Genetically predicted fatty liver disease and risk of psychiatric disorders: A mendelian randomization study

BACKGROUND Non-alcoholic fatty liver disease(NAFLD)and alcohol-related liver disease(Ar-LD)constitute the primary forms of chronic liver disease,and their incidence is progressively increasing with changes in lifestyle habits.Earlier studies have do-cumented a correlation between the occurrence and development of prevalent mental disorders and fatty liver.AIM To investigate the correlation between fatty liver and mental disorders,thus ne-cessitating the implementation of a mendelian randomization(MR)study to elu-cidate this association.METHODS Data on NAFLD and ArLD were retrieved from the genome-wide association studies catalog,while information on mental disorders,including Alzheimer's disease,schizophrenia,anxiety disorder,attention deficit hyperactivity disorder(ADHD),bipolar disorder,major depressive disorder,multiple personality dis-order,obsessive-compulsive disorder(OCD),post-traumatic stress disorder(PTSD),and schizophrenia was acquired from the psychiatric genomics consor-tium.A two-sample MR method was applied to investigate mediators in signifi-cant associations.RESULTS After excluding weak instrumental variables,a causal relationship was identified between fatty liver disease and the occurrence and development of some psychia-tric disorders.Specifically,the findings indicated that ArLD was associated with a significantly elevated risk of developing ADHD(OR:5.81,95%CI:5.59-6.03,P<0.01),bipolar disorder(OR:5.73,95%CI:5.42-6.05,P=0.03),OCD(OR:6.42,95%CI:5.60-7.36,P<0.01),and PTSD(OR:5.66,95%CI:5.33-6.01,P<0.01).Meanwhile,NAFLD significantly increased the risk of developing bipolar disorder(OR:55.08,95%CI:3.59-845.51,P<0.01),OCD(OR:61.50,95%CI:6.69-565.45,P<0.01),and PTSD(OR:52.09,95%CI:4.24-639.32,P<0.01).CONCLUSION Associations were found between genetic predisposition to fatty liver disease and an increased risk of a broad range of psychiatric disorders,namely bipolar disorder,OCD,and PTSD,highlighting the significance of preven-tive measures against psychiatric disorders in patients with fatty liver disease.

Heart abnormality associates with a wide spectrum of psychiatric disorders:Evidence from Mendelian randomization analyses

Psychiatric disorders and heart abnormality are closely interconnected.Previous knowledge has been well-established that psychiatric disorders can lead to increased cardiovascular morbidity and even sudden cardiac death.Conversely,whether heart abnormality contributes to psychiatric disorders remains rarely studied.The work by Zhang et al pointed out that chronic heart failure had effects on the anxiety and depression(AD)severity,and indices including left ventricular ejection fraction,N-terminal pro-brain natriuretic peptide and interleukin-6 were independent risk factors for AD severity.In addition to the aforementioned AD,we herein find that heart failure might additionally impact the development of autism spectrum disorder and post-traumatic stress disorder(albeit P>0.05),and significantly protects against the presence of attention deficit hyperactivity disorder(ADHD),[odds ratio(OR)=0.61,P=0.0071]by using a Mendelian randomization analysis.Bradycardia is also a protective factor for ADHD(OR=0.61,P=0.0095),whereas hypertrophic cardiomyopathy is a mild risk factor for schizophrenia(OR=1.02,P=0.032).These data suggest a wide spectrum of psychiatric disorders secondary to heart abnormality,and we highlight more psychiatric care that should be paid to patients with heart abnormality.

A Brief Review of Artificial Intelligence Applications and Algorithms for Psychiatric Disorders

A number of brain research projects have recently been carried out to study the etiology and mechanisms of psychiatric disorders.Although psychiatric disorders are part of the brain sciences,psychiatrists still diagnose them based on subjective experience rather than by gaining insights into the pathophysiology of the diseases.Therefore,it is urgent to have a clear understanding of the etiology and pathogenesis of major psychiatric diseases,which can help in the development of effective treatments and interventions.Artificial intelligence(AI)-based applications are being quickly developed for psychiatric research and diagnosis,but there is no systematic review that summarizes their applications.For this reason,this study briefly reviews three main brain observation techniques used to study psychiatric disorders-namely,magnetic resonance imaging(MRI),electroencephalography(EEG),and kinesics-based diagnoses-along with related AI applications and algorithms.Finally,we discuss the challenges,opportunities,and future study directions of AI-based applications.

