Changes in perceived peripersonal space following the rubber hand illusion.

Peripersonal space (PPS), the region immediately surrounding the body is essential for bodily protection and goal directed action. Previous studies have suggested that the PPS is anchored to one's own body and in the current study we investigated whether the PPS could be modulated by changes in perceived body ownership. While theoretically important, this anchoring can also have implications for patients with altered body perception. The rubber hand illusion (RHI) is a way to manipulate body ownership. We hypothesized that after induction of a left hand RHI, the perceived space around the body shifts to the right. Sixty-five participants performed a landmark task before and after a left hand RHI. In the landmark task, participants had to determine whether a vertical landmark line was left or right from the center of a horizontal screen. One group of the participants was exposed to synchronous stroking, the other group experienced asynchronous stroking. Results showed a shift in space to the right (e.g. away from the own arm), but only for the 'synchronous stroking' group. These results suggest that the relevant action space becomes linked to the fake hand. Critically, subjective ownership experience did not correlate with this shift, but proprioceptive drift did. This suggests that multisensory integration of bodily information drives this shift in space around the body and not feelings of ownership.

Grading bloodstream infection risk using citrulline as a biomarker of intestinal mucositis in patients receiving intensive therapy.

Earlier studies have suggested that severe intestinal mucositis (IM; citrulline < 10 µmol/L) is an independent risk factor for bloodstream infections (BSI) after cytotoxic therapy. Our aim was to grade IM in patients receiving commonly used chemotherapy and conditioning regimens, and characterize its relationship with BSI incidence. In a retrospective analysis of remission induction (RI) chemotherapy, or conditioning for autologous and allogeneic hematopoietic stem cell transplantation (HSCT; myeloablative conditioning [MAC] and non-myeloablative and reduced-intensity conditioning [NMA/RIC]), data were collected on central venous catheter (CVC) characteristics and BSI. The relationship between BSI occurrence and the degree of IM (determined by citrulline levels) and neutropenia was analyzed. In 626 CVC episodes, 268 (42.8%) laboratory-confirmed BSIs (LCBIs) occurred, classified as mucosal barrier injury (MBI)-LCBIs in 179 (28.6%) episodes, central line-associated BSIs in 113 (18.1%) episodes, and catheter-related BSIs in 55 (8.8%) episodes. In NMA/RIC, the mean duration of hypocitrullinemia was 0.77 days, with LCBI and MBI-LCBI occurring in 11.1% and 4.8% of episodes. In autologous HSCT, RI, and MAC allogeneic HSCT, LCBI and MBI-LCBI occurred frequently (40.0-63.8% and 22.8-53.2% of episodes, respectively) and the mean duration of hypocitrullinemia was significantly higher (9.2-13.8 days). There was a strong correlation between LCBI and the duration of hypocitrullinemia (Pearson's correlation coefficient R = 0.96), as opposed to the relationship between LCBI and the duration of neutropenia (R = 0.42). We conclude that citrulline can be used to grade BSI risk for commonly used intensive treatment regimens.

'Rapid speed of response to ECT in bipolar depression: A chart review.

OBJECTIVE: To validate a faster speed of response to electroconvulsive therapy (ECT) for bipolar depression (BPD) compared to major depressive disorder (MDD) METHOD: Retrospective chart review on an ECT cohort in an academic hospital setting. Speed of response was defined by the number of ECT treatments needed for response or remission. RESULTS: Sixty-four depressed patients were included, of whom 53 (MDD: 40, BPD: 13) could be analyzed. The bipolar group responded faster with a mean difference of 3.3 fewer ECT treatments to meet response criteria (MDD 10.4 vs. BPD 7.1, p = 0.054). When using mixed effects regression models for the response/remitter group (n = 35), a faster response for the bipolar group (AIC 252.83 vs 258.55, χ2 = 11.72, p = 0.008) was shown. Other factors, such as psychotic features or comorbidity, did not influence the speed of response. CONCLUSION: This chart review of an ECT cohort in an naturalistic academic hospital setting shows an evident and clinically relevant faster speed of response in bipolar depression.

Immediate implant placement in edentulous oral cancer patients: a long-term retrospective analysis of 207 patients.

