Neuropathic pain, whose symptoms are characterized by spontaneous and irritation-induced painful sensations, is a condition that poses a global burden. Numerous neurotransmitters and other chemicals play a role in the emergence and maintenance of neuropathic pain, which is strongly correlated with common clinical challenges, such as chronic pain and depression. However, the mechanism underlying its occurrence and development has not yet been fully elucidated, thus rendering the use of traditional painkillers, such as non-steroidal anti-inflammatory medications and opioids, relatively ineffective in its treatment. Astrocytes, which are abundant and occupy the largest volume in the central nervous system, contribute to physiological and pathological situations. In recent years, an increasing number of researchers have claimed that astrocytes contribute indispensably to the occurrence and progression of neuropathic pain. The activation of reactive astrocytes involves a variety of signal transduction mechanisms and molecules. Signal molecules in cells, including intracellular kinases, channels, receptors, and transcription factors, tend to play a role in regulating post-injury pain once they exhibit pathological changes. In addition, astrocytes regulate neuropathic pain by releasing a series of mediators of different molecular weights, actively participating in the regulation of neurons and synapses, which are associated with the onset and general maintenance of neuropathic pain. This review summarizes the progress made in elucidating the mechanism underlying the involvement of astrocytes in neuropathic pain regulation. As a result, astrocytes potentially transmit calcium waves and participate in the dissemination of various long-distance signaling molecules. Astrocytes also form a physical barrier around synapses, thus “shielding” them from glutamate overflow while simultaneously providing metabolic support. Furthermore, owing to their proximity to synapses, astrocytes modulate the local intervening ionic and chemical environment during synaptic formation and propagation. Thus, astrocytes play a pivotal role in governing synaptic formation, maturation, removal, and maintenance as well as supporting synaptic activity via a combination of diffusible and interaction factors. Loss-of-function disorders of astrocytes may constitute the basis of various forms of neurological dysfunction and pathology, including trauma, stroke, multiple sclerosis, and Alzheimer’s disease  to the sciatic nerve , partialIn the CNS, glial cells outnumber neurons by a factor of 10–50, predominantly including astrocytes, microglia, and oligodendrocytes . Astrocyin vivo non-traumatic approaches , astrocytes have been thoroughly studied, and their roles encompass a broad variety of dynamic physiological compositions and functionalized features: water and ion homeostasis, metabolic specialization, and brain oxidation  or hours  to follow also exist. Longer activation states, such as astrogliosis, may require longer periods of time, such as tens of hours or even days to appear .Astrocytes are generally believed to regulate pain mainly through the following three activation states: (1) changes in glial signaling pathways, such as changes in the phosphorylation level of mitogen-activated protein kinase (MAPK) and expression of transcription factors; (2) changes in the expression of receptors and channel proteins, such as the upregulation of inflammatory factor receptors and gap junction proteins and downregulation of glutamate transporters; and (3) continuous production and excretion of various glia-derived factors, such as cellular factors, chemokines, and proteinases .via obstructing a glial cell enzyme in the astrocytic Krebs cycle. Several mouse models of pain that had undergone intrathecal injection of FC or fluoroacetate demonstrated relief from pain sensation  inhibitors AG490 and JAK inhibitor I to the spine resulted in the inhibition of astrocyte proliferation during astrocyte restriction and STAT3 activation. Furthermore, the inhibition of astrocyte proliferation by JAK-STAT3 signaling inhibitors potentially leads to the recovery of haptic pain . Therefoin vitro studies have also confirmed that miR-135-5p potentially inhibits the JAK2-STAT3 signaling pathway in bone cancer pain, and histological staining has proven that miR-135-5p can directly interrupt the activity process of JAK2 and its upstream and downstream molecules in astrocytes (via the modulation of astrocyte activation.Some experiments have demonstrated that the proliferative capacity of astrocytes intervened by AG490 or with STAT3 defects is reduced to a certain extent . Liu et trocytes . These sOligodendrocyte transcription factor 2 (Olig2) is an essential transcription factor required for the proliferation and derivation of developmental astrocytes. Olig2-labeled subsets of astrocytes have been detected in clusters and in greater numbers in certain fixed zones of the thalamus, midbrain, and spinal cord of rodents . By ablaTransforming growth factor betas (TGF-βs), as versatile growth factors, are involved in critical events in the body that regulate growth, illness, and wound healing. TGF-β1 has been extensively known to be a cytokine implicated in injury, especially in the activation of astrocytes and scar production . TGFβ isAs a member of the Ras homolog gene family, the small G protein RhoA is widely expressed in astrocytes and participates in cytoskeletal regulation together with its downstream effector Rho-dependent kinase (ROCK) by regulating myosin and actin . The expMany signaling molecules exist in astrocytes, including intracellular kinases, channels, receptors, and transcription factors, exhibiting pathological changes and playing a role in pain regulation after injury.The MAPK family, which is composed of P38, extracellular signal-regulated kinase (ERK), and C-Jun N-terminal kinase (JNK), plays a crucial role in pain regulation . DifferePhosphorylated ERK has been observed in spinal astrocytes during the late stage of pain induced by complete Freund’s adjuvant . In an eJanus kinase has been shown to engage in the regulation and sustainment of nociception by astrocytes after nerve damage . P-JNK iTo date, relatively few ion channels and receptors that are involved in the activation of astrocytes, thus ultimately leading to the development of neuropathic pain, have been identified .Toll-like receptor 4 (TLR-4) is widely present throughout astrocytes. Overexpression of the high mobility group box-1 (HMGB1) protein potentially downregulates the paw withdrawal mechanical threshold and paw withdrawal thermal latency in CCI rodents by enhancing the activation of astrocytes, the TLR4/NF-κB axis, and its upstream and downstream molecules, resulting in the enhancement of neuropathic pain . A subjeA shortened isomeric form of tyrosine receptor kinase B (TrkB) has recently been found to be implicated in the pathological process of neuropathic pain . The TrkConsidering the prevalence of neuropathic pain and incurable suffering associated with it, the study of ion channels and receptors associated with astrocytes is a potentially new opportunity to bring hope to affected people worldwide. AV411 (ibudilast), an antagonist of TLR4, is currently undergoing phase II clinical trials and has previously been shown to exert satisfactory efficacy in various models of neuropathic pain by inhibiting cytokines produced by glial cells as well as promoting the production of the anti-inflammatory cytokine IL-10 and neurotrophic factors . This prAstrocytes form a network of gap junctions through Ca2+ signals in the form of calcium oscillations . The maiAstrocytes regulate neuropathic pain by releasing a series of mediators of different molecular weights. Macromolecular mediators are represented by cellular factors , chemokines , growth factors , and proteases , among others. Small molecular media predominantly comprise glutamic acid and ATP, among others. These mediators actively participate in the regulation of neurons and synapses and are inextricably linked to the onset and maintenance of neuropathic pain.IL-1β is a well-known proinflammatory cytokine. IL-1β upregulation has been observed in spinal cord astrocytes following peripheral nerve lesions. Increasing evidence suggests that IL-1β is involved in pain sensitivity . IntrathChemokines, a specific group of cell factors possessing over 50 family components, are widely believed to exist in the blood and immune system and have recently been found to be widespread in the CNS and particularly active in astrocytes . ChemokiCCL3 has also been found to cause neuropathic pain through IL-1β upregulation . CXCL1, Proteases expressed in astrocytes, such as matrix metalloproteinases (MMPs) and tissue-type plasminogen activators (tPAs), have been found to play a key role in the development of neuropathic pain driven by astrocytes . DiffereAs an extracellular serine protease, tPA participates in the regulation and revision of tissue components located outside the cell, leading to alterations in neuroplasticity . One stuGABA) and decreased conductance of presynaptic gamma-aminobutyric acid (GABA). These provide BDNF the ability to enhance the synaptic activity of excitatory neurons, thus promoting the development of neuropathic pain , which play a key role in nociceptive regulation . Belief CCL2 and CXCL1 have been found to be expressed in spinal cord astrocytes, act on CCR2 and CXCR2 in spinal cord neurons, and thus potentially play a role in increasing excitatory synaptic transmission. Studies on electrophysiological aspects found CCL2 to immediately enhance NMDA-induced currents and increase the frequency of excitatory postsynaptic currents in spinal cord lamina II neurons. Co-stimulation of spinal cord neurons with CCL2 and GABA resulted in a dose-dependent and rapid decrease in GABA-induced inward currents . CCL7 m. These fvia astrocytes may emerge as a new alternative for affected patients. In fact, several experimental studies are already underway. Dexmedetomidine has been found to effectively inhibit HMGB1-mediated astrocyte activation and the TLR4/NF-κB signaling pathway in CCI rats and successfully relieve neuropathic pain in rats , and some anticonvulsants. These drugs only provide pain relief but do not completely eradicate neuropathic pain, and they often produce a number of side effects . Other a in rats . Koumine in rats . Triptol effects . All theTo conclude, astrocyte activation and the changes in the signaling pathways and molecular mechanisms involved in the spinal cord and supraspinal structures contribute indispensably to the progression and sustainment of neuropathic pain. Elucidating the mechanism underlying astrocyte activation is of great significance to the progress and development of pain management worldwide. Currently, the exploration of new targeted pain treatments in the wake of opioid overdependence and overuse is of particular importance. Research on the role played by astrocytes in neuropathic pain is expected to realize the clinical transformation of animal experimental research, which is of great significance for human happiness and quality of life.XM: conceptualization, writing-reviewing, and editing. TC: writing-original draft preparation. ZX: supervision. All authors have approved the final version of the manuscript to be submitted.


