Introduction: IDegLira (brand name Xultophy) is a novel fixed ratio combination of insulin degludec and liraglutide for type 2 diabetes (T2D) patients. This study aimed to investigate the lifetime cost-effective value of IDegLira compared with its single component (Degludec or Liraglutide) and to explore the suitable annual cost of IDegLira if necessary.Methods: UKPDS OM2 was applied to determine the long-term quality-adjusted life years (QALYs) and total costs. The efficacy data that were inputted into the model were synthesized from 6 randomized clinical trials (RCTs) that directly assessed the clinical benefit of IDegLira and its components in the treatment of uncontrolled T2D patients. The economic results were examined by one-way sensitivity analysis (OSA) and probabilistic sensitivity analysis (PSA). Further price reduction of IDegLira was investigated by binary search.Results: The IDegLira, IDeg, and Lira yielded 11.79 QALYs, 11.62 QALYs, and 11.73 QALYs and total cost of $20281.61, $3726.76, and $11941.26, respectively. The incremental cost-utility ratio (ICUR) of IDegLira versus IDeg was $99464.12/QALYs, and the ICUR of IDegLira versus Lira was $143348.26/QALYs, which indicated that IDegLira was not a cost-effective therapy for T2D patients compared with its components at the current price from a Chinese national healthcare system perspective. Base case results were robust to OSA and PSA. A further binary search showed that IDegLira appears to only be cost-effective if the annual cost of IDegLira is decreased by 58% when IDeg is considered as a reference, or by 30.57% when Lira is considered as a reference.Conclusion: In conclusion, IDegLira appears to not be cost-effective when compared with the current prices of IDeg or Lira for T2D patients in China. However, after the binary search, IDegLira appears to only be cost-effective if the annual cost of IDegLira is decreased 58% when IDeg is considered as a reference, or by 30.57% when Lira is considered as a reference. Diabetes is becoming an increasingly urgent global public health problem. In 2021, it was reported that approximately 537 million adults worldwide have diabetes, and this number will increase to 643 million in 2030 and 783 million in 2045. The increasing global prevalence of diabetes appears to be related to the growing and aging population, which is an ongoing issue today . The IntMore than 90 of diabetes patients are diagnosed with type 2 diabetes (T2D). T2D is characterized by chronic progression and progressive beta cell damage, which requires treatment across the life span. Diabetes is an expensive and harmful disease, and personalized self-management of the condition depends on multidimensional treatments and has become essential for patients to achieve management goals. Diabetes managements initially starts with a healthy diet, regular exercise, and body weight management, followed by the addition of oral hypoglycemic drugs (OADs) and finally injectable hypoglycemic drugs. Although most diabetes cases eventually need insulin therapy, the initiation of insulin is often delayed . The reaIDegLira (brand name Xultophy) is a fixed ratio innovation of basal insulin [Degludec ([IDeg)] and GLP-1 RA analog [Liraglutide (Lira)] and is administered as a once-daily subcutaneous injection for the treatment of T2D. IDegLira could reduce the patients’ burden from multiple injections to a single injection every day , and itsCurrently, IDeglira received regulatory approval in Europe in September 2014 and in the US in November 2016, and its cost-utility has been evaluated in the UK, Sweden, Spain, and the US. RegardiIn China, IDeglira was introduced in April 2022. However, there is little economic evidence in the investigation of the fixed ratio combination of IDegLira and its monotherapy of IDeg or Lira in China. This research is the first to show an estimate of the long-term economic value of IDegLira, IDeg, and Lira from a Chinese national healthcare system perspective. If IDegLira appears to not be cost-effective compared with the current price of IDeg or Lira, then a binary search is conducted to determine the best price for IDegLira and to provide reasonable suggestions to policymakers and decision-makers.A cost-utility analysis based on data from six RCTs was conducted using the UK Prospective Diabetes Study Outcome Model version 2 (UKPDS OM2) . UKPDS Ohttps://www.clinicaltrials.gov. Detailed information about the six RCTs is shown in the Baseline cohort characteristics and clinical efficacy data were sourced from six RCTs. The specific screening process and bias risk assessments can be found in the Supplementary file 2. Five RCTs [NCT02607306 , NCT0139Costs were based on a Chinese national healthcare system perspective and were expressed in 2021 US dollars. Medication costs were calculated based on wholesale pack costs, mean daily doses and injection frequency. The wholesale costs per package of IDegLira, IDeg and Lira were sourced from the average official bid price in China in 2021. The mean daily doses were assumed to be the average of the maximum daily doses among the six RCTs. The injection frequency of the three drugs was once daily. According to new insulin delivery recommendations , IDegLirThe UKPDS OM2 model was applied to simulate the progression, health outcomes and relevant costs of T2D over a 40-year period, with a default cycle length of 1 year. The study showed a comparison of IDegLira, a novel fixed-ratio combination product, with its individual therapies, IDeg or Lira, as the comparators in the treatment of T2D patients. Incremental cost-utility ratios (ICUR) and incremental net monetary benefits (INMB) were adopted as results interpretation indicators. The calculation formula for ICUR was the ratio of incremental differences in costs (ΔCosts) and QALYs (ΔQALYs) between the intervention and the comparators. The formula for INMB was “ΔQALYs multiplied by the willingness-to-pay (WTP) threshold and then subtracting ΔCosts”. The WTP threshold of 1–3 times the gross domestic product (GDP) per capita as recommended in the WHO guidelines for developing countries was used to determine the pharmacoeconomic of the drugs, which was predefined as $37654.50/QALYs in this study. A positive value of INMB and a value of ICUR that surpasses the WTP threshold indicate that the intervention is cost-effective.Uncertainty analyses of OSA and PSA for all three groups were performed to evaluate the impacts of parameter uncertainty on the BCA results. The OSA was conducted to separately examine the robustness and generalizability of parameters including costs, utilities, discount rate, time horizon, and treatment time. Costs of complications and health disutility scores varied between their 95% confidence intervals (95% CIs). If their 95% CIs were not reported, costs and utility scores were adjusted by ± 20% and ±10%, respectively, such as IHD and ulcer. The detailed variations were shown in After a life year (40 years) simulation, the BCA results are shown in Compared with IDeg, IDegLira had an ICUR value of $99464.12/QALYs, which was surpassed the WTP threshold, indicating that IDegLira was not a cost-effective strategy. Compared with Lira, IDegLira, with an ICUR of $143348.26/QALYs that surpassed the WTP threshold, was not an economic strategy. The INMBs of IDegLira versus IDeg and IDegLira versus Lira were −10447.67 and −6200.68, respectively, demonstrating the same results as ICURs. The order of absolute NMB was IDeg, Lira, and IDegLira, further confirming the base case conclusion. In the base case analysis, IDegLira was not a cost-effective therapy because of high QALYs and high total costs compared with those of IDeg and Lira.The results of OSA are expressed as a tornado diagram and shown in The recommendation by the American and European Association for T2D patients emphasizes that the cornerstone of success for T2D treatment is based on the consideration of the needs, preferences, and tolerance of each patient, and more patient-centered individualized therapeutic strategies are needed . BecauseThe complementary mechanisms of a basal insulin and a GLP-1 RA allow IDegLira to achieve glycemic control and manage body weight when compared to other therapy strategies for patients with uncontrolled T2D on basal insulin, such as increasing doses of basal insulin. People who receive basal insulin may suffer from injection pain caused by approximately four daily injections as part of a basal-bolus regimen and two daily injections of Lira added to basal insulin . IDegLirIn our cost-utility analysis, the ICURs of IDegLira versus IDeg and IDegLira versus Lira are $99464.12/QALYs and $143348.26/QALYs, respectively, which both surpassed the WTP threshold. Although IDegLira achieved the highest QALYs among the three, it also has the highest expenditure as it is new to the Chinese market. We found that IDegLira, at the present price, appears to not be cost-effective when compared with its monotherapy. The BCA results are robust to OSA and PSA. Therefore, the market price of IDegLira may be further priced through government negotiation or volume-based procurement in the future. Our study found that IDegLira appears to only be cost-effective if the annual cost of IDegLira is decreased by 58% when considering IDeg as a reference or by 30.57% when considering Lira as a reference.Some potential limitations of this study are discussed as follows. First, due to the lack of long-term clinical evidence for the use of IDegLira, IDeg, and Lira in the treatment of T2D patients, short-term RCT data were applied to predict lifetime health outcomes. Second, long-term model simulations rely on model equations derived from the UKPDS 82 trial  that is In conclusion, from a Chinese national healthcare system perspective, IDegLira appears to not be cost-effective when compared with IDeg or Lira. However, after a binary search, IDegLira appears to only be cost-effective if the annual cost of IDegLira is decreased by 58% when considering IDeg as a reference or by 30.57% when considering Lira as a reference.


