CD8+ T cell targeting of tumor antigens presented by HLA-E.

The nonpolymorphic major histocompatibility complex E (MHC-E) molecule is up-regulated on many cancer cells, thus contributing to immune evasion by engaging inhibitory NKG2A/CD94 receptors on NK cells and tumor-infiltrating T cells. To investigate whether MHC-E expression by cancer cells can be targeted for MHC-E-restricted T cell control, we immunized rhesus macaques (RM) with rhesus cytomegalovirus (RhCMV) vectors genetically programmed to elicit MHC-E-restricted CD8+ T cells and to express established tumor-associated antigens (TAAs) including prostatic acidic phosphatase (PAP), Wilms tumor-1 protein, or Mesothelin. T cell responses to all three tumor antigens were comparable to viral antigen-specific responses with respect to frequency, duration, phenotype, epitope density, and MHC restriction. Thus, CMV-vectored cancer vaccines can bypass central tolerance by eliciting T cells to noncanonical epitopes. We further demonstrate that PAP-specific, MHC-E-restricted CD8+ T cells from RhCMV/PAP-immunized RM respond to PAP-expressing HLA-E+ prostate cancer cells, suggesting that the HLA-E/NKG2A immune checkpoint can be exploited for CD8+ T cell-based immunotherapies.

Evaluation of Neuromuscular Diseases and Complaints by Quantitative Muscle MRI.

Background: Quantitative muscle MRI (qMRI) is a promising tool for evaluating and monitoring neuromuscular disorders (NMD). However, the application of different imaging protocols and processing pipelines restricts comparison between patient cohorts and disorders. In this qMRI study, we aim to compare dystrophic (limb-girdle muscular dystrophy), inflammatory (inclusion body myositis), and metabolic myopathy (Pompe disease) as well as patients with post-COVID-19 conditions suffering from myalgia to healthy controls. Methods: Ten subjects of each group underwent a 3T lower extremity muscle MRI, including a multi-echo, gradient-echo, Dixon-based sequence, a multi-echo, spin-echo (MESE) T2 mapping sequence, and a spin-echo EPI diffusion-weighted sequence. Furthermore, the following clinical assessments were performed: Quick Motor Function Measure, patient questionnaires for daily life activities, and 6-min walking distance. Results: Different involvement patterns of conspicuous qMRI parameters for different NMDs were observed. qMRI metrics correlated significantly with clinical assessments. Conclusions: qMRI metrics are suitable for evaluating patients with NMD since they show differences in muscular involvement in different NMDs and correlate with clinical assessments. Still, standardisation of acquisition and processing is needed for broad clinical use.

Career and life planning in the context of the postgraduate medical training - current challenges and opportunities.

Introduction: The possibility of balancing career and family is meanwhile a central concern for most physicians when choosing a job. The aim of this study was to identify current barriers and opportunities for physician education and career planning. Methods: This cross-sectional study was conducted as an online survey between 11/2021 and 02/2022 and targeted physicians at all career levels in Germany who were members of a clinical professional association. Alternative and consent questions were used to assess experiences/attitudes toward various aspects of life and career planning, as well as alternative work and parental leave models, depending on gender, specialty, and hierarchical level. Results: The majority of the 2060 participants were female (69%) and had children (66%). Many childless residents reported that they felt they had to choose between children and a career. The majority of female residents, specialists and attending physicians (Ø 55.5%) stated that they had experienced career losses as a result of taking parental leave, while most men did not share this experience (Ø 53.7%). 92% of all participants agreed with the statement that men and women have different career opportunities. Job-sharing models were considered feasible at all levels of the hierarchy by an average of 55.6% of all medical executives. Conclusion: Parenthood and the use of parental leave and part-time work appear to have a significant impact on the career paths of those surveyed. Although the majority of directors of medical training programs are open to job-sharing models, further measures are needed in order to equalize career opportunities for men and women.

Prevention and Co-Management of Breast Cancer-Related Osteoporosis Using Resveratrol.

