Τετάρτη 4 Απριλίου 2018
Methodology of clinical trials evaluating the incorporation of new drugs in the first line treatment of patients with diffuse large B-cell lymphoma (DLBCL): a critical review
Abstract
Purpose
The first line treatment of diffuse large B-cell lymphoma (DLBCL) is the combination of rituximab with CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) chemotherapy, curing approximately 60% of patients. Many clinical trials have been performed over the last 10 years trying to improve the results of this treatment, but the appropriateness of their planning strategies could be rediscussed. Patients and Methods
Reports of phase 3 trials evaluating the addition of molecularly targeted agents (MTA) or new monoclonal antibodies to the classic R-CHOP backbone in first-line induction or maintenance treatment were reviewed. The trial design, primary end point, number of patients enrolled, patient selection criteria, treatment schedule and results were registered for each one. In addition, the phase1 and 2 trials which preceded these phase 3 trials were also reviewed. Results
Among six phase 3 trials with results, only one trial evaluating lenalidomide maintenance after response to R-CHOP induction was positive and reached its primary endpoint. The other 5 trials did not show an improved outcome with the addition of the new agent. The preceding phase 1 and 2 trials were very heterogeneous in their endpoints and design. Even though most of these trials were considered positive, thus encouraging further investigation, so far they failed to predict the results of the subsequent phase 3 trials. Conclusion
The standard of care for DLBCL is still R-CHOP. Phase 1/2 trials failed to predict the results of subsequent phase 3 trials evaluating non-chemotherapeutic agents added to R-CHOP. The methodology of phase 2 trials evaluating new agents in DLBCL needs to be better defined in the future.ADI-PEG 20 Plus Best Supportive Care versus Placebo Plus Best Supportive Care in Patients with Advanced Hepatocellular Carcinoma
Abstract
Background
Arginine depletion is a putative target in hepatocellular carcinoma (HCC). HCC often lacks argininosuccinate synthetase, a citrulline to arginine-repleting enzyme. ADI-PEG 20 is a cloned arginine degrading enzyme – arginine deiminase – conjugated with polyethylene glycol. The goal of this study was to evaluate this agent as a potential novel therapeutic for HCC after first line systemic therapy. Methods and Patients
Patients with histologically proven advanced HCC and Child-Pugh up to B7 with prior systemic therapy, were randomized 2:1 to ADI-PEG 20 18 mg/m2 vs. placebo intramuscular (IM) injection weekly. The primary endpoint was overall survival (OS), with 93% power to detect a 4 to 5.6 months increase in median OS (1-sided α = 0.025). Secondary endpoints included progression-free survival (PFS), safety, and arginine correlatives. Results
635 patients were enrolled: median age 61, 82% male, 60% Asian, 52% hepatitis B, 26% hepatitis C, 76% stage IV, 91% Child-Pugh A, 70% progressed on sorafenib and 16% were intolerant. Median OS was 7.8 months for ADI-PEG 20 vs 7.4 for placebo (p = 0.88, HR = 1.02) and median PFS 2.6 months vs. 2.6 (p = 0.07, HR = 1.17). Grade 3 fatigue and decreased appetite occurred in less than 5% of patients. Two patients on ADI-PEG 20 had ≥ grade 3 anaphylactic reaction. Death rate within 30 days of end of treatment was 15.2% on ADI-PEG 20 vs. 10.4% on placebo, none related to therapy. Post-hoc analyses of arginine assessment at 4, 8, 12 and 16 weeks, demonstrated a trend of improved OS for those with more prolonged arginine depletion. Conclusion
ADI-PEG 20 monotherapy did not demonstrate an OS benefit in second line setting for HCC. It was well tolerated. Strategies to enhance prolonged arginine depletion and synergize the effect of ADI-PEG 20 are underway. Clinical Trial number
www.clinicaltrials (NCT 01287585)Sorption of 17β-estradiol to the dissolved organic matter from animal wastes: effects of composting and the role of fulvic acid-like aggregates
Abstract
Steroid estrogens, such as 17β-estradiol (E2), in animal manure pose a potential threat to the aquatic environment. The transport and estrogenicity of estrogens influence the sorption of estrogens to dissolved organic matter (DOM) in animal manure, and composting treatment alters the structure and composition of the manure. The objectives of the present study were to identify the contribution of the molecular composition of DOM of composted manure to the sorption of E2 and then elucidate the dominant mechanisms involved in the interaction of E2 with manure-derived DOM. The excitation–emission matrix (EEM) spectra and atomic force microscopy (AFM) showed that composting significantly altered the chemical composition and structure of DOM. A decrease in the atomic ratios of oxygen (O)/carbon (C) occurred in conjunction with the formation of DOM aggregates in the composted manure, indicating that the hydrophilicity and polarity of the DOM decreased after composting. Composting increased the sorption coefficients (KDOC-E2) for E2 to DOM, and KDOC-E2 was positively correlated with the proportion of the fulvic acid (FA)-like fraction and molecular weight (MW) fractions of the DOM (range of 1.0 × 103–7.0 × 103 Da and 7.0 × 103–1.4 × 104 Da). Specifically, E2 showed a tendency for sorption to medium-sized FA-like molecules of DOM aggregates in composted manure. Hydrophobic forces and π-π binding appeared to be the main mechanisms underlying the aforementioned interaction.
Intraoperative anaphylaxis secondary to systemic cooling in a pediatric patient with cold-induced urticaria
Publication date: Available online 4 April 2018
Source:The Journal of Allergy and Clinical Immunology: In Practice
Author(s): Michelle C. Maciag, Charles Nargozian, Ana Dioun Broyles
Occupational exposures and asthma prevalence among US farmworkers: National Agricultural Workers Survey, 2003-2014
Publication date: Available online 4 April 2018
Source:The Journal of Allergy and Clinical Immunology: In Practice
Author(s): Anna J. Chen Arroyo, Lacey B. Robinson, N. Lance Downing, Carlos A. Camargo
Risk assessment, spatial distribution, and source apportionment of heavy metals in Chinese surface soils from a typically tobacco cultivated area
Abstract
The heavy metals (As, Cd, Cr, Cu, Hg, Ni, Pb, and Zn) in the surface soils of tobacco (Nicotiana tabacum L.) fields in Jiangxi Province were analyzed, and the mean heavy metal concentrations were 3.55, 0.19, 25.89, 14.96, 0.25, 10.89, 27.80, and 44.00 mg/kg, respectively. Spatial distribution analysis showed that the highest concentrations were recorded in the north-western, south-western, and mid-eastern parts of the study area. The index of geo-accumulation and pollution index indicated modest enrichment with Cd and Hg, which were the only two metals posing a potentially high ecological risk to the local agricultural environment. The health risk assessment showed no considerable non-carcinogenic or carcinogenic risks for children and adults from these elements. The principal component analysis (PCA) and cluster analysis (CA) found that the variations in the Cr and Ni concentrations were largely on account of the soil parent rocks, but the As, Cd, Cu, and Hg variations in the soil were largely owing to agricultural practices of years. However, the main factor influencing Pb and Zn was atmospheric deposition.
Efficient removal of arsenic(III) from aqueous media using magnetic polyaniline-doped strontium–titanium nanocomposite
Abstract
In this study, a novel nanocomposite adsorbent based on magnetic polyaniline and strontium–titanium (MP-SrTiO3) nanoparticles was synthesized via a simple and low-cost polymerization method for efficiently removing of arsenic(III) ions from aqueous samples. The chemical structure, surface properties, and morphology of the prepared adsorbent were studied using Fourier transform infrared spectroscopy (FTIR), energy-dispersive X-ray spectroscopy (EDX), and scanning electron microscopy (SEM). The main effective parameters on the removal efficiency, such as pH, adsorbent dosage, salt, and contact time, were studied and optimized. The validity of the proposed method was checked by adsorption isotherm and kinetics models. Consequently, the adsorption kinetics corresponded to the first order (R2 > 0.99), and the experimental equilibrium fitted the Langmuir model with a maximum monolayer adsorption capacity of 67.11 mg/g (R2 > 0.99) for arsenic(III) ions. Corresponding to thermodynamic Vant's Hof model (ΔG° (kJ/mol), ΔH° (kJ/mol), and ΔS° (kJ/mol K) − 8.19, − 60.61, and − 0.17, respectively), the mechanism and adsorption nature were investigated with that suggested exothermic and physisorption mechanism.
