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Since the beginning of the SARS-CoV-2 pandemic, COVID-19 appeared as a unique disease with unconventional tissue and systemic immune features. Here we show a COVID-19 immune signature associated with severity by integrating single-cell RNA-seq analysis from blood samples and broncho-alveolar lavage fluids with clinical, immunological and functional ex vivo data. This signature is characterized by lung accumulation of naïve lymphoid cells associated with a systemic expansion and activation of myeloid cells. Myeloid-driven immune suppression is a hallmark of COVID-19 evolution, highlighting arginase-1 expression with immune regulatory features of monocytes. Monocyte-dependent and neutrophil-dependent immune suppression loss is associated with fatal clinical outcome in severe patients. Additionally, our analysis shows a lung CXCR6 + effector memory T cell subset is associated with better prognosis in patients with severe COVID-19. In summary, COVID-19-induced myeloid dysregulation and lymphoid impairment establish a condition of ‘immune silence’ in patients with critical COVID-19. Integrated studies of matched tissue sites and cell types in COVID-19 patients are important to define the immune mechanisms of pathology. Here, the authors describe an immune signature in fatal COVID-19 patients harmonizing single-cell RNA sequencing of blood and matched BAL cells with deep clinical, immunological and functional data.

BackgroundNeoadjuvant therapy (NAT) is used for borderline-resectable or locally advanced pancreatic cancer (PDAC) and exhibits promising results in terms of pathological outcomes. However, little is known about its effect on surgical complications.MethodsWe analyzed 445 pancreatic resections for PDAC from 2014 to 2016 at The Pancreas Institute, Verona University Hospital. The Modified Accordion Severity Grading System and average complication burden (ACB) were used to compare patients treated with NAT with patients who underwent upfront surgery (UFS).ResultsOf 305 pancreaticoduodenectomies (PD), patients treated with NAT (n = 99) had less pancreatic fistula (POPF, 9.1% vs. 15.6%, p = 0.05) without grade C cases, but grade B ACB was increased (0.28 for NAT vs. 0.24 for UFS, p = 0.05). The postpancreatectomy hemorrhage (PPH) rate was lower in the NAT group (9.1% vs. 14.6%, p = 0.02), but ACB grades B (0.37 for NAT vs. 0.26 for UFS, p = 0.03) and C (0.43 for NAT vs. 0.29 for UFS, p = 0.05) were increased. Delayed gastric emptying (DGE) was increased in NAT cases (15.2% vs. 8.3%, p = 0.04), with higher grade C ACB (0.43 for NAT vs. 0.29 for UFS, p = 0.03). Of 94 distal pancreatectomies (DP), NAT patients (n = 26) developed more grade C POPF (11.5% vs. 1.5%, p = 0.04) and DGE (11.5% vs. 2.9%, p = 0.01) without differences in ACB.ConclusionsPatients undergoing PD for PDAC after NAT exhibited reduced incidence of POPF and PPH but increased incidence of DGE compared with patients treated with UFS. Among patients developing postoperative complications after PD, those receiving NAT were associated with increased clinical burden.

The Economy of action hypothesis postulates that bodily states rescale the perception of the individual’s environment’s spatial layout. The estimation of distances and slopes in navigation space (i.e. the space reachable by locomotion) is influenced by sensations relating to body condition and the metabolic cost of the actions. The results of the studies investigating the impact of pain on distance estimation remain inconclusive. 28 women suffering from chronic pain and fibromyalgia (FM), and 24 healthy women (HC) were assessed for musculoskeletal, neuropathic, and visceral pain by means of the Widespread Pain Index, the Symptom Severity Scale and an ad-hoc devised questionnaire for pain (the Verona Pain Questionnaire). In a VR-mediated task, they observed a 3D scenario and estimated the distance of a flag positioned at different distances (1, 2, 3, 4 or 5 m) on virtual ramps with either a 4% or 24% inclination in two different conditions: sitting and standing. Overestimation of distances in the steeper ramp condition was expected, if participants executed the task by internally simulating the movement. The results showed a dissociation between the effects of musculoskeletal and visceral-neuropathic pain on distance estimations. While, according to the Economy of Action hypothesis, the HCs estimated the distances as being farther away when the ramp was more inclined (i.e. with a 24% inclination), there was no effect related to the different ramp inclinations in the FM group. Furthermore, visceral and neuropathic pain were found to affect the performance of the FM group. These results suggest that chronic and widespread pain conditions, that typically characterize fibromyalgia, can affect space representations. In line with the Economy of Action hypothesis, bodily based estimation of distances is compromised in these patients.

