hArg  and higher ADMA concentrations  compared with AF patients in SR. hArg concentrations were lower in patients with advanced AF progression phenotypes (persistent AF with LVA (p = 0.046)) independent of heart rhythm at blood sampling. Summarizing, arginine metabolism imbalance is associated with AF in general and AF progression and may contribute to associated risk.Arginine, homoarginine (hArg), asymmetric dimethylarginine (ADMA), and symmetric dimethylarginine (SDMA) affect nitric oxide metabolism and altered concentrations are associated with cardiovascular morbidity and mortality. We analyzed these metabolites using liquid chromatography–tandem mass spectrometry in patients with atrial fibrillation (AF)  contains supplementary material, which is available to authorized users. Atrial fibrillation (AF) is the most common sustained arrhythmia worldwide . The proLA remodeling is associated with impaired myocardial mechanics and unfavorable pathophysiological conditions such as oxidative stress . OxidatiRestoration of SR in AF patients was also found to ameliorate endothelial function in AF patients , 17. Theĸ, 1)α × max − 1.209 × 0.993 age × 1.018 [if female] × 1.159 [if black], where Scr is serum creatinine, ĸ is 0.7 for females and 0.9 for males, α is − 0.329 for females and − 0.411 for males, min indicates the minimum of Scr/ĸ or 1, and max indicates the maximum of Scr/ĸ or 1 [The AF cohort was recruited from October 2015 until April 2017 including consecutively selected AF patients undergoing their first AF radiofrequency catheter ablation at the Heart Center Leipzig at the University of Leipzig  as previously described . PAF wasr/ĸ or 1 . Coronarα = 0.05, β = 0.8). Out of these 250 participants, nine had to be excluded due to insufficient sample quality or volume. We used all available samples (n = 241) for the secondary analyses reported herein.The cohort was initially recruited to detect an association of NT-proANP with LVA in AF patients . Based oThe study was approved by the local Ethical Committee  and all patients provided written informed consent for participation in accordance with the Declaration of Helsinki.We used standardized clinical AF phenotypes to build AF cohort subgroups: (1) LVA detection was performed peri-interventionally during AF catheter ablation and we compared patients with and without LVA , 3; (2) Catheter ablation procedure with isolation of the pulmonary veins and additional lesions if required was performed as reported previously  (see supg for 10 min at 20 °C) and aliquots were stored at − 70 °C for subsequent analysis.Blood samples from AF patients were obtained in EDTA tubes after fasting > 8 h from the femoral vein before trans-septal puncture and left atrial ablation. At follow-up examinations, blood was withdrawn from the cubital vein. Samples were processed within 1 h of collection. Blood plasma was prepared  were used to assess plasma arginine, ADMA, SDMA, and hArg concentrations –22 , Kruskal Wallis test (more than two groups), and Wilcoxon exact test was used for before-after ablation comparisons. Chi-square test was used for categorical variables. Correlations were analyzed using Spearman’s rank-order correlation.Data were analyzed for outliers by transformation into p value < 0.05 was considered statistically significant. All analyses were performed with IBM SPSS Statistics for Windows version 25 , SPSS statistical software version 23, and GraphPad Prism 8 .We analyzed arginine derivative concentrations in AF progression using different approaches. First, we compared the concentrations in patients with and without LVA and secondly, we used the concept of four AF progression stages Table . In a fi2, 41% PAF, 27% with LVA) were included. Patients with LVA were older, more often women, had more often persAF, hypertension, diabetes, vascular disease, lower eGFR, LA diameter, and CHAD2DS2-VASc score . Similarly, arginine concentration was higher in men compared with women .The baseline study cohort characteristics are presented in Table n = 128) or SR (n = 111) at the time of blood withdrawal. Patients in SR had significantly higher hArg  and lower ADMA . Heart rhythm was not related to arginine and SDMA concentration . Older age and AF at blood withdrawal were independent predictors of higher ADMA concentrations in multivariate analysis. Age correlated significantly with ADMA .Results of the univariate and multivariate regression analyses are presented in Table r = − 0.602, p < 0.0001). No associations were found for arginine in multivariate regression analysis.For SDMA, only eGFR was significantly associated in multivariate analysis Table . SDMA anp < 0.001 . ADMA and SDMA concentrations were not associated with LVA but were higher in advanced AF progression stages  . There was no relationship between arginine, ADMA, and SDMA concentrations and LVA or AF progression phenotypes.Due to a strong association between heart rhythm at blood withdrawal with hArg and ADMA concentrations as well as significant differences in sub-cohort characteristics, we used multivariate analysis to prove the association of arginine derivatives with LVA and AF progression stage Table . In multp < 0.01, Fig. p = 0.482). In patients with SR at baseline and follow-up arginine, ADMA and hArg concentrations did not change over time. ADMA concentrations were significantly