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Conclusions | EARLY PREGNANCY | We showed that fish oil administered from early pregnancy onwards increased the | PMC10751948 |
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Acknowledgements | Diabetes | DIABETES | We want to thank Helena Fisk and Chris Gelauf for their assistance with the fatty acid analyses.The work (clinical trial execution) was supported by the Academy of Finland (#258606), State research funding for university-level health research of the Turku University Hospital Expert Responsibility Area, the Diabetes Research Foundation, the Juho Vainio Foundation, Business Finland (#3486/31/2015), the Päivikki and Sakari Sohlberg Foundation (serum fatty acid analyses and personal support to NH) and the Finnish Food Research Foundation (personal support to NH) and The Finnish Cultural Foundation.Conceptualisation, K. L., N. H., P. C. C. and E. A. M.; methodology, N. H., T. V., E. A. M., P. C. C. and K. L.; supervision of formal analysis, T. V.; investigation, N. H.; resources, K. L.; data curation, N. H.; writing – original draft preparation, N. H.; writing – review and editing, N. H., T. V., E. A. M., P. C. C. and K. L.; visualisation, N. H.; supervision, K. L.; project administration, K. L. All authors have read and agreed to the published version of the manuscript.N. H., T. V., E. A. M., P. C. C. and K. L.: no conflicts of interest. | PMC10751948 |
Supplementary material | For supplementary material accompanying this paper visit https://doi.org/10.1017/S0007114523001915.click here to view supplementary material | PMC10751948 |
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References | PMC10751948 |
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Background | itching, hand and foot eczema, pain | SKIN | Chronic hand and foot eczema is a polyetiological dermatological condition. Patients experience pain, itching, and sleep disturbances and have a reduced quality of life. Skin care programs and patient education can improve the clinical outcome. eHealth devices offer a new opportunity to better inform and monitor patients. | PMC10031439 |
Objective | hand and foot eczema | This study aimed to systematically analyze the effect of a monitoring smartphone app combined with patient education on the quality of life and clinical outcome of patients with hand and foot eczema. | PMC10031439 |
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Methods | pruritus, Eczema, pain | SECONDARY, ECZEMA | Patients in the intervention group received an educational program; attended study visits on weeks 0, 12, and 24; and had access to the study app. Patients in the control group attended the study visits only. The primary end point was a statistically significant reduction in Dermatology Life Quality Index, pruritus, and pain at weeks 12 and 24. The secondary end point was a statistically significant reduction in the modified Hand Eczema Severity Index (HECSI) score at weeks 12 and 24. This is an interim analysis at week 24 of the 60-week randomized controlled study. | PMC10031439 |
Results | itch, pain | In total, 87 patients were included in the study and randomized to the intervention group (n=43, 49%) or control group (n=44, 51%). Of the 87 patients, 59 (68%) completed the study visit at week 24. There were no significant differences between the intervention and control groups regarding quality of life, pain, itch, activity, and clinical outcome at weeks 12 and 24. Subgroup analysis revealed that, compared with the control group, the intervention group with an app use frequency of fewer than once every 5 weeks had a significant improvement in the Dermatology Life Quality Index at weeks 12 ( | PMC10031439 |
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Conclusions | hand and foot eczema | An educational program combined with a monitoring app that connects patients with their treating dermatologists can improve quality of life if the app is not used too frequently. In addition, telemedical care can at least partially replace personal care in patients with hand and foot eczema because the analysis of the pictures taken by the patients correlates strongly with that of the in vivo images. A monitoring app such as the one presented in this study has the potential to improve patient care and should be implemented in daily practice. | PMC10031439 |
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Trial Registration | Deutsches Register Klinischer Studien DRKS00020963; https://drks.de/search/de/trial/DRKS00020963 | PMC10031439 |
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Introduction | PMC10031439 |
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Background | itching, injuries or disabilities, psoriasis, pain, eczema | DISEASE, DISEASES, PSORIASIS, SKIN CONDITION, PATHOGENESIS, ECZEMA, FOOT ECZEMA | The prevalence of combined chronic hand and foot eczema in industrialized cities is 5.4% [Hand and foot eczema is considered to be chronic if it persists for >3 months despite adequate therapy or recurs with a frequency of more than twice a year [The severity of eczema ranges from very mild to very severe, with therapy-refractory courses associated with intense pain and itching [More often than not, patients with eczema have limited knowledge of the pathogenesis of their skin condition and the correct disease management [In our department of dermatology, patient education alone for patients with psoriasis had no significant effect on the clinical outcome [eHealth-based supporting systems for patients are becoming popular and are incorporated more frequently into patient care. Germany recently set up the German acronym for Digital Health Applications (DiGA) directory, which lists Conformité Européenne–marked medical devices that aim to detect, monitor, treat, or alleviate diseases or to detect, treat, alleviate, or compensate for injuries or disabilities [ | PMC10031439 |
Objectives | Hand Eczema, hand and foot eczema, NRS, pain | DISEASE, FOOT ECZEMA | The aim of this prospective randomized controlled intervention study was to analyze whether a monitoring smartphone app combined with patient education would improve the quality of life and clinical outcome of patients with hand and foot eczema. The study app was developed specifically for this study. With the app, our patients were able to periodically measure Dermatology Life Quality Index (DLQI) and Hand Eczema Severity Index (HECSI; modified version for foot eczema) scores, as well as the impact on activity and pain (both measured on a numeric rating scale [NRS]), and document the progression of their disease through photographs [Furthermore, the DLQI, HECSI, and NRS (for activity and pain) scores were assessed by the treating physicians during personal visits at weeks 0 (before the intervention), 12, and 24.The final aim behind the development of the app was to reduce waiting time for a physician’s appointment in case of an emergency by expanding teledermatological services for patients with hand and foot eczema and to allow precise self-monitoring by the patients. | PMC10031439 |
Methods | PMC10031439 |
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Study Design | itching, itch, NRS, pain | DISEASE, PATHOGENESIS, SECONDARY, FOOT ECZEMA | The aim of this 60-week randomized controlled intervention study was to investigate the effect of patient education in combination with a monitoring smartphone app on patients experiencing chronic hand and foot eczema. This is an interim analysis of the data from study weeks 0, 12, and 24.The study was carried out at the department of dermatology, venereology, and allergology at the University Medical Center Mannheim in Mannheim, Germany, from August 13, 2018, to August 30, 2021. The inclusion criteria included a physician-confirmed diagnosis of chronic hand and foot eczema, ability to give informed consent, access to a smartphone, and patient age between 18 and 75 years. During the first study visit (week 0 [V1]), the study participants were randomly assigned to the control or intervention group in a ratio of 1:1.To assign patients to a group, we created 50 lots for the intervention group and 50 lots for the control group. These were sealed in an urn, and the patients were asked to draw lots.In total, 90 participants were included in the study, but 3 (3%) dropped out of the study before they were assigned to a group. Of the 87 remaining participants, 43 (49%) were assigned to the intervention group and 44 (51%) to the control group.The control group started the first study visit at week 0. Information on sociodemographic data, preexisting conditions, and previous and current therapies were collected, and standardized questionnaires such as the DLQI administered. In addition, patients’ current level of knowledge about their disease, severity of the disease measured using the HECSI or a modified form of the HECSI for foot eczema, and the intensity of the pain and itch measured using an NRS ranging from 0 to 10 were recorded. Furthermore, the negative impact on the activity measured using the NRS of patients was assessed. In-person follow-up visits were carried out at V2 and V3. The same parameters were recorded for the intervention group. In addition, these patients received a 2-hour detailed training session on pathogenesis, classification, therapeutic options, and behavioral recommendations from 2 dermatological specialists at our clinic. Each