ABSTRACT
Current evidence has associated caspase activation with the regulation of basic cellular functions without causing apoptosis. Malfunction of non-apoptotic caspase activities may contribute to specific neurological disorders, metabolic diseases, autoimmune conditions and cancers. However, our understanding of non-apoptotic caspase functions remains limited. Here, we show that non-apoptotic caspase activation prevents the intracellular accumulation of the Patched receptor in autophagosomes and the subsequent Patched-dependent induction of autophagy in Drosophila follicular stem cells. These events ultimately sustain Hedgehog signalling and the physiological properties of ovarian somatic stem cells and their progeny under moderate thermal stress. Importantly, our key findings are partially conserved in ovarian somatic cells of human origin. These observations attribute to caspases a pro-survival role under certain cellular conditions.
Subject(s)
Adult Stem Cells , Hedgehog Proteins , Animals , Humans , Hedgehog Proteins/metabolism , Cell Death , Apoptosis/physiology , Caspases/genetics , Caspases/metabolism , Drosophila/metabolism , Adult Stem Cells/metabolism , Homeostasis , Caspase 3/metabolism , Caspase 8/metabolism , Caspase 9/metabolismABSTRACT
BACKGROUND: Chronic kidney disease (CKD) is a complex disorder that has become a high prevalence global health problem, with diabetes being its predominant pathophysiologic driver. Autosomal genetic variation only explains some of the predisposition to kidney disease. Variations in the mitochondrial genome (mtDNA) and nuclear-encoded mitochondrial genes (NEMG) are implicated in susceptibility to kidney disease and CKD progression, but they have not been thoroughly explored. Our aim was to investigate the association of variation in both mtDNA and NEMG with CKD (and related traits), with a particular focus on diabetes. METHODS: We used the UK Biobank (UKB) and UK-ROI, an independent collection of individuals with type 1 diabetes mellitus (T1DM) patients. RESULTS: Fourteen mitochondrial variants were associated with estimated glomerular filtration rate (eGFR) in UKB. Mitochondrial variants and haplogroups U, H and J were associated with eGFR and serum variables. Mitochondrial haplogroup H was associated with all the serum variables regardless of the presence of diabetes. Mitochondrial haplogroup X was associated with end-stage kidney disease (ESKD) in UKB. We confirmed the influence of several known NEMG on kidney disease and function and found novel associations for SLC39A13, CFL1, ACP2 or ATP5G1 with serum variables and kidney damage, and for SLC4A1, NUP210 and MYH14 with ESKD. The G allele of TBC1D32-rs113987180 was associated with higher risk of ESKD in patients with diabetes (OR:9.879; CI95%:4.440-21.980; P = 2.0E-08). In UK-ROI, AGXT2-rs71615838 and SURF1-rs183853102 were associated with diabetic nephropathies, and TFB1M-rs869120 with eGFR. CONCLUSIONS: We identified novel variants both in mtDNA and NEMG which may explain some of the missing heritability for CKD and kidney phenotypes. We confirmed the role of MT-ND5 and mitochondrial haplogroup H on renal disease (serum variables), and identified the MT-ND5-rs41535848G variant, along with mitochondrial haplogroup X, associated with higher risk of ESKD. Despite most of the associations were independent of diabetes, we also showed potential roles for NEMG in T1DM.
Subject(s)
Mitochondria , Humans , Male , Mitochondria/genetics , Female , Middle Aged , Genetic Predisposition to Disease , Glomerular Filtration Rate , Genetic Variation , Haplotypes , Renal Insufficiency, Chronic/genetics , DNA, Mitochondrial/genetics , Diabetes Mellitus, Type 1/genetics , Diabetes Mellitus, Type 1/complications , Polymorphism, Single Nucleotide , Adult , AgedABSTRACT
Osteogenesis Imperfecta is a rare, hereditary bone condition with an incidence of 1/15,000-20,000. Symptoms include bone fragility, long bone deformity, scoliosis, hypermobility, alongside secondary features such as short stature, basilar invagination, pulmonary and cardiac complications, hearing loss, dentinogenesis imperfecta and malocclusion. Osteogenesis Imperfecta can have a large impact on the child and their family; this impact starts immediately after diagnosis. Fractures, pain, immobility, hospital admissions and the need for equipment and adaptations all influence the health-related quality of life of the individual and their family. This narrative review article aims to examine the impact the diagnosis and management of osteogenesis imperfecta has on the health-related quality of life of a child. It will touch on the effect this may have on the quality of life of their wider family and friends and identify strategies to optimise health-related quality of life in this population. Optimising health-related quality of life in children with Osteogenesis Imperfecta is often a complicated, multifaceted journey that involves the child, their extended family, school, extracurricular staff and numerous health professionals.
