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Sabrina Bimonte,1,* Cira Antonietta Forte,1,* Massimiliano Cuomo,2 Gennaro Esposito,1 Marco Cascella,1 Arturo Cuomo1 1Division of Anesthesia and Pain Medicine, Istituto Nazionale Tumori - IRCCS - Fondazione G. Pascale, Naples, Italy; 2S.C. Project Management e Formazione, Istituto Nazionale Tumori - IRCCS - Fondazione G. Pascale, Naples, Italy*These authors contributed equally to this workCorrespondence: Sabrina BimonteDivision of Anesthesia and Pain Medicine, Istituto Nazionale dei Tumori, IRCCS Fondazione G. Pascale, Naples, ItalyEmail s.bimonte@istitutotumori.na.itAbstract: Coronavirus disease-19 (COVID-19) pandemic is currently ongoing worldwide and causes a lot of deaths in many countries. Although different vaccines for the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection have been developed and are now available, there are no effective antiviral drugs to treat the disease, except for Remdesivir authorized by the US FDA to counteract the emergency. Thus, it can be useful to find alternative therapies based on the employment of natural compounds, with antiviral features, to circumvent SARS-CoV-2 infection. Pre-clinical studies highlighted the antiviral activities of epigallocatechin-3-gallate (EGCG), a catechin primarily found in green tea, against various viruses, including SARS-CoV-2. In this review, we summarize this experimental evidence and highlight the potential use of EGCG as an alternative therapeutic choice for the treatment of SARS-CoV-2 infection.Keywords: COVID-19, EGCG, SARS-CoV-2, tea polyphenols, antiviral properties

Marco Cascella,1 Alfredo Del Gaudio,2 Alessandro Vittori,3 Sabrina Bimonte,1 Paola Del Prete,4 Cira Antonietta Forte,1 Arturo Cuomo,1 Elvio De Blasio2,5 1Division of Anesthesia and Pain Medicine, Istituto Nazionale Tumori-IRCCS-“Fondazione G. Pascale”, Naples, 80131, Italy; 2DSC Anestesia e Rianimazione 2, IRCCS Casa Sollievo Della Sofferenza, San Giovanni Rotondo, 71013, FG, Italy; 3Department of Anesthesiology and Critical Care, ARCO, Bambino Gesù Children’s Hospital, Rome, Italy; 4Direzione Scientifica, Istituto Nazionale Tumori-IRCCS-“Fondazione G. Pascale”, Naples, 80131, Italy; 5Multidisciplinary Emergency Unit for COVID-19 Campania, Naples, 80100, ItalyCorrespondence: Sabrina BimonteDivision of Anesthesia and Pain Medicine, Istituto Nazionale Tumori-IRCCS-“Fondazione G. Pascale”, Naples, 80131, ItalyTel +39 0815903221Email s.bimonte@istitutotumori.na.itAbstract: Although the respiratory manifestations of COVID-19 are predominant, signs and symptoms of an extra-pulmonary involvement are usually encompassed among the clinical picture of the disease. Several painful manifestations can occur during the acute phase but also as short- or long-term complications. Myalgia, joint pain, sore throat, abdominal pain, chest pain, and headache usually accompany respiratory symptoms, but they can also occur as isolated clinical findings or can be expressed regardless of the severity of COVID-19. On these premises, given the vast spectrum of clinical manifestations and the complexity of their pathogenesis, it would be more appropriate to refer to “COVID-pain”, an umbrella term useful for encompassing all these clinical manifestations in a separate chapter of the disease. In this scenario, we addressed the topic from a molecular perspective, trying to provide explanations for the underlying pathophysiological processes. Consequently, this narrative review is aimed at dissecting the mechanisms of acute and chronic painful manifestations, summarizing fundamental concepts on the matter, controversies, current research gaps, and potential developments in this field.Keywords: COVID-19, SARS-CoV-2, COVID-pain, COVID-19 complications

