The relationship between the abrasion loss and the friction coefficient of the composites with different graphene contents was obtained. A thermogravimetric analyzer was used to investigate the crystallization and pyrolysis behavior of the composites; correspondingly, the temperature range that composites work in was determined. The heat conduction mechanism was analyzed through the thermal conductivity model of composite materials. The composite material is expected to play an important role in the development of high-performance thermal equipment.Perfluoroalkoxy (PFA) material exhibits perfect corrosion resistance under both acid or alkaline circumstances; thus, steel heat exchangers are being substituted by those made of PFA in high corrosion atmospheres. However, the low thermal conductivity of PFA degrades its heat transfer efficiency. Based on the extremely high heat conductivity of graphene, a novel grapheme-PFA composite was proposed to simultaneously meet the demands of heat transfer and corrosion resistance. Ultrasonic dispersion technology was used to disperse the aggregated graphene in the composite. Graphene–PFA composites with different graphene contents and using different dispersing solvents were prepared with a hot pressing method, and thermal conductivity, abrasion resistance, crystallization and pyrolysis properties were investigated. The thermal conductivity of PFA composites with graphene content of 20 wt % reached 5.017 W (m·k) Heat transfer materials can transfer the heat efficiently from hot fluid to cold fluid, improving the energy conversion efficiency and the cascade of energy utilization in the fields of electric heating, aerospace, chemical engineering, material science, and energy power. Metallic heat exchangers have been widely utilized in many industrial processes; however, when used in corrosive situations, their short campaign life has been a serious defect. Moreover, a heat dissipation component, characterized by high thermal conductivity, resistance to acid and alkali corrosion and anti-aging properties with a lightweight and flexible structure is widely required. Fluoropolymer is characterized by a high degree of crystallinity and high molecular weight and possesses excellent physical properties, especially for its corrosive resistance, whereas its low heat diffusion capacity hampers its application as a heat exchanging material ,2,3,4. GMeng et al.  preparedIn this study, grapheme-PFA composite was prepared, and the properties of thermal conductivity and abrasion resistance were investigated emphatically. Considering the strong aggregation tendency of graphene caused by strong van der Waals forces and π–π stacking between graphene layers , the ultThe PFA powder, supplied by Tenghai Engineering Plastics , was modified PFA, with a density was 2.16 and an average particle size of 21.816 μm. The infrared spectrum of PFA is shown in 3, respectively. The Raman spectrum is shown in The graphene nanosheet (GT-G03) was supplied by Kaina Graphene . The graphene layers were only 1 to 3 (manufacturer’s test report), and the water content was 1.08%. The average diameter , and bulk density of the nanosheet were 8.96 μm and 0.04 g/cmThe alcohol with 99.97% purity was supplied by the Sinopharm Group . The density was 0.79 g/mL.Graphene sheets are easily aggregated due to the extremely strong van der Waals forces and π–π stacking and formed multi-layered graphene platelets c. It hasUltrasonic treatment technology is often utilized to improve the dispersion effect of micro-particles in dispersions. In this study, the optical density of the dispersion liquid was used to evaluate the dispersion effect. The optical density of the dispersions was detected by spectrophotometer (TAS-990) immediately after the ultrasonic treatment was accomplished. Firstly, the dispersion effects of graphene in alcohol after ultrasonic treatment with different amounts of power and treating times were compared to obtain the optimal operation parameters. After that, the effects of the surface tension of dispersions were investigated. Dispersions with specific surface tensions were prepared through mixing alcohol and water at certain ratios. The surface tension of the dispersions was measured by the pendant drop method; the measurement results are listed in In order to minimize the effect of water on the experimental results, graphene and PFA were dried to remove moisture before the experiments. The preparation of graphene-PFA composites is shown in The fracture surface morphology of the graphene-PFA composite material was observed with a scanning electron microscope (SEM)  to determine the distribution of the graphene in the PFA. The morphology and layers of graphene were observed by transmission electron microscopy (TEM) .The friction and wear properties of the composites were tested through a reciprocating friction and wear testing machine; the schematic diagram is shown in The thermal stability of the graphene–PFA composites was investigated by thermogravimetry and differential scanning calorimetry (DSC) . A sample of approximately 15 mg was loaded into a crucible and then heated from 50 to 800 °C at a rate of 10 °C/min in an argon atmosphere and then immediately cooled from 800 to 50 °C at the same rate.The thermal conductivity of the composites was detected by the Hot Disk method  to ascertain the effects of the different dispersions and different graphene dosages on the thermal conductivity of the composites.Avoiding the agglomeration of graphene in PFA is a critical step for obtaining a good performance composite. The optical density of dispersions was detected to indicate the dispersion effect of graphene—the higher the optical density was, the better the graphene dispersed. 2, far smaller than that of the pure water, which was 73.1 mJ/m2. Therefore, alcohol exhibited a better wettability than water. 2 and the average value of three runs was 0.35. A higher or lower surface tension broke the equilibrium of forces between the micro-particles and liquid molecules, causing the agglomeration of graphene; thus, the optical density decreased.The properties of dispersions, especially the surface tension and wettability to graphene, are important factors for dispersion and for avoiding the re-agglomeration of graphene after complete dispersion. The surface tension of pure alcohol was only 21.6 mJ/m2 weres used in the subsequent experiments , and the graphene dispersion was sonicated for 120 min using a power of 300 W.Consequently, the dispersions with a surface tension of 29.6 mJ/mHm) of the composites tended to increase. In order to study the influence of the graphene content on the crystallinity of the PFA matrix, DSC was used to analyze the melting behaviors of the composites. Tm) of the five samples were similar and ranged from 299 to 301 °C. Clearly, compared to pure PFA, the melting enthalpy decreased slightly when 1% graphene was added, while improving the graphene contents further from 1% to 15% increased the melting enthalpy gradually. The crystallinity (Xc) of the composites was calculated using the formula, Xc = Hm/(WPFA × Hm*), where ΔHm* is the melting enthalpy of 100% crystalline PFA and WPFA is the mass fraction of the PFA [The melting temperatures ( the PFA . The cryThe thermogravimetric (TG) curves of pure PFA, graphene and five composites are shown in Besides improving the mechanical properties, another important role of nanocarbon material addition is to promote the electro-thermal properties. According to the evolution of thermal conductivity of the composites with graphene contents shown in 2. The ultrasonic power and processing time were 300 W and 120 min, respectively. The graphene dispersion in the PFA is the most critical factor affecting the thermal conductivity of a composite. Ultrasonic treatment and proper surface tension of dispersion can promote the effective dispersion of graphene. The optimum dispersions of the graphene were composed of 45% alcohol and 55% water, with a surface tension of 29.6 mJ/mThe melting temperatures of all prepared composites stabilized in the range of 299–300 °C, and there were never decomposition or phase transition occurrences below 300 °C. Thus, a high thermal stability was exhibited. The graphene was able to provide heterogeneous nucleation and crystallization sites for the PFA, but a large amount of fine graphene limited the diffusion and migration of the PFA segments, leading to a decrease in crystallinity. The friction coefficient of the composites increased with the addition of graphene. The transfer films and attached films of the self-lubricating graphene reduced the wear volume of the composites, improving the abrasion resistance. When the graphene content was higher than 10 wt %, the wear volume increased slightly due to the appearance of weak regions and the reduction in the crystallinity degree caused by excessive graphene. The thermal conductivity of the composite improved effectively by increasing the graphene content in PFA. The maximal thermal conductivity of PFA composites reached 5.017 W/(m·K) when the graphene content was 20% by weight, meeting the demands of many industrial applications. The SEM images of the composite materials indicated that the scaly substance increased when the graphene content increased; the graphene distribution in the PFA matrix also improved. The dispersed graphenes formed a scale-like structure and provided a large number of thermal conduction paths; therefore, the thermal conductivity was enhanced. Through hot pressing, the interlayer spacing and porosity decreased, favoring the reduction of the interfacial thermal resistance between graphene and PFA. Ultrasonic treatment improved the connectivity of graphenes, reducing the phonon scattering, resulting in good thermal conductivity of the composites.


