Radiotherapy for patients with ledderhose disease:long-term effects, side effects and patient-rated outcome

BACKGROUND: The purpose of this study was to investigate the long-term effects of radiotherapy for patients with Ledderhose disease. METHODS: Questionnaires were sent to all patients with Ledderhose disease who had been treated with radiotherapy at our centre between 2008 and 2017 and who consented to participate. Radiotherapy was performed with orthovolt or electrons in two separate courses of five daily fractions of 3 Gy. The questionnaires addressed items such as pain from Ledderhose disease (Brief Pain Inventory), quality of life (EURO-QOL-5D-5L), long-term side effects, and patients' levels of satisfaction with the effect of treatment. Descriptive statistics and non-parametric tests were used to analyse the results. RESULTS: A total of 102 feet were irradiated in 67 patients (28 men, 39 women). Radiotherapy resulted in significant pain reduction: the mean pain score prior to radiotherapy, collected retrospectively, was 5.7 and 1.7 at time of assessment (p-value<0.001). The following pain response scores were reported: progressive pain (0%), no change (22%; 22 feet), partial pain response (37%; 38 feet) and complete pain response (absence of pain) (41%; 42 feet). Seventy-eight percent of patients were satisfied with the treatment effect and 57% did not consider radiotherapy burdensome. The scores for societal perspective (0.856) and patients' perspective on quality of life (82.3) were each comparable to the reference values from the Dutch population in the same age category (0.857 and 80.6, respectively). The most commonly reported residual long-term side effect was dryness of the skin (n=10; 15%). CONCLUSION: Radiotherapy for Ledderhose disease results in long-term pain reduction in the majority of patients and has limited side effects. The treatment is well tolerated, patients feel satisfied, and quality of life is comparable to the reference population

Effect of painful Ledderhose disease on dynamic plantar foot pressure distribution during walking:a case-control study

Background: Plantar pressure distribution during walking in patients with painful Ledderhose disease is unknown.Research question: Do patients with painful Ledderhose disease have an altered plantar pressure distribution during walking compared to individuals without foot pathologies? It was hypothesized that plantar pressure is shifted away from the painful nodules.Methods: Pedobarography data of 41 patients with painful Ledderhose disease (cases, mean age: 54.2 ± 10.4 years) was collected and compared to pedobarography data from 41 individuals without foot pathologies (controls, mean age: 21.7 ± 2.0 years). Peak Pressure (PP), Maximum Mean Pressure (MMP) and Force-Time Integral (FTI) were calculated for eight regions (heel, medial midfoot, lateral midfoot, medial forefoot, central forefoot, lateral forefoot, hallux and other toes) under the soles of the feet. Differences between cases and controls were calculated and analysed by means of linear (mixed models) regression.Results: Proportional differences in PP, MMP and FTI showed increased values for the cases compared to the controls, especially in the heel, hallux and other toes regions, and decreased values in the medial- and lateral midfoot regions. In naïve regression analysis, being a patient was a predictor for increased- and decreased values for PP, MMP and FTI for several regions. When dependencies in the data were taken into account with linear mixed-model regression analysis, the increased- and decreased values for the patients were most prevalent for FTI at the heel, medial midfoot, hallux and other toes regions.Significance: In patients with painful Ledderhose disease, during walking, a shift of pressure was found towards the proximal and distal foot regions, while offloading the midfoot regions.</p

An economic evaluation of radiotherapy for patients with symptomatic Ledderhose disease

