Methamphetamine (METH) addiction and its induced mental disorders have become a severe worldwide problem. A candidate Chinese herbal medicine (CCHM) in our lab had therapeutic effects on METH-induced locomotor sensitization, however, its chemical and pharmacological profiles remain to be elucidated. The current study aimed to investigate the effect of CCHM on conditioned place preference (CPP) induced by METH and screen the main active ingredients and key targets by using network pharmacology and molecular docking methods. Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment, Gene ontology (GO) analysis and protein-protein interaction (PPI) network were performed to discover the potential mechanisms. Results showed that CCHM could significantly inhibit METH-induced CPP behaviors in mice. A total of 123 components and 43 targets were screened. According to the network pharmacology analysis, ten hub targets including D(2) dopamine receptor (DRD2) and 5-hydroxytryptamine receptor 3A (HTR3A) were screened. GO analysis and KEGG enrichment indicated that mechanisms of CCHM treatment of METH addiction were related to multiple pathways such as dopaminergic synapse and serotoninergic synapse. Western blot results showed that the protein expressions of DRD2 in nucleus accumbens and prefrontal cortex were significantly decreased in METH group, while the protein expressions of HTR3A were significantly increased. These changes caused by METH could be prevented by CCHM pretreatment. The results of molecular docking displayed that the five active ingredients such as (S)-Scoulerine, Hyndarin, and Beta-Sitosterol had good affinities with DRD2 and HTR3A. In conclusion, this study constructed the CCHM’s pharmacologic network for treating METH addiction based on the method of network analysis and experimental verification, and analyzed its major active ingredients and potential targets, indicating a new direction for further revealing its mechanisms of effect on METH addiction. Conditioned place preference (CPP) test was used to assess the potential therapeutic effects of CCHM on METH addiction. The active components and hub targets, which were screened by the network pharmacology analysis, were verified by further experiments. Drug addiction is a severe worldwide social problem, which has attracted great attention. Compared with drugs extracted from plants such as heroin and cocaine, the proportion of people who abuse amphetamine-type synthetic drugs is increasing year by year. According to reports released by United Nations Office on Drugs and Crime and the Ministry of Public Security of China, methamphetamine (METH) has become the most commonly abused amphetamine-type stimulant in Southeast Asia and North America. METH can easily enter the central nervous system through the blood-brain barrier, so its effect on brain is more evident than its peripheral effect . StudiesCorydalis yanhusuo and Codonopsis, could significantly improve the learning and memory impairment induced by METH, and inhibit the acquisition and expression of METH-induced locomotor sensitization  were purchased from Beijing Charles River Laboratories . Mice were housed in a temperature-controlled room with a humidity of 45∼55% and subjected to a 12-h cycle of alternating light and dark. All mice had free access to food and water, and were pre-adapted to the environment for at least 3 days before the experiment. All experiment procedures were approved by the Ethics Committee of Jianghan University. As shown in The conditioned place preference (CPP) facility was brought from Shanghai Xinruan Information Technology Co., Ltd.  and comprised three compartments. One chamber had a grid floor and black walls (L × W × H: 35 cm × 35 cm × 35 cm). Another same-sized chamber had a mesh floor and white walls. The middle chamber had a flat, gray floor and gray walls (L × W × H: 15 cm × 35 cm × 35 cm) and is connected to the other two compartments by removable doors. The white and black chamber had a ceiling light and camera, respectively. The general activity in the facility was monitored by video, and the time spent in each chamber was recorded using XR-XT401 software.The CPP procedure used in this experiment was performed as previously described . The preC. yanhusuo, Poria cocos, Codonopsis pilosula, Licorice, Atractylodes macrocephala Koidz, Astragalus membranaceus, Angelica sinensis, and American ginseng. The components of CCHM were retrieved from Traditional Chinese medicine system pharmacology (TCMSP) database.1 Oral Chinese medicine must overcome the obstacles of absorption, distribution, metabolism, and excretion (ADME) process in order to be effective, so oral bioavailability (OB) is one of the most important pharmacokinetic parameters in ADME. High OB is usually an important index for determining drug similarity (DL) of active substances  network. The network was visualized with Cytoscape (3.8.0) and CytoHubba, a plug-in in Cytoscape, to filter the modules from the PPI network and to obtain the most important hub genes based on the degree score.Potential targets of CCHM on METH addiction were analyzed by online STRING 11.09 was used to conduct the GO analysis and KEGG enrichment of hub targets. Top terms of GO analysis and KEGG enrichment with thresholds of p-values ≤ 0.05 were chosen in functional annotation clustering.To further characterize the molecular mechanism of CCHM on METH addiction, the DAVID websiteLiterature retrieval was used to excavate and analyze the active components and possible mechanisms of CCHM in the treatment of METH addiction. This may provide literature verification for prediction results of the network pharmacology.Mice were sacrificed by cervical dislocation under anesthesia after behavioral testing. Protein extracts in nucleus accumbens and prefrontal cortex were isolated, lysed, and the supernatant was collected after centrifugation. BCA Protein Assay Kit was used to detect the concentration of protein extracts. Protein samples were separated and electroblotted onto the PVDF membrane. After blocking, membranes were incubated with primary antibodies followed by a horseradish peroxide conjugated secondary antibody. Enhanced chemiluminescence was used to visualize the band, and the intensity of each sample was determined quantitatively using Image J. Actin was used as loading control, and the results were normalized to the control group.10 Furthermore, AutoDock v.4.2.6 was used to add the hydrogens, calculate charges, and merge the non-polar hydrogens of protein structure (11 The SDF format of main active compounds was converted to PDB format using OpenBabel 2.4.1 (The amino acid sequence of the two hub targets D(2) dopamine receptor (DRD2) and 5-hydroxytryptamine receptor 3A (HTR3A) were downloaded from the PDB protein structure database.tructure . Next, tel 2.4.1 . AutoDocpost-hoc test. Differences between groups were considered to be statistically significant if values of p < 0.05.Statistical analysis was processed with SPSS 23.0 and Prism 8 software. Data were shown as the mean ± SE and analyzed using one-way ANOVA and LSD p < 0.01). As shown in p < 0.05), and CPP scores decreased with the increase of CCHM dose. Taken together, the results suggested that 2 mg/kg of METH was sufficient to induce CPP behaviors, and the co-administration of CCHM attenuated the acquisition of METH-induced CPP in mice.Conditioned place preference, a classic model widely used to assess drug-seeking behaviors, was used in this study to assess the preference for visual and tactile cues associated with METH after being administered with varying doses of CCHM. As shown in C. yanhusuo, six to P. cocos, 16 to C. pilosula, 69 to Licorice, four to A. macrocephala Koidz, 12 to A. membranaceus, two to A. sinensis, and six to American ginseng. After eliminating the overlaps, 151 compounds were chosen as candidate bioactive compounds for further analyses, and the detailed information was shown in A total of 163 compounds in CCHM obtained from TCMSP database met the requirement of OB ≥ 30%, DL index ≥ 0.18 and BBB ≥ −0.3, and 48 of which belong to Sixty METH addiction-related targets were collected from OMIM, 356 targets were collected from the Genecards database, and 11 targets were obtained from Drugbank database. After eliminating the overlaps, 392 targets were obtained for further analyses. The detailed information was shown in O-Methylisomucronulatol, 7-Methoxy-2-Methylisoflavone, Formononetin, Beta- Sitosterol, S-Scoulerine, Isocorypalmine, Leonticine, Medicarpin, Licochalcone, and Hyndarin. The detailed information was shown in Cytoscape software was used to construct the of “herb-compound-target” network, as shown in via the functional annotation tool of DAVID Bioinformatics Resources 6.8. There were 116 terms of biological process (BP), 20 terms of cellular component (CC), and 31 terms of molecular function (MF) in total, which met the requirements of Count ≥ 2 and p-value ≤ 0.05. The detailed information was shown in via adrenergic receptor signaling pathway, dopamine neurotransmitter receptor activity, dopamine binding to exert its therapeutic effects on METH addiction. To explore the underlying involved pathways of CCHM on METH addiction, KEGG pathway analysis of involved targets was conducted. The detailed pathway information of CCHM on METH addiction was shown in To identify the biological characteristics of putative targets of CCHM on METH addiction in detail, the GO and KEGG enrichment of involved targets were conducted p-value of PPI enrichment was less than 1.0e-16. To obtain the hub genes in the PPI network, these node pairs were entered into the Cytoscape software. The scores of nodes were calculated by cytoHubba, and the top 10 hub genes were shown in The PPI network of possible targets involved in the treatment of CCHM on METH addiction was constructed using STRING . There wThe hub gene symbols, full names, and functions were shown in via DAVID 6.8. There were respectively 51 BP, 5 CC, and 10 MF terms in total, which met the requirements of Count ≥ 2 and p-value ≤ 0.05. The detailed information was shown in p-values ≤ 0.05. The detailed pathway information of hub genes was shown in via dopaminergic synapse, cocaine addiction, neuroactive ligand-receptor interaction, amphetamine addiction, and serotonergic synapse.The GO analyses and KEGG enrichment of hub genes were conducted L-tetrahydropalmatine, had significant inhibitory effects on locomotor sensitization, CPP behavior, self-administration behavior, and relapse behavior induced by METH . Numerous studies have identified the MLDS as a common reward circuit and main neuroanatomical basis for the rewarding or positive reinforcement of addictive drugs, involving in drug-induced reinforcement, pathological memory, craving, and relapse . Addictiehaviors . Michaelehaviors , and redehaviors . These sehaviors ,c. Afterehaviors . Dopaminehaviors . DRD2 anehaviors . METH abehaviors . Animal ehaviors , suggestI5–HT) in oocytes expressing HTR3A receptor, while high dose METH inhibited I5–HT, and HTR3A receptor antagonist MDL72222 had an inhibitory effect on the acquisition and expression of METH locomoter sensitization  can be found in the article/The animal study was reviewed and approved by the Ethics Committee of Jianghan University.QR, LC, and YW designed the study, analyzed the data, and prepared the manuscript together. QR, XT, CL, and QX performed the experiments. All authors have read and approved the final version of the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


