Variability in biological parameters has been reported to be associated with adverse health outcomes. We aimed to investigate the composite effect of the visit-to-visit variability in blood pressure, glucose, cholesterol, and body mass index on the risk of dementia.A population-based cohort study including 2,930,816 subjects without a history of dementia, hypertension, diabetes mellitus, and dyslipidemia who underwent ≥ 3 health examinations was performed. The coefficient of variation (CV), standard deviation, and variability independent of the mean were calculated as variability indices. High variability was defined as having values in the highest quartile for each parameter.A total of 32,901 (1.12%) participants developed dementia, of which 74.4% and 11.0% were attributable to Alzheimer’s disease and vascular dementia, respectively, during the median follow-up of 5.5 years. Individuals with higher variability of each parameter were at higher risk of future dementia. In the multivariable adjusted model, the hazard ratios and 95% confidence intervals of all-cause dementia were 1.22 (1.19–1.26) for one parameter, 1.39 (1.35–1.43) for two parameters, 1.54 (1.48–1.60) for three parameters, and 1.73 (1.60–1.88) for four parameters compared with subjects having no parameters of high variability measured as the CV. Consistent results were noted for Alzheimer’s disease and vascular dementia, using other indices of variability and in various sensitivity and subgroup analyses.There was a linear association between the number of high variability parameters and risk of dementia. Reducing variability of metabolic parameters would be a target to preserve cognitive reserve in the general population.The online version of this article (10.1186/s13195-018-0442-3) contains supplementary material, which is available to authorized users. Dementia, a clinical syndrome affecting memory, thinking, and social abilities primarily caused by neurodegeneration, is becoming one of the greatest health and socioeconomic burdens in an aging society. The age-standardized prevalence of dementia for people aged 60 years or older was 5–7% in most world regions, affecting 35.6 million people in 2010 [Recently, visit-to-visit or day-to-day variability in biological parameters has emerged as a previously unrecognized residual risk factor, which is related to the development of various health outcomes. For example, higher blood pressure (BP) variability and lower heart rate variability have been linked to cardiovascular or cerebrovascular events and mortality , 4. HighMetabolic risk factors are likely to cluster and influence interactively, resulting in a greater impact on an individual’s health status . HoweverThe National Health Insurance System (NHIS) is a single-payer organization, managed by the government, to which all residents in Korea subscribe. Because it has adopted a fee-for-service system to pay healthcare providers, the NHIS obtains varied information which represents the entire Korean population. The database (DB) contains a qualification DB , a claim DB , and prescription statements), a health check-up DB, and death information. Enrollees in the NHIS are recommended to undergo a standardized medical examination at least every 2 years. Details on the DB are described elsewhere , 18.n = 12,027,734), were younger than 45 years old , had data missing for at least one variable , and had a previous diagnosis of dementia (n = 5033). Because the presence of metabolic diseases or administration of medications might artificially influence the variability of metabolic parameters, those who had a history of hypertension , diabetes mellitus , or dyslipidemia  before the index year  were also excluded from the main analyses. Ultimately, the study population consisted of 2,930,816 subjects , four , or five . In order to examine whether our findings are reproducible in subjects having diabetes mellitus, hypertension, or dyslipidemia, additional analysis was performed in the subjects already having metabolic diseases and in the total population. This study was approved by the Institutional Review Board of Seoul St. Mary’s Hospital (No. KC17ZESI0505). Informed consent was not obtained because anonymous and de-identified information was used for the analysis.Among 23,503,802 subjects who underwent health examinations between 2009 and 2012 (index year), we excluded subjects who had fewer than three health examinations from 2005 , standard deviation (SD), and variability independent of the mean (VIM). The VIM was calculated as 100 × SD / meanThe end point of the study was newly diagnosed dementia, which was further classified as Alzheimer’s disease, vascular dementia, or other dementia. The definition of these diseases was based on the recording of relevant ICD-10 codes  and the prescription of medication for dementia . When both codes for Alzheimer’s disease and vascular dementia were recorded, we followed the principal diagnosis. If both were in the additional diagnosis up to the second claim DB, the subject was classified as other dementia. The study population was followed from baseline to the date of incident dementia or until December 31, 2015, whichever came first.P < 0.05 was considered to indicate statistical significance.Baseline characteristics are presented as the mean ± SD or number (percentage). Participants were classified into five groups according to the number of parameters with high variability. The incidence rate of dementia was calculated by dividing the number of incident cases by the total follow-up duration (person-years). The cumulative incidence of outcomes according to the number of parameters with high variability was calculated using Kaplan–Meier curves, and the log-rank test was performed to analyze differences among the groups. Hazard ratio (HR) and 95% confidence interval (CI) values were analyzed using the Cox proportional hazards model. The proportional hazards assumption was evaluated by the Schoenfeld Residuals Test with the logarithm of the cumulative hazards function based on Kaplan–Meier estimates for quartile groups of variability or groups based on the number of parameters with high variability. There was no significant departure from proportionality in hazards over time. The multivariable-adjusted proportional hazards model was applied: model 1 was adjusted for age, sex, smoking, alcohol consumption, regular exercise, and income; and model 2 was further adjusted for baseline glucose, systolic BP, TC, and BMI. Because an event of mortality could compete with our outcome of interest, we also performed competing risk analysis using a subdistribution hazards model , 20. To The proportions of participants having zero, one, two, three, or four parameters of high variability (measured using the CV) were 33.7, 39.5, 20.6, 5.6, and 0.7%, respectively. The characteristics of subjects by the number of parameters with high variability are presented in Table During a median (5–95%) follow-up of 5.5 (3.2–6.8) years, 32,901 (1.12%) participants developed dementia. Among them, 24,486 (74.4%) and 3629 (11.0%) cases were attributable to Alzheimer’s disease and vascular dementia, respectively. Subjects with incident dementia were older, were more likely to be female, were less obese, and had higher systolic BP and lower total cholesterol levels compared to the subjects without dementia. They also had higher variability indices for each of the metabolic parameters and were more likely to have undergone fewer health examinations  groups of BMI, systolic BP, glucose, and TC variability were 133, 67, 31, and 36% higher compared to the lowest CV quartile (Q1) groups, respectively. An incrementally higher risk of all-cause dementia was observed with higher CV quartiles of BMI, systolic BP, glucose, and TC compared to the lowest quartile groups in model 1   of all-cause dementia, Alzheimer’s disease, and vascular dementia were noted with a higher number of parameters with high variability  and male  subgroups. However, there was no difference in the risk of vascular dementia according to subgroups. Additionally, nonobese and obese subjects showed similar risks of outcomes. These findings were in common with other indices of variability  and using blood glucose, BP, and TC levels as time-dependent covariates. The HR (95% CI) was 1.74 (1.67–1.80) for all-cause dementia, 1.70 (1.63–1.78) for Alzheimer’s disease, and 1.77 (1.59–1.97) for vascular dementia when subjects having four parameters were compared with subjects having no parameters of high variability measured as the CV. Similar results were observed in the population having these metabolic diseases at baseline  were at higher risk of future dementia. Of note, a composite effect of these parameters was evident, showing a linear association between the number of parameters with high variability and outcome measures. The results were consistent by various sensitivity analyses and in different subgroups, confirming that this relationship is widely applicable.Hypertension, type 2 diabetes, and obesity are all well-established risk factors for dementia , proper While the exact mechanism for this phenomenon remains to be elucidated, several plausible explanations can be raised. First, hemodynamic instability leads to inflammation, endothelial dysfunction, and oxidative stress with consequent damage in brain structure and function , 29. TheAn important question that can be raised is whether the variability in metabolic parameters is really a risk factor or is merely an indicator of increased risk for major health outcomes. Patients with cognitive decline might have difficulties in self-care, disease management, and low compliance to medications with consequent instability in several biological parameters, increasing the possibility of reverse causation. It is also suggested that central autonomic dysfunction may accompany dementia, which could contribute to worsening of variability in BP and glucose . HoweverWe also showed that the association between metabolic parameter variability and all-cause dementia or Alzheimer’s disease was stronger in the younger population. It is likely that variability in metabolic parameters may contribute less in elderly people than in younger people, because there are other multiple risk factors associated with aging which increase the risk of developing dementia.This study has the strength of using a large-scale nationwide database representing the entire Korean population. Whereas other studies mostly focused on diseased patients, we excluded subjects with hypertension, diabetes mellitus, and dyslipidemia to exclude potential influences of medication compliance or the disease itself. Our data suggest that the variability of metabolic parameters is a significant risk factor for dementia, even