High-dimensional immune profiling identifies a biomarker to monitor dimethyl fumarate response in multiple sclerosis.

Dimethyl fumarate (DMF) is an immunomodulatory treatment for multiple sclerosis (MS). Despite its wide clinical use, the mechanisms underlying clinical response are not understood. This study aimed to reveal immune markers of therapeutic response to DMF treatment in MS. For this purpose, we prospectively collected peripheral blood mononuclear cells (PBMCs) from a highly characterized cohort of 44 individuals with MS before and at 12 and 48 wk of DMF treatment. Single cells were profiled using high-dimensional mass cytometry. To capture the heterogeneity of different immune subsets, we adopted a bioinformatic multipanel approach that allowed cell population-cluster assignment of more than 50 different parameters, including lineage and activation markers as well as chemokine receptors and cytokines. Data were further analyzed in a semiunbiased fashion implementing a supervised representation learning approach to capture subtle longitudinal immune changes characteristic for therapy response. With this approach, we identified a population of memory T helper cells expressing high levels of neuroinflammatory cytokines (granulocyte-macrophage colony-stimulating factor [GM-CSF], interferon γ [IFNγ]) as well as CXCR3, whose abundance correlated with treatment response. Using spectral flow cytometry, we confirmed these findings in a second cohort of patients. Serum neurofilament light-chain levels confirmed the correlation of this immune cell signature with axonal damage. The identified cell population is expanded in peripheral blood under natalizumab treatment, substantiating a specific role in treatment response. We propose that depletion of GM-CSF-, IFNγ-, and CXCR3-expressing T helper cells is the main mechanism of action of DMF and allows monitoring of treatment response.

[Radiofrequency denervation of the spine and the sacroiliac joint : A systematic literature search according to GRADE with new German S3 guideline]. / Radiofrequenzdenervation der Wirbelsäule und des Iliosakralgelenks : Eine systematische Literaturrecherche nach GRADE mit neuer S3-Leitlinie.

BACKGROUND: This article summarizes the results of the German guideline on radiofrequency denervation of the facet joints and the sacroiliac joint. Evidence on the indications, test blocks and technical parameters are presented. OBJECTIVE: The aim is to avoid overtreatment and undertreatment, which is also of socioeconomic importance. MATERIAL AND METHOD: A systematic evaluation of the literature was carried out according to the grading of recommendations assessment, development and evaluation (GRADE) approach. A multidisciplinary guideline group has developed recommendations and statements. RESULTS: Statements and recommendations were given for 20 key questions. There was an 87.5% consensus for 1 recommendation and 100% consensus for all other recommendations and statements. The guideline was approved by all scientific medical societies involved. Specific questions included the value of the medical history, examination and imaging, the need for conservative treatment prior to an intervention, the importance of test blocks (medial branch block and lateral branch block), choice of imaging for denervation, choice of trajectory, the possibility to influence the size of the lesion, stimulation, the possibility of revision, sedation and decision support for patients with anticoagulants, metal implants and pacemakers and advice on how to avoid complications. CONCLUSION: Selected patients can benefit from well-performed radiofrequency denervation. The guideline recommendations are based on very low to moderate quality of evidence.

Immunological Predictors of Dimethyl Fumarate-Induced Lymphopenia.

Treatment with dimethyl fumarate (DMF) leads to lymphopenia and infectious complications in a subset of patients with multiple sclerosis (MS). Here, we aimed to reveal immune markers of DMF-associated lymphopenia. This prospective observational study longitudinally assessed 31 individuals with MS by single-cell mass cytometry before and after 12 and 48 weeks of DMF therapy. Employing a neural network-based representation learning approach, we identified a CCR4-expressing T helper cell population negatively associated with relevant lymphopenia. CCR4-expressing T helper cells represent a candidate prognostic biomarker for the development of relevant lymphopenia in patients undergoing DMF treatment. ANN NEUROL 2022;91:676-681.

Mixture-of-Experts Variational Autoencoder for clustering and generating from similarity-based representations on single cell data.

