4-Hydroxybenzoic Acid-Based Hydrazide-Hydrazones as Potent Growth Inhibition Agents of Laccase-Producing Phytopathogenic Fungi That Are Useful in the Protection of Oilseed Crops.

The research on new compounds against plant pathogens is still socially and economically important. It results from the increasing resistance of pests to plant protection products and the need to maintain high yields of crops, particularly oilseed crops used to manufacture edible and industrial oils and biofuels. We tested thirty-five semi-synthetic hydrazide-hydrazones with aromatic fragments of natural origin against phytopathogenic laccase-producing fungi such as Botrytis cinerea, Sclerotinia sclerotiorum, and Cerrena unicolor. Among the investigated molecules previously identified as potent laccase inhibitors were also strong antifungal agents against the fungal species tested. The highest antifungal activity showed derivatives of 4-hydroxybenzoic acid and salicylic aldehydes with 3-tert-butyl, phenyl, or isopropyl substituents. S. sclerotiorum appeared to be the most susceptible to the tested compounds, with the lowest IC50 values between 0.5 and 1.8 µg/mL. We applied two variants of phytotoxicity tests for representative crop seeds and selected hydrazide-hydrazones. Most tested molecules show no or low phytotoxic effect for flax and sunflower seeds. Moreover, a positive impact on seed germination infected with fungi was observed. With the potential for application, the cytotoxicity of the hydrazide-hydrazones of choice toward MCF-10A and BALB/3T3 cell lines was lower than that of the azoxystrobin fungicide tested.

Molecular mechanisms of tigecycline-resistance among Enterobacterales.

The global emergence of antimicrobial resistance to multiple antibiotics has recently become a significant concern. Gram-negative bacteria, known for their ability to acquire mobile genetic elements such as plasmids, represent one of the most hazardous microorganisms. This phenomenon poses a serious threat to public health. Notably, the significance of tigecycline, a member of the antibiotic group glycylcyclines and derivative of tetracyclines has increased. Tigecycline is one of the last-resort antimicrobial drugs used to treat complicated infections caused by multidrug-resistant (MDR) bacteria, extensively drug-resistant (XDR) bacteria or even pan-drug-resistant (PDR) bacteria. The primary mechanisms of tigecycline resistance include efflux pumps' overexpression, tet genes and outer membrane porins. Efflux pumps are crucial in conferring multi-drug resistance by expelling antibiotics (such as tigecycline by direct expelling) and decreasing their concentration to sub-toxic levels. This review discusses the problem of tigecycline resistance, and provides important information for understanding the existing molecular mechanisms of tigecycline resistance in Enterobacterales. The emergence and spread of pathogens resistant to last-resort therapeutic options stands as a major global healthcare concern, especially when microorganisms are already resistant to carbapenems and/or colistin.

Passive or active drainage system for chronic subdural haematoma-a single-center retrospective follow-up study.

BACKGROUND: Postoperative drainage systems have become a standard treatment for chronic subdural hematoma (CSDH). We previously compared treatment results from three Scandinavian centers using three different postoperative drainage systems and concluded that the active subgaleal drainage was associated with lower recurrence and complication rates than the passive subdural drainage. We consequently changed clinical practice from using the passive subdural drainage to the active subgaleal drainage. OBJECTIVE: The aim of the present study was to assess a potential change in reoperation rates for CSDH after conversion to the active subgaleal drainage. METHODS: This single-center cohort study compared the reoperation rates for recurrent same-sided CSDH and postoperative complication rates between patients treated during two study periods (passive subdural drainage cohort versus active subgaleal drainage cohort). RESULTS: In total, 594 patients were included in the study. We found no significant difference in reoperation rates between the passive subdural drain group and the active subgaleal drain group (21.6%, 95% CI 17.5-26.4% vs. 18.0%, 95% CI 13.8-23.2%; p = 0.275). There was no statistical difference in the rate of serious complications between the groups. The operating time was significantly shorter for patients operated with the active subgaleal drain than patients with the passive subdural drain (32.8 min, 95% CI 31.2-34.5 min vs. 47.6 min, 95% CI 44.7-50.4 min; p < 0.001). CONCLUSIONS: Conversion from the passive subdural to the active subgaleal drainage did not result in a clear reduction of reoperation rates for CSDH in our center.

