Publications by authors named "John McGrath"

906 Publications

Comorbidity between types of eating disorder and general medical conditions.

Br J Psychiatry 2021 Jul 23:1-8. Epub 2021 Jul 23.

National Centre for Register-based Research, Aarhus BSS, Aarhus University, Denmark; and Lundbeck Foundation Initiative for Integrative Psychiatric Research (iPSYCH), Aarhus, Denmark.

Background: Comorbidity with general medical conditions is common in individuals with eating disorders. Many previous studies do not evaluate types of eating disorder.

Aims: To provide relative and absolute risks of bidirectional associations between (a) anorexia nervosa, bulimia nervosa and eating disorders not otherwise specified and (b) 12 general medical conditions.

Method: We included all people born in Denmark between 1977 and 2010. We collected information on eating disorders and considered the risk of subsequent medical conditions, using Cox proportional hazards regression. Absolute risks were calculated using competing risks survival analyses. We also considered risks for prior medical conditions and subsequent eating disorders.

Results: An increased risk was seen for almost all disorder pairs (69 of 70). Hazard ratios for those with a prior eating disorder receiving a subsequent diagnosis of a medical condition ranged from 0.94 (95% CI 0.57-1.55) to 2.05 (95% CI 1.86-2.27). For those with a prior medical condition, hazard ratios for later eating disorders ranged from 1.35 (95% CI 1.26-1.45) to 1.98 (95% CI 1.71-2.28). Absolute risks for most later disorders were increased for persons with prior disorders, compared with reference groups.

Conclusions: This is the largest and most detailed examination of eating disorder-medical condition comorbidity. The findings indicate that medical condition comorbidity is increased among those with eating disorders and vice versa. Although there was some variation in comorbidity observed across eating disorder types, magnitudes of relative risks did not differ greatly.
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http://dx.doi.org/10.1192/bjp.2021.104DOI Listing
July 2021

Autoinflammatory Keratinization Disease With Hepatitis and Autism Reveals Roles for JAK1 Kinase Hyperactivity in Autoinflammation.

Front Immunol 2021 3;12:737747. Epub 2022 Jan 3.

Department of Dermatology, Nagoya University Graduate School of Medicine, Nagoya, Japan.

Heterozygous mutations in which result in JAK-STAT hyperactivity have been implicated in an autosomal dominant disorder that features multi-organ immune dysregulation. This study identifies another previously unreported heterozygous missense mutation, H596D, in an individual with a unique autoinflammatory keratinization disease associated with early-onset liver dysfunction and autism. Using CRISPR-Cas9 gene targeting, we generated mice with an identical knock-in missense mutation ( mice) that recapitulated key aspects of the human phenotype. RNA sequencing of samples isolated from the mice revealed the upregulation of genes associated with the hyperactivation of tyrosine kinases and NF-κB signaling. Interestingly, there was a strong correlation between genes downregulated in mice and those downregulated in the brain of model mice with 22q11.2 deletion syndrome that showed cognitive and behavioral deficits, such as autism spectrum disorders. Our findings expand the phenotypic spectrum of -associated disease and underscore how JAK1 dysfunction contributes to this autoinflammatory disorder.
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http://dx.doi.org/10.3389/fimmu.2021.737747DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8761858PMC
January 2022

The Burden of schizophrenia.

Eur Neuropsychopharmacol 2022 Jan 10;57:33-35. Epub 2022 Jan 10.

National Centre for Register-based Research, Aarhus University, Aarhus BSS, Aarhus, Denmark; Queensland Brain Institute, University of Queensland, St Lucia QLD 4072, Australia; Queensland Centre for Mental Health Research, The Park Centre for Mental Health, Queensland, Australia.

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http://dx.doi.org/10.1016/j.euroneuro.2021.12.009DOI Listing
January 2022

Transcriptomic response of peripheral blood mononuclear cells to secukinumab in an 8-year-old boy with juvenile generalized pustular psoriasis.

J Eur Acad Dermatol Venereol 2022 Jan 12. Epub 2022 Jan 12.

Department of Dermatology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan, Taiwan.

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http://dx.doi.org/10.1111/jdv.17922DOI Listing
January 2022

Mutations in the ribosome biogenesis factor gene LTV1 are linked to LIPHAK syndrome, a novel poikiloderma-like disorder.

Hum Mol Genet 2022 Jan 6. Epub 2022 Jan 6.

Institute of Molecular and Clinical Ophthalmology Basel (IOB), Basel, Switzerland.

In the framework of the UK 100000 Genomes Project, we investigated the genetic origin of a previously undescribed recessive dermatological condition, which we named LIPHAK (LTV1-associated Inflammatory Poikiloderma with Hair abnormalities and Acral Keratoses), in four affected individuals from two UK families of Pakistani and Indian origins, respectively. Our analysis showed that only one gene, LTV1, carried rare biallelic variants that were shared in all affected individuals, and specifically they bore the NM_032860.5:c.503A > G, p.(Asn168Ser) change, found homozygously in all of them. In addition, high-resolution homozygosity mapping revealed the presence of a small 652-kb stretch on chromosome 6, encompassing LTV1, that was common to and haploidentical in all affected individuals. The c.503A > G variant was predicted by in silico tools to affect the correct splicing of LTV1's exon 5. Minigene-driven splicing assays in HEK293T cells and in a skin sample from one of the patients confirmed that this variant was indeed responsible for the creation of a new donor splice site, resulting in aberrant splicing and in a premature termination codon in exon 6 of this gene. LTV1 encodes one of the ribosome biogenesis factors that promote the assembly of the small (40S) ribosomal subunit. In yeast, defects in LTV1 alter the export of nascent ribosomal subunits to the cytoplasm; however, the role of this gene in human pathology is unknown to date. Our data suggest that LIPHAK could be a previously unrecognised ribosomopathy.
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http://dx.doi.org/10.1093/hmg/ddab368DOI Listing
January 2022

Effect of Vitamin D Supplementation on Outcomes in People With Early Psychosis: The DFEND Randomized Clinical Trial.

