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William Raffaeli,1 Michael Tenti,1 Annette Corraro,2 Valentina Malafoglia,1 Sara Ilari,3 Eleonora Balzani,4 Antonello Bonci1,5 1ISAL Foundation, Institute for Research on Pain, Rimini, Italy; 2Leiden University, Faculty of Social and Behavioural Sciences, Leiden, The Netherlands; 3Institute of Research for Food Safety & Health (IRC_FSH), Department of Health Sciences, University ‘Magna Graecia’ of Catanzaro, Catanzaro, Italy; 4Department of Surgical Science, University of Turin, Torino, Italy; 5Global Institutes on Addictions, Miami, FL, USACorrespondence: William RaffaeliFondazione ISAL, Via San Salvador, 204, Rimini, 47922, ItalyTel +390541725166Fax +390541725164Email isal@fondazioneisal.itAbstract: Chronic pain is nowadays used as an umbrella term referring to a wide range of clinical conditions, such as fibromyalgia, migraine, or long-standing pain states without actual known causes. However, labeling a patient’s clinical condition with the term “chronic pain”, when dealing with pain lasting longer than 3 months, might be misleading. This paper aims at analyzing the possible pitfalls related to the use of the term “chronic pain” in the clinical field. It appears, indeed, that the term “chronic pain” shows a semantic inaccuracy on the basis of emerging scientific evidences on the pathogenesis of different long-standing pain states. The major pitfalls in using this label emerge in clinical settings, especially with patients having a biomedical perspective on pain or from different cultures, or with healthcare providers of other medical specialties or different disciplines. A label solely emphasizing temporal features does not help to discern the multifaceted complexity of long-standing pain states, whose onset, maintenance and exacerbation are influenced by a complex and interdependent set of bio-psycho-social factors. Thus, finding a more meaningful name might be important. We call upon the necessity of bringing awareness and implementing educational activities for healthcare providers, as well as for the public, on the biopsychosocial approach to assess, prevent and care of chronic pain. Further research on the etiopathogenetic processes of chronic pain states is also required, together with examinative diagnostic methods, to individuate the most appropriate label(s) representing the complex long-standing pain states and to avoid adopting the term “chronic pain” inappropriately.Keywords: chronic pain, disease, diagnosis, label, meaning, biopsychosocial

Chronic pelvic pain is a chronic syndrome that affects patients' life quality and expectancy as far as bladder, bowel and sexual functioning are compromised. So far treatment options are limited since pharmaceutical research has not provided any specific drug therapy to manage chronic pelvic pain. Nutraceutical products represent useful tools to supply this lack of medications. The aim of this narrative review is to provide some insight from a neuroscience perspective on the nutraceuticals' use as adjuvant therapy in chronic pelvic pain. A review of the literature, between 2001 and 2019 on PMC and PubMed was performed in order to identify studies proving safety and efficacy of nutraceuticals in chronic pelvic pain. Inclusion criteria were nutraceutical compounds, namely curcumin, quercetin, bromelain, and diseases known for causing chronic pelvic pain. Nineteen studies were selected. Quercetin demonstrates to inhibit mast-cells, pro-inflammatory cytokines and regulate cell proliferation; curcumin suppresses inflammatory cytokines expression, inhibits invasion, angiogenesis of endometrial lesions. Bromelain resulted in a reduction of painkiller rescue doses required in endometriosis. Pre-clinical studies show promising effects of nutraceutical supplementation with selected enzymes and antioxidant compounds in patients suffering from chronic pelvic pain. Positive weak evidence suggests efficacy of these products in use as antiinflammatory and analgesic medications for chronic pelvic pain treatment. [ABSTRACT FROM AUTHOR]

Rationale: Despite the potential risks associated with sedation, there is a paucity of pharmacokinetic/pharmacodynamic (PK/PD) data for propofol and fentanyl in patients supported with veno-venous extracorporeal membrane oxygenation (V-V ECMO)., Objective: Describe propofol and fentanyl PK/PD profiles in V-V ECMO patients., Methods and Measurements: Prospective, single-center, open-label PK/PD study at the Toronto General Hospital ICU between July 2022 and January 2023. Using high-performance liquid chromatography-tandem mass spectrometry, propofol and fentanyl total concentrations were measured during V-V ECMO. Sequential PK/PD modeling, using sex as a covariate, was conducted with processed electroencephalography (PSI) for sedation, and expiratory occlusion pressure (P occ ), and airway occlusion pressure during the first 0.1 seconds (P 0.1 ) for respiratory effort., Main Results: Eleven patients underwent 106 evaluations over a median (IQR) follow-up of 146 (116-146) hours. Patient's average (±SD) age was 43 (±13) years, and 55% were female. Propofol and fentanyl PK were best described by a two-compartment model. Propofol-PSI PD was described using an effect compartment, with a coefficient of determination (ρ 2 ) of 0.78. There was a significant increase in propofol ( p =0.01) and fentanyl ( p =0.03) clearance within 10 minutes of ECMO initiation, plateauing after 8 hours of ECMO support. Despite this, patient over-sedation (PSI<40) occurred in 74% of the observations. Females exhibited higher sedative central volume of distribution and lower propofol clearance., Conclusion: ECMO initiation resulted in a time-limited increased sedative clearance. PSI accurately described sedative PD, but variable respiratory effort was observed irrespective of sedative plasma concentrations. Sex-based differences were found in sedative PK/PD parameters.