in a relatively low-risk population. In addition, similar results were observed in subjects with these metabolic diseases. However, limitations should also be acknowledged. First, there might be discrepancies between the actual diagnosis and the information recorded in the claim database. Classification of specific dementia subtypes could sometimes be difficult in clinical practice, leading to inaccurate recording of the diagnosis. We tried to overcome this issue by combining the diagnosis statements and the prescription statements. Second, because of the lack of cognitive function testing or imaging data, the severity of dementia could not be assessed. It would be interesting to examine the relationship between the degree of variability and the rate of cognitive decline in the future. Third, it is possible that some of the unknown factors influencing the variability of metabolic parameters might moderate the dementia risk. We tried to adjust covariates or exclude subjects with known risk factors to minimize this possibility. However, the effect of genetic factors still remains to be elucidated. Fourth, because the measurement of high-density and low-density lipoprotein cholesterol in the health examination of the NHIS was started in 2008, the association between variability of these parameters and dementia could not be explored due to an insufficient follow-up period. Fifth, exclusion of subjects with fewer than three health examinations or missing data might be a source of selection bias because employee subscribers with lower risk of dementia were more likely to participate in the regular health check-up . Lastly,We suggest that variability in metabolic parameters is an independent predictor for developing dementia. These findings indicate that reducing variability of metabolic parameters would be important in promoting resilience and preserving cognitive reserve in the general population. Further studies seeking optimal treatment modalities for the control and stabilization of metabolic parameters are warranted.Additional file 1:Table S1. Characteristics of subjects according to incident dementia. Tables S2–S4. HR (95% CI) of all-cause dementia, Alzheimer’s disease, and vascular dementia by quartiles of metabolic parameter variability measured as CV (model 1), as SD, and as VIM. Tables S5–S11. HR (95% CI) of all-cause dementia, Alzheimer’s disease, and vascular dementia by number of parameters with high variability with covariates selected by backward stepwise elimination, measured as SD, measured as VIM, by sensitivity analysis excluding subjects with the occurrence of end points within 3 years of follow-up, by sensitivity analysis excluding diseases known as a risk factor of dementia, by further adjusting for diseases known as a risk factor of dementia, and with high variability defined as > 1 SD. Table S12. HR (95% CI) of all-cause dementia, Alzheimer’s disease, and vascular dementia by weighted variability score. Tables S13–S14. HR (95% CI) of all-cause dementia, Alzheimer’s disease, and vascular dementia by number of parameters with high variability measured as CV by sensitivity analysis  and in total population or subjects with metabolic disease at baseline. Figures S1–S2. Cumulative incidence of all-cause dementia, Alzheimer’s disease, and vascular dementia according to number of metabolic parameters with high variability defined as highest quartile of SD and of VIM. Figures S3–S4. Incidence rate, HR (95% CI) of all-cause dementia, Alzheimer’s disease, and vascular dementia according to variability score as SD and as VIM. Figures S5–S6. HR (95% CI) of all-cause dementia (A), Alzheimer’s disease (B), and vascular dementia (C) by number of metabolic parameters with high variability defined as highest quartile of SD and VIM  (DOC 1137 kb)


In psoriasis, due to the proliferation of Th1, Th17, and Th22 cells, IL-22, among others, is produced in addition to the abovementioned cytokines. With respect to leptin and resistin, both of these adipokines are present in high levels in obese persons with psoriasis. Further, the plasma levels of leptin and resistin are related to the severity of psoriasis. These results strongly suggest that obesity, through proinflammatory pathways, is a predisposing factor to the development of psoriasis and that obesity aggravates existing psoriasis. Different inflammatory biomarkers link psoriasis and obesity. In this paper, the most important ones are described.Psoriasis is a common chronic inflammatory multisystemic disease with a complex pathogenesis consisting of genetic, immunological, and environmental components. It is associated with a number of comorbidities, including diabetes, metabolic syndrome, obesity, and myocardial infarction. In addition, the severity of psoriasis seems to be related to the severity of obesity. Patients with higher levels of obesity show poorer response to systemic treatments of psoriasis. Several studies have demonstrated that white adipose tissue is a crucial site of the formation of proinflammatory adipokines such as leptin, adiponectin, and resistin and classical cytokines such as interleukin- (IL-) 6 and tumour necrosis factor- Currently, obesity is considered a chronic, multifactorial disease and a result of interactions between genetic load and the environment that affect a large percentage of the population across all ages, sexes, and social conditions. It is defined as an abnormal or excessive accumulation of adipose tissue that can be harmful to health, and it affects a greater proportion of women than men .α), interleukin-6 (IL-6), and acute-phase proteins such as C-reactive protein (CRP). This condition associated with obesity is explained by the inflammatory activity of adipocytes. Adipose tissue, classically considered as an energy reservoir, is able to communicate with the rest of the body by secreting adipokines, which are molecules with proinflammatory, thrombotic, and vasoactive activity [α, plasminogen activator inhibitor 1, IL-6, and leptin [It is characterized by an elevation of plasma levels of proinflammatory cytokines, including tumour necrosis factor-alpha , inflammatory dendritic cells (DCs), neutrophils, mast cells, and T cells leads to the apparition of psoriatic lesions. These lesions, from the clinical point of view, are characterized by sharply demarked, erythematous, and scaly plaques. They are found predominantly in the scalp, knees, elbows, lumbosacral area, and body folds, with symmetrical distribution, and can develop in sites of injury (Koebner phenomenon). At the moment, there are no differential diagnostic criteria for psoriasis, and its diagnosis is based on examination of the morpho- and histological characteristics of the lesions, clinical history of patients, and the psoriasis area and severity index (PASI). It is usually accompanied by other morbidities that can further affect the quality of life and survival of patients .Therefore, epidemiological studies have identified a greater risk of development of metabolic alterations in these patients, among which obesity is highlighted , 11.Obesity and psoriasis are linked by a common pathophysiological mechanism, which is explained by low-grade chronic inflammation . ObesityThe effect of cytokines on insulin sensitivity in the liver and muscle has been widely studied . Unlike α)—a cytokine that is elevated in patients with psoriasis, rheumatic diseases, and obesity—induces insulin resistance through various mechanisms. Exposure of cells to TNF-α causes inhibitory phosphorylation by receptor 1 of TNF-α (TNF-R1) to the serine residues of substrate 1 of the insulin receptor (IRS-1), favouring development of insulin resistance [It is known that tumour necrosis factor alpha . Several studies have shown that control of these pathologies favours good evolution of psoriasis and concurrently that treatment with methotrexate and anti-TNF would reduce the risk of these comorbidities [Obesity and psoriasis share common pathogenic mechanisms, including increased proinflammatory cytokines  in adults  and 1.55 kg/m2 (95% CI 1.13–1.98) in children (5–18 years old). In the additional 21 studies, the researchers sought to find an association between BMI and obesity, which reported a positive association.Briefly, 56 studies reporting data about the relationship between psoriasis and BMI, obesity, or being overweight were identified. Among them, 35 compared BMI between psoriasis cases and controls, which were considered to be meta-analysed. It was then found a significant difference in BMI between cases and controls of 1.26 kg/mThe Genetic Risk Score for Body Mass Index (BMI GRS) was strongly associated with BMI in the UK Biobank and HUNT . In bothHigher BMI increases the risk of psoriases, both diseases, presenting a rising prevalence . Type 2 As reported by Carrascosa et al. , obese pP < 0.05). Psoriatic patients with MS had poorer improvement in comparison with those without MS using NB-UVB treatment. MS was an independent factor affecting NB-UVB treatment. In addition, psoriatic patients with MS showed much less reduction of systemic biomarkers (interleukin- (IL) 17, TNF-α, and IL-6) than patients without MS did. That is, they may need a longer treatment course to achieve improved skin lesions.Rui et al.  showed tSince 2004, it is possible to treat psoriasis with molecules generated by molecular biology using recombinant DNA technology. Biological treatments in psoriasis are directed against cytokines or surface proteins of lymphocytes blocking specific steps in the pathogenesis of psoriasis , 35.The most commonly active principles used in the treatment of psoriasis are described in Baerdazzi et al.  have stuα contributed to weight gain in patients with chronic plaque psoriasis. Thus, the clearance of adalimumab or ustekinumab was greater in obese patients, and the PASI75 or PASI90 response rate was higher in patients with low weight. In the case of etanercept, patients with lower weight had better response rates to the drug than those with obesity. However, PASI75 response rates at 10 weeks of treatment with infliximab were independent of BMI. Thus, in those patients with psoriasis and obesity, a treatment with infliximab could be more advisable in comparison with other biologics that are administered in fixed doses.As in Puig et al. , in thisIn addition, the response of obese patients with moderate or severe psoriatic plaques to treatment with low-dose cyclosporine showed improvements after loss of passage through diet or bariatric surgery, although there are studies that show a worsening of the disease after surgery or with rapid drops in weight .Petridis et al. , in a muFleming et al.  reviewedAccording to Klingberg et al. , psorias2 with weight loss treatment with very low energy diet (VLED) and