Breast cancer (BC) is currently one of the most common cancers in women worldwide with a rising tendency. Epigenetics, generally inherited variations in gene expression that occur independently of changes in DNA sequence, and their disruption could be one of the main causes of BC due to inflammatory processes often associated with different lifestyle habits. In particular, hormone therapies are often indicated for hormone-positive BC, which accounts for more than 50-80% of all BC subtypes. Although the cure rate in the early stage is more than 70%, serious negative side effects such as secondary osteoporosis (OP) due to induced estrogen deficiency and chemotherapy are increasingly reported. Approaches to the management of secondary OP in BC patients comprise adjunctive therapy with bisphosphonates, non-steroidal anti-inflammatory drugs (NSAIDs), and cortisone, which partially reduce bone resorption and musculoskeletal pain but which are not capable of stimulating the necessary intrinsic bone regeneration. Therefore, there is a great therapeutic need for novel multitarget treatment strategies for BC which hold back the risk of secondary OP. In this review, resveratrol, a multitargeting polyphenol that has been discussed as a phytoestrogen with anti-inflammatory and anti-tumor effects at the epigenetic level, is presented as a potential adjunct to both support BC therapy and prevent osteoporotic risks by positively promoting intrinsic regeneration. In this context, resveratrol is also known for its unique role as an epigenetic modifier in the regulation of essential signaling processes-both due to its catabolic effect on BC and its anabolic effect on bone tissue.

Erector spinae plane block for postoperative pain.

BACKGROUND: Acute and chronic postoperative pain are important healthcare problems, which can be treated with a combination of opioids and regional anaesthesia. The erector spinae plane block (ESPB) is a new regional anaesthesia technique, which might be able to reduce opioid consumption and related side effects. OBJECTIVES: To compare the analgesic effects and side effect profile of ESPB against no block, placebo block or other regional anaesthetic techniques. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase and Web of Science on 4 January 2021 and updated the search on 3 January 2022. SELECTION CRITERIA: Randomised controlled trials (RCTs) investigating adults undergoing surgery with general anaesthesia were included. We included ESPB in comparison with no block, placebo blocks or other regional anaesthesia techniques irrespective of language, publication year, publication status or technique of regional anaesthesia used (ultrasound, landmarks or peripheral nerve stimulator). Quasi-RCTs, cluster-RCTs, cross-over trials and studies investigating co-interventions in either arm were excluded. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed all trials for inclusion and exclusion criteria, and risk of bias (RoB), and extracted data. We assessed risk of bias using the Cochrane RoB 2 tool, and we used GRADE to rate the certainty of evidence for the primary outcomes. The primary outcomes were postoperative pain at rest at 24 hours and block-related adverse events. Secondary outcomes were postoperative pain at rest (2, 48 hours) and during activity (2, 24 and 48 hours after surgery), chronic pain after three and six months, as well as cumulative oral morphine requirements at 2, 24 and 48 hours after surgery and rates of opioid-related side effects. MAIN RESULTS: We identified 69 RCTs in the first search and included these in the systematic review. We included 64 RCTs (3973 participants) in the meta-analysis. The outcome postoperative pain was reported in 38 out of 64 studies; block-related adverse events were reported in 40 out of 64 studies. We assessed RoB as low in 44 (56%), some concerns in 24 (31%) and high in 10 (13%) of the study results. Overall, 57 studies reported one or both primary outcomes. Only one study reported results on chronic pain after surgery. In the updated literature search on 3 January 2022 we found 37 new studies and categorised these as awaiting classification. ESPB compared to no block There is probably a slight but not clinically relevant reduction in pain intensity at rest 24 hours after surgery in patients treated with ESPB compared to no block (visual analogue scale (VAS), 0 to 10 points) (mean difference (MD) -0.77 points, 95% confidence interval (CI) -1.08 to -0.46; 17 trials, 958 participants; moderate-certainty evidence). There may be no difference in block-related adverse events between the groups treated with ESPB and those receiving no block (no events in 18 trials reported, 1045 participants, low-certainty evidence). ESPB compared to placebo block ESPB probably has no effect on postoperative pain intensity at rest 24 hours after surgery compared to placebo block (MD -0.14 points, 95% CI -0.29 to 0.00; 8 trials, 499 participants; moderate-certainty evidence). There may be no difference in block-related adverse events between ESPB and placebo blocks (no events in 10 trials reported; 592 participants; low-certainty evidence). ESPB compared to other regional anaesthetic techniques Paravertebral block (PVB) ESPB may not have any additional effect on postoperative pain intensity at rest 24 hours after surgery compared to PVB (MD 0.23 points, 95% CI -0.06 to 0.52; 7 trials, 478 participants; low-certainty evidence). There is probably no difference in block-related adverse events (risk ratio (RR) 0.27, 95% CI 0.08 to 0.95; 7 trials, 522 participants; moderate-certainty evidence). Transversus abdominis plane block (TAPB) ESPB may not have any additional effect on postoperative pain intensity at rest 24 hours after surgery compared to TAPB (MD -0.16 points, 95% CI -0.46 to 0.14; 3 trials, 160 participants; low-certainty evidence). There may be no difference in block-related adverse events (RR 1.00, 95% CI 0.21 to 4.83; 4 trials, 202 participants; low-certainty evidence). Serratus anterior plane block (SAPB) The effect on postoperative pain could not be assessed because no studies reported this outcome. There may be no difference in block-related adverse events (RR 1.00, 95% CI 0.06 to 15.59; 2 trials, 110 participants; low-certainty evidence). Pectoralis plane block (PECSB) ESPB may not have any additional effect on postoperative pain intensity at rest 24 hours after surgery compared to PECSB (MD 0.24 points, 95% CI -0.11 to 0.58; 2 trials, 98 participants; low-certainty evidence). The effect on block-related adverse events could not be assessed. Quadratus lumborum block (QLB) Only one study reported on each of the primary outcomes. Intercostal nerve block (ICNB) ESPB may not have any additional effect on postoperative pain intensity at rest 24 hours after surgery compared to ICNB, but this is uncertain (MD -0.33 points, 95% CI -3.02 to 2.35; 2 trials, 131 participants; very low-certainty evidence). There may be no difference in block-related adverse events, but this is uncertain (RR 0.09, 95% CI 0.04 to 2.28; 3 trials, 181 participants; very low-certainty evidence). Epidural analgesia (EA) We are uncertain whether ESPB has an effect on postoperative pain intensity at rest 24 hours after surgery compared to EA (MD 1.20 points, 95% CI -2.52 to 4.93; 2 trials, 81 participants; very low-certainty evidence). A risk ratio for block-related adverse events was not estimable because only one study reported this outcome. AUTHORS' CONCLUSIONS: ESPB in addition to standard care probably does not improve postoperative pain intensity 24 hours after surgery compared to no block. The number of block-related adverse events following ESPB was low. Further research is required to study the possibility of extending the duration of analgesia. We identified 37 new studies in the updated search and there are three ongoing studies, suggesting possible changes to the effect estimates and the certainty of the evidence in the future.

