Fanconi anemia (FA) is a DNA repair syndrome generated by mutations in any of the 22 FA genes discovered to date
. Mutations in FANCA account for more than 60% of FA cases worldwide
. Clinically, FA ...is associated with congenital abnormalities and cancer predisposition. However, bone marrow failure is the primary pathological feature of FA that becomes evident in 70-80% of patients with FA during the first decade of life
. In this clinical study (ClinicalTrials.gov, NCT03157804 ; European Clinical Trials Database, 2011-006100-12), we demonstrate that lentiviral-mediated hematopoietic gene therapy reproducibly confers engraftment and proliferation advantages of gene-corrected hematopoietic stem cells (HSCs) in non-conditioned patients with FA subtype A. Insertion-site analyses revealed the multipotent nature of corrected HSCs and showed that the repopulation advantage of these cells was not due to genotoxic integrations of the therapeutic provirus. Phenotypic correction of blood and bone marrow cells was shown by the acquired resistance of hematopoietic progenitors and T lymphocytes to DNA cross-linking agents. Additionally, an arrest of bone marrow failure progression was observed in patients with the highest levels of gene marking. The progressive engraftment of corrected HSCs in non-conditioned patients with FA supports that gene therapy should constitute an innovative low-toxicity therapeutic option for this life-threatening disorder.
This paper is based on the combination of a Geographic Information System (GIS) and tools or multi-criteria decision making (MCDM) methods in order to obtain the evaluation of the optimal placement ...of photovoltaic solar power plants in the area of Cartagena (Region of Murcia), in southeast Spain.
The combination GIS–MCDM generates an excellent analysis tool that allows for the creation of an extensive cartographic and alphanumeric database that will later be used by multi-criteria methodologies to simplify problems to solve and promote the use of multiple criteria.
In GIS two types of criteria will be reflected: constraints or restrictive criteria, and weighting criteria or factors. Constraints or restrictive criteria will make it possible to reduce the area of study by discarding those areas that prevent the implementation of renewable energy plants. These criteria will be obtained from the legislation (planning regulations, protected areas, road networks, railways, waterways, mountains, etc). Weighting criteria or factors will be those which, according to the objective to be reached, influence the ability to solve a concrete alternative. The choice of such criteria is marked by the influence presented to the overall goal; in this case they will be location, geomorphological, environmental and climatic criteria.
Through the use of MCDM the criteria or factors mentioned will be weighted in order to evaluate potential sites to locate a solar plant. Analysis and calculation of the weights of these factors will be conducted using Analytic Hierarchy Process (AHP). The assessment of the alternatives according to their degree of adequacy is carried out through the TOPSIS method (Technique for Order Preference by Similarity to Ideal Solution).
The main purpose of this review was to systematically analyze the literature concerning studies which have investigated muscle activation when performing the Deadlift exercise and its variants. This ...study was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-Analysis Statement (PRISMA). Original studies from inception until March 2019 were sourced from four electronic databases including PubMed, OVID, Scopus and Web of Science. Inclusion criteria were as follows: (a) a cross-sectional or longitudinal study design; (b) evaluation of neuromuscular activation during Deadlift exercise or variants; (c) inclusion of healthy and trained participants, with no injury issues at least for six months before measurements; and (d) analyzed "sEMG amplitude", "muscle activation" or "muscular activity" with surface electromyography (sEMG) devices. Major findings indicate that the biceps femoris is the most studied muscle, followed by gluteus maximus, vastus lateralis and erector spinae. Erector spinae and quadriceps muscles reported greater activation than gluteus maximus and biceps femoris muscles during Deadlift exercise and its variants. However, the Romanian Deadlift is associated with lower activation for erector spinae than for biceps femoris and semitendinosus. Deadlift also showed greater activation of the quadriceps muscles than the gluteus maximus and hamstring muscles. In general, semitendinosus muscle activation predominates over that of biceps femoris within hamstring muscles complex. In conclusion 1) Biceps femoris is the most evaluated muscle, followed by gluteus maximus, vastus lateralis and erector spinae during Deadlift exercises; 2) Erector spinae and quadriceps muscles are more activated than gluteus maximus and biceps femoris muscles within Deadlift exercises; 3) Within the hamstring muscles complex, semitendinosus elicits slightly greater muscle activation than biceps femoris during Deadlift exercises; and 4) A unified criterion upon methodology is necessary in order to report reliable outcomes when using surface electromyography recordings.