daily intake of 640 kcal, including recommended doses of vitamins, minerals, and other essentials, following an initial period of 12 or 16 weeks. The association between BMI and disease activity at baseline BMI was positively correlated with several measures of disease activity and function. BMI decreased from median 35.2 kg/m2 to 29.7 kg/m2, and a significant reduction was seen in a majority of the disease activity measures. The improvement of the skin occurred later than for the other disease activity parameters (3 months). The treatment was generally well tolerated without serious adverse events occurring. Significant improvement in disease activity in joints, entheses, and skin and reduction in CRP, PLT, and parameters assessing function were found at the 6-month follow-up.Briefly, 41 patients with psoriatic arthritis (CASPAR criterion) completed the study, showing a BMI ≥ 33 kg/m2) was a negative cause for psoriasis treatment with etanercept. Thus, an increase in BMI may be a predictor to suspending use of the anti-TNF-α drug. Therefore, there is a consensus that a BMI of 25 kg/m2 is for a good response to treatment.Data from Giunta et al.  indicateIn this study by Hansel et al. , 30 pati2, 25 to <30 kg/m2, and ≥30 kg/m2). In normal weight, overweight, and patients at week 16, the respective PASI-75 response rates were 85.0%, 85.7%, and 61.3% with adalimumab; 43.3%, 29.3%, and 26.1% with methotrexate; and 28.6%, 16.7%, and 0% with placebo. Adalimumab was superior in all cases, although the result was also influenced by BMI.In another study conducted by Prussick et al.  with pson = 18), ustekinumab (n = 30), and secukinumab (n = 20). The treatment results appeared better in patients treated with ustekinumab and secukinumab.In this study, Takamura et al.  aimed toThere is still not much known in patients with a high BMI and high body weight with ixekizumab; however, the results were similar so that a high rate of BMI seemed to decrease the effectiveness of treatment in patients with moderate-to-severe plaque-type psoriasis .Finally, 48 patients were included in a study by Vujic et al. , who recRecent studies have revealed that there are some possible biological markers that can be used to detect psoriasis and evaluate the prognosis and response to treatment.γ-producing Th1 cells and IL-17A-producing Th17 cells.In this work from Yadav et al. , a globaFollowing with S100 proteins, there are 18 S100 family proteins. Among them, 13 are responsible for cellular differentiation of the epidermis and located on chromosome 1q21. In psoriasis, S100A7, S100A8, and S100A9 are expressed. S100A7 (Psoriasin) is involved in abnormal keratinocyte differentiation. Its overexpression is noticed in the nucleus and cytoplasm in keratinocytes and secretion from epithelial cells in psoriatic skin. S100A8 and S100A9 are very significant in psoriatic arthritis and rheumatoid arthritis as they are strongly expressed in inflamed tissue fluid. This is the reason why S100A8 and S100A9 are strong protein candidates for therapeutic targeting of psoriasis and PsA. Another important biomarker is Wnt5a, which is a transmission protein that has a key role in carcinogenesis and embryogenesis and regulates tissue regeneration in the intestine and skin. Wnt5a and its receptors fzd3 and fzd5 have a central role in adult skin cell differentiation and are located in hair follicles of normal epidermal skin, signifying their crucial role in skin cell differentiation in adults. In psoriasis, Wnt5a and fzd5 are overexpressed and relocated, which leads to anomalous differentiation of keratinocytes.p53/TP53 or tumour protein, one key factor of psoriasis, is a phosphoprotein that regulates cell cycle. Its presence in the layers of psoriatic skin suggests its involvement in the disease.As for enzyme biomarkers, exfoliations of epidermal cells followed by hyperproliferation are a distinct indication in psoriasis. The development, repair, and proliferation of keratinocytes are controlled by several proteins, enzymes, ions, cytokines, and growth factors. Targeting psoriasis with enzymes could be a unique treatment strategy as they offer insight into the disease progression by prognosis, diagnosis, and assessment of responses. Phospholipase C (PLC) has a key role in the formation of the stratum corneum barrier and keratinocyte differentiation.Although psoriasin (S100A7) and koebnerisin (S100A15) are distinct in tissue distribution, regulation, and function, both have functional roles in innate immunity, epidermal cell maturation, and epithelial tumourigenesis .Ekman et al.  suggest Importantly, banal infections or small lesions persisting over a long period of time may stimulate IL-22 production. According to Sabat et al. , endogenUpon activation, keratinocytes synthesize thymic stromal lymphopoietin (TSLP), which is considered an initiator of Th2-mediated immune responses in the skin  Figure .Adipocytes and cells residing within the adipose tissue secrete various soluble mediators involved in regulating organ function, metabolism, immunity, and inflammation. The plasma levels of adiponectin increase with weight loss and decrease in obesity. Adiponectin is an important regulator of metabolism and energy homeostasis, enhancing insulin sensitivity and decreasing hepatic glycogenesis.In this study from Batycka-Baran et al. , it inclPsoriasin, koebnerisin, IL-12, and IL-23 were significantly increased in all cases, and the risk of psoriasis development was directly related to BMI greater than 30. IL-12 was a good predictor of the psoriasis response to treatment, and IL-23 was decreased in psoriatic arthritis. The risk of developing psoriasis was directly related to increases in BMI greater than 30; thus, obesity will play as another factor along with genetic factors in developing psoriasis , 61. ChrIn this study from Vachatova et al. , the autAdiponectin, leptin, resistin, and lipoprotein-associated phospholipase A2 levels were determined using commercial ELISA kits following the manufacturer's instructions. All of them were considered selective inflammatory markers in psoriatic patients.Another group of researchers led by Kyriakou et al.  collecteThere is significant evidence that systemic inflammation increases cardiovascular risk and leads to metabolic dysregulation in psoriasis.In this study of cases and controls by Baran et al. , they evMyśliwiec et al.  conducteIn agreement with the previous results, it was determined that changes in the concentrations of certain sphingolipid species aided diagnosis of psoriasis and some of its comorbidities.Hyperuricaemia is usually associated with skin psoriasis or PsA, and variations in genetic factors, diet habits, and living areas might contribute to the wide range in its prevalence, as a manifestation of metabolic disorders .Lai et al.  carried Hong Kong Chinese PsA patients had 30.6% of hyperuricaemia , and overweight PsA patients were associated with hyperuricaemia, independent of psoriasis, arthritis severity, renal function, and disease duration. Further, BMI was significantly associated with SUA level, with a positive linear relationship .Baran et al.  reportedBased on their study, Watarai et al.  suggesteHe et al.  believe Gerdes et al.  conducteWith respect to visfatin, there is a correlation between increased level of this with severity of disease. Regarding the retinol-binding protein (RBP4) and omentin, a direct relationship with psoriasis has not been found; however, they have been associated with metabolic processes such as diabetes mellitus type 2 .α) and interleukin- (IL-) 6 have been found as important markers in obese patients with psoriasis diagnosis. According to the above, they highlighted that these adipokines can serve as biomarkers to determine the degree of disease advancement, the level of risk posed by comorbidities, and the success that can be obtained by different treatment options [Finally, altered serum values of tumour necrosis factor alpha  and 12% (resistin) when compared with the obese group. They were significantly correlated with PASI, plasma psoriasin, nestin, Krt16, and IL-21. IL-21 (inflammatory biomarker) was significantly increased in obese, psoriatic, and obese psoriatic patients. This interleukin has a key role in keratinocyte proliferation. Psoriasin and nestin were significantly raised in psoriatic and obese psoriatic patients. Psoriasin causes inhibition of differentiation in the epidermis because it reduces Krt1 and Krt10 expression. BMI has significant correlations with Krt16 and IL-21. Krt16 produces alterations in Krt filament organization, cell adhesion, differentiation, and migration, and PASI remained significantly associated with psoriasin. Finally, resistin showed a significant correlation with psoriasin, IL-21, and leptin .This study shows the possibility of using psoriasin, nestin, Krt16, and IL-21 as biochemical markers of psoriasis and highlights the correlation of these with biomarkers of obesity . Furthermore, it reveals the bidirectional association between psoriasis and obesity.Enany et al.  conducteMyśliwiec et al.  carried Moreover, in the group of psoriatic patients, they observed a significant negative correlation of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) with PASI. There was a positive correlation between PASI and the n-6/n-3 ratio.Nevertheless, in nonobese psoriatic patients, they observed a negative correlation between DHA, n-3 polyunsaturated FA (n-3 PUFA), and PASI and a positive correlation of the percentage of monounsaturated FA (MUFA) and PASI .In obese psoriatic patients, no significant correlations between FA and PASI were found. Further, there were no significant correlations between other metabolic parameters such as cholesterol, triglycerides, and fasting blood glucose and PASI in nonobese and obese psoriatic groups.Conversely, in the psoriatic patient groups with or without hypertension, hypertensive patients had significantly higher concentrations of total FA, percentage of SFA, n-3 PUFA, and SFA/UFA ratio. They also had a lower percentage of all PUFA and n-6/n-3 ratio in serum. The psoriatic group with type 2 diabetes compared to nondiabetic patients had significantly higher concentrations of total FA and a lower percentage of PUFA. Psoriatic patients with diabetes were older and had higher BMI than psoriatics without diabetes. Similarly, psoriatic patients with hypertension were older and had higher BMI than those without hypertension .Kustán et al. , in a stIn a revision carried out by Gisondi and Giromoloni , they evHyperhomocysteinaemia has been reported in psoriasis patients and was directly correlated with psoriasis severity according to the PASI score, whereas it was inversely correlated with plasma folic acid levels. Increased levels of serum C-reactive