Steady-state monitoring of oxygen in a high-throughput organ-on-chip platform enables rapid and non-invasive assessment of drug-induced nephrotoxicity.

High-throughput, rapid and non-invasive readouts of tissue health in microfluidic kidney co-culture models would expand their capabilities for pre-clinical assessment of drug-induced nephrotoxicity. Here, we demonstrate a technique for monitoring steady state oxygen levels in PREDICT96-O2, a high-throughput organ-on-chip platform with integrated optical-based oxygen sensors, for evaluation of drug-induced nephrotoxicity in a human microfluidic co-culture model of the kidney proximal tubule (PT). Oxygen consumption measurements in PREDICT96-O2 detected dose and time-dependent injury responses of human PT cells to cisplatin, a drug with known toxic effects in the PT. The injury concentration threshold of cisplatin decreased exponentially from 19.8 µM after 1 day to 2.3 µM following a clinically relevant exposure duration of 5 days. Additionally, oxygen consumption measurements resulted in a more robust and expected dose-dependent injury response over multiple days of cisplatin exposure compared to colorimetric-based cytotoxicity readouts. The results of this study demonstrate the utility of steady state oxygen measurements as a rapid, non-invasive, and kinetic readout of drug-induced injury in high-throughput microfluidic kidney co-culture models.

Toward microfluidic integration of respiratory and renal organ support in a single cartridge.

BACKGROUND: Extracorporeal organ assist devices provide lifesaving functions for acutely and chronically ill patients suffering from respiratory and renal failure, but their availability and use is severely limited by an extremely high level of operational complexity. While current hollow fiber-based devices provide high-efficiency blood gas transfer and waste removal in extracorporeal membrane oxygenation (ECMO) and hemodialysis, respectively, their impact on blood health is often highly deleterious and difficult to control. Further challenges are encountered when integrating multiple organ support functions, as is often required when ECMO and ultrafiltration (UF) are combined to deal with fluid overload in critically ill patients, necessitating an unwieldy circuit containing two separate cartridges. METHODS: We report the first laboratory demonstration of simultaneous blood gas oxygenation and fluid removal in single microfluidic circuit, an achievement enabled by the microchannel-based blood flow configuration of the device. Porcine blood is flowed through a stack of two microfluidic layers, one with a non-porous, gas-permeable silicone membrane separating blood and oxygen chambers, and the other containing a porous dialysis membrane separating blood and filtrate compartments. RESULTS: High levels of oxygen transfer are measured across the oxygenator, while tunable rates of fluid removal, governed by the transmembrane pressure (TMP), are achieved across the UF layer. Key parameters including the blood flow rate, TMP and hematocrit are monitored and compared with computationally predicted performance metrics. CONCLUSIONS: These results represent a model demonstration of a potential future clinical therapy where respiratory support and fluid removal are both realized through a single monolithic cartridge.

Long-term first-in-man Phase I/II study of an adjuvant dendritic cell vaccine in patients with high-risk prostate cancer after radical prostatectomy.

BACKGROUND: Patients with high-risk prostate cancer (PC) can experience biochemical relapse (BCR), despite surgery, and develop noncurative disease. The present study aimed to reduce the risk of BCR with a personalized dendritic cell (DC) vaccine, given as adjuvant therapy, after robot-assisted laparoscopic prostatectomy (RALP). METHODS: Twelve weeks after RALP, 20 patients with high-risk PC and undetectable PSA received DC vaccinations for 3 years or until BCR. The primary endpoint was the time to BCR. The immune response was assessed 7 weeks after surgery (baseline) and at one-time point during the vaccination period. RESULTS: Among 20 patients, 11 were BCR-free over a median of 96 months (range: 84-99). The median time from the end of vaccinations to the last follow-up was 57 months (range: 45-60). Nine patients developed BCR, either during (n = 4) or after (n = 5) the vaccination period. Among five patients diagnosed with intraductal carcinoma, three experienced early BCR during the vaccination period. All patients that developed BCR remained in stable disease within a median of 99 months (range: 74-99). The baseline immune response was significantly associated with the immune response during the vaccination period (p = 0.015). For patients diagnosed with extraprostatic extension (EPE), time to BCR was longer in vaccine responders than in non-responders (p = 0.09). Among 12 patients with the International Society of Urological Pathology (ISUP) grade 5 PC, five achieved remission after 84 months, and all mounted immune responses. CONCLUSION: Patients diagnosed with EPE and ISUP grade 5 PC were at particularly high risk of developing postsurgical BCR. In this subgroup, the vaccine response was related to a reduced BCR incidence. The vaccine was safe, without side effects. This adjuvant first-in-man Phase I/II DC vaccine study showed promising results. DC vaccines after curative surgery should be investigated further in a larger cohort of patients with high-risk PC.

