NSGO-OV-UMB1/ENGOT-OV30: A phase II study of durvalumab in combination with the anti-CD73 monoclonal antibody Oleclumab in patients with relapsed ovarian cancer.

OBJECTIVES: In patients with epithelial ovarian cancer (EOC), the clinical efficacy of monotherapy with immune checkpoint inhibitors (ICIs) against PD-1/PD-L1 is modest. To enhance response rates to these immunotherapeutic agents and broaden the indications for their use, new approaches involving combinational therapy are needed. The immune regulator CD73 is a potential target, as it promotes tumor escape by producing immunosuppressive extracellular adenosine in the tumor microenvironment. Here, we present the results from the NSGO-OV-UMB1/ENGOT-OV-30 trial evaluating the activity of combining the anti-CD73 antibody oleclumab with the anti-PD-L1 checkpoint inhibitor durvalumab in patients with recurrent EOC. METHODS: In this phase II open-label non-randomized study, patients with CD73-positive relapsed EOC were intravenously administered oleclumab (3000 mg, Q2W) and durvalumab (1500 mg, Q4W). The primary endpoint was disease control rate (DCR) at 16 weeks. The expression of PD-L1 and CD8 was assessed by immunohistochemistry of archival tumors. RESULTS: This trial included 25 patients with a median age of 66 years (47-77 years). Twenty-two patients were evaluable for treatment activity analysis. The DCR was 27%, the median progression-free survival was 2.7 months (95% CI: 2.2-4.2) and the median overall survival was 8.4 months (95% CI: 5.0-13.4). Infiltration of CD8+ cells and PD-L1 expression on tumor cells were observed in partially overlapping sets of 74% of the tumor samples. Neither CD8- nor PD-L1-positivity were significantly associated with better DCR. CONCLUSIONS: Combined treatment with oleclumab and durvalumab was safe and demonstrated limited anti-tumor activity in patients with recurrent EOC.

Determination of differences in ultrasound parameters for patellar tendons in males with unilateral patellar tendinopathy-An ancillary analysis of data from two randomized controlled trials.

PURPOSE: To investigate power Doppler (PD) activity and tendon structure (between the injured and contralateral limb) in patients with unilateral patellar tendinopathy (PT) using ultrasonography (US). Secondly, the aim was to determine the intra-rater reliability of the PD activity and tendon structure. METHODS: This study analyzed US baseline data from 57 male participants with symptomatic unilateral PT who had been enrolled in one of two randomized clinical trials. Data were analyzed to examine if systematic differences existed between injured and contralateral limbs using Fiji ImageJ. RESULTS: The PD activity of the symptomatic tendon was larger 25.6 (Q1 = 14.9; Q3 = 41.6) mm2 than the asymptomatic 0 (Q1 = 0.0; Q3 = 0.0) mm2 (p < 0.001). There was a significantly greater tendon thickness at the proximal (2.5 mm 95% CI [2.0; 3.0]), mid (0.8 mm 95% CI [0.5; 1.1]), and distal (0.2 mm 95% CI [0.1; 0.4]) part of the tendon for the symptomatic compared to the asymptomatic tendon. Intra-rater reliability for PD activity and tendon structure ranged from moderate-to-excellent (0.74; 0.99). CONCLUSION: These results provide mean estimates for tendon thickness of symptomatic and asymptomatic tendons, that can be used for clinicians to reliably estimate pathological tendon thickness.

The evolving landscape of publishing in the field of pain: An automated bibliometric analysis from 1975 to 2020.

BACKGROUND: The aims of this bibliometric analysis were (1) a longitudinal analysis of the publication landscape in the field of pain (1975-2020) and (2) to characterize the overall publication profiles for two selected journals: European Journal of Pain and PAIN® utilizing an automated approach. METHODS: Database searches in Scopus extracted all journals with 'pain' in their title. For the two specific journals, papers were manually/automatically profiled into preclinical, human and translational studies. RESULTS: A gross list of 64 journals in the field of pain consisting of both active and ceased journals in Scopus were included in this analysis which identified 62,565 papers with approximately 4000 papers published/year. These papers include 2759 and 9156 papers in Eur. J. Pain and PAIN®, respectively. Currently, there are 24 active 'pain' journals. Authors/paper increase from 2 to 7 indicating a development from mono-disciplinary to multi-disciplinary studies. The overall publication profiles assessing preclinical, human (experimental/clinical) and translational papers in Eur. J. Pain and PAIN® were almost similar (14%, 75% and 10% versus 26%, 63% and 10%). Papers have changed over the years from mono-disciplinary studies (e.g. behavioural studies) to multi-disciplinary studies (e.g. combined behavioural and cell studies). After optimization, the search model matched the manual screening by 100%, 98% and 96% for the preclinical, clinical and healthy volunteer categories. CONCLUSIONS: Over the last 45 years, more than 60,000 pain-related papers have been published. Papers develop over the years from mono-disciplinary to multi-disciplinary studies. The overall publication profile including preclinical, human (experimental/clinical) and translational papers was almost similar in Eur. J. Pain and PAIN®. SIGNIFICANCE: The bibliometric analysis of a pain journal provides information on which specific areas of research are published, how this may have changed over the years and how a journal is positioned compared with other journals in the field.