Clustering high-dimensional data, such as images or biological measurements, is a long-standing problem and has been studied extensively. Recently, Deep Clustering has gained popularity due to its flexibility in fitting the specific peculiarities of complex data. Here we introduce the Mixture-of-Experts Similarity Variational Autoencoder (MoE-Sim-VAE), a novel generative clustering model. The model can learn multi-modal distributions of high-dimensional data and use these to generate realistic data with high efficacy and efficiency. MoE-Sim-VAE is based on a Variational Autoencoder (VAE), where the decoder consists of a Mixture-of-Experts (MoE) architecture. This specific architecture allows for various modes of the data to be automatically learned by means of the experts. Additionally, we encourage the lower dimensional latent representation of our model to follow a Gaussian mixture distribution and to accurately represent the similarities between the data points. We assess the performance of our model on the MNIST benchmark data set and challenging real-world tasks of clustering mouse organs from single-cell RNA-sequencing measurements and defining cell subpopulations from mass cytometry (CyTOF) measurements on hundreds of different datasets. MoE-Sim-VAE exhibits superior clustering performance on all these tasks in comparison to the baselines as well as competitor methods.

Influence of high-dose intraoperative remifentanil with or without amantadine on postoperative pain intensity and morphine consumption in major abdominal surgery patients: a randomised trial.

BACKGROUND: Human volunteer studies demonstrate ketamine-reversible opioid-induced hyperalgesia, consistent with reports of increased postoperative pain and analgesic consumption. However, recent clinical trials showed controversial results after intraoperative administration of high-dose remifentanil. OBJECTIVE: To investigate in lower abdominal surgery patients whether postoperative pain intensity and analgesic consumption are increased following intraoperative high-dose vs. low-dose remifentanil, and whether this could be prevented by preoperative administration of the NMDA antagonist amantadine. DESIGN: Randomised, placebo-controlled, clinical study. SETTING: University hospital. PATIENTS: Sixty patients scheduled for elective major lower abdominal surgery. INTERVENTIONS: Patients were randomly assigned to one of three anaesthetic regimens. First, in the group 'low-dose remifentanil and preoperative isotonic saline' (n=15), a remifentanil infusion was maintained at a rate of 0.1 µg kg min throughout anaesthesia, and the end-tidal concentration of sevoflurane started at 0.5 minimum alveolar concentration (MAC) and was increased by 0.2% increments according to clinical demand. Preoperatively, 500 ml NaCl 0.9% were infused as study solution. Second, in the group 'high-dose remifentanil and preoperative saline' (n=17), the end-tidal concentration of sevoflurane was maintained at 0.5 MAC throughout anaesthesia. A remifentanil infusion was started at a rate of 0.2 µg kg min and subsequently increased by 0.05 µg kg min increments to clinical demand. Preoperatively, these patients also received a solution of 500 ml NaCl 0.9% as study solution. Third, the group 'high-dose remifentanil and preoperative amantadine' (n=16) received the same anaesthetic protocol as the second group, but the preoperative study solution was substituted by amantadine (200 mg/500 ml). MAIN OUTCOME MEASURES: Pain intensity measured by the numerical rating scale and cumulative morphine consumption. RESULTS: The remifentanil dose in both high-dose groups was significantly higher compared with the low-dose remifentanil group (0.20±0.04 and 0.23±0.02 vs. 0.08±0.04 µg kg min; P<0.001). Pain intensity gradually increased up to 45 min postoperatively in all groups, and then decreased again towards low levels in parallel with a linear increase in morphine consumption. Postoperative pain intensity and morphine consumption did not significantly differ between groups. Moreover, preoperative amantadine revealed no additional benefit. CONCLUSION: We were not able to demonstrate any influence on routine clinical outcome parameters of pain after high-dose remifentanil. Although not without limitations, these findings are in line with other clinical trials that could not detect an opioid-induced impact on postoperative pain parameters, which might be less sensitive to detect opioid-induced hyperalgesia compared with quantitative sensory testing. TRIAL REGISTRATION: DRKS00004626.

Radiofrequency Denervation of the Spine and the Sacroiliac Joint: A Systematic Review based on the Grades of Recommendations, Assesment, Development, and Evaluation Approach Resulting in a German National Guideline.

