Publications by authors named "John Dean"

191 Publications

A Novel Boot Camp Program to Help Guide Personalized Exercise in People with Parkinson Disease.

J Pers Med 2021 Sep 20;11(9). Epub 2021 Sep 20.

Grupo de Patologia Médica, Nutrição e Exercício Clínico (PaMNEC)-Centro de Investigação Interdisciplinar Egas Moniz (CiiEM), Escola Superior de Saúde Egas Moniz, Caparica, 2829-511 Almada, Portugal.

Given the variety of exercise programs available for people with Parkinson's disease (PD), such individuals may struggle to make decisions about what exercise to perform. The objective of this study was to assess the usefulness, satisfaction, and preferences regarding participation in a PD-personalized educational and exercise boot camp program. Attendees participated in a four-day program consisting of exercise sessions, workshops, and social activities. We collected demographic and clinical information. We assessed satisfaction and preferences immediately after. At one-month follow-up, participants assessed usefulness and changes in exercise habits. Eight individuals diagnosed with PD, with a mean age of 59.5 ± 6.8 years, participated. All participants felt "very satisfied" and likely to attend future events. The two favorite sessions were: cognitive stepping and dance-based movements. At one-month follow-up, participants considered the program "very useful" and reported changes in their exercise routine. Our results suggest that the boot camp program was considered useful and capable of influencing participants' exercise habits.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/jpm11090938DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8467248PMC
September 2021

Expanding the phenotype of ASXL3-related syndrome: A comprehensive description of 45 unpublished individuals with inherited and de novo pathogenic variants in ASXL3.

Am J Med Genet A 2021 Nov 26;185(11):3446-3458. Epub 2021 Aug 26.

Neurology Clinic, Department of Medicine, Santa Maria della Misericordia Hospital, University of Perugia, Perugia, Italy.

The study aimed at widening the clinical and genetic spectrum of ASXL3-related syndrome, a neurodevelopmental disorder, caused by truncating variants in the ASXL3 gene. In this international collaborative study, we have undertaken a detailed clinical and molecular analysis of 45 previously unpublished individuals with ASXL3-related syndrome, as well as a review of all previously published individuals. We have reviewed the rather limited functional characterization of pathogenic variants in ASXL3 and discuss current understanding of the consequences of the different ASXL3 variants. In this comprehensive analysis of ASXL3-related syndrome, we define its natural history and clinical evolution occurring with age. We report familial ASXL3 pathogenic variants, characterize the phenotype in mildly affected individuals and discuss nonpenetrance. We also discuss the role of missense variants in ASXL3. We delineate a variable but consistent phenotype. The most characteristic features are neurodevelopmental delay with consistently limited speech, significant neuro-behavioral issues, hypotonia, and feeding difficulties. Distinctive features include downslanting palpebral fissures, hypertelorism, tubular nose with a prominent nasal bridge, and low-hanging columella. The presented data will inform clinical management of individuals with ASXL3-related syndrome and improve interpretation of new ASXL3 sequence variants.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.a.62465DOI Listing
November 2021

Impact of pharmacist involvement on medication safety in interprofessional transfer of care activity.

N Z Med J 2021 Jul 30;134(1539):9-20. Epub 2021 Jul 30.

Associate Dean Medical Education, University of Otago, Christchurch, Specialist Respiratory Physician, Canterbury District Health Board.

Aim: Any transition of patient care is a high-risk time for communication error. This paper explores whether the presence of a pharmacist as part of an interprofessional group provides additional benefit and safety in transitions of care.

Method: Six pharmacy interns and newly qualified pharmacists joined participants from seven other health professional training programmes to take part in an interprofessional education activity. Participants were assigned to 24 mixed-professional groups. Each group was required to craft a discharge summary for the same simulated patient. Groups without a pharmacist were given additional written documentation, including medication reconciliation, discharge prescription and discharge recommendations. The 24 discharge summaries were assessed for any medication-related information, both positive and negative. Groups with a pharmacist (6) were compared with groups who did not have a pharmacist (18) for completeness and accuracy of medication management.

Results: An in-person pharmacist provided more thorough, comprehensive, accessible and accurate information for the community team (p=0.003). Although there was no difference in the absolute number of medication errors between the groups (p=0.057), the groups with a pharmacist showed a significant reduction in the severity of the errors (p=0.009). This result happened despite the groups without a pharmacist being provided with all the required medication information for safe transition of care.

