Several risk factors contribute to its development on a yet undefined genetic background. Cigarette smoking is the most important of them. Early diagnosis, control and removal of modifiable risk factors, early treatment of mild forms of GO may effectively limit the risk of progression to more severe forms, which have a profound and dramatic impact on the quality of life of affected individuals, and remain a therapeutic challenge, often requiring long-lasting and multiple medical and surgical therapies.GO is the most frequent extrathyroidal manifestation of Graves’ disease, although it may rarely occur in euthyroid/hypothyroid patients with chronic autoimmune thyroiditis. It is a relatively infrequent disorder, and men tend to have more severe ocular involvement at an older age. The prevalence of GO is lower than in the past among patients with recent onset Graves’ hyperthyroidism, and moderate-to-severe forms requiring aggressive treatments are no more than 5–6% of all cases of GO. After an initial inflammatory (active) phase and a phase of stabilization (plateau phase), GO tends to improve and eventually inactivates (inactive or burnt-out phase). Minimal-to-mild GO often remits spontaneously, but complete  Graves’ orbitopathy (GO), also named Graves’ ophthalmopathy, Thyroid-eye disease, or Thyroid-associated ophthalmopathy, is a relatively rare, but disabling and disfiguring disease of the orbit, in most cases associated with hyperthyroidism due to Graves’ disease . GO is aInformation on the incidence of GO is scant. In a study of residents in the Olmsted County, Minnesota, through a 15-year interval 1976–1990), 120 incident cases of GO were found, with an age-adjusted incidence of all-degree GO of 16/100,000 population/year for women and 2.9/100,000 population/year for men 76–1990, Table 1.A recent study from the European Group on Graves’ Orbitopathy (EUGOGO) used reported data on the incidence of GO , 11, 15 vs. 41.2%) and inactive forms (63.2 vs. 39.9%) of GO when compared with the 2000 cohort , and their median age was also higher than in women with similar severity of GO   ratio varies in different studies. In a study of 202 consecutive Graves’ patients, the F/M ratio was 3.4 in patients without GO, 2.1 in patients with GO, and 0.7 in euthyroid GO . Other sp <0.05) . Althougp <0.05) , it seemvs. 7.7%, p = 0.0002), with a risk of developing GO 6.4-fold higher in Caucasians, possibly in relation to the high prevalence of smokers (>60%) among Caucasians , the prevalence of GO was significantly higher in Caucasians than in Asians  patients without GO  improved substantially, 25 patients (42%) manifested only slight amelioration, 13 patients (22%) were stable, and 8 patients (14%) had a progression of GO over a median period of 12 months . In seriGO results from a complex interaction of endogenous (unmodifiable) and exogenous/environmental (modifiable) risk factors. The former include age, gender, and genetic factors. As described in a previous section of this manuscript, GO tends to be more severe in men, in whom it occurs at an older age than in women. A search for genetic factors did not provide unequivocal information, with particular regard to differentiation between Graves’ patients with or without GO –61. LikeSeveral modifiable risk factors for the occurrence/progression of GO have been identified. This is a very important issue, because controlling them may positively affect the course of GO    Amo1.1–3.2) ; iii) Sm1.1–3.2)   , 71; v)  smokers , 49, 72; smokers . Accordi smokers . It is p smokers . Whether smokers .We mentioned above that both hyperthyroidism and hypothyroidism represent risk factors for the occurrence of GO , 48. Accde novo occurrence of GO, probably due to antigen release and related exacerbation of autoimmune reactions following RAI administration  or without GO (n = 117), a correlation between serum total and LDL cholesterol and the presence and activity of GO was reported . A seconBecause of the major role of exogenous factors in the development of GO, a prospective observational study was carried out in 10 EUGOGO centers to construct a predictive score  for the development/progression of GO in 348 newly diagnosed and untreated Graves’ patients without obvious GO . Four inrestitutio ad integrum almost never occurs when GO is more than minimal-to-mild. Several risk factors contribute to its development on a yet undefined genetic background. Cigarette smoking is the most important risk factor. Early diagnosis, control and removal of modifiable risk factors, early treatment of mild forms, stable control of thyroid dysfunction may effectively limit the risk of progression to more severe forms of GO, which have a profound and dramatic impact on the quality of life of affected individuals, and remain a therapeutic challenge, often requiring long-lasting and multiple medical and surgical therapies.GO is the most frequent extrathyroidal manifestation of Graves’ disease, although it may rarely develop also in euthyroid/hypothyroid patients with chronic autoimmune thyroiditis. It is a relatively infrequent disorder, and men tend to have more severe ocular involvement at an older age. After an initial inflammatory (active) phase and a phase of stabilization (plateau phase), GO tends to improve and eventually inactivates (inactive or burnt-out phase). Mild GO tends spontaneously to remit spontaneously, but complete All the authors participated in searching literature, critically read the papers, critically revised the draft of the paper, checked illustrations, checked bibliography, and share responsibility for statements. All authors contributed to the article and approved the submitted version.This study was partly supported by funds from the University of Insubria  to LB, EP, and MT.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.


A massive outbreak of chikungunya virus (CHIKV) occurred in Bangladesh during the period of April-September 2017, and over two million people were at risk of getting infected by the virus. A prospective cohort of viremic patients was constituted and analyzed to define the clinical, hematological, and long-term aspects of this outbreak.A 35-day long comprehensive survey was conducted in two major, neighboring cities, Dhaka and Mymensingh. One-hundred and eighty-seven laboratory-confirmed CHIKV cases were enrolled in the cross-sectional cohort study. Additionally, a smaller group of 48 chikungunya patients was monitored for post-infection effects for 12 months.p < 0.01) and elevated erythrocyte sedimentation rate . Besides, a significant portion of the patients represented abnormal values for RBC  and WBC  counts. The post-infection study revealed that children had an early recovery from the infection compared to the adults. Moreover, post-infection weakness, successive relapse of arthralgic pain, and memory problems were the most significant aftereffects, which had an impact on the daily activities of patients.Clinical data revealed that a combination of fever and arthralgia  was the cardinal hallmark (97.9% of cases) of the infection. Hematological analysis showed that irrespective of age and sex groups, CHIKV patients had a decreased level of hemoglobin  was the cardinal hallmark in the acute phase of the infection. Hematological analysis showed that CHIKV infection features a significantly reduced hemoglobin and remarkably elevated erythrocyte sedimentation rate. Besides, RBC and WBC counts, especially in children and females, were beyond the reference values. The post-infection consequence study unveiled that children recovered better from the infection compared to the adults. Further, post-infection weakness, successive relapse of joint pain and memory problems were the most significant aftereffects. Overall, the infection had a moderate to severe impact on the daily activities of the respondents. This study provides insights into the clinical and hematological aspects of chikungunya infection during the acute phase as well as describes an account for its chronic outcomes, which puts forward to the knowledge for clinicians and epidemiologists regarding the infection diversity and to help improve patient management. The causal agent of this disease is the chikungunya virus bopictus –4. The gbopictus . In 2013bopictus . Epidemibopictus , 7.Like many of the viral zoonoses in the tropics, CHIKV lacks any specific nor pathognomonic symptoms. In the most typical form of the infection (72–97% of cases), acute commencement of fever and polyarthralgia predominantly in the limb extremities is reported after a short incubation period of about 1 to 5 days , 8. OtheCHIKV can infect a significant proportion of a population within a short period, and it affects the productivity of infected individuals to a great extent. Hence, outbreaks of this virus do not only affect the infected individual or his/her family but the entire community. The debilitating disease poses a massive burden to the entire health infrastructure of a country, especially in low and lower-middle-income countries like Bangladesh. It is generally recommended that countries should develop and maintain the capacity to diagnose cases, manage patients, and employ social communication strategies to reduce the presence of the mosquito vectors. However, both capacity building and access to a healthcare facility are perhaps very challenging in countries like Bangladesh, and consequently, the actual prevalence, clinical extents, and overall burden are still elusive .Till now, outbreaks of chikungunya have been reported in more than 60 countries . The IndIn this study, we assessed the complete blood counts in a cohort of 187 CHIKV patients enrolled during the CHIKV outbreak 2017 in Bangladesh. Besides, we have investigated the clinical features of these patients while a subgroup of this cohort was continuously followed until 12 months post-infection to understand the long-term effects better.The methods and protocols used for this study were reviewed and endorsed by the Graduate Research Ethics Committee (Headed by the Dean), School of Life Sciences, Shahjalal University of Science and Technology. All participants or their legal representative gave written informed consent according to the Declaration of Helsinki.From June 30, 2017, to August 4, 2017, we recruited 297 laboratory-confirmed CHIKV cases of all age groups from Dhaka and Mymensingh districts . A laborBiochemical and serological test results were collected after they were prescribed and performed by a specialist physician and a specialist diagnostic center, respectively. Hematological reference ranges were defined as the set of values 95% of the healthy people fall within. We interviewed all the patients with a detailed questionnaire . A team The relative intensity of joint pain was evaluated using a numerical rating (NR) scale starting from 0 to 10. A rating of 0 indicated that the individual had no joint pain, and a rating of 10 indicates intolerable joint pain. Using these relative scores given by the patients, the pain intensity was categorized as mild (NR 1–4), moderate (NR 5–7), and severe (8–10). The anatomical location(s) of the pain and how long it existed after CHIKV infection were also documented.