Federating distributed clinical data for the prediction of adverse hypotensive events

The ability to predict adverse hypotensive events, where a patient's arterial blood pressure drops to abnormally low (and dangerous) levels, would be of major benefit to the fields of primary and secondary health care, and especially to the traumatic brain injury domain. A wealth of data exist in health care systems providing information on the major health indicators of patients in hospitals (blood pressure, temperature, heart rate, etc.). It is believed that if enough of these data could be drawn together and analysed in a systematic way, then a system could be built that will trigger an alarm predicting the onset of a hypotensive event over a useful time scale, e.g. half an hour in advance. In such circumstances, avoidance measures can be taken to prevent such events arising. This is the basis for the Avert-IT project (http://www.avert-it.org), a collaborative EU-funded project involving the construction of a hypotension alarm system exploiting Bayesian neural networks using techniques of data federation to bring together the relevant information for study and system development

Functional loss of IKBE leads to NF-KB deregulation in aggressive chronic lymphocytic leukemia

NF-?B is constitutively activated in chronic lymphocytic leukemia (CLL); however, the implicated molecular mechanisms remain largely unknown. Thus, we performed targeted deep sequencing of 18 core complex genes within the NF-?B pathway in a discovery and validation CLL cohort totaling 315 cases. The most frequently mutated gene was NFKBIE (21/315 cases; 7%), which encodes I?B?, a negative regulator of NF-?B in normal B cells. Strikingly, 13 of these cases carried an identical 4-bp frameshift deletion, resulting in a truncated protein. Screening of an additional 377 CLL cases revealed that NFKBIE aberrations predominated in poor-prognostic patients and were associated with inferior outcome. Minor subclones and/or clonal evolution were also observed, thus potentially linking this recurrent event to disease progression. Compared with wild-type patients, NFKBIE-deleted cases showed reduced I?B? protein levels and decreased p65 inhibition, along with increased phosphorylation and nuclear translocation of p65. Considering the central role of B cell receptor (BcR) signaling in CLL pathobiology, it is notable that I?B? loss was enriched in aggressive cases with distinctive stereotyped BcR, likely contributing to their poor prognosis, and leading to an altered response to BcR inhibitors. Because NFKBIE deletions were observed in several other B cell lymphomas, our findings suggest a novel common mechanism of NF-?B deregulation during lymphomagenesis. <br/

Consensus statement from the 2014 International Microdialysis Forum.

Microdialysis enables the chemistry of the extracellular interstitial space to be monitored. Use of this technique in patients with acute brain injury has increased our understanding of the pathophysiology of several acute neurological disorders. In 2004, a consensus document on the clinical application of cerebral microdialysis was published. Since then, there have been significant advances in the clinical use of microdialysis in neurocritical care. The objective of this review is to report on the International Microdialysis Forum held in Cambridge, UK, in April 2014 and to produce a revised and updated consensus statement about its clinical use including technique, data interpretation, relationship with outcome, role in guiding therapy in neurocritical care and research applications.We gratefully acknowledge financial support for participants as follows: P.J.H. - National Institute for Health Research (NIHR) Professorship and the NIHR Biomedical Research Centre, Cambridge; I.J. – Medical Research Council (G1002277 ID 98489); A. H. - Medical Research Council, Royal College of Surgeons of England; K.L.H.C. - NIHR Biomedical Research Centre, Cambridge (Neuroscience Theme; Brain Injury and Repair Theme); M.G.B. - Wellcome Trust Dept Health Healthcare Innovation Challenge Fund (HICF-0510-080); L. H. - The Swedish Research Council, VINNOVA and Uppsala Berzelii Technology Centre for Neurodiagnostics; S. M. - Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico; D.K.M. - NIHR Senior Investigator Award to D.K.M., NIHR Cambridge Biomedical Research Centre (Neuroscience Theme), FP7 Program of the European Union; M. O. - Swiss National Science Foundation and the Novartis Foundation for Biomedical Research; J.S. - Fondo de Investigación Sanitaria (Instituto de Salud Carlos III) (PI11/00700) co-financed by the European Regional Development; M.S. – NIHR University College London Hospitals Biomedical Research Centre; N. S. - Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico.This is the final version of the article. It first appeared from Springer via http://dx.doi.org/10.1007/s00134-015-3930-