Older patients are increasingly showing multi-comorbidities, including advanced chronic diseases. When admitted to the emergency department (ED), the decision to pursue life-prolonging treatments or to initiate a palliative care approach is a challenge for clinicians. We test for the first time the diagnostic accuracy of the Supportive and Palliative Care Indicators Tool (SPICT) in the ED to identify older patients at risk of deteriorating and dying, and timely address palliative care needs.We conducted a prospective bicentric cohort study on 352 older patients (≥ 75 years) admitted to two EDs in Belgium between December 2019 and March 2020 and between August and November 2020. SPICT  variables were collected during the patients’ admission to the ED, along with socio-demographic, medical and functional data. The palliative profile was defined as a positive SPICT assessment. Survival, symptoms and health degradation  were followed at 12 months by phone. Main accuracy measures were sensitivity, specificity and likelihood ratios (LR) as well as cox regression, survival analysis using the Kaplan Meier method, and ordinal regression.Out of 352 patients included in the study , 167 patients (47%) had a positive SPICT profile. At one year follow up, SPICT positive patients presented significantly more health degradation (72%) compared with SPICT negative patients . SPICT positivity was correlated with 1-year health degradation . The sensitivity and specificity of SPICT to predict health degradation were 0.65  and 0.72  respectively, with a negative LR of 0.48  and a positive LR of 2.37 (1.78–3.16). The survival time was shorter in SPICT positive patients than in SPICT negative ones (p < 0.001), the former having a higher 1-year mortality rate .SPICT successfully identifies older patients at high risk of health degradation and death. It can support emergency clinicians to identify older patients with a palliative profile and subsequently initiate a palliative care approach with a discussion on goals of care. The benefits of a palliative care approach are well known. It increases patients’ chance of passing away in the comfort of their own home, improves the quality of life and alleviates burdensome symptoms such as depressive symptoms and pain –6. PatieUp to a quarter of ED patients are aged 65 and over . Older pInitiating a palliative care approach remains a challenge in EDs. It is difficult for emergency clinicians to decide whether to pursue invasive and uncomfortable life-prolonging treatments or to reassess intensity of treatment and consider a palliative care approach . For somInitiating a palliative care approach in EDs is not much studied, but presents interesting results such as shortened hospital stay , reducedHowever, a major challenge in implementing a palliative care approach is to identify which patients might benefit from such care. There is a lack of consensus about the illness stage from which it is advisable to initiate palliative care for each specific disease . TransitSeveral tools aim to identify patients who might benefit from a palliative care approach , 30. TheThe aim of this study is to assess the SPICT accuracy to predict 1-year health degradation and death in older patients admitted to ED.The paper is reported following the STROBE statement.www.spict.org.uk. Permission to use it was obtained.The aim of the study is to assess the SPICT  accuracy to predict 1-year health degradation and mortality while used during an ED admission of older patients aged 75 years old or more. The SPICT is a tool composed of 6 general indicators of health deterioration and 23 indicators of severity of specific-diseases which aim at identifying patients with a palliative profile . SPICT aWe conducted a prospective cohort study in the emergency department of two tertiary Belgian hospitals between end-December 2019 and November 2020. The patient’s inclusion lasted 6 months in total, with an interruption between mid-March to mid-August 2020 due to the Covid-19 pandemic.All French speaking patients of 75 years old or more admitted to ED were eligible for the study. Patients unable to give consent were included if their legal representative approved the participation. We excluded dying patients or patients previously included in the study. Dying patients were defined as likely to die within 24 h following admission to the ED.Three researchers collected data during office hours (8 am to 6 pm). Training and supervision on data collection was performed before and during the whole period to ensure the quality and homogeneity of data collection. The supervision was realised by the main investigator who is a geriatrician (IDB) and included weekly discussions on patient inclusion and random checks of SPICT completion based on medical records.The researchers carried out face-to-face interviews with the patient or their legal representative during ED admission to obtain data on demographic, psycho-social characteristics, functional status using Katz , Lawton From the beginning of the COVID-19 pandemic, we did not include patients admitted in COVID-area of the ED for practical and security reasons.The principal researcher (DB) followed-up patients by phone at 12 months after ED admission. Data collected in the follow-up calls were mortality , functional status (Katz), place of residence in the last 3 months of life, number of readmissions , palliative care in the last 3 months and symptoms  .The main outcome measure is health degradation. Health degradation is a composite outcome that intends to be more comprehensive than mortality alone, as mortality has its limits in justifying a palliative care approach. Health degradation combines the Katz score, the institutionalisation in a nursing home and mortality. Health degradation is a categorical variable with three levels. Score 1 corresponds to an improvement or constancy in the person’s health status . Score 2 corresponds to a decrease in functional capacity according to the Katz scale  or to a patient being institutionalized. Score 3 corresponds to death.The palliative profile was defined by a positive SPICT assessment, i.e. when at least one general and one disease specific indicator of the SPICT were identified . The indContinuous variables were described using mean and standard deviation. Categorical variables were described using the number and their percentage. Comparisons of patient characteristics, between patients with or without a palliative profile, were assessed with t-test for continuous variables and Chi-squared for categorical variables. Symptoms at 1 year after ED admission were compared between groups with and without a palliative profile with a non-parametric median test for independent groups, corrected for Yates continuity.The accuracy of SPICT to predict 1-year health degradation and death is assessed by sensitivity, specificity, likelihood ratio, positive and negative predictive values and the overall accuracy (proportion correctly classified). To perform these analyses, the variable “health degradation” was binarised, i.e., no health degradation (0 = score 1) and health degradation (1 = score 2 or 3). Association between SPICT and health degradation (3 levels variable) was assessed through a 3-level ordinal regression, adjusted for age (continuous variable) and gender . A multi-variable cox-regression was used to assess the association between SPICT and 1-year mortality, also adjusted for age (continuous variable) and gender . A survival analysis was performed on mortality using Kaplan Meier method.The statistical analyses were computed using IBM SPSS software V27 and NCSS 2021.The Ethical Committees of the two participating hospitals gave their agreement. The study registered number is B403201941609. Informed consent was signed before any data collection by the patients and/or their legal representative.The flowchart for the inclusion of patients in the study is presented in Fig. The mean age of our participants was 83 years old. Of the 352 patients included, 43% n = 150) were male and 49% (n = 172) were living in partnership. Wishes for end-of-life care or DNR code was known for 2.3% (n = 8). Results of advance care planning weren’t available for any patient. The main diagnoses (ICD-10CM chapters) at admission to ED were ‘abnormal signs’ (23%), circulatory system (19%), injury and other consequences of external causes (15%) and digestive system (9%)  had a palliative profile, i.e. a positive SPICT assessment. Patients with a