Precision Medicine Approaches For Heterogeneous Conditions Such As Autism Spectrum Disorders The Need For A Biomarker Exploration Phase In Clinical Trials Phase 2m

Download Precision Medicine Approaches For Heterogeneous Conditions Such As Autism Spectrum Disorders The Need For A Biomarker Exploration Phase In Clinical Trials Phase 2m full books in PDF, epub, and Kindle. Read online Precision Medicine Approaches For Heterogeneous Conditions Such As Autism Spectrum Disorders The Need For A Biomarker Exploration Phase In Clinical Trials Phase 2m ebook anywhere anytime directly on your device. Fast Download speed and no annoying ads. We cannot guarantee that every ebooks is available!

Precision medicine approaches for heterogeneous conditions such as autism spectrum disorders (The need for a biomarker exploration phase in clinical trials - Phase 2m)

Author : David Quentin Beversdorf
Publisher : Frontiers Media SA
ISBN 13 : 2832515681
Total Pages : 153 pages
Book Rating : 4.8/5 (325 download)

DOWNLOAD NOW!

Book Synopsis Precision medicine approaches for heterogeneous conditions such as autism spectrum disorders (The need for a biomarker exploration phase in clinical trials - Phase 2m) by : David Quentin Beversdorf

Download or read book Precision medicine approaches for heterogeneous conditions such as autism spectrum disorders (The need for a biomarker exploration phase in clinical trials - Phase 2m) written by David Quentin Beversdorf and published by Frontiers Media SA. This book was released on 2023-04-17 with total page 153 pages. Available in PDF, EPUB and Kindle. Book excerpt: Many therapeutic interventions for autism spectrum disorder fail when they are examined in a clinical trial. Frequently, there is a subset of patients that responds very well to the intervention, while others do not, and the overall result does not yield a positive result. As autism spectrum disorder is highly heterogeneous in its underlying genetics and other etiological risk factors, as well as its heterogeneous phenotypic manifestation, this variability in response to any specific treatment is not entirely surprising. However, it remains a challenge to meaningfully subtype this heterogeneity for targeted treatment. The purpose of this research topic is to solicit articles that address the heterogeneity in autism spectrum disorder in a manner that may meaningfully contribute to targeted treatment approaches. Studies that address the heterogeneity of autism that could theoretically lead to targeted treatment, and studies that more directly address the use of a marker in association with response to a treatment, are both aspects that will contribute to this purpose. It is hoped that this Research Topic will yield articles that can help advance the field towards precision medicine in autism spectrum disorders. Manuscripts that contribute to the specification of the heterogeneity of autism spectrum disorder in a manner that could theoretically lead to targeted treatment would be appropriate for this research topic. Additionally, articles that utilize subtyping in relation to response to treatment would be appropriate for this research topic.

Mesenchymal Stem Cell Derived Exosomes

Author : Yaoliang Tang
Publisher : Academic Press
ISBN 13 : 0128004975
Total Pages : 288 pages
Book Rating : 4.1/5 (28 download)

DOWNLOAD NOW!

Book Synopsis Mesenchymal Stem Cell Derived Exosomes by : Yaoliang Tang

Download or read book Mesenchymal Stem Cell Derived Exosomes written by Yaoliang Tang and published by Academic Press. This book was released on 2015-09-02 with total page 288 pages. Available in PDF, EPUB and Kindle. Book excerpt: Mesenchymal stem cell-derived exosomes are at the forefront of research in two of the most high profile and funded scientific areas – cardiovascular research and stem cells. Mesenchymal Stem Cell Derived Exosomes provides insight into the biofunction and molecular mechanisms, practical tools for research, and a look toward the clinical applications of this exciting phenomenon which is emerging as an effective diagnostic. Primarily focused on the cardiovascular applications where there have been the greatest advancements toward the clinic, this is the first compendium for clinical and biomedical researchers who are interested in integrating MSC-derived exosomes as a diagnostic and therapeutic tool. Introduces the MSC-exosome mediated cell-cell communication Covers the major functional benefits in current MSC-derived exosome studies Discusses strategies for the use of MSC-derived exosomes in cardiovascular therapies

The Handbook of Neuropsychiatric Biomarkers, Endophenotypes and Genes

Author : Michael S. Ritsner
Publisher : Springer Science & Business Media
ISBN 13 : 9048122988
Total Pages : 233 pages
Book Rating : 4.0/5 (481 download)

DOWNLOAD NOW!