Arturo Cuomo,1,* Sabrina Bimonte,1,* Cira Antonietta Forte,1 Gerardo Botti,2 Marco Cascella1 1Division of Anesthesia and Pain Medicine, Istituto Nazionale Tumori, IRCCS - Fondazione G Pascale, Naples, Italy; 2Scientific Direction, Istituto Nazionale Tumori, IRCCS - Fondazione G Pascale, Naples, Italy *These authors contributed equally to this work Abstract: Chronic pain is described as a manifestation of real or potential tissue damage. It is identified as a perception influenced by the complex interactions of biological, psychological, and social factors. Different types of pain and their comorbidities dramatically affect patients’ quality of life and their families. Due to diverse etiology and pathogenesis, pain management represents a controversial issue in clinical practice. In 1986, the WHO developed a three-step ladder model based on the use of analgesics for pain management according to pain intensity in a linear up or down movement. Despite its huge value for pain relief, this model has some limitations, and some controversies in the pharmacotherapy of pain management have arisen so far. To bypass these difficulties, the concept of WHO analgesic ladder has been contested and changed into a four bidirectional step model which postulates the use of the invasive procedures (neuromodulatory and neurosurgical procedures). Moreover, with the introduction of the neuromatrix theory for dealing the acute and the chronic pain, the WHO model was newly reinterpreted and changed into a platform analgesic model that includes multimodal pharmacological and alternative treatments applicable to all pain conditions, although excludes the precision therapies. Here, we summarize and revise these concepts in order to propose a new model termed “trolley analgesic model” that will allow adopting tailored therapies with dynamic multimodal approaches for pain management according to 1) the pain intensity, 2) the physiopathology of pain, 3) the complexity of symptoms, 4) the presence of comorbidity, and 5) the physiopathological factors and the social context. Keywords: cancer and no-cancer pain management, personalized treatment, analgesic trolley, multimodal approaches

M Cascella,1 CA Forte,1 S Bimonte,1 G Esposito,1 C Romano,2 R Costanzo,2 A Morabito,2 A Cuomo1 1Department of Anesthesia and Pain Medicine, Istituto Nazionale Tumori, IRCCS – Fondazione G Pascale, Naples, Italy; 2Thoracic Medical Oncology, Istituto Nazionale Tumori, IRCCS – Fondazione G Pascale, Naples, Italy Background: Previous studies have shown the efficacy of tapentadol (TP) for chronic cancer pain. We evaluated multiple effectiveness aspects of TP prolonged release on moderate–severe cancer-related pain, neuropathic pain (NeP), patient satisfaction, and quality of life. Methods: An observational prospective study was conducted on 80 cancer patients. Opioid-naïve patients received a starting dose of prolonged-release TP 50 mg twice daily, and opioid-experienced patients were switched to TP, not to exceed 500 mg/day. Treatment response was evaluated at 3, 6, 30–40, and 60–70 days through response rate, numeric rating-scale scoring, survival analysis (time to event for response), pain-intensity difference, TP escalation-index percentage, and effects on NeP. The drug-sparing effect on concomitant therapies was evaluated. Results: Seventy of 80 patients (88%) were responders to treatment (95% CI 78%–94%). Compared to T0, pain-intensity reductions were statistically significant for all intervals (P

