Pelvic Floor Rehabilitation After Rectal Cancer Surgery One-year follow-up of a Multicenter Randomized Clinical Trial (FORCE trial).

OBJECTIVE: This study aims to evaluate the effects of pelvic floor rehabilitation (PFR) after low anterior resection (LAR) at one-year follow-up. SUMMARY BACKGROUND DATA: After LAR, with restoration of bowel continuity, up to 90% of patients develop anorectal dysfunction, significantly impacting their quality of life. However, standardized treatment is currently unavailable. The FORCE trial demonstrated the beneficial effects of PFR after three months regarding specific domains of the Fecal Incontinence QoL (FIQL) questionnaire and urgency compared to usual care. METHODS: The FORCE trial is a multicenter, two-arm, randomized clinical trial. All patients undergoing LAR were randomly assigned to receive either usual care or a standardized PFR program. The primary outcome measure is the Wexner incontinence score, and the secondary endpoints included the LARS score, the EORTC colorectal-specific QoL questionnaire, and health- and fecal incontinence-related QoL. Assessments were conducted at baseline before randomization, at three months and one-year follow-ups. RESULTS: A total of 86 patients were included (PFR: n=40, control: n=46). After one year, PFR did not significantly improve Wexner incontinence scores (PFR: -3.33, 95% CI -4.41 to -2.26, control: -2.54, 95% CI -3.54 to -1.54, P=0.30). Similar to the three-month follow-up, patients without near-complete incontinence at baseline showed sustained improvement in fecal incontinence (PFR: -2.82, 95% CI -3.86 to -1.76, control: -1.43, 95% CI -2.36 to -0.50, P=0.06). Significant improvement was reported in the FIQL domains Lifestyle (PFR: 0.51, control: -0.13, P=0.03) and Coping and Behavior (PFR: 0.40, control: -0.24, P=0.01). CONCLUSION: At one-year follow-up, no significant differences were found in fecal incontinence scores; however, PFR was associated with improved fecal incontinence related QoL compared to usual care.

Implementation of Pelvic Floor Rehabilitation after rectal cancer surgery: A qualitative study guided by the Consolidated Framework for Implementation Research (CFIR).

BACKGROUND: Pelvic Floor Rehabilitation (PFR) is effective in a selection of patients with low anterior resection syndrome (LARS) after rectal cancer surgery. This study aimed to identify barriers and enablers to prepare for successful implementation into clinical practice. METHODS: A qualitative study was performed, guided by the Consolidated Framework for Implementation Research (CFIR). Individual interviews (n = 27) and two focus groups were conducted to synthesize the perspectives of rectal cancer patients, pelvic floor (PF) physiotherapists, and medical experts. RESULTS: Barriers were found to be the absence of guidelines about LARS treatment, underdeveloped network care, suboptimal patient information, and expectation management upfront to PFR. Financial status is frequently a barrier because insurance companies do not always reimburse PFR. Enablers were the current level of evidence for PFR, the positive relationship between patients and PF physiotherapists, and the level of self-motivation by patients. CONCLUSION: The factors identified in our study play a crucial role in ensuring a successful implementation of PFR after rectal cancer surgery.

Long-Term Functional Outcome After Early vs. Late Stoma Closure in Rectal Cancer Surgery: Sub-analysis of the Multicenter FORCE Trial.

