Policy Lessons From Quantitative Modeling of Leprosy

Abstract

Recent mathematical and statistical modeling of leprosy incidence data provides estimates of the current undiagnosed population and projections of diagnosed cases, as well as ongoing transmission. Furthermore, modeling studies have been used to evaluate the effectiveness of proposed intervention strategies, such as postleprosy exposure prophylaxis and novel diagnostics, relative to current approaches. Such modeling studies have revealed both a slow decline of new cases and a substantial pool of undiagnosed infections. These findings highlight the need for active case detection, particularly targeting leprosy foci, as well as for continued research into innovative accurate, rapid, and cost-effective diagnostics. As leprosy incidence continues to decline, targeted active case detection primarily in foci and connected areas will likely become increasingly important.

Counting Down the 2020 Goals for 9 Neglected Tropical Diseases: What Have We Learned From Quantitative Analysis and Transmission Modeling?

Abstract

The control of neglected tropical diseases (NTDs) has received huge investment in recent years, leading to large reductions in morbidity. In 2012, the World Health Organization set ambitious targets for eliminating many of these diseases as a public health problem by 2020, an aspiration that was supported by donations of treatments, intervention materials, and funding committed by a broad partnership of stakeholders in the London Declaration on NTDs. Alongside these efforts, there has been an increasing role for quantitative analysis and modeling to support the achievement of these goals through evaluation of the likely impact of interventions, the factors that could undermine these achievements, and the role of new diagnostics and treatments in reducing transmission. In this special issue, we aim to summarize those insights in an accessible way. This article acts as an introduction to the special issue, outlining key concepts in NTDs and insights from modeling as we approach 2020.

Are We on Our Way to Achieving the 2020 Goals for Schistosomiasis Morbidity Control Using Current World Health Organization Guidelines?

Abstract

Background

Schistosomiasis remains an endemic parasitic disease affecting millions of people around the world. The World Health Organization (WHO) has set goals of controlling morbidity to be reached by 2020, along with elimination as a public health problem in certain regions by 2025. Mathematical models of parasite transmission and treatment impact have been developed to assist in controlling the morbidity caused by schistosomiasis. These models can inform and guide implementation policy for mass drug administration programs, and help design monitoring and evaluation activities.

Methods

We use these models to predict whether the guidelines set by the WHO are on track for achieving their 2020 goal for the control of morbidity, specifically for Schistosoma mansoni. We examine whether programmatic adaptations; namely increases in treatment coverage and/or expansion to adult inclusion in treatment, will improve the likelihood of reaching the WHO goals.

Results

We find that in low-prevalence settings, the goals are likely to be attainable under current WHO guidelines, but in moderate to high-prevalence settings, the goals are less likely to be achieved unless treatment coverage is increased and expanded to at least 85% for school-aged children and 40% for adults.

Conclusions

To improve the likelihood of reaching the WHO goals, programmatic adaptations are required, particularly for moderate- to high-prevalence settings. Furthermore, improvements in adherence to treatment, potential development of candidate vaccines, and enhanced snail control and WASH (water, sanitation, and hygiene) measures will all assist in achieving the goals.

Complementary Paths to Chagas Disease Elimination: The Impact of Combining Vector Control With Etiological Treatment

Abstract

Background

The World Health Organization's 2020 goals for Chagas disease are (1) interrupting vector-borne intradomiciliary transmission and (2) having all infected people under care in endemic countries. Insecticide spraying has proved efficacious for reaching the first goal, but active transmission remains in several regions. For the second, treatment has mostly been restricted to recently infected patients, who comprise only a small proportion of all infected individuals.

Methods

We extended our previous dynamic transmission model to simulate a domestic Chagas disease transmission cycle and examined the effects of both vector control and etiological treatment on achieving the operational criterion proposed by the Pan American Health Organization for intradomiciliary, vectorial transmission interruption (ie, <2% seroprevalence in children <5 years of age).

Results

Depending on endemicity, an antivectorial intervention that decreases vector density by 90% annually would achieve the transmission interruption criterion in 2–3 years (low endemicity) to >30 years (high endemicity). When this strategy is combined with annual etiological treatment in 10% of the infected human population, the seroprevalence criterion would be achieved, respectively, in 1 and 11 years.

Conclusions

Combining highly effective vector control with etiological (trypanocidal) treatment in humans would substantially reduce time to transmission interruption as well as infection incidence and prevalence. However, the success of vector control may depend on prevailing vector species. It will be crucial to improve the coverage of screening programs, the performance of diagnostic tests, the proportion of people treated, and the efficacy of trypanocidal drugs. While screening and access can be incremented as part of strengthening the health systems response, improving diagnostics performance and drug efficacy will require further research.

Investigating the Effectiveness of Current and Modified World Health Organization Guidelines for the Control of Soil-Transmitted Helminth Infections

Abstract

Background

Considerable efforts have been made to better understand the effectiveness of large-scale preventive chemotherapy therapy for the control of morbidity caused by infection with soil-transmitted helminths (STHs): Ascaris lumbricoides, Trichuris trichiura, and the 2 hookworm species, Necator americanus and Ancylostoma duodenale. Current World Health Organization (WHO) guidelines for STH control include mass drug administration (MDA) programs based on prevalence measurements, aiming at reducing morbidity in pre–school-aged children (pre-SAC) and school-aged children (SAC) by lowering the prevalence of moderate- to heavy-intensity infections to <1%.

Methods

We project the likely impact of following the current WHO guidelines and assess whether the WHO morbidity goals will be achieved across a range of transmission settings. We also investigate modifications that could be made to the current WHO treatment guidelines, and project their potential impacts in achieving morbidity and transmission control.

Results

While the standard guidelines are sufficient at low transmission levels, community-wide treatment (ie, involving pre-SAC, SAC, and adults) is essential if WHO morbidity goals are to be met in moderate- to high-transmission settings. Moreover, removing the recommendation of decreasing the treatment frequency at midline (5–6 years after the start of MDA) further improves the likelihood of achieving morbidity control in SAC.

Conclusions

We meld analyses based on 2 mathematical models of parasite transmission and control by MDA for the dominant STH species, to generate a unified treatment approach applicable across all settings, regardless of which STH infection is most common. We recommend clearly defined changes to the current WHO guidelines.

Models of Trachoma Transmission and Their Policy Implications: From Control to Elimination

Abstract

Despite great progress in eliminating trachoma from the majority of worldwide districts, trachoma control seems to have stalled in some endemic districts. Can mathematical models help suggest the way forward? We review specific achievements of models in trachoma control in the past. Models showed that, even with incomplete coverage, mass drug administration could eliminate disease through a spillover effect, somewhat analogous to how incomplete vaccine campaigns can eliminate disease through herd protection. Models also suggest that elimination can always be achieved if enough people are treated often enough with an effective enough drug. Other models supported the idea that targeting ages at highest risk or continued improvements in hygiene and sanitation can contribute meaningfully to trachoma control. Models of intensive targeting of a core group may point the way to final eradication even in areas with substantial transmission and within-community heterogeneity.

Are Alternative Strategies Required to Accelerate the Global Elimination of Lymphatic Filariasis? Insights From Mathematical Models

Abstract

Background

With the 2020 target year for elimination of lymphatic filariasis (LF) approaching, there is an urgent need to assess how long mass drug administration (MDA) programs with annual ivermectin + albendazole (IA) or diethylcarbamazine + albendazole (DA) would still have to be continued, and how elimination can be accelerated. We addressed this using mathematical modeling.

Methods

We used 3 structurally different mathematical models for LF transmission (EPIFIL, LYMFASIM, TRANSFIL) to simulate trends in microfilariae (mf) prevalence for a range of endemic settings, both for the current annual MDA strategy and alternative strategies, assessing the required duration to bring mf prevalence below the critical threshold of 1%.

Results

Three annual MDA rounds with IA or DA and good coverage (≥65%) are sufficient to reach the threshold in settings that are currently at mf prevalence <4%, but the required duration increases with increasing mf prevalence. Switching to biannual MDA or employing triple-drug therapy (ivermectin, diethylcarbamazine, and albendazole [IDA]) could reduce program duration by about one-third. Optimization of coverage reduces the time to elimination and is particularly important for settings with a history of poorly implemented MDA (low coverage, high systematic noncompliance).

Conclusions

Modeling suggests that, in several settings, current annual MDA strategies will be insufficient to achieve the 2020 LF elimination targets, and programs could consider policy adjustment to accelerate, guided by recent monitoring and evaluation data. Biannual treatment and IDA hold promise in reducing program duration, provided that coverage is good, but their efficacy remains to be confirmed by more extensive field studies.

Assessing Strategies Against Gambiense Sleeping Sickness Through Mathematical Modeling

Abstract

Background

Control of gambiense sleeping sickness relies predominantly on passive and active screening of people, followed by treatment.

Methods

Mathematical modeling explores the potential of 3 complementary interventions in high- and low-transmission settings.

Results

Intervention strategies that included vector control are predicted to halt transmission most quickly. Targeted active screening, with better and more focused coverage, and enhanced passive surveillance, with improved access to diagnosis and treatment, are both estimated to avert many new infections but, when used alone, are unlikely to halt transmission before 2030 in high-risk settings.

Conclusions

There was general model consensus in the ranking of the 3 complementary interventions studied, although with discrepancies between the quantitative predictions due to differing epidemiological assumptions within the models. While these predictions provide generic insights into improving control, the most effective strategy in any situation depends on the specific epidemiology in the region and the associated costs.

How Can Onchocerciasis Elimination in Africa Be Accelerated? Modeling the Impact of Increased Ivermectin Treatment Frequency and Complementary Vector Control

Abstract

Background

Great strides have been made toward onchocerciasis elimination by mass drug administration (MDA) of ivermectin. Focusing on MDA-eligible areas, we investigated where the elimination goal can be achieved by 2025 by continuation of current practice (annual MDA with ivermectin) and where intensification or additional vector control is required. We did not consider areas hypoendemic for onchocerciasis with loiasis coendemicity where MDA is contraindicated.

Methods

We used 2 previously published mathematical models, ONCHOSIM and EPIONCHO, to simulate future trends in microfilarial prevalence for 80 different settings (defined by precontrol endemicity and past MDA frequency and coverage) under different future treatment scenarios (annual, biannual, or quarterly MDA with different treatment coverage through 2025, with or without vector control strategies), assessing for each strategy whether it eventually leads to elimination.

Results

Areas with 40%–50% precontrol microfilarial prevalence and ≥10 years of annual MDA may achieve elimination with a further 7 years of annual MDA, if not achieved already, according to both models. For most areas with 70%–80% precontrol prevalence, ONCHOSIM predicts that either annual or biannual MDA is sufficient to achieve elimination by 2025, whereas EPIONCHO predicts that elimination will not be achieved even with complementary vector control.

Conclusions

Whether elimination will be reached by 2025 depends on precontrol endemicity, control history, and strategies chosen from now until 2025. Biannual or quarterly MDA will accelerate progress toward elimination but cannot guarantee it by 2025 in high-endemicity areas. Long-term concomitant MDA and vector control for high-endemicity areas might be useful.