lower at FU when patients were in AF at blood withdrawal (p = 0.008).There were 22 AF patients with restored SR after catheter ablation and available blood samples at 12–18 months follow-up (FU). SDMA concentrations of these 22 AF patients with restored SR at FU were 0.465 ± 0.082 μmol/L compared with 0.570 ± 0.134 μmol/L at baseline  [hArg was independently associated with AF progression phenotypes after adjustment for heart rhythm and sub-cohort differences in multivariate analysis. Recent results from genome wide association studies identified a strong link between plasma hArg concentrations and the enzyme L-arginine:glycine amidinotransferase  , 32, whie locus) , brain [e locus) , and to e locus) . Likewise locus) , 37. In e locus) . The ATPe locus) . AGAT thIn our study, SDMA was generally higher in patients with AF, but was not associated with AF progression. In contrast to hArg and ADMA, SDMA concentrations were not affected by acute changes in heart rhythm. We thus assumed that SDMA increase is rather a long-term consequence of AF. In line with this assumption, we found that SDMA significantly decreased following SR restoration below the reference limit of 0.533 μmol/L (97.5th percentile) determined for healthy individuals. We observed a correlation of SDMA with eGFR that is in line with recent findings . Renal dThe use of AF progression phenotypes is an evidence-based model that helps to characterize AF sub-populations. We are well aware that individual AF progression not necessarily proceeds through the four progression stages and that particularly the patients with PAF and LVA may be an entity with specific risk factors and a different pathomechanistic background. Nevertheless, we found the concept very helpful for the characterization of AF progression–associated markers. The impact of smoking, the duration of AF, often complex individual medication, and other biomarkers were not analyzed in this study although they might be of importance. Also, our observations of arginine derivative concentrations in AF patients with restored SR are based only on a small subgroup, that is why interpretation of these results should be cautious. The potential of SDMA as a biomarker of AF recurrence should be examined in a larger cohort considering its connection to patient’s renal function, i.e., eGFR . NeverthHeart rhythm at blood withdrawal affects ADMA and hArg concentrations in AF patients. Advanced AF progression phenotypes are associated with lower hArg concentration. SDMA is higher in AF and is ameliorated after SR restoration. Further studies are needed to evaluate the impact of hArg supplementation and/or lowering of ADMA/SDMA on AF progression.ESM 1(DOCX 445 kb)


Parkinson's disease (PD) is a neurodegenerative disorder with a significant immune component, as demonstrated by changes in immune biomarkers in patients' biofluids. However, which specific cells are responsible for those changes is unclear because most immune biomarkers can be produced by various cell types.The aim of this study was to explore monocyte involvement in PD.in vitro.We investigated the monocyte‐specific biomarker sCD163, the soluble form of the receptor CD163, in cerebrospinal fluid (CSF) and serum in two experiments, and compared it with other biomarkers and clinical data. Potential connections between CD163 and alpha‐synuclein were studied in vitro study showed that alpha‐synuclein activates macrophages and induces shedding of sCD163, which in turn enhances alpha‐synuclein uptake by myeloid cells, potentially participating in its clearance.CSF‐sCD163 increased in late‐stage PD and correlated with the PD biomarkers alpha‐synuclein, Tau, and phosphorylated Tau, whereas it inversely correlated with the patients' cognitive scores, supporting monocyte involvement in neurodegeneration and cognition in PD. Serum‐sCD163 increased only in female patients, suggesting a sex‐distinctive monocyte response. CSF‐sCD163 also correlated with molecules associated with adaptive and innate immune system activation and with immune cell recruitment to the brain. Serum‐sCD163 correlated with proinflammatory cytokines and acute‐phase proteins, suggesting a relation to chronic systemic inflammation. Our Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder SocietyOur data present sCD163 as a potential cognition‐related biomarker in PD and suggest a role for monocytes in both peripheral and brain immune responses. This may be directly related to alpha‐synuclein's proinflammatory capacity but could also have consequences for alpha‐synuclein processing. © 2020 The Authors.  