Deep brain stimulation (DBS) is a neurosurgical procedure that allows targeted circuit-based neuromodulation. DBS is a standard of care in Parkinson disease, essential tremor and dystonia, and is ...also under active investigation for other conditions linked to pathological circuitry, including major depressive disorder and Alzheimer disease. Modern DBS systems, borrowed from the cardiac field, consist of an intracranial electrode, an extension wire and a pulse generator, and have evolved slowly over the past two decades. Advances in engineering and imaging along with an improved understanding of brain disorders are poised to reshape how DBS is viewed and delivered to patients. Breakthroughs in electrode and battery designs, stimulation paradigms, closed-loop and on-demand stimulation, and sensing technologies are expected to enhance the efficacy and tolerability of DBS. In this Review, we provide a comprehensive overview of the technical development of DBS, from its origins to its future. Understanding the evolution of DBS technology helps put the currently available systems in perspective and allows us to predict the next major technological advances and hurdles in the field.
Objective
Alzheimer disease (AD) is characterized by functional impairment in the neural elements and circuits underlying cognitive and memory functions. We hypothesized that fornix/hypothalamus deep ...brain stimulation (DBS) could modulate neurophysiological activity in these pathological circuits and possibly produce clinical benefits.
Methods
We conducted a phase I trial in 6 patients with mild AD receiving ongoing medication treatment. Patients received continuous stimulation for 12 months. Three main lines of investigation were pursued including: (1) mapping the brain areas whose physiological function was modulated by stimulation using standardized low‐resolution electromagnetic tomography, (2) assessing whether DBS could correct the regional alterations in cerebral glucose metabolism in AD using positron emission tomography (PET), and 3) measuring the effects of DBS on cognitive function over time using clinical scales and instruments.
Results
DBS drove neural activity in the memory circuit, including the entorhinal, and hippocampal areas and activated the brain's default mode network. PET scans showed an early and striking reversal of the impaired glucose utilization in the temporal and parietal lobes that was maintained after 12 months of continuous stimulation. Evaluation of the Alzheimer's Disease Assessment Scale cognitive subscale and the Mini Mental State Examination suggested possible improvements and/or slowing in the rate of cognitive decline at 6 and 12 months in some patients. There were no serious adverse events.
Interpretation
There is an urgent need for novel therapeutic approaches for AD. Modulating pathological brain activity in this illness with DBS merits further investigation. Ann Neurol 2010
Brain stimulation, a therapy increasingly used for neurological and psychiatric disease, traditionally is divided into invasive approaches, such as deep brain stimulation (DBS), and noninvasive ...approaches, such as transcranial magnetic stimulation. The relationship between these approaches is unknown, therapeutic mechanisms remain unclear, and the ideal stimulation site for a given technique is often ambiguous, limiting optimization of the stimulation and its application in further disorders. In this article, we identify diseases treated with both types of stimulation, list the stimulation sites thought to be most effective in each disease, and test the hypothesis that these sites are different nodes within the same brain network as defined by resting-state functional-connectivity MRI. Sites where DBS was effective were functionally connected to sites where noninvasive brain stimulation was effective across diseases including depression, Parkinson's disease, obsessive-compulsive disorder, essential tremor, addiction, pain, minimally conscious states, and Alzheimer's disease. A lack of functional connectivity identified sites where stimulation was ineffective, and the sign of the correlation related to whether excitatory or inhibitory noninvasive stimulation was found clinically effective. These results suggest that resting-state functional connectivity may be useful for translating therapy between stimulation modalities, optimizing treatment, and identifying new stimulation targets. More broadly, this work supports a network perspective toward understanding and treating neuropsychiatric disease, highlighting the therapeutic potential of targeted brain network modulation.