± 3 days, M2) from day 0, all patients were asked for their condition. For long-term consequences assessment (LCA) of the after-effect of chikungunya, consented patients were interviewed with a standard questionnaire 4, 6, 9, and 12 months after the viremic phase  . A team comprising of graduate students who majored in life sciences and public health disciplines administered the questionnaire.After 2 months (and M12) . A team s) test, and McNemar tests (for matched pairs of subjects) at a α-levels of 0.05 and 0.01 ..Data were analyzed using SPSS  and statistical significance was tested using and two-tailed experiments including Student t-test, χ2 test, Fisher’s exact test, Spearman’s rho test (ρ≤15 yrs) were included in this study.Among the 187 confirmed  chikungunya  patientsRandomly collected samples and demographic data analysis revealed that females were more prone to chikungunya (M:F = 1:1.34) . Among 1The symptoms of CHIKV infected patients are presented in Arthralgia was observed at 12 different anatomical sites , with haThe signs and symptoms pattern of chikungunya seemed remarkably different in children compared to adults . During p = 0.0158) (p <0.05). For CHIKV positive patients, the complete white blood cell (WBC) counts ranged from 2 to 12.6 K/μL, of which neutrophil (NTP) counts ranged between 32–80% and lymphocyte (LPC) counts ranged between 14–56%. Platelet counts ranged from 85 K/μL to 547 K/μL. Although the majority of the CHIKV positive patients were within normal ranges for whole WBC, neutrophils, LPC, and platelets (PLT), many patients represented varying degrees of lymphopenia when compared to reference values  . Among te values .p < 0.01), especially the children and women, had reduced levels of hemoglobin (p = 0.0158) (p <0.05) had reduced counts (p = 0.0005) WBC ) and parts of neutrophils  (p < 0.01) showed reduced counts  . Among td counts . Except  < 0.01) . Regardid counts . Across d counts , Fig 4.For all CHIKV positive patients, the complete white blood cell (WBC) counts ranged from 2 to 12.6 K/μL, of which neutrophil (NTP) counts ranged between 32–80% and lymphocyte (LPC) counts ranged between 14–56%. Platelet counts ranged from 85 K/μL to 547 K/μL. Although the majority of the CHIKV positive patients were within normal ranges for whole WBC, neutrophils, LPC, and platelets (PLT), many patients represented varying degrees of lymphopenia when compared to reference values .s = 0.02126, p = 0.88594, However, during the acute phase of the disease, no significant correlation was observed between the level of leukocytopenia and the intensity of arthralgic pain  after the acute phase of the infection and then raised to ~19% at M9 and M12. Most of our enrollees complained of intermittent arthralgia, with successive recovery and relapse; none of the patients complained of permanent arthralgia at any timepoint after the acute phase, and all of the respondents reported that the intensity of the pain was significantly reduced after M2. Of note, all of our enrolled patients in the LCA group suffered from arthralgia between days 0 to 7, and none of them suffered from joint pains before the CHIKV infection. The McNemar test for matched pairs of subjects revealed that the site of arthralgic pain (p <0.01). None of the patients reported having myalgia at M9 and M12 .We noted that the number of sites affected by arthralgia gradually diminished in patients still suffering until M2, with only 23% of patients (n = 11) suffering from polyarthralgia. However, the number of anatomical locations further decreased significantly in M4 and M6 and then stabilized at M9 and M12 . The most significant after-effect of the infection in our study population appeared to be the post-infection weakness. Around 40% of the patients reported having a continuous weakness at M2. The percentage decreased significantly at M6, increasing however again to ~17% at M9 and M12. Besides, more than 20% of patients complained about sleep disorder at M2 and M4, but the percentage diminished to less than 10% at M6. However, complaints of disturbed sleep slightly increased at M9 and M12  and M12  than males 38%) and female children (43.3%). However, previously published reports have indicated that both sexes suffer equal burdens of the disease , 37. The% and femIrrespective of sex, the combination of fever and severe arthralgia (present in 97.9% of cases) can be regarded as the cardinal hallmark of the chikungunya 2017 outbreak in Bangladesh. This is consistent with the previous outbreak report 83.3 to 98%), though the values were less in case of the children –46 , while a higher percentage of patients reported polyarthralgia (56.25%) than oligoarthralgia (43.75%). Also, we observed that finger joints (93.8%) and wrist (85.4%) joints were the most affected sites. In the acute phase, the frequency of incapacitating pain involving certain peripheral joints  was founOther symptoms including headache, itching, catarrh-cough, dizziness, and dysentery-like symptoms  were found to be similar to most of the previous studies, except for an unusually high frequency of rash (79.2%), swollen joints (72.9%) and redness of the eyes (64.17%) in the present study .Over 85% (41 of 48) of the patients complained of severe pain with a median NRS score of 9 throughout the acute phase , which wThe severity of certain clinical manifestations of chikungunya may perhaps depend on several factors, including age, gender, immune status, genetic predisposition, etc. . Our anap < 0.01)  documented several predictable laboratory tests for detecting CHIKV, e.g., a drop-in lymphocyte count and a higher count of platelets, leukocytes, and neutrophils . In our  < 0.01) . Based oBased on the follow-up of patients with acute CHIKV infection who consented to participate, this study shows the evolution of arthralgia, mapping the frequency and location of arthralgic sites during a 12-month time period. Our data reveals that the proportion of patients having CHIKV-induced arthralgia decreased at an almost constant rate at each time point . MyalgiaThere is evidence from different countries—notably France, India, Sri Lanka, Malaysia, Colombia, Venezuela, and the USA—to suggest that a sudden rise of heart rate was associated with the infection at both the acute and the chronic phases . In our Weakness during professional activities was noted to be the most prominent after effect of the infection, as almost 40% of our patients reported to have severe weaknesses at M4. The proportion diminished over time but relapsed several times in some patients till M12. In addition, many patients complained of disturbed sleep, swelling of joints, and suffered new symptoms, e.g., memory problems. Although the patients in our study did not display any significant neurological symptoms at the acute phase of disease, we were unable to exclude that these memory problems during the chronic phase resulting from CHIKV spread in the central nervous system, as it had been reported that CHIKV disseminates to the central nervous system in humans and animals –65. As wWhile the previous studies concerning chikungunya outbreak 2017 in Bangladesh were limited within the samples recruited from Dhaka only, this study represents a diverse sample population , 53, 66.Moreover, data regarding the clinical, chronic impact, and daily-life related parameters were collected through retrospective technique, which might be prone to the incompleteness of recalling. It is not unlikely that some respondents have overvalued some clinical symptoms due to the psychological impacts of massive social media coverage of the outbreak. Nevertheless, this study was conducted during the very peak of the outbreak, and the patients were monitored and interviewed rigorously at regular intervals; we assume any potential bias due to the incompleteness of recalling was minimized. Besides, this study involved the participation of the children, and a child may indeed respond differently as compared to an adult. Both children and older individuals may be prone to response effects, particularly when the question demands information retrieved from memory. Hence, the data presented on the effects of CHIKV infection on children may contain biases due to response effects; however, we tried to reduce the impacts of these types of biases.In summary, this study alludes to the clinical and epidemiological characteristics of the chikungunya outbreak of 2017 in Bangladesh. It facilitates our comprehension of the pathophysiology of the disease across age and sex groups and its chronic consequences till M12, a prerequisite for the development of efficient management and therapeutic strategies and for assessing the damage inflicted upon the population by a chikungunya outbreak.S1 Checklist(DOCX)Click here for additional data file.S1 Fig(DOCX)Click here for additional data file.S2 Fig(DOCX)Click here for additional data file.S3 Fig(DOCX)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.S2 Table(DOCX)Click here for additional data file.S3 TableA: LCA study. Demographic information of the patients as well as the presence of fever and joint pain at different time points. B: Outcomes of McNemar test. C: Number of patients visited a physician due to post-CHIKV complications (n = 48).(DOCX)Click here for additional data file.