Policy Recommendations From Transmission Modeling for the Elimination of Visceral Leishmaniasis in the Indian Subcontinent

Abstract

Background

Visceral leishmaniasis (VL) has been targeted by the World Health Organization (WHO) and 5 countries in the Indian subcontinent for elimination as a public health problem. To achieve this target, the WHO has developed guidelines consisting of 4 phases of different levels of interventions, based on vector control through indoor residual spraying of insecticide (IRS) and active case detection (ACD). Mathematical transmission models of VL are increasingly used for planning and assessing the efficacy of interventions and evaluating the intensity and timescale required to achieve the elimination target.

Methods

This paper draws together the key policy-relevant conclusions from recent transmission modeling of VL, and presents new predictions for VL incidence under the interventions recommended by the WHO using the latest transmission models.

Results

The model predictions suggest that the current WHO guidelines should be sufficient to reach the elimination target in areas that had medium VL endemicities (up to 5 VL cases per 10000 population per year) prior to the start of interventions. However, additional interventions, such as extending the WHO attack phase (intensive IRS and ACD), may be required to bring forward elimination in regions with high precontrol endemicities, depending on the relative infectiousness of different disease stages.

Conclusions

The potential hurdle that asymptomatic and, in particular, post-kala-azar dermal leishmaniasis cases may pose to reaching and sustaining the target needs to be addressed. As VL incidence decreases, the pool of immunologically naive individuals will grow, creating the potential for new outbreaks.

Regarding: "Localized Marked Elongation of the Distal Internal Carotid Artery with or without PHACE Syndrome: Segmental Dolichoectasia of the Distal Internal Carotid Artery" [LETTERS]

Reply: [LETTERS]

Global and Widespread Local White Matter Abnormalities in Juvenile Neuronal Ceroid Lipofuscinosis [PEDIATRICS]

BACKGROUND AND PURPOSE:

Juvenile neuronal ceroid lipofuscinosis is a progressive neurodegenerative lysosomal storage disease of childhood. It manifests with loss of vision, seizures, and loss of cognitive and motor functions leading to premature death. Previous MR imaging studies have reported cerebral and cerebellar atrophy, progressive hippocampal atrophy, thalamic signal intensity alterations, and decreased white matter volume in the corona radiata. However, conventional MR imaging findings are usually normal at younger than 10 years of age. The purpose of our study was to investigate whether diffusion MR imaging could reveal changes in white matter microstructure already present at a younger age.

MATERIALS AND METHODS:

We investigated global and local white matter abnormalities in 14 children with juvenile neuronal ceroid lipofuscinosis (mean age, 9.6 ± 3.4 years; 10 boys) and 14 control subjects (mean age, 11.2 ± 2.3 years; 7 boys). Twelve patients underwent follow-up MR imaging after 2 years (mean age, 11.4 ± 3.2 years; 8 boys). We performed a global analysis using 2 approaches: white matter tract skeleton and constrained spherical deconvolution–based whole-brain tractography. Then, we investigated local microstructural abnormalities using Tract-Based Spatial Statistics.

RESULTS:

We found globally decreased anisotropy (P = .000001) and increased diffusivity (P = .001) in patients with juvenile neuronal ceroid lipofuscinosis. In addition, we found widespread increased diffusivity and decreased anisotropy in, for example, the corona radiata (P < .001) and posterior thalamic radiation (P < .001). However, we found no differences between the first and second acquisitions.

CONCLUSIONS:

The patients with juvenile neuronal ceroid lipofuscinosis exhibited global and local abnormalities in white matter microstructure. Future studies could apply more specific microstructural models and study whether these abnormalities are already present at a younger age.

Detection of the Stellate and Thoracic Sympathetic Chain Ganglia with High-Resolution 3D-CISS MR Imaging [SPINE]

BACKGROUND AND PURPOSE:

Despite the importance of the sympathetic nervous system in homeostasis and its putative role in various disease states, little is known regarding our ability to image the sympathetic chain and sympathetic chain ganglia, perhaps owing to their small size. In this retrospective study, we sought to evaluate the normal anatomy of the sympathetic chain ganglia and assess the detectability of the sympathetic chain and sympathetic chain ganglia on high-resolution 3D-CISS images.

MATERIALS AND METHODS:

This study included 29 patients who underwent 3D-CISS MR imaging of the thoracic spine for reasons unrelated to abnormalities of the sympathetic nervous system. Patients with a prior spinal operation or visible spinal pathology were excluded. The sympathetic chain ganglia were evaluated using noncontrast 3D-CISS MR imaging. Statistical analyses included t tests and measures of central tendency. The Cohen statistic was calculated to evaluate interrater reliability.

RESULTS:

The stellate ganglion and thoracic chain ganglia were identified in all subjects except at the T10–T11 and T11–T12 levels. The stellate ganglion was found inferomedial to the subclavian artery and anterior and inferior to the transverse process of C7 in all subjects. Thoracic sympathetic chain ganglia were identified ventral to the costovertebral junction in all subjects from T2 to T10. There was strong interobserver agreement for the detection of the sympathetic chain ganglia with > 0.80. The size, shape, and location of these structures corresponded with gross anatomic and surgical observations.

CONCLUSIONS:

The thoracic sympathetic chain ganglia can be identified on precontrast 3D-CISS MR imaging. This technique may aid in the initial evaluation of stellate ganglion and/or sympathetic chain ganglia size and signal change for comparison in future studies.

Reversible Dilation of the Superior Ophthalmic Vein in Intubated Patients [HEAD & NECK]

BACKGROUND AND PURPOSE:

Superior ophthalmic vein enlargement has typically been associated with increased intracranial or orbital pressure. This study evaluates the incidence of superior ophthalmic vein enlargement in intubated patients without pre-existing intracranial or intraorbital pathologies.

MATERIALS AND METHODS:

Two cohorts (patients with trauma and epilepsy patients undergoing stereotactic intracranial lead placement) who underwent CT while intubated and shortly following extubation and a cohort of 30 outpatients with a history of headache and normal head CT findings (healthy controls) were included. The superior ophthalmic vein diameter was measured on all scans.

RESULTS:

Seventy patients intubated for trauma and 45 patients with intraoperative CT were included (n = 115). While intubated, 66% of the total sample had at least unilateral superior ophthalmic vein dilation of >2.5 mm and 48% had bilateral dilation. Fifty-seven percent of patients with trauma and 84% of intraoperative patients with dilated superior ophthalmic veins showed reversal of mean superior ophthalmic vein dilation to <2.5 mm on postextubation CT. The mean superior ophthalmic vein diameter decreased an average of 1.2 mm following extubation. Changes in superior ophthalmic vein diameter between intubated and extubated states were statistically significant (P < .001). Differences between the control group and the extubated subjects were not statistically significant (P = .21).

CONCLUSIONS:

Bilateral dilation of the superior ophthalmic vein is common in intubated patients and usually reverses following extubation. In the appropriate clinical setting, this knowledge will prevent misinterpretation of prominent superior ophthalmic veins as automatically indicative of an underlying pathology.

Geochemical, radiometric, and environmental approaches for the assessment of the intensity and chronology of metal contamination in the sediment cores from Oualidia lagoon (Morocco)

Abstract

The present study evaluates the distribution of metals over the last 100 years in the Oualidia lagoon by examining their concentrations in the sediment cores. The samples were analyzed by instrumental neutron activation analysis and inductively coupled plasma mass spectrometry. Activities of ²¹⁰Pb, ²²⁶Ra, and ¹³⁷Cs were determined by gamma-ray spectrometry for establishing the age-depth relationships throughout the sediment cores by applying conventional models. The results indicated that the study area is contaminated by As and Cd revealing a detectable anthropogenic input of occurring metals as a consequence of the continuous development of human activities around the lagoon since 1950. The enrichment factor calculated for each layer of the three cores revealed that the studied sediments present no enrichment by Pb, K, and Mn; minor enrichment by Zn, Cr, Co, Cu, V, and Ni; and a moderately to severe enrichment by As and Cd. The pollution load index values increase from the bottom to the top of cores, and ranged from 0.9 to 2.8, which indicates levels of pollutants ranging from background to relatively high concentrations in the investigated sediments.

Investigating the effect of MgO and CeO 2 metal nanoparticle on the gasoline fuel properties: empirical modeling and process optimization by surface methodology

Abstract

The main purpose of this paper is to investigate how to optimize gasoline in order to reduce the emitted pollutants caused by combustion, while the torque and power of the engine reach the maximum capabilities. To optimize gasoline formulation, an ethanol and magnesium oxide (MgO) or cerium oxide (CeO₂) mixture was added to gasoline. This study explores the role of main variables such as type of metal nanoparticle additive, engine speed, and throttle on engine performance and exhaust gas emissions through the modeling and optimization methods. Experimental design conducted through the implementation of D-optimal design, taking into account the three main parameters. To review the efficiency of this novel fuel, it was tested by a four-stroke engine connected to a dynamometer and an analyzer, under different controlled environments: speeds of 1500, 2000, 2500, and 3000 rpm at both half and full throttle conditions. The analyzed data are the power and torque of the engine, the amount of emitted CO, CO₂, HC, and NO_x, the octane index, and the viscosity. The analyzed data were calculated and turned into models. Applying the models to data (the optimization process), close correlation between predicted and actual outcomes was found, highlighting the validity of the work. A secondary finding is that the CeO₂ mixture used at higher speeds and throttles produces less emissions, while lower speeds and throttles using the MgO mixture produce less emissions.

Anti-Pruritic and Anti-Inflammatory Effects of Oxymatrine in a Mouse Model of Allergic Contact Dermatitis

Allergic contact dermatitis (ACD) [1] is a highly prevalent inflammatory disease of the skin, which is mediated by hapten-specific T-cells and caused by repeated exposure of the skin to the same hapten [2]. ACD usually presents with inflammatory responses including erythema, swelling and immune imbalances. Patients with ACD often also exhibit refractory pruritus. Pruritus is an uncomfortable sensation which can trigger the urge to scratch [3]. Refractory pruritus, also called chronic pruritus, occurs repeatedly and negatively affects attention and sleep quality.

“Determination of the impact of melanoma surgical timing on survival using the National Cancer Database”

Association of family structure with atopic dermatitis in United States children

The relationship between family structure and atopic dermatitis has not previously been elucidated., Children from family structures without two married, biological parents have increased odds of AD and poorer overall health outcomes., Children from family structures without two, married, biological parents may benefit from increased surveillance, closer follow-up and optimized treatment for incident AD.

Daily Oxymetazoline Cream Demonstrates High and Sustained Efficacy in Patients With Persistent Erythema of Rosacea Through 52 Weeks of Treatment

Long-term adalimumab efficacy in patients with moderate-to-severe hidradenitis suppurativa/acne inversa: 3-year results of a phase 3 open-label extension study

Adalimumab is approved for moderate-to-severe hidradenitis suppurativa/acne inversa., A sustained response is seen through week 168 in 52.3% of patients treated with adalimumab 40 mg weekly, with no additional safety issues identified. Adalimumab can be considered for long term control of moderate-to-severe hidradenitis suppurativa.