patient also received a personal access code to our app, DermaScope Mobile. Using this app, patients were able to take pictures of their hands and feet, use a chat function to ask questions that were answered by their treating dermatologists, and complete questionnaires on quality of life (DLQI) and current symptoms (NRS for itch and pain). Screenshots of the app can be found in the paper by Domogalla et al [The quality of each image uploaded in the app by the patients was categorized by the rater (YS) as good or bad based on the following criteria: well-illuminated picture, sharp and focused image, and complete presentation of the hands and feet. All 3 criteria had to be met for the image to be rated as good. Each image was assigned to the rater (YS), who checked its quality based on these 3 criteria. If all criteria were met, the image was rated as of good quality. We then calculated an electronic HECSI (eHECSI) score based on these images and statistically examined the extent to which this score correlated with the HECSI score collected in person.The primary end point of the study was to determine the effect of extensive patient training, physician-patient contact on demand, and our app on quality of life as well as itching and pain at weeks 12 and 24. The secondary end points were the effect on the disease outcome assessed with the HECSI at weeks 12 and 24. Modulating effects of sex, age, and disease duration were evaluated for each end point. | PMC10031439 |
Ethics Approval | The medical ethics committee of the Medical Faculty Mannheim, Heidelberg University, approved the study (2017-655N-MA), and the implementation complied with the Declaration of Helsinki. All participants were instructed in detail regarding the study design and gave their informed consent before participating in the study. | PMC10031439 |
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Results | PMC10031439 |
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Patient Demographics | hand and foot eczema | In total, 90 patients were included in the study. The main reasons for declining participation were lack of time, amelioration of hand and foot eczema, or distance to our outpatient clinic.Of the 90 patients who signed the informed consent form, 87 (97%) took part in the baseline visit and were randomized 1:1 to the intervention (n=43, 49%) or control (n=44, 51%) groups. Of the 90 patients initially included in the study, 3 (3%) dropped out of the study before the baseline visit. Of the 87 remaining patients, 23 (26%) discontinued the study after the baseline visit or the educational program (intervention group: 17/43, 40%, and control group: 6/44, 14%). Leading up to week 24, of the 64 remaining patients, 5 (8%) discontinued the study, resulting in 59 (92%) patients completing the week 24 visit ( | PMC10031439 |
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Male Patients Profit More From the Intervention Regarding the Clinical Outcome | In a further subgroup analysis of the intervention group in regard to the sex-specific development of the HECSI, we found a significant improvement in the HECSI compared with baseline only for male participants (V2: | PMC10031439 |
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Correlation of the eHECSI With the HECSI | Correlating the eHECSI assessed on the basis of pictures taken by the patients of their hands and feet with the HECSI recorded by physicians during regular personal visits, the eHECSI correlated strongly with the in-person–assessed HECSI ( | PMC10031439 |
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Discussion | PMC10031439 |
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Principal Findings | anxiety, psoriasis, pain, depressive, hand and foot eczema, eczema | DISEASE, PSORIASIS, DERMATOLOGICAL DISEASES, SKIN CONDITION, ECZEMA | In our intervention study, we showed that the use of our monitoring app in combination with a patient education session has a significant effect on quality of life, pain, activity, and clinical outcome if the app is not used more than once every 5 weeks. In addition, men seem to profit more from app use frequency than women regarding the clinical outcome.We first analyzed differences between the intervention and control groups in regard to amelioration of quality of life, pain, activity, and eczema. All our study patients, independent of group membership, had less pain, showed an enhanced quality of life, and participated more actively in life; in addition, their skin condition improved over time. Although the intervention group showed a stronger improvement at all times, the difference between the 2 groups never reached significance. As our patients received a physician’s appointment every 3 months regardless of their skin condition, we conclude that the regular physician-patient contact was crucial for the amelioration of the disease in both groups. This aligns with the observations of Riedl et al [In our previous intervention study involving a 60-week monitoring app for patients with psoriasis, we were able to show that patient education in combination with a monitoring app resulted in a significant amelioration of depressive and anxiety symptoms in patients who used the app fewer than once a month [We additionally assessed whether patients reduce the app use frequency as their outcomes improve, but the subgroup with <20% app use frequency showed lower app use frequency from the start, with no decrease in the use in the course of time.By contrast, the app provided in the study allowed direct contact between patients and their treating physicians, which probably reassured patients and improved quality of life in the intervention group when using the app fewer than once a week. We believe that the mere possibility of being able to contact the supervising physician if needed rather than the frequency of physician-patient contact is decisive to improved quality of life. In our clinical perception, frequent physician’s appointments to obtain a follow-up prescription may become a burden, in particular for younger patients who have less time because of their jobs. Such patients might benefit significantly from additional teledermatological care.Another finding of our study was that the HECSI of male participants decreased faster than those of female participants, independent of app use frequency, although women show higher adherence to topical therapy [One of the study’s great strengths was that we were able to show that telemedical care can at least partially replace personal care in patients with hand and foot eczema because the analysis of pictures taken by the patients correlates strongly with that of the in vivo images. Therefore, the HECSI assessed in the face-to-face visit correlated significantly with the eHECSI. This is surely not the case for all dermatological diseases in which the disease can affect the whole body, especially the genital area and the capillitium. A study by Zabludovska et al [Our study includes some limitations. A major limitation is the monocentric design and the small study cohort, which limits generalizability of the results. In particular, the group with <20% app use frequency is very small, which could have led to missed or overinterpreted differences between the groups, especially as we compared this subgroup of the intervention group with the control group. Further studies are necessary to verify our findings on a broader scale. | PMC10031439 |
Conclusions | hand and foot eczema, eczema, pain | ECZEMA | Overall, our intervention had a positive effect on quality of life, pain, activity, and possibly the clinical outcome in a subgroup of patients with hand and foot eczema.We were able to show that a monitoring app for patients with hand and foot eczema that allows direct contact with their treating physicians combined with patient education may have the potential to improve the eczema outcome of these patients, especially if the app is not used too frequently. We believe that a monitoring app such as the one presented in this study has the potential to improve patient care and should be implemented in daily practice. However, because of the small number of participants, especially in the subgroups of the intervention group, as well as missing data on treatment adherence of the control group, these data need to be re-examined in a larger sample with consideration of individual factors.The authors express special thanks to the team of the dermatology department of the University Hospital Mannheim. This work was sponsored by Novartis Pharma GmbH.Conflicts of Interest: AS received honoraria for presentations and as a member of the advisory boards of LEO Pharma, Novartis GmbH, and Almirall Hermal GmbH. AS is the CEO and owner of Derma Intelligence GmbH, which developed DermaScope Mobile.CONSORT-eHEALTH checklist (V 1.6.1). | PMC10031439 |
Abbreviations | Hand Eczema, Eczema | ECZEMA | German acronym for Digital Health ApplicationsDermatology Life Quality Indexelectronic Hand Eczema Severity IndexHand Eczema Severity Indexnumeric rating scalevisit time point | PMC10031439 |