protein (CRP) have been reported in patients with active psoriasis .Patients with pustular psoriasis have significant elevated hs-CRP compared with that of plaque psoriasis patients. A direct correlation between CRP and psoriasis severity was found. CRP elevation is attributable  to psoriasis inflammation.Platelet activation has been established in psoriasis patients; the hemostatic balance is deranged toward a prothrombotic state in psoriasis patients, which might be mainly sustained by platelet hyperactivity.Cytokines can also mediate several metabolic effects that, in the short term, result in an appropriate response to injury or infection; however, on a chronic basis, it can prove detrimental by accelerating the development of atherosclerosis and predisposing to thrombosis . All of Psoriasis is associated with obesity, dyslipidaemia, altered levels of HDL cholesterol, and impaired cholesterol efflux capacity.Oxidized LDL (oxLDL) contributes to the spread of atherosclerosis and is an important target for the treatment of cardiovascular disease (CVD). The oxidized phospholipids (oxPL) of lipoproteins A (LPa) increase the proinflammatory response and favour the progression of CVD. In addition, low levels of oxidized HDL (oxHDL) are also associated with an increased risk of CVD in a young healthy population .Sorokin et al.  studied The paraoxonase-1 (PON-1) system determines antioxidant properties and contributes to the CVD risk. Subjects with psoriasis have higher paraoxonase activity compared to healthy individuals; however, arylesterase levels are lower. Lactonase activity does not vary between people with psoriasis and the healthy population. In one part of the study, patients with psoriasis of a mean age of 47 years, with low cardiovascular risk, and treatment with anti-TNF and anti-IL7 were included. After 3–5 months of treatment, there was a significant increase in the levels of TG and LPa and a decrease in the levels of oxHDL with respect to the basal levels. After 1 year of follow-up, a reduction in the total coronary plaque burden was observed due to a reduction in NCB with changes in DCB.In summary, circulating lipid levels modified by oxidation can serve as useful markers of early atherosclerosis in psoriasis. This result could help to redirect the prognosis of psoriasis .Abud El-Hamd et al.  evaluateγ/RORγt). RORγt is a nuclear hormone receptor (NHR), which converts CD4+ immune cells into Th17 cells and is involved in cytokine production. GSK2981278 is a powerful inverse agonist of RORγ and appears to hinder Th17 expression, including the topical targeting of molecules of psoriatic lesions [Gege et al.  investig lesions .Aquaporin-3 (AQP3) is a protein that acts as a water channel, permitting water transport and glycerol permeability across cell membranes. It is involved in the regulation of differentiation and proliferation of keratinocytes as its expression is reduced in psoriasis. Targeting dry and itchy skin as one of the prime aspects of psoriasis, AQP3 is believed to be very relevant for its treatment .Ritchie et al.  found thBilgiç et al.  studied Finally, in this study of cases and controls, Gisondi et al.  enrolledThe objective was to measure serum adipokines in patients with plaque psoriasis, and serum levels of chemerin, resistin, and CRP were significantly higher in patients with chronic plaque psoriasis compared with controls independent of age, sex, BMI, and metabolic comorbidities. Further, they observed that chemerin levels were higher in patients with psoriatic arthritis than those without psoriatic arthritis. Chemerin was linearly correlated to CRP and resistin, but not with psoriasis severity measured with PASI or body surface area (BSA). After 2 and 12 months of treatment with infliximab, a significant reduction in chemerin, resistin, and CRP levels, as well as the PASI score, was observed. In contrast, visfatin levels significantly increased after 12 months of infliximab.The main biomarkers of inflammation involved on diagnose, prognosis, and treatment in obesity-psoriatic patients are collated in α (TNF-α) and different target organs (such as arthritis and Crohn's disease) and the increased risk of coronary heart disease and occlusive CVD. The severity of psoriasis measured by PASI, disease progression, and response to new treatments, with the so-called metabolic syndrome, is characterized by abdominal obesity, dyslipidemia aterogénica, hypertension, insulin resistance with or without glucose intolerance, and a proinflammatory and prothrombotic state as a risk factor for cardiovascular disease. Further, there is evidence that, in psoriasis, chronic inflammation has a pathogenic role in the metabolic syndrome and associated comorbidities, and its proper treatment could contribute to reversing it.For some time, the epidemiological association of psoriasis, especially in its severe forms, with various diseases with which it shares a common pathogenic substrate has been known, including the involvement of tumour necrosis factor It is an obligation of dermatologists to recognize elements of the metabolic syndrome and to propose to psoriatic patients, in addition to optimal treatment of their psoriasis, changes in life habits, and adequate pharmacological treatments to reduce the risk of cardiovascular morbidity and mortality.Thus, the patient with moderate-severe psoriasis has become the main therapeutic target. However, little has been documented about biomarkers that can objectively discriminate between states of disease activity. A biomarker of activity reflects an underlying inflammatory process, is reproducible, and allows patient monitoring, which is useful in making therapeutic decisions.In this study, we considered the principal biomarkers that could discriminate subjects with active disease or remission, prognosis, and response to treatment in obese patients with comorbidities derived from overweight and high BMI.Further research is required to achieve biomarkers that objectively discriminate the phases of reproducibility and can be applied in different clinical scenarios and by physicians with different levels of training.


Past environmental efficiency analyses have rarely examined economic development, air pollution and health as interacting systems; therefore, this study used a new two-stage DEA model, the Modified Undesirable EBM Two Stage DEA (Epsilon-Based Measure) to explore the environmental, economic and health efficiencies in thirty-one major cities in China. The results were as follows: while all cities needed to improve their GDP, the environmental efficiencies were continuing to rise in most cities. The health efficiency index indicated that disease efficiency had increased in most cities but declined in one third; therefore, it is necessary to strengthen treatment. The respiratory disease treatment efficiency in most cities was rising, and the room for improvement had significantly reduced. There were improvements in the mortality rate in 15 cities; however, the mortality rate treatment efficiency declined in 11 cities.The rapid economic growth of China in the last twenty years has caused a commensurate rise in atmospheric pollution which has had an impact on both the environment and public health. Since 2013, SO The World Meteorological Organization (WMO) reported that the current CO2, NO2, PM2.5 and CO2 on respiratory and cardiovascular diseases especially in children can be quite severe.Many countries are now seeking to limit their carbon emissions, and China is also aiming to have “ambient air quality standards”  by 2040 x) and found that under the CAA regulations, acid rain was effective in controlling the SO2 and NOx emissions from U.S. coal-fired power plants. Shi et al. [x, NOx, CO, VOC CO2, and GHG, in OECD countries. Some air pollutant emissions did not follow the shape of EKC, but SOX emissions show a U-shaped Environmental Kuznets Curve. He et al. [10 and SO2 in 74 cities in China in 2015. The above two air pollutants could cause economic losses related to health issues equal to 1.63 and 2.32% of the GDP. Wang et al. [2 emissions and economic growth. The results showed that urbanisation level has a more significant effect on carbon emission than Gross Domestic Product per capita and energy structure. Xie et al. [Environmental pollution research is generally linked to the assessment of the economy and energy efficiency. Zhou et al.  used noni et al.  used a Ri et al.  adopted i et al.  used an i et al.  used DEAi et al.  used thei et al.  used Radi et al.  used a Di et al.  used SBMi et al.  employedi et al.  evaluatee et al.  presentee et al.  measuredg et al.  estimatee et al.  used a c2.5 concentrations having a particularly significant impact on health. Fischer et al. [3 increase, PM10 and NO2 were significantly associated with non-accidental mortality; (2) PM10 was related to circulatory system mortality, but NO2 was not; and (3) Long-term exposure to PM10 and NO2 was associated with  mortality in The Netherlands for people over 30. Khafaie et al. [Environmental pollution and health have had two main research directions_ an assessment of the impact of environmental air pollutant exposure on health, and the impact of environmental air pollution on the health of children and the elderly. Liu et al.  investigr et al.  explorede et al.  focused e et al. , providi2.5 concentration of 100 μg/m3, the benefit from riding for one and a half hours a day or walking for more than 10 h a day was less than the damage from the air pollution, and in areas with a lower PM2.5 concentration, the benefit of cycling for 3 h and a half rather than staying home was greater than the damage from the air pollution. Jose et al. [x on health in Italy and provide governance recommendation to avoid health risk. Schiavon et al. [x emissions of road traffic. The results show that high emission concentrations can affect the human body.Tainio et al.  analyzede et al.  measurede et al.  discussee et al.  assessedn et al.  simulate2.5 ranked fifth among all mortality risk factors, with exposure to PM2.5 causing 42 million deaths, which was 7.6% of the total global mortality, and 1031 million disability-adjusted life years (DALYs). Johansson [x and black carbon (BC) on the mortality rate, and showed that a 7% decrease in the average exposure to nitrogen oxides and black carbon (BC) would reduce the relative risk of mortality by 8%. Newell et al. [3 increase in PM2.5 increased the risk of cardiovascular mortality by 0.47% and respiratory mortality by 0.57% (0.28–0.86), and a 10 μg/m3 increase in PM10 increased the risk of cardiovascular mortality by 0.27% (0.11–0.44) and respiratory mortality by 0.56% (0.24–0.87). Kinney [2.5 emissions increased, and ozone formation was faster in high sunlight and high