The readability of iPledge program patient education materials

A cohort study of risk factors, clinical presentations and outcomes for dermatophyte, non-dermatophyte and mixed toenail infections

Response to: Reply to:"Determination of the impact of melanoma surgical timing on survival using the National Cancer Database"

ScarCon ETRS 2018 Joint Meeting Scar Academy and the European Tissue Repair Society: Okura Hotel, Amsterdam, The Netherlands, May 31–June 2, 2018

Wound Repair and Regeneration, EarlyView.

Health care service provision in Europe and regional diversity: a stochastic metafrontier approach

In the last decades, demographic change coupled with new and expensive medical innovations have put most health care systems in developed countries under financial pressure. Therefore, ensuring efficient servi...

The effect of ICT on CO 2 emissions in emerging economies: does the level of income matters?

Abstract

In the modern era of globalization, the rapid increase in information and telecommunication technologies (ICTs) contributes in various sectors of an economy; however, the environmental consequences of ICTs cannot be ignored. Therefore, the study investigates the nexus between ICTs, economic growth, financial development, and environmental quality in emerging economies. The novel feature of the study is that the interaction term of ICT is introduced with economic growth and financial development. The empirical findings of the study are based on panel mean group (MG) and augmented mean group (AMG) estimation methods from 1990 to 2015. The following empirical results are established: first the ICTs significantly affect CO₂ emissions. Second, the moderating effect of ICT and financial development stimulate the level of CO₂ emissions. Third, economic growth contributes CO₂ emission; however, the interaction between ICT and GDP mitigates the level of pollution. Policy thresholds with the R&D in ICT sector are required to mitigate the level of CO₂ emission. Introduction of green ICTs projects in the financial sector is a better choice to improve the energy efficiency.

Study of ecological compensation in complex river networks based on a mathematical model

Abstract

Transboundary water pollution has resulted in increasing conflicts between upstream and downstream administrative districts. Ecological compensation is an efficient means of restricting pollutant discharge and achieving sustainable utilization of water resources. The tri-provincial region of Taihu Basin is a typical river networks area. Pollutant flux across provincial boundaries in the Taihu Basin is hard to determine due to complex hydrologic and hydrodynamic conditions. In this study, ecological compensation estimation for the tri-provincial area based on a mathematical model is investigated for better environmental management. River discharge and water quality are predicted with the one-dimensional mathematical model and validated with field measurements. Different ecological compensation criteria are identified considering the notable regional discrepancy in sewage treatment costs. Finally, the total compensation payment is estimated. Our study indicates that Shanghai should be the receiver of payment from both Jiangsu and Zhenjiang in 2013, with 305 million and 300 million CNY, respectively. Zhejiang also contributes more pollutants to Jiangsu, and the compensation to Jiangsu is estimated as 9.3 million CNY. The proposed ecological compensation method provides an efficient way for solving the transboundary conflicts in a complex river networks area and is instructive for future policy-making.

A better indicator to measure the effects of meteorological factors on cardiovascular mortality: heat index

Abstract

Although many studies have examined the correlation between temperature and mortality from cardiovascular diseases (CVD), other meteorological factors, such as relative humidity, may modify the relationship. Yet the studies on this aspect are relatively few. We chose a heat index (HI, which is an index that combines air temperature and relative humidity) as an alternative indicator of temperature, and used a distributed lag nonlinear model (DLNM) to analyze the combined effects of temperature and relative humidity on CVD mortality among all of the Beijing residents and subsociodemographic groups by age, sex, and occupation. The heat index can better reflect the human-perceived temperature when relative humidity is combined with air temperature. The results show that females, elderly people, and outdoor workers have higher vulnerability levels in regard to a high heat index. The strongest effect of heat index was found among females, for which the highest mortality risk was about 2.4 (95% CI 1.8–3) times greater than the lowest mortality risk. In addition, we found that there is a significant interaction effect of temperature and relative humidity on CVD mortality. The impact of extreme high temperature may be exacerbated by increases in humidity. Based on these results, we draw the risk level map of CVD death under different temperatures and grades of relative humidity. These findings may aid governments in the development of more accurate heat alerts and the provision of measures to prevent or reduce temperature-related deaths.

Review of Aesthetic Nasal Reconstruction: Principles and Practice

There are a limited number of people in our relatively broad subspecialty who have devoted their entire careers to a focused area, truly pioneering the way we approach and manage specific clinical problems in facial plastic surgery. There are even fewer who are so passionate about a specific topic that they have taken it upon themselves to share their knowledge and vast experience through extensive writing and publication, allowing this information to perpetuate and help others in our field grow and learn from their successes and their mistakes.

Primary Closure Technique for Conchal Auricular Composite Graft Donor Site

This article describes a simple technique for closing the donor site following conchal auricular composite graft.

Testing the agriculture-induced EKC hypothesis: the case of Pakistan

Abstract

This study investigates the long-run equilibrium relationship among carbon dioxide (CO₂) emissions, income growth, energy consumption, and agriculture, thus testing the existence of what we call the agriculture-induced environmental Kuznets' curve (EKC) hypothesis in the case of Pakistan for the period of 1971–2014. The long-run equilibrium relationship among the variables in the conducted model is confirmed by Maki's (EM 29(5), 2011–2015, 2012) co-integration test under multiple structural breaks. Toda-Yamamoto's (JE 66(1):225–250, 1995) causality test results reveal bidirectional causal relationships among gross domestic product (GDP), energy use, agriculture, and CO₂ emissions. Fully modified ordinary least squares (FMOLS) results suggest that GDP has elastic positive impacts on CO₂ emissions, and energy use and agricultural value added have inelastic positive impacts on CO₂ emissions, whereas squared GDP has an inelastic and negative effect on CO₂ emissions. This finding confirms the existence of the agriculture-induced EKC hypothesis in Pakistan and can be a guideline for other agrarian developing countries for the creation of effective policies around environmental degradation.

Does reliabilism have a temporality problem?

Abstract

Matthew Frise claims that reliabilist theories of justification have a temporality problem—the problem of providing a principled account of the temporal parameters of a process's performance that determine whether that process is reliable at a given time. Frise considers a representative sample of principled temporal parameters and argues that there are serious problems with all of them. He concludes that the prospects for solving the temporality problem are bleak. Importantly, Frise argues that the temporality problem constitutes a new reason to reject reliabilism. On this point, I argue that Frise is mistaken. There are serious interpretive difficulties with Frise's argument. In this essay, I show that there are principled and reasonable temporal parameters for the reliabilist to adopt that successfully undermine the interpretations of Frise's argument that only invoke plausible premises. There are interpretations of Frise's argument that leave reliabilism without a clear parameter solution. However, I argue that these interpretations invoke controversial premises that are at best unmotivated, and at worst they merely re-raise older disputes about reliabilism. In any event, the temporality problem fails to constitute a new reason to reject reliabilism.

Ce-Mn modify Al 2 O 3 adsorbent and the effect on adsorption and regeneration properties

Abstract

The regeneration of adsorbent by thermal method may transfer the adsorbed organic pollutants into the air phase. Herein, manganese and cerium are loaded on adsorbent as catalyst to mineralize the adsorbed organic pollutants during regeneration. The modified adsorbent is characterized by scanning electron microscope-energy dispersive spectrometer, Brunauer Emmett Teller-Barrett Joyner Halenda, and X-ray photoelectron spectroscopy. Regeneration of modified adsorbent is evaluated by adsorbent yield and mineralization percentage of the absorbed organic pollutants. The results demonstrate that the mineralization percentage of tetracycline increased about 100% after the modification. Besides, the loaded catalyst can significantly reduce the regeneration temperature. Furthermore, cerium can reduce the adverse impact causes by manganese which will decrease the adsorption capacity of adsorbent. Kinetics, equilibrium, thermodynamic, and other adsorption properties of modified adsorbent towards tetracycline are further studied. The theoretical maximum of adsorption capacity calculated by Langmuir model is 196.4 mg g⁻¹, and the kinetics of adsorption fits pseudo-second-order model. The adsorption of tetracycline on the adsorbent is feasible, spontaneous, and endothermic. The properties of synthesized composite material are stable; the yield of Ce/Mn/Al₂O₃ adsorbent can keep higher than 95% even after five adsorption/regeneration cycles. This research provides another perspective on the design and regeneration of adsorbent, which focus on reducing the secondary pollution during adsorbent regeneration process.

A modeling understanding on the phosphorous removal performances of A 2 O and reversed A 2 O processes in a full-scale wastewater treatment plant

Abstract

Reversed A²O process (anoxic-anaerobic-aerobic) and conventional A²O process (anaerobic-anoxic-aerobic) are widely used in many wastewater treatment plants (WWTPs) in Asia. However, at present, there are still no consistent results to figure out which process has better total phosphorous (TP) removal performance and the mechanism for this difference was not clear yet. In this study, the treatment performances of both processes were compared in the same full-scale WWTP and the TP removal dynamics was analyzed by a modeling method. The treatment performance of full-scale WWTP showed the TP removal efficiency of the reversed A²O process was more efficient than in the conventional A²O process. The modeling results further reveal that the TP removal depends highly on the concentration and composition of influent COD. It had more efficient TP removal than the conventional A²O process only under conditions of sufficient influent COD and high fermentation products content. This study may lay a foundation for appropriate selection and optimization of treatment processes to suit practical wastewater properties.

Antiaging effects of a novel facial serum containing L-ascorbic acid, proteoglycans, and proteoglycan-stimulating tripeptide: ex vivo skin explant studies and in vivo clinical studies in women

Tres casos de sarcoidosis del cuero cabelludo con alopecia

Publication date: Available online 30 May 2018
Source:Actas Dermo-Sifiliográficas
Author(s): M. Ishikawa, M. Ohtsuka, T. Yamamoto

Desaparición simultánea de nevus en un paciente con procesos autoinmunes asociados

Publication date: Available online 30 May 2018
Source:Actas Dermo-Sifiliográficas
Author(s): P.J. Álvarez-Chinchilla, I. Poveda Montoyo, B. Encabo-Durán, J. Bañuls Roca

Paniculitis por micobacterias atípicas tras mesoterapia

Publication date: Available online 30 May 2018
Source:Actas Dermo-Sifiliográficas
Author(s): C. García-Harana, M. Aguilar-Bernier, J.M. Segura-Palacios, M. de Troya-Martín

Horas de color verde, amarillo y rojo para ir a la playa

Publication date: Available online 30 May 2018
Source:Actas Dermo-Sifiliográficas
Author(s): O. Correia, A.F. Duarte, A. Picoto

Eficacia del láser de diodo de arseniuro de galio en el tratamiento de 2 casos de liquen plano oral

Publication date: Available online 30 May 2018
Source:Actas Dermo-Sifiliográficas
Author(s): P.T. Bhattacharya, K. Patil, M.V. Guledgud

Beyond the Brown Bag: Designing Effective Professional Development for Informal Educators

Abstract

Most researchers are keenly interested in disseminating their work beyond traditional publication routes. With an eye to increasing broader impacts, scientists can benefit from partnerships with informal educators who interact daily with the public and see their role as translating science to increase the public's intellectual and emotional connections with the natural world. Typically, researchers give a one-time lunch hour talk, generally a modified version of a presentation aimed at scientific peers. Talks during which scientists show slides and interpreters mainly listen are a missed opportunity. They leave the scientist no wiser about the public's interests and the nagging questions interpreters have. Such talks leave the conscientious park educator with insufficient resources for overcoming challenges in interpreting the science for the public. The iSWOOP project (Interpreters and Scientists Working on Our Parks) proposes a model of professional development that involves a deliberate partnership where scientists and educators work together. During site-based professional development sessions, they tease out the relevance to public audiences and begin to develop programs about the science. This article describes iSWOOP's approach to supporting productive collaborations that promote an understanding of scientific research to public audiences. Results from a pair of surveys indicate that both sides of this partnership benefit from extended contact and clear communication.