STUDY DESIGN: Systematic review of the literature and subsequent meta-analysis for the development of a new guideline. OBJECTIVES: This manuscript summarizes the recommendations from a new clinical guideline published by the German Spine Society. It covers the current evidence on recommendations regarding the indication, test blocks and use of radiofrequency denervation. The guidelines aim is to improve patient care and efficiency of the procedure. METHODS: A multidisciplinary working group formulated recommendations based on the Grades of Recommendations, Assessment, Development, and Evaluation (GRADE) approach and the Appraisal of Guidelines for Research and Evaluation II (AGREE II) instrument. RESULTS: 20 clinical questions were defined for guideline development, with 87.5% consensus achieved by committee members for one recommendation and 100% consensus for all other topics. Specific questions that were addressed included clinical history, examination and imaging, conservative treatment before injections, diagnostic blocks, the injected medications, the cut-off value in pain-reduction for a diagnostic block as well as the number of blocks, image guidance, the cannula trajectories, the lesion size, stimulation, repeat radiofrequency denervation, sedation, cessation or continuation of anticoagulants, the influence of metal hardware, and ways to mitigate complications. CONCLUSION: Radiofrequency (RF) denervation of the spine and the SI joint may provide benefit to well-selected individuals. The recommendations of this guideline are based on very low to moderate quality of evidence as well as professional consensus. The guideline working groups recommend that research efforts in relation to all aspects of management of facet joint pain and SI joint pain should be intensified.

Provision of palliative care and pain management services for oncology patients.

Early initiation of palliative care to address pain and other symptoms offers the potential to improve quality of life for patients with cancer. The approaches to implementing and delivering palliative care and pain management services vary depending on patient needs, available resources, provider training, and clinical setting. This article describes the experiences in developing programs in which the need for early palliative care or pain management services for patients with cancer was recognized. In each case, collaborative efforts, careful planning, administrative support, and ample time were needed to implement such services. To tailor services based on the available resources, different approaches were taken, including structuring of services within oncology units; creation of an integrated partnership between oncology and palliative care departments; establishment of a multidisciplinary comprehensive service; and incorporation of nurse-based pain services to address acute, chronic, and cancer pain. These examples offer insights into how to optimize delivery of services in a variety of settings with varying resources.

Spiritual needs among patients with chronic pain diseases and cancer living in a secular society.

OBJECTIVE: Research has shown that several patients report unmet psychosocial and spiritual needs. While most studies focus on patients with advanced stages of disease, we intended to identify unmet spiritual needs in patients with chronic pain diseases and cancer living in a secular society. METHODS: In an anonymous cross-sectional study, standardized questionnaires were provided to German patients with chronic pain diseases (and cancer), i.e., Spiritual Needs Questionnaire (SpNQ), Spirituality/Religiosity and Coping (SpREUK-15), Spiritual Well-being (FACIT-Sp), Brief Multidimensional Life Satisfaction Scale, Interpretation of Illness Questionnaire, and Escape from Illness (Escape). RESULTS: We enrolled 392 patients (67% women, mean age 56.3 ± 13.6 years; 61% Christian denomination) with chronic pain diseases (86%) and cancer (14%). Religious Needs (mean score 0.5 ± 0.8 on the scale) and Existential Needs (0.8 ± 0.8 on the scale) were low, while needs for Inner Peace (1.5 ± 0.9 on the scale) and Giving/Generativity were scored high (1.3 ± 1.0 on the scale). Regression analyses indicated that Religious Needs can be predicted best by (religious) "Trust," the illness interpretation "call for help," and living with a partner; Existential Needs can be predicted by "call for help" and to a weaker extent by (religious) "Trust." Existential Needs are influenced negatively by the illness interpretation "challenge." Needs for Inner Peace were predicted only in trend by the illness interpretation "threat," and there were no significant predictors for the Giving/Generativity needs in the respective regression model. CONCLUSIONS: Patients with chronic pain diseases predominantly report needs related to inner peace and generative relatedness on a personal level, whereas needs related to transcendent relatedness were of minor relevance. Nevertheless, even religious "skeptics" can express specific religious needs, and these should be recognized. Addressing patients' specific needs and also supporting them in their struggle with chronic illness remain a challenging task for the modern health care system.

