Developing an Imaging Biomarker to Detect Aberrant Brain Connectivity in Individual Patients

Resting state functional MRI (rsfMRI) has been proven to be a valuable tool in clinical applications such as pre-surgical mapping, but there is not yet a functional and usable algorithm that can be used by physicians in a clinical setting to evaluate an individual patient for diseases and aberrant brain connectivity. If a physician wants to evaluate a patient in this way, the rsfMRI data must be looked at “by hand,” i.e. the physician must manually evaluate the data and identify the functional ICN’s and whether they are normal or aberrant. An algorithm that would automate this process and supplement the physician’s evaluation would be very valuable and would decrease the time needed while increasing accuracy of the data analysis. The algorithm could be used in clinical applications as discussed, or academic and research applications to explore the neural basis of neurological disorders and deficits (epilepsy, etc). rsfMRI data is significant for the proposed solution as it provides maps of functional brain connectivity within functionally specific neural networks, and those connectivity maps can help identify normal and abnormal brain conditions. Whether an ICA approach based on standard networks or an ROI seed based approach which utilizes temporal correlation is used, the end goal of this research is to develop and refine an imaging biomarker for aberrant brain connectivity. The biomarker algorithm should be able to detect the two main types of aberrant connectivity: increased (when abnormal brain connections are present) and decreased (when normal brain connections are missing). The algorithm should then correlate the connectivity patterns to a normative reference data set and create prioritized classification matches to that reference data set. This will allow identification of the aberrant connectivity patterns. Data from the Human Connectome Project (HCP) will be used to create the normative reference data set. The algorithm will finally be verified using simulated test data and test statistics

Congenital Insensitivity to Pain: Novel SCN9A Missense and In-Frame Deletion Mutations

SCN9A encodes the voltage-gated sodium channel Nav1.7, a protein highly expressed in pain-sensing neurons. Mutations in SCN9A cause three human pain disorders: bi-allelic loss of function mutations result in Channelopathy-associated Insensitivity to Pain (CIP), whereas activating mutations cause severe episodic pain in Paroxysmal Extreme Pain Disorder (PEPD) and Primary Erythermalgia (PE). To date, all mutations in SCN9A that cause a complete inability to experience pain are protein truncating and presumably lead to no protein being produced. Here, we describe the identification and functional characterization of two novel non-truncating mutations in families with CIP: a homozygously-inherited missense mutation found in a consanguineous Israeli Bedouin family (Nav1.7-R896Q) and a five amino acid in-frame deletion found in a sporadic compound heterozygote (Nav1.7-ΔR1370-L1374). Both of these mutations map to the pore region of the Nav1.7 sodium channel. Using transient transfection of PC12 cells we found a significant reduction in membrane localization of the mutant protein compared to the wild type. Furthermore, voltage clamp experiments of mutant-transfected HEK293 cells show a complete loss of function of the sodium channel, consistent with the absence of pain phenotype. In summary, this study has identified critical amino acids needed for the normal subcellular localization and function of Nav1.7. © 2010 Wiley-Liss, Inc

The added value of H-2 antagonists in premedication regimens during paclitaxel treatment

BACKGROUND: Ranitidine, a histamine 2 blocker, is the standard of care to prevent hypersensitivity reactions (HSRs) caused by paclitaxel infusion. However, the added value of ranitidine in this premedication regimen is controversial. Therefore, we compared the incidence of HSRs during paclitaxel treatment between a standard regimen including ranitidine and a regimen without ranitidine. METHODS: This prospective, pre-post interventional, non-inferiority study compared the standard premedication regimen (N = 183) with dexamethasone, clemastine and ranitidine with a premedication regimen without ranitidine (N = 183). The primary outcome was the incidence of HSR grade >= 3. Non-inferiority was determined by checking whether the upper bound of the twosided 90% confidence interval (CI) for the difference in HSR rates excluded the +6% non-inferiority margin. RESULTS: In both the pre-intervention (with ranitidine) and post-intervention (without ranitidine) group 183 patients were included. The incidence of HSR grade >= 3 was 4.4% (N = 8) in the pre-intervention group and 1.6% (N = 3) in the post-intervention group: difference -2.7% (90% CI: -6.2 to 0.1). CONCLUSIONS: As the upper boundary of the 90% CI does not exceed the predefined non-inferiority margin of +6%, it can be concluded that a premedication regimen without ranitidine is non-inferior to a premedication regimen with ranitidine

Accurate MS-based Rab10 phosphorylation stoichiometry determination as readout for LRRK2 activity in Parkinson's disease