Do seasonal glucocorticoid changes depend on reproductive investment? A comparative approach in birds

Abstract

Animals go through different life history stages such as reproduction, moult, or migration, of which some are more energy-demanding than others. Baseline concentrations of glucocorticoid hormones increase during moderate, predictable challenges and thus are expected to be higher when seasonal energy demands increase, such as during reproduction. By contrast, stress-induced glucocorticoids prioritize a survival mode that includes reproductive inhibition. Thus, many species down-regulate stress-induced glucocorticoid concentrations during the breeding season. Interspecific variation in glucocorticoid levels during reproduction has been successfully mapped onto reproductive investment, with species investing strongly in current reproduction (fast pace of life) showing higher baseline and lower stress-induced glucocorticoid concentrations than species that prioritize future reproduction over current attempts (slow pace of life). Here we test the "glucocorticoid seasonal plasticity hypothesis", in which we propose that interspecific variation in seasonal changes in glucocorticoid concentrations from the non-breeding to the breeding season will be related to the degree of reproductive investment (and thus pace of life). We extracted population means for baseline (for 54 species) and stress-induced glucocorticoids (for 32 species) for the breeding and the non-breeding seasons from the database 'HormoneBase', also calculating seasonal glucocorticoid changes. We focused on birds because this group offered the largest sample size. Using phylogenetic comparative methods, we first showed that species differed consistently in both average glucocorticoid concentrations and their changes between the two seasons, while controlling for sex, latitude and hemisphere. Second, as predicted seasonal changes in baseline glucocorticoids were explained by clutch size (our proxy for reproductive investment), with species laying larger clutches showing a greater increase during the breeding season – especially in passerine species. In contrast, changes in seasonal stress-induced levels were not explained by clutch size, but sample sizes were more limited. Our findings highlight that seasonal changes in baseline glucocorticoids are associated with a species' reproductive investment, representing an overlooked physiological trait that may underlie the pace of life.

Muscle Function from Organisms to Molecules

Synopsis

Gaps in our understanding of muscle contraction at the molecular level limit the ability to predict in vivo muscle forces in humans and animals during natural movements. Because muscles function as motors, springs, brakes, or struts, it is not surprising that uncertainties remain as to how sarcomeres produce these different behaviors. Current theories fail to explain why a single extra stimulus, added shortly after the onset of a train of stimuli, doubles the rate of force development. When stretch and doublet stimulation are combined in a work loop, muscle force doubles and work increases by 50% per cycle, yet no theory explains why this occurs. Current theories also fail to predict persistent increases in force after stretch and decreases in force after shortening. Early studies suggested that all of the instantaneous elasticity of muscle resides in the cross-bridges. Subsequent cross-bridge models explained the increase in force during active stretch, but required ad hoc assumptions that are now thought to be unreasonable. Recent estimates suggest that cross-bridges account for only ∼12% of the energy stored by muscles during active stretch. The inability of cross-bridges to account for the increase in force that persists after active stretching led to development of the sarcomere inhomogeneity theory. Nearly all predictions of this theory fail, yet the theory persists. In stretch-shortening cycles, muscles with similar activation and contractile properties function as motors or brakes. A change in the phase of activation relative to the phase of length changes can convert a muscle from a motor into a spring or brake. Based on these considerations, it is apparent that the current paradigm of muscle mechanics is incomplete. Recent advances in our understanding of giant muscle proteins, including twitchin and titin, allow us to expand our vision beyond cross-bridges to understand how muscles contribute to the biomechanics and control of movement.

The right compound for the right target. Tackling RET

Man against machine: diagnostic performance of a deep learning convolutional neural network for dermoscopic melanoma recognition in comparison to 58 dermatologists

Abstract

Background

Deep learning convolutional neural networks (CNN) may facilitate melanoma detection, but data comparing a CNN's diagnostic performance to larger groups of dermatologists are lacking.

Methods

Google's Inception v4 CNN architecture was trained and validated using dermoscopic images and corresponding diagnoses. In a comparative cross-sectional reader study a 100-image test-set was used (level-I: dermoscopy only; level-II: dermoscopy plus clinical information and images). Main outcome measures were sensitivity, specificity and area under the curve (AUC) of receiver operating characteristics (ROC) for diagnostic classification (dichotomous) of lesions by the CNN versus an international group of 58 dermatologists during level-I or -II of the reader study. Secondary end points included the dermatologists' diagnostic performance in their management decisions and differences in the diagnostic performance of dermatologists during level-I and -II of the reader study. Additionally, the CNN's performance was compared with the top-five algorithms of the 2016 International Symposium on Biomedical Imaging (ISBI) challenge.

Results

In level-I dermatologists achieved a mean (±standard deviation) sensitivity and specificity for lesion classification of 86.6% (±9.3%) and 71.3% (±11.2%), respectively. More clinical information (level-II) improved the sensitivity to 88.9% (±9.6%, P = 0.19) and specificity to 75.7% (±11.7%, P < 0.05). The CNN ROC curve revealed a higher specificity of 82.5% when compared with dermatologists in level-I (71.3%, P < 0.01) and level-II (75.7%, P < 0.01) at their sensitivities of 86.6% and 88.9%, respectively. The CNN ROC AUC was greater than the mean ROC area of dermatologists (0.86 versus 0.79, P < 0.01). The CNN scored results close to the top three algorithms of the ISBI 2016 challenge.

Conclusions

For the first time we compared a CNN's diagnostic performance with a large international group of 58 dermatologists, including 30 experts. Most dermatologists were outperformed by the CNN. Irrespective of any physicians' experience, they may benefit from assistance by a CNN's image classification.

Clinical trial number

This study was registered at the German Clinical Trial Register (DRKS-Study-ID: DRKS00013570; https://www.drks.de/drks_web/).

Artificial intelligence for melanoma diagnosis: How can we deliver on the promise?

Facile synthesis of magnetic disinfectant immobilized with silver ions for water pathogenic microorganism’s deactivation

Abstract

One-pot synthesis of a new magnetic disinfectant was achieved through the polymerization of thiourea and formaldehyde in the presence of magnetite nanoparticles (MTUF). The obtained magnetic chelating resin was loaded with Ag(I) ions. This material was tested as a disinfectant for water pathogenic microorganism's deactivation. The toxicity of MTUF before and after Ag(I) loading was estimated. The antimicrobial activity tests of MTUF-Ag were carried out against Escherichia coli, Salmonella Typhimurium, and Pseudomonas aeruginosa as examples of Gram-negative bacteria; Listeria monocytogenes, Staphylococcus aureus, Enterococcus faecalis, and Bacillus subtilis as examples of Gram-positive bacteria; and Candida albicans as representative for fungi. The results showed that the minimum inhibitory dosage (MID) of MTF-Ag against Escherichia coli, Salmonella Typhimurium, Listeria monocytogenes, Staphylococcus aureus, and mixed culture were 1.5, 2.0, 1.0, 1.5, and 1.5 mg/mL, respectively, after 40 min of contact time. While C. albicans was more resistant to the magnetic disinfectant, only three log reductions were done at 2.5 mg/mL. The studied MTUF-Ag was successfully tested for water and wastewater pathogenic microorganism's deactivation. It can be concluded that MTUF-Ag could be a good candidate for water disinfection.

Lateral thermal spread and recurrent laryngeal nerve paralysis after minimally invasive esophagectomy in bipolar vessel sealing and ultrasonic energy devices: a comparative study

Abstract

Background

This study aimed to compare the extent of lateral thermal spread of surrounding tissues after the use of advanced bipolar and ultrasonic coagulation and shearing devices. Association between recurrent laryngeal nerve paralysis (RLNP) and such devices was assessed in patients who underwent minimally invasive esophagectomy (MIE).

Methods

LigaSure^™ (LS) and Sonicision^™ (SONIC) were used. In ex vivo experiments using the porcine muscle, blade temperature and tissue temperature were measured using a thermometer after the activation of both devices. For the clinical assessment, 46 consecutive patients who received MIE were retrospectively assessed.

Results

The temperature generated at the blade of both devices increased with the activation time. The blade temperature of LS was significantly lower than that of SONIC (P < 0.001). The blade temperature of SONIC exceeded 100 °C after 3-s activation. The temperature of surrounding tissues after a single activation of the devices decreased with the tissue distance from activation blade. The temperatures of tissues at 1 and 2 mm away from the blade side of LS were significantly lower than those of SONIC (P = 0.001 and P < 0.001, respectively). The temperature of tissue 2 mm away from the blade side of LS increased 6.4 °C from the baseline temperature. Furthermore, the incidence of RLNP in the LS group was lower than that in the SONIC group (P = 0.044).

Conclusion

This study highlights the necessity of spatial and temporal recognition of the thermal spread of coagulation and shearing devices to reduce the thermal injuries following MIE.

The effect of an elemental diet on oral mucositis of esophageal cancer patients treated with DCF chemotherapy: a multi-center prospective feasibility study (EPOC study)

Abstract

Purpose

Oral mucositis (OM) is one of the most uncomfortable adverse events experienced by cancer patients undergoing chemotherapy. Previous reports have revealed that the oral administration of an elemental diet (ED) may prevent OM. However, the incidence of OM has not been accurately determined by specialized diagnostic methods and the effects of an ED on OM remain unclear. We investigated the dose that could feasibly be administered and its effects with regard to the suppression of OM in esophageal cancer patients undergoing chemotherapy.

Methods

We performed a prospective multi-center feasibility study of the administration of an ED (160 g/day) with 2 cycles of docetaxel/cisplatin/5-FU (DCF) chemotherapy. We assessed compliance to the ED for 49 days and the incidence of OM according to the amount of the ED that was orally administered. The incidence of OM was graded by a dental specialist who was experienced in dental oncology using a central OM review system.

Results

Fourteen of 20 patients (70%) were able to complete the orally administered ED (160 g/day) during the course of chemotherapy. Three patients (15%) could not take the ED orally for 9, 14, and 21 days, respectively, while 1 patient (5%) took the ED orally at an average dose of 80 g/day for 35 days. The remaining 2 patients (10%) could not take the 80 g/day dose for 11 and 12 days, respectively. The incidence of grade ≥ 2 OM in the ED completion group (15.4%, 2 of 13 patients) was significantly lower than that in the non-completion group (66.7%, 4 of 6 patients) (p = 0.046).

Conclusions

An ED might be a one of the test treatment to reduce the incidence of OM in esophageal cancer patients treated with DCF and should be evaluated in further randomized study.

Clinical trial

The date of submission: Dec 08th, 2017.