The potential overtreatment of patients with papillary thyroid microcarcinoma (MPTC) has been an important clinical problem in endocrine oncology over the past decade. At the same time, current clinical guidelines tend to consider prior radiation exposure as a contraindication to less extensive surgery, even for low-risk thyroid carcinomas, which primarily include microcarcinomas. This study aims to determine whether there are differences in the behavior of MPTC of two etiological forms (radiogenic and sporadic), including invasive properties, clinical data, and recurrence in patients aged up to 30 years. For this purpose, 136 radiogenic (from patients aged up to 18 years at the time of the Chornobyl accident) and 83 sporadic (from patients born after the Chornobyl accident) MPTCs were selected and compared using univariate and multivariate statistical methods in a whole group and in age and tumor size subgroups. No evidence of more aggressive clinical and histopathological behavior of radiogenic MPTCs as compared to sporadic tumors for basic structural, invasive characteristics, treatment options, and postoperative follow-up results was found. Moreover, radiogenic MPTCs were characterized by the lower frequencies of oncocytic changes , nodal disease , and more frequent complete remission (excellent response) after radioiodine therapy . These results strongly suggest that internal irradiation does not affect tumor phenotype, does not associate with more pronounced invasive properties, and does not worsen prognosis in pediatric or young adult patients with MPTC, implying that radiation history may be not a pivotal factor for determining treatment strategy in such patients. Epidemiological studies have shown a worldwide increase in thyroid cancer incidence in recent decades , 2. To aThe notions of “overdiagnosis” and “overtreatment” are actively discussed over the past decade in many areas of contemporary medicine, including management of small thyroid nodules –5, 9–11.At the same time, clinical guidelines recommend considering prior head and neck radiation of a patient even with low-risk thyroid cancer as a potential contraindication to less extensive surgery, at least in adults , 22. Ind131I regions of Ukraine , Kyiv during the period from 1992 to 2016 when a significant increase in thyroid cancer incidence after the Chornobyl accident was documented , 27, 28. Ukraine , 27–29, st, 1987 or later, i.e. not affected by 131I) and lived in the same six northern regions at the time of the operation. Patients were operated on from 2001 to 2018.The sporadic MPTCs were from 83 patients aged 9.7-30.9 years at diagnosis who were born after the Chornobyl accident , and the absence of screening history in tumor detection . Since the oldest patient with sporadic MPTC at the time of this study was aged 30 years, the upper limit for the age of patients with radiogenic MPTC was also set to 30 years old. None of MPTCs in the study was familial.The study was conducted according to the guidelines of the Declaration of Helsinki and was approved by the IEM Bioethics Committee , the Chornobyl Tissue Bank , and the Ethics Committee of Nagasaki University . Informed consent was obtained from all patients enrolled in the study or their guardians (for minors).th edition of the WHO histological classification . The pathological diagnosis was based on the 4fication . Most cafication , 32. Thefication . Tumors As in our previous works , 34, 35,V600E and Ki67 were performed in 34 and 32 radiogenic, and in 38 and 36 sporadic MPTCs, respectively, for which the additional tissue sections were available.Immunohistochemical (IHC) staining for BRAFV600E was performed as described before  in a Ventana BenchMark ULTRA instrument. The Ki67 labeling index (Ki67 LI) was determined with the image-analyzing software  in a total of approximately 1,000 PTC cells per case (LZ). Image analysis was performed in a blind for the BRAF131I thyroid radiation doses were calculated for each patient from the radiogenic group in the Radiation Protection Laboratory of the State Institution “National Research Center for Radiation Medicine of the National Academy of Medical Sciences of Ukraine”, Kyiv using an ecological dosimetric model, which includes the system of ecological iodine transport and biokinetic models of iodine (“TD-CTB”) (131I thyroid radiation dose for radiogenic MPTCs were 106 (56–203) mGy.TD-CTB”) . The medThe Fisher’s exact test, Fisher-Freeman-Halton exact test, Cochran-Armitage test and the Kaplan-Meier test were used for univariate analysis of categorical data; the Mann-Whitney test was used to compare continuous data between any two groups. Logistic regression models were adjusted for age at operation and sex; models with very small numbers of outcomes (< 5 per cell) were conducted using Firth’s approach to bias-reducing penalized maximum likelihood fit. Multivariable linear regression models were used for continuous dependent variables. The Cox proportional hazard model was used to analyze disease-free survival. Calculations were performed using IBM SPSS Statistics Version 24 software  and/or the 9.4 version of SAS . Correspondence analysis was performed in R with the “ca” package . The “coMPTCs detected by ultrasound and assessed by FNA/cytology as malignant or suspicious for malignancy accounted for 136 and 83 cases in the radiogenic and sporadic groups, respectively. All data collected for or generated during this study are presented in V600EBRAF mutation or proliferative activity were not observed. The radiogenic MPTCs were less likely to display oncocytic changes , lymph node metastases  and signs of concomitant chronic thyroiditis . Of importance, the response to radioiodine therapy (RIT) was overall better among the radiogenic MPTCs  with the higher frequency of excellent response  and suggestively lower frequency  of radioiodine-refractory (RAI-R) recurrence . Of note, among the recurrent metastases , there were 0/3 RAI-R metastases in the radiogenic group and 2/2 in the sporadic group .Comparison of MPTCs from two etiological groups revealed significantly older age of patients in the radiogenic series . Therefore, multivariate analyses were adjusted for this parameter and sex Table 1.Another parameter that was different between the groups was the longer duration of postoperative follow-up  of radiogenic MPTCs. It is explained by the earlier calendar time of inclusion of patients with radiogenic MPTCs in the study.131I activity during RIT  were observed in the radiogenic subgroup. As in the whole series, the period of postoperative follow-up was longer for the radiogenic MPTCs ; recurrences were not documented in either etiological subgroup.In the pediatric subgroup aged ≤18years at diagnosis Table 2,In young adults aged 19-30 years at diagnosis Table 3,vs. any pediatric subgroup). The radiogenic and sporadic MPTCs from young adult patients also looked different (note the right angle between these subgroups). In agreement with the multivariate analysis , statistically significant differences between the radiogenic and sporadic series were found for a number of parameters Table 5.Correspondence analysis of MPTCs of different etiology and size subgroups Figure 4To further delineate the characteristics (parameters) that might be associated with the radiogenic or sporadic etiology of MPTCs in the current series, we applied several statistical algorithms of variable selection Table 6.A link between previous radiation exposure and MPTC has been established in atomic bomb victims, in whom an increased dose-dependent risk for developing tumors has been observed . HoweverThe rationale for focusing the study on young patients  was that our previous investigation found higher aggressiveness of radiogenic PTCs, especially in children and adolescents , 26. HowOur analysis of MPTCs from two etiological groups detected several statistically significant differences including older age of patients in the radiogenic series, less frequent oncocytic changes, lymph node metastases and concomitant chronic thyroiditis see Table 1.Comparison of MPTCs in the pediatric subgroup did not reveal significant differences in the clinical and histopathological characteristics between the radiogenic and sporadic pediatric MPTCs see Figure 2V600E-positive and RAI-R , lymph node metastases and even distant metastases see Table 1.It is worth noting that to draw more attention to the problem of treatment of microcarcinoma, a somewhat obscure and not necessarily correct – in our opinion – term “overdiagnosis” has been introduced and extensively used , 10, 11.Our study has certain strengths and limitations. Radiogenic and sporadic cases were selected from a single institution and were well matched by the place of residence. Although patients were not matched by age at surgery and sex, multivariate models were appropriately adjusted, and therefore confounding by these parameters is unlikely. Neither radiogenic, nor sporadic cases in the study were detected by active screening, implying that selection bias did not play a noticeable role. Some birth period or cohort effects might be expected stemming from the inclusion criterion for patients with sporadic MPTCs, which required that they were born since 1987 to ensure the lack of exposure to fallout. This led to the difference in calendar time of the first patient entry in the study between the radiogenic and sporadic groups . A rather limited number of patients in the pediatric and MPTCs measuring 1-5 mm subgroups might provide insufficient statistical power to detect the effects. Similarly, a very small number of recurrent tumors in the study and a relatively short follow-up period did not allow assessment of etiology-specific prognostic factors, pointing at the need for further research.In conclusion, our study did not find evidence in support of important effects of internal irradiation on histopathological characteristics, more pronounced invasive properties and prognosis worsening for MPTCs in pediatric or young adult patients. These results imply that young MPTC patients with a radiation history  may not require treatment strategies different from those for non-exposed MPTC patients. Of importance, some MPTCs in young patients may be locally advanced or develop distant metastasis indicating a need for risk stratification and tailored treatment, regardless of tumor etiology.The original contributions presented in the study are included in the article. Further inquiries can be directed to the corresponding author.The studies involving human participants were reviewed and approved by Bioethics Committee, State Institution V.P. Komisarenko Institute of Endocrinology and Metabolism of the National Academy of Medical Sciences of Ukraine, the Chornobyl Tissue Bank, Ethics Committee of Nagasaki University. Written informed consent to participate in this study was provided by the participants’ legal guardian/next of kin.TB, SC, LZ, NM, MT, SY, and VAS: study design and methodology. TB, SC, LZ, and MB: clinical and pathological data. LZ, TIR, and MI: investigation and formal analysis. SM: thyroid dosimetry. TB and VAS: statistical analysis, data interpretation, and writing of the manuscript. TB, SC, LZ, TIR, NM, MI, MT, MB, SM, SY, and VAS: revision of the manuscript. All authors have reviewed the manuscript and approved the final version.This research was supported in part by the Program of the Network-Type Joint Usage/Research Center for Radiation Disaster Medical Science, intramurally by the Atomic Bomb Disease Institute, Nagasaki University, and the Japan Society for the Promotion of Science (JSPS), KAKENHI Grant Numbers 19K07471, 19KK02670001, and 20KK0217.We gratefully acknowledge the commitment of the staff of the Laboratory of Morphology of Endocrine System and of the Department of Surgery of Endocrine Glands of IEM, who prepared all pathological material and operated on the patients, respectively. The authors gratefully acknowledge the confirmation of Ukrainian diagnoses by the International Pathology Panel of the Chornobyl Tissue Bank, which was supported by NCI grant number U24CA082102: A. Abrosimov, TB, G. Fadda, J. Hunt, MI, V. Livolsi, J. Rosai, E. D. Williams, N. Dvinskyh, and LZ.