Neurons in the hippocampus are correlated with different variables, including space, time, sensory cues, rewards, and actions, where the extent of tuning depends on ongoing task demands. However, it remains uncertain whether such diverse tuning corresponds to distinct functions within the hippocampal network or if a more generic computation can account for these observations. To disentangle the contribution of externally driven cues versus internal computation, we developed a task in mice where space, auditory tones, rewards, and context were juxtaposed with changing relevance. High-density electrophysiological recordings revealed that neurons were tuned to each of these modalities. By comparing movement paths and action sequences, we observed that external variables had limited direct influence on hippocampal firing. Instead, spiking was influenced by online action plans modulated by goal uncertainty. Our results suggest that internally generated cell assembly sequences are selected and updated by action plans toward deliberate goals. The apparent tuning of hippocampal neuronal spiking to different sensory modalities might emerge due to alignment to the afforded action progression within a task rather than representation of external cues.

Objectives : To investigate the impact of patient characteristics and treatment factors on excessive respiratory drive, effort, and lung-distending pressure during transitioning from controlled to spontaneous assisted ventilation in patients with acute respiratory distress syndrome (ARDS). Methods : Multicenter cohort observational study of patients with ARDS at four academic intensive care units. Respiratory drive (P 0.1 ), diaphragm electrical activity (EAdi), inspiratory effort derived from EAdi (∆Pmus EAdi ) and from occlusion of airway pressure (∆Pocc) (Pmus ΔPocc ), and dynamic transpulmonary driving pressure (ΔP L,dyn ) were measured at the first transition to assisted spontaneous breathing. Results : A total of 4171 breaths were analyzed in 48 patients. P 0.1 was >3.5 cmH 2 O in 10%, EAdi PEAK > 15 µV in 29%, ∆Pmus EAdi > 15 cmH 2 O in 28%, and ΔP L,dyn > 15 cmH 2 O in 60% of the studied breaths. COVID-19 etiology of ARDS was the strongest independent risk factor for a higher proportion of breaths with excessive respiratory drive (RR 3.00 [2.43-3.71], p < 0.0001), inspiratory effort (RR 1.84 [1.58-2.15], p < 0.0001), and transpulmonary driving pressure (RR 1.48 [1.36-1.62], p < 0.0001). The P/F ratio at ICU admission, days of deep sedation, and dose of steroids were additional risk factors for vigorous inspiratory effort. Age and dose of steroids were risk factors for high transpulmonary driving pressure. Days of deep sedation (aHR 1.15 [1.07-1.24], p = 0.0002) and COVID-19 diagnosis (aHR 6.96 [1-48.5], p = 0.05) of ARDS were independently associated with composite outcome of transitioning from light to deep sedation (RASS from 0/-3 to -4/-5) or return to controlled ventilation within 48 h of spontaneous assisted breathing. Conclusions : This study identified that specific patient characteristics, including age, COVID-19-related ARDS, and P/F ratio, along with treatment factors such as the duration of deep sedation and the dosage of steroids, are independently associated with an increased likelihood of assisted breaths reaching potentially harmful thresholds of drive, effort, and lung-distending pressure during the initial transition to spontaneous assisted breathing. It is noteworthy that patients who were subjected to prolonged deep sedation under controlled mechanical ventilation, as well as those with COVID-19, were more susceptible to failing the transition from controlled to assisted breathing.

Natural behaviors occur in closed action-perception loops and are supported by dynamic and flexible beliefs abstracted away from our immediate sensory milieu. How this real-world flexibility is instantiated in neural circuits remains unknown. Here, we have male macaques navigate in a virtual environment by primarily leveraging sensory (optic flow) signals, or by more heavily relying on acquired internal models. We record single-unit spiking activity simultaneously from the dorsomedial superior temporal area (MSTd), parietal area 7a, and the dorso-lateral prefrontal cortex (dlPFC). Results show that while animals were able to maintain adaptive task-relevant beliefs regardless of sensory context, the fine-grain statistical dependencies between neurons, particularly in 7a and dlPFC, dynamically remapped with the changing computational demands. In dlPFC, but not 7a, destroying these statistical dependencies abolished the area's ability for cross-context decoding. Lastly, correlational analyses suggested that the more unit-to-unit couplings remapped in dlPFC, and the less they did so in MSTd, the less were population codes and behavior impacted by the loss of sensory evidence. We conclude that dynamic functional connectivity between neurons in prefrontal cortex maintain a stable population code and context-invariant beliefs during naturalistic behavior., (© 2024. The Author(s).)

Across the life sciences, an ongoing effort over the last 50 years has made data and methods more reproducible and transparent. This openness has led to transformative insights and vastly accelerated scientific progress 1,2 . For example, structural biology 3 and genomics 4,5 have undertaken systematic collection and publication of protein sequences and structures over the past half-century, and these data have led to scientific breakthroughs that were unthinkable when data collection first began (e.g. 6 ). We believe that neuroscience is poised to follow the same path, and that principles of open data and open science will transform our understanding of the nervous system in ways that are impossible to predict at the moment. To this end, new social structures along with active and open scientific communities are essential 7 to facilitate and expand the still limited adoption of open science practices in our field 8 . Unified by shared values of openness, we set out to organize a symposium for Open Data in Neuroscience (ODIN) to strengthen our community and facilitate transformative neuroscience research at large. In this report, we share what we learned during this first ODIN event. We also lay out plans for how to grow this movement, document emerging conversations, and propose a path toward a better and more transparent science of tomorrow.