PURPOSE: The aim of this study was to assess the effect of early stoma closure on bowel function after low anterior resection (LAR) for rectal cancer. METHODS: Patients participating in the FORCE trial who underwent LAR with protective stoma were included in this study. Patients were subdivided into an early closure group (< 3 months) and late closure group (> 3 months). Endpoints of this study were the Wexner Incontinence, low anterior resection syndrome (LARS), EORTC QLQ-CR29, and fecal incontinence quality of life (FIQL) scores at 1 year. RESULTS: Between 2017 and 2020, 38 patients had received a diverting stoma after LAR for rectal cancer and could be included. There was no significant difference in LARS (31 vs. 30, p = 0.63) and Wexner score (6.2 vs. 5.8, p = 0.77) between the early and late closure groups. Time to stoma closure in days was not a predictor for LARS (R2 = 0.001, F (1,36) = 0.049, p = 0.83) or Wexner score (R2 = 0.008, F (1,36) = 0.287, p = 0.60) after restored continuity. There was no significant difference between any of the FIQL domains of lifestyle, coping, depression, and embarrassment. In the EORTC QLQ-29, body image scored higher in the late closure group (21.3 vs. 1.6, p = 0.004). CONCLUSION: Timing of stoma closure does not appear to affect long-term bowel function and quality of life, except for body image. To improve functional outcome, attention should be focused on other contributing factors.

Maleic acid is a biomarker for maleylacetoacetate isomerase deficiency; implications for newborn screening of tyrosinemia type 1.

Dried blood spot succinylacetone (SA) is often used as a 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 nine referred newborns (2 TT1, 7 false-positive), eight genetically confirmed MAAI-D children, and 66 controls. Maleic acid was elevated in uOA of 5/7 false-positive newborns and in the three 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 to 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 two newborns with normal Q-uMA. No sample was available for genetic analysis of the last false-positive infant with elevated Q-uMA. Our study shows that 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.

The behavioral variant of Alzheimer's disease does not show a selective loss of Von Economo and phylogenetically related neurons in the anterior cingulate cortex.

BACKGROUND: The neurobiological origins of the early and predominant behavioral changes seen in the behavioral variant of Alzheimer's disease (bvAD) remain unclear. A selective loss of Von Economo neurons (VENs) and phylogenetically related neurons have been observed in behavioral variant frontotemporal dementia (bvFTD) and several psychiatric diseases. Here, we assessed whether these specific neuronal populations show a selective loss in bvAD. METHODS: VENs and GABA receptor subunit theta (GABRQ)-immunoreactive pyramidal neurons of the anterior cingulate cortex (ACC) were quantified in post-mortem tissue of patients with bvAD (n = 9) and compared to typical AD (tAD, n = 6), bvFTD due to frontotemporal lobar degeneration based on TDP-43 pathology (FTLD, n = 18) and controls (n = 13) using ANCOVAs adjusted for age and Bonferroni corrected. In addition, ratios of VENs and GABRQ-immunoreactive (GABRQ-ir) pyramidal neurons over all Layer 5 neurons were compared between groups to correct for overall Layer 5 neuronal loss. RESULTS: The number of VENs or GABRQ-ir neurons did not differ significantly between bvAD (VENs: 26.0 ± 15.3, GABRQ-ir pyramidal: 260.4 ± 87.1) and tAD (VENs: 32.0 ± 18.1, p = 1.00, GABRQ-ir pyramidal: 349.8 ± 109.6, p = 0.38) and controls (VENs: 33.5 ± 20.3, p = 1.00, GABRQ-ir pyramidal: 339.4 ± 95.9, p = 0.37). Compared to bvFTD, patients with bvAD showed significantly more GABRQ-ir pyramidal neurons (bvFTD: 140.5 ± 82.658, p = 0.01) and no significant differences in number of VENs (bvFTD: 10.9 ± 13.8, p = 0.13). Results were similar when assessing the number of VENs and GABRQ-ir relative to all neurons of Layer 5. DISCUSSION: VENs and phylogenetically related neurons did not show a selective loss in the ACC in patients with bvAD. Our results suggest that, unlike in bvFTD, the clinical presentation in bvAD may not be related to the loss of VENs and related neurons in the ACC.

Pelvic Floor Rehabilitation After Rectal Cancer Surgery: A Multicenter Randomized Clinical Trial (FORCE Trial).