N-acetylcysteine (NAC).Idiopathic pulmonary fibrosis (IPF) is a major public health problem worldwide. There is no curative treatment for IPF except lung transplantation. Chinese herbal medicines (CHMs) are widely used in the treatment of IPF in China. However, their effectiveness and safety are still obscure and deserve further investigation. The aim of the study was to assess the efficacy and safety of CHMs in treating IPF compared with This review summarizes and meta-analyzes randomized controlled trials (RCTs) of CHMs for the treatment of IPF. RCTs compare either CHMs alone or in combination with NAC or conventional medicine treatment (CMT) vs NAC alone or in combination with CMT have been included. The following electronic databases have been searched: PubMed, Cochrane Library, Embase, CNKI, CBM, VIP, and WANFANG DATA. The methodologic quality of RCTs has been assessed using the Cochrane risk assessment tool. All trials included are analyzed according to the criteria of the Cochrane Handbook. Review Manager 5.3, R-3.5.1 software, and GRADE pro GDT web solution are used for data synthesis and analysis.2), and safety in patients with IPF.This review evaluates the effects of CHMs on acute exacerbation, mortality, the quality of life, 6-minute walking test distance, lung function , partial pressure of oxygen in blood (PaOThis review provides clear evidence to assess the effectiveness and safety of CHMs for IPF. Progression of IPF is characterized by increased respiratory symptoms such as dyspnea and cough, worsening lung function, and High Resolution CT with increased fibrosis or acute respiratory failure. The incidence of IPF increases with age. Typical symptoms usually appear in the 60 to 70 age group. More men have been reported with IPF than women, and most patients have a history of smoking. One study showed that the cumulative prevalence of IPF increased from 202 to 495 cases per 100,000 people aged 65 years and older from the years 2001 to 2011. Due to its rapid progress, poor prognosis, and high mortality, IPF has been called a refractory lung disease. The median survival time from respiratory symptoms to death is 2 to 3 years.–5 It has a very poor prognosis with a 5-year survival rate of 30% or below. The patient's survival rate is similar to that of a malignant tumor, which seriously threatens the health of human beings. Increasing rates of hospital admissions and deaths due to IPF also suggest an increasing burden of disease.–10Idiopathic pulmonary fibrosis (IPF) is defined as a special type of chronic, progressive, interstitial lung disease of unknown etiology. IPF occurs in the elderly and the lesion is confined to the lungs. Adults with chronic labor dyspnea due to unexplained causes, and the clinical manifestations of cough, lung bases  At present, glucocorticoids and immunosuppressive agents are widely used in clinical treatment, but their curative effect is not exact, what is worse, it is easy to form dependence with many side effects. The evidence-based guidelines of IPF have strongly rejected these therapies, so the prevention and treatment of IPF have become a problem in today's medical research. The 2015 edition of IPF's diagnostic and therapeutic guideline lists N-acetylcysteine (NAC) treatment as a weak and unrecommended level. Although the guideline suggests that IPF should not to be treated with NAC, NAC monotherapy can improve mental health and 6-minute walking distance. Therefore, patients who have started NAC monotherapy are not recommended to discontinue treatment.,13 Although Pirfenidone and Nintedanib administration have been shown to delay the decline in lung function, they are rarely used clinically in China because of their significant adverse events and long-term economic costs. Therefore, NAC is widely used in the treatment of IPF because of its low price, good tolerance, and easy oral administration. However, due to the lack of evidence-based medical research, its safety and effectiveness remain controversial.The pathogenesis of IPF is still unclear, and there is no definitive conclusion at home and abroad. In addition to lung transplantation, there is no specific treatment for IPF in Western medicine, and lung transplantation is also only available for a small number of patients who can tolerate surgery. As a result, there is currently no consensus on the optimal treatment of IPF. Unfortunately, there is no evidence to prove which drug is effective in treating the disease, and only a few studies suggest that certain drugs may be beneficial for IPF. Hundreds of different herbs have been used in numerous TCM formulations to treat IPF. These TCM formulations are derived from the wisdom of Chinese clinicians and the experience accumulated over thousands of years of using these herbs. In recent years, the experimental and clinical research on the treatment of IPF by TCM has gradually increased. Recent studies have shown that TCM treatment of IPF has become feasible and provide new ideas for solving the controversial problem of selecting effective drugs. It is important to highlight that more and more formulas, herbal compounds, and single herb extracts were proved to have an effect in preclinical experimental studies of IPF.–18 TCM is a potential therapy for IPF due to its advantages of syndrome differentiation and treatment, small adverse reactions, slow and long-lasting effects, overall regulation, and no obvious drug dependence. A widespread strategy underlying the TCM treatment of IPF is to effectively relieve clinical symptoms and improve the quality of life (QOL) and reduce mortality of the patients.–21 However, due to the small sample size, large difference of intervention measures, and the comparison of glucocorticoid not recommended in the guidelines, the evidence for the efficacy and safety evaluation of TCM treatment for IPF is insufficient.Today, traditional Chinese Medicine (TCM), as an adjuvant therapy to Western medicine, has its unique superiority and proper effect and is still used extensively for the treatment of IPF in China.The goals of this systematic review are to obtain evidence on the efficacy and safety of CHMs compared with NAC for IPF.2http://www.crd.york.ac.uk/PROSPERO), registration number: CRD 42018105348. The procedure of this protocol is based on PRISMA-P guidance.This study has been registered in PROSPERO  and 4 Chinese medical databases . The databases are extensively searched from their inceptions up to June 4, 2018. The search strategy is based on the guidance of the Cochrane Handbook. Terms searched include:  AND  AND (random∗). To guarantee comprehensive search, all relevant publications are researched, including academic dissertation and conference articles. The language is limited to Chinese and English.2.22.2.1Only randomized controlled trials (RCTs) are included.2.2.2 In addition, we also refer to the consensus of Chinese experts on IPF diagnosis and treatment formulate by the interstitial pulmonary disease group of the Chinese academy of respiratory medicine in 2016.Male or female patients of any age or ethnic origin who have been diagnosed with IPF have been included. Diagnostic criteria refer to the 2011 international evidence-based guidelines for IPF diagnosis and treatment jointly published by ATS/ERS/JRS/ALAT.2.2.3The experimental group is treated with Chinese herbal medicines , the control group is treated with NAC, and both groups are treated orally with a treatment period of not <12 weeks. CHMs include Chinese medicine decoction, Chinese medicine preparation , Chinese medicine single prescription, Chinese medicine compound prescription, and Chinese patent medicine. Both groups can receive the same routine western medicine treatment. Basic medical treatment of Western medicine includes oxygen therapy, infection control, and nutritional support.2.2.4Primary outcomes: The rate of acute exacerbation and mortality after treatment and the health-related QOL have been analyzed as the primary outcome. The health-related QOL has been assessed using St George's respiratory questionnaire scores.2), and adverse events. The time endpoint of the above outcomes is no earlier than 12 weeks after starting the medication.Secondary outcomes: The secondary outcome assessments consist of pulmonary function test—especially forced vital capacity (FVC), total lung capacity (TLC), the diffusing capacity of the lungs for carbon monoxide (DLCO), 6-minute walk test (6MWT) distance, partial pressure of oxygen in blood ; excluding the duplicate literature using NoteExpress3.2 and excluding the unrelated articles by reading the title and abstract; and reading the full text and reserving clinical studies that meet the inclusion criteria. Two researchers (GJ and LWY) extract the data independently using a self-developed data extraction form. The differences encountered in the process have been resolved by discussing with another team member (LB), to determine, by agreement, the final selection of studies.Referring to the Cochrane collaborative network system evaluator handbookData extraction contents include: general information: research ID, author, title, publication status, report sources, and fund support; methodology information: design, number of arms, random sequence generation, allocation concealment, blinding, incomplete outcome data, selective reporting, sample size calculation, and baseline comparability; participant information: diagnostic criteria, inclusion criteria, exclusion criteria, setting, population, sample size, age, gender, and course of disease; intervention information: name of intervention and comparation, syndrome differentiation of TCM, types of CHMs, dosage form, comparison, duration of treatment, and patient follow-up; outcomes; and adverse events.http://www.prisma-statement.org/)  Fig. .2.5 Risk of bias has been assessed as follows: adequacy of generation of the allocation sequence, allocation concealment, double blinding, incomplete outcome date, selective outcome reporting, follow-up, and other bias. These domains classify “Yes” if adequate, “No” if not adequate, and “Unclear” if not well described by the authors in such a way that its adequacy is describable.The Cochrane risk assessment tool has been used.The 2 researchers (GJ and LWY) independently assessed the risk of bias for each included study. “L,” “H,” and “U” have been used as a code for the evaluations of the above bias risks. “L” indicates a low risk of bias, “H” indicates a high risk of bias, and “U” indicates the risk of bias is unclear. Disagreements resolved by discussion between all the researchers. When necessary, the study authors have been contacted to inquire some missing information. Trials of high risk of bias will be considered when conducting sensitive analysis.2.6 Quantitative synthesis has been done when clinical heterogeneity is not considered by at least 2 authors in discussion. Continuous variable has been described by mean difference (MD), P–value, and 95% confidence interval (CI). For dichotomous outcomes, the relative risk (RR) has been used, with 95% CI and P-values, to evaluate the efficacy and safety of CHMs. I2 test has been used to judge the heterogeneity of meta-analysis. I2 value >50% or more will be considered as an indication of substantial heterogeneity. If heterogeneity exists in the pooled studies, the data have been analyzed using a random effects model. Otherwise, a fixed effect model has been adopted. If there is significant clinical heterogeneity, the cause