Assessing how routes to diagnosis vary by the age of patients with cancer: a nationwide register-based cohort study in Denmark.

BACKGROUND: Older patients with cancer have poorer prognosis compared to younger patients. Moreover, prognosis is related to how cancer is identified, and where in the healthcare system patients present, i.e. routes to diagnosis (RtD). We investigated whether RtD varied by patients' age. METHODS: This population-based national cohort study used Danish registry data. Patients were categorized into age groups and eight mutually exclusive RtD. We employed multinomial logistic regressions adjusted for sex, region, diagnosis year, cohabitation, education, income, immigration status and comorbidities. Screened and non-screened patients were analysed separately. RESULTS: The study included 137,876 patients. Both younger and older patients with cancer were less likely to get diagnosed after a cancer patient pathways referral from primary care physician compared to middle-aged patients. Older patients were more likely to get diagnosed via unplanned admission, death certificate only, and outpatient admission compared to younger patients. The patterns were similar across comorbidity levels. CONCLUSIONS: RtD varied by age groups, and middle-aged patients were the most likely to get diagnosed after cancer patient pathways with referral from primary care. Emphasis should be put on raising clinicians' awareness of cancer being the underlying cause of symptoms in both younger patients and in older patients.

An Eye-Tracking Study of Attention Biases in Children at High Familial Risk for Depression and Their Parents with Depression.

Attention biases (AB) are a core component of cognitive models of depression yet it is unclear what role they play in the transgenerational transmission of depression. 44 children (9-14 years) with a high familial risk of depression (HR) were compared on multiple measures of AB with 36 children with a low familial risk of depression (LR). Their parents: 44 adults with a history of depression (HD) and 36 adults with no history of psychiatric disorder (ND) were also compared. There was no evidence of group differences in AB; neither between the HR and LR children, nor between HD and ND parents. There was no evidence of a correlation between parent and child AB. The internal consistency of the tasks varied greatly. The Dot-Probe Task showed unacceptable reliability whereas the behavioral index of the Visual-Search Task and an eye-tracking index of the Passive-Viewing Task showed better reliability. There was little correlation between the AB tasks and the tasks showed minimal convergence with symptoms of depression or anxiety. The null-findings of the current study contradict our expectations and much of the previous literature. They may be due to the poor psychometric properties associated with some of the AB indices, the unreliability of AB in general, or the relatively modest sample size. The poor reliability of the tasks in our sample suggest caution should be taken when interpreting the positive findings of previous studies which have used similar methods and populations.

Increased incidence of genital warts among women and men with type 1 diabetes compared with the general population-results from a nationwide registry-based, cohort study.

AIMS: To estimate the incidence rates of genital warts (GWs) in women and men with type 1 diabetes compared to persons without diabetes. METHODS: In this nationwide registry-based cohort study, we included the entire population aged 15 to 49 years living in Denmark between 1996 and 2016. From national registries, we retrieved individual level information on diabetes status, diagnoses and treatment of GWs, and potential confounding variables. We used Poisson regression to model sex- and age-specific incidence rates of GWs in persons with type 1 diabetes and persons without diabetes. Based on the models, we computed sex-specific incidence rate ratios (IRRs) of GWs in persons with type 1 diabetes compared to persons without diabetes, overall and according to age. RESULTS: The analysis included 3,514,824 persons without type 2 diabetes and no GW diagnoses before baseline. The incidence rate of GWs in persons with type 1 diabetes was higher than in those without diabetes, both among women (IRR = 1.59; 95% CI, 1.42-1.78) and men (IRR = 1.36; 95% CI, 1.25-1.48). The pattern of increased incidence rates of GWs in persons with type 1 diabetes was seen at all ages. CONCLUSIONS: Persons with type 1 diabetes have higher incidence rates of GWs than persons without diabetes. This supports the importance of HPV vaccination of young girls and boys with type 1 diabetes.

