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Abstract Introduction Dorsal root ganglion pulsed radiofrequency (DRG-PRF) is frequently used for the treatment of chronic lumbar radicular pain with good outcomes in terms of pain management. Transforaminal epidural steroid injection (TFESI) is often administered immediately after DRG-PRF to increase the anti-inflammatory effects, but support for the synergic mechanism is lacking in the literature. The aim of this study was to investigate the potential role of TFESI immediately after DRG-PRF and its possible role on pain intensity and patient disability. Methods A database of patients who underwent DRG-PRF with or without TFESI immediately after DRG-PRF was retrospectively analysed; propensity score matching was applied to the analysis to reduce possible bias. Pain intensity (numerical rating scale [NRS]) and Oswestry disability index (ODI) were recorded pre-operatively and at the 1- and 3-month follow-up in the two groups of patients. Results A total of 252 patients were included in this retrospective analysis, 126 patients in the DRG-PRF + TFESI group and 126 patients in the DRG-PRF group after propensity score matching. Both groups displayed a significant reduction in pain intensity (NRS score reduction; p

Abstract Introduction The management of pain following a burn is extremely complex because of the multifactorial nature of burn pain (nociceptive and neuropathic). In the pre-hospital setting and emergency department (ED), the main goal of acute pain management is to reduce the patient’s pain, allowing them to maintain function and to prevent the chronification of pain. Opioids are used as first-line treatment in management of burn pain. The aim of our study was to evaluate the efficacy and adverse effects of intravenous (IV) morphine for burn pain management in the ED and to evaluate pain management in the pre-hospital setting. Methods In this single-center observational study, patients presenting with second- and third-degree burns were enrolled in our ED. Numerical Rating Scale (NRS) and Burn Specific Pain Anxiety Scale (BSPAS) were performed at ED admission and after 1 h. Pain medications administered before arrival in the ED were reported by the rescue team. All patients received IV acetaminophen every 8 h and IV morphine according NRS. Results Thirty patients were included in this study. At the time of arrival to the ED, > 90% of the patients reported severe pain; 95.8% of them received IV morphine to achieve pain relief. After 1 h, > 65% of patients had NRS < 3. The total amount of IV morphine was 18.12 ± 4.26 mg in the first hour. No adverse events were recorded. The BSPAS on admission to the ED was 34.8 ± 5.6, indicating severe anxiety. After 1 h, BSPAS was 12.8 ± 4.8, indicating mild anxiety. Conclusion IV morphine used for burn pain management in the emergency setting significantly improves patient outcomes in terms of pain. IV morphine also reduced anxiety scores at 1 h.

Bickerstaff brainstem encephalitis (BBE) is a rare autoimmune disease characterized by the subacute onset of bilateral external ophthalmoplegia, ataxia, and decreased level of consciousness. BBE is part of a group of rare autoimmune diseases in children that can affect the nervous system at any level. The onset of neurological deficits is often sudden and nonspecific. The diagnosis is based on clinical findings and abnormal findings on cerebrospinal fluid (CSF), electroencephalography (EEG), electromyography (EMG), and magnetic resonance imaging (MRI). BBE is associated with the presence of the antiganglioside antibody, anti-GQ1b and anti-GM1. Intravenous immunoglobulin (IVIg) and plasma exchange are often used as treatments for these patients. We conducted a review on clinical presentation, diagnosis, treatment and outcome of reported cases of BBE. 74 cases are reported in the literature from the first cases described in 1951 to today. The prevalence is unknown while the incidence is higher in males. In 50% of cases, BBE occurs following respiratory or gastrointestinal tract infections. The most frequent initial symptoms were consciousness disturbance, headache, vomiting, diplopia, gait disturbance, dysarthria and fever. During illness course, almost all the patients developed consciousness disturbance, external ophthalmoplegia, and ataxia. Lumbar puncture showed pleocytosis or cytoalbuminological dissociation. Abnormal EEG and MRI studies revealed abnormalities in most cases. Anti-GQ1b antibodies were detected in more than half of the patients; anti-GM1 antibodies were detected in almost 40% of patients. Treatment guidelines are missing. In our analysis, steroids and IVIg were administered alone or in combination; as last option, plasmapheresis was used. BBE has a good prognosis and recovery in childhood is faster than in adulthood; 70% of patients reported no sequelae in our analysis. Future studies need to investigate pathogenesis and possible triggers, and therapeutic possibilities.

