Τετάρτη 17 Οκτωβρίου 2018
Survival analysis of carboplatin added to an anthracycline/taxane-based neoadjuvant chemotherapy and HRD score as predictor of response – final results from GeparSixto
Abstract
Background
In the neoadjuvant GeparSixto study, adding carboplatin to taxane- and anthracycline-based chemotherapy improved pathological complete response (pCR) rates in patients with triple-negative breast cancer (TNBC). Here, we present survival data and the potential prognostic and predictive role of homologous recombination deficiency (HRD). Patients and Methods
Patients were randomized to paclitaxel plus non-pegylated liposomal doxorubicin (Myocet®) (PM) or PM plus carboplatin (PMCb). The secondary study endpoints disease-free survival (DFS) and overall survival (OS) were analyzed. Median follow-up was 47.3 months. HRD was among the exploratory analyses in GeparSixto and was successfully measured in FFPE tumor samples of 193/315 (61.3%) participants with TNBC. HR deficiency was defined as HRD score ≥42 and/or presence of tumor BRCA mutations (tmBRCA). Results
A significantly better DFS (hazard ratio 0.56, 95%CI 0.34-0.93; P=0.022) was observed in patients with TNBC when treated with PMCb. The improvement of OS with PMCb was not statistically significant. Additional carboplatin did not improve DFS or OS in patients with HER2-positive tumors.HR deficiency was detected in 136 (70.5%) of 193 triple-negative tumors, of which 82 (60.3%) showed high HRD score without tmBRCA. HR deficiency independently predicted pCR (ypT0 ypN0) (odds ratio (OR) 2.60, 95%CI 1.26-5.37, P=0.008). Adding carboplatin to PM significantly increased the pCR rate from 33.9% to 63.5% in HR deficient tumors (P=0.001), but only marginally in HR non-deficient tumors (from 20.0% to 29.6%, P=0.540; test for interaction P=0.327). pCR rates with carboplatin were also higher (63.2%) than without carboplatin (31.7%; OR 3.69, 1.46-9.37, P=0.005) in patients with high HRD score but no tmBRCA. DFS rates were improved with addition of carboplatin, both in HR non-deficient (hazard ratio 0.44, 0.17–1.17, P=0.086) and HR deficient tumors (hazard ratio 0.49, 0.23–1.04, P=0.059). Conclusions
The addition of carboplatin to neoadjuvant PM improved DFS significantly in TNBC. Long-term survival analyses support the neoadjuvant use of carboplatin in TNBC. HR deficiency in TNBC and HRD score in non-tmBRCA TNBC are predictors of response. HRD does not predict for carboplatin benefit.Interpretation of Time-to-event Outcomes in Randomized Trials: an online randomized experiment
Abstract
Background
Multiple features in the presentation of randomized controlled trial (RCT) results are known to influence comprehension and interpretation. We aimed to compare interpretation of cancer RCTs with time-to-event outcomes when the reported treatment effect measure is the hazard ratio (HR), difference in restricted mean survival times (RMSTD), or both (HR+RMSTD). We also assessed the prevalence of misinterpretation of the HR. Patients and methods
We performed a randomized experiment. We selected 15 cancer RCTs with statistically significant treatment effects for the primary outcome. We masked each abstract and created 3 versions reporting either the HR, RMSTD, or HR+RMSTD. We randomized corresponding authors of RCTs and medical residents and fellows to one of 15 abstracts and one of 3 versions. We asked how beneficial the experimental treatment was (0 to 10 Likert scale). All participants answered a multiple-choice question about interpretation of the HR. Participants were unaware of the study purpose. Results
We randomly allocated 160 participants to evaluate an abstract reporting the HR, 154 to the RMSTD, and 155 to both HR+RMSTD. The mean Likert score was statistically significantly lower in the RMSTD group as compared with the HR group (mean difference -0.8, 95% confidence interval, -1.3 to -0.4, p < 0.01) and as compared with the HR+RMSTD group (difference -0.6, -1.1 to -0.1, p = 0.05). In all, 47.2% (42.7% to 51.8%) of participants misinterpreted the HR, with 40% equating it with a reduction in absolute risk. Conclusion
Misinterpretation of the HR is common. Participants judged experimental treatments to be less beneficial when presented with RMSTD as compared with HR. We recommend that authors present RMST-based measures alongside the HR in reports of RCT results.Statistical challenges posed by uncontrolled master protocols: sensitivity analysis of the Vemurafenib study
Abstract
Within the evidentiary hierarchy of experimental inquiry, randomized trials are the gold standard. Oncology patients enter clinical studies with diverse lifestyles, treatment pathways, host tissue environments, and competing co-morbidities. Randomization attempts to balance prognostic characteristics among study arms, thereby enabling statistical inference of "average benefit" and attribution to the studied therapies. In contrast, interpretations of uncontrolled trials require additional scrutiny to attempt to place the findings in the context of external evidence. Counter-factual reasoning and speculation across trials may be obscured by the disproportionate enrollment of prognostic subpopulations which may be unknown from publications of trial reports. Recent modifications to the regulatory environment (Food and Drug Administration Safety and Innovation Act) have elevated the importance of non-comparative trials. Moreover, the emergence of recent innovations in precision medicine have yielded trial designs that partition potentially heterogeneous subpopulations into "statistically exchangeable" cohorts by histologies, or genetic alterations, further elevating the importance of single-cohort analyses. As patient cohorts become ever more refined into smaller targeted subsets, consumers of reports of uncontrolled trials should be further empowered with improvements in reporting practices that better describe the enrolled prognostic subpopulations and importantly their association with study endpoints. This article demonstrates the issue with a sensitivity analysis of the findings reported in a recent trial which was devised to evaluate the preliminary clinical efficacy of vemurafenib in BRAFV600 mutation–positive nonmelanoma cancers.Not Just For Cows Anymore: New Cottonseed Is Safe For People To Eat
Cottonseed is full of protein but toxic to humans and most animals. The USDA has approved a genetically engineered cotton with edible seeds. They could eventually feed chickens, fish — or even people.
(Image credit: Courtesy of Lacey Roberts/Texas A&M University)
Symptoms of premenstrual syndrome in female migraineurs with and without menstrual migraine
Menstrual migraine (MM) and premenstrual syndrome (PMS) are two conditions linked to specific phases of the menstrual cycle. The exact pathophysiological mechanisms are not fully understood, but both condition...
Epidemiology of Nickel Sensitivity: Retrospective Cross-Sectional Analysis of North American Contact Dermatitis Group (NACDG) Data 1994-2014
Detailed analyses of trends in nickel sensitivity in North America are lacking. Clinicians should be aware of a significant increase in nickel sensitivity over time (14.3% to 20.1% from 1994 to 2014) and significant increase in current clinical relevance of reactions over time (44.1% to 51.6% from 1994 to 2014).
Drug repurposing prediction for immune-mediated cutaneous diseases using a word-embedding based machine learning approach
Immune-mediated diseases affect >20% of the population and many autoimmune diseases affect the skin. Drug repurposing (aka repositioning) is a cost-effective approach for revealing drugs that can be used to treat diseases for which they are currently not prescribed. We implemented an efficient bioinformatics approach using "word embedding" to summarize drug information from >20 million articles, and applied machine learning to model the drug-disease relationship. We trained our drug repurposing approach separately on 9 cutaneous diseases (including psoriasis, atopic dermatitis and alopecia areata), as well as 8 other immune-mediated diseases, and obtained a mean AUROC of 0.93 in cross-validation.
Hippocampal-Evoked Feedforward Inhibition in the Nucleus Accumbens
The nucleus accumbens (NAc) is critical for motivated behavior and is rewired following exposure to drugs of abuse. Medium spiny neurons (MSNs) in the NAc express either D1 or D2 receptors and project to distinct downstream targets. Differential activation of these MSNs depends on both excitation from long-range inputs and inhibition via the local circuit. Assessing how long-range excitatory inputs engage inhibitory circuitry is therefore important for understanding NAc function. Here, we use slice electrophysiology and optogenetics to study ventral hippocampal (vHPC)-evoked feedforward inhibition in the NAc of male and female mice. We find that vHPC-evoked excitation is stronger at D1+ than D1– MSNs, whereas inhibition is unbiased at the two cell types. vHPC inputs contact both parvalbumin-positive (PV+) and somatostatin-positive (SOM+) interneurons, but PV+ cells are preferentially activated. Moreover, suppressing PV+ interneurons indicates they are primarily responsible for vHPC-evoked inhibition. Finally, repeated cocaine exposure alters the excitation of D1+ and D1– MSNs, without concomitant changes to inhibition, shifting the excitation/inhibition balance. Together, our results highlight the contributions of multiple interneuron populations to feedforward inhibition in the NAc. Moreover, they demonstrate that inhibition provides a stable backdrop on which drug-evoked changes to excitation occur within this circuit.
