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PURPOSE: This study uses free-floating contractile fibroblast-populated collagen matrices (FPCMs) to test the shrinkage of different hernia mesh products. We hope to present this model as a proof of concept for the development of in vitro hernia mesh testing-a novel technology with interesting potential. METHODS: FPCMs were formed by seeding Human Dermal Fibroblasts into collagen gels. FPCMs were seeded with three different cell densities and cast at a volume of 500 µl into 24-well plates. Five different mesh products were embedded within the collagen constructs. Gels were left to float freely within culture media and contract over 5 days. Photographs were taken daily and the area of the collagen gel and mesh were measured. Media samples were taken at days 2 and 4 for the purposes of measuring MMP-9 release. After 5 days, dehydrated FPCMs were also examined under light and fluorescence microscopy to assess cell morphology. RESULTS: Two mesh products-the mosquito net and large pore lightweight mesh were found to shrink notably more than others. This pattern persisted across all three cell densities. There were no appreciable differences observed in MMP-9 release between products. CONCLUSIONS: This study has successfully demonstrated that commercial mesh products can be successfully integrated into free-floating contractile FPCMs. Not only this, but FPCMs are capable of applying a contractile force upon those mesh products-eliciting different levels of contraction between mesh products. Such findings demonstrate this technique as a useful proof of concept for future development of in vitro hernia mesh testing.
Subject(s)
Matrix Metalloproteinase 9 , Surgical Mesh , Humans , Herniorrhaphy , Collagen , Hernia , Fibroblasts , GelsABSTRACT
Several long-period radio transients have recently been discovered, with strongly polarized coherent radio pulses appearing on timescales between tens to thousands of seconds1,2. In some cases, the radio pulses have been interpreted as coming from rotating neutron stars with extremely strong magnetic fields, known as magnetars; the origin of other, occasionally periodic and less-well-sampled radio transients is still debated3. Coherent periodic radio emission is usually explained by rotating dipolar magnetic fields and pair-production mechanisms, but such models do not easily predict radio emission from such slowly rotating neutron stars and maintain it for extended times. On the other hand, highly magnetic isolated white dwarfs would be expected to have long spin periodicities, but periodic coherent radio emission has not yet been directly detected from these sources. Here we report observations of a long-period (21 min) radio transient, which we have labelled GPM J1839-10. The pulses vary in brightness by two orders of magnitude, last between 30 and 300 s and have quasiperiodic substructure. The observations prompted a search of radio archives and we found that the source has been repeating since at least 1988. The archival data enabled constraint of the period derivative to <3.6 × 10-13 s s-1, which is at the very limit of any classical theoretical model that predicts dipolar radio emission from an isolated neutron star.
ABSTRACT
Objectives: The primary outcome of this study is to assess the perspectives of Hospitalists on their workload and their perceived effects on patient care. The secondary outcomes are to evaluate the satisfaction of the Hospitalists with their compensation, quality of life, scholarship activity and promotion in their department and the support received to achieve this. Methodology: We developed a 49-question questionnaire. The questionnaire was based on (a) Oldenburg Burnout Inventory and (b) topics specific to census, compensation, academic support with desire for promotion, and the effects of workload on patient care and teaching. All questions were formatted with a 4-point Likert-type response scale. The questionnaires were distributed electronically using an online survey platform to all 32 of the Hospitalists at our institution. Conclusion: Each institution needs to do a self-assessment based on clinician feedback: Hospitalists workload, burn-out and satisfaction to reduce the high turnover rates and brevity of this role. From this study in this academic institution, the perspectives of Hospitalists revealed a high level of burn out (exhaustion and disengagement) and high assigned patient censuses that negatively impact their ability to deliver optimal patient care. Most Hospitalists reported lack of mentorship and inadequate time allocated for scholarly activity. The majority reported not having their input on decisions made by the administration that directly affect them. Most were unsatisfied with their compensation and the lack of PTO (paid time off). The majority would like to be promoted in this academic institution but feel unsupported to achieve this goal.