Association of level of anastomosis and anastomotic leak after esophagectomy in anterior mediastinal reconstruction

Abstract

Aim

The purpose of this study was to investigate modifiable predisposing factors associated with anastomotic leak in the anterior mediastinal (AM) reconstruction route.

Methods

We reviewed the data on 154 patients who underwent esophagectomy and gastric tube reconstruction using the AM route between 2008 and 2016. The data included computed tomography (CT) scans with sagittal reconstruction of the thoracic section. The level of the esophagogastric anastomosis (LEA) and pretracheal distance (PTD) was measured from sagittal reconstructed CT images. Vascularization of the gastric tube was evaluated by postoperative endoscopy. Variables associated with anastomotic leak were determined using univariate and multivariate analyses.

Results

Anastomotic leak developed in 13 patients (8%). The cut-off level at which the anastomosis was less likely to develop a leak, as determined by Chi-square tests, was 1.5 cm for LEA and 1.3 cm for PTD. On univariate analysis, the factors that were significantly associated with the risk of anastomotic leak included diabetes, hand-sewn anastomosis, the LEA ≥ 1.5 cm, and severe mucosal degeneration. On multivariate analysis, diabetes (OR 4.7, 95% CI 1.29–17.2), LEA ≥ 1.5 cm (OR 20.1, 95% CI 3.15–128), and severe mucosal degeneration (OR 7.2, 95% CI 1.42–36.8) were found to be statistically significant independent risk factors.

Conclusion

Use of the AM route to place the cervical anastomosis within 1.5 cm above the suprasternal notch might avoid excessive pressure on the gastric tube from the surrounding structures, resulting in a reduction in the risk of an anastomotic leak.

An exploratory study of energy reserves and biometry as potential tools for assessing the effects of pest management strategies on the earwig, Forficula auricularia L

Abstract

Apple orchards are heavily treated crops and some sprayed insecticides are recognized to have toxic effects on non-target arthropods. Earwigs are important natural enemies in pip-fruit orchards and contribute to the biological control of aphids. In addition, due to their ease of capture and identification, they are an interesting potential bioindicator of the possible detrimental effects of different orchard management strategies. In this study, we measured the energy reserves and some morphological traits of Forficula auricularia L. sampled in apple orchards under management strategies (organic versus integrated pest management (IPM)). We observed a significant decrease in mass (22 to 27%), inter-eye width (3%), and prothorax width (2 to 5%) in earwigs from IPM compared to organic orchards. Energy body reserves also confirmed these results with a significant decrease of 48% in glycogen and 25 to 42% in lipid content in earwigs from IPM compared to organic orchards. However, the protein content was approximately 70% higher in earwigs from IPM than in organic orchards. Earwigs sampled in IPM orchards may adapt to minimize the adverse toxic effects of pesticide treatments using a large number of strategies, which are reflected in changes to their energy reserves. These strategies could, in turn, influence the population dynamics of natural enemies and impair their role in the biological control of pests in apple orchards.

Molecular assessment of glyphosate-degradation pathway via sarcosine intermediate in Lysinibacillus sphaericus

Abstract

The widespread use of glyphosate has permeated not only small- and large-scale agriculture, but also the fight against drug trafficking and illicit crops. Health, alimentary security, and the rights of peasant and indigenous communities have been compromised in countries with intensive use of glyphosate-based herbicides. In 2015, the International Agency for Research on Cancer classified this substance as probably carcinogenic to humans, leading to the suspension of aerial glyphosate spraying the same year in countries like Colombia, where glyphosate has been extensively used in illicit crop eradication. Notwithstanding, according to a study of the U.S. Geological Survey, traces of glyphosate and its main degradation product, AMPA, remain in soil year after year. This underscores the urgency and importance of assessing new technologies to degrade glyphosate present in soils and waterbodies without leaving persistent byproducts. The aim of this study was to evaluate Lysinibacillus sphaericus' glyphosate uptake as a carbon and phosphorous source by a sarcosine-mediated metabolic pathway that releases glycine as final degradation product. To accomplish this, molecular and analytic evidence were collected in vitro from sarcosine oxidase activity, a key enzyme of a degradation pathway which releases byproducts that are easy to incorporate into natural biosynthesis routes.

Characterising boiler ash from a circulating fluidised bed municipal solid waste incinerator and distribution of PCDD/F and PCB

Abstract

In this study, ash samples were collected from five locations situated in the boiler of a circulating fluidised bed municipal solid waste incinerator (high- and low-temperature superheater, evaporator tubes and upper and lower economiser). These samples represent a huge range of flue gas temperatures and were characterised for their particle size distribution, surface characteristics, elemental composition, chemical forms of carbon and chlorine and distribution of polychlorinated dibenzo-p-dioxins (PCDD), dibenzofurans (PCDF) and biphenyls (PCB). Enrichment of chlorine, one of the main elements of organochlorinated pollutants, and copper, zinc and lead, major catalytic metals for dioxin-like compounds, was observed in lower-temperature ash deposits. The speciation of carbon and chlorine on ash surfaces was established, showing a positive correlation between organic chlorine and oxygen-containing carbon functional groups. The load of PCDD/F and PCB (especially dioxin-like PCB) tends to rise rapidly with falling temperature of flue gas, reaching their highest value in economiser ashes. The formation of PCDD/F congeners through the chlorophenol precursor route apparently was enhanced downstream the boiler. Principal component analysis (PCA) was applied to study the links between the ash characteristics and distribution of chloro-aromatics. The primary purpose of this study is improving the understanding of any links between the characteristics of ash from waste heat systems and its potential to form PCDD/F and PCB. The question is raised whether further characterisation of fly ash may assist to establish a diagnosis of poor plant operation, inclusive the generation, destruction and eventual emission of persistent organic pollutants (POPs).

Co-N-doped MoO 2 modified carbon felt cathode for removal of EDTA-Ni in electro-Fenton process

Abstract

Metal ions removal is inhibited in aqueous solution containing ethylenediaminetetraacetic acid (EDTA). In this study, the non-noble metals-based Co-N-doped MoO₂ nanowires (Co-N-MoO₂) were successfully synthesized using cyanamide and Co(Ac)₂ as precursors by pyrolysis, then immobilized on carbon felt (CF), and firstly used as cathode to remove EDTA-Ni complex through oxygen reduction reaction (ORR) in electro-Fenton (EF) process. The X-ray diffraction (XRD) and scanning electron microscopy (SEM) results indicated that a synergetic coupling effect of doping of N and Co induced structural modifications of MoO₂ lattice, and produced more lattice defects. The electrochemical analysis results showed that the superior ORR electrochemical catalysis activities were obtained at pH = 3 with the lowest cathodic peak potentials (− 0.157 V vs. Ag/AgCl), the highest electrochemical active surface area (EASA: 3.971 mC cm⁻²), the extraordinarily high of the ring current (35.5 μA) and high H₂O₂ yield (> 20%). Under the optimum conditions, about 68% of EDTA-Ni was removed with the Co-N-MoO₂/CF as cathode after 120 min with lower specific energy consumption (0.0226 kW h mg⁻¹ (DOC)) in EF system. Mechanism analysis indicated that the production of strong oxidizing property of hydroxyl radical (•OH) on the cathode played an important role in the removal of EDTA-Ni in the EF process, synergetic effect of cobalt and nitrogen co-doped could facilitate the high generation of H₂O₂, which greatly promote the formation of •OH. The EF system with Co-N-MoO₂/CF cathode has a potential for breaking metal-complex with good stability, showing that this cathode is a candidate for application for applications in EAPOs.

Esophageal Squamous Cell Carcinoma Metastatic to the Orbit

A 74-year-old man presenting with proptosis and orbital inflammation was found on magnetic resonance imaging to have a unilateral intraconal mass. Biopsy revealed a high-grade malignant tumor that was interpreted as squamous cell carcinoma. Positron emission tomography-computed tomography imaging subsequently identified a primary lesion in the esophagus. Esophageal squamous cell carcinoma is a rare cause of orbital metastasis, with only 4 previously reported cases. The authors discuss an approach to orbital malignancies of obscure origin. Accepted for publication April 4, 2018. The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article. Address correspondence and reprint requests to Norman C. Charles, M.D., NYU Langone Medical Center, 550 First Avenue, New York, NY 10016. E-mail: norman.charles@nyumc.org © 2018 by The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc., All rights reserved.

Histopathologic Findings of Linear Scleroderma Displaying Focal Trichiasis Secondary to Tarsal Thinning

Linear scleroderma en coup de sabre with ophthalmic findings has been previously described in the literature on numerous occasions. A 57-year-old woman presented with focal trichiasis secondary to tarsal thinning, adjacent to a linear brow and forehead deformity consistent with linear scleroderma en coup de sabre. Cases of linear scleroderma en coup de sabre involving the eyelids have been reported, most often with madarosis, ptosis, or skin atrophy; however, to the authors' knowledge, this is the first reported case of linear scleroderma associated with trichiasis and involvement of the deeper eyelid tissues, particularly the tarsus. Accepted for publication April 4, 2018. N.W. is funded by a Heed Ophthalmic Fellowship. The authors have no financial or conflicts of interest to disclose. Address correspondence and reprint requests to Frederick A. Jakobiec, M.D., D.Sc, David G. Cogan Laboratory of Ophthalmic Pathology, Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, 243 Charles Street, Suite 328, Boston, MA 02114. E-mail: Fred_Jakobiec@meei.harvard.edu © 2018 by The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc., All rights reserved.

Greater Proptosis Is Not Associated With Improved Compressive Optic Neuropathy in Thyroid Eye Disease

Purpose: Despite the paucity of supporting data, it has generally been held that proptosis in thyroid eye disease (TED) may provide relative protection from compressive optic neuropathy (CON) by producing spontaneous decompression. The objective of this study was to investigate this phenomenon in patients with bilateral TED-CON. Methods: We retrospectively reviewed the charts of 67 patients (134 orbits) with bilateral TED-CON at Columbia-Presbyterian Medical Center. Significant asymmetric proptosis (Hertel) was defined as ≥ 2 mm.1 Significant asymmetric CON was defined first, as the presence of an relative afferent pupillary defect. Those without an relative afferent pupillary defect were evaluated according to the TED-CON formula y = –0.69 – 0.31 × (motility) – 0.2 × (mean deviation) – 0.02 × (color vision) as previously established for the diagnosis of TED-CON.2 A difference in the formula result ≥ 1.0 between eyes was considered significant. Patients were then divided into 4 groups. Results: Forty-one of 67 patients demonstrated asymmetric CON (29 by relative afferent pupillary defect, 12 by formula). Twenty-one of 67 patients demonstrated asymmetric proptosis. Only 5 of 12 (41.6%) of the patients who had both asymmetric proptosis and asymmetric CON (group 1) showed greater proptosis in the eye with less CON. Twenty-nine patients (group 2) showed that asymmetric CON occurred despite symmetrical proptosis. Seventeen patients (group 3), showed the inverse, that asymmetric differences in proptosis occurred with symmetrical CON. Conclusion: Despite commonly held assumptions, our results suggest that greater proptosis is not associated with improved TED-CON. Combining groups 1 to 3—all of which demonstrated asymmetry of either proptosis, CON, or both—91.4% of patients did not show a relationship between greater proptosis and improved CON. Accepted for publication March 27, 2018. This article was presented at the ASOPRS 48th Annual Fall Scientific Symposium, New Orleans, Louisiana on November 10th, 2017. The authors have no financial or conflicts of interest to disclose. Address correspondence and reprint requests to Michael Kazim, M.D., Harkness Eye Institute, Columbia University Medical Center, 635 West 165th Street, New York, NY 10032. E-mail: mk48@columbia.edu © 2018 by The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc., All rights reserved.

