The positive regulatory (PR) domain containing 13 (PRDM13) putative chromatin modifier and transcriptional regulator functions downstream of the transcription factor PTF1A, which controls GABAergic ...fate in the spinal cord and neurogenesis in the hypothalamus. Here, we report a recessive syndrome associated with PRDM13 mutation. Patients exhibited intellectual disability, ataxia with cerebellar hypoplasia, scoliosis, and delayed puberty with congenital hypogonadotropic hypogonadism (CHH). Expression studies revealed Prdm13/PRDM13 transcripts in the developing hypothalamus and cerebellum in mouse and human. An analysis of hypothalamus and cerebellum development in mice homozygous for a Prdm13 mutant allele revealed a significant reduction in the number of Kisspeptin (Kiss1) neurons in the hypothalamus and PAX2+ progenitors emerging from the cerebellar ventricular zone. The latter was accompanied by ectopic expression of the glutamatergic lineage marker TLX3. Prdm13-deficient mice displayed cerebellar hypoplasia and normal gonadal structure, but delayed pubertal onset. Together, these findings identify PRDM13 as a critical regulator of GABAergic cell fate in the cerebellum and of hypothalamic kisspeptin neuron development, providing a mechanistic explanation for the cooccurrence of CHH and cerebellar hypoplasia in this syndrome. To our knowledge, this is the first evidence linking disrupted PRDM13-mediated regulation of Kiss1 neurons to CHH in humans.
Adenosine deaminases acting on RNA (ADARs) catalyze the hydrolytic deamination of adenosine to inosine in double-stranded RNA (dsRNA) and thereby potentially alter the information content and ...structure of cellular RNAs. Notably, although the overwhelming majority of such editing events occur in transcripts derived from Alu repeat elements, the biological function of non-coding RNA editing remains uncertain. Here, we show that mutations in ADAR1 (also known as ADAR) cause the autoimmune disorder Aicardi-Goutières syndrome (AGS). As in Adar1-null mice, the human disease state is associated with upregulation of interferon-stimulated genes, indicating a possible role for ADAR1 as a suppressor of type I interferon signaling. Considering recent insights derived from the study of other AGS-related proteins, we speculate that ADAR1 may limit the cytoplasmic accumulation of the dsRNA generated from genomic repetitive elements.
Objectives The Newcastle 85+ Study aims to systematically study the clinical, biological, and psychosocial attributes of an unselected cohort of 85 year olds and to examine subsequent health ...trajectories as the cohort ages; health at baseline is reported.Design Cross sectional analysis of baseline data from a cohort study.Setting Newcastle upon Tyne and North Tyneside primary care trusts, United Kingdom.Participants 1042 people born in 1921 and registered with the participating general practices.Main outcome measures Detailed health assessment and review of general practice records (disease, medication, and use of general practice services); participants could decline elements of the protocol. Results Of the 1453 eligible people, 851 (58.6%) were recruited to health assessment plus record review, 188 (12.9%) to record review only, and 3 (0.2%) to health assessment only. Data from record review are reported on a maximum of 1030 and from health assessment on a maximum of 853; individual denominators differ owing to withdrawal and missing values. Of the health assessment sample (n=853), 62.1% (n=530) were women and 10.4% (n=89) were in institutional care. The most prevalent diseases were hypertension (57.5%, 592/1030) and osteoarthritis (51.8%, 534/1030). Moderate or severe cognitive impairment was present in 11.7% (96/824) of participants, severe or profound urinary incontinence in 21.3% (173/813), hearing impairment in 59.6% (505/848), and visual impairment in 37.2% (309/831). Health assessment identified participants with possible disease but without a previous diagnosis in their medical record for hypertension (25.1%, 206/821), ischaemic heart disease (12.6%, 99/788), depression (6.9%, 53/772), dementia (6.7%, 56/840), and atrial fibrillation (3.8%, 30/788). Undiagnosed diabetes mellitus and thyroid disease were rare (1%, 7/717 and 6/762, respectively). A median of 3 (interquartile range 1-8) activities of daily living were undertaken with difficulty. Overall, 77.6% (646/832) of participants rated their health compared with others of the same age as good, very good, or excellent. High contact rates in the previous year with general practitioners (93.8%, 960/1024) were recorded. Women had significantly higher disease counts (medians: women 5, men 4; P=0.033) and disability scores (medians: women 4, men 2; P=0.0006) than men, but were less likely to have attended outpatient clinics in the previous three months (women 29% (150/524), men 37% (118/320), odds ratio 0.7, 95% confidence interval 0.5 to 0.9).Conclusions This large cohort of 85 year olds showed good levels of both self rated health and functional ability despite significant levels of disease and impairment. Hypertension, ischaemic heart disease, atrial fibrillation, depression, and dementia may be underdiagnosed. Notable differences were found between the sexes: women outnumbered men and had more disease and disability.
People with dementia (PwD) face unique challenges with medicines management, yet little is known about these challenges from the perspectives of primary healthcare professionals, particularly general ...practitioners (GPs) and community pharmacists. Few medicines management interventions have been developed which are aimed at community-dwelling PwD. This study sought to develop an intervention to improve medicines management for PwD in primary care using a theory-informed approach.