This paper is an evaluation of seasonal influenza vaccination hesitancy (IVH) and its determinants among community HCWs in Chongqing, a city in southwest China. Methods: A cross-sectional survey of 1030 community HCWs with direct or indirect patient contact was conducted from July to September 2021 using a self-administered electronic questionnaire. Possible factors for IVH among community HCWs were investigated by multivariable logistic regression to yield adjusted odds ratios (ORs) and 95% confidence intervals (CIs). Results: Overall, 46.2% of community HCWs were vaccinated in the 2020–2021 season, while 65.8% of community HCWs had IVH. “Don’t know the coverage in China” , “complacency”  were positively related with having IVH. The community HCWs that had a history of influenza vaccination (OR: 0.67 95% CI: 0.48–0.95) and groups with confidence and convenience  were more likely to completely accept vaccination. Conclusions: Measures such as improving the awareness and knowledge of influenza and vaccination and expanding the free vaccination policy, combined with improving the convenience of the vaccination service, will promote increased seasonal influenza vaccination-coverage in community HCWs in Chongqing. Globally, influenza causes a highly contagious infection with a significant morbidity and mortality burden, which causes 3 to 5 million cases of severe illness, and 290,000 to 650,000 respiratory deaths annually ,2. HealtFirstly, vaccine hesitancy (VH) was identified as one of the 10 threats to global health by the WHO, in 2019. The use of vaccines has reduced the burden of infectious disease historically; however, VH is fueling the re-emergence of vaccine-preventable diseases and vaccination rates worldwide are plummeting . SimilarHowever, most of the studies ,18,19 onFrom July to September 2021, we conducted a cross-sectional design study to collect self-reported data through an online survey in six districts/counties from Chongqing (the districts and counties are of the same administrative level in Chongqing). A stratified cluster random sampling method was used to select six districts/counties based on geographic location and population composition. Then, we randomly selected 10 street (township) community health service centers (CHSCs) in each district/county. The inclusion criteria were (1) all community HCWs in 60 CHSCs and (2) age of 22 years or older. We defined community HCWs as those who worked at community health centers providing primary health services, including general practitioners, public health physicians, and nurses working on the front line. Community HCWs enrolled into this study with no incentives for participation and completed self-administered electronic questionnaires. 2 × P × (1 – P))/d2, where Z = value from standard normal distribution corresponding to the desired confidence level (Z = 1.96 for 95% CI), P is the estimated proportion (P = 50%), and d is the desired precision of estimate (margin of error) (d = 3%). The minimum required sample size of 1067 respondents was calculated using the formula: N = , knowledge, attitudes, practice related to influenza and influenza vaccine, and influenza vaccine hesitancy. More details are provided in the The WHO Strategic Advisory Group of Experts (SAGE) developed the definition and determinants of the matrix of VH . We defiThe IVH scales for community HCWs included a 9-item section on the 3Cs model determinants of influenza vaccination , assessed using a 5-point Likert scale . The IVH scales passed the reliability and validity test in the study. Complacency dimension from “strongly agree” to “strongly disagree” with a score of 5–1 . The othThe major outcome measures in this study were: (1) necessary to get influenza vaccination against influenza, with responses dichotomized as strongly agree, indicating completely accepted vs. hesitancy  vs. strongly disagree, indicating completely rejected; (2) influenza vaccine uptake in the last influenza season (yes vs. no); (3) willingness to get influenza vaccination in the next influenza season (yes vs. no/maybe); and (4) willingness to recommend the vaccine to the patients (yes vs. no/maybe). The possible correlated factors  were dichotomized based on the mean value of each subscale variable as follows : (1) conp value < 0.05 was considered statistically significant.Statistical analyses were performed using the Statistical Program for Social Sciences (SPSS) version 25.0 . To explore the structure of IVH scales, Exploratory Factor Analysis (EFA) was conducted on the samples using Principal Axis Factoring with orthogonal rotation (varimax). Cronbach’s α was calculated, and factors with eigenvalues greater than one were extracted to determine the internal consistency. Descriptive statistical method was used to calculate vaccination coverage and the number of respondents based on reasons for and against vaccination. Categorical variables were compared using the Pearson chi-squared test. The independent sample t-test was used to evaluate the differences between vaccine outcome questions (IVH) to examine the criterion validity of the scale. Logistic regression analysis was used to explore relative factors of IVH and acceptance, after adjusting for potential confounding variables based on the odds ratios (OR) and 95% confidence interval (CI). Participants who completely accepted influenza vaccination were considered as the reference group, and vaccine hesitancy was taken as the dependent variable in the analysis. Potential confounding factors included demographic characteristics, knowledge, experience, and the score of each dimension of the “3Cs” model. Subgroup analyses were conducted through an independent sample t-test, according to the characteristics of IVH in each item between mild and severe hesitancy. All statistical tests were two-sided, and a The study protocol and questionnaire were approved by the Research Ethics Committee of the Chongqing Centre for Disease Control and Prevention (2021(001)). The participants were reassured of the confidentiality of the collected information and signed informed consent. Overall, 1200 community HCWs were enrolled into this study. Of them, 1142 community HCWs completed the survey, so the response rate of this survey was 95.2%. However, 112 (9.8%) of 1142 eligible participants were excluded from the analysis because of failing to complete all items or pass the quality control questions.p < 0.05)  .Only 25 (2.4%) community HCWs completely rejected the vaccination; 677 (65.8%) HCWs had IVH; and 328 (31.8%) HCWs completely accepted vaccination .p < 0.001) indicated that sufficient correlations among the variables existed, allowing the study to proceed. EFA identified two factors with eigenvalues greater than one, explaining 59.50% of the common variance of nine items. All the standardized loadings were >0.6, and no cross-loading was >0.4, indicating that all items were significant. Finally, a reliability analysis revealed that the Cronbach’s α was 0.849. The t-test was performed on the scores of each dimension of the “3Cs” model, according to whether there was influenza vaccine hesitation or not (p < 0.05). For the community HCWs that were not IVH compared to those that were IVH, there was more trust, less complacency, and more perceived convenience and severity of influenza, as well as more trust in vaccine safety, effectiveness, and in vaccine delivery systems, so vaccination was considered more necessary and convenient.For the community HCWs’ IVH scale, the KMO measure of sampling adequacy was 0.894, and Bartlett’s test of sphericity (n or not . There wp < 0.001). HCWs who had received influenza vaccination before reported a higher IVH score than those who had no experience   . p < 0.001).We used the median score (34) of the 3Cs scale as a cutoff value and classified the subjects with IVH into two groups: those with mild hesitancy and severe hesitancy. Each item of the scales was different statistically between two groups  of the community HCWs confirmed being vaccinated the influenza vaccine in the 2020–2021 season. In total, 635 (61.7%) respondents in the community HCWs were willing to be vaccinated against influenza during the 2021–2022 season, while 959 (93.1%) of the community HCWs were willing to recommend the influenza vaccine to their patients .Out of 395 respondents who would not be vaccinated during the 2021–2022 season, the most common reason was that who believing vaccination was unnecessary, accounting for 60.8% (240/395) of respondents, followed by the vaccines not being free . The third reason was “the virus mutates quickly, concerns about inoculation effect”, which accounted for 25.1% (99/395) .2 = 56.712, p < 0.0001).The reasons for not recommending the influenza vaccine to patients among the 71 community HCWs included: concerns about patients misunderstanding the selling of vaccines (63.4%), uncertainty of vaccine effectiveness for their patients (35.2%), HCWs consider that patients do not accept their recommendation on vaccines (16.9%), and do not know the contraindications of the influenza vaccination and dare not recommend it to patients (14.1%) . FurtherTo the best of our knowledge, this is the first study to assess the profiles of IVH and its related determinants among community HCWs during the COVID-19 pandemic in mainland China. In 2009, China implemented a new round of healthcare reform to strengthen primary care networks, in which the development of Community Health Services (CHS) was the emphasis. Community HCWs provide primary healthcare, disease prevention, and health education, in the relevant jurisdiction to a key population, targeting pregnant women, young children, older adults, and adults with chronic diseases residing in the community . TherefoHesitancy profile and determinants are related to the country and the environment globally. Similarly to previous studies ,29,30, wAs vaccine safety has been one of the most important predictors of hesitancy worldwide, studies ,34 have A systematic literature review  showed tCoverage rates of the seasonal influenza vaccination in HCWs vary widely in different countries and regions. During the 2014–2015 influenza season, it was reported that influenza vaccine ranging from 2.6% to 99.5% among HCWs in 26 (56%) European countries . HoweverThe findings of the survey showed that the most common reasons for not being vaccinated during the 2021–2022 were necessity and the price of vaccination. Previous studies ,43 have A large number of studies ,50,51,52However, our study had several limitations. First, the cross-sectional research limited our exploration of the causal relationship between IVH and determinants, and the small sample size in the analysis may lead to the weak power of IVH and, thus, the generality may be hindered. Second, the results were self-reported, and vaccination records were not verified further. However, we think community HCWs are mostly professional, so the possibility of false reports was relatively low. Third, the participants in the current study were from one province in the southwest region of China, and, thus, the conclusions for IVH may not be generalized to other areas in the country. Fourth, potential selection bias may also arise. Since the two community health service centers that implemented the free policy also provided centralized vaccination services, the impact of the free policy and vaccination service could not be evaluated separately.This is the first study to assess the knowledge, attitudes, and practices of community HCWs regarding the seasonal influenza vaccine in southwest of China. The major findings of this study can be summarized by the following three points. First, influenza vaccine uptake was 46.2% during the last influenza season (2020/2021), which is slightly higher than the rates observed in other cities in China . Second,In order to increase seasonal influenza vaccination coverage in community HCWs, it is crucial to improve the community HCWs’ personal confidence, their awareness of influenza and vaccination, and their accurate knowledge of influenza vaccines, to engage them in activities targeting vaccine hesitancy among their patients. In addition, it is crucial to expand the free vaccination policy and improve the accessibility of vaccination service. Furthermore, we should continue to explore effective interventions to increase the coverage rate of community HCWs, in order to promote the vaccination of the general population at the individual and social levels.