Alcohol withdrawal syndrome (AWS) is defined as the cessation or reduction in heavy and prolonged alcohol use within several hours to a few days of cessation. The recommended first-line therapy for AWS ranging from mild to severe or complicated remains benzodiazepines; in cases where benzodiazepines are not adequate in controlling persistent autonomic hyperactivity or anxiety, dexmedetomidine could be utilized. The possible advantage of dexmedetomidine compared to benzodiazepines is that it does not cause respiratory depression, thus reducing the risk of intubation and hospitalization in the ICUs, with the potential reduction in healthcare costs. The purpose of this systematic review and meta-analysis (PROSPERO CRD42018084370) is to evaluate the effectiveness and safety of dexmedetomidine as adjunctive therapy to the standard of care for the treatment of AWS. We retrieved literature from PubMed, EMBASE, and CENTRAL until 10 January 2024. Eligible studies were both randomized trials and nonrandomised studies with a control group, published in the English language and peer-reviewed journals. The primary outcome was tracheal intubation; secondary outcomes were (i) bradycardia and (ii) hypotension. A total of 3585 papers were retrieved: 2635 from EMBASE, 930 from Medline, and 20 from CENTRAL. After eliminating duplicates, 2960 papers were screened by title and abstract; 75 out of the 2960 papers were read in full text. The qualitative synthesis included nine of all manuscripts read in full text. The quantitative synthesis included eight studies for the primary outcome (tracheal intubation), seven for the secondary outcome bradycardia, and six for the secondary outcome hypotension. The meta-analysis showed that Dexmedetomidine, as adjunctive therapy, is not more effective than standard therapy in reducing the risk of tracheal intubation in AWS [RR: 0.57, 95% CI: 0.25–1.3, p = 0.15]. It also appears to be less safe than sedative therapy as it significantly increases the risk of bradycardia [RR: 2.68, 95% CI: 1.79–4.16, p = 0.0016]. Hypotension was not significantly different in patients who received dexmedetomidine [RR: 1.5, 95% CI: 0.69–3.49, p = 0.21].

Amyotrophic lateral sclerosis (ALS) is the most frequent neurodegenerative disease of the motor system that affects upper and lower motor neurons, leading to progressive muscle weakness, spasticity, atrophy, and respiratory failure, with a life expectancy of 2–5 years after symptom onset. In addition to motor symptoms, patients with ALS have a multitude of nonmotor symptoms; in fact, it is currently considered a multisystem disease. The purpose of our narrative review is to evaluate the different types of pain, the correlation between pain and the disease’s stages, the pain assessment tools in ALS patients, and the available therapies focusing above all on the benefits of cannabis use. Pain is an underestimated and undertreated symptom that, in the last few years, has received more attention from research because it has a strong impact on the quality of life of these patients. The prevalence of pain is between 15% and 85% of ALS patients, and the studies on the type and intensity of pain are controversial. The absence of pain assessment tools validated in the ALS population and the dissimilar study designs influence the knowledge of ALS pain and consequently the pharmacological therapy. Several studies suggest that ALS is associated with changes in the endocannabinoid system, and the use of cannabis could slow the disease progression due to its neuroprotective action and act on pain, spasticity, cramps, sialorrhea, and depression. Our research has shown high patients’ satisfaction with the use of cannabis for the treatment of spasticity and related pain. However, especially due to the ethical problems and the lack of interest of pharmaceutical companies, further studies are needed to ensure the most appropriate care for ALS patients.

(1) Background: Infections caused by multidrug-resistant (MDR) bacteria represent one of the major global public health problems of the 21st century. Beta-lactam antibacterial agents are commonly used to treat infections due to Gram-negative pathogens. New β-lactam/β-lactamase inhibitor combinations are urgently needed. Combining relebactam (REL) with imipenem (IMI) and cilastatin (CS) can restore its activity against many imipenem-nonsusceptible Gram-negative pathogens. (2) Methods: we performed a systematic review of the studies reporting on the use of in vivo REAL/IPM/CS. (3) Results: A total of eight studies were included in this review. The primary diagnosis was as follows: complicated urinary tract infection (n = 234), complicated intra-abdominal infections (n = 220), hospital-acquired pneumonia (n = 276), and ventilator-associated pneumonia (n = 157). Patients with normal renal function received REL/IPM/CS (250 mg/500 mg/500 mg). The most frequently reported AEs occurring in patients treated with imipenem/cilastatin plus REL/IPM/CS were nausea (11.5%), diarrhea (9.8%), vomiting (9.8%), and infusion site disorders (4.0%). Treatment outcomes in these high-risk patients receiving REL/IPM/CS were generally favorable. A total of 70.6% of patients treated with REL/IPM/CS reported a favorable clinical response at follow-up. (4) Conclusions: this review indicates that REL/IPM/CS is active against important MDR Gram-negative organisms.

