Guillain–Barré syndrome (GBS) is a post-infectious disease in which the human peripheral nervous system is affected after infection by specific pathogenic bacteria, including
Campylobacter jejuni
. ...GBS is suggested to be provoked by molecular mimicry between sialylated lipooligosaccharide (LOS) structures on the cell envelope of these bacteria and ganglioside epitopes on the human peripheral nerves, resulting in autoimmune-driven nerve destruction. Earlier, the
C. jejuni
sialyltransferase (Cst-II) was found to be linked to GBS and demonstrated to be involved in the biosynthesis of the ganglioside-like LOS structures. Apart from a role in pathogenicity, we report here that Cst-II-generated ganglioside-like LOS structures confer efficient bacteriophage resistance in
C. jejuni
. By bioinformatic analysis, it is revealed that the presence of sialyltransferases in
C. jejuni
and other potential GBS-related pathogens correlated significantly with the apparent degeneration of an alternative anti-virus system: type II
C
lusters of
R
egularly
I
nterspaced
S
hort
P
alindromic
R
epeat and
as
sociated genes (CRISPR-Cas). Molecular analysis of the
C. jejuni
CRISPR-Cas system confirmed the bioinformatic investigation. CRISPR degeneration and mutations in the
cas
genes
cas2
,
cas1
and
csn1
were found to correlate with Cst-II sialyltransferase presence (
p
< 0.0001). Remarkably, type II CRISPR-Cas systems are mainly found in mammalian pathogens. To study the potential involvement of this system in pathogenicity, we inactivated the type II CRISPR-Cas marker gene
csn1
, which effectively reduced virulence in primarily
cst
-II-positive
C. jejuni
isolates. Our findings indicate a novel link between viral defence, virulence and GBS in a pathogenic bacterium.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
A low muscle mass before start of treatment and loss of muscle mass during chemotherapy is related to adverse outcomes in patients with cancer. In this randomized controlled trial, the effect of ...nutritional counseling on change in muscle mass and treatment outcome in patients with metastatic colorectal cancer during first-line chemotherapy was studied.
Patients scheduled for first-line chemotherapy (n = 107) were randomly assigned to individualized nutritional counseling by a dietitian (NC) or usual care (UC). NC was aimed at sufficient protein- and energy intake, supported by oral supplements or enteral feeding if indicated. Furthermore, physical activity was encouraged. Outcomes were assessed at baseline (T0) and the time of the first (T1) and second (T2) regular follow-up computed tomography scans. The proportion of patients with a clinically relevant decrease in skeletal muscle area of ≥6.0 cm2, measured by computed tomography, was the primary outcome. Secondary outcomes included body weight, quality of life, treatment toxicity and progression free and overall survival.
A total of 107 patients were enrolled (mean age, 65 years (SD, 11 years), 63% male). Mean change in skeletal muscle area from T0 till T1 was −2.5 (SD, 9.5) cm2, with no difference between NC versus UC (p = 0.891). The proportion of patients with a clinically relevant decrease in skeletal muscle area of ≥6.0 cm2 did not differ (NC 30% versus UC 31%, p = 0.467). NC compared with UC had a significant positive effect on body weight (B coefficient 1.7, p = 0.045), progression free survival (p = 0.039) and overall survival (p = 0.046).
NC of patients undergoing chemotherapy for metastatic colorectal cancer had no effect on muscle mass. However, we found that NC may increase body weight and improve progression free survival and overall survival compared to UC in this group of patients. These findings need further evaluation in future clinical trials.
ClinicalTrials.gov NCT01998152; Netherlands Trial Register NTR4223.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Objective
To compare the effectiveness of a hysteroscopic niche resection versus no treatment in women with postmenstrual spotting and a uterine caesarean scar defect.
Design
Multicentre randomised ...controlled trial.
Setting
Eleven hospitals collaborating in a consortium for women's health research in the Netherlands.