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Abnormal neurotransmission of glutamate and γ-aminobutyric acid (GABA) is a key characteristic of alcohol-related disorders. To track research output, we conducted a bibliometric analysis to explore the current status and trends in this field over the past decades.bibliometrix package was used for a descriptive analysis of the publications. Citespace, WOSviewer, and R–bibliometrix were used to construct networks of countries/institutions/authors based on co-authorship, co-citation analysis of cited references and co-occurrence as well as burst detection of keywords.Studies related to neurotransmitters and alcohol use disorder published in English from 2005–2021 were retrieved from the Web of Science Core Collection and Scopus databases. The R–Alcoholism: Clinical and Experimental Research. Comprehensive analyses have been conducted over past decades based on co-cited reference analysis, including modulators, transporters, receptor subtypes, and animal models. In recent years, the research frontiers have been shifting to the identification of risk factors/biomarkers, drug development for alcohol use disorder, and mechanisms related to alcoholic and non-alcoholic fatty liver.A total of 4,250 unique articles and reviews were included in the final analysis. The annual growth rate of publications was 5.4%. The USA was the most productive country in this field, contributing nearly half of the total documents. The top ten most productive institutions were all located in the USA. The most frequent worldwide collaboration was between the USA and Italy. The most productive and influential institution was the University of California. The author contributing the most productions to this field was Marisa Roberto from the Scripps Research Institute. The top co-cited reference was a review titled “Neurocircuitry of addiction.” The top journal in terms of the number of records and citations was Our bibliometric analysis shows that glutamate and GABA continue to be of interest in alcohol use disorder. The focus has evolved from mechanisms and medications related to glutamate and GABA in alcohol use disorder, to novel drug development, risk factor/biomarker identification targeting neurotransmitters, and the mechanisms of related diseases. The disruption of neurochemical homeostasis not only facilitates symptoms of alcohol-related disease, but also augments the sensitivity to harmful drinking behavior.Alcohol is the oldest and most extensively used addictive substance. Acute and chronic consumption of alcohol may lead to alcohol dependence, alcohol withdrawal syndrome and other alcohol-related disorders. Meanwhile, alcohol intake is a risk factor for a variety of diseases such as hypertension, diabetes, and liver cirrhosis. The harmful use of alcohol has become a severe global threat, leading to more than 3.3 million deaths every year . In somevia glutamate receptors and transporters in the mesocorticolimbic brain regions, and modulations to these targets attenuate alcohol-seeking behavior .A (ligand-gated ion channels) and GABAB (G-protein-coupled receptors). GABAARs are postsynaptic pentameric complexes assembled with various subunits. The functions of GABAAR subtypes are mainly defined by the specific α subunit: α1, α2, and α4 subunits are the most relevant subunits in alcohol dependence  (A expression by protein kinase A (PKA). The cAMP-PKA signaling pathway also plays an important role in the neurobiological responses and behavioral actions induced by alcohol. Apart from direct modulation of GABAARs, alcohol may influence functions of GABAARs in an indirect way via neurosteroids (B. GABA transporters (GAT1-3) are responsible for removing GABA from the synaptic cleft. GAT-1 is predominantly found in axon terminals and glial cells, and GAT-3 is exclusively located on glial cells  and GABA system modulators  have been recommended as pharmacotherapy for patients with alcohol use disorder . The search phrases associated with the neurotransmitters glutamic acid and GABA included gamma-aminobutyric acid, GABA, glutamate, glutamine, and glutamic acid, and the phrases associated with alcohol use disorder included alcohol use disorder, alcohol abuse, alcohol dependence, alcoholiThe data were obtained on April 22nd, 2022 from different databases. Data cleaning was conducted using CiteSpace software in combination with manual searching.bibliometrix was used to perform descriptive analysis of the leading research authors, countries, and journals, identify core journals, and produce a country/region collaboration map. Bradford's law ; the strength of links was calculated based on the Cosine algorithm; the selection was based on a modified g-index with a scale factor k = 25 for collaboration detection, and the top 50 items were selected for keyword analysis and reference co-citation analysis; a pruning with minimum spanning tree was used for concurrence analysis. Nodes and links were used to generate visualization knowledge maps. The size of nodes represents the number of citations. The color of rings indicates citation years: the transition from cool to warm represents early to recent publications. A link between two nodes suggests a co-occurrence or co-citation relationship. Line thickness represents the strength and the color corresponds to the first co-occurrence or co-citation time. In addition to the number of publications and citations, “centrality” was used as a measurement of significance. “Centrality” detects the interactions of a node with other nodes. Nodes with high centrality are considered as an important “bridge” between different groups and represent turning points or pivotal points in this field. Nodes with centrality > 0.1 were surrounded by a purple ring. Co-occurrence analysis of keywords was conducted using WOSviewer 1.6.18. Keywords occurring more than ten times were presented in three visualizations  to identify important terms.The total numbers of documents in the Scopus and WoSCC databases were 3,524 and 2,315. Duplicated records were identified and removed. A total of 4,250 unique records from Scopus and WoSCC, including 3,817 primary research articles and 433 reviews, were used for further analysis . The totThe total number of citations has increased in the past 17 years. Seventeen articles were qualified as “citation classics” in this area, i.e., having 400 or more citations . The mosAlcoholism: Clinical and Experimental Research . After Bradford's law was applied, the core distribution comprised 22 journals  and Proceedings of the National Academy of Sciences of the United States of America  exceeds 10.The literature was published in 1,248 sources. The journal with the highest number of publications was journals . Most ofEighty-one countries or regions have contributed to publications in the field of research on the involvement of glutamate and GABA in alcohol use disorder. The data extracted from Scopus and WoSCC indicated that the USA was the most productive country (52%), followed by the People's Republic of China (6%), Germany (4%), Italy (4%), and Australia (3%). The centralities of the USA (1.03), Italy (0.15), France (0.13), Canada (0.13), Ukraine (0.12), and the Russian Federation (0.12) are > 0.1, indicating that these countries might deeply cooperate with other countries and act as important intermediaries in this field. From 2005 to 2021 3,626 institutions in this field published papers. A total of 18,145 authors contributed relevant publications. Neuropsychopharmacology titled “Neurocircuitry of addiction” , #8 alcohol use disorder, #9 C57BL/6, #10 COR659 . In the research period, a comprehensive analysis referring to multiple studies mainly focused on the following: (1) mechanism, including modulators, transporters, receptor subtypes, and the development of animal models; (2) drug development targeting glutamate and the GABA system for the treatment of alcohol use disorder, including acamprosate, baclofen and COR659.The network map of the co-cited references is displayed in A keyword co-occurrence knowledge map was generated by WOSviewer . The fonA map based on the top 20 keywords with the strongest citation bursts was generated by Citespace . The notIn this study, bibliometric analyses and network visualizations were conducted to characterize the knowledge domains of glutamate and GABA related to alcohol use disorder. The contributions of countries, institutions, journals, and authors to this field were analyzed. Research frontiers and hot topics in the coming years were also identified. Since 2005, the annual publication number in the field has increased steadily.The USA has the largest number of publications and citations, the strongest collaborations worldwide, and the highest centrality among countries/regions. The following countries, China, Germany, Italy, Australia, and Korea, accounted for 20% of all studies included, whilst Argentina, Germany, Italy, Australia and the UK constituted 22% of total citations. China ranked second in the total number of publications, but ranked seventh in the total number of citations and ninth in collaboration with other countries/regions, reflecting China's lack of international cooperation in research. The top ten most productive institutions are located in the USA. Therefore, the USA is currently the world leader in this research domain, and has a significant impact on the direction of research in this field.Three of the most prolific authors were Marisa Roberto , Giancarlo Colombo , and Youssef Sari . Each of them was in discrete collaborative relationships. Marisa Roberto, Florence P. Varodayan, Amanda Roberts, Sophia Khom, and Michal Bajo, from the Scripps Research Institute, formed a close collaborative relationship, in which Melissa Herman from the University of North Carolina, R. Adron Harris, and Blednov Y.A. from the University of Texas participated. With the largest number of documents and the highest number of citations, Dr. Marisa Roberto is the most important researcher in this collaboration. Marisa Roberto identified the key role of the CeA in alcohol use disorder and that aberrant amygdala GABA transmission was associated with alcohol use disorder . Her mosB receptor in drinking behavior. His most co-cited document was about baclofen-induced reduction of alcohol reinforcement in alcohol-preferring rats , Karen Szumlinski , Deborah Finn , Howard J. Edenberg (Indiana University), Richard L. Bell (Indiana University), and Liang Jing  are in a loose collaborative relationship, in which Youssef Sari is the most important researcher. Dr. Youssef Sariis concerned with the association between brain glutamate homeostasis and substance abuse, and evaluates medications such as antibiotics targeting glutamate transporters to reduce ethanol consumption. His most co-cited document was about the use of ceftriaxone, a beta-lactam antibiotic, as a potential drug to reduce ethanol consumption in alcohol-preferring rats . He has In addition, Henry R Kranzler (University of Pennsylvania), John Krystal , Jonathan M. Covault  and Joel Gelernter , were in a collaborative relationship. Although the University of California is the most prolific institution, collaboration was not detected among its researchers.via changes in the basal ganglia, extended amygdala/habenula, and frontal cortex  at the National Institutes of Health, is an expert on substance addition not restricted to alcohol abuse. He conceptualized the substance addiction process into three stages  and three domains of dysfunction  l cortex . Koob etl cortex .Our co-occurrence network maps, clustered by keywords and co-cited references, indicate that the current hot topics and future directions in the association of glutamate and GABA with alcohol use disorder may be divided into several branches: clinical study and novel drug development; biomarker identification; neuropathology; risk factors. A short synopsis of the main trend topics is shown in Recently, multiple clinical studies have been conducted in different countries to evaluate the efficacy of baclofen in the treatment of alcohol dependence. However, the efficacy of baclofen was questioned. Baclofen did not show superiority over placebo in the maintenance of abstinence, while causing a reduction in alcohol consumption and craving, as observed in the ALPADIR study . The effAδ and GABAB subunit 1) was found. Analysis of DNA methylation may be a promising diagnostic test for heavy drinking. Harada et al. , Science and Technology Plan Project of Guangzhou (grant numbers 202102080030 and 202201010736), Scientific Research Project of Traditional Chinese Medicine Bureau of Guangdong Province (grant number 20222177), Science and Technology Plan Project of Guangdong Province (grant number 2019B0303160), and Guangzhou Municipal Key Discipline in Medicine (2021-2023).The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


