RESUMEN
Inherited glycosylphosphatidylinositol deficiency disorders (IGDs) are a group of rare multisystem disorders arising from pathogenic variants in glycosylphosphatidylinositol anchor pathway (GPI-AP) genes. Despite associating 24 of at least 31 GPI-AP genes with human neurogenetic disease, prior reports are limited to single genes without consideration of the GPI-AP as a whole and with limited natural history data. In this multinational retrospective observational study, we systematically analyse the molecular spectrum, phenotypic characteristics and natural history of 83 individuals from 75 unique families with IGDs, including 70 newly reported individuals; the largest single cohort to date. Core clinical features were developmental delay or intellectual disability (DD/ID, 90%), seizures (83%), hypotonia (72%) and motor symptoms (64%). Prognostic and biologically significant neuroimaging features included cerebral atrophy (75%), cerebellar atrophy (60%), callosal anomalies (57%) and symmetric restricted diffusion of the central tegmental tracts (60%). Sixty-one individuals had multisystem involvement including gastrointestinal (66%), cardiac (19%) and renal (14%) anomalies. Though dysmorphic features were appreciated in 82%, no single dysmorphic feature had a prevalence >30%, indicating substantial phenotypic heterogeneity. Follow-up data were available for all individuals, 15 of whom were deceased at the time of writing. Median age at seizure onset was 6 months. Individuals with variants in synthesis stage genes of the GPI-AP exhibited a significantly shorter time to seizure onset than individuals with variants in transamidase and remodelling stage genes of the GPI-AP (P = 0.046). Forty individuals had intractable epilepsy. The majority of individuals experienced delayed or absent speech (95%), motor delay with non-ambulance (64%), and severe-to-profound DD/ID (59%). Individuals with a developmental epileptic encephalopathy (51%) were at greater risk of intractable epilepsy (P = 0.003), non-ambulance (P = 0.035), ongoing enteral feeds (P < 0.001) and cortical visual impairment (P = 0.007). Serial neuroimaging showed progressive cerebral volume loss in 87.5% and progressive cerebellar atrophy in 70.8%, indicating a neurodegenerative process. Genetic analyses identified 93 unique variants (106 total), including 22 novel variants. Exploratory analyses of genotype-phenotype correlations using unsupervised hierarchical clustering identified novel genotypic predictors of clinical phenotype and long-term outcome with meaningful implications for management. In summary, we expand both the mild and severe phenotypic extremities of the IGDs, provide insights into their neurological basis, and vitally, enable meaningful genetic counselling for affected individuals and their families.
Asunto(s)
Glicosilfosfatidilinositoles , Humanos , Masculino , Femenino , Preescolar , Niño , Adolescente , Estudios Retrospectivos , Lactante , Adulto , Glicosilfosfatidilinositoles/deficiencia , Glicosilfosfatidilinositoles/genética , Discapacidad Intelectual/genética , Discapacidades del Desarrollo/genética , Adulto Joven , Trastornos Congénitos de Glicosilación/genética , Fenotipo , Convulsiones/genéticaRESUMEN
Over 2.5 million gastrointestinal endoscopic procedures are carried out in the United Kingdom (UK) every year. Procedures are carried out with local anaesthetic r with sedation. Sedation is commonly used for gastrointestinal endoscopy, but the type and amount of sedation administered is influenced by the complexity and nature of the procedure and patient factors. The elective and emergency nature of endoscopy procedures and local resources also have a significant impact on the delivery of sedation. In the UK, the vast majority of sedated procedures are carried out using benzodiazepines, with or without opiates, whereas deeper sedation using propofol or general anaesthetic requires the involvement of an anaesthetic team. Patients undergoing gastrointestinal endoscopy need to have good understanding of the options for sedation, including the option for no sedation and alternatives, balancing the intended aims of the procedure and reducing the risk of complications. These guidelines were commissioned by the British Society of Gastroenterology (BSG) Endoscopy Committee with input from major stakeholders, to provide a detailed update, incorporating recent advances in sedation for gastrointestinal endoscopy.This guideline covers aspects from pre-assessment of the elective 'well' patient to patients with significant comorbidity requiring emergency procedures. Types of sedation are discussed, procedure and room requirements and the recovery period, providing guidance to enhance safety and minimise complications. These guidelines are intended to inform practising clinicians and all staff involved in the delivery of gastrointestinal endoscopy with an expectation that this guideline will be revised in 5-years' time.