Conclusion: These findings support the case for greater involvement from a pharmacist in a patient's healthcare team, particularly for any transition of care. Healthcare teams that include a pharmacist are more likely to exceed minimum safety expectations and make less severe errors.
View Article and Find Full Text PDF

Download full-text PDF

Source
July 2021

Peroxisomes as cellular adaptors to metabolic and environmental stress.

Trends Cell Biol 2021 08 2;31(8):656-670. Epub 2021 Mar 2.

Division of Endocrinology, Metabolism and Lipid Research, Department of Medicine, Washington University School of Medicine, St Louis, MO 63110, USA. Electronic address:

Peroxisomes are involved in multiple metabolic processes, including fatty acid oxidation, ether lipid synthesis, and reactive oxygen species (ROS) metabolism. Recent studies suggest that peroxisomes are critical mediators of cellular responses to various forms of stress, including oxidative stress, hypoxia, starvation, cold exposure, and noise. As dynamic organelles, peroxisomes can modulate their proliferation, morphology, and movement within cells, and engage in crosstalk with other organelles in response to external cues. Although peroxisome-derived hydrogen peroxide has a key role in cellular signaling related to stress, emerging studies suggest that other products of peroxisomal metabolism, such as acetyl-CoA and ether lipids, are also important for metabolic adaptation to stress. Here, we review molecular mechanisms through which peroxisomes regulate metabolic and environmental stress.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.tcb.2021.02.005DOI Listing
August 2021

Paper Microfluidic Device with a Horizontal Motion Valve and a Localized Delay for Automatic Control of a Multistep Assay.

Anal Chem 2021 03 4;93(10):4497-4505. Epub 2021 Mar 4.

Department of Biomedical Engineering, Texas A&M University, 400 Bizzell St, College Station, Texas 77843, United States.

A microfluidic paper-based analytical device (μPAD) is a cost-effective platform to implement assays, especially for point-of-care testing. Developing μPADs with fluidic control is important to implement multistep assays and provide high sensitivities. However, current localized delays in μPADs made of sucrose have a limited ability to decrease the flow rate. In addition, existing μPADs for automatic multistep assays are limited by their need for auxiliary instruments, their false activation, or their unavoidable tradeoff between available fluid volumes and temporal differences between steps. Here, a novel μPAD composed of a localized dissolvable delay and a horizontal motion mechanical valve for use as an automatic multistep assay is reported. A mixture of fructose and sucrose was used in the localized dissolvable delay and it provided an effective decrease in the flow rate to ensure adequate sensitivity in an assay. The dissolvable delay effectively doubled the flow time. A mechanical valve using a horizontal movement was developed to automatically implement a multistep process. Two-step and four-step processes were enabled with the μPAD. Cardiac troponin I (cTnI), a gold-standard biomarker for myocardial infarction, was used as a model analyte to show the performance of the developed μPAD in an assay. The designed μPAD, with the simple-to-make localized dissolvable delay and the robust mechanical valve, provides the potential to automatically implement high-performance multistep assays toward a versatile platform for point-of-care diagnostics.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1021/acs.analchem.0c04706DOI Listing
March 2021

Systems approach to health service design, delivery and improvement: a systematic review and meta-analysis.

BMJ Open 2021 01 19;11(1):e037667. Epub 2021 Jan 19.

Department of Engineering, University of Cambridge, Cambridge, Cambridgeshire, UK.

Objectives: To systematically review the evidence base for a systems approach to healthcare design, delivery or improvement.

Design: Systematic review with meta-analyses.

Methods: Included were studies in any patients, in any healthcare setting where a systems approach was compared with usual care which reported quantitative results for any outcomes for both groups. We searched Medline, Embase, HMIC, Health Business Elite, Web of Science, Scopus, PsycINFO and CINAHL from inception to 28 May 2019 for relevant studies. These were screened, and data extracted independently and in duplicate. Study outcomes were stratified by study design and whether they reported patient and/or service outcomes. Meta-analysis was conducted with Revman software V.5.3 using ORs-heterogeneity was assessed using I statistics.

Results: Of 11 405 records 35 studies were included, of which 28 (80%) were before-and-after design only, five were both before-and-after and concurrent design, and two were randomised controlled trials (RCTs). There was heterogeneity of interventions and wide variation in reported outcome types. Almost all results showed health improvement where systems approaches were used. Study quality varied widely. Exploratory meta-analysis of these suggested favourable effects on both patient outcomes (n=14, OR=0.52 (95% CI 0.38 to 0.71) I=91%), and service outcomes (n=18, OR=0.40 (95% CI 0.31 to 0.52) I=97%).