The COVID-19 pandemic has considerably affected human beings most of whom are healthcare workers (HCWs) combating the disease in the front line.This cross-sectional study aims to explore the effects of stress and anxiety caused by COVID-19 on the quality of sleep and life in HCWs, including physicians, nurses, and other healthcare staff. In this global study, we asked 1,210 HCWs , who age 21–70, to participate in the test. Several measures of COVID-related stress, anxiety, sleep, and life quality, including the 12-item General Health Questionnaire (GHQ-12), Fear of COVID-19 scale (FCV-19S), Beck Anxiety Inventory (BAI), the Pittsburgh Sleep Quality Index (PSQI), and World Health Organization Quality of Life-BREF (WHOQOL-BREF) are recorded.p-values equal to 0.0357 and 0.0429 for GHQ-12, 0.0368, and 0.714 for BAI measure. Even though nurses reported the most stress, anxiety, fear of COVID-19, lower quality of life and sleep in both countries, and also an increase in other measures as well, there existed no statistically significant difference in FCV-19S, PSQI, and WHOQOL-BREF.Volunteers reported high rates of stress and anxiety and poor sleep quality as well as lower quality of life. The correlation analysis between the measures is reported. According to the results, regardless of the location, HCWs, predominantly female nurses, developed anxiety and stress symptoms which consequently resulted in lower sleep and life quality. Both for Iranian and the European HCWs, significant differences existed between nurses and the other two groups, with the This study helps to expand our knowledge the effects of pandemics on HCWs and also for healthcare management to predict HCW's mental health conditions in similar situations. A worldata.org) –18.Governments have taken different approaches, such as spatial distancing, quarantining, and lock-down, which have totally affected human beings –23. SeveHealthcare workers (HCWs), as part of society, are no exception. Due to limited knowledge about the disease, unknown surefire treatment for it, the workload in healthcare centers and referral hospitals, etc. HCWs have been under considerable mental pressure resulting in psychological distress, anxiety, and poor sleep quality , 32, 33.Strong associations between gender and COVID-19-related stress, fear, and anxiety have been reported by several studies. Generally, females consider this pandemic a more serious threat to personal health and the population compared to males –65. In sThe lockdown measures, workload, anxiety, and stress caused by this pandemic are highly associated and consequently result in sleep disturbance , 37, 66.Sleep is a biological imperative playing a crucial role in health and wellbeing. Stress and sleep quality are two important factors in one's quality of life. Previous studies suggest that sleep, stress, and anxiety are reciprocally connected –15. HighAll aforementioned reasons suggest that studying the effects of stress and anxiety, caused by the COVID-19 pandemic in HCWs, on their quality of sleep and life is of high importance. This motivated us to conduct this study. Considering the current situation in most countries and also the importance of this issue in health systems management, only a few studies have been conducted so far. It means that we need to view this topic from different aspects. Some studies have targeted the same issue during the pandemic. Authors in Korkmaz et al. , 323 HCWAs it can be seen, in these studies only one or two countries have been considered and fewer than 400 HCWs have participated. To have a wider view, it is necessary to conduct a more comprehensive study including more countries and a larger sample population. In some recent studies, only a limited number of a specific group of HCWs (like nurses) are just considered. As we know, all HCWs in the whole healthcare system are involved more or less and are under mental and physical pressure. So, we need to consider a larger sample population, including all groups of healthcare givers. In some studies, only one measure is used to assess the quality of life, the level of anxiety, etc. It is vital to utilize different assessment methods and factors to evaluate the effects of stress and anxiety fairly. So, the abovementioned issues motivated us to conduct the present study. We have employed different measures to analyze the problem among HCWs, including nurses, physicians, and other healthcare staff. Moreover, we spent almost 2 months collecting data in 2020 to have a more comprehensive study. Considering all the aspects, this study has made a significant contribution to future studies and our understanding of the recent pandemic and its effects on an extensive community like health care workers.In this paper, we are going to study the level of stress and anxiety among HCWs and the correlation between these factors and the quality of life and sleep. In the present study, we explore the association between stress caused by the COVID-19 pandemic and the quality of sleep and life in healthcare workers in Iran and the above-mentioned European countries. Our main aim is to study and compare the effects of stress and anxiety caused by the pandemic on the quality of sleep and life in the aforementioned groups among a large, international community sample.We collected data in 2 months, from September 2020 to October 2020 (during the severest period of the COVID-19 pandemic). This cross-sectional and descriptive study was conducted with the approval of the local ethics committee. The approval was obtained from the local ethics committee and in agreement with the Helsinki Declaration. All volunteers were asked to study our project's objectives and to read and sign a written consent on our forms before answering the questions. They were informed about the study and its goals and then were asked to read and sign a written consent. All forms, questionnaires, documents, and questions were translated into English and Farsi by the same translator who is also an expert in psychology. Our study inclusion criteria were signed informed consent, having been working as an HCW to combat COVID-19 for at least 2 months during the pandemic, aged between 20 and 70, and having Farsi or English literacy. All participants were asked to choose either Farsi or English to complete the forms. Some participants were excluded from the study due to their limited knowledge of Farsi or English languages. The included participants declared intermediate or advanced knowledge (native speakers) in English or Farsi. With the aim of decreasing the spread of COVID-19 disease and also to have data from two countries, we decided to collect data using Google forms on online platforms and social media.We employed the method of sample calculation for an unknown population and the following formula to calculate the sample size in our study , 19, 37.t is the value on the t-table at a certain degree of freedom and predetermined error rate. p and q represent the prevalence of the event and the prevalence of the absence of the event, respectively. d2 shows the deviation to be achieved based on the prevalence of the event. Our estimate was 593 for the number of individuals to be included. We used a confidence interval of 0.95%, 50% unknown prevalence, and a standard deviation of 5%.where Almost 2,000 HCWs from Iran and European countries participated in our experiment as we tried our best to share the link of our Google forms in the best possible way. We employed social media  to share study information and links with volunteers. We asked our colleagues working in foreign countries to help us and share the links as much as they could. Due to the number of participants and missing information in some cases, 1,210 forms were approved.The total numbers of participants were 799 and 723 HCWs in Iran and the studied European countries. It should be noted that the total numbers of approved cases were 620 for Iran and 590 for the aforementioned European HCWs. The response rates were 77.6 and 73.8% for Iran and the before-mentioned European countries, respectively. As the main reasons, in most failed cases, HCWs claimed that they had a problem with their internet connection while accessing the forms, or they did not meet the study criteria, or they were not able to fill in the forms on their cellphones, or they were not satisfied with the number of questions. In addition, we considered mental or physical disorders and records of psychiatric treatment as the participant exclusion criteria.Our protocol mainly includes preparing questionnaires in both English and Farsi, targeting potential volunteers in social media and networking applications, sending requests to a population of HCWs in the target countries, waiting for their responses and providing more information if required, collecting and preprocessing data, removing missing data and outliers, preparing the dataset for main analyses, conducting analysis, and reporting the results. These were the main steps that we took in this study.We selected 1,210 healthcare workers, out of 2,000, who worked in the departments or clinics combating COVID-19 and who met the study criteria. Participants provide health services for COVID-19 patients in different departments and have direct contact with COVID-19 patients. We tried to have almost the same sample size in both populations in order to compare the results fairly. From Iran, 620 HCWs including 179 physicians (Phs), 302 nurses (Nus), and 139 other healthcare staff (OHS) were considered for analysis. About 590 European HCWs including 185 physicians, 278 nurses and 127 other healthcare staff were considered. Both Iranian and European HCWs were working in COVID-19 departments, clinics, and wards. They had a close contact with patients. In both societies, the numbers of male participants outweigh the number of female participants. In Iran and in the European countries, 312 male HCWs (~50.3%) and 301 male HCWs (~51%) were selected in this study, respectively. For Iranian HCWs, the average age was 38.66 ± 9.1 years and in more detail for Iranian physicians, nurses, and OHS, it was 41.3 ± 7.8, 36.9 ± 8.2, and 37.8 ± 7.6, respectively. The average age among European HCWs who participated in this study was 38.8 ± 7.9 years. The average age for European physicians, nurses, and OHS was 40.1 ± 8.3, 38.4 ± 7.9, and 37.9 ± 6.4, respectively. Volunteer HCWs were literate and between the ages of 20 and 70. All participants were asked to submit their sociodemographic and clinical information and also to fill in the forms including the Fear of COVID-19 scale (FCV-19S), Pittsburgh Sleep Quality Index (PSQI), 12-item General Health Questionnaire (GHQ-12), World Health Organization Quality of Life-BREF (WHOQOL-BREF)—Short Version, Beck Anxiety Inventory (BAI). We employed SPSS Version 22 to perform statistical analysis.Institutional Review Board (IRB) approval was obtained before the study commenced. Research Ethics Committee of Islamic Azad University—Science and Research Branch found our study to be in accordance with ethical principles. The approval ID is IR.IAU.SRB.REC.1400.260. For participants' identities to be confidentially safe, we associated participants with some random pre-generated codes. These codes replaced the names and identities of participants in all the further steps and analyses. The recorded data are kept in a confidential and safe repository.We employed Google forms which had been previously prepared by the authors and are acknowledged in the literature. Our forms include socio-demographic and clinical information like age, sex, educational level, marital status, chronic illness, type of household, children, work shifts, type of workplace, their experience, their family, a record of COVID-19 in their family, death caused by COVID-19 in their immediate family, etc.In , 66, FCVThe Pittsburgh Sleep Quality Index (PSQI) is a 24-item standardized self-report assessment tool with seven subscales which is used in both clinical and non-clinical applications. PSQI is employed to diagnose sleep problems and to measure sleep difficulties over a 1-month interval. The test includes 24 questions, 19 questions of which are self-report and assess subjective sleep quality. Five questions are answered by a partner or roommate. We used these 24 questions in a four-point scale (0–3) to measure sleep quality in this study. These questions give scores for sleep quality, sleep latency, sleep duration, habitual sleep efficiency, sleep disturbance, use of sleeping medication, and daytime dysfunction. Participants should answer questions through a scoring scale between 0 and 3. All scores in all subdimensions are summed up resulting in the overall index score equal to 21. Scores >5 show low sleep quality or a disturbance in sleep quality. The higher the overall index, the poorer the sleep quality. PSQI is a reliable international scale that is widely used to measure subjective sleep quality . The intGHQ-12 is a 12-item subjective questionnaire that is employed to measure psychological distress or general wellbeing . A bimodWorld Health Organization (WHO) defines health as “A state of complete physical, mental, and social wellbeing not merely the absence of disease ....”