Optical neuroimaging:advancing transcranial magnetic stimulation treatments of psychiatric disorders

Transcranial magnetic stimulation(TMS)has been established as an important and effective treatment for various psychiatric disorders.However,its effectiveness has likely been limited due to the dearth of neuronavigational tools for targeting purposes,unclear ideal stimulation parameters,and a lack of knowledge regarding the physiological response of the brain to TMS in each psychiatric condition.Modern optical imaging modalities,such as functional near-infrared spectroscopy and diffuse optical tomography,are promising tools for the study of TMS optimization and functional targeting in psychiatric disorders.They possess a unique combination of high spatial and temporal resolutions,portability,real-time capability,and relatively low costs.In this mini-review,we discuss the advent of optical imaging techniques and their innovative use in several psychiatric conditions including depression,panic disorder,phobias,and eating disorders.With further investment and research in the development of these optical imaging approaches,their potential will be paramount for the advancement of TMS treatment protocols in psychiatry.

Relationship of functional gastrointestinal disorders and psychiatric disorders: Implications for treatment

This article revisits the links between psychopathology and functional gastrointestinal disorders such as irritable bowel syndrome （IBS）, discusses the rational use of antidepressants as well as non-pharmacological approaches to the management of IBS, and suggests guidelines for the treatment of IBS based on an interdisciplinary perspective from the present state of knowledge. Relevant published literature on psychiatric disorders, especially somatization disorder, in the context of [BS, and literature providing direction for management is reviewed, and new directions are provided from findings in the literature. IBS is a heterogeneous syndrome with various potential mechanisms responsible for its clinical presentations. IBS is typically complicated with psychiatric issues, unexplained symptoms, and functional syndromes in other organ systems. Most IBS patients have multiple complaints without demonstrated cause, and that these symptoms can involve systems other than the intestine, e.g. bones and joints （fibromyalgia, temporomandibular joint syndrome）, heart （non-cardiac chest pain）, vascular （post-menopausal syndrome）, and brain （anxiety, depression）. Host IBS patients do not have psychiatric illness per se, but a range of psychoform （psychological complaints in the absence of psychiatric disorder） symptoms that accompany their somatoform （physical symptoms in the absence of medical disorder） complaints. It is not correct to label IBS patients as psychiatric patients （except those more difficult patients with true somatization disorder）. One mode of treatment is unlikely to be universally effective or to resolve most symptoms. The techniques of psychotherapy or cognitive-behavioral therapy can allow IBS patients to cope more readily with their illness. Specific episodes of depressive or anxiety disorders can be managed as appropriate for those conditions. Medications designed to improve anxiety or depression are not uniformly useful for psychiatric complaints in IBS, because the psychoform symptoms that sound similar to those seen in psychiatric disorders may not have the same significance in patients with IBS.

Surgical Treatment of Lung Cancer in Patients with Psychiatric Disorders: A Retrospective Study

Background: The purpose of this retrospective study was to examine the clinical outcomes of patients with concomitant lung cancer and psychiatric disorders who underwent pulmonary resection at our institution and develop a strategy for treating such patients in the future. Methods: We retrospectively reviewed 23 patients with psychiatric disorders who underwent pulmonary resection for lung cancer at our institution between January 1984 and December 2011. Results: The study population comprised 13 men and 10 women with an average age of 67.4 years. The histological types of lung cancer included adenocarcinoma in 14 patients, squamous cell carcinoma in 4, and other types in 5. Fifteen patients were classified as having pathological TNM stage I cancer, four as having stage II, three as having stage III, and one as having stage IV. The coexisting psychiatric disorders were neurosis in eight patients, depression in seven, schizophrenia in five, dementia in two, and oligophrenia in one. Three patients were admitted without a full understanding of the operation. There were no major complications with the exception of delirium, which was seen in eight patients. None of these patients’ coexisting psychiatric disorders worsened. No perioperative death occurred. Conclusions: At our institution, we cooperate closely with psychiatrists to care for surgical patients with psychiatric disorders. There is a possibility that such cooperation will reduce the frequency of previously reported complications.

