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Objective: Complex regional pain syndrome (CRPS) represents a rare complication following injury to a limb. The DASH questionnaire (disability of arm, shoulder, and hand) evaluates everyday arm function. We assessed the DASH and its subitems in comparison to patients with brachial plexus lesions or fracture controls, analysed it over time, and in relation to active range of motion (ROM), to determine patients' impairment and trajectory., Methods: The dataset included 193 patients with upper extremity CRPS from the noncoding RNA (ncRNA) Pain cohort, 36 fracture controls, and 12 patients with traumatic brachial plexus lesions. For the clinical and psychological characterisation, questionnaires and a goniometer for the measurement of ROM were utilized. Thirty-three patients were followed up after approximately 2.5 years of guideline treatment., Results: CRPS patients had a similar mean DASH of 54.7 (standard deviation (S.D.) ±21) as brachial plexus lesion patients ( M  = 51.4, S.D. ± 16.1) but different significantly from fracture controls ( M  = 21.2, S.D. ± 21.1). Pain and older age were predictors of the DASH. Activities requiring force or impact on the arm, shoulder, or hand were mostly affected in patients with CRPS. After 2.5 years of standard treatment, the mean DASH score fell to 41.3 (S.D. ± 25.2), weakness in leisure activities was recuperated, pain feelings were lessened, and ROM, e.g., wrist flexion, recovered by 36°. Two-thirds of patients improved in both the DASH and the ROM., Conclusions: CRPS is as disabling as a complete loss of arm function in brachial plexus lesions and exhibits only partial recovery. Developing QuickDASH versions for CRPS patients could reduce the load of questions in clinical studies. It would be prudent to consider the unexpected age dependency of the DASH in future studies. This trial is registered with DRKS00008964., Competing Interests: H.L. Rittner and F. Birklein received EU funds for the ncRNAPain Study (FP7). The remaining authors declare that they have no conflicts of interest., (Copyright © 2024 Gudrun-Karin Kindl et al.)

Background: Cervical cancer often originates from cervical cell dysplasia. Previous studies mainly focused on surgical margins and high-risk human papillomavirus persistence as factors predicting recurrence. New research highlights the significance of positive findings from endocervical curettage (ECC) during excision treatment. However, the combined influence of surgical margin and ECC status on dysplasia recurrence risk has not been investigated., Methods: In this retrospective study, data from 404 women with high-grade squamous intraepithelial lesions (HSIL) who underwent large loop excision of the transformation zone (LLETZ) were analyzed. Records were obtained retrospectively from the hospital's patient database including information about histopathological finding from ECC, endocervical margin status with orientation of residual disease after LLETZ, recurrent/persistent dysplasia after surgical treatment and need for repeated surgery (LLETZ or hysterectomy)., Results: Patients with cranial (= endocervical) R1-resection together with cells of HSIL in the ECC experienced re-surgery 17 times. With statistical normal distribution, this would have been expected to happen 5 times (p < 0.001). The Fisher's exact test confirmed a statistically significant connection between the resection status together with the result of the ECC and the reoccurrence of dysplasia after surgery (p < 0,001). 40,6% of the patients with re-dysplasia after primary LLETZ had shown cranial R1-resection together with cells of HSIL in the ECC. Investigating the risk for a future abnormal Pap smear, patients with cranial R1-resection together with dysplastic cells in the ECC showed the greatest deviation of statistical normal distribution with SR = 2.6., Conclusion: Our results demonstrate that the future risk of re-dysplasia, re-surgery, and abnormal Pap smear for patients after LLETZ due to HSIL is highest within patients who were diagnosed with cranial (endocervical) R1-resection and with cells of HSIL in the ECC in their primary LLETZ. Consequently, the identification of patients, who could benefit of intensified observation or required intervention could be improved., (© 2024. The Author(s).)

