Does personality dysfunction add incremental utility over general psychopathology when modeling previous suicide attempts in adolescent patients?

BACKGROUND: Identifying patients at risk for a suicide attempt (SA) is critical in adolescents with mental disorders. The current study aimed to 1) examine whether personality dysfunction (PD) is associated with previous SA, 2) explore the incremental utility of PD over psychiatric disorders in modeling previous SA. METHODS: The sample comprised of n = 498 adolescent patients (mean age = 15.41 years, 79.12 % females, inpatient 48.8 %, outpatient 51.2 %). SA in the past year, PD according to the alternative DSM-5 model for personality disorders, and psychiatric diagnoses were assessed using semi-structured interviews. Logistic regression and principal component analysis examining the associations and specific patterns of PD and SA in the past year were conducted. Hierarchical (stepwise) logistic regression was applied to investigate the incremental utility of PD over that of psychiatric diagnoses to identify individuals with SA in the past year. RESULTS: Including all facets of PD revealed a significant model with SA in the past year as outcome (χ2(12) = 106.65, McFaddens Pseudo-R2 = 0.17, p < 0.01). Adding PD to the model explained a significant amount of variance in past SA over that of psychiatric diagnoses (Pseudo-R2 = 0.18, Wald χ2 = 43.05, p < 0.01). LIMITATIONS: As we only studied past SA and due to the cross-sectional design, no conclusion regarding the prediction of future SA can be drawn. DISCUSSION: PD should routinely be assessed in adolescent patients since individuals with PD are more likely to have attempted suicide even when controlling for comorbid psychiatric disorders. PD may represent an important target for intervention in those with suicidal thoughts and behaviors.

The Global Bioequivalence Harmonisation Initiative (GBHI): Report of the fifth international EUFEPS/AAPS conference.

The series of conferences of the Global Bioequivalence Harmonisation Initiative (GBHI) was started in 2015 by the European Federation for Pharmaceutical Sciences (EUFEPS). All GBHI meetings so far were co-organised together with the American Association of Pharmaceutical Scientists (AAPS). Beginning with the 3rd workshop US-FDA joined as co-sponsor - to support global harmonisation of regulatory recommendations for bioequivalence (BE) assessment. At the 5th GBHI conference, the following BE topics were intensively discussed, and the following main conclusions were drawn: (1) Statistical considerations for BE assessment in specific situations covering scaling approaches for highly variable drug (HVD) products, two-stage adaptive design and opportunities of modelling and simulation to support BE: even though special BE study concepts like adaptive designs are not often used in practise so far, a majority of the workshop participants were in favour of a more frequent application of such approaches. The regulatory conditions relevant in this context need further concretisation and harmonisation between the regions. Moreover, modelling and simulation were considered as a promising and evolving approach, also for BE development programmes. (2) Fed versus fasting conditions in BE trials: Findings that BE between generic products could be confirmed only after fasted administration but failed under fed conditions seem more an exception than the rule. Obviously, BCS class IV compounds are most problematic in this context. Differences in critical excipients such as surfactants or pH-modifiers may be relevant reasons for different sensitivity for interactions in fasted versus fed conditions. Consequently, such deviations in composition of generic preparations should be avoided. Moreover, confirmation of BE may be generally difficult comparing different dosage forms, such like capsules versus tablets, especially in fed state. (3) BE assessment of locally acting drug products applied topically to the skin: Appropriateness and potential benefit of in-vitro tests as alternatives to clinical efficacy studies have been comprehensively discussed. In addition to the already well-established in-vitro release and permeation tests, other techniques were suggested, e.g., Raman spectroscopy or dermal open flow microperfusion. Validation of those methods is challenging and, despite significant progress already achieved during previous years, more research is needed before they may be fully accepted for regulatory purposes. (4) BE evaluation of narrow therapeutic index (NTI) drugs: The discrepancies amongst regulatory agencies in necessity of tighter BE acceptance ranges, the recommendations for inclusion of peak and total drug exposure into BE assessment with more restrictive criteria and the importance of comparison of the product-related within-subject variability for NTI drugs were debated. Arguments in favour and against the different approaches were presented and discussed but need further consideration before harmonisation can be achieved. The highly interactive meeting and extensive exchange between regulators and scientists from industry and academia resulted in useful progress in open BE issues and supported the goal of science-driven harmonisation.

