Elevated levels of circulating invariant natural killer cell subsets are skewed toward Th2-like phenotype in children with sickle cell disease.

Invariant natural killer T (iNKT) cells are being considered as potential targets for immunotherapeutic strategies in a variety of conditions including sickle cell disease (SCD). However, relatively little is known about the fate of iNKT cell subsets in children with SCD. Herein, quantitative and qualitative analyses of circulating iNKT cell subsets were carried out in 120 children in steady state and 30 healthy controls. Children with SCD displayed significantly elevated levels of circulating iNKT cell subsets with a preferential polarization toward Th2-like cells. The known SCD modifiers did not influence levels of iNKT cell subsets, except that children carrying the Bantu haplotype exhibited elevated levels of CD4iNKT cells, and to a lesser degree CD8iNKT cells. Collectively, these findings indicate that circulating iNKT cell subsets are significantly increased in children with SCD, and highlight the existence of imbalanced production of cytokines toward Th2-like phenotype, which seems to be associated with genetic polymorphisms.

Hemoglobin F as a predictor of health-related quality of life in children with sickle cell anemia.

PURPOSE: As treatment options for children with sickle cell anemia (SCA) continue to expand survival, evaluation of factors associated with health-related quality of life (HRQoL) is becoming an important aspect for further improving clinical management. Although the general features of SCA are similar, factors influencing HRQoL within a country may differ from those of other countries, therefore this study aimed to explore factors affecting HRQoL in children with SCA living in the Sultanate of Oman. METHODS: This was a cross-sectional study in which the PedsQL™ Sickle Cell Disease Module was used to evaluate the overall HRQoL in children with SCA. The socio-demographic data, clinical, and treatment outcomes were collected. Univariate and multivariate linear regression analyses were used to identify predictors of HRQoL. RESULTS: A total of 123 children with SCA, aged from 2 to 16 years were enrolled. The mean total HRQoL score was 52 ± 15% (9-94), where Worry II scale recorded the highest score. The multiple regression analysis revealed that the only predictors of total HRQoL score were hemoglobin F (B = 0.64, 95% confidence interval [CI] 0.149-1.118, P = 0.009) and to a lesser degree white blood cell count (B = - 0.99, 95% CI - 1.761 to - 0.198, P = 0.01), independently of other study parameters such as age, gender, spleen status, and hydroxyurea therapy. CONCLUSIONS: Collectively, these findings indicated that hemoglobin F out-weighted white blood cell count in predicting HRQoL in Omani children with SCA. Recognition of these factors could help health professionals to develop effective strategies to improve the overall HRQoL in these young patients.

Programmed death-1 is a marker for abnormal distribution of naive/memory T cell subsets in HIV-1 infection.

Chronic activation of T cells is a hallmark of HIV-1 infection and plays an important role in disease progression. We previously showed that the engagement of the inhibitory receptor programmed death (PD)-1 on HIV-1-specific CD4(+) and CD8(+) T cells leads to their functional exhaustion in vitro. However, little is known about the impact of PD-1 expression on the turnover and maturation status of T cells during the course of the disease. In this study, we show that PD-1 is upregulated on all T cell subsets, including naive, central memory, and transitional memory T cells in HIV-1-infected subjects. PD-1 is expressed at similar levels on most CD4(+) T cells during the acute and the chronic phase of disease and identifies cells that have recently entered the cell cycle. In contrast, PD-1 expression is dramatically increased in CD8(+) T cells during the transition from acute to chronic infection, and this is associated with reduced levels of cell proliferation. The failure to downregulate expression of PD-1 in most T cells during chronic HIV-1 infection is associated with persistent alterations in the distribution of T cell subsets and is associated with impaired responses to IL-7. Our findings identify PD-1 as a marker for aberrant distribution of T cell subsets in HIV-1 infection.

CD160 and PD-1 co-expression on HIV-specific CD8 T cells defines a subset with advanced dysfunction.