Sudden unexpected postnatal collapse (SUPC) is a rare event, potentially associated with catastrophic consequences. Since the beginning of the 2000s, therapeutic hypothermia (TH) has been proposed as a treatment for asphyxiated neonates after SUPC. However, only a few studies have reported the outcome of SUPC after TH. The current study presents the long-term neurodevelopmental outcome of four cases of SUPC treated with TH in a single Italian center. Furthermore, we reviewed the previous literature concerning 49 cases of SUPC treated with TH. Among 53 total cases (of whom four occurred in our center), 15 (28.3%) died before discharge from the NICU. A neurodevelopmental follow-up was available only for 21 (55.3%) out of the 38 surviving cases, and seven infants developed neurodevelopmental sequelae. TH should be considered in neonates with asphyxia after SUPC. However, SUPC is a rare event, and there is a lack of comparative clinical data to establish the risk/benefit of TH after SUPC with different degrees of asphyxia. Analysis of large cohorts of newborns with SUPC, whether treated with TH or untreated, are needed in order to better identify infants who should undergo TH. Sudden unexpected postnatal collapse (SUPC) is a rare event, potentially associated with catastrophic consequences . SUPC isThe incidence of SUPC varies widely, from 2.6 to 34/100,000 live births, depending on the different definitions  and the type of the study (multiple- or single-center studies) , guideliWe reviewed, in detail, cases of SUPC undergoing TH who were admitted to our Neonatal Intensive Care Unit (NICU) during a 4-year period. Furthermore, we reviewed cases of SUPC treated with TH which had been reported in the literature.n = 1; level 2, n = 2; level 1, n = 2), with approximately 6000 live births/year.The NICU of Azienda Ospedaliero Universitaria di Modena  is a level 3, high volume center where critical newborns from the entire district are referred. The district of Modena consists of five centers  or no HIE (n = 1), and were not treated.During the study period, 27,450 live births were delivered in the district of Modena. From 2014 to 2019, six infants were admitted to NICU because of SUPC , of which four underwent TH; the remaining two infants had a normal polygraphic-EEG (p-EEG) with mild  have been treated with TH for SUPC ,16,17,18Neurodevelopmental outcome was within a normal range in 14 of 21 infants, and impaired (with a wide range of severity) in the remaining seven infants .TH has been proven to reduce death, severe cerebral lesions, and disabilities in asphyxiated full-term infants ; howeverWe report four cases of infants affected by SUPC who were treated with TH, as well as their long-term neurodevelopmental outcomes. All infants required resuscitation, but the severity of their asphyxia was variable. TH was performed according to Italian guidelines for TH in HIE , which sTo date, the rarity of SUPC has precluded randomized clinical trials of TH. Furthermore, it may be unethical not to treat, since TH has proven to be beneficial in perinatal asphyxia. Indeed, brain lesions after SUPC are comparable to those related to perinatal HIE. After SUPC, severe EEG abnormalities and severe injuries to the central grey matter and brainstem have been reported . In addiConcerning the 53 total cases (including our four cases) treated with TH and so far described in the literature ,16,17,18Since the incidence of SUPC is estimated to be from 2.6 to 34/100,000 live births, and because approximately 3,780,000 infants were born in Europe in 2019 , the numSUPC may lead to asphyxia of varying severity that may require TH. Only large prospective observational studies will more accurately describe the current clinical practice and the long-term outcomes after TH.


Pharmacotherapeutic management of immune-mediated inflammatory diseases (IMID) has become more complex due to the development of new treatments, such as biological therapies. Mobile health, especially apps, can provide IMID patients with greater autonomy and facilitate communication with healthcare professionals. Our objective was to design and implement an app for remote monitoring and communication with IMID patients.A multidisciplinary group was created to design and develop an app for IMID patients in a tertiary hospital. The app functionalities were identified through a focus group with IMID patients and through an observational, descriptive study of available apps for IMID patients at App Store and Play Store platforms. Once the app was designed and developed, we offered the app to IMID patients who initiated a new biological therapy. The inclusion period was from December 2020 to August 2021. We performed an observational, longitudinal study to assess the app’s impact on medication safety, communication, satisfaction, and usability.®) with the following modules: My Medication, My Questionnaires, Adverse Events, Useful Information, Messages, and Patient Profile. A total of 85 patients were installed with the app. The median (range) follow-up time for app use was 123 (5-270) days. In the My Medication module, 100% of patients registered their biological therapy and 25.9% also used this module to record each dose of medication administered. A total of 82 adverse events (AEs) were registered. Thirty-two percent of the patients registered at least 1 AE. The most frequent AEs were fatigue, injection site reaction, headache, and nausea. Fifty-two percent of patients used the Messages module to communicate with healthcare professionals. The most frequent messages concerned doubts about managing AEs (26.2%) and drug interactions (18.9%). The satisfaction survey yielded a median (range) score of 9.1 (7-10) out of 10.We designed an app (eMidCare®, which reminds patients to take their medication, enables them to record AEs, and helps them communicate with healthcare professionals. Approximately one-third of the patients registered the administration of the biological therapies and registered at least 1 AE. The most used and most satisfactory functionality was communication with health professionals.We developed an app, eMidCare The management of several immune-mediated inflammatory diseases (IMID) has changed dramatically owing to the development of biological therapies . These dThe quality of life of IMID patients is often affected by physical and psychological burdens –6. ThereInformation and communications technology, specifically mobile health , can provide IMID patients with greater autonomy, facilitate communication with healthcare professionals, and increase the quality of patient care . Remote Our objective was to design and implement an app for self-management of disease and thus promote home monitoring and communication with IMID patients. We also assessed the usability of and satisfaction with the app.A multidisciplinary working group comprising pharmacists, dermatologists, rheumatologists, gastroenterologists, and nurses was created to design and develop an app for IMID patients in a tertiary hospital. The functionalities of the app were based on the following: patients’ healthcare needs and their interest in the use of apps to manage their disease; and functionalities and uncertainties of currently available IMID apps.1) Patients’ healthcare needs and their interest in the use of apps to manage their diseaseWe used the focus group methodology with IMID patients. A meeting was organized with 7 patients . The median age was 47.7 (SD= 10.3) years, and all patients were receiving biological therapy.2) Functionalities and uncertainties characteristic of currently available IMID appsWe conducted a descriptive study of all apps for IMID patients to identify areas that could be improved with our new app. We searched the App Store (iOS) and Play Store (Android). The search terms used were “ankylosing spondylitis”, “Crohn’s disease”, “hidradenitis suppurativa”, “IBD”, “inflammatory bowel disease”, “immune-mediated inflammatory diseases”, “immune-mediated inflammatory disorders”, “juvenile idiopathic arthritis”, “psoriasis”, “psoriatic arthritis”, “rheumatoid arthritis”, and “ulcerative colitis”. The variables analyzed were app name, type of IMID, platform (Android or iOS), country of origin, language, category of the app, functionalities, date of the last update, downloads, and author affiliation.The app was designed and developed considering the points mentioned above. In December 2020, we started offering the app to all IMID patients who initiated a new biological therapy. We performed an observational, longitudinal study of patients diagnosed with an IMID and followed using the app eMidCare to assess the tool’s impact on medication safety, communication, satisfaction, and usability. The inclusion period was from December 2020 to August 2021. The inclusion criteria were age ≥ 18 years, diagnosis of an IMID , and ownership of a Smartphone. Patients with language barriers were excluded. The study was approved by the Hospital Clinical Research Ethics Committee (code MSS-APP-2019). All patients signed an informed consent document.Patients were offered the app by the pharmacist in the outpatient pharmaceutical care clinic. If the patient agreed to participate, the pharmacist registered the patient on the Content Management System (CMS) website, along with the delivery of the biological therapy and the usual information provided in the pharmaceutical care clinic. Once the patient downloaded the app, the pharmacist explained how to use it. Healthcare professionals then followed the patients up through the CMS. Health professionals can modify the contents of the app through the CMS .Medication safety was evaluated through a descriptive analysis of the patient’s recording of adverse events (AE) using the app, the percentage of patients who registered an AE, type of AE, time of onset, and severity according to CTCAE .Communication was evaluated through the messages sent through the app, the percentage of patients who used this module, whole messages, messages per patient, and type of messages.