The aim of this study was to determine whether a rowing training program leads to improvements in physical fitness and body composition in women who have survived breast cancer (53.70 ± 7.88 years). The participants (n = 30) completed a twelve-week training program consisting of three sessions per week, with each session lasting from sixty to ninety minutes. An anthropometric and general physical fitness assessment was performed before and after the program. The results showed statistically significant improvements in all the physical fitness tests performed: sit and reach (2.82 cm); back scratch, dominant (3.29 cm); back scratch, non-dominant (4.59 cm); counter movement jump (1.91 cm); hand grip, dominant (2.54 kgf); hand grip, non-dominant (2.53 kgf); chair stand (2.56 rep); and six-minute walk (51.56 m). In addition, a significant improvement was observed in the efficiency of the cardiovascular system measured by heart rate, in beats per minute (bpm), both before (−12.63 bpm) and after the six-minute walk test (−11.46 bpm). The evaluated body composition parameters also improved, specifically total lean mass (2.18 kg) and the percentage of total body fat (−2.63%). We can therefore conclude that rowing training programs can be a strategy to be considered for improving physical fitness in this population given the improvement obtained in both anthropometric and physical fitness variables, thus leading to better health and quality of life. According to the International Agency for Research on Cancer (IARC), breast cancer is the most common cancer worldwide, affecting 2.1 million individuals each year and is the leading cause of death among women. In 2018, approximately 627,000 women lost their lives to breast cancer [According to the 2018 IARC study, 4% of women worldwide will have breast cancer at some time in their lives . In contrast, breast cancer is no longer fatal but is becoming chronic, as the rate of survivors is above 70% five years after intervention. This percentage is associated with the effectiveness of treatments, to the increase in early diagnosis and to the prevention of relapse ,5. HowevPhysical activity decreases the duration and intensity of fatigue ,9, reducCurrently, the literature provides no scientific evidence on the prescription and structure of physical exercise for breast cancer survivors ,18. Cons2) and an increase in lean mass (0.5 kg), as well as improved upper and lower extremity strength [With regard to existing studies on physical activity and breast cancer, we highlight the study by Di Blasio et al. 2017) in which they carried out a strength program resulting in improved physical fitness . The stustrength . Modalit17 in whistrength ,27. Finastrength , strengtstrength ,39 and qstrength ,41,42.In our study, rowing was prescribed as the basis for a physical exercise program. This sport was chosen because it involves the muscles of both the lower and upper extremities  and almoThe aim of this study was to determine how a training program based on the sport of rowing may affect physical fitness and body composition in women who have survived breast cancer. The participants, all of whom were breast cancer survivors, and whose main characteristics are in Weight was measured to the nearest 0.1 kg using a Tanita model BC730 scale, following the protocol of the manufacturer for clothing and previous intake of liquids or food. Height was measured to the nearest 0.1 cm with a SECA model 213 portable stadiometer, according to the Frankfurt plane for body positioning. In the evaluation of body fat and muscle mass, a dual-energy X-ray densitometer  was used.In addition, participants completed the physical fitness tests described below: The sit and reach test  is used The hand grip test  is used The counter movement jump  measuresThe six-minute walk test  is a carThe chair stand test  assessesThe back scratch test  evaluateEach participant, barefoot and wearing light clothing, underwent an initial anthropometric assessment of weight and height to calculate BMI. Subsequently, each participant performed the physical tests in the following order: hand grip, counter movement jump, back scratch, sit and reach, chair stand and six-minute walk. After the initial assessment, the participants completed a program of twelve consecutive weeks of rowing training . For thiAt the end of the twelve-week training program, the participants were re-evaluated using the same procedure used in the initial evaluation.The data were collected in an Excel spreadsheet, including age, height, weight, BMI, the results of the different tests and participant affiliations. Statistical analyses were performed using the Statistical Package for Social Sciences, version 25 .t-test for related samples (paired data). Prior to this analysis, the normality of the distribution was verified through the Shapiro–Wilk test . Regarding women’s age, 30.43% are aged 41 to 50, 52.17% from 51 to 60 years old and 17.39% from 61 to 70 years old. To examine whether there were significant differences resulting from the rowing training, we analyzed the differences between the means of each variable pre- and post-training and then conducted parametric testing with Student’s Post-Pre = −0.37 ± 2.58; t = −0.798; p = 0.431; diffBMIPost-Pre = −0.14 ± 1.02; t = −0.786; p = 0.438; diffTotal Body FatPost-Pre = −1.77 ± 7.6; t = −1.28; p = 0.211). The variables sit and reach ; back scratch, dominant ; back scratch, non-dominant ; counter movement jump ; hand grip, right ; hand grip, left ; chair stand ; heart rate at the start of the 6-min walk test ; heart rate at the end of the 6-min walk test ; distance travelled in the 6-min walk test ; total lean mass ; and percentage of total body fat  all showed significantly positive differences between pre- and post-training. Practically all the variables that show statistically significant differences present the size of the effects, calculated from the Cohen’s d for a paired sample, being greater than 0.8. Therefore, the differences are statistically significant and clinically relevant.In the following graphs, the variables can be observed grouped according to strength, aerobic, heart rate, flexibility and anthropometry. The graphs show how the variables have evolved before and after training and ratify the differences that have been analyzed in To sum up, the results in The study of breast cancer from the perspective of physical activity is relatively recent, as demonstrated by the limited literature and recommendations published by the ACSM  less thaPhysical activity has been shown to improve quality of life in breast cancer survivors ,13 and fSeveral studies have conducted aerobic  or strenIn our study, based on the administration of a rowing training program, improvements were observed in all body composition parameters evaluated through DXA, which decreased total body fat and percentage of total body fat and increased lean mass . All of In addition, the results pertaining to physical fitness showed significant improvements in the different standardized tests that measure a wide range of manifestations of physical fitness including upper extremity and hip range of motion, lower and upper extremity strength, aerobic capacity and heart rate at rest and after prolonged effort. Consequently, the results of our study can contribute to improving the health and quality of life of women who have overcome breast cancer, offering them a new strategy for physical exercise prescription for a problem that affects more than two million women each year. Our research offers a novel methodological proposal for physical exercise prescription after breast cancer through a training program based on rowing, a cyclic and symmetrical sport that combines overall strength with aerobic endurance. This new proposal has a relatively short duration, twelve weeks, and is capable of bringing about improvements in all aspects of physical fitness and cardiac function during stress, as well as in anthropometric parameters such as fat and lean mass.


The incidence of primary liver cancer (PLC) is increasing in Western Europe. To understand trends over time and the current burden in the UK, a detailed analysis of the epidemiology of PLC and its subtypes was conducted.Data on PLCs diagnosed during 1997–2017 were obtained from population-based, nationwide registries in the UK. European age-standardised incidence (ASR) and incidence-based mortality rates (ASMR) per 100,000 person-years were calculated overall and by sex and UK-nation. Annual percentage change in rates was estimated using Joinpoint regression. One-, 2-, and 5-year age-standardised net survival was estimated.A total of 82,024 PLCs were diagnosed. Both hepatocellular carcinoma (HCC) incidence and mortality rates trebled . The rate of increase appeared to plateau around 2014/2015. Scottish men consistently had the highest HCC incidence rates. PLC survival increased, driven by a substantial increase in the proportion that are HCC (as prognosis is better than other PLCs) and in HCC survival . Intrahepatic cholangiocarcinoma was the most common PLC in women and 1-year survival improved from 22.6% to 30.5%.PLC incidence has been increasing rapidly but, as most risk factors are modifiable, it is largely a preventable cancer. This rate of increase has slowed in recent years, possibly attributable to effective treatment for hepatitis C. As other risk factors such as obesity and diabetes remain prevalent in the UK, it is unlikely the considerable burden of this disease will abate. While improvements in survival have been made, over half of patients are not alive after 1 year, therefore further progress in prevention, early detection, and treatment innovation are needed.Many more people are getting liver cancer, particularly the subtype hepatocellular carcinoma, than 20 years ago. Men in Scotland are most likely to get liver cancer and to die from it. Survival after liver cancer diagnosis is getting longer but still less than half are alive after 1 year.  •Primary liver cancer incidence and mortality rates have rapidly increased between 1997 and 2014.•The rate of increase in hepatocellular carcinoma incidence rates has plateaued since around 2014.•Hepatocellular carcinoma incidence and mortality rates were highest in Scottish men.•Survival has improved, particularly for hepatocellular carcinoma, but remains poor. Primary liver cancer (PLC) is the fourth leading cause of cancer-related mortality worldwide, causing an estimated 800,000 deaths in 2018.The main PLC subtype, hepatocellular carcinoma (HCC), is an epithelial tumour which shows hepatocytic differentiation and primarily occurs against a backdrop of cirrhosis, caused by factors such as chronic viral hepatitis, alcohol consumption, and non-alcoholic fatty liver disease. The second most common subtype, intrahepatic cholangiocarcinoma (ICCA), is an epithelial tumour showing biliary differentiation in the liver, and often occurs in patients with no known risk factors. A small proportion of PLCs have mixed features of both HCC and ICCA. There are also rare subtypes such as hepatoblastoma, Kupffer cell sarcoma, and other carcinomas and sarcomas. The distribution of risk factors, and subsequently liver cancer rates, change with time owing to factors such as changing behaviours, large-scale public health initiatives such as vaccination and other forms of infection prevention, and innovation in treatment of underlying liver diseases. Understanding the current burden of liver cancer and trends over time can quantify the public health concern, identify the need for public health interventions aimed at prevention and indicate whether it is necessary to scale-up facilities and training to meet increasing demand. Further examination by subtype is important as the causes, treatment, and outcomes are quite different.The HCC-UK BASL/National Cancer Registration and Analysis Service (NCRAS) partnership was formed to facilitate a wide programme of research relating to HCC, primarily using the detailed data available within the NCRAS on all cancer patients resident in England. Here, within the framework of this partnership and including corresponding data from the Welsh Cancer Intelligence and Surveillance Unit, the Northern Ireland Cancer Registry, and the Scottish Cancer Registry, the incidence, incidence-based mortality and survival trends in PLC and its subtypes in the UK and each constituent nation between 1997 and 2017 were examined.Patient-level data on PLC tumours, defined using the 10th edition of the International Classification of Diseases (ICD-10) code C22, diagnosed between 1997 and 2017 were obtained from the population-based, nationwide registries in Wales, Scotland, Northern Ireland (NI), and England. Patient-level data collected included ICD-10 code, second edition