Palmitoylethanolamide and polydatin in pediatric irritable bowel syndrome: A multicentric randomized controlled trial.

OBJECTIVE: This study aimed to evaluate the efficacy and safety of co-micronized palmitoylethanolamide (PEA)/polydatin (PD) in the treatment of abdominal pain symptoms in pediatric patients with irritable bowel syndrome (IBS). METHODS: This was a multicenter trial conducted at three Italian pediatric gastroenterology centers, employing a double-blind, placebo-controlled, parallel-arm design. Participants were ages 10 to 17 y and met Rome IV criteria for pediatric IBS. They were randomly allocated to receive either co-micronized PEA/PD or placebo, administered three times daily in a 1:1 ratio, over a 12-wk period. The study assessed baseline severity using the IBS-Severity Scoring System (IBS-SSS) at enrollment and after 4, 8, and 12 wk of treatment. Abdominal pain frequency was assessed on a scale from 1 to 7 d/wk, while stool consistency was classified using the Bristol Stool Scale (BSS) to categorize various IBS subtypes. The primary outcome was the percentage of patients who achieved complete remission, defined as IBS-SSS score <75 points after 12 wk of therapy. RESULTS: The study involved 70 children with IBS. Of the participants, 34 received co-micronized PEA/PD, and 36 received a placebo. As compared with the placebo group, the co-micronized therapy group had significantly more patients achieving complete remission after 12 wk (P = 0.015), with particular benefit in the IBS-diarrhea subtype (P = 0.01). The treatment group also experienced a significant reduction in abdominal pain intensity and frequency compared with the placebo group. No adverse events were recorded during the study period. CONCLUSIONS: Co-micronized PEA/PD is a safe and effective treatment to treat abdominal pain symptoms in pediatric IBS.

To Be Frail or Not to Be Frail: This Is the Question-A Critical Narrative Review of Frailty.

Many factors have contributed to rendering frailty an emerging, relevant, and very popular concept. First, many pandemics that have affected humanity in history, including COVID-19, most recently, have had more severe effects on frail people compared to non-frail ones. Second, the increase in human life expectancy observed in many developed countries, including Italy has led to a rise in the percentage of the older population that is more likely to be frail, which is why frailty is much a more common concern among geriatricians compared to other the various health-care professionals. Third, the stratification of people according to the occurrence and the degree of frailty allows healthcare decision makers to adequately plan for the allocation of available human professional and economic resources. Since frailty is considered to be fully preventable, there are relevant consequences in terms of potential benefits both in terms of the clinical outcome and healthcare costs. Frailty is becoming a popular, pervasive, and almost omnipresent concept in many different contexts, including clinical medicine, physical health, lifestyle behavior, mental health, health policy, and socio-economic planning sciences. The emergence of the new "science of frailty" has been recently acknowledged. However, there is still debate on the exact definition of frailty, the pathogenic mechanisms involved, the most appropriate method to assess frailty, and consequently, who should be considered frail. This narrative review aims to analyze frailty from many different aspects and points of view, with a special focus on the proposed pathogenic mechanisms, the various factors that have been considered in the assessment of frailty, and the emerging role of biomarkers in the early recognition of frailty, particularly on the role of mitochondria. According to the extensive literature on this topic, it is clear that frailty is a very complex syndrome, involving many different domains and affecting multiple physiological systems. Therefore, its management should be directed towards a comprehensive and multifaceted holistic approach and a personalized intervention strategy to slow down its progression or even to completely reverse the course of this condition.

Considerations for Pain Assessments in Cancer Patients: A Narrative Review of the Latin American Perspective.

Cancer incidence in Latin America is lower than in Europe or the United States but morbidity and mortality rates are disproportionately high. A barrier to adequate pain control is inadequate pain assessment, which is a relatively easy and inexpensive metric. The objective of this narrative review is to describe pain assessment for cancer patients in Latin America. Cultural factors may influence pain perception, including contextualizing pain as noble or natural suffering and aspects of what is now called "spiritual pain." Unlike other painful conditions, cancer pain may be strongly associated with existential fear, psychosocial distress, anxiety, and spiritual concerns. Pain assessment allows not just quantification of pain intensity but may elucidate pain mechanisms involved or psychosocial aspects that may color the pain. Many current pain assessment instruments capture only pain intensity, which is but one aspect of the pain experience; some have expanded to include functional assessments, mental health status evaluations, and quality of life metrics. A quality-of-life assessment may be appropriate for cancer patients since chronic pain can severely impact function, which can in turn create a vicious cycle by exacerbating pain. The incidence of cancer in Latin America is expected to increase in the ensuing years. Better pain assessment and clinician education are needed to help manage pain in this large and growing patient population.