Self-reported symptoms of binge-eating disorder among adolescents in a community-based Danish cohort-A study of prevalence, correlates, and impact.

OBJECTIVE: Binge-eating disorder (BED) was established as a diagnosis in 2013 with the DSM-5 and has been included in the ICD-11 in 2018. In adulthood, BED is prevalent and correlated with somatic and mental health problems. Less is known about BED in adolescence, although this age period could represent a window of opportunity for early intervention. This study aimed to investigate the 1-year prevalence, correlates, and impact of BED symptoms in a community sample of adolescents. METHOD: We included 1,404 girls and 1,105 boys from the 16-years-follow-up of the Copenhagen Child Cohort study, CCC2000. The adolescents self-reported on BED symptoms, weight-status, body perception, mental health problems, and self-rated impact of food and weight-related thoughts and behaviors. Information about socio-economic factors and hospital diagnosed psychiatric disorders were obtained from national registries. RESULTS: A total of 8.5% reported weekly overeating with loss of control (10.9% of girls, 4.8% of boys), and 2.6% (3.6% of girls, 1.2% of boys) reported symptoms consistent with BED according to the DSM-5. Regardless of sex, BED was correlated with concurrent overweight, body-dissatisfaction, low self-esteem, and mental health problems, especially emotional, but also with problems of behavior, inattention, and peer-relations, and with high self-rated impact on everyday life. Immigrant background and lower socio-economy were potential risk factors for BED in boys in this sample. DISCUSSION: BED was prevalent and correlated with mental health problems and overall impact among adolescents in this community sample, indicating the need for clinical attention and intervention towards binge-eating disorder in the adolescent period.

Mosaicism for copy number variations in the placenta is even more difficult to interpret than mosaicism for whole chromosome aneuploidy.

OBJECTIVE: To compare mosaicisms in prenatal chorionic villus samples (CVSs) with corresponding postpartum placental samples. METHOD: We collected placentas from 15 consecutive cases of mosaicism detected in CVSs and obtained five standardized samples on each placenta after delivery. All pre- and postnatal placental samples were uncultured and analyzed by high-resolution chromosomal microarray. RESULTS: Ten cases of mosaicism for whole chromosome aneuploidy (mWC) and five cases with mosaicism for (sub)chromosomal copy number variations (mCNVs) were included. In 5/10 mWC cases and in 4/5 mCNV cases the prenatally detected aberration was confirmed in the postpartum placenta. Three postpartum placentas revealed various complex aberrations differing from the prenatal results: (1) mosaicisms for different deletions/duplications on 9p and 9q in all samples (prenatal: mosaic 5.3 Mb duplication on 9p24), (2) different regions with deletions/duplications/loss of heterozygosity on 1p in all samples (prenatal: mosaic 2.3 Mb 1p36 duplication), and (3) mosaicism for a duplication on 5q and a deletion on 6p in one out of five samples (prenatal: mosaic trisomy 7). CONCLUSION: CNVs constitute a complex subgroup in placental mosaicism. Counseling of these couples after chorionic villus sampling should not focus on the specific CNV involved, but on the nature of mosaicism and the option of amniocentesis and ultrasound.

Exploring Fear of Cancer Recurrence in a Sample of Heterogeneous Distressed Cancer Patients with and Without a Psychiatric Disorder.