An ecological momentary assessment study of age effects on perceptive and non-perceptive clinical high-risk symptoms of psychosis.

Among individuals with clinical high risk for psychosis (CHR), perceptive symptoms are more frequent but have less clinical significance in children/adolescents compared to adults. However, findings are based on clinical interviews relying on patient's recall capacity. Ecological momentary assessment (EMA) can be used to explore experiences in real-time in the subject's daily life. The aim of this study was to assess frequency and stability of (perceptive and non-perceptive) CHR symptoms and to explore potential age effects. EMA was used in a sample of an early detection for psychosis service in Bern, Switzerland (N = 66; 11-36 years). CHR symptoms were recorded in random time intervals for seven days: eight assessments per day per subject, minimum time between prompts set at 25 min. CHR symptoms were additionally assessed with semi-structured interviews including the 'Structured Interview for Psychosis-Risk Syndromes' and the 'Schizophrenia Proneness Instruments'. Mixed-effects linear regression analysis on the frequency of CHR symptoms revealed a significant effect of age group, and the interaction CHR symptoms x age group for both perceptive and non-perceptive symptoms. Further, regarding stability of CHR symptoms, there was a significant effect of the interaction CHR symptoms x age group for perceptive symptoms only. Based on EMA, perceptive CHR symptoms were more frequently reported but less stable in children/adolescents compared with adults. Together with previous findings, our finding of higher instability/variability of perceptive symptoms in younger persons might suggest that with advancing age and more stability of CHR symptoms, clinical relevance (reduced psychosocial functioning) may increase.

The EMA assessment of encorafenib in combination with cetuximab for the treatment of adult patients with metastatic colorectal carcinoma harbouring the BRAFV600E mutation who have received prior therapy.

On 2 June 2020, a marketing authorisation valid through the European Union (EU) was issued for encorafenib in combination with cetuximab in adult patients with metastatic colorectal carcinoma (mCRC) with the BRAFV600E mutation who had received prior systemic therapy. Encorafenib plus cetuximab was evaluated in a randomised phase III trial of encorafenib plus binimetinib plus cetuximab versus encorafenib plus cetuximab versus cetuximab plus irinotecan or FOLFIRI (control arm) to adult patients with BRAFV600E mCRC who had received prior therapy for metastatic disease. The median overall survival was 9.3 months [95% confidence interval (CI): 8.05-11.30] versus 5.88 months (95% CI: 5.09-7.10) for encorafenib plus cetuximab (doublet) versus the control arm, respectively [hazard ratio (HR) 0.61, 95% CI: 0.48-0.77]. Progression-free survival (PFS) was 4.27 months (95% CI: 4.07-5.45) versus 1.54 months (95% CI: 1.48-1.91) (HR 0.44; 95% CI: 0.35-0.55). The most frequent adverse events in patients receiving encorafenib plus cetuximab were fatigue, nausea, diarrhoea, acneiform dermatitis, abdominal pain, arthralgia, decreased appetite, vomiting and rash. The aim of this manuscript is to summarise the scientific review of the application leading to regulatory approval in the EU.

Physical activity in an air-polluted environment: behavioral, psychological and neuroimaging protocol for a prospective cohort study (Healthy Aging in Industrial Environment study - Program 4).