Segmentation of glioblastomas in early post-operative multi-modal MRI with deep neural networks.

Extent of resection after surgery is one of the main prognostic factors for patients diagnosed with glioblastoma. To achieve this, accurate segmentation and classification of residual tumor from post-operative MR images is essential. The current standard method for estimating it is subject to high inter- and intra-rater variability, and an automated method for segmentation of residual tumor in early post-operative MRI could lead to a more accurate estimation of extent of resection. In this study, two state-of-the-art neural network architectures for pre-operative segmentation were trained for the task. The models were extensively validated on a multicenter dataset with nearly 1000 patients, from 12 hospitals in Europe and the United States. The best performance achieved was a 61% Dice score, and the best classification performance was about 80% balanced accuracy, with a demonstrated ability to generalize across hospitals. In addition, the segmentation performance of the best models was on par with human expert raters. The predicted segmentations can be used to accurately classify the patients into those with residual tumor, and those with gross total resection.

Return to Work after Surgical Clipping versus Endovascular Treatment of Unruptured Intracranial Aneurysms: A Nationwide Registry-Based Study.

PURPOSE: To assess return to work following the treatment of unruptured intracranial aneurysms (UIAs). MATERIALS AND METHODS: This retrospective, nationwide registry-based study included all adult patients of working age treated for a UIA in Norway between 2008 and 2018 who had a record of sickness leave on the day of treatment. Data from The Norwegian Patient Registry and The Norwegian Labour and Welfare Administration were linked on an individual level. Daily sickness and recipiency of disability benefits, as an indirect measure of working status, from 1 year before treatment to 1 year after treatment were analyzed. Return to work after endovascular treatment and surgical clipping was compared. RESULTS: In total, 412 patients were included. Of patients who worked 1 year before treatment, 83% returned to work 1 year after treatment. The number of days from treatment to the first day back at work in a continuous 3-month working period was lower in patients who underwent endovascular treatment than in those treated with surgical clipping (median, 69 days; 95% confidence interval [CI], 51-87; vs 201 days, 95% CI, 163-239; P < .001). Return to work was more likely in patients who underwent endovascular treatment at 3 months after treatment (hazard ratio, 3.53; 95% CI, 2.54-4.93; P < .001). There was no difference in return to work at 6 and 12 months after treatment. CONCLUSIONS: The treatment of UIAs affects patients' postoperative working status. Patients treated endovascularly return to work earlier than those who undergo open surgery.

Return to work after surgical clipping versus endovascular treatment for ruptured intracranial aneurysms - A nationwide registry-based study.

OBJECTIVES: The aim of this study was to assess return to work following aneurysmal subarachnoid haemorrhage (SAH) and compare working status after open surgical clipping and endovascular treatment. METHODS: This nationwide registry-based study included all adult patients in working age treated for a ruptured intracranial aneurysm in Norway between 2008 and 2018 who had a record of sickness leave on the day of treatment. Data from The Norwegian Patient Registry and The Norwegian Labour and Welfare Administration were linked on an individual level. Daily sickness and disability benefits recipiency one year preoperatively to one year postoperatively was analysed. Return to work after endovascular treatment and surgical clipping was compared. RESULTS: 183 patients were included in the study. Among patients who worked at one year preoperatively, 57% had returned to work one year after treatment. Mean number of days from treatment to the first day back at work in a continuous 3-month working period was 298 (95% CI: 276-321) vs. 319 (95% CI: 299-339) for patients who underwent endovascular treatment compared to patients treated with clipping (p = 0.365). Older patients were less likely to return to work after treatment (hazard ratio 0.977 per year of age, 95% CI 0.956-1.000, p = 0.046). There was no significant association between return to work and patient sex or location of the aneurysm. CONCLUSIONS: Aneurysmal SAH profoundly affects patient working status. This study found no significant difference in time to return to work after treatment between patients treated with endovascular techniques compared to patients undergoing open surgery.

Plasmid Mediated mcr-1.1 Colistin-Resistance in Clinical Extraintestinal Escherichia coli Strains Isolated in Poland.