ABSTRACT
PURPOSE: A robotic-assisted laparoscopic approach to appendicostomy offers the benefits of a minimally invasive approach to patients who would typically necessitate an open procedure, those with a larger body habitus, and those requiring combined complex colorectal and urologic reconstructive procedures. We present our experience performing robotic-assisted appendicostomies with a focus on patient selection, perioperative factors, and functional outcomes. METHODS: A retrospective review of patients who underwent a robotic-assisted appendicostomy/neoappendicostomy at our institution was performed. RESULTS: Twelve patients underwent robotic-assisted appendicostomy (n = 8) and neoappendicostomy (n = 4) at a range of 8.8-25.8 years. Five patients had a weight percentile > 50% for their age. Seven patients underwent combined procedures. Median operative time for appendicostomy/neoappendicostomy only was 185.0 min. Complications included surgical site infection (n = 3), stricture requiring minor operative revision (n = 2), conversion to an open procedure due to inadequate appendiceal length (prior to developing our technique for robotic neoappendicostomies; n = 1), and granuloma (n = 1). At a median follow-up of 10.8 months (range 1.7-74.3 months), 91.7% of patients were consistently clean with antegrade enemas. DISCUSSION: Robotic-assisted laparoscopic appendicostomy and neoappendicostomy with cecal flap is a safe and effective operative approach. A robotic approach can potentially overcome the technical difficulties encountered in obese patients and can aid in patients requiring both a Malone and a Mitrofanoff in a single, combined minimally invasive procedure.
Subject(s)
Fecal Incontinence , Laparoscopy , Robotic Surgical Procedures , Humans , Robotic Surgical Procedures/methods , Fecal Incontinence/surgery , Colostomy , Laparoscopy/methods , Enema/methods , Retrospective StudiesABSTRACT
Inadequate drug loading and control of payload leakage limit the duration of the effect of liposomal drug carriers and may cause toxicity. Here, we report a liposome system as a depot for sustained drug delivery whose design is inspired by the low permeability of Archaeal membranes to protons and solutes. Incorporating methyl-branched phospholipids into lipid bilayers decreased payload diffusion across liposomal membranes, thereby enhancing the drug load capacity by 10-16% and reducing the release of small molecules in the first 24 h by 40-48%. The in vivo impact of this approach was demonstrated by injection at the sciatic nerve. Methyl-branched liposomes encapsulating the anesthetic tetrodotoxin (TTX) achieved markedly prolonged local anesthesia lasting up to 70 h, in comparison to the 16 h achieved with liposomes containing conventional lipids. The present work demonstrates the usefulness of methyl-branched liposomes to enhance liposomal depot systems for sustained drug delivery.
Subject(s)
Drug Delivery Systems , Liposomes , Drug Carriers , Phospholipids , Lipid BilayersABSTRACT
Venous malformations (VMs) consist of hugely enlarged and dysmorphic veins. These lesions cause significant disfigurement, pain, and complications such as bleeding and coagulopathy. Pharmacotherapy for the treatment of VMs has limited efficacy and potentially limiting toxicity. Current treatment for patients with VMs entails life-long pharmacotherapy or surgical procedures. Here we explored whether intravenously administered agents can be used to destroy VMs by photothermal therapy (PTT), using gold nanoshells (AuNSs) that generated heat following irradiation with near-infrared (NIR) light. In a murine model of VMs, intravenous AuNSs accumulated within the VMs. Irradiation of the VMs induced marked regression and even elimination. Nanoparticle-based photothermal therapy can provide effective therapy for VMs, which are otherwise relatively refractory to treatment.