Fear of Cancer Recurrence (FCR) is a concern among cancer patients. Recent insights suggest that FCR should be viewed as a distinct syndrome. However, few studies have explored its overlap with psychiatric morbidity. We examined this overlap in a sample of distressed cancer patients. Self-referred patients (n = 245) were assessed with the Structured Clinical Interview for DSM-IV-TR Axis-I disorders and the Fear of Cancer Recurrence Inventory-Short Form. Proportions of patients with and without a psychiatric disorder meeting validated cut-offs for screening and clinically relevant FCR were compared. The prevalence of psychiatric disorders was 36%. Clinically relevant FCR was found in 198 patients (81%). Patients with a current psychiatric disorder reported clinically relevant FCR more frequently (89%) compared to those with no disorder (77%). Of patients reporting clinically relevant FCR, the majority (61%) did not additionally meet the criteria for a psychiatric disorder. These findings suggest that there should be particular attention for patients with elevated levels of FCR, warranting FCR-specific treatment.Trial registry number Clinicaltrials.gov NCT02138513.

Adrenal insufficiency in prednisolone-treated patients with polymyalgia rheumatica or giant cell arteritis-prevalence and clinical approach.

OBJECTIVES: Glucocorticoid treatment is fundamental in polymyalgia rheumatica (PMR) and giant cell arteritis (GCA), but carries a risk of glucocorticoid-induced adrenal insufficiency. Adrenal insufficiency can cause reluctance to stop glucocorticoid treatment after disease remission as symptoms can resemble PMR/GCA flare. We aimed to determine the prevalence of adrenal insufficiency in prednisolone-treated patients with PMR/GCA. METHODS: We included 47 patients with PMR (n = 37), GCA (n = 1) or both (n = 9), treated with prednisolone for ≥5.4 months, current dose 2.5-10 mg/day. Adrenal function was evaluated using a corticotropin (Synacthen®) stimulation test following 48 h prednisolone pause. Two years' clinical follow-up data are provided. RESULTS: Seven patients (15%) had adrenal insufficiency, 4 (11%) of the 37 patients with PMR alone, and 3 (30%) of the 10 patients with GCA. Corticotropin-stimulated P-cortisol was significantly associated with current prednisolone dose, mean daily dose the last 3 and 6 months before testing, and basal P-cortisol, but not with total dose or treatment duration. Adrenal insufficiency occurred with all current prednisolone doses (2.5-10 mg/day). Five (71%) of the glucocorticoid-insufficient patients could discontinue prednisolone treatment; two of them recovered glucocorticoid function, whereas three still needed hydrocortisone replacement 2 years later. Two patients experienced in total four acute hospital admissions with symptoms of adrenal crises. CONCLUSION: Glucocorticoid-induced adrenal insufficiency occurred in 15% of patients with PMR/GCA. Mean prednisolone dose the last 3 months and basal P-cortisol were the best and simplest predictors of adrenal function. Most of the glucocorticoid-insufficient patients could discontinue prednisolone with appropriate treatment for adrenal insufficiency.

Antibody-Mediated Neutralization of uPA Proteolytic Function Reduces Disease Progression in Mouse Arthritis Models.

Genetic absence of the urokinase-type plasminogen activator (uPA) reduces arthritis progression in the collagen-induced arthritis (CIA) mouse model to an extent just shy of disease abrogation, but this remarkable observation has not been translated into therapeutic intervention. Our aim was to test the potential in mice of an Ab that blocks the proteolytic capacity of uPA in the CIA model and the delayed-type hypersensitivity arthritis model. A second aim was to determine the cellular origins of uPA and the uPA receptor (uPAR) in joint tissue from patients with rheumatoid arthritis. A mAb that neutralizes mouse uPA significantly reduced arthritis progression in the CIA and delayed-type hypersensitivity arthritis models. In the CIA model, the impact of anti-uPA treatment was on par with the effect of blocking TNF-α by etanercept. A pharmacokinetics evaluation of the therapeutic Ab revealed target-mediated drug disposition consistent with a high turnover of endogenous uPA. The cellular expression patterns of uPA and uPAR were characterized by double immunofluorescence in the inflamed synovium from patients with rheumatoid arthritis and compared with synovium from healthy donors. The arthritic synovium showed expression of uPA and uPAR in neutrophils, macrophages, and a fraction of endothelial cells, whereas there was little or no expression in synovium from healthy donors. The data from animal models and human material provide preclinical proof-of-principle that validates uPA as a novel therapeutic target in rheumatic diseases.