Asunto(s)
Gastroenterología , Propofol , Humanos , Sedación Consciente , Endoscopía Gastrointestinal/efectos adversos , Endoscopía Gastrointestinal/métodos , BenzodiazepinasRESUMEN
BACKGROUND: The ITPR1 gene encodes the inositol 1,4,5-trisphosphate (IP3 ) receptor type 1 (IP3 R1), a critical player in cerebellar intracellular calcium signaling. Pathogenic missense variants in ITPR1 cause congenital spinocerebellar ataxia type 29 (SCA29), Gillespie syndrome (GLSP), and severe pontine/cerebellar hypoplasia. The pathophysiological basis of the different phenotypes is poorly understood. OBJECTIVES: We aimed to identify novel SCA29 and GLSP cases to define core phenotypes, describe the spectrum of missense variation across ITPR1, standardize the ITPR1 variant nomenclature, and investigate disease progression in relation to cerebellar atrophy. METHODS: Cases were identified using next-generation sequencing through the Deciphering Developmental Disorders study, the 100,000 Genomes project, and clinical collaborations. ITPR1 alternative splicing in the human cerebellum was investigated by quantitative polymerase chain reaction. RESULTS: We report the largest, multinational case series of 46 patients with 28 unique ITPR1 missense variants. Variants clustered in functional domains of the protein, especially in the N-terminal IP3 -binding domain, the carbonic anhydrase 8 (CA8)-binding region, and the C-terminal transmembrane channel domain. Variants outside these domains were of questionable clinical significance. Standardized transcript annotation, based on our ITPR1 transcript expression data, greatly facilitated analysis. Genotype-phenotype associations were highly variable. Importantly, while cerebellar atrophy was common, cerebellar volume loss did not correlate with symptom progression. CONCLUSIONS: This dataset represents the largest cohort of patients with ITPR1 missense variants, expanding the clinical spectrum of SCA29 and GLSP. Standardized transcript annotation is essential for future reporting. Our findings will aid in diagnostic interpretation in the clinic and guide selection of variants for preclinical studies. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.
Asunto(s)
Aniridia , Anhidrasas Carbónicas , Ataxia Cerebelosa , Discapacidad Intelectual , Trastornos del Movimiento , Degeneraciones Espinocerebelosas , Humanos , Ataxia Cerebelosa/genética , Mutación Missense/genética , Trastornos del Movimiento/complicaciones , Atrofia , Receptores de Inositol 1,4,5-Trifosfato/química , Receptores de Inositol 1,4,5-Trifosfato/genética , Receptores de Inositol 1,4,5-Trifosfato/metabolismo , Anhidrasas Carbónicas/genética , Anhidrasas Carbónicas/metabolismo , Péptidos y Proteínas de Señalización Intracelular/genéticaRESUMEN
ISG15 deficiency is a rare disease caused by autosomal recessive variants in the ISG15 gene, which encodes the ISG15 protein. The ISG15 protein plays a dual role in both the type I and II interferon (IFN) immune pathways. Extracellularly, the ISG15 protein is essential for IFN-γ-dependent anti-mycobacterial immunity, while intracellularly, ISG15 is necessary for USP18-mediated downregulation of IFN-α/ß signalling. Due to this dual role, ISG15 deficiency can present with various clinical phenotypes, ranging from susceptibility to mycobacterial infection to autoinflammation characterised by necrotising skin lesions, intracerebral calcification, and pulmonary involvement. In this report, we describe novel variants found in two different families that result in complete ISG15 deficiency and severe skin ulceration. Whole exome sequencing identified a heterozygous missense p.Q16X ISG15 variant and a heterozygous multigene 1p36.33 deletion in the proband from the first family. In the second family, a homozygous total ISG15 gene deletion was detected in two siblings. We also conducted further analysis, including characterisation of cytokine dysregulation, interferon-stimulated gene expression, and p-STAT1 activation in lymphocytes and lesional tissue. Finally, we demonstrate the complete and rapid resolution of clinical symptoms associated with ISG15 deficiency in one sibling from the second family following treatment with the Janus kinase (JAK) inhibitor baricitinib.
Asunto(s)
Citocinas , Ubiquitinas , Humanos , Ubiquitinas/metabolismo , Citocinas/metabolismo , Interferones , Ubiquitina Tiolesterasa/genética , Ubiquitina Tiolesterasa/metabolismoRESUMEN
PURPOSE: The purpose of the study was to investigate service-users' experiences of a therapist engaging with their voices (auditory hallucinations) using psychological formulation and direct dialogue. METHOD: A nested qualitative study was conducted within a randomised controlled trial of a novel intervention for supporting voice hearers with a diagnosis of psychosis (Talking With Voices: TwV). Of 24 participants allocated to therapy, 13 (54%) consented to a semi-structured, in-depth interview which was audio-recorded, transcribed verbatim and analysed using inductive thematic analysis. RESULTS: Participants described their experiences of using the intervention to improve the relationship between themselves and their voice(s). The findings are organised within three themes and associated subthemes: (1) A desire for suitable help (Motivation to reduce voice-related distress, Limitation of other treatment options); (2) Engaging with voices (Challenges, Support and safety, Exploration and revelation); and (3) Contemplating the future (The aftermath of adversity, Living well with voices, Resources for moving forward). CONCLUSION: Despite the emotional challenges of the work, many participants experienced tangible gains in the ways they related to their voices post-intervention. For those who responded well, the development of safety strategies, including a strong therapeutic alliance, could facilitate a basis for developing new insights about the origin/nature of the voices which could then be applied in constructive ways. Further research is needed to understand which client characteristics indicate suitability for TwV as opposed to relational therapies that require less direct engagement with voices and/or the psychosocial conflicts with which they may be associated.