Abstract Background We carry out a retrospective observational analysis of clinical records of patients with major placenta praevia who underwent cesarean section surgery over a period of 20 months in our hospital. Out of a total of 40 patients, 20 were subjected to Goal-Directed Therapy (GDT) implemented with non-invasive hemodynamic monitoring using the EV1000 ClearSight system (Group I) and 20 to standard hemodynamic monitoring (Group II). Given the risk of conspicuous blood loss, this study evaluate the impact on maternal and fetal health of GDT relative to standard hemodynamic monitoring. Results Average total infusion of fluids was 1600 +/− 350 ml. Use of blood products occurred in 29 patients (72,5%), of which 11 had a hysterectomy and 8 were treated with Bakri Balloons. For 2 patients > 1000 mL of concentrated red blood cells were used. When stroke volume index SVI dropped below 35 mL/m2/beat, it responded well to the infusion of at least 2 crystalloid boluses (5 ml/kg) in 7 patients. Cardiac index (CI) increased in 8 patients in concomitance with a reduction in medium arterial pressure (MAP), but the use of ephedrine (10 mg iv) re-established acceptable baseline values. Group I means are higher than Group II means for MAP, lower for RBC usage, end-of-surgery maternal lactates and fetal pH, and for LOS. Statistical analysis determines that the null hypotheses of equalities between Groups I and II can be rejected for all measures apart from MAP at baseline and induction. Proportions of serious complications in Groups I and II are respectively 10% and 32% and Boschloo’s test rejects the null of equality of proportions against the alternative hypothesis of lower proportion of occurrence in Group I than in Group II. Conclusions Hypovolemia can lead to vasoconstriction and inadequate perfusion with decreased oxygen delivery to organs and peripheral tissues and ultimately cause organ dysfunction. Despite the small sample size due to the rarity of the pathology, our statistical analysis finds evidence in favor of more favorable clinical outcomes for patients who received GDT implemented with non-invasive hemodynamic monitoring infusion relative to patients who received standard hemodynamic monitoring.

Abstract Background Dexmedetomidine is a highly selective alpha-2 receptor agonist without any effect on the GABA receptor. It provides an excellent sedative and analgesic profile with few side effects. We report our experience with dexmedetomidine use during orthopaedic surgery under locoregional anaesthesia to ensure adequate sedation and optimal postoperative pain control. Methods In this retrospective analysis, we included 128 patients who underwent orthopaedic surgery between January 2019 and December 2021. All patients received the same local anaesthetic dose of 20 ml of ropivacaine 0.375% + mepivacaine 0.5% for axillary and supraclavicular block and 35 ml of ropivacaine 0.375% + mepivacaine 0.5% for triple nerve block (femoral, obturator and sciatic nerve). The cohort was divided into two groups based on sedation drugs used during surgery (dexmedetomidine, or group D, vs midazolam, or group M). All patients received postoperative 24-h analgesia consisting of 60 mg of ketorolac, 200 mg of tramadol and 4 mg of ondansetron. The primary outcome measured how many patients in the two groups required an analgesic rescue dose of pethidine and the time to first pethidine administration. To reduce confounding, we included patients in two groups with non-statistically different demo-anamnestic parameters and who received the same dose of intraoperative local anaesthetic and postoperative analgesia. Results The number of patients in group D who did not require a rescue dose of analgesia was significantly greater than in group M (49 vs 11, p < 0.001). Time-to-first postoperative opioid administration did not show a fundamental difference between the two groups under examination (523.75 ± 131.55 min vs 564 ± 117.84 min). Total opioid consumption was higher in the M group than in the D group (3529.8 ± 30.36 μg vs 1864.8 ± 31.59 μg, p 0.075), with a mean opioid consumption significantly higher in the M group than in the D group (26.26 ± 42.8 μg vs 69.21 ± 46.1 μg, p < 0.001): D group received 62.06% less opioid than M group. Conclusions The continuous infusion of dexmedetomidine during orthopaedic surgery performed under locoregional anaesthesia has been shown to increase the analgesic effect of local anaesthetics and reduce the consumption of major opioids in the postoperative period. Dexmedetomidine offers a unique ability to supply sedation and analgesia without respiratory depression, having a wide safety margin and an excellent sedative capacity. It does not increase the rate of postoperative complications.

Abstract Estrogen receptor alpha (ERα) drives mammary gland development and breast cancer (BC) growth through an evolutionarily conserved linkage of DNA binding and hormone activation functions. Therapeutic targeting of the hormone binding pocket is a widely utilized and successful strategy for breast cancer prevention and treatment. However, resistance to this endocrine therapy is frequently encountered and may occur through bypass or reactivation of ER-regulated transcriptional programs. We now identify the induction of an ERα isoform, ERα-LBD, that is encoded by an alternative ESR1 transcript and lacks the activation function and DNA binding domains. Despite lacking the transcriptional activity, ERα-LBD is found to promote breast cancer growth and resistance to the ERα antagonist fulvestrant. ERα-LBD is predominantly localized to the cytoplasm and mitochondria of BC cells and leads to enhanced glycolysis, respiration and stem-like features. Intriguingly, ERα-LBD expression and function does not appear to be restricted to cancers that express full length ERα but also promotes growth of triple-negative breast cancers and ERα-LBD transcript (ESR1-LBD) is also present in BC samples from both ERα(+) and ERα(−) human tumors. These findings point to ERα-LBD as a potential mediator of breast cancer progression and therapy resistance.

(1) Background: Osteoarthritis (OA) is a debilitating joint disease. The are several therapies available for OA. According to current knowledge, the combination of Platelet-Rich Plasma (PRP) and Pulsed Radiofrequency (PRF) can be applied in the treatment of pain of nociceptive origin due to peripheral tissue damage. (2) Methods: We performed a narrative review identifying the articles by searching electronic databases. A retrospective analysis of patients with OA treated with PRF and PRP in “Vito Fazzi” Hospital (Lecce, Italy) was performed. (3) Results: A total of four publications on the use of PRP and PRF in degenerative joint arthritis were included in our review. In our experience, two patients with OA were treated with PRP and PRF after unsuccessful conservative treatment. Patient pain score, daily activity ability, active range of activity, and muscle strength improved after treatment. Patients reported a higher level of satisfaction. No major adverse events were reported. (4) Conclusions: The goal of the combined application of the two treatments is to make full use of the analgesic effect of PRF and the repairing effect of PRP. At present, the therapeutic potential of PRP and PRF in OA remains unmet.