Prevalence of mosaicism in uncultured chorionic villus samples after chromosomal microarray and clinical outcome in pregnancies affected by confined placental mosaicism.

OBJECTIVE: To evaluate the prevalence of mosaicism in chorionic villus sampling (CVS) samples after chromosomal microarray (CMA) and clinical outcome of pregnancies affected by confined placental mosaicism. METHOD: We retrieved all results from CMA, array-based comparative genomic hybridization, on CVS samples from January 2011 to November 2017 from Central and North Denmark Regions. Mosaic results from uncultured chorionic villi, cytotrophoblasts and mesenchymal cells, after CVS and follow-up on amniocytes, fetal tissue, or postnatal blood were studied and matched with clinical data from The Danish Fetal Medicine Database. RESULTS: Prevalence of mosaicism was 93 out of 2,288 (4.1%) CVS samples of which 17 (18.3%) concerned submicroscopic copy number variations (CNVs) <10 Mb. Follow-up analyses were performed in 62 cases. True fetal mosaicism (TFM) was confirmed in 18.4% (7/38) when mosaicism involved whole chromosome aneuploidy and in 25.0% (6/24), when involving a CNV (P = .59). Median birth weight z-score was higher in cases of confined placental mosaicism for a CNV (0.21) than cases involving whole chromosomes (-0.74) (P = .02). CONCLUSION: Prevalence of mosaicism in CVS samples is higher after CMA on uncultured tissue than after conventional karyotyping on cultured tissue. The risk of TFM is equally high in cases of mosaicism for CNVs and whole chromosomes.

Progression Over 5 Years of Prelaminar Hyperreflective Lines to Optic Disc Drusen in the Copenhagen Child Cohort 2000 Eye Study.

BACKGROUND: The purpose of the study was to examine 5-year changes in eyes with optic disc drusen at baseline on optical coherence tomography (OCT) scans and the relation of incident drusen to hyperreflective prelaminar lines. METHODS: The study included children who presented at baseline, when participants were aged 11-12 years, and again 5 years later. Grading for optic disc drusen was made in all. Grading for prelaminar lines was made in all children at follow-up and in eyes with optic disc drusen at baseline. Analyses included associations with scleral canal diameter at baseline in all children with optic disc drusen and a nested control group of 115 children without optic disc drusen. Data are reported as the number of children having at least one drusen or at least one hyperreflective line per person. RESULTS: The analysis included 724 children who attended both rounds of the study. Of these, 11 (1.5%) had optic disc drusen at baseline. Five additional children had developed optic disc drusen at follow-up, whereas optic disc drusen had disappeared in none, so that 16 (2.2%) children had optic disc drusen in one or both eyes at follow-up. Children with optic disc drusen at the 5-year follow-up had had a mean scleral canal diameter of 1,364 µm (interquartile range [IQR] 81 µm), compared with 1,457 µm (IQR 197) µm in 115 nested controls without optic disc drusen (P < 0.001). Optic disc drusen at follow-up were associated with more hypermetropic refraction. All children who had optic disc drusen at follow-up also had prelaminar hyperreflective lines. In addition, such lines were found at follow-up in 24 of the remaining 708 children without optic disc drusen (P < 0.001). Prelaminar hyperreflective lines with or without optic disc drusen were associated with a narrower scleral canal (diameter 1,364 µm, IQR 119 µm) compared with absence of prelaminar lines (1,486 µm, IQR 206 µm; P < 0.0001). CONCLUSION: This study provides the first evidence from a prospective study that small optic discs and prelaminar hyperreflective lines on OCT are risk factors for the development of optic disc drusen. The association between prelaminar hyperreflective lines, hypermetropia, and a narrow scleral canal supports that a crowded disc is an essential predisposing factor for the development of optic disc drusen.

Orthognathic Surgery-Induced Fibrinolytic Shutdown Is Amplified by Tranexamic Acid.