Background: According to the Common-Sense Model of Illness Representations, illness beliefs, such as causal attributions, can influence the way people assess and cope with their illness and vice versa. To date, causal attributions in people with depressive symptoms have been studied mainly cross-sectionally, quantitatively and independently. The purpose of this study is to examine the causal attributions of people with depressive symptoms in terms of their stability over time, dependence on treatment experience, and differentiation of causal concepts., Methods: In a population-based prospective sample, people with at least mild depressive symptoms (PHQ-9 Score ≥ 5) were interviewed via telephone at T0 and twelve months later (T1). Causal attributions were assessed using the Brief Illness Perception Questionnaire. After the open responses were qualitatively analysed using a deductive-inductive approach, stability over time was assessed for causal attributions and concepts by comparing answers between the two time points. Subsequent exploratory quantitative analyses were conducted using chi-square tests, t-tests, and logistic regression analyses., Results: A total of 471 individuals (age M = 53.9, 53.6% female) with a mean PHQ-9 Score of 8.4 were included in the analyses. Causal attributions related to participants' social environment, workplace, and past are the most stable over time. However, individuals with and without a time-stable causal concept showed no differences in terms of sociodemographic characteristics, severity of depressive symptoms, risk of comorbidity, and treatment experiences. Overall, the causal concepts of people with depressive symptoms appear to be very diverse. Those with treatment experience (M = 2.21, SD = 0.80) named significantly more causal attributions compared to people without treatment experience (M = 1.98, SD = 0.81, t(471) = -3.060, p < 0.01). In addition, logistic regression analyses revealed that treatment-experienced respondents were more likely to attribute "childhood/youth/parental home" and "predisposition"., Conclusions: Our study reveals that people with treatment experience tend to report treatment-congruent causal attributions, such as childhood and family environment, as well as predisposition, more frequently. Understanding how causal attributions and concepts are formed and change can be helpful for addressing causal attributions in treatment. Future studies should take into account the benefits of employing qualitative survey methods for exploring causal attributions., (© 2024. The Author(s).)

Chronic and neuropathic pain are a widespread burden. Incomplete understanding of underlying pathomechanisms is one crucial factor for insufficient treatment. Recently, impairment of the blood nerve barrier (BNB) has emerged as one key aspect of pain initiation and maintenance. In this narrative review, we discuss several mechanisms and putative targets for novel treatment strategies. Cells such as pericytes, local mediators like netrin-1 and specialized proresolving mediators (SPMs), will be covered as well as circulating factors including the hormones cortisol and oestrogen and microRNAs. They are crucial in either the BNB or similar barriers and associated with pain. While clinical studies are still scarce, these findings might provide valuable insight into mechanisms and nurture development of therapeutic approaches., Competing Interests: Declaration of Competing Interest The authors declare that there are no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Introduction: Bortezomib (BTZ) is a selective and reversible proteasome inhibitor and first line treatment for multiple myeloma (MM). One of the side effects is BTZ-induced peripheral neuropathy (BIPN). Until now there is no biomarker which can predict this side effect and its severity. Neurofilament light chain (NfL) is a neuron specific cytoskeletal protein, of which higher levels can be detected in peripheral blood in case of axon damage. In this study, we aimed to evaluate the relationship between NfL serum levels and characteristics of BIPN., Methods: We performed a first interim analysis of a monocentric, non-randomized, observational clinical trial including 70 patients (DRKS00025422) diagnosed with MM in the inclusion period of June 2021 until March 2022. Two groups of patients-one with ongoing BTZ treatment at the time of recruiting, and one with BTZ treatment in the past-were compared to controls. NfL in serum was analyzed via the ELLA™ device., Results: Both patients with previous and ongoing BTZ treatment had higher serum NfL levels than controls, and patients with ongoing BTZ treatment had higher NfL levels than patients with BTZ treatment in the past. Serum NfL levels correlated with electrophysiological measures of axonal damage in the group with ongoing BTZ treatment., Conclusion: Elevated NfL levels indicate acute axonal damage under BTZ in MM patients., (© 2023. The Author(s).)

Introduction: In patients with peripheral neuropathies (PNP), neuropathic pain is present in 50% of the cases, independent of the etiology. The pathophysiology of pain is poorly understood, and inflammatory processes have been found to be involved in neuro-degeneration, -regeneration and pain. While previous studies have found a local upregulation of inflammatory mediators in patients with PNP, there is a high variability described in the cytokines present systemically in sera and cerebrospinal fluid (CSF). We hypothesized that the development of PNP and neuropathic pain is associated with enhanced systemic inflammation., Methods: To test our hypothesis, we performed a comprehensive analysis of the protein, lipid and gene expression of different pro- and anti-inflammatory markers in blood and CSF from patients with PNP and controls., Results: While we found differences between PNP and controls in specific cytokines or lipids, such as CCL2 or oleoylcarnitine, PNP patients and controls did not present major differences in systemic inflammatory markers in general. IL-10 and CCL2 levels were related to measures of axonal damage and neuropathic pain. Lastly, we describe a strong interaction between inflammation and neurodegeneration at the nerve roots in a specific subgroup of PNP patients with blood-CSF barrier dysfunction., Conclusion: In patients with PNP systemic inflammatory, markers in blood or CSF do not differ from controls in general, but specific cytokines or lipids do. Our findings further highlight the importance of CSF analysis in patients with peripheral neuropathies., Competing Interests: Author CS has been a consultant for Merz, Omega, Ipsen and Bayer on the subject of neuropathic pain. She has given educational talks for GSK and Pfizer. Authors KS and AN are employed by Bionorica research GmbH. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 García-Fernández, Höfflin, Rausch, Strommer, Neumann, Cebulla, Reinhold, Rittner, Üçeyler and Sommer.)