Background: The COVID-19 pandemic has increased the incidence of ventilator-associated pneumonia (VAP) among critically ill patients. However, a comparison of VAP incidence in COVID-19 and non-COVID-19 cohorts, particularly in a context with a high prevalence of multidrug-resistant (MDR) organisms, is lacking., Material and Methods: We conducted a single-center, mixed prospective and retrospective cohort study comparing COVID-19 patients admitted to the intensive care unit (ICU) of the "Città della Salute e della Scienza" University Hospital in Turin, Italy, between March 2020 and December 2021 (COVID-19 group), with a historical cohort of ICU patients admitted between June 2016 and March 2018 (NON-COVID-19 group). The primary objective was to define the incidence of VAP in both cohorts. Secondary objectives were to evaluate the microbial cause, resistance patters, risk factors and impact on 28 days, ICU and in-hospital mortality, duration of ICU stay, and duration of hospitalization)., Results: We found a significantly higher incidence of VAP (51.9% - n = 125) among the 241 COVID-19 patients compared to that observed (31.2% - n = 78) among the 252 NON-COVID-19 patients. The median SOFA score was significantly lower in the COVID-19 group (9, Interquartile range, IQR: 7-11 vs. 10, IQR: 8-13, p < 0.001). The COVID-19 group had a higher prevalence of Gram-positive bacteria-related VAP (30% vs. 9%, p < 0.001), but no significant difference was observed in the prevalence of difficult-to-treat (DTR) or MDR bacteria. ICU and in-hospital mortality in the COVID-19 and NON-COVID-19 groups were 71% and 74%, vs. 33% and 43%, respectively. The presence of COVID-19 was significantly associated with an increased risk of 28-day all-cause hospital mortality (Hazard ratio, HR: 7.95, 95% Confidence Intervals, 95% CI: 3.10-20.36, p < 0.001). Tracheostomy and a shorter duration of mechanical ventilation were protective against 28-day mortality, while dialysis and a high SOFA score were associated with a higher risk of 28-day mortality., Conclusion: COVID-19 patients with VAP appear to have a significantly higher ICU and in-hospital mortality risk regardless of the presence of MDR and DTR pathogens. Tracheostomy and a shorter duration of mechanical ventilation appear to be associated with better outcomes., (© 2024. The Author(s).)

Aims: Percutaneous stellate ganglion block (PSGB) through single-bolus injection and thoracic epidural anaesthesia (TEA) have been proposed for the acute management of refractory ventricular arrhythmias (VAs). However, data on continuous PSGB (C-PSGB) are scant. The aim of this study is to report our dual-centre experience with C-PSGB and to perform a systematic review on C-PSGB and TEA., Methods and Results: Consecutive patients receiving C-PSGB at two centres were enrolled. The systematic literature review follows the latest Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria. Our case series (26 patients, 88% male, 60 ± 16 years, all with advanced structural heart disease, left ventricular ejection fraction 23 ± 11%, 32 C-PSGBs performed, with a median duration of 3 days) shows that C-PSGB is feasible and safe and leads to complete VAs suppression in 59% and to overall clinical benefit in 94% of cases. Overall, 61 patients received 68 C-PSGBs and 22 TEA, with complete VA suppression in 63% of C-PSGBs (61% of patients). Most TEA procedures (55%) were performed on intubated patients, as opposed to 28% of C-PSGBs (P = 0.02); 63% of cases were on full anticoagulation at C-PSGB, none at TEA (P < 0.001). Ropivacaine and lidocaine were the most used drugs for C-PSGB, and the available data support a starting dose of 12 and 100 mg/h, respectively. No major complications occurred, yet TEA discontinuation rate due to side effects was higher than C-PSGB (18 vs. 1%, P = 0.01)., Conclusion: Continuous PSGB seems feasible, safe, and effective for the acute management of refractory VAs. The antiarrhythmic effect may be accomplished with less concerns for concomitant anticoagulation compared with TEA and with a lower side-effect related discontinuation rate., Competing Interests: Conflict of interest: none declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the European Society of Cardiology.)

Background: Transversus abdominis plane (TAP) block has been utilized to alleviate pain following laparoscopic cholecystectomy (LC). However, the optimal timing of administration remains uncertain. This study aimed to compare the efficacy of pre-operative and postoperative TAP blocks as analgesic options after LC., Methods: A frequentist network meta-analysis of randomized controlled trials (RCTs) was conducted. We systematically searched PubMed (via the National Library of Medicine), EMBASE, Scopus, Cochrane Central Register of Controlled Trials (CENTRAL), and Web of Science up to March 2023. The study included RCTs that enrolled adult patients (≥ 18 years) who underwent LC and received either pre-operative or postoperative TAP blocks. The primary outcome assessed was 24-hour postoperative morphine consumption (mg). Additionally, pain rest scores within 3 hours, 12 hours, and 24 hours, as well as postoperative nausea and vomiting (PONV), were considered as pre-specified secondary outcomes., Results: A total of 34 trials with 2317 patients were included in the analysis. Postoperative TAP block demonstrated superiority over the pre-operative TAP block in reducing opioid consumption (MD 2.02, 95% CI 0.87 to 3.18, I2 98.6%, p < 0.001). However, with regards to postoperative pain, neither pre-operative nor postoperative TAP blocks exhibited superiority over each other at any of the assessed time points. The postoperative TAP block consistently ranked as the best intervention using SUCRA analysis. Moreover, the postoperative TAP block led to the most significant reduction in PONV., Conclusions: The findings suggest that the postoperative TAP block may be slightly more effective in reducing 24-hour postoperative opioid consumption and PONV when compared to the pre-operative TAP block., Trial Registration: PROSPERO, CRD42023396880 ., (© 2023. The Author(s).)