JAMA Netw Open 2021 12 1;4(12):e2140858. Epub 2021 Dec 1.

Queensland Centre for Mental Health Research, The Park Centre for Mental Health, Wacol, Queensland, Australia.

Importance: People with psychotic disorders have an increased risk of vitamin D deficiency, which is evident during first-episode psychosis (FEP) and associated with unfavorable mental and physical health outcomes.

Objective: To examine whether vitamin D supplementation contributes to improved clinical outcomes in FEP.

Design, Setting, And Participants: This multisite, double-blind, placebo-controlled, parallel-group randomized clinical trial from the UK examined adults 18 to 65 years of age within 3 years of a first presentation with a functional psychotic disorder who had no contraindication to vitamin D supplementation. A total of 2136 patients were assessed for eligibility, 835 were approached, 686 declined participation or were excluded, 149 were randomized, and 104 were followed up at 6 months. The study recruited participants from January 19, 2016, to June 14, 2019, with the final follow-up (after the last dose) completed on December 20, 2019.

Interventions: Monthly augmentation with 120 000 IU of cholecalciferol or placebo.

Main Outcomes And Measures: The primary outcome measure was total Positive and Negative Syndrome Scale (PANSS) score at 6 months. Secondary outcomes included total PANSS score at 3 months; PANSS positive, negative, and general psychopathology subscale scores at 3 and 6 months; Global Assessment of Function scores (for symptoms and disability); Calgary Depression Scale score, waist circumference, body mass index, and glycated hemoglobin, total cholesterol, C-reactive protein, and vitamin D concentrations at 6 months; and a planned sensitivity analysis in those with insufficient vitamin D levels at baseline.

Results: A total of 149 participants (mean [SD] age, 28.1 (8.5) years; 89 [59.7%] male; 65 [43.6%] Black or of other minoritized racial and ethnic group; 84 [56.4%] White [British, Irish, or of other White ethnicity]) were randomized. No differences were observed in the intention-to-treat analysis in the primary outcome, total PANSS score at 6 months (mean difference, 3.57; 95% CI, -1.11 to 8.25; P = .13), or the secondary outcomes at 3 and 6 months (PANSS positive subscore: mean difference, -0.98; 95% CI, -2.23 to 0.27 at 3 months; mean difference, 0.68; 95% CI, -0.69 to 1.99 at 6 months; PANSS negative subscore: mean difference, 0.68; 95% CI, -1.39 to 2.76 at 3 months; mean difference, 1.56; 95% CI, -0.31 to 3.44 at 6 months; and general psychopathology subscore: mean difference, -2.09; 95% CI, -4.36 to 0.18 at 3 months; mean difference, 1.31; 95% CI, -1.42 to 4.05 at 6 months). There also were no significant differences in the Global Assessment of Function symptom score (mean difference, 0.02; 95% CI, -4.60 to 4.94); Global Assessment of Function disability score (mean difference, -0.01; 95% CI, -5.25 to 5.23), or Calgary Depression Scale score (mean difference, -0.39; 95% CI, -2.05 to 1.26) at 6 months. Vitamin D levels were very low in the study group, especially in Black participants and those who identified as another minoritized racial and ethnic group, 57 of 61 (93.4%) of whom had insufficient vitamin D. The treatment was safe and led to a significant increase in 25-hydroxyvitamin D concentrations.

Conclusions And Relevance: In this randomized clinical trial, no association was found between vitamin D supplementation and mental health or metabolic outcomes at 6 months. Because so few patients with FEP were vitamin D replete, the results of this study suggest that this group would benefit from active consideration in future population health strategies.

Trial Registration: isrctn.org Identifier: ISRCTN12424842.
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http://dx.doi.org/10.1001/jamanetworkopen.2021.40858DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8715346PMC
December 2021

Developmental Vitamin D Deficiency in Pregnant Rats Does Not Induce Preeclampsia.

Nutrients 2021 Nov 26;13(12). Epub 2021 Nov 26.

Neurobiology, Queensland Brain Institute, University of Queensland, St. Lucia, QLD 4072, Australia.

Preeclampsia is a pregnancy disorder characterized by hypertension. Epidemiological studies have associated preeclampsia with an increased risk of neurodevelopmental disorders in offspring, such as autism and schizophrenia. Preeclampsia has also been linked with maternal vitamin D deficiency, another candidate risk factor also associated with autism. Our laboratory has established a gestational vitamin-D-deficient rat model that shows consistent and robust behavioural phenotypes associated with autism- and schizophrenia-related animal models. Therefore, we explored here whether this model also produces preeclampsia as a possible mediator of behavioural phenotypes in offspring. We showed that gestational vitamin D deficiency was not associated with maternal blood pressure or proteinuria during late gestation. Maternal and placental angiogenic and vasculogenic factors were also not affected by a vitamin-D-deficient diet. We further showed that exposure to low vitamin D levels did not expose the placenta to oxidative stress. Overall, gestational vitamin D deficiency in our rat model was not associated with preeclampsia-related features, suggesting that well-described behavioural phenotypes in offspring born to vitamin-D-deficient rat dams are unlikely to be mediated via a preeclampsia-related mechanism.
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http://dx.doi.org/10.3390/nu13124254DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8707812PMC
November 2021

Sensitive and Robust LC-MS/MS Assay to Quantify 25-Hydroxyvitamin D in Leftover Protein Extract from Dried Blood Spots.

Int J Neonatal Screen 2021 Dec 10;7(4). Epub 2021 Dec 10.

Center for Neonatal Screening, Department of Congenital Disorders-Clinical Mass Spectrometry Statens Serum Institut, Artillerivej 5, 2300 Copenhagen, Denmark.