Conclusions: This study suggests that a systems approaches to healthcare design and delivery results in a statistically significant improvement to both patient and service outcomes. However, better quality studies, particularly RCTs are needed.CRD42017065920.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/bmjopen-2020-037667DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7817809PMC
January 2021

Histone H3.3 beyond cancer: Germline mutations in cause a previously unidentified neurodegenerative disorder in 46 patients.

Sci Adv 2020 Dec 2;6(49). Epub 2020 Dec 2.

Institut für Neurogenomik, Helmholtz Zentrum München, Munich, Germany.

Although somatic mutations in Histone 3.3 (H3.3) are well-studied drivers of oncogenesis, the role of germline mutations remains unreported. We analyze 46 patients bearing de novo germline mutations in histone 3 family 3A () or with progressive neurologic dysfunction and congenital anomalies without malignancies. Molecular modeling of all 37 variants demonstrated clear disruptions in interactions with DNA, other histones, and histone chaperone proteins. Patient histone posttranslational modifications (PTMs) analysis revealed notably aberrant local PTM patterns distinct from the somatic lysine mutations that cause global PTM dysregulation. RNA sequencing on patient cells demonstrated up-regulated gene expression related to mitosis and cell division, and cellular assays confirmed an increased proliferative capacity. A zebrafish model showed craniofacial anomalies and a defect in Foxd3-derived glia. These data suggest that the mechanism of germline mutations are distinct from cancer-associated somatic histone mutations but may converge on control of cell proliferation.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1126/sciadv.abc9207DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7821880PMC
December 2020

Deletion of Exon 1 in in Osteopathia Striata with Cranial Sclerosis.

Genes (Basel) 2020 11 30;11(12). Epub 2020 Nov 30.

Department of Women's and Children's Health, Dunedin School of Medicine, University of Otago, Dunedin 9016, New Zealand.

Osteopathia striata with cranial sclerosis (OSCS) is an X-linked dominant condition characterised by metaphyseal striations, macrocephaly, cleft palate, and developmental delay in affected females. Males have a more severe phenotype with multi-organ malformations, and rarely survive. To date, only frameshift and nonsense variants in exon 2, the single coding exon of , or whole gene deletions have been reported to cause OSCS. In this study, we describe two families with phenotypic features typical of OSCS. Exome sequencing and multiplex ligation-dependent probe amplification (MLPA) did not identify pathogenic variants in . Therefore, genome sequencing was employed which identified two deletions containing the non-coding exon 1 of in the families. These families highlight the importance of considering variants or deletions of upstream non-coding exons in conditions such as OSCS, noting that often such exons are not captured on probe or enrichment-based platforms because of their high G/C content.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3390/genes11121439DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7760256PMC
November 2020

Opium Alkaloids in Harvested and Thermally Processed Poppy Seeds.

Front Chem 2020 27;8:737. Epub 2020 Aug 27.

Department of Applied Sciences, Northumbria University, Newcastle upon Tyne, United Kingdom.

The opium alkaloids (morphine, codeine, thebaine, noscapine, and papaverine) have been detected on poppy seeds; they are widely used by the food industry for decoration and flavor but can introduce opium alkaloids into the food chain. Of the opium alkaloids found on poppy seeds, morphine, and codeine are the most pharmacologically active and have been detected in biological matrices collected in workplace and roadside drug testing resulting in positive opiate results. The European Food Safety Authority introduced an acute reference dose of 10 μg morphine/kg of body weight as a safe level for morphine in food products. In this work, it was found that in harvested poppy seeds, and thermally processed poppy seeds (with and without a food matrix), if used in normal levels would not exceed the recommended acute reference dose. It was also shown that the levels of all alkaloids reduce when thermally processed, in comparison with harvested, untreated seeds.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.3389/fchem.2020.00737DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7482649PMC
August 2020

Improving care planning and communication for frail older persons across the primary-secondary care interface.

Future Healthc J 2020 Oct;7(3):e23-e26

East Lancashire Hospitals NHS Trust, Blackburn, UK.