COVID-19 Lung Ultrasound Scores and Lessons from the Pandemic: A Narrative Review.

The WHO recently declared that COVID-19 no longer constitutes a public health emergency of international concern; however, lessons learned through the pandemic should not be left behind. Lung ultrasound was largely utilized as a diagnostic tool thanks to its feasibility, easy application, and the possibility to reduce the source of infection for health personnel. Lung ultrasound scores consist of grading systems used to guide diagnosis and medical decisions, owning a good prognostic value. In the emergency context of the pandemic, several lung ultrasound scores emerged either as new scores or as modifications of pre-existing ones. Our aim is to clarify the key aspects of lung ultrasound and lung ultrasound scores to standardize their clinical use in a non-pandemic context. The authors searched on PubMed for articles related to "COVID-19", "ultrasound", and "Score" until 5 May 2023; other keywords were "thoracic", "lung", "echography", and "diaphragm". A narrative summary of the results was made. Lung ultrasound scores are demonstrated to be an important tool for triage, prediction of severity, and aid in medical decisions. Ultimately, the existence of numerous scores leads to a lack of clarity, confusion, and an absence of standardization.

A Closer Look at Opioid-Induced Adrenal Insufficiency: A Narrative Review.

Among several opioid-associated endocrinopathies, opioid-associated adrenal insufficiency (OIAI) is both common and not well understood by most clinicians, particularly those outside of endocrine specialization. OIAI is secondary to long-term opioid use and differs from primary adrenal insufficiency. Beyond chronic opioid use, risk factors for OIAI are not well known. OIAI can be diagnosed by a variety of tests, such as the morning cortisol test, but cutoff values are not well established and it is estimated that only about 10% of patients with OIAI will ever be properly diagnosed. This may be dangerous, as OIAI can lead to a potentially life-threatening adrenal crisis. OIAI can be treated and for patients who must continue opioid therapy, it can be clinically managed. OIAI resolves with opioid cessation. Better guidance for diagnosis and treatment is urgently needed, particularly in light of the fact that 5% of the United States population has a prescription for chronic opioid therapy.

New Perspectives on the Adverse Effects of NSAIDs in Cancer Pain: An Italian Delphi Study from the Rational Use of Analgesics (RUA) Group.

Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most frequently prescribed drugs for cancer pain. We used the Delphi methodology to evaluate the opinions of clinicians on NSAIDs and paracetamol, with a specific focus on their safety profile. Consensus was reached on seven statements. A high level of consensus was reached regarding the use of NSAIDs and gastrointestinal, cardiovascular, and renal risk in patients taking low-dose aspirin and assessment of liver function during long-term treatment with paracetamol. Consensus was also reached that assessment and monitoring of eGFR are important in the elderly being administered NSAIDs. It was further agreed that NSAIDs can often play a key role in association with opioids in the treatment of cancer pain and that paracetamol is the analgesic of first choice for patients with mild chronic pain. When NSAIDs are administered in combination with steroids, it was agreed that the risk of gastrointestinal damage is increased since steroids delay the healing of ulcers and that paracetamol can be used during pregnancy and does not affect the health of the fetus. This Delphi study highlights that there is poor agreement on how these drugs are routinely prescribed. However, a consensus was reached for seven key statements and may represent a valid contribution to daily practice.

The Impact of P-Glycoprotein on Opioid Analgesics: What's the Real Meaning in Pain Management and Palliative Care?