BACKGROUND: Air pollution has been linked to increased mortality and morbidity. The Program 4 of the Healthy Aging in Industrial Environment study investigates whether the health and wellbeing benefits of physical activity (PA) can be fully realized in individuals living in highly polluted environments. Herein, we introduce the behavioral, psychological and neuroimaging protocol of the study. METHODS: This is a prospective cohort study of N = 1500 individuals aged 18-65 years comparing: (1) individuals living in the highly polluted, industrial region surrounding the city of Ostrava (n = 750), and (2) controls from the comparison region with relative low pollution levels in Southern Bohemia (n = 750). Quota sampling is used to obtain samples balanced on age, gender, PA status (60% active runners vs. 40% insufficiently active). Participants are screened and complete baseline assessments through online questionnaires and in-person lab-based assessments of physiological, biomechanical, neuroimaging and cognitive function parameters. Prospective 12-month intensive monitoring of air pollution and behavioral parameters (PA, inactivity, and sleep) follows, with a focus on PA-related injuries and psychological factors through fitness trackers, smartphones, and mobile apps. Subsequently, there will be a 5-year follow-up of the study cohort. DISCUSSION: The design of the study will allow for (1) the assessment of both short-term variation and long-term change in behavioral parameters, (2) evaluation of the incidence of musculoskeletal injuries and psychological factors impacting behavior and injury recovery, and (3) the impact that air pollution status (and change) has on behavior, psychological resilience, and injury recovery. Furthermore, the integration of MRI techniques and cognitive assessment in combination with data on behavioral, biological and environmental variables will provide an opportunity to examine brain structure and cognitive function in relation to health behavior and air pollution, as well as other factors affecting resilience against and vulnerability to adverse changes in brain structure and cognitive aging. This study will help inform individuals about personal risk factors and decision-makers about the impact of environmental factors on negative health outcomes and potential underlying biological, behavioral and psychological mechanisms. Challenges and opportunities stemming from the timing of the study that coincided with the COVID-19 pandemic are also discussed.

Clinical outcomes after increasing bladder outlet resistance without augmentation cystoplasty in neurogenic bladder.

INTRODUCTION: Patients with neurogenic bladder (NGB) and urinary incontinence (UI) due to low bladder outlet resistance may require bladder neck procedures (BNPs) to achieve continence. These patients may also have reduced bladder capacity and or elevated detrusor storage pressures that require augmentation cystoplasty (AC). AC is not without complications that include risks for bladder rupture, urolithiasis, urinary tract infections and metabolic issues. Avoidance of AC would be helpful in patients with neurogenic urinary incontinence that have safe bladder parameters in the setting of low bladder outlet resistance. OBJECTIVE: To determine if pre-operative urodynamics could select children with NGBs and UI for isolated BNPs without AC. Additionally we sought to determine the safety of BNPs without AC and future need of AC with long-term follow-up. STUDY DESIGN: This is an IRB-approved retrospective analysis of all patients undergoing BNPs for management of neurogenic UI over a 17-year period. We separated these BNP patients into two groups: No AC + BNP (Group 1) vs. AC + BNP (Group 2). Our primary analyses focused on postoperative outcomes for patients in Group 1. Outcomes assessed included additional surgical procedures, urodynamic changes, development of CKD, new hydronephrosis (HDN) and vesicoureteral reflux (VUR). Secondary analysis included the timeline for the development of any bladder deterioration that necessitated AC in Group 1. RESULTS: 93 patients underwent BNP at a mean age of 10.8 years. Thirty did not have AC at the time of surgery (Group 1). These children had larger (p < 0.001) and more compliant (p < 0.001) bladders than Group 2 having simultaneous augmentation. At 6 years mean follow-up in Group 1 patients, three developed new reflux and three had new hydronephrosis. Nine (30%) had additional continence procedures. Twelve required (40%) AC at a mean of 23 months after the initial BNP. No patients had AC after 5 years. Detrusor end filling pressure increased 14.8 cm H2O (p = 0.028) and expected bladder capacity decreased 26.1% (p = 0.005) after isolated BNP. DISCUSSION: We found that from our cohort of patients who had normal bladder compliance and normal/near normal expected capacity preoperatively 40% required subsequent AC. We were unable to find pre-operative clinical parameters which predicted failure or conversion to AC. We found that 43.3% of our BNP without AC patients had no subsequent invasive procedures with mean 6-year follow-up. We found that none of our patients developed any degree of CKD. Finally, we found that the majority of patients that converted to AC after their BNP did so within the first 2 years after their initial BNP and no patients required augmentation 5 years post their initial BNP. This data validates that these patients require very strict follow up, particularly in the first 5 years after surgery. CONCLUSIONS: BNP without AC is safe in only a few selected patients with NGB. Despite preoperative selection, there are significant changes in bladder dynamics and 40% required subsequent augmentation. Bladder deterioration occurs early and generally in the first 2 years. Since there are no apparent reliable pre-operative variables predicting the need for subsequent AC, parents should be counseled regarding vigilant post-operative follow-up.