ABSTRACT
Fast radio bursts (FRBs) are flashes of unknown physical origin1. The majority of FRBs have been seen only once, although some are known to generate multiple flashes2,3. Many models invoke magnetically powered neutron stars (magnetars) as the source of the emission4,5. Recently, the discovery6 of another repeater (FRB 20200120E) was announced, in the direction of the nearby galaxy M81, with four potential counterparts at other wavelengths6. Here we report observations that localized the FRB to a globular cluster associated with M81, where it is 2 parsecs away from the optical centre of the cluster. Globular clusters host old stellar populations, challenging FRB models that invoke young magnetars formed in a core-collapse supernova. We propose instead that FRB 20200120E originates from a highly magnetized neutron star formed either through the accretion-induced collapse of a white dwarf, or the merger of compact stars in a binary system7. Compact binaries are efficiently formed inside globular clusters, so a model invoking them could also be responsible for the observed bursts.
ABSTRACT
PURPOSE: Before being marketed, hernia mesh must undergo in vivo testing, which often includes biomechanical and histological assessment. Currently, there are no universal standards for this testing and methods vary greatly within the literature. A scoping review of relevant studies was undertaken to analyse the methodologies used for in vivo mesh testing. METHODS: Medline and Embase databases were searched for relevant studies. 513 articles were identified and 231 duplicates excluded. 126 papers were included after abstract and full text review. The data extraction was undertaken using standardised forms. RESULTS: Mesh is most commonly tested in rats (53%). 78% of studies involve the formation of a defect; in 52% of which the fascia is not opposed. The most common hernia models use mesh to bridge an acute defect (50%). Tensile strength testing is the commonest form of mechanical testing (63%). Testing strip widths and test speeds vary greatly (4-30 mm and 1.625-240 mm/min, respectively). There is little consensus on which units to use for tensile strength testing. Collagen is assessed for its abundance (54 studies) more than its alignment (18 studies). Alignment is not measured quantitatively. At least 21 histological scoring systems are used for in vivo mesh testing. CONCLUSIONS: The current practice of in vivo mesh testing lacks standardisation. There is significant inconsistency in every category of testing, both in methodology and comparators. We would call upon hernia organisations and materials testing institutions to discuss the need for a standardised approach to this field.
Subject(s)
Herniorrhaphy , Surgical Mesh , Animals , Hernia , Herniorrhaphy/methods , Humans , Materials Testing , Prostheses and Implants , Rats , Surgical Mesh/adverse effects , Tensile StrengthABSTRACT
BACKGROUND: Prevalence of depression is increasing in young people, and there is a need to develop and evaluate behavioural interventions which may provide benefits equal to or greater than talking therapies or pharmacological alternatives. Exercise could be beneficial for young people living with depression, but robust, large-scale trials of effectiveness and the impact of exercise intensity are lacking. This study aims to test whether a randomised controlled trial (RCT) of an intervention targeting young people living with depression is feasible by determining whether it is possible to recruit and retain young people, develop and deliver the intervention as planned, and evaluate training and delivery. METHODS: The design is a three-arm cluster randomised controlled feasibility trial with embedded process evaluation. Participants will be help-seeking young people, aged 13-17 years experiencing mild to moderate low mood or depression, referred from three counties in England. The intervention will be delivered by registered exercise professionals, supported by mental health support workers, twice a week for 12 weeks. The three arms will be high-intensity exercise, low-intensity exercise, and a social activity control. All arms will receive a 'healthy living' behaviour change session prior to each exercise session and the two exercise groups are energy matched. The outcomes are referral, recruitment, and retention rates; attendance at exercise sessions; adherence to and ability to reach intensity during exercise sessions; proportions of missing data; adverse events, all measured at baseline, 3, and 6 months; resource use; and reach and representativeness. DISCUSSION: UK National Health Service (NHS) policy is to provide young people with advice about using exercise to help depression but there is no evidence-based exercise intervention to either complement or as an alternative to medication or talking therapies. UK National Institute for Health and Care Excellence (NICE) guidelines suggest that exercise can be an effective treatment, but the evidence base is relatively weak. This feasibility trial will provide evidence about whether it is feasible to recruit and retain young people to a full RCT to assess the effectiveness and cost-effectiveness of an exercise intervention for depression. TRIAL REGISTRATION: ISRCTN, ISRCTN66452702 . Registered 9 April 2020.