®.Usability was evaluated using Google Analytics for FirebaseSatisfaction with the app was assessed through a specific survey on the app. The survey included items on usability, ease of communication with healthcare professionals, utility for the management of treatment, and grade of recommendation (1) Patients’ healthcare needs and their interest in the use of apps to manage their diseaseThe patients in the focus group highlighted the following issues:General healthcare needs:Lack of information on diseases, lifestyles, and treatmentsLack of knowledge on the part of healthcare professionals  with respect to the disease and treatmentsLimited mobility owing to the consequences of the diseasesReduced possibility of communication with the medical specialist (only from Monday to Friday from 9 am to 2 pm)Considerable interest in using information and communication technologies, especially apps, to search for information about healthDesired health app functionalities:General information about the disease and treatments: symptoms, compatible medication, adverse effects, feeding, surgery, physical activity, vaccines, drug conservation, travelSpecific information about AE management Medication alarmsAbility to register the injection site in the case of subcutaneous medicationDiary to record AEs and symptomsAbility to take photographs of the skin and send them to specialistsQuestionnaires to assess and monitor physical and emotional states (patient-reported outcomes [PROs])Direct contact with health professionals to clarify doubtsKey elements of app design: Patients need information about their disease and treatments and must be able to communicate with healthcare professionals. They highlight different functionalities of the apps that will help them to manage their disease and should be incorporated in our app.2) Functionalities and uncertainties characteristic of currently available IMID appsWe analyzed 243 apps . The main functionalities were as follows: general information about lifestyles, nutrition, and exercise , specific information about the disease or treatment  , recording adverse events , agenda/calendar , medication reminder , and recording of patient-reported outcomes . Healthcare professionals were involved in the development of 100 apps (41.1%). Only 110/243 apps (44.5%) had been updated in the previous year. The mean time between the date of the analysis and the date of the last update was 18.5 months (SD= 19.3).Key points of app design: Functionalities and reliability were very heterogeneous. While most apps offer information, although information on biologic therapies is very scarce. Few apps allow patient interaction, such as recording AEs, setting alarms for medication, or recording PROs. Our app should have these functionalities under the supervision of healthcare professionals as a guarantee of reliability.®, which specializes in developing and implementing health apps, was contracted for development. A document was drawn up with the design and functional scope of the app, the support service, and the implementation plan. We decided to call the app eMidCare. The app was structured into 6 modules:The content of the app was defined based on the above key points and the experience of the multidisciplinary group. The computer company EnredartMy Medication: This module enables the patient to record the medicines he/she is taking , with details of the type of intake, dose, unit of measurement, frequency, and quantity. An icon for biological therapies makes it possible to obtain more detailed information about each drug. The medicines can be included in the app by patients or by healthcare professionals. Patients can receive reminders when they have to administer the medicines. They can also record when they administer each medication to monitor adherence . In the case of subcutaneous biological therapies, the patients may also register the injection site.1) My Questionnaires: Healthcare professionals can upload PRO measures (PROMs) in the app and define the frequency and the PROMs for each IMID (2) 3) Adverse Events: Patients can register the adverse events they experience, and the app offers various recommendations on the type of AE and its severity. The system acts based on a defined decision tree .4) Useful Information: This module contains recommendations and preventive information on various areas of treatment  and IMIDs. The information is structured as Frequently Asked Questions, Adverse Events, General Information , web links of interest, and a tutorial about the app. All the information was adapted to a language that patients can understand and is periodically updated.5) Messages: This module allows bidirectional communication between patients and healthcare professionals in real time.6) Patient Profile: This module contains information about the patient: sex, date of birth, weight, smoking habits, type of IMID, date of diagnosis, and secondary IMID and date of diagnosis (if applicable). The Patient profile module contains a section entitled “My achievements”, where patients can obtain “trophies” and “medals” depending on their adherence and the registration of the questionnaires.® for analysis.All the data registered in the app are recorded automatically in the web interface (CMS), which enables the healthcare professional to monitor patients in real time. The app also sends an automatic email to healthcare professionals when patients add a new medication, register an AE, or send a message. All the registered information can be exported to ExcelAll the data contained in the eMidCare platform is considered confidential and has the highest level of protection according to General Data Protection Regulation (GDPR).The app does not store data locally, so it is not possible to access it once the user is deactivated from the program. The data travels from the CMS on the server to the app through encrypted webservices. The platform is located in a hosting network at the company Gigas. The backup solution of the hosted data through advanced backup is implemented in virtual appliances R1Soft.Other characteristics concerning privacy and security are as follows:-The CMS and webservices will be under the Secure Sockets Layer (SSL) certificate.-Email and password of the user will be encrypted-The security password level is displayed to the user with a bar based on 3 factors: uppercase, lowercase, and numbers. The eMidCare prototypes for iOS and Android and the CMS were tested by end-users in a staging environment  and then in a production environment (beta testing). After 5 preliminary versions, the definitive version of the app was finally uploaded to the market in December 2020.The app eMidCare was offered to 97 patients during the inclusion period, although 85 patients finally installed the app and were analyzed  registered their biological therapy . Twenty-two (25.9%) also used this module to record each dose of medication administered. The median (range) adherence was 100% (50-100); adherence was >90% in 86.4% (19/22).p>.05). The median (range) time to the first AE was 16 (0-95) days.A total of 82 AEs were registered, and 31.8% (27/85) of patients registered at least 1 AE. The median (range) number of AEs per patient was 1 (1-17). The frequency and severity of AEs were as follows: fatigue, 26.8% ; injection site reaction, 25.6% ; headache, 15.9% ; nausea, 8.5% ; diarrhea, 4.9% ; upper respiratory infection, 3.7% ; and other AEs, 14.6% . There were no statistically significant differences in the recording of AEs between biological-naïve patients and biological-experienced patients . The most frequent messages concerned doubts about managing AEs and drug interactions (The satisfaction survey yielded a median (range) score of 9.1 (7-10) out of 10. The median (range) follow-up time for app use was 123 (5-270) days. The app sections that patients browsed for the longest time were Messages (21.9%), Start screen (20.9%), My questionnaires (20.4%), My medication (8.8%), Adverse events (7.1%), and reminders (5.7%). The median time per patient in each session with the app was 3.7 minutes.The patients interacted an average of 1.4 times with the app each week. We report on the design and successful implementation of the app eMidCare for the home follow-up of IMID patients undergoing treatment with biological therapies. We assessed the app impact in 85 IMID patients, with characteristics similar to those of patients treated with biologic therapies. Currently available apps for IMID patients are considerably heterogeneous with respect to functionalities and reliability. A recent review of similar apps for Android and iOS has shown that more than half of IMID-related apps are oriented toward offering information . NeverthConcerning reliability, only 15-42% of IMID patient apps have been developed by professionals, and approximately the half of the apps have not been updated recently , 12–14. eMidCare was designed based on the experience of the multidisciplinary team and on patients’ needs. Few IMID-related apps have taken patients into account in their design. The 6 modules defined in eMidCare—My Medication, My Questionnaires, Adverse Events, Useful Information, Messages, and Patient Profile—meet the requirements for achieving our ultimate goal of improving medication safety, adherence, and communication with patients.®, MySIMPONI®) were oriented solely towards biologic therapy . However, this type of app should enable patients to record their complete treatment regimen, including monitoring of drug-drug interactions and adherence  apps for IMID patients analyzed in a recent review had specific information on biologic therapies . Two of dherence , 15, 16.Apps are the preferred method for reminding patients to take their medication regularly , and num®, MediSafe®, MyTherapy®, Dosecast®, Care4Today®)  . HoweverIMIDs have a high impact on patients’ quality of life . PROs en® is an online interactive electronic e-health platform that enables self-assessment and self-monitoring in rheumatoid arthritis .We believe this app has greatly improved communication with our patients over the traditional model of care. The possibility of daily communication with health professionals reassures patients and gives them confidence. Thanks to eMidCare, we are helping patients who experience more difficulties contacting the health system and feel more helpless, since 33.5% of the queries answered through e-MidCare were made after 3:00 pm or at weekends. This communication proved to be worthwhile, since we likely avoided unscheduled visits.® e-health platform was compared with traditional follow-up for 12 months . All patients signed written informed consent.RR-J wrote the first draft. RR-J, VE-V, AH, and MS defined the research question and objectives. RR-J, VE-V, EC-d-V, AA-L, EL-M, CG, OB, LM, CL-R, and AH defined the app’s functionalities. RR-J, VE-V, EC-d-V, AA-L, EL-M, BS-F, and PR-B included the patients and followed them up. RR-J, VE-V, AH, and MS were responsible for the research activity plan and its execution. All authors reviewed and approved the manuscript.Novartis sponsored the technological development of the app. Novartis did not participate in the conception of the app, the inclusion and follow-up of patients, or the evaluation of results.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