. WHOQOL-BREF is a self-report assessment tool that is cross-culturally applicable and has been introduced by WHO in order to measure the quality of life , 73, 74.Beck Anxiety Inventory (BAI) is a subjective three-point measure that is used to evaluate the frequency of anxiety which is experienced in daily life by an individual. BAI was first introduced by Beck et al. . Each itt-test was performed for independent samples for more than two and two independent groups, respectively. Significant differences were determined with respect to the significance interval (p < 0.05). In addition, we utilize Pearson correlation analysis to test the correlation between the measures. To test the normality of recorded scores we used the Kolmogorov–Smirnov test.We employed Statistical Package for Social Sciences (SPSS 26) for statistical analysis. Arithmetic means, standard deviation, percentage, and frequency were calculated using SPSS 22 to analyze our data. A one-way analysis of variance (One-Way ANOVA) and This study aims to explore anxiety, psychological stress, quality of life and sleep among HCWs through sociodemographic and work-related characteristics which are represented in As can be seen in In Iran, for male HCWs, the oldest age period (61–70) had the least participation at about 3%. However, female Iranian HCWs showed 12% of participation which is considered a significant difference. It could be due to early retirement or less interest in filling out online questionnaires by this age group. In the studied European countries, this age group again showed the least participation with 5% for male and 9% for female HCWs suggesting a considerable difference between male and female HCWs in participation. In addition, it can be seen that while in Iran and the studied European countries, younger male HCWs [in the age gaps of –30 and –40 yearsp = 0.186) between HCWs who smoke in terms of the place of service. There was a statistically significant difference (p = 0.041) between physicians and the other two groups of Iranian HCWs with increased use of tobacco. Marital status, gender, educational level, lifestyle, having children, having a family member with chronic illness, having a family member at the age of or older than 65 years at home and professional experience did not affect the use of tobacco in Iranian HCWs. Smokers with a chronic illness or with a pregnant family member reported lower consumption during the pandemic.According to data collected in our study and p = 0.037) between physicians and the other two groups of European HCWs with increased use of tobacco. The highest tobacco use was detected among nurses and OHS working rotatory shifts. In contrast to Iran, their workplace had no considerable and significant effect on tobacco consumption. Similar to Iranian HCWs, according to statistics, European HCWs reported no significant change in tobacco consumption regarding gender, marital status, educational level, having chronic illness, etc.In the studied European countries, among 176 smokers (29.8%), 84 participants had an increased tobacco consumption, 56 reported a decreased consumption and 36 European HCWs reported no change in daily tobacco consumption. About 19.6% of physicians, 41.8% of US nurses, and 49.0% of European OHS, who participated in this study, have reported tobacco use in the pandemic. Similar to Iran, physicians have the lowest share in tobacco consumption. There was a statistically significant difference  in Iran and 348 (58.9%) in the European countries. The numbers of HCWs in Iran and the European countries who reported an increase in alcohol use due to the pandemic were 139 in Iran and 147 in the European countries. A decreased alcohol consumption was reported by 42 Iranian HCWs and 59 European ones. For 91 Iranian and 142 European HCWs, no change in alcohol use was experienced. In Iran, HCWs working in outpatient clinics reported more alcohol use in comparison with those working in clinics + departments or just departments. In the European countries, there was slightly higher alcohol consumption among HCWs working in departments. In both Iranian and European HCWs, we did not manage to find factors which considerably affect alcohol consumption at an acceptable significance level.Volunteers with a record of psychiatric treatment were excluded in our study. Five Iranian participants and two Europeans reported suicidal history. Among Iranian HCWs, 39 active suicidal ideation was observed while this number was 12 in European HCWs. In both Iranian and European HCWs, an increase in BAI, FCV-19S, GHQ-12, and PSQI can be seen for females, but there exists no statistically significant difference. In addition, there is no significant difference in terms of quality of life (WHOQOL-BREF) in male and female HCWs in both countries. For European HCWs, the significance levels , for BAI, FCV-19S, GHQ-12, WHOQOL-BREF, and PSQI were 0.1012, 0.0937, 0.1992, 0.2015, 0.0734, respectively. The confidence levels for Iranian HCWs for BAI, FCV-19S, GHQ-12, WHOQOL-BREF, and PSQI were 0.0986, 0.1259, 0.0873, 0.1430, and 0.0698, respectively. As can be seen in both societies, there is no significant difference between females and males suggesting that both genders in both countries follow almost the same pattern.p = 0.0357) and the studied European countries (p = 0.0429). In Iranian nurses, a significant difference (p = 0.0368) exists for the BAI measure (in comparison with physicians and OHS), while there is no such difference for European nurses. While in terms of other measures, although there is an increase for nurses in both countries, there exists no statistically significant difference. In an eye-bird view, nurses experience the most stress, anxiety, fear of COVID-19, and lower quality of life and sleep in both countries. Physicians come second in Iran and the studied European countries. They report lower anxiety but almost the same distress in comparison with nurses. There is a considerable (but slight compared to nurses) decrease in the quality of sleep and life for physicians. OHS groups in both countries have reported less anxiety and stress. They experience less fear of COVID-19 in comparison with nurses but more in comparison with nurses. However, the quality of life and sleep in OHS shows a decrease like nurses. Although there are increases in almost all measures for HCWs in both countries, as was mentioned, except for GHQ-12 (for Iranian and European nurses) and BAI (for Iranian nurses), no significant difference exists between physicians, nurses, and other healthcare staff in both countries. According to the recorded measures, HCWs in Iran are under more mental pressure and psychological distress. The level of anxiety, fear, and stress is much higher in Iranian HCWs, and there is also a significant difference in the quality of sleep and life. In Iran, nurses have reported the highest psychological distress and anxiety. However, in the studied European countries, nurses and physicians experience almost the same mental pressure, anxiety, and stress.No significant difference was determined in terms of educational level in both countries. Iranian and European nurses experience more anxiety and distress in comparison to physicians and OHS. They also claimed lower sleep quality and a decrease in the quality of their lives. For GHQ-12, there is a significant difference between nurses and the other two groups in Iran  are written in bold and marked by a star (*). In terms of FCV-19S and GHQ-12, for example, there are significant differences between Iranian and European HCWs.The prevalence of the measures in Iran, the above-mentioned European countries, and the full sample are described in p-values below 0.01 are considered with a normal distribution. For sake of space and due to a large number of recorded scores, we reported just the number of scores in each measure whose associated p-values were below 0.01. As it is clear, only some of the proposed measures have the normal distribution and passed the normality tests which we expected due to the small number of samples and the limitations we had while gathering data and conducting this study.To test the normality of the proposed measures, we conducted the normality test using Kolmogorov–Smirnov (K-S) normality test. Results are presented in r = 0.129 and p = 0.009), between age and PSQI (r = 0.237 and p = 0.009), and between BAI and PSQI (r = 0.209 and p = 0.001). There is also a negative correlation between FCV-19s and WHOQOL-BREF (r = −0.0141 and p = 0.031), between GHQ-12 and WHOQOL-BREF (r = −0.361 and p = 0.009), and also between BAI and WHOQOL-BREF (r = −0.195 and p = 0.002). Correlation analysis for the proposed measures is represented for Iran, the studied European countries, and the full sample in 7, respectively. Correlations with a p-value equal to or below 0.05 (p ≤ 0.05) are written in bold and marked by a star (*).In Iran, there is a positive correlation between age and FCV-19S (r = 0.287 and p = 0.041), between age and PSQI (r = 0.236 and r = 0.027), between GHQ-12 and PSQI (r = 0.086 and p = 0.009), and between BAI and PSQI (r = 0.291 and r = 0.007). On the other hand, there is a negative correlation between age and BAI (r = −0.197 and p = 0.036), between FCV-19S and WHOQOL-BREF (r = −0.021 and p = 0.030), and between BAI and WHOQOL-BREF (r = −0.175 and p = 0.012).Among the studied European countries, as can be seen in r = 0.236 and p = 0.012), also between age and PSQI (r = 0.193 and p = 0.016), between FCV-19S and PSQI (r = 0.182 and p = 0.001), between BAI and GHQ-12 (r = 0.097 and p = 0.021) and between BAI and PSQI (r = 0.302 and r = 0.002). There was also a negative correlation between GHQ-12 and WHOQOL-BREF (r = −0.129 and p = 0.006) and between BAI and WHOQOL-BREF (r = −0.286 and p = 0.001).According to The present study explores the most important measures regarding mental pressure, psychological distress, anxiety, quality of life, and sleep with respect to sociodemographic data recorded from HCWs in two target populations of HCWs including Iran and the studied European countries. In this study, we tried our best to fairly compare these two populations through the aforementioned measures. The present study identified almost 79 and 70% fear of COVID-19 among Iranian and European nurses, respectively. About 80 and 90% of Iranian and European nurses claim that they suffer from poor quality of sleep. Considering the results mentioned before, it should be noted that Iranian HCWs experience a worse situation considering all measures such as BAI, GHQ-12, FCV-19S, etc. Our findings are consistent with previously published studies in the same target populations such as Motahedi et al. . In addiThere was a considerable significant correlation between FCV-19S, BAI, GHQ-12, and PSQI. This shows that quality of sleep has been more affected in the pandemic in comparison to the quality of life. Most Iranian and European HCWs have claimed to suffer from poor sleep quality. Working hard for long hours, being exposed to the disease, witnessing death in each work shift, etc. were the main reasons for HCWs to be stress-out, feel anxiety, and suffer from poor sleep quality. During pandemics, governments should take serious actions to lower the workload to help HCWs as individuals fighting the disease on the front line. Poor sleep quality results in inaccuracy, making mistakes, and lower performance.Iranian HCWs used to experience tough situations and have not been satisfied with their jobs. They report suffering from too much workload, working for long hours, no appropriate salaries, low socioeconomic status in society, no job security, etc. Recently, several studies and news have reported suicides among Iranian HCWs. As there was almost no hope to receive surefire treatment for the disease and also vaccines to get immune, Iranian HCWs were under more psychological distress. However, European HCWs were more positive about receiving vaccines at the time of recording data.It should be noted that we gathered data during a period when HCWs are vulnerable to fatigue due to social restrictions. This can significantly affect the recorded measures such as the level of anxiety and the quality of life and sleep. As it is mentioned in Manchia et