Microplastics in soils have become an important threat for terrestrial systems as they may potentially alter the geochemical/biophysical soil environment and can interact with drought. As ...microplastics may affect soil water content, this could exacerbate the well‐known negative effects of drought on ecosystem functionality. Thus, functions including litter decomposition, soil aggregation or those related with nutrient cycling can be altered. Despite this potential interaction, we know relatively little about how microplastics, under different soil water conditions, affect ecosystem functions and multifunctionality.
To address this gap, we performed an experiment using grassland plant communities growing in microcosms. Microplastic fibres (absent, present) and soil water conditions (well‐watered, drought) were applied in a fully factorial design. At harvest, we measured soil ecosystem functions related to nutrient cycling (β‐glucosaminidase, β‐D‐cellobiosidase, phosphatase, β‐glucosidase enzymes), respiration, nutrient retention, pH, litter decomposition and soil aggregation (water stable aggregates). As terrestrial systems provide these functions simultaneously, we also assessed ecosystem multifunctionality, an index that encompasses the array of ecosystem functions measured here.
We found that the interaction between microplastic fibres and drought affected ecosystem functions and multifunctionality. Drought had negatively affected nutrient cycling by decreasing enzymatic activities by up to ~39%, while microplastics increased soil aggregation by ~18%, soil pH by ~4% and nutrient retention by up to ~70% by diminishing nutrient leaching. Microplastic fibres also impacted soil enzymes, respiration and ecosystem multifunctionality, but importantly, the direction of these effects depended on soil water status. That is, under well‐watered conditions, these functions decreased with microplastic fibres by up to ~34% while under drought they had similar values irrespective of the microplastic presence, or tended to increase with microplastics. Litter decomposition had a contrary pattern increasing with microplastics by ~6% under well‐watered conditions while decreasing to a similar percentage under drought.
Synthesis and applications. Single ecosystem functions can be positively or negatively affected by microplastics fibres depending on soil water status. However, our results suggest that microplastic fibres may cause negative effects on ecosystem soil multifunctionality of a similar magnitude as drought. Thus, strategies to counteract this new global change factor are necessary.
Single ecosystem functions can be positively or negatively affected by microplastics fibres depending on soil water status. However, our results suggest that microplastic fibres may cause negative effects on ecosystem soil multifunctionality of a similar magnitude as drought. Thus, strategies to counteract this new global change factor are necessary.
Background
The European Academy of Allergy and Clinical Immunology (EAACI) is developing Guidelines for Allergen Immunotherapy (AIT) for IgE‐mediated Food Allergy. To inform the development of ...clinical recommendations, we sought to critically assess evidence on the effectiveness, safety and cost‐effectiveness of AIT in the management of food allergy.
Methods
We undertook a systematic review and meta‐analysis that involved searching nine international electronic databases for randomized controlled trials (RCTs) and nonrandomized studies (NRS). Eligible studies were independently assessed by two reviewers against predefined eligibility criteria. The quality of studies was assessed using the Cochrane Risk of Bias tool for RCTs and the Cochrane ACROBAT‐NRS tool for quasi‐RCTs. Random‐effects meta‐analyses were undertaken, with planned subgroup and sensitivity analyses.