Objectives: The growing incidence of multidrug-resistant (MDR) bacteria is an inexorable and fatal challenge in modern medicine. Colistin is a cationic polypeptide considered a "last-resort" antimicrobial for treating infections caused by MDR Gram-negative bacterial pathogens. Plasmid-borne mcr colistin resistance emerged recently, and could potentially lead to essentially untreatable infections, particularly in hospital and veterinary (livestock farming) settings. In this study, we sought to establish the molecular basis of colistin-resistance in six extraintestinal Escherichia coli strains. Methods: Molecular investigation of colistin-resistance was performed in six extraintestinal E. coli strains isolated from patients hospitalized in Medical University Hospital, Bialystok, Poland. Complete structures of bacterial chromosomes and plasmids were recovered with use of both short- and long-read sequencing technologies and Unicycler hybrid assembly. Moreover, an electrotransformation assay was performed in order to confirm IncX4 plasmid influence on colistin-resistance phenotype in clinical E. coli strains. Results: Here we report on the emergence of six mcr-1.1-producing extraintestinal E. coli isolates with a number of virulence factors. Mobile pEtN transferase-encoding gene, mcr-1.1, has been proved to be encoded within a type IV secretion system (T4SS)-containing 33.3 kbp IncX4 plasmid pMUB-MCR, next to the PAP2-like membrane-associated lipid phosphatase gene. Conclusion: IncX4 mcr-containing plasmids are reported as increasingly disseminated among E. coli isolates, making it an "epidemic" plasmid, responsible for (i) dissemination of colistin-resistance determinants between different E. coli clones, and (ii) circulation between environmental, industrial, and clinical settings. Great effort needs to be taken to avoid further dissemination of plasmid-mediated colistin resistance among clinically relevant Gram-negative bacterial pathogens.

What is the current clinico-radiological diagnostic accuracy for intracranial tumours?

OBJECTIVE: To determine the diagnostic accuracy of routine clinico-radiological workup for a population-based selection of intracranial tumours. METHODS: In this prospective cohort study, we included consecutive adult patients who underwent a primary surgical intervention for a suspected intracranial tumour between 2015 and 2019 at a single-neurosurgical centre. The treating team estimated the expected diagnosis prior to surgery using predefined groups. The expected diagnosis was compared to final histopathology and the accuracy of preoperative clinico-radiological diagnosis (sensitivity, specificity, positive and negative predictive values) was calculated. RESULTS: 392 patients were included in the data analysis, of whom 319 underwent a primary surgical resection and 73 were operated with a diagnostic biopsy only. The diagnostic accuracy varied between different tumour types. The overall sensitivity, specificity and diagnostic mismatch rate of clinico-radiological diagnosis was 85.8%, 97.7% and 4.0%, respectively. For gliomas (including differentiation between low-grade and high-grade gliomas), the same diagnostic accuracy measures were found to be 82.2%, 97.2% and 5.6%, respectively. The most common diagnostic mismatch was between low-grade gliomas, high-grade gliomas and metastases. Accuracy of 90.2% was achieved for differentiation between diffuse low-grade gliomas and high-grade gliomas. CONCLUSIONS: The current accuracy of a preoperative clinico-radiological diagnosis of brain tumours is high. Future non-invasive diagnostic methods need to outperform our results in order to add much value in a routine clinical setting in unselected patients.

Phosphonates enantiomers receiving with fungal enzymatic systems.