Neonatal dried blood spots (DBS) provide a remarkable resource for biobanks. These microsamples can provide information related to the genetic correlates of disease and can be used to quantify a range of analytes, such as proteins and small molecules. However, after routine neonatal screening, the amount of DBS sample available is limited. To optimize the use of these samples, there is a need for sensitive assays which are integrated across different analytic platforms. For example, after DNA extraction, protein extracts are available for additional analyses. We describe a sensitive and robust LC-MS/MS method for 25-hydroxyvitamin D and 25-hydroxyvitamin D optimized for leftover protein extracts from DBS, which has excellent recovery, precision, and accuracy.
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http://dx.doi.org/10.3390/ijns7040082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8704356PMC
December 2021

Rosin Soap Exhibits Virucidal Activity.

Microbiol Spectr 2021 12 22;9(3):e0109121. Epub 2021 Dec 22.

School of Biological Sciences, Queen's University Belfast, Belfast, United Kingdom.

Chemical methods of virus inactivation are used routinely to prevent viral transmission in both a personal hygiene capacity but also in at-risk environments like hospitals. Several virucidal products exist, including hand soaps, gels, and surface disinfectants. Resin acids, which can be derived from tall oil, produced from trees, have been shown to exhibit antibacterial activity. However, whether these products or their derivatives have virucidal activity is unknown. Here, we assessed the capacity of rosin soap to inactivate a panel of pathogenic mammalian viruses . We show that rosin soap can inactivate human enveloped viruses: influenza A virus (IAV), respiratory syncytial virus, and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). For IAV, rosin soap could provide a 100,000-fold reduction in infectivity. However, rosin soap failed to affect the nonenveloped encephalomyocarditis virus (EMCV). The inhibitory effect of rosin soap against IAV infectivity was dependent on its concentration but not on the incubation time or temperature. In all, we demonstrate a novel chemical inactivation method against enveloped viruses, which could be of use for preventing virus infections in certain settings. Viruses remain a significant cause of human disease and death, most notably illustrated through the current coronavirus disease 2019 (COVID-19) pandemic. Control of virus infection continues to pose a significant global health challenge to the human population. Viruses can spread through multiple routes, including via environmental and surface contamination, where viruses can remain infectious for days. Methods for inactivating viruses on such surfaces may help mitigate infection. Here, we present evidence identifying a novel virucidal product, rosin soap, which is produced from tall oil from coniferous trees. Rosin soap was able to rapidly and potently inactivate influenza virus and other enveloped viruses.
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http://dx.doi.org/10.1128/spectrum.01091-21DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8693916PMC
December 2021

The epidemiology of epidermolysis bullosa in England and Wales: data from the national epidermolysis bullosa database.

Br J Dermatol 2021 Dec 20. Epub 2021 Dec 20.

University of Birmingham, Birmingham, UK.

Background: The NHS Epidermolysis Bullosa (EB) service set up in 2002 offers comprehensive, free care to all patients in England and Wales.

Objective: To quantify prevalence, incidence and mortality of EB in England and Wales.

Methods: Demographic data for patients in England and Wales was collected on a secure electronic database, prospectively from January 2002 to April 2021 and retrospectively before that. Vital status was verified using central NHS data.

Results: By March 2021, 2594 individuals were registered, of whom 2361 were living, giving prevalence per million of the population for all EB types of 34.8; EB simplex (EBS) 17, dystrophic EB (DEB) 10.7, junctional EB (JEB) 1 and Kindler EB 0.3. We recorded 1200 babies with EB born since 2002, average incidence per million live births, for EBS, DEB, JEB and Kindler EB being 32.5, 26.1, 8.9, 0.9 respectively, total 67.8 for all types of EB. Birth rates fell progressively over the 19-year period for JEB-severe (JEB-S) (r = - 0.56) and recessive DEB-severe (RDEB-S) (r = -0.44) and also for milder types of EB. We observed longer survival in JEB-S over the 19 years (r = 0.18) with a median of 12.7 months over the past 5 years.

Conclusions: We provide the first accurate epidemiological data for EB in England and Wales. We believe the observed reduction in birth incidence of severe types of EB reflects uptake of genetic counselling advice while that of milder types may be due to delayed presentation. A potential small trend towards longer survival of babies with JEB-S may reflect improved multidisciplinary care.
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http://dx.doi.org/10.1111/bjd.20958DOI Listing
December 2021

Current topics in Epidermolysis bullosa: Pathophysiology and therapeutic challenges.

J Dermatol Sci 2021 Dec;104(3):164-176

St. John's Institute of Dermatology, School of Basic and Medical Biosciences, King's College London, London, United Kingdom.

Epidermolysis bullosa (EB) is a group of inherited skin and mucosal fragility disorders resulting from mutations in genes encoding basement membrane zone (BMZ) components or proteins that maintain the integrity of BMZ and adjacent keratinocytes. More than 30 years have passed since the first causative gene for EB was identified, and over 40 genes are now known to be responsible for the protean collection of mechanobullous diseases included under the umbrella term of EB. Through the elucidation of disease mechanisms using human skin samples, animal models, and cultured cells, we have now reached the stage of developing more effective therapeutics for EB. This review will initially focus on what is known about blister wound healing in EB, since recent and emerging basic science data are very relevant to clinical translation and therapeutic strategies for patients. We then place these studies in the context of the latest information on gene therapy, read-through therapy, and cell therapy that provide optimism for improved clinical management of people living with EB.
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http://dx.doi.org/10.1016/j.jdermsci.2021.11.004DOI Listing
December 2021

α4/α9 Integrins Coordinate Epithelial Cell Migration Through Local Suppression of MAP Kinase Signaling Pathways.

Front Cell Dev Biol 2021 25;9:750771. Epub 2021 Nov 25.