Asunto(s)
Trastornos Psicóticos , Voz , Humanos , Emociones , Alucinaciones/terapia , Alucinaciones/psicología , Trastornos Psicóticos/terapia , Trastornos Psicóticos/psicología , Investigación CualitativaRESUMEN
Germline pathogenic variants in two genes encoding the lysine-specific histone methyltransferase genes SETD1A and SETD2 are associated with neurodevelopmental disorders (NDDs) characterized by developmental delay and congenital anomalies. The SETD1A and SETD2 gene products play a critical role in chromatin-mediated regulation of gene expression. Specific methylation episignatures have been detected for a range of chromatin gene-related NDDs and have impacted clinical practice by improving the interpretation of variant pathogenicity. To investigate if SETD1A and/or SETD2-related NDDs are associated with a detectable episignature, we undertook targeted genome-wide methylation profiling of > 2 M CpGs using a next-generation sequencing-based assay. A comparison of methylation profiles in patients with SETD1A variants (n = 6) did not reveal evidence of a strong methylation episignature. A review of the clinical and genetic features of the SETD2 patient group revealed that, as reported previously, there were phenotypic differences between patients with truncating mutations (n = 4, Luscan-Lumish syndrome; MIM:616831) and those with missense codon 1740 variants [p.Arg1740Trp (n = 4) and p.Arg1740Gln (n = 2)]. Both SETD2 subgroups demonstrated a methylation episignature, which was characterized by hypomethylation and hypermethylation events, respectively. Within the codon 1740 subgroup, both the methylation changes and clinical phenotype were more severe in those with p.Arg1740Trp variants. We also noted that two of 10 cases with a SETD2-NDD had developed a neoplasm. These findings reveal novel epigenotype-genotype-phenotype correlations in SETD2-NDDs and predict a gain-of-function mechanism for SETD2 codon 1740 pathogenic variants.
Asunto(s)
Cromatina , Trastornos del Neurodesarrollo , Humanos , Cromatina/genética , Metilación de ADN/genética , Mutación , Trastornos del Neurodesarrollo/genética , Estudios de Asociación Genética , CodónRESUMEN
TSPEAR variants cause autosomal recessive ectodermal dysplasia (ARED) 14. The function of TSPEAR is unknown. The clinical features, the mutation spectrum, and the underlying mechanisms of ARED14 are poorly understood. Combining data from new and previously published individuals established that ARED14 is primarily characterized by dental anomalies such as conical tooth cusps and hypodontia, like those seen in individuals with WNT10A-related odontoonychodermal dysplasia. AlphaFold-predicted structure-based analysis showed that most of the pathogenic TSPEAR missense variants likely destabilize the ß-propeller of the protein. Analysis of 100000 Genomes Project (100KGP) data revealed multiple founder TSPEAR variants across different populations. Mutational and recombination clock analyses demonstrated that non-Finnish European founder variants likely originated around the end of the last ice age, a period of major climatic transition. Analysis of gnomAD data showed that the non-Finnish European population TSPEAR gene-carrier rate is â¼1/140, making it one of the commonest AREDs. Phylogenetic and AlphaFold structural analyses showed that TSPEAR is an ortholog of drosophila Closca, an extracellular matrix-dependent signaling regulator. We, therefore, hypothesized that TSPEAR could have a role in enamel knot, a structure that coordinates patterning of developing tooth cusps. Analysis of mouse single-cell RNA sequencing (scRNA-seq) data revealed highly restricted expression of Tspear in clusters representing enamel knots. A tspeara -/-;tspearb -/- double-knockout zebrafish model recapitulated the clinical features of ARED14 and fin regeneration abnormalities of wnt10a knockout fish, thus suggesting interaction between tspear and wnt10a. In summary, we provide insights into the role of TSPEAR in ectodermal development and the evolutionary history, epidemiology, mechanisms, and consequences of its loss of function variants.