Book Synopsis The Handbook of Neuropsychiatric Biomarkers, Endophenotypes and Genes by : Michael S. Ritsner

Download or read book The Handbook of Neuropsychiatric Biomarkers, Endophenotypes and Genes written by Michael S. Ritsner and published by Springer Science & Business Media. This book was released on 2009-04-24 with total page 233 pages. Available in PDF, EPUB and Kindle. Book excerpt: Neuropsychiatric disorders such as schizophrenia, mood disorders, Alzheimer’s disease, epilepsy, alcoholism, substance abuse and others are one of the most debilitating illnesses worldwide characterizing by the complexity of the causes, and lacking the laboratory tests that may promote diagnostic and prognostic procedures. Recent advances in neuroscience, genomic, genetic, proteomic and metabolomic knowledge and technologies have opened the way to searching biomarkers and endophenotypes, which may offer powerful and exciting opportunity to understand the etiology and the underlying pathophysiological mechanisms of neuropsychiatric disorders. The challenge now is to translate these advances into meaningful diagnostic and therapeutic advances. This book offers a broad synthesis of the current knowledge about diverse topics of the biomarker and endophenotype strategies in neuropsychiatry. The book is organized into four interconnected volumes: “Neuropsychological Endophenotypes and Biomarkers” (with overview of methodological issues of the biomarker and endophenotype approaches in neuropsychiatry and some technological advances), “Neuroanatomical and Neuroimaging Endophenotypes and Biomarkers”, “Metabolic and Peripheral Biomarkers” and “Molecular Genetic and Genomic Markers”. The contributors are internationally and nationally recognized researchers and experts from 16 countries. This four-volume handbook is intended for a broad spectrum of readers including neuroscientists, psychiatrists, neurologists, endocrinologists, pharmacologists, clinical psychologists, general practitioners, geriatricians, health care providers in the field of neurology and mental health interested in trends that have crystallized in the last decade, and trends that can be expected to further evolve in the coming years. It is hoped that this book will also be a useful resource for the teaching of psychiatry, neurology, psychology and mental health.

Autism Spectrum Disorders (ASD) - Searching for the Biological Basis for Behavioral Symptoms and New Therapeutic Targets

Author :
Publisher :
ISBN 13 :
Total Pages : 0 pages
Book Rating : 4.:/5 (136 download)

DOWNLOAD NOW!

Book Synopsis Autism Spectrum Disorders (ASD) - Searching for the Biological Basis for Behavioral Symptoms and New Therapeutic Targets by :

Download or read book Autism Spectrum Disorders (ASD) - Searching for the Biological Basis for Behavioral Symptoms and New Therapeutic Targets written by and published by . This book was released on 2017 with total page 0 pages. Available in PDF, EPUB and Kindle. Book excerpt: Autism Spectrum Disorder (ASD) is currently diagnosed based on a series of behavioral tests. The challenge for researchers is to try to uncover the biological basis for these typical behaviors in order to improve diagnosis and identify potential targets for treatment. A multidisciplinary approach is necessary in order to move forward. This includes analysis of the current animal models for ASD and their suitability, reviewing immunological, immunogenetic and epigenetic research, reassessing clinical diagnostic tools, and surveying radiological, pathological, and serological records for clues. This volume includes research from some of the leading researchers on ASD. We are hopeful that it will stimulate further dialogue and research in this challenging field.

Infancy

Author :
Publisher :
ISBN 13 :
Total Pages : 200 pages
Book Rating : 4.F/5 ( download)

DOWNLOAD NOW!

Book Synopsis Infancy by :

Download or read book Infancy written by and published by . This book was released on 1910 with total page 200 pages. Available in PDF, EPUB and Kindle. Book excerpt:

PEERS® for Young Adults

Author : Elizabeth A. Laugeson
Publisher : Taylor & Francis
ISBN 13 : 1315297043
Total Pages : 539 pages
Book Rating : 4.3/5 (152 download)

DOWNLOAD NOW!