Abstract Introduction Low back pain (LBP) is a common problem, and facet joint pain is responsible for 15–45% of cases. Treatment is multidisciplinary, and when conservative measures are not sufficient, radiofrequency (RF) is often used. It allows the interruption of nociceptive input, producing a heat lesion in a continuous or pulsed mode. Methods Medical records of 60 patients who underwent pulsed RF denervation were examined. The standard procedure provided follow-up of pain intensity. Numerical rating scale (NRS) and Douleur Neuropathique en 4 Questions (DN4) were recorded before treatment, and 15 and 40 days, and 6 months after treatment. Oswestry Disability Index (ODI) and patient satisfaction were also recorded. Successful treatment was defined as more than a 50% reduction in the NRS scores at 6 months compared with pretreatment scores. Results Scores on the NRS and DN4 were statistically different over time (p

Abstract Objective The purpose of this review is to evaluate the use and effectiveness of the local administration of tramadol in reducing post-operative pain during surgical interventions. Methods The PubMed, EMBASE and Cochrane Central Register of Controlled Trials (CENTRAL) databases will be searched for this review. This systematic review will include studies evaluating the clinical efficacy of the local infiltration of tramadol, with no study design restrictions. Only studies that present clear descriptions of local tramadol administration are published in peer-reviewed journals in the English, Italian, Spanish, French, Portuguese or German language and are published in full will be taken into consideration. A meta-analysis will be performed when there is sufficient clinical homogeneity among the retrieved studies, and only randomized controlled studies and quasi-randomized controlled studies will be included. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach will be used to assess the certainty in the evidence. If a quantitative analysis cannot be conducted, a qualitative description of the results of the retrieved studies will be provided. Results A high-quality synthesis of the current evidence on the local administration of tramadol for managing post-surgical pain will be illustrated using subjective reports and objective measures of performance. The primary outcomes will include the magnitude of post-operative pain intensity improvement, with improvement being as defined by a reduction by at least 2 points in the visual analogue scale (VAS) score or numerical rating scale (NRS) score. The secondary outcomes will be the magnitude of reduction in tramadol rescue doses and in other analgesic drug doses. Conclusion This protocol will present evidence on the efficacy of tramadol in relieving post-surgical pain. Systemic review registration PROSPERO CRD42018087381

Abstract Context Pain is commonly experienced among patients after surgical procedures. Clinical pain management after surgery is far from being successful. Patients may control postoperative pain by self-administration of intravenous opioids using devices designed for this purpose (patient-controlled analgesia or PCA). PCA devices have been developed including the sufentanil sublingual tablet system (SSTS). A systematic review of the use of SSTS for postoperative pain is needed to identify an alternative method of pain management. Objectives To systematically review literature to establish the efficacy and the safety of PCA with SSTS used in the treatment of moderate-to-severe acute post-operative pain in a hospital setting. Methods Embase, MEDLINE, Google Scholar, and Cochrane Central Trials Register were systematically searched in December 2019 for studies examining SSTS for pain in adult after surgical procedures. The methodological quality of the studies and their results were appraised using the Consensus-based Standards for the Selection of Health Measurement Instruments (COSMIN) checklist and specific measurement properties criteria, respectively. Results Sixteen studies evaluating SSTS were included for a total of 2311 patients. All participants in the SSTS group reported NRS ≤ 4 within 24 h after surgery. Patient satisfaction was high, with a minimum of 70% satisfaction among patients treated with SSTS. The most common adverse events (AEs) overall for SSTS 15 and 30 mcg were nausea, vomiting, and headache. AEs observed in the studies were generally consistent with those associated with opioids and the postsurgical setting. Conclusions SSTS is an important system for the management of moderate-to-severe acute pain in a hospital setting. SSTS is well tolerated, with no unexpected adverse events (AEs) and no clinically meaningful vital sign changes. These data confirm the safety and tolerability of the SSTS. Successful pain management resulted in a high level of acceptance of the SSTS by patients with high satisfaction for the method of pain control.

Plazomicin is a next-generation semisynthetic aminoglycoside antibiotic that can be used to treat infections by multi-resistant bacteria. It is effective against many bacteria-producing carbapenemases or other specific hydrolases. This scoping review aims to define the role acquired by plazomicin from its approval by the FDA (US Food and Drug Administration) in 2018 to the present day. Furthermore, we aim to provide a base for a future meta-analysis. This project was conducted following the recommendations presented in the PRISMA extension for scoping reviews and the JBI Manual for Evidence Synthesis. Among 901 potentially engaging citations, 345 duplicates were removed, and only 81 articles were selected for the analysis. According to the data analysis, plazomicin has been used to treat urinary tract infections, bloodstream infections, and ventilation-associated pneumonia. The pathogens killed included multi-resistant E. coli, K. pneumoniae, A. baumannii, P. aeruginosa, and S. aureus. Plazomicin can be a manageable, valid non-beta-lactam alternative for treating multi-resistant bacteria infections.