Can combining vaginal and rectal progesterone achieve the optimum progesterone range required for implantation in the HRT-FET model?

RESEARCH QUESTION: What is the ongoing pregnancy rate (OPR) in frozen embryo transfer (FET) cycles, using combined rectal and vaginal progesterone in hormonal replacement therapy (HRT)? DESIGN: A prospective cohort study (n = 277) including 239 HRT-FET cycles with serum progesterone measurements studying combined vaginal (90 mg/12 h) and rectal (90 mg/12 h) progesterone administration and single blastocyst transfer on the sixth day of progesterone administration. A total of 134 responses to questionnaires covering convenience and side-effects were collected. RESULTS: The median serum progesterone level was 45 nmol/l (range 2-150 nmol/l). Overall positive HCG rate, OPR at week 12 and pregnancy loss rates were 62%, 44% and 29%, respectively. A non-linear relationship between serum progesterone levels and OPR was found. Crude odds ratio for OPR in the high progesterone group (>45 nmol/l) was 0.56 (95% CI 0.32 to 0.98; P = 0.04) compared with the intermediate progesterone group (28-45 nmol/l). Discomfort after rectal progesterone administration was reported on the embryo transfer day and on the day of pregnancy scan 5 weeks later by a total of 18% (16/87) and 17% (8/47) of patients, respectively. Discomfort related to vaginal administration increased significantly over time and was reported by 18% (16/87) on the day of embryo transfer compared with 45% (21/47) on the day of pregnancy scan (P < 0.002). CONCLUSIONS: Combined rectal and vaginal progesterone in HRT-FET cycles resulted in higher median progesterone levels compared with vaginal administration alone. This study suggests that an upper threshold for serum progesterone exists and that above this concentration serum progesterone levels decrease the OPR. Rectally administered progesterone was well tolerated by patients.

Exo-Ocean Exploration with Deep-Sea Sensor and Platform Technologies.

One of Saturn's largest moons, Enceladus, possesses a vast extraterrestrial ocean (i.e., exo-ocean) that is increasingly becoming the hotspot of future research initiatives dedicated to the exploration of putative life. Here, a new bio-exploration concept design for Enceladus' exo-ocean is proposed, focusing on the potential presence of organisms across a wide range of sizes (i.e., from uni- to multicellular and animal-like), according to state-of-the-art sensor and robotic platform technologies used in terrestrial deep-sea research. In particular, we focus on combined direct and indirect life-detection capabilities, based on optoacoustic imaging and passive acoustics, as well as molecular approaches. Such biologically oriented sampling can be accompanied by concomitant geochemical and oceanographic measurements to provide data relevant to exo-ocean exploration and understanding. Finally, we describe how this multidisciplinary monitoring approach is currently enabled in terrestrial oceans through cabled (fixed) observatories and their related mobile multiparametric platforms (i.e., Autonomous Underwater and Remotely Operated Vehicles, as well as crawlers, rovers, and biomimetic robots) and how their modified design can be used for exo-ocean exploration.

Nationwide cohort study of the impact of education, income and social isolation on survival after acute colorectal cancer surgery.

BACKGROUND: Acute colorectal cancer surgery has been associated with a high postoperative mortality. The primary aim of this study was to examine the association between socioeconomic position and the likelihood of undergoing acute versus elective colorectal cancer surgery. A secondary aim was to determine 1-year survival among patients treated with acute surgery. METHODS: All patients who had undergone a surgical procedure according to the Danish Colorectal Cancer Group (DCCG.dk) database, or who were registered with stent or diverting stoma in the National Patient Register from 2007 to 2015, were reviewed. Socioeconomic position was determined by highest attained educational level, income, urbanicity and cohabitation status, obtained from administrative registries. Co-variables included age, sex, year of surgery, Charlson Co-morbidity Index score, smoking status, alcohol consumption, BMI, stage and tumour localization. Logistic regression analysis was performed to determine the likelihood of acute colorectal cancer surgery, and Kaplan-Meier and Cox proportional hazards regression methods were used for analysis of 1-year overall survival. RESULTS: In total, 35 661 patients were included; 5310 (14·9 per cent) had acute surgery. Short and medium education in patients younger than 65 years (odds ratio (OR) 1·58, 95 per cent c.i. 1·32 to 1·91, and OR 1·34, 1·15 to 1·55 respectively), low income (OR 1·12, 1·01 to 1·24) and living alone (OR 1·35, 1·26 to 1·46) were associated with acute surgery. Overall, 40·7 per cent of patients died within 1 year of surgery. Short education (hazard ratio (HR) 1·18, 95 per cent c.i. 1·03 to 1·36), low income (HR 1·16, 1·01 to 1·34) and living alone (HR 1·25, 1·13 to 1·38) were associated with reduced 1-year survival after acute surgery. CONCLUSION: Low socioeconomic position was associated with an increased likelihood of undergoing acute colorectal cancer surgery, and with reduced 1-year overall survival after acute surgery.