OBJECTIVE: To investigate the effects of PFR after LAR compared to usual care without PFR. SUMMARY OF BACKGROUND DATA: Functional complaints, including fecal incontinence, often occur after LAR for rectal cancer. Controversy exists about the effectiveness of PFR in improving such postoperative functional outcomes. METHODS: This was a multicenter, randomized controlled trial involving 17 Dutch centers. Patients after LAR for rectal cancer were randomly assigned (1:1) to usual care or PFR and stratified by sex and administration of neoadjuvant therapy. Selection was not based on severity of complaints at baseline. Baseline measurements were taken 3 months after surgery without temporary stoma construction or 6 weeks after stoma closure. The primary outcome measure was the change in Wexner incontinence scores 3 months after randomization. Secondary outcomes were fecal incontinence-related quality of life, colorectal-specific quality of life, and the LARS scores. RESULTS: Between October 2017 and March 2020, 128 patients were enrolled and 106 randomly assigned (PFR n = 51, control n = 55); 95 patients (PFR n = 44, control n = 51) were assessable for final analysis. PFR did not lead to larger changes in Wexner incontinence scores in nonselected patients after LAR compared to usual care [PFR: -2.3, 95% confidence interval (CI) -3.3 to -1.4, control: -1.3, 95% CI -2.2 to -0.4, P = 0.13]. However, PFR was associated with less urgency at follow-up (odds ratio 0.22, 95% CI 0.06-0.86). Patients without near-complete incontinence reported larger Wexner score improvements after PFR (PFR: -2.1, 95% CI -3.1 to -1.1, control: -0.7, 95% CI -1.6 to 0.2, P = 0.045). For patients with at least moderate incontinence PFR resulted in relevant improvements in all fecal incontinence-related quality of life domains, while the control group deteriorated. These improvements were even larger when patients with near-complete incontinence were excluded. No serious adverse PFR-related events occurred. CONCLUSION: No benefit was found of PFR in all patients but several subgroups were identified that did benefit from PFR, such as patients with urgency or with at least moderate incontinence and no near-complete incontinence. A selective referral policy (65%-85% of all patients) is suggested to improve postoperative functional outcomes for patients after LAR for rectal cancer. TRIAL REGISTRATION: Netherlands Trial Registration, NTR5469, registered on 3 September 2015.

Late-onset presentation and phenotypic heterogeneity of the rare R377W PSEN1 mutation.

BACKGROUND AND PURPOSE: Mutations in the PSEN1 gene are the most common cause of autosomal-dominant Alzheimer's disease and have been associated with the earliest disease onset. We describe an unusual presentation of the rare R377W PSEN1 mutation with a late age of onset, and we provide for the first time in vivo pathological evidence for this mutation. METHODS: A 71-year-old female patient with progressive cognitive decline in the past 3 years and positive family history for dementia underwent neurological evaluation, neuropsychological testing, lumbar puncture, conventional brain imaging, amyloid-positron emission tomography (PET) and extensive genetic screening with a next-generation sequencing technique. RESULTS: The diagnostic workup revealed mixed behavioural and amnestic disease features on neuropsychological tests, magnetic resonance imaging, and 18-fluorodeoxyglucose (FDG)-PET. Amyloid-PET detected amyloid deposition in the frontal areas, in the parietal lobes and the precunei. The genetic screening revealed the presence of the rare R377W mutation in the PSEN1 gene. CONCLUSIONS: Extensive genetic screening is also advisable for late-onset presentations of Alzheimer's disease, especially in the presence of a positive family history or atypical clinical features.

Pelvic floor rehabilitation to improve functional outcome and quality of life after surgery for rectal cancer: study protocol for a randomized controlled trial (FORCE trial).