Increased Risk of Psychiatric Disorders in Women with Polycystic Ovary Syndrome in Southwest China

Background： Polycystic ovary syndrome （PCOS） and its characteristic symptoms have been associated with physical and psychological issues in women of reproductive age. The current study was conducted in response to the dearth of systematic research related to psychological functioning and quality of life in patients with PCOS in Southwest China, and to determine whether patients with PCOS exhibit poorer mental health （MH） compared to healthy women of the same age and living in the same region, without a PCOS diagnosis. Methods： We enrolled 120 outpatients with PCOS and 100 healthy controls in this study. Standardized questionnaires were administered to assess general MH conditions （General Health Questionnaire-12-item version）, anxiety （State-Trait Anxiety Inventory）, depression （Beck Depression Inventory）, as well as health-related quality of life （HRQoL） measured using the 36-item short-form health survey. The independent samples t-test was conducted for continuous study variables. For categorical variables, the Pearson Chi-square test, Fisher＇s exact test, and logistic regression were perlbrmed. Results： The prevalence of anxiety （13.3% vs. 2.0%） and depression （27.5% vs. 3.0%） was higher in patients with PCOS compared to the controls （both P 〈 0.05）. Patients with PCOS had decreased HRQoL. Patients with PCOS who had fertility requirements were more likely to be anxious and depressed than those without fertility requirements （anxiety： 22.6% [1 2/53] vs. 5.9% [4/67],Z： = 7.117, P = 0.008： depression： 37.7% （20/53） vs. 19.4% （13/67）, Х^2 = 4.988, P - 0.026）. Conclusions： PCOS and related synaptoms may be risk factors for depression and anxiety. Professionals should be concerned with the MH of women with PCOS, and psychological therapy should be considered.

Recent advances of deep learning in psychiatric disorders

Deep learning(DL)is a recently proposed subset of machine learning methods that has gained extensive attention in the academic world,breaking benchmark records in areas such as visual recognition and natural language processing.Different fromconventional machine learning algorithm,DL is able to learn useful representations and features directly from raw data through hierarchical nonlinear transformations.Because of its ability to detect abstract and complex patterns,DL has been used in neuroimaging studies of psychiatric disorders,which are characterized by subtle and diffuse alterations.Here,we provide a brief review of recent advances and associated challenges in neuroimaging studies of DL applied to psychiatric disorders.The results of these studies indicate that DL could be a powerful tool in assisting the diagnosis of psychiatric diseases.We conclude our review by clarifying the main promises and challenges of DL application in psychiatric disorders,and possible directions for future research.

Past,present,and future of deep transcranial magnetic stimulation:A review in psychiatric and neurological disorders

Deep transcranial magnetic stimulation(DTMS)is a new non-invasive neuromodulation technique based on repetitive transcranial magnetic stimulation technology.The new H-coil has significant advantages in the treatment and mechanism research of psychiatric and neurological disorders.This is due to its deep stimulation site and wide range of action.This paper reviews the clinical progress of DTMS in psychiatric and neurological disorders such as Parkinson’s disease,Alzheimer’s disease,post-stroke motor dysfunction,aphasia,and other neurological disorders,as well as anxiety,depression,and schizophrenia.

Deep brain stimulation for psychiatric disorders: roleof imaging in identifying/confirming DBS targets,predicting, and optimizing outcome and unravellingmechanisms of action

Following the established application of deep brain stimulation(DBS)in the treatment of movement disorders,new non-neurological indications have emerged,such as for obsessive–compulsive disorders,major depressive disorder,dementia,Gilles de la Tourette Syndrome,anorexia nervosa,and addictions.As DBS is a network mod-ulation surgical treatment,the development of DBS for both neurological and psychiatric disorders has been partly driven by advances in neuroimaging,which has helped explain the brain networks implicated.Advances in magnetic resonance imaging connectivity and electrophysiology have led to the development of the con-cept of modulating widely distributed,complex brain networks.Moreover,the increasing number of targets for treating psychiatric disorders have indicated that there may be a convergence of the effect of stimulating dif-ferent targets for the same disorder,and the effect of stimulating the same target for different disorders.The aim of this paper is to review the imaging studies of DBS for psychiatric disorders.Imaging,and particularly connectivity analysis,offers exceptional opportunities to better understand and even predict the clinical out-comes of DBS,especially where there is a lack of objective biomarkers that are essential to properly guide DBS pre-and post-operatively.In future,imaging might also prove useful to individualize DBS treatment.Finally,one of the most important aspects of imaging in DBS is that it allows us to better understand the brain through observing the changes of the functional connectome under neuromodulation,which may in turn help explain the mechanisms of action of DBS that remain elusive.