A psychophysiological investigation of the interplay between orienting and executive control during stimulus conflict: A heart rate variability study.

BACKGROUND: It has been hypothesized that resting state cardiac vagal activity (CVA) - an indicator of parasympathetic nervous system activity - is a specific psychophysiological marker of executive control function. Here, we propose an alternative hypothesis - that CVA is associated with early stage attention orientation, promoting the flexible uptake of new information, on which the later operation of such executive control functions depends. We therefore predicted that CVA would predict the interaction between orienting and executive control. This was tested using the revised version of the Attention Network Test (ANT-R) that was developed to distinguish between orienting and executive attention during a stimulus conflict task. METHODS: Healthy adults (N = 48) performed the ANT-R and their resting CVA was measured over a 5 min period using ECG recordings. RESULTS: Multiple regression analyses indicated that, when other factors were controlled for, CVA was more strongly associated with the interaction between the orienting and executive control terms than with either factor individually. CONCLUSION: Higher levels of CVA are specifically implicated in the modulation of executive control by intrinsic orientation operating at early stages of conflict detection. These initial findings of higher CVA on orienting attention in conflict detection need to be replicated in larger samples.

[Structured training curriculum for urological residents: chances and limits]. / Strukturiertes Curriculum für die urologische Facharztausbildung: Chancen und Grenzen.

Current surveys show that 45% of German urologic residents do not feel sufficiently prepared for their later urologic work, and 85% lack a structured training curriculum in their home institutions. Furthermore, they report a lack of transparency and evaluations as well as economic constraints. This gives reason to revise and adapt the current urologic training curriculum. In the following article we compare the current urologic curriculum with other disciplines and discuss chances and limits of possible future models. These include better definitions of basic training skills, specialization, a structured evaluation system, standardization of exams and room for research.

IgG1+ B-cell immunity predates IgE responses in epicutaneous sensitization to foods.

BACKGROUND: The generation of IgE-mediated food allergy in humans is silent and only diagnosed upon manifestation of clinical symptoms. While experimental models have been used to investigate some mechanisms of allergic sensitization, the generation of humoral immunity and memory remains to be elucidated. Here, we defined the evolution of allergen-specific B-cell responses during epicutaneous sensitization to foods. METHODS: Wild-type and genetic knockout animals, and drug or antibody strategies for cell depletion and immunoglobulin signaling blockade were used to investigate epicutaneous sensitization and disease progression; we analyzed allergen-specific germinal centers and IgG1+ memory B cells by flow cytometry, evaluated humoral responses, and determined clinical reactivity (anaphylaxis). RESULTS: Epicutaneous sensitization caused microscopic skin damage, inflammation, and recruitment of activated dendritic cells to the draining lymph nodes. This process generated allergen-specific IgG1+ germinal center B cells, serum IgG1, and anaphylaxis that was mediated by the alternative pathway. Whether we used peanut and/or ovalbumin from the egg white for sensitization, the allergen-specific IgG1+ memory compartment predominantly exhibited an immature, pro-germinal center phenotype (PDL-2- CD80- CD35+ CD73+ ). Subsequent subclinical exposures to the allergen induced IgE+ germinal center B cells, serum IgE, and likely activated the classical pathway of anaphylaxis. CONCLUSIONS: Our data demonstrate that IgG1+ B-cell immunity against food allergens in epicutaneous sensitization precedes the generation of IgE responses. Therefore, the assessment of allergen-specific cellular and humoral IgG1+ immunity may help to identify individuals at risk of developing IgE-mediated food allergy and hence provide a window for therapeutic interventions.