Although the functional benefits of implants in the rehabilitation of edentulous cancer patients are well-known, most studies report on postponed implant placement. The outcome of immediate implant placement regarding successful rehabilitation, implant loading and survival is unclear. Two hundred and seven edentulous oral cancer patients that received implants during ablative surgery at the Radboud University Medical Centre between 2000 and 2011 were included. Data regarding the oncological treatment, implant placement, follow-up and prosthodontic rehabilitation were recorded retrospectively with a follow-up period of 5-17 years. Functioning implant-retained dentures were made in 73.9% of the patients. Of the surviving patients, 81.9% had functioning dentures after 2 years and 86.3% after 10 years. Patients with ASA score 1 and younger patients were rehabilitated more frequently. The median time of functioning denture placement was 336 days after surgery, with a negative influence of postoperative radiotherapy. Implant survival was 90.7%, and was lower when the implant was placed in a jaw involved in the tumour. Immediate implant placement during oral cancer surgery led to a high number of edentulous patients rehabilitated with implant-retained dentures, which are placed at an early time.

First international quality control programme for laboratories measuring antimicrobial drugs to support dose individualization in critically ill patients.

OBJECTIVES: International quality control (proficiency testing) programmes are instituted to safeguard the analytical performance of laboratories and to aid these laboratories in identifying sources of error in their analytical methods. We describe the first international quality control programme for antimicrobial agents that are frequently used in critically ill patients. METHODS: Spiked plasma samples with ceftazidime, ciprofloxacin, flucloxacillin, piperacillin, sulfamethoxazole, N-acetyl sulfamethoxazole and trimethoprim were shipped to 22 laboratories from eight different countries. Acceptable accuracy by the performing laboratory was defined if measurements were within 80%-120% limits of the true weighed-in concentrations. RESULTS: A total of 81% of the measurements (ranging between 56% and 100%, dependent on drug) were within the 80%-120% limits of the true weighed-in concentrations. CONCLUSIONS: We found a relatively good performance of the participating laboratories in measuring eight different antimicrobial drugs. Nevertheless, some of the antimicrobial drugs were not measured properly as up to 44% of the measurements was inaccurate depending on the drug. Our results emphasize the need for and utility of an ongoing quality control programme.

Surveillance of catheter-related bloodstream infections in haemato-oncology patients: comparison of two definitions.

In the Netherlands, the PREZIES surveillance is used for registration and surveillance of central venous catheter (CVC) -related bloodstream infections (CRBSI). We investigated how this Dutch definition correlated with internationally used definitions for CRBSI, central line-associated bloodstream infections (CLABSI) and mucosal barrier injury laboratory-confirmed bloodstream infections (MBI-LCBI). We determined that the Dutch PREZIES definition of CRBSI is appropriate for surveillance control of CVC care bundle use in haemato-oncology patients managed with multi-lumen CVCs.

Autologous versus prosthetic nasal and auricular reconstruction - patient, professional and layperson perceptions.

The aim of this study was to retrospectively evaluate the perceptions of aesthetic outcome following the autologous and prosthetic reconstruction of nasal and auricular defects among patients, professionals (oral and maxillofacial surgeons and ear, nose and throat surgeons) and people unfamiliar with reconstructive surgery. The influence of anatomical subunits on the overall perception of nasal and auricular reconstructions was also determined. A total of 119 patients treated for nasal and auricular defects between 1997 and 2016, with a minimum follow-up period of 6 months, were selected, and photographs of 77 of these patients (65%) were presented in a digital survey and reviewed using a standardized questionnaire. No clinically relevant correlations were found between the age or gender of patients (as well as those of the respondents) and their scores. Prosthetic reconstructions of nasal and auricular defects were considered advantageous over autologous reconstructions in terms of the subjective aesthetic outcome in the view of the professionals, in particular oral and maxillofacial surgeons; however, the patients judged both techniques to be equally effective in terms of aesthetics. No anatomical subunits were found to have a significant impact on the overall match of a nasal or auricular reconstruction with the patient's face.

Molecular characteristics of carbapenemase-producing Enterobacterales in the Netherlands; results of the 2014-2018 national laboratory surveillance.