Epigenetic Regulation of Serotonin Transporter in Psychiatric Disorders

SLC6A4 （solute carrier family 6, member 4） gene encodes a serotonin transporter （5-hydroxytryptamine transporter, HTT）, which transports synaptic serotonin into presynaptic terminal. SLC6A4 is known to be the target of antidepressants such as selective serotonin reuptake inhibitors （SSRIs）. Inhibition of HTT increases synaptic serotonin concentration and thereby exerts antidepressant efficacy. A large number of genetic studies suggest the contribution of genetic variations of SLC6A4 to various psychiatric disorders. The most studied genetic variation, HTT-linked polymorphic region （HTTLPR）,

Reduced homotopic interhemispheric connectivity in psychiatric disorders:evidence for both transdiagnostic and disorder specific features

There is considerable interest in the significance of structural and functional connections between the two brain hemispheres in terms of both normal function and in relation to psychiatric disorders.In recent years,many studies have used voxel mirrored homotopic connectivity analysis of resting state data to investigate the importance of connectivity between homotopic regions in the brain hemispheres in a range of neuropsychiatric disorders.The current review summarizes findings fromthese voxel mirrored homotopic connectivity studies in individuals with autism spectrum disorder,addiction,attention deficit hyperactivity disorder,anxiety and depression disorders,and schizophrenia,aswell as disorders such as Alzheimer’s disease,mild cognitive impairment,epilepsy,and insomnia.Overall,other than attention deficit hyperactivity disorder,studies across psychiatric disorders report decreased homotopic resting state functional connectivity in the default mode,attention,salience,sensorimotor,social cognition,visual recognition,primary visual processing,and reward networks,which are often associated with symptom severity and/or illness onset/duration.Decreased homotopic resting state functional connectivity may therefore represent a transdiagnostic marker for general psychopathology.In terms of disorder specificity,the extensive decreases in homotopic resting state functional connectivity in autism differ markedly from attention deficit hyperactivity disorder,despite both occurring during early childhood and showing extensive co-morbidity.A pattern of more posterior than anterior regions showing reductions in schizophrenia is also distinctive.Going forward,more studies are needed to elucidate the functions of these homotopic functional connections in both health and disorder and focusing on associations with general psychopathology,and not only on disorder specific symptoms.

Progress in the application of molecular imaging inpsychiatric disorders

Psychiatric disorders have always attracted a lot of attention from researchers due to the difficulties in their diagnoses and treatments.Molecular imaging,as an emerging technology,has played an important role in the researchers of various diseases.In recent years,molecular imaging techniques including magnetic resonance spectroscopy,nuclear medicine imaging,and fluorescence imaging have been widely used in the study of psychiatric disorders.This review will briefly summarize the progression of molecular imaging in psychiatric disorders.

Large multimodal models assist in psychiatry disorders prevention and diagnosis of students

Students are considered one of the groups most affected by psychological pro-blems.Given the highly dangerous nature of mental illnesses and the increasing-ly serious state of global mental health,it is imperative for us to explore new me-thods and approaches concerning the prevention and treatment of mental illne-sses.Large multimodal models(LMMs),as the most advanced artificial intelligen-ce models(i.e.ChatGPT-4),have brought new hope to the accurate prevention,diagnosis,and treatment of psychiatric disorders.The assistance of these models in the promotion of mental health is critical,as the latter necessitates a strong foundation of medical knowledge and professional skills,emotional support,stigma mitigation,the encouragement of more honest patient self-disclosure,reduced health care costs,improved medical efficiency,and greater mental health service coverage.However,these models must address challenges related to health,safety,hallucinations,and ethics simultaneously.In the future,we should address these challenges by developing relevant usage manuals,accountability rules,and legal regulations;implementing a human-centered approach;and intelligently upgrading LMMs through the deep optimization of such models,their algorithms,and other means.This effort will thus substantially contribute not only to the maintenance of students’health but also to the achievement of global sustainable development goals.