palliative profile were significantly older  with a higher proportion of patients aged 85 or more . They more often lived in nursing homes  and received more formal or informal care . Patients with a palliative profile were more dependant for daily activities  and for the instrumental activities of daily living (iADL)  which means their functional status was poorer. They had more often comorbidities  and used more medications . During ED admission, patients with a palliative profile got more treatment limitations . After ED admission, patients with a palliative profile were more often hospitalised , and died significantly more at 6-month  and 12-month   Table .2 = 34.0, p < 0.001)   and they presented significantly more health degradation 72%) compared the non-palliatives ones . Most deaths occurred in the first 6 months after the ED admission. The odds ratio of health degradation was 5 times greater and the hazard ratio of death was 4 times greater for older patients with a palliative profile compared to the non-palliative ones. The results of the diagnostic accuracy of the SPICT were moderate in predicting 1-year health degradation (AUC: 0.69) and death (AUC: 0.65). Our preliminary analyses showed that using health degradation instead of death improved slightly the overall accuracy of the SPICT, the specificity (0.72 vs. 0.61), the positive LR (2.37 vs. 2.00) and the positive predictive value (0.72 vs. 0.37). However, it reduces the sensitivity (0.65 vs. 0.77)  0.82, sensitivity 0.82, specificity 0.49 ; AUC 0.7The main objective of the SPICT is to support clinician to early identify patient at risk of health degradation and death, who may benefit from palliative care approach, which is a major difficulty for clinicians (41). In our study we found that patients with a positive SPICT assessment have 72% risk of health degradation within the year. The overall accuracy of 69% to predict health degradation is satisfying. In addition, the SPICT positive patients surviving after one year have exacerbated symptoms compared to SPICT negative patients. These elements should alert clinicians to think about palliative care and adapt their routine of care in ED. The early identification of patients who might need palliative care is important for patients who will gradually present health degradation and die in the next months. SPICT can sensitise the ED clinicians on early palliative care which is not reserved for the very end-of-life (last days or weeks of life) and which is also appropriate for other chronic conditions than cancerous diseases . When a A strength of our study is our main outcome measure “health degradation” and the symptoms assessment during follow-up, while most studies on the SPICT measures death as main outcome. In testing SPICT within EDs, we tried to conciliate two “a priori” opposite logics of care, namely palliative care and urgent-life sustaining care. Research on palliative care in ED and their guidelines are quite rare and recent .The impact of covid-related deaths was not assessable because the cause of death was missing in 36% of the patients due to the follow-up by phone calls. For the other patients, covid was incriminated in 11% of cases (data not shown).Our cohort of old patients admitted in ED may differ from the entire population. We included patients during office hours, we collected data on patients we could not include during our shift. We do not have information about the patient’s characteristics outside office hours.SPICT successfully identifies older patients at high risk of health degradation and death within one year. SPICT could be an interesting tool to support emergency clinicians to identify older patients with a palliative profile and subsequently initiate a palliative care approach with a discussion on the goals of care. Further research is needed to assess the feasibility of implementing SPICT and the ED’s role in early introduction of a palliative care approach.


The GEMA presented good practicality, acceptability, and evidence of specificity regarding the stability of the INR. The validity of the construct was partially supported by the relationship with self‐reported measures of adherence.Although self‐report instruments are currently considered a valuable tool for measuring adherence, due to their low cost and ease of implementation, there are still important factors that impact measurement accuracy, such as social desirability and memory bias. Thus, the Global Assessment of Medication Adherence Instrument (GEMA) was developed to provide an accurate measure of this construct. The aim of this study was to evaluate the properties of the measurement of the Global Evaluation of Medication Adherence Instrument (GEMA) among patients with chronic diseases. A methodological study was conducted in the public hospital of the state of São Paulo, Brazil. The adherence to anticoagulants as well as the international normalized ratio (INR) was assessed on 127 patients. Besides GEMA, two other instruments were used to assess adherence: the Morisky Medication Adherence Scale‐8 (MMAS‐8) and the Measurement of Adhesion to Treatments (MAT). The GEMA presented a satisfactory level of specificity (0.76) to identify adherents among those with a stable INR, low sensitivity (0.43) for the identification of non‐adherents among those with an unstable INR, and a Positive Predictive Value of 0.70. Positive and weak to moderate correlations were observed between the proportion of doses assessed with GEMA and the scores on the MMAS‐8 ( COSMINConsensus‐based Standards for the Selection of Health Measurement InstrumentsGEMAGlobal Assessment of Medication Adherence InstrumentINRInternational Normalized RatioMATMeasurement of Adhesion to TreatmentsMMAS‐4Morisky Medication Adherence Scale‐4MMAS‐8Morisky Medication Adherence Scale‐8NCDsNo Communicable DiseasesNPVNegative Predictive ValueOACOral AnticoagulantsPPVPositive Predictive ValueTTRTime in therapeutic range1In the treatment of chronic no communicable diseases (NCDs), adherence to medication use has been associated with optimization of clinical outcomes, especially better disease control, reduction of hospitalizations, mortality, and health care costs.Theory of Self‐care of Chronic Illness, self‐care can be defined as a process of health maintenance by means of health practices and disease management, which can be applied to health and disease situations.Medication adherence is one of the most complex self‐care behaviors in the treatment of NCDs.Nurses have a central role in promoting self‐care,There are several difficulties in measuring adherence.Morisky Medication Adherence Scale (MMAS) consisting of four items (MMAS‐4)Several self‐report scales that measure adherence in chronic diseases are available in the literature.Global Evaluation of Medication Adherence Instrument (GEMA)In order to provide an accurate measure of medication adherence, the This new instrument seeks to fill the gaps in the literature regarding the imperfections of self‐report measures.22.1This was a methodological study outlined according to the COnsensus‐based Standards for the selection of health Measurement Instruments—COSMIN2.2The study included 127 adult patients taking OAC in an outpatient follow‐up service. Patients who had been using OAC for at least 6 months were included. Patients whose OAC dosage was modified in the last month prior to the interview, who presented hemorrhagic or thromboembolic complications in the last 3 months, or who underwent surgery in the last 6 months prior to the interview were excluded.2.3The sample size was calculated with the aim of estimating the sensitivity of the tool for assessing overall medication adherence. Sensitivity, in the present study, can be defined as the probability of an individual being classified as adherent by means of the global adherence assessment instrument, given that he/she has been classified as adherent by the gold standard instrument . To carry out the sample calculation, estimates of sensitivity, specificity and prevalence were obtained from a pilot sample composed of 50 subjects. In addition, a significance level of 5%, a test power of 80% and a sensitivity value equal to 0.50 were established as a null hypothesis. From the pilot sample, estimates of sensitivity, specificity and prevalence equal to 0.65, 0.57 and 0.86 were obtained, respectively. The results indicated a sample of 105 subjects. Considering a loss rate of 20%, the final sample will consist of 127 participants.2.4Data