Asunto(s)
Displasia Ectodérmica , Diente , Animales , Ratones , Filogenia , Pez Cebra , Displasia Ectodérmica/epidemiología , Diente/patologíaRESUMEN
Following the diagnosis of a paediatric disorder caused by an apparently de novo mutation, a recurrence risk of 1-2% is frequently quoted due to the possibility of parental germline mosaicism; but for any specific couple, this figure is usually incorrect. We present a systematic approach to providing individualized recurrence risk. By combining locus-specific sequencing of multiple tissues to detect occult mosaicism with long-read sequencing to determine the parent-of-origin of the mutation, we show that we can stratify the majority of couples into one of seven discrete categories associated with substantially different risks to future offspring. Among 58 families with a single affected offspring (representing 59 de novo mutations in 49 genes), the recurrence risk for 35 (59%) was decreased below 0.1%, but increased owing to parental mixed mosaicism for 5 (9%)-that could be quantified in semen for paternal cases (recurrence risks of 5.6-12.1%). Implementation of this strategy offers the prospect of driving a major transformation in the practice of genetic counselling.
Asunto(s)
Padre , Parto , Masculino , Embarazo , Femenino , Humanos , Niño , Mutación , Medición de Riesgo , Células Germinativas , Mosaicismo , Linaje , Mutación de Línea GerminalRESUMEN
DEPDC5 (DEP Domain-Containing Protein 5) encodes an inhibitory component of the mammalian target of rapamycin (mTOR) pathway and is commonly implicated in sporadic and familial focal epilepsies, both non-lesional and in association with focal cortical dysplasia. Germline pathogenic variants are typically heterozygous and inactivating. We describe a novel phenotype caused by germline biallelic missense variants in DEPDC5. Cases were identified clinically. Available records, including magnetic resonance imaging and electroencephalography, were reviewed. Genetic testing was performed by whole exome and whole-genome sequencing and cascade screening. In addition, immunohistochemistry was performed on skin biopsy. The phenotype was identified in nine children, eight of which are described in detail herein. Six of the children were of Irish Traveller, two of Tunisian and one of Lebanese origin. The Irish Traveller children shared the same DEPDC5 germline homozygous missense variant (p.Thr337Arg), whereas the Lebanese and Tunisian children shared a different germline homozygous variant (p.Arg806Cys). Consistent phenotypic features included extensive bilateral polymicrogyria, congenital macrocephaly and early-onset refractory epilepsy, in keeping with other mTOR-opathies. Eye and cardiac involvement and severe neutropenia were also observed in one or more patients. Five of the children died in infancy or childhood; the other four are currently aged between 5 months and 6 years. Skin biopsy immunohistochemistry was supportive of hyperactivation of the mTOR pathway. The clinical, histopathological and genetic evidence supports a causal role for the homozygous DEPDC5 variants, expanding our understanding of the biology of this gene.
Asunto(s)
Epilepsias Parciales , Síndromes Epilépticos , Megalencefalia , Polimicrogiria , Humanos , Mutación , Proteínas Activadoras de GTPasa/genética , Serina-Treonina Quinasas TOR/genética , Epilepsias Parciales/genética , Megalencefalia/genéticaRESUMEN
There is growing clinical interest in addressing relationship dynamics between service-users and their voices. The Talking With Voices (TwV) trial aimed to establish feasibility and acceptability of a novel dialogical intervention to reduce distress associated with voices amongst adults diagnosed with schizophrenia spectrum disorders. The single-site, single-blind (rater) randomised controlled trial recruited 50 participants who were allocated 1:1 to treatment as usual (TAU), or TAU plus up to 26 sessions of TwV therapy. Participants were assessed at baseline and again at end of treatment (six-months). The primary outcomes were quantitative and qualitative assessments of feasibility and acceptability. Secondary outcomes involved clinical measures, including targeted instruments for voice-hearing, dissociation, and emotional distress. The trial achieved 100 % of the target sample, 24 of whom were allocated to therapy and 26 to TAU. The trial had high retention (40/50 [80 %] participants at six-months) and high intervention adherence (21/24 [87.5 %] receiving ≥8 sessions). Signals of efficacy were shown in targeted measures of voice-hearing, dissociation, and perceptions of recovery. Analysis on the Positive and Negative Syndrome Scale indicated that there were no differences in means of general psychosis symptom scores in TwV compared to the control group. There were four serious adverse events in the therapy group and eight in TAU, none of which were related to study proceedings. The trial demonstrates the acceptability of the intervention and the feasibility of delivering it under controlled, randomised conditions. An adequately powered definitive trial is necessary to provide robust evidence regarding efficacy evaluation and cost-effectiveness. Trial registration: ISRCTN 45308981.