OBJECTIVES: Carbapenem resistance mediated by mobile genetic elements has emerged worldwide and has become a major public health threat. To gain insight into the molecular epidemiology of carbapenem resistance in The Netherlands, Dutch medical microbiology laboratories are requested to submit suspected carbapenemase-producing Enterobacterales (CPE) to the National Institute for Public Health and the Environment as part of a national surveillance system. METHODS: Meropenem MICs and species identification were confirmed by E-test and MALDI-TOF and carbapenemase production was assessed by the Carbapenem Inactivation Method. Of all submitted CPE, one species/carbapenemase gene combination per person per year was subjected to next-generation sequencing (NGS). RESULTS: In total, 1838 unique isolates were received between 2014 and 2018, of which 892 were unique CPE isolates with NGS data available. The predominant CPE species were Klebsiella pneumoniae (n = 388, 43%), Escherichia coli (n = 264, 30%) and Enterobacter cloacae complex (n = 116, 13%). Various carbapenemase alleles of the same carbapenemase gene resulted in different susceptibilities to meropenem and this effect varied between species. Analyses of NGS data showed variation of prevalence of carbapenemase alleles over time with blaOXA-48 being predominant (38%, 336/892), followed by blaNDM-1 (16%, 145/892). For the first time in the Netherlands, blaOXA-181, blaOXA-232 and blaVIM-4 were detected. The genetic background of K. pneumoniae and E. coli isolates was highly diverse. CONCLUSIONS: The CPE population in the Netherlands is diverse, suggesting multiple introductions. The predominant carbapenemase alleles are blaOXA-48 and blaNDM-1. There was a clear association between species, carbapenemase allele and susceptibility to meropenem.

Body representation does not lag behind in updating for the pubertal growth spurt.

Both making perceptual judgments about your own body and successfully moving your body through the world depend on a mental representation of the body. However, there are indications that moving might be challenging when your body is changing. For instance, the pubertal growth spurt has been reported to be negatively correlated to motor competence. A possible explanation for this clumsiness would be that when the body is growing fast, updating the body representation may lag behind, resulting in a mismatch between internal body representation and actual body size. The current study investigated this hypothesis by testing participants ranging from aged 6 to 50 years on both a tactile body image task and a motor body schema task. Separate groups of participants, including those in the age range when pubertal growth spurt occurs, were asked to estimate the distance between two simultaneously applied tactile stimuli on the arm and to move their hand through apertures of different widths. Tactile distance estimations were equal between participants before, during, and after the age range where the pubertal growth spurt is expected. Similarly, Bayesian evaluation of informative hypotheses showed that participants in the age range of the growth spurt did not move through the apertures as if their representation of the hand was smaller than its physical size. These results suggest that body representations do not lag behind in updating for the pubertal growth spurt.

Development of a Virosomal RSV Vaccine Containing 3D-PHAD® Adjuvant: Formulation, Composition, and Long-Term Stability.

PURPOSE: Characterization of virosomes, in late stage preclinical development as vaccines for Respiratory Syncytial Virus (RSV), with a membrane-incorporated synthetic monophosphoryl lipid A, 3D-PHAD® adjuvant. METHODS: Virosomes were initially formed by contacting a lipid film containing 3D-PHAD® with viral membranes solubilized with the short chain phospholipid DCPC, followed by dialysis, later by adding solubilized 3D-PHAD to viral membranes, or to preformed virosomes from DMSO. RESULTS: Virosomes formed from lipid films contained the membrane glycoproteins G and F, at similar F to G ratios but lower concentrations than in virus, and the added lipids, but only a fraction of the 3D-PHAD®. By single particle tracking (SPT), the virosome size distribution resembled that seen by cryo-electron microscopy, but dynamic light scattering showed much larger particles. These differences were caused by small virosome aggregates. Measured by SPT, virosomes were stable for 300 days. 3DPHAD ® incorporation in virosomes could be enhanced by providing the adjuvant from DCPC solubilized stock, but also by adding DMSO dissolved adjuvant to pre-formed virosomes. Virosomes with 0.1 mg/mg of 3D-PHAD®/viral protein from DMSO induced antibody titers similar to those by virosomes containing 0.2 mg/mg of DCPC-solubilized 3D-PHAD®. CONCLUSIONS: Stable 3D-PHAD® adjuvanted RSV virosomes can be formulated.