al. , fear ofAs was discussed, we decided to employ the most effective measures suggested by several previous studies like –7 to preDespite all the limitations we had in this project, we managed to conduct a comprehensive study with a rich dataset compared to previous studies. For example, the authors in Korkmaz et al.  performeConsidering the results of the present study, it is worth mentioning that Iranian nurses experienced more stressful situations and report more anxiety and stress and lower quality of life and sleep. Due to their insufficient salaries and also economic inflation, Iranian nurses and OHS tend to work in two or even three healthcare centers which play a crucial role in tolerance and the level of anxiety. They are highly exposed to patients and the disease. Some Iranian nurses and OHS have reported that they have not met their family members for months. Iranian physicians reported less anxiety and distress as some of them have quit their jobs in order not to be exposed to the disease.In pandemics, almost the whole society is affected, and HCWs who work on the front line are more prone to be infected by patients and thus are more stressed out. Intensive workload, several responsibilities, risk of exposure, etc. sharply increase in such crises. Serious actions should be taken by HCWs to protect themselves, and their family members which again leads to more stress and anxiety. In addition, they need to work hard to inform society about the disease and corresponding preventive actions. Moreover, HCWs need to be focused to use medical resources appropriately which, during pandemics and considering a load of patients, might result in more mental pressure. HCWs need to work harder during extended working hours when they witness more death. Several studies such as , 7, 34, In addition to psychological symptoms and disorders caused by COVID-19, several studies such as –86 workeThe present study suffers from some limitations. In this study, we focused on the level of self-reported symptoms and just employed online questionnaires and also self-report data which can be questioned. Due to the limitations imposed by the recent pandemic, we did not manage to utilize diagnostic tools or methods. Evaluation by an external and expert observer will result in more accurate and precise results. HCWs filled out the questionnaires online and under no supervision and submitted measures might be doubted since HCWs might have filled out forms in different mental states or when they were stressed out or tired of work. These factors affect HCWs, and they might take sides and fill the forms with mental bias.In addition, the fact of having a convenience sample should be noted as a limitation in our study. We used several applications to spread the questionnaires, and sometimes, it was a bit difficult to answer our participants' concerns appropriately. Gathering data in such studies like ours is challenging especially in terms of data collection from several districts all over the world. Moreover, there also existed some limitations regarding our methodology such as the short period of time for data collection and also the possibility of getting infected by COVID-19 during the data collection phase. Our proposed method can appropriately describe and compare HCWs in the two target populations; however, more analysis is required to fully explore the causes of low life and sleep quality and the relationship and correlation between the denominators and these important qualities of life and sleep. It is worth mentioning that another significant limitation was regarding the representativeness of respondents who were sometimes difficult to reach out to. Finding eligible participants from our target districts was one of our challenges and took a considerable amount of time. Although we have tried our best to collect as larger datasets as possible but larger datasets will open up new horizons and will result in new findings in future studies.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Research Ethics Committee of Islamic Azad University—Science and Research Branch. The patients/participants provided their written informed consent to participate in this study.MoZ proposed the first idea and managed the whole project. MoZ, PT, SK, MSK, SJ, and AS collected the data and performed data collection and analysis. MoZ, PT, MSK, and AS carried out statistical analysis and prepared the repots. MoZ, KM, MaZ, SJ, and NJD conducted data analysis and reviewed the results. MoZ and PT wrote the manuscript and edited it. MaZ, KM, and NJD supervised the project. All authors reviewed the results and the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Mentha arvensis L., Family: Lamiaceae), popularly known as corn mint or Japanese mint, is an important industrial crop that is widely grown for its valued essential oil. Nitrogen (N) is an important macro-nutrient and an essential factor for optimizing the yield and quality of crops. Hence, rapid and accurate estimation of the N content is crucial for nutrient diagnosis in plants and to make precise N fertilizer recommendations. Generally, N concentration is estimated by destructive sampling methods; however, an indirect assessment may be possible based on spectral characteristics. This study aimed to compare the foliar N concentration based on non-destructive (reflectance) and destructive  methods in menthol mint. Foliar N concentration was measured through the Kjeldahl method and reflectance by Miniature Leaf Spectrometer C-710 (CID Bio-Science). Using reflectance data, several vegetation indices (VIs), that is, normalized difference red edge (NDRE), red edge normalized difference vegetation index (reNDVI), simple ratio (SR), green–red vegetation index (GRVI), canopy chlorophyll content index (CCCI), photochemical reflectance index (PRI), green chlorophyll index (CIGreen), red edge chlorophyll index (CIRed Edge), canopy chlorophyll index (CCI), normalized pigment chlorophyll ratio index (NPCI), and structure insensitive pigment index (SIPI), were developed to determine the foliar N concentration. The highest correlation (r) between VIs and foliar N concentrations was achieved by NDRE (0.89), followed by reNDVI (0.84), SR (0.83), GRVI (0.78), and CCCI (0.76). Among the VIs, the NDRE index has been found to be the most accurate index that can precisely predict the foliar N concentration . In summary, the N deficiencies faced by the crop during its growth period can be detected effectively by calculating NDRE and reNDVI, which can be used as indicators for recommending precise management strategies for the application of nitrogenous fertilizers.Menthol mint ( Mentha arvensis L., Family: Lamiaceae), popularly known as corn mint or Japanese mint, is a short-term (90–110 days) cash crop that is widely grown for its valued essential oil and provides livelihood support to millions of smallholder farmers. India is the principal producer and supplier of mint oil in the world , followed by China, Brazil, and the United States (Menthol mint (d States . The higd States . The ecod States . Therefovia chlorophyll production (Nitrogen (N) is one of the most important macro-nutrients essential for plant growth, development, and quality of the crop . Plant goduction . On one oduction . TherefoThe traditional method for N measurement is tedious and time consuming, and is typically performed by destructive sampling and laboratory analyses, making it difficult to fulfill the challenges of precise crop management in large-scale agricultural fields. In recent years, remote sensing technologies have been established as effective methods for the non-destructive detection of N concentration in several crops, such as rice , wheat , oilseedAlthough N assessments in different crops have been widely reported, only a few efforts have been made in the menthol mint crops . TherefoMentha arvensis cv. Kosi, developed by CSIR-Central Institute of Medicinal and Aromatic Plants, was used to determine the correlation between different VIs and the foliar N concentration based on non-destructive (reflectance) and destructive  methods.The field experimentation site  is locat3 + H2O2 by the Kjeldahl method to assess the N content  and powdered, and were subjected to wet digestion with HNO content .Green), red edge chlorophyll index(CIRed Edge), canopy chlorophyll index (CCI), normalized pigment chlorophyll ratio index (NPCI), and structure insensitive pigment index (SIPI)  and analyzed using SpectraSnap! software. VIs were extensively utilized to differentiate plant nutrient concentration, and the selection of different VIs used in this study was based on their capacity to retrieve chlorophyll and N content according to the methods described in the literature. The following VIs were measured through reflectance spectra: normalized difference red edge (NDRE), red edge normalized difference vegetation index (reNDVI), simple ratio (SR), green–red vegetation index (GRVI), canopy chlorophyll content index (CCCI), photochemical reflectance index (PRI), green chlorophyll index (CIx (SIPI) .p ≤ 0.05 in SPSS 20.0. When a significant correlation was present between VIs and foliar N concentration, a linear model was tested for regression analysis. To study the linear relationship between variables, the partial least squares regression (PLSR) model was constructed, and the data were computed using Python 3.7.3. The standard PLSR equation can be expressed as follows:The relationship between VIs and foliar N concentration was assessed through Pearson correlations (r) and a test of significance at the level of y = response variable that represents foliar N,where i = predictor variable representing spectral data,xi = the estimated weighted regression coefficient, andβε = error vector.R2 (coefficient of determination) and the RMSE (root-mean-square error), which is calculated as follows:Partial least squares regression is the most popular linear model that has applications in a wide range of fields , 2018. Iwhere Yi = N concentration of the ith sample calculated by the equation,yi = N concentration analyzed in the lab for “i” sample, andn = total number of samples.R2 value was close to 1 and the RMSE value was close to 0  derived from spectral reflectance studies was evaluated for estimating foliar N concentration. It was observed that all the VIs significantly and positively correlated with foliar N concentration (Green (0.71), and CIRed Edge (0.71), while a weak correlation was demonstrated by CCI (0.68), NPCI (0.68), and SIPI (0.64).The performance of different VI  and provides the most accurate results among all the VIs used in this study , SR , GRVI , CCCI , CIGreen , PRI , and CIRed Edge  also provided good estimations for N concentration. Nevertheless, a weak correlation was observed between foliar N and VIs SIPI , NPCI , and CCI .According to is study . In compR2 = 0.95, RMSE = 0.08), suggesting that predicted N concentration is strongly correlated with measured N concentration. The sensitivity study was also performed using spectral variables to calculate their specific importance toward the reliability of the PLSR model. The outcomes (The association between measured N (Kjeldahl method) and predicted N (model) is shown in outcomes  showed tGreen, CIRed Edge, CCI, NPCI, and SIPI were measured and further used to determine the foliar N concentration. The Pearson correlation analysis showed that all the VIs were significantly and positively correlated to N concentration, signifying that these VIs were good indicators of N concentration in menthol mint plants. The highest correlation (r) between VIs and N concentrations was retrieved by NDRE, followed by reNDVI and SR. The VIs GRVI, CCCI, PRI, CIGreen, and CIRed Edge showed a medium correlation, while VIs CCI, NPCI, and SIPI exhibited a low correlation with N concentration. Similar findings were also reported by previous studies (Fertilizers play a vital role in improving crop yield and productivity. Among them, nitrogenous fertilizers are important to mineral nutrition and significantly affect the biological process of the plant, right from its germination stage till maturity, and thus have a considerable impact on crop yields. Excess amount of N fertilizers not only increases the cost of cultivation, but is also harmful to soil, environment, and human health . Hence,  studies .R2 values and lower RMSE values, which indicated that VIs based on the reflectance of the red-edge band were more sensitive toward the estimation of foliar N status than the other VIs evaluated in this study. These results are in agreement with the findings of Following the presence of a