Affective instability across the lifespan in borderline personality disorder - a cross-sectional e-diary study.

OBJECTIVE: Longitudinal and cross-sectional studies suggest that affective instability is inversely related to greater age in borderline personality disorder (BPD). However, existing studies relied on retrospective self-reports of perceived instability. We examined affective instability in everyday life in patients with BPD and healthy controls (HCs) by age in a cross-sectional e-diary study. METHODS: Two hundred and sixty female participants between 14 and 53 years of age (130 patients with BPD and 130 HCs) carried an e-diary over 4 days. The e-diaries emitted a prompting signal in approximately hourly intervals asking participants to rate their current affective state, that is valence (ranging from pleasant to unpleasant) and tense arousal (ranging from calm/relaxed to restless/under tension). RESULTS: Multilevel analyses revealed a significant interaction of age and group predicting affective instability (valence: F(1,255.6)  = 7.59; P < 0.01; tense arousal: F(1,252)  = 6.08; P < 0.01), suggesting that affective instability significantly declines with greater age in patients with BPD. Controlling for the number of comorbid disorders and BPD severity did not change the results, illustrating an inverse relationship between age and affective instability in BPD (significant interaction of age*group for valence: F(1,238.7)  = 5.74; P < 0.02 and tense arousal: F(1,235.2)  = 5.28; P < 0.02). CONCLUSION: Affective instability during daily life declines with greater age in BPD. This decline is irrespective of comorbidity and BPD severity.

Effects of Body Mass Index on Parasympathetic Nervous System Reactivity and Recovery Following Orthostatic Stress.

Vagally mediated heart rate variability (vmHRV), defined as the beat-to-beat fluctuations in a heart series mediated by the vagus nerve, serves as a non-invasive index of parasympathetic nervous system (PNS) activity. Lower resting state vmHRV is associated with greater body mass index (BMI), providing a psychophysiological pathway linking obesity with health and disease. However little research has been conducted to examine how BMI may influence PNS reactivity to orthostatic stress. The present study sought to explore this in a sample of 59 individuals (44 females, mean age = 24.37 years, age range 19-65 years). VmHRV was measured throughout the 5-minute baseline (sitting), orthostatic (standing), and recovery (sitting) conditions. Individuals were stratified into low (BMI < 20), moderate (BMI 20-25), and high (BMI > 25) BMI groups. Results indicate that the high BMI group had a greater decrease in vmHRV from baseline to standing in comparison to the moderate BMI group. Furthermore, the low BMI group showed lower vmHRV during recovery compared to baseline, suggesting that these individuals did not fully recover from the standing position. Taken together, these results extend previous literature showing that those with low and high BMI can show different yet maladaptive patterns of vmHRV in response to orthostatic stress.

Pre-operative risk factors for stomal stenosis with Malone antegrade continence enema procedures.

INTRODUCTION: The Malone antegrade continence enema (MACE) procedure remains an effective tool in providing independence to patients with refractory constipation. Appendiceal, ileal and colonic segments are all used depending upon the patient's individual anatomy and surgeon's preference. Unfortunately, MACE stomal stenosis (SS) remains a frustrating complication. It was hypothesized that SS is associated with the type of efferent limb used for MACE construction. OBJECTIVE: To perform a retrospective risk analysis of the pre-operative factors that correlated with postoperative stomal stenosis. MATERIALS AND METHODS: The study reviewed 39 consecutive patients treated with MACE by a single surgeon at the present institution. Collected data included: the type of channel construction, stoma site, pre-operative body mass index (BMI) z-score, pre-operative diagnosis, and development of SS. Stomal stenosis was defined as a documented inability to catheterize, requirement of a Chait tube, or a subsequent stomal revision. An odds ratio (OR) analysis was performed to evaluate the association with the development of SS. RESULTS: Stomal stenosis developed in 19 patients (49%) with an average follow-up of 4.7 years. The majority of patients had a diagnosis of myelomeningocele (90%), and there was no significant difference in gender distribution (54% males, 46% females). The distribution types of MACE efferent limbs consisted of appendicocecostomy in 20 (51%), cecal-wall flap in 16 (41%) and ileocecostomy in three patients (8%). Neither type of efferent limb, nor stomal location were significant predictors of postoperative SS. Pre-operative obesity (BMI ≥95%), however, demonstrated a significant risk of SS compared to non-obese patients (OR 4.44, 95% CI 1.08-18.4, P = 0.04). DISCUSSION: This was a single-institution study of a relatively small number of patients. However, examining consecutive patients with a common surgeon can minimize technique variability. Also, the rates of stenosis in this cohort were higher than most. This may have been due to a more broad definition (unable to catheterize). These findings complement recent literature showing an increased complication rate for the obese pediatric patient. CONCLUSION: Stomal stenosis remains a frustrating complication following creation of the MACE stoma. In the present series, neither a cecal wall flap, nor the stomal site location contributed to SS. Obesity was the only identified statistically significant risk factor that led to SS.