BACKGROUND: Evidence for effectiveness of radiotherapy for Ledderhose disease was demonstrated in the LedRad-study. However, the health economic impact of Ledderhose disease is unclear. Therefore, an economic evaluation alongside the LedRad-study was planned.METHODS: The economic evaluation was performed as a cost-effectiveness and cost-utility analysis from the societal perspective. Primary outcome parameters were pain burden and Quality Adjusted Life Years (QALY), until 12 months after the end of treatment. Secondary analyses were performed with outcomes until 18 months. Incremental cost-effectiveness (ICER) and cost-utility ratios (ICUR) were calculated to express costs per unit improvement in pain burden and costs per QALY gained, for radiotherapy compared to sham-radiotherapy. Bootstrap replication was used to assess uncertainty surrounding the ratios and to construct cost-effectiveness acceptability curves for QALY gain.RESULTS: Previous analysis showed a statistically significant improvement in pain- and QoL scores in favour of radiotherapy at 12 and 18 months. At these timepoints and excluding treatment costs, cumulative total costs were considerably lower in the radiotherapy group. The ICER until 12 months after treatment was 4987 euro per unit of pain burden reduction. The ICUR was 14249 euro per QALY gained. Most of the bootstrap replications were in the upper right quadrant, indicating that health gain can be achieved at higher costs. At increasing levels of willingness to pay for a gain in QALY, the probability of cost-utility gradually increased to approximately 85%.CONCLUSIONS: In patients with symptomatic Ledderhose disease, radiotherapy, at a moderate threshold for willingness to pay, is cost-effective in terms of QoL gain.TRIAL REGISTRATION NUMBERS: NCT03507010, NL62429.042.17.</p

Neural Representation of Motor Output, Context and Behavioral Adaptation in Rat Medial Prefrontal Cortex During Learned Behavior

Selecting behavioral outputs in a dynamic environment is the outcome of integrating multiple information streams and weighing possible action outcomes with their value. Integration depends on the medial prefrontal cortex (mPFC), but how mPFC neurons encode information necessary for appropriate behavioral adaptation is poorly understood. To identify spiking patterns of mPFC during learned behavior, we extracellularly recorded neuronal action potential firing in the mPFC of rats performing a whisker-based “Go”/“No-go” object localization task. First, we identify three functional groups of neurons, which show different degrees of spiking modulation during task performance. One group increased spiking activity during correct “Go” behavior (positively modulated), the second group decreased spiking (negatively modulated) and one group did not change spiking. Second, the relative change in spiking was context-dependent and largest when motor output had contextual value. Third, the negatively modulated population spiked more when rats updated behavior following an error compared to trials without integration of error information. Finally, insufficient spiking in the positively modulated population predicted erroneous behavior under dynamic “No-go” conditions. Thus, mPFC neuronal populations with opposite spike modulation characteristics differentially encode context and behavioral updating and enable flexible integration of error corrections in future actions

Radiotherapy for Ledderhose disease:Results of the LedRad-study, a prospective multicentre randomised double-blind phase 3 trial

Background and purpose: Radiotherapy is considered a treatment option for Ledderhose disease. However, its benefits have never been confirmed in a randomised controlled trial. Therefore, the LedRad-study was conducted. Materials and methods: The LedRad-study is a prospective multicentre randomised double-blind phase three trial. Patients were randomised to sham-radiotherapy (placebo) or radiotherapy. The primary endpoint was pain reduction at 12 months after treatment, measured with the Numeric Rating Scale (NRS). Secondary endpoints were pain reduction at 6 and 18 months after treatment, quality of life (QoL), walking abilities and toxicity.Results: A total of 84 patients were enrolled. At 12 and 18 months, patients in the radiotherapy group had a lower mean pain score compared to patients in the sham-radiotherapy group (2.5 versus 3.6 (p = 0.03) and 2.1 versus 3.4 (p = 0.008), respectively). Pain relief at 12 months was 74% in the radiotherapy group and 56% in the sham-radiotherapy group (p = 0.002). Multilevel testing for QoL scores showed higher QoL scores in the radiotherapy group compared to the sham-radiotherapy group (p &lt; 0.001). Moreover, patients in the radiotherapy group had a higher mean walking speed and step rate with barefoot speed walking (p = 0.02). Erythema, skin dryness, burning sensations and increased pain were the most frequently reported side effects. These side effects were generally graded as mild (95%) and the majority (87%) were resolved at 18 months follow-up.Conclusion: Radiotherapy for symptomatic Ledderhose disease is an effective treatment resulting in a significant pain reduction, improvement of QoL scores and bare feet walking abilities, in comparison to sham-radiotherapy.</p

Risk factors associated with Campylobacter jejuni infections in Curacao, Netherlands Antilles

