Resting state EEG relates to short- and long-term cognitive functioning after cardiac arrest.

BACKGROUND: Approximately half of cardiac arrest survivors have persistent cognitive impairment. Guidelines recommend early screening to identify patients at risk for cognitive impairment, but there is no consensus on the best screening method. We aimed to identify quantitative EEG measures relating with short- and long-term cognitive function after cardiac arrest for potential to cognitive outcome prediction. METHODS: We analyzed data from a prospective longitudinal multicenter cohort study designed to develop a prediction model for cognitive outcome after cardiac arrest. For the current analysis, we used twenty-minute EEG registrations from 80 patients around one week after cardiac arrest. We calculated power spectral density, normalized alpha-to-theta ratio (nATR), peak frequency, and center of gravity (CoG) of this peak frequency. We related these with global cognitive functioning (scores on the Montreal Cognitive Assessment (MoCA)) at one week, three and twelve months follow-up with multivariate mixed effect models, and with performance on standard neuropsychological examination at twelve months using Pearson correlation coefficients. RESULTS: Each individual EEG parameter related to MoCA at one week (ßnATR = 7.36; P < 0.01; ßpeak frequency = 1.73, P < 0.01; ßCoG = -9.88, P < 0.01). The nATR also related with the MoCA at three months ((ßnATR = 2.49; P 0.01). No EEG metrics significantly related to the MoCA score at twelve months. nATR and peak frequency related with memory performance at twelve months. Results were consistent in sensitivity analyses. CONCLUSION: Early resting-state EEG parameters relate with short-term global cognitive functioning and with memory function at one year after cardiac arrest. Additional predictive values in multimodal prediction models need further study.

Spatial transcriptomics reveal markers of histopathological changes in Duchenne muscular dystrophy mouse models.

Duchenne muscular dystrophy is caused by mutations in the DMD gene, leading to lack of dystrophin. Chronic muscle damage eventually leads to histological alterations in skeletal muscles. The identification of genes and cell types driving tissue remodeling is a key step to developing effective therapies. Here we use spatial transcriptomics in two Duchenne muscular dystrophy mouse models differing in disease severity to identify gene expression signatures underlying skeletal muscle pathology and to directly link gene expression to muscle histology. We perform deconvolution analysis to identify cell types contributing to histological alterations. We show increased expression of specific genes in areas of muscle regeneration (Myl4, Sparc, Hspg2), fibrosis (Vim, Fn1, Thbs4) and calcification (Bgn, Ctsk, Spp1). These findings are confirmed by smFISH. Finally, we use differentiation dynamic analysis in the D2-mdx muscle to identify muscle fibers in the present state that are predicted to become affected in the future state.

Dynamic functional connectivity of the EEG in relation to outcome of postanoxic coma.

OBJECTIVE: Early EEG contains reliable information for outcome prediction of comatose patients after cardiac arrest. We introduce dynamic functional connectivity measures and estimate additional predictive values. METHODS: We performed a prospective multicenter cohort study on continuous EEG for outcome prediction of comatose patients after cardiac arrest. We calculated Link Rates (LR) and Link Durations (LD) in the α, δ, and θ band, based on similarity of instantaneous frequencies in five-minute EEG epochs, hourly, during 3 days after cardiac arrest. We studied associations of LR and LD with good (Cerebral Performance Category (CPC) 1-2) or poor outcome (CPC 3-5) with univariate analyses. With random forest classification, we established EEG-based predictive models. We used receiver operating characteristics to estimate additional values of dynamic connectivity measures for outcome prediction. RESULTS: Of 683 patients, 369 (54%) had poor outcome. Patients with poor outcome had significantly lower LR and longer LD, with largest differences 12 h after cardiac arrest (LRθ 1.87 vs. 1.95 Hz and LDα 91 vs. 82 ms). Adding these measures to a model with classical EEG features increased sensitivity for reliable prediction of poor outcome from 34% to 38% at 12 h after cardiac arrest. CONCLUSION: Poor outcome is associated with lower dynamics of connectivity after cardiac arrest. SIGNIFICANCE: Dynamic functional connectivity analysis may improve EEG based outcome prediction.