Corrigendum to “Disinfection and healing effects of 222-nm UVC light on methicillin-resistant Staphylococcus aureus infection in mouse wounds” [J. Photochem. Photobiol. B Biol. 178 (January 2018) 10–18]
Publication date: Available online 4 April 2018
Source:Journal of Photochemistry and Photobiology B: Biology
Author(s): Kouji Narita, Krisana Asano, Yukihiro Morimoto, Tatsushi Igarashi, Michael R. Hamblin, Tianhong Dai, Akio Nakane
Improved chemo-photothermal therapy of hepatocellular carcinoma using chitosan-coated gold nanoparticles
Publication date: Available online 4 April 2018
Source:Journal of Photochemistry and Photobiology B: Biology
Author(s): Dina S. Salem, Mahmoud A. Sliem, Mohamed El-Sesy, Samia A. Shouman, Yehia Badr
A green method was used for producing gold nanoparticles (Au NPs) using chitosan as a natural cationic, biodegradable and biocompatible polymer. In this method, chitosan acts as a reducing and stabilizing agent for the synthesis of Au NPs. Different concentrations of chitosan solutions (0.01%, 0.05%, 0.1%, 0.2%, 0.5% and 1%) were applied. In an attempt to mitigate the side effects of anti-cancer drug, 5-fluorouracil (5-FU), through reducing drug doses in photothermal therapy, the formed positively-charged chitosan-wrapped Au NPs were used as a drug delivery system for negatively charged 5-FU to hepatocellular carcinoma cells (HepG2). Au NPs as well as 5-FU@Au nanocomposites were characterized with UV-VIS spectroscopy, particle size, zeta potential, Fourier transform infrared spectroscopy (FTIR), transmission electron microscopy (TEM) and High-Performance Liquid Chromatography (HPLC). The chitosan concentration was shown to be an important parameter for optimizing the dispersion of Au NPs and 5-FU@Au nanocomposites over long time. This stability offers the 5-FU@Au nanocomposites as good candidate for cancer treatment with reduced drug doses in photothermal therapy. A 72% loading-efficiency of 5-FU was obtained. Cytotoxic assay was carried out on HepG2 cell line and it reveals the effectiveness of 5-FU@Au nanocomposites in the presence and absence of laser irradiation compared with the free 5-FU. The cytotoxicity effect of free 5-FU and 5-FU@AuNPs nanocomposites was studied, and it was found that the concentration of 5-FU@Au nanocomposites required to attain 50% of inhibition growth rate was lower than that of free 5-FU in absence of laser radiation and was much lower in presence of laser radiation.
Graphical abstract
A novel approach to evaluate potential risk of organic enrichment in marine aquaculture farms: a case study in Sanggou Bay
Abstract
A novel approach was proposed to evaluate the potential risk of organic enrichment in marine aquaculture farms without obvious environmental degradation. The approach was based on historical environmental records preserved in sediment cores, and potential risk of organic enrichment can be effectively evaluated by comparing burial fluxes of marine organic carbon (OCM) during times before and after large-scale aquaculture. A case study was conducted in Sanggou Bay. The change trends on burial fluxes of organic carbon in sediment over the past 150 years were rebuilt. OCM burial fluxes have greatly increased since the beginning of large-scale aquaculture in 1980s, reaching 16.0~16.5 times higher than that before large-scale aquaculture. The results indicate that aquaculture activities have resulted in obvious accumulation of aquacultural organic matters, although sedimental environment has not degraded seriously. Besides, if the OCM burial fluxes further increase to 3.5~7.0 times higher than that in present, sedimental environment may degrade obviously. Therefore, potential risks of organic enrichment still exist with aquaculture development in Sanggou Bay.
Association of Hidradenitis Suppurativa With T Helper 1/T Helper 17 Phenotypes
This case series uses semantic map analysis to assess the association of hidradenitis suppurativa with T helper 1/T helper 17 phenotypes.
Task Shifting in Dermatology—A Call to Action
To the Editor In response to the Evidence Synopsis by Brown et al on the practice of task shifting, we would like to highlight how task shifting is currently being successfully implemented in health programs in India, with emphasis on National Leprosy Eradication Program.
Indoor Tanners as a Priority Population for Skin Cancer Screening
The study by Heckman et al published in this issue of JAMA Dermatology makes a significant contribution to our understanding of skin cancer screening for indoor tanners. The literature contains only a handful of studies that examined skin screening prevalence and factors that may be associated with this practice among indoor tanners. The National Health Interview Survey (NHIS), a national probability survey of the US adult population, collects data on skin screening and indoor tanning and provides a valuable opportunity to examine potential factors associated with these practices in a large sample. Results of previous studies of skin screening and indoor tanning using NHIS data have been mixed, possibly because of differences in methods and sampling. One study of 2010 NHIS data found a positive association between indoor tanning in the past year and ever having had a skin examination, whereas another study of a subsample of the 2015 NHIS data found no association.
Prevalence of Delusional Infestation—A Population-Based Study
This population-based study reports the prevalence of delusional infestation in Olmsted County, Minnesota.
Atorvastatin in Combination With Narrowband UV-B in Adult Patients With Active Vitiligo
This randomized clinical trial evaluates the use of atorvastatin combined with narrowband UV-B therapy vs narrowband UV-B therapy alone in adult patients with active vitiligo.
Task Shifting in Dermatology—A Call to Action—Reply
In Reply We greatly appreciate the response by Bishnoi et al to "Task Shifting in Dermatology: A Call to Action." Their group's use of task shifting for early diagnosis of leprosy throughout remote areas of India is highly commendable. They emphasize that the challenges of task shifting include both the need for well-resourced training centers and "meticulous strategies." As outlined in their letter, task shifting involves training of an available workforce to meet previously unmet needs in the health care system, which may include community and individual education, diagnosis, referral to tertiary care centers, or treatment. We propose task shifting as a potential means to meet dermatologic needs specifically in lower- and middle-income countries. Worldwide, there exists an inequitable dermatologic treatment gap, and dermatologic disease is the fourth leading cause of morbidity globally. What is lacking are large-scale trials assessing the efficacy of (1) training of these health care workers and (2) implementation of task-shifting interventions, specifically in areas of dermatology diagnosis, triage, and treatment. Assessment of efficacy in the dermatologic setting is necessary prior to scaling up task-shifting interventions. The field of psychiatry has demonstrated through large randomized clinical trials in lower- and middle-income countries that community health care providers can effectively implement psychological therapies for diseases such as depression and alcoholism, and we propose that task shifting in dermatology be similarly systematically assessed.
Skin Cancer Screening Among Indoor Tanners and Nontanners
This survey study of 30 352 participants investigates the association between indoor tanning and skin cancer screening.
Domain-General and Domain-Specific Patterns of Activity Supporting Metacognition in Human Prefrontal Cortex
Metacognition is the capacity to evaluate the success of one's own cognitive processes in various domains; for example, memory and perception. It remains controversial whether metacognition relies on a domain-general resource that is applied to different tasks or if self-evaluative processes are domain specific. Here, we investigated this issue directly by examining the neural substrates engaged when metacognitive judgments were made by human participants of both sexes during perceptual and memory tasks matched for stimulus and performance characteristics. By comparing patterns of fMRI activity while subjects evaluated their performance, we revealed both domain-specific and domain-general metacognitive representations. Multivoxel activity patterns in anterior prefrontal cortex predicted levels of confidence in a domain-specific fashion, whereas domain-general signals predicting confidence and accuracy were found in a widespread network in the frontal and posterior midline. The demonstration of domain-specific metacognitive representations suggests the presence of a content-rich mechanism available to introspection and cognitive control.
SIGNIFICANCE STATEMENT We used human neuroimaging to investigate processes supporting memory and perceptual metacognition. It remains controversial whether metacognition relies on a global resource that is applied to different tasks or if self-evaluative processes are specific to particular tasks. Using multivariate decoding methods, we provide evidence that perceptual- and memory-specific metacognitive representations coexist with generic confidence signals. Our findings reconcile previously conflicting results on the domain specificity/generality of metacognition and lay the groundwork for a mechanistic understanding of metacognitive judgments.
{beta}-Secretase BACE1 Promotes Surface Expression and Function of Kv3.4 at Hippocampal Mossy Fiber Synapses
The β-secretase β-site APP-cleaving enzyme 1 (BACE1) is deemed a major culprit in Alzheimer's disease, but accumulating evidence indicates that there is more to the enzyme than driving the amyloidogenic processing of the amyloid precursor protein. For example, BACE1 has emerged as an important regulator of neuronal activity through proteolytic and, most unexpectedly, also through nonproteolytic interactions with several ion channels. Here, we identify and characterize the voltage-gated K+ channel 3.4 (Kv3.4) as a new and functionally relevant interaction partner of BACE1. Kv3.4 gives rise to A-type current with fast activating and inactivating kinetics and serves to repolarize the presynaptic action potential. We found that BACE1 and Kv3.4 are highly enriched and remarkably colocalized in hippocampal mossy fibers (MFs). In BACE1–/– mice of either sex, Kv3.4 surface expression was significantly reduced in the hippocampus and, in synaptic fractions thereof, Kv3.4 was specifically diminished, whereas protein levels of other presynaptic K+ channels such as KCa1.1 and KCa2.3 remained unchanged. The apparent loss of presynaptic Kv3.4 affected the strength of excitatory transmission at the MF–CA3 synapse in hippocampal slices of BACE1–/– mice when probed with the Kv3 channel blocker BDS-I. The effect of BACE1 on Kv3.4 expression and function should be bidirectional, as predicted from a heterologous expression system, in which BACE1 cotransfection produced a concomitant upregulation of Kv3.4 surface level and current based on a physical interaction between the two proteins. Our data show that, by targeting Kv3.4 to presynaptic sites, BACE1 endows the terminal with a powerful means to regulate the strength of transmitter release.