Author summary | depression, psychiatric, treatment-resistant depression | DISEASE, DISORDERS, REMISSION, SYNDROME, CORTEX | The authors have declared that no competing interests exist.Repetitive transcranial magnetic stimulation (rTMS) is a promising alternative therapy for treatment-resistant depression, although its limited remission rate indicates room for improvement. As depression is a phenomenological construction, the biological heterogeneity within this syndrome needs to be considered to improve the existing therapies. Whole-brain modeling provides an integrative multi-modal framework for capturing disease heterogeneity in a holistic manner.Computational modelling combined with probabilistic nonparametric fitting was applied to the resting-state fMRI data from 42 patients (21 women), to parametrize baseline brain dynamics in depression. All patients were randomly assigned to two treatment groups, namely active (i.e., rTMS, n = 22) or sham (n = 20). The active treatment group received rTMS treatment with an accelerated intermittent theta burst protocol over the dorsomedial prefrontal cortex. The sham treatment group underwent the identical procedure but with the magnetically shielded side of the coil.We stratified the depression sample into distinct covert subtypes based on their baseline attractor dynamics captured by different model parameters. Notably, the two detected depression subtypes exhibited different phenotypic behaviors at baseline. Our stratification could predict the diverse response to the active treatment that could not be explained by the sham treatment. Critically, we further found that one group exhibited more distinct improvement in certain affective and negative symptoms. The subgroup of patients with higher responsiveness to treatment exhibited blunted frequency dynamics for intrinsic activity at baseline, as indexed by lower global metastability and synchrony.Our findings suggested that whole-brain modeling of intrinsic dynamics may constitute a determinant for stratifying patients into treatment groups and bringing us closer towards precision medicine.There are multiple therapeutic protocols with a limited remission rate, for treatment-resistant depression, using repetitive transcranial magnetic stimulation (rTMS). It is still unclear how we match different rTMS protocols to patients to optimize the therapy. Currently, the process of determining the best rTMS protocol for each individual involves trial and error. Whole-brain computational modelling paves the way to find the optimal therapeutic protocol for each patient, by integrating multi-modal neuroimaging through theoretical models of brain dynamics. In this work, whole-brain modelling helped us identify two covert clinically relevant subtypes in our depression cohort, exhibiting different responses to the same rTMS therapy applied over the dorsomedial prefrontal cortex. Patients who were assigned to the subtype with blunted resting-state frequency dynamics showed a greater improvement in specific affective and negative symptoms. Moreover, we further indicated that the summative scores of phenotypic behaviors for depression are not well-suited for dissociating the depression subtypes and measuring the treatment outcome. In conclusion, our results suggest that studying whole-brain dynamics could have profound implications for identifying reliable biomarkers and neurostimulation targets for the treatment of psychiatric disorders. | PMC10019702 |
Data Availability | The structural data used for creating the computational models is openly available at | PMC10019702 |
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1. Introduction | avolition, depression, treatment-resistant depression, anhedonia | SAID | Repetitive transcranial magnetic stimulation (rTMS), which consists of temporally structured magnetic pulse trains, is an emerging therapy for treatment-resistant depression [While rTMS is an effective treatment for decreasing the overall symptoms of depression, it has been found that conventional rTMS protocols over the dlPFC may not significantly treat symptoms related to anhedonia and avolition (i.e., loss of pleasure and motivation) in patients with depression [That being said, the existing rTMS protocols show high inter-individual variability in the treatment outcome and efficacy, and it is not yet understood how we might match different TMS protocols to the patients [In the present study, we evaluated the predictive value of whole-brain modeling for the therapeutic effect of applying accelerated iTBS over dmPFC for patients with depression, using a brief resting-state scan at baseline. We explored our depression sample using computational modeling to unveil covert subtypes exhibiting different whole-brain dynamics. Further, we aimed at testing if the detected subtypes differed in response to rTMS and symptom characteristics. Finding such a dichotomy further stresses the importance of stratification into treatment groups as a key step towards precision medicine. | PMC10019702 |
2. Materials and methods | PMC10019702 |
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2.1 Ethics statement | The study involved human participants and was accordingly reviewed and approved by the Central Ethical Review Board, Uppsala University, Sweden. Moreover, all aspects of the study comply with the ethical standards of relevant human experimentation and with the Helsinki Declaration of 1975, as revised in 2008. Written informed consent was obtained from the research participants. | PMC10019702 |
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2.2 Study design and participants | depression, bipolar depression, psychiatric, depressive | This study uses data from a randomized parallel double-blind sham-controlled trial that was pre-registered at the U.S. National Library of Medicine (i.e., ClinicalTrials.gov), with the registration ID of NCT02905604. In the current work, the sample size was based on a previous study with a similar design, in which the response rate was indicated as 17% for sham treatment and 52% for active treatment in the depression cohort [The 42 age-eligible (18–59 years old) patients (mean age: 29 ± 9.4, 21 women) who were included in the current study were recruited from the psychiatric outpatient clinic at the Uppsala University Hospital, Sweden. This data collection started in September 2016 and ended in January 2020. The experiment came to an end after collecting the required amount of data from the intended number of patients, as determined by the sample size assessment. All patients were diagnosed with either uni- or bipolar depression (n = 3) and fulfilled the criteria of an ongoing depressive episode determined through the Mini International Neuropsychiatric Interview [ | PMC10019702 |
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2.3 Treatment | ADVERSE EFFECTS | We applied the neuro-navigated iTBS [The iTBS treatment was applied twice daily with a 15-min interval to promote plasticity [Moreover, in all patients, two transcutaneous electrical nerve stimulation (TENS) electrodes were placed on the forehead directly beneath the center of the coil. Thereby, a current of up to 4 mA, synchronized with the TMS pulses and scaled to the magnetic stimulator’s output intensity, was delivered in the sham group, to simulate the tactile sensation of active stimulation on the scalp. Therefore, similar to the active treatment, sham treatment patients might require extra treatment days to achieve the intended strength of the TENS stimulation. Notably, because of this aspect of the study, we were able to have a similar number of treatment days for the active and sham groups.Prior to the first treatment session, the type of treatment (i.e., active or sham) was decided through a randomization process (computerized pseudorandom number with Mersenne Twister algorithm), determining which side of the coil (i.e., not shielded or shielded) to use for each patient. Specifically, a randomization code was prepared by a third person other than the magnetic stimulator’s operating nurse and entered in the stimulator’s research software. Consequently, the software guided the operator as to which side of the coil should be angled towards the patient. Not to mention that if the patient was assigned to the sham treatment group, the research software automatically activated the TENS stimulation. Moreover, during treatment, daily monitoring for potential adverse effects was conducted. No serious harm or unintended effect was observed in either of the treatment groups. It is worth to further noting that there was no difference in the number of treatment days across active and sham groups [ | PMC10019702 |
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2.4 Phenotype characterization and behavioral measurements | Depression | All participants were assessed using different symptom ratings and executive functioning tests at baseline and after the treatment, including Montgomery Åsberg Depression Rating Scale, self-report (MADRS-S), Brief Psychiatric Rating Scale (BPRS), Clinical Assessment Interview for Negative Symptoms (CAINS) and Trail Making Test (TMT). | PMC10019702 |
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2.4.1 Montgomery Åsberg Depression Rating Scale, Self-report (MADRS-S) | MADRS-S, mood disorders, depressive symptoms | MADRS-S is a self-reported questionnaire to assess the depressive symptoms in patients with mood disorders, based upon the individual’s ratings in the range of 0 (none) to 6 (severe) [ | PMC10019702 |
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2.4.2 Brief Psychiatric Rating Scale (BPRS) | psychotic symptoms, psychiatric, BPRS | The BPRS is a widely used test based on a clinician’s interview with the patient, that is used to comprehensively measure psychiatric symptoms ranging from affective to psychotic symptoms. We used the extended 24-item version [ | PMC10019702 |