Semi-structured interviews were conducted with GPs (n = 15) and community pharmacists (n = 15) to explore participants' views and experiences of medicines management for PwD, and their perceptions of barriers and facilitators to successful medicines management for PwD. The 14-domain Theoretical Domains Framework was the underpinning theoretical guide, allowing key theoretical domains to be identified and mapped to behaviour change techniques (BCTs) which are considered the 'active ingredients' of an intervention. Draft interventions were developed to operationalise selected BCTs and were presented to GPs and community pharmacists during task groups. Final selection of an intervention for feasibility testing was guided by feedback provided during these task groups and through application of the APEASE (Affordability, Practicability, Effectiveness/cost-effectiveness, Acceptability, Side-effects/safety, Equity) criteria.
Participants expressed a number of concerns about medicines management for PwD, particularly monitoring adherence to medication regimens and conducting medication review. Two draft interventions comprising selected BCTs ('Modelling or demonstration of behaviour'; 'Salience of consequences'; 'Health consequences'; 'Social and environmental consequences'; 'Action planning'; Social support or encouragement', 'Self-monitoring of behaviour') were developed, each targeting GPs and community pharmacists. Following the task groups and discussions within the research team, the community pharmacy-based intervention was selected for future feasibility testing. The intervention will target community pharmacists to conduct a medication review (incorporating an adherence check) with a PwD, delivered as an online video demonstrating key behaviours. The video will include feedback emphasising positive outcomes of performing the behaviours. Action planning and a quick reference guide will be used as complementary intervention components.
A community pharmacist-based intervention has been developed targeting medicines management for PwD in primary care using a systematic, theory-informed approach. Future work will determine the usability and acceptability of implementing this intervention in clinical practice.
Deep-sea corals are important benthic inhabitants that support the biodiversity and function of the wider faunal community; however, their taxonomy is underdeveloped and their accurate identification ...is often difficult. In our study, we investigated the utility of a superextended (>3000 bp) barcode and explored the effectiveness of various molecular species delimitation techniques with an aim to put upper and lower bounds on the estimated number of calcaxonian species in Irish waters. We collected 112 calcaxonians (70 Keratoisididae, 22 Primnoidae, 20 Chrysogorgiidae) and one chelidonisid from the Irish continental slope and sequenced a 3390 bp DNA barcode comprising four mitochondrial regions (mtMutS, COI + igr1, 16S rRNA-ND2, and igr4), recovering 38 haplotypes. Individuals that shared a haplotype were often morphologically distinct, and we thus undertook detailed morphological work, including SEM of sclerites, on one representative of each morphotype within each haplotype. GMYC, bGMYC, and mPTP returned incongruent estimates of species numbers. In total, there are between 25 and 40 species, although no definitive number could be assigned, primarily due to poorly defined keratoisidid species boundaries. As expected, the superextended barcode provided greater discrimination power than single markers; bGMYC appeared to be the most effective delimiter. Among the identified species were Chelidonisis aurantiaca, collected deeper than previously known at 1507 m, and Calyptrophora clinata, recorded for the second time from the Northeast Atlantic. A full understanding of the diversity and distribution of calcaxonians requires substantial taxonomic work, but we highlight the Irish continental slope as harbouring significant diversity.
Immunosenescence, a decline in immune system function, has been linked to several age-related diseases and ageing syndromes. Very old adults (aged ≥ 85 years) live with multiple long-term conditions ...(MLTC, also known as multimorbidity)—a complex phenomenon of poor health defined by either counts, indices, or patterns, but little is known about the relationship between an ageing immune system and MLTC in this age group. We utilised baseline data from the Newcastle 85+ Study to investigate the associations between previously defined immunosenescence profiles of lymphocyte compartments and MLTC counts and patterns (from 16 chronic diseases/ageing syndromes). Seven hundred and three participants had MLTC and complete data for all 16 conditions, a median and mean of 5 (range 2–11) and 62.2% had ≥ 5 conditions. Three distinct MLTC patterns emerged by clustering: Cluster 1 (‘Low frequency cardiometabolic-cerebrovascular diseases’, n = 209), Cluster 2 (‘High ageing syndromes-arthritis’, n = 240), and Cluster 3 (‘Hypertensive-renal impairment’, n = 254). Although having a more senescent phenotype, characterised by higher frequency of CD4 and CD8 senescence-like effector memory cells and lower CD4/CD8 ratio, was not associated with MLTC compared with less senescent phenotype, the results warrant further investigation, including whether immunosenescence drives change in MLTC and influences MLTC severity in late adulthood.
•Having ≥ 5 multiple long-term conditions (MLTC) was common in very old adults.•MLTC were defined by counts and clusters of 16 conditions.•Immunosenescence profiles were defined by clustering of 13 senescence biomarkers.•‘Senescence phenotype’ had T-cell senescence and elements of immune risk profile.•The role of immunosenescence in lymphocytes in MLTC warrants further investigation.