Chronic viral infections lead to persistent CD8 T cell activation and functional exhaustion. Expression of programmed cell death-1 (PD-1) has been associated to CD8 T cell dysfunction in HIV infection. Herein we report that another negative regulator of T cell activation, CD160, was also upregulated on HIV-specific CD8 T lymphocytes mostly during the chronic phase of infection. CD8 T cells that expressed CD160 or PD-1 were still functional whereas co-expression of CD160 and PD-1 on CD8 T cells defined a novel subset with all the characteristics of functionally exhausted T cells. Blocking the interaction of CD160 with HVEM, its natural ligand, increased HIV-specific CD8 T cell proliferation and cytokine production. Transcriptional profiling showed that CD160(-)PD-1(+)CD8 T cells encompassed a subset of CD8(+) T cells with activated transcriptional programs, while CD160(+)PD-1(+) T cells encompassed primarily CD8(+) T cells with an exhausted phenotype. The transcriptional profile of CD160(+)PD-1(+) T cells showed the downregulation of the NFκB transcriptional node and the upregulation of several inhibitors of T cell survival and function. Overall, we show that CD160 and PD-1 expressing subsets allow differentiating between activated and exhausted CD8 T cells further reinforcing the notion that restoration of function will require multipronged approaches that target several negative regulators.

Correlation of PD-L1 expression with different clinico-pathological and immunohistochemical features of ovarian surface epithelial tumors.

BACKGROUND: Primary carcinoma of the ovary (OCs) are responsible for a significant number of deaths related to cancer, and have the highest rate of death related to cancers of the female reproductive organs. Programmed cell death 1 (PD1) protein, acts as an immune checkpoint, and has an important role in the down-regulation of the immune system by preventing the activation of T-cells, which will weaken the autoimmunity and increases self-tolerance. This study aimed at the evaluation of the immunohistochemical (IHC) expression of PD-L1 in various primary surface ovarian epithelial tumours and to test its correlation with different clinicopathological parameters together with the expression of a panel of P53, ER and PR. METHODS: A set of 102 cases of primary ovarian surface epithelial neoplasms (benign, borderline and malignant) were collected to construct Tissue Microarray (TMA) using 3 tissue cores from each case. IHC for PD-L1, p53, PR and ER was performed. The expression of PD-L1 was evaluated in relation to some clinicopathological parameters and to the expression patterns of other markers. RESULTS: Expression of PD-L1 was detected in about 51% (n = 36) of malignant tumours. The malignant group significantly showed PD-L1 positivity compared to borderline and benign groups. The malignant tumours significantly showed PD-L1 and total p53 positivity in comparison to borderline group. Also, malignant tumours significantly showed higher combined positivity of PD-L1 and either PR or ER compared to borderline and benign lesions. No significant correlation was appreciated between PD-L1 expression and with any of the studied clinicopathological parameters. CONCLUSIONS: This study showed a significant PD-L1 expression in malignant primary surface epithelial tumours. Construction of a panel of IHC markers, including PD-L1, could have a potential value to define patients those would benefit from the addition of immunotherapy to the treatment plan.

Impact of splenectomy on circulating microparticles in patients with sickle cell anemia.

INTRODUCTION: Circulating microparticles (MP) are being described as potential biomarkers for disease activity in a variety of conditions including sickle cell anemia (SCA). However, relatively little is known about the influence of spleen status on MP levels in patients with SCA. METHODS: Using a prospective study design we characterize circulating MP in 144 patients with SCA in steady state by assessing their cellular origin and their relationships to spleen status defined by clinical and imaging findings. In addition, MP levels were studied according to demographic characteristics, clinical status, treatment modalities, and other hematological and biochemical parameters. Absolute plasma concentrations of MP were determined by flow cytometry. RESULTS: Patients with SCA displayed a 10-fold increase in levels of MP derived from red blood cell (RBC) and platelets (PLT) when compared to their healthy counterparts (p < 0.0001). Splenectomized patients with SCA have more pronounced levels of MPRBC and MPPLT, and remained elevated after several weeks of follow-up. Levels of MP were not significantly associated with spleen removal procedures, age, gender, clinical severity score, hydroxyurea therapy, hemoglobin F, and co-existence of glucose-6-phosphate dehydrogenase deficiency. CONCLUSION: Collectively, these results suggest that splenectomy affects circulating levels of MP regardless of the known SCA modifiers and correlates.

