bluuebunny/crossref_metadata_2025 huggingface dataset:
Probiotics and prebiotics: focus on psychiatric disorders – a systematic review
Authors: Barbosa Renata S D , Vieira-Coelho Maria A
Published: September 2019

Context

The gut-brain axis and microbial dysbiosis may play a role in psychiatric diseases. In this view, the gut microbiota has been considered a potential therapeutic target using probiotics and prebiotics.

Objective

This systematic review aims to find the existing clinical evidence that may justify the use of probiotics or prebiotics in psychiatric patients.

Data sources

PRISMA guidelines were followed for a systematic literature review of randomized controlled trials that assessed the effect of prebiotics or probiotics in patients diagnosed with a classified psychiatric disorder.

Data extraction

From a total of 212 studies screened, 11 were included in the final systematic review. Quality assessment of the included trials was assessed by the Jadad scale.

Results

Probiotics seem to offer some benefit in major depressive disorder and Alzheimer’s disease. One study showed that probiotics reduced rehospitalization in patients with acute mania. In autism spectrum disorders, the results were controversial; however a single study found that early administration of probiotics showed a preventive role. No benefits were found for patients with schizophrenia. In most studies, no major adverse effects were reported.

Conclusions

Although recent findings in specific psychiatric disorders are encouraging, the use of prebiotics and probiotics in clinical practice stills lacks sufficiently robust evidence.
Individual incentives and workers’ contracts: evidence from a field experiment
Authors: Choudhary M Ali , Gabriel Vasco J , Rickman Neil
Published: September 2019

We present evidence on the operation of incentive pay from a field experiment in Pakistan, looking at piece rates and pay based on rank achieved in a tournament. Importantly, some workers are in contracts ‘tying’ them to the employer for several picking seasons; others are ‘untied’, in the sense of being employed for only the current season. We find that incentive pay (of either type) improves productivity by 30%, on average, but that there are important differences across the types of workers: in particular, tournament incentives are less effective amongst the tied workers. We suggest that our main results have implications for tournament theory and the design of incentive pay schemes, particularly with regard to the fact that they may discourage some workers and, thus, reduce incentives.
Microsurgical Technique for Treatment of Perimedullary Spinal Arteriovenous Fistulae: 2-Dimensional Operative Video
Authors: Howard Brian M , Barrow Daniel L
Published: September 2019

The case is of a 49-yr-old female admitted after acute onset lower cervical/upper thoracic region pain with left hemi-body hypoesthesia below the C7 level. Magnetic resonance imaging showed a spinal cord intraparenchymal hemorrhage at the C6/7 levels. Physical exam revealed hypoesthesia on the left from C7 and below with associated 3/5 wrist and finger extensor and 4/5 triceps strength on the left. The remainder of the neurological exam was normal including lower extremity strength and bowel/bladder function. A craniocervical angiogram showed a perimedullary arteriovenous fistula on the left, ventrolateral aspect of the spinal cord with a single feeding artery that originated from the thyrocervical trunk and entered through the left C6 nerve root sleeve. Venous drainage was cephalad to cortical cerebellar veins and to the suboccipital plexus. A branch of the thyrocervical trunk supplying the ventral spinal cord originated close to the fistula, which precluded endovascular embolization. The patient underwent C6-T1 laminectomies for microsurgical treatment of the fistula. This case demonstrates multiple key concepts in the surgical management of these rare lesions as follows: the ventral aspect of the cervical spinal cord can be safely approached from posterior. The venous anatomy is often confusing and intraoperative angiography utilizing both indocyanine green and conventional digital subtraction techniques are of paramount importance. Unlike arteriovenous malformations, the venous drainage can be pruned to gain visualization and trace the venous anatomy retrograde to the point of the fistula. The patient awoke from surgery at her neurological baseline. The patient consented to de-identified publication of this case.
Productivity and Misallocation in General Equilibrium
Authors: Baqaee David Rezza , Farhi Emmanuel
Published: September 2019

This paper develops a general theory of aggregation in inefficient economies. We provide nonparametric formulas for aggregating microeconomic shocks in economies with distortions such as taxes, markups, frictions to resource reallocation, financial frictions, and nominal rigidities. We allow for arbitrary elasticities of substitution, returns to scale, factor mobility, and input-output network linkages. We show how to separately measure changes in technical and allocative efficiency. We also show how to compute the social cost of distortions. We pursue applications focusing on firm-level markups in the United States. We find that improvement in allocative efficiency, due to the reallocation over time of market share to high-markup firms, accounts for about half of aggregate TFP growth over the period 1997–2015. We also find that eliminating the misallocation resulting from the large and dispersed markups estimated in the data would raise aggregate TFP by about 15%, increasing the economy-wide cost of monopoly distortions by two orders of magnitude compared with the famous 0.1% estimate by Harberger (1954). These exact numbers should be interpreted with care because the data are imperfect and require substantial imputation.
The Exposure Problem and Market Design
Authors: Goeree Jacob K , Lindsay Luke
Published: September 2019