Book Synopsis PEERS® for Young Adults by : Elizabeth A. Laugeson

Download or read book PEERS® for Young Adults written by Elizabeth A. Laugeson and published by Taylor & Francis. This book was released on 2017-01-12 with total page 539 pages. Available in PDF, EPUB and Kindle. Book excerpt: Session 1. Trading information and starting conversations -- session 2. Trading information and maintaining conversations -- session 3. Finding a source of friends -- session 4. Electronic communication -- session 5. Appropriate use of humor -- session 6. Entering group conversations -- session 7. Exiting conversations -- session 8. Get-togethers -- session 9. Dating etiquette : letting someone know you like them -- session 10. Dating etiquette : asking someone on a date -- session 11. Dating etiquette : going on dates -- session 12. Dating etiquette : dating do's and don'ts -- session 13. Handling disagreements -- session 14. Handling direct bullying -- session 15. Handling indirect bullying -- session 16. Moving forward and graduation.

Primary Progressive Multiple Sclerosis

Author : M. Filippi
Publisher : Springer Science & Business Media
ISBN 13 : 8847022347
Total Pages : 128 pages
Book Rating : 4.8/5 (47 download)

DOWNLOAD NOW!

Book Synopsis Primary Progressive Multiple Sclerosis by : M. Filippi

Download or read book Primary Progressive Multiple Sclerosis written by M. Filippi and published by Springer Science & Business Media. This book was released on 2012-12-06 with total page 128 pages. Available in PDF, EPUB and Kindle. Book excerpt: "Why are there no effective treatments for my condition? Why do researchers exclude patients with primary progressive multiple sclerosis from enrolling in clinical trials? Please let me know if you hear of studies that I might be allowed to enter or treatments that I could try for my condition. " Thus, in recent years, the sad lament of the patient with primary progressive MS (PPMS). This variant, often in the guise of a chronic progressive myelopathy or, less commonly, progressive cerebellar or bulbar dysfunction, usually responds poorly to corticosteroids and rarely seems to benefit to a significant degree from intensive immunosuppressive treatments. In recent years, most randomized clin ical trials have excluded PPMS patients on two counts. Clinical worsening devel ops slowly in PPMS and may not be recognized during the course of a 2-or 3-year trial even in untreated control patients. This factor alone adds to the potential for a type 2 error or, at the very least, inflates the sample size and duration of the trial. In addition, there is mounting evidence that progressive axonal degeneration and neuronal loss (rather than active, recurrent inflammation) may be important components of the pathology in this form of the disease. Although contemporary trials are evaluating whether PPMS patients may benefit from treatment with the ~-interferons and glatiramer acetate, preliminary, uncontrolled clinical experi ence suggests that the results may not be dramatic.

Human Neural Stem Cells

Author : Leonora Buzanska
Publisher : Springer
ISBN 13 : 3319934856
Total Pages : 329 pages
Book Rating : 4.3/5 (199 download)

DOWNLOAD NOW!

Book Synopsis Human Neural Stem Cells by : Leonora Buzanska

Download or read book Human Neural Stem Cells written by Leonora Buzanska and published by Springer. This book was released on 2018-09-12 with total page 329 pages. Available in PDF, EPUB and Kindle. Book excerpt: This book summarizes early pioneering achievements in the field of human neural stem cell (hNSC) research and combines them with the latest advances in stem cell technology, including reprogramming and gene editing. The powerful potential of hNSC to generate and repair the developing and adult CNS has been confirmed by numerous experimental in vitro and in vivo studies. The book presents methods for hNSC derivation and discusses the mechanisms underlying NSC in vitro fate decisions and their in vivo therapeutic mode of action. The long-standing dogma that the human central nervous system (CNS) lacks the ability to regenerate was refuted at the end of the 20th century, when evidence of the presence of neurogenic zones in the adult human brain was found. These neurogenic zones are home to human neural stem cells (hNSCs), which are capable of self-renewing and differentiating into neurons, astrocytes and oligodendrocytes. NSCs isolated from human CNS have a number of clinical advantages, especially the innate potential to differentiate into functional neural cells. Nevertheless, their full clinical exploitation has been hindered by limited access to the tissue and low expansion potential. The search for an alternative to CNS sources of autologous, therapeutically competent hNSCs was the driving force for the many studies proving the in vitro plasticity of different somatic stem cells to generate NSCs and their functional progeny. Now the era of induced pluripotent stem cells has opened entirely new opportunities to achieve research and therapeutic goals with the aid of hNSCs.