Identification of an atypical etiological head and neck squamous carcinoma subtype featuring the CpG island methylator phenotype.

Head and neck squamous cell carcinoma (HNSCC) is broadly classified into HNSCC associated with human papilloma virus (HPV) infection, and HPV negative HNSCC, which is typically smoking-related. A subset of HPV negative HNSCCs occur in patients without smoking history, however, and these etiologically 'atypical' HNSCCs disproportionately occur in the oral cavity, and in female patients, suggesting a distinct etiology. To investigate the determinants of clinical and molecular heterogeneity, we performed unsupervised clustering to classify 528 HNSCC patients from The Cancer Genome Atlas (TCGA) into putative intrinsic subtypes based on their profiles of epigenetically (DNA methylation) deregulated genes. HNSCCs clustered into five subtypes, including one HPV positive subtype, two smoking-related subtypes, and two atypical subtypes. One atypical subtype was particularly genomically stable, but featured widespread gene silencing associated with the 'CpG island methylator phenotype' (CIMP). Further distinguishing features of this 'CIMP-Atypical' subtype include an antiviral gene expression profile associated with pro-inflammatory M1 macrophages and CD8+ T cell infiltration, CASP8 mutations, and a well-differentiated state corresponding to normal SOX2 copy number and SOX2OT hypermethylation. We developed a gene expression classifier for the CIMP-Atypical subtype that could classify atypical disease features in two independent patient cohorts, demonstrating the reproducibility of this subtype. Taken together, these findings provide unprecedented evidence that atypical HNSCC is molecularly distinct, and postulates the CIMP-Atypical subtype as a distinct clinical entity that may be caused by chronic inflammation.

Conditioning pain stimulation does not affect itch induced by intra-epidermal histamine pricks but aggravates neurogenic inflammation in healthy volunteers.

This study investigated whether itch induced by intra-epidermal histamine is subjected to modulation by a standardized conditioned pain modulation (CPM) paradigm in 24 healthy volunteers. CPM was induced by computer-controlled cuff pressure algometry and histamine was introduced to the volar forearm by skin prick test punctures. Moreover, neurogenic inflammation and wheal reactions induced by histamine and autonomic nervous system responses (heart rate variability and skin conductance) were monitored. CPM did not modulate the intensity of histamine-induced itch suggesting that pruriceptive signaling is not inhibited by pain-recruited endogenous modulation, however, CPM was found to aggravate histamine-induced neurogenic inflammation, likely facilitated by efferent sympathetic fibers.

A meta-analysis on pain sensitivity in self-injury.