Post-transplant Pneumocystis jirovecii pneumonia (PcP) is an uncommon but increasingly reported disease among solid organ transplantation (SOT) recipients, associated with significant morbidity and mortality. Although the introduction of PcP prophylaxis has reduced its overall incidence, its prevalence continues to be high, especially during the second year after transplant, the period following prophylaxis discontinuation. We recently described two cases of PcP occurring more than one year after heart transplantation (HT) in patients who were no longer receiving PcP prophylaxis according to the local protocol. In both cases, the disease was diagnosed following the diagnosis of a viral illness, resulting in a significantly increased risk for PcP. While current heart transplantation guidelines recommend Pneumocystis jirovecii prophylaxis for up to 6-12 months after transplantation, after that period they only suggest an extended prophylaxis regimen in high-risk patients. Recent studies have identified several new risk factors that may be linked to an increased risk of PcP infection, including medication regimens and patient characteristics. Similarly, the indication for PcP prophylaxis in non-HIV patients has been expanded in relation to the introduction of new medications and therapeutic regimens for immune-mediated diseases. In our experience, the first patient was successfully treated with non-invasive ventilation, while the second required tracheal intubation, invasive ventilation, and extracorporeal CO2 removal due to severe respiratory failure. The aim of this double case report is to review the current timing of PcP prophylaxis after HT, the specific potential risk factors for PcP after HT, and the determinants of a prompt diagnosis and therapeutic approach in critically ill patients. We will also present a possible proposal for future investigations on indications for long-term prophylaxis.

Introduction: The management of thoracic paravertebral block (TPVB) and erector spine plane block (ESPB) in patients treated with anticoagulant or antiplatelet therapy is based on limited clinical data, mostly from single case reports. Scientific societies and organizations do not provide strong detailed indications about the limitations of these regional anesthesia techniques in patients receiving antithrombotic therapy. This review summarizes evidence regarding TPVB and ESPB in patients under antithrombotic therapy., Evidence Acqusition: A literature review from PubMed/MEDLINE, EMBASE, Cochrane, Google Scholar and Web of Science databases was conducted from 1999 to 2022 to identify articles concerning TPVB and ESPB for cardio-thoracic surgery or thoracic procedures in patients under anticoagulant or antiplatelet therapy., Evidence Synthesis: A total of 1704 articles were identified from the initial search. After removing duplicates and not-pertinent articles, 15 articles were analyzed. The results demonstrated a low risk of bleeding for TPVB and minimal or absent risk for ESPB. Ultrasound guidance was extensively used to perform ESPB, but not for TPVB., Conclusions: Although the low level of evidence available, TPVB and ESPB are reasonably safe options in patients ineligible for epidural anesthesia due to antithrombotic therapy. The few published studies suggest that ESPB offers a risk profile safer than TPVB and the use of ultrasound guidance minimizes any complication. Since the literature available does not allow us to draw definitive conclusions, future adequately-powered trials are warranted to determine the indications and the safety of TPVB and ESPB in patients receiving anticoagulant or antiplatelet therapy.

Background: Mid-regional pro-adrenomedullin (MR-proADM), an endothelium-related peptide, is a predictor of death and multi-organ failure in respiratory infections and sepsis and seems to be effective in identifying COVID-19 severe forms. The study aims to evaluate the effectiveness of MR-proADM in comparison to routine inflammatory biomarkers, lymphocyte subpopulations, and immunoglobulin (Ig) at an intensive care unit (ICU) admission and over time in predicting mortality in patients with severe COVID-19., Methods: All adult patients with COVID-19 pneumonia admitted between March 2020 and June 2021 in the ICUs of a university hospital in Italy were enrolled. MR-proADM, lymphocyte subpopulations, Ig, and routine laboratory tests were measured within 48 h and on days 3 and 7. The log-rank test was used to compare survival curves with MR-proADM cutoff value of >1.5 nmol/L. Predictive ability was compared using the area under the curve (AUC) and 95% confidence interval (CI) of different receiver-operating characteristic curves., Results: A total of 209 patients, with high clinical severity [SOFA 7, IQR 4-9; SAPS II 52, IQR 41-59; median viral pneumonia mortality score (MuLBSTA)-11, IQR 9-13] were enrolled. ICU and overall mortality were 55.5 and 60.8%, respectively. Procalcitonin, lactate dehydrogenase, D-dimer, the N-terminal prohormone of brain natriuretic peptide, myoglobin, troponin, neutrophil count, lymphocyte count, and natural killer lymphocyte count were significantly different between survivors and non-survivors, while lymphocyte subpopulations and Ig were not different in the two groups. MR-proADM was significantly higher in non-survivors (1.17 ± 0.73 vs. 2.31 ± 2.63, p < 0.0001). A value of >1.5 nmol/L was an independent risk factor for mortality at day 28 [odds ratio of 1.9 (95% CI: 1.220-3.060)] after adjusting for age, lactate at admission, SOFA, MuLBSTA, superinfections, cardiovascular disease, and respiratory disease. On days 3 and 7 of the ICU stay, the MR-proADM trend evaluated within 48 h of admission maintained a correlation with mortality ( p < 0.0001). Compared to all other biomarkers considered, the MR-proADM value within 48 h had the best accuracy in predicting mortality at day 28 [AUC = 0.695 (95% CI: 0.624-0.759)]., Conclusion: MR-proADM seems to be the best biomarker for the stratification of mortality risk in critically ill patients with COVID-19. The Ig levels and lymphocyte subpopulations (except for natural killers) seem not to be correlated with mortality. Larger, multicentric studies are needed to confirm these findings., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Montrucchio, Sales, Balzani, Lombardo, Giaccone, Cantù, D'Antonio, Rumbolo, Corcione, Simonetti, Bonetto, Zanierato, Fanelli, Filippini, Mengozzi and Brazzi.)