Collaboration between general practitioners (GPs) and geriatricians should be at the forefront of the design and delivery of the care of frail older people. Primary care teams require high-quality, relevant and timely communication around assessment and care plans when patients return home from secondary care settings. The aim of this project was to develop effective handover communication between the frailty team and primary care for patients assessed and transferred home from an emergency department. The 'frailty letter to the GP' was designed, tested and adapted to accomplish this aim. This involved two PDSA (plan, do, study, act) cycles through which the letter was tested and adapted. Our measure of improvement was GPs' satisfaction with the letter with regards to its usefulness. Based on feedback, the letter was edited to reflect what the GPs needed in order to continue their patients' care. Joint planning with the clinical commissioning group GP leads, as well as the trust's transformation lead, was crucial to the final design of the letter that was well received by the GP colleagues. Local departments should examine current communication mechanisms for these patients, and, if found lacking, work collaboratively to improve these while also tracking relevant clinical outcomes.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7861/fhj.2019-0052DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7571748PMC
October 2020

MED19 Regulates Adipogenesis and Maintenance of White Adipose Tissue Mass by Mediating PPARγ-Dependent Gene Expression.

Cell Rep 2020 10;33(1):108228

Division of Endocrinology, Metabolism and Lipid Research, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address:

The Mediator complex relays regulatory signals from gene-specific transcription factors to the basal transcriptional machinery. However, the role of individual Mediator subunits in different tissues remains unclear. Here, we demonstrate that MED19 is essential for adipogenesis and maintenance of white adipose tissue (WAT) by mediating peroxisome proliferator-activated receptor gamma (PPARγ) transcriptional activity. MED19 knockdown blocks white adipogenesis, but not brown adipogenesis or C2C12 myoblast differentiation. Adipose-specific MED19 knockout (KO) in mice results in a striking loss of WAT, whitening of brown fat, hepatic steatosis, and insulin resistance. Inducible adipose-specific MED19 KO in adult animals also results in lipodystrophy, demonstrating its requirement for WAT maintenance. Global gene expression analysis reveals induction of genes involved in apoptosis and inflammation and impaired expression of adipose-specific genes, resulting from decreased PPARγ residency on adipocyte gene promoters and reduced association of PPARγ with RNA polymerase II. These results identify MED19 as a crucial facilitator of PPARγ-mediated gene expression in adipose tissue.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.celrep.2020.108228DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7561447PMC
October 2020

Salivary anti-SARS-CoV-2 IgA as an accessible biomarker of mucosal immunity against COVID-19.

medRxiv 2020 Aug 11. Epub 2020 Aug 11.

Background: Mucosal immunity, including secretory IgA (sIgA), plays an important role in early defenses against respiratory pathogens. Salivary testing, the most convenient way to measure sIgA, has been used to characterize mucosal immune responses to many viral infections including SARS, MERS, influenza, HIV, and RSV. However, its role has not yet been characterized in the COVID-19 pandemic. Here, we report development and validation of a rapid immunoassay for measuring salivary IgA against the SARS-CoV-2 virus, and report quantitative results in both pre-COVID-19 and muco-converted subjects.

Methods: We developed and refined a specific test for salivary IgA against SARS-CoV-2 on the Brevitest platform, a rapid immunoassay system designed for point-of-care use. A qualitative test was validated as per FDA guidelines with saliva obtained from subjects prior to the emergence of COVID-19, and from PCR-confirmed COVID-19 patients. We also generated a quantitative measure of anti-SARS-CoV-2 salivary IgA. Time taken for saliva self-collection was measured and its ease-of-use assessed.

Results: We successfully validated a qualitative salivary assay for SARS-CoV-2 IgA antibodies, with positive and negative predictive values of 92% and 97%, respectively, and no observable cross-reactivity with any of seven potential confounders. Pre-COVID-19 saliva samples showed an 8-fold range of IgA concentrations, suggesting a broad continuum of natural antibody resistance against the novel virus, though at levels lower than that observed in COVID-19 PCR-confirmed subjects. Samples from muco-positive subjects also shown a ~9-fold variation in salivary IgA levels, with elevated salivary IgA observed beyond three months after onset of symptoms. We observed a correlation (r=0.4405) between salivary IgA levels and COVID-19 disease severity. In anecdotal observations, we observed individuals who exhibited antibodies early in the course of their disease, contemporaneously with a positive PCR test, as well as individuals who muco-converted despite no known direct exposure to a COVID-19 patient, no symptoms, and negative molecular and/or serum antibody tests. Salivary collection took 5-10 minutes, and was reported as being easy (mean of 1.1 on a scale of 1 to 10).