Normalization of EEG in depression after antidepressant treatment with sertraline? A preliminary report.

BACKGROUND: MDD patients with abnormal EEG patterns seem more likely to be non-responsive to the antidepressants escitalopram and venlafaxine, but not sertraline, than patients without EEG abnormalities. This finding suggests that patients with both MDD and abnormal EEGs may differentially respond to antidepressant treatment. In the current study, we investigated whether depressed patients with an abnormal EEG show a normalization of the EEG related to antidepressant treatment and response and whether such effect is drug specific, and whether having had early life stress (ELS) increases the chance of abnormal activity. METHODS: Baseline and week 8 EEGs and depression symptoms were extracted from a large multicenter study (iSPOT-D, n = 1008) where depressed patients were randomized to escitalopram, sertraline, or venlafaxine-XR treatment. We calculated Odds Ratios of EEG normalization and depression response in patients with an abnormal EEG at baseline, comparing sertraline versus other antidepressants. RESULTS: Fifty seven patients with abnormal EEGs were included. EEGs did not normalize significantly more with sertraline compared to other antidepressants (OR = 1.9, p = .280). However, patients with a normalized EEG taking sertraline were 5.2 times more likely to respond than subjects taking other antidepressants (p = .019). ELS was not significantly related to abnormal activity. LIMITATIONS: Neurophysiological recordings were limited in time (two times 2-minute EEGs) and statistical power (n = 57 abnormal EEGs). CONCLUSIONS: Response rates in patients with normalized EEG taking sertraline were significantly larger than in subjects treated with escitalopram/venlafaxine. This adds to personalized medicine and suggests a possible drug repurposing for sertraline.

Recurrence after preoperative chemotherapy and surgery for gastric adenocarcinoma: a multicenter study.

BACKGROUND: In most western European countries perioperative chemotherapy is a part of standard curative treatment for gastric cancer. Nevertheless, recurrence rates remain high after multimodality treatment. This study examines patterns of recurrence in patients receiving perioperative chemotherapy with surgery for gastric cancer in a real-world setting. METHODS: All patients diagnosed with gastric adenocarcinoma between 2010 and 2015 who underwent at least preoperative chemotherapy and a gastrectomy with curative intent (cT1N+/cT2-4a,X; any cN; cM0) in 18 Dutch hospitals were selected from the Netherlands Cancer Registry. Additional data on chemotherapy and recurrence were collected from medical records. Rates, patterns, and timing of recurrence were examined. Multivariable Cox proportional hazard analyses were used to determine prognostic factors for recurrence. RESULTS: 408 patients were identified. After a median follow-up of 27.8 months, 36.8% of the gastric cancer patients had a recurrence of which the majority (88.8%) had distant metastasis. The 1-year recurrence-free survival was 71.8%. The risk of recurrence was higher in patients with an ypN+ stage (HR 4.92, 95% CI 3.35-7.24), partial or no tumor regression (HR 2.63, 95% CI 1.22-5.64), 3 instead of ≥ 6 chemotherapy cycles (HR 3.04, 95% CI 1.99-4.63), R1 resection (HR 1.52, 95% CI 1.02-2.26), and < 15 resected lymph nodes (HR 1.64, 95% CI 1.14-2.37). CONCLUSION: A considerable amount of gastric cancer patients who were treated with curative intent developed a recurrence despite surgery and perioperative treatment. The majority developed distant metastases, therefore, multimodality treatment approaches should be focused on the prevention of distant rather than locoregional recurrences to improve survival.

Impact of Age and Comorbidity on Choice and Outcome of Two Different Treatment Options for Patients with Potentially Curable Esophageal Cancer.