of the ICD for Oncology (ICD-O-2) morphology code, diagnosis year, death year, days from diagnosis to death, or latest vital status date , vital status , age at diagnosis (5-year age bands), sex, underlying cause of death (ICD-9 or ICD-10 code) and basis of diagnosis. Only those tumours with a malignant ICD-O-2 behaviour code were included.For incidence, all new diagnoses in the period 1997–2017 were included. For mortality and survival calculations, the first liver tumour only was included. Records with a date of death before date of diagnosis (N = 27) and those with the ICD-O-2 morphology code 8162, Klatskin tumour (perihilar CCA), were excluded (N = 298). For mortality, those with missing cause of death were excluded . For survival analyses those that embarked , registrations based on death certificate only (and autopsy diagnoses only in the Scottish data)  and those aged <15 years (N = 493) were excluded. ICD-10 codes and ICD-O-2 morphology codes were used to define subtypes of PLC as outlined in the Supplementary information and Mid-year population data for 1997–2017 were obtained from the Office for National Statistics.distrate command in Stata.European age-standardisedStandard mortality, which uses death certificate coding to count the number of deaths from a particular cause in a population per year, results in mortality rates that are higher than incidence rates for ICCA . This maJoinpoint regression modelling was used to model trends in incidence and incidence-based mortality rates and identify timepoints when significant changes occurred, constrained to a maximum of 3 joinpoints . Annual percentage change (APC) was calculated for each segment, and average APC (AAPC) for the whole period.strs command in Stata and the cohort approach.i.e. diagnosis and death on the same day). Survival estimates were supressed if there were no deaths or data in at least 1 age band, less than 10 in a group, the standard error was greater than 0.2, 2-year survival was greater than 1-year survival, and/or the follow-up time was insufficient in a cohort. Estimates from 5-year rolling cohorts were used for graph smoothing.One-, 2-, and 5-year age-standardised net survival was calculated for 2- and 5-year cohorts using the All analyses were conducted using Stata version 15.1 StataCorp, 2017, Stata Statistical Software: Release 15 .vs. 4.7 per 100,000, respectively). A total of 50.5% of PLCs were HCCs , 37.1% were ICCAs , and 12.4% other or unspecified liver cancers . These proportions varied by nation; in Scotland and NI approximately 60% of PLCs were HCC and 30% ICCA, whereas in England and Wales approximately 50% were HCC and 40% ICCA (p for from chi-squared test for difference between nations <0.001). Scotland had the highest PLC incidence rate  and NI the lowest . The overall incidence-based age-standardised mortality rate was 5.2 per 100,000. A total of 47.9% were deaths from HCCs, 42.5% from ICCA, and 9.5% from other and unspecified liver cancers. In general, mortality rates followed similar patterns to incidence (higher in men than in women and highest in Scotland and lowest in NI). However, the overall mortality rate for ICCA  was nearly as high as for HCC .Overall, in the UK 82,024 PLCs were diagnosed between 1997 and 2017 and 58,348 individuals died from their liver cancer between 1999 and 2017 . The ageIn the UK, PLC incidence increased from 4.4 per 100,000 in 1997 to 9.6 in 2017, an AAPC of 4.1% , after which it plateaued  and then this slowed to 2.0% per year (95% CI 0.8–3.2) between 2009 and 2017 . When anThere was variation but no clear trend in incidence rates  or mortality rates for other liver tumours , 27.2% (2012–2016) and 14.3% (2009–2013), respectively  and S6. These results from this HCC-UK BASL/NCRAS partnership study of PLC epidemiology in the UK over 20 years show that incidence and incidence-based mortality rates from this largely preventable disease more than doubled, primarily driven by a trebling in HCC rates. The rapid rate of increase in HCC appears to have plateaued since around 2014/15. Men in Scotland had the highest HCC burden, which reached a peak ASR of 15.0 per 100,000 in 2013. ICCA incidence also increased and was the most common PLC in women. PLC survival is improving; it has more than doubled in last 20 years mainly because of the increase in HCC survival, but also an increase in the proportion of PLCs that are HCCs (as prognosis is better in HCC than other PLCs). ICCA survival did not improve as substantially, and the incidence rates remained close to mortality rates. Despite improving PLC survival, mortality increased because of increasing incidence.e.g. across time points or regions. The incidence-based mortality method used gives a good estimation of the true mortality rates in a registry with long follow up and high and accurate population-based coverage of all tumours, such as those in the UK.,,This comprehensive analysis of the epidemiology of liver cancer in the UK over 20 years was conducted on population-level data from high quality cancer registries with near complete population coverage. It is the first study to examine PLC incidence, incidence-based mortality and survival by subtype, sex, and UK nation. Calculation of net-survival allows estimation of disease-specific survival and age-standardisation allows comparison of survival where the background mortality may differ, , 25% of other liver tumours were identified as having cirrhosis  therefore mortality will be underestimated. A total of 3,730 incidence cases, mainly DCO registrations, were excluded from survival analyses. These cases may have a different risk factor distribution to those that are included. Excluded cases were younger than included cases, and in England slightly more likely to be female. The liver is a common site of metastases and registry staff are trained to identify primary from secondary disease using multiple data sources, however, in some cases this may not have been possible and therefore some cancers included (particularly in the ‘Other’ category), may actually have been metastases incorrectly recorded as liver primaries. This would result in an overestimation of incidence and mortality; however, this would be less than standard mortality estimations that rely on death certificate information only. It is also possible some in the ‘Other’ category are actually HCCs or ICCAs with insufficient information provided to categorise them correctly at registration. Diagnosis is more likely to be based on the death certificate only in this category. Additionally, when English data records were linked to hospital episodes statistics data,vs. 25% in England) therefore the lower rates of ICCA, and hence overall PLC, apparent in NI are likely as a result of differences in coding. The WHO Classification of tumours recommended the addition of C24.3 to ICD-O-2 for perihilar CCA, and this has been adopted by the English, Welsh, and NI cancer registries for data from 2018.In the ICD-10 coding system, there is currently no specific code for perihilar CCA . BTG did not have any input into the study design, data collection, analysis or interpretation of the data, writing of the manuscript, review of the manuscript, the decision to submit the manuscript, or the writing of this statement.Acquired the data, performed the data analyses and drafted the manuscript: ABContributed to the development of the study design, interpretation of the results, and critical revision of the manuscript: all authorsRead and approved the final submitted version of the manuscript: all authorsData are available from the contributing cancer registries provided there is a justified purpose for the data release, and that there is an appropriate legal basis with safeguards in place to protect the data. Dependent on the request, ethical approval may be required: The National Cancer Registration and Analysis Service, Public Health England; The Welsh Cancer Intelligence and Surveillance Unit, Health Intelligence Division, Public Health Wales; The Scottish Cancer Registry, Information Services Division; The NI Cancer Registry, Queens University, Belfast.All of the authors completed the ICMJE uniform disclosure form; GA, AM, DT, DH, DW, TGB, and RJD have nothing to disclose. During the conduct of the study, AB reports grants from BTG International Ltd. Outside of the submitted work TJSC reports grants from Sirtex, Bristol-Myers-Squibb, and Bayer and personal fees from Eisai pharmaceuticals, Bayer, AstraZeneca, and Roche. IAR reports personal fees from Roche and Abbvie, outside the submitted work.Please refer to the accompanying ICMJE disclosure forms for further details.


The corrosion process is a major source of metallic material degradation, particularly in aggressive environments, such as marine ones. Corrosion progression affects the service life of a given metallic structure, which may end in structural failure, leakage, product loss and environmental pollution linked to large financial costs. According to NACE, the annual cost of corrosion worldwide was estimated, in 2016, to be around 3%–4% of the world’s gross domestic product. Therefore, the use of methodologies for corrosion mitigation are extremely important. The approaches used can be passive or active. A passive approach is preventive and may be achieved by emplacing a barrier layer, such as a coating that hinders the contact of the metallic substrate with the aggressive environment. An active approach is generally employed when the corrosion is set in. That seeks to reduce the corrosion rate when the protective barrier is already damaged and the aggressive species  are in contact with the metallic substrate. In this case, this is more a remediation methodology than a preventive action, such as the use of coatings. The sol-gel synthesis process, over the past few decades, gained remarkable importance in diverse areas of application. Sol–gel allows the combination of inorganic and organic materials in a single-phase and has led to the development of organic–inorganic hybrid (OIH) coatings for several applications, including for corrosion mitigation. This manuscript succinctly reviews the fundamentals of sol–gel concepts and the parameters that influence the processing techniques. The state-of-the-art of the OIH sol–gel coatings reported in the last few years for corrosion protection, are also assessed. Lastly, a brief perspective on the limitations, standing challenges and future perspectives of the field are critically discussed. The OIH material obtained by this route will display an organic component bonded to the inorganic network by van der Waals forces, or ionic or hydrogen bonds.2)Adding organic alkoxides (R’M(OR)x), in which an organic group R’ is bonded to the element M and it is not hydrolysable. In this case, the organic and inorganic components establish covalent bonds.The sol–gel synthesis process is a versatile method used to produce a wide diversity of materials, which range from inorganic glasses to complex organic–inorganic hybrid (OIH) materials ,4,5,6,7.e domain  8]. The. Themultetc. Moreover, it can be considered that the development of such materials is already impacting people’s lives with significant expression in the medical field [The simple sol–gel processing conditions and the possibility of tuning OIH materials for specific requirements are the main reasons for their development. Moreover, OIH gel materials combine both the advantages of organic polymers  and the properties of inorganic material components . Therefore, in the last few decades, a remarkable advance regarding OIH materials—controlling structure at a nanometric scale —was achial field ,23,24,25network modifiers or as network formers [network modifiers contribute to the functionalization of the matrix. For example, some organic precursors, such as methyltriethoxy-silane (MTES), provide flexibility [network formers are 3-(trimethoxysilyl)propyl-methacrylate (MEMO) [network former contributes to a double reticulation and creates a winding between the organic and inorganic networks [OIH materials, compared to pure inorganic glasses, show significant advantages, including: improvement/increase of the flexibility of the silica gel enabling one to produce thick and crack-free films; introduction of reactive functional groups within the OIH network that can be used to anchor molecular recognition groups and allow entrapping higher concentrations of species. The components employed during the synthesis will dictate the properties of the materials. For instance, the use of an inorganic network is limited in terms of implementation and new functionality input. A way to ease the shaping step and to tailor the bulk properties of the final materials is the introduction of an organic component covalently linked to the network. This can