significant correlation, the PLSR model was used to evaluate the linear relationship between variables, which revealed that the NDRE vegetation index has a significant correlation with foliar N concentration and provides the most precise results among all the VIs used in this analysis. This is in agreement with the findings of the previous studies . StudiesAnalyzing the model’s precision is an essential part of developing regression models because it describes how well the model performs in its predictions. In this study, the model precision and accuracy between measured N and predicted N concentration was found to be very high, indicating that the predicted N is strongly correlated with the measured N concentration. The results of the sensitivity analysis of the PLSR model revealed that all the independent variables had a significant impact on the model output.Green, PRI, and CIRed Edge indices also provided good estimations, whereas SIPI, NPCI, and CCI indices showed a weak correlation with foliar N concentration. The results of the sensitivity analysis of the PLSR model revealed that all the independent variables had a significant impact on the model output. The model precision and accuracy between measured N and predicted N concentration was found to be very high, indicating that the predicted N is strongly correlated with the measured N concentration. We firmly believe that this information can be used as an indicator for recommending the application of precise amounts of nitrogenous fertilizers.The revolutionary scientific and technological development, particularly in the field of remote sensing, has greatly influenced agricultural practices in the 21st century. Remote sensing techniques have been proved to be a promising method for monitoring health, nutrient evaluation, and yield prediction of crops. Constant monitoring of plant N content might be useful for farmers to expand their farming practices and facilitate real-time observation for site-specific fertilizer management, which would favor novel inventions in the coming years. Hence, the application of excess fertilizers should be reduced to prevent destructive consequences on the environment, which can simultaneously provide supportable benefits to the production capital. It is apparent from this study that NDRE and reNDVI are the most sensitive VIs for the estimation of foliar N concentration in menthol mint plants. This finding suggests that N deficiencies encountered during the growth of the menthol mint crops can be detected by calculating NDRE and reNDVI vegetative indices. In comparison, SR, GRVI, CCCI, CIThe raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.MS conceived and designed the experiment, and corrected and finalized the manuscript. PP, SS, and MSK conducted the experiments and collected the data. PP analyzed the data and wrote the manuscript. SS helped in manuscript preparation. All authors reviewed and agreed on the final version.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer RL declared a shared affiliation with the authors to the handling editor at the time of review.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Neonatal hyperbilirubinemia is a significant health problem in Myanmar. We introduced transcutaneous bilirubin (TcB) measurements in 2017 and developed an hour-specific TcB nomogram for early detection and treatment of hyperbilirubinemia in Myanmar neonates. This study aimed to evaluate whether our screening method for hyperbilirubinemia decreased the requirement of blood exchange therapy (ET).This retrospective cohort study was conducted at the Central Women’s Hospital, Yangon. Two groups were included as follows: group 1 , and group 2 . The number of ETs was analyzed based on causes of hyperbilirubinemia and number of days after birth.p = 0.000). Serum bilirubin values at the time ET was administered were significantly higher in Group 1 than those in Group 2 .Groups 1 and 2 comprised 12,968 and 10,090 infants, respectively. Forty-six and two infants in Groups 1 and 2, respectively, required an ET. The odds ratio for ET was 18.0  can effectively reduce the need for ET in neonates in Myanmar. Neonatal hyperbilirubinemia presents a significant health burden in developing countries, such as Myanmar , 2. It mIn Myanmar, the majority of newborns are delivered at home and may not receive adequate medical care at birth, including home visits and physical examinations by doctors. Some parents do not seek hospital checkups unless the infant shows obvious anomalies or neurological abnormalities. Home birth and self-referral to a hospital are significant risk factors for the presentation of acute bilirubin encephalopathy . On the Kramer’s rule identifies hyperbilirubinemia based on the dermal change of color on the head, hands, and feet . The KraIn 2017, we introduced transcutaneous bilirubin (TcB) measurement in a hospital in Yangon based on previous reports of its usefulness in developing countries in terms of feasibility –12. As pPediatricians and postgraduate students working at a neonatal unit at the hospital were offered training sessions on the use of TcB measurements and the nomogram developed by us. They have started to include hyperbilirubinemia screening with TcB measurement in routine work at the postnatal wards since 2018. Moreover, because this screening method is feasible, it has been widely used by medical professionals. In this study, we evaluated the effectiveness of this new screening method in reducing the number of ET cases.This single-center, retrospective cohort study included neonates born at the Central Women’s Hospital Yangon, Myanmar after 35 weeks of gestation with a birthweight > 2,000 g. These infants were divided into the following two groups : Group 1In Group 1, the management of hyperbilirubinemia was based on Kramer’s rule; the neonates were checked three times a day  from day 0 to day 3 after birth, and they were treated according to the AAP guidelines using the total serum bilirubin (TSB) level determined during blood sampling. In Group 2, TcB was measured by trained doctors using the JM-105 ; the measurements were performed three times a day  from day 0 to day 3 after birth. The mid-sternum point on the chest of the neonates was chosen as the site of measurement, and the median value of the three measurements was plotted on the hour-specific TcB nomogram . If the Opt-out was implemented given the retrospective cohort study design, which precluded the acquisition of informed consent prior to the study. A notice on the research and opt-out policies was put up on the wall at the neonatal unit, for the guardians of the sample infants. This study was approved by the Ethical Committee Registry of the Faculty of Medicine Kagawa University (2021-225) and conducted in accordance with the principles described in the Declaration of Helsinki.Categorical variables are presented as absolute numbers with percentages. Continuous variables are presented as medians with minimum and maximum values. The odds ratio of the number of ETs in Group 2 against the number of ETs in Group 1 was calculated using Microsoft Excel .p = 0.000; We initially included 15,254 neonates, of which 12,968 live-born neonates were categorized into Group 1 (2016), and 12,371 neonates, of which 10,090 were categorized into Group 2 (2019). Forty-six infants were treated with ET in Group 1, while only two infants were treated with ET in Group 2. The odds ratio for ET was 18.0 , and two nurses (one to assist and one to run errands). Furthermore, neonatal patients need to be intensively cared for after ET. In addition, extra care will be needed if any serious complications occur, such as thromboembolism, necrotic-enteritis, arrhythmia, metabolic abnormalities, abnormal coagulation abnormalities, and infections . TherefoIn our study, most patients that underwent ET had G6PD deficiency, which is common in malaria-endemic areas, such as tropical Africa and tropical and subtropical Asia . G6PD deCentral Women’s Hospital, this study’s site, had similar results to two previous hospital-based studies, which showed a similar incidence of G6PD deficiency in male infants (9%) , 24. SigThus, while the early detection of G6PD deficiency is difficult, the early detection of hyperbilirubinemia is feasible, particularly by following the screening method described in this study. Once hyperbilirubinemia is detected, irrespective of the cause, its timely and effective management by phototherapy, a non-invasive treatment, is possible. Consequently, early detection reduces the incidence of ET in patients with G6PD deficiency.In 2019, two infants with hyperbilirubinemia were detected by our screening method and underwent ET on the day of birth. One baby had significant hyperbilirubinemia due to an Rh incompatibility, and the other one was found to have hemolytic anemia at 6 h after birth. Interestingly, no patient with G6PD deficiency needed ET. The results demonstrated that our screening method could successfully detect all cases of significant hyperbilirubinemia and avoid unnecessary ET and its complications by providing early non-invasive interventions.Our study, which analyzed a screening method involving TcB measurements, identified an effective early detection of neonatal hyperbilirubinemia. With Kramer’s rule, TSB reached between 17.3 to 33.0 mg/dL when ET was administered, but TcB measurements could lead to early detection with TSB rising only between 6 to 13.8 mg/dL. Early detection leads to early treatment, which is a recommended convention as per the AAP guidelines. Indeed, we found that the number of cases requiring ET significantly differed between 2016 and 2019.There is a high risk for healthcare malfunctioning and/or mismanagement in situations where new medical management protocols are introduced. However, our study showed that after the screening method was introduced, no technical or feasibility challenges were observed at the healthcare and medical centers. This is crucial for developing countries, such as Myanmar. Therefore, we recommend that this screening method be expanded to other hospitals in Yangon, provincial areas, and remote areas where medical resources are scarce. Such improvements in neonatal care may decrease the neonatal morbidity and mortality rates in Myanmar.There are some limitations in our study that should be acknowledged. First, this was a single-center study. The hospital is a tertiary medical institution run by the government and is located in an urban area. Thus, it might be difficult to generalize the results to the entire country. Second, this was a retrospective study; accordingly, we could not prove causality between the screening method and the early treatment administered through phototherapy. Third, the reasons why some cases of hyperbilirubinemia led to ET are unknown because medical examinations are limited in Myanmar; routine examinations are limited to G6PD screening and ABO/Rh incompatibility, and do not include blood complete picture, bleeding and clotting profiles, cerebral hemorrhage, metabolic diseases, abnormalities on thyroid gland, or scrutiny on infection. Fourth, the contribution of this screening method to the early detection of severe neonatal hyperbilirubinemia 72 h after birth remains unclear, because the TcB nomogram for Myanmar neonates was applicable within 72 h of birth.In conclusion, the management of hyperbilirubinemia with our screening method using an hour-specific TcB nomogram and TcB measurement is effective in reducing ETs in Myanmar neonates. Our study might contribute to a reduction in the medical burdens in neonatal care. Further research is urgently needed to examine the effectiveness of this screening method in other hospitals in different areas, especially where medical resources are scarce.The original contributions presented in this study are included in the article/The studies involving human participants were reviewed and approved by Ethical Committee Registry of the Faculty of Medicine Kagawa University (2021-225). Written informed consent from the participants or their legal guardian/next of kin was not required to participate in this study in accordance with the national legislation and the institutional requirements.HS, SY, and YH conceptualized the study. HS, SY, NA, and TK designed the study. HS, SY, YH, TO, and ZH collected and analyzed the data. SY, NA, HO, and TK coordinated and supervised the data collection. HS drafted the initial manuscript. SY, YH, KK, SN, and TK critically reviewed and revised the manuscript. All authors approved the final manuscript as submitted and agreed to be accountable for all aspects of the work.