Markets have an exposure problem when getting to the optimal allocation requires a sequence of transactions which if started but not completed leaves at least one trader with losses. We use laboratory experiments to evaluate the effect of the exposure problem on alternative market mechanisms. The continuous double auction performs poorly: efficiency is only 20% when exposure is high and 55% when it is low. A package market effectively eliminates the exposure problem: in low and high-exposure treatments efficiency is 82% and 89%, respectively. Building on stability notions from matching theory we introduce the concept of mechanism stability. A model of trade that combines mechanism stability with noisy best responses and imperfect foresight explains the difference in market performance. Finally, decentralized bargaining with contingent contracts performs well with perfect information and communication but not in the more realistic case when traders’ preferences are privately known.
Externalities and Benefit Design in Health Insurance
Authors: Starc Amanda , Town Robert J
Published: September 2019

Insurance benefit design has important implications for consumer welfare. In this article, we model insurer behaviour in the Medicare prescription drug coverage market and show that strategic private insurer incentives impose a fiscal externality on the traditional Medicare program. We document that plans covering medical expenses have more generous drug coverage than plans that are only responsible for prescription drug spending, which translates into higher drug utilization by enrolees. The effect is driven by drugs that reduce medical expenditure and treat chronic conditions. Our equilibrium model of benefit design endogenizes plan characteristics and accounts for asymmetric information; the model estimates confirm that differential incentives to internalize medical care offsets can explain disparities across plans. Counterfactuals show that strategic insurer incentives are as important as asymmetric information in determining benefit design.
Cardiopulmonary exercise testing in a combined screening approach to individuate pulmonary arterial hypertension in systemic sclerosis
Authors: Santaniello Alessandro , Casella Rosa , Vicenzi Marco , Rota Irene , Montanelli Gaia , De Santis Maria , Bellocchi Chiara , Lombardi Federico , Beretta Lorenzo
Published: September 2019

Objectives

The DETECT algorithm has been developed to identify SSc patients at risk for pulmonary arterial hypertension (PAH) yielding high sensitivity but low specificity, and positive predictive value. We tested whether cardiopulmonary exercise testing (CPET) could improve the performance of the DETECT screening strategy.

Methods

Consecutive SSc patients over a 30-month period were screened with the DETECT algorithm and positive subjects were referred for CPET before the execution of right-heart catheterization. The predictive performance of CPET on top of DETECT was evaluated and internally validated via bootstrap replicates.

Results

Out of 314 patients, 96 satisfied the DETECT application criteria and 54 were positive. PAH was ascertained in 17 (31.5%) and pre-capillary pulmonary hypertension in 23 (42.6%) patients. Within CPET variables, the slope of the minute ventilation to carbon dioxide production relationship (VE/VCO2 slope) had the best performance to predict PAH at right-heart catheterization [median (interquartile range) of specificity 0.778 (0.714–0.846), positive predictive value 0.636 (0.556–0.750)]; exploratory analysis on pre-capillary yielded a specificity of 0.714 (0.636–0.8) and positive predictive value of 0.714 (0.636–0.8).

Conclusion

In association with the DETECT algorithm, CPET may be considered as a useful tool in the workup of SSc-related pulmonary hypertension. The sequential determination of the VE/VCO2 slope in DETECT-positive subjects may reduce the number of unnecessary invasive procedures without any loss in the capability to capture PAH. This strategy had also a remarkable performance in highlighting the presence of pre-capillary pulmonary hypertension.
Heritability and Functional Importance of the Setaria viridis Bacterial Seed Microbiome
Authors: Rodríguez Carolina Escobar , Antonielli Livio , Mitter Birgit , Trognitz Friederike , Sessitsch Angela
Published: September 2019

Seed-associated bacteria represent an important reservoir of microorganisms passed onto progeny plants and have been postulated to be important for early plant development and early plant vigor. According to a few reports, some bacterial taxa seem to be transferred from seed to seed and some seed-associated microorganisms may derive from insect visits during flowering; however, the origin of seed endophytes is poorly understood. To better understand the origin, ecology, and functional role of seed bacterial endophytes, we planted Setaria viridis seeds over several generations in a sterile growth substrate. Seed microbiota of each generation were analyzed by next generation sequencing of 16S rRNA genes and seeds were characterized regarding to their germination and plant growth. Growing plants in a sterile (or highly depleted) substrate resulted in seed microbiota, which were largely less diverse and which had altered community composition, particularly at later generations, indicating that soil is an important reservoir of seed microbiota. Some taxa were inherited to the next generations seeds; however, different subsets of taxa were inherited in different seeds/seed batches and across different generations. This suggests that other factors than the host control the establishment of most seed endophytes and only few, e.g., obligate endophytes, might be consistently inherited. Furthermore, we observed a drastic decline in seed vigor and later generations were particularly affected. Overall, our results demonstrated that the supply of endophytes from external sources such as the soil/rhizosphere environment is highly important for the build-up of a healthy seed microbiome warranting early plant establishment and vigor of next generation plants.
Impact of Lygus hesperus (Hemiptera: Miridae) Feeding and Oviposition on Lettuce
Authors: Joseph Shimat V.
Published: September 2019