Background: Complex regional pain syndrome (CRPS) is marked by disproportionate pain after trauma. Whilst the long-term outcome is crucial to patients, predictors or biomarkers of the course of pain or CRPS symptoms are still lacking. In particular, microRNAs, such as miR-223, decreased in CRPS, have been described only in cross-sectional studies., Methods: In this study, we characterised CRPS patients over a course of 2.5 years of standard treatment. The patient underwent clinical examination including pain measurement, symptom questionnaires, quantitative sensory testing (QST) and blood sampling. Exosomal microRNA levels were measured via qPCR. After follow-up, patients were stratified into 'pain relief' (mean pain reduced by ≥2 numeric rating scale) or 'persistence' (mean pain unchanged or worsened). The primary outcome was miR-223 and miR-939 expression, secondary outcomes were differences in clinical parameters between groups and time points., Results: Thirty-nine patients were included, 33 of whom qualified for stratification. Overall, patients reported lower pain and improved clinical characteristics after 2.5 years, but no significant changes in QST or miR-223 and miR-939 expression levels. 16 patients met the criteria for pain relief. This was associated with stable exosomal miR-223 expression, whilst levels further decreased in pain persistence. Clinically, pain relief was marked by shorter disease duration and correlated positively with high initial pain., Conclusion: We identified progressively reduced miR-223 as a putative biomarker of chronic CRPS pain. Clinically, this study underlines the importance of early diagnosis and treatment showing that high initial pain does not predict an unfavourable outcome. Finally, pain relief and recovery of sensory disturbances seem independent processes., (© 2022 The Authors. European Journal of Pain published by John Wiley & Sons Ltd on behalf of European Pain Federation - EFIC ®.)

Competing Interests: Declaration of Competing Interest The authors have no conflicts of interest to disclose.

Background: Epilepsy and neurocysticercosis (NCC) prevalence estimates in sub-Saharan Africa are still scarce but show important variation due to the population studied and different screening and diagnosis strategies used. The aims of this study were to estimate the prevalence of epileptic seizures and epilepsy in the sampled population, and the proportion of NCC among people with epilepsy (PWE) in a large cross-sectional study in a rural district of southern Malawi., Methods: We conducted a community-based door-to-door screening study for epileptic seizures in Balaka, Malawi between October and December 2012. Past epileptic seizures were reported through a 15-item questionnaire answered by at least one person per household generating five major criteria. People who screened positive were further examined by a neurologist to establish diagnosis. Patients diagnosed with epilepsy were examined and offered Taenia solium cyst antigen and antibody serological tests, and a CT scan for the diagnosis of NCC., Results: In total, screening information on 69,595 individuals was obtained for lifetime occurrence of epileptic seizures. 3,100 (4.5%) participants screened positive, of whom 1,913 (62%) could be followed-up and underwent further assessment. Lifetime prevalence was 3.0% (95% Bayesian credible interval [CI] 2.8 to 3.1%) and 1.2% (95%BCI 0.9 to 1.6%) for epileptic seizures and epilepsy, respectively. NCC prevalence among PWE was estimated to be 4.4% (95%BCI 0.8 to 8.5%). A diagnosis of epilepsy was ultimately reached for 455 participants., Conclusion: The results of this large community-based study contribute to the evaluation and understanding of the burden of epilepsy in the population and of NCC among PWE in sub-Saharan Africa., Competing Interests: The authors have declared that no competing interests exist.

Both nerve injury and complex regional pain syndrome (CRPS) can result in chronic pain. In traumatic neuropathy, the blood nerve barrier (BNB) shielding the nerve is impaired-partly due to dysregulated microRNAs (miRNAs). Upregulation of microRNA-21-5p (miR-21) has previously been documented in neuropathic pain, predominantly due to its proinflammatory features. However, little is known about other functions. Here, we characterized miR-21 in neuropathic pain and its impact on the BNB in a human-murine back translational approach. MiR-21 expression was elevated in plasma of patients with CRPS as well as in nerves of mice after transient and persistent nerve injury. Mice presented with BNB leakage, as well as loss of claudin-1 in both injured and spared nerves. Moreover, the putative miR-21 target RECK was decreased and downstream Mmp9 upregulated, as was Tgfb. In vitro experiments in human epithelial cells confirmed a downregulation of CLDN1 by miR-21 mimics via inhibition of the RECK/MMP9 pathway but not TGFB. Perineurial miR-21 mimic application in mice elicited mechanical hypersensitivity, while local inhibition of miR-21 after nerve injury reversed it. In summary, the data support a novel role for miR-21, independent of prior inflammation, in elicitation of pain and impairment of the BNB via RECK/MMP9., (© 2022 The Authors. Annals of the New York Academy of Sciences published by Wiley Periodicals LLC on behalf of New York Academy of Sciences.)