This comprehensive review of the recently published literature offers an overview of a very topical and complex healthcare problem: secondary peritonitis from multidrug-resistant pathogens, especially carbapenem-resistant Enterobacterales (CRE). Spontaneous secondary peritonitis and postsurgical secondary peritonitis are among the major causes of community- and healthcare- acquired sepsis, respectively. A large number of patients enter ICUs with a diagnosis of secondary peritonitis, and a high number of them reveal infection by CRE, P. aeruginosa or A. baumannii. For this reason, we conceived the idea to create a synthetic report on this topic including updated epidemiology data, a description of CRE resistance patterns, current strategies of antimicrobial treatment, and future perspectives. From this update it is clear that antimicrobial stewardship and precision medicine are becoming essential to fight the emergence of antimicrobial resistance and that even if there are new drugs effective against CRE causing secondary peritonitis, these drugs have to be used carefully especially in empirical therapy.

(1) Background: The aim of this study was to assess the clinical and microbiological characteristics of multidrug-resistant infections in a neuromuscular semi-intensive/sub-intensive care unit; (2) Methods: Retrospective analysis on data from 18 patients with NMD with proven MDRO/XDRO colonisation/infection from August 2021 to March 2022 was carried out; (3) Results: Ten patients were males (55.6%), with a median age of 54 years, and there were fourteen patients (77.8%) with amyotrophic lateral sclerosis. All patients had at least one invasive device. Ten (55.6%) patients developed MDRO/XDRO infection (with a median time of 24 days) while six (33.3%) were colonised. The Charlson comorbidity index was >2 in both groups but higher in the infected compared with the colonised (4.5 vs. 3). Infected patients were mostly females (seven patients) with a median age of 62 years. The most common pathogens were Acinetobacter baumannii and Pseudomonas aeruginosa, infecting four (28.6%) patients each. Of eighteen infectious episodes, nine were pneumonia (hospital-acquired in seven cases). Colistin was the most commonly active antibiotic while carbapenems were largely inactive. Eradication of infection occurred in seven infectious episodes (38.9%). None of those with infection died; (4) Conclusions: MDRO/XDRO infections are common in patients with neuromuscular diseases, with carbapenem-resistant non-fermenting Gram-negative bacilli prevailing. These infections were numerically associated with the female sex, greater age, and comorbidities. Both eradication and infection-related mortality appeared low. We highlight the importance of infection prevention in this vulnerable population.

Background To evaluate whether pre‐emptive skin analgesia using a lidocaine patch 5% would improve the effects of systemic morphine analgesia for controlling acute post‐thoracotomy pain. Methods This was a double‐blind, placebo controlled, prospective study. Patients were randomly assigned to receive lidocaine 5% patch (lidocaine group) or a placebo (placebo group) three days before thoracotomy. Postoperative analgesia was induced in all cases with intravenous morphine analgesia. The intergroup differences were assessed in order to evaluate whether the lidocaine patch 5% would have effects on pain intensity when at rest and after coughing (primary end‐point) on morphine consumption, on the recovery of respiratory function, and on peripheral painful pathways measured with N2 and P2 laser‐evoked potential (secondary end‐points). Results A total of 90 patients were randomized, of whom 45 were allocated to the lidocaine group and 45 to the placebo group. Lidocaine compared with the placebo group showed a significant reduction in pain intensity both at rest (P = 0.013) and after coughing (P = 0.015), and in total morphine consumption (P = 0.001); and also showed a better recovery of flow expiratory volume in one second (P = 0.025) and of forced vital capacity (P = 0.037). The placebo group compared with the lidocaine group presented a reduction in amplitude of N2 (P = 0.001) and P2 (P = 0.03), and an increase in the latency of N2 (P = 0.023) and P2 (P = 0.025) laser‐evoked potential. Conclusions The preventive skin analgesia with lidocaine patch 5% seems to be a valid adjunct to intravenous morphine analgesia for controlling post‐thoracotomy pain. However, our initial results should be corroborated/confirmed by larger studies.

Abstract Background Palmitoylethanolamide (PEA) belong to endocannabinoid family, a group of fatty acid amides. PEA has been proven to have analgesic and anti-inflammatory activity and has been used in several controlled studies focused on the management of chronic pain among adult patients with different underlying clinical conditions. Methods/design A literature search will be performed using PubMed, EMBASE, and the Cochrane Central Register of Controlled Trials (CENTRAL). The population will be patients who have chronic pain, the intervention will be the administration of PEA alone or in combination with other drugs for the pain management; the comparison will be the standard therapy in accordance with the current guidelines for the treatment of pain. The Outcomes will be the reduction of pain not restricted to specific scales laying out the pain outcome data described in the included studies. Discussion This scoping review aims to describe the clinical applications of the PEA in chronic pain management and its outcome. Scoping review registration Open Science Framework https://osf.io/74tmx/.