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2.4.3 Clinical Assessment Interview for Negative Symptoms (CAINS) | The CAINS is a semi-structured interview, mainly performed by RB in this study, and a rating scale with items ranging from 0 (none) to 4 (severe), assessing motivation and pleasure (based on patient report), and emotional expression (based on observation of the patient during the interview) [ | PMC10019702 |
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2.4.4 Trail Making Test (TMT) | depressive symptoms | The patients completed a computerized cognitive test battery starting with the TMT, which is a test of visual attention and task switching. TMT consists of two tasks with an increasing level of difficulty from task A to task B [After the last day of active (i.e., iTBS over dmPFC) or sham treatment, all participants completed the same tests as they did prior to treatment. High scores in all the above-mentioned tests reflect more severe symptoms. The main objective was a treatment-related reduction in different depressive symptoms from baseline to after the rTMS treatment course. | PMC10019702 |
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2.5 Acquisition and prepossessing of resting state functional MRI data | REGRESSION, BEST | We acquired T1-weighted and functional scans in a Philips 3T Achieva scanner (Philips Medical Systems, Best, Netherlands), with a 32-channel head coil. The image acquisition consisted of structural T1-weighted scans with a 3D Turbo Spin Echo sequence and the following parameters: TR/TE = 8.2/3.8 ms, flip angle = 8°, field of view = 256 × 256 mmWe performed standard fMRI preprocessing and denoising steps, using Statistical Parametric Mapping 12 (SPM12) and functional connectivity toolbox (CONN 20.b) in MATLAB 2021b. To summarize the preprocessing steps, we conducted functional realignment and unwarping, artifact detection by artifact detection tool (using an intermediate setting with 97%-percentiles), segmentation and direct normalization of both functional and structural data to the MNI space, and finally spatial smoothing of functional data with a Gaussian kernel with a size of 6 mm full width at half maximum.We further accomplished the denoising by applying a linear regression of confounding effects, including nuisance signals from white matter and cerebrospinal fluid areas [Moreover, we assessed frame-wise displacement (FD) [ | PMC10019702 |
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2.6 Whole-brain computational modeling of resting-state network | To be able to assess the resting-state functional architecture of the brain beyond the conventional large sample statistical approach, we used our previously developed whole-brain model that is based on weakly coupled oscillators [Here, every individual’s brain was parceled into 68 regions based on Desikan-Killiany parcellation, and each region was modeled as a nonlinear oscillator. To achieve the macroscopic computational model of the brain, local oscillators are coupled through a structural connectome which was obtained by applying streamline tractography to the large sample diffusion-weighted MRI data from HCP 500 release [When coupled together, the collective behavior of interacting oscillators reproduces key features of brain dynamics, including functional connectivity (FC) patterns. The dynamics of each oscillator is defined by coupled differential equations as below:
Where, z and ω are each oscillator’s state variables and describe the regional amplitude and angular frequency. The real part of the variable z (i.e., Rel{z}) acts as an indirect measure of brain activity acquired by the MR scanner, whereas the imaginary part (i.e., Imag{z}) can be interpreted as the hidden state of the system that is unobservable. In the | PMC10019702 |
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2.7 Parameter optimization | In order to fit the model to the fMRI data, we need to find an optimal working point, which is a combination of parameters (i.e., A, G, F and M) within the search interval that maximizes the similarity between the simulated and empirical FC patterns and captures the intrinsic attractor dynamics of the brain. Therefore, the similarity between the empirical and simulated FC was measured to quantify the goodness of fitting. Accordingly, in the grid-search framework, we searched for parameter A from −0.2 to 0.2 with a step-size of 0.01, G from 0.005 to 0.05 with a step-size of 0.005, F from 0 to 1 with a step-size of 0.1, and M from 0.10 to 0.50 with a step-size of 0.03.Our search protocol resulted in 63,140 simulated sets of whole-brain signals. It is worth noting that the real part of state variable z was taken as the simulated regional BOLD signal. Next, simulated BOLD signals were band-pass filtered (0.008–0.1Hz), followed by computing and the Pearson correlation coefficients among all regions. Identical analysis was performed on the empirical data to achieve the empirical FC matrices. Of note, Fisher’s z-transformation was applied to both simulated and empirical FC measures with the aim of performing a subsequent correlation between the simulated and empirical FCs as an index of the goodness of fit of the model. The FC maps of a varying percentage of the patients (i.e., Monte Carlo thresholds) were randomly selected over 1500 Monte Carlo iterations to find the optimal parameter-sets within the search intervals for the whole-brain model. We sampled the FC maps for 500 iterations per threshold (i.e., 30%, 50% and 70%) to remove the dependency of our results on the percentage of patients randomly selected in Monte Carlo resampling procedure. We assessed the similarity between the simulated and empirical FC by taking the correlation between the upper triangles of the simulated and empirical FC matrices in each iteration of Monte Carlo resampling [Next, based on the similarity between each individual’s empirical FC and either of the two model-derived FC maps (i.e., simulated FC | PMC10019702 |
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2.8 Statistical analysis | depression, MADRS-S, AFF | REGRESSION | All statistical analysis was performed using Statistical and Machine Learning toolboxes in MATLAB 2021b. At the optimal working point within the search interval, our whole-brain model simulated BOLD signals with FC patterns similar to the empirical resting state data. Based on the similarity between each individual’s empirical and simulated FC, we assigned patients to one of the identified depression models/subtypes.We further indicated that there is no evidence that these two subtypes are allocated to treatment groups in a biased manner using a Pearson’s chi squared test. Yet to remove any potential bias driven by having different numbers of individuals associated with subtypes across two treatment groups, we used bootstrap method for hypothesis testing. Thereby, we equalized the number of individuals assigned to each subtype in every treatment group using resampling with replacement as implemented in the bootstrapping method.At baseline, we fitted separate logistic regression models (LoM) for MADRS-S total, BPRS AFF and CAINS. Hence, in total, three LoMs were fitted alongside with 1000-bootstrap resampling to assess the effect of depression subtype on the individual items of the three depression symptom ratings (i.e., MADRS-S total, BPRS AFF and CAINS), In the follow-up session, subsequent to the treatment (i.e., either active or sham iTBS over dmPFC), the behavioral measures consisting of MADRS-S total, BPRS AFF, CAINS and TMT were collected and contrasted to values at the baseline to generate the change score across two sessions. The main effects of treatment (active or sham), depression subtypes and their interaction on behavioral change scores (follow-up session contrasted to the baseline session) were assessed using a linear regression model (LiM) and 1000-bootstrap resampling of the coefficients (In the follow-up analysis, we used a nested ANOVA model to determine if there was any difference between the depression subtypes nested in the treatment, explaining the change in the individual symptom ratings. Age and sex were controlled in the nested ANOVA model. We complemented our analysis with a subsequent post-hoc 1000-resampling bootstrap test to determine which depression subtype showed more improvement after receiving the active treatment, with regard to individual items of MADRS-S, BPRS AFF and CAINS. It should be further noted that the change score of each individual item was quantified as symptom improvement for active treatment contrasted against the median improvement of sham treatment. | PMC10019702 |
3. Results | PMC10019702 |
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3.1 Baseline data | depression | There were no statistical differences in demographics or baseline summative clinical measures across the two treatment groups, as well as the two detected depression subtypes | PMC10019702 |