Introduction: Many countries face an increased use of emergency medical services (EMS) with a decreasing percentage of life-threatening complaints. Though there is a broad discussion among experts about the cause, patients' self-perceived, non-medical reasons for using EMS remain largely unknown., Methods: The written survey included EMS patients who had≥1 case of prehospital emergency care in 2016. Four German health insurance companies sent out postal questionnaires to 1312 insured patients. The response rate was 20%; 254 questionnaires were eligible for descriptive and interferential analyses (t-tests, chi2-tests, logistic models)., Results: The majority of respondents indicated that their EMS use was due to an emergency or someone else's decision (≥84%; multiple checks allowed); 56% gave need for a quick transport as a reason. Other frequently stated reasons addressed the health care system (e. g., complaints outside of physicians' opening hours) and insecurity/anxiety about one's state of health (>45% of the respondents). "Social factors" were similarly important (e. g., 42% affirming, "No one could give me a ride to the emergency department or doctor's office."). Every fifth person had contact with other emergency care providers prior to EMS use. Respondents negating an emergency as a reason were less likely to confirm wanting immediate medical care on site or quick transports compared to those affirming an emergency. Patients using EMS at night more often denied having an emergency compared to patients with access to care during the day., Conclusion: The study identified a bundle of reasons leading to EMS use apart from medical complaints. Attempts for needs-oriented EMS use should essentially include optimization of the health care and social support system and measures to reduce patients' insecurity., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Blood nerve barrier disruption and edema are common in neuropathic pain as well as in complex regional pain syndrome (CRPS). MicroRNAs (miRNA) are epigenetic multitarget switches controlling neuronal and non-neuronal cells in pain. The miR-183 complex attenuates hyperexcitability in nociceptors, but additional non-neuronal effects via transcription factors could contribute as well. This study explored exosomal miR-183 in CRPS and murine neuropathy, its effect on the microvascular barrier via transcription factor FoxO1 and tight junction protein claudin-5, and its antihyperalgesic potential. Sciatic miR-183 decreased after CCI. Substitution with perineural miR-183 mimic attenuated mechanical hypersensitivity and restored blood nerve barrier function. In vitro, serum from CCI mice und CRPS patients weakened the microvascular barrier of murine cerebellar endothelial cells, increased active FoxO1 and reduced claudin-5, concomitant with a lack of exosomal miR-183 in CRPS patients. Cellular stress also compromised the microvascular barrier which was rescued either by miR-183 mimic via FoxO1 repression or by prior silencing of Foxo1. PERSPECTIVE: Low miR-183 leading to barrier impairment via FoxO1 and subsequent claudin-5 suppression is a new aspect in the pathophysiology of CRPS and neuropathic pain. This pathway might help untangle the wide symptomatic range of CRPS and nurture further research into miRNA mimics or FoxO1 inhibitors., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Due to an increasing prevalence of heart failure and persistent shortage of donor hearts, the number of left ventricular assist device (LVAD) implantations is growing. As more patients live with LVADs for prolonged periods of time, psychosocial outcomes are becoming more relevant. This particularly applies to destination therapy (DT) patients, who live with the LVAD for the rest of their lives., Methods: We used a cross-sectional qualitative design to explore psychological burden, coping strategies, and resources from the perspective of DT patients. Data were collected via semi-structured in-depth interviews with 18 patients who lived with the LVAD for 3 months to over 10 years. These were analyzed using an inductive content analysis. Due to the COVID-19 pandemic, changes to the recruitment strategy and data collection strategies of the original study protocol were applied. Patients and clinicians were involved throughout the research process to ensure the validity of the results and implications., Results: We synthesized 10 psychosocial, health, and treatment-related burdens and identified 15 problem- and emotion-focused coping strategies and 5 personal and environmental resources patients used to cope with the burden., Conclusions: The findings provide deeper insights into the complex and specific situation of LVAD patients to better address the patient situation in health care and promote positive psychosocial outcomes. So far, health care practice and quality vary significantly between clinics due to individual treatment protocols. Our results highlight the need to improve medical and psychosocial care. Overarching care concepts may be developed based on the implications., (© 2021 The Authors. Artificial Organs published by International Center for Artificial Organ and Transplantation (ICAOT) and Wiley Periodicals LLC.)