SIGNIFICANCE STATEMENT The β-secretase β-site APP-cleaving enzyme 1 (BACE1) is infamous for its crucial role in the pathogenesis of Alzheimer's disease, but its physiological functions in the intact nervous system are only gradually being unveiled. Here, we extend previous work implicating BACE1 in the expression and function of voltage-gated Na+ and K+ channels. Specifically, we characterize voltage-gated K+ channel 3.4 (Kv3.4), a presynaptic K+ channel required for action potential repolarization, as a novel interaction partner of BACE1 at the mossy fiber (MF)–CA3 synapse of the hippocampus. BACE1 promotes surface expression of Kv3.4 at MF terminals, most likely by physically associating with the channel protein in a nonenzymatic fashion. We advance the BACE1–Kv3.4 interaction as a mechanism to strengthen the temporal control over transmitter release from MF terminals.
Excreted Steroids in Vertebrate Social Communication
Steroids play vital roles in animal physiology across species, and the production of specific steroids is associated with particular internal biological functions. The internal functions of steroids are, in most cases, quite clear. However, an important feature of many steroids (their chemical stability) allows these molecules to play secondary, external roles as chemical messengers after their excretion via urine, feces, or other shed substances. The presence of steroids in animal excretions has long been appreciated, but their capacity to serve as chemosignals has not received as much attention. In theory, the blend of steroids excreted by an animal contains a readout of its own biological state. Initial mechanistic evidence for external steroid chemosensation arose from studies of many species of fish. In sea lampreys and ray-finned fishes, bile salts were identified as potent olfactory cues and later found to serve as pheromones. Recently, we and others have discovered that neurons in amphibian and mammalian olfactory systems are also highly sensitive to excreted glucocorticoids, sex steroids, and bile acids, and some of these molecules have been confirmed as mammalian pheromones. Steroid chemosensation in olfactory systems, unlike steroid detection in most tissues, is performed by plasma membrane receptors, but the details remain largely unclear. In this review, we present a broad view of steroid detection by vertebrate olfactory systems, focusing on recent research in fishes, amphibians, and mammals. We review confirmed and hypothesized mechanisms of steroid chemosensation in each group and discuss potential impacts on vertebrate social communication.
Role of Rostral Fastigial Neurons in Encoding a Body-Centered Representation of Translation in Three Dimensions
Many daily behaviors rely critically on estimates of our body motion. Such estimates must be computed by combining neck proprioceptive signals with vestibular signals that have been transformed from a head- to a body-centered reference frame. Recent studies showed that deep cerebellar neurons in the rostral fastigial nucleus (rFN) reflect these computations, but whether they explicitly encode estimates of body motion remains unclear. A key limitation in addressing this question is that, to date, cell tuning properties have only been characterized for a restricted set of motions across head-re-body orientations in the horizontal plane. Here we examined, for the first time, how 3D spatiotemporal tuning for translational motion varies with head-re-body orientation in both horizontal and vertical planes in the rFN of male macaques. While vestibular coding was profoundly influenced by head-re-body position in both planes, neurons typically reflected at most a partial transformation. However, their tuning shifts were not random but followed the specific spatial trajectories predicted for a 3D transformation. We show that these properties facilitate the linear decoding of fully body-centered motion representations in 3D with a broad range of temporal characteristics from small groups of 5–7 cells. These results demonstrate that the vestibular reference frame transformation required to compute body motion is indeed encoded by cerebellar neurons. We propose that maintaining partially transformed rFN responses with different spatiotemporal properties facilitates the creation of downstream body motion representations with a range of dynamic characteristics, consistent with the functional requirements for tasks such as postural control and reaching.
SIGNIFICANCE STATEMENT Estimates of body motion are essential for many daily activities. Vestibular signals are important contributors to such estimates but must be transformed from a head- to a body-centered reference frame. Here, we provide the first direct demonstration that the cerebellum computes this transformation fully in 3D. We show that the output of these computations is reflected in the tuning properties of deep cerebellar rostral fastigial nucleus neurons in a specific distributed fashion that facilitates the efficient creation of body-centered translation estimates with a broad range of temporal properties (i.e., from acceleration to position). These findings support an important role for the rostral fastigial nucleus as a source of body translation estimates functionally relevant for behaviors ranging from postural control to perception.
Choice for Drug or Natural Reward Engages Largely Overlapping Neuronal Ensembles in the Infralimbic Prefrontal Cortex
Cue-reward associations form distinct memories that can drive appetitive behaviors and are involved in craving for both drugs and natural rewards. Distinct sets of neurons, so-called neuronal ensembles, in the infralimbic area (IL) of the medial prefrontal cortex (mPFC) play a key role in alcohol seeking. Whether this ensemble is specific for alcohol or controls reward seeking in general remains unclear. Here, we compared IL ensembles formed upon recall of drug (alcohol) or natural reward (saccharin) memories in male Wistar rats. Using an experimental framework that allows identification of two distinct reward-associated ensembles within the same animal, we found that cue-induced seeking of either alcohol or saccharin activated ensembles of similar size and organization, whereby these ensembles consist of largely overlapping neuronal populations. Thus, the IL seems to act as a general integration hub for reward seeking behavior, but also contains subsets of neurons that encode for the different rewards.
SIGNIFICANCE STATEMENT Cue-reward associations form distinct memories that can act as drivers of appetitive behaviors and are involved in craving for natural rewards as well as for drugs. Distinct sets of neurons, so-called neuronal ensembles, in the infralimbic area of the mPFC play a key role in cue-triggered reward seeking. However, it is unclear whether these ensembles act as broadly tuned controllers of approach behavior or represent the learned associations between specific cues and rewards. Using an experimental framework that allows identification of two distinct reward-associated ensembles within the same animal we find largely overlapping neuronal populations. Repeated activation by two distinct events could reflect the linking of the two memory traces within the same neuron.
The Integration of Functional Brain Activity from Adolescence to Adulthood
Age-related changes in human functional neuroanatomy are poorly understood. This is partly due to the limits of interpretation of standard fMRI. These limits relate to age-related variation in noise levels in data from different subjects, and the common use of standard adult brain parcellations for developmental studies. Here we used an emerging MRI approach called multiecho (ME)-fMRI to characterize functional brain changes with age. ME-fMRI acquires blood oxygenation level-dependent (BOLD) signals while also quantifying susceptibility-weighted transverse relaxation time (T2*) signal decay. This approach newly enables reliable detection of BOLD signal components at the subject level as opposed to solely at the group-average level. In turn, it supports more robust characterization of the variability in functional brain organization across individuals. We hypothesized that BOLD components in the resting state are not stable with age, and would decrease in number from adolescence to adulthood. This runs counter to the current assumptions in neurodevelopmental analyses of brain connectivity that the number of BOLD signal components is a random effect. From resting-state ME-fMRI of 51 healthy subjects of both sexes, between 8.3 and 46.2 years of age, we found a highly significant (r = –0.55, p << 0.001) exponential decrease in the number of BOLD components with age. The number of BOLD components were halved from adolescence to the fifth decade of life, stabilizing in middle adulthood. The regions driving this change were dorsolateral prefrontal cortices, parietal cortex, and cerebellum. The functional network of these regions centered on the cerebellum. We conclude that an age-related decrease in BOLD component number concurs with the hypothesis of neurodevelopmental integration of functional brain activity. We show evidence that the cerebellum may play a key role in this process.
SIGNIFICANCE STATEMENT Human brain development is ongoing from childhood to at least 30 years of age. Functional MRI (fMRI) is key for characterizing changes in brain function that accompany development. However, developmental fMRI studies have relied on reference maps of adult brain organization in the analysis of data from younger subjects. This approach may limit the characterization of functional activity patterns that are particular to children and adolescents. Here we used an emerging fMRI approach called multi-echo fMRI that is not susceptible to such biases when analyzing the variation in functional brain organization over development. We hypothesized an integration of the components of brain activity over development, and found that the number of components decreases exponentially, halving from 8 to 35 years of age. The brain regions most affected underlie executive function and coordination. In summary, we show major changes in the organization and integration of functional networks over development into adulthood, with both methodological and neurobiological implications for future lifespan and disease studies on brain connectivity.
Swedish Nerve Growth Factor Mutation (NGFR100W) Defines a Role for TrkA and p75NTR in Nociception
Nerve growth factor (NGF) exerts multiple functions on target neurons throughout development. The recent discovery of a point mutation leading to a change from arginine to tryptophan at residue 100 in the mature NGFβ sequence (NGFR100W) in patients with hereditary sensory and autonomic neuropathy type V (HSAN V) made it possible to distinguish the signaling mechanisms that lead to two functionally different outcomes of NGF: trophic versus nociceptive. We performed extensive biochemical, cellular, and live-imaging experiments to examine the binding and signaling properties of NGFR100W. Our results show that, similar to the wild-type NGF (wtNGF), the naturally occurring NGFR100W mutant was capable of binding to and activating the TrkA receptor and its downstream signaling pathways to support neuronal survival and differentiation. However, NGFR100W failed to bind and stimulate the 75 kDa neurotrophic factor receptor (p75NTR)-mediated signaling cascades (i.e., the RhoA-Cofilin pathway). Intraplantar injection of NGFR100W into adult rats induced neither TrkA-mediated thermal nor mechanical acute hyperalgesia, but retained the ability to induce chronic hyperalgesia based on agonism for TrkA signaling. Together, our studies provide evidence that NGFR100W retains trophic support capability through TrkA and one aspect of its nociceptive signaling, but fails to engage p75NTR signaling pathways. Our findings suggest that wtNGF acts via TrkA to regulate the delayed priming of nociceptive responses. The integration of both TrkA and p75NTR signaling thus appears to regulate neuroplastic effects of NGF in peripheral nociception.