Parkinson's disease (PD) is characterized by intraneuronal aggregations of alpha‐synuclein (α‐syn) and dopaminergic neuronal death in the midbrain. PD also involves early and chronic immune activation,These PD‐related immune biomarkers can be produced by multiple cell typesPatients with PD were recruited from the outpatient clinic and/or ward for PD, University Hospital of Tuebingen, Germany. Healthy control subjects (HCs) were assessed as having no neurodegenerative disease. All participants were examined by a neurologist specialized in movement disorders. A PD diagnosis was made according to the UK Brain Bank Society Criteria.This cross‐sectional study included serum and CSF from patients with idiopathic PD [early (<5 years) and late (≥5 years from diagnosis)] and HCs , and total α‐syn . MSD MULTI‐SPOT Assay System  was used to measure 40 different molecules in serum and CSF (see Supporting Information).sCD163 was measured in serum and CSF using an in‐house ELISA.Evaluation of sCD163‐α‐syn binding was done using Microscale Thermophoresis.Monocyte‐derived macrophages (MDMs) from isolated and maturated human monocytes125I‐α‐syn fibril uptake (50 ng/mL) alone or with sCD163 (5 μg/mL) as a co‐treatment or pre‐treatment. Full‐length (domains 1–9) or truncated (domains 1–5) sCD163 was used, and when stated, lipopolysaccharide (LPS) was removed from sCD163 preparations as described previouslyDifferentiated THP‐1 macrophage‐like cells or BV‐2 murine microglia cells were used to study GraphPad Prism V7, JMP 14, and STATA v15 IC were used for statistical analyses where normality was first informed (see Supporting Information).P = 0.008], sex effect P = 0.039, treatment effect P = 0.017). Therefore, we separated the data by sex, and to eliminate the treatment variable, we analyzed only treated patients. We found elevated serum‐sCD163 levels in women with late PD (versus early), but not in men , confirming elevated cerebral CD163 shedding.First, we investigated any PD‐related changes in sCD163 in Exp#1: biobank samples from 109 patients with PD and 44 HCs  and p‐Tau  in HCs. Because these biomarkers have been related to PD symptomatology, we examined putative correlations between sCD163 and patients' clinical scores. Remarkably, CSF‐sCD163 was negatively correlated with the cognitive scores Montreal Cognitive Assessment (MoCA) and Mini‐Mental State Examination (MMSE) in the patients with PD , even after compensating for age and disease duration Fig. . sCD163  PD Fig. . Serum‐s PD Fig. , even af PD Fig. . HoweverP = 0.004) and versus HCs . This suggests increased cerebral sCD163 production. We also confirmed the sex difference observed for serum‐sCD163 with an increase in female patients only  with a 2‐year time gap between experiments  and p‐Tau . Moreover, in Exp#2, CSF‐sCD163 was significantly correlated with levels of Abeta1–42  in Exp#2 Fig. . CSF‐sCD–42 Fig. . The ass–42 Fig. .Notably, this was also true for cognitive scores, which decreased while sCD163 increased in patients with PD Fig. . Age infP < 0.05: VCAM‐1 (vascular cell adhesion molecule 1), ICAM‐1 (Intercellular Adhesion Molecule 1), IL‐8, SAA (Serum amyloid A), PIGF , IL‐15, and VEGF‐D  were increased in patients with PD  and a significant linear regression Fig.  as expecTo statistically evaluate the potential of sCD163 and the other assayed markers to predict PD diagnosis (PD versus HC) and PD phenotypic scores , we used receiver‐operating characteristic (ROC) analysis [area under the curve (AUC) estimates] and linear regression (regression slopes)  . However, the specificity and sensitivity of sCD163 were not enough to be used alone. Therefore, we aimed to compute combined biomarker panels to address PD diagnosis and phenotypic scores using three variants of stepwise forward modeling with variable probability for biomarkers to enter the model (M) and with sCD163 being forced in M3  Fig. . After 5in vitro studies suggest that α‐syn itself can induce macrophage activation and sCD163 shedding, while sCD163 might enhance α‐syn uptake by myeloid cells and participate in the clearance of α‐syn. In conclusion, our data suggest that sCD163 is a promising biomarker associated with inflammation in PD, thereby supporting a role for α‐syn in monocyte activation and sCD163 shedding that could have direct consequences for α‐syn processing.Genetic data suggest that the PD inflammatory component is driven by the myeloid immune compartment, which includes microglia and monocytes/macrophage.Our analysis of the two experiments in the PD cohort showed increased sCD163 in biofluids from patients with PD. CD163 is cleaved by ADAM17,+ monocytes in the different PD stages. Higher CSF‐sCD163 levels were not a simple leakage from serum, because the increase was not found in male serum. Furthermore, the estimated amount of sCD163 produced intrathecally was, indeed, elevated in PD. The sCD163 found in CSF can be produced by CD163‐expressing meningeal, choroid plexus, and perivascular macrophages, as well as by infiltrating macrophages.+ cells has been observed in brain parenchyma in rodent PD models+ monocytes/macrophages and their subsequent local activation. Accordingly, CSF‐sCD163 was correlated with CCL2, CCL4, and CXCL10, chemokines involved in monocyte recruitment and previously correlated with PD symptoms.Our data from this cross‐sectional cohort showed increased sCD163 with time from onset, supporting increasing involvement of CD163+) on TLR activation, whereas IL‐15 induces dendritic cell differentiation; thus, both are involved in T cell modulation.sCD163 is a biomarker widely used to measure an inflammatory component. Accordingly, in PD serum, sCD163 was associated with an increase in the acute‐phase proteins SAA and CRP, which were previously associated with motor impairment and PD dementia.Surprisingly, IL‐15 was the only biomarker elevated in PD serum and CSF correlating with cognitive scores in both biofluids, thus revealing that IL‐15 may be another putative biomarker. However, despite the relevance of IL‐15 in BBB permeability, brain immunomodulation, and its connection to mood and memory,in vitro.3 