Background: In the current pandemic regarding the infection with the SARS-CoV-2-virus and COVID-19 as the disease, concerns about pregnant women, effects on childbirth and the health of the newborn remain high. Initially, due to the early manifestation of the disease in younger patients, high numbers of COVID-19 patients in women needing peripartum care were expected., Objective: This article aims to provide a general overview over the beginning of the pandemic as well as the second wave of infections in Germany and Switzerland, regarding SARS-CoV‑2 positive pregnant women hospitalized for childbirth. We therefore launched a registry to gain timely information over the dynamic situation during the SARS-CoV‑2 pandemic in Germany., Material and Methods: As part of the COVID-19-related Obstetric Anesthesia Longitudinal Assessment (COALA) registry, centers reported weekly birth rates, numbers of suspected SARS-CoV‑2 cases, as well as the numbers of confirmed cases between 16 March and 3 May 2020. Data acquisition was continued from 18 October 2020 till 28 February 2021. The data were analyzed regarding distribution of SARS-CoV‑2 positive pregnant women hospitalized for childbirth between centers, calendar weeks and birth rates as well as maternal characteristics, course of disease and outcomes of SARS-CoV‑2 positive pregnant women., Results: A total of 9 German centers reported 2270 deliveries over 7 weeks during the first wave of infections including 3 SARS-CoV‑2 positive cases and 9 suspected cases. During the second survey period, 6 centers from Germany and Switzerland reported 41 positive cases out of 4897 deliveries. One woman presented with a severe and ultimately fatal course of the disease, while another one needed prolonged ECMO treatment. Of the women 28 presented with asymptomatic infections and 6 neonates were admitted to a neonatal intensive care unit for further treatment. There was one case of neonatal SARS-CoV‑2 infection., Conclusion: The number of pregnant women infected with SARS-CoV‑2 was at a very low level at the time of delivery, with only sporadic suspected or confirmed cases. Due to the lack of comprehensive testing in the first survey period, however, a certain number of asymptomatic cases are to be assumed. Of the cases 68% presented as asymptomatic or as mild courses of disease but the data showed that even in young healthy patients without the presence of typical risk factors, serious progression can occur. These outcomes should raise awareness for anesthesiologists, obstetricians, pediatricians and intensive care physicians to identify severe cases of COVID-19 in pregnant women during childbirth and to take the necessary precautions to ensure the best treatment of mother and neonate. The prospective acquisition of data allowed a timely assessment of the highly dynamic situation and gain knowledge regarding this vulnerable group of patients., (© 2021. The Author(s).)

Background: Besides increasing numbers of cases in German emergency departments (ED), the spectrum of attending patients is also changing. Patients with acute illnesses tend to prefer EDs to ambulatory care as primary contact point. This study examines the motives for use and use behavior of low-urgent ED-patients., Methods: Anonymous patient survey in the ED of Wolfsburg Hospital between 12/2015 and 03/2016 with descriptive analysis. All patients with low urgency (Manchester-Triage-System (MTS), levels blue and green) were eligible., Results: 81.5% of respondents (729 evaluable out of 7000 questionnaires distributed) attended the ED between 8:00 a. m. and 5:00 p. m., 70.1 % of them were walk-in patients. The motive most frequently cited was that they would receive better care in the ED (48.3 %). Contrary to acuity assessment, 67.8 % of respondents considered themselves a medium to life-threatening emergency. As alternative option, 49.2 % would choose a nearby clinic in the region for their complaints., Conclusion: Self-assessed urgency differs with acuity assessment according to MTS. Patients who fear an acute threat to their health do not use services provided in the ambulatory sector such as the emergency practice of the Association of Statutory Health Insurance Physicians in the immediate proximity sufficiently. Previous approaches for patient navigation do not seem to be successful in this setting. Strengthening of EDs as a single 24/7 access point for emergency care with simultaneous abolition of parallel care structures should be discussed., (© 2020. Springer Medizin Verlag GmbH, ein Teil von Springer Nature.)

Purpose of Review: Major trauma remains one of the leading causes of death worldwide with traumatic brain injury and uncontrolled traumatic bleeding as the main determinants of fatal outcome. Interestingly, the therapeutic approach to trauma-associated bleeding and coagulopathy shows differences between geographic regions, that are reflected in different guidelines and protocols., Recent Findings: This article summarizes main principles in coagulation diagnostics and compares different strategies for treatment of massive hemorrhage after trauma in different regions of the world. How would a bleeding trauma patient be managed if they got hit by the bus in the United States, United Kingdom, Germany, Switzerland, Austria, Denmark, Australia, or in Japan?, Summary: There are multiple coexistent treatment standards for trauma-induced coagulopathy in different countries and different trauma centers. Most of them initially follow a protocol-based approach and subsequently focus on predefined clinical and laboratory targets., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

The therapy of brain-dead pregnant women is an extreme example not only of the possibilities in current critical care, but also of resulting ethical, social and legal controversies, an area not familiar to most clinicians. Based on the case of a patient with fatal traumatic brain injury, a previously unknown early pregnancy and stated will to donate organs, we will discuss several aspects using published case reports: therapeutic goals, especially palliative care vs. continuation; implications of brain death diagnosis; considerations on legal care; involvement of relatives, especially the child's father; dynamics within the care team; and finally the issue of putative organ donation. This complex case once more depicts that even facing such highly unfavourable framework and seemingly irreconcilable factors, pregnancy can prevail. The researched facts and considerations in this article are intended to give an overview of potential dilemmas and might serve as a starting point in similar situations., Competing Interests: Die Autorinnen/Autoren erklären, dass kein Interessenkonflikt vorliegt., (Thieme. All rights reserved.)

