An open label trial of nemiralisib, an inhaled PI3 kinase delta inhibitor for the treatment of Activated PI3 kinase Delta Syndrome.

Activated PI3Kδ Syndrome (APDS) is a rare inherited inborn error of immunity caused by mutations that constitutively activate the p110 delta isoform of phosphoinositide 3-kinase (PI3Kδ), resulting in recurring pulmonary infections. Currently no licensed therapies are available. Here we report the results of an open-label trial in which five subjects were treated for 12 weeks with nemiralisib, an inhaled inhibitor of PI3Kδ, to determine safety, systemic exposure, together with lung and systemic biomarker profiles (Clinicaltrial.gov: NCT02593539). Induced sputum was captured to measure changes in phospholipids and inflammatory mediators, and blood samples were collected to assess pharmacokinetics of nemiralisib, and systemic biomarkers. Nemiralisib was shown to have an acceptable safety and tolerability profile, with cough being the most common adverse event, and no severe adverse events reported during the study. No meaningful changes in phosphatidylinositol (3,4,5)-trisphosphate (PIP3; the enzyme product of PI3Kδ) or downstream inflammatory markers in induced sputum, were observed following nemiralisib treatment. Similarly, there were no meaningful changes in blood inflammatory markers, or lymphocytes subsets. Systemic levels of nemiralisib were higher in subjects in this study compared to previous observations. While nemiralisib had an acceptable safety profile, there was no convincing evidence of target engagement in the lung following inhaled dosing and no downstream effects observed in either the lung or blood compartments. We speculate that this could be explained by nemiralisib not being retained in the lung for sufficient duration, suggested by the increased systemic exposure, perhaps due to pre-existing structural lung damage. In this study investigating a small number of subjects with APDS, nemiralisib appeared to be safe and well-tolerated. However, data from this study do not support the hypothesis that inhaled treatment with nemiralisib would benefit patients with APDS.

Synthesis of silver nanoclusters in colloidal scaffold for biolabeling and antimicrobial applications.

A robust method to prepare silver nanoclusters (AgNCs) inside a methacrylic acid-ethyl acrylate (MAA-EA) nanogel is proposed, where AgNCs were produced within the nanogel scaffold via UV-photoreduction. The impact of UV irradiation time on the formation of AgNCs and their application in biolabeling and antimicrobial properties were examined. The AgNCs formation is described by two stages; (1) Agn (n = 2-8) nanoclusters formation between 0 and 25 min, and (2) larger silver nanoparticles (AgNPs) formed via aggregation inside the nanogel. The antimicrobial performance depended on the size and concentration of silver ions (Ag+). A maximum inhibitory concentration (MIC) of 1.1 ppm was observed for antimicrobial test with yeast, and a MIC of 11 and 22 ppm was recorded for Escherichia. coli and Staphylococcus aureus respectively. Combining with the green illumination property of AgNCs (emitted at 525 nm) with dead yeast, it could be used for biolabeling. By tuning the size through photoirradiation, the nanogel templated AgNCs is a promising candidate for antimicrobial and biolabeling applications.

ColourSpot, a novel gamified tablet-based test for accurate diagnosis of color vision deficiency in young children.

There is a need for a straightforward, accessible and accurate pediatric test for color vision deficiency (CVD). We present and evaluate ColourSpot, a self-administered, gamified and color calibrated tablet-based app, which diagnoses CVD from age 4. Children tap colored targets with saturations that are altered adaptively along the three dichromatic confusion lines. Two cohorts (Total, N = 772; Discovery, N = 236; Validation, N = 536) of 4-7-year-old boys were screened using the Ishihara test for Unlettered Persons and the Neitz Test of Color Vision. ColourSpot was evaluated by testing any child who made an error on the Ishihara Unlettered test alongside a randomly selected control group who made no errors. Psychometric functions were fit to the data and "threshold ratios" were calculated as the ratio of tritan to protan or deutan thresholds. Based on the threshold ratios derived using an optimal fitting procedure that best categorized children in the discovery cohort, ColourSpot showed a sensitivity of 1.00 and a specificity of 0.97 for classifying CVD against the Ishihara Unlettered in the independent validation cohort. ColourSpot was also able to categorize individuals with ambiguous results on the Ishihara Unlettered. Compared to the Ishihara Unlettered, the Neitz Test generated an unacceptably high level of false positives. ColourSpot is an accurate test for CVD, which could be used by anyone to diagnose CVD in children from the start of their education. ColourSpot could also have a wider impact: its interface could be adapted for measuring other aspects of children's visual performance.