SIGNIFICANCE STATEMENT Given the importance of the nucleus accumbens (NAc) in reward learning and drug-seeking behaviors, it is critical to understand what controls the activity of cells in this region. While excitatory inputs to projection neurons in the NAc have been identified, it is unclear how the local inhibitory network becomes engaged. Here, we identify a sparse population of interneurons responsible for feedforward inhibition evoked by ventral hippocampal input and characterize their connections within the NAc. We also demonstrate that the balance of excitation and inhibition that projection neurons experience is altered by exposure to cocaine. Together, this work provides insight into the fundamental circuitry of this region as well as the effects of drugs of abuse.
Early Appearance and Spread of Fast Ripples in the Hippocampus in a Model of Cortical Traumatic Brain Injury
Fast ripples (FRs; activity of >250 Hz) have been considered as a biomarker of epileptic activity in the hippocampus and entorhinal cortex; it is thought that they signal the focus of seizure generation. Similar high-frequency network activity has been produced in vitro by changing extracellular medium composition, by using pro-epileptic substances, or by electrical stimulation. Here we study the propagation of these events between different subregions of the male rat hippocampus in a recently introduced experimental model of FRs in entorhinal cortex–hippocampal slices in vitro. By using a matrix of 4096 microelectrodes, the sites of initiation, propagation pathways, and spatiotemporal characteristics of activity patterns could be studied with unprecedented high resolution. To this end, we developed an analytic tool based on bidimensional current source density estimation, which delimits sinks and sources with a high precision and evaluates their trajectories using the concept of center of mass. With this methodology, we found that FRs can arise almost simultaneously at noncontiguous sites in the CA3-to-CA1 direction, underlying the spatial heterogeneity of epileptogenic foci, while continuous somatodendritic waves of activity develop. An unexpected, yet important propagation route is the propagation of activity from CA3 into the hilus and dentate gyrus. This pathway may cause reverberating activation of both regions, supporting sustained pathological network events and altered information processing in hippocampal networks.
SIGNIFICANCE STATEMENT Fast ripples (FRs) have been considered as a biomarker of epileptic activity and may signal the focus of seizure generation. In a model of traumatic brain injury in the rat, FRs appear in the hippocampus within a couple of hours after an extrahippocampal, cortical lesion. We analyzed the origin and dynamics of the FRs in the hippocampus using massive electrophysiological recordings, allowing an unprecedented high spatiotemporal resolution. We show that FRs originate in distinct and noncontiguous locations within the CA3 region and uncover, with high precision, the extent and dynamics of their current density. This activity propagates toward CA1 but also backpropagates to the hilus and the dentate gyrus, suggesting activation of defined microcircuits that can sustain recurrent excitation.
TOM1 Regulates Neuronal Accumulation of Amyloid-{beta} Oligomers by Fc{gamma}RIIb2 Variant in Alzheimer's Disease
Emerging evidences suggest that intraneuronal Aβ correlates with the onset of Alzheimer's disease (AD) and highly contributes to neurodegeneration. However, critical mediator responsible for Aβ uptake in AD pathology needs to be clarified. Here, we report that FcRIIb2, a variant of Fc-receptor IIb (FcRIIb), functions in neuronal uptake of pathogenic Aβ. Cellular accumulation of oligomeric Aβ1–42, not monomeric Aβ1–42 or oligomeric Aβ1–40, was blocked by Fcgr2b knock-out in neurons and partially in astrocytes. Aβ1–42 internalization was FcRIIb2 di-leucine motif-dependent and attenuated by TOM1, a FcRIIb2-binding protein that repressed the receptor recycling. TOM1 expression was downregulated in the hippocampus of male 3xTg-AD mice and AD patients, and regulated by miR-126-3p in neuronal cells after exposure to Aβ1–42. In addition, memory impairments in male 3xTg-AD mice were rescued by the lentiviral administration of TOM1 gene. Augmented Aβ uptake into lysosome caused its accumulation in cytoplasm and mitochondria. Moreover, neuronal accumulation of Aβ in both sexes of 3xTg-AD mice and memory deficits in male 3xTg-AD mice were ameliorated by forebrain-specific expression of Aβ-uptake-defective Fcgr2b mutant. Our findings suggest that FcRIIb2 is essential for neuropathic uptake of Aβ in AD.
SIGNIFICANCE STATEMENT Accumulating evidences suggest that intraneuronal Aβ is found in the early step of AD brain and is implicated in the pathogenesis of AD. However, the critical mediator involved in these processes is uncertain. Here, we describe that the FcRIIb2 variant is responsible for both neuronal uptake and intraneuronal distribution of pathogenic Aβ linked to memory deficits in AD mice, showing a pathologic significance of the internalized Aβ. Further, Aβ internalization is attenuated by TOM1, a novel FcRIIb2-binding protein. Together, we provide a molecular mechanism responsible for neuronal uptake of pathogenic Aβ found in AD.
Dorsal BNST {alpha}2A-Adrenergic Receptors Produce HCN-Dependent Excitatory Actions That Initiate Anxiogenic Behaviors
Stress is a precipitating agent in neuropsychiatric disease and initiates relapse to drug-seeking behavior in addicted patients. Targeting the stress system in protracted abstinence from drugs of abuse with anxiolytics may be an effective treatment modality for substance use disorders. α2A-adrenergic receptors (α2A-ARs) in extended amygdala structures play key roles in dampening stress responses. Contrary to early thinking, α2A-ARs are expressed at non-noradrenergic sites in the brain. These non-noradrenergic α2A-ARs play important roles in stress responses, but their cellular mechanisms of action are unclear. In humans, the α2A-AR agonist guanfacine reduces overall craving and uncouples craving from stress, yet minimally affects relapse, potentially due to competing actions in the brain. Here, we show that heteroceptor α2A-ARs postsynaptically enhance dorsal bed nucleus of the stria terminalis (dBNST) neuronal activity in mice of both sexes. This effect is mediated by hyperpolarization-activated cyclic nucleotide-gated cation channels because inhibition of these channels is necessary and sufficient for excitatory actions. Finally, this excitatory action is mimicked by clozapine-N-oxide activation of the Gi-coupled DREADD hM4Di in dBNST neurons and its activation elicits anxiety-like behavior in the elevated plus maze. Together, these data provide a framework for elucidating cell-specific actions of GPCR signaling and provide a potential mechanism whereby competing anxiogenic and anxiolytic actions of guanfacine may affect its clinical utility in the treatment of addiction.
SIGNIFICANCE STATEMENT Stress affects the development of neuropsychiatric disorders including anxiety and addiction. Guanfacine is an α2A-adrenergic receptor (α2A-AR) agonist with actions in the bed nucleus of the stria terminalis (BNST) that produces antidepressant actions and uncouples stress from reward-related behaviors. Here, we show that guanfacine increases dorsal BNST neuronal activity through actions at postsynaptic α2A-ARs via a mechanism that involves hyperpolarization-activated cyclic nucleotide gated cation channels. This action is mimicked by activation of the designer receptor hM4Di expressed in the BNST, which also induces anxiety-like behaviors. Together, these data suggest that postsynaptic α2A-ARs in BNST have excitatory actions on BNST neurons and that these actions can be phenocopied by the so-called "inhibitory" DREADDs, suggesting that care must be taken regarding interpretation of data obtained with these tools.
Control of Sleep Onset by Shal/Kv4 Channels in Drosophila Circadian Neurons
Sleep is highly conserved across animal species. Both wake- and sleep-promoting neurons are implicated in the regulation of wake–sleep transition at dusk in Drosophila. However, little is known about how they cooperate and whether they act via different mechanisms. Here, we demonstrated that in female Drosophila, sleep onset was specifically delayed by blocking the Shaker cognate L channels [Shal; also known as voltage-gated K+ channel 4 (Kv4)] in wake-promoting cells, including large ventral lateral neurons (l-LNvs) and pars intercerebralis (PI), but not in sleep-promoting dorsal neurons (DN1s). Delayed sleep onset was also observed in males by blocking Kv4 activity in wake-promoting neurons. Electrophysiological recordings show that Kv4 channels contribute A-type currents in LNvs and PI cells, but are much less conspicuous in DN1s. Interestingly, blocking Kv4 in wake-promoting neurons preferentially increased firing rates at dusk ~ZT13, when the resting membrane potentials and firing rates were at lower levels. Furthermore, pigment-dispersing factor (PDF) is essential for the regulation of sleep onset by Kv4 in l-LNvs, and downregulation of PDF receptor (PDFR) in PI neurons advanced sleep onset, indicating Kv4 controls sleep onset via regulating PDF/PDFR signaling in wake-promoting neurons. We propose that Kv4 acts as a sleep onset controller by suppressing membrane excitability in a clock-dependent manner to balance the wake–sleep transition at dusk. Our results have important implications for the understanding and treatment of sleep disorders such as insomnia.
SIGNIFICANCE STATEMENT The mechanisms by which our brains reversibly switch from waking to sleep state remain an unanswered and intriguing question in biological research. In this study, we identified that Shal/Kv4, a well known voltage-gated K+ channel, acts as a controller of wake–sleep transition at dusk in Drosophila circadian neurons. We find that interference of Kv4 function with a dominant-negative form (DNKv4) in subsets of circadian neurons specifically disrupts sleep onset at dusk, although Kv4 itself does not exhibit circadian oscillation. Kv4 preferentially downregulates neuronal firings at ZT9–ZT17, supporting that it plays an essential role in wake–sleep transition at dusk. Our findings may help understand and eventually treat sleep disorders such as insomnia.