Implications: Mucosal immunity, including secretory IgA, plays an important role in host defense against respiratory pathogens, and our early data suggest it may do so in COVID-19. Salivary IgA, an accessible marker of mucosal immunity, may be a useful indicator of several key parameters including individual and community immune response, disease severity, clinical risk, and herd immunity. The non-invasive nature and ease of saliva collection facilitates its potential use as a biomarker for ongoing patient assessment and management, as well as a community surveillance tool. By measuring mucosal immune responses directly and systemic immune responses indirectly, salivary IgA could be useful in developing and deploying a vaccine(s) against COVID-19. Quantitative IgA assessment could also potentially serve as a tool to segment the population into different risk categories and inform individual and collective decisions relating to appropriate activities and vaccine prioritization/delivery. These data reinforce the importance of further investigation into the role of mucosal immunity and IgA in host responses against COVID-19.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1101/2020.08.07.20170258DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7430621PMC
August 2020

The occurrence and distribution of polycyclic aromatic hydrocarbons, bisphenol A and organophosphate flame retardants in indoor dust and soils from public open spaces: Implications for human exposure.

Environ Pollut 2020 Nov 13;266(Pt 1):115372. Epub 2020 Aug 13.

Department of Applied Sciences, Northumbria University, Newcastle Upon Tyne, NE1 8ST, UK. Electronic address:

Global concern exists regarding human exposure to organic pollutants derived from public open spaces and indoor dust. This study has evaluated the occurrence of 18 polycyclic aromatic hydrocarbons (PAHs), 11 organophosphorus flame retardants (OPFRs) and bisphenol A (BPA). To achieve this, a new simple, efficient and fast multi-residue analytical method based on a fully automated pressurised liquid extraction (PLE) and subsequent quantification by gas chromatography coupled to electron ionization-mass spectrometry (GC-EI-MS) in selected ion monitoring (SIM) mode was developed. The developed method was applied to indoor dust (12 sampling households) and soil derived from two public open spaces (POSs). Among all compounds studied, PAHs were the most ubiquitous contaminants detected in POS soils and indoor dust although some OPFRs and BPA were detected in lower concentrations. An assessment of the incremental lifetime cancer risk (ILCR) was done and indicated a high potential cancer risk from the POS sites and some of the indoor dust sampled sites. However, key variables, such as the actual exposure duration, frequency of contact and indoor cleaning protocols will significantly reduce the potential risk. Finally, the ingestion of soils and indoor dust contaminated with OPFRs and BPA was investigated and noted in almost all cases to be below the USEPA reference doses.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.envpol.2020.115372DOI Listing
November 2020

Hepatic peroxisomal β-oxidation suppresses lipophagy via RPTOR acetylation and MTOR activation.

Autophagy 2020 09 27;16(9):1727-1728. Epub 2020 Jul 27.

Division of Endocrinology, Metabolism and Lipid Research, Department of Medicine, Washington University School of Medicine , St. Louis, MO, USA.

Hepatic lipid homeostasis is controlled by a coordinated regulation of various metabolic pathways involved in de novo synthesis, uptake, storage, and catabolism of lipids. Disruption of this balance could lead to hepatic steatosis. Peroxisomes play an essential role in lipid metabolism, yet their importance is often overlooked. In a recent study, we demonstrated a role for hepatic peroxisomal β-oxidation in autophagic degradation of lipid droplets. ACOX1 (acyl-Coenzyme A oxidase 1, palmitoyl), the rate-limiting enzyme of peroxisomal β-oxidation, increases with fasting or high-fat diet (HFD). Liver-specific knockout (-LKO) protects mice from hepatic steatosis induced by starvation or HFD via induction of lipophagy. Mechanistically, we showed that hepatic ACOX1 deficiency decreases the total cytosolic acetyl-CoA levels, which leads to reduced acetylation of RPTOR/RAPTOR, a component of MTORC1, which is a key regulator of macroautophagy/autophagy. These results identify peroxisome-derived acetyl-CoA as a critical metabolic regulator of autophagy that controls hepatic lipid homeostasis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1080/15548627.2020.1797288DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8386617PMC
September 2020

A critical evaluation of the use and 'misuse' of As and Pb bioaccessibility data in human health risk assessments.

Environ Res 2020 10 11;189:109915. Epub 2020 Jul 11.

Department of Geography and Environmental Sciences, Northumbria University, Ellison Building, Newcastle Upon Tyne, NE1 8ST, UK.

