EPIdemiology of Surgery-Associated Acute Kidney Injury (EPIS-AKI) : Study protocol for a multicentre, observational trial

More than 300 million surgical procedures are performed each year. Acute kidney injury (AKI) is a common complication after major surgery and is associated with adverse short-term and long-term outcomes. However, there is a large variation in the incidence of reported AKI rates. The establishment of an accurate epidemiology of surgery-associated AKI is important for healthcare policy, quality initiatives, clinical trials, as well as for improving guidelines. The objective of the Epidemiology of Surgery-associated Acute Kidney Injury (EPIS-AKI) trial is to prospectively evaluate the epidemiology of AKI after major surgery using the latest Kidney Disease: Improving Global Outcomes (KDIGO) consensus definition of AKI. EPIS-AKI is an international prospective, observational, multicentre cohort study including 10 000 patients undergoing major surgery who are subsequently admitted to the ICU or a similar high dependency unit. The primary endpoint is the incidence of AKI within 72 hours after surgery according to the KDIGO criteria. Secondary endpoints include use of renal replacement therapy (RRT), mortality during ICU and hospital stay, length of ICU and hospital stay and major adverse kidney events (combined endpoint consisting of persistent renal dysfunction, RRT and mortality) at day 90. Further, we will evaluate preoperative and intraoperative risk factors affecting the incidence of postoperative AKI. In an add-on analysis, we will assess urinary biomarkers for early detection of AKI. EPIS-AKI has been approved by the leading Ethics Committee of the Medical Council North Rhine-Westphalia, of the Westphalian Wilhelms-University Münster and the corresponding Ethics Committee at each participating site. Results will be disseminated widely and published in peer-reviewed journals, presented at conferences and used to design further AKI-related trials. Trial registration number NCT04165369

Are patients at risk for psychological maladjustment during fertility treatment less willing to comply with treatment? Results from the Portuguese validation of the SCREENIVF

Item does not contain fulltextSTUDY QUESTION: Do patients at risk for psychological maladjustment during fertility treatment present lower intentions to comply with recommended treatment than patients not at risk? SUMMARY ANSWER: Patients at risk of psychological maladjustment present similar high intentions to comply with recommended fertility treatment to those not at risk but their intentions are conditioned by the degree of control they perceive over their fertility and its treatment and their capacity to accept a future without biological children. WHAT IS KNOWN ALREADY: Infertile couples refer to the psychological burden of treatment as one of the most important reasons for withdrawal from recommended treatment. The SCREENIVF can be used before treatment to screen patients at risk for psychological maladjustment by assessing five risk factors: anxiety, depression, helplessness and lack of acceptance cognitions and social support. STUDY DESIGN, SIZE, DURATION: Cross-sectional study. First, we investigated the psychometric properties of the Portuguese version of the SCREENIVF. Secondly, we investigated associations between risk for psychological maladjustment and intentions to comply with treatment. PARTICIPANTS/ MATERIALS, SETTING, METHODS: Two hundred and ninety-one women and 92 men undergoing any stage of fertility treatment at Portuguese infertility clinics were recruited online or in the clinical setting (55% response rate). Participants completed questionnaires that assessed their emotional adjustment, quality of life and compliance intentions. MAIN RESULTS AND ROLE OF CHANCE: The confirmatory factor analysis for the SCREENIVF indicated good fit [chi(2) = 188.50, P /= 0.70, except depression for men: alpha = 0.66). Fifty-two percent of women and 30% of men were at risk for maladjustment. Women and men at risk and not at risk for maladjustment reported similar intentions to comply with treatment (P > 0.05). Cognitive risk factors moderated negative associations found between distress and compliance intentions. Higher anxiety was associated with lower compliance intentions for patients with lower helplessness cognitions (beta = -0.45, P = 0.01) and men with higher acceptance cognitions (beta = -0.60; P = 0.03), but not for patients with higher helplessness cognitions (beta = 0.25, P = 0.13) and men with lower acceptance cognitions (beta = 0.38; P = 0.21). Higher depression was associated with lower compliance intentions for patients with higher helplessness cognitions (beta = -0.33, P = 0.02), but not for patients with lower helplessness cognitions (beta = 0.19, P = 0.30). LIMITATIONS, REASONS FOR CAUTION: Few men participated and thus only medium-to-large effect sizes could be detected for them. Forty-eight percent of participants were recruited online and this could have resulted in higher rates of patients at risk. WIDER IMPLICATIONS OF THE FINDINGS: The SCREENIVF is not useful to identify patients at risk for non-compliance. However, the clinic staff should be aware that patients who score high on helplessness cognitions and low on acceptance may need additional decisional aid to make autonomous and satisfying decisions about uptake of treatment. The Portuguese version of the SCREENIVF is valid and reliable and can be used with women undergoing any type of fertility treatment. STUDY FUNDING/ COMPETING INTEREST(S): S.G. received a postdoctoral fellowship from the Portuguese Foundation for Science and Technology (FCT-SFRH/BPD/63063/2009). There are no conflicts of interest to declare