Handbook of hair in health and disease

Author : Victor R. Preedy
Publisher : Springer
ISBN 13 : 9086867286
Total Pages : 493 pages
Book Rating : 4.0/5 (868 download)

DOWNLOAD NOW!

Book Synopsis Handbook of hair in health and disease by : Victor R. Preedy

Download or read book Handbook of hair in health and disease written by Victor R. Preedy and published by Springer. This book was released on 2012-05-23 with total page 493 pages. Available in PDF, EPUB and Kindle. Book excerpt: Hair is a major component of the body's tissue system that contributes to the individual's make up and confers a large degree of personal identity. Apart from its visible façade, hair also has a functional role. It has an unique structure and complex molecular development. The very nature of hair makes it a suitable marker for the prognosis of disease. Hair can also be used to screen for toxins and changes in the diet. However, there are currently no suitable publications available that describe hair in a rational scientific context. This handbook provides an academic approach to hair in health and disease. Divided into five sections the Handbook of Hair in Health and Disease provides an insight into hair growth and loss, molecular and cellular biology of hair, dietary toxicity and pathological history, diseases and treatments of hair, as well as shampoos and conditioners. Unique features of each chapter in this volume include relevant and useful 'Key facts' which highlight interesting or important findings of the specific subjects and 'Summary points' that will give a clear overview of the subjects treated in each chapter. The Handbook of Hair in Health and Disease will be essential to a variety of users, such as trichologists, doctors and nurses and all those interested or working within the area of hair health. This includes nutritionists and dieticians, scientific beauticians, health workers and practitioners, college and university lecturers and undergraduate and graduate students.

ADI-R

Author : Michael Rutter
Publisher :
ISBN 13 : 9781925120479
Total Pages : 64 pages
Book Rating : 4.1/5 (24 download)

DOWNLOAD NOW!

Book Synopsis ADI-R by : Michael Rutter

Download or read book ADI-R written by Michael Rutter and published by . This book was released on 2013 with total page 64 pages. Available in PDF, EPUB and Kindle. Book excerpt:

Anorexia and Bulimia Nervosa

Author : Hubertus Himmerich
Publisher : BoD – Books on Demand
ISBN 13 : 1789239818
Total Pages : 193 pages
Book Rating : 4.7/5 (892 download)

DOWNLOAD NOW!

Book Synopsis Anorexia and Bulimia Nervosa by : Hubertus Himmerich

Download or read book Anorexia and Bulimia Nervosa written by Hubertus Himmerich and published by BoD – Books on Demand. This book was released on 2019-10-02 with total page 193 pages. Available in PDF, EPUB and Kindle. Book excerpt: The prevalence of eating disorders such as anorexia and bulimia nervosa is growing, and these disorders are affecting adolescents and young adults at increasingly younger ages. This has led to a greater number of patients presenting to health services. Although novel therapeutic approaches have been introduced in recent decades, the mortality rates of patients with anorexia and bulimia nervosa remain alarmingly high. The course of anorexia nervosa in particular is often chronic and can lead to persistent disability. This book covers the clinical features and symptoms, neurobiology, pathophysiology, and current and potential future treatment options for both anorexia and bulimia nervosa. It also highlights the important aspects of support for families and their perspectives on these disorders.

Autism Spectrum Conditions

Author : Sven Bölte
Publisher : Hogrefe Publishing GmbH
ISBN 13 : 1616763930
Total Pages : 294 pages
Book Rating : 4.6/5 (167 download)

DOWNLOAD NOW!

Book Synopsis Autism Spectrum Conditions by : Sven Bölte

Download or read book Autism Spectrum Conditions written by Sven Bölte and published by Hogrefe Publishing GmbH. This book was released on 2011-01-01 with total page 294 pages. Available in PDF, EPUB and Kindle. Book excerpt: Autism Spectrum Conditions (ASC), which include autism, Asperger syndrome, and atypical autism, are puzzling, controversial, and a challenge – and the subject of both increasing interest and a multitude of myths. While many questions about ASC remain unanswered to date, our knowledge of the roots, characteristics, outcome, and effective intervention options has improved hugely in recent years. In this unique book, leading clinical and research authorities help explode myths and answer frequently asked questions on ASC: What are ASC? What are their causes? How prevalent are they? How are ASC diagnosed and by whom? What are the first signs? How should people with ASC be educated and treated? How do people with ASC think? What can parents, teachers, and experts do? What can be done for adults with ASC? Where can information and support be found? These and other areas are covered by this clearly written book to provide concise, scientifically sound, state-of-the-art, and practical information about autism spectrum conditions for all who work with ASC clients, as well as for families and friends.