BACKGROUND: Phosphonates derivatives are in the area of interests because of their unique chemical-physical features. These compounds manifest variety of biological interactions within the sensitive living cells, including impact on particular enzymes activities. Biological "cause and effect" interactions are based upon the specific matching between the structures and/or compounds and this is usually the result of proper optical configurations of particular chiral moieties. Presented research is targeted to the phosphonates with the heteroatom incorporated in their side functionalities. Such molecules are described as possible substrates of bioconversion for the first time lately and this field is not fully explored. RESULTS: Presented research is targeted to the synthesis of pure hetero-phosphonates enantiomers. The catalytic activity of yeasts and moulds were tested towards two substrates: the thienyl and imidazole phosphonates to resolve their racemic mixtures. Biotransformations conditions differed depending on the outcome, what included changing of following parameters: type of cultivation media, bioprocess duration (24-72 h), additional biocatalyst pre-treatment (24-48 h starvation step triggering the secondary metabolism). (S)-1-amino-1-(3-thienyl)methylphosphonate was produced with the assistance of R. mucilaginosa or A. niger (e.e. up to 98% and yield up to 100%), starting from the 3 mM of substrate racemic mixture. Bioconversion of racemic mixture of 3 mM of (1-amino-1-(4-imidazole)methylphosphonic acid) resulted in the synthesis of S-isomer (up to 95% of e.e.; 100% of yield) with assistance of R. mucilaginosa. 24 h biotransformation was conducted with biomass preincubated under 48-hour starvation conditions. Such stereoselective resolution of the racemic mixtures of substrates undergoes under kinetic control with the conversion of one from the enantiomers. CONCLUSIONS: Composition of the culturing media and pre-incubation in conditions of nutrient deficiency were significant factors influencing the results of kinetic resolution of racemic mixtures of phosphonic substrates and influencing the economic side of the biocatalysis e.g. by determining the duration of whole biocatalytic process.

Association between transcranial Doppler vasospasm and functional outcome after subarachnoid hemorrhage.

AIM OF THE STUDY: This study aimed to investigate the association between transcranial Doppler (TCD) vasospasm and patient outcome and to assess the predictive factors for developing TCD vasospasm after subarachnoid hemorrhage (SAH). MATERIALS AND METHODS: This retrospective observational study included adult patients with nontraumatic SAH. Patient characteristics and TCD values were recorded retrospectively from patient records. Data on maxTCD (maximal TCD value recorded on any side between day 1 and day 14) as well as Δ TCD (maximal difference between mean velocity measured on days 1-3 and days 4-14 on any side) were calculated. The modified Rankin Score was recorded from electronic patient notes at discharge and 3, 6, and 12 months after ictus. The effect of TCD vasospasm, maxTCD, and Δ TCD on the clinical outcome was investigated. Potential predictive factors for developing TCD vasospasm were assessed. The association between the same factors and maxTCD and Δ TCD were explored. RESULTS: One hundred and thirty-eight patients were included in the study. Higher age was associated with a lower risk of developing TCD vasospasm (odds ratio: 0.952, 95% confidence interval: 0.924-0.982, P = 0.002). Fisher grade was a predictor of developing TCD vasospasm (P = 0.05). Age was negatively correlated with maxTCD (R = -0.47, P = 0.01). There was no statistically significant difference in patient outcome at hospital discharge and at 3, 6, and 12 months between patients with and without TCD vasospasm. Higher maxTCD and Δ TCD were associated with a worse clinical outcome at 3 months after SAH ictus. CONCLUSIONS: The clinical benefit of routine TCD assessments in SAH patients remains uncertain.

Smoking habits and detection rate of unruptured intracranial aneurysms and incidence rate of subarachnoid haemorrhage in Norway between 2008 and 2015.

OBJECTIVE: The aim of this study was to investigate the detection rate of unruptured intracranial aneurysms (UIAs) and incidence of aneurysmal subarachnoid haemorrhage (SAH) in relation to the rapidly changing smoking rates in Norway between 2008 and 2015. METHODS: The registry-based study included all patients (≥ 16 years old) admitted to a hospital in Norway between 2008 and 2015 with a primary diagnosis of aneurysmal SAH or an outpatient diagnosis of UIAs. Age group-specific and total detection rate of UIAs and incidence rate of SAH over the years were calculated. Age group-specific data on smoking habits was retrieved from a national annual survey representative of the whole Norwegian population. RESULTS: The rate of daily smokers decreased by 48% between 2008 and 2015. The detection rate of UIAs decreased by 47% from 17.3 in 2008 to 9.3 per 100,000 persons in 2015, and the incidence of SAH decreased by 30% from 11.3 in 2008 to 7.9 per 100,000 persons in 2015. The average annual decline in prevalence of daily smoking, UIA detection rate, and SAH incidence was 6.9%, 6.7%, and 4.3% per year, respectively. Multinomial logistic regression analyses revealed that the correlation between the decline in estimated daily smoking rates and decline in detection rate of UIAs (hazard ratio 52.5 CI = (14.9,∞), p < 0.00001) and incidence of SAH (hazard ratio 11.8 CI=(5.6,32.5), p < 0.00001) are statistically significant. The association is particularly strong in young and middle-aged cohorts (< 66 years old). CONCLUSION: It is likely that reducing cigarette smoking on a population-based level strongly reduces the rates of UIAs and SAH.