Network Architecture Underlying Basal Autonomic Outflow: Evidence from Frontotemporal Dementia
The salience network is a distributed neural system that maintains homeostasis by regulating autonomic nervous system activity and social-emotional function. Here we examined how within-network connectivity relates to individual differences in human (including males and females) baseline parasympathetic and sympathetic nervous activity. We measured resting autonomic nervous system physiology in 24 healthy controls and 23 patients with behavioral variant frontotemporal dementia (bvFTD), a neurodegenerative disease characterized by baseline autonomic deficits. Participants also underwent structural and task-free fMRI. First, we used voxel-based morphometry to determine whether salience network atrophy was associated with lower baseline respiratory sinus arrhythmia (a parasympathetic measure) and skin conductance level (a sympathetic measure) in bvFTD. Next, we examined whether functional connectivity deficits in 21 autonomic-relevant, salience network node-pairs related to baseline autonomic dysfunction. Lower baseline respiratory sinus arrhythmia was associated with smaller volume in left ventral anterior insula (vAI), weaker connectivity between bilateral vAI and bilateral anterior cingulate cortex (ACC), and stronger connectivity between bilateral ACC and bilateral hypothalamus/amygdala. Lower baseline skin conductance level, in contrast, was associated with smaller volume in inferior temporal gyrus, dorsal mid-insula, and hypothalamus; weaker connectivity between bilateral ACC and right hypothalamus/amygdala; and stronger connectivity between bilateral dorsal anterior insula and periaqueductal gray. Our results suggest that baseline parasympathetic and sympathetic tone depends on the integrity of lateralized salience network hubs (left vAI for parasympathetic and right hypothalamus/amygdala for sympathetic) and highly calibrated ipsilateral and contralateral network connections. In bvFTD, deficits in this system may underlie resting parasympathetic and sympathetic disruption.
SIGNIFICANCE STATEMENT The salience network maintains homeostasis and regulates autonomic nervous system activity. Whether within-network connectivity patterns underlie individual differences in resting parasympathetic and sympathetic nervous system activity, however, is not well understood. We measured baseline autonomic nervous system activity in healthy controls and patients with behavioral variant frontotemporal dementia, a neurodegenerative disease characterized by resting autonomic deficits, and probed how salience network dysfunction relates to diminished parasympathetic and sympathetic outflow. Our results indicate that baseline parasympathetic and sympathetic tone are the product of complex, opposing intranetwork nodal interactions and depend on the integrity of highly tuned, lateralized salience network hubs (i.e., left ventral anterior insula for parasympathetic activity and right hypothalamus/amygdala for sympathetic activity).
Divergent Prelimbic Cortical Pathways Interact with BDNF to Regulate Cocaine-seeking
A single BDNF microinfusion into prelimbic (PrL) cortex immediately after the last cocaine self-administration session decreases relapse to cocaine-seeking. The BDNF effect is blocked by NMDAR antagonists. To determine whether synaptic activity in putative excitatory projection neurons in PrL cortex is sufficient for BDNF's effect on relapse, the PrL cortex of male rats was infused with an inhibitory Designer Receptor Exclusively Activated by Designer Drugs (DREADD) viral vector driven by an αCaMKII promoter. Immediately after the last cocaine self-administration session, rats were injected with clozapine-N-oxide 30 min before an intra-PrL BDNF microinfusion. DREADD-mediated inhibition of the PrL cortex blocked the BDNF-induced decrease in cocaine-seeking after abstinence and cue-induced reinstatement after extinction. Unexpectedly, DREADD inhibition of PrL neurons in PBS-infused rats also reduced cocaine-seeking, suggesting that divergent PrL pathways affect relapse. Next, using a cre-dependent retroviral approach, we tested the ability of DREADD inhibition of PrL projections to the NAc core or the paraventricular thalamic nucleus (PVT) to alter cocaine-seeking in BDNF- and PBS-infused rats. Selective inhibition of the PrL-NAc pathway at the end of cocaine self-administration blocked the BDNF-induced decrease in cocaine-seeking but had no effect in PBS-infused rats. In contrast, selective inhibition of the PrL-PVT pathway in PBS-infused rats decreased cocaine-seeking, and this effect was prevented in BDNF-infused rats. Thus, activity in the PrL-NAc pathway is responsible for the therapeutic effect of BDNF on cocaine-seeking whereas inhibition of activity in the PrL-pPVT pathway elicits a similar therapeutic effect in the absence of BDNF.
SIGNIFICANCE STATEMENT The major issue in cocaine addiction is the high rate of relapse. However, the neuronal pathways governing relapse remain unclear. Using a pathway-specific chemogenetic approach, we found that BDNF differentially regulates two key prelimbic pathways to guide long-term relapse. Infusion of BDNF in the prelimbic cortex during early withdrawal from cocaine self-administration decreases relapse that is prevented when neurons projecting from the prelimbic cortex to the nucleus accumbens core are inhibited. In contrast, BDNF restores relapse when neurons projecting from the prelimbic cortex to the posterior paraventricular thalamic nucleus are inhibited. This study demonstrates that two divergent cortical outputs mediate relapse that is regulated in opposite directions by infusing BDNF in the prelimbic cortex during early withdrawal from cocaine.
Reduced Microglial Activity and Enhanced Glutamate Transmission in the Basolateral Amygdala in Early CNS Autoimmunity
Emotional dysfunction is common in multiple sclerosis (MS) patients and in mouse models of MS, including experimental autoimmune encephalomyelitis (EAE); however, the etiology of these behaviors is poorly understood. To identify CNS changes associated with these behaviors, we focused on the basolateral amygdala (BLA) because of its central role in the regulation of emotional behavior. Whole-cell recordings were performed in the principal neurons of the BLA in early EAE, before demyelination, T-cell invasion, and motor dysfunction. EAE female mice displayed increased frequency of mEPSCs, with no alteration in amplitude or evoked EPSC paired-pulse ratio compared with controls. We found an increase in the AMPA-NMDA ratio and dendritic spine density, indicating increased numbers of glutamatergic synapses. We saw similar electrophysiological changes in BLA principal neurons after microglia were either inactivated (minocycline) or depleted (Mac1-Saporin) in the BLA. Microglia regulate synapses through pruning, directed by complement protein 3 (C3) expression. C3 was downregulated in the BLA in EAE. Ultrastructural analysis of microglia revealed more complex ramifications and reduced extracellular digestion of cellular elements. We also observed reduced IBA-1 and CD68 staining and lack of proinflammatory cytokine expression in the amygdala. Thus, early EAE is a state of microglial "deactivation" associated with reduced synaptic pruning. This contrasts with the prototypic microglial activation commonly associated with inflammatory CNS disease. Additionally, these data support a role for the acquired immune system to influence both neuronal and microglial function in early CNS autoimmunity.
SIGNIFICANCE STATEMENT Microglia help regulate synaptic homeostasis, but there has been little evidence for how this might be important in neuroinflammatory diseases. The data from this study reveal increased synaptic activity and spine density in early stages of experimental autoimmune encephalomyelitis (an animal model of multiple sclerosis) in the basolateral amygdala, a nucleus important in the types of behavioral changes we have previously described. These electrophysiological and morphological effects occurred without significant elevation of local inflammatory cytokines or local demyelination. Unexpectedly, in the context of inflammatory state, we found that microglia were "deactivated." This study provides strong evidence for a link between microglial activity and synaptic function; the conclusions contrast with the generally accepted view that microglia are activated in inflammatory disease.
Neural Correlate of Visual Familiarity in Macaque Area V2
Neurons in macaque inferotemporal cortex (ITC) respond less strongly to familiar than to novel images. It is commonly assumed that this effect arises within ITC because its neurons respond selectively to complex images and thus encode in an explicit form information sufficient for identifying a particular image as familiar. However, no prior study has examined whether neurons in low-order visual areas selective for local features also exhibit familiarity suppression. To address this issue, we recorded from neurons in macaque area V2 with semichronic microelectrode arrays while monkeys repeatedly viewed a set of large complex natural images. We report here that V2 neurons exhibit familiarity suppression. The effect develops over several days with a trajectory well fitted by an exponential function with a rate constant of ~100 exposures. Suppression occurs in V2 at a latency following image onset shorter than its reported latency in ITC.
SIGNIFICANCE STATEMENT Familiarity suppression, the tendency for neurons to respond less strongly to familiar than novel images, is well known in monkey inferotemporal cortex. Suppression has been thought to arise in inferotemporal cortex because its neurons respond selectively to large complex images and thus explicitly to encode information sufficient for identifying a particular image as familiar. No previous study has explored the possibility that familiarity suppression occurs even in early-stage visual areas where neurons are selective for simple features in confined receptive fields. We now report that neurons in area V2 exhibit familiarity suppression. This finding challenges our current understanding of information processing in V2 as well as our understanding of the mechanisms that underlie familiarity suppression.