Therefore, the observed differences could be a result of sex‐specific immune divergences with consequences for the risk and presentation of PD.Serum‐sCD163 levels were only significantly changed in women with PD. To our knowledge, only urate has been proposed as a PD biomarker with sex relevance.CSF‐sCD163 was strongly correlated with the disease biomarkers α‐syn, h‐Tau, and p‐Tau, which have been associated with PD diagnosis, clinical symptoms, and cognition.in vitro study suggests that α‐syn can induce monocyte activation and sCD163 shedding, which in turns increases the capacity of monocytes and microglia to uptake extracellular α‐syn. In vitro, T cell‐internalized sCD163 binds myosin,in vitro experiments, a high‐end (5 mg/L) sCD163 concentration was used compared with reported physiologically relevant serum level . Further investigation is required to fully understand the sCD163 effect on myeloid response to α‐syn during PD.sCD163 function is unclear, but it was shown to potentiate IL‐10 expression in allergen‐activated PBMCsThe findings of this study may be somewhat limited by the cross‐sectional study design, low numbers of HCs, and potential cofounding inflammatory diseases (with anti‐inflammatory medication) among study participants. The increase in sCD163 in late PD compared with early PD and HCs, as well as the negative correlation with cognitive scores, suggests a relation between sCD163 and PD stages. However, we cannot exclude a possible relation with sCD163 and cognitive decline during aging in other synucleinopathies and neurodegenerative diseases. Nevertheless, our mathematical modeling proposes a prognostic power for biomarker panels including sCD163 as one of the analytes. However, this has to be examined in a prospective longitudinal study to truly determine the potential of sCD163 as a PD and cognition biomarker.in vitro studies suggest that α‐syn could activate myeloid cells and induce sCD163 release, which enhances the myeloid cells' capacity to uptake α‐syn, indicative of a relevant role for disease progression.In conclusion, we show a PD‐related increase in sCD163 in serum (in women) and CSF, supporting a role for monocytes in the PD immune response. The increase in sCD163 paralleled those of accepted neuronal biomarkers, therefore relating monocytic and neuronal events. In addition, higher sCD163 levels were associated with lower cognitive scores, indicative of an association between the monocytes' immune response and cognitive decline. The CSF‐sCD163 increase was associated with immune biomarkers, suggestive of a permissive BBB and activation of adaptive immune cells. Moreover, our S.K.N., S.A.F., and M.R.‐R. developed the concept and designed the study. S.K.N., S.A.F., D.H., A.P., M.C.N., J.H.G., and A.E. performed experiments. S.K.N., S.A.F., K.S., A.P., and M.R.‐R. analyzed the data. S.K.N. and M.R.‐R. drafted the manuscript. C.S. coordinated sample selection and collected biobank archive info. S.A.F., S.K.N., and M.R.‐R. wrote jointly the final version of the manuscript. All authors critically revised the manuscript and approved the final version.Marlene C. Nielsen has received research grants from Dr. Sofus Carl Emil Friis and Olga Doris Friis, the Frimodt Heineke Foundation, the Harboe Foundation, and Thora and Viggo Groves' memorial trust, and reagent for the cell study was partly covered by Central Denmark Region.Anders Etzerodt received research support from the Novo Nordisk Foundation (NNF).Jonas H. Graversen is part of the management of Deliver Pharma and receives support from the Danish National Research Foundation and the NNF.Daniela Berg reports advisory board service for Biogen, BIAL, Lundbeck, and UCB Pharma GmbH; honoraria from AbbVie, Biogen, BIAL, Lundbeck, UCB Pharma GmbH, Zambon, and Desitin; and grants from Michael J. Fox Foundation (MJFF), Janssen Pharmaceutica N.V., German Parkinson's Disease Association (dPV), BMWi, BMBF, Parkinson Fonds Deutschland GmbH, UCB Pharma GmbH, TEVA Pharma GmbH, EU, Novartis Pharma GmbH, Lundbeck Foundation (LF), and Damp foundation.Holger J. Møller received research support from the Danish Innovation Fund and the Danish Central Region.Walter Maetzler is the co‐chair of the MDS Technology Task Force and receives or received funding from the EU, the MJFF, Robert Bosch Foundation, Neuroalliance, Lundbeck, and Janssen. He received speaker honoraria from GlaxoSmithKline, AbbVie, Bayer, UCB, Licher MT, and Rölke Pharma, and was invited to Advisory Boards of Market Access & Pricing Strategy GmbH, AbbVie, Roche, and Biogen.Anne Panhelainen received research support from the Cure Parkinson's Trust.Kathrin Brockmann has received a research grant from the University of Tuebingen (Clinician Scientist), the dPV, the MJFF, and the German Centre for Neurodegenerative Diseases ; travel grants from the Movement Disorders Society; and speaker honoraria from AbbVie, Lundbeck, UCB, and Zambon.Marina Romero‐Ramos serves on the editorial board of Brain Research and receives research support from NNF, Aarhus University Research Foundation, the Danish Medical Research Council, the Danish Parkinson Foundation, Desiree and Niels Ydes Foundation, and the MJFF.Sara K. Nissen, Sara A. Ferreira, Kalpana Shrivastava, Dorle Hennig, and Claudia Schulte report no disclosures.Appendix S1. Supporting InformationClick here for additional data file.