ANTECEDENTES: La cirugía urgente del cáncer colorrectal se ha asociado con una mortalidad postoperatoria elevada. El objetivo principal de este estudio fue determinar la relación entre el estatus socioeconómico y la probabilidad de indicación de cirugía de cáncer colorrectal de forma urgente o electiva. El objetivo secundario fue determinar la supervivencia a 1 año en los pacientes tratados con cirugía urgente. MÉTODOS: Se revisaron todos los pacientes en los que se había realizado un procedimiento quirúrgico recogidos en la base de datos Danish Colorectal Cancer (DCCG.dk) o que se hubiera colocado una prótesis o efectuado un estoma de derivación que constasen en el National Patient Register entre 2007 y 2015. El estatus socioeconómico se estableció según el nivel más alto de educación alcanzado, los ingresos, el lugar de residencia y la situación de convivencia, datos que se obtuvieron de registros administrativos. Las covariables analizadas fueron el género, la edad, el año de la cirugía, el índice de comorbilidad de Charlson, el hábito tabáquico, el consumo de alcohol, el índice de masa corporal, el estadio y la localización del tumor. Se calcularon las regresiones logísticas según la probabilidad de cirugía de cáncer colorrectal urgente y se utilizó el método de Kaplan Meier y Cox para el análisis de la supervivencia global a 1 año. RESULTADOS: Se incluyeron 35.661 pacientes, de los que a 5.310 (15%) se realizó un procedimiento quirúrgico de urgencia. Los factores que se asociaron a cirugía urgente fueron un nivel educativo bajo o medio en menores de 65 años (razón de oportunidades, odds ratio, OR = 1,58, i.c del 95% 1,32-1,91 y OR = 1,34, i.c. del 95% 1,15-1,55, respectivamente), los bajos ingresos (OR = 1,12, i.c del 95% 1,01 -1,24) y vivir solo (OR = 1,35, i.c. del 95% 1,26-1,46). El 41,0% de los pacientes a los que se realizó cirugía urgente fallecieron en el primer año postoperatorio. Los factores asociados con una baja tasa de supervivencia al año de la cirugía urgente fueron un nivel educativo bajo (cociente de riesgos instantáneos, hazard ratio, HR = 1,18, i.c. del 95% 1,03-1,36), unos ingresos bajos (HR = 1,16, i.c. del 95% 1,01-1,34) y vivir solo (HR = 1,25, i.c. del 95% 1,13-1,38). CONCLUSIÓN: La probabilidad de ser sometido a cirugía urgente por un cáncer colorrectal y ver reducida la probabilidad de supervivencia en el primer año postoperatorio es mayor en pacientes con un estatus socioeconómico bajo.

Fractional exhaled nitric oxide as a potential biomarker for radiation pneumonitis in patients with non-small cell lung cancer: A pilot study.

INTRODUCTION: The aim of the study was to investigate repetitive fractional exhaled nitric oxide (FeNO) measurements during high-dose radiation therapy (HDRT) and to evaluate the use of FeNO to predict symptomatic radiation pneumonitis (RP) in patients being treated for non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: A total of 50 patients with NSCLC referred for HDRT were enrolled. FeNO was measured at baseline, weekly during HDRT, one month- and every third month after HDRT for a one-year follow-up period. The mean FeNO(visit 0-6) was calculated using the arithmetic mean of the baseline and weekly measurements during HDRT. Patients with grade ≥ 2 of RP according to the Common Terminology Criteria for Adverse Events (CTCAE) were considered symptomatic. RESULTS: A total of 42 patients completed HDRT and weekly FeNO measurements. Grade ≥ 2 of RP was diagnosed in 24 (57%) patients. The mean FeNO(visit 0-6) ±â€¯standard deviation in patients with and without RP was 15.0 ±â€¯7.1 ppb (95%CI: 12.0-18.0) and 10.3 ±â€¯3.4 ppb (95%CI: 8.6-11.9) respectively with significant differences between the groups (p = 0.0169, 95%CI: 2.3-2.6). The leave-one-out cross-validated cut-off value of the mean FeNO(visit 0-6) ≥ 14.8 ppb was predictive of grade ≥ 2 RP with a specificity of 71% and a positive predictive value of 78%. CONCLUSIONS: The mean FeNO(visit 0-6) in patients with symptomatic RP after HDRT for NSCLC was significantly higher than in patients without RP and may serve as a potential biomarker for RP.