The western tarnished plant bug, Lygus hesperus Knight (Hemiptera: Miridae), is an important insect pest of lettuce, Lactuca sativa L. in the central coast region of California. However, little is documented on the injury symptoms relative to levels of L. hesperus infestation on lettuce. Experiments were conducted in which lettuce plants were exposed to 0, 1, 3, 5, and 10 L. hesperus adults for 2 and 7 days. The major injury symptom observed was lesions on the midrib of the leaves, and under low to moderate infestation (e.g., one to five adults per plant) after 2 days of exposure these lesions were not significantly different from the insect-free control. Under heavy infestation (e.g., 10 adults per plant), however, lesions developed rather quickly after 2 days of exposure. The number of lesions was positively associated with numbers of feeding sites and eggs. When heavy infestation lasted for a week, most of the plants died. At low to moderate infestation, more lesions developed compared with the insect-free control. After a weeklong exposure, an increase in number of lesions was negatively associated with plant height. The results emphasize the need for regular scouting to facilitate immediate management decisions and actions to reduce losses from L. hesperus feeding and oviposition injury in lettuce.
Dynamic Transcriptional Profiles ofArabidopsis thalianaInfected byTomato spotted wilt virus
Authors: Xu Min , Chen Jing , Huang Ying , Shen Danyu , Sun Peng , Xu Yi , Tao Xiaorong
Published: September 2019

Tomato spotted wilt virus (TSWV) is a negative-stranded RNA virus that infects hundreds of plant species, causing great economic loss. Infected Arabidopsis thaliana plants develop symptoms including chlorosis and wilt, which can lead to cell death. From 9 to 15 days after TSWV infection, symptoms progress through a three-stage process of appearance, severity, and death. In this study, deep sequencing technology was first used to explore gene expression in response to TSWV infection in model plant A. thaliana at different symptom development stages. We found that plant immune defense and protein degradation are induced by TSWV infection and that both inductions became stronger over time. The photosynthesis pathway was attenuated with TSWV infection. Cell wall metabolism had a large extent of downregulation while some genes were upregulated. These results illustrate the dynamic nature of TSWV infection in A. thaliana at the whole-transcriptome level. The link between biological processes and subpathway metabolism was further analyzed. Our study provides new insight into host regulatory networks and dynamic processes in response to TSWV infection.
When Viruses Play Team Sports: Mixed Infections in Plants
Authors: Moreno Ana Beatriz , López-Moya Juan José
Published: September 2019

The pathological importance of mixed viral infections in plants might be underestimated except for a few well-characterized synergistic combinations in certain crops. Considering that the host ranges of many viruses often overlap and that most plant species can be infected by several unrelated viruses, it is not surprising to find more than one virus simultaneously in the same plant. Furthermore, dispersal of the majority of plant viruses relies on efficient transmission mechanisms mediated by vector organisms, mainly but not exclusively insects, which can contribute to the occurrence of multiple infections in the same plant. Recent work using different experimental approaches has shown that mixed viral infections can be remarkably frequent, up to the point that they could be considered the rule more than the exception. The purpose of this review is to describe the impact of multiple infections not only on the participating viruses themselves but also on their vectors and on the common host. From this standpoint, mixed infections arise as complex events that involve several cross-interacting players, and they consequently require a more general perspective than the analysis of single-virus/single-host approaches for a full understanding of their relevance.
Short‐chain fatty acids and microbiota metabolites attenuate ghrelin receptor signaling
Authors: Torres‐Fuentes Cristina , Golubeva Anna V. , Zhdanov Alexander V. , Wallace Shauna , Arboleya Silvia , Papkovsky Dimitri B. , Aidy Sahar El , Ross Paul , Roy Bernard L. , Stanton Catherine , Dinan Timothy G. , Cryan John F. , Schellekens Harriet
Published: September 2019

The gastrointestinal microbiota is emerging as a unique and inexhaustible source for metabolites with potential to modulate G‐protein coupled receptors (GPCRs). The ghrelin receptor [growth hormone secretagogue receptor (GHSR)‐1a] is a GPCR expressed throughout both the gut and the brain and plays a crucial role in maintaining energy balance, metabolism, and the central modulation of food intake, motivation, reward, and mood. To date, few studies have investigated the potential of the gastrointestinal microbiota and its metabolites to modulate GPCR signaling. Here we investigate the ability of short‐chain fatty acids (SCFAs), lactate, and different bacterial strains, including Bifidobacterium and Lactobacillus genera, to modulate GHSR‐1a signaling. We identify, for what is to our knowledge the first time, a potent effect of microbiota‐derived metabolites on GHSR‐1a signaling with potential significant consequences for host metabolism and physiology. We show that SCFAs, lactate, and bacterial supernatants are able to attenuate ghrelin‐mediated signaling through the GHSR‐1a. We suggest a novel route of communication between the gut microbiota and the host via modulation of GHSR‐1a receptor signaling. Together, this highlights the emerging therapeutic potential in the exploration of the microbiota metabolome in the specific targeting of key GPCRs, with pleiotropic actions that span both the CNS and periphery.—Torres‐Fuentes, C., Golubeva, A. V., Zhdanov, A. V., Wallace, S., Arboleya, S., Papkovsky, D. B., El Aidy, S., Ross, P., Roy, B. L., Stanton, C., Dinan, T. G., Cryan, J. F., Schellekens, H. Short‐chain fatty acids and microbiota metabolites attenuate ghrelin receptor signaling. FASEB J. 33, 13546‐13559 (2019). www.fasebj.org
Adaptive mechanisms driving maladaptive pain: how chronic ongoing activity in primary nociceptors can enhance evolutionary fitness after severe injury
Authors: Walters Edgar T.
Published: September 2019