ABSTRACT
We present a rare and previously undocumented potential complication of computed tomography (CT) colonography. CT colonography is a commonly performed investigation with a relatively low risk of complications. While splenic injury is a well-documented complication after colonoscopy, it has never been reported following CT colonography. A 64-year-old man presented with severe abdominal pain four hours after CT colonography. CT of his abdomen and pelvis revealed appearances consistent with intra-abdominal bleeding secondary to splenic injury. The patient immediately underwent an emergency laparotomy and splenectomy, revealing a grade III splenic capsular tear. Histological evaluation of splenic tissue showed normal morphology with no evidence of malignancy. While the aetiology of the patient's splenic injury remains uncertain, normal histopathology and the chronology of events represents an almost certain link to CT colonography.
Subject(s)
Colonography, Computed Tomographic/adverse effects , Spleen/injuries , Abdominal Pain/etiology , Colon/diagnostic imaging , Humans , Male , Middle Aged , Spleen/surgery , SplenectomyABSTRACT
To survive in terrestrial and aquatic environments, spiders often rely heavily on their silk. The vast majority of silks that have been studied are from orb-web or cob-web weaving species, leaving the silks of water-associated spiders largely undescribed. We characterize transcripts, proteins, and silk fibres from the semi-aquatic spider Dolomedes triton. From silk gland RNAseq libraries, we report 18 silk transcripts representing four categories of known silk protein types: aciniform, ampullate, pyriform, and tubuliform. Proteomic and structural analyses (scanning electron microscopy, energy dispersive X-ray spectrometry, contact angle) of the D. triton submersible egg sac reveal similarities to silks from aquatic caddisfly larvae. We identified two layers in D. triton egg sacs, notably a highly hydrophobic outer layer with a different elemental composition compared to egg sacs of terrestrial spiders. These features may provide D. triton egg sacs with their water repellent properties.
Subject(s)
Fibroins/chemistry , Spiders/metabolism , Animals , Female , Fibroins/genetics , Hydrophobic and Hydrophilic Interactions , Microscopy, Electron, Scanning , Sex Characteristics , Spiders/genetics , Transcriptome , WaterABSTRACT
ABSTRACT The medical records of 983 patients diagnosed with the human immunodeficiency virus (HIV) were reviewed, 501 of whom were female and 482 were male. The mean age was 42.1 years, the mean number of years since diagnosis of HIV was 7.4, and the average duration of highly active antiretroviral therapy (HAART) was 51.7 months. The mean CD4 count at diagnosis was 268.5 cells/μL, but the most recent CD4 count was 461 cells/μL, and 85.8% of the patients were on HAART. The mean CD4 count was lower in those with a glomerular filtration rate (GFR) of < 60 ml/minute/1.73m2 compared to those patients with only proteinuria and a GFR of > 60 ml/minute/1.73m2. In the sample population, 76.9% of the patients had chronic kidney disease stage 3, 7.7% were in stage 4 and 15.4% in stage 5. There were 3.1% of patients with persistent proteinuria. Hypertension and diabetes mellitus were co-morbidities.
RESUMEN Se revisaron las historias clínicas de 983 pacientes diagnosticados con el virus de la inmunodeficiencia humana (VIH), 501 de los cuales eran mujeres, y 482 hombres. La edad promedio fue de 42.1 años, el número promedio de años a partir del diagnóstico de VIH fue 7.4, y la duración promedio de la terapia antirretroviral altamente activa (TARAA) fue de 51.7 meses. El conteo de CD4 promedio en el momento del diagnóstico fue de 268.5 células/μl pero el más reciente conteo de CD4 fue de 461 células/μl y el 85.8% de los pacientes se encontraban bajo terapia TARAA. El conteo de CD4 promedio fue menor en aquellos pacientes con una tasa de filtrado glomerular (TFG) de < 60 ml/minuto/1.73 m2, en comparación con los pacientes que tenían sólo proteinuria y una TFG de > 60 ml/minute/1.73 m2. En la población de la muestra, el 76.9% de los pacientes tenía enfermedad renal crónica en etapa 3, el 7.7% estaba en la etapa 4, y el 15.4% en la etapa 5. Había 3.1% de pacientes con proteinuria persistente. La hipertensión y la diabetes mellitus fueron comorbilidades.