Admissions to intensive treatment (i.e., inpatient IP and/or day patient DP) for individuals with severe anorexia nervosa (AN) are common. Growing literature indicates potential risks and benefits of ...each intensive treatment approach; however, existing research has focused on patient and carer perspectives of these treatments. Also, there is scant empirical evidence available for guiding the parameters of intensive treatments for AN. We therefore explored clinicians' perspectives and experience of supporting adults with severe AN in intensive settings.
We conducted twenty one semi-structured interviews with clinicians who deliver intensive treatments (i.e., IP and/or DP) for individuals with severe AN across four specialist Eating Disorder Services in the United Kingdom between May 2020 and June 2021. We asked clinicians about their views and experiences of supporting individuals with severe AN in intensive treatment settings and the challenges and opportunities associated with IP and DP treatment. Data were analysed using reflexive thematic analysis supported by NVivo software.
Five broad and interrelated themes were identified: (1) Intensive Support; (2) The Severity of Patients' Illnesses; (3) Hope and Recovery; (4) Which Treatment When; (5) Limited Resources; and (6) Carer Burden. We identified various similarities between the two intensive treatment approaches, including the value of intensive and multidisciplinary support and carer involvement, and the challenge of managing complex and unique needs in resource-limited intensive settings. We also found differences in the relationship of treatment to patients' home environments, the necessity of patient motivation, and the management of risk.
Both intensive treatment settings are valued by clinicians; however, there are unique challenges and opportunities for supporting individuals with severe AN within each. Our findings suggest DP treatment may be used as an alternative to IP treatment for individuals with severe AN. However, clear questions remain over which intensive treatment setting is best suited to which patient when and should be the focus of future research.
Telecare could greatly facilitate chronic disease management in the community, but despite government promotion and positive demonstrations its implementation has been limited. This study aimed to ...identify factors inhibiting the implementation and integration of telecare systems for chronic disease management in the community.
Large scale comparative study employing qualitative data collection techniques: semi-structured interviews with key informants, task-groups, and workshops; framework analysis of qualitative data informed by Normalization Process Theory. Drawn from telecare services in community and domestic settings in England and Scotland, 221 participants were included, consisting of health professionals and managers; patients and carers; social care professionals and managers; and service suppliers and manufacturers.
Key barriers to telecare integration were uncertainties about coherent and sustainable service and business models; lack of coordination across social and primary care boundaries, lack of financial or other incentives to include telecare within primary care services; a lack of a sense of continuity with previous service provision and self-care work undertaken by patients; and general uncertainty about the adequacy of telecare systems. These problems led to poor integration of policy and practice.
Telecare services may offer a cost effective and safe form of care for some people living with chronic illness. Slow and uneven implementation and integration do not stem from problems of adoption. They result from incomplete understanding of the role of telecare systems and subsequent adaption and embeddedness to context, and uncertainties about the best way to develop, coordinate, and sustain services that assist with chronic disease management. Interventions are therefore needed that (i) reduce uncertainty about the ownership of implementation processes and that lock together health and social care agencies; and (ii) ensure user centred rather than biomedical/service-centred models of care.
Abstract
Background
Anorexia nervosa (AN) is a serious and disabling mental disorder with a high disease burden. In a proportion of cases, intensive hospital-based treatments, i.e. inpatient or day ...patient treatment, are required, with day patient treatment often being used as a ‘step-down’ treatment after a period of inpatient treatment. Demand for such treatment approaches has seen a sharp rise. Despite this, the relative merits of these approaches for patients, their families, and the NHS and wider society are relatively unknown. This paper describes the rationale for, and protocol of, a two-arm multi-centre open-label parallel group non-inferiority randomised controlled trial, evaluating the effectiveness and cost-effectiveness of these two intensive treatments for adults with severe AN: inpatient treatment as usual and a stepped care day patient approach (the combination of day patient treatment with the option of initial inpatient treatment for medical stabilisation). The main aim of this trial is to establish whether, in adults with severe AN, a stepped care day patient approach is non-inferior to inpatient treatment as usual in relation to improving body mass index (BMI) at 12 months post-randomisation.
Methods
386 patients with a Diagnostic and Statistical Manual 5th edition diagnosis of severe AN or related disorder, with a BMI of ≤16 kg/m
2
and in need of intensive treatment will be randomly allocated to either inpatient treatment as usual or a stepped care day patient approach. Patients in both groups will receive treatment until they reach a healthy weight or get as close to this point as possible. Assessments will be conducted at baseline (prior to randomisation), and at 6 and 12 months post-randomisation, with additional monthly symptom monitoring. The primary outcome will be BMI at the 12-month post-randomisation assessment. Other outcomes will include psychosocial adjustment; treatment motivation, expectations and experiences; cost-effectiveness; and carer burden.
Discussion
The results of this study will provide a rigorous evaluation of two intensive treatment approaches which will inform future national and international treatment guidelines and service provision.
Trial registration
ISRCTN ISRCTN10166784. Registered 28 February 2020. ISRCTN is a primary registry of the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) network and includes all items from the WHO Trial Registration Data Set.
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