Parsons Group, Randall Centre for Cell and Molecular Biophysics, King's College London, London, United Kingdom.

Adhesion of basal keratinocytes to the underlying extracellular matrix (ECM) plays a key role in the control of skin homeostasis and response to injury. Integrin receptors indirectly link the ECM to the cell cytoskeleton through large protein complexes called focal adhesions (FA). FA also function as intracellular biochemical signaling platforms to enable cells to respond to changing extracellular cues. The α4β1 and α9β1 integrins are both expressed in basal keratinocytes, share some common ECM ligands, and have been shown to promote wound healing and However, their roles in maintaining epidermal homeostasis and relative contributions to pathological processes in the skin remain unclear. We found that α4β1 and α9β1 occupied distinct regions in monolayers of a basal keratinocyte cell line (NEB-1). During collective cell migration (CCM), α4 and α9 integrins co-localized along the leading edge. Pharmacological inhibition of α4β1 and α9β1 integrins increased keratinocyte proliferation and induced a dramatic change in cytoskeletal remodeling and FA rearrangement, detrimentally affecting CCM. Further analysis revealed that α4β1/α9β1 integrins suppress extracellular signal-regulated kinase (ERK1/2) activity to control migration through the regulation of downstream kinases including Mitogen and Stress Activated Kinase 1 (MSK1). This work demonstrates the roles of α4β1 and α9β1 in regulating migration in response to damage cues.
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http://dx.doi.org/10.3389/fcell.2021.750771DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8655878PMC
November 2021

Active single cell encapsulation using SAW overcoming the limitations of Poisson distribution.

Lab Chip 2021 12 21;22(1):193-200. Epub 2021 Dec 21.

Division of Biomedical Engineering, School of Engineering, University of Glasgow, Oakfield Avenue, G12 8LT Glasgow, UK.

We demonstrate the use of an acoustic device to actively encapsulate single red blood cells into individual droplets in a T-junction. We compare the active encapsulation with the passive encapsulation depending on the number of loaded cells as well as the created droplet volumes. This method overcomes the Poisson limitation statistical loading of cells for the passive encapsulation. In our experiments we reach a single cell encapsulation efficiency of 97.9 ± 2.1% at droplet formation rates exceeding 15 Hz.
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http://dx.doi.org/10.1039/d1lc00880cDOI Listing
December 2021

Microfluidics as a Novel Technique for Tuberculosis: From Diagnostics to Drug Discovery.

Microorganisms 2021 Nov 11;9(11). Epub 2021 Nov 11.

School of Life and Health Sciences, Aston University, Aston Triangle, Birmingham B4 7ET, UK.

Tuberculosis (TB) remains a global healthcare crisis, with an estimated 5.8 million new cases and 1.5 million deaths in 2020. TB is caused by infection with the major human pathogen , which is difficult to rapidly diagnose and treat. There is an urgent need for new methods of diagnosis, sufficient in vitro models that capably mimic all physiological conditions of the infection, and high-throughput drug screening platforms. Microfluidic-based techniques provide single-cell analysis which reduces experimental time and the cost of reagents, and have been extremely useful for gaining insight into monitoring microorganisms. This review outlines the field of microfluidics and discusses the use of this novel technique so far in diagnostics, research methods, and drug discovery platforms. The practices of microfluidics have promising future applications for diagnosing and treating TB.
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http://dx.doi.org/10.3390/microorganisms9112330DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8618277PMC
November 2021

Perceived helpfulness of treatment for alcohol use disorders: Findings from the World Mental Health Surveys.

Drug Alcohol Depend 2021 12 1;229(Pt B):109158. Epub 2021 Nov 1.

National Institute of Mental Health, National Center for Neurology and Psychiatry, 4 Chome-1-1 Ogawahigashicho, Kodaira, Tokyo 187-8551, Japan.

Aim: We examined prevalence and factors associated with receiving perceived helpful alcohol use disorder (AUD) treatment, and persistence in help-seeking after earlier unhelpful treatment.

Methods: Data came from 27 community epidemiologic surveys of adults in 24 countries using the World Health Organization World Mental Health surveys (n = 93,843). Participants with a lifetime history of treated AUD were asked if they ever received helpful AUD treatment, and how many professionals they had talked to up to and including the first time they received helpful treatment (or how many ever, if they had not received helpful treatment).

Results: 11.8% of respondents with lifetime AUD reported ever obtaining treatment (n = 9378); of these, 44% reported that treatment was helpful. The probability of obtaining helpful treatment from the first professional seen was 21.8%; the conditional probability of subsequent professionals being helpful after earlier unhelpful treatment tended to decrease as more professionals were seen. The cumulative probability of receiving helpful treatment at least once increased from 21.8% after the first professional to 79.7% after the seventh professional seen, following earlier unhelpful treatment. However, the cumulative probability of persisting with up to seven professionals in the face of prior treatments being unhelpful was only 13.2%.

Conclusion: Fewer than half of people with AUDs who sought treatment found treatment helpful; the most important factor was persistence in seeking further treatment if a previous professional had not helped. Future research should examine how to increase the likelihood that AUD treatment is found to be helpful on any given contact.
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http://dx.doi.org/10.1016/j.drugalcdep.2021.109158DOI Listing
December 2021

Previous disorders and depression outcomes in individuals with 12-month major depressive disorder in the World Mental Health surveys.

Epidemiol Psychiatr Sci 2021 Nov 11;30:e70. Epub 2021 Nov 11.

Department of Mental Health, National Center of Public Health and Analyses, Sofia, Bulgaria.

Aims: Major depressive disorder (MDD) is characterised by a recurrent course and high comorbidity rates. A lifespan perspective may therefore provide important information regarding health outcomes. The aim of the present study is to examine mental disorders that preceded 12-month MDD diagnosis and the impact of these disorders on depression outcomes.