The impact of luteal serum progesterone levels on live birth rates-a prospective study of 602 IVF/ICSI cycles.

STUDY QUESTION: Is the chance of a live birth following IVF treatment and fresh embryo transfer affected by early and mid-luteal serum progesterone (P4) levels? SUMMARY ANSWER: Low as well as high serum P4 levels in the early and mid-luteal phase reduce the chance of a live birth following IVF treatment with fresh embryo transfer. WHAT IS KNOWN ALREADY: Data from non-human studies and studies of frozen-thawed embryo transfer cycles indicate that low as well as high P4 levels during the mid-luteal phase decrease the chance of pregnancy. The altered P4 pattern may disrupt the endometrial maturation leading to asynchrony between embryonic development and endometrial receptivity, thereby, compromising implantation and early development of pregnancy. STUDY DESIGN, SIZE, DURATION: Prospective multicenter cohort study of 602 women undergoing IVF treatment. Patients were recruited from four Danish public Fertility Centers from May 2014 to June 2017. The study population was unselected, thus, representing a normal everyday patient cohort. Patients were treated in a long GnRH-agonist protocol or a GnRH-antagonist protocol and triggered for final oocyte maturation with either hCG or a GnRH-agonist. The same vaginal luteal support regimen was applied in all patients. PARTICIPANTS/MATERIALS, SETTING, METHODS: Serum P4 levels from the early or mid-luteal phase were correlated to positive hCG and live birth rates (delivery > gestational week 20). Patients were divided into four P4 groups based on raw data of P4 serum levels and reproductive outcomes during early luteal phase (P4<60 nmol/l, P4 60-100 nmol/l, P4 101-400 nmol/l and P4>400 nmol/l) and during mid-luteal phase (P4<150 nmol/l, P4 150-250 nmol/l, P4 251-400 nmol/l and P4>400 nmol/l). MAIN RESULTS AND THE ROLE OF CHANCE: The optimal chance of pregnancy was achieved with serum P4 levels of 60-100 nmol/l in the early luteal phase whereas the optimal P4 level during the mid-luteal phase was 150-250 nmol/l. Below, but most distinctly above these levels, the chance of pregnancy was consistently reduced. With an early luteal P4 level of 60-100 nmol/l, the chance of a positive hCG-test was 73%, 95% CI: [59, 84] following cleavage stage embryo transfer. In contrast, with P4 levels >400 nmol/l, the chance of a positive hCG-test was significantly reduced to 35%, 95% CI: [17, 57], thus, an absolute risk difference of -38%, P = 0.01. A similar negative association between early luteal P4 and live birth rate was found, although it did not reach statistical significance. During the mid-luteal phase, a P4 level of 150-250 nmol/l resulted in an optimal chance of live birth: 54%, 95% CI: [37, 70] compared to 38%, 95% CI: [20, 60] with a P4 level >400 nmol/l, thus, an absolute risk difference of -16%, P = 0.14. All estimates were adjusted for maternal age, maternal BMI, study site, final follicle count and late follicular P4 levels. LIMITATIONS, REASONS FOR CAUTION: This study is the first to explore the possible upper and lower thresholds for luteal P4 following IVF treatment and fresh embryo transfer, and the optimal P4 ranges found in this study should be corroborated in future clinical trials. Furthermore, the P4 thresholds in this study only apply to fresh IVF cycles, using vaginal luteal phase support, as the optimal P4 level in cycles using intramuscular P4 may be different. WIDER IMPLICATIONS OF THE FINDINGS: Future studies are necessary to explore whether additional exogenous luteal P4 supplementation in the low P4 group could increase the chance of a live birth following fresh embryo transfer, and whether patients with luteal P4 levels >400 nmol/l would benefit from segmentation followed by subsequent transfer in frozen/thawed cycles. TRIAL REGISTRATION NUMBER: NCT02129998 (Clinicaltrials.gov). STUDY FUNDING/COMPETING INTEREST(S): L.H.T. received an unrestricted grant from Ferring Pharmaceuticals, Denmark, to support this study. P.H. received unrestricted research grants from MSD, Merck, Gedeon Richter and Ferring Pharmaceuticals outside of this work as well as honoraria for lectures from MSD, Merck and Gedeon Richter outside of this work. U.K. received honoraria for lectures from MSD and Ferring Pharmaceuticals outside of this work. C.A. received unrestricted research grants from MSD, IBSA, and Ferring Pharmaceuticals outside of this work as well as honoraria for lectures from MSD and IBSA. H.O.E. and B.B.P. received an unrestricted research grant from Gedeon Richter outside of this work. K.E., L.B., D.P. and B.H. have no conflict of interest. Furthermore, grants from 'The Health Research Fund of Central Denmark Region', 'The Research Foundation of the Hospital of Central Jutland', 'The Research Foundation of A.P. Møller', 'The Research Foundation of Aase & Ejnar Danielsen', 'The Research Foundation of Dagmar Marshall', 'The Research Foundation of Dir. Jacob Madsen & Hustru Olga Madsen', 'The Research Foundation of Fam. Hede Nielsen' and 'The Danish Medical Research Grant' supported conducting this study. The providers of funding were neither involved in the conduction of the study nor in the writing of the scientific report.