(1) Background: healthcare-associated infections are one of the most frequent adverse events in healthcare delivery worldwide. Several antibiotic resistance mechanisms have been developed, including those to carbapenemase. Cefiderocol (CFD) is a novel siderophore cephalosporin designed to treat carbapenem-resistant bacteria. (2) Methods: we performed a systematic review of all cases reported in the literature to outline the existing evidence. We evaluated real-world evidence studies of CFD in the treatment of carbapenem-resistant (CR) bacteria. (3) Results: a total of 19 publications treating cases of infection by CR bacteria were included. The three most frequent CR pathogens were Acinetobacter baumannii, Pseudomonas aeruginosa, and Klebsiella pneumoniae. A regimen of 2 g every 8 h was most frequently adopted for CFD with a mean treatment duration of 25.6 days. CFD was generally well tolerated, with fewer side effects. The success rate of CFD therapy was satisfactory and almost 70% of patients showed clinical recovery; of these, nearly half showed negative blood cultures and infection-free status. (4) Conclusions: This review indicates that CFD is active against important GN organisms including Enterobacteriaceae, P. aeruginosa, and A. baumannii. CFD seems to have a safe profile.

Abstract Tracheobronchial ruptures are very severe and life-threatening injuries. The origin of such airway damage is trauma or an iatrogenic event. Last year, we operated on three different cases of tracheal ruptures using endobronchial suture with three different airway management. We exposed the description of three different techniques to manage the airway during an endoscopic suture of tracheobronchial rupture with fibrin glue (laryngeal mask, orotracheal tube positioned distally the lesion, one lung ventilation with a small size single tube). Using this kind of technique, we have obtained a protective ventilation on tracheal rupture, a rapid healing, and fast recovery of spontaneous breathing.

Carbapenem antibiotics are the most effective antimicrobials for the treatment of infections caused by the most resistant bacteria. They belong to the category of β-lactams that include the penicillins, cephalosporins, monobactams and carbapenems. This class of antimicrobials has a broader spectrum of activity than most other beta-lactams antibiotics and are the most effective against Gram-positive and Gram-negative bacteria. All β-lactams antibiotics have a similar molecular structure: the carbapenems together with the β-lactams. This combination gives an extraordinary stability to the molecule against the enzymes inactivating the β-lactams. They are safe to use and therefore widespread use in many countries has given rise to carbapenem resistance which is a major global public health problem. The carbapenem resistance in some species is intrinsic and consists of the capacity to resist the action of antibiotics with several mechanisms: for the absence of a specific target, or an intrinsic difference in the composition of cytoplasmatic membrane or the inability to cross the outer membrane. In addition to intrinsic resistance, bacteria can develop resistance to antibiotics with several mechanisms that can be gathered in three main groups. The first group includes antibiotics with poor penetration into the outer membrane of bacterium or antibiotic efflux. The second includes bacteria that modify the target of the antibiotics through genetic mutations or post-translational modification of the target. The third includes bacteria that act with enzyme-catalyzed modification and this is due to the production of beta-lactamases, that are able to inactivate carbapenems and so called carbapenemases. In this review, we focus on the mode of action of carbapenem and the mechanisms of carbapenem resistance.

Abstract Background Descending necrotizing mediastinitis is a common and progressive polymicrobial infection involving the neck and chest with a high death rate (10 to 40%). From a microbiological point of view, descending necrotizing mediastinitis is sustained by Gram-positive bacteria (43–62%), anaerobes (46–78%), and, rarely, Gram-negative bacteria. Data collected during the Antibiotic Resistance-Istituto Superiore di Sanità project confirmed that Italy is positioned among the countries with the highest levels of resistance in most pathogenic species under surveillance. In particular, 32.9% of Klebsiella pneumoniae isolates were resistant to carbapenem, 33.6% of Staphylococcus aureus to methicillin, and 28.7% and 43.9% of Escherichia coli isolates to third-generation cephalosporins and fluoroquinolones, respectively. Case presentation We describe the case of a 38-year-old white man with septic shock due to descending necrotizing mediastinitis sustained by multidrug-resistant Gram-negative and Gram-positive bacteria treated after surgery with an IgM-enriched immunoglobulin preparation and polymyxin B hemoperfusion therapy. Conclusion Despite the contrasting data on the use of immunoglobulins and polymyxin B hemoperfusion in septic shock and the lack of literature in cases of acute mediastinitis caused by both Gram-negative and Gram-positive multidrug-resistant bacteria, we obtained an improvement in clinical conditions and the survival of our patient, against all odds.