Incidence and case fatality of aneurysmal subarachnoid hemorrhage admitted to hospital between 2008 and 2014 in Norway.

BACKGROUND: To provide age- and sex-specific incidence and case fatality rates for non-traumatic aneurysmal subarachnoid hemorrhage (aSAH) in Norway. We also studied time trends in incidence and case fatality, as well as predictors of death following aSAH. METHODS: A nationwide study using discharge data for patients admitted with aSAH between 2008 and 2014. RESULTS: A total of 1732 patients with aSAH were included. The mean age was 60 years (SD 14) and 63% were females. Crude annual incidence was 5.7 per 100,000 person-years (95% CI 5.4-6.0) and was higher in females (6.3 per 100,000, 95% CI 5.9-6.7) compared with males (4.9 per 100,000, 95% CI 4.5-5.3). The annual decline in aSAH incidence was 3.2% per year (p = 0.007). The cumulative proportions of fatalities at days 30, 90, and 1 year were 22%, 25%, and 37%, respectively. The 30-day mortality rate did not change during the study period. Age (HR 0.7-2.2) and aneurysms in the posterior circulation (HR 1.7, 95% CI 1.3-2.3, p = 0.001) were associated with higher 30-day case fatality following aSAH, while aneurysm repair (HR 0.2, 95% CI 0.2-0.3, p < 0.001) was associated with lower risk. CONCLUSIONS: The incidence of aSAH declined in Norway between 2008 and 2014. Case fatality following aSAH continues to be high, and the 30-day mortality during the study period was unchanged. Increasing age and aneurysms in the posterior circulation were associated with increased risk of death within 30 days following aSAH.

Expression of AraC/XylS stress response regulators in two distinct carbapenem-resistant Enterobacter cloacae ST89 biotypes.

BACKGROUND: The growing incidence of MDR Gram-negative bacteria is a rapidly emerging challenge in modern medicine. OBJECTIVES: We sought to establish the role of intrinsic drug-resistance regulators in combination with specific genetic mutations in 11 Enterobacter cloacae isolates obtained from a single patient within a 7 week period. METHODS: The molecular characterization of eight carbapenem-resistant and three carbapenem-susceptible E. cloacae ST89 isolates included expression-level analysis and WGS. Quantitative PCR included: (i) chromosomal cephalosporinase gene (ampC); (ii) membrane permeability factor genes, e.g. ompF, ompC, acrA, acrB and tolC; and (iii) intrinsic regulatory genes, e.g. ramA, ampR, rob, marA and soxS, which confer reductions in antibiotic susceptibility. RESULTS: In this study we describe the influence of the alterations in membrane permeability (ompF and ompC levels), intrinsic regulatory genes (ramA, marA, soxS) and intrinsic chromosomal cephalosporinase AmpC on reductions in carbapenem susceptibility of E. cloacae clinical isolates. Interestingly, only the first isolate possessed the acquired VIM-4 carbapenemase, which has been lost in subsequent isolates. The remaining XDR E. cloacae ST89 isolates presented complex carbapenem-resistance pathways, which included perturbations in permeability of bacterial membranes mediated by overexpression of ramA, encoding an AraC/XylS global regulator. Moreover, susceptible isolates differed significantly from other isolates in terms of marA down-regulation and soxS up-regulation. CONCLUSIONS: Molecular mechanisms of resistance among carbapenem-resistant E. cloacae included production of acquired VIM-4 carbapenemase, significant alterations in membrane permeability due to increased expression of ramA, encoding an AraC/XylS global regulator, and the overproduction of chromosomal AmpC cephalosporinase.

Evaluation of nationwide referral pathways, investigation and treatment of suspected cauda equina syndrome in the United Kingdom.