Subject(s)
Hyperthermia, Induced , Nanoshells , Humans , Mice , Animals , Photothermal Therapy , Gold/therapeutic use , Nanoshells/therapeutic use , Hyperthermia, Induced/methods , PhototherapyABSTRACT
Misuse of opioids can lead to a potential lethal overdose. Timely administration of naloxone is critical for survival. Here, we designed a polymer-naloxone conjugate that can provide on-demand phototriggered opioid reversal. Naloxone was attached to the polymer poly(lactic-co-glycolic acid) via a photocleavable coumarin linkage and formulated as injectable nanoparticles. In the absence of irradiation, the formulation did not release naloxone. Upon irradiation with blue (400 nm) light, the nanoparticles released free naloxone, reversing the effect of morphine in mice. Such triggered events could be performed days and weeks after the initial administration of the nanoparticles and could be performed repeatedly.
Subject(s)
Drug Overdose , Naloxone , Mice , Animals , Naloxone/pharmacology , Naloxone/therapeutic use , Analgesics, Opioid/therapeutic use , Narcotic Antagonists/therapeutic use , Polymers/pharmacology , Polymers/therapeutic use , Drug Overdose/drug therapyABSTRACT
BACKGROUND: Capillary malformation-arteriovenous malformation (CM-AVM) is characterized by multifocal fast-flow capillary malformations, sometimes with arteriovenous malformations/fistulas, skeletal/soft tissue overgrowth, telangiectasias, or Bier spots. Lymphatic abnormalities are infrequently reported. We describe seven patients with CM-AVM and lymphatic anomalies. METHODS: Following IRB approval, we identified patients with CM-AVM and lymphatic anomalies seen at the Vascular Anomalies Center at Boston Children's Hospital from 2003 to 2023. We retrospectively reviewed records for clinical, genetic, laboratory, and imaging findings. RESULTS: We found seven patients with CM-AVM and lymphatic abnormalities. Five patients were diagnosed prenatally: four with pleural effusions (including one suspected chylothorax) and one with ascites. Pleural effusions resolved after neonatal drainage in three patients and fetal thoracentesis in the fourth; however, fluid rapidly reaccumulated in this fetus causing hydrops. Ascites resolved after neonatal paracentesis, recurred at 2 months, and spontaneously resolved at 5 years; magnetic resonance lymphangiography for recurrence at age 19 years suggested a central conducting lymphatic anomaly (CCLA), and at age 20 years a right spermatic cord/scrotal lymphatic malformation (LM) was detected. Chylous pericardial effusion presented in a sixth patient at 2 months and disappeared after pericardiocentesis. A seventh patient was diagnosed with a left lower extremity LM at 16 months. Six patients underwent genetic testing, and all had RASA1 mutation. RASA1 variant was novel in three patients (c.1495delinsCTACC, c.434_451delinsA, c.2648del), previously reported in two (c.2603+1G>A, c.475_476del), and unavailable in another. Median follow-up age was 5.8 years (4 months-20 years). CONCLUSION: CM-AVM may be associated with lymphatic anomalies, including pericardial/pleural effusions, ascites, CCLA, and LM.
Subject(s)
Arteriovenous Fistula , Arteriovenous Malformations , Lymphatic Abnormalities , Pleural Effusion , Male , Child , Infant, Newborn , Female , Humans , Young Adult , Adult , Child, Preschool , Retrospective Studies , Ascites/pathology , p120 GTPase Activating Protein/genetics , Capillaries/abnormalities , Arteriovenous Malformations/genetics , Pleural Effusion/pathology , Lymphatic Abnormalities/diagnosis , Lymphatic Abnormalities/genetics , Lymphatic Abnormalities/pathology , Hydrops FetalisABSTRACT
BACKGROUND: Wound dehiscence of the anocutaneous anastomosis and/or reconstructed perineal body is a feared perioperative complication after posterior sagittal anorectoplasty (PSARP). Dehiscence of the perineal body can have long-term negative implications for fecal continence, sexual intimacy, obstetrical outcomes, and the need for reoperative surgery. We describe a modification to the traditional PSARP for repair of an imperforate anus with a rectovestibular, perineal, or absent fistula by sparing the perineal body, eliminating postoperative perineal body dehiscence and potentially improving long-term functional outcomes. METHODS: A retrospective review of female patients with a rectovestibular, perineal, or absent fistula who underwent PSARP with sparing of the perineal body was performed. RESULTS: Six patients underwent PSARP with sparing of the perineal body between 2019 and 2022. There were no perioperative complications. At follow-up, all patients are having regular bowel function without difficulty and have an excellent appearance of their perineal body. CONCLUSIONS: PSARP for a rectovestibular, perineal, or absent fistula can be safely performed with a more limited incision to avoid disruption of the perineal body. This eliminates the need for perineal body reconstruction during the procedure, thereby preventing wound dehiscence. Given the significant long-term adverse sequelae of wound dehiscence and resultant inadequate perineal body, we believe this modification to the PSARP warrants strong consideration.