Exploring the role of interleukin-6 receptor blockade in epilepsy and associated neuropsychiatric conditions through a mendelian randomization study

BACKGROUND The interplay between inflammation,immune dysregulation,and the onset of neurological disorders,including epilepsy,has become increasingly recognized.Interleukin(IL)-6,a pro-inflammatory cytokine,is suspected to not only mediate traditional inflammatory pathways but also contribute to neuroinflammatory responses that could underpin neuropsychiatric symptoms and broader psychiatric disorders in epilepsy patients.The role of IL-6 receptor(IL6R)blockade presents an intriguing target for therapeutic intervention due to its potential to attenuate these processes.neuropsychiatric conditions due to neuroinflammation.METHODS Mendelian randomization(MR)analysis employing single nucleotide poly-morphisms(SNPs)in the vicinity of the IL6R gene(total individuals=408225)was used to evaluate the putative causal relationship between IL6R blockade and epilepsy(total cases/controls=12891/312803),focal epilepsy(cases/controls=7526/399290),and generalized epilepsy(cases/controls=1413/399287).SNP weights were determined by their effect on C-reactive protein(CRP)levels and integrated using inverse variance-weighted meta-analysis as surrogates for IL6R effects.To address potential outlier and pleiotropic influences,sensitivity analyses were conducted employing a variety of MR methods under different modeling assumptions.RESULTS The genetic simulation targeting IL6R blockade revealed a modest but significant reduction in overall epilepsy risk[inverse variance weighting:Odds ratio(OR):0.827;95%confidence interval(CI):0.685-1.000;P=0.05].Subtype analysis showed variability,with no significant effect observed in generalized,focal,or specific childhood and juvenile epilepsy forms.Beyond the primary inflammatory marker CRP,the findings also suggested potential non-inflammatory pathways mediated by IL-6 signaling contributing to the neurobiological landscape of epilepsy,hinting at possible links to neuroinflammation,psychiatric symptoms,and associated mental disorders.CONCLUSION The investigation underscored a tentative causal relationship between IL6R blockade and decreased epilepsy incidence,likely mediated via complex neuroinflammatory pathways.These results encouraged further in-depth studies involving larger cohorts and multifaceted psychiatric assessments to corroborate these findings and more thoroughly delineate the neuro-psychiatric implications of IL-6 signaling in epilepsy.The exploration of IL6R blockade could herald a novel therapeutic avenue not just for seizure management but also for addressing the broader psychiatric and cognitive disturbances often associated with epilepsy.

Research progress of functional near-infrared spectroscopy in patients with psychiatric disorders

Functional near-infrared spectroscopy(fNIRS)is a technique of detecting cerebral cortical function by using near-infrared light,which is a multifunctional neuroimaging technique and provides a convenient and efficient detection method in neuroscience.In consideration of acceptability,safety,high spatial and temporal resolutions compared with electroencephalogram(EEG)and functional magnetic resonance imaging(fMRI),fNIRS is widely used to study different psychiatric disorders,most prominently affective disorders,schizophrenic illnesses,brain organic mental disorders and neurodevelopmental disorders,etc.The article focuses on the latest research progress and practical application of fNIRS in psychiatric disorders,especially traumatic brain,including studies on the characterization of phenomenology,treatment effects and descriptions of neuroimaging data.

Advancement in utilization of magnetic resonance imaging and biomarkers in the understanding of schizophrenia

Historically,psychiatric diagnoses have been made based on patient’s reported symptoms applying the criteria from diagnostic and statistical manual of mental disorders.The utilization of neuroimaging or biomarkers to make the diagnosis and manage psychiatric disorders remains a distant goal.There have been several studies that examine brain imaging in psychiatric disorders,but more work is needed to elucidate the complexities of the human brain.In this editorial,we examine two articles by Xu et al and Stoyanov et al,that show developments in the direction of using neuroimaging to examine the brains of people with schizo-phrenia and depression.Xu et al used magnetic resonance imaging to examine the brain structure of patients with schizophrenia,in addition to examining neurotransmitter levels as biomarkers.Stoyanov et al used functional magnetic resonance imaging to look at modulation of different neural circuits by diagnostic-specific scales in patients with schizophrenia and depression.These two studies provide crucial evidence in advancing our understanding of the brain in prevalent psychiatric disorders.