Methods: Data came from 29 cross-sectional community epidemiological surveys of adults in 27 countries (n = 80 190). The Composite International Diagnostic Interview (CIDI) was used to assess 12-month MDD and lifetime DSM-IV disorders with onset prior to the respondent's age at interview. Disorders were grouped into depressive distress disorders, non-depressive distress disorders, fear disorders and externalising disorders. Depression outcomes included 12-month suicidality, days out of role and impairment in role functioning.

Results: Among respondents with 12-month MDD, 94.9% (s.e. = 0.4) had at least one prior disorder (including previous MDD), and 64.6% (s.e. = 0.9) had at least one prior, non-MDD disorder. Previous non-depressive distress, fear and externalising disorders, but not depressive distress disorders, predicted higher impairment (OR = 1.4-1.6) and suicidality (OR = 1.5-2.5), after adjustment for sociodemographic variables. Further adjustment for MDD characteristics weakened, but did not eliminate, these associations. Associations were largely driven by current comorbidities, but both remitted and current externalising disorders predicted suicidality among respondents with 12-month MDD.

Conclusions: These results illustrate the importance of careful psychiatric history taking regarding current anxiety disorders and lifetime externalising disorders in individuals with MDD.
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http://dx.doi.org/10.1017/S2045796021000573DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8611932PMC
November 2021

Corrigendum to "Metabolic perturbations in fibrosis disease" [Int. J. Biochem. Cell Biol. 139 (2021) 106073].

Int J Biochem Cell Biol 2021 Dec 30;141:106109. Epub 2021 Oct 30.

Centre for Inflammation Biology & Cancer Immunology, King's College London, London SE1 1UL, UK. Electronic address:

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http://dx.doi.org/10.1016/j.biocel.2021.106109DOI Listing
December 2021

Pathogenesis of solar urticaria: Classic perspectives and emerging concepts.

Exp Dermatol 2021 Nov 2. Epub 2021 Nov 2.

St. John's Institute of Dermatology, Guy's Hospital, London, UK.

Solar urticaria is a rare, immunologically mediated photodermatosis in which activation of cutaneous mast cells is triggered by specific wavelengths of solar electromagnetic radiation. This manifests clinically as the rapid development of cutaneous itch, erythema and wheal formation after several minutes of sun exposure. Disease mechanisms in solar urticaria remain incompletely elucidated and there have been few recent investigations of its pathobiology. Historic passive transfer experiments performed during the twentieth century provide support for a 'photoallergy' model of disease pathogenesis, wherein molecular alteration of a putative chromophore by solar electromagnetic radiation produces mast cell activation via an IgE-dependent mechanism. However, this model does not account for several observations made during passive transfer experiments nor does it explain a range of subsequent clinical and photobiological observations made in solar urticaria patients. Furthermore, increased understanding of the molecular dynamics underpinning cutaneous mast cell responses highlights the need to reformulate our understanding of solar urticaria pathogenesis in the context of this contemporary scientific landscape. In this review, we discuss the current understanding of solar urticaria pathogenesis and, by incorporating recent scientific and clinical observations, develop new hypotheses to drive future investigation into this intriguing disorder.
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http://dx.doi.org/10.1111/exd.14493DOI Listing
November 2021

Comorbidity between mood and substance-related disorders: A systematic review and meta-analysis.

Aust N Z J Psychiatry 2021 Oct 28:48674211054740. Epub 2021 Oct 28.

Queensland Brain Institute, The University of Queensland, St Lucia, QLD, Australia.

Background And Objectives: Evidence indicates that mood disorders often co-occur with substance-related disorders. However, pooling comorbidity estimates can be challenging due to heterogeneity in diagnostic criteria and in the overall study design. The aim of this study was to systematically review and, where appropriate, meta-analyse estimates related to the pairwise comorbidity between mood disorders and substance-related disorders, after sorting these estimates by various study designs.

Methods: We searched PubMed (MEDLINE), Embase, CINAHL and Web of Science for publications between 1980 and 2017 regardless of geographical location and language. We meta-analysed estimates from original articles in 4 broadly defined mood and 35 substance-related disorders.

Results: After multiple eligibility steps, we included 120 studies for quantitative analysis. In general, regardless of variations in diagnosis type, temporal order or use of adjustments, there was substantial comorbidity between mood and substance-related disorders. We found a sixfold elevated risk between broadly defined mood disorder and drug dependence (odds ratio = 5.7) and fivefold risk between depression and cannabis dependence (odds ratio = 4.9) while the highest pooled estimate, based on period prevalence risk, was found between broadly defined dysthymic disorder and drug dependence (odds ratio = 11.3). Based on 56 separate meta-analyses, all pooled odds ratios were above 1, and 46 were significantly greater than 1 (i.e. the 95% confidence intervals did not include 1).

Conclusion: This review found robust and consistent evidence of an increased risk of comorbidity between many combinations of mood and substance-related disorders. We also identified a number of under-researched mood and substance-related disorders, suitable for future scrutiny. This review reinforces the need for clinicians to remain vigilant in order to promptly identify and treat these common types of comorbidity.
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http://dx.doi.org/10.1177/00048674211054740DOI Listing
October 2021

Transcriptomic profiling of recessive dystrophic epidermolysis bullosa wounded skin highlights drug repurposing opportunities to improve wound healing.

Exp Dermatol 2021 Oct 25. Epub 2021 Oct 25.

St John's Institute of Dermatology, School of Basic and Medical Biosciences, King's College London, London, UK.