Subject(s)
Anorectal Malformations , Anus, Imperforate , Fistula , Humans , Female , Infant , Anorectal Malformations/surgery , Rectum/surgery , Fistula/surgery , Postoperative Complications/prevention & control , Postoperative Complications/surgery , Anus, Imperforate/surgery , Retrospective Studies , Anal Canal/surgery , Treatment Outcome , Follow-Up StudiesABSTRACT
BACKGROUND: Anxiety problems are extremely common and have an early age of onset. We previously found, in a study in England, that fewer than 3% of children with an anxiety disorder identified in the community had accessed an evidence-based treatment (Cognitive Behavioural Therapy; CBT). Key ways to increase access to CBT for primary school-aged children with anxiety problems include (a) proactive identification through screening in schools, (b) supporting parents and (c) the provision of brief, accessible interventions (and capitalising on technology to do this). METHOD: We provided a brief, therapist guided treatment called Online Support and Intervention (OSI) to parents/carers of children identified, through school-based screening, as likely to have anxiety problems. Fifty out of 131 children from 17 Year 4 classes in schools in England screened positive for 'possible anxiety problems' and 42 (84%) of these (and 7 who did not) took up the offer of OSI. We applied quantitative and qualitative approaches to assess children's outcomes and families' experiences of this approach. RESULTS: Inbuilt outcome monitoring indicated session on session improvements throughout the course of treatment, with substantial changes across measures by the final module (e.g. Child Outcome Rating Scale d = 0.84; Goal Based Outcomes d = 1.52). Parent engagement and satisfaction was high as indicated by quantitative and qualitative assessments, and intervention usage. CONCLUSIONS: We provide promising preliminary evidence for the use of OSI as an early intervention for children identified as having anxiety problems through school-based screening.
Subject(s)
Anxiety Disorders , Cognitive Behavioral Therapy , Humans , Child , Anxiety Disorders/therapy , Anxiety Disorders/psychology , Parents/education , Parents/psychology , Schools , Anxiety/therapyABSTRACT
BACKGROUND: Online treatments for child anxiety offer a potentially cost-effective and non-stigmatizing means to widen access to evidence-based treatments and meet the increasing demand on services; however, uptake in routine clinical practice remains a challenge. This study conducted an initial evaluation of the clinical effectiveness, feasibility and acceptability of OSI (Online Support and Intervention for child anxiety) within clinical practice. OSI is a co-designed online therapist-supported, parent-led CBT treatment for pre-adolescent children with anxiety problems. METHOD: This case series was part of routine service evaluation in a clinic in England where families were offered OSI to treat a primary anxiety difficulty among 7- to 12-year-old children; 24 families were offered OSI, and 23 took it up. Measures of anxiety symptomatology, functional impairment and progress towards therapeutic goals were taken at pre-treatment, post-treatment and 4-week follow-up. Treatment satisfaction and engagement were also measured throughout the intervention. RESULTS: Mean anxiety symptoms significantly improved to below the clinical cut-off post-treatment, with further reduction at follow-up. Functional impairment also significantly improved and significant progress was made towards treatment goals. The majority of children showed reliable change in anxiety symptoms and reliable recovery by follow-up, and were discharged without needing further treatment for anxiety. Uptake, adherence and engagement in OSI were excellent, and parents reported high levels of satisfaction with the treatment. CONCLUSIONS: We have provided initial evidence that OSI is feasible, acceptable to families, and appears to be associated with good outcomes within routine clinical practice.