Latent representation learning in biology and translational medicine.

Current data generation capabilities in the life sciences render scientists in an apparently contradicting situation. While it is possible to simultaneously measure an ever-increasing number of systems parameters, the resulting data are becoming increasingly difficult to interpret. Latent variable modeling allows for such interpretation by learning non-measurable hidden variables from observations. This review gives an overview over the different formal approaches to latent variable modeling, as well as applications at different scales of biological systems, such as molecular structures, intra- and intercellular regulatory up to physiological networks. The focus is on demonstrating how these approaches have enabled interpretable representations and ultimately insights in each of these domains. We anticipate that a wider dissemination of latent variable modeling in the life sciences will enable a more effective and productive interpretation of studies based on heterogeneous and high-dimensional data modalities.

Hydrogen bonded network properties in liquid formamide.

Molecular dynamics simulations have been performed for liquid formamide using two different types of potential model (OPLS, Cordeiro). The structural results obtained from simulation were compared to experimental (x-ray and neutron diffraction measurements) outcomes. A generally good agreement for both models examined has been found, but in the hydrogen bonded region (2.9 A) the Cordeiro model shows a slightly better fit. Besides the evaluation of partial radial distribution functions, orientational correlation functions and energy distribution functions, describing the hydrogen bonded structure, have been calculated based on the statistical analysis of configurations, resulting into a new insight in the clustering properties and topology of hydrogen bonded network. It has been shown that in liquid formamide exists a continuous hydrogen bonded network and from the analysis of the distribution of small rings revealed the ring size distribution in liquid formamide. Our study resulted that the ring size distribution of the hydrogen bonded liquid formamide shows a broad distribution with a maximum around 11. It has been found that the topology in formamide is significantly different than in water.

The influence of peritoneal endometriotic lesions on the generation of endometriosis-related pain and pain reduction after surgical excision.

PURPOSE: To investigate the influence of different kinds of endometriotic lesions, especially peritoneal endometriotic implants in pain generation and the pain reduction after surgical excision in a prospective study. METHODS: Fifty-one pre-menopausal patients underwent surgical laparoscopy due to chronic pelvic pain, dysmenorrhoea and/or for ovarian cysts. In 44 patients, endometriosis was diagnosed. The pre- and post-operative pain score was determined using a standardized questionnaire with a visual analogue scale. Patients with peritoneal endometriosis were divided into two different groups depending on their pre-operative pain score: group A had a pain score of 3 or more, while group B a pain score of 2 or less. Patients without peritoneal endometriosis were classified as group C, and patients without endometriosis were classified as group D. The pre- and post-operative pelvic pain and/or dysmenorrhoea was analysed according to the different types of endometriotic lesions. RESULTS: In groups A and C, the post-operative pain score decreased by at least 2 grades or more (p < 0.0). In group D, the post-operative pain score showed no significant reduction. CONCLUSION: The present study suggests that the surgical excision of endometriotic lesions -- including peritoneal implants -- is an effective treatment of endometriosis-associated pelvic pain and/or dysmenorrhoea.

Pain therapy - Are there new options on the horizon?

This article reviews the role of analgesic drugs with a particular emphasis on opioids. Opioids are the oldest and most potent drugs for the treatment of severe pain, but they are burdened by detrimental side effects such as respiratory depression, addiction, sedation, nausea, and constipation. Their clinical application is undisputed in acute (e.g., perioperative) and cancer pain, but their long-term use in chronic pain has met increasing scrutiny and has contributed to the current opioid crisis. We discuss epidemiological data, pharmacological principles, clinical applications, and research strategies aiming at novel opioids with reduced side effects.

Improving perioperative pain management: a preintervention and postintervention study in 7 developing countries.