PURPOSE: This study was designed to assess the impact of age and comorbidity on choice and outcome of definitive chemoradiotherapy (dCRT) or neoadjuvant chemoradiotherapy plus surgery. METHODS: In this population-based study, all patients with potentially curable EC (cT1N+/cT2-3, TX, any cN, cM0) diagnosed in the South East of the Netherlands between 2004 and 2014 were included. Kaplan-Meier method with log-rank tests and multivariable Cox regression analysis were used to compare overall survival (OS). RESULTS: A total of 702 patients was included. Age ≥ 75 years and multiple comorbidities were associated with a higher probability for dCRT (odds ratio [OR] 8.58; 95% confidence interval [CI] 4.72-15.58; and OR 3.09; 95% CI 1.93-4.93). The strongest associations were found for the combination of hypertension plus diabetes (OR 3.80; 95% CI 1.97-7.32) and the combination of cardiovascular with pulmonary comorbidity (OR 3.18; 95% CI 1.57-6.46). Patients with EC who underwent dCRT had a poorer prognosis than those who underwent nCRT plus surgery, irrespective of age, number, and type of comorbidities. In contrast, for patients with squamous cell carcinoma with ≥ 2 comorbidities or age ≥ 75 years, OS was comparable between both groups (hazard ratio [HR] 1.52; 95% CI 0.78-2.97; and HR 0.73; 95% CI 0.13-4.14). CONCLUSIONS: Histological tumor type should be acknowledged in treatment choices for patients with esophageal cancer. Neoadjuvant chemoradiotherapy plus surgery should basically be advised as treatment of choice for operable esophageal adenocarcinoma patients. For patients with esophageal squamous cell carcinoma with ≥ 2 comorbidities or age ≥ 75 years, dCRT may be the preferred strategy.

Detecting abnormal electroencephalograms using deep convolutional networks.

OBJECTIVES: Electroencephalography (EEG) is a central part of the medical evaluation for patients with neurological disorders. Training an algorithm to label the EEG normal vs abnormal seems challenging, because of EEG heterogeneity and dependence of contextual factors, including age and sleep stage. Our objectives were to validate prior work on an independent data set suggesting that deep learning methods can discriminate between normal vs abnormal EEGs, to understand whether age and sleep stage information can improve discrimination, and to understand what factors lead to errors. METHODS: We train a deep convolutional neural network on a heterogeneous set of 8522 routine EEGs from the Massachusetts General Hospital. We explore several strategies for optimizing model performance, including accounting for age and sleep stage. RESULTS: The area under the receiver operating characteristic curve (AUC) on an independent test set (n = 851) is 0.917 marginally improved by including age (AUC = 0.924), and both age and sleep stages (AUC = 0.925), though not statistically significant. CONCLUSIONS: The model architecture generalizes well to an independent dataset. Adding age and sleep stage to the model does not significantly improve performance. SIGNIFICANCE: Insights learned from misclassified examples, and minimal improvement by adding sleep stage and age suggest fruitful directions for further research.

Timing of postoperative chemotherapy in patients undergoing perioperative chemotherapy and gastrectomy for gastric cancer.