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3.2 Whole-brain dynamics of depression is heterogeneous | personality disorder, comorbidity, anxiety, attention deficit hyperactivity disorder, depression, autism | DISORDERS | Parameter-sets were estimated by non-parametric fitting of the model to the resting-state FC at baseline (Global feedback parameter F and global modulation index M were larger for DEP1 compared with DEP2; however, the bifurcation parameter A and global coupling parameter G were larger in DEP2 subtype compared to DEP1. A larger bifurcation parameter A indicates a potential higher neural excitability. In a system with a larger global modulation index M, the angular frequency dynamics of individual oscillators (i.e., regions) have higher sensitivity to the subsiding ensemble activity in their immediate neighboring regions (i.e., the ones which are structurally connected together). The attractor space for the two estimated optimal parameter-sets within the search interval was illustrated in To ensure that the two unraveled subtypes (i.e., DEP1, n = 20 and DEP2, n = 22, for more information on the demographic and treatment allocation of depression subtypes, please refer to We also assessed whether the two subtypes were associated with the comorbidity of depression with anxiety, autism, attention deficit hyperactivity disorder or personality disorder, using Pearson’s chi-squared tests. We found no association between the detected subtypes and the comorbidity with any of the above-mentioned disorders (all | PMC10019702 |
Whole-brain modeling stratifies the depression sample. | (A) The whole-brain model was constructed from oscillators with amplitude and angular frequency dynamics, which were coupled through the structural connectome. The model parameters were optimized in an iterative Monte Carlo procedure based on the similarity between model-derived functional connectivity with that of the empirical data. The white matter fiber tracks figure was adopted from Wikipedia.com ( | PMC10019702 |
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3.3 Individual factors of MADRS-S total, BPRS AFF and CAINS differentiate depression subtypes at baseline | depression, MADRS-S, AFF | Our modelling approach resulted in the detection of two covert subtypes exhibiting different pre-treatment attractor dynamics. We asked whether the specific symptoms of MADRS-S total or BPRS AFF or CAINS dissociated the depression subtypes at baseline. Therefore, we fitted a LoM, separately for MADRS-S total, BPRS AFF and CAINS. We found that some individual items of MADRS-S total, BPRS AFF and CAINS at baseline were related to the depression subtypes. Particularly, we found larger odds ratio for MADRS-S2 ( | PMC10019702 |
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Specific symptoms of MADRS-S, BPRS AFF and CAINS predict depression subtypes at baseline. | depression, AFF | REGRESSION | The bootstrap 95% confidence intervals of the logistic regression coefficients for MADRS-S, BPRS AFF and CAINS at baseline. The numbers on the horizontal axes of each panel correspond to the symptoms listed in Treatment section for a given symptom rating. The blue and orange colors indicate the individual items that were significantly different for a specific depression subtype.We also observed that the odds ratio of BPRS AFF3 (CAINS7 ( | PMC10019702 |
Depression subtypes modulate the changes in behavior. | depression, MADRS-S, AFF | Violin plots show the distributions of changes in MADRS-S total, BPRS AFF, CAINS total, CAINS motivation and pleasure subscale (CAINS MAP), CAINS expression subscale (CAINS EXP), TMT A and TMT B across two depression subtypes and treatments. Within each violin plot, there is a box plot summarizing the bootstrap results by indicating the median (depicted by white dot), the first and third quadrants, represented by the lower and upper edges of the black box, and interquartile range by the whiskers. The dots within violin plots represent the resampled data points. Note, the full name of the behavioral measures can be found in the bottom right corner of the figure.The bootstrap distribution for individual items of MADRS-S, BPRS AFF and CAINS at baseline and follow-up can be found in the | PMC10019702 |
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3.4 The therapeutic effect of iTBS on dmPFC is modulated by intrinsic brain dynamics at baseline | depression, affective psychiatric | Prior to assessing the effect of iTBS and the depression subtypes, we checked the integrity of our blinding. After the first treatment day, two thirds of patients in both groups correctly anticipated the treatment allocation. Yet, because there was no difference in the number of patients who correctly guessed their treatment across the two groups, we regarded it as an adequate level of blinding. It should be noted that the number of patients who correctly anticipated their treatment allocation decreased to two-fifths in the active group and increased to four-fifths in the sham group by the last treatment day [In the previous sections, we indicated that the attractor dynamics at baseline dissociates the depression cohort into two subtypes (i.e., DEP1 and DEP2), exhibiting distinct phenotypical behaviors. Next, we assessed whether the two subtypes responded differently to the treatment. Hence, the cohort was grouped with four levels (i.e., Sham:DEP1, n = 10; Sham:DEP1, n = 10; Active:DEP1, n = 10; Active:DEP2, n = 12) for the LiM analysis. The outcome measures were summative scores of depression (i.e., MADRS-S total), affective psychiatric (i.e., BPRS AFF) and negative symptoms (i.e., CAINS). Using bootstrapping of the LiM’s coefficients, we found a significant effect for the interaction of treatment and depression subtypes, for BPRS AFF, 95% | PMC10019702 |
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3.5 The iTBS treatment modulates individual items in a certain depression subgroup | depression, MADRS-S, AFF | Earlier we found that BPRS AFF and CAINS MAP were modulated by the interaction of the treatment and depression subtype. To increase the sensitivity of our analysis we further assessed if the treatment modulated any of the individual items of the behavioral measure as a function of depression subtype. We used a nested 2-way ANOVA to assess whether the specific symptoms of MADRS-S total, BPRS AFF and CAINS, were modulated by treatment and depression subtypes.We found that there was an effect of depression subtype nested within treatment groups for MADRS-S1( | PMC10019702 |
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Treatment and depression subtypes modulate certain items of MADRS-S, BPRS AFF and CAINS. | depression, AFF | (A) The table summarizes the nested ANOVA results for MADRS-S, BPRS AFF and CAINS items. (B) Violin plots depict the distributions of the differences in MADRS-S1, MADRS-S6, BPRS AFF3, BPRS AFF4 and CAINS 5 changes (follow-up–baseline) between active treatment and the median score in the sham treatment for each depression subtype. The boxplot summarizes the statistical parameters of the distribution. The white dot represents the median, the lower and upper edges of the black box show the first and third quadrants, and the interquartile range is shown by the whiskers. The dots within the violin plot represent the individual data points. | PMC10019702 |
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4. Discussion | depression, depressive symptoms, treatment-resistant depression, AFF | Whole-brain computational modeling combined with nonparametric probabilistic fitting applied to the pre-treatment resting-state fMRI data from patients with treatment-resistant depression, disclosed a dichotomy in the attractor dynamics of our depression sample. According to the derived optimal model parameters within the search interval, we could stratify the patients into the DEP1 and DEP2 subtypes based on their pretreatment FC patterns. We indicated that the two detected depression subtypes exhibited different phenotypic behavior related to certain affective and negative symptoms at baseline. We further found that the effect of treatment on the summative scores for the affect subscale of BPRS, motivation and pleasure subscale of CAINS varied as a function of depression subtypes. Nevertheless, the effect on the summative scores was mostly driven by the worsening of DEP2 by active treatment, potentially due to the heterogeneity of DEP2’s response to individual items of the measurements. We followed up on this observation by assessing the individual items of MADRS-S total, BPRS AFF and CAINS using nested ANOVA. We found that the behavior related to mood, initiative/lassitude, suicidality and motivation for work and school activities was indeed improved in the subtype with a lower metastable and synchronous pretreatment intrinsic brain activity (i.e., DEP2), despite worsening of the summative scores. Hence, our results suggested that the summative scores of phenotypic behaviors for depression are not well-suited for dissociating the depression subtypes.There are diverging neurophysiological mechanisms involved in depression, and therefore, large-scale multimodal analysis of depression cohorts has failed to uncover distinctive neurobiological biomarkers [Fortunately, there is a growing momentum in psychiatry research to disclose the heterogeneity in the cohorts and unravel different subtypes based on neuroimaging data [It is worth noting we used a new rTMS protocol, namely the accelerated dmPFC iTBS, compared to commonly used non-invasive stimulation protocols for depression (i.e., high- or low-frequency rTMS over the dlPFC). Specifically based on lesion and meta-analysis studies, stimulating the dmPFC has been suggested to be a promising