SIGNIFICANCE STATEMENT In the present study, we characterized the naturally occurring nerve growth factor NGFR100W mutant that is associated with hereditary sensory and autonomic neuropathy type V. We have demonstrated for the first time that NGFR100W retains trophic support capability through TrkA, but fails to engage p75NTR signaling pathways. Furthermore, after intraplantar injection into adult rats, NGFR100W induced neither thermal nor mechanical acute hyperalgesia, but retained the ability to induce chronic hyperalgesia. We have also provided evidence that the integration of both TrkA- and p75NTR-mediated signaling appears to regulate neuroplastic effects of NGF in peripheral nociception. Our study with NGFR100W suggests that it is possible to uncouple trophic effect from nociceptive function, both induced by wild-type NGF.
Heteromeric KV2/KV8.2 Channels Mediate Delayed Rectifier Potassium Currents in Primate Photoreceptors
Silent voltage-gated potassium channel subunits (KVS) interact selectively with members of the KV2 channel family to modify their functional properties. The localization and functional roles of these silent subunits remain poorly understood. Mutations in the KVS subunit, KV8.2 (KCNV2), lead to severe visual impairment in humans, but the basis of these deficits remains unclear. Here, we examined the localization, native interactions, and functional properties of KV8.2-containing channels in mouse, macaque, and human photoreceptors of either sex. In human retina, KV8.2 colocalized with KV2.1 and KV2.2 in cone inner segments and with KV2.1 in rod inner segments. KV2.1 and KV2.2 could be coimmunoprecipitated with KV8.2 in retinal lysates indicating that these subunits likely interact directly. Retinal KV2.1 was less phosphorylated than cortical KV2.1, a difference expected to alter the biophysical properties of these channels. Using voltage-clamp recordings and pharmacology, we provide functional evidence for Kv2-containing channels in primate rods and cones. We propose that the presence of KV8.2, and low levels of KV2.1 phosphorylation shift the activation range of KV2 channels to align with the operating range of rod and cone photoreceptors. Our data indicate a role for KV2/KV8.2 channels in human photoreceptor function and suggest that the visual deficits in patients with KCNV2 mutations arise from inadequate resting activation of KV channels in rod and cone inner segments.
SIGNIFICANCE STATEMENT Mutations in a voltage-gated potassium channel subunit, KV8.2, underlie a blinding inherited photoreceptor dystrophy, indicating an important role for these channels in human vision. Here, we have defined the localization and subunit interactions of KV8.2 channels in primate photoreceptors. We show that the KV8.2 subunit interacts with different Kv2 channels in rods and cones, giving rise to potassium currents with distinct functional properties. Our results provide a molecular basis for retinal dysfunction in patients with mutations in the KCNV2 gene encoding KV8.2.
Can Serial Dependencies in Choices and Neural Activity Explain Choice Probabilities?
During perceptual decisions the activity of sensory neurons covaries with choice, a covariation often quantified as "choice-probability". Moreover, choices are influenced by a subject's previous choice (serial dependence) and neuronal activity often shows temporal correlations on long (seconds) timescales. Here, we test whether these findings are linked. Using generalized linear models, we analyze simultaneous measurements of behavior and V2 neural activity in macaques performing a visual discrimination task. Both, decisions and spiking activity show substantial temporal correlations and cross-correlations but seem to reflect two mostly separate processes. Indeed, removing history effects using semipartial correlation analysis leaves choice probabilities largely unchanged. The serial dependencies in choices and neural activity therefore cannot explain the observed choice probability. Rather, serial dependencies in choices and spiking activity reflect two predominantly separate but parallel processes, which are coupled on each trial by covariations between choices and activity. These findings provide important constraints for computational models of perceptual decision-making that include feedback signals.
SIGNIFICANCE STATEMENT Correlations, unexplained by the sensory input, between the activity of sensory neurons and an animal's perceptual choice ("choice probabilities") have received attention from both a systems and computational neuroscience perspective. Conversely, whereas temporal correlations for both spiking activity ("non-stationarities") and for a subject's choices in perceptual tasks ("serial dependencies") have long been established, they have typically been ignored when measuring choice probabilities. Some accounts of choice probabilities incorporating feedback predict that these observations are linked. Here, we explore the extent to which this is the case. We find that, contrasting with these predictions, choice probabilities are largely independent of serial dependencies, which adds new constraints to accounts of choice probabilities that include feedback.
The Sync/deSync Model: How a Synchronized Hippocampus and a Desynchronized Neocortex Code Memories
Neural oscillations are important for memory formation in the brain. The desynchronization of alpha (10 Hz) oscillations in the neocortex has been shown to predict successful memory encoding and retrieval. However, when engaging in learning, it has been found that the hippocampus synchronizes in theta (4 Hz) oscillations, and that learning is dependent on the phase of theta. This inconsistency as to whether synchronization is "good" for memory formation leads to confusion over which oscillations we should expect to see and where during learning paradigm experiments. This paper seeks to respond to this inconsistency by presenting a neural network model of how a well functioning learning system could exhibit both of these phenomena, i.e., desynchronization of alpha and synchronization of theta during successful memory encoding.
We present a spiking neural network (the Sync/deSync model) of the neocortical and hippocampal system. The simulated hippocampus learns through an adapted spike-time dependent plasticity rule, in which weight change is modulated by the phase of an extrinsically generated theta oscillation. Additionally, a global passive weight decay is incorporated, which is also modulated by theta phase. In this way, the Sync/deSync model exhibits theta phase-dependent long-term potentiation and long-term depression. We simulated a learning paradigm experiment and compared the oscillatory dynamics of our model with those observed in single-cell and scalp-EEG studies of the medial temporal lobe. Our Sync/deSync model suggests that both the desynchronization of neocortical alpha and the synchronization of hippocampal theta are necessary for successful memory encoding and retrieval.
SIGNIFICANCE STATEMENT A fundamental question is the role of rhythmic activation of neurons, i.e., how and why their firing oscillates between high and low rates. A particularly important question is how oscillatory dynamics between the neocortex and hippocampus support memory formation. We present a spiking neural-network model of such memory formation, with the central ideas that (1) in neocortex, neurons need to break out of an alpha oscillation to represent a stimulus (i.e., alpha desynchronizes), whereas (2) in hippocampus, the firing of neurons at theta facilitates formation of memories (i.e., theta synchronizes). Accordingly, successful memory formation is marked by reduced neocortical alpha and increased hippocampal theta. This pattern has been observed experimentally and gives our model its name—the Sync/deSync model.
TRPM2 Channel Aggravates CNS Inflammation and Cognitive Impairment via Activation of Microglia in Chronic Cerebral Hypoperfusion
Chronic cerebral hypoperfusion is a characteristic seen in widespread CNS diseases, including neurodegenerative and mental disorders, and is commonly accompanied by cognitive impairment. Recently, several studies demonstrated that chronic cerebral hypoperfusion can induce the excessive inflammatory responses that precede neuronal dysfunction; however, the precise mechanism of cognitive impairment due to chronic cerebral hypoperfusion remains unknown. Transient receptor potential melastatin 2 (TRPM2) is a Ca2+-permeable channel that is abundantly expressed in immune cells and is involved in aggravation of inflammatory responses. Therefore, we investigated the pathophysiological role of TRPM2 in a mouse chronic cerebral hypoperfusion model with bilateral common carotid artery stenosis (BCAS). When male mice were subjected to BCAS, cognitive dysfunction and white matter injury at day 28 were significantly improved in TRPM2 knock-out (TRPM2-KO) mice compared with wild-type (WT) mice, whereas hippocampal damage was not observed. There were no differences in blood–brain barrier breakdown and H2O2 production between the two genotypes at 14 and 28 d after BCAS. Cytokine production was significantly suppressed in BCAS-operated TRPM2-KO mice compared with WT mice at day 28. In addition, the number of Iba1-positive cells gradually decreased from day 14. Moreover, daily treatment with minocycline significantly improved cognitive perturbation. Surgical techniques using bone marrow chimeric mice revealed that activated Iba1-positive cells in white matter could be brain-resident microglia, not peripheral macrophages. Together, these findings suggest that microglia contribute to the aggravation of cognitive impairment by chronic cerebral hypoperfusion, and that TRPM2 may be a potential target for chronic cerebral hypoperfusion-related disorders.