The CA3 Region of the Hippocampus: How is it? What is it for? How does it do it?

Author : Enrico Cherubini
Publisher : Frontiers Media SA
ISBN 13 : 2889196313
Total Pages : 167 pages
Book Rating : 4.8/5 (891 download)

DOWNLOAD NOW!

Book Synopsis The CA3 Region of the Hippocampus: How is it? What is it for? How does it do it? by : Enrico Cherubini

Download or read book The CA3 Region of the Hippocampus: How is it? What is it for? How does it do it? written by Enrico Cherubini and published by Frontiers Media SA. This book was released on 2015-08-19 with total page 167 pages. Available in PDF, EPUB and Kindle. Book excerpt: The CA3 hippocampal region receives information from the entorhinal cortex either directly from the perforant path or indirectly from the dentate gyrus via the mossy fibers (MFs). According to their specific targets (principal/mossy cells or interneurons), MFs terminate with large boutons or small filopodial extensions, respectively. MF-CA3 synapses are characterized by a low probability of release and pronounced frequency-dependent facilitation. In addition MF terminals are endowed with mGluRs that regulate their own release. We will describe the intrinsic membrane properties of pyramidal cells, which can sometimes fire in bursts, together with the geometry of their dendritic arborization. The single layer of pyramidal cells is quite distinct from the six-layered neocortical arrangement. The resulting aligned dendrites provides the substrate for laminated excitatory inputs. They also underlie a precise, diversity of inhibitory control which we will also describe in detail. The CA3 region has an especially rich internal connectivity, with recurrent excitatory and inhibitory loops. In recent years both in vivo and in vitro studies have allowed to better understand functional properties of the CA3 auto-associative network and its role in information processing. This circuit is implicated in encoding spatial representations and episodic memories. It generates physiological population synchronies, including gamma, theta and sharp-waves that are presumed to associate firing in selected assemblies of cells in different behavioral conditions. The CA3 region is susceptible to neurodegeneration during aging and after stresses such as infection or injury. Loss of some CA3 neurones has striking effects on mossy fiber inputs and can facilitate the generation of pathologic synchrony within the CA3 micro-circuit. The aim of this special topic is to bring together experts on the cellular and molecular mechanisms regulating the wiring properties of the CA3 hippocampal microcircuit in both physiological and pathological conditions, synaptic plasticity, behavior and cognition.We will particularly emphasize the dual glutamatergic and GABAergic phenotype of MF-CA3 synapses at early developmental stages and the steps that regulate the integration of newly generated neurons into the adult dentate gyrus-CA3 circuit.

Hypocretins

Author : Luis De Lecea
Publisher : Springer Science & Business Media
ISBN 13 : 0387254463
Total Pages : 438 pages
Book Rating : 4.3/5 (872 download)

DOWNLOAD NOW!

Book Synopsis Hypocretins by : Luis De Lecea

Download or read book Hypocretins written by Luis De Lecea and published by Springer Science & Business Media. This book was released on 2007-04-25 with total page 438 pages. Available in PDF, EPUB and Kindle. Book excerpt: The first report that rapid eye movements occur in sleep in humans was published in 1953. The research journey from this point to the realization that sleep consists of two entirely independent states of being (eventually labeled REM sleep and non-REM sleep) was convoluted, but by 1960 the fundamental duality of sleep was well established including the description of REM sleep in cats associated with “wide awake” EEG patterns and EMG suppression. The first report linking REM sleep to a pathology occurred in 1961 and a clear association of sleep onset REM periods, cataplexy, hypnagogic hallucinations and sleep paralysis was fully established by 1966. When a naïve individual happens to observe a full-blown cataplexy attack, it is both dramatic and unnerving. Usually the observer assumes that the loss of muscle tone represents syncope or seizure. In order to educate health professionals and the general public, Christian Guilleminault and I made movies of full-blown cataplectic episodes (not an easy task). We showed these movies of cataplexy attacks to a number of professional audiences, and were eventually rewarded with the report of a similar abrupt loss of muscle tone in a dog. We were able to bring the dog to Stanford University and with this as the trigger, we were able to develop the Stanford Canine Narcolepsy Colony. Breeding studies revealed the genetic determinants of canine narcolepsy, an autosomal recessive gene we termed canarc1. Emmanuel Mignot took over the colony in 1986 and began sequencing DNA, finally isolating canarc1 in 1999.