Opioids are widely used in cancer and non-cancer pain management. However, many transporters at the blood-brain barrier (BBB), such as P-glycoprotein (P-gp, ABCB1/MDR1), may impair their delivery to the brain, thus leading to opioid tolerance. Nonetheless, opioids may regulate P-gp expression, thus altering the transport of other compounds, namely chemotherapeutic agents, resulting in pharmacoresistance. Other kinds of painkillers (e.g., acetaminophen, dexamethasone) and adjuvant drugs used for neuropathic pain may act as P-gp substrates and modulate its expression, thus making pain management challenging. Inflammatory conditions are also believed to upregulate P-gp. The role of P-gp in drug-drug interactions is currently under investigation, since many P-gp substrates may also act as substrates for the cytochrome P450 enzymes, which metabolize a wide range of xenobiotics and endobiotics. Genetic variability of the ABCB1/MDR1 gene may be accountable for inter-individual variation in opioid-induced analgesia. P-gp also plays a role in the management of opioid-induced adverse effects, such as constipation. Peripherally acting mu-opioid receptors antagonists (PAMORAs), such as naloxegol and naldemedine, are substrates of P-gp, which prevent their penetration in the central nervous system. In our review, we explore the interactions between P-gp and opioidergic drugs, with their implications in clinical practice.

Opposite Effect of Thyroid Hormones on Oxidative Stress and on Mitochondrial Respiration in COVID-19 Patients.

BACKGROUND: Thyroid hormones (TH)s are master regulators of mitochondrial activity and biogenesis. Nonthyroidal illness syndrome (NTIS) is generally considered an adaptative response to reduced energy that is secondary to critical illness, including COVID-19. COVID-19 has been associated with profound changes in the cell energy metabolism, especially in the cells of the immune system, with a central role played by the mitochondria, considered the power units of every cell. Infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) affects and alters mitochondrial functions, both to influence its intracellular survival and to evade host immunity. AIM OF THE STUDY: This study was undertaken to analyze the oxidative balance and mitochondrial respiration in COVID-19 patients with and without NTIS to elucidate the role that thyroid hormones (TH)s play in this context. METHODS: In our cohort of 54 COVID-19 patients, admitted to our University Hospital during the COVID-19 pandemic, we evaluated the generation of reactive oxygen species (ROS) by measuring the serum levels of derivatives of reactive oxygen metabolites (dROMs), and we analyzed the antioxidant capacity by measuring the serum biological antioxidant potential (BAP). We then analyzed the mitochondrial respiration in peripheral blood mononuclear cells (PBMC)s of 28 of our COVID-19 patients, using the seahorse instrument (Agilent). Results were correlated with the serum levels of THs and, in particular, of FT3. In addition, the role of T3 on bioelectrical impedance analysis (BIA) and mitochondrial respiration parameters was directly evaluated in two COVID-19 patients with NTIS, in which treatment with synthetic liothyronine (LT3) was given both in vivo and in vitro. RESULTS: In our COVID-19 patients with NTIS, the dROMs values were significantly lower and the BAP values were significantly higher. Consequently, the oxidative stress index (OSi), measured as BAP/dROMs ratio was reduced compared to that observed in COVID-19 patients without NTIS, indicating a protective role exerted by NTIS on oxidative stress. In our COVID-19 patients, the mitochondrial respiration, measured in PBMCs, was reduced compared to healthy controls. Those with NTIS showed a reduced maximal respiratory capacity and a reduced proton leak, compared to those with normal FT3 serum values. Such lowered mitochondrial respiratory capacity makes the cells more vulnerable to bioenergetic exhaustion. In a pilot study involving two COVID-19 patients with NTIS, we could reinforce our previous observation regarding the role of T3 in the maintenance of adequate peripheral hydroelectrolytic balance. In addition, in these two patients, we demonstrated that by treating their PBMCs with LT3, both in vitro and in vivo, all mitochondrial respiration parameters significantly increased. CONCLUSIONS: Our results regarding the reduction in the serum levels of the reactive oxygen species (ROS) of COVID-19 patients with NTIS support the hypothesis that NTIS could represent an adaptative response to severe COVID-19. However, beside this beneficial effect, we demonstrate that, in the presence of an acute reduction of FT3 serum levels, the mitochondrial respiration is greatly impaired, with a consequent establishment of a hypoenergetic state of the immune cells that may hamper their capacity to react to massive viral infection.

Targeting Neuroinflammation in Osteoarthritis with Intra-Articular Adelmidrol.