Opportunistic and hospital-acquired infections are common among recipients of solid organ transplantation. New pathogens are increasingly reported in the intensive care unit (ICU) population. We report a case of a patient who developed Trichoderma spp.-related pneumonia (TRP) after heart-lung transplantation. In the absence of antifungal susceptibility testing, TRP was confirmed by histological examination, and empirical therapy with voriconazole and caspofungin was swiftly initiated. Complete resolution of pneumonia was obtained after prolonged combination therapy. Given the lack of guidelines, we conducted a systematic review to elucidate the diagnostic and therapeutic strategies to apply during Trichoderma infection. After deduplication and selection of full texts, we found 42 articles eligible for the systematic review. Pneumonia seems to be the most common clinical manifestation (31.8%). The most used antifungal therapy was amphotericin B, while combination therapy was also reported (27.3%). All the patients were immunocompromised except for one case. Despite the rarity of Trichoderma spp. infection, the increase in invasive fungal infections is of growing importance in ICU, considering their impact on mortality and the emergence of antifungal resistance. In the absence of prospective and multicenter studies, a review can provide useful insight regarding the epidemiology, clinical manifestations, and management of these unexpected challenges.

Background: Several peripheral regional anaesthesia (RA) techniques are commonly used in thoracic surgery even in the absence of precise indications regarding their effectiveness on postoperative pain management., Objective: This systematic review and meta-analysis aims to describe and evaluate the relative effectiveness of different peripheral regional blocks and systemic analgesia in the context of video-assisted thoracoscopic surgery (VATS) or thoracotomy., Design: Systematic review of randomized controlled clinical trials (RCTs) with meta-analyses., Data Sources: We searched PubMed and Embase for all RCTs comparing the 24 hour morphine equivalents (MMEs) consumption following peripheral regional blocks and systemic analgesia (SA)., Eligibility Criteria: We selected only RCTs including adult participants undergoing thoracic surgery, including esophagectomy and reporting on postoperative pain outcomes including 24 hour MMEs consumption., Results: Among the 28 randomized studies including adult participants undergoing thoracic surgery and reporting on 24 hour opioid consumption, 11 reporting a comparison of individual blocks with systemic analgesia were meta-analyzed. RA was effective for almost all peripheral blocks. Regarding intercostal block, its antalgic effect was not well evaluated SMD -1.57 (CI -3.88, 0.73). RA in VATS was more effective in reducing MMEs than thoracotomy SMD -1.10 (CI -1.78, -0.41)., Conclusions: RA is a useful choice in thoracic surgery. However, it is still not possible to determine the most appropriate block in the individual surgical settings to be performed due to RCTs paucity.

Background: The objective of this systematic review and network meta-analysis was to compare the effects of single-shot ultrasound-guided regional anesthesia techniques on postoperative opioid consumption in patients undergoing open cardiac surgery., Methods: This systematic review and network meta-analysis involved cardiac surgical patients (age > 18 y) requiring median sternotomy. We searched PubMed, EMBASE, The Cochrane Central Register of Controlled Trials (CENTRAL), Scopus, and Web of Science. The effects of the single-shot ultrasound-guided regional anesthesia technique were compared with those of placebo and no intervention. We conducted a risk assessment of bias for eligible studies and assessed the overall quality of evidence for each outcome., Results: The primary outcome was opioid consumption during the first 24 h after surgery. The secondary outcomes were pain after extubation at 12 and 24 h, postoperative nausea and vomiting, extubation time, intensive care unit discharge time, and length of hospital stay. Fifteen studies with 849 patients were included. The regional anesthesia techniques included pecto-intercostal fascial block, transversus thoracis muscle plane block, erector spinae plane (ESP) block, and pectoralis nerve block I. All the regional anesthesia techniques included significantly reduced postoperative opioid consumption at 24 h, expressed as morphine milligram equivalents (MME). The ESP block was the most effective treatment (-22.93 MME [-34.29;-11.56])., Conclusions: In this meta-analysis, we concluded that fascial plane blocks were better than placebo when evaluating 24 h MMEs. However, it is still challenging to determine which is better, given the paucity of studies available in the literature. More randomized controlled trials are required to determine which regional anesthesia technique is better., Trial Registration: PROSPERO; CRD42022315497., (© 2022. The Author(s).)