Subject(s)
Humans , Male , Female , Adult , HIV Infections/epidemiology , Renal Insufficiency, Chronic/epidemiology , Prevalence , Risk Factors , Jamaica/epidemiologyABSTRACT
BACKGROUND: Schizophrenia is a highly heritable disorder, linked to several structural abnormalities of the brain. More specifically, previous findings have suggested that increased gyrification in frontal and temporal regions are implicated in the pathogenesis of schizophrenia. METHODS: The current study included participants at high familial risk of schizophrenia who remained well (n = 31), who developed sub-diagnostic symptoms (n = 28) and who developed schizophrenia (n = 9) as well as healthy controls (HC) (n = 16). We first tested whether individuals at high familial risk of schizophrenia carried an increased burden of trait-associated alleles using polygenic risk score analysis. We then assessed the extent to which polygenic risk was associated with gyral folding in the frontal and temporal lobes. RESULTS: We found that individuals at high familial risk of schizophrenia who developed schizophrenia carried a significantly greater burden of risk-conferring variants for the disorder compared to those at high risk (HR) who developed sub-diagnostic symptoms or remained well and HC. Furthermore, within the HR cohort, there was a significant and positive association between schizophrenia polygenic risk score and bilateral frontal gyrification. CONCLUSIONS: These results suggest that polygenic risk for schizophrenia impacts upon early neurodevelopment to confer greater gyral folding in adulthood and an increased risk of developing the disorder.
Subject(s)
Multifactorial Inheritance , Schizophrenia/genetics , Schizophrenia/pathology , Temporal Lobe/pathology , Adolescent , Adult , Female , Genetic Predisposition to Disease , Humans , Longitudinal Studies , Magnetic Resonance Imaging , Male , Polymorphism, Single Nucleotide , Prospective Studies , Risk Assessment , Young AdultSubject(s)
Depressive Disorder, Major/psychology , Resilience, Psychological , Adaptation, Psychological , Aged , Cohort Studies , Cross-Sectional Studies , Depressive Disorder, Major/epidemiology , Family Health , Female , Health Status , Humans , Male , Mental Health , Middle Aged , Scotland/epidemiology , Socioeconomic Factors , Substance-Related Disorders/epidemiology , Substance-Related Disorders/psychology , Surveys and QuestionnairesABSTRACT
Gravitational waves have been detected from a binary neutron star merger event, GW170817. The detection of electromagnetic radiation from the same source has shown that the merger occurred in the outskirts of the galaxy NGC 4993, at a distance of 40 megaparsecs from Earth. We report the detection of a counterpart radio source that appears 16 days after the event, allowing us to diagnose the energetics and environment of the merger. The observed radio emission can be explained by either a collimated ultrarelativistic jet, viewed off-axis, or a cocoon of mildly relativistic ejecta. Within 100 days of the merger, the radio light curves will enable observers to distinguish between these models, and the angular velocity and geometry of the debris will be directly measurable by very long baseline interferometry.
ABSTRACT
Alcohol consumption has been linked to over 200 diseases and is responsible for over 5% of the global disease burden. Well-known genetic variants in alcohol metabolizing genes, for example, ALDH2 and ADH1B, are strongly associated with alcohol consumption but have limited impact in European populations where they are found at low frequency. We performed a genome-wide association study (GWAS) of self-reported alcohol consumption in 112 117 individuals in the UK Biobank (UKB) sample of white British individuals. We report significant genome-wide associations at 14 loci. These include single-nucleotide polymorphisms (SNPs) in alcohol metabolizing genes (ADH1B/ADH1C/ADH5) and two loci in KLB, a gene recently associated with alcohol consumption. We also identify SNPs at novel loci including GCKR, CADM2 and FAM69C. Gene-based analyses found significant associations with genes implicated in the neurobiology of substance use (DRD2, PDE4B). GCTA analyses found a significant SNP-based heritability of self-reported alcohol consumption of 13% (se=0.01). Sex-specific analyses found largely overlapping GWAS loci and the genetic correlation (rG) between male and female alcohol consumption was 0.90 (s.e.=0.09, P-value=7.16 × 10-23). Using LD score regression, genetic overlap was found between alcohol consumption and years of schooling (rG=0.18, s.e.=0.03), high-density lipoprotein cholesterol (rG=0.28, s.e.=0.05), smoking (rG=0.40, s.e.=0.06) and various anthropometric traits (for example, overweight, rG=-0.19, s.e.=0.05). This study replicates the association between alcohol consumption and alcohol metabolizing genes and KLB, and identifies novel gene associations that should be the focus of future studies investigating the neurobiology of alcohol consumption.