However, it remains uncertain whether it is cost‐effective, especially in a population‐based screening strategy.The introduction of multiparametric magnetic resonance imaging We used a micro‐simulation model to assess the cost‐effectiveness of an MRI‐based prostate cancer screening in comparison to the classical prostate‐specific antigen (PSA) screening, at a population level. The test sensitivity parameters for the mpMRI and MRI‐guided biopsy, grade misclassification rates, utility estimates, and the unit costs of different interventions were obtained from literature. We assumed the same screening attendance rate and biopsy compliance rate for both strategies. A probabilistic sensitivity analysis, consisting of 1000 model runs, was performed to estimate a mean incremental cost‐effectiveness ratio (ICER) and assess uncertainty. A €20,000 willingness‐to‐pay (WTP) threshold per quality‐adjusted life year (QALY) gained, and a discounting rate of 3.5% was considered in the analysis.The MRI‐based screening improved the life‐years (LY) and QALYs gained by 3.5 and 3, respectively, in comparison to the classical screening pathway. Based on the probabilistic sensitivity analyses, the MRI screening pathway leads to total discounted mean incremental costs of €15,413  of €14,556–€16,272) compared to the classical screening pathway. The corresponding discounted mean incremental QALYs gained was 1.36 (95% CI of 1.31–1.40), resulting in a mean ICER of €11,355 per QALY gained. At a WTP threshold of €20,000, the MRI screening pathway has about 84% chance to be more cost‐effective than the classical screening pathway.For triennial screening from age 55–64, incorporation of mpMRI as a reflex test after a positive PSA test result with a subsequent MRI‐guided biopsy has a high probability to be more cost‐effective as compared with the classical prostate cancer screening pathway. Incorporation of mpMRI as a triage test before biopsy followed by MRI‐guided biopsy improved the life‐years (LY) and QALYs gained, and has a high probability to be more cost‐effective as compared with the regular prostate cancer screening pathway. Several studies reported that the use of mpMR as a triage before biopsy and followed by MRI‐guided biopsy can substantially reduce the detection of low‐grade prostate cancers and also result in a better detection of clinically significant cancers compared to the classical screening with an upfront transrectal ultrasound‐guided biopsy (TRUSGB) for all men with a positive PSA test result.et al.Although some studies reported the cost‐effectiveness of mpMRI and subsequent targeted biopsy,22.1In the present study, the micro‐simulation screening analysis (MISCAN) prostate cancer model was used.https://cisnet.flexkb.net/mp/pub/cisnet_modelprofile_prostate_erasmus_001_12152009_69754.pdfUsing Surveillance, Epidemiology, and End Results (SEER) data (1983–1986), baseline prostate cancer survival  in the model was determined at clinical diagnosis.2.2The screening intervals, start and end age in the present study was based on the optimal screening strategy reported in a cost‐effectiveness analyses using the same base model, which is from age 55–64 at 3 years interval with an 80% screening attendance.2.3All the unit costs included in this study were obtained from literature and reported in Euros Table . The num2.4Most of the utility values and duration of health states were obtained from literature,2.5For both strategies, the undiscounted LY gained, QALYs gained, and the number of men biopsied were from a single model run. The net effects and costs in each strategy were compared with a no screening strategy. The mean discounted total net costs of screening, diagnosis, and treatment, and palliative care, the mean discounted net QALYs gained and the mean total incremental net costs along with 95% CI, the mean incremental cost‐effectiveness ratio (ICER), and the mean incremental net monetary benefit (iNMB) were based on probabilistic sensitivity analyses. To estimate the ICER, we divided the difference in total net costs between the MRI screening pathway and the classical screening pathway by the difference in net QALYs gained between the two strategies. A willingness‐to‐pay threshold (WTP) of €20,000, which is a common Dutch WTP,In the probabilistic sensitivity analyses, we performed 1,000 simulations in which selected model parameters were varied (based on distribution) simultaneously. A large sample size (10 million men) was used in each simulation, which eliminated stochastic noise in the model. The parameters included in the probabilistic sensitivity analyses were mainly those parameters which are not common in the two strategies. This includes the test sensitivity values of mpMRI, sensitivity values of MRI‐guided biopsy, costs of mpMRI, costs of MRI‐ guided biopsy, and costs of TRUSGB. The test sensitivity values were varied using their base value and standard deviation. For the costs, we used a Pert distribution with the most likely (base) value and an assumption of ±15% for the minimum and maximum values  and ggplot2 packages to obtain the cost‐effectiveness plain with