Neuroinflammation is an emerging therapeutic target in chronic degenerative and autoimmune diseases, such as osteoarthritis (OA) and rheumatoid arthritis. Mast cells (MCs) play a key role in the homeostasis of joints and the activation of MCs induces the release of a huge number of mediators, which fuel the fire of neuroinflammation. Particularly, synovial MCs release substances which accelerate the degradation of the extra-cellular matrix causing morphological joint changes and cartilage damage and inducing the proliferation of synovial fibroblasts, angiogenesis, and the sprouting of sensory nerve fibers, which mediate chronic pain. Palmitoylethanolamide (PEA) is a well-known MCs modulator, but in osteoarthritic joints, its levels are significantly reduced. Adelmidrol, a synthetic derivate of azelaic acid belonging to the ALIAmides family, is a PEA enhancer. Preclinical and clinical investigations showed that the intra-articular administration of Adelmidrol significantly reduced MC infiltration, pro-inflammatory cytokine release, and cartilage degeneration. The combination of 1% high molecular weight hyaluronic acid and 2% Adelmidrol has been effectively used for knee osteoarthritis and, a significant improvement in analgesia and functionality has been recorded.

Multimechanistic Single-Entity Combinations for Chronic Pain Control: A Narrative Review.

Atypical opioids such as tramadol, tapentadol, and cebranopadol combine two complementary mechanisms of action into a single molecule, creating novel analgesic agents. These are synthetic small molecules: cebranopadol is not yet market released; tramadol and tapentadol are commercially available and have immediate-release (IR) and extended-release (ER) formulations. Tramadol has been widely used in the United States in recent years and works as a prodrug in that its metabolites are active in inhibiting serotonin and norepinephrine reuptake. Tapentadol is a direct-acting agent with a faster onset of action and is a mu-opioid-receptor agonist and also inhibits noradrenaline reuptake. Cebranopadol is the newest of these drugs, a first-in-class atypical analgesic that combines mu-opioid receptor (MOR) agonism with activity at the nociception/orphanin (NOP) FQ petide receptors. Cebranopadol may be considered a partial kappa-opioid receptor agonist as well. The pharmacology of these unique single-entity agents allows them to offer analgesic benefit with fewer side effects and risks. Clinical studies have demonstrated the safety and efficacy of tramadol and tapentadol, and promising but limited studies for cebranopadol show good analgesic effect and safety. Serotonin toxicity or 'serotonin syndrome' may occur with accumulation of serotonin with tramadol. While the misuse of these agents is limited in the United States, tramadol misuse is prevalent in Iran and parts of Africa. Patients have been successfully rotated from one of these agents to another. All three agents show promise in the treatment of cancer and non-cancer pain and their unique formulation in a single molecule reduces the pill burden.

Nonthyroidal Illness Syndrome: To Treat or Not to Treat? Have We Answered the Question? A Review of Metanalyses.

Background and Objective: Nonthyroidal Illness Syndrome (NTIS) occurs in approximately 70% of patients admitted to Intensive Care Units (ICU)s and has been associated with increased risk of death. Whether patients with NTIS should receive treatment with thyroid hormones (TH)s is still debated. Since many interventional randomized clinical trials (IRCT)s were not conclusive, current guidelines do not recommend treatment for these patients. In this review, we analyze the reasons why TH treatment did not furnish convincing results regarding possible beneficial effects in reported IRCTs. Methods: We performed a review of the metanalyses focused on NTIS in critically ill patients. After a careful selection, we extracted data from four metanalyses, performed in different clinical conditions and diseases. In particular, we analyzed the type of TH supplementation, the route of administration, the dosages and duration of treatment and the outcomes chosen to evaluate the results. Results: We observed a marked heterogeneity among the IRCTs, in terms of type of TH supplementation, route of administration, dosages and duration of treatment. We also found great variability in the primary outcomes, such as prevention of neurological alterations, reduction of oxygen requirements, restoration of endocrinological and clinical parameters and reduction of mortality. Conclusions: NTIS is a frequent finding in critical ill patients. Despite several available IRCTs, it is still unclear whether NTIS should be treated or not. New primary endpoints should be identified to adequately validate the efficacy of TH treatment and to obtain a clear answer to the question raised some years ago.

Current and Future Therapeutic Options in Pain Management: Multi-mechanistic Opioids Involving Both MOR and NOP Receptor Activation.