Chronic pain is considered maladaptive by clinicians because it provides no apparent protective or recuperative benefits. Similarly, evolutionary speculations have assumed that chronic pain represents maladaptive or evolutionarily neutral dysregulation of acute pain mechanisms. By contrast, the present hypothesis proposes that chronic pain can be driven by mechanisms that evolved to reduce increased vulnerability to attack from predators and aggressive conspecifics, which often target prey showing physical impairment after severe injury. Ongoing pain and anxiety persisting long after severe injury continue to enhance vigilance and behavioural caution, decreasing the heightened vulnerability to attack that results from motor impairment and disfigurement, thereby increasing survival and reproduction (fitness). This hypothesis is supported by evidence of animals surviving and reproducing after traumatic amputations, and by complex specializations that enable primary nociceptors to detect local and systemic signs of injury and inflammation, and to maintain low-frequency discharge that can promote ongoing pain indefinitely. Ongoing activity in nociceptors involves intricate electrophysiological and anatomical specializations, including inducible alterations in the expression of ion channels and receptors that produce persistent hyperexcitability and hypersensitivity to chemical signals of injury. Clinically maladaptive chronic pain may sometimes result from the recruitment of this powerful evolutionary adaptation to severe bodily injury.

This article is part of the Theo Murphy meeting issue ‘Evolution of mechanisms and behaviour important for pain’.
Comparative studies of endocannabinoid modulation of pain
Authors: Paulsen Riley T. , Burrell Brian D.
Published: September 2019

Cannabinoid-based therapies have long been used to treat pain, but there remain questions about their actual mechanisms and efficacy. From an evolutionary perspective, the cannabinoid system would appear to be highly conserved given that the most prevalent endogenous cannabinoid (endocannabinoid) transmitters, 2-arachidonyl glycerol and anandamide, have been found throughout the animal kingdom, at least in the species that have been analysed to date. This review will first examine recent findings regarding the potential conservation across invertebrates and chordates of the enzymes responsible for endocannabinoid synthesis and degradation and the receptors that these transmitters act on. Next, comparisons of how endocannabinoids modulate nociception will be examined for commonalities between vertebrates and invertebrates, with a focus on the medicinal leechHirudo verbana. Evidence is presented that there are distinct, evolutionarily conserved anti-nociceptive and pro-nociceptive effects. The combined studies across various animal phyla demonstrate the utility of using comparative approaches to understand conserved mechanisms for modulating nociception.

This article is part of the Theo Murphy meeting issue ‘Evolution of mechanisms and behaviour important for pain’.
An assay for chemical nociception inDrosophilalarvae
Authors: Lopez-Bellido Roger , Himmel Nathaniel J. , Gutstein Howard B. , Cox Daniel N. , Galko Michael J.
Published: September 2019

Chemically induced nociception has not yet been studied intensively in genetically tractable models. Hence, our goal was to establish aDrosophilaassay that can be used to study the cellular and molecular/genetic bases of chemically induced nociception.Drosophilalarvae exposed to increasing concentrations of hydrochloric acid (HCl) produced an increasingly intense aversive rolling response. HCl (0.5%) was subthreshold and provoked no response. All classes of peripheral multidendritic (md) sensory neurons (classes I–IV) are required for full responsiveness to acid, with class IV making the largest contribution. At the cellular level, classes IV, III and I showed increases in calcium following acid exposure. In the central nervous system, Basin-4 second-order neurons are the key regulators of chemically induced nociception, with a slight contribution from other types. Finally, chemical nociception can be sensitized by tissue damage. Subthreshold HCl provoked chemical allodynia in larvae 4 h after physical puncture wounding. Pinch wounding and UV irradiation, which do not compromise the cuticle, did not cause chemical allodynia. In sum, we developed a novel assay to study chemically induced nociception inDrosophilalarvae. This assay, combined with the high genetic resolving power ofDrosophila,should improve our basic understanding of fundamental mechanisms of chemical nociception.

This article is part of the Theo Murphy meeting issue ‘Evolution of mechanisms and behaviour important for pain’.
An evolutionary medicine perspective on pain and its disorders
Authors: Nesse Randolph M. , Schulkin Jay
Published: September 2019

Enormous progress in understanding the mechanisms that mediate pain can be augmented by an evolutionary medicine perspective on how the capacity for pain gives selective advantages, the trade-offs that shaped the mechanisms, and evolutionary explanations for the system's vulnerability to excessive and chronic pain. Syndromes of deficient pain document tragically the utility of pain to motivate escape from and avoidance of situations causing tissue damage. Much apparently excessive pain is actually normal because the cost of more pain is often vastly less than the cost of too little pain (the smoke detector principle). Vulnerability to pathological pain may be explained in part because natural selection has shaped mechanisms that respond adaptively to repeated tissue damage by decreasing the pain threshold and increasing pain salience. The other half of an evolutionary approach describes the phylogeny of pain mechanisms; the apparent independence of different kinds of pain is of special interest. Painful mental states such as anxiety, guilt and low mood may have evolved from physical pain precursors. Preliminary evidence for this is found in anatomic and genetic data. Such insights from evolutionary medicine may help in understanding vulnerability to chronic pain.