Diversity in the American Society of Ophthalmic Plastic and Reconstructive Surgery

Purpose: To assess the epidemiology of women and underrepresented minorities (URMs; Hispanic, African American, and Native American) in the American Society of Ophthalmic Plastic and Reconstructive Surgery (ASOPRS). Methods: An observational retrospective study of living ASOPRS members was identified through the ASOPRS member directory, search engine-driven informatics, and direct communication. Members were profiled for gender, race, geographic location, and academic rank (or not). The percentage of women and URMs in the society over time was also assessed. Results: The authors identified 617 living ASOPRS members as of June 2017. Of these, 109 (17.7%) were female and 58 (9.4%) were URMs. Surgeons completed fellowships from 1961 (male) or 1973 (female) until 2015. Women members significantly increased from 7 (4.9% of the total) before 1986 to 24 (30.4%) between 2011 and 2015 (last 5 years). URMs significantly increased over time, with 0 female and 5 (3.4%) male minorities before 1985 to 5 (6.3%) females and 13 (16.5%) males within the last 5 years (p

Integrated rice-duck farming decreases global warming potential and increases net ecosystem economic budget in central China

Abstract

Over the past decades, many attempts have been made to assess the effects of integrated rice-duck farming on greenhouse gas emissions, use efficient of energy, soil fertility, and economic significance. However, very few studies have been focused on the effects of the farming on net ecosystem economic budget (NEEB). Here, a 2-year field experiment was conducted to comprehensively investigate the effects of ducks raised in paddy fields on CH₄ and N₂O emissions, global warming potential (GWP), rice grain yield, and NEEB in central China. The experiment included two treatments: integrated rice-duck farming (RD) and conventional rice farming (R). The introduction of ducks into the paddy fields markedly increased the rice grain yield due to enhanced tiller number and root bleeding rate. RD treatment significantly elevated the N₂O emissions (p < 0.05) but decreased CH₄ emissions (p < 0.05) during rice growing seasons compared with R treatment. Analysis of GWP based on CH₄ and N₂O emissions showed that compared with R treatment, RD treatment significantly decreased the GWP by 28.1 and 28.0% and reduced the greenhouse gas intensity by 30.6 and 29.8% in 2009 and 2010, respectively. In addition, RD treatment increased NEEB by 40.8 and 39.7% respectively in 2009 and 2010 relative to R treatment. Taken together, our results suggest that the integrated rice-duck farming system is an effective strategy to optimize the economic and environmental benefits of paddy fields in central China.

Estimation of soil-specific microbial degradation of alpha-cypermethrin by compound-specific stable isotope analysis

Abstract

In this study, the microbial degradation of alpha-cypermethrin was investigated in 14 different soil samples by compound-specific stable isotope analysis. After 40 and 80 days of microbial degradation, the stable carbon isotope ratios of alpha-cypermethrin shifted from − 32.18 to − 31.87‰ ~ − 31.12 and − 31.45‰ ~ − 29.75‰ in the soils, respectively. The microbial degradation percentages of alpha-cypermethrin were calculated as 15.6~44.3% after 40 days of incubation and 33.3~73.9% after 80 days of incubation. The effects of physicochemical properties of soil samples were then explored on the microbial degradation of alpha-cypermethrin. The results revealed that the microbial degradation percentages were positively correlated with the contents of organic carbon in soils with Pearson correlation coefficients of 0.794 and 0.843 for 40 and 80 days of microbial degradation, respectively, indicating that the microbial degradation of alpha-cypermethrin was faster in the soil with higher content of organic carbon. Accordingly, soil-specific use should be considered in practical agricultural application of alpha-cypermethrin to reduce the residue of the pesticide.

How does intensification influence the operational and environmental performance of photo-Fenton processes at acidic and circumneutral pH

Abstract

This study evaluates the technical, economical, and environmental impact of sodium persulfate (Na₂S₂O₈) as an enhancing agent in a photo-Fenton process within a solar-pond type reactor (SPR). Photo-Fenton (PF) and photo-Fenton intensified with the addition of persulfate (PFPS) processes decolorize 97% the azo dye direct blue 71 (DB71) and allow producing a highly biodegradable effluent. Intensification with persulfate allowed reducing treatment time in 33% (from 120 to 80 min) and the consumption of chemical auxiliaries needed for pH adjustment. Energy, reagents, and chemical auxiliaries are still and environmental hotspot for PF and PFPS; however, it is worth mentioning that their environmental footprint is lower than that observed for compound parabolic concentrator (CPC)-type reactors. A life-cycle assessment (LCA) confirms that H₂O₂, NaOH, and energy consumption are the variables with the highest impact from an environmental standpoint. The use of persulfate reduced the relative impact in 1.2 to 12% in 12 of the 18 environmental categories studied using the ReCiPe method. The PFPS process emits 1.23 kg CO₂ (CO₂-Eqv/m³ treated water). On the other hand, the PF process emits 1.28 kg CO₂ (CO₂-Eqv/m³ treated water). Process intensification, chemometric techniques, and the use of SPRs minimize the impact of some barriers (reagent and energy consumption, technical complexity of reactors, pressure drops, dirt on the reflecting surfaces, fragility of reactor materials), limiting the application of advanced oxidation systems at an industrial level, and decrease treatment cost as well as potential environmental impacts associated with energy and reagents consumption. Treatment costs for PF processes (US$0.78/m³) and PFPS processes (US$0.63/m³) were 20 times lower than those reported for photo-Fenton processes in CPC-type reactors.

Climate change and economic growth: a heterogeneous panel data approach

Abstract

Climate change is a global phenomenon. Its impact on economic growth must therefore be analyzed in accordance with its (time-varying) common effects. We present an econometric analysis that evaluates this effect taking into account its global nature. Contrary to previous evidence that ignores the global effects, we obtain that the rising temperature has not decreased growth in real GDP per capita in the second half of the twentieth century for the world countries. However, we obtain a negative effect of rising temperatures and a positive effect of rising precipitation in poor countries. This positive effect of rising precipitation is also confirmed for hot and temperate countries.

Hydrothermal synthesis of a magnetic adsorbent from wasted iron mud for effective removal of heavy metals from smelting wastewater

Abstract

A magnetic adsorbent (MA) was synthesized from wasted iron mud of a groundwater treatment plant using a novel one-step hydrothermal method. The results showed that Fe content of MA was 41.8 wt%, 2.5 times higher than that of iron mud, which was caused by hydrothermal dissolution of non-ferrous impurities under alkaline condition, such as quartz and albite, regardless of addition of ascorbic acid or not. Ferrihydrite was 92.7% in dry iron mud before adding ascorbic acid and gradually decreased to 58.1% by increasing the molar ratio of ascorbic acid to Fe following hydrothermal treatment. The strongest saturation magnetization of 16.29 emu/g was observed in the prepared MA-4 when the ascorbic acid to Fe molar ratio was 1. The highest surface site concentration of 1.31 mmol/g was observed in MA-2 when the ratio was 0.02. The mechanism of hydrothermal conversion of wasted iron mud to MA was reductive dissolution of ferrihydrite to form siderite, which was then reoxidized to maghemite. When 12.5 g/L of MA-2 was applied to treat smelting wastewater, over 99% removal of Cu²⁺, Zn²⁺, Pb²⁺, and Cd²⁺ was achieved. The major mechanisms of Cu²⁺ and Zn²⁺ adsorption by the adsorbent were cationic exchange.

Study of zinc oxide nanoparticles and zinc chloride toxicity to annelid Enchytraeus crypticus in modified agar-based media

Abstract

Acute toxicity of zinc oxide nanoparticle (ZnO-NP, mean particle size diameter of 10 nm) powder and water-soluble salt of zinc (ZnCl₂) to annelid Enchytraeus crypticus was tested using an agar-based nutrient-enriched medium with the addition of kaolin and humic acids (HA). Adults of the E. crypticus were cultivated in pure agar and in three types of modified exposure media containing different proportions of model soil constituents. Potworms were exposed to zinc in both forms (1–1000 mg kg⁻¹ of agar) for 96 h. In experiments with ZnCl₂, toxicity of zinc was the highest in pure agar followed by agar with HA and agar with kaolin and HA and the lowest toxicity was observed in agar with kaolin. The corresponding LC₅₀ values were 13.2, 28.8, 39.4, and 75.4 mg kg⁻¹ respectively. In contrast, zinc in the form of ZnO-NPs was most toxic in the presence of HA followed by pure agar, agar with kaolin, and kaolin with HA. In this case, LC₅₀ values were 15.8, 43.5, 111, and 122 mg kg⁻¹ respectively. Scanning electron microscopy revealed that the smallest agglomerates occurred in the presence of kaolin, where ZnO-NPs were sealed in a kaolin shell. This effect reduced the bioavailability and toxicity of the NPs. In contrast, larger agglomerates were observed in the presence of HA but a larger amount of zinc was dispersed in the volume of agar.

Ecological quality status evaluation of a monsoonal tropical estuary using benthic indices: comparison via a seasonal approach

Abstract

The use of biotic indices has garnered attention during the last decade due to its extensive application in evaluating ecological quality status (EcoQS) of marine waters and estuaries. Three seasonal surveys were conducted in the Kundalika estuary, India to evaluate the ecostatus using five benthic indices and comparing their effectiveness considering the estuarine salinity gradient and seasonality. All indices gave divergent results displaying a wide range of classes (good to bad) across salinity zones and seasons. Comparatively, M-AMBI discriminated the EcoQS suitably than other indices. Hence, a seasonally averaged approach for M-AMBI was proposed to obtain a final mean EcoQS which assigned moderate status to the euhaline and poly-mesohaline zones and poor status to the oligohaline zone. Considering the high degree of spatial heterogeneity and seasonality in the estuary, the monsoon data was found to lower the EcoQS due to natural stress in some cases; the exclusion of the monsoon season resulted in a more valid ecostatus. Therefore, this approach which combines information from the non-monsoon seasons stands out in providing a useful basis for ecological management by scrutinizing responses of macrobenthos. Also, we suggest salinity zone-wise evaluation for more effective classification chiefly in tropical monsoonal estuaries. An effort to establish a final EcoQS was performed; however, future in-depth studies are necessary to ascertain the reliability of the successful biotic index (M-AMBI) in estuaries with different stressors.