A 29-year-old woman suffered major traumatic brain injury caused by a car accident. As diagnostic measures had revealed an early pregnancy (9th week), treatment on the intensive care unit was continued for 5 months, after unfavourable cerebral prognosis was followed by an irreversible loss of brain function in the 10th week of pregnancy. After assisted vaginal delivery of a healthy child in the 31th week of pregnancy on the critical care unit, organ procurement took place according to the presumed will of the patient. The article presents the details of the critical care therapy and discusses the supportive medical measures. Those measures served primarily to uphold the pregnancy und support the healthy development and delivery of the fetus and only in second instance the organ preservation aiming on organ donation. Necessary measures included maintenance of vital functions, hemostasis of electrolytes, nutrition, treatment of infection, prevention of adverse effects on the fetus, substitution of hormones and vitamins as well as the preparation of a planned or an unplanned delivery., Competing Interests: Die Autorinnen/Autoren erklären, dass kein Interessenkonflikt vorliegt., (Thieme. All rights reserved.)

Background: Approximately one out of every three people in Germany who meets the diagnostic criteria for major depression has contact with mental health services. Therefore, according to treatment guidelines, two thirds of all individuals with depression are insufficiently treated. In the past, the subjective perspective of people who (do not) make use of mental health services has been neglected. Factors related to the use of health services are described in Andersen's Behavioral Model of Health Services Use (ABM). The aim of this study is to supplement operationalizations of subjectively perceived and evaluated individual characteristics in the ABM and to evaluate whether the supplemented model can better explain mental health services use in individuals with depression than established operationalizations., Methods: A representative telephone study with two measurement points will be conducted. In an explanatory mixed-methods design, qualitative interviews will be added to further interpret the quantitative data. A nationwide sample scoring 5 or more on the Patient Health Questionnaire (PHQ-9) will be recruited and interviewed via telephone at T0 and 12 months later (T1). Data on established and subjective characteristics as well as mental health service use will be collected. At T1, conducting a diagnostic interview (Composite International Diagnostic Interview, DIA-X-12/M-CIDI) enables the recording of 12-month diagnoses according to DSM-IV-TR criteria. Ideally, n = 768 datasets will be available and analyzed descriptively by means of regression analysis. Up to n = 32 persons who use or do not use depression-specific health services incongruent with their objective or subjective needs will be interviewed (face-to-face) to better explain their behavior. In addition, theories of non-need-based mental health service use are developed within the framework of the grounded theory-based analysis of the qualitative interviews., Discussion: The study intends to contribute to the theoretical foundation of health services research and to specify the characteristics described in the ABM. Thus, after completion of the study, a further sophisticated and empirically tested model will be available to explain mental health services. The identified modifiable influencing factors are relevant for the development of strategies to increase mental health service use in line with the objective and subjective needs of individuals with depression.

For a long time considered ineffective, placebos nowadays have an accepted role in studies as well as clinical practice. The identification of psychological as well as neurophysiological mechanisms helped to conceptualize and legitimize the placebo effect. Moreover, studies have even proven a therapeutic value. Consequently, the benefits of a thoughtfully applied placebo effect are increasingly being exploited. This article reviews the concept and current understanding of the placebo effect and depicts its use in the field of pain management., Competing Interests: Die Autorinnen/Autoren geben an, dass kein Interessenkonflikt besteht., (Thieme. All rights reserved.)