BACKGROUND: After low anterior resection (LAR), up to 90% of patients develop anorectal dysfunction. Especially fecal incontinence has a major impact on the physical, psychological, social, and emotional functioning of the patient but also on the Dutch National Healthcare budget with more than €2000 spent per patient per year. No standardized treatment is available to help these patients. Common treatment nowadays is focused on symptom relief, consisting of lifestyle advices and pharmacotherapy with bulking agents or antidiarrheal medication. Another possibility is pelvic floor rehabilitation (PFR), which is one of the most important treatments for fecal incontinence in general, with success rates of 50-80%. No strong evidence is available for the use of PFR after LAR. This study aims to prove a beneficial effect of PFR on fecal incontinence, quality of life, and costs in rectal cancer patients after sphincter-saving surgery compared to standard treatment. METHODS: The FORCE trial is a multicenter, two-armed, randomized clinical trial. All patients that underwent LAR are recruited from the participating hospitals and randomized for either standard treatment or a standardized PFR program. A total of 128 patients should be randomized. Optimal blinding is not possible. Stratification will be done in variable blocks (gender and additional radiotherapy). The primary endpoint is the Wexner incontinence score; secondary endpoints are health-related and fecal-incontinence-related QoL and cost-effectiveness. Baseline measurements take place before randomization. The primary endpoint is measured 3 months after the start of the intervention, with a 1-year follow-up for sustainability research purposes. DISCUSSION: The results of this study may substantially improve postoperative care for patients with fecal incontinence or anorectal dysfunction after LAR. This section provides insight in the decisions that were made in the organization of this trial. TRIAL REGISTRATION: Netherlands Trial Registration, NTR5469, registered on 03-09-2015. Protocol FORCE trial V18, 19-09-2019. Sponsor Radboud University Medical Center, Nijmegen.

Monozygotic multiple pregnancies after transfer of single in vitro produced equine embryos.

BACKGROUND: Monozygotic multiple pregnancy is rare in horses, but may be more common after transfer of an in vitro produced (IVP) embryo. OBJECTIVES: To determine the occurrence, incidence, characteristics and outcome of monozygotic siblings arising from in vivo and IVP equine embryos. STUDY DESIGN: Retrospective case series. METHODS: A total of 496 fresh in vivo and 410 frozen-thawed IVP blastocysts, produced by intracytoplasmic sperm injection (ICSI) of in vitro matured oocytes from Warmblood mares, were transferred into recipient mares. The likelihoods of pregnancy and multiple pregnancy were calculated, and the clinical features and outcome of any multiple pregnancy were recorded. RESULTS: The likelihood of pregnancy after transfer of a single IVP or in vivo embryo was 62% (254/410) and 83% (413/496) respectively. The incidence of multiple pregnancy was 1.6% (4/254) and 0% (0/413) for IVP and in vivo blastocysts, respectively. More specifically, three IVP blastocysts yielded twin embryo propers/fetuses, and one IVP conceptus developed three distinct embryonic bodies. Interestingly, only one embryonic vesicle was detected at all ultrasonographic examinations prior to embryo proper development. Multiple embryonic bodies only became apparent at later scans to check for an embryo proper and heartbeat, or when the recipient mare aborted. Two twin pregnancies aborted spontaneously at 3 and 9 months, respectively, while the heartbeat was lost from all three embryos in the triplet pregnancy before day 35 of gestation. Twin reduction by per rectum compression of one fetal thorax was attempted at day 50 of gestation in the fourth case; however, both fetuses were lost. MAIN LIMITATIONS: Small number of cases. CONCLUSIONS: In vitro embryo production resulted in a higher incidence of multiple monozygotic pregnancy, which could only be diagnosed after development of the embryo proper and is likely to result in pregnancy loss later in gestation if left untreated.

The effect of a breastfeeding support programme on breastfeeding duration and exclusivity: a quasi-experiment.