alternative target for neurostimulation therapy in depression [Nevertheless, applying iTBS over dmPFC has yielded mixed results in treating the overall depressive symptoms [Our study had several limitations, our grid-search spanned a limited interval of the parameter space and therefore the obtained optimal parameter-sets are contingent on our defined search scope. Moreover, the small sample size bounded our model prediction and the statistical analysis. Furthermore, because our nested ANOVA analysis was an exploratory analysis, our findings should be considered as preliminary and should be validated in an independent sample. However, we speculate that with a larger sample, several finer grained depression subtypes might be identified. Another possible limitation of the current study is that instead of using sample-specific structural connectivity, we used the structural connectivity estimated from HCP to minimize the possible errors arising from an under-sampled dataset. Furthermore, we included only 68 cortical regions in our model. Future studies with more realistic computational models based on a higher spatial resolution and larger sample sizes are required to further assess the heterogeneity in depression. Notably, computational modeling based on longitudinal functional data collected during the treatment course as well as the follow-up session are required to shed light on the underlying mechanism of iTBS in depression.In conclusion, we used a novel approach based on the attractor dynamics of whole-brain model to delineate the depression cohort in a clinically relevant manner. Our approach provided a mathematical platform to efficiently combine the tractography and functional imaging data, while taking the nonlinear dynamics of the brain into account. We found improvements in mood, initiative/lassitude, suicidality, motivation for work and schools in response to applying iTBS to dmPFC, in the subgroup with blunted frequency dynamics and less global metastability and synchrony. This finding highlights the importance of designing stratified treatment protocols in order to increase the success rate of rTMS therapies. Nevertheless, it should be noted that this type of stratification of the depression cohort is novel and has to be further validated in independent samples before finding its way into clinical practices. | PMC10019702 |
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Supporting information | PMC10019702 |
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The distribution of intrinsic angular frequencies. | The peak of spectral density that was derived from Welch method was identified for each region at the individual level. The median value across the cohort was used as the group-representative value of (TIF)Click here for additional data file. | PMC10019702 |
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Estimated intrinsic angular frequency map. | The intrinsic angular frequency is represented on the Desikan-Killany atlas using a color-coded scheme. Warmer colors indicate a higher intrinsic angular frequency whereas the cooler colors indicate a lower intrinsic angular frequency.(TIF)Click here for additional data file. | PMC10019702 |
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Distribution of parameter-sets as a function of Monte Carlo threshold. | In Monte Carlo resampling, we randomly selected 30%, 50% or 70% (i.e., Monte Carlo threshold) of patients with 500 iterations per threshold. In all three threshold choices, we observed bimodal distributions with similar peak values (optimal parameter-sets), indicating that two subtypes were detectable at all three thresholds.(TIF)Click here for additional data file. | PMC10019702 |
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Bootstrap distribution for the logistic regression models. | depression, AFF | REGRESSION | The distributions in each column represent a coefficient in the logistic regression model for MADRS-S (upper panel), BPRS AFF (middle panel) and CAINS (bottom panel) at baseline. The dashed red line depicts 0, which represents no association with the stratification of the depression cohort. At baseline, the bootstrap 95% confidence interval for MADRS-S2, MADRS-S4, MADRS-S6, MADRS-S7, BPRS AFF1, BPRS AFF3, BPRS AFF4, CAINS3, CAINS7, CAINS8, CAINS9, CAINS11, CAINS12 and CAINS13 did not include 0 at baseline, indicating a statistically significant association with the stratification of the depression cohort.(TIF)Click here for additional data file. | PMC10019702 |
Bootstrap distribution for the linear regression models predicting behavioural change from baseline to follow-up session. | AFF | REGRESSION | The distributions in each column represent a coefficient in the linear regression model where each row corresponds to a behavioral measure (i.e., outcome). The dashed red line depicts 0, which represents no association with the outcome. In this analysis, the coefficient of interest was the last column (treatment_active:subtype(DEP1/DEP2)). For BPRS AFF and CAINS MAP, the bootstrap 95% confidence interval for the treatment_active:subtype(DEP1/DEP2) did not include 0, indicating a statistically significant association with the outcome from baseline to follow-up.(TIF)Click here for additional data file. | PMC10019702 |
Functional connectome for depression subtypes. | The empirical functional connectivity (FC) was derived from band-pass filtered BOLD signals. The resulting FCs were Fisher’s z-transformed, and any negative values were replaced with 0.(TIF)Click here for additional data file. | PMC10019702 |
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Functional connectome as a function of subtypes and treatment. | depression | The band-pass filtered BOLD time-series were used to compute functional connectivity (FC) for depression subtypes and treatment groups. The resulting FCs were Fisher’s z-transformed, and any negative values were replaced with 0. The number of individuals contributing to each FC plot is written in the second line of the title.(TIF)Click here for additional data file. | PMC10019702 |
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Demographic, treatment allocation and dynamical brain measures: individual model-driven prediction and correlations with empirical data. | (XLSX)Click here for additional data file.We appreciate the Human Connectome Project for providing the open access data used in this study. | PMC10019702 |
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ABSTRACT | infectious, itch, swelling, lymphadenopathy, erythema, tuberculosis, pain, abscess, tenderness | LYMPHADENOPATHY, ADVERSE EVENTS, ERYTHEMA, TUBERCULOSIS, ABSCESS, REGIONAL LYMPHADENOPATHY, INJECTION SITE REACTION, HAND SWELLING, DISEASES | Joint Senior AuthorsBCG vaccination and revaccination are increasingly being considered for the protection of adolescents and adults against tuberculosis and, more broadly, for the off-target protective immunological effects against other infectious and noninfectious diseases. Within an international randomized controlled trial of BCG vaccination in healthcare workers (the BRACE trial), we evaluated the incidence of local and serious adverse events, as well as the impact of previous BCG vaccination on local injection site reactions (BCG revaccination). Prospectively collected data from 99% (5351/5393) of participants in Australia, Brazil, Spain, The Netherlands and the UK was available for analysis. Most BCG recipients experienced the expected self-limiting local injection site reactions (pain, tenderness, erythema, swelling). BCG injection site itch was an additional common initial local symptom reported in 49% of BCG recipients. Compared to BCG vaccination in BCG-naïve individuals, BCG revaccination was associated with increased frequency of mild injection site reactions, as well as earlier onset and shorter duration of erythema and swelling, which were generally self-limiting. Injection site abscess and regional lymphadenopathy were the most common adverse events and had a benign course. Self-resolution occurred within a month in 80% of abscess cases and 100% of lymphadenopathy cases. At a time when BCG is being increasingly considered for its off-target effects, our findings indicate that BCG vaccination and revaccination have an acceptable safety profile in adults. | PMC10411308 |
KEYWORDS | PMC10411308 |
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Introduction | tuberculosis, coronavirus disease 2019 | CORONAVIRUS DISEASE 2019, TUBERCULOSIS | Bacille Calmette-Guérin (BCG) vaccine is extensively and safely used in children in over 150 countries, to protect against tuberculosis (TB).BRACE (BCG vaccination to reduce the impact of COVID-19 in healthcare workers) is a multicentre randomized controlled trial (ClinicalTrials.gov NCT04327206; date of registration 31/03/2020) that investigated whether BCG vaccination protects against coronavirus disease 2019 (Covid-19). | PMC10411308 |
Materials and methods | PMC10411308 |
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Setting and participants | This prospective cohort study is nested within the BRACE trial, which recruited healthcare workers (HCW) in two stages. The trial protocol is described in detail elsewhere. | PMC10411308 |
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Intervention | Participants randomized to BCG received a single dose of BCG-Denmark (AJ Vaccines, Copenhagen), 0.1 ml (corresponding to 2–8 × 10 | PMC10411308 |