Individuals engaging in self-injurious behavior (SIB) frequently report absence of pain during acts of SIB. While altered pain sensitivity is discussed as a risk factor for the engagement in SIB, results have been mixed with considerable variance across reported effect sizes, in particular with respect to the effect of co-morbid psychopathology. The present meta-analysis aimed to summarize the current evidence on pain sensitivity in individuals engaging in SIB and to identify covariates of altered pain processing. Three databases were searched without restrictions. Additionally a hand search was performed and reference lists of included studies were checked for potential studies eligible for inclusion. Thirty-two studies were identified after screening 720 abstracts by two independent reviewers. Studies were included if they reported (i) an empirical investigation, in (ii) humans, including a sample of individuals engaging in (iii) SIB and a group of (iv) healthy controls, (v) receiving painful stimulation. Random-effects meta-analysis was performed on three pain-related outcomes (pain threshold, pain tolerance, pain intensity) and several population- and study-level covariates (i.e. age, sex, clinical etiology) were subjected to meta-regression. Meta-analysis revealed significant main effects associated with medium to large effect sizes for all included outcomes. Individuals engaging in SIB show greater pain threshold and tolerance and report less pain intensity compared to healthy controls. Clinical etiology and age are significant covariates of pain sensitivity in individuals engaging in SIB, such that pain threshold is further increased in borderline personality disorder compared to non-suicidal self-injury. Mechanisms underlying altered pain sensitivity are discussed.

Does the onset of bone metastasis in sunitinib-treated renal cell carcinoma patients impact the overall survival?

PURPOSE: To evaluate the impact of bone metastasis (BM) onset toward prognosis in metastatic renal cell carcinoma (mRCC) patients treated with sunitinib. METHODS: mRCC patients with BM and sunitinib as first targeted therapy between May 2005 and December 2012 were retrospectively analyzed. Patients with synchronous (s) BM or metachronous (m) BM were compared with regard to treatment and outcome [time to clinical progression (TTcP), overall survival (OS), skeletal-related events (SRE)]. Descriptive statistics, Kaplan-Meier estimation of TTcP and OS, Cox regression analyses, and a landmark analysis were administered. RESULTS: BM was identified in 127 mRCC patients; thereof, 82 sunitinib-treated patients were analyzed [sBM n = 57 (69.5 %), mBM n = 25 (30.5 %)]. Higher tumor grading (p = 0.029), male predominance (p = 0.02), and less second-line therapy (p = 0.001) were detected in sBM compared to mBM. SRE remained similar between subgroups (p = 0.462). TTcP during sunitinib was similar [median sBM 8.1 (95 % CI 3.9-12.3) vs. mBM 8.7 (95 % CI 2.7-14.8) months, p = 0.903]. OS remained significantly inferior in sBM patients compared to mBM [median sBM 21.1 (95 % CI 16-26.2) months vs. mBM 38.5 (95 % CI 15-62) months, p = 0.001], which was confirmed by landmark analyses at 1.5, 3, 6, 9, and 12 months. However, OS after occurrence of BM was similar in both groups [median sBM 24.2 (95 % CI 17.3-31.1) months vs. mBM 17.2 (95 % CI 8.4-26) months, p = 0.519]. CONCLUSIONS: mBM is associated with an improved OS compared to sBM in mRCC with sunitinib treatment, despite similar efficacy of sunitinib treatment in both groups of patients.

Equine allogeneic umbilical cord blood derived mesenchymal stromal cells reduce synovial fluid nucleated cell count and induce mild self-limiting inflammation when evaluated in an lipopolysaccharide induced synovitis model.