Multiple cycles of rituximab therapy in chronic refractory immune thrombocytopenia: a case report with a 10-year follow-up.

Immune thrombocytopenia (ITP) is an autoimmune disease characterized by isolated low platelet counts often leading to mucocutaneous bleeding. Administration of rituximab was shown to increase platelet counts in patients relapsing chronic ITP. However, duration of response with rituximab and the long-term benefit remains unknown. Herein, the authors presented a case of a 36-year-old splenectomised man with a relapsing ITP who received a total of 10 cycles of rituximab over the last decade with the concomitant assessments of circulating B cells. The data show that rituximab can be an effective therapy over 10 years, and monitoring B cells may help to herald ITP recurrence.

Forced expression of HLA-DM at the surface of dendritic cells increases loading of synthetic peptides on MHC class II molecules and modulates T cell responses.

Adoptive transfer of autologous dendritic cells (DCs) loaded with tumor-associated CD4 and CD8 T cell epitopes represents a promising avenue for the immunotherapy of cancer. In an effort to increase the loading of therapeutic synthetic peptides on MHC II molecules, we used a mutant of HLA-DM (DMY) devoid of its lysosomal sorting motif and that accumulates at the cell surface. Transfection of DMY into HLA-DR(+) cells resulted in increased loading of the exogenously supplied HA(307-318) peptide, as well as increased stimulation of HA-specific T cells. Also, on transduction in mouse and human DCs, DMY increased loading of HEL(48-61) and of the tumor Ag-derived gp100(174-190) peptides, respectively. Interestingly, expression of DMY at the surface of APCs favored Th1 differentiation over Th2. Finally, we found that DMY(-) and DMY(+) mouse APCs differentially stimulated T cell hybridomas sensitive to the fine conformation of peptide-MHC II complexes. Taken together, our results suggest that the overexpression of HLA-DMY at the plasma membrane of DCs may improve quantitatively, but also qualitatively, the presentation of CD4 T cell epitopes in cellular vaccine therapies for cancer.

Memory CCR6+CD4+ T cells are preferential targets for productive HIV type 1 infection regardless of their expression of integrin ß7.

HIV type 1 infection is associated with a rapid depletion of Th17 cells from the GALT. The chemokine receptor CCR6 is a marker for Th17 lineage polarization and HIV permissiveness in memory CD4(+) T cells. CCR6(+) T cells have the potential to migrate into the GALT via the gut-homing integrin α(4)ß(7), a newly identified HIV-gp120 binding receptor. In this study, we investigated whether memory T cells coexpressing CCR6 and integrin ß(7) are selective HIV targets and whether retinoic acid (RA)-induced imprinting for gut-homing selectively increases CCR6(+) T cell permissiveness to infection. We demonstrated that ß(7)(-)R6(+) and ß(7)(+)R6(+) compared with ß(7)(-)R6(-) and ß(7)(+)R6(-) T cells were highly permissive to HIV, produced Th17 cytokines, and their frequency was decreased in the peripheral blood of HIV-infected subjects. RA upregulated integrin α(4) and ß(7) coexpression in both CCR6(+) and CCR6(-) T cells, but increased HIV permissiveness selectively in CCR6(+) T cells via entry (CCR5 upregulation) and postentry mechanisms. In conclusion, these results demonstrate that CCR6, but not the integrin ß(7), is a discriminative marker for memory T cells imprinted with a transcriptional program favorable to HIV replication. Nevertheless, given the ability of integrin ß(7) to regulate cell migration into the GALT and bind HIV-gp120, CCR6(+) T cells coexpressing integrin ß(7) and CCR5 might have an extraordinary ability to disseminate HIV from the portal sites of entry. Understanding the molecular mechanisms of memory CCR6(+) T cell differentiation is critical for the design of new therapeutic strategies that should interfere with viral permissiveness but not Th17 lineage commitment and gut-homing potential in CCR6(+) T cells.