Pathogenic mutations in the Leucine-rich repeat kinase 2 (LRRK2) increase its activity leading to increased phosphorylation of Rab proteins. Here we introduce a sensitive and accurate assay to measure increased phospho Rab levels using synthetic stable isotope-labeled analogues for both phosphorylated and non-phosphorylated tryptic peptides surrounding Rab10-Thr73. Compared to healthy controls, carriers of mutated LRRK2 had 1.9-fold and those with VPS35 mutation 3.7-fold increased pRab10 levels in their neutrophils. Our generic MS-based assay helps to stratify PD patient and determine LRRK2 inhibitor efficiency in clinical trials. Pathogenic mutations in the Leucine-rich repeat kinase 2 (LRRK2) are the predominant genetic cause of Parkinson's disease (PD). They increase its activity, resulting in augmented Rab10-Thr73 phosphorylation and conversely, LRRK2 inhibition decreases pRab10 levels. Currently, there is no assay to quantify pRab10 levels for drug target engagement or patient stratification. To meet this challenge, we developed an high accuracy and sensitivity targeted mass spectrometry (MS)-based assay for determining Rab10-Thr73 phosphorylation stoichiometry in human samples. It uses synthetic stable isotope-labeled (SIL) analogues for both phosphorylated and nonphosphorylated tryptic peptides surrounding Rab10-Thr73 to directly derive the percentage of Rab10 phosphorylation from attomole amounts of the endogenous phosphopeptide. The SIL and the endogenous phosphopeptides are separately admitted into an Orbitrap analyzer with the appropriate injection times. We test the reproducibility of our assay by determining Rab10-Thr73 phosphorylation stoichiometry in neutrophils of LRRK2 mutation carriers before and after LRRK2 inhibition. Compared with healthy controls, the PD predisposing mutation carriers LRRK2 G2019S and VPS35 D620N display 1.9-fold and 3.7-fold increased pRab10 levels, respectively. Our generic MS-based assay further establishes the relevance of pRab10 as a prognostic PD marker and is a powerful tool for determining LRRK2 inhibitor efficacy and for stratifying PD patients for LRRK2 inhibitor treatment.Acknowledgments: We thank Sabine Suppmann, Leopold Urich, Stephan Uebel, Stefan Pettera, Martin Spitaler, Nagarjuna Nagaraj, Victoria Sanchez and Antonio Piras from the MPIB Biochemistry Core Facility

System-level policies on appropriate opioid use, a multi-stakeholder consensus

Background:  This consensus statement was developed because there are concerns about the appropriate use of opioids for acute pain management, with opposing views in the literature. Consensus statement on policies for system-level interventions may help inform organisations such as management structures, government agencies and funding bodies. Methods:  We conducted a multi-stakeholder survey using a modified Delphi methodology focusing on policies, at the system level, rather than at the prescriber or patient level. We aimed to provide consensus statements for current developments and priorities for future developments. Results:  Twenty-five experts from a variety of fields with experience in acute pain management were invited to join a review panel, of whom 23 completed a modified Delphi survey of policies designed to improve the safety and quality of opioids prescribing for acute pain in the secondary care setting. Strong agreement, defined as consistent among> 75% of panellists, was observed for ten statements. Conclusions:  Using a modified Delphi study, we found agreement among a multidisciplinary panel, including patient representation, on prioritisation of policies for system-level interventions, to improve governance, pain management, patient/consumers care, safety and engagement.Publisher PDFPeer reviewe

Pressure injury and risk in the inpatient paediatric and neonatal populations: a single centre point-prevalence study

Introduction: Prevention and management of pressure injury is a key nurse-sensitive quality indicator. From clinical insights, pressure injury effects hospitalised neonates and children, however it is unclear how prevalent this is. The aim of this study was to quantify prevalence of pressure injury, assess skin integrity risk level, and quantify preventive interventions in both neonatal and child inpatient populations at a large children’s hospital in the UK. Methods: A cross-sectional study was undertaken, assessing the skin integrity of all children allocated to a paediatric or neonatal bed in June/July 2020. A data collection tool was adapted from two established pressure ulcer point prevalence surveys (EUPAP and Medstrom pre-prevalence survey). Risk assessment was performed using the Braden QD scale.Results: Eighty-eight participants were included, with median age of 0.85 years [range 0-17.5 years), with 32 (36%) of participants being preterm. Median length of hospital stay was 11 days [range 0 – 174 days]. Pressure ulcer prevalence was 3.4%. The majority of participants had at least two medical devices, with 16 (18.2%) having more than four. Having a medical device was associated with increased risk score of developing pressure injury (odds ratio [OR] 0.03, 95% Confidence Interval [CI] 0.01 – 0.05, p = 0.02). Most children (39 (44%)) were reported not having proposed preventive measures in place aligned to their risk assessment. However, for those that did , 2 to 4 hourly repositioning was associated with a risk reduction on pressure damage (OR 0.13, 95% CI 0.03 – 0.23, p = 0.01).Conclusion: Overall, we found a low prevalence of pressure injury across preterm infants, children and young people at a tertiary children’s hospital. Accurate risk assessment as well as availability and implementation of preventive interventions are a priority for healthcare institutes to avoid pressure injury