SIGNIFICANCE STATEMENT Chronic cerebral hypoperfusion is manifested in a wide variety of CNS diseases, including neurodegenerative and mental disorders that are accompanied by cognitive impairment; however, the underlying mechanisms require clarification. Here, we used a chronic cerebral hypoperfusion mouse model to investigate whether TRPM2, a Ca2+-permeable cation channel highly expressed in immune cells, plays a destructive role in the development of chronic cerebral hypoperfusion-induced cognitive impairment, and propose a new hypothesis in which TRPM2-mediated activation of microglia, not macrophages, specifically contributes to the pathology through the aggravation of inflammatory responses. These findings shed light on the understanding of the mechanisms of chronic cerebral hypoperfusion-related inflammation, and are expected to provide a novel therapeutic molecule for cognitive impairment in CNS diseases.
Attention Selectively Gates Afferent Signal Transmission to Area V4
Selective attention allows focusing on only part of the incoming sensory information. Neurons in the extrastriate visual cortex reflect such selective processing when different stimuli are simultaneously present in their large receptive fields. Their spiking response then resembles the response to the attended stimulus when presented in isolation. Unclear is where in the neuronal pathway attention intervenes to achieve such selective signal routing and processing. To investigate this question, we tagged two equivalent visual stimuli by independent broadband luminance noise and used the spectral coherence of these behaviorally irrelevant signals with the field potential of a local neuronal population in male macaque monkeys' area V4 as a measure for their respective causal influences. This new experimental paradigm revealed that signal transmission was considerably weaker for the not-attended stimulus. Furthermore, our results show that attention does not need to modulate responses in the input populations sending signals to V4 to selectively represent a stimulus, nor do they suggest a change of the V4 neurons' output gain depending on their feature similarity with the stimuli. Our results rather imply that selective attention uses a gating mechanism comprising the synaptic "inputs" that transmit signals from upstream areas into the V4 neurons. A minimal model implementing attention-dependent routing by gamma-band synchrony replicated the attentional gating effect and the signals' spectral transfer characteristics. It supports the proposal that selective interareal gamma-band synchrony subserves signal routing and explains our experimental finding that attention selectively gates signals already at the level of afferent synaptic input.
SIGNIFICANCE STATEMENT Depending on the behavioral context, the brain needs to channel the flow of information through its networks of massively interconnected neurons. We designed an experiment that allows to causally assess routing of information originating from an attended object. We found that attention "gates" signals at the interplay between afferent fibers and the local neurons. A minimal model demonstrated that coherent gamma-rhythmic activity (~60 Hz) between local neurons and their afferent-providing input neurons can realize the gating. Importantly, the attended signals did not need to be amplified already in an earlier processing stage, nor did they get amplified by a simple output response modulation. The method provides a useful tool to study mechanisms of dynamic network configuration underlying cognitive processes.
Coordinated Ramping of Dorsal Striatal Pathways preceding Food Approach and Consumption
The striatum controls food-related actions and consumption and is linked to feeding disorders, including obesity and anorexia nervosa. Two populations of neurons project from the striatum: direct pathway medium spiny neurons and indirect pathway medium spiny neurons. The selective contribution of direct pathway medium spiny neurons and indirect pathway medium spiny neurons to food-related actions and consumption remains unknown. Here, we used in vivo electrophysiology and fiber photometry in mice (of both sexes) to record both spiking activity and pathway-specific calcium activity of dorsal striatal neurons during approach to and consumption of food pellets. While electrophysiology revealed complex task-related dynamics across neurons, population calcium was enhanced during approach and inhibited during consumption in both pathways. We also observed ramping changes in activity that preceded both pellet-directed actions and spontaneous movements. These signals were heterogeneous in the spiking units, with neurons exhibiting either increasing or decreasing ramps. In contrast, the population calcium signals were homogeneous, with both pathways having increasing ramps of activity for several seconds before actions were initiated. An analysis comparing population firing rates to population calcium signals also revealed stronger ramping dynamics in the calcium signals than in the spiking data. In a second experiment, we trained the mice to perform an action sequence to evaluate when the ramping signals terminated. We found that the ramping signals terminated at the beginning of the action sequence, suggesting they may reflect upcoming actions and not preconsumption activity. Plasticity of such mechanisms may underlie disorders that alter action selection, such as drug addiction or obesity.
SIGNIFICANCE STATEMENT Alterations in striatal function have been linked to pathological consumption in disorders, such as obesity and drug addiction. We recorded spiking and population calcium activity from the dorsal striatum during ad libitum feeding and an operant task that resulted in mice obtaining food pellets. Dorsal striatal neurons exhibited long ramps in activity that preceded actions by several seconds, and may reflect upcoming actions. Understanding how the striatum controls the preparation and generation of actions may lead to improved therapies for disorders, such as drug addiction or obesity.
Development of the Mechanisms Governing Midbrain Multisensory Integration
The ability to integrate information across multiple senses enhances the brain's ability to detect, localize, and identify external events. This process has been well documented in single neurons in the superior colliculus (SC), which synthesize concordant combinations of visual, auditory, and/or somatosensory signals to enhance the vigor of their responses. This increases the physiological salience of crossmodal events and, in turn, the speed and accuracy of SC-mediated behavioral responses to them. However, this capability is not an innate feature of the circuit and only develops postnatally after the animal acquires sufficient experience with covariant crossmodal events to form links between their modality-specific components. Of critical importance in this process are tectopetal influences from association cortex. Recent findings suggest that, despite its intuitive appeal, a simple generic associative rule cannot explain how this circuit develops its ability to integrate those crossmodal inputs to produce enhanced multisensory responses. The present neurocomputational model explains how this development can be understood as a transition from a default state in which crossmodal SC inputs interact competitively to one in which they interact cooperatively. Crucial to this transition is the operation of a learning rule requiring coactivation among tectopetal afferents for engagement. The model successfully replicates findings of multisensory development in normal cats and cats of either sex reared with special experience. In doing so, it explains how the cortico–SC projections can use crossmodal experience to craft the multisensory integration capabilities of the SC and adapt them to the environment in which they will be used.
SIGNIFICANCE STATEMENT The brain's remarkable ability to integrate information across the senses is not present at birth, but typically develops in early life as experience with crossmodal cues is acquired. Recent empirical findings suggest that the mechanisms supporting this development must be more complex than previously believed. The present work integrates these data with what is already known about the underlying circuit in the midbrain to create and test a mechanistic model of multisensory development. This model represents a novel and comprehensive framework that explains how midbrain circuits acquire multisensory experience and reveals how disruptions in this neurotypic developmental trajectory yield divergent outcomes that will affect the multisensory processing capabilities of the mature brain.
Cereblon Maintains Synaptic and Cognitive Function by Regulating BK Channel
Mutations in the cereblon (CRBN) gene cause human intellectual disability, one of the most common cognitive disorders. However, the molecular mechanisms of CRBN-related intellectual disability remain poorly understood. We investigated the role of CRBN in synaptic function and animal behavior using male mouse and Drosophila models. Crbn knock-out (KO) mice showed normal brain and spine morphology as well as intact synaptic plasticity; however, they also exhibited decreases in synaptic transmission and presynaptic release probability exclusively in excitatory synapses. Presynaptic function was impaired not only by loss of CRBN expression, but also by expression of pathogenic CRBN mutants (human R419X mutant and Drosophila G552X mutant). We found that the BK channel blockers paxilline and iberiotoxin reversed this decrease in presynaptic release probability in Crbn KO mice. In addition, paxilline treatment also restored normal cognitive behavior in Crbn KO mice. These results strongly suggest that increased BK channel activity is the pathological mechanism of intellectual disability in CRBN mutations.
SIGNIFICANCE STATEMENT Cereblon (CRBN), a well known target of the immunomodulatory drug thalidomide, was originally identified as a gene that causes human intellectual disability when mutated. However, the molecular mechanisms of CRBN-related intellectual disability remain poorly understood. Based on the idea that synaptic abnormalities are the most common factor in cognitive dysfunction, we monitored the synaptic structure and function of Crbn knock-out (KO) animals to identify the molecular mechanisms of intellectual disability. Here, we found that Crbn KO animals showed cognitive deficits caused by enhanced BK channel activity and reduced presynaptic glutamate release. Our findings suggest a physiological pathomechanism of the intellectual disability-related gene CRBN and will contribute to the development of therapeutic strategies for CRBN-related intellectual disability.
Glutathione Conjugation at the Blood-CSF Barrier Efficiently Prevents Exposure of the Developing Brain Fluid Environment to Blood-Borne Reactive Electrophilic Substances
Exposure of the developing brain to toxins, drugs, or deleterious endogenous compounds during the perinatal period can trigger alterations in cell division, migration, differentiation, and synaptogenesis, leading to lifelong neurological impairment. The brain is protected by cellular barriers acting through multiple mechanisms, some of which are still poorly explored. We used a combination of enzymatic assays, live tissue fluorescence microscopy, and an in vitro cellular model of the blood–CSF barrier to investigate an enzymatic detoxification pathway in the developing male and female rat brain. We show that during the early postnatal period the choroid plexus epithelium forming the blood–CSF barrier and the ependymal cell layer bordering the ventricles harbor a high detoxifying capacity that involves glutathione S-transferases. Using a functional knock-down rat model for choroidal glutathione conjugation, we demonstrate that already in neonates, this metabolic pathway efficiently prevents the penetration of blood-borne reactive compounds into CSF. The versatility of the protective mechanism results from the multiplicity of the glutathione S-transferase isoenzymes, which are differently expressed between the choroidal epithelium and the ependyma. The various isoenzymes display differential substrate specificities, which greatly widen the spectrum of molecules that can be inactivated by this pathway. In conclusion, the blood–CSF barrier and the ependyma are identified as key cellular structures in the CNS to protect the brain fluid environment from different chemical classes of potentially toxic compounds during the postnatal period. This metabolic neuroprotective function of brain interfaces ought to compensate for the liver postnatal immaturity.