Upregulation of PD-1 expression on HIV-specific CD8+ T cells leads to reversible immune dysfunction.

The engagement of programmed death 1 (PD-1) to its ligands, PD-L1 and PD-L2, inhibits proliferation and cytokine production mediated by antibodies to CD3 (refs. 5,6,7). Blocking the PD-1-PD-L1 pathway in mice chronically infected with lymphocytic choriomeningitis virus restores the capacity of exhausted CD8(+) T cells to undergo proliferation, cytokine production and cytotoxic activity and, consequently, results in reduced viral load. During chronic HIV infection, HIV-specific CD8(+) T cells are functionally impaired, showing a reduced capacity to produce cytokines and effector molecules as well as an impaired capacity to proliferate. Here, we found that PD-1 was upregulated on HIV-specific CD8(+) T cells; PD-1 expression levels were significantly correlated both with viral load and with the reduced capacity for cytokine production and proliferation of HIV-specific CD8(+) T cells. Notably, cytomegalovirus (CMV)-specific CD8(+) T cells from the same donors did not upregulate PD-1 and maintained the production of high levels of cytokines. Blocking PD-1 engagement to its ligand (PD-L1) enhanced the capacity of HIV-specific CD8(+) T cells to survive and proliferate and led to an increased production of cytokines and cytotoxic molecules in response to cognate antigen. The accumulation of HIV-specific dysfunctional CD8(+) T cells in the infected host could prevent the renewal of a functionally competent HIV-specific CD8(+) repertoire.

Receptor-ligand requirements for increased NK cell polyfunctional potential in slow progressors infected with HIV-1 coexpressing KIR3DL1*h/*y and HLA-B*57.

Carriage of the natural killer (NK) receptor genotype KIR3DL1*h/*y with its HLA-B*57 ligand (*h/*y+B*57) is associated with slow time to AIDS and low viral load (VL). To provide a functional basis for these epidemiological observations, we assessed whether HIV-1-infected slow progressors (SP) carrying the *h/*y+B*57 compound genotype would have increased NK cell polyfunctional potential in comparison to SP with other killer immunoglobulin-like receptor (KIR)/HLA compound genotypes and whether this enhanced polyfunctionality was dependent upon the coexpression of both KIR3DL1*h/*y and HLA-B*57. The functional potential of NK cells was investigated by stimulating peripheral blood mononuclear cells with HLA-devoid targets or single HLA transfectants. Multiparametric flow cytometry was used to detect NK cells with seven functional profiles representing all permutations of CD107a expression and gamma interferon (IFN-γ) and tumor necrosis factor alpha (TNF-α) secretion. NK cells from individuals carrying KIR3DL1 receptor-HLA-Bw4 ligand pairs had greater trifunctional responses than those from KIR3DL1 homozygotes (hmz), who were Bw6 homozygotes. NK cells from subjects carrying the *h/*y+B*57 genotypes exhibited the highest trifunctional potential, and this was dependent on cocarriage of the NK receptor and its ligand. Trifunctional cells secreted more of each function tested on a per-cell basis than each corresponding monofunctional NK subset. Although VL influenced NK functionality, individuals with defined KIR/HLA genotypes exhibited differences in NK cell polyfunctionality that could not be accounted for by VL alone. The protective effect of HLA-B*57 on slow progression to AIDS and low VL may be mediated through its interaction with KIR3DL1 alleles to educate NK cells for potent activity upon stimulation.