Background: Farmworkers in the United States, especially migrant workers, face unique barriers to healthcare and have documented disparities in health outcomes. Exposure to pesticides, especially those persistent in the environment, may contribute to these health disparities., Objective: Quantify differences in pesticide exposure bioactivity by farmworker category and US citizenship status., Methods: We queried the National Health and Nutrition Examination Study (NHANES) from 1999-2014 for pesticide exposure biomarker concentrations among farmworkers and non-farmworkers by citizenship status. We combined this with toxicity assay data from the US Environmental Protection Agency's (EPA's) Toxicity Forecaster (ToxCast). We estimated adverse biological effects that occur across a range of human population-relevant pesticide doses., Results: In total, there were 844 people with any farmwork history and 23,592 non-farmworkers. Of 12 commonly detectable pesticide biomarkers in NHANES, 2,4-dichlorophenoxyacetic acid (OR = 3.76, p = 1.33 × 10 -6 ) was significantly higher in farmworkers than non-farmworkers. Farmworkers were 1.15 times more likely to have a bioactive pesticide biomarker measurement in comparison to non-farmworkers (adjusted OR = 1.15, 95% CI: 0.87, 1.51). Non-U.S. citizens were 1.39 times more likely to have bioactive pesticide biomarker concentrations compared to people with U.S. citizenship (adjusted OR 1.39, 95% CI: 1.17, 1.64). Additionally, non-citizens were significantly more exposed to bioactive levels of β-hexachlorocyclohexane (BHC) (OR = 8.10, p = 1.33 × 10 -6 ), p,p-DDE (OR = 2.60, p = 0.02), and p,p'-DDT (OR = 7.75, p = 0.01)., Impact Statement: Farmworkers are a vulnerable population due to social determinants of health and occupational exposures. Here, we integrate US population chemical biomonitoring data and toxicity outcome data to assess pesticide exposure by farmwork history and citizenship. We find that farmworkers and those without US citizenship are significantly more likely to be exposed to concentrations of pesticides which are bioactive in toxicological assays. Thus, farmworkers employed in the US but who are not citizens could be at increased risk of harm to their health due to pesticides. These findings are important to shape evidence-based policies in regulatory science to promote worker safety., (© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Objectives: To assess pesticide exposure and understand the resultant health effects of agricultural workers in Northern Thailand., Methods: This was a cross-sectional study. We quantified exposure to pesticides, including chlorpyrifos, methomyl, and metalaxyl, by air sampling and liquid chromatography/mass spectrometry. We estimated differences in self-reported health outcomes, complete blood counts, cholinesterase activity, and serum/urine calcium and creatinine concentrations at baseline between farmworkers and comparison workers, and after pesticide spraying in farmworkers only., Results: This study included 97 men between the ages of 22 and 76 years; 70 were conventional farmworkers; and 27 did not report any prior farmwork or pesticide spraying. None of the farmworkers wore standardized personal protective equipment (PPE) for the concentrated chemicals they were working with. Methomyl (8.4-13 481.9 ng/m 3 ), ethyl chlorpyrifos (11.6-67 759 ng/m 3 ), and metalaxyl (13.9-41 191.3 ng/m 3 ) were detected via personal air sampling. When it came to reporting confidence in the ability to handle personal problems, only 43% of farmworkers reported feeling confident, which reflects higher stress levels in comparison to 78% of comparison workers (P = .028). Farmworkers also had significantly lower monocyte counts (P = .01), serum calcium (P = .01), red blood count (P = .01), white blood cell count (P = .04), and butyrylcholinesterase activity (P < .0001), relative to comparison workers. After adjusting for body mass index (BMI), age, and smoking, methomyl air concentrations were associated with a decrease in farmworker acetylcholinesterase activity (beta = -0.327, P = .016)., Conclusions: This population of farmworkers had significant alterations in stress measures and clinical biomarkers, including decreased blood cell counts and cholinesterase activity, relative to matched controls. These changes are potentially linked to occupational pesticide exposures. Improving PPE use presents a likely route for preventive intervention in this population., (© 2021 The Authors. Journal of Occupational Health published by John Wiley & Sons Australia, Ltd on behalf of The Japan Society for Occupational Health.)

An estimated 70-90% of all cancers are linked to exposure to environmental risk factors. In parallel, the number of stem cells in a tissue has been shown to be a strong predictor of risk of developing cancer in that tissue. Tumors themselves are characterized by an acquisition of "stem cell" characteristics, and a growing body of evidence points to tumors themselves being sustained and propagated by a stem cell-like population. Here, we review our understanding of the interplay between environmental exposures, stem cell biology, and cancer. We provide an overview of the role of stem cells in development, tissue homeostasis, and wound repair. We discuss the pathways and mechanisms governing stem cell plasticity and regulation of the stem cell state, and describe experimental methods for assessment of stem cells. We then review the current understanding of how environmental exposures impact stem cell function relevant to carcinogenesis and cancer prevention, with a focus on environmental and occupational exposures to chemical, physical, and biological hazards. We also highlight key areas for future research in this area, including defining whether the biological basis for cancer disparities is related to effects of complex exposure mixtures on stem cell biology., (Copyright © 2019. Published by Elsevier Inc.)

Adolescent tobacco use is influenced by intrapersonal (e.g., impulse control) and external factors, such as behaviors of friends and peers. The relationships of these factors to smokeless tobacco (ST) use are not yet fully understood. This is especially true as it pertains to the simultaneous examination of psychological and normative perceptions. Using constructs of the Biopsychosocial Model, this study investigates factors associated with lifetime ST use among middle and high school students. Data were analyzed from 938 Indiana middle and high school students. Binary sequential logistic regression was performed to examine the relationship of personal characteristics and psychosocial measures to adolescent lifetime ST use. Approximately 9 % reported having ever used ST, among which 78.6 % were male. Females and younger students were less likely to have used ST in their lifetime, whereas participants with a sibling smoker and those who compared their life to the lives of others were more likely to report lifetime ST usage. In the presence of psychological and normative variables, sex, age, and comparing one's life to others remained significant. Additionally, participants who perceived higher friend approval of substance use were significantly more likely to report lifetime ST use. Understanding the normative perceptions of adolescents may lend insight into the drivers of ST use adolescent subgroups and, which may enable community and school officials to tailor interventions to prevent ST initiation and promote cessation.