Chronic pain represents one of the most serious worldwide medical problems, in terms of both social and economic costs, often causing severe and intractable physical and psychological suffering. The lack of biological markers for pain, which could assist in forming clearer diagnoses and prognoses, makes chronic pain therapy particularly arduous and sometimes harmful. Opioids are used worldwide to treat chronic pain conditions, but there is still an ambiguous and inadequate understanding about their therapeutic use, mostly because of their dual effect in acutely reducing pain and inducing, at the same time, tolerance, dependence, and a risk for opioid use disorder. In addition, clinical studies suggest that opioid treatment can be associated with a high risk of immune suppression and the development of inflammatory events, worsening the chronic pain status itself. While opioid peptides and receptors are expressed in both central and peripheral nervous cells, immune cells, and tissues, the role of opioids and their receptors, when and why they are activated endogenously and what their exact role is in chronic pain pathways is still poorly understood. Thus, in this review we aim to highlight the interplay between pain and immune system, focusing on opioids and their receptors.

We do not understand how neural nodes operate and coordinate within the recurrent action-perception loops that characterize naturalistic self-environment interactions. Here, we record single-unit spiking activity and local field potentials (LFPs) simultaneously from the dorsomedial superior temporal area (MSTd), parietal area 7a, and dorsolateral prefrontal cortex (dlPFC) as monkeys navigate in virtual reality to 'catch fireflies'. This task requires animals to actively sample from a closed-loop virtual environment while concurrently computing continuous latent variables: (i) the distance and angle travelled (i.e., path integration) and (ii) the distance and angle to a memorized firefly location (i.e., a hidden spatial goal). We observed a patterned mixed selectivity, with the prefrontal cortex most prominently coding for latent variables, parietal cortex coding for sensorimotor variables, and MSTd most often coding for eye movements. However, even the traditionally considered sensory area (i.e., MSTd) tracked latent variables, demonstrating path integration and vector coding of hidden spatial goals. Further, global encoding profiles and unit-to-unit coupling (i.e., noise correlations) suggested a functional subnetwork composed by MSTd and dlPFC, and not between these and 7a, as anatomy would suggest. We show that the greater the unit-to-unit coupling between MSTd and dlPFC, the more the animals' gaze position was indicative of the ongoing location of the hidden spatial goal. We suggest this MSTd-dlPFC subnetwork reflects the monkeys' natural and adaptive task strategy wherein they continuously gaze toward the location of the (invisible) target. Together, these results highlight the distributed nature of neural coding during closed action-perception loops and suggest that fine-grain functional subnetworks may be dynamically established to subserve (embodied) task strategies., Competing Interests: JN, EB, EA, KL, SB, PA, CS, DA No competing interests declared, (© 2022, Noel et al.)

Extracellular vesicles form a complex intercellular communication network, shuttling a variety of proteins, lipids, and nucleic acids, including regulatory RNAs, such as microRNAs. Transfer of these molecules to target cells allows for the modulation of sets of genes and mediates multiple paracrine and endocrine actions. EVs exert broad pro-inflammatory, pro-oxidant, and pro-apoptotic effects in sepsis, mediating microvascular dysfunction and multiple organ damage. This deleterious role is well documented in sepsis-associated acute kidney injury and acute respiratory distress syndrome. On the other hand, protective effects of stem cell-derived extracellular vesicles have been reported in experimental models of sepsis. Stem cell-derived extracellular vesicles recapitulate beneficial cytoprotective, regenerative, and immunomodulatory properties of parental cells and have shown therapeutic effects in experimental models of sepsis with kidney and lung involvement. Extracellular vesicles are also likely to play a role in deranged kidney-lung crosstalk, a hallmark of sepsis, and may be key to a better understanding of shared mechanisms underlying multiple organ dysfunction. In this review, we analyze the state-of-the-art knowledge on the dual role of EVs in sepsis-associated kidney/lung injury and repair. PubMed library was searched from inception to July 2022, using a combination of medical subject headings (MeSH) and keywords related to EVs, sepsis, acute kidney injury (AKI), acute lung injury (ALI), and acute respiratory distress syndrome (ARDS). Key findings are summarized into two sections on detrimental and beneficial mechanisms of actions of EVs in kidney and lung injury, respectively. The role of EVs in kidney-lung crosstalk is then outlined. Efforts to expand knowledge on EVs may pave the way to employ them as prognostic biomarkers or therapeutic targets to prevent or reduce organ damage in sepsis.