Opioid-Independent and Opioid-Mediated Modes of Pain Modulation
Pain is regulated endogenously through both opioid and non-opioid mechanisms. We hypothesized that two novel pain modulation tasks, one drawing on context/expectations and one using voluntary reappraisal, would show differing levels of opioid dependence. Specifically, we expected that naloxone would block context-related analgesia, whereas mental imagery-based pain reappraisal would be opioid-independent.
A double-blind, placebo-controlled intravenous naloxone versus saline crossover design was used. Twenty healthy volunteers completed the two modulation tasks with acute heat stimuli calibrated to induce moderate pain. In the mental imagery task, participants imagined either a "pleasant" or a "comparison" scenario during painful heat. In the relative relief task, moderate heat stimuli coincided with visual cues eliciting relief from the expectation of intense pain, and were compared with moderate heat stimuli delivered under the expectation of non-painful warmth. Both "pleasant imagery" and "relative relief" conditions significantly improved ratings of pain intensity and pleasantness during saline treatment. Indeed, the target stimuli in both tasks, which had been calibrated to induce moderate pain, were rated as mildly pleasant. Furthermore, consistently with the main hypothesis, blocking endogenous opioid signaling with naloxone did not significantly affect imagery-induced regulation of pain intensity or pleasantness. In contrast, the relative relief-induced pain regulation (i.e., context/expectation) was blocked by naloxone. We conclude that endogenous opioid signaling is necessary for expectation-related relative relief analgesia, but not for pain reappraisal through mental imagery. These results support mental imagery as a powerful and clinically relevant strategy for regulating pain affect also in patients where endogenous opioid mechanisms might be compromised.
SIGNIFICANCE STATEMENT Neurotransmitter systems in the human brain can be probed through antagonist drugs. Studies using the opioid antagonist naloxone have demonstrated that the brain relies on both opioid and non-opioid mechanisms to downregulate pain. This holds clinical relevance given altered endogenous opioid processes in many chronic pain conditions. The present study used a double-blinded, placebo-controlled naloxone blockage of endogenous opioids in healthy humans to show differential opioid involvement in two pain modulation tasks. Context/expectation-driven (relative relief-related) analgesia was blocked by naloxone. In contrast, pain reappraisal through mental imagery was intact despite opioid receptor blockade, suggesting opioid independence. These results support mental imagery as a powerful, clinically relevant strategy for regulating pain as it does not rely on a functioning opioidergic system.
Graded Transmission without Action Potentials Sustains Rhythmic Activity in Some But Not All Modulators That Activate the Same Current
Neurons in the central pattern-generating circuits in the crustacean stomatogastric ganglion (STG) release neurotransmitter both as a graded function of presynaptic membrane potential that persists in TTX and in response to action potentials. In the STG of the male crab Cancer borealis, the modulators oxotremorine, C. borealis tachykinin-related peptide Ia (CabTRP1a), red pigment concentrating hormone (RPCH), proctolin, TNRNFLRFamide, and crustacean cardioactive peptide (CCAP) produce and sustain robust pyloric rhythms by activating the same modulatory current (IMI), albeit on different subsets of pyloric network targets. The muscarinic agonist oxotremorine, and the peptides CabTRP1a and RPCH elicited rhythmic triphasic intracellular alternating fluctuations of activity in the presence of TTX. Intracellular waveforms of pyloric neurons in oxotremorine and CabTRP1a in TTX were similar to those in the intact rhythm, and phase relationships among neurons were conserved. Although cycle frequency was conserved in oxotremorine and TTX, it was altered in CabTRP1a in the presence of TTX. Both rhythms were primarily driven by the pacemaker kernel consisting of the Anterior Burster and Pyloric Dilator neurons. In contrast, in TTX the circuit remained silent in proctolin, TNRNFLRFamide, and CCAP. These experiments show that graded synaptic transmission in the absence of voltage-gated Na+ current is sufficient to sustain rhythmic motor activity in some, but not other, modulatory conditions, even when each modulator activates the same ionic current. This further demonstrates that similar rhythmic motor patterns can be produced by qualitatively different mechanisms, one that depends on the activity of voltage-gated Na+ channels, and one that can persist in their absence.
SIGNIFICANCE STATEMENT The pyloric rhythm of the crab stomatogastric ganglion depends both on spike-mediated and graded synaptic transmission. We activate the pyloric rhythm with a wide variety of different neuromodulators, all of which converge on the same voltage-dependent inward current. Interestingly, when action potentials and spike-mediated transmission are blocked using TTX, we find that the muscarinic agonist oxotremorine and the neuropeptide CabTRP1a sustain rhythmic alternations and appropriate phases of activity in the absence of action potentials. In contrast, TTX blocks rhythmic activity in the presence of other modulators. This demonstrates fundamental differences in the burst-generation mechanisms in different modulators that would not be suspected on the basis of their cellular actions at the level of the targeted current.
Hypothalamic CCL2/CCR2 Chemokine System: Role in Sexually Dimorphic Effects of Maternal Ethanol Exposure on Melanin-Concentrating Hormone and Behavior in Adolescent Offspring
Clinical and animal studies show that ethanol exposure and inflammation during pregnancy cause similar behavioral disturbances in the offspring. While ethanol is shown to stimulate both neuroimmune and neurochemical systems in adults, little is known about their anatomical relationship in response to ethanol in utero and whether neuroimmune factors mediate ethanol's effects on neuronal development and behavior in offspring. Here we examined in female and male adolescent rats a specific population of neurons concentrated in lateral hypothalamus, which coexpress the inflammatory chemokine C-C motif ligand 2 (CCL2) or its receptor CCR2 with the orexigenic neuropeptide, melanin-concentrating hormone (MCH), that promotes ethanol drinking behavior. We demonstrate that maternal administration of ethanol (2 g/kg/d) from embryonic day 10 (E10) to E15, while having little impact on glia, stimulates expression of neuronal CCL2 and CCR2, increases density of both large CCL2 neurons colocalizing MCH and small CCL2 neurons surrounding MCH neurons, and stimulates ethanol drinking and anxiety in adolescent offspring. We show that these neuronal and behavioral changes are similarly produced by maternal administration of CCL2 (4 or 8 μg/kg/d, E10–E15) and blocked by maternal administration of a CCR2 antagonist INCB3344 (1 mg/kg/d, E10–E15), and these effects of ethanol and CCL2 are sexually dimorphic, consistently stronger in females. These results suggest that this neuronal CCL2/CCR2 system closely linked to MCH neurons has a role in mediating the effects of maternal ethanol exposure on adolescent offspring and contributes to the higher levels of adolescent risk factors for alcohol use disorders described in women.
SIGNIFICANCE STATEMENT Ethanol consumption and inflammatory agents during pregnancy similarly increase alcohol intake and anxiety in adolescent offspring. To investigate how neurochemical and neuroimmune systems interact to mediate these disturbances, we examined a specific population of hypothalamic neurons coexpressing the inflammatory chemokine CCL2 and its receptor CCR2 with the neuropeptide, melanin-concentrating hormone. We demonstrate in adolescent offspring that maternal administration of CCL2, like ethanol, stimulates these neurons and increases ethanol drinking and anxiety, and these effects of ethanol are blocked by maternal CCR2 antagonist and consistently stronger in females. This suggests that neuronal chemokine signaling linked to neuropeptides mediates effects of maternal ethanol exposure on adolescent offspring and contributes to higher levels of adolescent risk factors for alcohol use disorders in women.
Sleep Strengthens Predictive Sequence Coding
Predictive-coding theories assume that perception and action are based on internal models derived from previous experience. Such internal models require selection and consolidation to be stored over time. Sleep is known to support memory consolidation. We hypothesized that sleep supports both consolidation and abstraction of an internal task model that is subsequently used to predict upcoming stimuli. Human subjects (of either sex) were trained on deterministic visual sequences and tested with interleaved deviant stimuli after retention intervals of sleep or wakefulness. Adopting a predictive-coding approach, we found increased prediction strength after sleep, as expressed by increased error rates to deviant stimuli, but fewer errors for the immediately following standard stimuli. Sleep likewise enhanced the formation of an abstract sequence model, independent of the temporal context during training. Moreover, sleep increased confidence for sequence knowledge, reflecting enhanced metacognitive access to the model. Our results suggest that sleep supports the formation of internal models which can be used to predict upcoming events in different contexts.
SIGNIFICANCE STATEMENT To efficiently interact with the ever-changing world, we predict upcoming events based on similar previous experiences. Sleep is known to benefit memory consolidation. However, it is not clear whether sleep specifically supports the transformation of past experience into predictions of future events. Here, we find that, when human subjects sleep after learning a sequence of predictable visual events, they make better predictions about upcoming events compared with subjects who stayed awake for an equivalent period of time. In addition, sleep supports the transfer of such knowledge between different temporal contexts (i.e., when sequences unfold at different speeds). Thus, sleep supports perception and action by enhancing the predictive utility of previous experiences.