were obtained by means of interview, using instruments. The results of the last three INR dosages, and the individual therapeutic goal recommended for each patient, were obtained from the medical record.2.5Instrument of sociodemographic and clinical characteristics: was developed in a previous study2.5.1Part I: Completed by the interviewer, in order to transcribe the OAC prescribed, and in use by the patient, considering the dose, the dosing schedule (number of tablets/day), how to use it, , as well as calculating the total pills taken per day , care taken when taking the OAC, the proportion of adherence, and classification of care, in the past day, past week and past month. Items regarding medication intake in the previous day and week, were aimed at minimizing memory bias. The percentage of adherence to the prescribed dose is estimated considering the dose prescribed and the dose missed or taken beyond prescribed according to the calculation: ([prescribed doses−wrong doses] × 100/prescribed doses). Considering that the use of OAC than those prescribed does not result in adherence, the adherence results higher than 100% are converted by subtracting the percentage related to the over dosage, as shown below: 120% adherence, subtraction of the overdose (20%) resulting in adherence (100%–20% = 80%).2.5.2Is composed of eight items: seven with dichotomous answers (yes/no), and one Likert‐type item .2.5.3The Measurement of Adherence to Treatments (MAT) consists of seven items that evaluate the daily behavior of medication intake, and whether the patient stopped taking the medications, for any reason. These items were adapted from other adherence measures. The Brazilian version of the MAT was adapted in patients using OAC,2.5.4In order to determinate of the stability of the INR, three INR dosage results, performed up to 4 months prior to and on the day of the interview, were used to calculate INR stability2.6p‐value lower than .0167 was considering after applying the Bonferroni correction to the significance level in the McNemar's test. The Bonferroni correction in the significance level was applied because the same comparison was done in each of the three time points . To the remaining tests the significance level was of 5%. The Shapiro–Wilk test was applied to evaluate the data distribution.Sociodemographic/clinical characteristics and adherence data were submitted to descriptive analysis. Friedman's ANOVA test was used to identify the differences in adherence ratios estimated by GEMA on the past month prior to the interview, using Dunn–Bonferroni post‐test to locate the differences. The McNemar's test was used to compare adherent and non‐adherent individuals the previous day, the past week, and the past month prior to the interview. A Practicality and acceptability: Evaluated by the mean time spent administering the questionnaire, and by the percentage of respondents who answered all the items, respectively.Sensitivity, specificity, PPV and NPV: The sensitivity and specificity of the GEMA, MMAS‐8 and MAT in relation to the INR stability, the clinical reference pattern for assessing the level of anticoagulation, were tested. Sensitivity was defined as the proportion of patients who were classified as non‐adherent in the instruments among all patients that were classified as having an unstable INR (by means of the INR stability criteria). Specificity was defined as the proportion of patients who were classified as adherent among all patients that were classified as having a stable INR. The PPV was defined as the proportion of patients who were classified as having an unstable INR among all patients that were classified as non‐adherent. The NPV was defined as the proportion of patients who were classified as having a stable INR among all patients that were classified as adherent.Construct validity: It was tested considering the hypothesis that the global adherence measure provided by the GEMA and the measurements of the MAT and MMAS‐8 evaluate related but not identical constructs. This validity was estimated by the relationship between the percentage of doses (past month) of GEMA and MAT and MMAS‐8 scores. The Spearman correlation coefficient was used; the magnitude of the correlations was considered: weak for correlations close to 0.29; moderate for correlations between 0.30 and 0.49; and strong for those with correlations >0.50.Convergence construct validity was also tested by agreement between the GEMA—global evaluation adherence (percentage of doses and care taken in medication intake) and the adherence score obtained by the MAT and the MMAS‐8. It was assumed that the GEMA evaluates adherence based on the proportion of medication effectively taken according to medical prescription as well as on medication‐taking self‐care to classify patients into adherents and non‐adherents. MAT and MMAS‐8, in turn, are based on factors related to nonadherence to proceed the classification. Thus, as the tools are not measuring the same factors underlying adherence, agreement of weak or moderate magnitude were hypothesized between the classifications of adherents and non‐adherents by GEMA (past month), and those based on the MAT and the MMAS‐8. The Kappa coefficient was used, considering: poor agreement <.00; negligible = 0.00–0.20; weak = 0.21–0.40; moderate = 0.41–0.60; strong = 0.61–0.80; and almost perfect = 081–1.0.A significance level of 5% was adopted for these analyses.3The sample consisted of 50.4% women, married (63.8%), aged 56.5 (12.1) years, with 5.5 (3.7) years of study, unemployed (65.4%), and with a mean monthly family income of 2.6 (2.2). The sample presented about 1.9 (1.3) clinical conditions associated and mean time of anticoagulation was 55.5 (51.8) months.3.1The descriptive data for adherence measurements are presented in Table p = .0027 and <.0001, respectively, McNemar's test).The values of adherence provided by GEMA presented a progressive reduction as the period of reference of the measure passed from the day prior the interview to the last past month. These differences were significant to the proportion of patients classified as adherents 84.2% (107); 72.4% (92) 65.3% (83)  were considered unstable in relation to the individual therapeutic goal. The mean stability of INR was 44.1% (34.7).3.2Regarding practicality, the application of GEMA by interview took a mean time of 3.6 (1.6) min. Regarding acceptability, the rate of responses for the items was 100%.The sensitivity and the specificity of the GEMA in the past month were tested against the INR, considering its stability in the last three measurements, according to the indicated therapeutic goal.It was observed that GEMA is specific (0.76) for detecting the proportion of people who were adherent among those with a stable INR, but the GEMA is less sensitive (0.43) for detecting who was non‐adherent among those with an unstable INR. In other words, among the patients with a stable INR, most are assessed as adherent; among those with the non‐stable INR, although there are more adherents than non‐adherent's patients, there is a good concentration of non‐adherent patients. The GEMA also presented a PPV of 0.70 and NPV of 0.52.It was verified that the performance of the GEMA is more consistent with the stability and instability results of the INR, when compared to the other adherence measures used in the present study. The MAT does not distinguish between adherence and non‐adherence among patients who present stable and unstable INR, as it classifies the expressive majority as adherents. The MMAS‐8 performs more similarly to GEMA, but among patients with stable INR, most patients are considered non‐adherent. The limits of both tools (MAT and MMAS‐8) in detecting those who were non‐adherent seems to be related to an overestimating of adherence in the studied sample Table .3.3The convergent construct validity was tested by correlation between the adherence ratio, estimated by proportion of doses of the GEMA, and the adherence scores obtained by MAT and MMAS‐8. Positive low magnitude correlations were expected between the percentages of doses obtained  and the adherence scores of the MAT and MMAS‐8 Table .r = .30) and in the past week (r = .22), estimated by the GEMA and MAT scores. Correlations of low magnitude were identified between the proportion of GEMA adherence in the past week, and the total score of MMAS‐8 (r = .26), and in the month prior to the interview . The agreement among GEMA and the adherence classification of