Subject(s)
Alcohol Dehydrogenase/genetics , Alcohol Drinking/genetics , Adult , Aged , Alcohol Dehydrogenase/metabolism , Alcoholism/genetics , Aldehyde Dehydrogenase/genetics , Biological Specimen Banks , Female , Genetic Predisposition to Disease/genetics , Genetic Testing , Genetic Variation , Genome-Wide Association Study , Humans , Klotho Proteins , Male , Membrane Proteins/genetics , Middle Aged , Polymorphism, Single Nucleotide/genetics , United Kingdom , White People/geneticsABSTRACT
Major depressive disorder (MDD) is a heritable and highly debilitating condition. It is commonly associated with subcortical volumetric abnormalities, the most replicated of these being reduced hippocampal volume. Using the most recent published data from Enhancing Neuroimaging Genetics through Meta-analysis (ENIGMA) consortium's genome-wide association study of regional brain volume, we sought to test whether there is shared genetic architecture between seven subcortical brain volumes and intracranial volume (ICV) and MDD. We explored this using linkage disequilibrium score regression, polygenic risk scoring (PRS) techniques, Mendelian randomisation (MR) analysis and BUHMBOX. Utilising summary statistics from ENIGMA and Psychiatric Genomics Consortium, we demonstrated that hippocampal volume was positively genetically correlated with MDD (rG=0.46, P=0.02), although this did not survive multiple comparison testing. None of the other six brain regions studied were genetically correlated and amygdala volume heritability was too low for analysis. Using PRS analysis, no regional volumetric PRS demonstrated a significant association with MDD or recurrent MDD. MR analysis in hippocampal volume and MDD identified no causal association, however, BUHMBOX analysis identified genetic subgrouping in GS:SFHS MDD cases only (P=0.00281). In this study, we provide some evidence that hippocampal volume and MDD may share genetic architecture in a subgroup of individuals, albeit the genetic correlation did not survive multiple testing correction and genetic subgroup heterogeneity was not replicated. In contrast, we found no evidence to support a shared genetic architecture between MDD and other regional subcortical volumes or ICV.
Subject(s)
Brain/pathology , Depressive Disorder, Major/genetics , Depressive Disorder, Major/pathology , Adult , Aged , Cohort Studies , Female , Genetic Predisposition to Disease , Genome-Wide Association Study , Genotype , Hippocampus/pathology , Humans , Male , Middle Aged , United KingdomABSTRACT
Borderline personality disorder (BOR) is determined by environmental and genetic factors, and characterized by affective instability and impulsivity, diagnostic symptoms also observed in manic phases of bipolar disorder (BIP). Up to 20% of BIP patients show comorbidity with BOR. This report describes the first case-control genome-wide association study (GWAS) of BOR, performed in one of the largest BOR patient samples worldwide. The focus of our analysis was (i) to detect genes and gene sets involved in BOR and (ii) to investigate the genetic overlap with BIP. As there is considerable genetic overlap between BIP, major depression (MDD) and schizophrenia (SCZ) and a high comorbidity of BOR and MDD, we also analyzed the genetic overlap of BOR with SCZ and MDD. GWAS, gene-based tests and gene-set analyses were performed in 998 BOR patients and 1545 controls. Linkage disequilibrium score regression was used to detect the genetic overlap between BOR and these disorders. Single marker analysis revealed no significant association after correction for multiple testing. Gene-based analysis yielded two significant genes: DPYD (P=4.42 × 10-7) and PKP4 (P=8.67 × 10-7); and gene-set analysis yielded a significant finding for exocytosis (GO:0006887, PFDR=0.019; FDR, false discovery rate). Prior studies have implicated DPYD, PKP4 and exocytosis in BIP and SCZ. The most notable finding of the present study was the genetic overlap of BOR with BIP (rg=0.28 [P=2.99 × 10-3]), SCZ (rg=0.34 [P=4.37 × 10-5]) and MDD (rg=0.57 [P=1.04 × 10-3]). We believe our study is the first to demonstrate that BOR overlaps with BIP, MDD and SCZ on the genetic level. Whether this is confined to transdiagnostic clinical symptoms should be examined in future studies.