Assessing infertility stress: Re-examining the factor structure of the Fertility Problem Inventory

Background: Research has documented that fertility problems can negatively affect infertile patients life, by imposing an obstacle to one important life goal: the achievement of parenthood. The Fertility Problem Inventory (FPI) proposes a comprehensive approach in assessing infertility stress, by measuring the impact on social, marital and sexual life dimensions and the importance of parenthood in infertile patients’ life. This study examined the factor structure of the FPI, testing two alternative models. Method: A sample of 209 infertile patients was recruited in two public hospital departments of assisted reproductive technology. Measures included the FPI, the Brief Symptom Inventory, and the ENRICH Marital Inventory. Two higher-order factor models were tested using a confirmatory factor analysis. Results: Results confirmed the original measurement model of the instrument but suggested that the inclusion of an intermediate conceptual level resulted in a better fit to the model, i.e., the instrument assesses infertility related stress by assessing two main conceptual domains: the impact of infertility in infertile patients’ life and representations about the importance of parenthood in one’s life. The instrument revealed measurement and structure invariance. The FPI also revealed good construct validity by correlating with other measures assessing similar constructs. Conclusions: This approach to the FPI has important contributions for both research and clinical practice by distinguishing between the impact of infertility on different dimensions couples’ life and representations about the importance of parenthood in one’s life, therefore extending the utility of the FPI in research and clinical practice

Independent research needed to inform end-of-life policy choices

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Anti-Ly6G binding and trafficking mediate positive neutrophil selection to unleash the anti-tumor efficacy of radiation therapy.

The anti-Ly6G antibody is used to deplete Ly6G <sup>pos</sup> neutrophils and study their role in diverse pathologies. However, depletion is never absolute, as Ly6G <sup>low</sup> neutrophils resistant to depletion rapidly emerge. Studying the functionality of these residual neutrophils is necessary to interpret anti-Ly6G-based experimental designs. In vitro, we found anti-Ly6G binding induced Ly6G internalization, surface Ly6G paucity, and primed the oxidative burst of neutrophils upon TNF α co-stimulation. In vivo, we found neutrophils resistant to anti-Ly6G depletion exhibited anti-neutrophil-cytoplasmic-antibodies. In the pre-clinical Kras <sup>Lox-STOP-Lox-G12D/WT</sup> ; Trp53 <sup>Flox/Flox</sup> mouse lung tumor model, abnormal neutrophil accumulation and aging was accompanied with an N2-like SiglecF <sup>pos</sup> polarization and ly6g downregulation. Consequently, SiglecF <sup>pos</sup> neutrophils exposed to anti-Ly6G reverted to Ly6G <sup>low</sup> and were resistant to depletion. Noting that anti-Ly6G mediated neutrophil depletion alone had no anti-tumor effect, we found a long-lasting rate of tumor regression (50%) by combining anti-Ly6G with radiation-therapy, in this model reputed to be refractory to standard anticancer therapies. Mechanistically, anti-Ly6G regulated neutrophil aging while radiation-therapy enhanced the homing of anti-Ly6G-boundSiglecF <sup>neg</sup> neutrophils to tumors. This anti-tumor effect was recapitulated by G-CSF administration prior to RT and abrogated with an anti-TNFα antibody co-administration. In summary, we report that incomplete depletion of neutrophils using targeted antibodies can intrinsically promote their oxidative activity. This effect depends on antigen/antibody trafficking and can be harnessed locally using select delivery of radiation-therapy to impair tumor progression. This underutilized aspect of immune physiology may be adapted to expand the scope of neutrophil-related research

GLUT1 Expression in Tumor-Associated Neutrophils Promotes Lung Cancer Growth and Resistance to Radiotherapy.

Neutrophils are the most abundant circulating leucocytes and are essential for innate immunity. In cancer, pro- or antitumor properties have been attributed to tumor-associated neutrophils (TAN). Here, focusing on TAN accumulation within lung tumors, we identify GLUT1 as an essential glucose transporter for their tumor supportive behavior. Compared with normal neutrophils, GLUT1 and glucose metabolism increased in TANs from a mouse model of lung adenocarcinoma. To elucidate the impact of glucose uptake on TANs, we used a strategy with two recombinases, dissociating tumor initiation from neutrophil-specific Glut1 deletion. Loss of GLUT1 accelerated neutrophil turnover in tumors and reduced a subset of TANs expressing SiglecF. In the absence of GLUT1 expression by TANs, tumor growth was diminished and the efficacy of radiotherapy was augmented. Our results demonstrate the importance of GLUT1 in TANs, which may affect their pro- versus antitumor behavior. These results also suggest targeting metabolic vulnerabilities to favor antitumor neutrophils. SIGNIFICANCE: Lung tumor support and radiotherapy resistance depend on GLUT1-mediated glucose uptake in tumor-associated neutrophils, indicating that metabolic vulnerabilities should be considered to target both tumor cells as well as innate immune cells. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/81/9/2345/F1.large.jpg