of heterogeneity should be explored, and sensitivity analysis or subgroup analysis should be performed when necessary. Sensitivity analysis has been used to ensure the robustness of results by eliminating low-quality trials. Subgroup analysis will be performed according to the characteristics of the study subjects, such as different interventions, treatment duration, and outcome measures. If the data extraction is insufficient, qualitative analysis will be adopted.Review Manager Software  has been used to analyze and synthesize the outcomes. Clinical heterogeneity is the primary source of heterogeneity in the systematic reviews of TCM. Clinical heterogeneity can be derived from the potential factors such as the ingredients and formulations of CHMs.2.7The publication bias has been analyzed using funnel plot when the number of studies included in a meta-analysis is no <10. If the number of included studies is <10, the Egger test will be applied. The analysis software is R 3.5.1 for Windows.2.8This study evaluates the evidence according to GRADE standard, which refers grading of recommendations assessment, development and evaluation. These factors that may reduce the quality of evidence should be considered, such as limitations in study design, inconsistency of results, indirectness of evidence, inaccuracies, and publication bias. In addition, large magnitude effect, possible confounders that can reduce the effect and dose-response gradient that increase the quality of evidence cannot be ignored. GRADE Pro GDT online software will be used to form the summary of findings table (SoF table).3 These problems are caused by the complexity of the TCM treatment and the difficulty to clarify the heterogeneity of the scheme, resulting in the low reliability of evaluation. It is well known that CHMs in China are based on thousands of years of clinical observation and practice by Chinese doctors. In general, many herbs are used in combination to treat diseases. Each herb in Chinese medicine preparations may have several different active ingredients. The content and bioactivity of these ingredients can be affected according to the cultivation region, soil, climate and sunshine, as well as the season of cultivation and harvesting and the method of preparation. Therefore, clinical trials must provide detailed information about the CHMs used. Different from modern clinical research, it is difficult to compare the results of TCM research. Properly speaking, in the same Chinese medicine prescriptions, batch, medicinal processing, dosage, dosage form of the herbs, route of administration, and duration of therapy are all factors that lead to different characteristics of the CHMs, and more importantly, these factors will affect the treatment effect of the disease. Therefore, we believe that the combination of CHMs and modern medical technologies and therapies is the premise and foundation for understanding the potential effectiveness of CHMs in IPF treatment.The CHMs have been used for thousands of years in China, and now it is widely used in the world. Currently, several types of CHM extracts are reported to be effective in animal models of IPF. The purpose of this study is to summarize and analyze the efficacy and safety of clinical trials using CHMs to treat IPF. Although there are many trials on the treatment of diseases by CHMs in China, the overall quality is not high. Comparing with the systematic review of modern medicine, there are few studies on high-quality systematic review of CHMs and lack of reasonable evaluation system leads to insufficient reliable evidence for clinical use of CHMs. However, the pharmacologic mechanism of TCM treatment of IPF and more large-scale studies and randomized, placebo-controlled studies are needed. Furthermore, the morbidity, survival time and mortality of patients with IPF require further attention and research. It is important to highlight that this review wants to determine whether CHMs, comparing with NAC, can improve acute exacerbation, mortality, the QOL, 6MWT, lung function , PaO2 and adverse events in patients with IPF. Previous clinical studies have paid little attention to the acute exacerbation and mortality of patients with IPF. Only 1 relevant systematic review mentions the impact of CHMs on acute exacerbation and mortality in patients with IPF and concludes that CHMs can reduce the acute exacerbation rate but have no effect on mortality. However, due to the problems of small sample size, poor methodologic quality, and large variability of CHMs, the evidence for the result is weak. To avoid these limitations as much as possible, the clinical trials of TCM included this review will be conducted strictly and carefully and recommended to follow the CONSORT—CHM Formulas 2017. Besides, we also achieve important implications from this review for future high-quality clinical trials to get explicit evidence. We hope this review will stimulate proper evaluation of CHMs.The mechanism of TCM treatment of IPF is not completely clear. One possible explanation is that the mechanism of TCM prevention and treatment of IPF mainly regulates cytokines and signal transduction pathways, inhibits extracellular matrix synthesis, and regulates oxidative stress and coagulation-fibrinolysis systems. This hypothesis has been supported by a number of recent clinical trials, which have demonstrated that CHMs for activating blood circulation and removing blood stasis, tonifying qi and nourishing Yin, clearing heat and reducing phlegm and tongluo are effective in improving pulmonary fibrosis.3.1This review does not require ethical approval because the included studies are published data and do not involve the patients’ privacy. The results of this review will be reported in accordance with the PRISMA extension statement and disseminated to a peer-reviewed journal.This study is initiated by Fei Wang and Jing Guo. Fei Wang and Jing Guo were involved in the design of the study and the interventions of the protocol. Jing Guo, Bin Li, and Wenyuan Li will develop the search strategies, conduct data collection, and analyze independently. Yi Pan, Zhichao Wang, and Yuxiao Wu will revise it.All authors have approved the final manuscript.Conceptualization: Fei Wang.Methodology: Jing Guo, Bin Li, Wenyuan Li, Yuxiao Wu.Software: Zhichao Wang.Supervision: Fei Wang.Writing – original draft: Jing Guo, Bin Li.Writing – review & editing: Jing Guo, Bin Li, Wenyuan Li, Yi Pan.


Background: In recent years, great improvement has been made in immunotherapies for non-small cell lung cancer (NSCLC). Current data have suggested that Programmed cell death ligand 1 (PD-L1) expression might not be an ideal marker for patient selection in isolation. Evidence has been increasing that alternative markers, such as neutrophil-to-lymphocyte ratio (NLR), a biomarker of systemic inflammation response (SIR) previously associated with outcomes in a variety of cancers including NSCLC, might be a predictor for patient selection and the response to therapy. No reports have examined the prognostic value of combination of PD-L1 expression and inflammatory markers such as NLR in NSCLC. This retrospective study explores the relationship between NLR and PD-L1 expression in NSCLC as well as the prognostic value of combination of PD-L1 expression and NLR.Method: We evaluated tumor PD-L1 expression in 235 surgically resected NSCLC cases by immunohistochemical analysis. Carcinoma cells showing membranous staining for PD-L1 were considered PD-L1-positive cells . Cases with ≥1% tumor membrane staining were considered PD-L1-positive. The association of clinicopathological characteristics with PD-L1 expression was assessed by univariate and multivariate analyses. Moreover, univariate and multivariate analyses were performed to evaluate the predictive impact of PD-L1 expression and other factors on disease-free survival (DFS) and overall survival (OS).Result: PD-L1 protein expression was elevated in 34.0% of patients at cut-off value of 1%. Univariate analyses showed that PD-L1 expression was significantly higher in men , heavy smokers , and patients with squamous cell carcinoma . No correlations were noted between PD-L1 expression and age, EGFR mutation status or clinical stage. No significant correlations between PD-L1 protein expression and NLR were found. Multivariate logistic regression revealed that smoking index ≥400 was independent predictor of PD-L1 expression . The results of univariate survival analyses showed that clinical stage  was associated with DFS. Smoking index , clinical stage  and adjuvant treatment  were significantly associated with OS. Neither PD-L1 expression nor NLR was found to be associated with DFS or OS. Of interest, when patients were divided in two groups according to combined PD-L1/NLR: patients with PD-L1+/ high NLR as Group 1, other patients as Group 2, Group 1 had significantly shorter DFS as well as OS than Group 2 . In the multivariate analysis, Cox proportional hazards regression models showed that, PD-L1+/ high NLR was associated with a significantly shorter DFS and OS . Stratified analysis showed that the prognostic value of combined PD-L1/NLR can only be observed in cases without epidermal growth factor receptor (EGFR) mutations . In EGFR mutation subgroup, combination of PD-L1 expression and NLR has no relationship with DFS or OS.Conclusion: We found that combination of PD-L1 expression and NLR may be a promising prognostic indicator, and may also be a good marker for tumor recurrence, especially in the patients with wild-type EGFR. Lung cancer is currently the top cause of cancer deaths worldwide Accordingly, the identification of biomarkers that predict the clinical efficacy of immune checkpoint blockade therapy is urgent. Furthermore, effective combined therapies with immunotherapy are required for improved clinical benefit. Current data have indicated that the correlation between PD-L1 expression by immunohistochemistry and the response to immune checkpoint inhibition varies by both tumors histologic features, suggesting that PD-L1 might not be an ideal marker for patient selection in isolation Patients who underwent surgery for primary adenocarcinoma (AD) and squamous cell carcinoma (SCC) between 2012 and 2015 were identified from a retrospective review of a prospectively maintained database at Tianjin Cancer Institute & Hospital, Tianjin Medical University, Tianjin P.R. China. We excluded patients: (1) who were lost to follow up, (2) without R0 resections, (3) with distant metastases, (4) had insufficient laboratory data, (5) had clinical evidence of infection or other inflammatory conditions, (6) had received preoperative chemotherapy or irradiation, (7) whose matched paraffin embedded formalin-fixed (FFPE) tissue specimens were unavailable. Finally, 235 patients entered our study. Information about demographics, data regarding surgical procedures, preoperative blood variables, postoperative course, pathologic findings, and follow-up was collected. The NLR was defined as the absolute neutrophil count divided by the absolute lymphocyte count. DFS and OS were stratified by median of NLR (2.3), which was also consisting with previous studies All Patients were observed until death or July 1, 2017. The median follow-up period was 35 months. Disease-free survival (DFS) was defined as the time from resection to the first disease recurrence and was censored at the last follow-up date if no events had occurred. Overall survival (OS) was calculated