Seasonal variations of contamination and exoskeletal malformations in the white shrimps Palaemon longirostris in the Gironde estuary, France

Abstract

Since the end of the 1980s, white shrimps (Palaemon longirostris) from the Gironde estuary have exhibited exoskeletal malformations, mainly involving cephalothorax, rostrum, scaphocerites and uropods. An 8-month study was carried out in 2015. Each month, 200 individuals were sampled and examined for exoskeletal malformations. Temporal variations in malformation frequency were noted, particularly during the breeding period, along with decreases in the size of non-deformed shrimps related to the appearance of juveniles in breeding sites, and high mortality among deformed shrimps. A significant increase in proportions of deformed shrimp was observed, relating particularly to the size (and therefore the age) of individuals. No significant difference was found between shrimp proportions with different numbers of malformations (one to four) for a fixed size class, nor was there any variation in proportions within different size classes for a fixed number of malformations. This would appear to indicate that the number of malformations is acquired and new malformations do not seem to appear during the life cycle, except for the smallest (youngest) shrimps. The malformation spectrum showed no significant differences between the biggest and smallest individuals for the different malformation associations, except for those involving cephalothorax, rostrum and uropods. This would suggest that some malformation associations lead to a higher mortality rate in shrimps subjected to them, due to greater impairment of feeding and/or swimming behaviour. Multiple component analysis of the different types of malformation showed correlations between exoskeletal pieces (rostrum and cephalothorax) and appendixes (scaphocerites and uropods). Regarding metal contamination in shrimp, no significant difference was highlighted between deformed and non-deformed shrimps. Organic pollutants were not measured in tissues. Certain herbicides such as metolachlore and chlortoluron were detected at high concentrations in the Gironde estuary during the breeding period corresponding to the higher occurrence of exoskeletal malformations.

Guest Editor Introduction to the Book Symposium on Shannon Vallor, Technology and the Virtues: A Philosophical Guide to a Future Worth Wanting. Oxford: Oxford University Press, 2016

JSID's Fellowship Shiseido Research Grant

Conditional Bistability, a Generic Cellular Mnemonic Mechanism for Robust and Flexible Working Memory Computations

Persistent neural activity, the substrate of working memory, is thought to emerge from synaptic reverberation within recurrent networks. However, reverberation models do not robustly explain the fundamental dynamics of persistent activity, including high-spiking irregularity, large intertrial variability, and state transitions. While cellular bistability may contribute to persistent activity, its rigidity appears incompatible with persistent activity labile characteristics. Here, we unravel in a cellular model a form of spike-mediated conditional bistability that is robust and generic. and provides a rich repertoire of mnemonic computations. Under asynchronous synaptic inputs of the awakened state, conditional bistability generates spiking/bursting episodes, accounting for the irregularity, variability, and state transitions characterizing persistent activity. This mechanism has likely been overlooked because of the subthreshold input it requires, and we predict how to assess it experimentally. Our results suggest a reexamination of the role of intrinsic properties in the collective network dynamics responsible for flexible working memory.

SIGNIFICANCE STATEMENT This study unravels a novel form of intrinsic neuronal property: conditional bistability. We show that, thanks to its conditional character, conditional bistability favors the emergence of flexible and robust forms of persistent activity in PFC neural networks, in opposition to previously studied classical forms of absolute bistability. Specifically, we demonstrate for the first time that conditional bistability (1) is a generic biophysical spike-dependent mechanism of layer V pyramidal neurons in the PFC and that (2) it accounts for essential neurodynamical features for the organization and flexibility of PFC persistent activity (the large irregularity and intertrial variability of the discharge and its organization under discrete stable states), which remain unexplained in a robust fashion by current models.

Exploring Executive Functions Using a Distributed Circuit Model

Short-Term Plasticity Combines with Excitation-Inhibition Balance to Expand Cerebellar Purkinje Cell Dynamic Range

The balance between excitation (E) and inhibition (I) in neuronal networks controls the firing rate of principal cells through simple network organization, such as feedforward inhibitory circuits. Here, we demonstrate in male mice, that at the granule cell (GrC)-molecular layer interneuron (MLI)-Purkinje cell (PC) pathway of the cerebellar cortex, E/I balance is dynamically controlled by short-term dynamics during bursts of stimuli, shaping cerebellar output. Using a combination of electrophysiological recordings, optogenetic stimulation, and modeling, we describe the wide range of bidirectional changes in PC discharge triggered by GrC bursts, from robust excitation to complete inhibition. At high frequency (200 Hz), increasing the number of pulses in a burst (from 3 to 7) can switch a net inhibition of PC to a net excitation. Measurements of EPSCs and IPSCs during bursts and modeling showed that this feature can be explained by the interplay between short-term dynamics of the GrC-MLI-PC pathway and E/I balance impinging on PC. Our findings demonstrate that PC firing rate is highly sensitive to the duration of GrC bursts, which may define a temporal-to-rate code transformation in the cerebellar cortex.

SIGNIFICANCE STATEMENT Sensorimotor information processing in the cerebellar cortex leads to the occurrence of a sequence of synaptic excitation and inhibition in Purkinje cells. Granule cells convey direct excitatory inputs and indirect inhibitory inputs to the Purkinje cells, through molecular layer interneurons, forming a feedforward inhibitory pathway. Using electrophysiological recordings, optogenetic stimulation, and mathematical modeling, we found that presynaptic short-term dynamics affect the balance between synaptic excitation and inhibition on Purkinje cells during high-frequency bursts and can reverse the sign of granule cell influence on Purkinje cell discharge when burst duration increases. We conclude that short-term dynamics may play an important role in transforming the duration of sensory inputs arriving on cerebellar granule cells into cerebellar cortical output firing rate.

Remote Memory and Cortical Synaptic Plasticity Require Neuronal CCCTC-Binding Factor (CTCF)

The molecular mechanism of long-term memory has been extensively studied in the context of the hippocampus-dependent recent memory examined within several days. However, months-old remote memory maintained in the cortex for long-term has not been investigated much at the molecular level yet. Various epigenetic mechanisms are known to be important for long-term memory, but how the 3D chromatin architecture and its regulator molecules contribute to neuronal plasticity and systems consolidation is still largely unknown. CCCTC-binding factor (CTCF) is an 11-zinc finger protein well known for its role as a genome architecture molecule. Male conditional knock-out mice in which CTCF is lost in excitatory neurons during adulthood showed normal recent memory in the contextual fear conditioning and spatial water maze tasks. However, they showed remarkable impairments in remote memory in both tasks. Underlying the remote memory-specific phenotypes, we observed that female CTCF conditional knock-out mice exhibit disrupted cortical LTP, but not hippocampal LTP. Similarly, we observed that CTCF deletion in inhibitory neurons caused partial impairment of remote memory. Through RNA sequencing, we observed that CTCF knockdown in cortical neuron culture caused altered expression of genes that are highly involved in cell adhesion, synaptic plasticity, and memory. These results suggest that remote memory storage in the cortex requires CTCF-mediated gene regulation in neurons, whereas recent memory formation in the hippocampus does not.

SIGNIFICANCE STATEMENT CCCTC-binding factor (CTCF) is a well-known 3D genome architectural protein that regulates gene expression. Here, we use two different CTCF conditional knock-out mouse lines and reveal, for the first time, that CTCF is critically involved in the regulation of remote memory. We also show that CTCF is necessary for appropriate expression of genes, many of which we found to be involved in the learning- and memory-related processes. Our study provides behavioral and physiological evidence for the involvement of CTCF-mediated gene regulation in the remote long-term memory and elucidates our understanding of systems consolidation mechanisms.

Structural and Functional Rescue of Chronic Metabolically Stressed Optic Nerves through Respiration

Axon degeneration can arise from metabolic stress, potentially a result of mitochondrial dysfunction or lack of appropriate substrate input. In this study, we investigated whether the metabolic vulnerability observed during optic neuropathy in the DBA/2J (D2) model of glaucoma is due to dysfunctional mitochondria or impaired substrate delivery to axons, the latter based on our observation of significantly decreased glucose and monocarboxylate transporters in D2 optic nerve (ON), human ON, and mice subjected to acute glaucoma injury. We placed both sexes of D2 mice destined to develop glaucoma and mice of a control strain, the DBA/2J-Gpnmb⁺, on a ketogenic diet to encourage mitochondrial function. Eight weeks of the diet generated mitochondria, improved energy availability by reversing monocarboxylate transporter decline, reduced glial hypertrophy, protected retinal ganglion cells and their axons from degeneration, and maintained physiological signaling to the brain. A robust antioxidant response also accompanied the response to the diet. These results suggest that energy compromise and subsequent axon degeneration in the D2 is due to low substrate availability secondary to transporter downregulation.

SIGNIFICANCE STATEMENT We show axons in glaucomatous optic nerve are energy depleted and exhibit chronic metabolic stress. Underlying the metabolic stress are low levels of glucose and monocarboxylate transporters that compromise axon metabolism by limiting substrate availability. Axonal metabolic decline was reversed by upregulating monocarboxylate transporters as a result of placing the animals on a ketogenic diet. Optic nerve mitochondria responded capably to the oxidative phosphorylation necessitated by the diet and showed increased number. These findings indicate that the source of metabolic challenge can occur upstream of mitochondrial dysfunction. Importantly, the intervention was successful despite the animals being on the cusp of significant glaucoma progression.

Dissociation between CSD-Evoked Metabolic Perturbations and Meningeal Afferent Activation and Sensitization: Implications for Mechanisms of Migraine Headache Onset

The onset of the headache phase during attacks of migraine with aura, which occur in ~30% of migraineurs, is believed to involve cortical spreading depression (CSD) and the ensuing activation and sensitization of primary afferent neurons that innervate the intracranial meninges, and their related large vessels. The mechanism by which CSD enhances the activity and mechanosensitivity of meningeal afferents remains poorly understood, but may involve cortical metabolic perturbations. We used extracellular single-unit recording of meningeal afferent activity and monitored changes in cortical blood flow and tissue partial pressure of oxygen (tpO₂) in anesthetized male rats to test whether the prolonged cortical hypoperfusion and reduction in tissue oxygenation that occur in the wake of CSD contribute to meningeal nociception. Suppression of CSD-evoked cortical hypoperfusion with the cyclooxygenase inhibitor naproxen blocked the reduction in cortical tpO₂, but had no effect on the activation of meningeal afferents. Naproxen, however, distinctly prevented CSD-induced afferent mechanical sensitization. Counteracting the CSD-evoked persistent hypoperfusion and reduced tpO₂ by preemptively increasing cortical blood flow using the ATP-sensitive potassium [K(ATP)] channel opener levcromakalim did not inhibit the sensitization of meningeal afferents, but prevented their activation. Our data show that the cortical hypoperfusion and reduction in tpO₂ that occur in the wake of CSD can be dissociated from the activation and mechanical sensitization of meningeal afferent responses, suggesting that the metabolic changes do not contribute directly to these neuronal nociceptive responses.

SIGNIFICANCE STATEMENT Cortical spreading depression (CSD)-evoked activation and mechanical sensitization of meningeal afferents is thought to mediate the headache phase in migraine with aura. We report that blocking the CSD-evoked cortical hypoperfusion and reduced tissue partial pressure of oxygen by cyclooxygenase inhibition is associated with the inhibition of the afferent sensitization, but not their activation. Normalization of these CSD-evoked metabolic perturbations by activating K(ATP) channels is, however, associated with the inhibition of afferent activation but not sensitization. These results question the contribution of cortical metabolic perturbations to the triggering mechanism underlying meningeal nociception and the ensuing headache in migraine with aura, further point to distinct mechanisms underlying the activation and sensitization of meningeal afferents in migraine, and highlight the need to target both processes for an effective migraine therapy.