Peripheral Regional Anesthetic Techniques in Cardiac Surgery: A Systematic Review and Meta-Analysis.

OBJECTIVE: The aim of this systematic review was to investigate postoperative pain outcomes and adverse events after peripheral regional anesthesia (PRA) compared to no regional anesthesia (RA), placebo, or neuraxial anesthesia in children and adults undergoing cardiac surgery. DESIGN: A systematic review and meta-analysis with an assessment of the risk of bias (Cochrane RoB 1) and certainty of evidence (Grading of Recommendations, Assessment, Development, and Evaluation). SETTING: Randomized controlled trials (RCTs). PARTICIPANTS: Adults and children undergoing heart surgery. INTERVENTIONS: Any kind of PRA compared to no RA or placebo or neuraxial anesthesia. MEASUREMENTS AND MAIN RESULTS: In total, 33 RCTs (2,044 patients) were included-24 of these had a high risk of bias, and 28 were performed in adults. Compared to no RA, PRA may reduce pain intensity at rest 24 hours after surgery (mean difference [MD] -0.81 points, 95% CI -1.51 to -0.10; I2 = 92%; very low certainty evidence). Peripheral regional anesthesia, compared to placebo, may reduce pain intensity at rest (MD -1.36 points, 95% CI -1.59 to -1.13; I2 = 54%; very low certainty evidence) and during movement (MD -1.00 points, 95% CI -1.34 to -0.67; I² = 72%; very low certainty evidence) 24 hours after surgery. No data after pediatric cardiac surgery could be meta-analyzed due to the low number of included trials. CONCLUSIONS: Compared to no RA or placebo, PRA may reduce pain intensity at rest and during movement. However, these results should be interpreted cautiously because the certainty of evidence is only very low.

[Frequency of Chronic Pain after Work-Related Trauma: A Preliminary Status Survey during Workers' Compensation Rehabilitation in a Tertiary Clinic]. / Häufigkeit chronischer Schmerzen nach Arbeitsunfall ­ Eine erste Statuserhebung im BG-lichen Heilverfahren einer Tertiärklinik.