BACKGROUND: For patients who qualify for perioperative chemotherapy and gastrectomy for gastric cancer, the optimal timing of the postoperative chemotherapy (PC) seems equivocal. The aim of this study was to evaluate the influence of timing of PC on overall survival (OS) in patients receiving perioperative chemotherapy. METHODS: Patients undergoing perioperative chemotherapy and gastrectomy with curative intent (2010-2014) were extracted from the nationwide population-based Netherlands Cancer Registry. Timing of PC was analyzed as a linear and categorical variable (<6 weeks, 6-8 weeks, and >8 weeks). Risk factors for a late start of PC (≥6 weeks), and the association between timing of PC and OS were assessed by multivariable regression analyses. RESULTS: Among 1066 patients who underwent perioperative chemotherapy and gastrectomy, 463 (43%) patients started PC. PC was administered within 6 weeks in 208 (45%) patients, within 6-8 weeks in 155 (33%) patients, and after 8 weeks in 100 (22%) patients. A total of 419 (91%) and 351 (76%) patients finished all cycles of preoperative and PC, respectively. A late start of PC was associated with a longer hospital stay (+1 hospital day: OR 1.15, 95% CI [1.08-1.23], p < 0.001). Timing of PC was not associated with OS (6-8 weeks vs. <6 weeks, HR 1.14, 95% CI [0.79-1.65], p = 0.471; >8 weeks vs. <6 weeks, HR 1.04, 95% CI [0.79-1.65], p = 0.872). CONCLUSION: Timing of postoperative chemotherapy does not influence survival in patients receiving perioperative chemotherapy for gastric cancer. The results suggest that the early postoperative period may be safely used for recovery and optimizing patients for the start of PC.

Overall survival before and after centralization of gastric cancer surgery in the Netherlands.

BACKGROUND: Centralization of surgery has been shown to improve outcomes for oesophageal and pancreatic cancer, and has been implemented for gastric cancer since 2012 in the Netherlands. This study evaluated the impact of centralizing gastric cancer surgery on outcomes for all patients with gastric cancer. METHODS: Patients diagnosed with non-cardia gastric adenocarcinoma in the intervals 2009-2011 and 2013-2015 were selected from the Netherlands Cancer Registry. Clinicopathological data, treatment characteristics and mortality were assessed for the periods before (2009-2011) and after (2013-2015) centralization. Cox regression analyses were used to assess differences in overall survival between these intervals. RESULTS: A total of 7204 patients were included. Resection rates increased slightly from 37·6 per cent before to 39·6 per cent after centralization (P = 0·023). Before centralization, 50·1 per cent of surgically treated patients underwent gastrectomy in hospitals that performed fewer than ten procedures annually, compared with 9·2 per cent after centralization. Patients who had gastrectomy in the second interval were younger and more often underwent total gastrectomy (29·3 per cent before versus 41·2 per cent after centralization). Thirty-day postoperative mortality rates dropped from 6·5 to 4·1 per cent (P = 0·004), and 90-day mortality rates decreased from 10·6 to 7·2 per cent (P = 0·002). Two-year overall survival rates increased from 55·4 to 58·5 per cent among patients who had gastrectomy (P = 0·031) and from 27·1 to 29·6 per cent for all patients (P = 0·003). Improvements remained after adjustment for case mix; however, adjustment for hospital volume attenuated this association for surgically treated patients. CONCLUSION: Centralization of gastric cancer surgery was associated with reduced postoperative mortality and improved survival.

Natural disease history of the dy2J mouse model of laminin α2 (merosin)-deficient congenital muscular dystrophy.

Merosin deficient congenital muscular dystrophy 1A (MDC1A) is a very rare autosomal recessive disorder caused by mutations in the LAMA2 gene leading to severe and progressive muscle weakness and atrophy. Although over 350 causative mutations have been identified for MDC1A, no treatment is yet available. There are many therapeutic approaches in development, but the lack of natural history data of the mouse model and standardized outcome measures makes it difficult to transit these pre-clinical findings to clinical trials. Therefore, in the present study, we collected natural history data and assessed pre-clinical outcome measures for the dy2J/dy2J mouse model using standardized operating procedures available from the TREAT-NMD Alliance. Wild type and dy2J/dy2J mice were subjected to five different functional tests from the age of four to 32 weeks. Non-tested control groups were taken along to assess whether the functional test regime interfered with muscle pathology. Respiratory function, body weights and creatine kinase levels were recorded. Lastly, skeletal muscles were collected for further histopathological and gene expression analyses. Muscle function of dy2J/dy2J mice was severely impaired at four weeks of age and all mice lost the ability to use their hind limbs. Moreover, respiratory function was altered in dy2J/dy2J mice. Interestingly, the respiration rate was decreased and declined with age, whereas the respiration amplitude was increased in dy2J/dy2J mice when compared to wild type mice. Creatine kinase levels were comparable to wild type mice. Muscle histopathology and gene expression analysis revealed that there was a specific regional distribution pattern of muscle damage in dy2J/dy2J mice. Gastrocnemius appeared to be the most severely affected muscle with a high proportion of atrophic fibers, increased fibrosis and inflammation. By contrast, triceps was affected moderately and diaphragm only mildly. Our study presents a complete natural history dataset which can be used in setting up standardized studies in dy2J/dy2J mice.