DMRT5, DMRT3, and EMX2 Cooperatively Repress Gsx2 at the Pallium-Subpallium Boundary to Maintain Cortical Identity in Dorsal Telencephalic Progenitors
Specification of dorsoventral regional identity in progenitors of the developing telencephalon is a first pivotal step in the development of the cerebral cortex and basal ganglia. Previously, we demonstrated that the two zinc finger doublesex and mab-3 related (Dmrt) genes, Dmrt5 (Dmrta2) and Dmrt3, which are coexpressed in high caudomedial to low rostrolateral gradients in the cerebral cortical primordium, are separately needed for normal formation of the cortical hem, hippocampus, and caudomedial neocortex. We have now addressed the role of Dmrt3 and Dmrt5 in controlling dorsoventral division of the telencephalon in mice of either sex by comparing the phenotypes of single knock-out (KO) with double KO embryos and by misexpressing Dmrt5 in the ventral telencephalon. We find that DMRT3 and DMRT5 act as critical regulators of progenitor cell dorsoventral identity by repressing ventralizing regulators. Early ventral fate transcriptional regulators expressed in the dorsal lateral ganglionic eminence, such as Gsx2, are upregulated in the dorsal telencephalon of Dmrt3;Dmrt5 double KO embryos and downregulated when ventral telencephalic progenitors express ectopic Dmrt5. Conditional overexpression of Dmrt5 throughout the telencephalon produces gene expression and structural defects that are highly consistent with reduced GSX2 activity. Further, Emx2;Dmrt5 double KO embryos show a phenotype similar to Dmrt3;Dmrt5 double KO embryos, and both DMRT3, DMRT5 and the homeobox transcription factor EMX2 bind to a ventral telencephalon-specific enhancer in the Gsx2 locus. Together, our findings uncover cooperative functions of DMRT3, DMRT5, and EMX2 in dividing dorsal from ventral in the telencephalon.
SIGNIFICANCE STATEMENT We identified the DMRT3 and DMRT5 zinc finger transcription factors as novel regulators of dorsoventral patterning in the telencephalon. Our data indicate that they have overlapping functions and compensate for one another. The double, but not the single, knock-out produces a dorsal telencephalon that is ventralized, and olfactory bulb tissue takes over most remaining cortex. Conversely, overexpressing Dmrt5 throughout the telencephalon causes expanded expression of dorsal gene determinants and smaller olfactory bulbs. Furthermore, we show that the homeobox transcription factor EMX2 that is coexpressed with DMRT3 and DMRT5 in cortical progenitors cooperates with them to maintain dorsoventral patterning in the telencephalon. Our study suggests that DMRT3/5 function with EMX2 in positioning the pallial-subpallial boundary by antagonizing the ventral homeobox transcription factor GSX2.
Association of Caffeine and Caffeinated Coffee Intake With Risk of Incident Rosacea in Women
This large cohort study of participants in the Nurses' Health Study II evaluates the association between risk of incident rosacea in women and caffeine intake, including caffeinated coffee consumption.
One More Reason to Continue Drinking Coffee—It May Be Good for Your Skin
Who does not love a study that validates one of life's habitual pleasures? Whether it is an iced latte, a double espresso, or simply a hot cup of brown liquid in the hospital cafeteria, many of us in medicine have an emotional attachment as well as a physiologic dependence on coffee.
Utility of Test Result Monitoring in Patients Taking Terbinafine or Griseofulvin for Dermatophyte Infections
This study assesses the rate and utility of monitoring laboratory test result abnormalities in adults and children taking terbinafine and griseofulvin for treatment of dermatophyte infections.
Cicatrizing Blepharoconjunctivitis During Dupilumab Treatment and an Algorithm for Its Management
This case report describes a patient who developed cicatrizing blepharoconjunctivitis while undergoing dupilumab treatment and proposes an algorithm for the management of dupilumab-associated conjunctivitis.
Analyzing Vaccine Trials in Epidemics with Mild and Asymptomatic Infection
Abstract
Vaccine efficacy against susceptibility to infection (VES), regardless of symptoms, is an important endpoint of vaccine trials for pathogens with a high proportion of asymptomatic infection, as such infections may contribute to onward transmission and long-term sequelae such as Congenital Zika Syndrome. However, estimating VES is resource-intensive. We aim to identify approaches to accurately estimate VES when limited information is available and resources are constrained. We model an individually randomized vaccine trial by generating a network of individuals and simulating an epidemic. The disease natural history follows a Susceptible, Exposed, Infectious/Symptomatic or Infectious/Asymptomatic, Recovered model. We then use seven approaches to estimate VES, and we also estimate vaccine efficacy against progression to symptoms (VEP). A corrected relative risk and an interval censored Cox model accurately estimate VES and only require serologic testing of participants once, while a Cox model using only symptomatic infections returns biased estimates. Only acquiring serological endpoints in a 10% sample and imputing the remaining infection statuses yields unbiased VES estimates across values of R0 and accurate estimates of VEP for higher R0 values. Identifying resource-preserving methods for accurately estimating VES and VEP is important in designing trials for diseases with a high proportion of asymptomatic infection.A Dynamic Model for Evaluation of the Bias of Influenza Vaccine Effectiveness Estimates from Observational Studies
Abstract
As influenza vaccination is now widely recommended in the United States, observational studies based on patients with acute respiratory illness (ARI) remain the only option to estimate influenza vaccine effectiveness (VE). We developed a dynamic probability model to evaluate bias of VE estimates from passive surveillance cohort, test-negative, and traditional case-control studies. The model includes two covariates (health status and health awareness), which may affect the probabilities of vaccination, developing ARI, and seeking medical care. Our results suggest that test-negative studies produce unbiased estimates of VE against medically-attended influenza when (1) vaccination does not affect the probability of non-influenza ARI and (2) health status has the same effect on the probability of influenza and non-influenza ARIs. The same estimate may be severely biased (i.e., estimated VE – true VE ≥ 0.20) for estimating VE against symptomatic influenza if the vaccine affects the probability of seeking care against influenza ARI. VE estimates from test-negative studies may also be severely biased for both outcomes of interest when vaccination affects the probability of non-influenza ARI, but estimates from passive surveillance cohort studies are unbiased in this case. Finally, VE estimates from traditional case-control studies suffer from bias regardless of the source of bias.Social Isolation and Mortality in US Black and White Men and Women
Abstract
Social isolation is associated with higher mortality in studies of mostly white adults, yet associations among black adults is unclear. This prospective cohort study evaluated whether associations of social isolation with all-cause, cardiovascular disease and cancer mortality differ by race and sex. Adults enrolled into Cancer Prevention Study-II in 1982/1983 were followed for mortality through 2012 (n = 580,182). Sex- and race-specific multivariable-adjusted hazard ratios and 95% confidence intervals were estimated for associations of a five-point social isolation score with risk of death. Social isolation was associated with all-cause mortality in all subgroups (P-trend ≤ 0.005); for the most versus the least isolated, the hazard ratios (95% confidence intervals) were 2.34 (1.58, 3.46) and 1.60 (1.41, 1.82) among black and white men, respectively (P-interaction = 0.40), and 2.13 (1.44, 3.15) and 1.84 (1.68, 2.01) among black and white women, respectively (P-interaction = 0.89). The association did not differ between black men and women (P-interaction = 0.33) but was slightly stronger in white women than white men (P-interaction = 0.01). Social isolation was associated with cardiovascular disease mortality in each subgroup (P-trend < 0.03) but with cancer mortality only among whites (P-trend < 0.0001). Subgroup differences in the influence of specific social isolation components were identified. Identifying and intervening with socially isolated adults could improve health outcomes.Patient reported outcome measures for soft tissue facial reconstruction: a systematic review and evaluation of the quality of their measurement properties
Background: A patient's health-related quality of life (HRQoL) can be significantly impacted by facial scarring and disfigurement. Facial soft tissue reconstruction should aim to improve HRQoL, with outcomes measured from the patient's perspective using patient-reported outcome measures (PROMs). This systematic review identifies PROMs for soft tissue facial reconstruction and appraises their methodological and psychometric properties using up-to-date methods. Methods: A systematic search of MEDLINE, EMBASE, PsychINFO and Cochrane was performed in line with the PRISMA guidelines. Identified PROMs were assessed using the updated COnsensus-based Standards for the Selection of Health Measurement INstruments (COSMIN) checklist. Psychometric properties were also assessed and a modified GRADE analysis was performed to aid in recommendations for future PROM use. Results: Thirty-four studies covering 9 PROMs were included. Methodological quality and psychometric evidence was variable. FACE-Q, Skin Cancer Index (SCI), Patient Outcome of Surgery – Head/Neck (POS-Head/Neck) and the Derriford Appearance Scale 59/24 all demonstrated high enough evidence to be recommended as having potential for inclusion in future studies. Conclusion: This is the first systematic review to identify and critically appraise PROMs for soft tissue facial reconstruction using internationally accepted criteria. Four PROMs were deemed to have adequate levels of methodological and psychometric evidence, although further studies should be conducted before their routine use in patients undergoing facial reconstruction. Through the use of psychometrically well-validated PROMs it is hoped that patients' concerns can be truly appreciated, level of care improved, and the quality of reconstructive options offered progressed. Meetings: This work has not yet been presented at any meetings. Acknowledgements: We would like to acknowledge the help of Anne Powell, retired librarian at Abertawe Bro Morgannwg University Health Board. Conflicts of Interest and Funding: None of the authors has a financial interest in any of the products, devices, or drugs mentioned in this manuscript. This work has received no specific funding. Mr Thomas Dobbs is funded by the Welsh Clinical Academic Training Fellowship. Author role: TD, HH and ISW developed the idea for this systematic review. TD, JG, AT, BP performed the literature review and data extraction. TD and SH assessed all included papers according to the methodology. TD produced the first draft of the manuscript and all authors were then involved in editing to reach the final, submitted version. Corresponding Author: Mr Thomas Dobbs, The Welsh Centre for Burns and Plastic Surgery, Morriston Hospital, Swansea. SA6 6NL, e: tomdobbs@doctors.org.uk ©2018American Society of Plastic Surgeons
Secukinumab is Superior to Ustekinumab in Clearing Skin in Patients with Moderate to Severe Plaque Psoriasis (16-Week CLARITY Results)
Abstract
Introduction
Secukinumab, a fully human anti-interleukin-17A monoclonal antibody, has demonstrated superior efficacy to ustekinumab in the phase 3b CLEAR study of moderate to severe plaque psoriasis. Here, we report 16-week results from CLARITY, a second head-to-head trial comparing secukinumab with ustekinumab.