Chronic wounds present a major disease burden in people with recessive dystrophic epidermolysis bullosa (RDEB), an inherited blistering skin disorder caused by mutations in COL7A1 encoding type VII collagen, the major component of anchoring fibrils at the dermal-epidermal junction. Treatment of RDEB wounds is mostly symptomatic, and there is considerable unmet need in trying to improve and accelerate wound healing. In this study, we defined transcriptomic profiles and gene pathways in RDEB wounds and compared these to intact skin in RDEB and healthy control subjects. We then used a reverse transcriptomics approach to discover drugs or compounds, which might restore RDEB wound profiles towards intact skin. Differential expression analysis identified >2000 differences between RDEB wounds and intact skin, with RDEB wounds displaying aberrant cytokine-cytokine interactions, Toll-like receptor signalling, and JAK-STAT signalling pathways. In-silico prediction for compounds that reverse gene expression signatures highlighted methotrexate as a leading candidate. Overall, this study provides insight into the molecular profiles of RDEB wounds and underscores the possible clinical value of reverse transcriptomics data analysis in RDEB, and the potential of this approach in discovering or repurposing drugs for other diseases.
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http://dx.doi.org/10.1111/exd.14481DOI Listing
October 2021

A prospective prostate cancer screening programme for men with pathogenic variants in mismatch repair genes (IMPACT): initial results from an international prospective study.

Lancet Oncol 2021 11 19;22(11):1618-1631. Epub 2021 Oct 19.

University Hospital Southampton, Southampton, UK; Wessex Clinical Genetics Service, Princess Anne Hospital, Southampton, UK.

Background: Lynch syndrome is a rare familial cancer syndrome caused by pathogenic variants in the mismatch repair genes MLH1, MSH2, MSH6, or PMS2, that cause predisposition to various cancers, predominantly colorectal and endometrial cancer. Data are emerging that pathogenic variants in mismatch repair genes increase the risk of early-onset aggressive prostate cancer. The IMPACT study is prospectively assessing prostate-specific antigen (PSA) screening in men with germline mismatch repair pathogenic variants. Here, we report the usefulness of PSA screening, prostate cancer incidence, and tumour characteristics after the first screening round in men with and without these germline pathogenic variants.

Methods: The IMPACT study is an international, prospective study. Men aged 40-69 years without a previous prostate cancer diagnosis and with a known germline pathogenic variant in the MLH1, MSH2, or MSH6 gene, and age-matched male controls who tested negative for a familial pathogenic variant in these genes were recruited from 34 genetic and urology clinics in eight countries, and underwent a baseline PSA screening. Men who had a PSA level higher than 3·0 ng/mL were offered a transrectal, ultrasound-guided, prostate biopsy and a histopathological analysis was done. All participants are undergoing a minimum of 5 years' annual screening. The primary endpoint was to determine the incidence, stage, and pathology of screening-detected prostate cancer in carriers of pathogenic variants compared with non-carrier controls. We used Fisher's exact test to compare the number of cases, cancer incidence, and positive predictive values of the PSA cutoff and biopsy between carriers and non-carriers and the differences between disease types (ie, cancer vs no cancer, clinically significant cancer vs no cancer). We assessed screening outcomes and tumour characteristics by pathogenic variant status. Here we present results from the first round of PSA screening in the IMPACT study. This study is registered with ClinicalTrials.gov, NCT00261456, and is now closed to accrual.

Findings: Between Sept 28, 2012, and March 1, 2020, 828 men were recruited (644 carriers of mismatch repair pathogenic variants [204 carriers of MLH1, 305 carriers of MSH2, and 135 carriers of MSH6] and 184 non-carrier controls [65 non-carriers of MLH1, 76 non-carriers of MSH2, and 43 non-carriers of MSH6]), and in order to boost the sample size for the non-carrier control groups, we randomly selected 134 non-carriers from the BRCA1 and BRCA2 cohort of the IMPACT study, who were included in all three non-carrier cohorts. Men were predominantly of European ancestry (899 [93%] of 953 with available data), with a mean age of 52·8 years (SD 8·3). Within the first screening round, 56 (6%) men had a PSA concentration of more than 3·0 ng/mL and 35 (4%) biopsies were done. The overall incidence of prostate cancer was 1·9% (18 of 962; 95% CI 1·1-2·9). The incidence among MSH2 carriers was 4·3% (13 of 305; 95% CI 2·3-7·2), MSH2 non-carrier controls was 0·5% (one of 210; 0·0-2·6), MSH6 carriers was 3·0% (four of 135; 0·8-7·4), and none were detected among the MLH1 carriers, MLH1 non-carrier controls, and MSH6 non-carrier controls. Prostate cancer incidence, using a PSA threshold of higher than 3·0 ng/mL, was higher in MSH2 carriers than in MSH2 non-carrier controls (4·3% vs 0·5%; p=0·011) and MSH6 carriers than MSH6 non-carrier controls (3·0% vs 0%; p=0·034). The overall positive predictive value of biopsy using a PSA threshold of 3·0 ng/mL was 51·4% (95% CI 34·0-68·6), and the overall positive predictive value of a PSA threshold of 3·0 ng/mL was 32·1% (20·3-46·0).

Interpretation: After the first screening round, carriers of MSH2 and MSH6 pathogenic variants had a higher incidence of prostate cancer compared with age-matched non-carrier controls. These findings support the use of targeted PSA screening in these men to identify those with clinically significant prostate cancer. Further annual screening rounds will need to confirm these findings.

Funding: Cancer Research UK, The Ronald and Rita McAulay Foundation, the National Institute for Health Research support to Biomedical Research Centres (The Institute of Cancer Research and Royal Marsden NHS Foundation Trust; Oxford; Manchester and the Cambridge Clinical Research Centre), Mr and Mrs Jack Baker, the Cancer Council of Tasmania, Cancer Australia, Prostate Cancer Foundation of Australia, Cancer Council of Victoria, Cancer Council of South Australia, the Victorian Cancer Agency, Cancer Australia, Prostate Cancer Foundation of Australia, Asociación Española Contra el Cáncer (AECC), the Instituto de Salud Carlos III, Fondo Europeo de Desarrollo Regional (FEDER), the Institut Català de la Salut, Autonomous Government of Catalonia, Fundação para a Ciência e a Tecnologia, National Institutes of Health National Cancer Institute, Swedish Cancer Society, General Hospital in Malmö Foundation for Combating Cancer.
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http://dx.doi.org/10.1016/S1470-2045(21)00522-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8576477PMC
November 2021

Plasma metabolomic and lipidomic profiling highlights metabolic changes in keloid-prone individuals.