Background. Fibromyalgia Syndrome (FMS) is characterized by chronic widespread pain, sleep disturbances, fatigue and cognitive impairment. Methods. In this retrospective study, we analyzed data collected between 2017 and 2022 regarding Acetyl-L-Carnitine (ALC) as an add-on treatment in 183 adult patients with FMS according to the 2016 ACR (American College of Rheumatology) criteria and patients’ pain lasting for over three months. Patients with prior exposure to ALC or without informed consent were excluded. Results. Regarding efficacy, in the 137 analyzed patients, the change from baseline to the end of observation in Visual Analogue Scale score (VAS) was statistically significant, ranging from 75.9 ± 1.56 to 51.9 ± 1.99 (p < 0.001). Patients without FMS concomitant drug treatments achieved better VAS reduction than patients who were not drug-free at baseline. Regarding quality of life, a significant improvement in the Revised Fibromyalgia Impact Questionnaire (FIQ-R) score was evidenced, ranging from 75.1 ± 1.13 to 53.5 ± 1.34 (p < 0.001). The Short Form 12 Health Survey (SF12) scores showed a statistically significant improvement in both physical and mental components. Finally, the Pittsburgh Sleep Quality Index (PSQI) did not show a statistically significant difference from baseline. In the whole population, 23 patients (16.7%) reported Adverse Events (AEs), predominantly insomnia, shivering, headaches, and nausea. Only six patients reporting AEs discontinued the ALC treatment. Conclusions. This retrospective study evidenced the efficacy and safety of ALC in FMS patients. This may represent a useful approach, particularly for long-term treatments. Methodologically stronger studies will be necessary to validate our observations.

Fibromyalgia is characterised by chronic, continuous, widespread pain, often associated with a sense of fatigue, non-restorative sleep and physical exhaustion. Due to the nature of this condition and the absence of other neurological issues potentially able to induce disorders in body representations per se, it represents a perfect model since it provides an opportunity to study the relationship between pain and the bodily self. Corporeal illusions were investigated in 60 participants with or without a diagnosis of fibromyalgia by means of an ad-hoc devised interview. In addition, motor imagery was investigated and illusions relating to body part movements and changes in body size, feelings of alienness and sensations of body parts not belonging to one’s own body (disownership and somatoparaphrenic-like sensations) were found. Crucially, these symptoms do not correlate with any of the clinical measures of pain or functional deficits. The results showed that motor imagery was also impaired, and the severity of the deficits found correlated with the functional impairment of the participant. This indicates that disorders in body representations and motor imagery are part of the clinical expression of fibromyalgia. However, while motor imagery seems to be linked to reduced autonomy and functional deficits, bodily illusions are independent and potentially represent a concurrent symptom.

BackgroundTransversus abdominis plane (TAP) block is considered a reliable locoregional technique for pain control after laparoscopic colorectal surgery. However, no clear benefit of TAP block over wound infiltration has been demonstrated by the current literature. This multicenter randomized clinical trial tested the non-inferiority of wound infiltration (WI) compared to WI plus laparoscopic-assisted TAP block (L-TAP).MethodsAll patients with colorectal cancer and diverticular disease scheduled for laparoscopic resection at the Division of General and Hepatobiliary Surgery, University of Verona Hospital Trust, Verona, Italy and at the Colorectal Cancer Center, Kyungpook National University Medical Center, Kyungpook National University, Daegu, Korea, between April 2018 and March 2019 were considered for the trial. Patients were randomly allocated to either the WI group or the WI plus L-TAP group in a 1:1 allocation ratio. In total, 108 patients entered the study and 102 patients were analyzed; 50 patients received WI plus L-TAP and 52 patients received WI. The primary end point was the efficacy in pain control at 6 h measured according to Numeric Rating Scale (NRS). Secondary aims evaluated pain control at 12, 24, 48 and 72 h and other short-term results related to pain management.ResultsEstimation of pain intensity at 6 h was comparable between the two groups (p = 0.16) with a mean (95% CI) difference in pain scores of 0.94 (− 0.13 to 2.02). No differences in pain scores were observed at other interval times or considering analgesic consumption, return of bowel function, postoperative complications and length of hospital stay.ConclusionThis study suggests that adding TAP block to WI does not affect pain control, amount of analgesics and other short-term outcomes.Trial registrationNCT03376048 (https://www.clinicaltrials.gov).

Inflammatory responses rapidly detect pathogen invasion and mount a regulated reaction. However, dysregulated anti-pathogen immune responses can provoke life-threatening inflammatory pathologies collectively known as cytokine release syndrome (CRS), exemplified by key clinical phenotypes unearthed during the SARS-CoV-2 pandemic. The underlying pathophysiology of CRS remains elusive. We found that FLIP, a protein that controls caspase-8 death pathways, was highly expressed in myeloid cells of COVID-19 lungs. FLIP controlled CRS by fueling a STAT3-dependent inflammatory program. Indeed, constitutive expression of a viral FLIP homolog in myeloid cells triggered a STAT3-linked, progressive, and fatal inflammatory syndrome in mice, characterized by elevated cytokine output, lymphopenia, lung injury, and multiple organ dysfunctions that mimicked human CRS. As STAT3-targeting approaches relieved inflammation, immune disorders, and organ failures in these mice, targeted intervention towards this pathway could suppress the lethal CRS inflammatory state.