the MMAS‐8 was higher, according Landis & Koch,4The study aimed to evaluate the properties of measurement of the GEMA instrument, when administered to outpatients in use of OAC.The application of GEMA by interview seems to be relatively fast, even with the need of thinking about the use of the medication in three different periods, what reinforces the acceptability of the tool. The short time of application of instrument is an important aspect, especially in patients with chronic diseases, whose treatment involves several simultaneous evaluations. Consequently, the use of measurement with a long time of application can imply in the commitment of the dynamism in the care of these patients.The rate of responses to the items was 100%, although it could be facilitated by the mode of interview. With the sample population, the interview was the choice for the application of the tool due to the low level of schooling. It would be interesting in further studies to analyze the potential of self‐administration of the tool.Regarding, the GEMA sensitivity, specificity, PPV and NPV analyses, in relation to INR stability, considered as the clinical reference measure, the data showed that the GEMA is an instrument capable of identifying those who are adherent among those who had a stable INR. There was a limited ability noted to identify individuals who were non‐adherent among those with unstable INRs, which makes it possible to classify a large proportion of individuals with unstable INRs as non‐adherent (PPV = 0.70).However, the GEMA presents an overall better performance to the Brazilian versions of MAT and MMAS‐8, considering that MAT seems to overestimate adhesion, while MMAS‐8 overestimates non‐adhesion, and a possible explanation is that both instruments (MAT and MMAS‐8) do not consider self‐care, which includes the assessment of adequate dose implementation, schedule, time frames associated with taking the OAC, and adoption of specific care. On the other hand, the MMAS‐8 showed a slightly higher sensitivity to INR stability than the GEMA, that is, a better ability to identify those who were non‐adherent among individuals with unstable INR, but with limited capacity to identify who was adherent among those with stable INRs.A Korean validation study of the MMAS‐8, which adherence to antihypertensive medication was classified as low (score <6) and medium/high adherence (score ≥6), showed sensitivity, specificity, PPV and NPV in relation to blood pressure measurement of 64.3%, 72.9%, 29.5% and 92%, respectively. However, when the classification of low and medium adherence (score <8) and high adherence (score = 8) were used, the MMAS‐8 presented sensitivity, specificity, PPV and NPV of 82.1%, 36.9%, 18, 7% and 92.1%, respectively.In contrast, in the MMAS‐8 validation study performed in Singapore that considered those with a score <8 to be non‐adherent, and which used the time in therapeutic range (TTR) of the INR as the gold standard, the sensitivity, specificity, PPV and NPV results were 73%, 35.6%, 49.5% and 60.5%, respectively,GEMA performs better probably because it considers factors that describe behavior more than the other two measures, which are based on factors that influence adherence and the establishment of arbitrary cutoff points.The convergent construct validity of the GEMA, tested by means of the ratio between the proportion of doses , and the MAT and MMAS‐8, showed significant positive correlations between low and moderate magnitude between the estimated proportion of GEMA in the past month prior to the interview, and the MAT and MMAS‐8 scores, partially supporting the validity convergent construct of the GEMA.As to the agreement between the global adherence (proportion and care) of the GEMA and the Brazilian versions of the MAT and MMAS‐8, used to test validity, showed a negligible agreement with the MAT and weak agreement with the MMAS‐8, according to the Brazilian classification, which corroborates the hypothesis that the MAT and MMAS‐8 instruments measure related constructs, but not concepts that are identical to the GEMA adherence measure. The MMAS‐8 items evaluate different aspects related to nonadherence, while the GEMA, when measuring the percentage of doses and the care taken in the medication, deviates the focus away from nonadherence factors. In fact, these factors are investigated among patients classified as non‐adherent, but are not considered in the measurement of the adherence measure provided by the GEMA, which may have contributed to the poor agreement obtained among the instruments.The findings obtained with the use of GEMA suggest that the search in one's memory for the behavior of adhering to medications at different moments in time, that is, from the day before the interview to the past month , enable more accurate measurement, evidencing an important role of the GEMA in reducing memory bias in adherence measurement.Gagné and Godin consider that memory bias should be minimized by specifying the period of time for questions that investigate nonadherence.The measurement provided by GEMA has potential applications for clinical and research practice. With regard to clinical implications, this instrument can be used to identify specific situations in different chronic conditions, related to the proportion of adherence and self‐care in taking medication as prescribed by the physician, thus enabling health professionals to direct actions toward promoting adherence to pharmacological treatment.As a research tool, the medication adherence construct provided by GEMA could be a valuable variable of outcome, which could be measured over time in response to a behavioral, cognitive or educational intervention, providing evidence on the effectiveness of different strategies for promoting health. Thus, the instrument can be used in studies that aim to deepen knowledge about the mediating and/or moderating variables of this complex behavior.In the present study, limitations such as the administration of the GEMA by means of interview can contribute to overestimation of adherence; the small sample size may also have influenced the findings. We recommend continuity of investigation on the GEMAS's measurement properties, especially the refinement of its validity, analyzing the relationship with direct measurement of adherence—concentration of the medicine or its metabolite in body fluids and/or the use of biological markers.5In conclusion, GEMA is a practical instrument, easy to administer by means of interviews, with little time and resources required for its administration. In addition, this measurement presents evidence of acceptable, sensitivity and specificity considering self‐reported measures of adherence available in the Brazilian culture (MMAS‐8 and MAT). The GEMA is a sensitive and specific tool regarding the stability of the INR. Construct validity was partially supported by significant positive correlations of low to moderate magnitude between the mean proportions of doses of the GEMA and scores of the MAT and MMAS‐8.Mariana Dolce Marques, Rafaela Batista dos Santos Pedrosa, Henrique Ceretta Oliveira, Maria Cecília Bueno Jayme Gallani, Roberta Cunha Matheus Rodrigues participated in research conception and design. Mariana Dolce Marques, Rafaela Batista dos Santos Pedrosa, Henrique Ceretta Oliveira collected and assembled the study data, and execute the study including informed consent. Mariana Dolce Marques, Rafaela Batista dos Santos Pedrosa, Henrique Ceretta Oliveira, Maria Cecília Bueno Jayme Gallani, Roberta Cunha Matheus Rodrigues considered the study result and method of analysis. Mariana Dolce Marques, Rafaela Batista dos Santos Pedrosa, Henrique Ceretta Oliveira, Maria Cecília Bueno Jayme Gallani, Roberta Cunha Matheus Rodrigues provided final approval of the manuscript. Henrique Ceretta Oliveira performed the statistical analysis. All authors read and approved the final manuscript.The authors report no conflicts of interest in this work.The authors confirm that the research carried out in this study was conducted in accordance with the ethical guidelines and regulations of their institution. The study was approved by the Ethics Committee of the University in the state of São Paulo, Brazil (document no. 928.775) and the enrolled patients signed the Informed Consent Form. Confidentiality and anonymity of the participants were maintained throughout the study, and any personal information was protected in accordance with institutional policies and regulations.