A variety of barriers ensures the protection of the peripheral nervous system from noxious blood-borne or surrounding stimuli. In this review, anatomy and functioning of the blood nerve barrier (BNB) and the blood DRG barrier (BDB) will be presented and key tight junction proteins described: ZO-1, claudin-1, -3, -5, -11, -12, -19, occludin, and tricellulin. Different diseases can lead to or be accompanied by nerve barrier disruption; impairment of nerve barriers in turn worsens pathology. Peripheral nerve injury, diabetic neuropathy and inflammatory polyneuropathy cause an increased permeability of BNB and BDB. Knowledge and understanding of these mechanisms might ultimately lead to the invention of drugs to control barrier function and help ameliorating neurological diseases., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Complex regional pain syndrome (CRPS) typically develops after fracture or trauma. Many of the studies so far have analyzed clinical and molecular markers of CRPS in comparison with healthy or pain controls. This approach, however, neglects mechanisms occurring during physiological trauma recovery. Therefore, we compared the clinical phenotype, sensory profiles, patient-reported outcomes, and exosomal immunobarrier microRNAs (miRs) regulating barrier function and immune response between CRPS and fracture controls (FCs) not fulfilling the CRPS diagnostic criteria. We included upper-extremity FCs, acute CRPS I patients within 1 year after trauma, a second disease control group (painful diabetic polyneuropathy), and healthy controls. Fracture controls were not symptoms-free, but reported some pain, disability, anxiety, and cold pain hyperalgesia in quantitative sensory testing. Patients with CRPS had higher scores for pain, disability, and all patient-reported outcomes. In quantitative sensory testing, ipsilateral and contralateral sides differed significantly. However, on the affected side, patients with CRPS were more sensitive in only 3 parameters (pinprick pain and blunt pressure) when compared to FCs. Two principal components were identified in the cohort: pain and psychological parameters distinguishing FC and CPRS. Furthermore, the immunobarrier-protective hsa-miR-223-5p was increased in plasma exosomes in FCs with normal healing, but not in CRPS and healthy controls. Low hsa-miR-223-5p was particularly observed in subjects with edema pointing towards barrier breakdown. In summary, normal trauma healing includes some CRPS signs and symptoms. It is the combination of different factors that distinguish CRPS and FC. Fracture control as a control group can assist to discover resolution factors after trauma.

A 28-year-old woman suffered a traffic accident resulting in severe head injuries with deleterious prognosis. Diagnostics further revealed a hitherto unknown pregnancy, at suspected week 9. Based on the patient's wish to donate organs, brain death protocol confirmed irreversible loss of brain function. Yet, vital pregnancy rendered organ transplantation impossible. Multiple ethical and legal issues arose, from invalidation of established legal care after brain death to the delivery of a healthy child after trauma and long-term critical care. After medicolegal and ethical counselling, pregnancy was sustained, and the goal of organ donation postponed. Critical care focused on foetal homeostasis. At 30+4 weeks, a viable girl was born via assisted vaginal delivery. Postpartal organ donation resulted in heart, kidney and pancreas transplantation. The case emphasises the medical, legal and ethical challenges to combine two apparently diametrical goals: the successful full-term pregnancy and the fulfilment of a patient's wish to donate organs., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2019. No commercial re-use. See rights and permissions. Published by BMJ.)

The blood-nerve barrier (BNB) consisting of the perineurium and endoneurial vessels is sealed by tight junction proteins. BNB alterations are a crucial factor in the pathogenesis of peripheral neuropathies. However, barrier opening, e.g. by tissue plasminogen activator (tPA), can also facilitate topical application of analgesics. Here, we examined tPA both in the pathophysiology of neuropathy-induced BNB opening or via exogenous application and its effect on the cytoplasmatic tight junction protein anchoring protein, zona occludens-1 (ZO-1), the adherens molecule JAM-C and microRNA(miR)-155-5p. Specifically, we investigated whether tPA alone and barrier opening lead to pain behavioral changes, i.e. hyperalgesia, or whether these effects require further factors. Male Wistar rats underwent chronic constriction injury (CCI) or were treated by a single perisciatic application of recombinant (r)tPA. CCI elicited mechanical allodynia, tPA mRNA upregulation, macrophage invasion, BNB leakage for large molecule tracers, downregulation of ZO-1 and JAM-C mRNA/protein, and a loss of immunoreactivity of both in perineurium and endoneurial cells. Similarly, after perisciatic rtPA injection, ZO-1 and JAM-C mRNA as well as cytosolic/membrane protein and ZO-1 immunoreactivity were downregulated, and the BNB was opened. Neither mechanical hypersensitivity nor macrophage infiltration was observed after rtPA in contrast to CCI. Mechanistically, miR-155-5p, which is known to destabilize barriers and tight junction proteins like claudin-1 and ZO-1, was increased in CCI and to lesser extent after rtPA application. In summary, tPA transiently opens the BNB possibly via miR-155-5p. However, tPA does not provoke allodynia in the absence of a neuropathic stimulus like a ligation or inflammation., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Peripheral neuropathy is accompanied by changes in the neuronal environment. The blood-nerve barrier (BNB) is crucial in protecting the neural homeostasis: Tight junctions (TJ) seal paracellular spaces and thus prevent external stimuli from entering. In different models of neuropathic pain, the BNB is impaired, thus contributing to local damage, immune cell invasion and, ultimately, the development of neuropathy with its symptoms. In this study, we examined changes in expression and microstructural localization of two key tight junction proteins (TJP), claudin-1 and the cytoplasmic anchoring ZO-1, in the sciatic nerve of mice subjected to chronic constriction injury (CCI). Via qPCR and analysis of fluorescence immunohistochemistry, a marked downregulation of mRNA as well as decreased fluorescence intensity were observed in the nerve for both proteins. Moreover, a distinct zig-zag structure for both proteins located at cell-cell contacts, indicative of the localization of TJs, was observed in the perineurial compartment of sham-operated animals. This microstructural location in cell-cell-contacts was lost in neuropathy as semiquantified via computational analysis, based on a novel algorithm. In summary, we provide evidence that peripheral neuropathy is not only associated with decrease in relevant TJPs but also exhibits alterations in TJP arrangement and loss in barrier tightness, presumably due to internalization. Specifically, semiquantification of TJP in cell-cell-contacts of microcompartments could be used in the future for routine clinical samples of patients with neuropathy.