Definitive chemoradiation or surgery in elderly patients with potentially curable esophageal cancer in the Netherlands: a nationwide population-based study on patterns of care and survival.

BACKGROUND: The aim of our study was to describe treatment patterns and the impact on overall survival among elderly patients (75 years and older) with potentially curable esophageal cancer. MATERIAL AND METHODS: Between 2003 and 2013, 13,244 patients from the nationwide population-based Netherlands Cancer Registry (NCR) were diagnosed with potentially curable esophageal cancer (cT2-3, X, any cN, cM0, X) of which 34% were elderly patients (n = 4501). RESULTS: Surgical treatment with or without neoadjuvant treatment remained stable among elderly patients (around the 16% between 2003 and 2013). However, among younger patients, surgical treatment increased from 60.2 to 67.0%. The use of definitive chemoradiation (dCRT) increased in elderly patients from 1.9 to 19.5% and in younger patients from 5.2 to 17.2%. Due to the increase in dCRT, treatment with curative intent doubled in the elderly from 17 to 37.1%. Multivariable Cox regression revealed that elderly patients with an adenocarcinoma receiving surgery alone or dCRT had a significantly worse overall survival compared to those receiving surgery with neoadjuvant chemo (radio) therapy (nCRT/CT) (HR: 1.7 95% CI 1.4-2.0 and HR: 1.9 95% CI 1.5-2.3). However, among elderly with squamous cell carcinoma overall survival was comparable between dCRT, surgery alone and surgery with nCRT/CT. CONCLUSIONS: Survival was comparable among elderly patients with squamous cell carcinoma who underwent surgery with nCRT/CT, surgery alone or received dCRT, while elderly patients with an adenocarcinoma who underwent surgery with nCRT/CT had a better overall survival when compared with surgery alone or dCRT. Therefore, dCRT can be considered as a reasonable alternative for surgery among potentially curable elderly patients with esophageal squamous cell carcinoma. However, in elderly patients with esophageal adenocarcinoma surgery with nCRT/CT is still preferable regarding overall survival.

[Hospital of diagnosis influences the probability of receiving curative treatment for oesophageal and gastric cancer]. / Ziekenhuis van diagnose beïnvloedt kans op curatieve behandeling voor slokdarm- en maagkanker.

OBJECTIVE: The aim of these studies was to examine the influence of hospital of diagnosis on the probability of receiving curative treatment and its impact on survival among oesophageal and gastric cancer. DESIGN: Although oesophageal and gastric cancer surgery is centralised in the Netherlands, the disease is often diagnosed in hospitals that do not perform this procedure. METHOD: Patients with potentially curable oesophageal or gastric cancer tumours diagnosed between 2005 and 2013 were selected from the Netherlands Cancer Registry. The probability to undergo curative treatment was examined for each hospital of diagnosis after adjustment for case-mix. Effects of variation in probability of undergoing curative treatment among these hospitals on survival were investigated Cox regression. RESULTS: All 13,017 patients with potentially curable oesophageal and 5,620 patients with potentially curable gastric cancer, diagnosed in 91 hospitals, were included. After adjustment, the proportion of oesophageal cancer patients receiving curative treatment ranged from 50% to 82% and from 48% to 78% for patients with gastric cancer in 2010-2013, depending on hospital of diagnosis (both P < 0.001). Furthermore, patients diagnosed in hospitals with a low probability of undergoing curative treatment had a worse overall survival in the period 2010-2013 (oesophageal cancer hazard ratio (HR): 1,15; 95%-CI: 1,07-1,24; gastric cancer HR: 1,21; 95%-CI: 1,04-1,41). CONCLUSION: The variation in probability of undergoing potentially curative treatment for oesophageal and gastric cancer between hospitals of diagnosis and its impact on survival indicates that treatment decision-making for these patients may be improved. Regional expert multidisciplinary team meetings in this field may improve the selection of patients for curative treatment.