mean ICER and the cost acceptability curves.33.1For triennial screening from age 55–64, the MRI screening pathway resulted in additional 3.5 life‐years gained and 3 additional QALYs gained per 1,000 men invited to screening and followed over their lifetime period. Furthermore, the number of biopsied men reduced by 30% when the MRI screening pathway was used Table .3.2The results show that the mean discounted incremental costs of screening, diagnosis and treatment, and palliative care of the MRI screening pathway versus the classical pathway were €76,300, €‐59,793, and €‐1,105, respectively, resulting in a total mean incremental costs of €15,413  for 1,000 men invited. The associated discounted mean incremental QALYs gained was 1.36, with a 95% confidence interval of 1.31–1.40 Table .The cost‐effectiveness acceptability curves at Figure The one‐way sensitivity analysis did not change the ICER substantially, ranging only between €10,000 and €13,700 Table . Althoug4The results from the model that accounts for long‐term prediction of costs and effects suggest that the use of MRI screening pathway is more cost‐effective than the classical prostate cancer screening pathway. The MRI pathway reduced the diagnosis and treatment costs by 19% and that of palliative care by 2% in comparison to the classical pathway. This reduction in diagnosis and treatment costs is mainly due to the lower sensitivity of mpMRI and MRI‐guided biopsy for low‐grade prostate cancer that reduces unnecessary biopsy and treatment. Generally, mpMRI and MRI‐guided biopsy have lower sensitivity for low‐grade cancer and higher sensitivity for clinically significant cancer Although their screening strategies differed, some published studies showed that the use of mpMRI and MRI‐guided biopsy is cost‐effective,Major strength of the present study is that we determined the cost‐effectiveness of the MRI screening pathway at population level which was not reported before, particularly in the European situation. Another strength of the present study is that the MISCAN prostate model, we used in this study, includes the unobservable prostate cancer natural history, and also allows us to estimate effects of screening over life time periods, which is unlikely in trial studies, and most of other modeling cost‐effectiveness studies.This study is also subjected to certain limitations. First, we did not account costs of biopsy complications. There is more risks of complication and subsequent increment of health care costs due to TRUSGB biopsy than MRI‐guided biopsy.In conclusion, our study suggests that for triennial screening from age 55 to 64, incorporating mpMRI as a triage test in prostate cancer screening before biopsy with subsequent MRI‐guided biopsy has a high probability to be more cost‐effective than the classical screening pathway.5Not applicable .None.Conceptualization: all authors. Data curation: A.M.G. and E.A.M.H. Formal analysis: A.M.G. Funding acquisition: H.J.K. Investigation: all authors. Methodology: all authors. Writing—original draft: A.M.G. Writing—review and editing: all authors. All authors have read and approved the manuscript.Figure S1Click here for additional data file.Figure S2Click here for additional data file.Figure S3Click here for additional data file.Table S1Click here for additional data file.


Previous work in Huntington’s disease (HD) has shown that a sense of meaning and purpose (M&P) is positively associated with positive affect and well‐being (PAW); however, it was unknown whether HD‐validated patient‐reported outcomes (PROs) influence this association and how M&P impacts PROs in the future. Our study was designed to examine if HD‐validated PROs moderate the relationship between M&P and PAW and to evaluate if baseline M&P predicts 12‐ and 24‐month changes in HD‐validated PROs.n = 50 prodromal, n = 171 early‐stage manifest, and n = 101 late‐stage manifest HD). A single, multivariate linear mixed‐effects model was performed with PAW as the outcome predicted by main effects for M&P and several moderators  and interactions between M&P and a given PRO. Linear‐mixed models were also used to assess if baseline M&P predicted HD‐validated PROs at 12 and 24 months.This was a longitudinal, multicenter study to develop several PROs  for people with HD (HDQLIFE). The sample consisted of 322 people with HD (Higher M&P was positively associated with higher PAW regardless of the magnitude of symptom burden, as represented by HD‐validated PROs, and independent of disease stage. In our primary analysis, baseline M&P predicted increased PAW and decreased depression, anxiety, anger, emotional/behavioral disruptions, and cognitive decline at 12 and 24 months across all disease stages.These findings parallel those seen in the oncology population and have implications for adapting and developing psychotherapeutic and palliative HD interventions. Huntington’s disease (HD) is an autosomal dominant, progressive neurodegenerative disease. There is currently no available cure or disease‐modifying agent.As part of a national initiative to improve the measurement of health‐related quality of life (HRQOL) in HD, several stakeholders  convened and identified several symptoms significant within the HD triad .Despite the multitude of PROs, the non‐motor ones  seem to be more potent contributors to HRQOL scores than do the motor impairments, and perhaps more so in the earlier disease stages.Work within oncology has suggested that a sense of meaning and purpose may buffer against depression and suicidality.Therefore, our overall goal of the study was to establish whether “meaning” represents a rational therapeutic target for intervention development to alleviate spiritual and existential suffering among people with HD gene mutation. Our objectives were twofold. Our first objective was to determine if an HD PRO, M&P, as embodied by the HDQLIFE M&P questionnaire,n = 50 prodromal, n = 171 early‐stage manifest, and n = 101 late‐stage manifest HD). Participants were part of a larger study, conducted between 2012 and 2016, designed to develop and validate new measures of HRQOL; full details of that study are reported elsewhere.This analysis included 322 people with the gene mutation for HD . A score of “0” means no symptoms and “4” means symptoms are occurring daily. Eighty‐four percent of our cohort had a PBA‐s score of 0; the remaining were >0. The Total Functional Capacity (TFC) from the Unified Huntington’s Disease Ratings Scales (UHDRS)M = 50; SD = 10) are relative to the development population and indicate more of that domain being measured . The degree of symptom severity was defined based on one standard deviation above and below, which was used to generate groups of high and low people, respectively, on a given PRO.All PROs, except M&P and Anger, were administered as computer adaptive tests (CATs) followed by the fixed short‐forms (SFs); M&P and Anger were administered as SFs only. We examined scores from the CAT administrations for all PROs when available . The resulting T‐scores HDQLIFE ChoreaHDQLIFE Speech DifficultiesHDQLIFE Swallowing DifficultiesHDQLIFE Concern with Death and DyingHDQLIFE End of Life PlanningNeuroQOL Cognitive FunctionNeuroQOL Emotional and Behavioral DyscontrolSMParticipants completed assessments at baseline, 12 and 24 months. All study visits were approximately 2 h in duration and involved completing an in‐person assessment and an online survey  to aid in interpreting interactions. A significant p‐value (<0.05) was interpreted as evidence of effect modification in the relationship between M&P and PAW; a non‐significant p‐value (≥0.05) suggested that the relationship between M&P and PAW was the same across levels of the moderator.PAW at each visit was modeled using linear mixed‐effects repeated measures models with a compound symmetry covariance structure (determined based on the mode of fit). A single model was performed with PAW as the outcome predicted by main effects for M&P and PRO moderators ; that is, an interaction between M&P and a moderator—while adjusted for other PROs and other interactions. All variables were treated as continuous except suicidality, which was dichotomized as any versus none. All moderators were tested in a multivariate linear mixed effect model . The slopes for the relationship between M&P and PAW were reported and plotted for low and high levels of each moderator .p = 0.0258), indicating a stronger relationship among those with higher depression, and negative interaction with chorea (p = 0.0048), indicating a weaker relationship among those with higher chorea. Model estimates were used to calculate strata‐specific slopes for those with low and high levels of each symptom; slopes for the relationship between M&P and PAW are shown in Table t‐score increase in PAW per 1 point increase in M&P among those with low depression; among those with high depression, there was a 0.44‐point t‐score increase. For low and high chorea, the M&P slopes were 0.46 and 0.19, respectively, but both were statistically significant. These relationships are plotted as line graphs in Figure In a previous bivariate analysis, M&P was moderately correlated with PAW (p = 0.0030), decreased anxiety , decreased anger , decreased emotional/behavioral disruptions , and slowed cognitive decline , at both 12 and 24 months. The strongest relationship was seen with anger: a 1 t‐score increase in M&P at baseline is associated with a 0.2 t‐score decrease in anger at follow‐up (regardless of where anger was at baseline). Our analysis that adjusted for multiple comparisons maintained that PAW, depression, anger, and emotional/behavioral disruptions were still significant; however, anxiety and cognition were not. Additionally, no evidence of subgroup variation was seen, except a positive association between baseline M&P and follow‐up social participation, as assessed through NeuroQOL SRA, among the prodromal group  but was not found in other groups.The predictors are baseline M&P and baseline levels of the outcome. Scores from baseline, 12, and 24 months are modeled—after adjusting for what the levels of each of the outcomes were at baseline .In conclusion, this study provides a generalization on the value of M&P to people with the HD gene mutation, and