Exp Dermatol 2021 Oct 19. Epub 2021 Oct 19.

St John's Institute of Dermatology, School of Basic and Medical Biosciences, King's College London, London, UK.

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http://dx.doi.org/10.1111/exd.14472DOI Listing
October 2021

Clinical trial of ABCB5+ mesenchymal stem cells for recessive dystrophic epidermolysis bullosa.

JCI Insight 2021 11 22;6(22). Epub 2021 Nov 22.

RHEACELL GmbH & Co. KG, Heidelberg, Germany.

BACKGROUNDRecessive dystrophic epidermolysis bullosa (RDEB) is a rare, devastating, and life-threatening inherited skin fragility disorder that comes about due to a lack of functional type VII collagen, for which no effective therapy exists. ABCB5+ dermal mesenchymal stem cells (ABCB5+ MSCs) possess immunomodulatory, inflammation-dampening, and tissue-healing capacities. In a Col7a1-/- mouse model of RDEB, treatment with ABCB5+ MSCs markedly extended the animals' lifespans.METHODSIn this international, multicentric, single-arm, phase I/IIa clinical trial, 16 patients (aged 4-36 years) enrolled into 4 age cohorts received 3 i.v. infusions of 2 × 106 ABCB5+ MSCs/kg on days 0, 17, and 35. Patients were followed up for 12 weeks regarding efficacy and 12 months regarding safety.RESULTSAt 12 weeks, statistically significant median (IQR) reductions in the Epidermolysis Bullosa Disease Activity and Scarring Index activity (EBDASI activity) score of 13.0% (2.9%-30%; P = 0.049) and the Instrument for Scoring Clinical Outcome of Research for Epidermolysis Bullosa clinician (iscorEB‑c) score of 18.2% (1.9%-39.8%; P = 0.037) were observed. Reductions in itch and pain numerical rating scale scores were greatest on day 35, amounting to 37.5% (0.0%-42.9%; P = 0.033) and 25.0% (-8.4% to 46.4%; P = 0.168), respectively. Three adverse events were considered related to the cell product: 1 mild lymphadenopathy and 2 hypersensitivity reactions. The latter 2 were serious but resolved without sequelae shortly after withdrawal of treatment.CONCLUSIONThis trial demonstrates good tolerability, manageable safety, and potential efficacy of i.v. ABCB5+ MSCs as a readily available disease-modifying therapy for RDEB and provides a rationale for further clinical evaluation.TRIAL REGISTRATIONClinicaltrials.gov NCT03529877; EudraCT 2018-001009-98.FUNDINGThe trial was sponsored by RHEACELL GmbH & Co. KG. Contributions by NYF and MHF to this work were supported by the NIH/National Eye Institute (NEI) grants RO1EY025794 and R24EY028767.
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http://dx.doi.org/10.1172/jci.insight.151922DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8663784PMC
November 2021

Understanding and managing uncertainty and variability for wastewater monitoring beyond the pandemic: Lessons learned from the United Kingdom national COVID-19 surveillance programmes.

J Hazard Mater 2022 Feb 8;424(Pt B):127456. Epub 2021 Oct 8.

Cardiff University, Cardiff School of Biosciences, The Sir Martin Evans Building, Museum Avenue, Cardiff CF10 3AX, UK.

The COVID-19 pandemic has put unprecedented pressure on public health resources around the world. From adversity, opportunities have arisen to measure the state and dynamics of human disease at a scale not seen before. In the United Kingdom, the evidence that wastewater could be used to monitor the SARS-CoV-2 virus prompted the development of National wastewater surveillance programmes. The scale and pace of this work has proven to be unique in monitoring of virus dynamics at a national level, demonstrating the importance of wastewater-based epidemiology (WBE) for public health protection. Beyond COVID-19, it can provide additional value for monitoring and informing on a range of biological and chemical markers of human health. A discussion of measurement uncertainty associated with surveillance of wastewater, focusing on lessons-learned from the UK programmes monitoring COVID-19 is presented, showing that sources of uncertainty impacting measurement quality and interpretation of data for public health decision-making, are varied and complex. While some factors remain poorly understood, we present approaches taken by the UK programmes to manage and mitigate the more tractable sources of uncertainty. This work provides a platform to integrate uncertainty management into WBE activities as part of global One Health initiatives beyond the pandemic.
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http://dx.doi.org/10.1016/j.jhazmat.2021.127456DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8498793PMC
February 2022

Seven short reflections on the notion of schizophrenia.

Schizophr Res 2021 Oct 8. Epub 2021 Oct 8.

Queensland Brain Institute, University of Queensland, St Lucia, Queensland, Australia; Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia. Electronic address:

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http://dx.doi.org/10.1016/j.schres.2021.09.026DOI Listing
October 2021

Performance evaluation of a PET insert for preclinical MRI in stand-alone PET and simultaneous PET-MRI modes.

EJNMMI Phys 2021 Oct 9;8(1):68. Epub 2021 Oct 9.

Sydney School of Health Sciences, The University of Sydney, Camperdown, NSW, 2050, Australia.

Background: This study aimed to evaluate the performance of a preclinical PET insert in three configurations: as a stand-alone unit outside the MRI bore, inside the bore of a cryogen-free 3T MRI and, finally, while performing simultaneous PET/MRI studies.