BACKGROUND: Chronic pain after trauma and surgery is a long-term complication. Its relevance for patients within the workers' compensation rehabilitation process has not been adequately investigated. OBJECTIVES: Initial evaluation of frequency of chronic pain after occupational accidents. METHODS: In 2017, surgical inpatients (18-65 y) treated in a tertiary hospital were asked about chronic pain arising from an occupational trauma recognized by statutory occupation insurance (interval 2.8±6.9 years), regardless of care received, first at the time of hospitalization and then by telephone interview 6 months later. The focus was on patients with a work-related trauma (A) within the past month or (B) >6 months. PRIMARY OUTCOME: frequency of work trauma-related chronic pain (>6 months) at the initial interview (point prevalence), secondary outcomes: frequency of chronicity at 6 months (A) and persistence of chronic pain (B). Tertiary outcomes: ability to work, occupational injury classification, burden based on pain intensity, localization, and medication, functional deficits due to the existence of chronic pain, and comorbidity. RESULTS: Out of 415 patients included in the survey, 85% (160/188) reported accident-related chronic pain (predominantly moderate to highly severe in intensity, localized at joints and bones). 90% (131/145) also reported this pain six months later. 67% (64/96) reported chronic pain for the first time. Patients with chronic pain at follow-up (281/369) were less likely to return to work (p=0.003), required analgesics in 60%, were more often comorbid (p<0.002) and had greater functional deficits (p<0.002). CONCLUSION: Despite the preliminary nature of the data, chronic pain seems to be common after occupational trauma and negatively affects the recovery of work ability in the long term. Based on the present observational data, a further differentiated re-evaluation of prospective data considering therapeutic measures is strongly recommended.

Erector spinae plane block for postoperative pain.

BACKGROUND: Acute and chronic postoperative pain are important healthcare problems, which can be treated with a combination of opioids and regional anaesthesia. The erector spinae plane block (ESPB) is a new regional anaesthesia technique, which might be able to reduce opioid consumption and related side effects. OBJECTIVES: To compare the analgesic effects and side effect profile of ESPB against no block, placebo block or other regional anaesthetic techniques. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase and Web of Science on 4 January 2021 and updated the search on 3 January 2022. SELECTION CRITERIA: Randomised controlled trials (RCTs) investigating adults undergoing surgery with general anaesthesia were included. We included ESPB in comparison with no block, placebo blocks or other regional anaesthesia techniques irrespective of language, publication year, publication status or technique of regional anaesthesia used (ultrasound, landmarks or peripheral nerve stimulator). Quasi-RCTs, cluster-RCTs, cross-over trials and studies investigating co-interventions in either arm were excluded. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed all trials for inclusion and exclusion criteria, and risk of bias (RoB), and extracted data. We assessed risk of bias using the Cochrane RoB 2 tool, and we used GRADE to rate the certainty of evidence for the primary outcomes. The primary outcomes were postoperative pain at rest at 24 hours and block-related adverse events. Secondary outcomes were postoperative pain at rest (2, 48 hours) and during activity (2, 24 and 48 hours after surgery), chronic pain after three and six months, as well as cumulative oral morphine requirements at 2, 24 and 48 hours after surgery and rates of opioid-related side effects. MAIN RESULTS: We identified 69 RCTs in the first search and included these in the systematic review. We included 64 RCTs (3973 participants) in the meta-analysis. The outcome postoperative pain was reported in 38 out of 64 studies; block-related adverse events were reported in 40 out of 64 studies. We assessed RoB as low in 44 (56%), some concerns in 24 (31%) and high in 10 (13%) of the study results. Overall, 57 studies reported one or both primary outcomes. Only one study reported results on chronic pain after surgery. In the updated literature search on 3 January 2022 we found 37 new studies and categorised these as awaiting classification. ESPB compared to no block There is probably a slight but not clinically relevant reduction in pain intensity at rest 24 hours after surgery in patients treated with ESPB compared to no block (visual analogue scale (VAS), 0 to 10 points) (mean difference (MD) -0.77 points, 95% confidence interval (CI) -1.08 to -0.46; 17 trials, 958 participants; moderate-certainty evidence). There may be no difference in block-related adverse events between the groups treated with ESPB and those receiving no block (no events in 18 trials reported, 1045 participants, low-certainty evidence). ESPB compared to placebo block ESPB probably has no effect on postoperative pain intensity at rest 24 hours after surgery compared to placebo block (MD -0.14 points, 95% CI -0.29 to 0.00; 8 trials, 499 participants; moderate-certainty evidence). There may be no difference in block-related adverse events between ESPB and placebo blocks (no events in 10 trials reported; 592 participants; low-certainty evidence). ESPB compared to other regional anaesthetic techniques Paravertebral block (PVB) ESPB may not have any additional effect on postoperative pain intensity at rest 24 hours after surgery compared to PVB (MD 0.23 points, 95% CI -0.06 to 0.52; 7 trials, 478 participants; low-certainty evidence). There is probably no difference in block-related adverse events (risk ratio (RR) 0.27, 95% CI 0.08 to 0.95; 7 trials, 522 participants; moderate-certainty evidence). Transversus abdominis plane block (TAPB) ESPB may not have any additional effect on postoperative pain intensity at rest 24 hours after surgery compared to TAPB (MD -0.16 points, 95% CI -0.46 to 0.14; 3 trials, 160 participants; low-certainty evidence). There may be no difference in block-related adverse events (RR 1.00, 95% CI 0.21 to 4.83; 4 trials, 202 participants; low-certainty evidence). Serratus anterior plane block (SAPB) The effect on postoperative pain could not be assessed because no studies reported this outcome. There may be no difference in block-related adverse events (RR 1.00, 95% CI 0.06 to 15.59; 2 trials, 110 participants; low-certainty evidence). Pectoralis plane block (PECSB) ESPB may not have any additional effect on postoperative pain intensity at rest 24 hours after surgery compared to PECSB (MD 0.24 points, 95% CI -0.11 to 0.58; 2 trials, 98 participants; low-certainty evidence). The effect on block-related adverse events could not be assessed. Quadratus lumborum block (QLB) Only one study reported on each of the primary outcomes. Intercostal nerve block (ICNB) ESPB may not have any additional effect on postoperative pain intensity at rest 24 hours after surgery compared to ICNB, but this is uncertain (MD -0.33 points, 95% CI -3.02 to 2.35; 2 trials, 131 participants; very low-certainty evidence). There may be no difference in block-related adverse events, but this is uncertain (RR 0.09, 95% CI 0.04 to 2.28; 3 trials, 181 participants; very low-certainty evidence). Epidural analgesia (EA) We are uncertain whether ESPB has an effect on postoperative pain intensity at rest 24 hours after surgery compared to EA (MD 1.20 points, 95% CI -2.52 to 4.93; 2 trials, 81 participants; very low-certainty evidence). A risk ratio for block-related adverse events was not estimable because only one study reported this outcome. AUTHORS' CONCLUSIONS: ESPB in addition to standard care probably does not improve postoperative pain intensity 24 hours after surgery compared to no block. The number of block-related adverse events following ESPB was low. Further research is required to study the possibility of extending the duration of analgesia. We identified 37 new studies in the updated search and there are three ongoing studies, suggesting possible changes to the effect estimates and the certainty of the evidence in the future.