be achieved through the use of an organo-alkoxysilane. The organic component will bring flexibility to the final network modulating either the chemical or the mechanical properties . Organic formers . The netxibility ,28, whilxibility ,29,30. Te (MEMO) ,31, (3-ae (MEMO) ,33 and (e (MEMO) ,34,35. Tnetworks .The development of OIH sol–gel coatings, based on siloxanes, for corrosion mitigation, has been widely studied in the last few years ,36,37,38−), O2, and H2O, including the electron transport, play important roles in this process. The deterioration of the metallic substrates may lead to defects that may threaten its performance and lead to earlier failure, which is always linked to high costs, and the resulting losses each year are huge. Several cost-of-corrosion studies have been conducted by several countries . All the studies agreed that the annual corrosion costs ranged from approximately 1% to 5% of the gross domestic product (GDP) of each nation. In 2016, a NACE study estimated a global cost of corrosion at $2.5 trillion annually, equivalent to roughly 3.4% of the global GDP [360 Market Updates [et al. synthesized OIH sol–gel materials based on zirconia (ZrO2) and poly(ε-caprolactone) to coat pure titanium for implants application [2 for the inorganic matrix and poly(ε-caprolactone) as organic component. The material produced was used to improve the performance of Ti6Al4V implants [Corrosion is known as one of the most severe complications in modern societies. The corrosion degradation process and subsequent rate of reaction depend on both the physical and chemical properties of the metallic substrates . Furthermore, the type of corrosion  is also determined by the metallic substrate and environment ,45,46. Aobal GDP . Moreove Updates  the glob Updates ,50,51. T Updates ,54,55,56 Updates ,57,58 an Updates . M. Cataimplants ,75,76,77The current review includes four main sections: the first section is dedicated to the concepts of sol–gel process from a historical perspective. The second section describes the fundamentals of the sol–gel method. The third section covers, succinctly, the main progress on the development of OIH sol–gel coatings for corrosion mitigation, including self-healing, anti-fouling and superhydrophobic functions. Finally, the fourth section outlines the challenges and prospects for future research. This section will briefly focus on the historical perspective of the first industrial interest in sol–gel materials, followed by their commercialization as coatings. A detailed and very complete historical perception on the evolution of OIH material can be found elsewhere . solution-sol–gel, commonly known as the sol–gel process, became increasingly exploited for the preparation of glasses and other ceramic materials [The commercialization of sol–gel coatings appeared about a century after publication of the first scientific papers with Ebelman and Graham’s studies, in 1846, on silica gels . Althougaterials . Graham aterials . Howeveraterials . Later, aterials . In the aterials . At thataterials ,85,86, iaterials ,89,90,91aterials ,93,94,95aterials ,99,100; aterials ,107,108;aterials ; environaterials ,110,111;aterials ,112,113;aterials ,116,117;aterials ,73,118; aterials ,121,122;aterials ,124 , such as tetraethoxysilane (TEOS) or tetramethoxysilane (TMOS). This process is influenced by several factors; namely: pH, temperature, catalyst, solvent, nature of alkyl group, water to alkoxide molar ratio, etc. Alkoxysilanes generally show a slow kinetic rate when compared to the titanium, aluminum or zirconium alkoxides. This allows a higher chemical control of the process, leading to materials with different properties, such as pore size and distribution, dimension and shape of the particles. Furthermore, silicon shows lower reactivity regarding chelating groups and redox process, which may lead to the formation of sub-products [Over the last five decades, an exhaustive development of the synthetic approaches to various oxide materials has been based on the polymerization of metal alkoxides, M(OR)products . e.g., epoxide (GPTMS), vinyl (VTMS) or methacrylate (MAPTS), besides allowing the formation of an organic network, also contribute to further densification of the OIH material.N2, characterized by a transition state in which the silicon atom is penta-coordinated. The replacement extension of the OR groups by OH groups in the silicon atoms depends on the molar ratio Si/H2O:The chemical reactions involved in the sol–gel process are usually divided into two steps. The first step involves the hydrolysis of metal alkoxides producing hydroxyl groups in the presence of water. The second step is followed by polycondensation of the resulting hydroxyl groups and residual alkoxyl groups, forming a three-dimensional (3D) network, establishing covalent bonds Si–O–Si in the case of silicon alkoxides. Therefore, the alkoxides and esters of inorganic acids are raw materials of utmost importance in the sol–gel technology. In the case of silicon alkoxides, the hydrolysis and condensation reactions may be catalyzed by acids or bases . The strFor acidic catalysis, the following reaction takes place:For basic catalysis, the following reaction takes place:n4-(OH)n may also be catalyzed by acids or basis. The reactions for acidic catalysis are: The condensation reaction of Si(OR)The reaction mechanism of condensation by acidic catalysis starts with the protonation of the silanol species ending with the formation of a Si–O–Si bond.The reactions for alkaline catalysis are: − removes the proton from the silanol group, forming a silanolate anion ending with the formation of a Si–O–Si bond. The reactions of alkoxysilanes, in which monomers form polymeric structures by loss of substituents, involve the formation of a colloidal suspension—Sol—followed by the polymerization that will lead to the formation of a 3D structure—gel. For acid catalysis, the alkoxysilane hydrolysis rate shows higher kinetics when compared to basic catalysis. Therefore, the acidic catalysis leads to the formation of a highly branched polymeric structure, while alkaline catalysis leads to colloidal particles with linear chains or a ringed shape. Once the gel is formed, the hybrid network needs to be dried in order to remove the water, alcohol and solvents that are formed during the hydrolysis/condensation reactions.For alkaline catalysis, the specie HOxerogel, may shrink between five to ten times in volume when compared to the gel before drying. The shrinkage process includes the transport of the liquid through the pores of structure and contraction of the network [xerogel is suitable for substrate catalysis, filters, among other applications, mainly due to low porosity and large surface area [xerogels in the field of filters and membranes [aerogel [monolith if the dimensions of the gel are greater than scarcely millimeters [The drying step has an important role, since, depending on the process used, different materials will be obtained. For instance, if the drying process takes place under normal conditions, a contraction of the gelled network occurs. The obtained dry gel, which is known as  network ,15,38. Tace area . Severalembranes  and for embranes . If the [aerogel ,161. Thelimeters ,163,164.limeters ,154,165.Nevertheless, it should be kept in mind that during the loss of volatile by-products, formed through the hydrolysis and condensation reactions, controlling the sample shrinkage during the 3D network development may be challenging and puzzling ,6,7. ThiOIHs have numerous remarkable and attractive properties with application in a wide range of fields . HoweverThe properties of OIH sol–gel materials, such as homogeneity, stability and transparency, are largely dominated by the concentrations and types of precursors, the solvent’s nature, the concentrations and types of additives , the pH of the reactional media, the heat treatment and the curing time ,166. FurThe nature of each of the interactions between the organic and inorganic components, within the hybrid networks, was used to establish an OIH classification. The first classification was introduced in 1994 by Sanchez and Ribot  and the 3 in which R’ may be H, CH3, CH2CH3 or an aromatic group (1.5) [network modifiers and reduce the functionality of the silicon atoms, turning the silica network less brittle and rigid [2 network by the co-condensation of PDMS oligomers in a sol–gel reaction [3, in which R’ is an organic reactive group, such as amine, isocyanate, vinyl or epoxide  ,173,174 nd rigid . Anotherreaction ,177. Mon epoxide , may be In the last few years, the interest in developing materials with self-healing ability led to outstanding developments ,229,230.2 NPs and Ce(III) ions as corrosion inhibitors in silica-alumina OIH sol–gel coatings. The coatings doped with cerium nitrate (Ce(NO3)3) showed poorer corrosion behavior when compared to CeO2 NPs. The authors attributed this difference to the leaching out of Ce(III) ions in case of coatings doped with Ce(NO3)3. This behavior was not reported for coatings doped with CeO2 NPs. It was also concluded that the coatings doped with CeO2 NPs were more “compact,” minimizing the electrolyte ingress and therefore providing improved protection. U. Tiringer et al. [2 particles and Ce(NO3)3 for corrosion mitigation of aluminum alloy AA7075 in the presence of Cl−. The authors concluded that the curing procedure affected the coating properties obtaining coatings with lower roughness, reduced thickness and higher density by using a curing heating ramp. The incorporation of Ce(NO3)3 increased the roughness and thickness linked to a network with higher porosity. The authors showed that the porosity allowed the release and migration of the incorporated Ce(III) ions. The electrochemical data indicated that the coatings doped with Ce(NO3)3 and cured with heating ramp exhibited improved corrosion properties. Later, in 2019 the same authors [3)3. The effects of curing temperature and the addition of Ce(NO3)3 on the degree of polycondensation of the OIH sols were studied. It was concluded that the addition of Ce(NO3)3 did not affect the viscosity of sols and improved their thermal stability. Furthermore, the authors revealed that the addition of Ce(NO3)3 acted as an initiator, stimulating the polycondensation reaction at lower temperatures. Earlier this year [2, strengthening the corrosion protection of the OIH coating [Strategies such as the addition of polymerizable agents ,209 to rr et al.  produced authors , reportehis year , T.T. Th coating .3+ cations in amorphous silica NPs before being embedded into the silane film. Two years later, J. Peña-Poza et al. [2O3 was adequate to incorporate La3+ ions within the silica matrix. Furthermore, the produced coatings mitigated the corrosion process on copper, bronze and lead, while steel substrates required thicker coatings.In the case of using lanthanum as a corrosion inhibitor, P. Balan et al.  in 2016 a et al.  studied Ideally, the addition of species  to improve the OIH coating’s performance must be incorporated within the coating matrix and released when required, i.e., when corrosion the process initiates, in order to delay further corrosion development. It has been reported in different studies that the direct incorporation of these species may interfere with the curing of the coating material and compromise its physico-chemical performances ,203,245.3+/Zr4+) into halloysite nanotubes, which were afterwards incorporated within an OIH sol–gel matrix and deposited on magnesium alloy substrates. The authors concluded the Ce3+/Zr4+ loaded halloysite nanotubes dispersed within the OIH coating provided suitable corrosion protection of the substrate when exposed to 3.5% NaCl. The healing properties were confirmed through weight loss and electrochemical techniques. The same research group [Adsul et al. ,213 studch group  also stuThe self-healing mechanism in corrosion mitigation may be assessed and validated by several electrochemical tools. The most common techniques reported to assess the self-healing and corrosion inhibition of such materials are scanning vibrating electrode technique (SVET), scanning ion selective electrode technique (SIET) and localized impedance spectroscopy (LEIS) . Anti-fouling is another important function to enhance the corrosion protection of a coating. Coatings designed for this purpose are generally based on dense organic matrices, containing wide-spectrum biocides such as tributyltin and tributyltin oxide. These biocides are one of the major contaminants in marine and freshwater ecosystems , and nowIn the last 20 years, anti-fouling coatings have been extensively studied ,273,274,2 NPs [Pseudomonas aeruginosa culture test was reduced compared to PDMS without PEG or to steel.A wide range of encapsulated