Long-term survival improvement in oesophageal cancer in the Netherlands.

BACKGROUND: Treatment for oesophageal cancer has evolved due to developments including the centralisation of surgery and introduction of neoadjuvant treatment. Therefore, this study evaluated trends in stage distribution, treatment and survival of oesophageal cancer patients in the last 26 years in the Netherlands. PATIENTS AND METHODS: Patients with oesophageal cancer diagnosed in the period 1989-2014 were selected from the Netherlands Cancer Registry. Patients were divided into two groups: non-metastatic (M0) and metastatic (M1). Trends in stage distribution, treatment and relative survival rates were evaluated according to histology. RESULTS: Among all 35,760 patients, the percentage of an unknown tumour stage decreased from 34% to 10% during the study period, whereas the percentage of patients with metastatic disease increased from 21% to 34%. Among surgically treated patients 32% underwent a resection in a high-volume hospital in 2005 which increased to 92% in 2014. Use of neoadjuvant chemoradiotherapy increased in non-metastatic oesophageal adenocarcinoma (OAC) and squamous cell carcinoma (OSCC) patients from respectively 4% and 2% in 2000-2004 to 43% and 26% in 2010-2014. Five-year relative survival increased from 8% to 22% for all patients; from 12% to 36% for non-metastatic OAC and from 9% to 27% for non-metastatic OSCC over 26 years. Median overall survival of metastatic patients improved from 18 to 22 weeks. CONCLUSION: In the Netherlands, survival for oesophageal cancer patients improved significantly, especially in the period 2005-2014 which might be the result of better treatment related to the centralisation of surgery and introduction of neoadjuvant chemoradiotherapy.

Detecting interictal discharges in first seizure patients: ambulatory EEG or EEG after sleep deprivation?

PURPOSE: Uncertainty about recurrence after a first unprovoked seizure is a significant psychological burden for patients, and motivates the need for diagnostic tools with high sensitivity and specificity to assess recurrence risk. As the sensitivity of a routine EEG after a first unprovoked seizure is limited, patients often require further diagnostics. Here, we study if ambulatory EEG (aEEG) has similar diagnostic accuracy as sleep deprived EEG (sdEEG). METHODS: In this retrospective cohort, we included patients with an unprovoked first seizure and a normal routine EEG who subsequently underwent an sdEEG or aEEG. All EEGs were reviewed for the presence of interictal epileptiform discharges (IEDs). We calculated specificity and sensitivity of sdEEG and aEEG, using the clinical diagnosis of epilepsy as golden standard. All patients had a follow-up of one year. RESULTS: We included 104 patients. Sensitivities for sdEEG and aEEG were 45% (specificity 91%) and 63% (specificity 95%), respectively. Independent risk factor for recurrent seizure were IEDs on the additional EEG, with a relative risk of 1.5 of having a recurrent seizure within a year. CONCLUSION: Diagnostic accuracies of sdEEG and aEEG are similar and depending on patients' and clinicians' preference both can be considered in patients with a first seizure and a normal routine EEG to determine recurrence risk.

Effect of age on rates of palliative surgery and chemotherapy use in patients with locally advanced or metastatic gastric cancer.