Methods: The PET insert consists of two rings of six detectors, each detector comprising 8 × 12 SiPMs reading out dual offset layers of pixelated LYSO crystals with a 1.4-mm pitch. The inner diameter is 60 mm, transaxial field of view (FoV) 40 mm and axial FoV 98 mm. Evaluation was based on NEMA NU 4-2008 guidelines with appropriate modifications. Spatial resolution and sensitivity were measured inside and outside the MR bore. Image quality, count rate and quantitative performance were measured in all three configurations. The effect of temperature stability on PET sensitivity during fast spin echo sequences was also evaluated. B field homogeneity and T1 and T2 relaxation times were measured using a water-filled phantom, with and without simultaneous PET operation. Finally, PET and MRI scans of a mouse injected with 10 MBq [F]NaF and a mouse injected with 16 MBq [F]FDG were performed in sequential and simultaneous modes.

Results: Peak absolute sensitivity was 10.15% with an energy window of 250-750 keV. Absolute sensitivity values outside and inside the MR bore with MR idle agreed to within 0.1%. Outside the MR bore, spatial resolution was 1.21/1.59 mm FWHM (radial/tangential) 5 mm from the centre of the FoV which compared well with 1.19/1.26 mm FWHM inside the MR bore. There were no substantial differences between all three scan configurations in terms of peak NEC rate (175 kcps at 17 MBq), scatter or random fractions. Uniformity and recovery coefficients were also consistent between scanning modes. B field homogeneity and T1 and T2 relaxation times were unaltered by the presence of the PET insert. No significant differences were observed between sequential and simultaneous scans of the animals.

Conclusions: We conclude that the performance of the PET insert and MRI system is not significantly affected by the scanning mode.
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http://dx.doi.org/10.1186/s40658-021-00415-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8502182PMC
October 2021

UK national bladder outlet obstruction surgery snapshot audit.

BJU Int 2021 Oct 7. Epub 2021 Oct 7.

Department of Urology, University Hospitals Plymouth, Plymouth, UK.

Objectives: To determine the preoperative assessment and perioperative outcomes of men undergoing bladder outlet obstruction (BOO) surgery in the UK.

Patients And Methods: A retrospective cohort study was conducted of all men undergoing BOO surgery in 105 UK hospitals over a 1-month period. The study included 1456 men, of whom 42% were catheter dependent prior to undergoing surgery.

Results: There was no evidence that a frequency-volume chart or urinary symptom questionnaire had been completed in 73% or 50% of men, respectively in the non-catheter-dependent group. Bipolar transurethral resection of the prostate (TURP) was the most common BOO surgical procedure performed (38%). Monopolar TURP was the next most prevalent modality (23%); however, minimally invasive BOO surgical procedures combined accounted for 17% of all procedures performed. Of the cohort 5% of men had complications within 30 days of surgery, only 1% had Clavien-Dindo Grade ≥III complications. Less than 1% of the cohort received a blood transfusion after BOO surgery and 2% were re-admitted to hospital after their BOO surgery. In total only 4% of the whole cohort were catheter dependent after BOO surgery. Pre- and postoperative paired International Prostate Symptom Score scores reviewed suggest that minimally invasive surgical procedures achieved comparable levels of improvement in both symptoms and bother at 3 months postoperatively in men who were not catheter dependent preoperatively.

Conclusions: There has been a substantial shift in the available choice of procedure for BOO surgery around the UK in recent years. However, men can be reassured that overall BOO surgery treatments are safe and effective. Evidence of adherence to guidelines in the preoperative assessment of men with lower urinary tract symptoms undergoing surgery was poorly documented and must be improved.
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http://dx.doi.org/10.1111/bju.15610DOI Listing
October 2021

Unravelling the genetic basis of contact allergy.

Contact Dermatitis 2022 Jan 19;86(1):1-2. Epub 2021 Oct 19.

Department of Cutaneous Allergy, St. John's Institute of Dermatology, London, UK.

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http://dx.doi.org/10.1111/cod.13983DOI Listing
January 2022

The natural history of laryngo-onycho-cutaneous syndrome: A case series of six pediatric patients and literature review.

Pediatr Dermatol 2021 Sep 13;38(5):1094-1101. Epub 2021 Sep 13.

Department of Dermatology, Great Ormond Street Hospital for Children, NHS Foundation Trust, London, UK.

Background/objectives: Laryngo-onycho-cutaneous syndrome (LOC) is a rare subtype of junctional epidermolysis bullosa (JEB), featuring aberrant granulation tissue formation in the skin, larynx, and eyes. So far, three mutations including the specific (founder) mutation in exon 39 of LAMA3 (c.151dup) have been identified, but sparse data exists regarding the natural history, the genotype-phenotype correlation, and its differentiation from other JEB types.

Methods: We reviewed our pediatric EB database to identify English children with clinical and genetically diagnosed LOC within the last 15 years. Their demographic, clinical, and laboratory data were examined. We searched three databases for case reports of LOC between January 1986 and November 2020 and extracted clinical and molecular details.

Results: We identified 6 LOC patients, all female (mean age 5.4 years). Periungual hypergranulation and skin fragility were the earliest presenting signs (0-3 months), followed by laryngeal stenosis, symblepharon (mean onset 10.7 and 11.8 months, respectively), and dental abnormalities. Five children developed anemia at an average of 19.2 months. We identified 22 published studies in English with 31 cases.

Conclusions: This study delineates the disease course of LOC and highlights the overlap with some forms of JEB. Classical signs/symptoms including anemia appear early in life. Genetic analysis revealed three new LOC-associated variants and underscores the finding that interpretation of skin immunolabeling and molecular diagnostics can be challenging. We provide recommendations on management of this complex syndrome.
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http://dx.doi.org/10.1111/pde.14790DOI Listing
September 2021
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