[Application possibilities of digital tools in postoperative pain therapy]. / Einsatzmöglichkeiten digitaler Tools in der postoperativen Schmerztherapie.

BACKGROUND: Recently, digital tools, such as smartphone-based applications and the use of artificial intelligence have increasingly found their way into pain medicine. This could enable new treatment approaches in postoperative pain management. Therefore, this article provides an overview of various digital tools and their potential application options in postoperative pain management. MATERIAL AND METHODS: An orienting literature search was carried out in the MEDLINE and Web of Science databases, and a targeted selection of essential key publications was made in order to provide a structured presentation of different current possible applications and a discussion based on the most recent knowledge. RESULTS: Today, possible applications of digital tools, even if they mostly have only a model character, include pain documentation and assessment, patient self-management and education, pain prediction, decision support for medical staff, and supportive pain therapy, for example in the form of virtual reality and videos. These tools offer advantages such as individualized treatment concepts, addressing specific patient groups, reduction of pain and analgesics, and the potential for early warning or detection of postoperative pain. Furthermore, the challenges of the technical implementation and appropriate user training are highlighted. CONCLUSION: The use of digital tools, although so far integrated in clinical routine in a relatively selective and exemplary manner, promises to be an innovative approach for personalized postoperative pain therapy in the future. Future studies and projects should help to integrate the promising research approaches into everyday clinical practice.

Quantitative muscle magnetic resonance imaging depicts microstructural abnormalities but no signs of inflammation or dystrophy in post-COVID-19 condition.