Epigenetics, i.e. an altered reading of the genome without altering the genes themselves is a growing scientific field. A distinction is made between changes in the DNA by modification of the histones and non-coding RNA that alter the messenger (m)RNAs. Epigenetic modifications can be triggered by personal circumstances or other external factors and therefore influence the occurrence of diseases. Epigenetics are therefore of particular interest to anesthesiologists, pain specialists and intensive care physicians, as anesthetic drugs may have a long-term influence on protein transcription leading for example to alterations in neurocognition after anesthesia, chronification of postoperative pain and immune response in sepsis. Non-coding microRNAs known to be altered in a variety of perioperatively relevant diseases e. g. heart infarct, might serve as prognostic factors of perioperative outcome. Moreover, there are ways to influence epigenetic changes through life style and certain medications. In this review article, examples of anesthesia, intensive care and pain medicine-relevant diseases and the influence of epigenetics on them are presented.

The peripheral nerve contains three barriers which include the blood-nerve barrier consisting of endoneurial vessels and the perineurium as well as autotypic junctions in Schwann cells. The perineurium prevents diffusion of perineurally injected drugs that can be used for selective regional pain control. It is composed of a basal membrane and layers of perineurial cells sealed by tight junction proteins like claudin-1. Claudin-1 expression and barrier function are regulated via low-density lipoprotein receptor-related protein (LRP-1). Perisciatic application of recombinant tissue plasminogen activator (rtPA) or the catalytically inactive rtPAi - both agonists of LRP-1 - reduced claudin-1 mRNA and protein expression in the rat nerve. This facilitated an increase of nociceptive thresholds after local application of hydrophilic opioids or the voltage gated sodium channel blocker (NaV1.7) ProToxin-II without apparent nerve toxicity. RtPA-induced barrier opening was mediated by LRP-1 and intracellularly by Erk phosphorylation. In silico, microRNA (miR)-rno-29b-2-5p and rno-miR-183-5p were identified as potential regulators of claudin-1 transcription in the rat. RtPA application increased miR-183-5p in the sciatic nerve. MiR-183-5p mimics functionally opened the perineurium and downregulated claudin-1 expression in vivo. In vitro, hsa-miR-183-3p mimics reduced claudin-1 expression in human HT-29/B6 cells. Overall, rtPA regulates perineurial barrier tightness via LRP-1, Erk phosphorylation and miR-183-5p/3p. This mechanism might serve as a new principle to facilitate drug delivery to peripheral nerves in humans., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Neuropathic pain, caused by a lesion in the somatosensory system, is a severely impairing mostly chronic disease. While its underlying molecular mechanisms are not thoroughly understood, neuroimmune interactions as well as changes in the pain pathway such as sensitization of nociceptors have been implicated. It has been shown that not only are different cell types involved in generation and maintenance of neuropathic pain, like neurons, immune and glial cells, but, also, intact adjacent neurons are relevant to the process. Here, we describe an experimental approach to discriminate damaged from intact adjacent neurons in the same dorsal root ganglion (DRG) using differential fluorescent neuronal labelling and fluorescence-activated cell sorting (FACS). Two fluorescent tracers, Fluoroemerald (FE) and 1-dioctadecyl-3,3,3,3-tetramethylindocarbocyanine perchlorate (DiI), were used, whose properties allow us to distinguish between damaged and intact neurons. Subsequent sorting permitted transcriptional analysis of both groups. Results and qPCR validation show a strong regulation in damaged neurons versus contralateral controls as well as a moderate regulation in adjacent neurons. Data for damaged neurons reveal an mRNA expression pattern consistent with established upregulated genes like galanin, which supports our approach. Moreover, novel genes were found strongly regulated such as corticotropin-releasing hormone (CRH), providing novel targets for further research. Differential fluorescent neuronal labelling and sorting allows for a clear distinction between primarily damaged neuropathic neurons and "bystanders," thereby facilitating a more detailed understanding of their respective roles in neuropathic processes in the DRG.