agents for fouling mitigation were proposed and assessed, including enzymes ,282,283,2 NPs , silver 2 NPs , zinc py2 NPs  and chlo2 NPs . The enc2 NPs ,282,283.2 NPs ,286,287.2 NPs  reported2 NPs  in 2016,2 NPs  develope2 NPs  recentlythe difference between the advancing and the receding WCA of a water droplet that expands or shrinks on the surface [lowest angle that a surface needs to be inclined at before the water droplet slide or rolls off it [Micro- and nanopores in the coatings may lead to the entrance of water and aggressive species, causing coating blistering; then peeling; and subsequently, corrosion of the metallic substrates. Therefore, an interesting approach to prevent corrosion is the development of superhydrophobic surfaces. A coating shows hydrophobic properties when the WCA on a surface is above 90°. In the case of superhydrophobic coatings, they require a WCA above 150° and a contact angle hysteresis (CAH) lower than 10° ,289. CAH surface . Additios off it . The reds off it ,294,295.s off it ,298,299.s off it ,301,302,s off it ,306,307.s off it . The chas off it , anti-ics off it  and bio-s off it . Accordis off it  in 2014,s off it ,311,312.s off it ,300,313.2 inside microcapsules and concluded that these show appropriate superhydrophobic performances, including regenerative ability [OIH sol–gel coatings with superhydrophobic properties for corrosion mitigation have been reported for different substrates, such as aluminum ,317,318, ability . Porous  ability ,327,328. ability  reported ability , in 2016A. Fihri et al.  publisheSuperhydrophobicity, besides improving anti-fouling function, allows the encapsulation of active agents, as mentioned earlier. Therefore, the surface finishing can deliver both functionalities . The solNowadays, many of the effective coatings for corrosion protection represent dangers to the environment. Therefore, the key is the development of innovative materials with improved performances and promoting a sustainable environment at the same time. −) and water behave and react within the coating at atomic and nanoscales are needed. The corrosion mitigation/prevention of metallic substrates is not only an engineering effort, but also a fundamental scientific difficulty. Ideally, an anticorrosion coating should be designed to be stimulus-responsive, multifunctional, resistant and durable in a wide range of applications. Coatings for corrosion mitigation are normally exposed to complex environments. Therefore, studies on how the different aggressive species . Additionally, multi-damaging and the size of the area damaged may be a drawback for these coatings and should be further investigated. On the other hand, sustainability at a large scale, toxicity and the effects of inherent properties of OIH coatings remain only vaguely explored. Although several OIH coatings for corrosion mitigation have been subjected to intensive research, it seems that further investigations are still necessary for both fundamental and applied aspects. The synthesis of OIH multifunctional coatings  with extended service lives—highly required in order to develop commercial scale products—has not been accomplished yet.−, UV, temperature and/or humidity), the restoration of the material structure and recover the integrity of the protective coating. Hence, suppressing the beginning of corrosion process and increasing the service life of the metallic materials. Additionally, the incorporation of inhibitors that can mitigate and control the corrosive substances ingress will provide extra protection together with the coating structure restored. This direction in the development of smart coatings for corrosion mitigation will for certain mark the 21st century achievements.Smart coatings with self-healing functions and stimulus-responsiveness are potentially the future of developments. Self-heling by the incorporation of responsive additives within the OIH coating materials enables, due to external stimulus (e.g., pH, the presence of Cl


Bisphenols (BPs), and especially bisphenol A (BPA), are known endocrine disruptors (EDCs), capable of interfering with estrogen and androgen activities, as well as being suspected of other health outcomes. Given the crucial role of thyroid hormones and the increasing incidence of thyroid carcinoma in the last few decades, this review analyzes the effects of BPS on the thyroid, considering original research in vitro, in vivo, and in humans published from January 2000 to October 2019. Both in vitro and in vivo studies reported the ability of BPs to disrupt thyroid function through multiple mechanisms. The antagonism with thyroid receptors (TRs), which affects TR-mediated transcriptional activity, the direct action of BPs on gene expression at the thyroid and the pituitary level, the competitive binding with thyroid transport proteins, and the induction of toxicity in several cell lines are likely the main mechanisms leading to thyroid dysfunction. In humans, results are more contradictory, though some evidence suggests the potential of BPs in increasing the risk of thyroid nodules. A standardized methodology in toxicological studies and prospective epidemiological studies with individual exposure assessments are warranted to evaluate the pathophysiology resulting in the damage and to establish the temporal relationship between markers of exposure and long-term effects. Thyroid hormones (THs) play a critical role in the regulation of physical development, somatic growth, metabolism, and energy provision and are essential for normal brain development in humans . Thus, aAccording to a recent statement by the Endocrine Society, endocrine disrupting chemicals (EDCs) are defined as single exogenous agents or mixture of compounds capable of interfering with any aspect of hormone action, from the synthesis to the transport, catabolism, and elimination of the hormones produced ,7. One oBisphenol A propane) is described as an EDC able to interact with human estrogen receptors (ERs) . In rodeThough not systematic, the present effort is a thorough review (173 references included in the full text), comprising in vitro, in vivo, and epidemiological studies that have assessed the effects of bisphenols (BPs), namely bisphenol A (BPA), its analogues, and its halogenated derivatives on the thyroid, considering their actions at different levels in cells or organs, in different animal models and in humans and their potential to exert a risk in causing a direct impact on the gland. Original studies published in English in peer-reviewed journals from 1 January 2000 to 31 October 2019 were searched in Pubmed through the search strategy: ((bisphenol* OR BPA OR tetrabromobisphenol* OR TBBP* OR tetrachlorobisphenol OR TCBPA) [ALL FIELDS]) AND (thyroid OR thyroid disorders OR thyroid function OR thyroid cancer OR thyroid nodule [ALL FIELDS]). From the initial search of 303 records, a total of 82 studies were selected by two authors on the basis of adherence to the purposes mentioned above. BPA is a monomer in the manufacture of polycarbonate plastics and epoxy resins widely used in diverse consumer products such as food and liquid containers, protective coatings inside metallic food and beverage cans and medical devices, as well as in flame retardants and thermal papers . It is oBPA can be released from both effluent discharge of manufacturing plants and from transport, processing, and disposal of waste of BPA-containing products in landfills and incinerators . Less thDue to its lipophilicity, detectable levels of the unconjugated form of BPA were measured in adipose tissue, brain, liver, and breast milk in humans a. MoreovThe first safety standard for humans set by the US-Environmental Protection Agency in 1988, adopted by the Food and Drug Administration as the reference dose and based on the LOAEL for BPA, was 50 micrograms per kilogram of body weight per day . In 2013BPA has a half-life in humans of about 6 h . FollowiSeveral structural analogues were introduced in the market to replace BPA . BisphenTetrabromobisphenol A (TBBPA), a persistent compound synthesized by bromination of BPA initially replaced polybrominated diphenylthers, at present is the most widely employed brominated flame retardant, with a reported 2011 volume of 120 million pounds in the United States . In the Biological function of thyroid hormone triiodothyronine (T3) is generally mediated by the nuclear receptors TRα1, TRβ1, and TRβ2 that are conserved in all vertebrates. T3 binds to the TRs with similar affinities mediating TH-regulated transcription with different levels in different tissues . TRα1 isIn vitro models have tested and verified the ability of BPs to disturb thyroid function through multiple mechanisms that may produce different consequences depending on the heterogeneity of experimental conditions among studies such as the chemical tested, the concentrations used, and the presence/absence of T3 or T3 antagonists. BPs were reported to exert numerous effects on the thyroid, and each affected pathway may lead to perturbations of thyroid hormone levels, leading to a dysregulation of thyroid function. The pathways are not necessarily inter-connected, but there is some evidence that BPs may lead to an impact on the gland and its function at multiple levels, as reported in the following paragraphs.Numerous studies have evaluated the ability of BPs to suppress hormonal transcriptional activities mediated by TRα1 and TRβ1 in competitive binding and transient expression assays .6–10−4 M [BPs mainly acts as TR antagonists, inhibiting crucial processes related to development ,65,66,676–10−4 M ,72,73,746–10−4 M .Whereas BPA alone did not induce visible effects on T3-induced transcription ,73,75,76BPA may exert disrupting effects on TH-mediated transcription interfering with a different non-genomic mechanism mediated by integrin αvβ3, a heterodimeric transmembrane glycoprotein . In norm−8–10−7 M) [−4 M) [A few studies observed that, in the absence of T3, BPs behave as TR agonists ,70,72,80–10−7 M) ,70 and d) [−4 M) ,69, showThe rat tumor pituitary cell line GH3 has been frequently employed as a standard pituitary cell model for assessing TH effects . Indeed,−6–10−4 M [A series of investigations assessed the agonistic and antagonistic properties of BPs in GH3 cell growth both in absence and in presence of T3 . BPA, an6–10−4 M ,81,83. I6–10−4 M ,84, wher6–10−4 M ,85.2 [2 potentiated the increased GH3 cell proliferation (from 190% to 252% after 96 h) by BPA and BPAF [Effects of BPs on cell growth were antagonized by amiodarone, a known TR antagonist . Nonethe2 , and conand BPAF . In contand BPAF .Cell growth was further antagonized by U0126, an inhibitor of MEK, the kinase responsible for the activation of ERK in the Raf–MEK–ERK pathway in mammalian cells . SimilarMAPKs have an important role in cellular signaling pathways, and the kinases JNKs/SAPKs and p38 MAPKs are often activated by cellular stresses and thus primarily linked to cytokine biosynthesis and induction of apoptosis . Thus, aSimilar to cell proliferation, cell viability has been evaluated in cell lines exposed to BPs .−5–10−4 M; alone and/or with T3 [Cytotoxicity was observed after exposure to BPA and its halogenated derivatives at a concentration range of 10 with T3 ,76,82,87 with T3  although with T3 ,70,89.One of the possible mechanisms of BPs for disrupting TH homeostasis is the competitive binding with serum transport proteins due to the structural similarity to T4 and T3. THs mainly bind to three transport proteins in human serum, namely thyroxine-binding globulin (TBG), which is responsible for 75% of the specific T4 binding activity, transthyretin (TTR), and human serum albumin . A few spara position with at least one adjacent halogen substituent could represent a prerequisite for TTR binding. Indeed, TBBPA was the most potent competitor among the phenolic compounds tested, binding to TTR in a range from 1.6 [Meertz et al.  found nofrom 1.6  to 10.6-from 1.6  strongerfrom 1.6 , and thifrom 1.6 . Actuallfrom 1.6 . Using afrom 1.6 .MCT8 gene cause a severe X-linked psychomotor retardation associated with highly elevated serum T3 levels and decreased T4 concentrations whereas the thyroid-stimulating hormone (TSH) values remain in the normal or slightly elevated range levels [Thyroid hormone uptake into target cells is controlled by membrane bound transporters, such as monocarboxylate transporter (MCT) 8, MCT10, and multiple members of the Na-independent organic anion transport protein (OATP) family . OATP1C1e levels .In a recent study performed in cells overexpressing the human MCT8 gene, among the several common environmental contaminants classified as flame retardants, pesticides, plasticizers, and others that are suspected to disrupt TH signaling, only BPA was observed to reduce T3 uptakes to around 60% and 40% of the control at concentrations (125 μM) below those that reduced cell viability <80% . This fiIn addition to the ability to interfere with TR signaling throughout a direct binding to the receptor, a number of studies observed that BPs may directly affect thyroid gene expression .