Subject(s)
Bipolar Disorder/genetics , Borderline Personality Disorder/genetics , Depressive Disorder, Major/genetics , Schizophrenia/genetics , Adolescent , Adult , Aged , Case-Control Studies , Female , Genetic Predisposition to Disease , Genome-Wide Association Study , Genotype , Humans , Male , Middle Aged , Multifactorial Inheritance , Young AdultABSTRACT
Introduction The aim of this study was to identify patient factors including serum biomarkers that may predict response to neoadjuvant chemoradiotherapy (CRT) in patients with locally advanced rectal cancer staged on magnetic resonance imaging. Prediction of response may be helpful when selecting patients for a non-operative programme. Methods A retrospective review was carried out of patients undergoing neoadjuvant CRT for rectal cancer, conducted at the Royal Devon and Exeter Hospital. All patients were managed through the multidisciplinary team. Receiver operating characteristic (ROC) curve analysis was undertaken to assess the ability of biomarkers to predict response to neoadjuvant CRT. The biomarkers assessed included neutrophils, lymphocytes, monocytes, haemoglobin, platelets, C-reactive protein and carcinoembryonic antigen. Results Seventy-three patients underwent neoadjuvant CRT between January 2006 and December 2011. Nine (12.3%) of these experienced a clinical complete response and were managed with a 'watch and wait' approach. An additional ten patients (13.7%) had a pathological complete response following surgery. Using ROC curve analysis, the biomarkers with the largest area under the curve (AUC) were pre-CRT haemoglobin and post-CRT lymphocyte concentrations, producing AUC values of 0.673 and 0.618 respectively for clinical complete response. Pre-CRT haemoglobin and neutrophil concentrations produced the highest AUC values for pathological complete response at 0.591 and 0.614 respectively. Conclusions None of the assessed biomarkers offer the ability to predict response to neoadjuvant CRT in patients with rectal cancer. They cannot therefore assist in identifying complete clinical or pathological responders who could be considered for a non-operative, observational approach.
Subject(s)
Biomarkers, Tumor/blood , Chemoradiotherapy , Neoadjuvant Therapy , Rectal Neoplasms/blood , Rectal Neoplasms/therapy , Aged , Female , Humans , Male , Middle Aged , Neoplasm Recurrence, Local , Predictive Value of Tests , Retrospective Studies , Treatment OutcomeABSTRACT
Major depressive disorder (MDD) and Alzheimer's disease (AD) are both common in older age and frequently co-occur. Numerous phenotypic studies based on clinical diagnoses suggest that a history of depression increases risk of subsequent AD, although the basis of this relationship is uncertain. Both illnesses are polygenic, and shared genetic risk factors could explain some of the observed association. We used genotype data to test whether MDD and AD have an overlapping polygenic architecture in two large population-based cohorts, Generation Scotland's Scottish Family Health Study (GS:SFHS; N=19 889) and UK Biobank (N=25 118), and whether age of depression onset influences any relationship. Using two complementary techniques, we found no evidence that the disorders are influenced by common genetic variants. Using linkage disequilibrium score regression with genome-wide association study (GWAS) summary statistics from the International Genomics of Alzheimer's Project, we report no significant genetic correlation between AD and MDD (rG=-0.103, P=0.59). Polygenic risk scores (PRS) generated using summary data from International Genomics of Alzheimer's Project (IGAP) and the Psychiatric Genomics Consortium were used to assess potential pleiotropy between the disorders. PRS for MDD were nominally associated with participant-recalled AD family history in GS:SFHS, although this association did not survive multiple comparison testing. AD PRS were not associated with depression status or late-onset depression, and a survival analysis showed no association between age of depression onset and genetic risk for AD. This study found no evidence to support a common polygenic structure for AD and MDD, suggesting that the comorbidity of these disorders is not explained by common genetic variants.