Methods
In the phase 3b CLARITY study, patients were randomized 1:1 to receive subcutaneous secukinumab 300 mg or ustekinumab per label. The co-primary objectives were to demonstrate the superiority of secukinumab over ustekinumab at Week 12 in relation to the proportion of patients with (1) 90% or more improvement from baseline Psoriasis Area and Severity Index (PASI 90) and (2) a score of 0/1 (clear/almost clear) on the modified Investigator's Global Assessment (IGA mod 2011 0/1). Key secondary objectives were also assessed, as was Dermatology Life Quality Index (DLQI) 0/1 (no impact of skin disease on patients' quality of life) response. Missing values were handled by multiple imputation except for DLQI 0/1, where last observation carried forward techniques were utilized.
Results
Both co-primary objectives were met: secukinumab was superior to ustekinumab for the proportion of patients achieving a PASI 90 (66.5% vs. 47.9%) and IGA mod 2011 0/1 response (72.3% vs. 55.4%) at Week 12 (p < 0.0001). PASI 90 responses were greater with secukinumab compared to ustekinumab from as early as Week 4 (16.7% vs. 4.0%) and out to Week 16 (76.6% vs. 54.2%). Similarly, IGA mod 2011 0/1 findings were greater with secukinumab at Week 4 (26.9% vs. 7.8%) and at Week 16 (78.6% vs. 59.1%). DLQI 0/1 response rates were also greater with secukinumab compared to ustekinumab at Week 4 (33.9% vs. 18.0%), Week 12 (64.0% vs. 51.7%), and Week 16 (68.4% vs. 55.9%).
Conclusion
The results of this study confirm the superior efficacy of secukinumab over ustekinumab in treating patients with moderate to severe psoriasis.
Trial Registration
Clinicaltrials.gov Identifier, NCT02826603.
Funding
Novartis Pharma AG, Basel, Switzerland.
Les toxidermies graves sont-elles évitables ?
Publication date: Available online 16 October 2018
Source: Annales de Dermatologie et de Vénéréologie
Author(s): J.-L. Schmutz
-Asthma Prevalence Among Medicaid-Enrolled Children
Publication date: Available online 17 October 2018
Source: The Journal of Allergy and Clinical Immunology: In Practice
Author(s): Anna Smith, Nicoleta Serban, Anne Fitzpatrick
Abstract
Background
Small-area asthma prevalence measures, which are crucial for targeting interventions, are currently sparsely available for children.
Objective
This study aims to provide measures of in-contact asthma prevalence for the 2012 Medicaid child population, to highlight areas in need of targeted asthma interventions.
Methods
Using the 2012 Medicaid Analytic eXtract (MAX) claims files, we develop two prevalence metrics differentiated by persistent or diagnosed asthma. We develop prevalence measures at the state, county, and census tract levels, with statistical inferences to highlight areas of high-prevalence where intervention should be focused. We compare the measures to asthma prevalence estimates derived from a sample of the child population who have self-reported whether they have been diagnosed with asthma regardless whether in-contact.
Results
1.98 million (8.1%) and 1.71 million (6.9%) Medicaid-enrolled children are identified with in-contact asthma diagnosis and persistent asthma, respectively. Among 40 states, 17 have lower prevalence estimates for the Medicaid-enrolled children than similar Centers for Disease Control and Prevention (CDC) child asthma self-reported prevalence estimates. High prevalence regions span primarily in the southern Midwest region, from Texas to West Virginia and Illinois to north Florida.
Conclusions
There are large variations in the differences between CDC self-reported estimates for the general population and the in-contact estimates for the Medicaid-enrolled children, highlighting potential asthma misdiagnosis in the Medicaid population in many states. Small area estimates point to areas of high prevalence, consistently throughout the south and southeast.
Oral direct-acting antiviral therapy for hepatitis C virus (HCV) infection in X-linked agammaglobulinemia
Publication date: Available online 17 October 2018
Source: The Journal of Allergy and Clinical Immunology: In Practice
Author(s): Hermann M. . Wolf, Martha M. Eibl, Christian J. Müller
Atopic Dermatitis is associated with increased prevalence of multiple ocular comorbidities
Publication date: Available online 17 October 2018
Source: The Journal of Allergy and Clinical Immunology: In Practice
Author(s): Kishan Govind, Katherine Whang, Raveena Khanna, Adrienne W. Scott, Shawn G. Kwatra
Nitrate allergy and desensitization in a patient with refractory angina
Publication date: Available online 16 October 2018
Source: The Journal of Allergy and Clinical Immunology: In Practice
Author(s): Sarah G. Kessler, Amanda R. Gillion, Debendra Pattanaik, Kelly C. Rogers
Inhaled corticosteroid-related tuberculosis in the real world among patients with asthma and COPD: A 10-year nationwide population-based study
Publication date: Available online 16 October 2018
Source: The Journal of Allergy and Clinical Immunology: In Practice
Author(s): Chang-Min Lee, Jeongwon Heo, Seon-Sook Han, Ki Won Moon, Seung-Hwan Lee, Young-Ju Kim, Seung-Joon Lee, Jae-Woo Kwon
Abstract
Background
There have been concerns about the risk of ICS-related tuberculosis (TB) development.
Objective
We investigated the occurrence of TB among ICS users according to underlying respiratory diseases and type of ICS.
Methods
A 12-year population cohort comprising about 1 million subjects collected from the Korean claims database were used. Adult ICS users (budesonide or fluticasone) were enrolled. The temporal relationship between TB development and the last ICS prescription before TB development was evaluated. A nested case-control study was performed with 1:4 matching for age, sex, and the initiation date of the ICS.
Results
There were 17,991 ICS users, and 175 developed TB during the study period. About 80% (140/175) of patients who developed TB were diagnosed within 3 years after the last ICS prescription. In the nested case-control study, the occurrence of TB was not related to the type of ICS, but was related to a higher annual admission rate and a higher comorbidity score. The risk of TB was higher in patients with chronic obstructive pulmonary disease (COPD) than in those with asthma (OR: 2.31, CI 95%: 1.39-3.38, p= 0.0011) after adjusting for covariates. The subgroup analysis revealed no difference between budesonide and fluticasone with respect to the risk of developing TB in patients with asthma, COPD, or asthma-COPD overlap syndrome.
Conclusion
An increased risk of TB development may persist for 3 years after stopping the ICS and the risk is higher in patients with COPD regardless of the type of ICS used.
National ENT workforce planning in the United Kingdom; An increasing cause for concern?
Clinical Otolaryngology, Volume 0, Issue ja, -Not available-.
Generalized Fixed Drug Eruption Mimicking CD8+ Cutaneous T‐cell Lymphoma in HIV
Journal of Cutaneous Pathology, Volume 0, Issue ja, -Not available-.
Utility of CD30, Ki67 and p53 in assisting with the diagnosis Mycosis Fungoides with Large Cell Transformation
Journal of Cutaneous Pathology, Volume 0, Issue ja, -Not available-.
Novel immune signatures associated with dysplastic nevi and primary cutaneous melanoma in human skin
Experimental Dermatology, Volume 0, Issue ja, -Not available-.
Photodynamic Therapy with a 5‐ALA‐Patch Does Not Increase the Risk of Conversion of Actinic Keratoses into Squamous Cell Carcinoma
Experimental Dermatology, Volume 0, Issue ja, -Not available-.
Transcranial magnetic stimulation over contralateral primary somatosensory cortex disrupts perception of itch intensity
Experimental Dermatology, Volume 0, Issue ja, -Not available-.
Multiple yellowish white papules on the trunk and upper arms
International Journal of Dermatology, EarlyView.