−6 M, BPA and its analogues induced expression of transcripts of genes implicated in thyroid cell activity and proliferation ), TH biosynthesis , Thyroid-peroxidase (Tpo) and their transcription regulators , NK2 homeobox 1 (Nkx2-1), and Forkhead box E1 (Foxe1)) by over 1.5 fold [Slc5a5, Nkx2-1, and Tpo but inhibited NIS-mediated iodide uptake [Tg gene in the presence of increasing TSH amounts, suggesting a potency similar to that of TSH in enhancing Tg-promoter activity [Tg promoter, were not able to enhance BPA activity on the Tg promoter, indicating that the effects triggered by BPA do not necessarily involve ER signaling [At doses as low as 101.5 fold ,99,100. activity . The autignaling . BPA at TSH-specific β subunit (Tshβ), Thyroid hormone receptors (Trα and Trβ), and Deiodinases (Dio1 and Dio2)) in a concentration range of 10−7–10−6 M, with BPA substitutes being able to disrupt thyroid regulation at lower doses than BPA [2 potentiated decreased expression of Trα, Trβ and Dio2 [BPA and its analogues BPZ, BPF, and bisphenol M bisphenol) suppressed the transcription of several genes involved in the regulation of the HPT axis  and UDP-glucuronosyltransferases (Ugt)) [Ttr gene [BPA inhibited the activities of DIO1 and DIO2 , and botplacenta , and heps (Ugt)) . TBBPA, Ttr gene , an actiTtr gene ,84.In vivo effects of BP exposure on thyroid function/action are contradictory and difficult to compare, as a consequence of the scarce number of studies performed especially in mammals, the different models, and diversity of the experimental conditions, i.e., the chemical used, the time and dose of treatments, the outcomes assessed. In regards the risk of thyroid cancer associated to BPs exposure, the subject remains almost entirely unexplored.In rodents, most of the studies have been performed in pregnant females, and have evaluated the variations of TH levels in mothers and pups following prenatal and/or lactational exposures .In accordance with numerous in vitro studies, BPA can act as a selective TH antagonist on TRβ, inhibiting TH-negative feedback. Indeed, Zoeller et al.  and ZhanIn other experiments, BPA exposure did not produce significant variations in plasma T4 levels ,108,109 Perinatal or neonatal exposure to BPA was associated with a significant increase of TSH levels in juvenile males  and in fTshβ was reported in female rat neonates exposed to BPA [Tshβ mRNA levels in treated female rats [Adult males treated with BPA showed a decrease activity of hepatic DIO1, coherently with what has been reported in vitro . Moreoved to BPA , whereasale rats .To date, it remains unclear whether BPA plays a role in the pathogenesis of thyroid carcinoma. Zhang et al. recently demonstrated that BPA could enhance the susceptibility to TC . Rats prSheep are considered a more relevant model to humans than rodents to evaluate fetal exposure to thyroid disruptors and their effects on the mother/newborn thyroid functions because of a similarity in the timing of the ontogenesis of thyroid . In bothTwo studies have investigated the relationship of BPA exposure with thyroid function . Viguié Danio rerio) to explore the effects of EDCs on the thyroid, due to several advantages: a short life cycle, high rates of production, real-time observations during the entire embryonic development, and high conservation of the molecular mechanisms regulating thyroid development with those of mammals [Numerous studies have been published on the use of zebrafish , TH activity , and transport (Ttr) can be up- [Hematopoietically expressed homeobox (Hhex) was up-regulated in larval fish following exposure to BPA or BPF, although it is important to note that the Hhex gene is expressed in early life, contributing to differentiation and development of the thyroid gland, as well as of other organs, such as the pancreas and liver [Similarly, BPs disrupting effects on thyroid gene expression vary according to the different experimental conditions, especially the duration of exposure . Hence, n be up- ,132,133 n be up- ,130,133.nd liver .Slc5a5, Tpo, Pax8, and Tg transcripts was dependent on the dose and window of exposure. Additionally, BPA and BPS appeared to interact with PAX8 and thyroid transcription factor 1 (TTF1) in silico [Tpo, Tg, and Slc5a5 have binding sites for PAX8 or TTF1 on their enhancer or promoting regions. Differences of interactions between BPs and the transcription factors could be attributable to stimulation or inhibition with varying BPs doses, and produced as final effect altered expression of the genes controlled by PAX and TTF1 [Increased ,128,129 n silico . Genes sand TTF1 .Corticotrophin-releasing hormone (Crh) mRNA in the hypothalamus [Tsh and Tshβ in the pituitary gland [Tshβ mRNA in embryos [BPs stimulated thyroid signaling increases expression of thalamus ,38,129 ary gland ,133,134,Dio1 and/or Dio2 [Ugt1ab [Exposure to BPA and BPA analogues further induced transcription of genes involved in TH metabolism, i.e., /or Dio2 ,132,134,/or Dio2 ,137, and [Ugt1ab ,129.Notably, co-treatment with T3 appeared to reverse or eliminate thyroid disrupting effects of TBBPA on THs levels and gene transcription in zebrafish larvae , whereasPerturbations in THs parameters consequent to exposure to BPA have been documented in humans, i.e., the general population, pregnant women, or occupational settings, although the study design, predominantly cross-sectional, does not allow establishment of any causal relationship. Research has highlighted positive, negative, or null associations with T4 levels, whereas a few prospective birth cohort studies suggest that prenatal BPA exposure may modify THs normal serum concentration in a sex-specific manner. Several investigations have demonstrated BPA-induced disruption of thyroid function by altering serum TSH levels. This effect could occur from a direct action of BPA on the pituitary gland via the estrogen signaling pathway or, alternatively, from a transient increase of T3 or T4 production that could lead to a feedback mechanism and the subsequent release inhibition of TSH. Overall, discrepant results among studies may be attributable to BPA levels, time of exposure, iodine intake, differences in age, ethnicity, diet, socioeconomic status, and the determination methods of THs, while at present the potential role of BPs in thyroid carcinogenesis in humans remains to be deeply explored . It is nStudies carried out in the general population and in mother/child cohorts showed positive ,140,141,In agreement with results from studies in animals ,105,108,There was no association of BPA with hypothyroidism in Japanese women with a history of recurrent miscarriages , nor anyuridinediphosphate-glucuronosyltransferase 2B1 in male compared to female livers [Sex-related differences in the relationship between BPA and THs were reported both in the general population  and in ne livers , or to ae livers .The interactions between BPA and THs during pregnancy and fetal development have been recently studied. The association between BPA and TSH levels in newborns was stronger when the time elapsed between the two measurements was shorter ,148, sugThe influence of BPA on thyroid autoimmunity is controversial . WhereasKim and Oh reported a slight positive correlation between serum TBBPA and thyroid-stimulating hormone receptor antibodies, indicative of metabolic diseases, in mothers of infants with congenital hypothyroidism, suggesting that brominated derivatives of BPA might affect thyroid function status .Recent investigations have explored the role of BPs as risk factors of occurrence of thyroid nodules (TNs), palpably and/or ultrasonographically discrete lesions, distinct from the surrounding parenchyma of the thyroid gland, which are either benign or malignant . A studyThe thyroid is highly susceptible to environmental pollutants, which may act as either genotoxic or non-genotoxic carcinogens . BPA is Trβ expression following BPs exposure were observed in in vivo models. THs and their receptors regulate many important processes such as proliferation, differentiation, and apoptosis, and since TRβ is the major isoform in the thyroid, it can be hypothesized that disruption of its expression, leading to abnormalities in T3-induced transcriptional activity, could be involved in tumorigenesis [Overall, the in vitro studies demonstrate that BPs may bind to TRs, acting mainly as TR antagonists, but also as agonists or without exerting any effect on TH signaling. Similarly, different patterns of igenesis ,162.Tg and Slc5a5 transcript levels may promote thyroid development to compensate for the depressed T4 concentration, as also reported for polybrominated diphenyl ethers [Dio2 [In vivo experiments, supported by in vitro evidence, highlighted the ability of BPA and its substituting chemicals to affect thyroid follicular cell gene expression, particularly transcriptional levels of those genes encoding for factors involved in THs synthesis . Up-regulation of l ethers . Transcrrs [Dio2 . On the rs [Dio2 , which irs [Dio2 .Pax8 transcripts, suggesting a role of BPA in increasing Pax8 expression independent from the cellular context [In rodents and in two different types of cell lines, BPA up-regulated  context . PAX8 is context .2 could further induce release of TSH desensitizing the response to thyrotropin releasing hormone from hypothalamus [TSH should represent an effective index of activation of the HPT axis to evaluate central effects of xenobiotics on thyroid function through measurement of TSH secretion or expression as a compensatory mechanism for maintaining TH homeostasis. Moreover, TSH levels are an independent predictor of thyroid nodule malignancy regardless of age, sex or family history . Increasthalamus . In contthalamus .The frequency of chronic autoimmune Hashimoto’s thyroiditis, the most common cause of primary hypothyroidism in western countries, has increased in the last two decades, and a variety of factors such as tobacco smoking, iodine and selenium intake, and exposure to EDCs, may contribute to the elevated incidence by interacting with susceptibility genes (6). Autoimmune thyroiditis may coexist with TC , and a r2O2, the iodination of tyrosyl residues in Tg [It cannot be excluded that exposure of thyrocytes to BPA involves hydrogen peroxide generation due to an elevated activity of a calcium-dependent NAPDH oxidase (DUOX) . TPO is es in Tg . Thus, tes in Tg . Furtheres in Tg .BRAF mutations [Finally, BPA is potentially linked to excess iodine in the pathogenesis of the nodular goiter and TC in animals  and humautations , which autations .This review aims at evaluating the extensive body of experimental and human studies that in the last two decades have attempted to explore the effects of BPA, its substitutes, and its halogenated derivatives on the thyroid at different levels. Despite the variety of approaches applied and the heterogeneous and sometimes even conflicting results from the examined studies, a series of interesting indications supports the hypothesis of a role of BPs in interfering with the normal thyroid function. Although the toxicity pathways of BPs on the thyroid need to be further elucidated, BPA analogues and halogenated derivatives do not emerge as safer alternatives to BPA in term of TH disruption. There is evidence that BPs alters THs circulating levels, inhibiting TH-negative feedback, act as selective TR antagonists, and interfere with expression of genes involved in thyroid stimulation, TH synthesis, TH activity, and TH transport and metabolism. Several reported findings, mainly from experimental studies, are, however, rather inconsistent, while the association of BPs exposure with thyroid cancer is so far almost unexplored. The lack of uniformity in experimental methodology, as well as substantial differences in populations investigated in epidemiological studies, do not allow definitive conclusions to be drawn. Standardized in vivo, in vitro, and in silico studies are recommended to evaluate the physiopathology of the damage associated with exposure to environmentally relevant levels of BPs, identify other potential molecular targets, and clarify the structure−activity relationship of BPs. At the same time, large population-based human studies with prospective designs and repeated measures of urine BPs concentrations and thyroid volume over time, as well as an accurate control of confounders, should be performed for the assessment of the temporal relationship between markers of exposure and long-term effects.