At 1 week post-ceremony, the non-judging facet of the mindfulness scale was increased (p = 0.03), while the personality trait neuroticism decreased (p = 0.005), when compared to baseline. Additionally, we found ratings of ego dissolution  and changes in neuroticism to be the strongest predictors of reductions in state and trait anxiety, respectively. In sum, results suggest rapid and persisting (up to 1 week) anxiolytic effects in individuals with sub-clinical anxiety symptoms, which are related to the acute experience of ego dissolution, as well as lasting changes in trait neuroticism. Results also add support to the feasibility and potential efficacy of group sessions with psychedelics. To understand whether these effects extend to wider populations suffering from heightened anxiety, and the mechanisms involved, further experimental research is needed.Anxiety disorders are the most common type of psychiatric disorders among Western countries. Evidence-based treatment modalities including pharmacological and cognitive-behavioral therapy result in deficient treatment responses. Historical and recent research suggests psychedelic drugs may be efficacious in alleviating anxiety-related symptoms among healthy and clinical populations. The main aim of the present study was investigation of the effects of psilocybin-containing truffles, when taken in a supportive group setting, on ratings of state and trait anxiety across self-reported healthy volunteers. Attendees of psilocybin ceremonies were asked to complete a test battery at three separate occasions: before the ceremony (baseline), the morning after, and 1 week after the ceremony. The test battery included questionnaires assessing state and trait anxiety (State-Trait Anxiety Inventory), mindfulness capacities (Five Facet Mindfulness Questionnaire), and personality (Big Five Inventory). Additionally, the psychedelic experience was quantified with the Persisting Effects Questionnaire and the Ego Dissolution Inventory. The total amount of psilocybin-containing truffles consumed by each participant was recorded, and a sample of the truffles was analyzed to determine psilocin concentrations. Fifty-two attendees  completed parts of the baseline assessment, 46  completed assessments the morning after the ceremony, and 23  completed assessments at the 1-week follow-up. Average psilocin consumption across individuals was 27.1 mg. The morning after the ceremony, we observed medium reductions in anxiety measures (both state and trait) compared to baseline ( Anxiety disorders  are the most common psychiatric disorders, with a current worldwide prevalence of 7.3% , 2. Theydo reduce anxiety, it is of interest to understand what psychological processes may be at play.Before criminalization of psychedelic drugs in the 1970s, studies combining administration of a psychedelic drug and psychological therapy found significant improvements in anxiety-related symptomatology –14. MoreThe personality trait neuroticism, reflecting an individual’s tendency to experience negative emotions, sensitivity to aversive cues, and insufficient ability to cope with stress, has been found to be the personality trait that is the most strongly associated with many forms of psychopathology –31, and A further psychological process which may be of particular salience when discussing therapeutic efficacy for anxiety, and which psychedelics have been repeatedly found to enhance, are mindfulness capacities , 42–46. Finally, another important factor when thinking about therapeutic applications is the longevity of effects. Usually when taking conventional anxiolytics the treatment duration will vary but might extend over months , 6. For In sum, anxiety symptoms and disorders evoke a notable impact on people’s lives, yet the existing treatment options are of limited success. Based on this and previous findings of psychedelic-induced alleviation of anxiety in clinical populations, the present study was designed to assess the sub-acute effects of psilocybin in self-reported healthy retreat attendees on state and trait anxiety, when taken in a supportive group setting. The population is informative to investigate as sub-clinical, “healthy” samples often report meaningful anxiety symptoms that impact one’s well-being and quality of life –63, howeWe hypothesized that, compared to baseline, reductions in state and trait anxiety and neuroticism would be observed 24 h and 7 days after ingestion of psilocybin, whereas mindfulness capacities would be enhanced. Furthermore, we hypothesized that reductions in ratings on both aspects of anxiety would be negatively correlated with enhancements in mindfulness capacities and positively correlated with reductions in the personality trait, neuroticism. Finally, we hypothesized that positive changes in ratings of anxiety would be correlated with higher subjective ratings of ego dissolution, the latter measured with the Ego Dissolution Inventory .Participants were volunteers attending legal psilocybin retreats in the Netherlands, organized by the Psychedelic Society UK. Attendees of those ceremonies were either invited to participate in the study on site, or contacted the researchers by email after hearing about the study through the retreat organizers. To participate in the study, volunteers had to be a minimum of 18 years old and proficient in English. Participants were assessed 3 times: at baseline (the evening before psilocybin ingestion), within 24 h after psilocybin ingestion (hereafter referred to as: sub-acute) and 7 days after psilocybin ingestion (hereafter referred to as: follow-up). Seven-days later, participants received the final follow-up measurement online . The total amount of truffles (g) taken by each participant was recorded, and a sample of the truffles was taken to determine the concentrations of alkaloids afterwards.The study was conducted in accordance with the Declaration of Helsinki and subsequent amendments concerning research in humans and was approved by the Ethics Review Committee of Psychology and Neuroscience and Maastricht University (ERCPN-175_03_2017_A5). Participation was voluntary and no incentives to participate were provided. All volunteers gave their written informed consent prior to participation. The research team was not involved in the screening, preparation, organization, administration, and supervision of the psilocybin ceremonies that were visited.Prior to participation in the retreat, personal intakes were done by the facilitators, which included screening for (and excluding) individuals with psychiatric disorders or taking psychiatric medications, and medical factors like high blood pressure.The setting in which psilocybin was taken was the same throughout all of the retreats. Participants stayed in a large house set in nature, hosted by at least two or more experienced psilocybin facilitators. They arrived the evening before psilocybin administration, and were able to get acquainted with each other, the facilitators, and the schedule of the retreat. Participants were able to discuss their intentions in the group, and participated in group activities to get to know each other. The next day, after a group breakfast, participants received the psilocybin-containing truffles around noon, in a tea form. Facilitators provided music, tools to draw and/or write, food, and overall support. Support was not a guiding of the experience, but more so making sure participants were safe, comfortable, and holding space when necessary. In the evening, all participants and facilitators came back together as a group. The next morning, all participants had breakfast together, had time for integration experiences  and had a closing group meeting. To note: the retreat attendees were individuals who wanted to have a safe psychedelic experience. No therapy was given during the retreat, but rather the role of the facilitators was to provide a safe space for this experience, and to encourage reflection on the experience in the following days.Participants ingested the truffles in a tea form, guided by the facilitators. To do this, the truffles were crushed, and boiling hot ginger tea was added. After infusing for a few minutes, the participants drank the tea, and were subsequently free to add more water and repeat the process 2–3 times. Afterwards participants could eat the remaining truffle contents in the cup. Previous experimental studies have demonstrated that subjective alterations after psilocybin intake begin 20–40 min following administration, peak around 60–90 min, and subside by 6 h post-intake . HoweverThe total amount of psilocybin truffles taken by each participant was recorded, and a sample of the truffles was taken to determine concentrations of psilocybin and its metabolite, psilocin. The German Central Customs Authority determined the contents of psilocin and psilocybin after freeze-drying the truffles using a previously described HPLC method .The assessments included a basic demographic section and six questionnaires: the State-Trait Anxiety Inventory (STAI), the Five Facet Mindfulness Questionnaire (FFMQ), the Big Five Inventory (BFI), the Persisting Effects Questionnaire (PEQ), and the Ego Dissolution Inventory (EDI). All materials were provided in English. The STAI and FFMQ were filled out three times, i.e., at baseline, sub-acute session, and follow-up. The BFI was administered twice, during the baseline and the follow-up session. Whereas the remaining 2 questionnaires were only completed once; the EDI during the sub-acute session, to assess the magnitude of the psychedelic experience in retrospect, and the PEQ at the 7 day follow-up, to assess persisting effects and the significance of the experience.almost never) to 4  that is scored into two sub-scales (state anxiety and trait anxiety). For “state” anxiety questions, participants were asked to select the response for each item that best describes how they feel “right now, that is, at this moment.” For “trait” anxiety questions, participants were asked to select the response that best describes how they “generally feel, that is, most of the time.” The reverse-scored and  and direct-scored  items are summed per each subscale to create a total score which ranges between 20 and 80, with higher scores indicating greater anxiety. Internal consistency coefficients for the scale have been shown to range from 0.86 to 0.95 and test-retest reliability coefficients from 0.65 to 0.75 over a 2-month interval  to 5 , for 39 statements. The FFMQ has shown adequate psychometric properties in both non-clinical and clinical samples. Cronbach’s α for each individual sub-scale range from 0.75 to 0.91  to 5 (agree strongly). The direct and reverse-scored items for each dimension are summed together to create a total score, which, given the variability in terms of number of items, ranges between 8 and 40, 9 and 45, or 10 and 50. The BFI scales have shown substantial internal consistency, retest reliability, and clear factor structure, as well as considerable convergent and discriminant validity with longer Big Five measures  = 26); attitudes about self (N = 22); mood changes (N = 18); relationships (N = 18); and behavioral changes (N = 2). The 86 items of these five categories were rated on a 6-point scale (ranging from 0 = none to 5 = extreme). The scores of the resulting 10 scales  were assessed by calculating mean (SE) separately for each category.The Persisting Effects Questionnaire (PEQ) is a 143-item long scale aiming to assess changes in attitudes, moods, behavior, and spiritual experience . Prior rno more than routine, and 8 = the single most meaningful experience of my life): (1) “How personally meaningful was the experience?”; (2) “Indicate the degree to which the experience was spiritually significant to you?”; (3) “How psychologically challenging were the most psychologically challenging portions of the experiences?”; (4) “How personally psychologically insightful to you were the experiences?”  