future efforts are warranted to adapt and develop meaning‐ and palliative‐ centered interventions to this population.The authors report no potential conflicts of interest related to the research covered in the article.All authors contributed to the conception, organization, execution of the project, and revising and critiquing the manuscript for important intellectual content.1. Research project: A. Conception, B. Organization, C. Execution;2. Statistical Analysis: A. Design, B. Execution, C. Review, and Critique;3. Manuscript Preparation: A. Writing of the first draft, B. Review, and Critique.LLS: 1A, 1B, 1C, 2A, 2C, 3A, 3B.JT: 1B, 1C, 2A, 2B, 2C, 3B.NC: 1A, 1B, 1C, 2A, 2B, 2C, 3B.B.M.K, A.J.A., J.S.P., D.B., S.F., J.M.H., N.R.B., C.A.D., D.C.: 1A, 1B, 1C, 2C, 3B.Dr Sokol is an ad‐hoc consultant for Tikvah for Parkinson in the range of $0–$499, ad‐hoc consultant for the American Film Institute on end‐of‐life care/palliative care in the enrage of $500–$999; and receives financial support from the Northwestern PSTP Program in Neurology as well as the R25 NCI 2R25CA190169. Dr Troost has research funding through the University of Michigan with Complexa Inc, Retrophin Inc, and Goldfinch Bio, and the University of Michigan with Vertex Pharmaceuticals and Pfizer Inc. Dr Kluger received research grant support from the National Institute of Aging, National Institute of Nursing Research, and Patient‐Centered Outcomes Research Institute; he has received speaker honoraria from the Parkinson’s Foundation. Dr Applebaum receives financial support from the National Cancer Institute. Dr Paulsen receives support from the NINDS and NIBIB and has received personal compensation in the range of $0–$499 for serving on a Scientific Advisory or Data Safety Monitoring Board for Wave Life Sciences, has received personal compensation in the range of $0–$499 for serving on a Speakers Bureau for HDSA, and has received personal compensation in the range of $0–$499 for serving as a consultant with Acadia. Dr Bega has received personal compensation for consulting, serving on a scientific advisory board, speaking, or other activities with Speaker: Teva Pharmaceuticals, Acorda Therapeutics, Neurocrine Biosciences, Adamas Pharmaceuticals Consulting: Biogen Pharmaceuticals, Amgen Pharmaceuticals, Acadia Pharmaceuticals, Genentech, Inc, GE Healthcare, Gerson Lehrman Group, Guidepoint, L.E.K. C., and has received personal compensation in an editorial capacity for Editor: Annals of Clinical & Translational Neurology. Dr Frank has received personal compensation in the range of $500–$4999 for serving as a Consultant for Oscine Therapeutics. Dr Frank has received personal compensation in the range of $500–$4999 for serving as a Consultant for uniQure, has received personal compensation in the range of $500–$4999 for serving as a Consultant for MCG Health. The institution of Dr Frank has received research support from the Huntington’s Disease Society of America. The institution of Dr Frank has received research support from Michael J Fox Foundation. The institution of Dr Frank has received research support from Roche/Genentech. The institution of Dr Frank has received research support from CHDI Foundation. The institution of Dr Frank has received research support from the Huntington Study Group. The institution of Dr Frank has received research support from Triplet Therapeutics. Dr Hauser is supported or has received support from the Coleman Foundation, University of Florida, Instituto Nacional de Caˆncer, American Academy of Hospice and Palliative Medicine, Arnold P. Gold Foundation, National Institute on Aging, Seasons Hospice Foundation, Woodstock, HCSC Insurance Services Company, National Heart, Lung, and Blood Institute, Canadian Patient Safety Institute, Health Research, and Educational Trust, Icahn School of Medicine at Mount Sinai, Centers for Medicare and Medicaid Services, Agency for Healthcare Research and Quality, Children’s Hospitals and Clinics of Minnesota, Instituto Nacional de Caˆncer, Department of Veterans Affairs, National Center for Research Resources, NOVA Research Company, Instituto Nacional de Caˆncer, Lance Armstrong Foundation, Retirement Research Foundation, Society for the Arts in Healthcare, Medical College of Wisconsin, and the National Institute of Nursing Research. Dr Boileau reports no disclosures. Dr Depp receives support from the NIMH, VA, and NCATS. Dr Cella has research funding to his institution from NIH, Abbvie, Amgen, Bayer Healthcare, Bristol‐Myers Squibb, Clovis, Eli Lilly and Company, Glaxo Smith‐Kline, Johnson and Johnson, Novartis, Pfizer, and PledPharma; he has served as a consultant to Abbvie, Bristol‐Myers Squibb, Eli Lilly and Company, Johnson and Johnson, Novartis, and Pfizer. Dr Cella is the president of FACIT.org. Dr Carlozzi reports research grants from the NIH, the Neilsen Foundation, and CHDI, as well as contracts from Goldfinch, LLC, and Health and Human Services – Centers for Medicare & Medicaid Services; she receives honoraria for her role on the CHDI scientific advisory board and is a consultant on the TBI Congressionally mandated study.