A steady increase in the incidence of Guillain-Barre syndrome (GBS) with a seasonal preponderance, almost exclusively related to Campylobacter jejuni, and a rise in the incidence of laboratory-confirmed Campylobacter enteritis have been reported from Curacao, Netherlands Antilles. We therefore investigated possible risk factors associated with diarrhea due to epidemic C. jejuni. Typing by pulsed-field gel electrophoresis identified four epidemic clones which accounted for almost 60% of the infections. One hundred six cases were included in a case-control study. Infections with epidemic clones were more frequently observed in specific districts in Willemstad, the capital of Curacao. One of these clones caused infections during the rainy season only and was associated with the presence of a deep well around the house. Two out of three GBS-related C. jejuni isolates belonged to an epidemic clone. The observations presented point toward water as a possible source of Campylobacter infections

A Genetic Deconstruction of Neurocognitive Traits in Schizophrenia and Bipolar Disorder

Background: Impairments in cognitive functions are common in patients suffering from psychiatric disorders, such as schizophrenia and bipolar disorder. Cognitive traits have been proposed as useful for understanding the biological and genetic mechanisms implicated in cognitive function in healthy individuals and in the dysfunction observed in psychiatric disorders. Methods: Sets of genes associated with a range of cognitive functions often impaired in schizophrenia and bipolar disorder were generated from a genome-wide association study (GWAS) on a sample comprising 670 healthy Norwegian adults who were phenotyped for a broad battery of cognitive tests. These gene sets were then tested for enrichment of association in GWASs of schizophrenia and bipolar disorder. The GWAS data was derived from three independent single-centre schizophrenia samples, three independent single-centre bipolar disorder samples, and the multi-centre schizophrenia and bipolar disorder samples from the Psychiatric Genomics Consortium. Results: The strongest enrichments were observed for visuospatial attention and verbal abilities sets in bipolar disorder. Delayed verbal memory was also enriched in one sample of bipolar disorder. For schizophrenia, the strongest evidence of enrichment was observed for the sets of genes associated with performance in a colour-word interference test and for sets associated with memory learning slope. Conclusions: Our results are consistent with the increasing evidence that cognitive functions share genetic factors with schizophrenia and bipolar disorder. Our data provides evidence that genetic studies using polygenic and pleiotropic models can be used to link specific cognitive functions with psychiatric disorders

Psychometrics of Disembodiment and Its Differential Modulation by Visuomotor and Visuotactile Mismatches

Altered states of embodiment are fundamental to the scientific understanding of bodily self consciousness. The feeling of disembodiment during everyday activities is common to clinical conditions; however, the direct study of disembodiment in experimental setups is rare compared to the extensive investigation of illusory embodiment of an external object. Using mixed reality to modulate embodiment through temporally mismatching sensory signals from the own body, we assessed how such mismatches affect phenomenal and physiological aspects of embodiment and measured perceptual thresholds for these across multimodal signals. The results of a principal component analysis suggest that multimodal mismatches generally induce disembodiment by increasing the sense of disownership and deafference and decreasing embodiment; however, this was not generally reflected in physiological changes. Although visual delay decreased embodiment both during active movement and passive touch, the effect was stronger for the former. We discuss the relevance of these findings for understanding bodily self plasticity

Reply to: New Meta- and Mega-analyses of Magnetic Resonance Imaging Findings in Schizophrenia: Do They Really Increase Our Knowledge About the Nature of the Disease Process?

This work was supported by National Institute of Biomedical Imaging and Bioengineering Grant No. U54EB020403 (to the ENIGMA consortium)

Genetic copy number variants, cognition and psychosis: a meta-analysis and a family study