Dynamics and consequences of IL-21 production in HIV-infected individuals: a longitudinal and cross-sectional study.

IL-21 is a relatively newly discovered immune-enhancing cytokine that plays an essential role in controlling chronic viral infections. It is produced mainly by CD4(+) T cells, which are also the main targets of HIV-1 and are often depleted in HIV-infected individuals. Therefore, we sought to determine the dynamics of IL-21 production and its potential consequences for the survival of CD4(+) T cells and frequencies of HIV-specific CTL. For this purpose, we conducted a series of cross-sectional and longitudinal studies on different groups of HIV-infected patients and show in this study that the cytokine production is compromised early in the course of the infection. The serum cytokine concentrations correlate with CD4(+) T cell counts in the infected persons. Among different groups of HIV-infected individuals, only elite controllers maintain normal production of the cytokine. Highly active antiretroviral therapy only partially restores the production of this cytokine. Interestingly, HIV infection of human CD4(+) T cells inhibits cytokine production by decreasing the expression of c-Maf in virus-infected cells, not in uninfected bystander cells. We also show that the frequencies of IL-21-producing HIV-specific, but not human CMV-specific, Ag-experienced CD4(+) T cells are decreased in HIV-infected viremic patients. Furthermore, we demonstrate in this study that recombinant human IL-21 prevents enhanced spontaneous ex vivo death of CD4(+) T cells from HIV-infected patients. Together, our results suggest that serum IL-21 concentrations may serve as a useful biomarker for monitoring HIV disease progression and the cytokine may be considered for immunotherapy in HIV-infected patients.

Peripheral blood CCR4+CCR6+ and CXCR3+CCR6+CD4+ T cells are highly permissive to HIV-1 infection.

There is limited knowledge on the identity of primary CD4(+) T cell subsets selectively targeted by HIV-1 in vivo. In this study, we established a link between HIV permissiveness, phenotype/homing potential, and lineage commitment in primary CD4(+) T cells. CCR4(+)CCR6(+), CCR4(+)CCR6(-), CXCR3(+)CCR6(+), and CXCR3(+)CCR6(-) T cells expressed cytokines and transcription factors specific for Th17, Th2, Th1Th17, and Th1 lineages, respectively. CCR4(+)CCR6(+) and CXCR3(+)CCR6(+) T cells expressed the HIV coreceptors CCR5 and CXCR4 and were permissive to R5 and X4 HIV replication. CCR4(+)CCR6(-) T cells expressed CXCR4 but not CCR5 and were permissive to X4 HIV only. CXCR3(+)CCR6(-) T cells expressed CCR5 and CXCR4 but were relatively resistant to R5 and X4 HIV in vitro. Total CCR6(+) T cells compared with CCR6(-) T cells harbored higher levels of integrated HIV DNA in treatment-naive HIV-infected subjects. The frequency of total CCR6(+) T cells and those of CCR4(+)CCR6(+) and CXCR3(+)CCR6(+) T cells were diminished in chronically infected HIV-positive subjects, despite viral-suppressive therapy. A high-throughput analysis of cytokine profiles identified CXCR3(+)CCR6(+) T cells as a major source of TNF-alpha and CCL20 and demonstrated a decreased TNF-alpha/IL-10 ratio in CXCR3(+)CCR6(-) T cells. Finally, CCR4(+)CCR6(+) and CXCR3(+)CCR6(+) T cells exhibited gut- and lymph node-homing potential. Thus, we identified CCR4(+)CCR6(+) and CXCR3(+)CCR6(+) T cells as highly permissive to HIV replication, with potential to infiltrate and recruit more CCR6(+) T cells into anatomic sites of viral replication. It is necessary that new therapeutic strategies against HIV interfere with viral replication/persistence in discrete CCR6(+) T cell subsets.