SIGNIFICANCE STATEMENT Brain homeostasis requires a stable and controlled internal environment. Defective brain protection during the perinatal period can lead to lifelong neurological impairment. We demonstrate that the choroid plexus forming the blood–CSF barrier is a key player in the protection of the developing brain. Glutathione-dependent enzymatic metabolism in the choroidal epithelium inactivates a broad spectrum of noxious compounds, efficiently preventing their penetration into the CSF. A second line of detoxification is located in the ependyma separating the CSF from brain tissue. Our study reveals a novel facet of the mechanisms by which the brain is protected at a period of high vulnerability, at a time when the astrocytic network is still immature and liver xenobiotic metabolism is limited.
Self-guided training for deep brain stimulation planning using objective assessment
Abstract
Objective
Deep brain stimulation (DBS) is an increasingly common treatment for neurodegenerative diseases. Neurosurgeons must have thorough procedural, anatomical, and functional knowledge to plan electrode trajectories and thus ensure treatment efficacy and patient safety. Developing this knowledge requires extensive training. We propose a training approach with objective assessment of neurosurgeon proficiency in DBS planning.
Methods
To assess proficiency, we propose analyzing both the viability of the planned trajectory and the manner in which the operator arrived at the trajectory. To improve understanding, we suggest a self-guided training course for DBS planning using real-time feedback. To validate the proposed measures of proficiency and training course, two experts and six novices followed the training course, and we monitored their proficiency measures throughout.
Results
At baseline, experts planned higher quality trajectories and did so more efficiently. As novices progressed through the training course, their proficiency measures increased significantly, trending toward expert measures.
Conclusion
We developed and validated measures which reliably discriminate proficiency levels. These measures are integrated into a training course, which quantitatively improves trainee performance. The proposed training course can be used to improve trainees' proficiency, and the quantitative measures allow trainees' progress to be monitored.
Discovery of PACAP and its receptors in the brain
Pituitary adenylate-cyclase-activating polypeptide (PACAP) is a 27- or 38-amino acid neuropeptide, which belongs to the vasoactive intestinal polypeptide (VIP)/glucagon/secretin family. PACAP shows particularl...
Microbial activity during a coastal phytoplankton bloom on the Western Antarctic Peninsula in late summer
Abstract
Phytoplankton biomass during the austral summer is influenced by freezing and melting cycles, as well as oceanographic processes that enable nutrient redistribution in the West Antarctic Peninsula (WAP). Microbial functional capabilities, metagenomic and metatranscriptomic activities, as well as inorganic 13C- and 15N-assimilation rates were studied in the surface waters of Chile Bay during two contrasting summer periods in 2014. Concentrations of Chlorophyll a (Chla) varied from 0.3 mg m−3 in February to a maximum of 2.5 mg m−3 in March, together with a decrease in nutrients, however nutrients were never depleted. The microbial community composition remained similar throughout both sampling periods, however, microbial abundance and activity changed with Chla levels. An increased biomass of Bacillariophyta, Haptophyceae, Cryptophyceae was observed along with night-grazing activity of Dinophyceae and ciliates (Alveolates). During high Chla conditions, HCO3− uptake rates during daytime incubations increased 5-fold (>2516 nmol C L−1 d−1), and increased photosynthetic transcript numbers that were mainly associated with cryptophytes; meanwhile night time NO3− (>706 nmol N L−1 d−1) and NH4+ (41.7 nmol N L−1 d−1) uptake rates were 2- and 3-fold higher, respectively, due to activity from alpha-/gamma-Proteobacteria and Bacteroidetes (Flavobacteriia). Due to a projected acceleration in climate change in the WAP, this information is valuable for predicting the composition and functional changes in Antarctic microbial communities.Bacterial machineries for the assembly of membrane-embedded β-barrel proteins
Abstract
The outer membrane (OM) of Gram-negative bacteria is an essential organelle that protects cells from external aggressions and mediates the secretion of virulence factors. Efficient assembly of integral outer membrane β-barrel proteins (OMPs) is crucial for the correct functioning of the OM. Biogenesis of OMPs occurs in a step-wise manner that is finalized by the β-barrel assembly machinery (BAM complex). Some OMPs further require the translocation and assembly module (TAM) for efficient and correct integration into the OM. Both the BAM complex and the TAM contain a protein of the Omp85 superfamily and distinct interacting factors. Their mechanism of action, however, remains largely elusive. We summarize and discuss recent structural and biochemical analyses that are helping to elucidate the molecular pathways of OMP assembly.Climate Change and One Health
Abstract
The journal The Lancet recently published a countdown on health and climate change. Attention was focused solely on humans. However, animals, including wildlife, livestock and pets, may also be impacted by climate change. Complementary to the high relevance of awareness rising for protecting humans against climate change, here we present a One Health approach, which aims at the simultaneous protection of humans, animals and the environment from climate change impacts (climate change adaptation). We postulate that integrated approaches save human and animal lives and reduce costs when compared to public and animal health sectors working separately. A One Health approach to climate change adaptation may significantly contribute to food security with emphasis on animal source foods, extensive livestock systems, particularly ruminant livestock, environmental sanitation, and steps towards regional and global integrated syndromic surveillance and response systems. The cost of outbreaks of emerging vector borne zoonotic pathogens may be much lower if they are detected early in the vector or in livestock rather than later in humans. Therefore, integrated community-based surveillance of zoonoses is a promising avenue to reduce health effects of climate change.Antibiotic resistance phenotypes and virulence-associated genes in Escherichia coli isolated from animals and animal food products in Tunisia
Abstract
Livestock and food products of animal origin constitute important reservoirs of intestinal and extraintestinal pathogenic Escherichia coli including antibiotic-resistant E. coli isolates. To assess potential risks to public health related to E. coli strains of animal origin in Tunisia, 65 E. coli isolates recovered from healthy animals and food products of animal origin were studied. Antimicrobial susceptibility was determined according to CLSI guidelines and genes encoding antibiotic resistance as well as virulence factors were investigated by PCR. High rates of antibiotic resistance were observed to kanamycin (78.4%), gentamicin (75.3%), and streptomycin (75.3%; encoded by strA-strB (7 isolates)), amoxicillin (64.6%), amoxicillin/clavulanic acid (60%), tetracycline (44.6%; tetA (8 isolates) and tetB (7 isolates)), nalidixic acid (27.6%; qnrS (3 isolates), qnrB (2 isolates), and qnrA (one isolate)), and sulfonamides (36.9%; sul1 (1 isolate), sul2 (4 isolates), and sul3 (1 isolate)). Virulotypes classified some isolates as STEC (3%), MNEC (1.5%), and atypical EPEC (1.5%). This study demonstrated high rates of antimicrobial resistance and the presence of some pathogenic pathovars from animal origins that are a cause of concern for public health.Ultrasound thermal monitoring with an external ultrasound source for customized bipolar RF ablation shapes
Abstract
Purpose
Thermotherapy is a clinical procedure which delivers thermal energy to a target, and it has been applied for various medical treatments. Temperature monitoring during thermotherapy is important to achieve precise and reproducible results. Medical ultrasound can be used for thermal monitoring and is an attractive medical imaging modality due to its advantages including non-ionizing radiation, cost-effectiveness and portability. We propose an ultrasound thermal monitoring method using a speed-of-sound tomographic approach coupled with a biophysical heat diffusion model.
Methods
We implement an ultrasound thermometry approach using an external ultrasound source. We reconstruct the speed-of-sound images using time-of-flight information from the external ultrasound source and convert the speed-of-sound information into temperature by using the a priori knowledge brought by a biophysical heat diffusion model.
Results
Customized treatment shapes can be created using switching channels of radio frequency bipolar needle electrodes. Simulations of various ablation lesion shapes in the temperature range of 21–59 \(^\circ \) C are performed to study the feasibility of the proposed method. We also evaluated our method with ex vivo porcine liver experiments, in which we generated temperature images between 22 and 45 \(^\circ \) C.
Conclusion
In this paper, we present a proof of concept showing the feasibility of our ultrasound thermal monitoring method. The proposed method could be applied to various thermotherapy procedures by only adding an ultrasound source.
Biomechanics-based graph matching for augmented CT-CBCT
Abstract
Purpose
Augmenting intraoperative cone beam computed tomography (CBCT) images with preoperative computed tomography data in the context of image-guided liver therapy is proposed. The expected benefit is an improved visualization of tumor(s), vascular system and other internal structures of interest.