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Data collection | Data were collected using REDCap web applicationInformation on hospitalizations was collected through questionnaires at 3, 6, 9 and 12 months following vaccination. In the latter questionnaire, female participants were additionally asked regarding any pregnancy during the trial, to follow-up any participants who were inadvertently pregnant at the time of vaccination. | PMC10411308 |
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Active safety surveillance | Toxicity | ABSCESSES, ADVERSE EVENT FOLLOWING IMMUNIZATION | Designated safety medical doctors actively followed-up participants who reported a potential adverse event following immunization (AEFI) through the questionnaires or by notification of the study team. Reactions of grade 1 or 2 severity (as per the Food and Drug Administration (FDA) Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials)Photographs of potential injection site abscesses, keloid scars, and unusual local reactions were reviewed by safety medical doctors at regular quality and safety team meetings for consensus decision on classification and whether any local clinical follow-up was required. | PMC10411308 |
Case definitions | BCG-osis, allergic reaction, regional lymphadenopathy, abscess, osteitis/osteomyelitis, ulcer | SCAR, ALLERGIC REACTION, ADVERSE EVENT, BCG INFECTION, ABSCESS, REGIONAL LYMPHADENOPATHY, VASOVAGAL EPISODE, ULCER | BCG-revaccination was defined as BCG vaccination in a participant who had any prior BCG vaccination history. Adverse events of special interest included: injection site abscess, large ulcer (>1.5 cm diameter), keloid scar, unusual local reaction, regional lymphadenopathy, BCG osteitis/osteomyelitis, disseminated BCG infection (BCG-osis), allergic reaction due to vaccination or vasovagal episode following vaccination. Further details on case definitions are provided in Supplementary Material 1. | PMC10411308 |
Statistical analysis | swelling, toxicity, erythema, pain, tenderness | VACCINATION SITE REACTIONS, ERYTHEMA | StataIC 14.0 (Statacorp LP, College Station, TX, USA) was used for statistical analysis. The cumulative incidence of AEFI in the three-month post vaccination was calculated among participants who received either BCG or placebo, and who provided vaccine safety data. Local vaccination site reactions (pain, tenderness, erythema, swelling) were categorized according to the FDA toxicity grading scaleEthical approval was obtained from The Royal Children’s Hospital Human Research Ethics Committee (HREC 62586) with subsequent approvals from all participating sites. All research was performed in accordance with relevant guidelines and regulations. All participants provided signed informed consent prior to enrollment. | PMC10411308 |
Results | PMC10411308 |
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Demographics | TUBERCULOSIS INFECTION | Among 3411 participants who received BCG (1415 in BRACE Stage 1 and 1996 in Stage 2) and 1982 participants who received placebo in Stage 2, 5351 (99%) provided vaccine safety data (BRACE participants who received BCG or placebo in a) Stage 1 and b) Stage 2.Demographics.Abbreviations: BCG, Bacille Calmette-Guérin; LTBI, latent tuberculosis infection; IQR, interquartile range; PSA, patient services assistant; TST, tuberculin skin test. | PMC10411308 |
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Local injection site reactions | PMC10411308 |
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Itch | itching | A significantly higher proportion of participants in the BCG group experienced itching at the vaccination site, compared with the placebo group (862/1900 [45.4%] versus 64/1872 [3.4%], | PMC10411308 |
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Injection site abscess | pain, abscess | ADVERSE REACTIONS, INFECTIOUS DISEASES, LYMPHADENOPATHY, ABSCESS, ABSCESSES | The median time of onset was 20 days (IQR 9–26), with a median diameter of 2.0 cm (IQR 2.0–2.5) (Clinical features of BCG local adverse reactions (abscess and lymphadenopathy).Abbreviations: FNA, fine needle aspiration; nr, not reported.*Two participants took opioid analgesia for axillary pain associated with lymphadenopathy; one took codeine for two days and the other buprenorphine for four days following an emergency department presentation for the axillary pain.Categorical variables are reported as number (%), continuous variables are reported as median (range).The safety medical doctors recommended a conservative approach for all abscesses, except in two participants who were referred to an Infectious Diseases specialist due to persistent large abscesses (average size 4.3 cm diameter) and subsequently received 3 months of isoniazid. Nine other participants sought advice from external providers, who prescribed antimicrobial treatment, including three who additionally underwent fine needle aspiration and one who had surgical excision of the injection site. The other 44/55 (80%) of injection site abscesses resolved spontaneously without treatment, in a median time of 27 days (IQR 10–45). | PMC10411308 |
Regional lymphadenopathy | lymphadenopathy | REGIONAL LYMPHADENOPATHY, LYMPHADENOPATHY | Location of BCG-associated lymphadenopathy was ipsilateral axillary (Among the placebo group, regional lymphadenopathy was ipsilateral axillary ( | PMC10411308 |
Other adverse events of special interest | allergic reaction | ALLERGIC REACTION | Keloid scars occurred in 2/3379 (0.06%) BCG recipients and BCG-related allergic reaction in 1/3379 (0.03%) within the study period ( | PMC10411308 |
Serious adverse events | lethargy, death, Crohn’s disease, abscess | ADVERSE EVENT, ABSCESS | Overall, 38 participants reported a serious adverse event (SAE): 9 BCG recipients in Stage 1, 29 participants in Stage 2 including 20 in the BCG group and 9 in the placebo group (see Supplementary Table S2). All but two SAE were deemed ‘unrelated’ to the intervention by the study site investigator and the BRACE expert vaccine safety group (Table S1). One SAE (hospitalization in a participant with BCG injection site abscess and lethargy) was reported as a SUSAR, as aforementioned. Another BCG recipient was hospitalized and diagnosed with Crohn’s disease more than 2 months following vaccination, subsequently deemed ‘unlikely related’ to vaccination. There was one death (COVID-19 related) in a participant hospitalized with COVID-19 who had received placebo. | PMC10411308 |
Vaccination during pregnancy | birth defects, congenital anomalies | BCG VACCINE | Four female participants were vaccinated whilst unknowingly pregnant at the time; one of these received the BCG vaccine at gestational age of 2 weeks and the other three placebo (see Supplementary Table S3). There were no congenital anomalies or birth defects. All pregnancies resulted in healthy babies born at term gestation. | PMC10411308 |
Discussion | itch, lymphadenopathy, swelling, erythema, non-suppurative lymphadenopathy, regional lymphadenopathy, Crohn’s disease, abscess, osteitis/osteomyelitis, urticarial reaction, ulcer | SCAR, LYMPHADENOPATHY, BCG VACCINE, ADVERSE EVENTS, EVENT, ERYTHEMA, BCG INFECTION, ABSCESS, REGIONAL LYMPHADENOPATHY, INJECTION SITE REACTION, ABSCESSES, HAND SWELLING, ULCER, COMPLICATIONS | Using active safety surveillance, we evaluated the safety of BCG vaccination and revaccination in over 5000 healthcare workers within a large international trial. The majority of BCG recipients experienced the expected normal well-described local injection site reactions characterized by the appearance of a small, red papule or swelling at the injection site within 2–3 weeks. Usually, the papule softens, resulting in a small ulcer, healing over several weeks to months into a small flat scar.In a study of BCG-vaccinated infants in Guinea-Bissau, those who developed a BCG skin reaction by age 2 months had associated better survival, correlating with reaction size.Itch at the BCG injection site was reported by half of BCG recipients with a median duration of 10 days following vaccination. This symptom has not been previously reported in relation to the BCG vaccine,Revaccination has been associated with an increased risk of common local injection site reactions, as well as adverse events, such as injection site abscess and lymphadenopathy.Our study is the first to compare injection site reactions between BCG-naïve and BCG-revaccinated adults. Two previous smaller studies have reported similar proportions of injection site reactions (93%–98%) in BCG-revaccinated adults; one study was in 500 HCW in South Africa revaccinated with BCG-Denmark,The most common adverse events of special interest in our study were abscess (incidence 1.6%) and regional lymphadenopathy (incidence 3.0%). The incidence of injection site abscess is consistent with studies of BCG-Denmark (1.3%–2.5%) in infantsCharacteristics of BCG injection site abscesses in both trial stages were similar and most (80%) healed within 1 month without medical intervention. Various treatment strategies (antibiotics with and without fine needle aspiration or surgery) were used in the minority of participants who sought external medical advice, reflective of the paucity of robust evidence for the best management approach.The incidence of BCG-associated lymphadenopathy in our study was also consistent with large studies of BCG-Denmark reporting incidence of