or 100% . The EDI was scored by calculating the mean of all items, with a higher total score indicating a stronger experience of ego dissolution. The scale has been shown to have excellent internal consistency (The Ego Dissolution Inventory (EDI) is an eight-item self-report scale that assesses the participant’s experience of ego dissolution . In the sistency . The invsistency .Session encoded as a dummy independent variable of three levels: baseline, the sub-acute and follow-up sessions. Subsequently, separate contrasts were performed between baseline and sub-acute as well as baseline and follow-up sessions.Data analyses and visualizations were performed using the Seaborn (version 0.11.2), Statsmodels (version 0.12.2), Scipy (version 1.7.1), and Patsy (version 0.5.1) packages for Python 3.8. A separate multi-linear regression model using the ordinary least square method (OLS) was fit for each outcome variable. The model included Quantification of the acute experience was done by analyzing the results of EDI. Descriptive statistics  were calculated for the ratings of ego dissolution, together with a visual representation of kernel density estimation. To quantify the persisting functional outcomes of the experience, main outcome measures and additional questions of the PEQ were aggregated and reported in a tabular form.Additionally, we sought to examine previously reported associations between anxiety and personality , 78 as wt-tests and chi-square tests) with a twofold purpose: (1) to examine if there are differences between psilocybin-naïve and experienced participants on the anxiety measures (both state and trait anxiety); (2) to assess attrition factors for variables that have previously found to be significant in similar studies  on scores capturing state anxiety. Compared to baseline, participants’ state anxiety reports were 6.4 points lower the morning after the psilocybin ceremony , and 6.7 points lower 1 week after the ceremony  = 10.13; p = 0.002]. Specifically, compared to baseline, self-rated trait anxiety was about 6 points lower the morning after the ceremony  and 8.6 points lower 1 week after the ceremony , 42 (at the morning after the ceremony), and 22 (at 1 week after the ceremony) participants completed all the parts of STAI and were included into analyses. The OLS multi-linear regression revealed a significant main effect of Session on the Non-judge dimension  of the FFMQ. The contrasts analysis showed, in comparison to the baseline, a 0.5 increase in non-judgmental mindfulness capacities the morning after the ceremony  and 1.5 increase at the follow-up . There was no main effect of Session on the remaining, four facets , 46 (at the sub-acute session), and 23 (at the follow-up session) participants completed the FFMQ. The OLS multi-linear regression revealed a significant main effect of r facets .Session on Neuroticism  and Agreeableness  of the BFI. The two traits showed an opposite pattern of changes over time. While, in comparison with baseline, participants scored 5.2 points lower on Neuroticism (d = 0.76) at the follow-up, they scored 3.8 points higher on Agreeableness (d = 0.78). There were no main effects of Session on the remaining three personality traits  of the positive and negative ratings assessing attitudes, mood, social effects, and behavior are presented in On the question, “how personally meaningful was the experience,” 2 (10%) rated it as the single most meaningful experience of their lives, whereas 10 (50%) and 2 (10%), rated it as among the 5 and 10 most meaningful experiences of their lives, respectively. Two participants (10%) rated it as similar to the meaningful experiences that occur on average once every 5 years, three (15%) stated it to be similar to meaningful experiences that occur once a year, and one (5.0%) stated it was similar to experiences that occur on average once a month.On the question, “how spiritually significant was the experience,” 3 (15%) rated it as the most spiritually significant experience of their lives, whereas 8 (40%) and 3 (15%) rated it as among the 5 and 10 most spiritual experiences of their lives, respectively. Three participants (15%) rated it as similar to the spiritually meaningful experiences that occur on average once every year, 2 (10%) stated it was similar to spiritually meaningful experiences that occur once a month, and one (5.0%) stated it was no more spiritual than a routine, everyday experience.In regards to how psychologically challenging the experience was, 1 (5%) rated it as the single most difficult or challenging experience of their lives, 6 (30%) rated it as among the 5 most challenging experiences of their life, and 1 (5%) rated it as among the top 10 most challenging experiences of their lives, followed by 3 (15%) stating it was similar to the challenging experiences that occur every 5 years, 3 (15%) who said occur every once a year, 4 (20%) who said occur once a month, 1 (10%) who said occur once a week, and 1 (10%) who stated it was no more psychologically challenging than a routine, everyday experience.Finally, regarding the psychological insightfulness of the experience, 7 (35%) stated the experience to be the single most psychologically insightful experience of their life, 6 (30%) and 2 (10%) stated among the 5 and 10 most insightful experiences, respectively. Three (15%) stated that the experience was similar to psychologically insightful experiences that occur on average once every 5 years, one (5%) stated similar to experiences that occur on average once a month, and one (5%) stated the experience was no different from every psychologically insightful experience.The EDI was completed by 47 participants the morning after the ceremony. The mean (SD) of participants who filled in the Ego Dissolution Inventory was 59.7 (28.3), with ratings varying between 3  and 100 . The kernel density estimate of the probability density function of the individual EDI scores is presented in Rc2) of 0.891, 0.324, and 0.096 for each successive function. The full model across all functions was statistically significant , explaining 93.4% of the variance. From this model, the first two functions were considered noteworthy in the context of this study, explaining 89.1% and 32.4% of the variance, respectively.A canonical correlation analysis was conducted using the three psychological variables which demonstrated significant effects as predictors (follow-up (change) scores on non-judge dimension of FFMQ, follow-up (change) neuroticism scores, and EDI scores) of the four anxiety outcome measures: sub-acute and follow-up (change) scores on state and trait anxiety measures. The analysis yielded three functions with squared canonical correlations (rs), and the squared structure coefficients (rs2) for each function, as well as the communalities (h2) across the functions for each variable [for an in-depth explanation and interpretation of canonical correlations and associated terminology, the reader is referred to  differed from the naïve participants (N = 21) on measures of anxiety. None of the six independent sample t-tests (2 STAI measurements × 3 assessment points) found significant differences between the groups  revealed significant differences for the age , education , and baseline state anxiety  between those who completed the 1-week follow-up assessment (N = 23) and those who did not (N = 32). Analysis indicated that those who dropped out were younger, reached a lower level of education, and had higher baseline state anxiety levels than those who completed the study. There were no significant differences between the groups in terms of gender, personality traits, baseline trait anxiety, or ego dissolution . Reasons included travel, as many people attended the retreat from abroad, and stayed in the Netherlands for some time afterward to travel around, or work, as some people took time off to attend the retreat, and thus used the following week to catch up on work.The impact of anxiety symptoms and disorders on people’s lives and the treatment challenges are well-known within the field of mental health , 83, 84.The present study’s findings are in line with results from historical  studies, which suggest reductions of anxiety symptoms after a combination of psychedelic drug administration and psychological therapy . SimilarThat said, two previous experimental studies assessing the effect of a psychedelic on anxiety symptoms in healthy volunteers have demonstrated mixed results. Whereas one study showed reductions in state anxiety 1 week post administration, and reductions in trait anxiety 1 month post-administration, of a high dose of psilocybin 25 mg/70 kg), another study found no changes in trait anxiety one and 12 months after a high dose of LSD (200 μg) , 25. Add mg/70 kg2A receptor binding, the latter being the main target of psychedelic drugs , which may have been due to dropout rate and decreased power during the 1-week assessment. In sum, the effects of psychedelic substances on neuroticism seem to be more robust and more frequently reported, compared to changes in other personality traits such as agreeableness or openness.In line with previous studies –39, we dic drugs , 91, sugs et al. . Other ss et al.  or highes et al. . In conts et al. , 43, we Lastly, the present study aimed to further explore hypothesis-driven correlational relationships between changes in mindfulness and neuroticism and changes in anxiety. Although there was an increase in mindfulness capacities following intake of psilocybin, there were no strong associations between changes in mindfulness capacities and anxiety ratings. In regards to neuroticism, in line with theoretical conceptualizations of neuroticism and trait anxiety as stable, personality-dependent dispositions, we found that sub-acute and 1-week reductions in trait anxiety were most strongly correlated with reductions in neuroticism. Namely, change scores in neuroticism and trait anxiety shared about 89% of the variance variability, pointing out a strong interdependency between the two variables. Although trait anxiety and neuroticism inherently share overlapping constructs, it is important to state that they are not identical , 93. Neuinsight/breakthrough or catharsis, suggestibility, and reliving of trauma have been suggested as important factors determining the psychedelic experience (Additionally, we also found that the strongest correlator of sub-acute and 1-week changes in state anxiety were ratings of ego dissolution, sharing about 32% of the variance. Specifically, the higher the rating of ego dissolution during the acute experience, the larger the decrease in state anxiety scores both 24 h and 1 week after the experience. A recent review of twenty studies assessing the clinical response to psychedelics in patients with a range of psychological disorders concluded that the main predictive factor of a response to a psychedelic is the intensity of the acute psychedelic experience . That saperience , 96–100.The objectives were tested using a naturalistic, observational design, with attendees of psilocybin ceremonies. Although, this sort of setting has high rates of ecological validity, as it closely resembles a typical environment associated with psychedelic usage –104, it Taken together, the present study suggests persisting reductions in anxiety symptoms and trait neuroticism, and increases in mindfulness capacities, after ingestion of psilocybin in a supportive group setting. Given the important role of set and setting on the outcome of psychedelic experience , 104, fuThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Ethics Review Committee of Psychology and Neuroscience, Maastricht University, Faculty of Psychology and Neuroscience, Maastricht, Netherlands. The patients/participants