Although there is great emphasis on nursing care interaction, there is a lack of knowledge about the quality of nurse-patient care interactions in Iran. The lack of knowledge is mainly related to a lack of short Persian instruments that measure nurse-patient interaction from a caring perspective. The present study aimed to validate a Persian version of the nurse and patient versions of the Caring Nurse-Patient Interaction scale (CNPI-23).The scale (CNPI-23) was translated to Persian using the forward-backward translation method. After translation and re-translation, the scale was given to 15 nurses and faculty members of Kerman University of Medical Sciences, and CVI and CVR indices were calculated based on their opinions. The analytical cross-sectional study was conducted in Kerman/Iran in 2022. In this study, 230 working nurses and 230 hospitalized patients in hospitals affiliated with Kerman University of Medical Sciences were recruited using the convenience method to complete the 23-item Caring Nurse-Patient Interaction scale. Exploratory and confirmatory factor analyses were used to analyze the validity of the scale, and Cronbach’s alpha and Raykov’s rho indices were also calculated to evaluate internal consistency and composite reliability. Data were analyzed using R 4-1-2 software.The scale was completed by 230 nurses and 230 patients. It included four dimensions: humanitarian care, clinical care, comforting care, and communication care. The results of the content validity ratio (CVR) and content validity index (CVI) were acceptable for all items. The minimum value of reliability was 0.49. All the items were approved at the end of the content validity assessment. In the patients’ scale, these four factors explained 81% of the total variance, and for the exploratory model, all the indices show the adequacy of the model. All factor loadings were significant and higher than 0.5. Raycov’s rho and Cronbach’s alpha indices for all numbers were higher than 0.7. The findings of the exploratory factor analysis showed that the nurses’ scale reflected four caring domains, which explained about 62% of the total variance, and the results of Raycov’s rho and Cronbach’s alpha indices confirmed the final fit of this model.In general, the Persian version of the Caring Nurse-Patient Interaction scale has good validity and reliability and can be used to evaluate the quality of care interaction between Persian-speaking nurses and patients. Nursing is a process of interpersonal interaction and care provision because every day, nurses encounter different patients and have to meet their varying needs and expectations . CommuniCare interaction is one of the most necessary skills in nursing practice, and the correct implementation of nursing interventions requires proper and correct interaction between nurses and other nurses, managers, and patients. Because effective interaction is among the important needs of the patient, it is considered the basis of nurses’ work in caring for patients. The meaning of interaction is mutual respect for professional values and individual abilities using the knowledge and experiences of colleagues through asking for opinions and advice during decision-making . Caring The quality of nursing care means providing safe services that satisfy the patient according to nursing standards. Interactions are important sources for evaluating the quality-of-care interaction for the patient and the nurse, but most studies only address the patient’s perspective . Nurse-pJean Watson’s theory emphasizes how nurses care for patients, how care affects recovery, and how care enhances health. She describes care in nursing as a scientific, ethical, esthetic and professional process that involves physical, mental, psychological, and socio-cultural interactions between two people. She guides nurses to maintain a caring interaction with love, respect, and trust. Her goal is to help nurses create a treatment setting that meets the patients’ needs. Her theory of human care enables nurses to improve the nurse-patient relationship . She lisThe Caring Nurse-Patient Interaction-Long Scale was created by Cossette et al. They created it to evaluate attitudes and behaviors connected to Watson’s 10 factors. They made a shorter version  because the 70-item questionnaire was too long for clinical research, especially with very ill patients. The shorter scale has three caring domains that come from the original 10 factors [Some studies have used and psychometrically tested this scale in different languages. For instance, Calong et al. validated the scale among Filipino nurses , and ShaThe present study is an analytical cross-sectional study with validation and psychometric testing conducted in 2022 in Iran.The study was done in Kerman, Iran. Kerman is the largest province in Iran. The study recruited participants from three major hospitals affiliated with Kerman University of Medical Sciences.The statistical population of this study consisted of 230 working nurses and 230 patients hospitalized in hospitals affiliated with Kerman University of Medical Sciences in 2022. The researchers selected the patients and the nurses randomly by checklist.Inclusion criteria for nurses included having at least six months of clinical work experience and enough time to complete the scale.Inclusion criteria for patients included being hospitalized in the heart or general departments for at least three days, having a good general condition, reading and writing literacy in the Persian language, and consent to participate in the study.Exclusion criteria included failure to complete the scale (more than 10%) and having dementia or psychological problems according to self-report.The researchers translated and validated the Caring Nurse-Patient Interaction Scale (CNPI-23), This scale consists of 23 items rated using a five-point Likert scale from 1 (never) to 5 , which reflects four caring domains: humanistic care (questions 1 to 4), relational care (questions 5 to 11), clinical care (questions 12 to 20), and comforting care (questions 21 to 23). In the present research, two separate scales were used to examine the caring interaction from the patient’s and nurse’s perspectives, the patient’s scale from the patient’s point of view and the nurses’ scale from the nurses’ point of view, but the options of both scales were the same. Each question is stated positively, and the scores range from 23 to 115, with a minimum score of 23 and a maximum score of 115. A higher score indicates a higher quantity and quality of interaction between the nurse and patient [In the first step, the English version of the Caring Nurse-Patient Interaction scale was translated to Persian. The researchers of this study obtained permission from the author of the scale through email, and then the English scale was translated through forward-backward translation. At first, the researcher, whose native language was Persian and who had sufficient knowledge about the concepts raised in the scale, translated the English scale to Persian. It should be noted that more attention has been paid to the meaning of the translations for the patients than verbal similarity with the original . In the second stage, two faculty members of Kerman Razi Midwifery and Nursing Faculty who were familiar with Persian and English reviewed the instrument translation and discussed the inconsistencies between the original and the translated version, applied the necessary corrections, and translated it into English. In the next stage, the translation was checked by 15 faculty members of Kerman University of Medical Sciences and nurses with a master’s degrees who were fluent in Persian and English for content validity and compatibility with Iranian culture. Then, the final corrections were made, and the scale was compiled.The statistical population of this study consisted of 230 working nurses and 230 patients. For each item, 10 people were recruited to complete the caring nurse-patient interaction scale. These samples were used for exploratory and confirmatory analysis. The researchers selected nurses and patients randomly. First, the researchers explained the aim of the study to them, and then the participants completed the scale.The psychometric properties of the scale were evaluated using the content validity index and the content validity ratio. A form including an explanation of the study topic and the objectives was prepared to check the content validity. Then, the experts, including 15 faculty members of Razi School of Nursing and Midwifery and nurses with master’s degrees were asked to examine each area based on a three-part spectrum from the point of view of necessity , and then the CVR was calculated. Also, the experts panel evaluated the CVI of each item using the three criteria of simplicity , clarity , and relevance . After collecting the experts’ opinions, the necessary corrections were made to the scale. The CVI of each item was calculated as the number of respondents giving a 3 or 4 rating divided by the total number of respondents. The validated scale was administered among the patients and nurses of selected hospitals of the Kerman University of Medical Sciences.P-values