BACKGROUND AND PURPOSE: Post-COVID-19 condition (PCC) has high impact on quality of life, with myalgia and fatigue affecting at least 25% of PCC patients. This case-control study aims to noninvasively assess muscular alterations via quantitative muscle magnetic resonance imaging (MRI) as possible mechanisms for ongoing musculoskeletal complaints and premature exhaustion in PCC. METHODS: Quantitative muscle MRI was performed on a 3 Tesla MRI scanner of the whole legs in PCC patients compared to age- and sex-matched healthy controls, including a Dixon sequence to determine muscle fat fraction (FF), a multi-echo spin-echo sequence for quantitative water mapping reflecting putative edema, and a diffusion-weighted spin-echo echo-planar imaging sequence to assess microstructural alterations. Clinical examination, nerve conduction studies, and serum creatine kinase were performed in all patients. Quantitative muscle MRI results were correlated to the results of the 6-min walk test and standardized questionnaires assessing quality of life, fatigue, and depression. RESULTS: Twenty PCC patients (female: n = 15, age = 48.8 ± 10.1 years, symptoms duration = 13.4 ± 4.2 months, body mass index [BMI] = 28.8 ± 4.7 kg/m2 ) were compared to 20 healthy controls (female: n = 15, age = 48.1 ± 11.1 years, BMI = 22.9 ± 2.2 kg/m2 ). Neither FF nor T2 revealed signs of muscle degeneration or inflammation in either study groups. Diffusion tensor imaging (DTI) revealed reduced mean, axial, and radial diffusivity in the PCC group. CONCLUSIONS: Quantitative muscle MRI did not depict any signs of ongoing inflammation or dystrophic process in the skeletal muscles in PCC patients. However, differences observed in muscle DTI depict microstructural abnormalities, which may reflect potentially reversible fiber hypotrophy due to deconditioning. Further longitudinal and interventional studies should prove this hypothesis.

Between clinical practice, teaching and research - a project report on the development and implementation of a career mentoring curriculum for female clinician scientists.

Objectives: Despite the high proportion of female medical students, the leading positions in almost all medical departments are still considerably less often held by female clinicians than by male. The aim of this project report is to introduce a career mentoring curriculum for female clinician scientists at Ruhr-University of Bochum in Germany. Methods: The career mentoring program was developed for young female clinician scientists who aim for a leading position in academic medicine. We describe and discuss herein its planning and implementation over two years (11/2020-11/2022) focusing on the needs of the target group. Results: The mentoring program is based on an agile twin-track strategy. It includes peer mentoring, content-related input and interdisciplinary three-to-one mentoring by the coordinators. Additionally, the mentees develop and conduct a scientific project to practice their acquired skills in a protected environment. The quality assurance system of the mentoring program includes a continuous evaluation of the mentees' satisfaction with the content and organisation of the program, whose results serve as the basis of the prompt adjustment of the latter. It also includes an evaluation of the sustainable impact of the program on the mentees' career development based on an adapted role matrix. The role matrix addresses the mentees to acquire the competencies required for them to become a successful clinician, scientist and academic teacher. Conclusions: A 2-year innovative and unique career mentoring program for female clinician scientists was developed and already successfully launched. Making use of different mentoring strategies, the program has the potential to promote gender equality and encourage female physicians to pursue a career in academic medicine.

Perioperative ketamine for postoperative pain management in patients with preoperative opioid intake: A systematic review and meta-analysis.

STUDY OBJECTIVE: Postoperative pain management in opioid users remains challenging. The perioperative administration of ketamine might lead to favourable pain outcomes in these patients. STUDY DESIGN: A systematic review of randomised controlled trials (RCT) with meta-analysis and assessment of the quality of evidence by GRADE was performed. SETTING: Perioperative pain treatment. PATIENTS: Adult opioid users undergoing surgery. INTERVENTIONS: Perioperative administration of ketamine. MEASUREMENTS: Primary outcomes were postoperative acute pain at rest/during movement after 24 h and number of patients with ketamine-related adverse events. MAIN RESULTS: Nine RCTs (802 patients with at least two weeks opioid-intake) were included. There is low-quality evidence that ketamine may slightly reduce postoperative pain during movement after 24 h (mean difference: -0.79; 95% confidence interval (CI): -1.22 to -0.36). Based on a very low-quality of evidence, we are uncertain on any effect of ketamine on pain at rest after 24 h and incidences of adverse events like hallucinations and confusion within 48 h. However, perioperative ketamine reduced cumulative mean opioid consumption by 97.3 mg (95%CI: -164.8 to -29.7) after 24 h and 186.4 mg (95%CI: -347.6 to -25.2) after 48 h. The relative risks (RR) for opioid-related adverse events were significantly different for sedation within 24 h (RR: 0.54; 95%CI 0.37 to 0.78). CONCLUSIONS: There is currently limited evidence for a reduced postoperative pain intensity using perioperative ketamine in preoperative opioid-consuming patients. However, a clinically relevant opioid-sparing effect was evident associated with a reduced risk for postoperative sedation and without increased harm. Therefore, ketamine might be a useful anti-hyperalgesic adjuvant in these patients. Nevertheless, with clinical heterogeneity being considerable, it's too premature to suggest any specific ketamine protocol. Furthermore, many questions (like ideal dosing, treatment duration and more favourable patient-related outcome measures including long-term effects) remain open and need to be addressed in future studies. PROTOCOL REGISTRATION: Prospero CRD42020185497.