Mid-regional proadrenomedullin (MR-proADM) is a new biomarker of endothelial damage and its clinical use is increasing in sepsis and respiratory infections and recently in SARS-CoV-2 infection. We conducted a systematic review and meta-analysis to clarify the use of MR-proADM in severe COVID-19 disease. After Pubmed, Embase, and Scopus search, registries, and gray literature, deduplication, and selection of full-texts, we found 21 studies addressing the use of proadrenomedullin in COVID-19. All the studies were published between 2020 and 2022 from European countries. A total of 9 studies enrolled Intensive Care Unit (ICU) patients, 4 were conducted in the Emergency Department, and 8 had mixed populations. Regarding the ICU critically ill patients, 4 studies evaluating survival as primary outcome were available, of which 3 reported completed data. Combining the selected studies in a meta-analysis, a total of 252 patients were enrolled; of these, 182 were survivors and 70 were non-survivors. At the admission to the ICU, the average MR-proADM level in survivor patients was 1.01 versus 1.64 in non-survivor patients. The mean differences of MR-proADM values in survivors vs. non-survivors was −0.96 (95% CI from −1.26, to −0.65). Test for overall effect: Z = 6.19 (p < 0.00001) and heterogeneity was I2 = 0%. MR-proADM ICU admission levels seem to predict mortality among the critical COVID-19 population. Further, prospective studies, focused on critically ill patients and investigating a reliable MR-proADM cut-off, are needed to provide adequate guidance to its use in severe COVID-19.

Competing Interests: Declaration of competing interest None.

Objective: The choice of analgesia after cancer surgery may play a role in the onset of cancer recurrence. Particularly opioids seem to promote cancer cell proliferation and migration. Based on this consideration, we assessed the impact of perioperative analgesia choice on cancer recurrence after curative surgery for stage I non-small cell lung cancer (NSCLC)., Methods: We retrospectively reviewed the records of all patients undergoing lung resection for stage I NSCLC between January 2005 and December 2012. Patients received analgesia either by peridural (PERI group) or intravenous analgesia with opioids (EV group). Follow-up was concluded in August 2019. Five-year cumulative incidence of recurrence and overall survival were evaluated and adjusted using a propensity score matching method., Results: A total of 382 patients were evaluated, 312 belonging to the PERI group (81.7%) and 70 to the EV group (18.3%). There was no statistically significant difference between the two groups in 5-year cumulative incidence of recurrence ( p = 0.679) or overall survival rates ( p = 0.767). These results were confirmed after adjustment for propensity score matching for cumulative incidence of recurrence ( p = 0.925) or overall survival ( p = 0.663)., Conclusions: We found no evidence suggesting an association between perioperative analgesia choice and recurrence-free survival or overall survival in patients undergoing surgical resection of stage I NSCLC.

Introduction: Postoperative delirium is a frequent occurrence in the elderly surgical population. As a comprehensive list of predictive factors remains unknown, an opioid-sparing approach incorporating regional anesthesia techniques has been suggested to decrease its incidence. Due to the lack of conclusive evidence on the topic, we conducted a systematic review and meta-analysis to investigate the potential impact of regional anesthesia and analgesia on postoperative delirium., Evidence Acquisition: PubMed, Embase, and the Cochrane central register of Controlled trials (CENTRAL) databases were searched for randomized trials comparing regional anesthesia or analgesia to systemic treatments in patients having any type of surgery. This systematic review and meta-analysis followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. We pooled the results separately for each of these two applications by random effects modelling. Grading of Recommendations Assessment, Development and Evaluation (GRADE) system was used to evaluate the certainty of evidence and strength of conclusions., Evidence Synthesis: Eighteen trials (3361 subjects) were included. Using regional techniques for surgical anesthesia failed to reduce the risk of postoperative delirium, with a relative risk (RR) of 1.21 (95% CI: 0.79 to 1.85); P=0.3800. In contrast, regional analgesia reduced the relative risk of perioperative delirium by a RR of 0.53 (95% CI: 0.42 to 0.68; P<0.0001), when compared to systemic analgesia. Post-hoc subgroup analysis for hip fracture surgery yielded similar findings., Conclusions: These results show that postoperative delirium may be decreased when regional techniques are used in the postoperative period as an analgesic strategy. Intraoperative regional anesthesia alone may not decrease postoperative delirium since there are other factors that may influence this outcome.

Background: Non-Intubated Thoracic Surgery (NITS) is becoming increasingly adopted all over the world. Although it is mainly used for pleural operations,, non-intubated parenchymal lung surgery has been less frequently reported. Recently, NITS utilization seems to be increased also in Italy, albeit there are no multi-center studies confirming this finding. The objective of this survey is to assess quantitatively and qualitatively the performance of NITS in Italy., Methods: In 2018 a web-based national survey on Non-Intubated management including both thoracic surgeons and anesthesiologists was carried out. Reference centers have been asked to answer 32 questions. Replies were collected from June 26 to November 31, 2019., Results: We raised feedbacks from 95% (55/58) of Italian centers. Seventy-eight percent of the respondents perform NITS but only 38% of them used this strategy for parenchymal surgery. These procedures are more frequently carried out in patients with severe comorbidities and/or with poor lung function. Several issues as obesity, previous non-invasive ventilation and/or oxygen therapy are considered contraindications to NITS. The regional anesthesia technique most used to provide intra- and postoperative analgesia was the paravertebral block (37%). Conversion to general anesthesia is not anecdotal (31% of answerers). More than half of the centers believed that NITS may reduce postoperative intensive care unit admissions. Approximately a quarter of the centers are conducting trials on NITS and, three quarters of the respondent suppose that the number of these procedures will increase in the future., Conclusions: There is a growing interest in Italy for NITS and this survey provides a clear view of the national management framework of these procedures., (© 2021. The Author(s).)