This article is part of the Theo Murphy meeting issue ‘Evolution of mechanisms and behaviour important for pain’.
The neuroscience of vision and pain: evolution of two disciplines
Authors: Finlay Barbara L.
Published: September 2019

Research in the neuroscience of pain perception and visual perception has taken contrasting paths. The contextual and the social aspects of pain judgements predisposed pain researchers to develop computational and functional accounts early, while vision researchers tended to simple localizationist or descriptive approaches first. Evolutionary thought was applied to distinct domains, such as game-theoretic approaches to cheater detection in pain research, versus vision scientists' studies of comparative visual ecologies. Both fields now contemplate current motor or decision-based accounts of perception, particularly predictive coding. Vision researchers do so without the benefit of earlier attention to social and motivational aspects of vision, while pain researchers lack a comparative behavioural ecology of pain, the normal incidence and utility of responses to tissue damage. Hybrid hypotheses arising from predictive coding as used in both domains are applied to some perplexing phenomena in pain perception to suggest future directions. The contingent and predictive interpretation of complex sensations, in such domains as ‘runner's high’, multiple cosmetic procedures, self-harm and circadian rhythms in pain sensitivity is one example. The second, in an evolutionary time frame, considers enhancement of primary perception and expression of pain in social species, when expressions of pain might reliably elicit useful help.

This article is part of the Theo Murphy meeting issue ‘Evolution of mechanisms and behaviour important for pain’.
Drosophila
menthol sensitivity and the Precambrian origins of transient receptor potential-dependent chemosensation
Authors: Himmel Nathaniel J. , Letcher Jamin M. , Sakurai Akira , Gray Thomas R. , Benson Maggie N. , Cox Daniel N.
Published: September 2019

Transient receptor potential (TRP) cation channels are highly conserved, polymodal sensors which respond to a wide variety of stimuli. Perhaps most notably, TRP channels serve critical functions in nociception and pain. A growing body of evidence suggests that transient receptor potential melastatin (TRPM) and transient receptor potential ankyrin (TRPA) thermal and electrophile sensitivities predate the protostome–deuterostome split (greater than 550 Ma). However, TRPM and TRPA channels are also thought to detect modified terpenes (e.g. menthol). Although terpenoids like menthol are thought to be aversive and/or harmful to insects, mechanistic sensitivity studies have been largely restricted to chordates. Furthermore, it is unknown if TRP-menthol sensing is as ancient as thermal and/or electrophile sensitivity. Combining genetic, optical, electrophysiological, behavioural and phylogenetic approaches, we tested the hypothesis that insect TRP channels play a conserved role in menthol sensing. We found that topical application of menthol to
Drosophila melanogaster
larvae elicits a
Trpm
- and
TrpA1
-dependent nocifensive rolling behaviour, which requires activation of Class IV nociceptor neurons. Further, in characterizing the evolution of TRP channels, we put forth the hypotheses that three previously undescribed TRPM channel clades (basal, αTRPM and βTRPM), as well as TRPs with residues critical for menthol sensing, were present in ancestral bilaterians.

This article is part of the Theo Murphy meeting issue ‘Evolution of mechanisms and behaviour important for pain’.
Pain in dinosaurs: what is the evidence?
Authors: Hearn Les , Williams Amanda C. de C.
Published: September 2019

How far back can we trace behaviour associated with pain? Behaviour is not preserved in the palaeontological record, so, for dinosaurs, we are restricted to what we can deduce from fossilized bones and tracks. This review is a thought experiment using circumstantial evidence from dinosaur fossils and from the behaviour of their extant relatives to describe probable responses of dinosaurs to serious injuries. Searches yielded 196 papers and chapters with: reports of healed serious injuries, and limping gait and injured feet in trackways; information about physiology and behaviour relevant to healing; evidence of evolutionary connections with birds and crocodilians, and their behaviour; and information about relevant aspects of evolution. Clearly, many dinosaurs survived injuries that would have seriously hampered mobility, impairing hunting or escape from predators, and affecting social interactions. Recovery from severe injuries implies pain-mediated responses. Rates of healing seem faster than for other reptiles, possibily aided by warm-bloodedness. Nesting was often communal, raising the possibility of parental and group protection for injured young. The existence of family groups, packs or herds raises the possibility of protection or feeding from pack kills. This is the first study, to our knowledge, of possible pain behaviour and responses to injury in dinosaurs.