temperatures. Lua et al. [2.5 on health in China from 2001 to 2017. The PM2.5 is related to the mortality rate in urban. The reduction of the PM2.5 can brings the benefit about $193,800 in 2017.Cohen et al.  exploredl et al.  explored. Kinney  revieweda et al.  measure 2.5, and found that at all research sites, any reductions in environmental PM2.5 and health insurance could not be attributed to the substandard conditions in eastern United States. A hierarchical analysis showed that if PM2.5 reduced to levels beyond the regional measures, mortality, chronic obstructive pulmonary disease, heart failure, ischemic heart disease, and respiratory infections would be significantly reduced.Zigler  used cau1), forced vital capacity (FVC), and maximal expiratory flow at 50% of the vital flow capacity (MEF50). However, PM10, SO2, NO2 were not found to have a significant negative effect on lung function. Ye et al. [2 had a significant effect on angina, cardiac insufficiency, myocardial infarction, and acute bronchitis, and PM10 had a significant effect on asthma, chronic bronchitis, and pneumonia.Some research has discussed the impact of environmental air pollution on the health of children and the elderly. Frischer et al.  used rege et al.  used gen2), nitrogen dioxide (NO2), ozone (O3), carbon monoxide (CO) and airborne particles less than or equal to 10 μg/m3 in aerodynamic diameter (PM10); on the health of children under 15 years old in Seoul from 1997 to 1999, and found that nitrogen dioxide and ozone were the main factors for childhood asthma. Gauderman et al. [2.5, PM2.5–10, PM10 and NO2 had significantly negative effects on the first second of forced expiration (FEV), forced vital capacity (FVC), maximal mid-expiratory flow (MMEF), and improved forced expiratory flow at 75% of vital capacity (FEF75); however, ozone was not found to have a significant negative effect on lung function.Lee et al.  used a gn et al.  estimate2.5, PM2.5–10 and PM10 all had significant effects.Chen et al.  used gen2, PM10 and O3; however, no consistent positive association was found for NO2; and that long-term exposure to background ambient air pollution increased the prevalence of respiratory and atopic problems in children. Barnet et al. [2.5, PM10, SO2, NO2 and O3 had significant effects on pneumonia and acute bronchitis for children less than 1 and 1–4 years old, on respiratory problems in all three groups, and on asthma in 5–14 year old. SO2 has also been found to have an effect on pregnant women by shortening pregnancies, and causing premature births and low birth weights  was 1.021 (95% CI: 1.019 to 1.022).Penard-Morand et al.  used a ct et al.  conducte et al., ). A stud and Shi ) that foCooper, Charanes and Rhodes Model or Banker, Chames and Cooper Model) or non-radial (Slack Based Model) Data Envelopment Analyses (DEA) and Distance Function Models . However, the radial DEA model ignores non-radial slacks and non-radial DEA models ignore characteristics of the same proportion. As traditional environmental pollution and economic research have tended to employ one-stage DEA as the main methodology, health issues have generally been ignored. Therefore, to resolve the issues associated with radial and non-radial bias, this research proposes a Modified Undesirable EBM Two stage model.However, there have been few studies that have considered the interactions between economic growth, environmental pollution, and community health. Most environmental pollution and economic analysis research has employed radial . In health stage the health expenditure is input indicator; the output indicators are birth rate, respiratory system and mortality rate.The main contribution of this paper is that the economic, environmental, and health efficiencies are jointly analyzed, which avoids under- or overestimation. Data from 31 Chinese cities from 2013–2016 were examined in two stages: a production stage and a health stage. In the production stage, labor, fixed assets, and energy consumption were the input indicators Gross Domestic Product (GDP) as output indicator, linkage and health stage variable are COThe remainder of this paper is organized as follows: Data envelopment analysis (DEA) uses linear programming techniques to assess the relative efficiency of decision making units (DMU) based on a Pareto optimal solution concept. Charnes et al.  developeWhen evaluating efficiency, traditional DEA models convert the efficiency between the two variables through the input and output, with the conversion process being a “black box”. Fare et al.  then proAlthough the EBM DEA model overcame the shortcomings of the radial and the non-radial DEA models, it is still unable to solve the issues associated with two-stage undesirable output, and while Network DEA models can solve the multi-stage problems, they fail to solve the radial and non-radial problems. Therefore, this paper proposes a modified EBM Two-stage DEA model based on Tone and Tsutsui’s  Two-stagThe Non-oriented EBM DEA description in Tone and Tsutsui  is as fojDMU = , there are jX = , and there are s outputs, where jY = ; the efficiency of the DMU unit is therefore [There are herefore (1)θ*=miY: DMU output, X: DMU input, S, Subject to:For DMU0, when e needed :(2)X0*=XIn 2009, Tone and Tsutsui proposed a weighted slack-based measures (DEM) model to measure the overall efficiency of decision-making units and the efficiency of each department and included an SBM mode non-radial measure when the input and output items could not be adjusted in equal proportions. The network DEA model based on the weighted SBM is introduced in the following: Considering both the input and output slacks, Equation (3) represents non-oriented efficiency :Minρ0∗=∑k-th department of oDMU is non-oriented efficient, and indicates that oDMU has non-oriented overall efficiency.According to Equation (4), the definition for the non-oriented department efficiency is as follows :(4)ρk=1−By combining the modified EBM DEA with a Two-stage DEA and undesirable factors, this paper proposes a modified EBM Two stage DEA model to evaluate the energy efficiency of 31 cities in China, which avoids the efficiency and need for improvement being under or overestimated.The modified undesirable EBM Two stage DEA is as follows:n, the number of divisions is k, where jDMU = . there are m input types jX = , and there are s outputs where jY = , therefore, the efficiency of the DMU unit is:The number of DMUs is Y: DMU output, X: DMU input, S,k, h): the link from Division k to Division h.Subject to:k is given by: k is the department, oDMU is non-oriented efficient and when oDMU has non-oriented overall efficiency. The DMU and division overall efficiency is assessed as the non-oriented unit the efficiency value and the measurement unit selected by the input, output, and the intermediaries are independent of each other.The efficiency score for Division If an inefficient decision-making unit needs to achieve an optimal efficiency goal, the following adjustments are needed:In this model, we assess the relative efficiency of decision making units (DMU) based on a DEA method. DMU with good efficiency score merely means that it has a “good rank” in comparison. However, it does not indicate that these municipalities have excellent air quality in the real world. Precisely, the air quality of these municipalities is “comparatively better”, thus, these municipalities perform better than other cities in the research sample in air pollutant reduction. In realistic, most cities in China have a large room for improvement in air quality. Since the “Air Pollution Prevention Action Plan” was ordained in China, every city has worked hard on air pollution issues. The cities with good rank in this paper have more chance to succeed in environment protection, due to their comparatively higher air pollution treatment efficiency.2 and AQI.In addition to finding the overall efficiency, the efficiency value for a single input or output can be found. Hu and Wang’s  total-faIn this study, “I” represents area and “t” represents time. The ten efficiency models are defined in the following expression:If the target fixed assets, labor, energy consumption and health expenditure input equals the actual input, then the fixed assets, labor, energy consumption and health expenditure efficiencies equal 1, indicating overall efficiency. If the target fixed assets, labor, energy consumption and health expenditure input is less than the actual input, then the fixed assets, labor, energy consumption and health expenditure efficiencies are less than 1, indicating overall inefficiency.If the target GDP and birth rate desirable output is equal to the actual GDP and birth rate desirable output, then the GDP and birth rate efficiency equals 1, indicating overall efficiency. If the actual GDP and birth rate desirable output is less than the target GDP and birth rate desirable output, then the GDP and birth rate efficiency is less than 1, indicating overall inefficiency.2 and AQI undesirable output is equal to the actual respiratory diseases, mortality rate, CO2 and AQI undesirable output level, then respiratory diseases, mortality rate, CO2 and AQI efficiency equals 1, and is efficient. If target respiratory diseases, mortality rate, CO2 and AQI undesirable output is less than the actual respiratory diseases, mortality rate, CO2 and AQI undesirable output level, then Mortality Rate efficiency is less than 1, and is inefficient.If target respiratory diseases, mortality rate, CODemographics and Employment Statistical Yearbook of China, and the City Statistical Yearbooks [China Environmental and Protection Bureau Annual Reports and China Environmental Statistical Yearbook [This study used panel data for 31 cities of the most developed cities from eastern China to western China. Economics and social development data from 2013 to 2016 were collected from the Statistical Yearbook of China , the Demearbooks . Air polYearbook . This stThe input and output variables are outlined in Labor input (lab): employees in each city at the end of each year; unit: person. Fixed Assets (assets): fixed assets investment in each city; unit: 100 million CNY; Energy consumption (con): total energy consumption in each city; unit: 100 million Dun.Desirable output (GDP): GDP in each city; unit: 100 million CNY;Production Stage and health stage link variables:2; a common greenhouse gas.Carbon dioxide: CO2.5, PM10), sulfur dioxide (SO2), nitrogen dioxide (NO2), ozone (O3), and carbon monoxide (CO). PM2.5 and PM10 were taken as the 24-h average concentration, and the CO2 emissions data for each city were estimated from the energy consumption breakdown by fuel category.The Air quality Index (AQI) is the measured concentration of pollutants; particulate matter Of the 31 cities, only Lhasa, Guangzhou, and Shanghai had overall efficiency scores of 1 for all four years. Nanning’s total efficiency score was 1 from 2013 to 2015 but fluctuated down in 2016. The overall efficiency in Beijing was 1 in 2013 and 2015, 0.94 in 2014, and 0.84 in 2016, indicating that the need for improvements in Beijing was expanding, which was also true for most other cities.