A Comparison of Two Scales to Determine Prevalence of Mood Disorders in Omani Patients Recently Diagnosed with Cancer.

OBJECTIVES: Studies on the prevalence rate of mood disorders in patients recently diagnosed with cancer from Middle East are scare in the literature. Therefore, this study assesses the prevalence rates of anxiety and depression, and their associations with socio-demographic factors, in recently diagnosed patients with cancer living in the Sultanate of Oman. METHODS: In this prospective study, adult patients were interviewed within the first three months of diagnosis of cancer using the Hospital Anxiety and Depression Scale (HADS), and the Centre for Epidemiological Studies Depression (CES-D) Scale. Associations were studied among symptoms of anxiety and depression, and the socio-demographic factors, along with levels of agreement between the two scales. RESULTS: Eighty-nine patients were interviewed, and 65% were females. Using the HADS tool, 41.6% of patients had anxiety, 28% had depression, whereas 5.6% displayed severe depression. Using the CES-D tool, 41.6% of patients had depression, and 11.2% had severe depression. A fair correlation between the CES-D and HADS tools was evidenced with a Cohen's Kappa coefficient value of 0.37 (P<0.001). The socio-demographic factors were not significantly associated with the presence of anxiety and depression (P >0.05). CONCLUSION: Collectively, these findings indicate high prevalence rates of anxiety and depression in Omani patients recently diagnosed with cancer along with a significant correlation between the two scales. These results support the implementation of screening tools early in the trajectory of cancer illness to improve the overall healthcare of these patients.

Coexistence of sickle cell disease and systemic lupus erythematosus is associated with quantitative and qualitative impairments in circulating regulatory B cells.

The incidence of connective tissue diseases such as systemic lupus erythematous (SLE), in adult patients with sickle cell disease (SCD), appears to be increasing. The exact causes underlying this increased risk are still unknown, but a link with B regulatory (Breg) cells is possible as these cells suppress inflammatory responses, and maintain tolerance. Quantitative and qualitative analyses of circulating Breg cells were performed in a cohort of SCD patients with SLE, and their levels were correlated with key soluble mediators promoting autoreactive B cells. We demonstrated that levels of Breg cells were significantly decreased in SCD patients with SLE compared to patients with SCD only or healthy controls. Functional analysis of Breg cells from SCD patients with SLE revealed impairments in IL-10 production that correlated with lower levels of STAT3 phosphorylation, without abnormal expression of IL-10 receptor on Breg cells. On the other hand, BAFF levels were substantially elevated in SCD patients with SLE, but not significantly associated with Breg cell levels. Collectively, these results indicated numerical and functional deficits of Breg cells in SCD patients with SLE and their capacity to maintain tolerance and control inflammation is imbalanced, which leads to the development of autoimmune responses.

Human activated T lymphocytes modulate IDO expression in tumors through Th1/Th2 balance.

Previous cancer vaccination approaches have shown some efficiency in generating measurable immune responses, but they have rarely led to tumor regression. It is therefore possible that tumors emerge with the capacity to down-regulate immune counterparts, through the local production of immunosuppressive molecules, such as IDO. Although it is known that IDO exerts suppressive effects on T cell functions, the mechanisms of IDO regulation in tumor cells remain to be characterized. Here, we demonstrate that activated T cells can induce functional IDO expression in breast and kidney tumor cell lines, and that this is partly attributable to IFN-gamma. Moreover, we found that IL-13, a Th2 cytokine, has a negative modulatory effect on IDO expression. Furthermore, we report IDO expression in the majority of breast and kidney carcinoma samples, with infiltration of activated Th1-polarized T cells in human tumors. These findings demonstrate complex control of immune activity within tumors. Future immune therapeutic interventions should thus include strategies to counteract these negative mechanisms.

T cell Activation does not drive CD4 decline in longitudinally followed HIV-infected Elite Controllers.