Opioids are widely used in chronic pain management, despite major concerns about their risk of adverse events, particularly abuse, misuse, and respiratory depression from overdose. Multi-mechanistic opioids, such as tapentadol and buprenorphine, have been widely studied as a valid alternative to traditional opioids for their safer profile. Special interest was focused on the role of the nociceptin opioid peptide (NOP) receptor in terms of analgesia and improved tolerability. Nociceptin opioid peptide receptor agonists were shown to reinforce the antinociceptive effect of mu opioid receptor (MOR) agonists and modulate some of their adverse effects. Therefore, multi-mechanistic opioids involving both MOR and NOP receptor activation became a major field of pharmaceutical and clinical investigations. Buprenorphine was re-discovered in a new perspective, as an atypical analgesic and as a substitution therapy for opioid use disorders; and buprenorphine derivatives have been tested in animal models of nociceptive and neuropathic pain. Similarly, cebranopadol, a full MOR/NOP receptor agonist, has been clinically evaluated for its potent analgesic efficacy and better tolerability profile, compared with traditional opioids. This review overviews pharmacological mechanisms of the NOP receptor system, including its role in pain management and in the development of opioid tolerance. Clinical data on buprenorphine suggest its role as a safer alternative to traditional opioids, particularly in patients with non-cancer pain; while data on cebranopadol still require phase III study results to approve its introduction on the market. Other bifunctional MOR/NOP receptor ligands, such as BU08028, BU10038, and AT-121, are currently under pharmacological investigations and could represent promising analgesic agents for the future.

Opioid-Induced Constipation in Real-World Practice: A Physician Survey, 1 Year Later.

INTRODUCTION: Opioid-induced constipation (OIC) is the most common adverse effect of opioid therapy, but it is underdiagnosed and undertreated. Last year, a survey among Italian healthcare providers revealed important differences in the clinical management of OIC across physician specialties, the need of standardization of diagnosis and treatment, and the urgency of further education. Herein, we submitted an updated version of the survey to the same cohort of experts to evaluate potential progress. METHODS: The online survey included 15 questions about OIC. Responses were analyzed descriptively and aggregated by physician specialty. RESULTS: A total of 190 physicians completed the survey. Most respondents (65%) did not feel adequately educated about OIC despite general consensus regarding interest in the topic and acknowledgement of OIC impact on patients' QoL and adherence to opioid therapy. Overall, 55-77% of physicians regularly evaluated intestinal function or OIC symptoms in patients receiving opioid therapy, with one-third of respondents implementing it in the past year. Even though the most common method for assessment was still patient diary, the use of specific scales underwent a small but significant increase compared to the previous year, with major implementation in the use of Rome IV criteria. As regards first-line treatment, most respondents (49%) preferred macrogol prophylaxis followed by macrogol plus another laxative. For second-line treatment, we revealed a growth in the prescription of peripherally acting mu-opioid receptor antagonists (PAMORAs), with 46% of all the respondents having increased their use during the past year. CONCLUSIONS: Despite some limitations, our study demonstrated a slow but important step closer to standardization of diagnosis and treatment of OIC. Further educational and training efforts should be put in place to favor best evidence-based clinical practice.

Pharmacologic agents directed at the treatment of pain associated with maladaptive neuronal plasticity.

INTRODUCTION: The definition of nociplastic pain in 2016 has changed the way maladaptive chronic pain is viewed in that it may emerge without neural lesions or neural disease. Many endogenous and pharmacologic substances are being investigated for their role in treating the pain associated with neuronal plasticity. AREAS COVERED: The authors review promising pharmacologic agents for the treatment of pain associated with maladaptive neuronal plasticity. The authors then provide the reader with their expert opinion and provide their perspectives for the future. EXPERT OPINION: An imbalance between the amplification of ascending pain signals and the poor activation of descending inhibitory signals may be at the root of many chronic pain syndromes. The inhibitory activity of noradrenaline reuptake may play a role in neuropathic and nociplastic analgesia. A better understanding of the brain's pain matrix, its signaling cascades, and the complex bidirectional communication between the immune system and the nervous system may help meet the urgent and unmet medical need for safe, effective chronic pain treatment, particularly for pain with a neuropathic and/or nociplastic component.

Lung Ultrasound: A Diagnostic Leading Tool for SARS-CoV-2 Pneumonia: A Narrative Review.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has spread worldwide causing a global pandemic. In this context, lung ultrasound (LUS) has played an important role due to its high diagnostic sensitivity, low costs, simplicity of execution and radiation safeness. Despite computed tomography (CT) being the imaging gold standard, lung ultrasound point of care exam is essential in every situation where CT is not readily available nor applicable. The aim of our review is to highlight the considerable versatility of LUS in diagnosis, framing the therapeutic route and follow-up for SARS-CoV-2 interstitial syndrome.