provided their written informed consent to participate in this study.NM, KK, and JR conceived of the presented idea. NM and MU collected the data. MK and NM conducted the statistical analysis. MK, NM, and KK prepared the first draft of the manuscript. All authors discussed the results and contributed to the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Density and biomass of major macrozoobenthos classes  differed across sites and months, displaying an overall increase in density towards the final months of the dry season (March and April). Similarly, community composition also differed significantly between sites and throughout the season. The site with most distinct community composition (Adonga) supported low diversity and high abundance of a few bivalve species, whilst other two sites that hosted the most diverse communities, were also the most similar between them (Anrumai and Abu). These spatial and temporal patterns constitute an important baseline to improve knowledge of this intertidal ecosystem and will contribute towards a better understanding of the spatial and temporal distribution patterns of their consumers.The coastal intertidal ecosystem of the Bijagós Archipelago, Guinea-Bissau, one of the largest and most important in West Africa, sustains a considerable proportion of the migratory shorebird populations of the East Atlantic Flyway and operates as a nursery area for benthic fish in the region. The macrozoobenthos in these mudflats constitute the main food source for both groups so that spatial and temporal variation in their abundance and community composition is likely to influence the abundance and distribution of fish and birds. In this study we described the spatial and temporal dynamics in the density, biomass, and community composition of macrozoobenthos across six intertidal flats in three islands of the Bijagós Archipelago. Overall, the Bijagós Archipelago was characterised by a highly species-rich macrozoobenthic community, with ca. 88 taxa identified across all sites, reaching a mean density of 1871 ± 58.3 ind.m Intertidal systems tend to be highly productive and provide numerous ecosystem services, from nutrient recycling to shoreline stabilisation and food production , 2. ThesAfruca tangeri), an ecosystem engineer in intertidal sediments, has been shown to strongly limit the abundance and diversity of macrozoobenthos communities in the Bijagós Archipelago, Guinea-Bissau [Intertidal flats host macrozoobenthos communities, a diverse group of species adapted to the variable environmental conditions associated with tidal regimes . These ca-Bissau . Similara-Bissau . The disa-Bissau –31, whica-Bissau , 32.Compared with temperate systems, tropical intertidal flats are often characterised by a relatively higher species richness but lower density and biomass of macrozoobenthos , 20, 33.The Bijagós Archipelago, located off the West African coast, is an inverse deltaic estuary system , with more than 80 islands, and is surrounded by vast intertidal flats that are mostly fringed by dense mangrove forests , 36. TheStudies on the macrozoobenthos of the Bijagós Archipelago are scarce, but recent papers reported overall low densities and biomass, with considerable variation in species composition between sites  and habi2 of intertidal flats [2) [The Bijagós Archipelago is a group of 88 islands and islets off the coast of Guinea-Bissau, in West Africa, encompassing ca. 450 kmal flats , 49. Itslats [2) , 51 and lats [2) , 49, 52.lats [2) , contriblats [2) , 45).Sampling was carried out in six sites across three islands : the isl2 of area for all sites except for Adonga, where cores had an area of 0.0113 m2, and max depth of 15 to 20 cm (often limited by rocks or shell banks). Sampling at all sites was conducted in areas where shorebirds where observed feeding. Except in one site (Adonga), polychaetes were not quantified in 2020, only bivalves, gastropods and malacostracans, as fieldwork came to a sudden halt due to the Covid-19 pandemic (www.marinespecies.org).Macrozoobenthos from four Classes  were collected using sediment cores of 0.00785 mpandemic . Core sapandemic , and alsA total of 26 taxa were considered for the biomass estimation, by including all taxa with densities above 0.8% of the total density of macrozoobenthos. The biomass of each individual found in almost all the core samples, was estimated from their size through taxa specific regression equations . But forb [nls function in R Software version 3.5.0 [Previously published equations relating size to biomass for the study area were used whenever available , and forb –59 whereon 3.5.0 . WheneveTemporal variation was analysed using two variables: 1) month, a continuous variable that consisted of a pool of the samples of each sampled month in any year; and 2) period, a categorical variable that consisted in aggregating months into three main periods: end of wet season (October and November), early dry season  and late dry season  and biomass (mg of AFDM.m-2) of macrozoobenthos, and to assess if temporal patterns varied between sites, we conducted a Generalised Linear Model with negative binomial family (GLMnb), to account for overdispersion, and used the log link function. To model the variation in density, we used the number of individuals  counted in each core as the dependent variable, and to model variation in the biomass we used mg of AFDM in each core. The log of the area of each sampling core was used as an offset in all models, as this varied between sites, and the explanatory variables were site (with six levels) and month . We also explored the interaction between the two explanatory variables. Model selection was undertaken using Akaike Information Criterion (AIC), by fitting all possible model combinations and selecting the model with the lowest AIC. When AIC differ less than two, a common “rule of thumb”, indicating no support for differences between competing models , we selWe computed Shannon-Wiener diversity index and species richness for each site and overall to compare with previous studies in the Bijagós Archipelago and with macrozoobenthos communities in other tropical and temperate intertidal systems elsewhere.-2) among samples (cores) with many zeros, using a log (x+1) transformation to reduce the weight of the most abundant species. We then used this dissimilarity matrix as the dependent variable on a permutational analysis of variance (PERMANOVA), with site (six levels) and period (three levels) as explanatory variables. We also tested the interaction between site and period and when the interaction was significant, we further inspected differences among sites separately for each level of period using PERMANOVAs, having site as the explanatory variable. Post-hoc PERMANOVAs with Bonferroni’s p-value adjustment for multiple comparisons were used to assess significant differences between sites. PERMANOVA’s assumption of homogeneity of multivariate dispersal was tested using betadisper and permutest functions of the VEGAN package, which simultaneously tested differences in community diversity between sites. In the event of heterogeneity of multivariate dispersal, PERMANOVA remains a robust test in the presence of balanced designs [In order to explore spatial variation in the community composition  and assess if temporal variation is similar between sites, we first calculated zero-adjusted Bray-Curtis dissimilarities , which s designs . NonetheCAPdiscrim, from the BiodiverityR package [2≥ 0.15 were plotted as vector arrows over the CAP ordinations, with arrow length proportional to R2 value of the regression, thus informing on the importance of each species in the macrozoobenthic community. Plots showing all the species with significant fits, regardless of their R2, were also performed and presented in the Supporting Information. All the analysis were performed in R Software version 3.5.0 [To visualize the differences in the centroids and in multivariate dispersal of the community composition among sites for each period, we computed Canonical Analysis of Principal Coordinates based on discriminant analysis , using the function  package  followin package . We usedon 3.5.0  and resuPermits to access field sites and sample were given by Instituto da Biodiversidade e das Áreas Protegidas Dr. Alfredo Simão da Silva, under the guardianship of the Ministry of Environment. Additional information regarding the ethical, cultural, and scientific considerations specific to inclusivity in global research is included in the Supporting Information .-2, corresponding to a mean biomass of 5.65 ± 0.41 gAFDM.m-2 , with Adonga having the highest mean density, significantly higher than all sites except Bijante, and followed by Abu, Anrumai, Bruce and Escadinhas, the later having significantly lower densities than all other sites  Tables. At the (sub)class level, Adonga had highest mean density of bivalves and sedentary polychaetes (the later together with Bijante), but lowest of gastropods and malacostracans  Tables. Bivalve density increased significantly across months regardless of site , Fig 3. The biomass of macrozoobenthos varied significantly among sites (p<0.001), with Abu, Adonga, and Anrumai having significantly higher biomass than all other sites, followed by Bijante, with Bruce and Escadinhas having significantly less biomass than the remaining sites  Tables. At the (sub)class level, Abu, Adonga and Anrumai had the highest biomass of bivalves, with the last two sites having the lowest biomass values of gastropod and malacostracans, respectively  Tables. Bivalve biomass did not vary across months, whereas the remaining (sub)classes showed different patterns of monthly variation, the majority of which were positive , Fig 4. Overall, at least 88 taxa were identified in all sites, at different taxonomical levels . To asse5,507 = 22.76, R2 = 0.17, p<0.001) and periods , and the variation between periods was significantly different among the sites . CAP ordinations of sites suggest that Adonga has the most different community composition, mostly due to the high densities of the bivalves P. isocardia, A. nymphalis, Keletistes sp. and T. adansonii  were significantly different across the sites , with Adonga as the only site with significantly smaller dispersion than all the others .The macrozoobenthic community composition showed overall significant differences among sites . The same holds for differences between sites in the multivariate dispersion .When comparing the community composition in each period, there were significant differences between sites in all periods  the most similar communities were those in Anrumai and Abu . Adonga  Bijante . The sig Bijante ; Fig 6A.P. isocardia , the communities in Adonga remained the most distinct , Fig 6B. instead , Fig 6B.P. isocardia and A. nymphalis, which increased markedly from early dry season to late dry season, as well as the bivalve T. adansonii, that became important in Adonga only in late dry season. In Bruce, Orbiniidae maintained its importance from early to late dry season, while in Bijante Orbiniidae’s importance increased to a similar importance as at the end of the wet season. The community in Escadinhas shifted to be dominated by sedentary polychaetes (including Capitellidae) and the