Population
Women reporting postmenstrual spotting after a caesarean section who had a niche with a residual myometrium of ≥3 mm, measured during sonohysterography.
Methods
Women were randomly allocated to hysteroscopic niche resection or expectant management for 6 months.
Main outcome measures
The primary outcome was the number of days of postmenstrual spotting 6 months after randomisation. Secondary outcomes were spotting at the end of menstruation, intermenstrual spotting, dysuria, sonographic niche measurements, surgical parameters, quality of life, women's satisfaction, sexual function, and additional therapy. Outcomes were measured at 3 months and, except for niche measurements, also at 6 months after randomisation.
Results
We randomised 52 women to hysteroscopic niche resection and 51 women to expectant management. The median number of days of postmenstrual spotting at baseline was 8 days in both groups. At 6 months after randomisation, the median number of days of postmenstrual spotting was 4 days (interquartile range, IQR 2–7 days) in the intervention group and 7 days (IQR 3–10 days) in the control group (P = 0.04); on a scale of 0–10, discomfort as a result of spotting had a median score of 2 (IQR 0–7) in the intervention group, compared with 7 (IQR 0–8) in the control group (P = 0.02).
Conclusions
In women with a niche with a residual myometrium of ≥3 mm, hysteroscopic niche resection reduced postmenstrual spotting and spotting‐related discomfort.
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A hysteroscopic niche resection is an effective treatment to reduce niche‐related spotting.
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A hysteroscopic niche resection is an effective treatment to reduce niche‐related spotting.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Abstract
To alleviate anti-cancer treatment burden in advanced breast cancer, patient-clinician communication strategies based on nocebo-effect mechanisms are promising. We assessed distinct/combined ...effects on psychological outcomes (e.g. anxiety; main outcome) and side-effect expectations of (1) nocebo information about the (non)pharmacological origin of side effects, and (2) clinician-expressed empathy through reassurance of continuing support. Furthermore, we explored whether information and empathy effects on side-effect expectations were mediated by decreased anxiety. In a two-by-two experimental video-vignette design, 160 cancer patients/survivors and healthy women watched one of four videos differing in level of nocebo information (±) and empathy (±). Regression and mediation analysis were used to determine effects of information/empathy and explore anxiety’s mediating role. Anxiety was not influenced by empathy or information (Stai-state: p = 0.281; p = 0.410, VAS p = 0.387; p = 0.838). Information improved (specific) side-effect coping expectations (p < 0.01). Empathy improved side-effect intensity expectations (p < 0.01 = specific; p < 0.05 = non-specific/partial) and specific side-effect probability expectations (p < 0.01), and increased satisfaction, trust, and self-efficacy (p < 0.001). No mediating effects were found of anxiety on expectations. Mainly empathy, but also nocebo information improved psychological outcomes and—mainly specific—side-effect expectations. Exploring the power of these communication elements in clinical practice is essential to diminish the anti-cancer treatment burden in advanced breast cancer.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Background
It would be helpful for the decision-making process of patients with metastatic bone disease to understand which patients are at risk for worse quality of life (QOL), pain, anxiety, and ...depression. Normative data, and where these stand compared with general population scores, can be useful to compare and interpret results of similar patients or patient groups, but to our knowledge, there are no such robust data.
Questions/Purposes
We wished (1) to assess what factors are independently associated with QOL, pain interference, anxiety, and depression in patients with metastatic bone disease, and (2) to compare these outcomes with general US population values.
Methods
Between November 2011 and February 2015, 859 patients with metastatic bone disease presented to our orthopaedic oncology clinic; 202 (24%) were included as they completed the EuroQOL-5 Dimension (EQ-5D
TM
), PROMIS
®
Pain Interference, PROMIS
®
Anxiety, and PROMIS
®
Depression questionnaires as part of a quality improvement program. We did not record reasons for not responding and found no differences between survey respondents and nonrespondents in terms of age (63 versus 64 years; p = 0.916), gender (51% men versus 47% men; p = 0.228), and race (91% white versus 88% white; p = 0.306), but survey responders were more likely to be married or living with a partner (72%, versus 62%; p = 0.001). We assessed risk factors for QOL, pain interference, anxiety, and depression using multivariable linear regression analysis. We used the one-sample signed rank test to assess whether scores differed from US population averages drawn from earlier large epidemiologic studies.