Asunto(s)
Intervención Psicosocial , Trastornos Psicóticos , Adulto , Humanos , Estudios de Factibilidad , Método Simple Ciego , Alucinaciones/etiología , Alucinaciones/terapia , Alucinaciones/psicología , Trastornos Psicóticos/complicaciones , Trastornos Psicóticos/terapiaRESUMEN
BACKGROUND: Late diagnosis of HIV remains a challenge, despite improved testing and treatment. Testing is often targeted at high-risk groups; workplace events might normalise testing and allow access to a wider population. The construction workforce has a number of risk factors for HIV. In the Test@Work study, HIV tests were delivered within general health checks to construction employees, with high uptake and acceptability. This paper reports on the experiences of construction managers and health professionals involved in Test@Work and explores the suitability of construction worksites as a venue for opt-in HIV testing. METHODS: Qualitative interviews (n = 24) were conducted with construction managers who had facilitated health check/HIV testing (n = 13), and delivery partners (n = 11) including i) healthcare volunteers who had delivered general health checks (n = 7) and, ii) HIV professionals who had conducted HIV testing (n = 4) at 21 Test@Work events held on construction sites. Interviews explored their experiences of these events and views towards HIV testing in the workplace. Exit questionnaires (n = 107) were completed by delivery partners after every event, providing qualitative data identifying facilitators and barriers to effective delivery. Thematic analysis identified themes that were mapped against a socioecological framework. RESULTS: Delivery partners reported high engagement of construction workers with workplace HIV testing, peer-to-peer encouragement for uptake, and value for accessibility of onsite testing. HIV professionals valued the opportunity to reach an untested population, many of whom had a poor understanding of their exposure to HIV risk. Managers valued the opportunity to offer workplace health checks to employees but some identified challenges with event planning, or provision of private facilities. CONCLUSIONS: The construction sector is complex with a largely male workforce. Providing worksite HIV testing and education to an untested population who have poor knowledge about HIV risk helped to normalise testing, encourage uptake and reduce HIV-related stigma. However, there are practical barriers to testing in the construction environment. Rapid testing may not be the most suitable approach given the challenges of maintaining confidentiality on construction worksites and alternatives should be explored.
Asunto(s)
Infecciones por VIH , Lugar de Trabajo , Infecciones por VIH/diagnóstico , Infecciones por VIH/prevención & control , Prueba de VIH , Personal de Salud , Humanos , Masculino , Estigma SocialRESUMEN
The COVID-19 vaccine is being rolled out globally. High and ongoing public uptake of the vaccine relies on health and social care professionals having the knowledge and confidence to actively and effectively advocate it. An internationally relevant, interactive multimedia training resource called COVID-19 Vaccine Education (CoVE) was developed using ASPIRE methodology. This rigorous six-step process included: (1) establishing the aims, (2) storyboarding and co-design, (3) populating and producing, (4) implementation, (5) release, and (6) mixed-methods evaluation aligned with the New World Kirkpatrick Model. Two synchronous consultations with members of the target audience identified the support need and established the key aim (Step 1: 2 groups: n = 48). Asynchronous storyboarding was used to co-construct the content, ordering, presentation, and interactive elements (Step 2: n = 14). Iterative two-stage peer review was undertaken of content and technical presentation (Step 3: n = 23). The final resource was released in June 2021 (Step 4: >3653 views). Evaluation with health and social care professionals from 26 countries (survey, n = 162; qualitative interviews, n = 15) established that CoVE has high satisfaction, usability, and relevance to the target audience. Engagement with CoVE increased participants' knowledge and confidence relating to vaccine promotion and facilitated vaccine-promoting behaviours and vaccine uptake. The CoVE digital training package is open access and provides a valuable mechanism for supporting health and care professionals in promoting COVID-19 vaccination uptake.
Asunto(s)
COVID-19 , Vacunas , Vacunas contra la COVID-19 , Personal de Salud , Humanos , SARS-CoV-2 , VacunaciónRESUMEN
PURPOSE: To investigate the clinical perspectives and experiences of therapists when engaging in direct dialogue with auditory hallucinations. METHOD: Therapist accounts were explored via a qualitative study nested within a pilot randomized controlled trial of a novel intervention for supporting distressed voice-hearers (Talking with Voices). Five therapists were involved, none of whom had substantive previous experience of the technique. All agreed to take part in two semi-structured, in-depth interviews which were arranged prior to delivering therapy and again after therapists had experience of conducting dialogues. Data were analysed using inductive thematic analysis. RESULTS: Participants described their impressions of seeking to improve the relationship between voice(s) and voice-hearer using dialogue. The findings are organized within three main themes and associated subthemes: (1) Commitment to delivery (professional values, mentorship, professional growth); (2) Communication and collaboration (therapeutic alliance, relationships with voices, managing clinical perceptions); and (3) Challenges of delivery (client/voice engagement, impact of trauma, systemic issues). A series of recommendations are derived from the findings to support implementation and guide the practice of therapists undertaking dialogue work with clients who hear voices. CONCLUSION: Despite clinical challenges, therapists also identified professional gains from conducting their work. Their accounts demonstrate that it is possible for practitioners with no previous formal experience to engage in direct communication with voices within a context of appropriate training and supervision. PRACTITIONER POINTS: Therapists with no previous experience of dialogue work can be trained and supported to verbally engage with the voices heard by people experiencing psychosis. Therapeutic alliance and therapist values are important components of successful therapy. Confidence for dialoguing with voices can be increased through drawing on therapist's existing transferable clinical skills. The emotional and practical needs of therapists undertaking such work should be addressed through training and regular group supervision.