PURPOSE: Little is known of the systemic effects of oral and maxillofacial surgery on the hemostatic balance, including the biochemical effects of tranexamic acid (TXA), on fibrin clot lysis. The present study investigated the effects of orthognathic surgery on fibrin lysis, fibrin structure, and D-dimer and evaluated the effect of TXA on these fibrinolytic measures. MATERIALS AND METHODS: The present double-blind, controlled, and randomized, placebo study included patients referred to the Department of Oral and Maxillofacial Surgery at the University Hospital of Southern Denmark-Esbjerg from August 2014 through September 2016. The patients were elective and had a diagnosis of maxillary or mandibular deficiency, either excessive or asymmetric. All patients underwent bimaxillary orthognathic surgery (OS) with or without maxillary segmentation or additional genioplasty. The patients were blindly randomized to treatment with TXA or placebo. The primary predictor variable was OS. The secondary predictor variable was an intravenous dose of 1 g of TXA or equivalent placebo preoperatively. Blood samples were collected before surgery and 5 hours after the initiation of surgery. The primary outcome variable was lysis of fibrin. The fibrin structure properties and D-dimer were secondary outcome measures. The Mann-Whitney U test was used for the within-group comparisons. The Wilcoxon signed rank test was used for the between-group comparisons. RESULTS: The sample included 96 patients; 45 received placebo and 51 received TXA. Fibrin lysis decreased after OS (P < .001). The fibrinolytic shutdown decreased significantly more in the TXA group than in the placebo group (P < .001). OS altered the fibrin structure properties with comparable effects in the 2 groups. D-dimer increased postoperatively but significantly less so in the TXA group than in the control group (P < .001). CONCLUSIONS: OS is associated with fibrinolytic shutdown and alters fibrin structure properties, driving the hemostatic balance in a prothrombotic direction. The fibrinolytic shutdown is significantly amplified by TXA.

Predictors and Effects of Usage of an Online Mindfulness Intervention for Distressed Cancer Patients: Usability Study.

BACKGROUND: One in three cancer patients experience high psychological distress. Mindfulness-based interventions are effective in reducing psychological distress in this patient group. However, these interventions lack availability and flexibility, which may compromise participation in the intervention for cancer patients experiencing late symptoms like fatigue or pain. Therefore, mindfulness-based interventions are increasingly offered via the internet. However, little is known about the usage of these online mindfulness-based interventions. OBJECTIVE: The aim of this study was to (1) predict uptake of and adherence to online mindfulness-based cognitive therapy (eMBCT) using baseline patient characteristics (demographic, cancer-related, personality, and psychological variables) and (2) examine the relations between adherence and treatment outcomes in eMBCT for cancer patients. METHODS: A total of 125 cancer patients were assigned to eMBCT in a parent randomized controlled trial comparing MBCT and eMBCT with treatment as usual in distressed cancer patients. Various usage measures of eMBCT were automatically tracked within the online program. Based on activity of use, participants were classified as nonusers, minimal users, low users, and intended users. Questionnaires were used to assess baseline characteristics (preintervention) and outcomes (pre- and postintervention). To answer the research questions, data were analyzed with t tests, χ2 tests, and linear regression models. RESULTS: Based on weekly activity, participants were classified as nonusers (n=17, 13.6%), who completed no exercises in MBCT; minimal users (n=31, 24.8%), who completed at least one exercise of one to three sessions; low users (n=12, 9.6%), who completed at least one exercise of four to seven sessions; and intended users (n=65, 52.0%), who completed at least one exercise of eight to nine sessions. Nonusers had more fear of cancer recurrence at baseline than users (uptake), and intended users were more conscientious than minimal and low users (adherence). Intended users reported a larger reduction in psychological distress and more improvement of positive mental health (ie, emotional, psychological, and social well-being) after the intervention than other participants. CONCLUSIONS: This study showed that adherence was related to improved patient outcomes. Patients with strong fear of recurrence or low levels of conscientiousness should receive extra attention, as they are less likely to respectively start or complete eMBCT. Future research may focus on the development of flexible and adaptive eMBCT programs to fit individual needs.