Chronic Pain Following Fracture-Related Surgery: Posttraumatic Rather Than Postsurgical Origin Promotes Chronification-A Prospective Observational Study With 1-Year Follow-up.

BACKGROUND: Chronic posttraumatic/postsurgical pain (CPSP) is common after traumatic or surgical damage. Exposure to both trauma and surgery, with the potential for repeated bone and nerve damage, may increase the risk of CPSP after fracture-related surgery. But the (long-term) incidences of CPSP and neuropathic CPSP and the ensuing burdens are unknown. Therefore, the patients were prospectively assessed within 1 year, and the patient-specific characteristics were explored. METHODS: Between 2017 and 2018, 127 patients (age: 52.9 ± 17.1 years, male: 55.1%) with traumatic fractures needing osteosynthesis (extremities: 91.3%) were assessed posttrauma (before surgery), postsurgery at days 1 to 5, 6 weeks, 3 and 12 months. The primary outcomes are as follows: incidence at 3 and 12 months of CPSP (defined as pain intensity on a numerical rating scale [NRS: 0-10] ≥3), secondary exploration: neuropathic CPSP (NRS ≥3 and Douleur Neuropathique 4 interview [DN4i] score ≥3 [Douleur Neuropathique interview: 0-7]); burden: quality of life (QoL, the EuroQOL five dimensions questionnaire [EQ-5D-3L] descriptive system); and inter alia, the number of analgesics (trial registration: DRKS00011601). RESULTS: The incidence of CPSP was 57.1% (52/91, n/N) at 3 and 42.7% (35/82) at 12 months postsurgery, including neuropathic CPSP 7.7% (4/52) and 17.1% (6/35), respectively. Descriptively, posttraumatic higher pain intensity at rest (difference of 0.9 ± 1.8 NRS) and the need for more frequent analgesics (by 34.3%) were associated with CPSP a year after surgery compared to those without. As soon as week 6, these patients had developed descriptively a 15% more impaired QoL, with 25% more impairment after 1 year. The patients with CPSP presented with at least 1 neuropathic symptom 12 months later in 68.6% (24/35) of cases, mainly with an early posttraumatic occurrence (without fulfilling the definition of neuropathic CPSP). CONCLUSIONS: After early fracture-related surgery, high incidences of CPSP (43%) were prospectively observed 1 year postsurgery, up to approximately 1 in 5 patients who had neuropathic CPSP. At the same time, CPSP was accompanied with an impacted QoL and analgesic dependence, both indicating clinical relevance. Moreover, the high incidence and the early posttraumatic occurrence of more intense pain suggest that the initial fracture-related trauma, rather than the surgical trauma, may predominantly trigger CPSP at Y1 (1 year). Therefore, these exploratory results set the direction of required future research. A future clinical hypothesis might be: treat first what hurts first.

Isoflurane not at the expense of postoperative nausea and vomiting in cardiac anesthesia - an observational study.

OBJECTIVES: Inhalative anesthesia is of common use, but is generally known to potentiate postoperative nausea and vomiting (PONV). With an internal change of anesthesia regimen from total intravenous anesthesia (TIVA) to isoflurane (in terms of myocardial protection) in cardiac anesthesia a higher incidence of PONV was to be expected. Therefore, we evaluated the incidence of PONV after the simultaneous implementation of PONV prophylaxis. METHODS: The incidence of PONV, prospectively assessed in 197 cardiac surgery patients (68 y ± 10.4, 66.5% male) having isoflurane plus dual PONV prophylaxis with dexamethasone and droperidol, was compared with previous data of 190 controls (67 y ± 9.6, 71% male) having TIVA without and with single or dual PONV prophylaxis (n = 64 dexamethasone and droperidol, n = 25 dexamethasone, n = 101 only TIVA), and the Apfel-scoring (0-4 depending on PONV-risk). DRKS00014275. Statistics: Chi2-test, p < .05 (Bonferroni). RESULTS: The incidence of PONV under isoflurane with antiemetic prophylaxis was 20.8% (95% confidence interval (CI) 15.4; 27.4) compared to 30.5% (95%CI 24; 37.6) under TIVA (p = .029; dexamethasone and droperidol 23.4% (95%CI 13.8; 35.7); dexamethasone 32% (95%CI 14.9; 53.5); only TIVA 34.7% (95%CI 25.5; 44.8)), but was not lower in high-risk patients than predicted according to Apfel-scoring 4 (71.4 vs. 78%). CONCLUSION: In cardiac anesthesia, the use of isoflurane is not at the expense of PONV when using a risk-independent two-drug-prophylaxis. It is even beneficial resulting surprisingly in a lower incidence of PONV than under TIVA unless with and without prophylaxis. Patients with the highest risk for PONV and receiving isoflurane should receive a third antiemetic prophylactic drug.