Atypical presentation of immunoglobulin A vasculitis in disseminated tuberculosis
International Journal of Dermatology, EarlyView.
Noninvasive diagnosis of liquefied gouty tophus: Reflectance confocal microscopy as an alternative to polarizing light microscopy analysis
Skin Research and Technology, EarlyView.
Th17 responses to pneumococcus in blood and adenoidal cells in children
Clinical &Experimental Immunology, Volume 0, Issue ja, -Not available-.
Use of Absolute Risk Measurements in Dermatologic Observational Studies: Important Information For Decision Making Is Frequently Absent
British Journal of Dermatology, Volume 0, Issue ja, -Not available-.
A case of Incontinentia Pigmenti associated with congenital absence of portal vein system and nodular regenerative hyperplasia
British Journal of Dermatology, Volume 0, Issue ja, -Not available-.
Association of auto‐immunity and long‐term complete remission in Sezary patients treated with mogamulizumab
British Journal of Dermatology, Volume 0, Issue ja, -Not available-.
The burden of cutaneous adnexal carcinomas and the risk of associated squamous cell carcinoma: a population‐based study
British Journal of Dermatology, Volume 0, Issue ja, -Not available-.
The good, the bad and the malignant
British Journal of Dermatology, Volume 179, Issue 4, Page 809-810, October 2018.
隐性 XLI: 神经系统疾病的高患病率
British Journal of Dermatology, Volume 179, Issue 4, Page e192-e192, October 2018.
An Oral Disease Severity Score for pemphigus vulgaris
British Journal of Dermatology, Volume 179, Issue 4, Page e169-e169, October 2018.
Revealing the mysteries of X‐linked recessive ichthyosis
British Journal of Dermatology, Volume 179, Issue 4, Page 821-822, October 2018.
Image Gallery: Granulomatous dermatitis due to infection with the chlorophyllic green alga Desmodesmus
British Journal of Dermatology, Volume 179, Issue 4, Page e167-e167, October 2018.
The utility of understanding atrophic acne scar formation for prevention and treatment
British Journal of Dermatology, Volume 179, Issue 4, Page 819-819, October 2018.
A promising new treatment for SAPHO syndrome that deserves further studies
British Journal of Dermatology, Volume 179, Issue 4, Page 823-823, October 2018.
Can antibiotics be harmful in atopic dermatitis?
British Journal of Dermatology, Volume 179, Issue 4, Page 807-808, October 2018.
Assessing benefits and risks of holiday sun exposure in children
British Journal of Dermatology, Volume 179, Issue 4, Page 822-823, October 2018.
Generating new evidence for old medications: the TREAT trial in paediatric atopic dermatitis
British Journal of Dermatology, Volume 179, Issue 4, Page 813-814, October 2018.
Is the Oral Disease Severity Score going to be useful for dermatologists when assessing pemphigus?
British Journal of Dermatology, Volume 179, Issue 4, Page 816-817, October 2018.
来自 AD 患者的金黄色葡萄球菌的局部抗生素耐药性
British Journal of Dermatology, Volume 179, Issue 4, Page e188-e188, October 2018.
A Prospective Randomized Blinded Trial Comparing Digital Simulation to Textbook for Cleft Surgery Education
Background: Simulation is progressively being integrated into surgical training, yet its utility in plastic surgery has not been well described. We present a prospective, randomized, blinded trial comparing digital simulation to a surgical textbook for conceptualization of cleft-lip repair. Methods: Thirty-five medical students were randomized to learning cleft repair using a simulator or textbook. Participants outlined markings for a standard cleft-lip repair before (pre-intervention) and after (post-intervention) 20 minutes of studying their respective resource. Two expert reviewers blindly graded markings according to a 10-point scale, on two separate occasions. Intra-rater and inter-rater reliability were calculated using intra-class correlation coefficients. Paired and independent t-tests were performed to compare scoring between study groups. A validated student satisfaction survey was administered to assess the two resources separately. Results: Intra-rater grading reliability was excellent among both raters for pre-intervention and post-intervention grading (rater 1 ICC=0.94 and 0.95, respectively; rater 2 ICC=0.60 and 0.92, respectively; p
“Flap Preconditioning with the Cyclic Mode (Triangular Waveform) of Pressure-Controlled Cupping in a Rat Model: An Alternative Mode to the Continuous System”
Background: Improving flap survival is essential for successful soft-tissue reconstruction. Although many methods have been attempted to increase the survival of the distal flap portion, there has been no widely adopted procedure. We evaluated the effect of flap preconditioning with two different modes (continuous and cyclic) of external volume expansion (pressure-controlled cupping) in a rat dorsal flap model. Methods: Thirty rats were randomly assigned to the control group and two experimental groups (n=10/group). The continuous group underwent 30 min of preconditioning with -25 mmHg pressure once daily for 5 days. The cyclic group received 0 to -25 mmHg pressure for 30 min with the cyclic mode once daily for 5 days. On the day after the final preconditioning, caudally based 2x8-cm dorsal random-pattern flaps were raised and replaced in the native position. On postoperative day 9, the surviving flap area was evaluated. Results: The cyclic group showed the highest flap survival rate (76.02%), followed by the continuous and control groups (64.96% and 51.53%, respectively). All inter-group differences were statistically significant. Tissue perfusion of the entire flap showed similar results (cyclic, 87.13%; continuous, 66.64%; control, 49.32%). Histologic analysis with hematoxylin and eosin, Masson trichrome, and CD31 staining showed the most increased and organized collagen production with hypertrophy of the attached muscle and vascular density in the cyclic group, followed by the continuous and control groups. Conclusions: Flap preconditioning with the cyclic mode of external volume expansion is more effective than the continuous mode in an experimental rat model. Further studies will be necessary for clinical application. Financial Disclosure Statement: None of the authors has a financial interest in any of the products, devices, or drugs mentioned in this manuscript Authors' Contributions: K.S.K. came up with the main idea and its concept of hypothesis in this experiment. He led the process of this study. Y.G.H. mainly conducted the animal experiment and further organized and analyzed histologic results. He wrote the article. S.C.K. supervised and advised the experimental process and participated in the laboratory meeting with the team and gave several opinions during discussion. Ethics Statement: All procedures were conducted in accordance with the Guide for the Care and Use of Laboratory Animals of the Asan Life Science Research Center animal review board (document no. 2017-13-113). Corresponding author: Kyung S. Koh, MD, PhD, Professor, Department of Plastic and Reconstructive Surgery, Asan Medical Center, University of Ulsan College of Medicine, 88 Olympic-ro 43-gil, Sonpa-gu, Seoul 05505, Korea. Tel.: +82-2-3010-3600, Fax: +2-476-7471, E-mail: kskoh@amc.seoul.kr, kyungskoh@gmail.com ©2018American Society of Plastic Surgeons
Outcomes of Elbow Flexion Reconstruction in Patients Over 50 with Traumatic Brachial Plexus Injury
Background: There is controversy regarding the effectiveness of brachial plexus (BP) reconstruction for elbow function in older patients as reported outcomes are generally poor. The purpose of this study is to evaluate elbow function outcomes in patients over 50. Methods: Fifty-eight patients over the age of 50 underwent nerve grafting, transfers or free functioning muscle transfer (FFMT) to improve elbow function after traumatic BP injury. Patients were evaluated pre- and post-operatively for elbow flexion strength and range of motion (ROM), Disability of the Arm, Shoulder, and Hand (DASH) scores, pain, delay from injury to operation, concomitant trauma, severity of trauma, and type of reconstruction. Results: The average age was 57.8 years (range 50-72) with an average follow-up of 24.0 months. The average modified BMRC (British Medical Research Council) elbow flexion grade improved significantly from 0.26 to 2.63. Thirty-three patients (60%) achieved functional flexion ≥M3 post-operatively, compared to zero patients pre-operatively. There was no correlation between age and modified BMRC grade. Active elbow ROM improved significantly post-operatively, with no effect of age on flexion motion. More patients achieved ≥M3 flexion with nerve transfers (69%) compared to FFMT (43%). Patients had worse outcomes with high energy injuries. The mean DASH score decreased from 51.5 to 49.6 post-operatively and the average pain score decreased from 5.0 to 4.3. Conclusion: BP reconstruction for elbow function in patients over the age of 50 can yield useful flexion. Conflicts of Interest: We have no conflicts of interest or financial interest to disclose. Corresponding author: Alexander Shin, MD, shin.alexander@mayo.edu, Division of Orthopedic Surgery, Mayo Clinic, 200 First Street, SW, 55905 Rochester, MN ©2018American Society of Plastic Surgeons
Wide-awake flexor pollicis longus tendon reconstruction with evaluation of the active voluntary contraction of the ruptured muscle-tendon