Effect of spironolactone for 1 yr on endothelial function and vascular inflammation biomarkers in renal transplant recipients.

Kidney transplantation is associated with increased cardiovascular risk. Endothelial dysfunction and vascular inflammation contribute to negative outcome. In experimental models, mineralocorticoid receptor antagonists improved endothelial function and reduced inflammation. The present study tested the hypothesis that the mineralocorticoid receptor antagonist spironolactone improves endothelial function and reduces vascular inflammation in renal transplant patients. Eighty prevalent renal transplant patients from an ongoing, double-blind randomized placebo-controlled trial were included. Paired plasma samples before and after 1 yr of treatment (n = 39 in the spironolactone-treated group and 41 in the placebo-treated group) were used to determine markers of endothelial dysfunction (nitrite, nitrate, cGMP, arginine, citrulline, ornithine, asymmetric dimethylarginine, symmetric dimethylarginine, NG-monomethyl-l-arginine, von Willebrand factor, tissue-type plasminogen activator antigen, and plasminogen activator inhibitor 1 antigen) and markers of inflammation (intercellular adhesion molecule, vascular adhesion molecule, high-sensitivity C-reactive protein, and serum amyloid protein A). The median time since the transplantation was 4.6 (0.12-22.3) yr in the spironolactone-treated group and 2.1 (0.17-13.9) yr in the placebo-treated group (P > 0.05). Spironolactone increased plasma aldosterone (P < 0.001) and K+ (P < 0.001). Blood pressure did not change significantly. No significant differences were detected between groups in any of the measured markers of endothelial dysfunction or inflammation except in the subgroup analysis of patients with diabetes, where spironolactone decreased nitrite compared with placebo. In this study, mineralocorticoid receptor antagonism did not improve biomarkers of endothelial dysfunction or vascular inflammation in prevalent renal transplant patients. Further studies are needed to evaluate the potential beneficial effect of early or late mineralocorticoid receptor antagonism on vascular outcomes in renal transplant patients.

Caspase-1 induces smooth muscle cell growth in hypoxia-induced pulmonary hypertension.

Lung diseases with hypoxia are complicated by pulmonary hypertension, leading to heart failure and death. No pharmacological treatment exists. Increased proinflammatory cytokines are found in hypoxic patients, suggesting an inflammatory pathogenesis. Caspase-1, the effector of the inflammasome, mediates inflammation through activation of the proinflammatory cytokines interleukin (IL)-18 and IL-1ß. Here, we investigate inflammasome-related mechanisms that can trigger hypoxia-induced pulmonary hypertension. Our aim was to examine whether caspase-1 induces development of hypoxia-related pulmonary hypertension and is a suitable target for therapy. Wild-type (WT) and caspase-1-/- mice were exposed to 10% oxygen for 14 days. Hypoxic caspase-1-/- mice showed lower pressure and reduced muscularization in pulmonary arteries, as well as reduced right ventricular remodeling compared with WT. Smooth muscle cell (SMC) proliferation was reduced in caspase-1-deficient pulmonary arteries and in WT arteries treated with a caspase-1 inhibitor. Impaired inflammation was shown in hypoxic caspase-1-/- mice by abolished pulmonary influx of immune cells and lower levels of IL-18, IL-1ß, and IL-6, which were also reduced in the medium surrounding caspase-1 abrogated pulmonary arteries. By adding IL-18 or IL-1ß to caspase-1-deficient pulmonary arteries, SMC proliferation was retained. Furthermore, inhibition of both IL-6 and phosphorylated STAT3 reduced proliferation of SMC in vitro, indicating IL-18, IL-6, and STAT3 as downstream mediators of caspase-1-induced SMC proliferation in pulmonary arteries. Caspase-1 induces SMC proliferation in pulmonary arteries through the caspase-1/IL-18/IL-6/STAT3 pathway, leading to pulmonary hypertension in mice exposed to hypoxia. We propose that caspase-1 inhibition is a potential target for treatment of pulmonary hypertension.

Implications of different guidelines for surveillance after serrated polyp resection in United States of America and Europe.