BACKGROUND: This study assessed trends in the treatment and survival of palliatively treated patients with gastric cancer, with a focus on age-related differences. METHODS: For this retrospective, population-based, nationwide cohort study, all patients diagnosed between 1989 and 2013 with non-cardia gastric cancer with metastasized disease or invasion into adjacent structures were selected from the Netherlands Cancer Registry. Trends in treatment and 2-year overall survival were analysed and compared between younger (age less than 70 years) and older (aged 70 years or more) patients. Analyses were done for five consecutive periods of 5 years, from 1989-1993 to 2009-2013. Multivariable logistic regression analysis was used to examine the probability of undergoing surgery. Multivariable Cox regression analysis was used to identify independent risk factors for death. RESULTS: Palliative resection rates decreased significantly in both younger and older patients, from 24·5 and 26·2 per cent to 3·0 and 5·0 per cent respectively. Compared with patients who received chemotherapy alone, both younger (21·6 versus 6·3 per cent respectively; P < 0·001) and older (14·7 versus 4·6 per cent; P < 0·001) patients who underwent surgery had better 2-year overall survival rates. Multivariable analysis demonstrated that younger and older patients who received chemotherapy alone had worse overall survival than patients who had surgery only (younger: hazard ratio (HR) 1·22, 95 per cent c.i. 1·12 to 1·33; older: HR 1·12, 1·01 to 1·24). After 2003 there was no association between period of diagnosis and overall survival in younger or older patients. CONCLUSION: Despite changes in the use of resection and chemotherapy as palliative treatment, overall survival rates of patients with advanced and metastatic gastric cancer did not improve.

Natural disease history of mouse models for limb girdle muscular dystrophy types 2D and 2F.

Limb-girdle muscular dystrophy types 2D and 2F (LGMD 2D and 2F) are autosomal recessive disorders caused by mutations in the alpha- and delta sarcoglycan genes, respectively, leading to severe muscle weakness and degeneration. The cause of the disease has been well characterized and a number of animal models are available for pre-clinical studies to test potential therapeutic interventions. To facilitate transition from drug discovery to clinical trials, standardized procedures and natural disease history data were collected for these mouse models. Implementing the TREAD-NMD standardized operating procedures, we here subjected LGMD2D (SGCA-null), LGMD2F (SGCD-null) and wild type (C57BL/6J) mice to five functional tests from the age of 4 to 32 weeks. To assess whether the functional test regime interfered with disease pathology, sedentary groups were taken along. Muscle physiology testing of tibialis anterior muscle was performed at the age of 34 weeks. Muscle histopathology and gene expression was analysed in skeletal muscles and heart. Muscle histopathology and gene expression was analysed in skeletal muscles and heart. Mice successfully accomplished the functional tests, which did not interfere with disease pathology. Muscle function of SGCA- and SGCD-null mice was impaired and declined over time. Interestingly, female SGCD-null mice outperformed males in the two and four limb hanging tests, which proved the most suitable non-invasive tests to assess muscle function. Muscle physiology testing of tibialis anterior muscle revealed lower specific force and higher susceptibility to eccentric-induced damage in LGMD mice. Analyzing muscle histopathology and gene expression, we identified the diaphragm as the most affected muscle in LGMD strains. Cardiac fibrosis was found in SGCD-null mice, being more severe in males than in females. Our study offers a comprehensive natural history dataset which will be useful to design standardized tests and future pre-clinical studies in LGMD2D and 2F mice.

Synaptic damage underlies EEG abnormalities in postanoxic encephalopathy: A computational study.