Subject(s)
Cognitive Behavioral Therapy , Adolescent , Anxiety/therapy , Anxiety Disorders/therapy , Child , Humans , Parents , Treatment OutcomeABSTRACT
BACKGROUND: Mental health problems in children and young people are common and can lead to poor long-term outcomes. Despite the availability of effective psychological interventions for mental health disorders, only a minority of affected children and young people access treatment. Digital interventions, such as applied games and virtual reality (VR), that target mental health problems in children and young people may hold a key to increasing access to, engagement with, and potentially the effectiveness of psychological treatments. To date, several applied games and VR interventions have been specifically developed for children and young people. This systematic review aims to identify and synthesize current data on the experience and effectiveness of applied games and VR for targeting mental health problems in children and young people (defined as average age of 18 years or below). METHODS: Electronic systematic searches were conducted in Medline, PsycINFO, CINAHL, and Web of Science. RESULTS: Nineteen studies were identified that examined nine applied games and two VR applications, and targeted symptoms of anxiety, depression, and phobias using both quantitative and qualitative methodologies. Existing evidence is at a very early stage and studies vary extensively in key methodological characteristics. For applied games, the most robust evidence is for adolescent depressive symptoms (medium clinical effect sizes). Insufficient research attention has been given to the efficacy of VR interventions in children and young people. CONCLUSIONS: The evidence to date is at a very early stage. Despite the enthusiasm for applied games and VR, existing interventions are limited in number and evidence of efficacy, and there is a clear need for further co-design, development, and evaluation of applied games and VR before they are routinely offered as treatments for children and young people with mental health problems.
Subject(s)
Video Games , Virtual Reality , Adolescent , Anxiety , Anxiety Disorders , Child , Humans , Infant, Newborn , Mental HealthABSTRACT
In Arabidopsis thaliana, changes in metabolism and gene expression drive increased drought tolerance and initiate diverse drought avoidance and escape responses. To address regulatory processes that link these responses, we set out to identify genes that govern early responses to drought. To do this, a high-resolution time series transcriptomics data set was produced, coupled with detailed physiological and metabolic analyses of plants subjected to a slow transition from well-watered to drought conditions. A total of 1815 drought-responsive differentially expressed genes were identified. The early changes in gene expression coincided with a drop in carbon assimilation, and only in the late stages with an increase in foliar abscisic acid content. To identify gene regulatory networks (GRNs) mediating the transition between the early and late stages of drought, we used Bayesian network modeling of differentially expressed transcription factor (TF) genes. This approach identified AGAMOUS-LIKE22 (AGL22), as key hub gene in a TF GRN. It has previously been shown that AGL22 is involved in the transition from vegetative state to flowering but here we show that AGL22 expression influences steady state photosynthetic rates and lifetime water use. This suggests that AGL22 uniquely regulates a transcriptional network during drought stress, linking changes in primary metabolism and the initiation of stress responses.
Subject(s)
Abscisic Acid/metabolism , Arabidopsis Proteins/metabolism , Arabidopsis/genetics , Gene Expression Regulation, Plant , Plant Growth Regulators/metabolism , Transcription Factors/metabolism , Arabidopsis/growth & development , Arabidopsis/physiology , Arabidopsis Proteins/genetics , Bayes Theorem , Cluster Analysis , Droughts , Gene Regulatory Networks , Mutation , Phenotype , Photosynthesis/physiology , Stress, Physiological , Transcription Factors/geneticsABSTRACT
BACKGROUND: Randomised controlled trials suggest that cognitive behavioural therapy (CBT) delivered by parents who are guided, in groups, by clinicians (Group GPD-CBT) is an efficacious and potentially efficient treatment approach for child anxiety. The extent to which these results translate to routine settings is unclear. We evaluated Group GPD-CBT as delivered in UK routine clinical services. METHOD: Retrospective data regarding attendance and outcomes were routinely collected for 83 children whose parent(s) had attended Group GPD-CBT. Semistructured interviews were conducted with 14 clinicians who had delivered Group GPD-CBT. RESULTS: By 3-8 months (M = 5.22, SD = 1.17) post-treatment, 70% of children were discharged or referred for support for other (non-anxiety) conditions, without any further intervention for anxiety. Of the subset (N = 20) with available parent-report symptom data, there was a significant decline in total anxiety score from pre- to post-treatment. Clinician interviews were analysed using thematic analysis. This revealed that clinicians found Group GPD-CBT to be acceptable and described it as a helpful, practical and empowering treatment for child anxiety. They highlighted additional benefits associated with group process factors (e.g. peer support, enhanced engagement), although noted that some, particularly anxious, parents were reluctant to attend a group format. CONCLUSIONS: Results were promising regarding children's outcomes following Group GPD-CBT delivered in routine practice. Group GPD-CBT was viewed by clinicians as acceptable and helpful, and group process factors were seen to provide additional benefits. Some parents may find it difficult to attend a group format, suggesting that services should give careful consideration to how groups are presented and introduced to parents.