Results
Younger age (β regression coefficient β, < 0.01; 95% CI, 0.00–0.01; p = 0.041), smoking (β, −0.12; 95% CI, −0.22 to −0.01; p = 0.026), pathologic fracture (β, −0.10; 95% CI, −0.18 to −0.02; p = 0.012), and being unemployed (β, −0.09; 95% CI, −0.17 to −0.02; p = 0.017) were associated with worse QOL. Current smoking status was associated with more pain interference (β, 6.0; 95% CI, 1.6–11; p = 0.008). Poor-prognosis cancers (β, 3.8; 95% CI, 0.37–7.2; p = 0.030), and pathologic fracture (β, 6.3; 95% CI, 2.5–7.2; p = 0.001) were associated with more anxiety. Being single (β, 5.9; 95% CI, 0.83–11; p = 0.023), and pathologic fracture (β, 4.4; 95% CI, 0.8–8.0; p = 0.017) were associated with depression. QOL scores (0.68 versus 0.85; p < 0.001), pain interference scores (65 versus 50; p < 0.001), and anxiety scores (53 versus 50; p = 0.011) were worse for patients with bone metastases compared with general US population values, whereas depression scores were comparable (48 versus 50; p = 0.171).
Conclusions
Impending pathologic fractures should be treated promptly to prevent deterioration in QOL, anxiety, and depression. Our normative data can be used to compare and interpret results of similar patients or patient groups. Future studies could focus on specific cancers metastasizing to the bone, to further understand which patients are at risk for worse patient-reported outcomes.
Level of evidence
Level III, prognostic study.
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FZAB, GEOZS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
A homozygous mutation of the CNTNAP2 gene has been associated with a syndrome of focal epilepsy, mental retardation, language regression and other neuropsychiatric problems in children of the Old ...Order Amish community. Here we report genomic rearrangements resulting in haploinsufficiency of the CNTNAP2 gene in association with epilepsy and schizophrenia. Genomic deletions of varying sizes affecting the CNTNAP2 gene were identified in three non-related Caucasian patients. In contrast, we did not observe any dosage variation for this gene in 512 healthy controls. Moreover, this genomic region has not been identified as showing large-scale copy number variation. Our data thus confirm an association of CNTNAP2 to epilepsy outside the Old Order Amish population and suggest that dosage alteration of this gene may lead to a complex phenotype of schizophrenia, epilepsy and cognitive impairment.
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DOBA, EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, IZUM, KILJ, KISLJ, MFDPS, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UILJ, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Objective
To evaluate long‐term effects of maintenance tocolysis with nifedipine on neurodevelopmental outcome of the infant.
Design, Setting and Population
Follow up of infants of women who ...participated in a multicentre randomised controlled trial on maintenance tocolysis with nifedipine versus placebo.
Methods
Two years after the APOSTEL II trial on maintenance tocolysis with nifedipine versus placebo, we asked participants to complete the Ages and Stages Questionnaire.
Main outcome measures
Infant development was measured in five domains. Developmental delay was defined as a score of ≤1 SD in one or more developmental domains. We performed exploratory subgroup analysis in women with preterm prolonged rupture of the membranes, and in women with a cervical length <10 mm at study entry.
Results
Of the 276 women eligible for follow up, 135 (52.5%) returned the questionnaire, encompassing data of 170 infants. At 2 years of age, infants of women with nifedipine maintenance tocolysis compared with placebo had a higher overall incidence of fine motor problems (22.2 versus 7.6%, OR 3.43, 95% CI 1.29–9.14, P = 0.01), and a lower incidence of poor problem‐solving (21.1 versus 29.1%, OR 0.27, 95% CI 0.08‐0.95, P = 0.04).