Abstract Background This pilot study was designed to compare the efficacy of ultramicronized palmitoylethanolamide (um-PEA) as add-on therapy to tapentadol (TP) with TP therapy only in patients suffering from chronic low back pain (LBP). Methods This pilot observational study consists in two arms: the prospective arm and the retrospective one. In the prospective arm patients consecutively selected received um-PEA as add-on therapy to TP for 6 months; in the retrospective arm patients were treated with TP only for 6 months. Pain intensity and neuropathic component were evaluated at baseline, during and after 6 months. The degree of disability and TP dosage assumption were evaluated at baseline and after 6 months. Results Statistical analysis performed with generalized linear mixed model on 55 patients (30 in the prospective group and 25 in the retrospective group) demonstrated that um-PEA as add-on treatment to TP in patients with chronic LBP, in comparison to TP alone, led to a significantly higher reduction in pain intensity, in the neuropathic component, the degree of disability and TP dosage assumption. No serious side effects were observed. Conclusion Overall, the present findings suggest that um-PEA may be an innovative therapeutic intervention as add-on therapy to TP for the management of chronic LBP with a neuropathic component, as well as to improve patient quality of life. Additionally, this combination treatment allowed a reduction in TP dose over time and did not show any serious side effects.

Antimicrobial resistance (AMR) remains one of the top public health issues of global concern. Among the most important strategies for AMR control there is the correct and appropriate use of antibiotics, including those available for the treatment of AMR pathogens. In this article, after briefly reviewing the most important and clinically relevant multi-drug-resistant bacteria and their main resistance mechanisms, we describe the emerging antimicrobial options for both MDR Gram-positive cocci and Gram-negative bacilli, including recently marketed agents, molecules just approved or under evaluation and rediscovered older antibiotics that have regained importance due to their antimicrobial spectrum. Specifically, emerging options for Gram-positive cocci we reviewed include ceftaroline, ceftobiprole, tedizolid, dalbavancin, and fosfomycin. Emerging treatment options for Gram-negative bacilli we considered comprise ceftolozane-tazobactam, ceftazidime-avibactam, meropenem-vaborbactam, imipenem-relebactam, aztreonam-avibactam, minocycline, fosfomycin, eravacycline, plazomicin, and cefiderocol. An exciting scenario is opening today with the long awaited growing availability of novel molecules for the treatment of AMR bacteria. Knowledge of mechanisms of action and resistance patterns allows physicians to increasingly drive antimicrobial treatment towards a precision medicine approach. Strict adherence to antimicrobial stewardship practices will allow us to preserve the emerging antimicrobials for our future.

Coronavirus disease 2019 (COVID-19), caused by SARS-CoV-2, is often complicated by severe acute respiratory syndrome. The new coronavirus outbreak started in China in December 2019 and rapidly spread around the world. The high diffusibility of the virus was the reason for the outbreak of the pandemic viral disease, reaching more than 100 million infected people globally by the first three months of 2021. In the various treatments used up to now, the use of antimicrobial drugs for the management, especially of bacterial co-infections, is very frequent in patients admitted to intensive care. In addition, critically ill patients with SARS-CoV-2 infection are subjected to prolonged mechanical ventilation and other therapeutic procedures often responsible for developing hospital co-infections due to multidrug-resistant bacteria. Co-infections contribute to the increase in the morbidity–mortality of viral respiratory infections. We performed this study to review the recent articles published on the antibiotic bacterial resistance and viruses to predict risk factors of coronavirus disease 2019 and to assess the multidrug resistance in patients hospitalized in the COVID-19 area.

Background: Bloodstream infections (BSIs) constitute a growing public health concern, are among the most severe nosocomial pathologies, and are considered a worldwide cause of unfaithful outcomes, increasing treatment costs and diagnostic uncertainties. BSIs are one of the most frequent lethal conditions that are managed in intensive care units (ICUs). In the case of septic shock, immune deficiency, and delayed treatment, even with adequate antimicrobial therapy and/or source control, the outcomes are often unfavorable. Methods: this review article summarizes the epidemiological and microbiological characteristics of BSIs with a particular focus on ICU acquired BSIs (ICU-BSIs), which are usually caused by multidrug-resistant (MDR) pathogens. For this reason, their antimicrobial resistance patterns and therapeutic options have also been compiled. Results: ICU-acquired BSIs prevail in 5–7% of ICU patients. Klebsiella pneumoniae, Escherichia coli, Acinetobacter baumannii, and Pseudomonas aeruginosae are the pathogens most often responsible for MDR infections. MDR Enterobacteriaceae have seen their prevalence increase from 6.2% (1997–2000) to 15.8% (2013–2016) in recent years. Conclusions: Considering that prevention and treatment of sepsis is nowadays considered a global health priority by the World Health Organization, it is our obligation to invest more resources into solving or reducing the spread of these unfaithful infections. It is relevant to identify patients with risk factors that make them more susceptible to BSIs, to guarantee earlier molecular or microbiological diagnoses, and more rapidly appropriate treatment by using de-escalation strategies where possible.

A causal link between Human Papillomavirus (HPV) and breast cancer (BC) remains controversial. In spite of this, the observation that HPV DNA is over-represented in the Triple Negative (TN) BC has been reported. Here we remark the high prevalence of HPV DNA (44.4%) in aggressive BC subtypes (TN and HER2+) in a population of 273 Italian women and we convey the presence of HPV DNA in the epithelial and stromal compartments by in situ hybridization. As previously reported, we also found that serum derived-extracellular vesicles (EVs) from BC affected patients contain HPV DNA. Interestingly, in one TNBC patient, the same HPV DNA type was detected in the serum-derived EVs, cervical and BC tissue samples. Then, we report that HPV DNA can be transferred by EVs to recipient BC stromal cells that show an activated phenotype (e.g., CD44, IL6 expression) and an enhanced capability to sustain mammospheres (MS) formation. These data suggest that HPV DNA vehiculated by EVs is a potential trigger for BC niche aggressiveness.