BACKGROUND: Breastfeeding has important positive long-term health consequences for infants and mothers. The World Health Organization recommends that all infants should be exclusively breastfed for six months or longer, and advises continuation of breastfeeding for two years or beyond. However, these recommendations are not met in many countries. This study examined whether a comprehensive, evidence-based breastfeeding intervention, the Breastfeeding Support Programme (BSP), promotes prolonged duration and exclusivity of breastfeeding among its participants. METHODS: A quasi-experimental design was used to compare breastfeeding duration and exclusivity in the BSP group (N = 66) to breastfeeding duration and exclusivity in a control group (N = 72). Participants who followed the BSP were provided with 6 consults delivered by a lactation consultant. The consults started during pregnancy and continued up until 10 weeks after delivery. Participants in the control group did not follow the BSP. Pretest and posttest questionnaires were administered through the internet. A Cox proportional hazards regression analysis was used to estimate adjusted hazard ratios (HR) and 95% confidence intervals (CI) for cessation of any and exclusive breastfeeding, while controlling for differences at baseline. RESULTS: The effect of the BSP on survival rates for any and exclusive breastfeeding were significant while controlling for differences between the two groups at baseline (respectively HR = 0.34, p < .001 [95% CI = 0.18-0.61] and HR = 0.46, p < .001 [95% CI = 0.29-0.72]). Among mothers in the BSP group there was on average 66% less risk of cessation of any breastfeeding and on average 54% less risk of cessation of exclusive breastfeeding at any point in time compared to those in the control group. CONCLUSIONS: The BSP appears to be an effective means to delay cessation of any and exclusive breastfeeding cessation and therefore to increase breastfeeding duration and exclusivity. This is an important finding, because earlier cessation of breastfeeding than desired is a common problem in many countries. Future research into the effectiveness of the BSP could consider random assignment to conditions and test the effectiveness of the intervention in other populations to investigate further whether wide-scale implementation of this intervention could be useful to promote breastfeeding.

Von Economo neurons are part of a larger neuronal population that are selectively vulnerable in C9orf72 frontotemporal dementia.

AIMS: The behavioural variant of frontotemporal dementia with a C9orf72 expansion (C9-bvFTD) is characterised by early changes in social-emotional cognition that are linked to the loss of von Economo neurons (VENs). Together with a subset of neighbouring pyramidal neurons, VENs express the GABA receptor subunit theta (GABRQ). It is not known if the selective vulnerability of VENs in C9-bvFTD also includes this GABRQ-expressing population. METHODS: We quantified VENs and GABRQ immunopositive neurons in the anterior cingulate cortex (ACC) in C9-bvFTD (n = 16), controls (n = 12) and Alzheimer's disease (AD) (n = 7). Second, we assessed VENs and GABRQ-expressing populations in relation to the clinicopathological profiles. RESULTS: We found the number of VENs and GABRQ-expressing neurons and their ratio over the total layer 5 neuronal population was lower in C9-bvFTD compared to control and AD. C9-bvFTD donors with underlying TDP43 type A pathology in the ACC showed the highest loss of GABRQ-expressing neurons. C9-bvFTD donors that did not present with motor neuron disease (MND) symptoms in the first half of their disease course showed a prominent loss of GABRQ-expressing neurons compared to controls. C9-bvFTD donors with no symptoms of psychosis showed a higher loss compared to controls. Across all donors, the number of VENs correlated strongly with the number of GABRQ-expressing neurons. CONCLUSION: We show that VENs, together with GABRQ-expressing neurons, are selectively vulnerable in C9-bvFTD but are both spared in AD. This suggests they are related and that this GABRQ-expressing population of VENs and pyramidal neurons, is a key modulator of social-emotional functioning.

A longitudinal study into the reciprocal effects of identities and smoking behaviour: Findings from the ITC Netherlands Survey.

OBJECTIVE: Although it has been found that identity constructs related to smoking are associated with changes in smoking behaviour, the direction of causal associations is as yet unclear. This study aims to clarify the nature and direction of these associations. METHODS: In this longitudinal study we examined the reciprocal relations between identity constructs (i.e., smoker self-identity, quitter self-identity and smoker group-identity), intention to quit and smoking and quitting behaviour among a sample of 1036 smokers and ex-smokers, using cross-lagged structural equation modelling. Moreover, we tested whether these relations differed by socio-economic status (SES). RESULTS: Identity and smoking behaviour were reciprocally related in that in intention to quit and smoking behaviour consistently predicted identity change, and identity predicted (changes in) intentions to quit and smoking behaviour. Behaviour appears more important for identity change than identity for behaviour change. Furthermore, quitter self-identity appears more important than smoker self- and group-identity. Relationships did not differ significantly between SES-groups. The findings were replicated using a cross-validation sample. CONCLUSION: Results imply that changing smoking behaviour may be a vehicle to change smoking-related identity. Moreover, strengthening identification with quitting is more crucial for quit success than decreasing smoker identities. The finding that behaviour may be more important for identity than vice versa, if replicated, may call for additions to identity theories.