Nonthyroidal illness syndrome (NTIS) in severe COVID-19 patients: role of T3 on the Na/K pump gene expression and on hydroelectrolytic equilibrium.

BACKGROUND: Nonthyroidal Illness Syndrome (NTIS) can be detected in many critical illnesses. Recently, we demonstrated that this condition is frequently observed in COVID-19 patients too and it is correlated with the severity the disease. However, the exact mechanism through which thyroid hormones influence the course of COVID-19, as well as that of many other critical illnesses, is not clear yet and treatment with T4, T3 or a combination of both is still controversial. Aim of this study was to analyze body composition in COVID-19 patients in search of possible correlation with the thyroid function. METHODS AND FINDINGS: We report here our experience performed in 74 critically ill COVID-19 patients hospitalized in the intensive care unit (ICU) of our University Hospital in Rome. In these patients, we evaluated the thyroid hormone function and body composition by Bioelectrical Impedance Analysis (BIA) during the acute phase of the disease at admission in the ICU. To examine the effects of thyroid function on BIA parameters we analyzed also 96 outpatients, affected by thyroid diseases in different functional conditions. We demonstrated that COVID-19 patients with low FT3 serum values exhibited increased values of the Total Body Water/Free Fat Mass (TBW/FFM) ratio. Patients with the lowest FT3 serum values had also the highest level of TBW/FFM ratio. This ratio is an indicator of the fraction of FFM as water and represents one of the best-known body-composition constants in mammals. We found an inverse correlation between FT3 serum values and this constant. Reduced FT3 serum values in COVID-19 patients were correlated with the increase in the total body water (TBW), the extracellular water (ECW) and the sodium/potassium exchangeable ratio (Nae:Ke), and with the reduction of the intracellular water (ICW). No specific correlation was observed in thyroid patients at different functional conditions between any BIA parameters and FT3 serum values, except for the patient with myxedema, that showed a picture similar to that seen in COVID-19 patients with NTIS. Since the Na+/K+ pump is a well-known T3 target, we measured the mRNA expression levels of the two genes coding for the two major isoforms of this pump. We demonstrated that COVID-19 patients with NTIS had lower levels of mRNA of both genes in the peripheral blood mononuclear cells (PBMC)s obtained from our patients during the acute phase of the disease. In addition, we retrieved data from transcriptome analysis, performed on human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM)s treated with T3 and we demonstrated that in these cells T3 is able to stimulate the expression of these two genes in a dose-dependent manner. CONCLUSIONS: In conclusion, we demonstrated that measurement of BIA parameters is a useful method to analyze water and salt retention in COVID-19 patients hospitalized in ICU and, in particular, in those that develop NTIS. Our results indicate that NTIS has peculiar similarities with myxedema seen in severe hypothyroid patients, albeit it occurs more rapidly. The Na+/K+ pump is a possible target of T3 action, involved in the pathogenesis of the anasarcatic condition observed in our COVID-19 patients with NTIS. Finally, measurement of BIA parameters may represent good endpoints to evaluate the benefit of future clinical interventional trials, based on the administration of T3 in patients with NTIS.

Endoscopic Transforaminal Lumbar Foraminotomy: A Systematic Review and Meta-Analysis.

INTRODUCTION: Spinal endoscopic techniques have recently been applied to complex degenerative conditions or failed back surgery syndrome. We performed a systematic review and meta-analysis to assess transforaminal endoscopic lumbar foraminotomy (TELF) outcomes and adverse event rates. We also analyzed the effectiveness of the technique for chronic pain after arthrodesis or previous spinal surgery. METHODS: Multiple databases were searched for studies published in the English language, involving patients > 18 years old who underwent endoscopic foraminotomy. Outcomes included the rate of patients who showed "excellent" and "good" postoperative improvement, decreased leg pain, and improved Oswestry Disability Index (ODI) scores. Adverse events considered in the analysis included nerve root damage and intraoperative dural tear, the proportion of patients requiring revision surgery or recurrences, and infections. RESULTS: A total of 14 studies, encompassing 600 patients, were identified. Approximately 85% of patients improved significantly after TELF, without significant differences among different groups (85% vs. 78%, respectively). Mean leg pain decreased an average of 5.2 points, and ODI scores improved by 41.2%. Patients with previous spine surgery or failed back surgery syndrome had higher postoperative leg dysesthesia rates after TELF (14% vs. 1%, respectively). CONCLUSION: TELF is a useful and safe method to achieve decompression in foraminal stenosis. This technique is indicated in the elderly or patients with comorbidities. Preoperative planning is paramount in determining the foraminal size and endoscope trajectory. A diamond burr is recommended because it has an advantage over the regular endoscopic shaver in bleeding control and complication avoidance.