Bactrian camels can adapt to harsh natural environments. This unique tolerance of camels is tightly linked to their hematological traits, which are related to their immune, metabolic, and disease status. Therefore, mapping genomic regions that affect blood cell traits can help identify genomic characteristics that can be used as biomarkers of immune, metabolic, and disease states. This knowledge will further our understanding of the camel’s tolerance mechanisms.Camelus bactrianus) are one of the few large livestock species that can survive in the Gobi Desert. Animal immunity and disease resistance are related to hematological traits, which are also associated with tolerance observed in Bactrian camels. However, no genome-wide association studies have examined the genetic mechanism of the immune capability of Bactrian camels. In the present study, we used genotyping-by-sequencing data generated from 366 Bactrian camel accessions to perform a genome-wide association study for 17 hematological traits. Of the 256,616 single-nucleotide polymorphisms (SNPs) obtained, 1,635 trait–SNP associations were among the top quantitative trait locus candidates. Lastly, 664 candidate genes associated with 13 blood traits were identified. The most significant were ZNF772, MTX2, ESRRG, MEI4, IL11, FRMPD4, GABPA, NTF4, CRYBG3, ENPP5, COL16A1, and CD207. The results of our genome-wide association study provide a list of significant SNPs and candidate genes, which offer valuable information for further dissection of the molecular mechanisms that regulate the camel’s hematological traits to ultimately reveal their tolerance mechanisms.Bactrian camels ( Animal metabolism and immune status can be directly reflected by their hematological traits . TherefoCamelus bactrianus) and the one-humped dromedary (Camelus dromedarius) [Camelus ferus) are only distributed in these two countries [Camelus bactrianus is one of the few large livestock animals that can survive in the Gobi Desert because of their ability to withstand the harsh natural environment. This tolerance is largely associated with their metabolic and immune states. Because the hematological characteristics of mammals reflect their immunity and disease resistance [Camelus bactrianus. Camel species include the two-humped Bactrian camel (edarius) ,4. Chinaedarius) ,6 prevenountries ,8. Camelsistance ,10, decisistance ,13,14,15A GWAS is a powerful approach for identifying genomic regions that control important zoological traits in non-structured germplasms ,17. A suThe procedures and protocols for animal use were carried out according to the national codes of practice for the care and handling of farm animals and were approved by the animal care committee of the Camel Protection Association of Inner Mongolia.Camelus bactrianus breeds in East Asia, including four Chinese domestic breeds  and three Mongolian domestic breeds  was used to analyze the separated serum using the manufacturer’s reagents. The analyzer calculated the levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), cholesterol (CHO), and glutamyl transpeptidase (GGT) (This study included 366 domestic Bactrian camels. The sample population represented the seven main domestic amel see ). Whole se (GGT) .The sequence data were generated using genotyping-by-sequencing (GBS) ,21. The The raw sequencing data were submitted to the National Center for Biotechnology Information (NCBI) Sequence Read Archive (SRA) in the GenBank database under accession number PRJNA565837.Camelus ferus genome [ftp://ftp.ncbi.nih.gov/genomes/Camelus_ferus/CHR_Un/. Population single-nucleotide polymorphism (SNPs) were detected using the SAMtools software [High-quality sequencing data were aligned to the s genome  using ths genome  (parametsoftware . Bayesiasoftware .http://treesoft.sourceforge.net/treebest.shtml) was used to calculate the distance matrix, which was the basis for constructing the phylogenetic tree using the neighbor-joining method. The distance between two bodies i and j was calculated using the following formula.L is the length of the SNP region, and the allele at position 1 is A/C. If the genotypes of the two individuals are AA and AA, then ijd = 0. If they are AA and AC or AC and AC, then ijd = 0.5. If they are AA and CC, then ijd = 1.A phylogenetic tree and principal component analysis (PCA) were used to investigate the population structure. The TreeBeST software (http://cnsgenomics.com/software/gcta/pca.html) was used to calculate the feature vectors and eigenvalues. The R software was used to draw the PCA distribution map. The SNP at position k in individual i is represented by ikd. If individual i is homozygous with the reference allele, then ikd = 0. If it is heterozygous, then ikd = 1. If individual i is homozygous with the non-reference allele, then ikd = 2. M is a matrix of n × S containing the standard genotype.The GCTA software (http://pngu.mgh.harvard.edu/~purcell/plink/), a Ped file, and then used the Frappe software to construct the population genetic structure and group lineage information.The SNP data of the 366 camels were analyzed using the Frappe software to establish the population structure. First, we created an input file for software tool, PLINK, (−6 (0.05/256616).The Bonferroni calibrated multiple test was used to determine the significance threshold, with a genomic significant level threshold of 0.05 per effective SNP locus and a chromosomal significant horizontal threshold of 1 per effective SNP locus. For the purpose of this study, the corresponding thresholds were set as 6.71 × 10http://www.xzlab.org/software.html), and the population structure and individual kinship were corrected using the mixed linear model (MLM).y is the phenotypic trait, X is the indicator matrix of the fixed effect, α is the estimated parameter of the fixed effect, Z is the indicator matrix of the SNP, β is the effect of the SNP, W is the indicator matrix of the random effect, μ is the predicted random individual, and e is a random residual and obeys e~.GWAS analysis was performed using the GEMMA software  was above 6.46% .At the genomic level, DNA sequence variations can be caused by an SNP, including single-base conversions and transversions. A total of 2,433,732 SNPs were identified using the SAMtools software, and the obtained SNPs were filtered . Lastly, 256,616 SNPs were obtained for subsequent analysis. The results of the ANNOVAR software analysis for SNP annotations are shown in The GWAS data were corrected for the presence of a population structure using three methods to identify relationships among the analyzed genotypes. The results of the phylogenetic tree showed that the 366 genotypes could be divided into seven groups, which is consistent with the number of breeds in the analysis . PCA resA structural analysis was performed on the 366 samples. Each column in p-value of 10−6, the analysis identified 1,635 trait–SNP associations as the top quantitative trait loci (QTLs)  . Howeveri (QTLs) .p-value < 10−6). WBC traits and RBC traits , platelet traits , GGT, and CHO were identified as associated with 5, 226, 41, 50, and 342 genes, respectively. To further evaluate the SNPs associated with the chosen traits, we aligned the tag sequence in which the SNP is located with all known sequences to infer its location and identify potential candidate genes that carry true etiological polymorphisms. The upstream and downstream 20 kb of 1635 SNP sites, which are known to be candidate genes in the camel genome, were searched randomly. Lastly, we identified 664 candidate genes associated with 13 blood traits (In this study, we performed a GWAS for camel hematological traits using the genotypes of 366 domestic Bactrian camels from China and Mongolia. To the best of our knowledge, this is the first GWAS for camel hematological traits using GBS.Population stratification affects the proportion of false positives in genome-wide association analysis. Therefore, corrections are needed to ensure the reliability of the statistical analysis ,26,27. VZNF772, MTX2, ESRRG, MEI4, IL11, FRMPD4, GABPA, NTF4, CRYBG3, ENPP5, COL16A1, and CD207 (for their full names, see The identification of markers that are tightly linked to phenotypic characteristics is the ultimate goal of genetic mapping ,33. The ZNF772 is likely to be involved in the regulation of early white blood cell differentiation [CRYBG3 and ENPP5, as important protein structure regulators, are likely to be involved in the regulation of platelet volume and size.WBCs are involved in the phagocytosis of bacteria and disease prevention. RBCs are essential for oxygen transport within the organism and the removal of the byproducts of respiration. The platelets play an important role in blood coagulation, wound healing, inflammatory response, and organ transplant rejection . The whintiation . Red blontiation . Gene ESntiation  and mighAlthough we identified 12 candidate genes, their mechanism of action remains unclear and requires further study and confirmation. These candidate genes lay the foundation for further exploration of the characteristics of blood traits in Bactrian camels to reveal their tolerance mechanisms.Camelus bactrianus. As a result, we identified 12 candidate genes and associated genetic markers, which provide a reference for further research on the camel’s special immune metabolism and disease resistance. Therefore, this study contributes to the understanding of the molecular regulation of blood traits in domestic animals.In conclusion, because blood traits are effective indicators of the camel’s immune and metabolic status, we attempted to identify genomic regions that control hematological traits in