Method
An automatic elastic registration based on matching of vascular trees extracted from both the preoperative and intraoperative images is presented. Although methods dedicated to nonrigid graph matching exist, they are not efficient when large intraoperative deformations of tissues occur, as is the case during the liver surgery. The contribution is an extension of the graph matching algorithm using Gaussian process regression (GPR) (Serradell et al. in IEEE Trans Pattern Anal Mach Intell 37(3):625–638, 2015): First, an improved GPR matching is introduced by imposing additional constraints during the matching when the number of hypothesis is large; like the original algorithm, this extended version does not require a manual initialization of matching. Second, a fast biomechanical model is employed to make the method capable of handling large deformations.
Results
The proposed automatic intraoperative augmentation is evaluated on both synthetic and real data. It is demonstrated that the algorithm is capable of handling large deformations, thus being more robust and reliable than previous approaches. Moreover, the time required to perform the elastic registration is compatible with the intraoperative navigation scenario.
Conclusion
A biomechanics-based graph matching method, which can handle large deformations and augment intraoperative CBCT, is presented and evaluated.
Experimental validation of robot-assisted cardiovascular catheterization: model-based versus model-free control
Abstract
Purpose
In cardiac electrophysiology, a long and flexible catheter is delivered to a cardiac chamber for the treatment of arrhythmias. Although several robot-assisted platforms have been commercialized, the disorientation in tele-operation is still not well solved. We propose a validation platform for robot-assisted cardiac EP catheterization, integrating a customized MR Safe robot, a standard clinically used EP catheter, and a human–robot interface. Both model-based and model-free control methods are implemented in the platform for quantitative evaluation and comparison.
Methods
The model-based and model-free control methods were validated by subject test (ten participants), in which the subjects have to perform a simulated radiofrequency ablation task using both methods. A virtual endoscopic view of the catheter is also provided to enhance hand-to-eye coordination. Assessment indices for targeting accuracy and efficiency were acquired for the evaluation.
Results
(1) Accuracy: The average distance measured from catheter tip to the closest lesion target during ablation of model-free method was 19.1% shorter than that of model-based control. (2) Efficiency: The model-free control reduced the total missed targets by 35.8% and the maximum continuously missed targets by 46.2%, both indices corresponded to a low p value ( \(\le 0.05\) ).
Conclusion
The model-free method performed better in terms of both accuracy and efficiency, indicating the model-free control could adapt to soft interaction with environment, as compared with the model-based control that does not consider contacts.
Kalman filter-based EM-optical sensor fusion for needle deflection estimation
Abstract
Purpose
In many clinical procedures such as cryoablation that involves needle insertion, accurate placement of the needle's tip at the desired target is the major issue for optimizing the treatment and minimizing damage to the neighboring anatomy. However, due to the interaction force between the needle and tissue, considerable error in intraoperative tracking of the needle tip can be observed as needle deflects.
Methods
In this paper, measurements data from an optical sensor at the needle base and a magnetic resonance (MR) gradient field-driven electromagnetic (EM) sensor placed 10 cm from the needle tip are used within a model-integrated Kalman filter-based sensor fusion scheme. Bending model-based estimations and EM-based direct estimation are used as the measurement vectors in the Kalman filter, thus establishing an online estimation approach.
Results
Static tip bending experiments show that the fusion method can reduce the mean error of the tip position estimation from 29.23 mm of the optical sensor-based approach to 3.15 mm of the fusion-based approach and from 39.96 to 6.90 mm, at the MRI isocenter and the MRI entrance, respectively.
Conclusion
This work established a novel sensor fusion scheme that incorporates model information, which enables real-time tracking of needle deflection with MRI compatibility, in a free-hand operating setup.
Agile convolutional neural network for pulmonary nodule classification using CT images
Abstract
Objective
To distinguish benign from malignant pulmonary nodules using CT images is critical for their precise diagnosis and treatment. A new Agile convolutional neural network (CNN) framework is proposed to conquer the challenges of a small-scale medical image database and the small size of the nodules, and it improves the performance of pulmonary nodule classification using CT images.
Methods
A hybrid CNN of LeNet and AlexNet is constructed through combining the layer settings of LeNet and the parameter settings of AlexNet. A dataset with 743 CT image nodule samples is built up based on the 1018 CT scans of LIDC to train and evaluate the Agile CNN model. Through adjusting the parameters of the kernel size, learning rate, and other factors, the effect of these parameters on the performance of the CNN model is investigated, and an optimized setting of the CNN is obtained finally.
Results
After finely optimizing the settings of the CNN, the estimation accuracy and the area under the curve can reach 0.822 and 0.877, respectively. The accuracy of the CNN is significantly dependent on the kernel size, learning rate, training batch size, dropout, and weight initializations. The best performance is achieved when the kernel size is set to \(7\times 7\) , the learning rate is 0.005, the batch size is 32, and dropout and Gaussian initialization are used.
Conclusions
This competitive performance demonstrates that our proposed CNN framework and the optimization strategy of the CNN parameters are suitable for pulmonary nodule classification characterized by small medical datasets and small targets. The classification model might help diagnose and treat pulmonary nodules effectively.
Landmark-based evaluation of a deformable motion correction for DCE-MRI of the liver
Abstract
Purpose
Annotation of meaningful landmark ground truth on DCE-MRI is difficult and laborious. Motion correction methods applied to DCE-MRI of the liver are thus mostly evaluated using qualitative or indirect measures. We propose a novel landmark annotation scheme that facilitates the generation of landmark ground truth on larger clinical datasets.
Methods
In our annotation scheme, landmarks are equally distributed over all time points of all available dataset cases and annotated by multiple observers on a per-pair basis. The scheme is used to annotate 26 DCE-MRI of the liver. A subset of the ground truth is used to optimize parameters of a deformable motion correction. Several variants of the motion correction are evaluated on the remaining cases with respect to distances of corresponding landmarks after registration, deformation field properties, and qualitative measures.
Results
A landmark ground truth on 26 cases could be generated in under 12 h per observer with a mean inter-observer distance below the mean voxel diagonal. Furthermore, the landmarks are spatially well distributed within the liver. Parameter optimization significantly improves the performance of the motion correction, and landmark distance after registration is 2 mm. Qualitative evaluation of the motion correction reflects the quantitative results.
Conclusions
The annotation scheme makes a landmark-based evaluation of motion corrections for hepatic DCE-MRI practically feasible for larger clinical datasets. The comparably large number of cases enables both optimization and evaluation of motion correction methods.
The role of exposure time in computerized training of prostate cryosurgery: performance comparison of surgical residents with engineering students
Abstract
Purpose
This study aims at the evaluation of a prototype of a computerized trainer for cryosurgery—the controlled destruction of cancer tumors by freezing. The hypothesis in this study is that computer-based cryosurgery training for an optimal cryoprobe layout is essentially a matter of exposure time, rather than trainee background or the specific computer-generated planning target. Key geometric features under considerations are associated with spatial limitations on cryoprobes placement and the match between the resulted thermal field and the unique anatomy of the prostate.
Methods
All experiments in this study were performed on the cryosurgery trainer—a prototype platform for computerized cryosurgery training, which has been presented previously. Among its key features, the cryosurgery trainer displays the prostate shape and its contours and provides a distance measurement tool on demand, in order to address spatial constraints during ultrasound imaging guidance. Another unique feature of the cryosurgery trainer is an output movie, displaying the simulated thermal field at the end of the cryoprocedure.
Results
The current study was performed on graduate engineering students having no formal background in medicine, and the results were benchmarked against data obtained on surgical residents having no experience with cryosurgery. Despite fundamental differences in background and experience, neither group displayed superior performance when it comes to cryoprobe layout planning.
Conclusions
This study demonstrates that computer-based training of an optimal cryoprobe layout is feasible. This study demonstrates that the training quality is essentially related to the training exposure time, rather than to a specific planning strategy from those investigated.