ABSTRACT
Transcriptional reprogramming is integral to effective plant defense. Pathogen effectors act transcriptionally and posttranscriptionally to suppress defense responses. A major challenge to understanding disease and defense responses is discriminating between transcriptional reprogramming associated with microbial-associated molecular pattern (MAMP)-triggered immunity (MTI) and that orchestrated by effectors. A high-resolution time course of genome-wide expression changes following challenge with Pseudomonas syringae pv tomato DC3000 and the nonpathogenic mutant strain DC3000hrpA- allowed us to establish causal links between the activities of pathogen effectors and suppression of MTI and infer with high confidence a range of processes specifically targeted by effectors. Analysis of this information-rich data set with a range of computational tools provided insights into the earliest transcriptional events triggered by effector delivery, regulatory mechanisms recruited, and biological processes targeted. We show that the majority of genes contributing to disease or defense are induced within 6 h postinfection, significantly before pathogen multiplication. Suppression of chloroplast-associated genes is a rapid MAMP-triggered defense response, and suppression of genes involved in chromatin assembly and induction of ubiquitin-related genes coincide with pathogen-induced abscisic acid accumulation. Specific combinations of promoter motifs are engaged in fine-tuning the MTI response and active transcriptional suppression at specific promoter configurations by P. syringae.
Subject(s)
Arabidopsis/immunology , Immunosuppression Therapy , Pathogen-Associated Molecular Pattern Molecules/metabolism , Plant Immunity/genetics , Plant Leaves/immunology , Pseudomonas syringae/physiology , Transcription, Genetic , Arabidopsis/genetics , Arabidopsis/microbiology , Base Sequence , Chromatin/metabolism , Gene Expression Profiling , Gene Expression Regulation, Plant , Gene Ontology , Gene Regulatory Networks , Genes, Plant , Molecular Sequence Data , Nucleotide Motifs/genetics , Plant Diseases/genetics , Plant Diseases/immunology , Plant Diseases/microbiology , Plant Leaves/genetics , Plant Leaves/microbiology , Promoter Regions, Genetic/genetics , Pseudomonas syringae/growth & development , Transcription Factors/metabolismABSTRACT
Repeated taste exposure is an established means of increasing children's liking and intake of fruit and vegetables. However, parents find it difficult to offer children disliked foods repeatedly, often giving up after a few attempts. Studies show that familiarizing children to fruit and vegetables through picture books can increase their interest in tasting targeted foods. This study explored whether looking at picture books before providing foods to taste improved the outcomes of a home-delivered taste exposure regime. Parents of 127 toddlers (aged 21-24 months) identified two 'target' foods they wanted their child to eat (1 fruit, 1 vegetable). Families were randomly assigned to one of three groups. Parents and children in two experimental groups looked at books about either the target fruit or vegetable every day for two weeks; the control group did not receive a book. Parents in all three groups were then asked to offer their child both target foods every day during a 2-week taste-exposure phase. Parental ratings of children's liking and consumption of the foods were collected at baseline, immediately following taste-exposure (post-intervention), and 3 months later (follow-up). In all groups, liking of both foods increased following taste exposure and remained above baseline at follow-up (all psâ¯<â¯.001). In addition, compared to the control group who experienced only taste exposure, looking at vegetable books enhanced children's liking of their target vegetable post-intervention (pâ¯<â¯.001) and at follow-up (pâ¯<â¯.05), and increased consumption of the vegetable at follow-up (pâ¯<â¯.01). Exposure to vegetable books was also associated with smaller increases in neophobia and food fussiness over the period of the study compared to controls (psâ¯<â¯.01), suggesting that picture books may have positive, long-term impacts on children's attitudes towards new foods.