Neurological and psychiatric effects of hepatitis C virus infection

Hepatitis C virus(HCV)infection is widespread and affects 71 million people worldwide.Although hepatic manifestations are the most frequent,ranging from chronic hepatitis to cirrhosis and hepatocellular carcinoma,it is also associated with several extrahepatic manifestations.Infected patients may present nonspecific neurological symptoms,regardless of the presence of liver cirrhosis.Several pathogenetic mechanisms underlying neurological symptoms have been hypothesized:neuroinvasion,immune-mediated damage,neurotransmitter alterations and cryoglobulinemia.Alterations of the central nervous system include cerebral vasculopathy,acute or subacute encephalopathy and inflammatory disorders.HCV infection may be responsible for neuropathies,of which the most frequent form is symmetrical axonal sensory or sensory-motor polyneuropathy which causes loss of leg sensitivity and weakness.Up to 50%of patients with HCV infection may experience cognitive decline and psychological disorders,such as depression and fatigue.HCV associated neurocognitive disorder is independent of the presence of liver cirrhosis and affects different domains than in patients with hepatic encephalopathy.It can be studied using specific tests that mainly explore executive functions,verbal learning and verbal recall.These disorders significantly reduce the quality of life.The new antiviral therapies improve the extrahepatic symptoms of HCV infection and their success depends on the achievement of sustained virological response.However,the effect of therapy may differ depending on the type of organ involved;neurological symptoms can be irreversible if there is organic liver damage.The aim of this review is to provide a critical overview of physiopathological mechanisms,diagnostic and therapeutic strategies of the neurological and psychiatric effects of HCV infection.

Connecting brain and body:Transdiagnostic relevance of connective tissue variants to neuropsychiatric symptom expression

The mind is embodied;thoughts and feelings interact with states of physiological arousal and physical integrity of the body.In this context,there is mounting evidence for an association between psychiatric presentations and the expression variant connective tissue,commonly recognised as joint hypermobility.Joint hypermobility is common,frequently under-recognised,significantly impacts quality of life,and can exist in isolation or as the hallmark of hypermobility spectrum disorders(encompassing joint hypermobility syndrome and hypermobile Ehlers-Danlos syndrome).In this narrative review,we appraise the current evidence linking psychiatric disorders across the lifespan,beginning with the relatively well-established connection with anxiety,to hypermobility.We next consider emerging associations with affective illnesses,eating disorders,alongside less well researched links with personality disorders,substance misuse and psychosis.We then review related findings relevant to neurodevelopmental disorders and stress-sensitive medical conditions.With growing understanding of mind-body interactions,we discuss potential aetiopathogenetic contributions of dysautonomia,aberrant interoceptive processing,immune dysregulation and proprioceptive impairments in the context of psychosocial stressors and genetic predisposition.We examine clinical implications of these evolving findings,calling for increased awareness amongst healthcare professionals of the transdiagnostic nature of hypermobility and related disorders.A role for early screening and detection of hypermobility in those presenting with mental health and somatic symptoms is further highlighted,with a view to facilitate preventative approaches alongside longer-term holistic management strategies.Finally,suggestions are offered for directions of future scientific exploration which may be key to further delineating fundamental mind-body-brain interactions.

Optimising validity and translational potential in rodent models of brain disorders

Neurological and psychiatric disorders collectively constitute the greatest burden of disease. However, the human brain is the most complex of biological systems and therefore accurately modeling brain disorders presents enormous challenges. A large range of therapeutic approaches across a diverse collection of brain disorders have been found to show great promise in preclinical testing and then failed during clinical trials. There are a variety of potential reasons for such failures, on both the preclinical and clinical sides of the equation. In this article, I wi l l focus on the key issues of validity in animal models. I wi l l discuss two forms of construct validity,‘genetic construct validity’ and ‘environmental construct val idity’,which model specific aspects of the genome and ‘envirome’ relevant to the disorder in question. The generation of new gene-edited animal models has been facilitated by new technologies, the most notable of which are CRISPR-Cas systems. These and other technologies can be used to enhance contruct validity. Finally, I wi l l discuss how face validity can be optimized, via more sophisticated cognitive, affective and motor behavioural tests, translational tools and the integration of molecular, cellular and systems data. Predictive validity cannot yet be assessed for the many preclinical models where we currently lack effective clinical interventions, however this wi l l change as the translational pipeline is honed to deliver therapies for a range of devastating disorders.