Growth and Optical Properties of Direct Band Gap Ge/Ge0.87Sn0.13 Core/Shell Nanowire Arrays.

Group IV semiconductor optoelectronic devices are now possible by using strain-free direct band gap GeSn alloys grown on a Ge/Si virtual substrate with Sn contents above 9%. Here, we demonstrate the growth of Ge/GeSn core/shell nanowire arrays with Sn incorporation up to 13% and without the formation of Sn clusters. The nanowire geometry promotes strain relaxation in the Ge0.87Sn0.13 shell and limits the formation of structural defects. This results in room-temperature photoluminescence centered at 0.465 eV and enhanced absorption above 98%. Therefore, direct band gap GeSn grown in a nanowire geometry holds promise as a low-cost and high-efficiency material for photodetectors operating in the short-wave infrared and thermal imaging devices.

Vibrio vulnificus outbreaks in Dutch eel farms since 1996: strain diversity and impact.

Vibrio vulnificus is a potentially zoonotic bacterial pathogen of fish, which can infect humans (causing necrotic fasciitis). We analysed 24 V. vulnificus isolates (from 23 severe eel disease outbreaks in 8 Dutch eel farms during 1996 to 2009, and 1 clinical strain from an eel farmer) for genetic correlation and zoonotic potential. Strains were typed using biotyping and molecular typing by high-throughput multilocus sequence typing (hiMLST) and REP-PCR (Diversilab®). We identified 19 strains of biotype 1 and 5 of biotype 2 (4 from eels, 1 from the eel farmer), that were subdivided into 8 MLST types (ST) according to the international standard method. This is the first report of V. vulnificus biotype 1 outbreaks in Dutch eel farms. Seven of the 8 STs, of unknown zoonotic potential, were newly identified and were deposited in the MLST database. The REP-PCR and the MLST were highly concordant, indicating that the REP-PCR is a useful alternative for MLST. The strains isolated from the farmer and his eels were ST 112, a known potential zoonotic strain. Antimicrobial resistance to cefoxitin was found in most of the V. vulnificus strains, and an increasing resistance to quinolones, trimethoprim + sulphonamide and tetracycline was found over time in strain ST 140. Virulence testing of isolates from diseased eels is recommended, and medical practitioners should be informed about the potential risk of zoonotic infections by V. vulnificus from eels for the prevention of infection especially among high-risk individuals. Additional use of molecular typing methods such as hiMLST and Diversilab® is recommended for epidemiological purposes during V. vulnificus outbreaks.

Calculating two-dimensional spectra with the mixed quantum-classical Ehrenfest method.

We present a mixed quantum-classical simulation approach to calculate two-dimensional spectra of coupled two-level electronic model systems. We include the change in potential energy of the classical system due to transitions in the quantum system using the Ehrenfest method. We study how this feedback of the quantum system on the classical system influences the shape of two-dimensional spectra. We show that the feedback leads to the expected Stokes shift of the energy levels in the quantum system. This subsequently leads to changes in the population transfer between quantum sites, which in turn influence the intensities of the peaks in two-dimensional spectra. The obtained spectra are compared with spectra calculated using the Hierarchical Equations of Motion method which is exact. While the spectra match perfectly for short waiting times, clear differences are found for longer waiting times. This is attributed to a violation of detailed balance between the quantum states in the Ehrenfest method. The energy of the total quantum-classical system however does obey a Boltzmann distribution, when coupled to a stochastic heat bath.

SERPINE1 -675 4G/5G polymorphism is associated with asthma severity and inhaled corticosteroid response.