Background: Erector spinae plane block (ESPB) has been described as an effective regional anesthesia technique in thoracic parenchymal surgery. Evidence highlighting the use of this technique continuously via perifascial catheter is lacking., Case Presentation: In this case report, we present the case of a patient scheduled for robotic-assisted thoracic surgery for a pulmonary neoformation in the lower right lobe. We decided to manage this patient with a multimodal approach in order to have an opioid-sparing effect. This is the first reported case of continuous ESPB in robot-assisted thoracic surgery., Conclusions: Anesthesiologists should consider this method in surgery that is slower than conventional surgery, such as robot-assisted, and less invasive than thoracotomy, which does not warrant the use of neuroaxial or paravertebral techniques that increase the risk of iatrogenic complications.

This study aimed to investigate DNA methylation levels in patients undergoing major breast surgery under opioid-based general anesthesia. Blood samples were collected from eleven enrolled patients, before, during and after anesthesia. PBMC were isolated and global DNA methylation levels as well as DNA methyltransferase (DNMT) and cytokine gene expression were assessed. DNA methylation levels significantly declined by 26%, reversing the direction after the end of surgery. Likewise, DNMT1a mRNA expression was significantly reduced at all time points, with lowest level of -68%. DNMT3a and DNMT3b decreased by 65 and 71%, respectively. Inflammatory cytokines IL6 and TNFα mRNA levels showed a trend for increased expression at early time-points to end with a significant decrease at 48 h after surgery. This exploratory study revealed for the first time intraoperative global DNA hypomethylation in patients undergoing major breast surgery under general anesthesia with fentanyl. The alterations of global DNA methylation here observed seem to be in agreement with DNMTs gene expression changes. Furthermore, based on perioperative variations of IL6 and TNFα gene expression, we hypothesize that DNA hypomethylation may occur as a response to surgical stress rather than to opiate exposure ., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Caputi, Carboni, Rullo, Alessandrini, Balzani, Melotti, Romualdi, Candeletti and Fanelli.)

Understanding neuropathic pain presents several challenges, given the various mechanisms underlying its pathophysiological classification and the lack of suitable tools to assess its diagnosis. Furthermore, the response of this pathology to available drugs is still often unpredictable, leaving the treatment of neuropathic pain still questionable. In addition, the rise of personalized treatments further extends the ramified classification of neuropathic pain. While a few authors have focused on neuropathic pain clustering, by analyzing, for example, the presence of specific TRP channels, others have evaluated the presence of alterations in microRNAs to find tailored therapies. Thus, this review aims to synthesize the available evidence on the topic from a clinical perspective and provide a list of current demonstrations on the treatment of this disease.

Introduction: The erector spinae plane block (ESPB) is a newer fascial plane block which has been broadly applied for postoperative analgesia after various surgeries, but the effectiveness in these populations is not well established., Evidence Acquisition: A systematic database search was conducted in PubMed, PMC, Embase, and Scopus for randomized controlled trials (RCTs) comparing ESPB with control, placebo, or other blocks. The primary outcome was intravenous opioid consumption in milligram morphine equivalents 24 h after surgery. Standardized mean differences (SMDs) with 95% confidence intervals (CI) were calculated using a random-effects model., Evidence Synthesis: A total of 29 RCTs were included. An analysis was conducted by subgroups differentiated by surgery type, 'no block' vs. ESPB, and other blocks vs. ESPB. ESPB was effective in reducing opioid consumption against no block for breast surgery (SMD -1.13; 95% CI), thoracic surgery (SMD -3.00; 95% CI), and vertebral surgery (SMD -1.78; 95% CI). ESPB was effective against alternative blocks for breast surgery (vs. paravertebral, SMD -1.07; 95% CI) and abdominal surgery (SMD -1.77; 95% CI). ESPB showed moderate effect in thoracic surgery against paravertebral (SMD 0.58; 95% CI) and against no block in abdominal surgery (SMD 0.80; 95% CI). In only one case did ESPB perform worse than another block: vs. PECS block for breast surgery (SMD 1.66; 95% CI)., Conclusions: ESPB may be a useful addition to the multimodal analgesic regimen for a variety of surgeries especially when the alternative is no block. Unanswered questions include determining of the mechanism of action, refining of the EPSB technique, and establishing recommended local anesthetic dose and volume.

The worlds of chronic pain and addiction continue to intersect too often in many ways. Chronic pain significantly impairs and disrupts the quality of life of millions of people worldwide. Opioids remain the most prescribed pharmacotherapy offered to patients to alleviate chronic pain. The extensive and often unnecessary prescription of opioids has created a surge in the prevalence of opioid use disorders and opioid overdose-related deaths. In this brief review, we aim to provide a bench-to-bedside overview of promising biomarkers, therapeutic targets, and challenges related to treating patients with chronic pain. We hope this review will inspire new opportunities and insights into the development of novel, nonaddictive treatments for chronic pain that will be available to patients in the near future., Competing Interests: Conflict of interest statement All authors have participated in conception and design, or analysis and interpretation of the data; drafting the article or revising it critically for important intellectual content; and approval of the final version. This manuscript has not been submitted to, nor is under review at, another journal or other publishing venue. The authors have no affiliation with any organization with a direct or indirect financial interest in the subject matter discussed in the manuscript., (Copyright © 2021. Published by Elsevier Ltd.)