This article is part of the Theo Murphy meeting issue ‘Evolution of mechanisms and behaviour important for pain’.
Demonstration of a portable intracortical brain-computer interface
Authors: Weiss Jeffrey M. , Gaunt Robert A. , Franklin Robert , Boninger Michael , Collinger Jennifer L.
Published: September 2019

While recent advances in intracortical brain-computer interfaces (iBCI) have demonstrated the ability to restore motor and communication functions, such demonstrations have generally been confined to controlled experimental settings and have required bulky laboratory hardware. Here, we developed and evaluated a self-contained portable iBCI that enabled the user to interact with various computer programs. The iBCI, which weighs 1.5 kg, consists of digital headstages, a small signal processing hub, and a tablet PC. A human participant tested the portable iBCI in laboratory and home settings under an FDA Investigational Device Exemption (NCT01894802). The participant successfully completed 96% of trials in a 2D cursor center-out task with the portable iBCI, a rate indistinguishable from that achieved with the standard laboratory iBCI. The participant also completed a variety of free-form tasks, including drawing, gaming, and typing.
Rate and predictors of Treatment Failure among pediatric population taking Highly Active Antiretroviral Therapy in Ethiopia
Authors: Getaneh Yimam , Yizengaw Ajanaw , Likie Agajie , Getahun Mulusew , Feleke Altaye , Kidane Eleni , Yilma Amelework , Mulugeta Achamyeleh , Moshago Tezera , Assefa Yibeltal
Published: September 2019

Background

Though the unprecedented global effort at scaling up universal access to antiretroviral therapy (ART) has decreased the progression of HIV, treatment failure (TF) among pediatric patients receiving ART against human immunodeficiency virus (HIV) is becoming a global public health concern which may impact on treatment outcome. Thus, the aim of this study was to determine the rate and predictors of treatment failure (TF) among HIV-infected pediatric patients taking ART in Ethiopia.

Methods

A prospective and retrospective follow-up study was conducted from March 2016 to 2017. Retrospective clinical and laboratory data were captured from patients’ medical record. Socio-demographics and explanatory variables of participants were collected using pre-tested structured questionnaire and study participants were followed for three to six month after baseline viral load has been done to classify virologic failure (VF). TF was ascertained from population who virally failed with the denominator of population taking ART. Chi-square test and multiple logistic regressions were conducted to assess predictors TF. Statistical significance was set at P-value less than 0.05.

Results

A total of 554 pediatrics patients taking ART from 40 selected health facilities were included in the study. Viral load suppression (VLS) (VL<1000 copies/ml) among pediatric population taking ART in Ethiopia were found to be 344 (62.1%). From those who was not virally suppressed at baseline of the study 210 (37.9%), 99 (51.6%) were re-suppressed after three to six month of enhanced adherence and counseling, leading the overall virologic failure (VF) among pediatric population taking ART in Ethiopia to be 93 (17.3%). The mean CD4 count was improved from 490 cells/ml at ART initiation to 921 cells/ml after 80 months of ART exposure. Moreover, the clinical outcome was improved from 42% to 89% at ART initiation and after 80 month of ART experience. CD4 count, clinical stage, Hemoglobin and weight were found to be predictors of VF. Moreover; family HIV and disclosure status, duration on ART, age, being orphan, stigma and medication adherence have significant association with VF.

Conclusions

The low level of VLS (62.1%) and the high level of VF (18.3%) could explain the challenge on the national ART program among pediatric population. The significant improvement on immunologic and clinical outcome could indicate the success of ART on treatment outcome among pediatric population. CD4 count, clinical stage, Hemoglobin and weight could be good predictors of TF among pediatric population. Improving disclosure status, stigma and medication adherence could improve the treatment outcome of pediatric population taking ART in Ethiopia.
Excess Pneumonia Mortality During a Legionnaires’ Disease Outbreak in Flint, Michigan
Authors: Binney ZO , Nelson KN , Chamberlain AT
Published: September 2019

Introduction

From June 2014-October 2015, the Michigan Department of Health and Human Services (MDHHS) reported a Legionnaires’ disease (LD) outbreak in Genesee County, Michigan, of which Flint is the county seat. MDHHS’ final case count for the outbreak was 90 cases, including 10 deaths among Genesee County residents. As LD is not routinely tested for as a cause of community-acquired pneumonia, the size of the outbreak may have been underestimated. Specifically, some LD cases may have been classified as pneumonias of other or unexplained etiologies.

Objective

To estimate excess pneumonia deaths in Genesee County during the 2014-15 LD outbreak and compare this with reported deaths due to LD.

Methods

We used data from the CDC WONDER database, which contains monthly county-level counts of death certificates, on all pneumonia deaths among residents of Genesee and a set of similar counties from 2011-2017. We calculated excess pneumonia deaths in Genesee during the period of the LD outbreak (May 2014-October 2015). We used data from the Genesee County Vital Records Division to map pneumonia deaths by census tract to assess geographic overlap with reported LD cases.

Results

We estimated 70.0 excess pneumonia deaths (90% uncertainty interval (UI): 36 to 103) in Genesee County during the LD outbreak. This is substantially higher than the 10 LD deaths among Genesee County residents reported by MDHHS. Areas of high pneumonia mortality overlapped with those with high LD incidence and were primarily located in western Flint and northwestern non-Flint Genesee County.