Placental inflammation in pre-eclampsia by Nod-like receptor protein (NLRP)3 inflammasome activation in trophoblasts.

Pre-eclampsia is associated with increased levels of cholesterol and uric acid and an inflamed placenta expressing danger-sensing pattern recognition receptors (PRRs). Crystalline cholesterol and uric acid activate the PRR Nod-like receptor protein (NLRP)3 inflammasome to release interleukin (IL)-1ß and result in vigorous inflammation. We aimed to characterize crystal-induced NLRP3 activation in placental inflammation and examine its role in pre-eclampsia. We confirmed that serum total cholesterol and uric acid were elevated in pre-eclamptic compared to healthy pregnancies and correlated positively to high sensitivity C-reactive protein (hsCRP) and the pre-eclampsia marker soluble fms-like tyrosine kinase-1 (sFlt-1). The NLRP3 inflammasome pathway components (NLRP3, caspase-1, IL-1ß) and priming factors [complement component 5a (C5a) and terminal complement complex (TCC)] were co-expressed by the syncytiotrophoblast layer which covers the placental surface and interacts with maternal blood. The expression of IL-1ß and TCC was increased significantly and C5a-positive regions in the syncytiotrophoblast layer appeared more frequent in pre-eclamptic compared to normal pregnancies. In-vitro activation of placental explants and trophoblasts confirmed NLRP3 inflammasome pathway functionality by complement-primed crystal-induced release of IL-1ß. This study confirms crystal-induced NLRP3 inflammasome activation located at the syncytiotrophoblast layer as a mechanism of placental inflammation and suggests contribution of enhanced NLRP3 activation to the harmful placental inflammation in pre-eclampsia.

Prevalence of Human Papillomavirus in Self-Taken Samples from Screening Nonattenders.

The Copenhagen Self-Sampling Initiative (CSi) has shown how human papillomavirus (HPV)-based self-sampling can be used to increase screening participation among 23,632 nonattenders in the Capital Region of Denmark. In this study, we describe HPV prevalence and genotype frequency in 4,824 self-samples as determined by three HPV assays (the CLART, Onclarity, and Hybrid Capture 2 [HC2] assays) and compare the results with those for physician-taken follow-up samples. The HPV self-sample findings were also compared to the findings for a reference population of 3,347 routinely screened women from the Horizon study, which had been undertaken in the same screening laboratory. Nonattenders had an HPV prevalence of 11.3% as determined by the CLART assay, which was lower than that for women from the Horizon study (18.5%). One-third of the CSi women who tested HPV positive by self-sampling tested HPV negative on the physician-taken follow-up sample. The CLART and Onclarity assays agreed on 64% (95% confidence interval [CI], 60 to 68%) of the HPV-positive self-taken samples. When the HC2 assay results were added into a three-way comparison, the level of agreement decreased to 27% (95% CI, 24 to 29%). Our findings suggest that further validation of HPV assays on self-taken samples is needed for optimal HPV detection and correct clinical management of HPV-positive women.

Single-dose intravenous iron infusion or oral iron for treatment of fatigue after postpartum haemorrhage: a randomized controlled trial.