Results
We identified 1814 potentially relevant papers from which we selected 31 eligible studies, comprising of 25 RCTs and six NRS, studying a total of 1259 patients. Twenty‐five trials evaluated oral immunotherapy (OIT), five studies investigated sublingual immunotherapy, and one study evaluated epicutaneous immunotherapy. The majority of these studies were in children. Twenty‐seven studies assessed desensitization, and eight studies investigated sustained unresponsiveness postdiscontinuation of AIT. Meta‐analyses demonstrated a substantial benefit in terms of desensitization (risk ratio (RR) = 0.16, 95% CI 0.10, 0.26) and suggested, but did not confirm sustained unresponsiveness (RR = 0.29, 95% CI 0.08, 1.13). Only one study reported on disease‐specific quality of life (QoL), which reported no comparative results between OIT and control group. Meta‐analyses revealed that the risk of experiencing a systemic adverse reaction was higher in those receiving AIT, with a more marked increase in the risk of local adverse reactions. Sensitivity analysis excluding those studies judged to be at high risk of bias demonstrated the robustness of summary estimates of effectiveness and safety of AIT for food allergy. None of the studies reported data on health economic analyses.
Conclusions
AIT may be effective in raising the threshold of reactivity to a range of foods in children with IgE‐mediated food allergy whilst receiving (i.e. desensitization) and post‐discontinuation of AIT. It is, however, associated with a modest increased risk in serious systemic adverse reactions and a substantial increase in minor local adverse reactions. More data are needed in relation to adults, long term effects, the impact on QoL and the cost‐effectiveness of AIT.
This paper aims to provide insights into the environmental, social and governance (ESG) performance of firms from emerging and developed countries relative to their control mechanisms and ...institutional framework. The main objective is to determine which of these board, ownership and country-level drivers exert the greatest explanatory power in ESG performance. In other words, this paper examines the behaviour of the board of directors, ownership and the effect of institutional pressure. Using a sample of 69 461 firm-year observations from 2012 to 2018, and following a two-stage analysis model, the results point to interesting findings for both blocks of countries. In emerging environments, the country effect prevails and the positive effect of the board of directors guarantees its efficiency, while in developed countries, the main mechanism affecting ESG performance is the board of directors, with the ownership effect also playing a key role.
Insights into the environmental, social and governance (ESG) performance of firms from emerging and developed countries relative to their control mechanisms and institutional framework. In emerging environments, the country effect prevails and the positive effect of the board of directors guarantees its efficiency. In developed countries, the main mechanism affecting ESG performance is the board of directors, with the ownership effect also playing a key role. Display omitted
•We fill an unexplored gap about the different behaviour of companies in emerging and non-emerging countries.•We identify a set of individual factors which promote and reinforce ESG performance in emerging and non-emerging markets.•We explore the role firms play by analysing board of directors, ownership and country-effect related to ESG performance.•We enhance emerging countries where sustainability and corporate governance practices can help boost their development.•Policy-makers should consider the special relevance of the institutional development effect in developing economies.•We offer guidelines to policies and regulators on the different treatment they must follow in each institutional context.
The fornix is a white matter bundle located in the mesial aspect of the cerebral hemispheres, which connects various nodes of a limbic circuitry and is believed to play a key role in cognition and ...episodic memory recall. As the most prevalent cause of dementia, Alzheimer's disease (AD) dramatically impairs the quality of life of patients and imposes a significant societal burden on the healthcare system. As an established treatment for movement disorders, deep brain stimulation (DBS) is currently being investigated in preclinical and clinical studies for treatment of memory impairment in AD by modulating fornix activity. Optimal target and stimulation parameters to potentially rescue memory deficits have yet to be determined. The aim of this review is to consolidate the structural and functional aspects of the fornix in the context of neuromodulation for memory deficits. We first present an anatomical and functional overview of the fibres and structures interconnected by the fornix. Recent evidence from preclinical models suggests that the fornix is subdivided into two distinct functional axes: a septohippocampal pathway and a subiculothalamic pathway. Each pathway's target and origin structures are presented, followed by a discussion of their oscillatory dynamics and functional connectivity. Overall, neuromodulation of each pathway of the fornix is discussed in the context of evidence-based forniceal DBS strategies. It is not yet known whether driving fornix activity can enhance cognition-optimal target and stimulation parameters to rescue memory deficits have yet to be determined.
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