less than 0.05 were considered significant. Univariate normality was assessed through the Anderson-Darling test, and multivariate normality was evaluated using the Henze-Zirkler’s test. Exploratory factor analysis (EFA) and confirmatory factor analysis (CFA) was used for construct validity analysis for both groups of nurses and patients separately. Cronbach’s alpha and Raykov’s rho indices were calculated to evaluate internal consistency and composite reliability. The polychoric correlation coefficient matrix was used in exploratory factor analysis and varimax rotation was used to determine the dimensions. The KMO index was calculated and Bartlett’s P-value was also calculated to evaluate the sufficiency of the data for exploratory factor analysis. The number of factors was examined using the scree plot. Confirmatory factor analysis was evaluated using the robust maximum likelihood method. Indices like X2/df, comparative fit index (CFI), Tucker-Lewis index (TLI), root-mean-square error (RMSE), and standardized root mean square residual (SRMR) were also used to determine the model’s appropriate fit.Data were analyzed using R 4-1-2 software. Among the 230 patients and 230 nurses participating in this study, the average age of patients was 54.3 years old, and the average age of nurses was 37.22 years old. The number of participating female patients and nurses was slightly higher than males . The awareness level of patient communication methods among nurses was 66.5%, which is average, and 69.6% of nurses had completed patient communication or patient training courses. Among the patients, 36.5% had more than one underlying disease, and in about 40% of them, the disease started or was diagnosed about a year ago (Table The results of the reliability ratio (CVR) and content validity index (CVI) were also evaluated, according to Lavshe’s table. The minimum value of the reliability ratio for 15 experts was 0.49, which was acceptable for all items. At the end of the content validity check, all the items were approved.P-value for both scales showed that the exploratory factor analysis was suitable for the data . The present study indicated the Persian version of the Caring Nurse-Patient Interaction scale has good validity and reliability and can be used to evaluate the quality of the care interaction between Persian-speaking nurses and patients.Access to valid and reliable instruments for measuring caring nurse-patient interaction is considered the first requirement for planning and measures related to maintaining and improving the quality of nursing care . Due to The CNPI-23 is commonly used for measuring the caring nurse-patient interaction. The scale has been used in many countries –16. In SThe results of the content validity in present study showed that the process used in translating the scale into Persian was correct and logical and the Persian content is not only consistent with the original version but also clear and expressive for the target population. Repeatability is the reliability of a test, which is measured by different methods .The internal stability of the instrument method was used to assess the reliability of the scale. Cronbach’s alpha coefficient was used for the whole scale and also for each of the dimensions separately. Cronbach’s alpha coefficient for all factors in the present study ranged from 0.73 to 0.96. In a study by Kathyrine Calong and Gil Platon Soriano (2019) in the Philippines, the internal correlation of the instrument for all sub-dimensions was reported between 0.81 and 0.94, and in this study also the instrument had good internal consistency . By compIn the present study, exploratory and confirmatory factor analysis was used to investigate the structure of the factors. Factor analysis with different factor rotation methods extracted four factors that explain about 62% of the variance. These factors, as in the original version, include clinical care, relational care, humanistic care, and comforting care . The facColang et al., using a sample consisting of 124 subjects in Manila, reported that the Caring Nurse-Patient Interaction scale developed by Cossette et al. is a valid and reliable instrument . These fThe strengths of the current study include the use of 10 participants per item. However, the generalizability of the findings of this research may be limited because the samples were selected only from patients who were hospitalized in heart and general wards and nurses who worked in Kerman hospitals. Therefore, to confirm the results, it is suggested that research be conducted on larger samples and nurses working in other parts of Iran in the future. Also, as in this research, a questionnaire was used to collect data, some people may have refused to provide real answers and given unrealistic answers.The Caring Nurse-Patient Interaction scale (CNPI-23) has good validity and reliability to evaluate the caring nurse-patient interaction and can be used to measure the caring nurse-patient interaction in all research and treatment departments. The use of the scale in future studies is recommended to researchers interested in this field.CNPI-23 can be used in all nursing fields to improve the quality-of-care interactions. Nursing managers can also use this scale to check the quality-of-care interactions and provide solutions for improvement.


The purpose of this paper is to present evidence regarding the associations between smoking and the following urologic cancers: prostate, bladder, renal, and upper tract urothelial cancer (UTUC).This is a narrative review. PubMed was queried for evidence-based analyses and trials regarding the associations between smoking and prostate, bladder, renal, and UTUC tumors from inception to September 1, 2022. Emphasis was placed on articles referenced in national guidelines and protocols.Prostate—multiple studies associate smoking with higher Gleason score, higher tumor stage, and extracapsular invasion. Though smoking has not yet been linked to tumorigenesis, there is evidence that it plays a role in biochemical recurrence and cancer-specific mortality. Bladder—smoking is strongly associated with bladder cancer, likely due to DNA damage from the release of carcinogenic compounds. Additionally, smoking has been linked to increased cancer-specific mortality and higher risk of tumor recurrence. Renal—smoking tobacco has been associated with tumorigenesis, higher tumor grade and stage, poorer mortality rates, and a greater risk of tumor recurrence. UTUC—tumorigenesis has been associated with smoking tobacco. Additionally, more advanced disease, higher stage, lymph node metastases, poorer survival outcomes, and tumor recurrence have been linked to smoking.Smoking has been shown to significantly affect most urologic cancers and has been associated with more aggressive disease, poorer outcomes, and tumor recurrence. The role of smoking cessation is still unclear, but appears to provide some protective effect. Urologists have an opportunity to engage in primary prevention by encouraging cessation practices. The association between smoking tobacco and urologic cancers has been extensively studied. While it is well known that smoking is among the leading predisposing factors for bladder cancer, prostate cancer, renal cancer, and upper tract urothelial cancer (UTUC) –4, the iIt should be noted that—just as cessation methods are evolving—consumption methods are evolving as well. Tobacco is more frequently partaken through the use of e-cigarettes and waterpipes . While data on these methods is lacking, preliminary studies reveal potential evidence of cytotoxic effects, cell damage, DNA damage, and oxidative stress –11.Importantly, cancer and subsequent therapy is a powerful teaching moment for patients. The role of the urologist in smoking cessation should not be understated, and efforts to quit tobacco and its products should be undertaken if possible. Evidence has demonstrated that cessation efforts by urologists can have significant effects on smoking cessation and readiness to quit . FurtherIn this narrative review, we observe and compile current evidence regarding the impact of smoking on the following cancers: prostate, bladder, renal, and UTUC.Prostate cancer (PCa) is the second most diagnosed cancer in men worldwide . Many poHowever, while the existence and mechanism of an etiologic link between smoking and prostate cancer is unclear, there have been several proposed mechanisms. The prevalent hypothesis involves the mutation of various cancer progression genes by tobacco-related carcinogens. Other proposals involve inflammatory response, hormone alterations, proliferation of tumor angiogenesis, and immune suppression , 18.The same report by the Surgeon General in 2014 also concluded that “in men who have prostate cancer, the evidence is suggestive of a higher risk of advanced-stage disease and less-well-differentiated cancer in smokers than in non-smokers, and—independent of stage and histologic grade—a higher risk of disease progression” .p = 0.01) and extracapsular extension (p = 0.004) [A study by Mari et al. in 2017 assessed 214 patients, and found that patients with a higher cumulating smoking history reported a higher