BACKGROUND AND OBJECTIVES: To evaluate the clinical efficacy of a single-dose intravenous infusion of iron isomaltoside compared with current treatment practice with oral iron measured by physical fatigue in women after postpartum haemorrhage. MATERIALS AND METHODS: Single-centre, open-label, randomized controlled trial. Participants received intravenous iron (n = 97) or oral iron (n = 99), and completed the Multidimensional Fatigue Inventory and Edinburgh Postnatal Depression Scale, and haematological and iron parameters were measured. Primary outcome was the aggregated change in physical fatigue score from baseline to 12 weeks postpartum. RESULTS: The difference in physical fatigue score was -0·97 (95% CI: -1·65; -0·28, P = 0·006) in favour of intravenous iron, but did not meet the predefined difference of 1·8. Across visits, we found statistically significant differences in fatigue and depression scores, as well as in haematological and iron parameters, all in favour of intravenous iron. There were no serious adverse reactions. CONCLUSION: A single dose of intravenous iron was associated with a statistically significant reduction in aggregated physical fatigue within 12 weeks after postpartum haemorrhage compared to standard medical care with oral iron below the prespecified criteria of clinical superiority. As patient-reported outcomes improved significantly and intravenous iron resulted in a fast hematopoietic response without serious adverse reactions, intravenous iron may be a useful alternative after postpartum haemorrhage if oral iron is not absorbed or tolerated.

Single-dose intravenous iron infusion versus red blood cell transfusion for the treatment of severe postpartum anaemia: a randomized controlled pilot study.

BACKGROUND AND OBJECTIVES: There are no randomized trials comparing intravenous iron to RBC transfusion for the treatment of severe postpartum anaemia. The objectives of this study were to evaluate the feasibility of randomizing women with severe postpartum anaemia secondary to postpartum haemorrhage to RBC transfusion or intravenous iron, and to describe patient-reported outcomes, and haematological and iron parameters. MATERIALS AND METHODS: Women with a postpartum haemorrhage exceeding 1000 ml and an Hb between 5·6 and 8·1 g/dl were randomized to 1500 mg of intravenous iron (n = 7) isomaltoside or RBC transfusion (n = 6). Participants completed the Multidimensional Fatigue Inventory and Edinburgh Postnatal Depression Scale, and blood samples were drawn at inclusion, daily during the first week and at weeks 3, 8 and 12. RESULTS: We screened 162 women and included 13 (8%). There was no significant difference between groups in fatigue or depression scores. RBC transfusion was associated with a higher Hb on day 1, inhibition of reticulocytosis during the first week and low iron levels. Intravenous iron was associated with increased reticulocytosis during the first week, repleted iron stores and a higher Hb in weeks 3-12. CONCLUSION: This pilot study shows that intravenous iron could be an attractive alternative to RBC transfusion in severe postpartum anaemia, and that a larger trial is needed and feasible.

Orientation and stability of a bi-functional aromatic organic molecular adsorbate on silicon.

In this work we combine scanning tunneling microscopy, near-edge X-ray absorption fine structure spectroscopy, X-ray photoemission spectroscopy and density functional theory to resolve a long-standing confusion regarding the adsorption behaviour of benzonitrile on Si(001) at room temperature. We find that a trough-bridging structure is sufficient to explain adsorption at low coverages. At higher coverages when steric hindrance prevents the phenyl ring lying flat on the surface, the 2+2 cycloaddition structure dominates.

Abnormal vaginal microbiota may be associated with poor reproductive outcomes: a prospective study in IVF patients.