from the date of surgery to the date of death or last follow-up. Prior consent from all patients and approval from the Research Ethics Committee of Tianjin University were obtained for the use of clinical and pathological data.2O). Antigen retrieval was performed with EDTA buffer per the manufacture's, then sections were incubated in 3% hydrogen peroxide (H2O2) for 10min in order to inhibit endogenous peroxidase activity. The sections were incubated overnight at 4℃ with the monoclonal antibodies at 4°C overnight. To visualize the antigen, the immune complex was detected with a DAKO EnVision Detection System (Dako). Finally, sections were then counterstained with hematoxylin, and mounted. The primary antibody was an anti-human PD-L1 rabbit monoclonal antibody ). Carcinoma cells showing membranous staining for PD-L1 were considered PD-L1-positive cells. The proportion of PD-L1-positive cells was independently estimated as the percentage of total carcinoma cells in whole sections by two investigators (X.W. and L.C.). Cases with ≥1% tumor membrane staining were considered PD-L1-positive.Tumor PD-L1 expression was evaluated by immunohistochemistry on formalin-fixed and paraffin embedded tumor tissue sections according to the previously described PD-L1 immunohistochemistry protocol 2 test or Fisher's exact test when necessary. The logistic regression model was used to estimate influence of preoperative factors on PD-L1 expression. Survival probability was estimated by the Kaplan-Meier method, and log-rank test was used for the comparison of survival. Multivariate analyses were performed using the Cox proportional hazards regression model to evaluate significant recurrence predictors and prognostic factors. All tests were 2-sided. Statistical analyses were performed in SPSS 17.0 for Windows software (SPSS Inc). P values of <0.05 were considered to indicate statistical significance.Categorical variables are presented as numbers and percentages. Distribution of continuous variables is reported as median and range. Qualitative data were compared by the χThe clinicopathological characteristics of the 235 patients with NSCLC (130 with AD and 105 with SCC) are summarized in Table P < 0.001), was found to be independently associated with PD-L1 expression.Immunohistochemical staining for PD-L1 was detected at the membrane of tumor cells  was associated with DFS. Smoking index , clinical stage  and adjuvant treatment  were significantly associated with OS. Neither PD-L1 expression nor NLR was found to be associated with DFS or OS. Of interest, when patients were divided in two groups according to combined PD-L1/NLR: patients with PD-L1+/ high NLR as Group 1, other patients as Group 2, DFS and OS showed significant difference between groups. Group 1 had significantly shorter DFS as well as OS than Group 2  patients died. Univariate and multivariate analyses were performed to evaluate the predictive impact of PD-L1 expression and other clinicopathological factors on OS and DFS . Moreover, clinical stage, smoking index, adjuvant treatment, and combined PD-L1/NLR remained independent factors of OS  and a trend for worse DFS  in patients without adjuvant chemotherapies. In patients received adjuvant chemotherapies, PD-L1+/ high NLR was identified to be associated with worse DFS  but not OS .Subgroup analyses were performed for EGFR mutation status and adjuvant treatment Table . In EGFRIn the present study, PD-L1 protein expression was elevated in 34.0% of patients with NSCLC who underwent surgery (41.0% of lung SCC samples and 28.5% of lung AD samples). PD-L1-positive expression was more frequently observed in male, heavy smokers and patients with SCC. Multivariate analysis revealed that smoking index ≥400 was independent predictor of PD-L1 expression. No significant correlations between PD-L1 protein expression and NLR or EGFR mutation status had been found. Patients with pretreatment NLR > 2.3 and PD-L1 expression was associated with inferior DFS and OS. Moreover, we demonstrated that such poor prognosis was only observable in cases without EGFR mutations, and the prognostic effect for NLR/PD-L1 might be affected by adjuvant therapy and subsequent treatment.In previous reports, clinical factors, such as smoking history, were reported to be associated with the PD-L1 expression. Wu et al. reported that PD-L1 protein expression is higher in men than women, smokers than never smokers Previous researches have also shown that PD-L1 protein expression is associated with EGFR mutations. Takada et al. pointed out that PD-L1 positivity was significantly associated with wild-type EGFR Many studies have evaluated the prognostic impact of PD-L1 protein expression in NSCLC, including the present study. However, the results of these studies vary: some studies have shown that expression of PD-L1 was correlated with poor clinical outcomes in NSCLCThere are a number of well-established systemic inflammation-based prognostic scores for patients with NSCLC Mechanism of regulation of PD-L1 expression has not yet been sufficiently clarified. Previous reports often focused on oncogene-driven mechanisms The validation of PD-L1 expression and inflammatory markers may be significant because they offer the potential for a feasible test that can be used to help evaluate the patient's prognosis. However, the tumor-host immune and inflammatory response is a complex interaction, with the key processes underlying this response still unclear. Our study has several limitations. First, the current study included patients with only operable NSCLC, and these patients were not treated with PD-1 or PD-L1 axis therapies. Further studies in patients treated with PD-1 axis therapies should be performed to confirm the findings obtained in the current study. Second, the PD-L1 analysis for surgically resected NSCLC was conducted using a specific antibody against PD-L1 (E1L3N) and with one cut-off value. Immunohistochemical staining of PD-L1 had been performed using different PD-L1 antibody clones in the different studies and clinical trialsTaken together, our findings indicate that combination of PD-L1 expression and NLR may be a promising prognostic indicator, and may also be a good marker for tumor recurrence. However, to suggest potential intervention strategies aimed at cancer-associated inflammation so as to improve outcome of immune checkpoint blockade, further study of these mechanisms, including research from a molecular biological approach, and covering more advanced NSCLC cases, is required.


Bladder cancer (BC) is the second most common urologic malignancy and the ninth most common malignancy worldwide. Surgical resection is the mainstay of treatment for patients with early-stage disease, whereas therapeutic options are limited for patients with advanced-stage or residual BC. Programmed cell death ligand-1 (PD-L1) is an important target for immunotherapy. It is known that PD-L1 is overexpressed in BC; a clinical trial involving PD-L1 immune checkpoint inhibitors in advanced BC is ongoing. In the present study, we used Western blot and quantitative real-time PCR (qPCR) to define the expression level of PD-L1 after cisplatin treatment in BC-derived cell lines. The signal activation was also evaluated by Western blot in BC-derived cell lines. We found that chemotherapeutic drug cisplatin can induce PD-L1 but not PD-L2 expression in BC-derived cell lines. Furthermore, the expression level of PD-L1 was increased in a dose- and time-dependent manner after cisplatin treatment. The cisplatin-induced PD-L1 expression is mainly mediated by ERK1/2 but not Akt/mTOR signal pathway. Moreover, we found that cisplatin activates transcription factor activator protein-1 (AP-1) to regulate PD-L1 expression. The chemotherapy drug such as cisplatin may trigger resistance of BC through PD-L1 up-regulation. The present study suggests that PD-L1 antibody should be used concomitantly with chemotherapy in the setting of advanced and metastatic BC. Bladder cancer (BC) is a commonly diagnosed urological malignancy with a very high recurrence rate. The standard treatment for managing BC is a complete transurethral resection of the bladder tumor (TURBT). Intravesical chemotherapy including mitomycin C, epirubicin, and doxorubicin or Bacillus Calmette-Guérin (BCG) for non-muscle-invasive BC is generally used as adjuvant therapy after complete endoscopic resection . For musEvasion of the immune system is a hallmark of cancer. Cancer cells can express many immune inhibitory signaling proteins that cause immune cell dysfunction and apoptosis . One of Avelumab, an immune checkpoint inhibitor of the PD-L1/PD-1 axis, has shown anti-tumor activity in patients with platinum-refractory metastatic urothelial carcinoma . However2448; cat. no. 2971), p-Akt , p-ERK1/2 , p-p38 , p-JNK , p-c-jun , Akt (cat. no. 9272), p38 (cat. no. 9212), c-jun (cat. no. 9165), mTOR (cat. no. 2983), PD-L1 (cat. no. 13684) were purchased from Cell Signaling Technology . ERK1/2 (cat. no. sc-94), JNK (cat. no. sc-7345), and β-Actin (cat. no. sc-47778) were purchased from Santa Cruz Biotechnology . Cisplatin (cat. no. 232120), Akt inhibitor (cat. no. 124005), PD98059 (cat. no. 19-143), U0126 (cat. no. 19-147), SP600125 (cat. no. S5567), SB203580 (cat. no. S8307) and Tanshinone IIA (cat. no. T4952) and all other chemicals were obtained from Sigma–Aldrich .Anti-mouse or anti-rabbit IgG–conjugated horseradish peroxidase, rabbit polyclonal antibodies specific for p-mTOR  or 10-cm dishes for cell viability assays and collecting RNA or protein samples.Human BC cell lines (5637 and T24) were obtained from Bioresource Collection and Research Center  and maintained at 37°C under 5% COThe cellular lysates were prepared and proteins were then resolved on SDS/PAGE and transferred to Immobilon polyvinyldifluoride (PVDF) membranes. The blots were blocked with 4% BSA for 1 h at room temperature and then probed with rabbit primary antibodies against human proteins (1:1000) for 1 h at room temperature. After three washes, the blots were subsequently incubated with a donkey anti-rabbit peroxidase–conjugated secondary antibody (1:1000) for 1 h at room temperature. After three washes with TBST, the blots were then detected with Amersham ECL Western Blotting Detection Reagents  and photographed by using a ChemiDoc-It® Imaging Systems . Quantification of Western blot results was performed using ImageJ software1.49v . β-actin was used as internal control and densitometry values of each detected proteins were normalized to β-actin. Results are expressed as the mean ± standard deviation (SD) of three independent experiments.T).The quantitative real-time PCR (qPCR) analysis was performed using Taqman® one-step PCR Master Mix . A total of 100 ng of total cDNA was added per 25-µl reaction with sequence-specific primers and Taqman® probes. Sequences for all target gene primers and probes were purchased commercially from Applied Biosystems ; β-actin was used as the internal control. Quantitative RT-PCR assays were carried out in triplicate on a StepOnePlus sequence detection system. The cycling conditions were 10 min of polymerase activation at 95°C followed by 40 cycles at 95°C for 15 s and at 60°C for 60 s. The threshold was set above the non-template control background and within the linear phase of target gene amplification, to calculate the cycle number at which the transcript was detected  for 1 h at room temperature, washed again, and incubated with FITC–conjugated secondary antibody (1:100) for 1 h. Finally, cells were washed, mounted with DAPI containing solution, and photographed with a Nikon Ti2 microscopy System.t test for statistical significance and expressed as the means ± standard deviation (S.D.). A P<0.05 was considered statistically significant. The data containing more than two groups were performed using one-way analysis of variance (ANOVA) with Bonferroni’s post-hoc test. The difference was considered to be significant if the P-value was <0.05.All experiments were performed at least three times, each time in triplicate. Statistical comparisons between two samples were analyzed by Student’s Since PD-1/PD-L1 expression is the main indication for these immune checkpoint inhibitors, and the expression of these immune checkpoint proteins is up-regulated with the progression of BC, it is reasonable to hypothesize that PD-L1 overexpression may be involved in the progression of BC by providing an escape route for tumor cells to evade immune detection. Suppression of these proteins by immune checkpoint inhibitors or other strategies may effectively treat BC. Our results found that cisplatin dose-dependently promoted PD-L1 mRNA expression but not that of PD-L2 (another ligand for PD-1), in BC-derived cell lines A,B. The Multiple mechanisms can contribute to intrinsic tumor PD-L1 expression. Previous research indicates that activation of the Akt/mTOR pathway promotes immune escape by driving PD-L1 expression in lung cancer . TherefoThe AP-1 transcription factor is a dimeric transcription factor that is composed of c-Jun, c-Fos, activating transcription factor (ATF). The main AP-1 proteins in mammalian cells are c-Jun and c-Fos. When the cellular counterparts of the viral oncoproteins were discovered, the up-regulation of AP-1 proteins by overexpression or by oncogenic RAS was found to correlate with a positive effect on cell transformation . MAPK faThe anti-PD-L1 antibody MPDL3280A, a systemic cancer immunotherapy, has proven efficacy in the treatment of metastatic BC; tumors expressing high levels of PD-L1 had particularly high response rates . Here, wNumerous reports have suggested that intrinsic cellular changes are associated with carcinogenesis-induced PD-L1 expression. T-cell lymphoma cells carrying the oncogenic nucleophosmin/anaplastic lymphoma kinase (NPM/ALK), which is involved in malignant transformation, induce high levels of PD-L1 expression via STAT3 and ERK activation ,19. MoleAP-1 protein is a well-established pro-oncogenic transcription factor. The activation of AP-1 is rapidly induced by growth factors, cytokines and oncoproteins, which are implicated in the proliferation, survival, differentiation, and transformation of cells . A mouseThe MAPK cell signaling pathways play important roles in the regulation of cell growth, proliferation, and survival. Mutations within these pathways are frequently implicated in the pathogenesis of solid tumors . Agents In the present study, we demonstrate that cisplatin promotes PD-L1 expression through the ERK1/2 signaling pathway. This work provides evidence in support of the development of combination therapy using a conventional chemotherapy drug and a PD-L1 antibody for the treatment of BC.


Azadirachta indica A. Juss secondary metabolites (AISM) formulated soap and cream for management of infectious and oxidative stress-related diseases (OSD).Infectious diseases, particularly those due to multi-drug resistant bacterial strains are almost impossible to cure globally. In this study we investigated the inhibitory effects of The antibacterial, radical scavenging and cytotoxic effects of the neem cosmetics were examined by serial dilution, spectrophotometric and hemolytic techniques respectively, while the AISM in the essential oils (EOs) were elucidated by Gas chromatography-mass spectrometry (GC-MS) and retention index.Staphylococcus aureus, Listeria ivanovii, Enterobacter cloacae, Mycobacterium smegmatis, and Streptococcus uberis) and two confirmed multi-drug resistant bacterial strains  at 0.80 mg/mL. Conversely, at less than 0.50 mg/mL the neem soap produced with AISM demonstrated bactericidal effects against most of these test pathogens linked to infectious diseases. The neem soap containing AISMs displayed noteworthy effects in scavenging radicals associated with OSD at < 1.76 mg/mL. The cosmetics were not toxic to human red blood cells below 0.70 mg/ mL. To our known, the AISM predominantly caryophyllene (30.02%), phytol (14.12%), elemene (13.40%) and linoleic acid (10.5%) exceptional inhibitory effects in neem cosmetics are reported here for the first time.The neem cosmetics without AISM exhibited bacteriostatic effects against five reference bacterial strains  contains supplementary material, which is available to authorized users. Escherichia coli, vancomycin-resistant Enterococcus faecalis, Vibrio Spp., and methicillin-resistant Staphylococcus aureus (MRSA) are known public threats in hospitals and have become more resistant because of natural selection processes, and over-prescription and misuse of antibiotics  as shown in Table The inhibitory effects (supporting document 1) of the neem cosmetics produced with and without AISM on test pathogens are as presented in Tables E. cloacae, the four creams exhibited a similar effect, while NMLSBC displayed a superior MIC value (0.400 mg/mL). The NMLSBC displayed higher inhibitory effects than other neem cream products with lower MBC values against the five test pathogens, however, its effect was lower than that of positive control drug  had better effects against the pathogens Table . However value 0.00 mg/mL.p < 0.05), while the effect of NMSBS against LP •, and NO • were similar (s). At a higher dose (0.20 mg/ mL) all test neem soap samples scavenged the three radicals differently , creams  as well as neem cosmetics (NMS and NMC) produced devoid of AISM were examined on three different radicals . The radical scavenging effects of neem soaps and positive control (ascorbic acid and rutin) on the radicals were concentration dependent Figs. , 2 and 350 values for the different soaps and creams, regression equations from the standard curves generated for each radical was used while t-test analysis was employed for significantly different of % radical scavenging effects against the concentrations . Interestingly, the antioxidant capacities of NMLSBS and NMLSBC were remarkably better than the two positive control drugs  of the investigated substance because of formation of a neutral molecule of DPPH-H upon donation of H atom from the substance . The strns Figs. , 2 and 3p < 0.05) than that reported for neem seed oil (0.939) by Akpan, [The physicochemical properties (PCP) of the crude neem seed oil (NSO) and essential oils (EOs) extracted by mechanical cold press and hydrodistillation from the aerial parts respectively are as presented in Table y Akpan,  and highy Akpan, . The RD 2O) for the neem soap (NMS) produced without AISM. Nevertheless, the total fatty matter (77.30–80.14%) for the four neem soaps and other physicochemical parameters were better than the specifications of the SON for toilet soap and similar to neem soap produced elsewhere [The physicochemical properties of neem soaps produced with and without the AISM are as presented in Table lsewhere .Table 8PThe cytotoxicity effects on neem cosmetics are as presented in Table A. indica leaf and stem-bark incorporated unto the recipes of neem cosmetics are as presented in Table The chemical profiles of secondary metabolites (SM) isolated from A. indica SMs are reported here for the first time in the genus Azadirachta. The neem cosmetics produced with AISM were more active against Gram-positive bacterial than the test Gram-negative bacterial strains. This may be linked to net repulsion of the complex outer membrane in Gram-negative bacterial, reported in previous studies to contain hydrophilic lipopolysaccharide which exhibits higher tolerance toward hydrophobic terpenes and oxygenated terpenes [Biochemical investigations of inhibitory effects on pathogens and radicals of two different neem extracts (neem seed oil and EO) revealed higher bioactive and physicochemical properties of NC formulated with SM from the EO. Characterization of SM in the leaf and stem EOs integrated into the recipe of NC shown more terpenoids including phytol 18, one sesquiterpenoid ledol 14), a monoterpene (camphene 2) and sesquiterpene (curcumene 8) in the stem-bark (SBEO). Moreover, the content of bioactive linoleic acid (17), hexadecenoic acid (15), caryophyllene oxide (12), linalool oxide (6) and terpinene (5) were more in SBEO. Accordingly, the NC made incorporating SMs from SBEO and LEO had the highest activity followed by NC produced with the SM from the SBEO, while NC produced with only crude neem seed oil (NSO) displayed the least activity. To the best of our knowledge, this enhanced bioactivity of neem cosmetics formulated from the leaves and stem bark of , a monotterpenes . Anotherterpenes .A. indica is known to inhibit low-density lipoprotein oxidation even in the early phase [Phytol one of the major SM in the SBEO was reported  to demonly phase . Other bly phase , pinene ly phase  and linoly phase  may haveA. indica, especially in the stem-bark  indicates that the stem-bark EO will be feasible as a fresh potent source in the hunt for principal agent for the management of oxidative stress-related ailments such as skin cancers , scabiesA. indica leaves and stem-bark in tropical and subtropical countries.None of the neem cosmetics displayed hemolytic effects on human red blood cells (HRBC) below 0.68 mg/ mL. Mild cytotoxic effect was observed in neem soap formulated with combined stem-bark and leaf SMs at > 0.69 mg/ mL. This may be attributed to the frail nature of HRBC since there has never been any report on human toxicity after using a decoction of This present study indicates that besides the known uses neem tree, the neem cosmetics integrated with the stem-bark and leaf essential oil has robust bioactive secondary metabolites; therefore, the EO could be a novel applicant as new antimicrobial agent in this current era of rising multidrug-resistant bacterial strains, likewise as an alternative to synthetic antioxidant and effective bioactive chemical in pharmaceutical and cosmetics industries.Additional file 1:Screening of the products against 7 Bacterial strains at different concentrations. (DOCX 4399 kb)