Purpose: Cauda equina syndrome (CES) is a spinal emergency with clinical symptoms and signs that have low diagnostic accuracy. National guidelines in the United Kingdom (UK) state that all patients should undergo an MRI prior to referral to specialist spinal units and surgery should be performed at the earliest opportunity. We aimed to evaluate the current practice of investigating and treating suspected CES in the UK. Materials and Methods: A retrospective, multicentre observational study of the investigation and management of patients with suspected CES was conducted across the UK, including all patients referred to a spinal unit over 6 months between 1st October 2016 and 31st March 2017. Results: A total of 28 UK spinal units submitted data on 4441 referrals. Over half of referrals were made without any previous imaging (n = 2572, 57.9%). Of all referrals, 695 underwent surgical decompression (15.6%). The majority of referrals were made out-of-hours (n = 2229/3517, 63.4%). Patient location and pre-referral imaging were not associated with time intervals from symptom onset or presentation to decompression. Patients investigated outside of the spinal unit experienced longer time intervals from referral to undergoing the MRI scan. Conclusions: This is the largest known study of the investigation and management of suspected CES. We found that the majority of referrals were made without adequate investigations. Most patients were referred out-of-hours and many were transferred for an MRI without subsequently requiring surgery. Adherence to guidelines would reduce the number of referrals to spinal services by 72% and reduce the number of patient transfers by 79%.

Membrane-mediated fibrillation and toxicity of the tau hexapeptide PHF6.

The aggregation of the tau protein into neurofibrillary tangles is believed to correlate with cognitive decline in several neurodegenerative disorders, including Alzheimer's disease. Recent studies suggest that tau's interactions with the cell membrane could serve as a toxicity pathway and also enhance fibrillation into paired helical filaments (PHFs). Conformational changes associated with tau-membrane interactions are poorly understood, and their characterization could improve our understanding of tau pathogenicity. In this study, we investigated the molecular level structural changes associated with the interaction of the tau hexapeptide PHF6 with model lipid membranes and characterized the effects of these interactions on membrane stability and peptide fibrillation. We used two PHF6 forms, the aggregation-prone PHF6 with N-terminal acetylation (Ac-PHF6) and the non-aggregation prone PHF6 with a standard N terminus (NH3+-PHF6). We found that both PHF6 peptides are neurotoxic and exhibit similar membrane-mediated changes, consisting of: 1) favorable interactions with anionic membranes, 2) membrane destabilization through lipid extraction, and 3) membrane-mediated fibrillation. The rate at which these changes occurred was the main difference between the two peptides. NH3+-PHF6 displayed slow membrane-mediated fibrillation after 6 days of incubation, whereas Ac-PHF6 adopted a ß-sheet conformation at the surface of the membrane within hours. Ac-PHF6 interactions with the membrane were also accompanied by membrane invagination and rapid membrane destabilization. Overall, our results reveal that membrane interactions could play a critical role in tau toxicity and fibrillation, and highlight that unraveling these interactions is important for significantly advancing the development of therapeutic strategies to manage tau-associated neurodegenerative diseases.

Postprogression survival in patients with glioblastoma treated with concurrent chemoradiotherapy: a routine care cohort study.

Glioblastoma is the commonest malignant brain tumor in adults. Most patients develop progressive disease before they die. However, survival after developing progressive disease is infrequently reported. We identified patients with histologically proven disease who were treated with concurrent chemoradiotherapy during 2006-2013. We analyzed overall survival (OS), progression-free survival and postprogression survival (PPS) in relation to age, O6-methylguanine-DNA methyltransferase promoter methylation and extent of surgical resection. We identified 166 patients. Median survival was 13.5 months; 2-year OS was 21.7%. Median progression-free survival and PPS were 7.03 and 4.53 months, respectively. Age and extent of surgical resection were correlated with OS. Only the extent of surgical resection was associated with PPS. Our work suggests that the established prognostic factors for glioblastoma do not appear to help predict PPS.

Estimating progression-free survival in patients with glioblastoma using routinely collected data.