INTRODUCTION: The burden of untreated postoperative pain is high. OBJECTIVE: This study assessed feasibility of using quality improvement (QI) tools to improve management of perioperative pain in hospitals in multiple developing countries. METHODS: The International Pain Registry and Developing Countries working groups, from the International Association for the Study of Pain (IASP), sponsored the project and PAIN OUT, a QI and research network, coordinated it, and provided the research tools. The IASP published a call about the project on its website. Principal investigators (PIs) were responsible for implementing a preintervention and postintervention study in 1 to 2 surgical wards in their hospitals, and they were free to choose the QI intervention. Trained surveyors used standardized and validated web-based tools for collecting findings about perioperative pain management and patient reported outcomes (PROs). Four processes and PROs, independent of surgery type, assessed effectiveness of the interventions. RESULTS: Forty-three providers responded to the call; 13 applications were selected; and PIs from 8 hospitals, in 14 wards, in 7 countries, completed the study. Interventions focused on teaching providers about pain management. Processes improved in 35% and PROs in 37.5% of wards. CONCLUSIONS: The project proved useful on multiple levels. It offered PIs a framework and tools to perform QI work and findings to present to colleagues and administration. Management practices and PROs improved on some wards. Interpretation of change proved complex, site-dependent, and related to multiple factors. PAIN OUT gained experience coordinating a multicentre, international QI project. The IASP promoted research, education, and QI work.

The dynamics of root cap sloughing in Arabidopsis is regulated by peptide signalling.

The root cap protects the stem cell niche of angiosperm roots from damage. In Arabidopsis, lateral root cap (LRC) cells covering the meristematic zone are regularly lost through programmed cell death, while the outermost layer of the root cap covering the tip is repeatedly sloughed. Efficient coordination with stem cells producing new layers is needed to maintain a constant size of the cap. We present a signalling pair, the peptide IDA-LIKE1 (IDL1) and its receptor HAESA-LIKE2 (HSL2), mediating such communication. Live imaging over several days characterized this process from initial fractures in LRC cell files to full separation of a layer. Enhanced expression of IDL1 in the separating root cap layers resulted in increased frequency of sloughing, balanced with generation of new layers in a HSL2-dependent manner. Transcriptome analyses linked IDL1-HSL2 signalling to the transcription factors BEARSKIN1/2 and genes associated with programmed cell death. Mutations in either IDL1 or HSL2 slowed down cell division, maturation and separation. Thus, IDL1-HSL2 signalling potentiates dynamic regulation of the homeostatic balance between stem cell division and sloughing activity.

[Case report: obstacles in pain therapy--is pain relief always achievable?]. / Kasuistik interaktiv: An den Grenzen der Schmerztherapie--Wenn Schmerzfreiheit nicht erreichbar ist.

No patient needs to have pain? Providing the best possible pain relief is as challenging for the anaesthesiologist as it is necessary for the patient's quality of life. The WHO algorithm allows sufficient and satisfactory treatment of 90 % of all cancer patients. This case report describes alternatives to the WHO algorithm for the remaining 10 % of cases. The alternatives concern opioid rotation, intravenous administration, and neuroaxial application. Indications for these alternative strategies are either opiod-insensitive incidental pain or neuropathic pain. Procedure and complications are discussed with the reader.

Chronic sensory stroke with and without central pain is associated with bilaterally distributed sensory abnormalities as detected by quantitative sensory testing.

Approximately 20% of patients suffering from stroke with pure or predominant sensory symptoms (referred to as sensory stroke patients) develop central poststroke pain (CPSP). It is largely unknown what distinguishes these patients from those who remain pain free. Using quantitative sensory testing (QST), we analyzed the somatosensory profiles of 50 patients with chronic sensory stroke, of which 25 suffered from CPSP. As compared with reference data from healthy controls, patients with CPSP showed alterations of thermal and mechanical thresholds on the body area contralateral to their stroke (P < 0.01). Patients with sensory stroke but without CPSP (non-pain sensory stroke [NPSS] patients) exhibited similar albeit less pronounced contralesional changes. Paradoxical heat sensation (PHS) and dynamic mechanical allodynia (DMA) showed higher values in CPSP, and an elevated cold detection threshold (CDT) was seen more often in CPSP than in patients with NPSS (P < 0.05). In patients with CPSP, changes in CDT, PHS, dynamic mechanical allodynia, and temporal pain summation (wind-up ratio) each correlated with the presence of pain (P < 0.05). On the homologous ipsilesional body area, both patient groups showed additional significant abnormalities as compared with the reference data, which strongly resembled the contralesional changes. In summary, our analysis reveals that CPSP is associated with impaired temperature perception and positive sensory signs, but differences between patients with CPSP and NPSS are subtle. Both patients with CPSP and NPSS show considerable QST changes on the ipsilesional body side. These results are in part paralleled by recent findings of bilaterally spread cortical atrophy in CPSP and might reflect chronic maladaptive cortical plasticity, particularly in patients with CPSP.