Asunto(s)
Trastornos Psicóticos , Voz , Emociones , Alucinaciones/psicología , Alucinaciones/terapia , Humanos , Trastornos Psicóticos/terapia , Investigación CualitativaRESUMEN
BACKGROUND: Community testing for HIV can reach previously untested populations but is rarely offered in workplaces. Targeting the construction sector could reach workers from high risk populations. METHODS: The RE-AIM framework was used to evaluate Test@Work, a workplace HIV testing intervention for construction workers implemented at 21 events (10 companies) in the UK. Test@Work had three components: 1) an online health toolkit to inform managers about health screening and HIV testing; 2) general health checks; and 3) opt-in HIV consultation and testing. Quantitative data were collected using registration and exit questionnaires with workers (n = 426) and pre/post-event questionnaires with managers (n = 15), with qualitative analysis of free text responses. RESULTS: Reach 426 individuals had health checks. Participants were broadly representative of the UK construction workforce, but with a higher proportion of permanent workers. Most workers reported being in good health but also believed their work had an adverse impact on their health. Effectiveness: 97% of health check participants opted to have a consultation about sexual health (n = 413) and 82% had an HIV test (n = 348), of whom 78% had not previously been tested. All HIV tests were non-reactive. HIV testing at work was considered acceptable by most participants. Participants reported learning new things about their health (74%), said they would make changes as a result (70%) and felt confident of success (median score 8/10). Adoption: Recruitment of companies was challenging and time consuming. Seven of the participating companies were very large, employing over 1000 workers, which is atypical of construction generally. IMPLEMENTATION: All events were completed as planned and were considered successful by all parties. Maintenance: All managers would arrange further events if they were offered them. Six managers incorporated sexual health awareness into their health programmes, but this was not possible for many as health agendas were set centrally by their organisations. CONCLUSIONS: Opt-in HIV testing, when embedded within a general health check, has high uptake and acceptability in the UK construction sector, and reaches individuals at risk for HIV who may not otherwise attend for testing. Cost-effectiveness of this approach is yet to be determined. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04292002 .
Asunto(s)
Infecciones por VIH , Envío de Mensajes de Texto , Infecciones por VIH/diagnóstico , Prueba de VIH , Humanos , Encuestas y Cuestionarios , Lugar de TrabajoRESUMEN
We report new genetic diagnoses of Dravet syndrome in a group of adults with complex epilepsy of unknown cause, under follow-up at a tertiary epilepsy center. Individuals with epilepsy and other features of unknown cause from our unit underwent whole-genome sequencing through the 100 000 Genomes Project. Virtual gene panels were applied to frequency-filtered variants based on phenotype summary. Of 1078 individuals recruited, 8 (0.74%) were identified to have a pathogenic or likely pathogenic variant in SCN1A. Variant types were as follows: nonsense (stopgain) in five (62.5%) and missense in three (37.5%). Detailed review of childhood history confirmed a phenotype compatible with Dravet syndrome. Median age at genetic diagnosis was 44.5 years (range 28-52 years). Tonic-clonic seizures were ongoing in all despite polytherapy including valproate. All had a history of fever sensitivity and myoclonic seizures, which were ongoing in two (25%) and three (37.5%) individuals, respectively. Salient features of Dravet syndrome may be less apparent in adulthood, making clinical diagnosis difficult. Regardless of age, benefits of a genetic diagnosis include access to syndrome-specific treatment options, avoidance of harmful drugs, and monitoring for common complications.
Asunto(s)
Epilepsias Mioclónicas , Espasmos Infantiles , Adulto , Diagnóstico Tardío , Epilepsias Mioclónicas/diagnóstico , Epilepsias Mioclónicas/genética , Humanos , Mutación , Canal de Sodio Activado por Voltaje NAV1.1/genéticaRESUMEN
INTRODUCTION: Vulvodynia is a difficult condition to treat due to both the uncertain etiology of the disorder and poorly available therapies. This difficulty leads to a disproportionately high prevalence and cost of treatment for this condition. Candida vulvovaginitis is a frequent co-present diagnosis in vulvodynia patients. Whether through treatment of co-present, candida vulvovaginitis or by systemic interaction, itraconazole has been proposed as a treatment for vulvodynia. AIM: To describe objective change in vulvodynia pain in a cohort of patients treated with itraconazole. METHODS: This study was a retrospective cohort study comprised of women diagnosed with vulvodynia who were treated with itraconazole between January 1, 2011 and October 17, 2017. Patients had failed fluconazole treatment and had negative fungus cultures for >2 months before itraconazole treatment. All other vulvovaginal disorders were excluded. MAIN OUTCOME MEASURE: The main outcome measure was the change in pain before and after treatment as measured by cotton swab testing. RESULTS: 106 patients met inclusion criteria. Average pain reduction for the entire cohort was 60.7%. Patients who continued itraconazole for 5 to 8 weeks demonstrated a 69.6% reduction in cotton swab test pain. Pain reduction as a percentage of total patients showed complete resolution of pain in 37.7% of patients and >50% reduction in 66.0% of patients. Two-sample paired T-tests for means analysis of pain scores disproved the null hypothesis (P < .01, α = 0.01) and showed a 50% reduction in pain to be significant (P = 0.043, α = 0.05). Two-tailed Wilcoxon signed rank test also demonstrated rejection of the null hypothesis (α = 0.05). CONCLUSIONS: Itraconazole therapy is associated with a significant reduction in vulvovaginal pain in patients with negative fungus cultures and no other identifiable disease in this pilot study. A randomized placebo-controlled trial is warranted. Rothenberger R, Jones W, MacNeill C. Itraconazole Improves Vulvodynia in Fungus Culture-Negative Patients Post Fluconazole Failure. J Sex Med 2021;9:100383.