Efficacy and adverse events of selective serotonin noradrenaline reuptake inhibitors in the management of postoperative pain: A systematic review and meta-analysis.

STUDY OBJECTIVE: Selective-serotonin-noradrenaline-reuptake inhibitors (SSNRI) might be an interesting option for postoperative pain treatment. Objective was to investigate postoperative pain outcomes of perioperative SSNRI compared to placebo or other additives in adults undergoing surgery. DESIGN: Systematic review of randomised controlled trials (RCT) with meta-analysis and GRADE assessment. SETTING: Acute and chronic postoperative pain treatment. PATIENTS: Adult patients undergoing surgery. INTERVENTIONS: Perioperative administration of SSNRI. MEASUREMENTS: Primary outcomes were postoperative acute pain at rest/during movement (measured on a scale from 0 to 10), number of patients with chronic postsurgical pain (CPSP) and with SSNRI-related adverse events. MAIN RESULTS: Fourteen RCTs (908 patients) were included. We have high-quality evidence that duloxetine has no effect on pain at rest at 2 h (MD: -0.02; 95% confidence interval (CI) -0.51 to 0.47), but probably reduces it at 48 h (MD: -1.16; 95%CI -1.78 to -0.54). There is low- and moderate-quality evidence that duloxetine has no effects on pain during movement at 2 h (MD: -0.42; 95%CI -1.53 to 0.69) and 48 h (MD: -0.91; 95% CI -2.08 to 0.26), respectively. We have very low-quality evidence that duloxetine might reduce pain at rest (MD: -0.45; 95%CI -0.74 to -0.15) and movement (MD: -1.19; 95%CI -2.32 to -0.06) after 24 h. We have low-quality evidence that duloxetine may reduce the risk of CPSP at 6 months (RR:0.35; 95%CI 0.14 to 0.90). There is moderate-quality evidence that duloxetine increases the risk of dizziness (RR:1.72; 95%CI 1.26 to 2.34). CONCLUSION: At the expense of a higher risk for dizziness, SSNRI may be effective in reducing postoperative pain between 24 and 48 h after surgery. However, the results of the meta-analyses are mostly imprecise and duloxetine might only be used in individual cases. Protocol registration: CRD42018094699.

Rat and human cytomegalovirus ORF116 encodes a virion envelope glycoprotein required for infectivity.

Herpesviruses encode multiple glycoproteins required for different stages of viral attachment, fusion, and envelopment. The protein encoded by the human cytomegalovirus (HCMV) open reading frame UL116 forms a stable complex with glycoprotein H that is incorporated into virions. However, the function of this complex remains unknown. Herein, we characterize R116, the rat CMV (RCMV) putative homolog of UL116. Two R116 transcripts were identified in fibroblasts with three proteins expressed with molecular weights of 42, 58, and 82 kDa. R116 is N-glycosylated, expressed with late viral gene kinetics, and is incorporated into the virion envelope. RCMV lacking R116 failed to result in productive infection of fibroblasts and siRNA knockdown of R116 substantially reduced RCMV infectivity. Complementation in trans of an R116-deficient virus restored ability of the virus to infect fibroblasts. Finally, UL116 knockdown also decreased HCMV infectivity indicating that R116 and UL116 both contribute to viral infectivity.

Pain during and after COVID-19 in Germany and worldwide: a narrative review of current knowledge.

Pain is a common symptom accompanying the coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). Nonspecific discomfort such as sore throat and body ache are frequent. Parainfectious pain such as headache, myalgia, or neuropathic pain has also been reported. The latter seems to be associated with an autoimmune response or an affection of the peripheral neuromuscular system or the central nervous system because of the viral infection. Furthermore, chronic pain can be a complication of intensive care unit treatment due to COVID-19 itself (such as intensive care-acquired weakness) or of secondary diseases associated with the SARS-CoV-2 infection, including Guillain-Barré syndrome, polyneuritis, critical illness polyneuropathy, or central pain following cerebrovascular events. Data on long-lasting painful symptoms after clinically manifest COVID-19 and their consequences are lacking. In addition, preexisting chronic pain may be exacerbated by limited and disrupted health care and the psychological burden of the COVID-19 pandemic. Medical providers should be vigilant on pain during and after COVID-19.