Serum concentrations of Thymidine kinase 1 measured using a novel antibody-based assay in patients with Hodgkin Lymphoma

Background: Thymidine kinase 1 (TK1) is an intracellular protein associated with DNA synthesis, expressed during the G1 phase and remained elevated through the M phase, with a potential as a biomarker for cell proliferation. In this study, we explore the possible use of TK1 in Hodgkin lymphoma (HL).Methods: Serum concentrations of TK1 (S-TK1) were measured in 46 newly diagnosed HL patients using prospectively collected biobanked serum samples. The samples were analyzed using a novel antibody-based TK1 immunosorbent assay (ELISA).Results: The concentrations of S-TK1 were elevated in HL patients compared with healthy controls (median 0.32 mu g/L vs. 0.24 mu g/L, P = 0.003). A further increase in S-TK1 was observed during the treatment. The S-TK1 concentrations were higher in patients with advanced stage disease, low B-Hb, elevated P-LD and in those with B-symptoms. A high ESR correlated with low S-TK1.Conclusions: The study results suggest that S-TK1, measured using a novel antibody-based assay, has the potential to be a biomarker in HL. However, while S-TK1 levels are elevated at baseline compared with healthy controls, a limited number of patients and comparatively short follow-up time render reliable -conclusions difficult

Cerebral Blood Flow Measurement in Healthy Children and Children Suffering Severe Traumatic Brain Injury—What Do We Know?

Traumatic brain injury is the leading cause of death in children. Children with severe TBI are in need of neurointensive care where the goal is to prevent secondary brain injury by avoiding secondary insults. Monitoring of cerebral blood flow (CBF) and autoregulation in the injured brain is crucial. However, there are limited studies performed in children to investigate this. Current studies report on age dependent increase in CBF with narrow age range. Low initial CBF following TBI has been correlated to poor outcome and may be more prevalent than hyperemia as previously suggested. Impaired cerebral pressure autoregulation is also detected and correlated with poor outcome but it remains to be elucidated if there is a causal relationship. Current studies are few and mainly based on small number of patients between the age of 0–18 years. Considering the changes of CBF and cerebral pressure autoregulation with increasing age, larger studies with more narrow age ranges and multimodality monitoring are required in order to generate data that can optimize the therapy and clinical management of children suffering TBI

International e-Delphi survey to define best practice in the reporting of intracranial pressure monitoring recording data.

INTRODUCTION: Intracranial pressure (ICP) monitoring is a very commonly performed neurosurgical procedure but there is a wide variation in how it is reported, hindering analysis of it. The current study sought to generate consensus on the reporting of ICP monitoring recording data. RESEARCH QUESTION: What should be included in an ICP monitoring report? MATERIAL AND METHODS: The exercise was completed via a modified eDelphi survey. An expert panel discussion was held from which themes were identified and used to produce a code to annotate the transcript of the discussion. Statements were generated for a further two rounds of electronic questionnaires distributed via the REDcap platform. A Likert scale was used to grade agreement with each statement in the survey. A statement was accepted if more than 70% agreement was achieved between respondents. Data was collated using Microsoft Excel and analysed using R. RESULTS: 149 relevant statements were identified from the transcript and categorised into recording parameters, waveform characteristics or reporting. A total of 22 statements were generated for the first round of the survey which was answered by 39 respondents. Following the electronic round of surveys consensus was achieved for all but one statement regarding the acceptability of automating ICP reporting. This was put forward to a second round after which 79% agreement was reached. DISCUSSION AND CONCLUSION: The themes and statements from this eDelphi can be used as a framework to allow the standardisation of the reporting of intracranial pressure monitoring data

Long-Term Follow-Up of the Response-Adjusted Therapy for Advanced Hodgkin Lymphoma Trial