(2)Compared with the number of cities with increasing overall efficiency scores, most cities had decreasing overall efficiency scores; therefore, the improvements in overall efficiencies were not optimistic.(3)Health expenditure efficiency in most cities was rising except for the input efficiencies in Beijing, Wuhan, Xining, and Nanning, all of which dropped significantly.(4)Except for the cities that had GDP efficiencies of 1, there were less cities with rising GDP efficiencies (6) than cities with decreasing GDP efficiencies (11); therefore, the need for GDP efficiency improvements was expanding.(5)The birth rate efficiency scores in Fuzhou, Guangzhou, Haikou, Lhasa, Nanning, and Shanghai were all 1, 7 cities had downward trends while the other 28 cities had upward trends; therefore, in general, this indicator was improving in most cities.(6)The respiratory diseases treatment efficiencies decreased in 10 cities; however, in all other cities it was rising, and the need for improvements was significantly reducing.(7)Five cities had mortality rate efficiencies of 1 and the efficiency increased significantly in 15 other cities; however, the mortality rate efficiencies declined in 11 cities.(8)The carbon emissions efficiencies rose in most cities.This research used a two-stage network model and undesirable output to assess the urban environmental efficiencies and health efficiencies in 31 Chinese cities from 2013 to 2016, the results from which were as follows:(1)Carbon dioxide emissions and air pollutants have brought great challenges to the environmental governance of central and local governments. The impact of air pollutants on human health is large and long-lasting and should be prioritized in governance work. Even the air pollutant efficiency of some cities is better than the carbon dioxide emissions, the reduction of air pollutants cannot be overlooked. Chengdu, Hangzhou, Hefei, Huhehot, Jinan, Lanzhou, Nanchang, Nanjing, Shenyang, Shijiazhuang, Urumqi, Yinchuan should be more effective in controlling carbon dioxide emissions and air pollution emissions, using industrial transformation, and energy transformation to achieve emission reduction. Beijing, Changchun, Wuhan, Xian, Xining, Zhengzhou should control air pollutants first and then consider carbon dioxide emissions reduction. Changsha, Chongqing, Guiyang, Harbin, Kunming, Nanning, Taiyuan, Tianjin, should control carbon dioxide emissions first and then consider the treatment and control of air pollutants. Fuzhou, Guangzhou, Haikou, Lhasa, Shanghai should maintain better environmental efficiency and continue to improve air pollutants and carbon dioxide emissions.(2)Because China has a vast territory, there are very large differences in economic and social development. The economy in most regions in the east is significantly better than in the central and western regions. Therefore, the efficiency scores in most eastern cities  were at a higher level and there was less need for improvement. With rapid economic development being at the cost of increased energy consumption and environmental pollution, it is necessary to use comprehensive treatments and increase the sustainable development of the cities. As Beijing is the capital, it attracts significant government investment. However, the treatment efficiency was not high and was on a downward trend. Urban development consumes a great deal of energy that generates pollution, which had led to a significant decline in environmental efficiency; therefore, the treatments associated with respiratory diseases, air pollution, and carbon emissions should be strengthened.(3)For inland cities, such as Chengdu and Chongqing, the efficiency scores in 2016 were significantly higher than in 2014 and 2015, indicating that the treatment effects were improving the overall environment. Compared with the coastal cities, many mid-western cities had lower efficiency scores, with many experiencing significant declines in treatment efficiencies in 2016. Therefore, while investment in many cities in 2016 increased, the effects have not yet been realized and it is still necessary to reduce excessive investment and resource waste.(4)Environmental pollution in cities is associated with respiratory diseases, which was measured in terms of the respiratory disease treatment and mortality rate efficiencies. Environmental pollution problems should be solved from the source and treatment efficiency increased. Also, Beijing, Changchun, Guiyang, Harbin, Kunming, Shenyang Shijiazhuang, Tianjin should pay attention to respiratory diseases and mortality, fund improvements to the quality of medical equipment and reduce disease.The results indicate that there was still a significant need for improvement in most cities. Therefore, it is necessary to strengthen investments in treatments, and more specific measures should be taken to effectively to increase urban pollution and health treatment efficiencies. Based on the above research conclusions, this study gives the following policy recommendations:


They also scored the possibility of images being original. Although there was no significant difference between the images synthesized with 1000 and 500 epochs, the latter were evaluated as being of higher quality than all other images. Moreover, 2.5%, 0%, 12.5%, 37.5%, and 22.5% of the images synthesized with 50, 100, 200, 500, and 1000 epochs, respectively, and 14% of the original images were indistinguishable from one another. Interobserver agreement was very good . Therefore, DCGAN can generate high-quality and realistic synthesized breast ultrasound images that are indistinguishable from the original images.Deep convolutional generative adversarial networks (DCGANs) are newly developed tools for generating synthesized images. To determine the clinical utility of synthesized images, we generated breast ultrasound images and assessed their quality and clinical value. After retrospectively collecting 528 images of 144 benign masses and 529 images of 216 malignant masses in the breasts, synthesized images were generated using a DCGAN with 50, 100, 200, 500, and 1000 epochs. The synthesized ( With the recent development of deep learning technology, the use of deep learning methods for medical image synthesis has increased dramatically ,2,3. OneTo this end, the purpose of this study was to use a DCGAN to generate breast ultrasound images and evaluate their clinical value.Our medical ethics committee  approved the retrospective study in 20 September 2019 and waived the requirement for written informed consent from patients. In the present study, the inclusion criteria were as follows: (a) those who underwent breast ultrasound examination at our hospital between January 2010 and December 2017 and presented with breast masses and (b) those whose masses were diagnosed as being benign or malignant by histopathological examination or >2-year follow-up. The exclusion criteria were as follows: (a) those who received hormone therapy, chemotherapy, or radiation therapy and (b) those who were <20 years of age. A breast radiologist (Tomoyuki Fujioka) and medical student (Mizuki Kimura) randomly selected and extracted the maximum six different cross-sectional images of one mass and the maximum two masses in one patient. Ultrasound images with strong artifacts were excluded.Five radiologists with 4–20 years of experience performed the ultrasound examinations using an Aplio XG scanner with a PLT-805AT 8.0-MHz linear probe , an Aplio 500 scanner with a PLT-805AT 8.0-MHz linear probe , or an EUB-7500 scanner with a EUP-L54MA 9.75-MHz linear probe . The radiologists acquired static images in the vertical and horizontal planes and measured the maximum diameter of the masses.In this study, all solid and cystic masses, including simple cysts, were evaluated. We used the same set of data that were employed in our previous work . Ultraso−8). The image data were set to be input at a pixel size of 256 × 256 and output at a pixel size of 256 × 256. After building the models, we generated 20 images with 50, 100, 200, 500, and 1000 epochs. Moreover, we randomly selected 40 original images. Image synthesis was performed on DEEPstation DK-1000  containing the graphics processing unit GeForce GTX 1080 , central processing unit Core i7-8700 , and graphical user interface-based deep learning tool Deep Analyzer . Images were constructed using a DCGAN . The DCGIn the present study, two breast radiologists  assessed the ultrasound images. The radiologists subjectively evaluated the 20 generated images with 50, 100, 200, 500, and 1000 epochs and 40 original images on a scale of 1–5  for overall image quality, definition of anatomic structures, and visualization of the masses. The quality of the original breast ultrasound image at our facility was used as the standard for score 1. They also score the possibility of the images being original on a scale of 1–5 .All statistical analyses were performed using the EZR software package version 1.31  .p value of <0.05 was considered to be statistically significant.In this work, the data are presented as the mean and standard deviation. Mann–Whitney U-tests were used for the analysis of characteristics, including patient age, maximum mass diameter, and image quality  using the mean five-point assessment scores given by readers 1 and 2. The interobserver agreement of scores given by readers 1 and 2 was assessed using Spearman’s coefficient of correlation. A Malignant masses were larger than benign masses, and patients with malignant masses were significantly older than those with benign masses .p < 0.001). Although there was no significant difference between images synthesized with 1000 and 500 epochs (p = 0.725–1.000), the latter were evaluated as being of better quality than all other images. Images synthesized with 500 epochs were significantly different from those synthesized with 50, 100, or 200 epochs in terms of overall quality (p < 0.016) and visualization of the masses (p < 0.006). Moreover, images synthesized with 500 epochs were significantly different from those synthesized with 50 or 100 epochs in terms of the definition of anatomic structures (p < 0.001). Interobserver agreement was very good for overall quality , definition of anatomic structures , and visualization of the masses . In the evaluation of the possibility of images being originals, 2.5%, 0%, 12.5%, 37.5%, and 22.5% of the