The burden of large and rare copy number genetic variants (CNVs) as well as certain specific CNVs increase the risk of developing schizophrenia. Several cognitive measures are purported schizophrenia endophenotypes and may represent an intermediate point between genetics and the illness. This paper investigates the influence of CNVs on cognition. We conducted a systematic review and meta-analysis of the literature exploring the effect of CNV burden on general intelligence. We included ten primary studies with a total of 18,847 participants and found no evidence of association. In a new psychosis family study, we investigated the effects of CNVs on specific cognitive abilities. We examined the burden of large and rare CNVs (>200 kb, <1% MAF) as well as known schizophrenia-associated CNVs in patients with psychotic disorders, their unaffected relatives and controls (N = 3428) from the Psychosis Endophenotypes International Consortium (PEIC). The carriers of specific schizophrenia-associated CNVs showed poorer performance than non-carriers in immediate (P = 0.0036) and delayed (P = 0.0115) verbal recall. We found suggestive evidence that carriers of schizophrenia-associated CNVs had poorer block design performance (P = 0.0307). We do not find any association between CNV burden and cognition. Our findings show that the known high-risk CNVs are not only associated with schizophrenia and other neurodevelopmental disorders, but are also a contributing factor to impairment in cognitive domains such as memory and perceptual reasoning, and act as intermediate biomarkers of disease risk.This work was supported by the Medical Research Council (G0901310) and the Wellcome Trust (grants 085475/B/08/Z, 085475/Z/08/Z). This study was supported by the NIHR Biomedical Research Centre at University College London Hospitals NHS Foundation Trust and University College London and by the NIHR Biomedical Research Centre for Mental Health at the South London and Maudsley NHS Foundation Trust at King’s College London. Further support to EB: Mental Health Research UK’s John Grace QC award, BMA Margaret Temple grants 2016 and 2006, MRC—Korean Health Industry Development Institute Partnering Award (MC_PC_16014), MRC New Investigator Award and a MRC Centenary Award (G0901310), National Institute of Health Research UK post-doctoral fellowship, the Psychiatry Research Trust, the Schizophrenia Research Fund, the Brain and Behaviour Research foundation’s NARSAD Young Investigator Awards 2005, 2008, Wellcome Trust Research Training Fellowship, the NIHR Biomedical Research Centre at UCLH, and the NIHR Biomedical Research Centre for Mental Health at the South London and Maudsley NHS Foundation Trust and Institute of Psychiatry King’s College London. Further support to co-authors: The Brain and Behaviour Research foundation’s (NARSAD’s) Young Investigator Award (Grant 22604, awarded to CI). The BMA Margaret Temple grant 2016 to JT. A 2014 European Research Council Marie Curie award to A Díez-Revuelta. HI has received funding from the European Union’s Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 747429. A Medical Research Council doctoral studentship to JH-S, IA-Z and AB. A Mental Health Research UK studentship to RM. VB is supported by a Wellcome Trust Seed Award in Science (200589/Z/16/Z). FWO Senior Clinical Fellowship to RvW. The infrastructure for the GROUP consortium is funded through the Geestkracht programme of the Dutch Health Research Council (ZON-MW, grant number 10-000-1001), and matching funds from participating pharmaceutical companies (Lundbeck, AstraZeneca, Eli Lilly, Janssen Cilag) and universities and mental health care organisations (Amsterdam: Academic Psychiatric Centre of the Academic Medical Centre and the mental health institutions: GGZ Ingeest, Arkin, Dijk en Duin, GGZ Rivierduinen, Erasmus Medical Centre, GGZ Noord Holland Noord. Groningen: University Medical Centre Groningen and the mental health institutions: Lentis, GGZ Friesland, GGZ Drenthe, Dimence, Mediant, GGNet Warnsveld, Yulius Dordrecht and Parnassia psycho-medical centre The Hague. Maastricht: Maastricht University Medical Centre and the mental health institutions: GGZ Eindhoven en De Kempen, GGZ Breburg, GGZ Oost-Brabant, Vincent van Gogh voor Geestelijke Gezondheid, Mondriaan, Virenze riagg, Zuyderland GGZ, MET ggz, Universitair Centrum Sint-Jozef Kortenberg, CAPRI University of Antwerp, PC Ziekeren Sint-Truiden, PZ Sancta Maria Sint-Truiden, GGZ Overpelt, OPZ Rekem. Utrecht: University Medical Centre Utrecht and the mental health institutions Altrecht, GGZ Centraal and Delta). The Santander cohort was supported by Instituto de Salud Carlos III (PI020499, PI050427, PI060507), SENY Fundació (CI 2005-0308007), Fundacion Ramón Areces and Fundacion Marqués de Valdecilla (API07/011, API10/13). We thank Valdecilla Biobank for providing the biological PAFIP samples and associated data included in this study and for its help in the technical execution of this work; we also thank IDIVAL Neuroimaging Unit for its help in the acquisition and processing of imaging PAFIP data