Conclusions

These findings are consistent with the hypothesis that the LD outbreak was larger than reported. Earlier detection and response to this outbreak may have facilitated identification of these additional cases.
medExtractR: A medication extraction algorithm for electronic health records using the R programming language
Authors: Weeks Hannah L. , Beck Cole , McNeer Elizabeth , Bejan Cosmin A. , Denny Joshua C. , Choi Leena
Published: September 2019

Objective

We developed medExtractR, a natural language processing system to extract medication dose and timing information from clinical notes. Our system facilitates creation of medication-specific research datasets from electronic health records.

Materials and Methods

Written using the R programming language, medExtractR combines lexicon dictionaries and regular expression patterns to identify relevant medication information (‘drug entities’). The system is designed to extract particular medications of interest, rather than all possible medications mentioned in a clinical note. MedExtractR was developed on notes from Vanderbilt University’s Synthetic Derivative, using two medications (tacrolimus and lamotrigine) prescribed with varying complexity, and with a third drug (allopurinol) used for testing generalizability of results. We evaluated medExtractR and compared it to three existing systems: MedEx, MedXN, and CLAMP.

Results

On 50 test notes for each development drug and 110 test notes for the additional drug, medExtractR achieved high overall performance (F-measures > 0.95). This exceeded the performance of the three existing systems across all drugs, with the exception of a couple specific entity-level evaluations including dose amount for lamotrigine and allopurinol.

Discussion

MedExtractR successfully extracted medication entities for medications of interest. High performance in entity-level extraction tasks provides a strong foundation for developing robust research datasets for pharmacological research. However, its targeted approach provides a narrower scope compared with existing systems.

Conclusion

MedExtractR (available as an R package) achieved high performance values in extracting specific medications from clinical text, leading to higher quality research datasets for drug-related studies than some existing general-purpose medication extraction tools.
Mammalian RAD51 prevents non-conservative alternative end-joining and single strand annealing through non-catalytic mechanisms
Authors: So Ayeong , Muhammad Ali , Chailleux Catherine , Sanz Laura Sesma , Ragu Sandrine , Le Cam Eric , Canitrot Yvan , Masson Jean Yves , Dupaigne Pauline , Lopez Bernard S. , Guirouilh-Barbat Josée
Published: September 2019

The selection of the DNA double-strand breaks (DSBs) repair pathway is decisive for genetic stability/instability. We proposed that it acts according to two successive steps: 1-canonical non-homologous end-joining (C-NHEJ)versussingle-strand DNA (ssDNA) resection; 2- on ssDNA, gene conversion (GC)versusnon-conservative single-strand annealing (SSA) or alternative end-joining (A-EJ).

Using intramolecular substrates, we systematically analysed the equilibrium between the different DSB repair pathways. We show that ablation of RAD51 stimulated both SSA and A-EJ but did not stimulate C-NHEJ, validating the two-step model. Moreover, we found that two ATP-mutant dominant-negative forms of RAD51 that stimulated non-conservative repair, failed to load into damaged chromatin, clarifying the role of ATP in RAD51-mediated HR, also. In contrast, another dominant-negative form of RAD51, which retains its DNA binding capacities, repressed SSA and A-EJ, revealing two separable functions of RAD51 i.e. GC and non-conservative repair inhibition. In vitroassays show that the binding of RAD51 on both complementary ssDNA is required to block both spontaneous and RAD52-induced strand annealing. Therefore, RAD51 represses non-conservative repair (SSA and A-EJ), by inhibiting the annealing step through ssDNA occupancy, independently of the catalytic strand-exchange activity required for GC.
Genetic liability for internalizing versus externalizing behavior manifests in the developing and adult hippocampus: Insight from a meta-analysis of transcriptional profiling studies in a selectively-bred rat model
Authors: Birt Isabelle A. , Hagenauer Megan H. , Clinton Sarah M. , Aydin Cigdem , Blandino Peter , Stead John D. H. , Hilde Kathryn L. , Meng Fan , Thompson Robert C. , Khalil Huzefa , Stefanov Alex , Maras Pamela , Zhou Zhifeng , Hebda-Bauer Elaine K. , Goldman David , Watson Stanley J. , Akil Huda
Published: September 2019

Background

For over 16 years, we have selectively bred rats to show either high or low levels of exploratory activity within a novel environment. These “bred High Responder” (bHR) and “bred Low Responder” (bLR) rats serve as a model for temperamental extremes, exhibiting large differences in many internalizing and externalizing behaviors relevant to mood and substance abuse disorders.

Methods

Our study elucidated persistent differences in gene expression related to bHR/bLR phenotype across development and adulthood in the hippocampus, a region critical for emotional regulation. We meta-analyzed eight transcriptional profiling datasets (microarray, RNA-Seq) spanning 43 generations of selective breeding (adult: n=46, P7: n=22, P14: n=49, P21: n=21; all male). We cross-referenced these results with exome sequencing performed on our colony to pinpoint candidates likely to mediate the effect of selective breeding on behavioral phenotype.