pathologic Gleason score (= 0.004) .Another study by Kenfield et al. included 5366 patients. This study found that 14.7% of patient with current smoking status had stage T3 or higher disease compared to 8.3% of never-smokers. Additionally, 16.0% of current smokers had a Gleason score of 7 or more compared to 10.7% of never-smokers .Smoking is a known risk factor for poorer surgical recovery times and increased post-operative complications . AdditioTobacco smoking has been associated with recurrence of disease following therapy for prostate cancer.p < 0.001). Similarly, an integration of 7 studies showed that former smoking status was significantly associated with biochemical recurrence  [A systematic review and meta-analysis by Foerster et al. analyzed a total of 16 studies assessing the effect of smoking tobacco on biochemical recurrence. These studies observed 21,797 participants over a median of 61 months. Of the studies assessing the effects of current smoking status, 10 studies had a hazard ratio permitting inclusion into the meta-analysis, which showed a significant association with biochemical recurrence  or stage (p = 0.166) between smokers and non-smokers, high-dose smokers were found to have significantly higher grade (p = 0.026) and stage (p = 0.037) compared to other assessed groups [It is unclear if smoking is associated with higher grade or stage of bladder cancer at diagnosis. Several studies show a potential association, with several possible acknowledged confounding factors. One study by Chamssudin et al. evaluated 300 patients with bladder cancer to assess if smoking status could be associated with advance tumor grade or stage. While the study could not find a significant difference between tumor grade (d groups .p < 0.001) and were at increased risk of a higher grade initial tumor  [A retrospective study by Pietzak et al. queried the records of 1795 patients with urothelial cell carcinoma of the bladder. A multivariate analysis showed that patients who met the National Lung Cancer Screening Trial selection criteria were at a higher risk of initial muscle invasive tumor  .p = 0.008), duration in years (p = 0.007), and cumulative amount in pack-years (p = 0.003) was associated with increased tumor aggressiveness. However, this association was not observed in current smokers [A retrospective study by Barbosa et al. in 2018 assessed 1859 patients. Among former smokers, increased smoking amount per day  .A large-scale database analysis by Al Hussein Al Awamlh et al. assessed 493,282 patients, 42.6% of whom reported having smoked tobacco. This study showed a significant association between smoking initiation in teenage years and bladder cancer-specific mortality  .Smoking tobacco has been associated with poorer outcomes and recovery following both trans-urethral resection and radical cystectomy , 24. OneThe role of smoking cessation should not be understated. For cases of non-muscle invasive bladder cancer, smoking cessation has been shown to decrease the risk of disease progression and progression . Though p < 0.0001). In an analysis of patients who specifically underwent neoadjuvant chemotherapy, smokers were found to have a higher rate of recurrence , but this was not statistically significant [Smoking status has been associated with recurrence of bladder cancer. One systematic review and meta-analysis found that current smokers have a significantly higher risk for recurrence than former and never-smokers (Hazard Ratio (HR) = 1.24, nificant .Rink et al. in 2012 found a dose–response relationship between smoking and disease recurrence. Heavy short-term smoking (HR = 1.54), light long-term (HR = 1.70), and heavy long-term smoking (HR = 2.22) were all found to be associated with a progressively higher, statistically significant risk of disease recurrence compared to light short-term smoking. Additionally, smoking cessation for 10 years or more was associated with a lower risk of disease recurrence (HR = 0.44) .Wang et al. found a similar association, where light long-term (HR = 1.4), heavy short-term (HR = 1.4), and heavy long-term smoking (HR = 2.0) all conveyed a higher risk of disease recurrence compared to light short-term smoking .The strong association between smoking and renal cancer has been known for decades, and even published in the 1982 report of the surgeon general , which sIn particular, smoking and increased smoking intensity have been linked to renal cell carcinoma (RCC) , 42, thoA Study by Macleod et al. found a dose-dependent increase in risk for RCC. Patients who had smoked up to 7.5 pack-years experienced a slightly increased risk of RCC . This rate increased for patient who smoked between 22.5 and 37.5 pack-years  .An analysis by Lotan et al. utilized the data from the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial and the National Lung Screening Trial (NLST). The PLCO data generally showed a gradually increasing trend in RCC incidence as cumulative smoking in pack-years increased up to ≥ 50 pack-years . Similarly, the NLST showed a dose-dependent increase in RCC risk with cumulative smoking trends up to ≥ 50 pack-years  .A study of 30,282 RCC cases by Gansler et al. in 2020 showed an increase in an adjusted prevalence ratio (aPR) for chromophobe RCC in smokers  compared to non-smokers  .p < 0.001) when compared to non-smokers. This risk was increased in current smokers  [One meta-analysis by Cumberbatch et al. found the relative risk of developing RCC was significantly higher for smokers  .A study by Setiawan et al. analyzed 347 cases of RCC, found an increase in incidence in RCC in men  and women . This risk decreased with former smoking status in men  and  in women .Smoking has been associated with higher stage cancer and more aggressive phenotypes at diagnosis. This in turn likely increases disease-specific mortality. A study by Sweeney et al. assessed 132 cases of RCC, finding that current smokers were slightly over twice as likely to be diagnosed with distant or unknown stage disease compared to non-smokers  .Smoking has been linked to poor perioperative outcomes, recovery, post-operative complications, and disease progression. Additionally, smoking has been linked to poorer disease-specific mortality. The aforementioned study by Sweeney et al. found that current smokers experienced an increased risk of death following RCC diagnosis  compared to former smokers  .p = 0.430). Rather, other risk factors were found to be significantly associated, including male gender, increased T stage, nuclear grade, clear cell histology, and presence of diabetes or hypertension.Data regarding any association between smoking tobacco and recurrence of renal cancer is lacking, but in 2019, van der Mjin et al. analyzed 873 patients and found that a history of smoking was not significantly associated with recurrence of RCC  and more lymph node metastases (p ≤ 0.003) compared to non-smokers [Another study by Rink et al. assessed 865 patients undergoing RNU for UTUC, and found that current smokers had a higher stage , which may cause increased and higher grade complications .Following radical nephroureterectomy for UTUC, studies have shown that smoking has been associated with intravesical recurrence, disease recurrence, and cancer-specific mortality.One systematic review found that the majority of studies following patients after radical nephroureterectomy for UTUC were able to associate tobacco smoking with intravesical recurrence, disease recurrence, cancer-specific mortality, and/or any cause mortality . This reA study in 2012 by Rink et al. found that current smokers had a significantly increased risk of UTUC disease recurrence after therapy. In addition, both current and former smokers had a higher risk of cancer-specific mortality. Additionally, a dose-dependent relationship was found between smoking and the risk of disease recurrence. Heavy-long-term smoking was found to be independently associated with the highest risk of disease recurrence .p ≤ 0.031). In women, a similar risk of recurrence was observed (p ≤ 0.003).Another study by Rink et al. containing 865 patients found that in men, current smokers experienced an increased risk of recurrence (p = 0.045) and metastases (log-rank p = 0.016).Additionally, the aforementioned paper by Miyata et al. analyzed 134 patients, and found that the smoking status of a patient was a significant predictor of tumor recurrence (A meta-analysis by Crivelli et al. in 2014 found that of six criteria-appropriate studies that assessed intra-vesicular recurrence, five found a statistically significant increase in risk associated with smoking tobacco .Smoking has been firmly linked to most urologic cancers including prostate, bladder, renal, and upper tract urothelial cancers. In general, tobacco smoking has been associated with higher grade and stage tumors, increased disease recurrence, poor surgical outcomes, worse postoperative complications, disease progression, and tumor recurrence. Smoking cessation appears to have beneficial effects with most urologic cancers, particularly if maintained in the long term. Curbing smoking habits is therefore critical for urologic health and should be a priority for urologists.