Objectives: Fibromyalgia syndrome (FMS) is a chronic clinical condition characterized by pain, fatigue, altered sleep, and cognitive disturbances. The purpose of this study was to compare two alternative treatments (nutraceutical and acupuncture) in FMS patients through a randomized clinical trial. Research Methods: A total of 60 FMS female patients were randomized for treatment with a nutritional combination containing coenzyme Q10, vitamin D, alpha-lipoic acid, magnesium, and tryptophan (Migratens® Group) or acupuncture treatment (Acupuncture Group) performed according the principles of traditional Chinese medicine (TCM), both for 3 months. Changes in pain and in quality of life (QoL) measured with a Fibromyalgia Impact Questionnaire Score-Revised (FIQ-R) and the Fibromyalgia Severity Scale (FSS) were performed at 1, 3, and 6 months after the start of treatments. Results: A total of 55 patient completed the study (21 in the Migratens® Group and 34 in the Acupuncture Group). Migratens® treatment shows a statistically significant reduction of pain 1 month after the start of therapy (T1, p = 0.025), strengthened after 3 months with maintenance of treatment (p = 0.012). The efficacy in reducing pain was apparent in the Acupuncture Group at all post-treatment determinations and at follow-up (T1 and T2 p = <0.001). Regarding QoL, improvement in FIQ-R and FSS values was revealed in both groups. Conclusion: The nutraceutical approach with Migratens® seems to be an effective option to for patients with FMS. Our experience confirmed also the validity of acupuncture in these patients. Considering the complexity of the management of FMS patients, our results suggest a cyclical and sequential, or even concurrent treatment with different approaches, to improve the efficacy and the compliance of patients to long-term treatment

Background Optimization of perioperative fluid management is a controversial issue. Weight-adjusted, fixed fluid strategies do not take into account patient hemodynamic status, so that individualized strategies guided by relevant variables may be preferable. We studied this issue in patients undergoing pancreatic surgery within our institution. Methods All patients who underwent a laparotomy for pancreatic cancer during a 5-month period at our hospital (AOUI of Verona, Italy) were eligible to be included in this prospective, observational study. According to the responsible anesthesiologist’s free choice, patients received, during surgery, either liberal (12 ml/kg/h) or restricted (4 ml/kg/h) fixed-volume weight-guided replacement fluids or goal-directed (GD) fluid replacement using stroke volume variation (SVV) determined by the FloTrac Vigileo device. Results Eighty-six patients were included: 29 in the liberal group, 23 in the restricted group, and 34 in the GD group. The mean duration of surgery was 6 [4–7] h. Patients in the liberal group received more perioperative fluid than those in the GD and restricted groups. Nearly one third of all patients had a major complication, including delayed enteral feeding, and presented a longer duration of hospital stay. Despite the biases related to our limited cohort, there were significantly fewer postoperative complications (such as postoperative fistula, abdominal collection, and hemorrhage) in the restricted and GD groups of patients than in the liberal one. Conclusion In patients undergoing pancreatic surgery, a restricted or individually guided GD strategy for management of perioperative fluids can result in fewer complications than a liberal fluid strategy. Larger and randomized investigations are warranted to confirm these data on this domain.

Background and Objectives: Fibromyalgia syndrome (FMS) is a multifaceted disease with a strong preference for the female sex. It is characterised by chronic widespread pain, sleep–wake disorders, fatigue, cognitive disturbances, and several other somatic symptoms. Materials and Methods: In this prospective observational study, we analysed data regarding 302 patients who were referred to our pain centre for a first clinical assessment evaluation and were then inspected for the physician-based 2016 revision of the ACR diagnostic criteria for FMS, regardless of the final diagnosis previously made by the pain therapist. Results: Among the 280 patients who adhered to the 2016 ACR questionnaire, 20.3% displayed positive criteria for FMS diagnosis. The level of agreement between the FMS discharge diagnosis made by the pain clinician and the ACR 2016 criteria-positivity was moderate (kappa = 0.599, with moderate agreement set at a kappa value of 0.6). Only four patients (1.7%) diagnosed as suffering from FMS at discharge did not satisfy the minimal 2016 ACR diagnostic criteria. Conclusions: This prospective observational study confirmed the diagnostic challenge with FMS, as demonstrated by the moderate grade of agreement between the FMS diagnosis at discharge and the positivity for 2016 ACR criteria. In our opinion, the use of widely accepted diagnostic guidelines should be implemented in clinical scenarios and should become a common language among clinicians who evaluate and treat patients reporting widespread pain and FMS-suggestive symptoms. Further methodologically stronger studies will be necessary to validate our observation.