INTRODUCTION: Because individuals with serrated polyps and adenomas are at increased risk of developing new polyps and colorectal cancer (CRC), surveillance after resection is justified. After adenoma resection, most international guidelines are consistent, but recommendations for surveillance after serrated polyp resection vary. The United States Multi-Society Taskforce on CRC (US-MSTF) base surveillance intervals on serrated polyp subtype (traditional serrated adenoma, sessile serrated polyp, hyperplastic polyps), while the European Society of Gastrointestinal Endoscopy (ESGE) guidelines do not take serrated polyp subtype into account. We evaluated the implications of this difference in a primary colonoscopy screening cohort. METHODS: We included participants from a large colonoscopy screening trial. In a post-hoc simulation, assuming full protocol adherence, we determined the surveillance interval for each subject based on their polyp burden, using the most recent US-MSTF and ESGE guidelines. RESULTS: We included 5323 participants, of whom 1228 had one or more serrated polyps. In 5201 of all participants (98 %; Cohen's kappa 0.90) and in 1106 of those with serrated polyps (90 %; Cohen's kappa 0.80), both guidelines recommended identical surveillance intervals. Recommendations for a 3-year surveillance interval were identical between the two guidelines. All 122 subjects with discordant recommendations would receive a follow-up colonoscopy after 10 years using ESGE guidance and after 5 years using US-MSTF guidance. CONCLUSION: Despite the different criteria used to determine surveillance after serrated polyp resection, most individuals are recommended identical colonoscopy surveillance intervals whether following the ESGE or US-MSTF guidelines. This suggests that surveillance recommendations do not need to consider the serrated polyp subtype.

Therapeutic alliance-not therapist competence or group cohesion-contributes to reduction of psychological distress in group-based mindfulness-based cognitive therapy for cancer patients.

Mindfulness-based cognitive therapy (MBCT) is an innovative evidence-based intervention in mental and somatic health care. Gaining knowledge of therapeutic factors associated with treatment outcome can improve MBCT. This study focused on predictors of treatment outcome of MBCT for cancer patients and examined whether group cohesion, therapeutic alliance, and therapist competence predicted reduction of psychological distress after MBCT for cancer patients. Moreover, it was examined whether therapist competence facilitated therapeutic alliance or group cohesion. Multilevel analyses were conducted on a subsample of patients collected in a larger randomized controlled trial on individual internet-based versus group-based MBCT versus treatment as usual in distressed cancer patients. The current analyses included the 84 patients who completed group-based MBCT out of 120 patients who were randomized to group-based MBCT. Group cohesion and therapist competence did not predict reduction in psychological distress, whereas therapeutic alliance did. In addition, therapist competence did not predict therapeutic alliance but was associated with reduced group cohesion. Our findings revealed that therapeutic alliance significantly contributed to reduction of psychological distress in MBCT for cancer patients. Elaborating the clinical implications of the predictive significance of therapeutic alliance might be of added value to enhance the potential effect of MBCT.

SLC30A8 polymorphism and BMI complement HLA-A*24 as risk factors for poor graft function in islet allograft recipients.

AIMS/HYPOTHESIS: HLA-A*24 carriership hampers achievement of insulin independence in islet allograft recipients. However, less than half of those who fail to achieve insulin independence carry the allele. We investigated whether genetic polymorphism at the recipients' zinc transporter 8-encoding SLC30A8 gene (rs13266634) could complement their HLA-A*24 status in predicting functional graft outcome. METHODS: We retrospectively analysed data of a hospital-based patient cohort followed for 18 months post transplantation. Forty C-peptide-negative type 1 diabetic individuals who received >2 million beta cells (>4000 islet equivalents) per kg body weight in one or two intraportal implantations under similar immunosuppression were genotyped for SLC30A8. Outcome measurements included achievement and maintenance of graft function. Metabolic benefit was defined as <25% CV of fasting glycaemia in the presence of >331 pmol/l C-peptide, in addition to achievement of insulin independence and maintenance of C-peptide positivity. RESULTS: In multivariate analysis, HLA-A*24 positivity, presence of SLC30A8 CT or TT genotypes and BMI more than or equal to the group median (23.9 kg/m2) were independently associated with failure to achieve insulin independence (p = 0.015-0.046). The risk increased with the number of factors present (p < 0.001). High BMI interacted with SLC30A8 T allele carriership to independently predict difficulty in achieving graft function with metabolic benefit (p = 0.015). Maintenance of C-peptide positivity was mainly associated with older age at the time of implantation. Only HLA-A*24 carriership independently predicted failure to maintain acceptable graft function once achieved (p = 0.012). CONCLUSIONS/INTERPRETATION: HLA-A*24, the SLC30A8 T allele and high BMI are associated with poor graft outcome and should be considered in the interpretation of future transplantation trials. TRIAL REGISTRATION: ClinicalTrials.gov NCT00798785 and NCT00623610.