Exploring PI3Kδ Molecular Pathways in Stable COPD and Following an Acute Exacerbation, Two Randomized Controlled Trials.

Background: Inhibition of phosphoinositide 3-kinase δ (PI3Kδ) exerts corrective effects on the dysregulated migration characteristics of neutrophils isolated from patients with chronic obstructive pulmonary disease (COPD). Objective: To develop novel, induced sputum endpoints to demonstrate changes in neutrophil phenotype in the lung by administering nemiralisib, a potent and selective inhaled PI3Kδ inhibitor, to patients with stable COPD or patients with acute exacerbation (AE) of COPD. Methods: In two randomized, double-blind, placebo-controlled clinical trials patients with A) stable COPD (N=28, randomized 3:1) or B) AECOPD (N=44, randomized 1:1) received treatment with inhaled nemiralisib (1mg). Endpoints included induced sputum at various time points before and during treatment for the measurement of transcriptomics (primary endpoint), inflammatory mediators, functional respiratory imaging (FRI), and spirometry. Results: In stable COPD patients, the use of nemiralisib was associated with alterations in sputum neutrophil transcriptomics suggestive of an improvement in migration phenotype; however, the same nemiralisib-evoked effects were not observed in AECOPD. Inhibition of sputum inflammatory mediators was also observed in stable but not AECOPD patients. In contrast, a placebo-corrected improvement in forced expiratory volume in 1 sec of 136 mL (95% Credible Intervals -46, 315mL) with a probability that the true treatment ratio was >0% (Pr(θ>0)) of 93% was observed in AECOPD. However, FRI endpoints remained unchanged. Conclusion: We provide evidence for nemiralisib-evoked changes in neutrophil migration phenotype in stable COPD but not AECOPD, despite improving lung function in the latter group. We conclude that induced sputum can be used for measuring evidence of alteration of neutrophil phenotype in stable patients, and our study provides a data set of the sputum transcriptomic changes during recovery from AECOPD.

NMR Quantification of Halogen-Bonding Ability To Evaluate Catalyst Activity.

Quantification of halogen-bonding abilities is described for a series of benzimidazolium-, imidazolium- and bis(imidazolium) halogen-bond donors (XBDs) using 31P NMR spectroscopy. The measured Δδ(31P) values correlate with calculated activation free energy ΔG‡ and catalytic activity for a Friedel-Crafts indole addition. This rapid method also serves as a sensitive indicator for Brønsted acid impurities.

Advanced Image-Guided Procedures for Painful Spine.

In addition to basic image-guided injections, there are many advanced procedures to address the challenges of spine pain. Patients with debilitating symptoms are offered relief, a shorter recovery period, and fewer potential complications. Pain arises from numerous sites along the spine, presenting as spine pain or radiculopathy. This article is an overview of advanced techniques in this rapidly progressing field, including neuromodulation, radiofrequency thermocoagulation, discography, intradiscal thermocoagulation, and percutaneous image-guided lumbar decompression; and it highlights etiologic factors and their relationship to therapeutic technique and clinical evidence.

Synthesis and Optoelectronic Properties of New Methoxy-Substituted Diketopyrrolopyrrole Polymers.

The introduction of functional groups with varying electron-donating/-withdrawing properties at the ß-position of diketopyrrolopyrrole (DPP) has been shown to affect the optoelectronic properties of the polymers. We report the synthesis of a new diketopyrrolopyrrole monomer wherein a strong electron-donating substituent, a methoxy group, was incorporated at the ß-position in an effort to modulate polymer properties. Homopolymers and co-polymers of the new ß-methoxy DPP and nonderivatized DPP were synthesized, and their properties were measured by cyclic voltammetry and UV-vis-near-infrared. Density functional theory computations also were employed to predict the degree of planarity of ß-methoxy oligomers to probe the significance of the newly introduced S-O conformational lock. The combined experimental and computational results showed a reduction in the gap between highest occupied molecular orbital/lowest unoccupied molecular orbital levels, a redshift toward the near-infrared region, and an increased planarity in the ß-methoxy polymers.

Implementing an Opioid Risk Reduction Program in the Acute Comprehensive Inpatient Rehabilitation Setting.