OBJECTIVE: In postanoxic coma, EEG patterns indicate the severity of encephalopathy and typically evolve in time. We aim to improve the understanding of pathophysiological mechanisms underlying these EEG abnormalities. METHODS: We used a mean field model comprising excitatory and inhibitory neurons, local synaptic connections, and input from thalamic afferents. Anoxic damage is modeled as aggravated short-term synaptic depression, with gradual recovery over many hours. Additionally, excitatory neurotransmission is potentiated, scaling with the severity of anoxic encephalopathy. Simulations were compared with continuous EEG recordings of 155 comatose patients after cardiac arrest. RESULTS: The simulations agree well with six common categories of EEG rhythms in postanoxic encephalopathy, including typical transitions in time. Plausible results were only obtained if excitatory synapses were more severely affected by short-term synaptic depression than inhibitory synapses. CONCLUSIONS: In postanoxic encephalopathy, the evolution of EEG patterns presumably results from gradual improvement of complete synaptic failure, where excitatory synapses are more severely affected than inhibitory synapses. The range of EEG patterns depends on the excitation-inhibition imbalance, probably resulting from long-term potentiation of excitatory neurotransmission. SIGNIFICANCE: Our study is the first to relate microscopic synaptic dynamics in anoxic brain injury to both typical EEG observations and their evolution in time.

Volume-outcome relation in palliative systemic treatment of metastatic oesophagogastric cancer.

INTRODUCTION: Palliative systemic therapy has been shown to improve survival in metastatic oesophagogastric cancer. Administration of palliative systemic therapy in metastatic oesophagogastric cancer varies between hospitals. We aimed to explore the association between the annual hospital volume of oesophagogastric cancer patients and survival. METHODS: Patients diagnosed in the Netherlands between 2005 and 2013 with metastatic oesophagogastric cancer were identified in the Netherlands Cancer Registry. Patients were attributed according to three definitions of high volume: (1) high-volume incidence centre, (2) high-volume treatment centre and (3) high-volume surgical centre. Independent predictors for administration of palliative chemotherapy were evaluated by means of multivariable logistic regression analysis, and multivariable Cox proportional hazard regression analysis was performed to assess the impact of high-volume centres on survival. RESULTS: Our data set comprised 4078 patients with metastatic oesophageal cancer, and 5425 patients with metastatic gastric cancer, with a median overall survival of 20 weeks (95% confidence interval [CI] 19-21 weeks) and 16 weeks (95% CI 15-17 weeks), respectively. Patients with oesophageal cancer treated in a high-volume surgical centre (adjusted hazard ratio [HR] 0.80, 95% CI 0.70-0.91) and a high-volume treatment centre (adjusted HR 0.88, 95% CI 0.78-0.99) exhibited a decreased risk of death. For gastric cancer, patients treated in a high-volume surgical centre (adjusted HR 0.83, 95% CI 0.74-0.92) had a superior outcome. CONCLUSION: Improved survival in patients undergoing palliative systemic therapy for oesophagogastric cancer was associated with treatment in high-volume treatment and surgical centres. Further research should be implemented to explore which specific factors of high-volume centres are associated with improved outcomes.

Cognitive flexibility deficits in a mouse model for the absence of full-length dystrophin.

Duchenne muscular dystrophy (DMD) is a progressive muscle-wasting disorder, caused by mutations in the DMD gene and the resulting lack of dystrophin. The DMD gene has seven promoters, giving rise to multiple full-length and shorter isoforms. Besides the expression of dystrophin in muscles, the majority of dystrophin isoforms is expressed in brain and dystrophinopathy can lead to cognitive deficits, including intellectual impairments and deficits in executive function. In contrast to the muscle pathology, the impact of the lack of dystrophin on the brain is not very well studied. Here, we study the behavioral consequences of a lack of full-length dystrophin isoforms in mdx mice, particularly with regard to domains of executive functions and anxiety. We observed a deficit in cognitive flexibility in mdx mice in the absence of motor dysfunction or general learning impairments using two independent behavioral tests. In addition, increased anxiety was observed, but its expression depended on the context. Overall, these results suggest that the absence of full-length dystrophin in mice has specific behavioral effects that compare well to deficits observed in DMD patients.