REASONS FOR PERFORMING STUDY: Improvement has been reported following intra-articular (i.a.) injection of mesenchymal stromal cells (MSCs) in several species. These observations have led to the use of i.a. MSCs in equine practice with little understanding of the mechanisms by which perceived improvement occurs. OBJECTIVES: To evaluate the effect of i.a. allogeneic umbilical cord blood (CB-) derived MSCs using a lipopolysaccharide (LPS) induced synovitis model. We hypothesised that i.a. CB-MSCs would reduce the inflammatory response associated with LPS injection. STUDY DESIGN: Randomised, blinded experimental study. METHODS: Feasibility studies evaluated i.a. LPS or CB-MSCs alone into the tarsocrural joint. In the principal study, middle carpal joint synovitis was induced bilaterally with LPS and then CB-MSCs were injected into one middle carpal joint. Lameness, routine synovial fluid analysis, and synovial fluid biomarkers were evaluated at 0, 8, 24, 48 and 72 h. RESULTS: LPS injection alone resulted in transient lameness and signs of inflammation. In joints untreated with LPS, injection of 30 million CB-MSCs resulted in mild synovitis that resolved without treatment. Mild (grade 1-2) lameness in the CB-MSC-treated limb was observed in 2 horses and severe lameness (grade 4) in the 3rd, 24 h post injection. Lameness did not correlate with synovitis induced by CB-MSC injection. Simultaneous injection of LPS and CB-MSCs resulted in significant reduction in synovial fluid total nucleated, neutrophil and mononuclear cell numbers compared with contralateral LPS-only joints. No difference was detected in other parameters associated with synovial fluid analysis or in synovial fluid biomarkers. The incidence of lameness was only different from baseline at 8 h, where horses were lame in CB-MSC limbs. CONCLUSIONS: Allogeneic CB-MSCs reduced synovial fluid cell populations and stimulated mild self-limiting inflammation in the synovitis model. Continued evaluation of the effects of i.a. CB-MSC therapy on synovitis in horses is needed to evaluate anti- and proinflammatory properties of CB-MSCs. Immediate interests are dose, timing of treatment, and treatment frequency.

Association Strength of Three Adiposity Measures with Autonomic Nervous System Function in Apparently Healthy Employees.

OBJECTIVES: To investigate the association of different measures of central (abdominal) and overall adiposity with autonomic nervous system (ANS) function, indexed by heart rate variability (HRV), in apparently healthy human adults. DESIGN AND MEASUREMENTS: Cross-sectional data of 8,538 participants (20% female, age: 41 ± 11 years, body mass index (BMI): 24 ± 4 kg/m2, waist circumference (WC): 91 ± 12 cm, waist-to-height ratio (WHtR): 0.45 ± 0.08) were available for analysis. RESULTS: All measures of adiposity were inversely correlated with vagally-mediated HRV indexed by RMSSD (all p<0.001). Strongest associations were found with WC and RMSSD (r = -0.29). Associations were stronger in males (WC r = -0.32) than in females (WC r = -0.23). Partial correlations revealed the same pattern for RMSSD (WC all pcc = -0.12 p<0.001; WC male pcc = -0.14 p<0.001; WC female pcc = -0.06 p<0.05). Correlation strength of BMI and WHtR with RMSSD were similar and significantly weaker compared to WC (p < .001) in unadjusted analysis. Overall, nonparametric Kendall's τb led to the same conclusions. CONCLUSION: The present data supports previous findings, that HRV is related to measures of adiposity in healthy individuals. In line with previous research, we found that WC is more strongly related to measures of HRV, indicating that WC best captures adiposity related risk.

Does visualisation during urethrocystoscopy provide pain relief? Results of an observational study.

BACKGROUND: To measure the effects of real-time visualisation during urethrocystoscopy on pain in patients who underwent ambulatory urethrocystoscopy. METHODS: An observational study was designed. From June 2012 to June 2013 patients who had ambulatory urethrocystoscopy participated in the study. In order to measure pain perception we used a numeric rating scale (NRS) 0 to 10. Additional data was collected including gender, reason for intervention, use of a rigid or a flexible instrument and whether the patient had had urethrocystoscopy before. RESULTS: 185 patients were evaluated. 125 patients preferred to watch their urethrocystoscopy on a real-time video screen, 60 patients did not. There was no statistically relevant difference in pain perception between those patients who watched their urethrocystoscopy on a real-time video screen and those who did not (p = 0.063). However, men who were allowed to watch their flexible urethrocystoscopy experienced significantly less pain, than those who did not (p = 0.007). No such effects could be measured for rigid urethrocystoscopy (p = 0.317). Furthermore, women experienced significantly higher levels of pain during the urethrocystoscopy than men (p = 0.032). CONCLUSIONS: Visualisation during urethrocystoscopy procedures in general does not significantly decrease pain in patients. Nevertheless, men who undergo flexible urethrocystoscopy should be offered to watch their procedure in real-time on a video screen. To make urethrocystoscopy less painful for both genders, especially for women, should be subject to further research.