Conclusions
This follow‐up study revealed no clear benefit of nifedipine maintenance tocolysis at 2 years of age. As short‐term adverse perinatal outcome was not reduced in the original APOSTEL II trial, we conclude that maintenance tocolysis does not appear to be beneficial at this time.
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No clear benefit of nifedipine maintenance tocolysis in preterm labour on 2‐year infant outcome.
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No clear benefit of nifedipine maintenance tocolysis in preterm labour on 2‐year infant outcome.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
Natural killer (NK) cells are innate lymphocytes capable to recognize and kill virus-infected and cancer cells. In the past years, the use of allogeneic NK cells as anti-cancer therapy gained ...interest due to their ability to induce graft-versus-cancer responses without causing graft-versus-host disease and multiple protocols have been developed to produce high numbers of activated NK cells. While the ability of these cells to mediate tumor kill has been extensively studied, less is known about their capacity to influence the activity of other immune cells that may contribute to a concerted anti-tumor response in the tumor microenvironment (TME). In this study, we analyzed how an allogeneic off-the-shelf cord blood stem cell-derived NK-cell product influenced the activation of dendritic cells (DC). Crosstalk between NK cells and healthy donor monocyte-derived DC (MoDC) resulted in the release of IFNγ and TNF, MoDC activation, and the release of the T-cell-recruiting chemokines CXCL9 and CXCL10. Moreover, in the presence of prostaglandin-E2, NK cell/MoDC crosstalk antagonized the detrimental effect of IL-10 on MoDC maturation leading to higher expression of multiple (co-)stimulatory markers. The NK cells also induced activation of conventional DC2 (cDC2) and CD8+ T cells, and the release of TNF, GM-CSF, and CXCL9/10 in peripheral blood mononuclear cells of patients with metastatic colorectal cancer. The activated phenotype of MoDC/cDC2 and the increased release of pro-inflammatory cytokines and T-cell-recruiting chemokines resulting from NK cell/DC crosstalk should contribute to a more inflamed TME and may thus enhance the efficacy of T-cell-based therapies.
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BFBNIB, FZAB, GIS, IJS, KILJ, OILJ, SBCE, SBMB, UPUK
Dried blood spot succinylacetone (SA) is often used as biomarker for newborn screening (NBS) for Tyrosinemia type 1 (TT1). However, false-positive SA results are often observed. Elevated SA may also ...be due to maleylacetoacetate isomerase deficiency (MAAI-D), which appears to be clinically insignificant. This study investigated whether urine organic acid (uOA) and quantitative urine maleic acid (Q-uMA) analyses can distinguish between TT1 and MAAI-D.
We reevaluated/measured uOA (GC-MS) and/or Q-uMA (LC-MS/MS) in available urine samples of 9 referred newborns (2 TT1, 7 false-positive), 8 genetically confirmed MAAI-D children and 66 controls.
Maleic acid was elevated in uOA of 5/7 false-positive newborns and in the 3 available samples of confirmed MAAI-D children, but not in TT1 patients. Q-uMA ranged from not detectable to 1.16 mmol/mol creatinine in controls (n=66), and from 0.95-192.06 mmol/mol creatinine in false-positive newborns and MAAI-D children (n=10). MAAI-D was genetically confirmed in 4/7 false-positive newborns, all with elevated Q-uMA, and rejected in the 2 newborns with normal Q-uMA. No sample was available for genetic analysis of the last false-positive infant with elevated Q-uMA.
MAAI-D is a recognizable cause of false-positive TT1 NBS results. Elevated urine maleic acid excretion seems highly effective in discriminating MAAI-D from TT1. This article is protected by copyright. All rights reserved.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
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