With the now widescale reporting of oral bioaccessibility data at contaminated sites, following our investigation of three sites (one public open space and two residential) for As and Pb contamination, a critical evaluation of the application and utility of such bioaccessibility testing was undertaken to better inform future use. Mean As and Pb soil levels across the sites varied between 12.5 and 24,900 mg/kg and 149-5930 mg/kg, respectively. Using the Unified Bioaccessibility Method (UBM) for in vitro bioaccessibility testing the highest bioaccessible concentrations were identified in the gastric phase. At site 1, a residential urban garden site the maximum bioaccessible As was 50.2% while the maximum bioaccessible Pb was 64.8%; similarly in site 2, also a residential urban garden site the maximum bioaccessible As was 38.72% while the maximum bioaccessible Pb was 66.0%. However, at site 3, a public open space site, the maximum bioaccessible As was 29.7% while the maximum bioaccessible Pb was 38.4%. Using the appropriate soil screening values and recommended statistical testing, we highlight that the use of bioaccessibility testing was unnecessary at sites 1 and 2 (residential urban garden sites), while at site 3 the value of oral bioaccessibility testing is highlighted as part of a 'lines of evidence approach' to support the site's specific risk assessment. We need to move away from the uncritical, blanket application of oral bioacessibility testing and strategically target where the results of these data add real value to site determination.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.envres.2020.109915DOI Listing
October 2020

Guidance for the prevention and emergency management of adult patients with adrenal insufficiency.

Clin Med (Lond) 2020 07;20(4):371-378

Institute of Metabolism and Systems Research, University of Birmingham, Birmingham, UK.

Adrenal insufficiency (AI) is an often-unrecognised endocrine disorder, which can lead to adrenal crisis and death if not identified and treated. Omission of steroids in patients with AI, particularly during physiological stress such as an intercurrent illness or surgery, can also lead to an adrenal crisis. The National Reporting and Learning System (NRLS) identified 78 incidents including two deaths and six incidents of severe harm to patients in a recent 4-year period. This guidance will go through causes of adrenal insufficiency, groups at risk of an adrenal crisis, emergency management and management for surgical procedures. A new NHS Steroid Emergency Card has been developed to be carried by patients at risk of adrenal crisis. We hope the new emergency card and this guidance will increase awareness of the need to start steroids promptly in patients at risk of an adrenal crisis, particularly those presenting in the emergency department or to acute medicine teams and those undergoing surgery or invasive procedures.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.7861/clinmed.2019-0324DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7385786PMC
July 2020

SLC12A2 variants cause a neurodevelopmental disorder or cochleovestibular defect.

Brain 2020 08;143(8):2380-2387

Department of Anesthesiology, Vanderbilt University School of Medicine, Nashville, TN, USA.

The SLC12 gene family consists of SLC12A1-SLC12A9, encoding electroneutral cation-coupled chloride co-transporters. SCL12A2 has been shown to play a role in corticogenesis and therefore represents a strong candidate neurodevelopmental disorder gene. Through trio exome sequencing we identified de novo mutations in SLC12A2 in six children with neurodevelopmental disorders. All had developmental delay or intellectual disability ranging from mild to severe. Two had sensorineural deafness. We also identified SLC12A2 variants in three individuals with non-syndromic bilateral sensorineural hearing loss and vestibular areflexia. The SLC12A2 de novo mutation rate was demonstrated to be significantly elevated in the deciphering developmental disorders cohort. All tested variants were shown to reduce co-transporter function in Xenopus laevis oocytes. Analysis of SLC12A2 expression in foetal brain at 16-18 weeks post-conception revealed high expression in radial glial cells, compatible with a role in neurogenesis. Gene co-expression analysis in cells robustly expressing SLC12A2 at 16-18 weeks post-conception identified a transcriptomic programme associated with active neurogenesis. We identify SLC12A2 de novo mutations as the cause of a novel neurodevelopmental disorder and bilateral non-syndromic sensorineural hearing loss and provide further data supporting a role for this gene in human neurodevelopment.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1093/brain/awaa176DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7447514PMC
August 2020

Microfiber release from real soiled consumer laundry and the impact of fabric care products and washing conditions.

PLoS One 2020 5;15(6):e0233332. Epub 2020 Jun 5.

Department of Applied Sciences, Northumbria University, Newcastle upon Tyne, United Kingdom.