Improving Estimation of HIV Viral Suppression in the United States: A Method to Adjust HIV Surveillance Estimates From the Medical Monitoring Project Using Cohort Data
Abstract
CDC has estimated HIV viral suppression (VS) using two data sources. The National HIV Surveillance System estimate (50% of HIV-diagnosed persons in 2012) is derived from viral load reporting from a subset of jurisdictions that vary yearly. The Medical Monitoring Project (MMP) estimate (42% in 2012) is based on a sample of persons receiving HIV care during the first 4 months of each year. We developed the Cohort-adjustment Method to reconstruct VS estimates, accounting for persons receiving care later in the year. Using the HIV Outpatient Study cohort, we assessed timing of care receipt, demographics, and VS at last test (<200 vs. ≥200 copies/mL), standardizing MMP to HIV Outpatient Study data using multivariable regression models and yielding adjusted VS estimates. We estimated 52% (95% CI: 48, 56) of HIV-diagnosed persons achieved VS in 2012. Differences from previously published estimate were due to: 1) 23% underestimation of persons receiving HIV care and 2) lower VS rates among persons receiving care outside versus inside the 4-month MMP sampling period (79% vs. 88%). This methodology yielded VS estimates closer to the National HIV Surveillance System estimate than previously published. Use of more, geographically diverse cohort data may enable assessment of temporal trends.Chlamydial ompA Diversity in Trachoma-Hyperendemic Communities Treated With Azithromycin
Abstract
Prior studies have theorized that low chlamydial genetic diversity following mass azithromycin treatments for trachoma may create a population bottleneck that prevents the return of infection, but little empiric evidence exists to support this hypothesis. In this study, a single mass azithromycin distribution was administered to 21 communities in the Gurage Zone of Ethiopia in 2003. All children aged 1–5 years had conjunctival swabs performed before treatment, and at 2 and 6 months following treatment. All swabs positive for Chlamydia trachomatis at 2 months underwent ompA typing, as did the same number of swabs per community from the pre-treatment and 6-month visits. ompA diversity, expressed as the reciprocal of Simpson's index, was calculated for each community. In total, 15 ompA types belonging to the A and B genovars were identified. The mean diversity was 2.11 (95% confidence interval: 1.79, 2.43) before treatment and 2.16 (95% confidence interval: 1.76, 2.55) two months after treatment (P = 0.78, paired t-test). ompA diversity was not associated with the prevalence of ocular chlamydia (P = 0.76), and did not predict subsequent changes in the prevalence of ocular chlamydia (P = 0.32). This study found no evidence to support the theory that ompA diversity is associated with transmission of ocular chlamydia.Causal Model of Social Support on Antepartum Depression: A Marginal Structural Modeling Approach
Abstract:
We used marginal structural models to evaluate associations of social support with antepartum depression in late pregnancy, had everyone had high social support both pre-pregnancy and during early pregnancy, as compared to having low social support at one of the two-time points or low social support at both time points. In 2012-2014, pregnant Peruvian women (N = 3,336) were recruited into a prospective cohort study (mean gestational age: 9 weeks). A follow-up interview (N = 2,279) was conducted (26-28 weeks of gestation). Number of available support providers and satisfaction with social support were measured using Sarason Social Support Questionnaire-6. Depression was measured using Edinburgh Postnatal Depression Scale. Low number of support providers (Odds Ratio = 1.62, 95% Confidence Interval:1.12-2.34) at both time points was associated with increased risk of depression. The association for low satisfaction at both time points was marginally significant (Odds Ratio = 1.41, 95% Confidence Interval: 0.99-1.99). Depression risk was not significantly increased for women who reported high social support at one of the two-time points. Our study reinforces the importance of assessing social support before and during pregnancy and underscores the need for future interventions targeted at increasing the number of support providers to prevent antepartum depression.Breastfeeding And Childhood Wheeze: Age-Specific Analyses And Longitudinal Wheezing Phenotypes As Complimentary Approaches To The Analysis Of Cohort Data
Abstract
Systematic reviews suggest that breastfeeding is associated with a lower risk of asthma, although marked heterogeneity exists. Using UK Millennium Cohort Study data (n = 10,126 children born 2000-2001), we examined the association between breastfeeding duration and wheezing in the past year, first at each age-group separately (age 9 months, 3, 5, 7 and 11 years) and then as a longitudinal wheezing phenotype: 'early transient' (wheezing any time up to age 5 but not thereafter); 'late onset' (any time from age 7 but not beforehand); 'persistent' (any time up to age 5 and any time from age 7). The association between breastfeeding and wheeze varied by age (interaction two-sided P = 0.0003). For example, breastfeeding for 6-9 months was associated with lower odds of wheezing at age 9 months, 3, and 5 years, but less so at age 7 and 11 years (adjusted odds ratios 0.73, 0.78, 0.79, 0.84, 1.06 respectively). There was a strong dose response relationship for breastfeeding per month and early transient wheeze (adjusted linear trend OR 0.961, 95% CI: 0.942, 0.980), but no clear trend for late onset or persistent wheeze. Our results identified heterogeneity in the association between breastfeeding and wheezing according to age at wheezing and wheezing phenotype.Estimating Counterfactual Risk Under Hypothetical Interventions in the Presence of Competing Events: Crystalline Silica Exposure and Mortality From two Causes of Death
Abstract
Exposure to silica has been linked to excess risk of lung cancer and non-malignant respiratory disease mortality. In this study we estimated risk for both these outcomes in relation to occupational silica exposure as well as the reduction in risk that would result from hypothetical interventions on exposure in a cohort of exposed workers. Analyses were carried out in an all-male study population consisting of 2342 California diatomaceous earth workers regularly exposed to crystalline silica, followed between 1942 and 2011. We estimated subdistribution risk for each event under the natural course and interventions of interest using the parametric g-formula to adjust for healthy worker survivor bias. The risk ratio for lung cancer mortality comparing an intervention in which a theoretical maximum exposure limit was set at 0.05 mg/m3 (the current U.S. regulatory limit) to the observed exposure concentrations was 0.86 (95% confidence interval: 0.63, 1.22). The corresponding risk ratio for non-malignant respiratory disease mortality was 0.69 (95% confidence interval: 0.52, 0.93). Our findings suggest that risks from both outcomes would have been considerably lower if historical silica exposures in this cohort had not exceeded current regulatory limits.Job Stressors and Employment Precarity as Risks for Thoughts About Suicide: An Australian Study Using the Ten to Men Cohort
Abstract
Aims
Past research suggests that adverse experiences at work (such as job stressors and precarious employment) are associated with thoughts about suicide, especially among males. A limitation of this research is that it is largely cross-sectional. Thus, it is unknown whether job stressors are a prior cause of thoughts about suicide. This study examined the baseline association between adverse experiences at work and thoughts about suicide at follow-up in a large nationally representative cohort of employed men. Methods
We used data from the Australian Longitudinal Study on Male Health (Ten to Men). The outcome was thoughts about suicide in the prior 12 months (reported in wave 2) and the key exposure variables were: high job demands, low job control, job insecurity, perceived unfairness of pay, occupational skill level, and employment arrangement (all reported in wave 1). We adjusted for possible confounders, including mental health and suicidal thoughts (wave 1). Results
In a sample of 8379 and after adjustment, job insecurity (OR 1.35, 95% CI 1.13–1.61, P = 0.001), low job control (OR 1.19, 95% CI 1.06–1.33, P = 0.004), and employment on a casual or on a fixed term basis (OR 1.30, 95% 1.01–1.67, P = 0.041) were associated with a greater odds of thoughts about suicide at follow up. Results for all by job control were maintained after removing those who reported thoughts of suicide at baseline. Conclusion
This study suggests that experiences at work may be risk factors for thoughts about suicide among employed men. More research is needed to unpack the complex associations between, employment, and experiences of suicide.Toxicological evaluation of nail polish waste discarded in the environment
Abstract
Nail polish has been widely used around the world. However, the hazards of nail polishes discarded in the environment are still poorly investigated. Thus, the toxicogenetic effects of solubilized (SE) and leached (LE) extracts from nail polishes were investigated, simulating their disposal on water and landfill, respectively, and identifying their physicochemical properties and chemical constituents. Organic compounds and metals were detected in both extracts. SE and LE only induced mutagenic effects in TA98 Salmonella strain in the presence and absence of exogenous metabolic activation. Although both extracts did not significantly increase the frequency of micronucleated HepG2 cells, the cell viability was affected by 24-h exposure. No DNA damage was observed in gonad fish cells (RTG-2) exposed to both extracts; however, the highest SE and LE concentrations induced significant lethal and sublethal effects on zebrafish early-life stages during 96-h exposure. Based on our findings, it can be concluded that if nail polishes enter aquatic systems, it may cause negative impacts to the environment.
Assessing links between energy consumption, freight transport, and economic growth: evidence from dynamic simultaneous equation models
Abstract
We investigate this study to examine the relationship between economic growth, freight transport, and energy consumption for 63 developing countries over the period of 1990–2016. In order to make the panel data analysis more homogeneous, we apply the income level of countries to divide the global panel into three sub-panels, namely, lower-middle income countries (LMIC), upper-middle income countries (UMIC), and high-income countries (HIC). Using the generalized method of moments (GMM), the results prove evidence of bidirectional causal relationship between economic growth and freight transport for all selected panels and between economic growth and energy consumption for the high- and upper-middle income panels. For the lower-middle income panel, the causality is unidirectional running from energy consumption to economic growth. Also, the results indicate that the relationship between freight transport and energy use is bidirectional for the high-income countries and unidirectional from freight transport to energy consumption for the upper-middle and lower-middle income countries. Empirical evidence demonstrates the importance of energy for economic activity and rejects the neo-classical assumption that energy is neutral for growth. An important policy recommendation is that there is need of advancements in vehicle technology which can reduce energy intensity from transport sector and improve the energy efficiency in transport activity which in turn allows a greater positive role of transport in global economic activity.
Modernizing Regulation of Cosmetic Products: Reintroduction of the Personal Care Products Safety Act
Publication date: Available online 3 April 2018
Source:Journal of the American Academy of Dermatology
Author(s): Harrison P. Nguyen, Wilma F. Bergfeld, Howard P. Forman, Donald V. Belsito, Jean L. Bolognia
Does biologic treatment of psoriasis lower the risk of cardiovascular events and mortality? A critical question that we are only just beginning to answer
Publication date: Available online 3 April 2018
Source:Journal of the American Academy of Dermatology
Author(s): Joel M. Gelfand
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