Background: Ceftolozane/tazobactam (C/T) is a β-lactam/β-lactamase inhibitor combination that mainly targets Gram-negative bacteria. The current international guidelines recommend including C/T treatment in the empirical therapy for hospital-acquired pneumonia (HAP) and ventilator-associated pneumonia (VAP). Pseudomonas aeruginosa (PA) is one of the most challenging Gram-negative bacteria. We conducted a systematic review of all cases reported in the literature to summarize the existing evidence. Methods: The main electronic databases were screened to identify case reports of patients with drug-resistant PA respiratory infections treated with C/T. Results: A total of 22 publications were included for a total of 84 infective episodes. The clinical success rate was 72.6% across a wide range of comorbidities. The 45.8% of patients treated with C/T presented colonization by PA. C/T was well tolerated. Only six patients presented adverse events, but none had to stop treatment. The most common therapeutic regimens were 1.5 g every 8 h and 3 g every 8 h. Conclusion: C/T may be a valid therapeutic option to treat multidrug-resistant (MDR), extensively drug-resistant (XDR), pandrug-resistant (PDR), and carbapenem-resistant (CR) PA infections. However, further data are necessary to define the optimal treatment dosage and duration.

Background. Guillain-Barré syndrome (GBS) is the most common cause of flaccid paralysis, with about 100,000 people developing the disorder every year worldwide. Recently, the incidence of GBS has increased during the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) epidemics. We reviewed the literature to give a comprehensive overview of the demographic characteristics, clinical features, diagnostic investigations, and outcome of SARS-CoV-2-related GBS patients. Methods. Embase, MEDLINE, Google Scholar, and Cochrane Central Trials Register were systematically searched on 24 September 2020 for studies reporting on GBS secondary to COVID-19. Results. We identified 63 articles; we included 32 studies in our review. A total of 41 GBS cases with a confirmed or probable COVID-19 infection were reported: 26 of them were single case reports and 6 case series. Published studies on SARS-CoV-2-related GBS typically report a classic sensorimotor type of GBS often with a demyelinating electrophysiological subtype. Miller Fisher syndrome was reported in a quarter of the cases. In 78.1% of the cases, the response to immunomodulating therapy is favourable. The disease course is frequently severe and about one-third of the patients with SARS-CoV-2-associated GBS requires mechanical ventilation and Intensive Care Unit (ICU) admission. Rarely the outcome is poor or even fatal (10.8% of the cases). Conclusion. Clinical presentation, course, response to treatment, and outcome are similar in SARS-CoV-2-associated GBS and GBS due to other triggers.

ER+ breast cancer patients treated with endocrine therapies often acquire resistance and develop metastasis. In this study, the authors demonstrate that endocrine therapies can promote the self-renewal of CD133hi/ERlodrug resistant cells with metastatic potential driven through the IL6-Notch3 axis activation.

We have investigated the importance of interleukin-6 (IL-6) in promoting tumor growth and metastasis. In human primary breast cancers, increased levels of IL-6 were found at the tumor leading edge and positively correlated with advanced stage, suggesting a mechanistic link between tumor cell production of IL-6 and invasion. In support of this hypothesis, we showed that the IL-6/Janus kinase (JAK)/signal transducer and activator of transcription 3 (Stat3) pathway drives tumor progression through the stroma and metastatic niche. Overexpression of IL-6 in tumor cell lines promoted myeloid cell recruitment, angiogenesis, and induced metastases. We demonstrated the therapeutic potential of interrupting this pathway with IL-6 receptor blockade or by inhibiting its downstream effectors JAK1/2 or Stat3. These clinically relevant interventions did not inhibit tumor cell proliferation in vitro but had profound effects in vivo on tumor progression, interfering broadly with tumor-supportive stromal functions, including angiogenesis, fibroblast infiltration, and myeloid suppressor cell recruitment in both the tumor and pre-metastatic niche. This study provides the first evidence for IL-6 expression at the leading edge of invasive human breast tumors and demonstrates mechanistically that IL-6/JAK/Stat3 signaling plays a critical and pharmacologically targetable role in orchestrating the composition of the tumor microenvironment that promotes growth, invasion, and metastasis.

There are a lot of individual differences in the effectiveness of opioids. The reasons of this variability could be the heterogeneity of underlying diseases, the ineffective doses administered and finally, an individual’s pharmacogenetics. Pharmacogenetics is the study of genetics in interindividual variability to drug response and therapy. Genetic variation leads to interpersonal variability in drug absorption, distribution, metabolism and excretion, and so affects a drug’s effi cacy and toxicity. The understanding of the role and the mechanism of a patient’s genetic background could help us organize a target antalgic therapy in order to optimize the effectiveness of every opioid and reduce the adverse event.