OBJECTIVE: To describe the implementation and evaluation of an interdisciplinary quality improvement (QI) project to increase prescription of take-home naloxone (THN) to reduce risks associated with opioids for patients admitted to an acute inpatient rehabilitation unit. DESIGN: Prospective cohort quality improvement project. SETTING: Eighteen-bed acute comprehensive inpatient rehabilitation (ACIR) unit at a large academic institution. PARTICIPANTS: Patients admitted to ACIR between December 2015-November 2016 (N=788). INTERVENTIONS: An interdisciplinary QI model comprised of planning, education, implementation, and maintenance was used to implement a THN and opioid risk-reduction program involving provider and patient education. Analyses consisted of comparisons between baseline, early, and late phases of the project. MAIN OUTCOME MEASURES: (1) The proportion of eligible patients who received a prescription for naloxone upon discharge from ACIR; (2) the proportion of patients originally admitted to ACIR on opioids that were weaned off upon discharge. RESULTS: The adjusted odds of eligible patients being discharged from ACIR with a naloxone prescription during the late QI period were 7 (95% confidence interval [CI]: 3-21) times higher than during the early QI period (late QI period: 43%, 95% CI: 25%-63%; early QI period: 10%, 95% CI: 3%-28%; P<.001). For patients admitted on opioids, the adjusted odds of being weaned off opioids during the late QI period were 10 (95% CI: 4-25) times higher than during baseline (late QI period: 29%, 95% CI: 17%-45%; baseline: 4%, 95% CI: 1%-10%; P<.001). CONCLUSIONS: Implementation of a THN and opioid risk reduction QI project in an inpatient rehabilitation setting led to significantly more eligible patients receiving naloxone and more patients weaned off schedule II opioids.

Inciting Events Associated With Lumbar Facet Joint Pain.

BACKGROUND: Low back pain is the leading cause of years lost to disability with approximately 15%-25% of the chronic back pain population suffering from lumbar facet arthropathy. No large-scale study has sought to systematically identify inciting events for lumbar facet arthropathy. The aim of this study is to quantify the proportion of individuals with lumbar facetogenic pain who report a specific precipitating event(s) and to determine if there is a correlation between these events and treatment outcome. METHODS: Institutional electronic medical records were searched based on the current procedural terminology (CPT) codes representing lumbar facet joint radiofrequency ablation for procedures performed between January 2007 and December 2015. All patients had obtained ≥50% pain relief based on 6-hour pain diaries after 1 or more diagnostic facet blocks. A positive outcome was defined as ≥50% pain relief sustained for longer than 3-month after procedure, without additional procedural interventions. RESULTS: One thousand sixty-nine people were included in analysis. In the 52% of individuals who described an inciting event, the most commonly reported causes were falls (11%), motor vehicle collisions (11%), sports-related injuries (11%, of which weightlifting accounted for 62%), nonspine postsurgical injuries (2%), and "other" (17%). Six hundred seventeen (57.7%) individuals experienced ≥50% pain relief sustained for >3 months. Patients whose pain was preceded by an inciting event were more likely to have a positive outcome than those who could not recall a specific precipitating factor (odds ratio, 1.5; confidence interval, 1.02-2.1, P = .01). Another factor associated with outcome was shorter duration of pain (8.1 ± 9.2 vs 9.7 ± 10.1 years, P = .02), with an observed modifier effect of age on outcomes. For a 1-year increase in age, there was a 10% increase in the odds of a positive response. CONCLUSIONS: Inciting events are common in patients diagnosed with lumbar facetogenic pain and may be associated with a positive outcome.

Neurobehavioral evidence of interoceptive sensitivity in early infancy.

Interoception, the sensitivity to visceral sensations, plays an important role in homeostasis and guiding motivated behaviour. It is also considered to be fundamental to self-awareness. Despite its importance, the developmental origins of interoceptive sensitivity remain unexplored. We here provide the first evidence for implicit, flexible interoceptive sensitivity in 5 month old infants using a novel behavioural measure, coupled with an established cortical index of interoceptive processing. These findings have important implications for the understanding of the early developmental stages of self-awareness, self-regulation and socio-emotional abilities.

Bilateral Intra-Articular Radiofrequency Ablation for Cervicogenic Headache.

Introduction. Cervicogenic headache is characterized by unilateral neck or face pain referred from various structures such as the cervical joints and intervertebral disks. A recent study of patients with cervical pain showed significant pain relief after cervical medial branch neurotomy but excluded patients with C1-2 joint pain. It remains unclear whether targeting this joint has potential for symptomatic relief. To address this issue, we present a case report of C1-2 joint ablation with positive outcomes. Case Presentation. A 27-year-old female presented with worsening cervicogenic headache. Her pain was 9/10 by visual analog scale (VAS) and described as cramping and aching. Pain was localized suboccipitally with radiation to her jaw and posterior neck, worse on the right. Associated symptoms included clicking of her temporomandibular joint, neck stiffness, bilateral headaches with periorbital pain, numbness, and tingling. History, physical exam, and diagnostic studies indicated localization to the C1-2 joint with 80% decrease in pain after C1-2 diagnostic blocks. She underwent bilateral intra-articular radiofrequency ablation of the C1-C2 joint. Follow-up at 2, 4, 8, and 12 weeks showed improved function and pain relief with peak results at 12 weeks. Conclusion. Clinicians may consider C1-C2 joint ablation as a viable long-term treatment option for cervicogenic headaches.