RESUMEN
OBJECTIVE: The term 'precision medicine' describes a rational treatment strategy tailored to one person that reverses or modifies the disease pathophysiology. In epilepsy, single case and small cohort reports document nascent precision medicine strategies in specific genetic epilepsies. The aim of this multicentre observational study was to investigate the deeper complexity of precision medicine in epilepsy. METHODS: A systematic survey of patients with epilepsy with a molecular genetic diagnosis was conducted in six tertiary epilepsy centres including children and adults. A standardised questionnaire was used for data collection, including genetic findings and impact on clinical and therapeutic management. RESULTS: We included 293 patients with genetic epilepsies, 137 children and 156 adults, 162 females and 131 males. Treatment changes were undertaken because of the genetic findings in 94 patients (32%), including rational precision medicine treatment and/or a treatment change prompted by the genetic diagnosis, but not directly related to known pathophysiological mechanisms. There was a rational precision medicine treatment for 56 patients (19%), and this was tried in 33/56 (59%) and was successful (ie, >50% seizure reduction) in 10/33 (30%) patients. In 73/293 (25%) patients there was a treatment change prompted by the genetic diagnosis, but not directly related to known pathophysiological mechanisms, and this was successful in 24/73 (33%). SIGNIFICANCE: Our survey of clinical practice in specialised epilepsy centres shows high variability of clinical outcomes following the identification of a genetic cause for an epilepsy. Meaningful change in the treatment paradigm after genetic testing is not yet possible for many people with epilepsy. This systematic survey provides an overview of the current application of precision medicine in the epilepsies, and suggests the adoption of a more considered approach.
Asunto(s)
Epilepsia/genética , Medicina de Precisión , Adolescente , Adulto , Anciano , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Persona de Mediana Edad , Técnicas de Diagnóstico Molecular , Estudios Retrospectivos , Adulto JovenRESUMEN
BACKGROUND: When psychosis emerges in young people there is a risk of poorer outcomes, and access to evidence-based treatments is paramount. The current evidence base is limited. Antipsychotic medications show only a small benefit over placebo, but young people experience more side effects than adults. There is sparse evidence for psychological intervention. Research is needed to determine the clinical effectiveness and cost-effectiveness of psychological intervention versus antipsychotic medication versus a combined treatment for adolescents with psychosis. OBJECTIVES: The objective of Managing Adolescent first-episode Psychosis: a feasibility Study (MAPS) was to determine the feasibility of conducting a definitive trial to answer the question of clinical effectiveness and cost-effectiveness of these three treatment options. DESIGN: This was a prospective, randomised, open-blinded, evaluation feasibility trial with a single blind. Participants were allocated 1 : 1 : 1 to receive antipsychotic medication, psychological intervention or a combination of both. A thematic qualitative study explored the acceptability and feasibility of the trial. SETTING: Early intervention in psychosis services and child and adolescent mental health services in Manchester, Oxford, Lancashire, Sussex, Birmingham, Norfolk and Suffolk, and Northumberland, Tyne and Wear. PARTICIPANTS: People aged 14-18 years experiencing a first episode of psychosis either with an International Classification of Diseases, Tenth Revision, schizophrenia spectrum diagnosis or meeting the entry criteria for early intervention in psychosis who had not received antipsychotic medication or psychological intervention within the last 3 months. INTERVENTIONS: Psychological intervention involved up to 26 hours of cognitive-behavioural therapy and six family intervention sessions over 6 months, with up to four booster sessions. Antipsychotic medication was prescribed by the participant's psychiatrist in line with usual practice. Combined treatment was a combination of psychological intervention and antipsychotic medication. MAIN OUTCOME MEASURES: The primary outcome was feasibility (recruitment, treatment adherence and retention). We used a three-stage progression criterion to determine feasibility. Secondary outcomes were psychosis symptoms, recovery, anxiety and depression, social and educational/occupational functioning, drug and alcohol use, health economics, adverse/metabolic side effects and adverse/serious adverse events. RESULTS: We recruited 61 out of 90 (67.8%; amber zone) potential participants (psychological intervention, n = 18; antipsychotic medication, n = 22; combined treatment, n = 21). Retention to follow-up was 51 out of 61 participants (83.6%; green zone). In the psychological intervention arm and the combined treatment arm, 32 out of 39 (82.1%) participants received six or more sessions of cognitive-behavioural therapy (green zone). In the combined treatment