Subject(s)
Child Behavior/psychology , Diet/psychology , Feeding Behavior/psychology , Parenting/psychology , Vegetables , Adult , Books , Child, Preschool , Female , Food Preferences/psychology , Humans , Male , Parents/psychology , Pisum sativum , Reading , Recognition, PsychologyABSTRACT
This article presents an analysis of challenges and considerations when developing digital mental health innovations. Recommendations include collaborative working between clinicians, researchers, industry and service users in order to successfully navigate challenges and to ensure e-therapies are engaging, acceptable, evidence based, scalable and sustainable.
Subject(s)
Mental Health Services , Telemedicine/methods , Cooperative Behavior , HumansSubject(s)
Anxiety Disorders , Anxiety , Anxiety Disorders/therapy , Child , Family , Humans , Treatment OutcomeABSTRACT
Takayasu arteritis is a rare, chronic large vessel vasculitis of unknown etiology which predominantly affects women younger than 40 years of age. Symptoms are highly variable based on the location and extent of the stenosis, arterial occlusion, aneurysm, and thrombosis. Diagnosis is based on clinical presentation, relevant laboratory work-up, and imaging findings of wall thickening and stenosis of medium and large vessels. Management includes glucocorticoid therapy, frequently paired with adjunctive immunosuppressants, and sometimes surgical intervention in severe cases. Here, we present a unique case of Takayasu arteritis with critical distal aortic stenosis with very severe wall thickening involving the bilateral common iliac artery and leading to left iliac artery thrombosis. Based on our literature review, our article represents a very rare presentation of Takayasu arteritis with severe iliac artery thrombosis.
Subject(s)
Aortic Diseases/etiology , Arterial Occlusive Diseases/etiology , Iliac Artery , Takayasu Arteritis/complications , Thrombosis/etiology , Aortic Diseases/diagnostic imaging , Aortic Diseases/therapy , Aortography/methods , Arterial Occlusive Diseases/diagnostic imaging , Arterial Occlusive Diseases/therapy , Computed Tomography Angiography , Critical Illness , Female , Humans , Iliac Artery/diagnostic imaging , Middle Aged , Severity of Illness Index , Takayasu Arteritis/diagnostic imaging , Takayasu Arteritis/therapy , Thrombosis/diagnostic imaging , Thrombosis/therapyABSTRACT
MOTIVATION: Identification of modules of co-regulated genes is a crucial first step towards dissecting the regulatory circuitry underlying biological processes. Co-regulated genes are likely to reveal themselves by showing tight co-expression, e.g. high correlation of expression profiles across multiple time series datasets. However, numbers of up- or downregulated genes are often large, making it difficult to discriminate between dependent co-expression resulting from co-regulation and independent co-expression. Furthermore, modules of co-regulated genes may only show tight co-expression across a subset of the time series, i.e. show condition-dependent regulation. RESULTS: Wigwams is a simple and efficient method to identify gene modules showing evidence for co-regulation in multiple time series of gene expression data. Wigwams analyzes similarities of gene expression patterns within each time series (condition) and directly tests the dependence or independence of these across different conditions. The expression pattern of each gene in each subset of conditions is tested statistically as a potential signature of a condition-dependent regulatory mechanism regulating multiple genes. Wigwams does not require particular time points and can process datasets that are on different time scales. Differential expression relative to control conditions can be taken into account. The output is succinct and non-redundant, enabling gene network reconstruction to be focused on those gene modules and combinations of conditions that show evidence for shared regulatory mechanisms. Wigwams was run using six Arabidopsis time series expression datasets, producing a set of biologically significant modules spanning different combinations of conditions. AVAILABILITY AND IMPLEMENTATION: A Matlab implementation of Wigwams, complete with graphical user interfaces and documentation, is available at: warwick.ac.uk/wigwams. .