errant polychaete Sigambra sp. The multivariate dispersion also differs significantly, mostly because of the significantly higher dispersion in Anrumai and Abu in this final period , to describe the spatial and temporal variation of macrozoobenthos density, biomass, and community diversity and composition. We found a highly diverse community, with more than 88 taxa, but with typically modest densities and biomass. With both univariate and multivariate approaches, we showed significant differences in the macrozoobenthos density and community structure among sites. Interestingly, overall density increased linearly throughout months, with all significant relationships being positive across sites and (sub)classes. However, contrarily to the expected reduction in biomass due to shorebird predation in this period, we found no clear overall trends for biomass when aggregating all sites, and at the site level most of the significant relationships across sub(classes) were positive . These patterns dispute the expected depletion in the macrozoobenthos community by the end of the dry season due to intense predation pressure from migratory shorebirds, which adds to the local fish predation over the studied period. The findings are at odds with the observation at Banc d’Arguin, Mauritania, where depletions over the shorebird predation season did seem to occur .58 ind.m-2, corresponding to an average biomass of 5.65 ± 0.41 gAFDM.m-2. These values are in accordance with previous studies done locally at smaller spatial and temporal frames [-2 [-2 and 26.6 gAFDM.m-2 respectively) [On average, macrozoobenthos of the Bijagós Archipelago had a density of 1871 ± l frames , 72. Butl frames , our bioames [-2 . Even lactively) , 74.Scrobicularia plana is responsible for most of the biomass [Anadara granosa takes that role [S. senilis (Arcidae family), which is in line with previous studies in the Bijagós Archipelago [We found that sedentary polychaetes, the most abundant taxonomic group , accounted for only 17% of the total macrozoobenthos biomass, whereas the second most common group, bivalves , had a disproportionally high contribution towards biomass, representing 72% of the total. This pattern of bivalves occurring at low densities but high biomass is typical in other intertidal systems, both temperate, such as the Tagus estuary where the bivalve  biomass , 76, andhat role . In our hipelago , 46 and hipelago , 78. Thihipelago  and somehipelago , and althipelago , on somehipelago , while ahipelago .Tropical intertidal flats are known to often show higher macrozoobenthos diversity than their temperate counterparts , 20, 33,Afruca tangeri as a key species in Lourenço et al. (2018) [The macrozoobenthic community composition was shown to be overall well segregated in the CAP space, with the community structure gradients particularly dominated by the differences in the occurrence and density between eight key taxa. The first axis of the CAP ordination showed mainly the distribution of sampling cores along the gradients of abundance of the bivalve species, while the second axis mainly reflected the gradient along the abundance of the polychaete taxa. This suggests a diverse community that depends on several important taxa, an important trait of stable and resilient ecosystems , 85. The. (2018) , which w. (2018)  conducte. (2018) , they mi. (2018) . Thus, t. (2018) .-2 and 2321 ± 149 ind.m-2, respectively), and Escadinhas and Bruce with lower densities , than all other sites. These patterns were the same for Adonga, Escadinhas and Bruce when considering mean biomass , but the high density found in Bijante did not translate into high mean biomass (4.68 ± 0.67 g AFDM m-2). This is likely due to the comparatively lower prevalence of bivalves in this site (which represented the main source of biomass in the whole system), in comparison to other sites like Anrumai, Abu and Adonga, and which in Bijante were replaced by higher density of sedentary polychaetes. Additionally, the mean size of bivalves in Bijante was the lowest of all sites , which also contributes to lower overall biomass. Lourenço et al. (2018) [-2 in Bijante; 5.5 vs 2.08 g AFDM m-2 in Bruce), while for Escadinhas, values were similar. These differences may derive from the different methods used to estimate biomass (direct measure vs. estimates from equations in our study) and/or a lower contribution from fiddler crabs in our study because of the sampling method used.We showed overall significant spatial variation in both density and biomass of macrozoobenthos when comparing sites, and this was also true at the (sub)class level for the majority of macrozoobenthos. Considering density, when aggregating all macrozoobenthos (sub)classes, four sites stand out, Adonga and Bijante with comparatively high mean densities (2507 ± 157 ind.m. (2018)  also fouThe spatial variation at the (sub)class level in terms of density and biomass was translated in marked differences in the most important (sub)classes between the sites. Furthermore, spatial differences were also apparent in the results of the multivariate analysis, with overall significant differences between sites in the community composition and in community diversity . The aggregated results of all analysis clearly indicate that spatial variation needs to be taken into account to understand the intertidal ecosystem of the Bijagós Archipelago. Spatially heterogeneous intertidal landscapes have been reported in tropical systems elsewhere , 87, 88,P. isocardia, Keletistes sp., A. nymphalis and T. adansonii were the main taxa driving the marked differences to the community compositions of the other sites. Pelecyora isocardia is a small sized bivalve that constitutes the most important prey item for Red knots Calidris canutus in the Bijagós Archipelago, totalling more than 80% of the proportion of biomass consumed by this shorebird [Pelecyora isocardia is also important for Bar-tailed godwits Limosa lapponica, although to a lesser extent, for which it was found as a prey item in 30% of the droppings analysed in the Bijagós Archipelago [T. adansonii and T. nymphalis are consumed to some extent by Red knots and Bar-tailed godwits [Various macrozoobenthos taxa were found to have high importance in characterizing the community composition of each site. In Adonga, the bivalves horebird . Pelecyohipelago . Also, T godwits . Sites l godwits , 72, 91  godwits , 92. Due godwits –95.In the CAP analysis we compared the community composition and diversity among sites for each period , with significant differences between most sites emerging in all periods. It is noteworthy that Adonga was the site showing the largest separation from the other sites, with the macrozoobenthic community being characterized by high densities of bivalve taxa, and a significantly lower community variability . Moreover, when considering the weighted mean Shannon-Wiener diversity index and species richness in each site, Adonga was also the least diverse and poorest site , and the smallest in the dry season (2.5 ± 0.1 mm in the beginning and 3.9 ± 0.1 mm in the end of the season) and the same happened with body sizes of the Orbiniidae polychaetes . These results contrast with the findings from Banc d’Arguin, where the timing of the wet season is similar to that of the Bijagós, but where, next to the Sahara, the magnitude of the wet is of course much smaller. At the Banc d’Arguin intertidal flats most bivalve species densities peaked in October and declined until March, declines which were argued to be explained by depletion by molluscivore shorebirds [Interestingly, the overall density of macrozoobenthos increased from the end of the wet season to the end of the dry season. After the wet season, the number of individuals started to increase despite the presence of their seasonal predators (shorebirds), suggesting recruitment at this stage . This reorebirds . In the orebirds . The subPugilina morio), while some additionally show a preference for mudflat channels (e.g. Cymbium sp). Biomass at temperate intertidal sites is typically higher in spring, when macrozoobenthic species’ growth rates are high due to increasing temperatures, and is followed by a decrease until winter [Overall biomass did not vary significantly through time. However, these results must be interpreted with caution, as they were extremely influenced by the dominance of bivalve biomass , which remained stable throughout the sampling season. Regardless, no clear pattern in the variation of the majority of (sub)classes emerged, with some sites showing a significant increase in biomass over time, while others showed a decrease. Only gastropod biomass increased consistently across sites, even though values were overall very low. This is likely due to the sampling strategy, as the larger gastropod species have very sparse distribution  and the absence of a decrease in biomass throughout the study period, which coincides with the presence of large numbers of migratory shorebirds wintering in the Bijagós Archipelago, together with the fact that communities remain rather stable between periods, suggests that despite their large numbers, shorebirds do not cause depletion of macroinvertebrates at this site.In this work we tackled an evident knowledge gap, by providing a detailed description of the composition, density and biomass of macrozoobenthic communities at a wide spatial-temporal scale within the Bijagós Archipelago. This constitutes an important contribution for the understanding of the intertidal ecosystem of this key biodiversity site, which harbours important benthic fish communities and is a key non-breeding area for Palearctic migratory shorebirds, for which macrozoobenthos constitutes an important prey group. This baseline knowledge will be relevant for subsequent ecological studies in this area focused on the populations of these high-level consumers and on further assessing the interactions within the whole intertidal food web.Given the high sample size and wide spatial and temporal representativeness, the main findings of this study allow for the conclusion that the macrozoobenthic community of the Bijagós Archipelago is diverse but has relatively low biomass values, is highly variable between sites, and presents densities that increase towards the end of the dry season, despite the high predation pressure by migratory shorebirds during this period. Furthermore, our results suggested that there is a high number of important macrozoobenthic taxa, possibly indicating a resilient intertidal ecosystem. These traits may well be among the important services that the Bijagós Archipelago offers and that may help explain the regional and international importance of this site, for benthic fish in the West African region, and within the East Atlantic Flyway for migratory shorebirds.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S3 Table(DOCX)Click here for additional data file.S4 Table(DOCX)Click here for additional data file.S5 Table(DOCX)Click here for additional data file.S6 Table(DOCX)Click here for additional data file.S1 Fig(DOCX)Click here for additional data file.S1 Appendix(DOCX)Click here for additional data file.S2 Appendix(DOCX)Click here for additional data file.S1 Checklist(DOCX)Click here for additional data file.