Glioblastoma (GBM) represents 80% of all primary malignant brain tumours in adults. Prognosis is poor, and there is a clear correlation between disease progression and deterioration in functional status. In this pilot study we assess whether we can estimate disease progression and progression free survival (PFS) from routinely collected electronic healthcare data. We identified fifty patients with glioblastoma who had chemo-radiotherapy. For each patient we manually collected a reference data set recording demographics, surgery, radiotherapy, chemotherapy, follow-up and death. We also obtained an electronic routine data set for each patient by combining local data on chemotherapy/radiotherapy and hospital admissions. We calculated overall survival (OS) and PFS using the reference data set, and estimated them using the routine data sets using two different methods, and compared the estimated measures with the reference measures. Overall survival was 68% at 1 year and median OS was 12.8 months. The routine data correctly identified progressive disease in 37 of 40 patients and stable disease in 7 of 10 patients. PFS was 7.4 months and the estimated PFS using routine data was 9.1 and 7.8 months with methods 1 and 2 respectively. There was acceptable agreement between reference and routine data in 49 of 50 patients for OS and 35 of 50 patients for PFS. The event of progression, subsequent treatment and OS are well estimated using our approach, but PFS estimation is less accurate. Our approach could refine our understanding of the disease course and allow us to report PFS, OS and treatment nationally.

Delayed symptomatic haemorrhage from the remnants of a thalamic arteriovenous malformation after previous angiographic cure with radiotherapy.

In 1995 a 16-year old girl was diagnosed with a large left thalamic AVM that was considered unsuitable for microsurgical resection and was treated with radiotherapy twice, which led to angiographic cure. She re-presented 19 years after initial treatment with a symptomatic acute thalamic haemorrhage. Her digital subtraction angiography was negative for arterio-venous shunting. MRI/MRA showed cystic change with adjacent contrast enhancement in the region of the previously irradiated arteriovenous malformation. The patient underwent an interhemispheric transcallosal resection of the left thalamic haemorrhagic lesion via a contralateral craniotomy. Intra-operatively there was a cystic cavity filled with blood products in association with thrombosed, calcified vessels as well as actively filling vessels. Histologically there were aggregated abnormal blood vessels with a dilated lumen and surrounded by brain parenchyma. Some of the vessel walls were thickened with fibrosis and some were arterialised with presence of elastin fibres. Potential mechanisms for the delayed haemorrhage are discussed.

Disconnection between the default mode network and medial temporal lobes in post-traumatic amnesia.

SEE BIGLER DOI101093/AWW277 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: Post-traumatic amnesia is very common immediately after traumatic brain injury. It is characterized by a confused, agitated state and a pronounced inability to encode new memories and sustain attention. Clinically, post-traumatic amnesia is an important predictor of functional outcome. However, despite its prevalence and functional importance, the pathophysiology of post-traumatic amnesia is not understood. Memory processing relies on limbic structures such as the hippocampus, parahippocampus and parts of the cingulate cortex. These structures are connected within an intrinsic connectivity network, the default mode network. Interactions within the default mode network can be assessed using resting state functional magnetic resonance imaging, which can be acquired in confused patients unable to perform tasks in the scanner. Here we used this approach to test the hypothesis that the mnemonic symptoms of post-traumatic amnesia are caused by functional disconnection within the default mode network. We assessed whether the hippocampus and parahippocampus showed evidence of transient disconnection from cortical brain regions involved in memory processing. Nineteen patients with traumatic brain injury were classified into post-traumatic amnesia and traumatic brain injury control groups, based on their performance on a paired associates learning task. Cognitive function was also assessed with a detailed neuropsychological test battery. Functional interactions between brain regions were investigated using resting-state functional magnetic resonance imaging. Together with impairments in associative memory, patients in post-traumatic amnesia demonstrated impairments in information processing speed and spatial working memory. Patients in post-traumatic amnesia showed abnormal functional connectivity between the parahippocampal gyrus and posterior cingulate cortex. The strength of this functional connection correlated with both associative memory and information processing speed and normalized when these functions improved. We have previously shown abnormally high posterior cingulate cortex connectivity in the chronic phase after traumatic brain injury, and this abnormality was also observed in patients with post-traumatic amnesia. Patients with post-traumatic amnesia showed evidence of widespread traumatic axonal injury measured using diffusion magnetic resonance imaging. This change was more marked within the cingulum bundle, the tract connecting the parahippocampal gyrus to the posterior cingulate cortex. These findings provide novel insights into the pathophysiology of post-traumatic amnesia and evidence that memory impairment acutely after traumatic brain injury results from altered parahippocampal functional connectivity, perhaps secondary to the effects of axonal injury on white matter tracts connecting limbic structures involved in memory processing.