Extensive abscess formation after repeated paravertebral injections for the treatment of chronic back pain.

Paravertebral injections are commonly used for the treatment of chronic back pain despite the lack of evidence for their efficacy. Here, we report a case in which repeated paravertebral injections of local anesthetics, corticosteroids and botulinum toxin resulted in extensive abscess formation involving the entire paravertebral musculature descending to the level of the midthighs. These abscesses induced a systemic inflammatory response syndrome and required surgical drainage as well as broad-spectrum antibiotic therapy.

Current pain education within undergraduate medical studies across Europe: Advancing the Provision of Pain Education and Learning (APPEAL) study.

OBJECTIVES: Unrelieved pain is a substantial public health concern necessitating improvements in medical education. The Advancing the Provision of Pain Education and Learning (APPEAL) study aimed to determine current levels and methods of undergraduate pain medicine education in Europe. DESIGN AND METHODS: Using a cross-sectional design, publicly available curriculum information was sought from all medical schools in 15 representative European countries in 2012-2013. Descriptive analyses were performed on: the provision of pain teaching in dedicated pain modules, other modules or within the broader curriculum; whether pain teaching was compulsory or elective; the number of hours/credits spent teaching pain; pain topics; and teaching and assessment methods. RESULTS: Curriculum elements were publicly available from 242 of 249 identified schools (97%). In 55% (133/242) of schools, pain was taught only within compulsory non-pain-specific modules. The next most common approaches were for pain teaching to be provided wholly or in part via a dedicated pain module (74/242; 31%) or via a vertical or integrated approach to teaching through the broader curriculum, rather than within any specific module (17/242; 7%). The curricula of 17/242 schools (7%) showed no evidence of any pain teaching. Dedicated pain modules were most common in France (27/31 schools; 87%). Excluding France, only 22% (47/211 schools) provided a dedicated pain module and in only 9% (18/211) was this compulsory. Overall, the median number of hours spent teaching pain was 12.0 (range 4-56.0 h; IQR: 12.0) for compulsory dedicated pain modules and 9.0 (range 1.0-60.0 h; IQR: 10.5) for other compulsory (non-pain specific) modules. Pain medicine was principally taught in classrooms and assessed by conventional examinations. There was substantial international variation throughout. CONCLUSIONS: Documented pain teaching in many European medical schools falls far short of what might be expected given the prevalence and public health burden of pain.

Influence of exercise induced hyperlactatemia on retinal blood flow during normo- and hyperglycemia.

PURPOSE: Short term hyperglycemia has previously been shown to induce a blood flow increase in the retina. The mechanism behind this effect is poorly understood. We set out to investigate whether exercise-induced hyperlactatemia may alter the response of retinal blood flow to hyperglycemia. METHODS: We performed a randomized, controlled two-way cross over study comprising 12 healthy subjects, performed a 6-minutes period of dynamic exercise during an euglcaemic or hyperglycaemic insulin clamp. Retinal blood flow was assessed by combined vessel size measurement with the Zeiss retinal vessel analyzer and measurement of red blood cell velocities using bi-directional laser Doppler velocimetry. Retinal and systemic hemodynamic parameters were measured before, immediately after and 10 and 20 minutes after isometric exercise. RESULTS: On the euglycemic study day retinal blood flow increased after dynamic exercise. The maximum increase in retinal blood flow was observed 10 minutes after the end of exercise when lactate plasma concentration peaked. Hyperglycemia increased retinal blood flow under basal conditions, but had no incremental effect during exercise induced hyperlactatemia. CONCLUSIONS: Our results indicate that both lactate and glucose induce an increase in retinal blood flow in healthy humans. This may indicate a common pathway between glucose and lactate induced blood flow changes in the human retina.