Fiber release during domestic textile washing is a cause of marine microplastic pollution, but better understanding of the magnitude of the issue and role of fabric care products, appliances and washing cycles is needed. Soiled consumer wash loads from U.K. households were found to release a mean of 114 ± 66.8 ppm (mg microfiber per kg fabric) (n = 79) fibers during typical washing conditions and these were mainly composed of natural fibers. Microfiber release decreased with increasing wash load size and hence decreasing water to fabric ratio, with mean microfiber release from wash loads in the mass range 1.0-3.5 kg (n = 57) found to be 132.4 ± 68.6 ppm, significantly (p = 3.3 x 10-8) higher than the 66.3 ± 27.0 ppm of those in the 3.5-6.0 kg range (n = 22). In further tests with similar soiled consumer wash loads, moving to colder and quicker washing cycles (i.e. 15°C for 30 mins, as opposed to 40°C for 85 mins) significantly reduced microfiber generation by 30% (p = 0.036) and reduced whiteness loss by 42% (p = 0.000) through reduced dye transfer and soil re-deposition, compared to conventional 40°C cycles. In multicycle technical testing, detergent pods were selected for investigation and found to have no impact on microfiber release compared to washing in water alone. Fabric softeners were also found to have no direct impact on microfiber release in testing under both European and North American washing conditions. Extended testing of polyester fleece garments up to a 48-wash cycle history under European conditions found that microfiber release significantly reduced to a consistent low level of 28.7 ± 10.9 ppm from eight through 64 washes. Emerging North American High-Efficiency top-loading washing machines generated significantly lower microfiber release than traditional top-loading machines, likely due to their lower water fill volumes and hence lower water to fabric ratio, with a 69.7% reduction observed for polyester fleece (n = 32, p = 7.9 x 10-6) and 37.4% reduction for polyester T-shirt (n = 32, p = 0.0032). These results conclude that consumers can directly reduce the levels of microfibers generated per wash during domestic textile washing by using colder and quicker wash cycles, washing complete (but not overfilled) loads, and (in North America) converting to High-Efficiency washing machines. Moving to colder and quicker cycles will also indirectly reduce microfiber release by extending the lifetime of clothing, leading to fewer new garments being purchased and hence lower incidence of the high microfiber release occurring during the first few washes of a new item.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0233332PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7274375PMC
August 2020

Acetyl-CoA Derived from Hepatic Peroxisomal β-Oxidation Inhibits Autophagy and Promotes Steatosis via mTORC1 Activation.

Mol Cell 2020 07 29;79(1):30-42.e4. Epub 2020 May 29.

Division of Endocrinology, Metabolism and Lipid Research, Department of Medicine, Washington University School of Medicine, St. Louis, MO 63110, USA. Electronic address:

Autophagy is activated by prolonged fasting but cannot overcome the ensuing hepatic lipid overload, resulting in fatty liver. Here, we describe a peroxisome-lysosome metabolic link that restricts autophagic degradation of lipids. Acyl-CoA oxidase 1 (Acox1), the enzyme that catalyzes the first step in peroxisomal β-oxidation, is enriched in liver and further increases with fasting or high-fat diet (HFD). Liver-specific Acox1 knockout (Acox1-LKO) protected mice against hepatic steatosis caused by starvation or HFD due to induction of autophagic degradation of lipid droplets. Hepatic Acox1 deficiency markedly lowered total cytosolic acetyl-CoA levels, which led to decreased Raptor acetylation and reduced lysosomal localization of mTOR, resulting in impaired activation of mTORC1, a central regulator of autophagy. Dichloroacetic acid treatment elevated acetyl-CoA levels, restored mTORC1 activation, inhibited autophagy, and increased hepatic triglycerides in Acox1-LKO mice. These results identify peroxisome-derived acetyl-CoA as a key metabolic regulator of autophagy that controls hepatic lipid homeostasis.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.molcel.2020.05.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7335356PMC
July 2020

Safety of referred doctors: All doctors are human and therefore vulnerable.

Authors:
John Dean

BMJ 2020 04 2;369:m1293. Epub 2020 Apr 2.

Royal Devon and Exeter NHS Foundation Trust, Exeter EX2 5DW, UK.

View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/bmj.m1293DOI Listing
April 2020

Recurrent De Novo NAHR Reciprocal Duplications in the ATAD3 Gene Cluster Cause a Neurogenetic Trait with Perturbed Cholesterol and Mitochondrial Metabolism.

Am J Hum Genet 2020 02 30;106(2):272-279. Epub 2020 Jan 30.