Human islets and dendritic cells generate post-translationally modified islet autoantigens.

The initiation of type 1 diabetes (T1D) requires a break in peripheral tolerance. New insights into neoepitope formation indicate that post-translational modification of islet autoantigens, for example via deamidation, may be an important component of disease initiation or exacerbation. Indeed, deamidation of islet autoantigens increases their binding affinity to the T1D highest-risk human leucocyte antigen (HLA) haplotypes HLA-DR3/DQ2 and -DR4/DQ8, increasing the chance that T cells reactive to deamidated autoantigens can be activated upon T cell receptor ligation. Here we investigated human pancreatic islets and inflammatory and tolerogenic human dendritic cells (DC and tolDC) as potential sources of deamidated islet autoantigens and examined whether deamidation is altered in an inflammatory environment. Islets, DC and tolDC contained tissue transglutaminase, the key enzyme responsible for peptide deamidation, and enzyme activity increased following an inflammatory insult. Islets treated with inflammatory cytokines were found to contain deamidated insulin C-peptide. DC, heterozygous for the T1D highest-risk DQ2/8, pulsed with native islet autoantigens could present naturally processed deamidated neoepitopes. HLA-DQ2 or -DQ8 homozygous DC did not present deamidated islet peptides. This study identifies both human islets and DC as sources of deamidated islet autoantigens and implicates inflammatory activation of tissue transglutaminase as a potential mechanism for islet and DC deamidation.

Laparoscopic repair of perineal hernia after abdominoperineal excision.

PURPOSE: Perineal hernia is a challenging complication after abdominoperineal excision (APE) of the rectum. Surgical repair can be accomplished using challenging abdominal or transperineal approaches. A laparoscopic repair using a Proceed mesh might be an easy and effective alternative. METHODS: We describe a multi-center case-series of twelve patients with a symptomatic perineal hernia treated by laparoscopic mesh repair. A cone-shaped 10 × 15 cm Proceed Mesh was tacked to the promontory or sacrum and sutured to the pelvic sidewalls and the anterior peritoneum. RESULTS: Twelve patients underwent laparoscopic repair of their perineal hernia. Four men and eight women presented with a symptomatic perineal hernia after abdominoperineal excision between 2008 and 2013 and underwent a laparoscopic repair with a Proceed mesh. The median age at presentation was 53 years (range 39-68 years). The mean total theater time was 119 min (range 75-200 min). No conversion to an open procedure was needed. No early complications where seen. The mean hospital stay was 2.25 days (range 1-4 days). Three patients showed recurrence, of whom two had a defect in the middle of the proceed mesh, one had a defect anterior to the previous perineal hernia. All 3 patients underwent a redo-laparoscopic repair with mesh. CONCLUSION: In this case series we present an alternative approach for the surgical repair of perineal hernias. Based on our experience, perineal hernia after APE can be repaired safely and effectively using the described laparoscopic technique.

ACE inhibition modifies exercise-induced pro-angiogenic and mitochondrial gene transcript expression.

Skeletal muscle responds to endurance exercise with an improvement of biochemical pathways that support substrate supply and oxygen-dependent metabolism. This is reflected by enhanced expression of associated factors after exercise and is specifically modulated by tissue perfusion and oxygenation. We hypothesized that transcript expression of pro-angiogenic factors (VEGF, tenascin-C, Angpt1, Angpt1R) and oxygen metabolism (COX4I1, COX4I2, HIF-1α) in human muscle after an endurance stimulus depends on vasoconstriction, and would be modulated through angiotensin-converting enzyme inhibition by intake of lisinopril. Fourteen non-specifically trained, male Caucasians subjects, carried out a single bout of standardized one-legged bicycle exercise. Seven of the participants consumed lisinopril in the 3 days before exercise. Biopsies were collected pre- and 3 h post-exercise from the m. vastus lateralis. COX4I1 (P = 0.03), COX4I2 (P = 0.04) mRNA and HIF-1α (P = 0.05) mRNA and protein levels (P = 0.01) showed an exercise-induced increase in the group not consuming the ACE inhibitor. Conversely, there was a specific exercise-induced increase in VEGF transcript (P = 0.04) and protein levels (P = 0.03) and a trend for increased tenascin-c transcript levels (P = 0.09) for subjects consuming lisinopril. The observations indicate that exercise-induced expression of transcripts involved in angiogenesis and mitochondrial energy metabolism are to some extent regulated via a hypoxia-related ACE-dependent mechanism.