Connecting the Dots: A Comparative Global Multi-Institutional Study of Prohibitive Factors Affecting Cancer Pain Management.

Objective: The goal of this study was to elucidate the attitudes, beliefs, and barriers interfering with cancer pain management, the degree of barrier interference with trainees' care of patients, and the relationships among prohibitive factors to pain management for physicians in a low­middle-income countries (LMICs) vs high-income countries (HICs). Design and Setting: A multi-institutional cross-sectional survey of physicians in specialties with a focus in pain management training was performed. All surveys were completed anonymously from July 1, 2015, to November 30, 2015. Subjects: One hundred and twenty physicians participated in the survey. Methods: Surveys were based on prior questionnaires published in the literature. Descriptive statistics were calculated, and chi-square (ℵ2) analysis, Fisher's exact test, and Spearman rank correlation analyses were performed. Results: Compared with their peers in HICs, physicians in LMICs reported less experience with cancer pain management despite seeing more cancer patients with advanced disease (41% vs 15.2%, p < 0.05). Some barriers were common to both environments, but a few were unique to each setting. Organized by percentage of severity of interference, cultural values/beliefs about pain (84% vs 76%) and lack of training and expertise (87% vs 78%) were significantly more prohibitive for physicians in LMICs than those in HICs; p < 0.05. Conclusion: There are significant differences in perceived barriers and degree of prohibitive factors to cancer pain management among trainee physicians in low- vs high-resource environments. Understanding these differences may spur further collaboration in the design of contextually relevant solutions, which could potentially help improve the adequacy of cancer pain management

Forming tool use representations: a neurophysiological investigation into tool exposure.

Prior work has identified a common left parietofrontal network for storage of tool-related information for various tasks. How these representations become established within this network on the basis of different modes of exposure is unclear. Here, healthy subjects engaged in physical practice (direct exposure) with familiar and unfamiliar tools. A separate group of subjects engaged in video-based observation (indirect exposure) of the same tools to understand how these learning strategies create representations. To assess neural mechanisms engaged for pantomime after different modes of exposure, a pantomime task was performed for both tools while recording neural activation with high-density EEG. Motor planning-related neural activation was evaluated using beta band (13-22 Hz) event-related desynchronization. Hemispheric dominance was assessed, and activation maps were generated to understand topography of activations. Comparison of conditions (effects of tool familiarity and tool exposure) was performed with standardized low-resolution brain electromagnetic tomography. Novel tool pantomime following direct exposure resulted in greater activations of bilateral parietofrontal regions. Activations following indirect training varied by tool familiarity; pantomime of the familiar tool showed greater activations in left parietofrontal areas, whereas the novel tool showed greater activations at right temporoparieto-occipital areas. These findings have relevance to the mechanisms for understanding motor-related behaviors involved in new tools that we have little or no experience with and can extend into advancing theories of tool use motor learning.

Quality of information accompanying on-line marketing of home diagnostic tests.

OBJECTIVE: To assess the quality of information provided to consumers by websites marketing medical home diagnostic tests. DESIGN: A cross-sectional analysis of a database developed from searching targeted websites. SETTING: Data sources were websites written in English which marketed medical home diagnostic tests. MAIN OUTCOME MEASURES: A meta-search engine was used to identify the first 20 citations for each type of home diagnostic medical test. Relevant websites limited to those written in English were reviewed independently and in triplicate, with disputes resolved by two further reviewers. Information on the quality of these sites was extracted using a pre-piloted performer. RESULTS: 168 websites were suitable for inclusion in the review. The quality of these sites showed marked variation. Only 24 of 168 (14.2%) complied with at least three-quarters of the quality items and just over half (95 of 168, 56.5%) reported official approval or certification of the test. Information on accuracy of the test marketed was reported by 87 of 168 (51.7%) websites, with 15 of 168 (8.9%) providing a scientific reference. Instructions for use of the product were found in 97 of 168 (57.9%). However, the course of action to be taken after obtaining the test result was stated in only 63 of 168 (37.5%) for a positive result and 43 of 168 (25.5%) for a negative result. CONCLUSIONS: The quality of information posted on commercial websites marketing home tests online is unsatisfactory and potentially misleading for consumers.

The aminoguanidine carboxylate BVT.12777 activates ATP-sensitive K+ channels in the rat insulinoma cell line, CRI-G1.