Asthma is characterised by chronic airway inflammation and remodelling, which can be (partially) suppressed by inhaled corticosteroids (ICSs). Plasminogen activator inhibitor-1, encoded by the SERPINE1 gene, is the key inhibitor of the plasminogen activator system, which affects tissue repair and remodelling. We studied associations between a functional SERPINE1 -675 4G/5G promoter polymorphism and asthma development, severity and response to ICSs. Longitudinal cohorts of 281 asthmatics and their nonasthmatic spouses, and the general population (n=1,390) were studied. No significant associations were found with asthma development and immunoglobulin (Ig)E levels, or with forced expiratory volume in 1 s (FEV1) in nonasthmatic controls. Asthmatic subjects carrying the SERPINE1 5G allele had higher IgE and lower lung function levels at follow-up, lower maximally attained lung function levels, and faster lung function decline compared with individuals with the 4G/4G genotype. ICS treatment showed an immediate improvement in FEV1 in asthmatics carrying the 5G allele. However, these asthmatics still had the fastest rate of FEV1 decline after initiating ICS treatment. Finally, the 5G allele was associated with a lower prevalence of complete asthma remission at follow-up. These findings suggest that SERPINE1 is not an asthma susceptibility gene, but rather affects the severity, progression and long-term ICS response in asthma.

Airway eosinophilia in remission and progression of asthma: accumulation with a fast decline of FEV(1).

BACKGROUND: As it is unknown whether complete asthma remission or progression of asthma is associated with airway inflammation and remodeling, we assessed these characteristics in bronchial biopsies of relevant subsets of asthma patients. METHODS: Sputum and bronchial biopsies were obtained from asthma patients in remission (PC(20) histamine> 32 mg/ml, PC(20) AMP> 320 mg/ml) and from those with either a slow FEV(1) decline (< 30 ml/year) or fast decline (> 30 ml/year). Inflammatory cells and mediators were determined in sputum, inflammatory cells and aspects of airway remodeling in bronchial biopsies. RESULTS: Asthmatics in remission and asthma patients with a slow FEV(1) decline had a similar extent of airway inflammation and remodeling in sputum and bronchial biopsies. Asthma patients with a fast FEV(1) decline had high sputum eosinophil numbers. Moreover, FEV(1) decline (ml/year) correlated with sputum eosinophil numbers (Rs=0.51, p=0.003) and ECP levels (Rs=0.57, p=0.001). Airway remodeling, i.e. basement membrane thickness, correlated with sputum eosinophils (Rs=0.69, p<0.001), sputum ECP (Rs=0.46, p=0.018) and airway wall eosinophil numbers (Rs=0.49, p=0.002). CONCLUSIONS: Asthma, even when in remission, is accompanied by airway inflammation and remodeling. Data suggest that eosinophils are important in a subset of asthma patients by association to accelerated FEV(1) decline and change of basement membrane thickness.

Validation of a Novel Semiautomated Segmentation Method for MRI Detection of Cartilage-Related Bone Marrow Lesions.

OBJECTIVE: To determine the relationship of bone marrow lesions (BMLs) with phenomena such as clinical symptoms, histological subchondral bone damage, and development of osteoarthritis, a reliable and reproducible method to localize and quantify BMLs accurately is indispensable. Therefore, the goal of the current study was to develop and validate a novel semiautomated segmentation method based on the KNN classification technique on T2-weighted (T2w) SPIR and proton density-weighted (PDw) magnetic resonance images (MRIs), as this would provide an accurate, reliable, and reproducible tool. MATERIALS AND METHODS: Twenty PDw and T2w SPIR MRIs were selected and manually segmented as a learning set for the software system. The manual segmentations were considered the gold standard. Automated segmentation based on the KNN classification technique was carried out on the same MRIs. To determine the accuracy and validity of the system, the automated segmentations were compared to the gold standard using the Dice Similarity Index (DSI). RESULTS: The KNN classification system resulted both visually and statistically in an accurate segmentation of BMLs on T2w SPIR MRIs with an excellent mean optimal DSI of 0.702 (±0.202; range, 0.409-0.908). Elimination of specific areas smaller than 10 voxels improved the accuracy. The accuracy was independent of BML size. The segmentation of BMLs on PDw MRIs was less reliable with a mean optimal DSI of 0.536 (±0.156). CONCLUSION: Although the applicability of this method is limited on PDw MRIs, the KNN classification system provides an accurate, reliable, and reproducible tool for semiautomated segmentation of BMLs in T2w SPIR MRIs of the knee.