Background: The purpose of this study was to investigate the clinical outcome of the wide-awake tendon reconstruction for chronic rupture of the flexor pollicis longus (FPL) tendon with evaluation of the voluntary active contraction distance (ACD) of the ruptured musculotendinous unit. Methods: Eleven consecutive patients underwent tendon reconstruction under wide-awake surgery for chronic tendon rupture of the FPL. If the total of the passive distraction distance (PDD) and the ACD of the ruptured FPL musculotendinous unit was greater than 30 mm, tendon grafting was performed. If not, tendon transfer was performed using the 4th flexor digitorum superficialis (FDS). Patients were evaluated with total active motion (TAM) before surgery, during surgery, and in final follow-up and subjectively surveyed with quick Disability of the Arm, Shoulder, and Hand (q-DASH) scores. The final outcomes of tendon grafting and of tendon transfer were compared. Results: Tendon grafting was performed in 4 patients, and tendon transfer was performed in 7 patients while maintaining finger active motion during surgery. The final follow-up %TAM was 84.3%±12.7% in the tendon transfer group and 80.7%±10.2% in the tendon grafting group. There were no significant differences between tendon transfer and tendon grafting in the final follow-up %TAM and q-DASH scores. Conclusions: The functional outcomes of both tendon grafting and tendon transfer were acceptable based on evaluating the ACD and PDD of the ruptured musculotendinous unit during wide-awake surgery. Evaluating the ACD and PDD may be a useful index to assess the ruptured musculotendinous unit. The greatest advantage of the wide-awake tendon reconstruction is that surgeons can evaluate the ruptured musculotendinous unit and measure TAM during surgery while adjusting suture tension. Financial Disclosure: none Acknowledgements: none This report was approved by the Ethics Comitee, University of Toyama (Toyama, Japan) and clinical reaserch number "21-22" was granted. Corresponding auther: Mineyuki Zukawa. MD ©2018American Society of Plastic Surgeons
“Delayed Post-conditioning with External Volume Expansion (EVE) Improves Survival of Adipose Tissue Grafts in a Murine Model”
Background: External volume expansion (EVE) improves the survival of adipose tissue grafts by pre-operatively conditioning ('pre-conditioning') tissues that will receive the graft. EVE's mechanisms of action (induction of angiogenesis and of adipogenesis) could improve graft survival also when applied post-operatively (post-conditioning). We tested this hypothesis and optimized the parameters of post-operative application of EVE in a murine model. Methods: Fifty-six 8-week-old athymic (nu/nu) mice received dorsal subcutaneous grafts of human lipoaspirate (0.3 ml each) bilaterally before undergoing EVE (left dorsum) or no treatment (right dorsum, controls). EVE was started either on the same day of (Immediate group), two days after (Early group), or one week after surgery (Delayed group). At follow-up, grafts were analyzed for tissue survival, remodeling, adipogenesis, and angiogenesis using histology. Volume retention was assessed by MRI. We subsequently assessed the effects of the Delayed application of EVE adopting a foam-shaped interface (F-EVE) to deliver the treatment. Results: At 28 days follow-up delayed post-conditioning with EVE significantly improved the survival of grafts (+18%) compared to controls (viable graft thickness ratio: 58 ±15% vs 49 ±13%) and increased the density of blood vessels within the graft (+63%: blood vessels/ 10x magnification field: 44 ±12 vs 27 ±11). Other groups did not lead to significant changes. Adoption of F-EVE similarly improved outcomes while further reducing fibrosis within the grafts. Conclusions: Post-operative delayed application of EVE modestly improves the survival of adipose tissue grafts by inducing adipogenesis and angiogenesis. Use of a foam-shaped interface decreases the fibrosis induced in the grafts. # co-first authors Acknowledgments, conflict of interest and role of funding sources disclosure statement: Dr. Orgill receives research funding through grants from Acelity L.P. to Brigham and Women's Hospital and is a consultant for Acelity L.P. All other authors declare no actual or potential conflict of interests: in addition, they disclose no commercial or financial associations, personal or other relationships with other people or organizations that could inappropriately influence the reported manuscript or create a conflict of interest with the information presented. This study was funded by a research grant from Acelity L.P. Inc. to Brigham and Women's Hospital and a research grant by the Gillian Reny Stepping Strong Foundation to Brigham and Women's Hospital. Authorship: All authors had full access to the data and take responsibility for the integrity of the data and the accuracy of the data analysis. All authors have seen and agreed to the submitted version of the manuscript and bear responsibility for it. Ethics: The study was carried out under high ethical standards. All the studies have been approved, when required, by the appropriate ethics committee and have been performed in accordance and in conformity to the World Medical Association Declaration of Helsinki (June 1964) and subsequent amendments. Meetings at which the paper has been presented: None. Corresponding authors: Dennis P. Orgill (* corresponding author), Tissue Engineering and Wound Healing Laboratory, Department of Surgery, Division of Plastic Surgery, Brigham and Women's Hospital - Harvard Medical School, 75 Francis St., Boston MA 02115 (USA). T: 617-732-5456F: 617-730-2855E:dorgill@partners.org ©2018American Society of Plastic Surgeons
“Craniometric Analysis of Endoscopic Suturectomy for Bilateral Coronal Craniosynostosis.”
Background: Endoscopic suturectomy and helmeting represents a successful first-line surgical treatment for bilateral coronal craniosynostosis. Its effect on cranial morphology has not been previously described. Methods: Patients were identified who had bilateral coronal craniosynostosis treated with endoscopic suturectomy and postoperative helmeting at Boston Children's Hospital between 2005 and 2013 and who received pre- and post-operative CT scans. Two normative patient populations were identified from our trauma registry with CT scans completed at the same age as our pre- and post-treatment scans. Craniometric indices were utilized to quantify the effect of treatment. Results: Twenty-seven patients were identified who underwent bilateral coronal suturectomy. Twelve patients had preoperative and postoperative CT studies. Eight patients (66.7%) were syndromic. The average ages for preoperative and postoperative CT scan was 1.1 months (0.03–2.6) and 19.6 months (10.8–37.5). Thirteen patients with an average age of 1.1 months (0.5–1.6) were identified as a preoperative control group. Fourteen patients with an average age of 18.5 months (15.5–22.9) were identified as a postoperative control group. The anterior cranial height (ACH) stabilized with treatment and the anterior cranial base length increased (ACBL). The ACH:ACBL ratio significantly decreased with treatment (p=0.128). Frontal bossing normalized with endoscopic suturectomy (CS vs control; pre-op: p=0.001, post-op (p=0.8). Cephalic indices also normalized with treatment (CS vs control; pre-op: p=0.02, post-op, p=0.13). No cases of hydrocephalus were observed. Conclusion: Endoscopic suturectomy and helmeting improves anterior turricephaly and corrects frontal bossing and brachycephaly in patients with bilateral coronal craniosynostosis. FD - None of the authors has a financial interest in any of the products, devices, or drugs mentioned in this manuscript. Corresponding author: S. Alex Rottgers MD, Assistant Professor of Plastic Reconstructive Surgery, John Hopkins All Children's Hospital, Division of Plastic and Reconstructive Surgery, 601 Fifth Street South, Suite 306, St. Petersburg, FL. srottge1@jhmi.edu ©2018American Society of Plastic Surgeons
Evaluation of Donor Morbidity Following Single-Stage Latissimus Dorsi Neuromuscular Transfer for Facial Reanimation
Background: Single-stage latissimus dorsi (LD) neuromuscular transfer has been a valuable option for dynamic smile reanimation. However, there is a paucity of studies evaluating the potential donor morbidity in such cases. The present study aimed to comprehensively analyze the donor morbidity following functional LD muscle transfer. Methods: Patients who underwent single-stage functional LD muscle transfer for smile reanimation between 2002 and 2016 were reviewed. Postoperative complications and functional impairments at the donor sites were evaluated. The Quick-Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire was used for assessing postoperative donor-site function. Results: Sixty patients including 12 pediatric (≤ 18 years) were analyzed. Mean length of a harvested thoracodorsal nerve was 14.9 cm. Fourteen patients were treated with dual innervation technique, in which both a descending and transverse branch of the thoracodorsal nerve were harvested. Donor complications were observed in seven cases; all of them were seroma and resolved by simple aspiration. No other complications including scoliosis and sensory and/or motor disturbances in the upper extremities were encountered. Fifty patients responded to the Quick-DASH questionnaire at a median follow-up period of 51 months. The average score was 2.64 and all but three patients scored less than 10. No variables, including patient age (pediatric versus adult) and the use of dual innervation technique, affected the donor morbidities including the functional deficits. Conclusions: Single-stage LD neuromuscular transfer for facial reanimation might be associated with a low rate of complications and minimal functional morbidity at the donor site. Financial Disclosure:None of the authors has a financial interest in any of the products, devices, or drugs mentioned in this manuscript. Presented at:13thInternational Facial Nerve Symposium, August 3-6, 2017, Los Angeles, CA (Podium) Corresponding Author Contact Information: Dr. Goo-Hyun Mun, MD, Ph D., Department of Plastic Surgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Irwon-dong 50, Gangnam-gu, Seoul, S. Korea. 135-710.,Tel.: 82-2-3410-2233, Fax: 82-2-3410-0036, E-mail: supramicro@gmail.com ©2018American Society of Plastic Surgeons
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Publication date: Available online 28 September 2017 Source: Actas Dermo-Sifiliográficas Author(s): F.J. Navarro-Triviño