arm and the antipsychotic medication arm, 28 out of 43 (65.1%) participants received antipsychotic medication for 6 consecutive weeks (amber zone). There were no serious adverse events related to the trial and one related adverse event. Overall, the number of completed secondary outcome measures, including health economics, was small. LIMITATIONS: Medication adherence was determined by clinician report, which can be biased. The response to secondary outcomes was low, including health economics. The small sample size obtained means that the study lacked statistical power and there will be considerable uncertainty regarding estimates of treatment effects. CONCLUSIONS: It is feasible to conduct a trial comparing psychological intervention with antipsychotic medication and a combination treatment in young people with psychosis with some adaptations to the design, including adaptations to collection of health economic data to determine cost-effectiveness. FUTURE WORK: An adequately powered definitive trial is required to provide robust evidence. TRIAL REGISTRATION: Current Controlled Trials ISRCTN80567433. FUNDING: This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 25, No. 4. See the NIHR Journals Library website for further project information.
Psychosis is a mental health problem that can involve hearing, seeing or believing things that others do not. Although many young people who experience psychosis recover well from their first episode of psychosis, others can have more serious, longer-lasting problems. There has not been a large amount of research into the treatment of psychosis in young people; therefore, it is important to test different treatments against each other in clinical trials. 'Feasibility' trials, such as the one we carried out [Managing Adolescent first-episode Psychosis: a feasibility Study (MAPS)], test whether or not it is possible to run larger trials. MAPS was a small trial that was run in seven locations in the UK. People who were aged 1418 years and experiencing psychosis were able to take part. Each participant was randomly assigned to receive psychological treatment (cognitivebehavioural therapy and optional family therapy), antipsychotic medication or a combination of both. All of the participants met with a trial research assistant three times for assessments about well-being and symptoms. Some clinicians, participants and family members were interviewed about their opinions of the trial and treatments. The trial also had patient and public involvement; service user researchers were involved in design, interview data collection, analysis and report writing. Sixty-one young people took part in MAPS, which was around 68% of our target number. In total, 84% completed the assessments with research assistants. The results showed that, overall, all treatments were acceptable to young people and their family members. However, a higher percentage of young people actually received the 'minimum dose' of psychological treatment than the 'minimum dose' of antipsychotic medication (82% vs. 65%). Results showed that it was possible to run a larger trial such as this. However, some changes would be required to run a larger trial, such as location (focusing on urban areas with well established early intervention in psychosis teams), increasing involvement of psychiatrists and increasing the age limit for participation to 25 years.
Asunto(s)
Antipsicóticos , Trastornos Psicóticos , Adolescente , Antipsicóticos/uso terapéutico , Análisis Costo-Beneficio , Estudios de Factibilidad , Humanos , Estudios Prospectivos , Intervención Psicosocial , Trastornos Psicóticos/tratamiento farmacológico , Método Simple CiegoRESUMEN
Bone dysplasias (osteochondrodysplasias) are a large group of conditions associated with short stature, skeletal disproportion, and radiographic abnormalities of skeletal elements. Nearly all are genetic in origin. We report a series of seven children with similar findings of chondrodysplasia and growth failure following early hematopoietic stem cell transplantation (HSCT) for pediatric non-oncologic disease: hemophagocytic lymphohistiocytosis or HLH (five children, three with biallelic HLH-associated variants [in PRF1 and UNC13D] and one with HLH secondary to visceral Leishmaniasis), one child with severe combined immunodeficiency and one with Omenn syndrome (both children had biallelic RAG1 pathogenic variants). All children had normal growth and no sign of chondrodysplasia at birth and prior to their primary disease. After HSCT, all children developed growth failure, with standard deviation scores for height at or below -3. Radiographically, all children had changes in the spine, metaphyses and epiphyses, compatible with a spondyloepimetaphyseal dysplasia. Genomic sequencing failed to detect pathogenic variants in genes associated with osteochondrodysplasias. We propose that such chondrodysplasia with growth failure is a novel, rare, but clinically important complication following early HSCT for non-oncologic pediatric diseases. The pathogenesis is unknown but could possibly involve loss or perturbation of the cartilage-bone stem cell population.