BACKGROUND: 3-guanidinopropionic acid derivatives reduce body weight in obese, diabetic mice. We have assessed whether one of these analogues, the aminoguanidine carboxylate BVT.12777, opens KATP channels in rat insulinoma cells, by the same mechanism as leptin. RESULTS: BVT.12777 hyperpolarized CRI-G1 rat insulinoma cells by activation of KATP channels. In contrast, BVT.12777 did not activate heterologously expressed pancreatic beta-cell KATP subunits directly. Although BVT.12777 stimulated phosphorylation of MAPK and STAT3, there was no effect on enzymes downstream of PI3K. Activation of KATP in CRI-G1 cells by BVT.12777 was not dependent on MAPK or PI3K activity. Confocal imaging showed that BVT.12777 induced a re-organization of cellular actin. Furthermore, the activation of KATP by BVT.12777 in CRI-G1 cells was demonstrated to be dependent on actin cytoskeletal dynamics, similar to that observed for leptin. CONCLUSIONS: This study shows that BVT.12777, like leptin, activates KATP channels in insulinoma cells. Unlike leptin, BVT.12777 activates KATP channels in a PI3K-independent manner, but, like leptin, channel activation is dependent on actin cytoskeleton remodelling. Thus, BVT.12777 appears to act as a leptin mimetic, at least with respect to KATP channel activation, and may bypass up-stream signalling components of the leptin pathway.

Antibodies in myasthenia gravis and related disorders.

Acetylcholine receptor (AChR) antibodies are present in around 85% of patients with myasthenia gravis (MG) as measured by the conventional radioimmunoprecipitation assay. Antibodies that block the fetal form of the AChR are occasionally present in mothers who develop MG after pregnancy, especially in those whose babies are born with arthrogryposis multiplex congenita. The antibodies cross the placenta and block neuromuscular transmission, leading to joint deformities and often stillbirth. In these mothers, antibodies made in the thymus are mainly specific for fetal AChR and show restricted germline origins, suggesting a highly mutated clonal response; subsequent spread to involve adult AChR could explain development of maternal MG in those cases who first present after pregnancy. In the 15% of "seronegative" MG patients without AChR antibodies (SNMG), there are serum factors that increase AChR phosphorylation and reduce AChR function, probably acting via a different membrane receptor. These factors are not IgG and could be IgM or even non-Ig serum proteins. In a proportion of SNMG patients, however, IgG antibodies to the muscle-specific kinase, MuSK, are present. These antibodies are not found in AChR antibody-positive MG and are predominantly IgG4. MuSK antibody positivity appears to be associated with more severe bulbar disease that can be difficult to treat effectively.

Dynamic imaging of free cytosolic ATP concentration during fuel sensing by rat hypothalamic neurones: evidence for ATP-independent control of ATP-sensitive K(+) channels.

Glucose-responsive (GR) neurons from hypothalamic nuclei are implicated in the regulation of feeding and satiety. To determine the role of intracellular ATP in the closure of ATP-sensitive K(+) (K(ATP)) channels in these cells and associated glia, the cytosolic ATP concentration ([ATP](c)) was monitored in vivo using adenoviral-driven expression of recombinant targeted luciferases and bioluminescence imaging. Arguing against a role for ATP in the closure of K(ATP) channels in GR neurons, glucose (3 or 15 mM) caused no detectable increase in [ATP](c), monitored with cytosolic luciferase, and only a small decrease in the concentration of ATP immediately beneath the plasma membrane, monitored with a SNAP25-luciferase fusion protein. In contrast to hypothalamic neurons, hypothalamic glia responded to glucose (3 and 15 mM) with a significant increase in [ATP](c). Both neurons and glia from the cerebellum, a glucose-unresponsive region of the brain, responded robustly to 3 or 15 mM glucose with increases in [ATP](c). Further implicating an ATP-independent mechanism of K(ATP) channel closure in hypothalamic neurons, removal of extracellular glucose (10 mM) suppressed the electrical activity of GR neurons in the presence of a fixed, high concentration (3 mM) of intracellular ATP. Neurons from both brain regions responded to 5 mM lactate (but not pyruvate) with an oligomycin-sensitive increase in [ATP](c). High levels of the plasma membrane lactate-monocarboxylate transporter, MCT1, were found in both cell types, and exogenous lactate efficiently closed K(ATP) channels in GR neurons. These data suggest that (1) ATP-independent intracellular signalling mechanisms lead to the stimulation of hypothalamic neurons by glucose, and (2) these effects may be potentiated in vivo by the release of lactate from neighbouring glial cells.