Cost-Effectiveness Analysis of Tapentadol Versus Oxycodone/Naloxone in both Branded and Generic Formulations in Patients with Musculoskeletal Pain.

BACKGROUND AND OBJECTIVES: Current evidence shows that tapentadol hydrochloride prolonged-release is more cost effective than other opioids. However, the introduction into the market of generic formulations of traditional comparators, leading to potential savings due to their lower price, creates space for further research. The objective of this study is to evaluate and compare the efficacy of tapentadol versus oxycodone/naloxone and the economic impact of the two alternatives in both branded and generic formulations. METHODS: A cost-effectiveness analysis was performed using the third-payer perspective (TPP), with specific reference to the Italian National Health Service. A Markov model was implemented to simulate transitions between states, comparing two arms: The first arm simulated the administration of tapentadol, while the second simulated the administration of oxycodone/naloxone, both branded and generic. The results were reported in terms of net monetary benefit (NMB). The willingness to pay (WPT) was estimated at €35,000/quality-adjusted life year. RESULTS: Tapentadol was dominant in all scenarios, assuming a population of 1000 individuals over a 1-year time horizon. In all cases, although the prices of oxycodone/naloxone generic formulations were lower, the costs associated with treatment discontinuation were always higher than those associated with tapentadol. The comparison with the branded formulation of oxycodone/naloxone was associated with the highest savings of €431.77 per patient, and with the highest NMB of €1943.77 per patient. CONCLUSION: The results of this pharmacoeconomic evaluation promote the use of tapentadol in comparison with oxycodone/naloxone, confirming the results obtained in previous studies with reference to the generic formulations.

Common Clinical Practice for Opioid-Induced Constipation: A Physician Survey.

BACKGROUND: Opioid-induced constipation (OIC) remains an important clinical obstacle despite the availability of several guidelines and pharmacological options for its management. Here, we surveyed common practices and perceptions about OIC among physicians who prescribe opioids in Italy. METHODS: The online survey included 26 questions about OIC. Responses were analyzed descriptively and aggregated by physician specialty. RESULTS: A total of 501 physicians completed the survey. Most respondents (67%) did not feel adequately educated about OIC despite general consensus regarding interest in the topic. Overall, 62-75% of physicians regularly evaluated intestinal function or OIC symptoms in patients receiving opioid therapy. The most common method for assessment was patient diary; few physicians used a validated instrument such as the Rome IV criteria. Psychiatrists and addiction specialists showed the lowest interest and poorest practices. Most respondents (78%) preferred macrogol prophylaxis followed by macrogol plus another laxative for first-line treatment of OIC symptoms. Peripheral-acting mu opioid receptor antagonists (PAMORAs) were not widely used among physicians; 61% had never prescribed a PAMORA for OIC. CONCLUSION: Our findings reveal important differences in clinical practice for OIC across physician specialties. Additional formative efforts are necessary to improve awareness about best practices in OIC.

H-Ras gene takes part to the host immune response to COVID-19.

Ras gene family members play a relevant role in cancer, especially when they are mutated. However, they may play additional roles in other conditions beside cancer. We performed gene expression analysis using the NanoString PanCancer IO 360 panel in the peripheral blood mononuclear cell (PBMC) of six COVID-19 patients and we found that H-Ras gene was significantly upregulated, while both K-Ras and N-Ras genes were downregulated. In particular, H-Ras gene upregulation was more evident in COVID-19 patients with a more severe disease. We compared our results with those obtained by analyzing two different and independent datasets, including a total of 53 COVID-19 patients, in which the gene expression analysis was performed using the Immunology_V2 panel. Comparative analysis of the H-Ras gene expression in these patients confirmed our preliminary results. In both of them, in fact, we were able to confirm the upregulation of the expression of the H-Ras gene. The exact role of this specific upregulation of the H-Ras gene in response to SARS-CoV-2 infection and its possible role in cancer still remains to be elucidated. In conclusion, H-Ras gene participates to the host immune response to SARS-CoV-2 virus infection, especially in patients affected by the most severe form of the COVID-19.