Does diastolic dysfunction precede systolic dysfunction in trastuzumab-induced cardiotoxicity? Assessment with multigated radionuclide angiography (MUGA).

BACKGROUND: Trastuzumab is successfully used for the treatment of HER2-positive breast cancer. Because of its association with cardiotoxicity, LVEF is monitored by MUGA, though this is a relatively late measure of cardiac function. Diastolic dysfunction (DD) is believed to be an early predictor of cardiac impairment. We evaluate the merit of MUGA-derived diastolic function parameters in the early detection of trastuzumab-induced cardiotoxicity (TIC). METHODS AND RESULTS: 77 trastuzumab-treated patients with normal baseline systolic and diastolic function were retrospectively selected (n = 77). All serial MUGA examinations were re-analyzed for systolic and diastolic function parameters. 36 patients (47%) developed SD and 45 patients (58%) DD during treatment. Both systolic and diastolic parameters significantly decreased. Of the patients with SD, 24 (67%) also developed DD. DD developed prior to systolic impairment in 54% of cases, in 42% vice versa, while time to occurrence did not differ significantly (P = .52). This also applied to the subgroup of advanced stage breast cancer patients (P = .1). CONCLUSIONS: Trastzumab-induced SD and DD can be detected by MUGA. An impairment of MUGA-derived diastolic parameters does not occur prior to SD and therefore cannot be used as earlier predictors of TIC.

Trypsin diminishes the rat potency of polio serotype 3.

This study addresses observations made in view of testing in practice the guideline in the European Pharmacopoeia (EP) on omitting the rat potency test for release of polio containing vaccines. In general, use of the guideline is valid and the D-antigen ELISA can indeed be used as an in vitro alternative for the in vivo test. However, the set-up of the ELISA is crucial and should include detection of antigenic site 1 in polio serotype 3 as destruction of that site by trypsin results in a reduced rat potency. Antigenic site 1 in polio serotype 2 may also be modified by trypsin, but the cleavage of viral protein 1 (VP1) did not affect the rat potency. Therefore, any antigenic site, except site 1, can be used for detection of polio serotype 2. It is advised to include testing of the effect of trypsin treatment in the EP-guideline. This allows polio vaccine manufacturers to check whether their in-house ELISA needs improvement.

Mitochondrial microsatellite instability in patients with metastatic colorectal cancer.

Mitochondrial microsatellite instability (mtMSI), a change in length in mtDNA microsatellite sequences between normal and tumor tissue, has been described as a frequent occurrence in colorectal cancer (CRC). We evaluated the prevalence and prognostic value of mtMSI and its relation to nuclear microsatellite instability (MSI) in patients with metastatic CRC (mCRC). At six loci (D310, D514, D16184, ND1, ND5, and COX1), the mitochondrial DNA sequence was analyzed in normal and tumor tissue, and the mtMSI status was determined. We evaluated the prevalence and outcome in terms of overall survival (OS) in 83 CRC patients with a MSI tumor (including 39 patients with Lynch syndrome) and in 99 mCRC patients with a microsatellite stable (MSS) tumor. A meta-analysis was performed to compare our findings with existing data. mtMSI at the D-loop region was found in 54.4 % (99 out of 182) of all patients. Prevalence of mtMSI was most pronounced at the D310 locus (50.5 %). Prevalence of mtMSI at the D-loop region was not different among patients with MSI compared to MSS tumors. There was no effect of mtMSI on prognosis in patients with MSI or MSS tumors. Prevalence of mtMSI was high in mCRC patients with both MSI and MSS tumors, but there was no correlation with prognosis. mtMSI was particularly present at the D310 locus.