Optic Disc Drusen in Children: The Copenhagen Child Cohort 2000 Eye Study.

BACKGROUND: Optic disc drusen (ODD) are seen in up to 2.4% of the general population, but the etiology and pathophysiology of the condition is still unknown. The purpose of this study was to determine the prevalence of ODD in a population-based child cohort and to determine if scleral canal diameter and fetal birth and pubertal parameters are associated with the presence of ODD. METHODS: This observational, longitudinal population-based birth cohort study, with a nested case-control, included 1,406 children. Eye examinations were performed when the children were between 11 and 12 years of age. Assessment was performed of optical coherence tomography (OCT) scans from 1,304 children with gradable enhanced depth imaging scans of the optic disc. RESULTS: ODD in one or both eyes were found in 13 (1.0%) of all children. All but one of the cases were found in children with scleral canal diameter in the lowest quartile (1,182-1,399 µm) in the nested case-control study. Children with ODD had a mean disc diameter of 1,339 µm (interquartile range, 30 µm), whereas it was 1,508 µm (interquartile range, 196 µm) in the 130 controls without ODD (P < 0.001). No differences in sex, birth weight, refractive error, and Tanner stages (of puberty) were found between children with and without ODD. CONCLUSIONS: The prevalence of ODD was 1% in a large child cohort examined by OCT. ODD was found only in eyes with a narrow scleral canal, which is consistent with the hypothesis that ODD might arise as a consequence of retinal nerve fiber congestion in the scleral canal.

Modest heterologous protection after Plasmodium falciparum sporozoite immunization: a double-blind randomized controlled clinical trial.

BACKGROUND: A highly efficacious vaccine is needed for malaria control and eradication. Immunization with Plasmodium falciparum NF54 parasites under chemoprophylaxis (chemoprophylaxis and sporozoite (CPS)-immunization) induces the most efficient long-lasting protection against a homologous parasite. However, parasite genetic diversity is a major hurdle for protection against heterologous strains. METHODS: We conducted a double-blind, randomized controlled trial in 39 healthy participants of NF54-CPS immunization by bites of 45 NF54-infected (n = 24 volunteers) or uninfected mosquitoes (placebo; n = 15 volunteers) against a controlled human malaria infection with the homologous NF54 or the genetically distinct NF135.C10 and NF166.C8 clones. Cellular and humoral immune assays were performed as well as genetic characterization of the parasite clones. RESULTS: NF54-CPS immunization induced complete protection in 5/5 volunteers against NF54 challenge infection at 14 weeks post-immunization, but sterilely protected only 2/10 and 1/9 volunteers against NF135.C10 and NF166.C8 challenge infection, respectively. Post-immunization plasma showed a significantly lower capacity to block heterologous parasite development in primary human hepatocytes compared to NF54. Whole genome sequencing showed that NF135.C10 and NF166.C8 have amino acid changes in multiple antigens targeted by CPS-induced antibodies. Volunteers protected against heterologous challenge were among the stronger immune responders to in vitro parasite stimulation. CONCLUSIONS: Although highly protective against homologous parasites, NF54-CPS-induced immunity is less effective against heterologous parasite clones both in vivo and in vitro. Our data indicate that whole sporozoite-based vaccine approaches require more potent immune responses for heterologous protection. TRIAL REGISTRATION: This trial is registered in clinicaltrials.gov, under identifier NCT02098590 .