Strong light-graphene interaction is essential for the integration of graphene to nanophotonic and optoelectronic devices. The plasmonic response of graphene in terahertz and mid-infrared regions enhances this interaction, and other resonance mechanisms can be adopted in near-infrared and visible ranges to achieve perfect light absorption. However, obtaining near-absolute polarization insensitivity with ultra-narrow absorption bandwidth in the visible and near-infrared regimes remains a challenge. In this regard, we numerically propose a graphene perfect absorber, utilizing the excitation of guided-modes of a dielectric slab waveguide by a novel sub-wavelength dielectric grating structure. When the guided-mode resonance is critically coupled to the graphene, we obtain perfect absorption with an ultra-narrow bandwidth  of 0.8 nm. The proposed design not only preserves the spectral position of the resonance, but also maintains >98% absorption at all polarization angles. The spectral position of the resonance can be tuned as much as 400 nm in visible and near-infrared regimes by tailoring geometrical parameters. The proposed device has great potential in efficient, tunable, ultra-sensitive, compact and easy-to-fabricate advanced photodetectors and color filters. The ultra-wideband spectral response and the huge carrier mobilities make graphene a strong candidate as a backbone of novel nanophotonic and optoelectronic devices. Indeed, graphene-based solar cells8, saturable absorbers for the mode-locked ultra-fast lasers11, photodetectors13, transparent electrodes16, optical modulators18 and third harmonic generation20 are demonstrated. Further incorporation of graphene into high-performance optical devices makes strong light-graphene interaction compulsory. Localized surface plasmons and surface plasmon polaritons supported by graphene in the terahertz (THz) and mid-infrared (MIR) regimes can enhance this interaction and perfect absorption can be achieved25. In contrast, in the visible and near-infrared range (Vis-NIR), graphene’s optical response is dominated by interband transitions, giving a real conductivity with no plasmonic response and graphene effectively mimics a dielectric with considerable loss26. Unpatterned and suspended graphene absorbs A = πα = 2.3% of the normally incident light without spectral selectivity, defined by the fine structure constant α = e2/ℏc. A = 2.3% is actually a significant value for a one-atom thick material. Nevertheless, the absolute strength of the absorption is low and it limits graphene’s further application in optoelectronics and photovoltaics in the visible spectrum, an example related to our work being low responsivity in photodetectors28.Ever since the experimental isolation of graphene in 200430. This method can confine large optical fields and significantly enhance the absorption in graphene. However, these designs require deposition of a large number of dielectric layers  on top of graphene. This results in not only fabrication difficulty, but also bulky devices. Another option is placing graphene near plasmonic nanostructures34 and relying on the near-field enhancement effect of surface plasmons or surface plasmon polaritons. This method suffers from absorption peak broadening because of the background absorption coming from the metals, which is detrimental to color sensitivity. Moreover, significant Joule losses decrease device efficiencies35.Since graphene plasmons cannot be excited outside the THz and MIR ranges, graphene has to be coupled to other resonant mechanisms to improve the light absorption in the Vis-NIR ranges. Enormous research efforts have been devoted to enhancing the local optical field around graphene and increase light-graphene interaction in the Vis-NIR ranges. The methods to achieve these can be classified into four categories. First, graphene can be placed inside a Fabry-Pérot (FP) cavity42. The difference between two methods is the structures where GMRs are excited. The third method is to couple graphene to the GMRs of photonic crystal slabs (PhCs)43 or 1-dimensional photonic crystals (1DPCs), excited by sub-wavelength grating (SWG) couplers45. The guided-mode leaks out evanescent waves to graphene. Critical coupling of the guided-modes to graphene then produces perfect absorption. Notably, the latter can achieve an ultra-narrow absorption bandwidth of 0.03 nm due to placing graphene far away from 1DPC45. Although promising in theory, this method enforces extreme fabrication accuracy on not only the SWG, but also on the 1DPCs to achieve the target wavelength and store very high energy in 1DPC to achieve critical coupling. Similar to the methods that adopt FP cavity, this method also results in bulky components. The final method is to excite the GMRs of either unmodulated slab-waveguide structures beneath the grating50, or the grating itself  51, which acts as a waveguide whose core is refractive-index modulated bulk38. These GMRs then interact with graphene to increase light-graphene interaction. Compared to the third method, this method offers more compact designs and a more facile fabrication process. This is because it does not require 1DPC, but only a SWG, two or three dielectric films with only one being patterned, and possibly a perfect back metal mirror or Bragg reflector. However, the downside is the larger bandwidth because low-Q resonances can be coupled to graphene, due to the smaller distance between GMR and graphene. Thus, there is a fundamental trade-off between the two methods in terms of the fabrication complexity and Q-factor of resonances. While the previous studies for the guided-mode resonances focused mainly on the absorption enhancement, polarization insensitivity remained an issue, because of incorporating 1-dimensional SWGs. Although polarization-insensitivity between s and p-polarizations is achieved by the square lattice in ref.43, the bandwidth, measured as full-width at half-maximum (FWHM), 14 nm is quite high because of the circular shape of the holes. The sharp features of gratings allow for enhanced field localizations and high-Q resonances. Hence, an ideal unit-cell would use a rectangular grating structure with rotational symmetry to preserve both strong light absorption and achieve polarization insensitivity.The third and fourth methods can be classified together as coupling of graphene to guided-mode resonances (GMRs) that define the phase-matched coupling between the free-space radiation and the supported (guided) modes with a leaky nature due to their complex wavenumberIn the present paper, we employ the finite-difference-time-domain (FDTD) method to numerically propose a novel design that uses a 2-dimensional sub-wavelength grating structure to excite the GMRs of an unmodulated slab waveguide. The critical coupling of the GMRs to graphene yields 99.2% light absorption with 0.8 nm FWHM at 678 nm, under p-polarized (TM) light. The proposed device preserves perfect absorption >98% at all source polarizations as well as the spectral position of the resonance. To the best of our knowledge, this is the first study that illustrates an FWHM below 1 nm with near-absolute polarization independence. Furthermore, the presence of a waveguide structure, instead of 1DPCs or FP cavities, relaxes the device fabrication. The spectral position of the resonance is easily tunable by changing the key geometrical parameters of the device. We first show the enhancement of graphene absorption in a simple optimized grating-core-substrate structure and scrutinize the effect of geometrical parameters on the device characteristics. In the second part, we add a metal back mirror and optimize the geometry accordingly to achieve critical coupling, and hence perfect absorption with the ultra-narrow bandwidth. We discuss the design considerations to maximize absorption strength and minimize absorption bandwidth, for each case.2O5), unmodulated core dielectric region by a unique 2-dimensional sub-wavelength polymethyl-methacrylate (PMMA) dielectric grating. The structure is supported by glass (SiO2) substrate. We call this two-port structure Device I. Figure 52. Another equivalent unit-cell for the structure is presented in Fig. PMMA.Our proposed device in Fig. ϕ = 0, p-polarization). In the x and y directions, we use periodic boundary conditions, while in the z-direction perfectly matched layers (PML) are adopted and they are placed 5 wavelengths away from the structure. We use two monitors that are at an adequate distance away from the structure to find the reflected (R) and transmitted (T) power. Absorption is then found by using A = 1 − R − T formula. The dispersion effect of the dielectric materials are retrieved by ellipsometric measurements, and they are in good agreement with the models based on Sellmeier equation53. In the material fits, the only non-zero extinction coefficient comes from Ta2O5, and is equal to 10−5. It is then reasonable to regard the device as lossless without graphene. Graphene is modeled as a 2-dimensional material with infinitesimal thickness and a complex surface conductivity that includes the chemical potential, scattering rate and temperature effects, based on Kubo formulation54. The surface conductivity is divided into intraband and interband contributions, as given in Eqns j is the imaginary unit, e is the elemental charge, w is the angular frequency, T is the temperature, ℏ = h/2π is the reduced Planck’s constant, Γ is the scattering rate, and μc is the chemical potential. kb is Boltzmann’s constant.To investigate the spectral response of Device I, we utilize finite-difference-time-domain simulations. In the numerical simulations, we illuminated the unit-cell with a broadband plane-wave at normal incidence whose electric-field is polarized in x-direction  and 220 nm, respectively. We simulated Device I without graphene to gain insight about the resonance excitation and to confirm that the device is almost lossless. The simulation result in Fig. 2O5. It is then safe to associate the absorption in subsequent simulations to graphene. In Fig. 36. Another condition for the occurrence of the resonance is the phase-matching condition, i.e. the real part of the complex wavevector component in the travelling direction of the guided-mode is equal to the components coming from the reciprocal lattice vector of grating and the incident wave48. Eq. β is the propagation wavenumber along the guiding direction, k0 is the free-space wavenumber, neff is the effective refractive index of the mode inside the core, m is the diffraction order, λ0 is the free-space wavelength and Λ is the grating period. Writing an analytical expression for the phase-matching condition in Device I is cumbersome because our grating diffracts incoming waves in not only the x-direction but also in the y-direction, as opposed to the explicitly used devices with 1D grating51 does. Therefore, the guided-mode’s propagation direction is not simply the x-direction as in Device 0. This makes numerical methods necessary to fully discern the resonances. Another interesting feature of GMRs is their Fano lineshape. It arises due to the interaction between a sharp resonance channel and the broad radiation continuum55. Critically, the zeroth order diffracted wave is a propagating wave, while all other diffracted orders are evanescent due to the sub-wavelength nature of the grating. Therefore, we have evanescent coupling of the incident wave to the guided-mode.First of all, we set the design parameters 2O5 to increase the light-graphene interaction, thanks to the guided-wave confined in the waveguide28. The spectral response of the configuration is shown in Fig. 47 also found that simple 1D grating and unmodulated slab waveguide structure has a theoretical maximum absorption of 60% without the addition on back-mirror. We, therefore, attribute both the near-stable spectral position of resonance and slightly enhanced absorption to our novel grating design.We then sandwiched monolayer graphene between the grating and Ta47. While Fig. Figure 2 is enhanced two orders of magnitude with respect to the incident light, |H|2 is enhanced one order of magnitude. The enhanced optical field on graphene is directly responsible for the absorption enhancement, in accordance with Eq. 457,ε0 is the vacuum permittivity, λ and I(λ) are the wavelength and the intensity of the light, respectively, n″ and n′ denote the imaginary part (extinction coefficient) and real part of the complex refractive index, respectively. The enhancement of fields is slightly higher than the