Women’s survivability was worse than men’s in the case of multiple cancers and in the group of people who quit smoking . To conclude, smoking tobacco affects the survival of patients with lung cancer. Smoking cessation improves overall survival.Lung cancer is the leading cause of death worldwide among men and women. Tobacco smoking is the number one risk factor for lung cancer. The aim of our study was to evaluate the survivability of patients with single lung cancer in relation to the survival time in patients with multiple neoplasms whose last neoplasm was a lung cancer. A retrospective analysis was con-ducted of data from medical histories of patients hospitalized at the Pulmonary Hospital in Olsztyn (Poland) from 2012 to 2017, with a lung cancer diagnosis as the first or subsequent cancer. The total longevity of women with diagnosed multiple cancers was found to be shorter than that of men: 67.60 years (SD: 7.77) and 69.91 years (SD: 7.97), respectively. Among the ex-smokers, the longevity of men (68.93 years) was longer than that of women (66.18 years). Survival time, counted from the diagnosis of both the first and subsequent cancer, was longer among patients with multiple cancers than among patients with single lung cancer ( Lung cancer is one of the most frequently diagnosed neoplasms and the main cause of death due to neoplasms globally, among both men and women . Every yPatients with a second or even third neoplasm constitute an ever-growing population that requires special attention. Primary multiple neoplasms develop in their location and are not part of an existing neoplastic process, nor are they spread, metastasized, or recurrent .The development of another neoplastic process is influenced by a combination of genetic and external factors, for example, environmental or occupational circumstances or previous oncological treatment. The group of environmental factors increasing the risk of oncogenesis includes: ultraviolet radiation, atmospheric pollution, e.g., diesel exhaust, as well as some viral infections , obesity, smoking, and alcohol consumption ,6. PestiThe data obtained from many scientific studies confirm the direct influence of both active and passive smoking on the development of lung cancer . AccordiFor the present study, we considered the influence of environmental factors, which include all occupational exposures and, in particular, smoking. The aim of our study was to evaluate the survivability of patients with single lung cancer in relation to the survival time in patients with multiple neoplasms whose last neoplasm was lung cancer.Particular emphasis in the paper was placed on the influence of environmental factors, especially the impact of smoking.Smoking is an important factor in the development of neoplastic diseases and affects the survival of patients.Smoking cessation contributes to extending the life span of patients.The patients’ survival depends on the risk factors, including the previous treatment of the neoplastic disease.Patients with multiple cancers whose last cancer process was lung cancer live longer than patients with single lung cancer.The following hypotheses were put forward in the article: The Warmińsko-Mazurskie Centre for Pulmonary Diseases is a reference pulmonological center in north-eastern Poland. A large proportion of patients with changes in lungs suspected to be neoplastic in character are hospitalized in this hospital.Among all hospitalized patients from the beginning of 2012 to the end of 2017, 2321 patients were identified with the diagnosis D38.1 (according to ICD10). The inclusion criterion was a histopathologically confirmed diagnosis of lung cancer—in total, 2301 persons (2079 with a single cancer and 222 with multiple cancers). The exclusion criterion was a lack of a histopathological diagnosis for various reasons  or a diagnosis of disseminated neoplastic disease with a point of origin outside the lung. The adopted time criteria were based on the availability of medical data from the IT system and the assumption of a 5-year observation period for patient survival.The study consisted of a retrospective analysis of data collected from medical histories of patients hospitalized in the Warmińsko-Mazurskie Centre for Pulmonary Diseases in Olsztyn, having obtained the consent of the Centre’s authorities and the Bioethics Committee. The patients were divided into two groups: those with a single cancer and those with multiple cancers. Multiple cancers were identified according to the IARC definition. In line with the time criterion (6 months), patients with synchronous and metachronous cancers were distinguished . The folp < 0.05.The statistical analysis was conducted in Statistica 13.3 . The mean, median and standard deviations were determined for the analyzed data. The normality of the distribution of variables was verified with the W Shapiro–Wilk test, and the equality of variances in groups was assessed with Levene’s test. Differences between the groups of the variables with a normal distribution and equality of variances were determined with the parametric t-Student test (for two groups) or the ANOVA with LSD post-hoc analysis (for more than two groups). The variables whose distribution deviated from normal or which did not reveal an equality of variances were submitted to the non-parametric U Mann–Whitney test or ANOVA Kruskal–Wallis with a two-sided multiple comparison test, respectively. The survival time of patients was analyzed using the Kaplan–Meier test. The Pearson chi-square test was used to compare the number of qualitative variables. The statistical significance level for all the tests was set at Dependent variables, namely, packyears, age of 1st cancer, age of 2nd cancer, interval between 1st and 2nd cancer, general total survival time in years, smokers’, ex-smokers’, and non-smokers’ total survival time in years, and survival time since 1st cancer (years), were tested in relation to gender, single and multiple neoplasms, and tobacco intake status (independent variables).The study is a retrospective analysis of data from the medical histories of patients, such as date of birth, date of death, sex, age, comorbidities, and risk factors of developing cancer. No personal data of patients were processed. The study was issued a positive opinion by the Bioethics Committee at the Nicolas Copernicus University in Toruń, Collegium Medicum in Bydgoszcz, on 23 June 2020 (KB 355/2020).The retrospective analysis of data comprised 2321 medical histories, including histories of 2301 persons (724 women and 1577 men) with a histopathologically confirmed diagnosis of a malignant lung neoplasm. A total of 2079 patients had a single cancer diagnosed, while 222 patients had multiple cancers diagnosed of which the last neoplastic growth was of lung cancer. The first primary cancers in patients with multiple neoplasms were: leukemia, lymphoma, head and neck cancer, ovaries cancer, uterus cancer, kidney cancer, bladder cancer, breast cancer, prostate cancer, colon cancer, sarcoma, skin cancer, thyroid cancer, Hodgkin cancer, and stomach cancer. More detailed information about the patients is shown in p = 0.000) and the subgroups of patients with a single tumor (p = 0.000) and multiple neoplasms (p = 0.002). Significant statistical differences were also observed between the number of patients with single tumors compared to patients with multiple neoplasms in all three groups related to tobacco intake.The Pearson chi-square test showed significant differences in the number of non-smoking patients of both sexes in the whole group (p = 0.000) counted from the diagnosis of the first cancer (p = 0.000). The exact data on the survival of the patients are presented in Based on the collected data, it was demonstrated that the survival time of patients with single lung cancer  was considerably shorter than that of patients with multiple neoplasms   versus 5.76 years (6.52); p = 0.015.The research shows that the total longevity of women with a diagnosis of multiple neoplasms was shorter than that of men: 67.60 years (SD: 7.77) versus 69.91 years (SD: 7.97);  = 0.037 . Howeverp = 0.014).In the group of smokers, also having included the division into the groups of women and men, the patients with single neoplasms  lived statistically significantly shorter lives than patients with multiple neoplasms  (p = 0.001) among ex-smokers. These data are illustrated in p = 0.010).It was also shown, in the group of patients with multiple neoplasms, that men had a statistically significantly longer survival time than women  (p < 0.05) in total survival time between groups of smokers, ex-smokers, and non-smokers, taking into consideration gender and single/multiple neoplasms. The results of the performed tests are shown in Analysis of variance (ANOVA) showed statistically significant differences (p = 0.000)  were patients with a history of tobacco addiction. In this group, there were 65.01% (n = 1496) smokers and 29.46% (n = 678) people who quit smoking . In our = 0.000) . Althougp = 0.015) ; 5.76 (6.52); = 0.015) . The tim= 0.015) . There ap = 0.000). As already mentioned, most  cases we analyzed were patients with medical histories indicating tobacco dependence. This group was found to comprise 65.01% (n = 1496) of smokers and 29.46% (n = 678) ex-smokers . In addition, some of the tests were performed outside the Hospital, in cooperating units . These data were delivered to the Hospital with a delay and have not been computerized so far.Tobacco smoking is a significant factor influencing the survivability of patients with lung cancer. Smoking cessation results in a longer survival time. Patients with single lung cancer have a poorer prognosis than those with an earlier neoplastic process.