Development of a three-dimensional hand model using 3D stereophotogrammetry: Evaluation of landmark reproducibility.

BACKGROUND: Using three-dimensional (3D) photography, exact images of the human body can be produced. Over the last few years, this technique is mainly being developed in the field of maxillofacial reconstructive surgery, creating fusion images with computed tomography (CT) data for accurate planning and prediction of treatment outcome. However, in hand surgery, 3D photography is not yet being used in clinical settings. METHODS: The aim of this study was to develop a valid method for imaging the hand using 3D stereophotogrammetry. The reproducibility of 30 soft tissue landmarks was determined using 3D stereophotogrammetric images. Analysis was performed by two observers on 20 3D photographs. Reproducibility and reliability of the landmark identification were determined using statistical analysis. RESULTS: The intra- and interobserver reproducibility of the landmarks were high. This study showed a high reliability coefficient for intraobserver (1.00) and interobserver reliability (0.99). Identification of the landmarks on the palmar aspect of individual fingers was more precise than the identification of landmarks of the thumb. CONCLUSIONS: This study shows that 3D photography can safely produce accurate and reproducible images of the hand, which makes the technique a reliable method for soft tissue analysis. 3D images can be a helpful tool in pre- and postoperative evaluation of reconstructive trauma surgery, in aesthetic surgery of the hand, and for educational purposes. The use in everyday practice of hand surgery and the concept of fusing 3D photography images with radiologic images of the interior hand structures needs to be further explored.

Rituximab impairs immunoglobulin (Ig)M and IgG (subclass) responses after influenza vaccination in rheumatoid arthritis patients.

Rituximab (RTX) treatment in rheumatoid arthritis (RA) patients severely hampers humoral response after influenza vaccination as determined by haemagglutination inhibition assay (HI). It is not known whether HI reflects both immunoglobulin (Ig)M and IgG (subclass) influenza response, and whether IgM antibodies contribute to the low rate of influenza infection seen in RA patients. Twenty RA patients on methotrexate (MTX), 23 on RTX and 28 healthy controls (HC) received trivalent influenza subunit vaccination. Before and 28 days after vaccination, H1N1- and H3N2-specific antibodies were measured by HI and by IgM and IgG (subclass) enzyme-linked immunosorbent assay (ELISA). B cell activating factor (BAFF) levels were determined in serum samples before vaccination. Vaccination induced a significant increase of IgM and IgG (IgG1 and IgG3) antibodies against both strains in the HC and MTX groups (all P < 0·01), but not in the RTX group. HI correlated significantly in all cases with IgG (IgG1) but not with IgM. In RTX late patients (RTX treatment 6-10 months before vaccination), IgG (IgG1 and IgG3) response to vaccination was restored, but not IgM response. BAFF levels were significantly increased in RA-RTX patients and correlated with total IgG levels. Haemagglutination inhibition assay, used as gold standard, detects primarily IgG (IgG1) responses. IgM- and IgG influenza-specific antibodies increase after vaccination in HC and RA patients except in patients on RTX treatment. BAFF levels are increased in both early and late RTX-treated patients, but do not correlate with an influenza-specific antibody response.

The influence of object identity on obstacle avoidance reaching behaviour.

When reaching for target objects, we hardly ever collide with other objects located in our working environment. Behavioural studies have demonstrated that the introduction of non-target objects into the workspace alters both spatial and temporal parameters of reaching trajectories. Previous studies have shown the influence of spatial object features (e.g. size and position) on obstacle avoidance movements. However, obstacle identity may also play a role in the preparation of avoidance responses as this allows prediction of possible negative consequences of collision based on recognition of the obstacle. In this study we test this hypothesis by asking participants to reach towards a target as quickly as possible, in the presence of an empty or full glass of water placed about half way between the target and the starting position, at 8 cm either left or right of the virtual midline. While the spatial features of full and empty glasses of water are the same, the consequences of collision are clearly different. Indeed, when there was a high chance of collision, reaching trajectories veered away more from filled than from empty glasses. This shows that the identity of potential obstacles, which allows for estimating the predicted consequences of collision, is taken into account during obstacle avoidance.