designs incorporating slab waveguide as the guiding layer50. We also observe that the standing wave pattern is created in both the z and x-directions. While the former is because of the waveguiding effect, the latter is due to the refractive index modulation in the x-direction45. The electric field profile in Fig. 59.To get further comprehension about the improvement in the light-graphene interaction, we extracted the electric and magnetic field profiles for both off-resonant and on-resonant cases. A comparison of the fields in the off and on-resonant cases, shown in Fig. 60. In addition, when the guided-mode travels along the periodically segmented waveguide61, the periodicity of the grating defines Bloch modes. Different effective refractive indices of the Bloch modes in the grating region42 consequently define different effective mode refractive indices for TE and TM modes of the waveguide. The excitation condition of TE and TM modes are different on top of this62. Thus, the devices utilizing 1D gratings show polarization dependency42 as they excite the GMRs at different wavelengths. Moreover, dissimilar field distributions result in different absorption strengths.Because it is the most important aspect of our design, we devoted this subsection to the further dissection of polarization insensitivity in Device I, by analyzing what causes the devices with 1D grating, such as Device 0, to be polarization sensitive in the first place. Firstly, different boundary conditions imposed on different polarization states, which results in form birefringence63.f is the fill-factor of grating, n1 and n2 are the refractive indices of the grating material, and its surrounding, respectively. n⊥ are the refractive indices of the effective medium for the s-polarized , and p-polarized waves (E-field perpendicular to grating grooves), respectively. Any arbitrary incident polarization can then be decomposed into a superposition of s and p-polarizations to find the effective refractive index as a weighted sum of n⊥.Without considering the waveguiding effects and the complicated properties of Bloch modes, we adopted Rytov’s formulas given in Eqns 52. To compare Device I with the devices using 1D grating, we kept the polarization angle at ϕ = 0 degrees, and rotated the unit-cells of each for 0, 30, 60, and 90 degrees. The result of this comparison is shown in Fig. From Eqns 2O5-PMMA (core-PMMA) and Ta2O5-SiO2 (core-substrate) boundaries are highly related to the effective mode index, neff, of the guided-mode if we regard the structure as an asymmetric dielectric slab waveguide. This is done by considering the SWG as a medium with an effective dielectric permittivity58. Therefore, we start our discussion here by briefly reviewing the fundamental results of asymmetric dielectric slab waveguide theory64.Results of the previous subsection demonstrate that GMRs can be excited when the phase-matching condition is satisfied, and the evanescent wave from the diffraction grating can be coupled to one of the guided waveguide modes. Although the waveguiding effects on the Bloch modes of the periodically patterned waveguide are complicated, we can still sufficiently understand how the spectral response of Device I depends on the structural parameters, by considering the optical field around graphene. Optical fields at the Ta2 regions, respectively. nSWG is the effective refractive index of the SWG, different for TE and TM modes. Eqs eff is determined primarily by the thickness of the core to the wavelength ratio  are satisfied, whereupon the interference and dissipation leads to perfect absorptionA = 1 − R formula, and maximizing it requires minimizing the reflection, which is due to the externally leaked energy from the system that is not harnessed on graphene. This can occur due to either undercoupling or overcoupling of the GMR to graphene43. In both cases, the external leakage rate is not equal to the intrinsic absorption in graphene. The fact that critical coupling depends on the external leakage rate makes SiO2 thickness a critical parameter, as it controls the FP cavity modes in it46 and consequently reflection losses25.To achieve perfect absorption and retain the sub-micron thickness of Device I, we added a thick gold layer beneath Device I, to arrive at Device II, shown in Fig. PMMA, and To achieve critical coupling, we set the geometrical parameters to their optimized values, i.e. 45. Thus, the bandwidth is narrower in devices where graphene is placed far away from the optical field confined by GMR. Although this strategy results in a narrower bandwidth, the necessity of creating a very high-Q GMR puts vigorous stress on the fabrication process. To increase the Q-factor of resonances in Device II, it is better to confine the mode to the core, i.e. increase neff. The narrower resonances at larger core thicknesses and smaller unit-cell periods in Fig. eff increases the energy storage inside the core region and decreases the leakage to the graphene58. The critical coupling condition is then satisfied by the very high-Q GMR, and the resultant bandwidth is low. This is the reason why PMMA and w are tailored accordingly to meet critical coupling condition.We now want to emphasize the key design strategy in achieving the ultra-narrow bandwidth. To achieve critical coupling in a system where the external leakage rate is low, a very high energy storage, or equivalently, a very high-Q GMR in the resonant structure is needed2 thickness in the absorption spectrum, we varied it over a wide range from 100 nm to 500 nm, and the result is shown in Fig. 46 and it is because of the phase-shift introduced by the SiO2 layer and the FP modes defined by it46. Another reason may be that the system evolves from critical coupling to overcoupling or undercoupling, as altering glass thickness changes external leakage rate43, while the intrinsic loss rate remains almost the same. An interesting observation is that glass thickness starts having an effect on resonance wavelength below a certain value. Besides this, when To examine the effect of the SiO68 means that although the grating has 60° rotational symmetry, overall structure will not have this feature.We inspected the polarization-independence of Device II, and the result is shown in Fig. eff increases. 69.The sensitivity of GMR to geometrical parameters gives Device II a great tunability in visible and NIR ranges. As a general guideline, the resonance can be red-shifted by an increase in We now accentuate the fundamental difference in the design methodologies of Device I and Device II. In Device I, the effective mode refractive index had to be kept at an intermediate value because too high or too weak confinement of the mode to the core was detrimental to absorption. However, in Device II we could be able to confine the mode as much as we can to the core, without considering transmitted losses, and critical coupling gives both perfect absorption and ultra-narrow bandwidth. The same design strategy in Device I would result in absorption and transmission approaching each other, and to 50%.66. Other 2D materials, such as transition-metal dichalcogenides show stronger light-matter interaction than graphene, in the order of 10% in the visible range70. Compared to the intrinsic 2.3% absorption in graphene, larger intrinsic absorption in TMDs would mean satisfying the critical coupling condition requires a larger external leakage rate for matching. So, the absorption spectrum associated with them are inherently broader. From the viewpoint of light sensing or biosensing applications, using graphene is advantageous due to narrower bandwidth. However, the broader resonances associated with TMDs would mean a larger average absorption in the visible spectrum and the presence of a direct bandgap combined with it makes monolayer TMDs a great candidate for photodetection and photovoltaics72.Up to now, this paper dealt with achieving perfect absorption with monolayer graphene. However, the concept of critical coupling is general and can be applied to other 2D materials, such as transition-metal dichalcogenides (TMDs), and multilayer graphene to yield perfect absorption with polarization insensitivity. To explain the effect of multilayer graphene, we increased the number of graphene layers in the simulations, and the result is demonstrated in Fig. 2 and Ta2O5 can all be coated by Physical Vapor Deposition (PVD) methods such as sputtering. Chemical Vapor Deposition (CVD) grown graphene can be transferred and PMMA grating structure can be realized by electron-beam lithography. The numerical findings of this paper propose that the core thickness and the unit-cell periodicity are the most important factors in determining the resonance position and bandwidth, as well as the absorption strength. This makes the precise deposition of Ta2O5 and electron-beam lithography of the 2D grating structure the most important steps. The fabricated samples can be characterized by Fourier Transform Infrared Spectroscopy (FTIR) technique for the resonances in NIR, whereas confocal microscopy can be utilized for resonances in visible range. We believe that the deviations of experimental findings from theoretical results can be restricted to a controlled region by the physical laws and explanations presented in this paper.The experimental verification of this work starts with the fabrication flow of choosing a Silicon or quartz substrate. Choice of substrate does not affect Device II as the thick gold layer means that there will be insignificant amount of light reaching there. Thus, a thin (5–10 nm) Titanium layer can be coated beneath gold for better adhesion, without affecting the optical properties. After that gold, SiOIn conclusion, the enhancement of light-graphene interaction is numerically analyzed in this paper and the near-perfect polarization insensitivity of proposed design to incident light is verified. Our novel sub-wavelength dielectric grating excites the guided modes of an asymmetric dielectric slab waveguide. The critical coupling of the guided mode resonances to graphene resulted in perfect light absorption that is tunable by structural parameters in the visible and NIR ranges. The bandwidth of the resonance, 0.8 nm resulted in a very high Q-factor of 850. To the best of our knowledge, this bandwidth is smaller than all of the relevant device proposals with sub-micron thickness. Overall, our simple yet robust, and easy-to-fabricate device holds great promise in ultra-sensitive color detection and design of advanced photodetectors. Our future work will focus on the fabrication of the device and extending the tunability range of the guided-mode resonance.Supplementary Information