non-suppurative lymphadenopathy in children and adolescents (range <1% to 4.8%).The incidence of urticarial reaction (0.03% (1/3379)) is within range of the reported rate of this rare event (≥1/10000 to <1/1000).All SAE were hospital presentations deemed unrelated to vaccination, except for one SUSAR (causal relationship assigned as ‘probable’) and one participant hospitalized with Crohn’s disease (causal relationship assigned as ‘unlikely’). Importantly, there were no disseminated BCG infection or BCG osteitis/osteomyelitis cases (rare severe complications, seen in infants with undiagnosed immunodeficiency).BCG vaccination during pregnancy is generally not recommended.Our study has several limitations. First, prior BCG vaccination classification relied on participant self-report without vaccination record confirmation and no information on BCG strain (most participants had their primary BCG vaccination in childhood). However, the majority who reported having received prior BCG also had scar evidence (data not shown). Second, even though the same BCG strain was used for all sites in this study, the vaccinators differed. Vaccine administration technique has been previously shown to influence the incidence of AEFI.Strengths of our study include the active safety surveillance of over 5000 healthcare workers across three continents comprising both high and low TB-prevalence settings, using standard case definitions for adverse events, with safety data available for 99% participants. Safety medical doctors met regularly to discuss AE as they occurred, reaching consensus decisions on classification.In conclusion, BCG revaccination was found to be safe and well tolerated in adults. Although local injection site reactions were more common in BCG-revaccinated than in BCG-naïve adults, these were usually self-limited and the duration of erythema and swelling was shorter. We found itch at the BCG injection site to be a common initial symptom and recommend its addition to the list of expected BCG reactions. Injection site abscess and regional lymphadenopathy, the most common significant adverse events, had a benign course and self-resolved within a month in most participants. This study shows that BCG vaccination and revaccination has an acceptable safety profile in adults at a time when BCG is being increasingly considered for its novel indications. | PMC10411308 |
Supplementary Material | PMC10411308 |
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Supplemental Material | Click here for additional data file. | PMC10411308 |
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Supplemental Material | Click here for additional data file. | PMC10411308 |
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Acknowledgments | Alison, Joyce Chan | BANNISTER, GOODALL | We thank the BRACE trial participants for making this study possible. We also thank the researchers involved in establishing the BRACE trial (see Supplementary Material 2 for the BRACE trial Consortium Group), in particular: Ms Veronica Abruzzo, Ms Sonja Elia, Ms Casey Goodall, Dr Ellie McDonald, Ms Ann Krastev, Dr Samantha Bannister, Ms Grace Gell, Dr Wendy Norton, Dr Joyce Chan, A/Prof. Laurens Manning, A/Prof. Peter Richmond, Prof. Michaela Lucas, Prof. Tobias Kollmann, Dr Susan Hermann, Ms Erin Latkovic, Ms Michelle England, Dr Roberto Oliveira, Dr Estela Carvalho, Dr Helen Catterick, Ms Glauce Dos Santos, Ms Catriona Doran, Dr Alison Gifford, Dr Telma Goldenberg, Dr Christina Guo, Dr Georgina Newman, Dr Ligia Olivio, Dr Lorrie Symons, Dr Niki Tan, Dr Laura Tate, Dr Tina Zhou. | PMC10411308 |
Disclosure statement | No potential conflict of interest was reported by the authors. | PMC10411308 |
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Author contributions | Conceptualization or design of the work: P.V., L.P., N.M. and N.C. Acquisition of data: all authors. Analysis, or interpretation of data: P.V. and L.P. Original drafting: P.V. Revising, editing, and final approval of the manuscript: all authors. | PMC10411308 |
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Data availability statement | Deidentified participant data and data dictionary are available to others on request and on completion of a signed data access agreement. Requests can be made in writing to [email protected]. | PMC10411308 |
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Supplementary data | Supplemental data for this article can be accessed on the publisher’s website at | PMC10411308 |
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References | PMC10411308 |
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Objective | acute stroke, spasticity | ACUTE STROKE | To estimate the cost-consequence of treating spasticity early with botulinum
toxin in the acute stroke unit. | PMC9912301 |
Design | Secondary cost-consequence analysis, using data from a double-blind
randomised-controlled trial. | PMC9912301 |
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Setting | stroke | STROKE | Single-centre specialised stroke unit. | PMC9912301 |
Subjects and Interventions | stroke, spasticity | STROKE | Patients with Action Research Arm Test grasp-score of <2 and who developed
spasticity within six weeks of a first stroke were randomised to receive
injections of: 0.9% sodium-chloride solution (placebo) or
onabotulinumtoxin-A (treatment). | PMC9912301 |
Main measures | contracture | Resource use costs were calculated for the study. Mean contracture costs for
each group were calculated. The Barthel Index and Action Research Arm Test
were used to generate a cost per unit of improvement. | PMC9912301 |
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Results | contracture | There were no significant differences associated with early treatment use.
The mean contracture cost for the treatment group was £817 and for the
control group was £2298 (mean difference = −£1481.1(95% CI −£2893.5, −£68.7)
( | PMC9912301 |
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Conclusions | stroke, contracture, spasticity | STROKE | Treating spasticity early in stroke patients at risk of contractures with
botulinum toxin leads to a significant reduction in contracture costs. The
cost per improvement of Barthel and Action Research Arm Test indicates that
the intervention costs less and is more effective. | PMC9912301 |
Trial Registration data | EudraCT(2010-021257-39) and ClinicalTrials.gov-Identifier:NCT01882556. | PMC9912301 |
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Introduction | stroke, post-stroke spasticity, spasticity, pain | STROKE | The cost of managing stroke places a significant burden on the individual, families
and the economy.Botulinum toxin is one treatment that can reduce spasticityWe have previously demonstrated that screening and treating spasticity early, on
first presentation after the first stroke in patients who have no useful arm
function, with botulinum toxin prevents contractures, reduces pain, and does not
interfere with functional recovery (EUBoSS Trial).Using data from the previous trial we aim to Identify the major cost drivers in the management of patients with
post-stroke spasticity and contractures.Conduct a cost-consequences analysis of botulinum toxin in the management
of patients with post-stroke spasticity and
contractures. | PMC9912301 |
Methods | protocolFurther, post-stroke spasticity, post-stroke | WEST | This study reports on the cost-consequences of the early use of botulinum toxin in
post-stroke spasticity. The trial was approved by North West – Greater Manchester
South Ethics Committee Reference number 10/H1003/111. It was registered with EudraCT
(2010-021257-39) and at ClinicalTrials.gov-Identifier: NCT01882556.The protocolFurther, details regarding participants’ use of health services were documented at
two, four, six and 12 weeks following treatment and at six months post-stroke. These
included GP visits, hospital visits and admissions. Current medication use and any
changes from discharge were documented. Treatments to manage contractures were also
recorded. Patients were encouraged to document such activities in a diary and this
additional informal questioning was completed at each review to ensure all
information was provided.Resource use costs associated with the study were summarised into relevant categories
and valued in £ sterling using a price year of 2017/18. The costs were determined
from national published sources of unit costs British National Formulary,The Barthel Index and Action Research Arm Test were used to generate a cost per unit
of improvement in each of the measures. A one-way sensitivity analysis was
undertaken (using IBM SPSS 27) to assess the extent of potential changes in the main
cost parameters and outcomes of the treatment using the mean difference and lower
and upper bounds of the confidence intervals. The 95% confidence interval of net
cost and changes in outcomes were used to generate a series of potential scenarios
and explore the changes in the estimated cost per unit of improvement. | PMC9912301 |
Results | SAH | SUBARACHNOID HAEMORRHAGE | Between January 2012 and December 2013, 93 participants were randomised and received
injections (see Consort flow chart summarising the flow of participants through the study.
The last value was carried forward in cases of missing values. SAH:
subarachnoid haemorrhage; SOL: space occupying lesion. | PMC9912301 |
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