images synthesized with 50, 100, 200, 500, and 1000 epochs, respectively, were misinterpreted as being original images  or were indistinguishable from the original images . Moreover, 14.0% of the original images were indistinguishable from the synthesized images  (ith 50%) .In this study, we used a DCGAN to synthesize breast ultrasound images and asked two experienced breast radiologists to evaluate those images from a clinical perspective. Our results indicate that high-quality breast ultrasound images that are indistinguishable from the original images can be generated using the DCGAN.The concept of adversarial training is relatively new, and great progress has recently been made in this area of research . In our Previously, Beers et al. showed realistic medical images in two different domains, namely retinal fundus photographs showing retinopathy associated with prematurity and two-dimensional magnetic resonance images of gliomas using progressive growing of GANs, which can create photorealistic images at high resolutions . AdditioIn this study, we generated synthetic images with 50, 100, 200, 500, and 1000 epochs and demonstrated that as the number of learning repetitions increased, the quality of the final image increased. Although there was no significant difference between the images synthesized with 1000 and 500 epochs, the latter showed a better quality than all other images. Therefore, to generate a high-quality synthetic image, multiple epochs are necessary. However, if the number of learning repetitions is very high, overlearning may occur and the accuracy of the generated images may decrease. In this study, we adopted the parameters for the generator and discriminator from our previous work  and geneIn reference to the synthetic images derived using 500 epochs, 37.5% of the images were misinterpreted as being original or were indistinguishable from the original images and, interestingly, 14.0% of the original images were indistinguishable from the synthesized images. This finding demonstrates that the quality of the realistic and phenotypically diverse synthetic images was such that they perplexed the readers so that they could not confidently assert which images were original.As research on generated synthetic images using GANs progresses, we may generate realistic data that can be applied to training materials for radiologists and deep learning networks that resolve problems such as the requirement for patient agreement when publishing images and the time and effort required to collect images . The ratThis study has several limitations. First, the retrospective study was conducted at a single institution using three ultrasound systems from two companies. Therefore, extensive, multicenter studies are warranted to validate our findings. Second, not all recurrent lesions were diagnosed using cytological or histological diagnoses. Third, we performed this study using images that were converted to 256 × 256 pixel JPEG images. This image processing step might result in loss of information and influence the performance of the generating models. Fourth, the synthetic images were generated using data from a mixture of benign and malignant masses. It may be possible to improve the reliability of the synthetic images by collecting data from more cases, generating classified ultrasound images representing different pathological cases, and comparing original date and patient information. Fifth, the readers subjectively evaluated the generated images and original images; therefore, bias of the evaluation could not be completely removed. Finally, we examined only ultrasound images of breast masses; we have not fully verified whether images of normal breast tissues and non-mass-containing breast lesions can be applied.DCGANs can generate high-quality and realistic breast ultrasound images that are indistinguishable from original images.


In the system related to health care, shifting duties are considered essential and obligatory to make sure the stability of care in hospitals. Scheduling and shifting are the key uniqueness of shift work and nurses are mostly bounded into different schedules that facilitate 24-hour care. Our objective was to identify the impact of morning and rotational duties on physical health of nurses working in tertiary care hospitals.A total of 154 nurses from two tertiary care hospitals in Karachi were included in this study. Data were collected through the Short Form Health Servay-26 between May to June 2017. Questionnaire form consisted of five domains including Physical functioning, Role limitations due to physical health, Energy/Fatigue, Pain and General health.Most of the study participants were staff nurses (66.9%) and few were head nurse and assistant head nurses 13.6% and 8.4% respectively. Nurses’ characteristics such as gender, age, educational level, designation and monthly income were found significant with duty shift with p-values 0.049, 0.007, <0.001 and 0.017 respectively. Energy/Fatigue was only domain of SF-26 which showed significant mean difference  between morning and rotational duties.This research concludes that nurses working in rotational duties were more prone to develop physical problem as compared to morning duties. Energy/Fatigue showed significant mean difference. Currently, approximately every fifth of the global workforce is occupied in shift work, 20% of European and American workers are busy at night shifts.3During Shift duties and night shift duties, in particular are the most common reasons for the disturbance of circadian rhythms, causing significant alteration in biological functions and sleep pattern, which can cause a disturbance in physical and psychological functions and also affect negatively on work performance.6Many studies have showed that sleep pattern among nurses of night shift were considerably of poorer quality than that of fixed/morning duties and morning and evening-rotating workers.9Many researches have provided evidence that fatigue is associated with night shifts duties, can add the risk of human errors, injuries and can affect negatively on patient care.14The results of several studies have revealed that shift workers, compared with fixed day workers with a regular routine are more prone to experience from poor sleep.17Nurses have a very important part in provision of quality care to patients. There are limited studies which have explored the importance of nurses’ concerns in Pakistan. The primary focus of this study was to find out the physical problems faced by nurses due to shift duties and its associated factors. More importantly, this is perhaps the first-ever study in Pakistani context on the nurses’ physical health and duty shift. The aim of this study was to identify the impact of morning and rotational duties on physical health of nurses working in tertiary care hospital.A total of 154 nurses from Civil and Dow University Hospitals, Karachi participated in this study. Study participants were included after taking written informed consent and approval was taken from the Institutional Review Board (IRB) - DUHS to conduct this study. Data were collected between May to June 2017 through the Short Form Health Survey-26, which is brief 26-item questionnaire designed to detect the physical health of nurses. The questionnaire form consists of five domains including Physical functioning, Role limitations due to physical health, Energy/fatigue, Pain and General health with 10, 04, 04, 02 & 05 numbers of questions respectively. Each domain of SF-26 consists of different response categories and value. Physical functioning includes values 0, 50 &100 , Role limitation due to physical health 0 &100 , Energy/Fatigue 100, 80, 60, 40, 20&0, and 0, 20, 40, 60, 80&100 . Whereas, Pain includes value 100, 80, 60, 40, 20 &0 and 100, 75, 50, 25 & 0  and General health 100, 75, 50, 25 & 0 and 0, 25, 50, 75, 100 . All data were analyzed through SPSS version 21.0. Categorical variables were reported through frequencies and percentages whereas means and standard deviations were calculated for quantitative variables. Two sample independent t-tests were performed for identifying significant mean difference for each domain of SF-26 between morning and rotational duties nurses. The chi-square test of independence was also used to explore the association of nurses’ characteristics with morning and rotational duties.The distribution of nurses’ characteristics with respect to duty shift are shown in For each domain physical functioning, role limitation due to physical health, energy/fatigue, pain, and general health there were 10, 4, 4, 2, 4 items respectively. The mean (SD) of each domain of SF-26 scale with 95% CI is described in The difference of mean scores between morning and rotation duties for each domain of SF-26 scale is shown in This research confirms the impact of rational duties on physical health. All five domains of SF-26 were reliable internally. Domains’ mean scores were compared with morning and rotation duties. Mean scores of general health for morning and rotational duties were found to be closest among all other domains whereas, pain score showed the largest mean difference. In this study fatigue/energy was significantly associated  with duty shift which was supported by the studies conducted in Italy and Brazil in 2016.20Present study has also highlighted that other domains, including physical functioning, role limitation due to physical health, pain and general health did not show significant association with morning and rotational duties. These findings were not supported by the study conducted in Egypt,In this study majority of the participants were younger than 35 years and study participants’ age found to significantly associated with duty shift variable . These findings were supported by the studies conducted in Italy18As this is a cross-sectional study, it is hard to establish causality between morning and rotational duties with the physical health of nurses. Further longitudinal studies would be conducted to confirm the present conclusions. Furthermore, the sample was taken from nurses working in two public hospitals in Karachi, Pakistan; Findings can be tested in private setup, to find out the comparison in public and private setup.Nurses working in rotational duties were more prone to develop physical problem as compared to morning duties. Energy/Fatigue showed significant mean difference. Moreover, nurses’ characteristics such as age, education level, designation and monthly income showed significant association with duty shift.AA: Conceived Idea, Designed Research Methodology, Manuscript Writing and approval of final version of manuscript.AR: Statistical Analysis, interpreted data.SN: Data Collection and compilation, Literature Review, Manuscript drafting.