The Affective and Neural Correlates of Heroin versus Cocaine Use in Addiction Are Influenced by Environmental Setting But in Opposite Directions

Previous studies have shown that individuals with heroin and cocaine addiction prefer to use these drugs in distinct settings: mostly at home in the case of heroin and mostly outside the home in the case of cocaine. Here we investigated whether the context would modulate the affective and neural responses to these drugs in a similar way. First, we used a novel emotional task to assess the affective state produced by heroin or cocaine in different settings, based on the recollections of male and female drug users. Then we used fMRI to monitor neural activity during drug imagery (re-creating the setting of drug use) in male drug users. Consistent with our working hypothesis, the majority of participants reported a shift in the affective valence of heroin from mostly pleasant at home to mostly unpleasant outside the home (p < 0.0001). The opposite shift was observed for cocaine; that is, most participants who found cocaine pleasant outside the home found it unpleasant when taken at home (p < 0.0014). Furthermore, we found a double dissociation, as a function of drug and setting imagery, in BOLD signal changes in the left PFC and caudate, and bilaterally in the cerebellum (all p values <0.01), suggesting that the fronto-striatal-cerebellar network is implicated in the contextualization of drug-induced affect. In summary, we report that the same setting can influence in opposite directions the affective and neural response to psychostimulants versus opiates in humans, adding to growing evidence of distinct substrates for the rewarding effects of these two drug classes.

SIGNIFICANCE STATEMENT The rewarding effects of addictive drugs are often thought to depend on shared substrates. Yet, environmental influences can unmask striking differences between psychostimulants and opiates. Here we used emotional tasks and fMRI to explore the influence of setting on the response to heroin versus cocaine in individuals with addiction. Simply moving from one setting to another significantly decreased heroin pleasure but increased cocaine pleasure, and vice versa. Similar double dissociation was observed in the activity of the fronto-striatal-cerebellar network. These findings suggest that the effects of opiates and psychostimulants depend on dissociable psychological and neural substrates and that therapeutic approaches to addiction should take into account the peculiarities of different drug classes and the settings of drug use.

GAD65 Promoter Polymorphism rs2236418 Modulates Harm Avoidance in Women via Inhibition/Excitation Balance in the Rostral ACC

Anxiety disorders are common and debilitating conditions with higher prevalence in women. However, factors that predispose women to anxiety phenotypes are not clarified. Here we investigated potential contribution of the single nucleotide polymorphism rs2236418 in GAD2 gene to changes in regional inhibition/excitation balance, anxiety-like traits, and related neural activity in both sexes. One hundred and five healthy individuals were examined with high-field (7T) multimodal magnetic resonance imaging (MRI); including resting-state functional MRI in combination with assessment of GABA and glutamate (Glu) levels via MR spectroscopy. Regional GABA/Glu levels in anterior cingulate cortex (ACC) subregions were assessed as mediators of gene–personality interaction for the trait harm avoidance and moderation by sex was tested. In AA homozygotes, with putatively lower GAD2 promoter activity, we observed increased intrinsic neuronal activity and higher inhibition/excitation balance in pregenual ACC (pgACC) compared with G carriers. The pgACC drove a significant interaction of genotype, region, and sex, where inhibition/excitation balance was significantly reduced only in female AA carriers. This finding was specific for rs2236418 as other investigated single nucleotide polymorphisms of the GABA synthesis related enzymes (GAD1, GAD2, and GLS) were not significant. Furthermore, only in women there was a negative association of pgACC GABA/Glu ratios with harm avoidance. A moderated-mediation model revealed that pgACC GABA/Glu also mediated the association between the genotype variant and level of harm avoidance, dependent on sex. Our data thus provide new insights into the neurochemical mechanisms that control emotional endophenotypes in humans and constitute predisposing factors for the development of anxiety disorders in women.

SIGNIFICANCE STATEMENT Anxiety disorders are among the most common and burdensome psychiatric disorders, with higher prevalence rates in women. The causal mechanisms are, however, poorly understood. In this study we propose a neurobiological basis that could help to explain female bias of anxiety endophenotypes. Using magnetic resonance brain imaging and personality questionnaires we show an interaction of the genetic variation rs2236418 in the GAD2 gene and sex on GABA/glutamate (Glu) balance in the pregenual anterior cingulate cortex (pgACC), a region previously connected to affect regulation and anxiety disorders. The GAD2 gene polymorphism further influenced baseline neuronal activity in the pgACC. Importantly, GABA/Glu was shown to mediate the relationship between the genetic variant and harm avoidance, however, only in women.

This Week in The Journal

Distinguishing the Roles of Dorsolateral and Anterior PFC in Visual Metacognition

Visual metacognition depends on regions within the prefrontal cortex (PFC). Two areas in particular have been implicated repeatedly: the dorsolateral PFC (DLPFC) and the anterior PFC (aPFC). However, it is still unclear what the function of each of these areas is and how they differ from each other. To establish the specific roles of DLPFC and aPFC in metacognition, we used online transcranial magnetic stimulation (TMS) to interfere causally with their functioning during confidence generation. Human subjects from both sexes performed a perceptual decision making and provided confidence ratings. We found a clear dissociation between the two areas: DLPFC TMS lowered confidence ratings, whereas aPFC TMS increased metacognitive ability, but only for the second half of the experimental blocks. These results support a functional architecture in which DLPFC reads out the strength of the sensory evidence and relays it to aPFC, which makes the confidence judgment by potentially incorporating additional, nonperceptual information. Indeed, simulations from a model that incorporates these putative DLPFC and aPFC functions reproduced our behavioral results. These findings establish DLPFC and aPFC as distinct nodes in a metacognitive network and suggest specific contributions from each of these regions to confidence generation.

SIGNIFICANCE STATEMENT The prefrontal cortex (PFC) is known to be critical for metacognition. Two of its subregions, the dorsolateral PFC (DLPFC) and the anterior PFC (aPFC), have been specifically implicated in confidence generation. However, it is unclear whether these regions have distinct functions related to the underlying metacognitive computation. Using a causal intervention with transcranial magnetic stimulation, we demonstrate that DLPFC and aPFC have dissociable contributions: targeting DLPFC decreased average confidence ratings, whereas targeting aPFC affected metacognitive scores specifically. Based on these results, we postulated specific functions for DLPFC and aPFC in metacognitive computation and corroborated them using a computational model that reproduced our results. Our causal results reveal the existence of a specialized modular organization in PFC for confidence generation.

Schaffer Collateral Inputs to CA1 Excitatory and Inhibitory Neurons Follow Different Connectivity Rules

Neural circuits, governed by a complex interplay between excitatory and inhibitory neurons, are the substrate for information processing, and the organization of synaptic connectivity in neural network is an important determinant of circuit function. Here, we analyzed the fine structure of connectivity in hippocampal CA1 excitatory and inhibitory neurons innervated by Schaffer collaterals (SCs) using mGRASP in male mice. Our previous study revealed spatially structured synaptic connectivity between CA3 and CA1 pyramidal cells (PCs). Surprisingly, parvalbumin-positive interneurons (PVs) showed a significantly more random pattern spatial structure. Notably, application of Peters' rule for synapse prediction by random overlap between axons and dendrites enhanced structured connectivity in PCs, but, by contrast, made the connectivity pattern in PVs more random. In addition, PCs in a deep sublayer of striatum pyramidale appeared more highly structured than PCs in superficial layers, and little or no sublayer specificity was found in PVs. Our results show that CA1 excitatory PCs and inhibitory PVs innervated by the same SC inputs follow different connectivity rules. The different organizations of fine scale structured connectivity in hippocampal excitatory and inhibitory neurons provide important insights into the development and functions of neural networks.

SIGNIFICANCE STATEMENT Understanding how neural circuits generate behavior is one of the central goals of neuroscience. An important component of this endeavor is the mapping of fine-scale connection patterns that underlie, and help us infer, signal processing in the brain. Here, using our recently developed synapse detection technology (mGRASP and neuTube), we provide detailed profiles of synaptic connectivity in excitatory (CA1 pyramidal) and inhibitory (CA1 parvalbumin-positive) neurons innervated by the same presynaptic inputs (CA3 Schaffer collaterals). Our results reveal that these two types of CA1 neurons follow different connectivity patterns. Our new evidence for differently structured connectivity at a fine scale in hippocampal excitatory and inhibitory neurons provides a better understanding of hippocampal networks and will guide theoretical and experimental studies.

Time-Restricted Feeding Prevents Ablation of Diurnal Rhythms in Gastric Vagal Afferent Mechanosensitivity Observed in High-Fat Diet-Induced Obese Mice

Mechanosensitive gastric vagal afferents (GVAs) are involved in the regulation of food intake. GVAs exhibit diurnal rhythmicity in their response to food-related stimuli, allowing time of day-specific satiety signaling. This diurnal rhythmicity is ablated in high-fat-diet (HFD)-induced obesity. Time-restricted feeding (TRF) has a strong influence on peripheral clocks. This study aimed to determine whether diurnal patterns in GVA mechanosensitivity are entrained by TRF. Eight-week-old male C57BL/6 mice (N = 256) were fed a standard laboratory diet (SLD) or HFD for 12 weeks. After 4 weeks of diet acclimatization, the mice were fed either ad libitum or only during the light phase [Zeitgeber time (ZT) 0–12] or dark phase (ZT12–24) for 8 weeks. A subgroup of mice from all conditions (n = 8/condition) were placed in metabolic cages. After 12 weeks, ex vivo GVA recordings were taken at 3 h intervals starting at ZT0. HFD mice gained more weight than SLD mice. TRF did not affect weight gain in the SLD mice, but decreased weight gain in the HFD mice regardless of the TRF period. In SLD mice, diurnal rhythms in food intake were inversely associated with diurnal rhythmicity of GVA mechanosensitivity. These diurnal rhythms were entrained by the timing of food intake. In HFD mice, diurnal rhythms in food intake and diurnal rhythmicity of GVA mechanosensitivity were dampened. Loss of diurnal rhythmicity in HFD mice was abrogated by TRF. In conclusion, diurnal rhythmicity in GVA responses to food-related stimuli can be entrained by food intake. TRF prevents the loss of diurnal rhythmicity that occurs in HFD-induced obesity.

SIGNIFICANCE STATEMENT Diurnal control of food intake is vital for maintaining metabolic health. Diet-induced obesity is associated with strong diurnal changes in food intake. Vagal afferents are involved in regulation of feeding behavior, particularly meal size, and exhibit diurnal fluctuations in mechanosensitivity. These diurnal fluctuations in vagal afferent mechanosensitivity are lost in diet-induced obesity. This study provides evidence that time-restricted feeding entrains diurnal rhythmicity in vagal afferent mechanosensitivity in lean and high-fat-diet (HFD)-induced obese mice and, more importantly, prevents the loss of rhythmicity in HFD-induced obesity. These data have important implications for the development of strategies to treat obesity.