Results

Genetic and transcriptional profiling results converged to implicate two genes with previous associations with metabolism and mood: Thyrotropin releasing hormone receptor and Uncoupling protein 2. Our results also highlighted bHR/bLR functional differences in the hippocampus, including a network essential for neurodevelopmental programming, proliferation, and differentiation, containing hub genes Bone morphogenetic protein 4 and Marker of proliferation ki-67. Finally, we observed differential expression related to microglial activation, which is important for synaptic pruning, including two genes within implicated chromosomal regions: Complement C1q A chain and Milk fat globule-EGF factor 8.

Conclusion

These candidate genes and functional pathways have the capability to direct bHR/bLR rats along divergent developmental trajectories and promote a widely different reactivity to the environment.
Struo: a pipeline for building custom databases for common metagenome profilers
Authors: de la Cuesta-Zuluaga Jacobo , Ley Ruth E. , Youngblut Nicholas D.
Published: September 2019

Taxonomic and functional information from microbial communities can be efficiently obtained by metagenome profiling, which requires databases of genes and genomes to which sequence reads are mapped. However, the databases that accompany metagenome profilers are not updated at a pace that matches the increase in available microbial genomes. To address this, we developed Struo, a modular pipeline that automatizes the acquisition of genomes from public repositories and the construction of custom databases for multiple metagenome profilers. The use of custom databases that broadly represent the known microbial diversity by incorporating novel genomes results in a substantial increase in mappability of reads in synthetic and real metagenome datasets.

Availability and implementation

Source code available for download at https://github.com/leylabmpi/Struo. Custom GTDB databases available at http://ftp.tue.mpg.de/ebio/projects/struo/

Contact

nicholas.youngblut@tuebingen.mpg.de
Re-evaluation of a Tn5::gacAmutant ofPseudomonas syringaepv.tomatoDC3000 uncovers roles foruvrCandanmKin promoting virulence
Authors: O’Malley Megan R. , Weisberg Alexandra J. , Chang Jeff H. , Anderson Jeffrey C.
Published: September 2019

Pseudomonas syringaeis a taxon of plant pathogenic bacteria that can colonize and proliferate within the interior space of leaf tissue. This process requiresP. syringaeto rapidly upregulate the production of virulence factors including a type III secretion system (T3SS) that suppress host defenses. GacS/A is a two-component system that regulates virulence of many plant and animal pathogenic bacteria includingP. syringae. We recently investigated the virulence defect of strain AC811, a Tn5::gacAmutant ofP. syringae pv.tomatoDC3000 that is less virulent on Arabidopsis. We discovered that decreased virulence of AC811 is not caused by loss of GacA function. Here, we report the molecular basis of the virulence defect of AC811. We show that AC811 possesses a nonsense mutation inanmK, a gene predicted to encode a 1,6-anhydromuramic acid kinase involved in cell wall recycling. Expression of a wild-type allele ofanmKpartially increased growth of AC811 in Arabidopsis leaves. In addition to the defectiveanmKallele, we also show that the Tn5insertion ingacAexerts a polar effect onuvrC, a downstream gene encoding a regulator of DNA damage repair. Expression of the wild-typeanmKallele together with increased expression ofuvrCfully restored the virulence of AC811 during infection of Arabidopsis. These results demonstrate that defects inanmKanduvrCare together sufficient to account for the decreased virulence of AC811, and suggest caution is warranted in assigning phenotypes to GacA function based on insertional mutagenesis of thegacA-uvrClocus.
Exploring the role of mass immunisation in influenza pandemic preparedness: a modelling study for the UK context
Authors: Grieco Luca , Panovska-Griffiths Jasmina , van Leeuwen Edwin , Grove Peter , Utley Martin
Published: September 2019

Existing modelling work on preparedness to pandemic influenza has focused on evaluating specific countermeasures for pandemics with specific characteristics (typically based on historical instances). The aim of this study was to inform policy on preparedness planning for pandemic influenza based on the assessment of a wide range of scenarios and free from restrictive assumptions about timing and features of the next pandemic.

We carried out epidemiological modelling and health economic analysis of an extensive set of scenarios, each comprising a combination of pandemic, vaccine and immunisation programme characteristics in presence or absence of access to effective antivirals. Preparedness policies that incorporate mass immunisation were evaluated on the basis of there being a given chance of a pandemic each year. To support understanding and exploration of model output, an interactive visualisation tool was devised and made available online.

We evaluated over 29 million combinations of pandemic and policy characteristics. Preparedness plans incorporating mass immunisation show positive net present value for a wide range of pandemic scenarios, predominantly in the absence of effective antivirals. Plans based on the responsive purchase of vaccine have greater benefit than plans reliant on the purchase and maintenance of a stockpile if immunisation can start without extensive delays. This finding is not dependent on responsively purchased vaccine being more effective than stockpiled vaccine, but rather is driven by avoiding the costs of storing and replenishing a stockpile.

While emerging technologies for rapid vaccine development and production increase the prospects for mass immunisation to be an effective countermeasure, policies based on the responsive purchase of vaccine not tailored to the pandemic should be explored. Focus is also required on the pandemic intelligence, decision, contractual and logistical processes on which timely commencement of immunisation in a pandemic is reliant.