STUDY QUESTION: What is the diagnostic performance of qPCR assays compared with Nugent scoring for abnormal vaginal microbiota and for predicting the success rate of IVF treatment? SUMMARY ANSWER: The vaginal microbiota of IVF patients can be characterized with qPCR tests which may be promising tools for diagnosing abnormal vaginal microbiota and for prediction of clinical pregnancy in IVF treatment. WHAT IS KNOWN ALREADY: Bacterial vaginosis (BV) is a common genital disorder with a prevalence of approximately 19% in the infertile population. BV is often sub-clinical with a change of the vaginal microbiota from being Lactobacillus spp. dominated to a more heterogeneous environment with anaerobic bacteria, such as Gardnerella vaginalis and Atopobium vaginae. Few studies have been conducted in infertile women, and some have suggested a negative impact on fecundity in the presence of BV. STUDY DESIGN, SIZE, DURATION: A cohort of 130 infertile patients, 90% Caucasians, attending two Danish fertility clinics for in vitro fertilization (IVF) treatment from April 2014-December 2014 were prospectively enrolled in the trial. PARTICIPANTS/MATERIALS, SETTING AND METHODS: Vaginal swabs from IVF patients were obtained from the posterior fornix. Gram stained slides were assessed according to Nugent's criteria. PCR primers were specific for four common Lactobacillus spp., G. vaginalis and A. vaginae. Threshold levels were established using ROC curve analysis. MAIN RESULTS AND THE ROLE OF CHANCE: The prevalence of BV defined by Nugent score was 21% (27/130), whereas the prevalence of an abnormal vaginal microbiota was 28% (36/130) defined by qPCR with high concentrations of Gardnerella vaginalis and/or Atopobium vaginae. The qPCR diagnostic approach had a sensitivity and specificity of respectively 93% and 93% for Nugent-defined BV. Furthermore, qPCR enabled the stratification of Nugent intermediate flora. Eighty-four patients completed IVF treatment. The overall clinical pregnancy rate was 35% (29/84). Interestingly, only 9% (2/22) with qPCR defined abnormal vaginal microbiota obtained a clinical pregnancy (P = 0.004). LIMITATIONS, REASONS FOR CAUTION: Although a total of 130 IVF patients were included in the study, a larger sample size is needed to draw firm conclusions regarding the possible adverse effect of an abnormal vaginal microbiota in relation to the clinical pregnancy rate and other reproductive outcomes. WIDER IMPLICATIONS OF THE FINDINGS: Abnormal vaginal microbiota may negatively affect the clinical pregnancy rate in IVF patients. If a negative correlation between abnormal vaginal microbiota and the clinical pregnancy rate is corroborated, patients could be screened and subsequently treated for abnormal vaginal microbiota prior to fertility treatment. STUDY FUNDING/COMPETING INTERESTS: This study was funded by The AP Møller Maersk Foundation for the advancement of Medical Science and Hospital of Central Jutland Research Fund, Denmark. No competing interests. TRIAL REGISTRATION NUMBER: The project was registered at clinicaltrials.gov (file number NCT02042352).

Intravenous iron isomaltoside 1000 (Monofer®) reduces postoperative anaemia in preoperatively non-anaemic patients undergoing elective or subacute coronary artery bypass graft, valve replacement or a combination thereof: a randomized double-blind placebo-controlled clinical trial (the PROTECT trial).

BACKGROUND AND OBJECTIVES: This trial explores whether intravenous iron isomaltoside 1000 (Monofer®) results in a better regeneration of haemoglobin levels and prevents anaemia compared to placebo in preoperative non-anaemic patients undergoing cardiac surgery. STUDY DESIGN AND METHODS: The trial is a prospective, double-blind, comparative, placebo-controlled trial of 60 non-anaemic patients undergoing cardiac surgery. The patients were randomized 1:1 to either 1000 mg intravenous iron isomaltoside 1000 administered perioperatively by infusion or placebo. RESULTS: Mean preoperative haemoglobin in the active treatment group was 14·3 g/dl vs. 14·0 g/dl in the placebo group. At discharge 5 days after surgery, haemoglobin levels were reduced to 10·7 and 10·5 g/dl, respectively. One month after surgery, haemoglobin concentration had increased to an average of 12·6 g/dl vs. 11·8 g/dl (p = 0·012) and significantly more patients were non-anaemic in the intravenous iron isomaltoside 1000-treated group compared to the placebo group (38·5% vs. 8·0%; p = 0·019). There were no differences in side-effects between the groups. CONCLUSION: A single perioperative 1000 mg dose of intravenous iron isomaltoside 1000 significantly increased the haemoglobin level and prevented anaemia 4 weeks after surgery, with a short-term safety profile similar to placebo. Future trials on potential clinical benefits of preoperative treatment with intravenous iron in non-anaemic patients are needed.

Accessing targeted nanoparticles to the brain: the vascular route.

The blood-brain barrier (BBB), formed by brain capillary endothelial cells, prevents the entry of several drug molecules to the brain, especially molecules hydrophilic in nature. Advanced drug carriers like nanoparticles share the potential to allow entry of therapeutic proteins and genetic molecules into the central nervous system (CNS). Taking a targeting approach by conjugating molecules acting as ligands or monoclonal antibodies with affinity for proteins expressed on the luminal side of brain capillary endothelial cells, the nanoparticles can be designed to enable transport into the brain endothelium, or perhaps even through the endothelium leading to blood to brain transport. Currently, the iron-binding protein transferrin or antibodies raised against the transferrin receptor denote the most feasible molecule for targeting purposes at the BBB. This manuscript reviews the targetability of nanoparticles to the brain capillary endothelial cells, how nanocarriers may enter and transfer through the brain endothelium, and how likely restraints denoted by the threedimensional mesh of the extracellular proteins forming the brain capillary basement membrane challenge the possibilities for enabling transport of large molecules through the BBB encapsulated in nanoparticles.