Objective Biometric Methods for the Diagnosis and Treatment of Nervous System Disorders

Author : Elizabeth B. Torres
Publisher : Academic Press
ISBN 13 : 0128041188
Total Pages : 580 pages
Book Rating : 4.1/5 (28 download)

DOWNLOAD NOW!

Book Synopsis Objective Biometric Methods for the Diagnosis and Treatment of Nervous System Disorders by : Elizabeth B. Torres

Download or read book Objective Biometric Methods for the Diagnosis and Treatment of Nervous System Disorders written by Elizabeth B. Torres and published by Academic Press. This book was released on 2018-06-29 with total page 580 pages. Available in PDF, EPUB and Kindle. Book excerpt: Objective Biometric Methods for the Diagnosis and Treatment of Nervous System Disorders provides a new and unifying methodological framework, introducing new objective biometrics to characterize patterns of sensory motor control underlying symptoms. Its goal is to radically transform the ways in which disorders of the nervous system are currently diagnosed, tracked, researched and treated. This book introduces new ways to bring the laboratory to the clinical setting, to schools and to settings of occupational and physical therapy. Ready-to-use, graphic user interfaces are introduced to provide outcome measures from wearable sensors that automatically assess in near real time the effectiveness of interventions. Lastly, examples of how the new framework has been effectively utilized in the context of clinical trials are provided. Provides methods and implementation strategies using real data and simple computer programs that less technical students and researchers can utilize Contains appendices with computer code in MATLAB, along with data samples to generate graphics displayed on figures in each chapter Presents videos that illustrate the experimental setup for each situation/method described

Autism

Author : Taylor & Francis Group
Publisher : CRC Press
ISBN 13 : 9780367657666
Total Pages : 386 pages
Book Rating : 4.6/5 (576 download)

DOWNLOAD NOW!

Book Synopsis Autism by : Taylor & Francis Group

Download or read book Autism written by Taylor & Francis Group and published by CRC Press. This book was released on 2021-03-30 with total page 386 pages. Available in PDF, EPUB and Kindle. Book excerpt: Autism: The Movement Sensing Perspective is the result of a collaborative effort by parents, therapists, clinicians, and researchers from all disciplines in science including physics, engineering, and applied mathematics. This book poses questions regarding the current conceptualization and approach to the study of autism, providing an alternative unifying data-driven framework grounded in physiological factors. This book reaches beyond subjective descriptions of autistic phenomena and embraces a new era of objective measurements, analyses, and statistical inferences. The authors harness activities from the nervous systems across the brain and body (often in tandem), and introduce a platform for the comprehensive personalized phenotyping of individuals with autism. The impact of this approach is discussed to advance the development of tailored treatments options, enhance the ability to longitudinally track symptomatology, and to fundamentally empower affected individuals and their families. This book encompasses a new era for autism research and treatments, and our continuous effort to collectively empower and embrace the autistic community.

Computer Methods in Biomechanics and Biomedical Engineering

Author : J. Middleton
Publisher : CRC Press
ISBN 13 : 9782919875009
Total Pages : 582 pages
Book Rating : 4.8/5 (75 download)

DOWNLOAD NOW!

Book Synopsis Computer Methods in Biomechanics and Biomedical Engineering by : J. Middleton

Download or read book Computer Methods in Biomechanics and Biomedical Engineering written by J. Middleton and published by CRC Press. This book was released on 1996-03-18 with total page 582 pages. Available in PDF, EPUB and Kindle. Book excerpt: These papers are concerned with new advances and novel solutions in the areas of biofluids, image-guided surgery, tissue engineering and cardovascular mechanics, implant analysis, soft tissue mechanics, bone remodeling and motion analysis. The contents also feature a special section on dental materials, dental adhesives and orthodontic mechanics. This edition contains many examples, tables and figures, and together with the many references, provides the reader with invaluable information on the latest theoretical developments and applications.