Exeter Genomics Laboratory, Royal Devon and Exeter NHS Foundation Trust, Exeter EX2 5DW, UK; Institute of Biomedical and Clinical Science, College of Medicine and Health, University of Exeter, Exeter EX2 5DW, UK. Electronic address:

Recent studies have identified both recessive and dominant forms of mitochondrial disease that result from ATAD3A variants. The recessive form includes subjects with biallelic deletions mediated by non-allelic homologous recombination. We report five unrelated neonates with a lethal metabolic disorder characterized by cardiomyopathy, corneal opacities, encephalopathy, hypotonia, and seizures in whom a monoallelic reciprocal duplication at the ATAD3 locus was identified. Analysis of the breakpoint junction fragment indicated that these 67 kb heterozygous duplications were likely mediated by non-allelic homologous recombination at regions of high sequence identity in ATAD3A exon 11 and ATAD3C exon 7. At the recombinant junction, the duplication allele produces a fusion gene derived from ATAD3A and ATAD3C, the protein product of which lacks key functional residues. Analysis of fibroblasts derived from two affected individuals shows that the fusion gene product is expressed and stable. These cells display perturbed cholesterol and mitochondrial DNA organization similar to that observed for individuals with severe ATAD3A deficiency. We hypothesize that the fusion protein acts through a dominant-negative mechanism to cause this fatal mitochondrial disorder. Our data delineate a molecular diagnosis for this disorder, extend the clinical spectrum associated with structural variation at the ATAD3 locus, and identify a third mutational mechanism for ATAD3 gene cluster variants. These results further affirm structural variant mutagenesis mechanisms in sporadic disease traits, emphasize the importance of copy number analysis in molecular genomic diagnosis, and highlight some of the challenges of detecting and interpreting clinically relevant rare gene rearrangements from next-generation sequencing data.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1016/j.ajhg.2020.01.007DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7010973PMC
February 2020

The CHD8 overgrowth syndrome: A detailed evaluation of an emerging overgrowth phenotype in 27 patients.

Am J Med Genet C Semin Med Genet 2019 12 13;181(4):557-564. Epub 2019 Nov 13.

David Geffen School of Medicine at the University of California, Los Angeles (UCLA), Los Angeles, California.

CHD8 has been reported as an autism susceptibility/intellectual disability gene but emerging evidence suggests that it additionally causes an overgrowth phenotype. This study reports 27 unrelated patients with pathogenic or likely pathogenic CHD8 variants (25 null variants, two missense variants) and a male:female ratio of 21:6 (3.5:1, p < .01). All patients presented with intellectual disability, with 85% in the mild or moderate range, and 85% had a height and/or head circumference ≥2 standard deviations above the mean, meeting our clinical criteria for overgrowth. Behavioral problems were reported in the majority of patients (78%), with over half (56%) either formally diagnosed with an autistic spectrum disorder or described as having autistic traits. Additional clinical features included neonatal hypotonia (33%), and less frequently seizures, pes planus, scoliosis, fifth finger clinodactyly, umbilical hernia, and glabellar hemangioma (≤15% each). These results suggest that, in addition to its established link with autism and intellectual disability, CHD8 causes an overgrowth phenotype, and should be considered in the differential diagnosis of patients presenting with increased height and/or head circumference in association with intellectual disability.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/ajmg.c.31749DOI Listing
December 2019

Exome sequencing in patients with antiepileptic drug exposure and complex phenotypes.

Arch Dis Child 2020 04 3;105(4):384-389. Epub 2019 Sep 3.

Genetic Medicine, Central Manchester University Hospitals Foundation Trust, Manchester, UK.

Introduction: Fetal anticonvulsant syndrome (FACS) describes the pattern of physical and developmental problems seen in those children exposed to certain antiepileptic drugs (AEDs) in utero. The diagnosis of FACS is a clinical one and so excluding alternative diagnoses such as genetic disorders is essential.

Methods: We reviewed the pathogenicity of reported variants identified on exome sequencing in the Deciphering Developmental Disorders (DDD) Study in 42 children exposed to AEDs in utero, but where a diagnosis other than FACS was suspected. In addition, we analysed chromosome microarray data from 10 patients with FACS seen in a Regional Genetics Service.

Results: Seven children (17%) from the DDD Study had a copy number variant or pathogenic variant in a developmental disorder gene which was considered to explain or partially explain their phenotype. Across the AED exposure types, variants were found in 2/15 (13%) valproate exposed cases and 3/14 (21%) carbamazepine exposed cases. No pathogenic copy number variants were identified in our local sample (n=10).

Conclusions: This study is the first of its kind to analyse the exomes of children with developmental disorders who were exposed to AEDs in utero. Though we acknowledge that the results are subject to bias, a significant number of children were identified with alternate diagnoses which had an impact on counselling and management. We suggest that consideration is given to performing whole exome sequencing as part of the diagnostic work-up for children exposed to AEDs in utero.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/archdischild-2018-316547DOI Listing
April 2020
-->