In the context of a large treatment gap for common mental disorders (CMDs) and shortage of mental health specialists in low- and middle-income countries, there is increasing evidence of the effectiveness of task sharing of counselling interventions to increase access to mental health care for CMDs at primary health care level. This study evaluated the relationship between levels of exposure to a task-shared counselling intervention and psychosocial outcomes  in chronic care service users with comorbid depression in South Africa guided by the Medical Research Council process evaluation framework. Implementation and participant-level factors that promote greater exposure were also investigated.The study design was a cohort study comprising of 173 participants referred by primary health care nurses for the task-shared counselling intervention. The study site comprised four primary health care facilities in a sub-district of the Dr. Kenneth Kaunda district in the North West Province of South Africa. The participants were assessed for psychosocial outcomes at three time points: baseline, 3 months and at 12 months. The number of counselling sessions each participant was exposed to was collected for each participant. Linear regression models were used to test the influence of counselling exposure on each of the psychosocial variables between baseline and endline. In-depth qualitative interviews were conducted on 29 randomly selected participants, stratified according to exposure to counselling sessions, and analysed using framework analysis.p = 0.064). The WHODAS scores decreased significantly more from baseline to endline among those who received 5–8 sessions  compared to those with 0 sessions . No significant differences as a function of levels of counselling exposure from baseline to endline was observed for OSS-3 scores. An improvement in ISMI scores from 1–4 sessions to 5–8 sessions was found . The qualitative process evaluation indicated that the service was acceptable and accessible; but that session attendance was hindered by women’s’ caregiving burden, poor counsellor attributes and poor referral processes.Findings from the cohort study indicated a significant reduction in depression severity at 12 months. Internalised stigma and functional disability improved from baseline to endline. Participants receiving 5–8 sessions have the greatest reduction in PHQ9 scores from baseline to endline  compared to those with 0 sessions  was found to optimize functional ability, reduce stigma, and potentially reduce depression symptoms. In order to enhance session attendance, lay counsellor delivered psychosocial interventions need to pay attention to (i) counsellor selection criteria, particularly person-centred care qualities; and (ii) strengthening referral processes in contexts where mental health literacy is low. Non communicable diseases (NCDs) have become the leading cause of global mortality, accounting for 68% (38 million) of deaths in 2012  I could not [cook or do laundry] before as I wanted to do nothing when I woke up in the morning all I wanted to do was to just sit. [I: Mmm] So now I have the strength to do it I wake up in the morning and do everything that I am supposed to do She […] gave me a paper and told me to go to [the lay counsellor] I did not know who [the counsellor] was and she took me to her […] Yes, she [explained the referral process]. I wouldn’t have gone anywhere if she didn’t.  reported being walked over to the counsellor’s room or getting introduced to the counsellor after being diagnosed/identified with depression.Participant 9; 1–4 sessions)I was very nervous, not knowing the outcome got me feeling scared. I am at fault because I did not come and I promised them (I: Mmm) I did not know what was going to happen (I: Mmm) That is the reason - I do not want to lie. Alright, the sessions really changed me a lot the first time when I attended the session I would shout (at) my children at home for nothing and I would feel hurt, now it has brought back my life because I would sleep the whole time and would not cook and eat, I would not wash the dishes living in unkempt conditions but now it was helped me a lot as I do not do those things anymore and I do not undermine myself […] .I would say the sessions made that possible, because it helped me to want to get up and do something with my life, like selling achar for income, and not just sitting waiting on my husband. […] right now, I’m making means to get extra money for the household, when my husband can’t buy some things I can use some of the money to supplement. I can now talk [about my condition] I have informed my children about my status […] when I came I told [the counsellor] I want to tell my children that I am HIV positive […] I was afraid of telling them but I ended up telling them and they accepted me […] I now don’t hide when I take my medication […]  to deal with poverty through improved budgeting and identifying income generating opportunities as ability to manage identified problems.Yes, it was easy for me to accept because as the scenarios were being read, I could relate them to my personal experiences. […] The depression counselling manual and sessions were designed and structured (using vignettes and protagonists) so as to help service users feel safe and not exposed while sharing their experiences. Identifying with the protagonist’s experience of the depression-stress-factor of the day allowed for the group to discuss the issue in a safe way. The vignettes presented depression factors in a way that was relatable for the service users.Participant 16; 1–4 sessions; emphasis added).[Thandi’s story] is the one that made us talk about life […] It had an impact because I had similarities with her I have to look after my husband as he uses a wheelchair and the baby so at times the time that’s set which is mostly 8am to 9am I don’t have time because I have to prepare for the people going to school first then I have to attend to my husband and I have a baby on the other side so it’s just lack of time for me I saw that going for counselling will help me in a lot of ways [compared to what] I had received before.  to continue with the counselling sessions with expectation for further improvement.Participant 18; 5–8 sessions)[[The counsellor] is good. She does her job with integrity without discrimination […] she is not the type of person that judges people; she just really knows how to talk to people, with everyone […] she [made telephone reminders], but then I already knew when to attend my sessions, if I had an issue with attending I’d phone to alert her.  framework for the evaluation of complex interventions, this study had two objectives: (i) to evaluate the relationship between levels of exposure to the task-shared counselling intervention component of the collaborative care model, and psychosocial outcomes  in chronic care service users with comorbid depression; and (ii) to understand implementation and participant-level mechanisms of impact that promoted greater exposure to the intervention guided by the MRC framework for process evaluation. The majority of the sample enrolled in the study were women, a demographic feature characteristic of primary health facilities providing chronic care in South Africa –48.The intervention led to a clinically significant reduction of depression symptoms at 12 months follow up. Service users who were exposed to 5–8 counselling sessions showed greater reduction in PHQ9 scores  compared to those who had no exposure to the intervention. This outcome corroborates international findings of similar studies with lay counsellor led interventions  and addsParticipants who received of 5–8 sessions had better PHQ 9 outcomes at 12 months compared to those having zero or 1–4 sessions, suggesting 5–8 sessions to be the optimal dosage. It is not clear why service users who did not take up the intervention had similar PHQ9 outcomes to those who received 1 to 4 counselling sessions. One explanation could be service users with 0 counselling sessions did not, in-fact, need the service while those with 1 to 4 counselling sessions needed to continue with the counselling sessions. More robust methods are needed to investigate this further. Qualitative interviews with participants who received 5–8 sessions suggests that more sessions helped to promote greater attainment of skills to help negotiate life circumstances better. This finding is supportive of the NICE guidelines based on evidence from mostly high-income countries that recommends 6 to 8 sessions for low-intensity psychosocial intervention as optimal .Evidence shows that functional disability is strongly associated with depression –55. WhilExposure to more sessions also produced better benefits for self-stigma. There was a significant difference in reduction in internalized stigma between participants who attended 1–4 sessions compared to those who attended 5–8 sessions at endline. The fact that the session on internalized stigma was generally delivered later in the programme could potentially explain this finding. It is not clear why service users who did not take up the intervention had better self-stigma outcomes than those who received 1 to 4 counselling sessions. As with the PHQ9 outcomes it could be service users with 0 counselling sessions did not need the service while those with 1 to 4 counselling sessions needed to continue with the counselling sessions. More robust methods are needed to further investigate this. Self-stigma has a negative impact on self-esteem and self-efficacy and is considered a risk factor for poor mental health , 59. LitIn relation to social support, the overall OSS-3 mean scores showed no significant improvement for perceived social support. This is similar to Petersen et al.’s  findingsIn relation to reasons for greater counselling attendance, the qualitative process evaluation interviews revealed that availability of services, awareness of helpfulness of counselling sessions and counsellor qualities helped with attending more counselling session. It appears having insight, the process of becoming increasingly aware of one’s mental state , promoteIn addition, the referral process emerged as important in promoting greater uptake and adherence to the counselling sessions. Service users who had received 5–8 sessions reported that the referring nurse accompanied them to the counselling room or introduced them to the counsellor following the referral. This group also reported meeting with the counsellor at set times. In contrast, participants who did not take up the service and those who attended 1–4 sessions reported unexplained referral process, contextual issues making it difficult to attend counselling sessions, inconsistent appointments and not meeting with the counsellor on the day the referral was made. Linking service users with service providers can help with improving access to health services . From thFeeling better, contextual issues including having a day job, caring for sick family members and helping with funeral arrangements were reasons reported for dropping out before completion of counselling sessions. This tended to affect female service users who played the role of primary care giver more. Not only were their services seen as expendable, they were not able to attend to their own health care needs, with the needs of other family members outweighing their own.The findings of this evaluation of a lay-counsellor delivered psychosocial counselling intervention for chronic service users found that it helped reduce depression symptoms, at 12 months follow-up; with 5–8 sessions found to be optimal in this regard. Participants receiving this optimal number of sessions displayed improved functionality and reduced self-stigma, reported to have been empowered to self-manage, be more self-reliant, and capacitated with skills to improve their quality of life. Factors found to optimize attendance of counselling sessions included counsellors with person-centred care qualities, referral processes that included being provided with an explanation as to how counselling could benefit the service user by the referring nurse, and being connected to the counsellor either by being walked to the counselling room or introduced to the counsellor.