Disengagement beliefs in smokers: do they influence the effects of a tailored persuasive message advocating smoking cessation?

Disengagement beliefs function to reduce cognitive dissonance and a number of predictions with regard to disengagement beliefs have been tested and verified. However, the influence of disengagement beliefs on persuasion has not been studied yet. In a field-experiment, 254 smokers were randomly assigned to a persuasive message condition or a no-information control condition. First, it was assessed to what extent disengagement beliefs influenced persuasion. In smokers with low adherence to disengagement beliefs, quitting activity (attempting to quit) in the control condition was high, but this was not further increased by persuasive information on the negative outcomes of smoking. In contrast, smokers who strongly adhered to disengagement beliefs showed low quitting activity in the control condition, but significantly more quitting activity when they received the persuasive message. Second, it was studied what smokers do when they experience negative affect caused by the persuasive message. The results show that in smokers who strongly adhered to disengagement beliefs, negative affect was associated with less quitting activity. Although these results show that quitting activity as assessed at 2 and 8 months follow-ups was influenced by disengagement beliefs, point prevalence seven-day quitting was not. This study shows that adherence to disengagement beliefs is a relevant individual difference in understanding effects of smoking cessation interventions.

The effect of physical, social and psychological factors on drug compliance in patients with mild hypertension.

BACKGROUND: In patients with hypertension noncompliance with drug treatment is between 15 to 54%, and has been recognised as a relevant contributor to the burden of cardiovascular morbidity. Up to 92% of patients experience unpleasant symptoms with their condition and, particularly in these patients, the symptoms experienced may enhance compliance. OBJECTIVE: To simultaneously assess the effects of physical, social and psychological factors on noncompliance. METHODS: Patients with mild hypertension despite drug treatment, from the departments of cardiology and internal medicine, were requested to answer a self-administered questionnaire addressing the presence of physical symptoms as well as psychosocial factors. The questionnaire was based on previously used test batteries and consisted of two lists of physical complaints and four lists addressing the four domains of planned behaviour regarding medical non-adherence according to Baron and Byrne. These domains mainly assess psychosocial factors. Each list consisted of three or more items and each item was scored on fiveto seven-point scales. Mean scores were used for assessment. The lists were also separately assessed for internal consistency and reliability using Cronbach's alphas. One-way analysis of variance and multivariate analysis of variance (MANOVA) with compliance as outcome variable and the physical, social and psychological variables as indicator variables were used for data analysis. MANOVA was adjusted for multiple testing. RESULTS: Many patients experienced physical symptoms due to hypertension, such as tiredness (31%), hot flushes (28%), headache (24%), reduced daily life energy (23%), palpitations (22%), with 95% confidence intervals between 16 to 38%. Scores for physical symptoms and social factors did not differ between self-reported adherers (n=165) and nonadherers (n=11). However, the score for psychological factors was significantly larger in the adherers than in the non-adherers, 5.05 versus 3.06, p<0.018. The MANOVA showed a significant overall difference between the adherers and non-adherers in the data at p<0.012, which was mainly due to the score for psychological factors. Conclusion. The effect of physical symptoms on non-compliance in mildly hypertensive patients is negligible. So is the effect of social factors. Psychological factors such as lacking a sense of guilt, regret and shame are major determinants of non-compliance. Physicians may play an educational role in improving their patients' compliance by addressing these determinants. We should add that the conclusions should be made with reservations, given the small number of non-adherers in our sample. (Neth Heart J 2008;16:197-200.).