BACKGROUND: Elite controllers (EC) are a rare subset of HIV infected individuals who control viral load below 50 copies/ml of plasma without treatment. METHODS: Thirty four EC were studied. The slope of CD4 count change was available for 25 of these subjects. We assessed immune activation by measuring the percent of CD38+HLA-DR+CD8+ T cells in the EC group and comparing it with that in 24 treatment-naïve HIV disease progressors and 13 HIV uninfected healthy controls. RESULTS: Compared to HIV uninfected subjects, EC had higher percentages of CD38+HLA-DR+CD8+ T cells (p < 0.001) that was lower than that observed in progressors (p < 0.01). Fifteen of 25 EC had a slope of CD4 count change that was not significantly different from 0 while 3 had a positive and 7 a negative CD4 count slope. Immune activation did not distinguish EC subsets with stable/increasing versus declining CD4 counts. CONCLUSIONS: Elevated immune activation in ECs is not associated with a faster rate of CD4 decline.

HIV-1 causes an imbalance in the production of interleukin-18 and its natural antagonist in HIV-infected individuals: implications for enhanced viral replication.

BACKGROUND: Concentrations of interleukin (IL)-18 increase in the circulation of human immunodeficiency virus (HIV)-infected persons. However, nothing is known concerning the regulation of IL-18-binding protein (IL-18BP), which neutralizes IL-18 in vivo. This issue is addressed in the present study. METHODS: Serum samples obtained from healthy subjects and HIV-infected patients were analyzed by enzyme-linked immunosorbent assay to determine their IL-18 and IL-18BP contents. Human monocyte-derived macrophages (MDMs) were infected in vitro with HIV type 1 (HIV-1), and the production of these 2 cytokines by these cells was measured. Finally, we determined the effect of IL-18 on HIV-1 replication in human cells. RESULTS: In contrast to IL-18 levels, IL-18BP levels decreased in the serum of HIV-infected patients. This decrease resulted in enhanced levels of free IL-18 in the serum of such patients. The infection increased production of IL-18 but decreased that of IL-18BP in MDMs. IL-10 and transforming growth factor-beta, concentrations of which are increased in HIV-infected persons, also decreased production of IL-18BP by human MDMs. Finally, recombinant human IL-18 enhanced HIV-1 replication in human CD4(+) T cells. CONCLUSIONS: Production of IL-18 and its antagonist becomes imbalanced in HIV-1-infected persons. The infection and the cytokine milieu play a role in this decreased production. The increased biological activities of IL-18 may enhance viral replication in human CD4(+) T cells.

A Surrogate Water Quality Index to assess groundwater using a unified DEA-OWA framework.

In this paper, we introduce a new approach, based on a unified framework incorporating Data Envelopment Analysis (DEA) and Ordered Weighted Averaging (OWA), for assessing water quality in contextual settings that involve a large number of hydrochemical parameters. In order to enhance discrimination among water sources, the DEA model is adopted with data-driven input variables, called "surrogate optimistic closeness values," computed through an aggregation procedure that includes the observed values of the hydrochemical parameters with OWA weights. The proposed DEA-OWA methodology has been employed to assess the quality of 51 water samples, collected from irrigation wells in Sereflikochisar Basin, Turkey, by means of 19 hydrochemical parameters. Using different subjectivity levels, the Surrogate Water Quality Indices (SWQIs) that are produced are proven effective in enhancing discrimination among the water sources while enabling a more robust water quality-based ranking. The k-means analysis has been used for clustering the water quality of the wells into Excellent, Good, Permissible, and Unsuitable rather than using pre-set boundaries. Only one water source has been identified as Excellent, whereas 17.65%, 45.10%, and 35.29% of the sampled wells, respectively, are categorized with Good, Permissible, and Unsuitable water quality. Inferred from wells' location, the results suggest that the groundwater might be drastically affected by saline water intrusion from Lake Tuz. The latter conclusion has been corroborated through a Tobit regression analysis.