Clinical trials frequently include multiple end points that mature at different times. The initial report, typically based on the primary end point, may be published when key planned co-primary or secondary analyses are not yet available. Clinical Trial Updates provide an opportunity to disseminate additional results from studies, published in JCO or elsewhere, for which the primary end point has already been reported.We analyzed long-term results of the response-adapted trial for adult patients with advanced-stage Hodgkin lymphoma. The aim was to confirm noninferiority of treatment de-escalation by omission of bleomycin from doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) for interim fluorodeoxyglucose positron emission tomography (iPET)-negative patients and assess efficacy and long-term safety for iPET-positive patients who underwent treatment intensification with escalated bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisolone (BEACOPP/BEACOPP14). The median follow-up is 7.3 years. For all patients, the 7-year progression-free survival (PFS) and overall survival (OS) are 78.2% (95% CI, 75.6 to 80.5) and 91.6% (95% CI, 89.7 to 93.2), respectively. The 1.3% difference in 3-year PFS (95% CI, -3.0 to 4.7) between ABVD and doxorubicin, vinblastine, and dacarbazine (AVD) now falls within the predefined noninferiority margin. Among 172 patients with positive iPET, the 7-year PFS was 65.9% (95% CI, 58.1 to 72.6) and the 7-year OS was 83.2% (95% CI, 76.2 to 88.3). The cumulative incidence of second malignancies at 7 years was 5.5% (95% CI, 4.0 to 7.5) for those receiving ABVD/AVD and 2.5% (95% CI, 0.8 to 7.7) for those escalated to BEACOPP. With extended follow-up, these results confirm noninferiority of treatment de-escalation after a negative iPET. Escalation with BEACOPP for iPET-positive patients is effective and safe, with no increase in second malignancies

Detailed genetic mapping of the von Hippel-Lindau disease tumour suppressor gene.

Von Hippel-Lindau (VHL) disease is an autosomal dominant inherited familial cancer syndrome characterised by a predisposition to the development of retinal, cerebellar, and spinal haemangioblastomas, renal cell carcinoma, and phaeochromocytoma. The gene for VHL disease has been mapped to chromosome 3p25-p26 and flanking markers identified. We report the detailed genetic mapping of the VHL disease locus in 38 families. Significant linkage was detected between VHL disease and D3S601 (Zmax = 18.86 at theta = 0.0, CI 0.0-0.025), D3S18 (Zmax = 11.42 at theta = 0.03, CI 0.005-0.08), RAF1 (Zmax = 11.02 at theta = 0.04, CI 0.007-0.01), and D3S1250 (Zmax = 4.73 at theta = 0.05, CI 0.005-0.15). Multipoint linkage analysis mapped the VHL disease locus between D3S1250 and D3S18 close to D3S601. There was no evidence of locus heterogeneity. This study has (1) confirmed the tight linkage between VHL disease and D3S601, (2) identified D3S1250 as the first marker telomeric to RAF1 which maps centromeric to the VHL disease gene, and (3) narrowed the target region for isolation of the VHL disease gene by positional cloning techniques to a 4 cM interval between D3S1250 and D3S18. These findings will improve the clinical management of families with VHL disease by improving the accuracy of presymptomatic diagnosis using linked DNA markers, and will enhance progress towards isolating the VHL disease gene

Cerebrovascular reserve in moyamoya disease: relation to cerebral blood flow, capillary dysfunction, oxygenation, and energy metabolism

BackgroundCerebral hemodynamics in moyamoya disease (MMD) is complex and needs further elucidation. The primary aim of the study was to determine the association of the cerebrovascular reserve (CVR) with cerebral blood flow (CBF) disturbances, oxygen extraction fraction (OEFmax), and energy metabolism (CMRO2max) in MMD, using arterial spin label magnetic resonance imaging (ASL-MRI) before and after acetazolamide administration.MethodsThirty-nine ASL-MRI scans with a concurrent acetazolamide challenge from 16 MMD patients at the Uppsala University Hospital, Sweden, 2016–2021, were retrospectively analyzed. CBF was assessed before and 5, 15, and 25 min after acetazolamide administration, and the maximal response CVRmax was used for further analyses. Dynamic susceptibility contrast (DSC) MRI was performed 30 min after acetazolamide injection, and the data were analyzed using the Cercare Medical Neurosuite to assess capillary transit time heterogeneity (CTTH; indicating microvascular function), OEFmax, and CMRO2max.ResultsIn the ACA territory, a lower CVRmax was associated with lower baseline CBF, higher CTTH, and higher OEFmax but not with CMRO2max in generalized estimating equation models. In the MCA territory, lower CVRmax was associated with lower baseline CBF and higher CMRO2max but not with CTTH and OEFmax..ConclusionAltogether, a compromised CVR in MMD patients reflected disturbances in macro-/microvascular blood flow, oxygenation, and CMRO2. ASL-MRI with acetazolamide challenge is a feasible and radiation-free alternative to positron emission tomography (PET) imaging in MMD