Small molecule inhibitors of adipocyte fatty-acid binding protein 4 (FABP4) have received interest following the recent publication of their pharmacologically beneficial effects. Recently, it was revealed that FABP4 is an attractive molecular target for the treatment of type 2 diabetes, other metabolic diseases, and some type of cancers. In past years, hundreds of effective FABP4 inhibitors have been synthesized and discovered, but, unfortunately, none have reached the clinical research phase. The field of computer-aided drug design seems to be promising and useful for the identification of FABP4 inhibitors; hence, different structure- and ligand-based computational approaches have been used for their identification. In this paper, we searched for new potentially active FABP4 ligands in the Marine Natural Products (MNP) database. We retrieved 14,492 compounds from this database and filtered through them with a statistical and computational filter. Seven compounds were suggested by our methodology to possess a potential inhibitory activity upon FABP4 in the range of 97–331 nM. ADMET property prediction was performed to validate the hypothesis of the interaction with the intended target and to assess the drug-likeness of these derivatives. From these analyses, three molecules that are excellent candidates for becoming new drugs were found. Fatty acids (FAs) are a class of carboxylic acids that have many functions of vital importance in humans . It was The adipocyte FABP  is a highly expressed FABP in adipocytes. Its levels are regulated by peroxisome-proliferator-activated receptor-c agonists, as well as by the levels of insulin and free FAs . StudiesThe family of FABP proteins also has a significant role in cancer cells and cancer progression . Up to nRecently, a variety of effective FABP4 inhibitors have been developed , but, unComputer-aided drug design shows a promising and useful tool for the identification of novel molecules able to bind FAPB4. Notably, different structure-based computational approaches  have already been performed in this context with different libraries of compounds, leading to important results ,19.50 values between 3.70 and 5.59 M.In line with our recent interest in the development of QSAR models and related applications ,25,26,27Given the excellent result in identifying novel structures and in assisting in the design of novel FABP4 binders with this 3D-QSAR model, in this work, we decided to combine the ligand-based approach with a structure-based one (docking) to screen a large dataset of marine products for the identification of novel hit-compounds among the marine word. This purpose was pursued using a statistical and computational approach, as already successfully reported, for the identification of sigma-2 receptor ligands  and hemeThe first filter used for the identification of FABP4 ligands was a statistical (based on 2D and 3D descriptors) one, as already used successfully by us . We sele50 activity between 6.0 and 7.6. The 3D molecular structures of the 2922 marine compounds were then passed to the structure-based approach, adapting the docking procedure already reported for the identification of FABP4 inhibitors [These skimmed molecules were then subjected to a second filtration using a mixed ligand- and structure-based approach. Firstly, the 3D molecular structures of the 2922 marine compounds were aligned to our previous published 3D-QSAR model for the FABP4 protein, and the compounds were then evaluated, as previously reported, employing Forge software  . Over thhibitors ,35. The hibitors  was usedAll of the generated binding poses were manually inspected in order to ensure correct positioning within the binding pocket with respect to the interactions of ligand moieties with the amino acid residues relevant for the catalytic activity. The residues Phe19, Met20, Ala33, Pro38, Lys58, Phe57, Ala75, Glu72, Arg106, and Arg126 play an important role in the interactions of FABP4 with inhibitors ,38. Initπ-π stack interactions with the residue Pro38, and hydrophobic interactions with the residues Phe16, Ala 33, Ala36, Phe57, Ile62, and Ala75 with aromatic regions of the ligand. Compound 13575 establishes hydrogen bonds with the residues Tyr19 and Ala75, and the hydrophobic region of the molecule establishes hydrophobic interactions with the residues Phe16, Ala33, Pro38, Phe57, and Ile 62  2% and 5% of the molecules obtained from each of the two approaches were retrieved, and those simultaneously present in both filters were selected  and the structure-based calculation  were then merged with the aim to create a final filter. For this purpose, the best  [Among the seven filtered best potential inhibitors, molecule 5339  has been reported as an inhibitor of the Ca (SERCA) . Compoun (SERCA) . Compoun (SERCA) . Compoun (SERCA) . Compoun (SERCA) . Compoun (SERCA) . Compoun (SERCA) . Interes (SERCA) , and dua (SERCA) .http://swissadme.ch) and pkCSM (http://biosig.unimelb.edu.au/pkcsm/) web platforms. Importantly, the technologies implemented in these platforms are able to predict, with a fair degree of certainty, the false-positive results commonly observed in biochemical assays of small molecules [As the interaction of an inhibitor with an enzyme cannot guarantee its suitability as a drug, to further strengthen the results of 3D-QSAR and docking studies, we also performed in silico ADMET studies on the seven molecules reported in olecules .The oral availability of our proposed bioactive compounds is shown in the bioavailability radar plots , which pIn addition to the Lipinski rule of five , anotherFinally, the outcome of the pan assay interference structures (PAINS) model , conceivHuman gastrointestinal absorption (HIA) and blood–brain barrier penetration (BBB), relative to the absorption and distribution parameters, respectively, have been graphically represented by the extended and renewed version of the Edan–Egg model, named the Brain or IntestinaL EstimateD (BOILED) permeation predictive model (BOILED-Egg). The visual analysis of Kp < −2.5, Regarding the absorption parameters, compounds 5339, 14123, 13575, and 2076 present a promising oral availability, due to the optimal Caco-2 cell permeability and HIA  and unbound fraction are two of the most important pharmacokinetic drug parameters. Values of the VDss > 0.45 indicate that the drug will be distributed in tissue, whereas values < −0.15 indicate that the drug will be distributed in plasma. So, VDss describes the extent of drug distribution, and the unbound fraction describes the portion of free drug in plasma that may extravasate. Except for compounds 3164, the other ones showed intermediate values of VDss, and should have an adequate plasma distribution profile, with a fraction of the unbound drug between 0 and 0.157. These values indicate that the molecules can be well distributed and present a significant unbound fraction in the plasma, thus becoming available to interact with the pharmacological target. Only compound 3164 is entirely unable to penetrate the central nervous system (CNS).The volume of distribution . The full list of the 2922 molecules that passed the first statistical filter, including the MNP ID, SMILES, ligand-, and structural-based evaluation results, are available in the The chemical structures of the marine dataset were retrieved from Marine Natural Products  . A firstThe alignment and evaluation of the 2922 selected marine products were performed as follows. Firstly, the 3D structures of the molecules were imported into the software Forge . The molecules were then aligned by a maximum common substructure algorithm using a customized and validated set-up ,22,24, ihttp://www.rcsb.org/pdb), and the Lamarckian genetic algorithm (LGA). The maps were generated by the program AutoGrid (4.2.6) with a spacing of 0.375 Å and dimensions that encompass all atoms extending 5 Å from the surface of the structure of the crystallized ligands. All parameters were inserted at their default settings as previously reported [Flexible ligand docking experiments were performed by employing AutoDock 4.2.6 software implemented in YASARA  ,64, usinreported . In the 42− buffer molecules and ions were removed. Linear regression analysis was used to validate the correspondence between the experimental pKi values and the calculated ones from docking scores, utilizing a benchmark data set of 34 known FABP4 inhibitors possessing pKi values in the range of 1–5000 nM, to be reliable, chosen from those reported in the reference [All crystallographic water and SOeference   in