Subject(s)
Alzheimer Disease/genetics , Depressive Disorder, Major/genetics , Genome-Wide Association Study , Multifactorial Inheritance/genetics , Adult , Age Factors , Age of Onset , Alzheimer Disease/diagnosis , Alzheimer Disease/mortality , Case-Control Studies , Cohort Studies , Depressive Disorder, Major/diagnosis , Depressive Disorder, Major/mortality , Female , Genetic Predisposition to Disease/genetics , Humans , Male , Middle Aged , Polymorphism, Single Nucleotide/genetics , Statistics as Topic , Survival AnalysisABSTRACT
Major depressive disorder (MDD) is a common, complex psychiatric disorder and a leading cause of disability worldwide. Despite twin studies indicating its modest heritability (~30-40%), extensive heterogeneity and a complex genetic architecture have complicated efforts to detect associated genetic risk variants. We combined single-nucleotide polymorphism (SNP) summary statistics from the CONVERGE and PGC studies of MDD, representing 10 502 Chinese (5282 cases and 5220 controls) and 18 663 European (9447 cases and 9215 controls) subjects. We determined the fraction of SNPs displaying consistent directions of effect, assessed the significance of polygenic risk scores and estimated the genetic correlation of MDD across ancestries. Subsequent trans-ancestry meta-analyses combined SNP-level evidence of association. Sign tests and polygenic score profiling weakly support an overlap of SNP effects between East Asian and European populations. We estimated the trans-ancestry genetic correlation of lifetime MDD as 0.33; female-only and recurrent MDD yielded estimates of 0.40 and 0.41, respectively. Common variants downstream of GPHN achieved genome-wide significance by Bayesian trans-ancestry meta-analysis (rs9323497; log10 Bayes Factor=8.08) but failed to replicate in an independent European sample (P=0.911). Gene-set enrichment analyses indicate enrichment of genes involved in neuronal development and axonal trafficking. We successfully demonstrate a partially shared polygenic basis of MDD in East Asian and European populations. Taken together, these findings support a complex etiology for MDD and possible population differences in predisposing genetic factors, with important implications for future genetic studies.
Subject(s)
Asian People/genetics , Depressive Disorder, Major/genetics , White People/genetics , Bayes Theorem , Case-Control Studies , China , Europe , Female , Genetic Predisposition to Disease , Humans , Male , Multifactorial Inheritance , Polymorphism, Single NucleotideABSTRACT
Nitrite, in equilibrium with free nitrous acid (FNA), can inhibit both aerobic and anaerobic growth of microbial communities through bactericidal activities that have considerable potential for control of microbial growth in a range of water systems. There has been much focus on the effect of nitrite/FNA on anaerobic metabolism and so, to enhance understanding of the metabolic impact of nitrite/FNA on aerobic metabolism, a study was undertaken with a model denitrifying bacterium Paracoccus denitrificans PD1222. Extracellular nitrite inhibits aerobic growth of P. denitrificans in a pH-dependent manner that is likely to be a result of both nitrite and free nitrous acid (pKa = 3.25) and subsequent reactive nitrogen oxides generated from the intracellular passage of FNA into P. denitrificans. Increased expression of a gene encoding a flavohemoglobin protein (Fhp) (Pden_1689) was observed in response to extracellular nitrite. Construction and analysis of a deletion mutant established Fhp to be involved in endowing nitrite/FNA resistance at high extracellular nitrite concentrations. Global transcriptional analysis confirmed nitrite-dependent expression of fhp and indicated that P. denitrificans expressed a number of stress response systems associated with protein, DNA and lipid repair. It is therefore suggested that nitrite causes a pH-dependent stress response that is due to the production of associated reactive nitrogen species, such as nitric oxide from the internalisation of FNA.
Subject(s)
Nitrites/metabolism , Paracoccus denitrificans , Denitrification , Nitric Oxide/metabolism , Oxidation-ReductionABSTRACT
Introduction Pseudoaneurysm formation following ankle arthroscopy is a rare but potentially catastrophic complication. The placement of anterior ankle portals carries inherent risk to the superficial and deep peroneal nerves, as well as to the dorsalis pedis artery. Anatomical variations in the dorsalis pedis and the presence of branches at the joint line may increase the risk of vascular injury and pseudoaneurysm formation during arthroscopy. There is limited anatomical evidence available regarding the branches of the dorsalis pedis artery, which occur at the point at which they cross the ankle joint. Objectives The objective of the study was to describe the frequency and direction of branches of the dorsalis pedis crossing the ankle joint. Materials and Methods Nineteen cadaveric feet were carefully dissected to explore the course of the dorsalis pedis artery, noting in particular the branching pattern at the joint line. Results Eleven of the nineteen feet had a branch of the dorsalis pedis artery that crossed the level of the ankle joint. Out of these, six were lateral, four medial and one bilateral. Eight of the eleven specimens had one branch at, or just before, the level of the joint. Two specimens had two branches and one had three branches crossing the ankle, which were all in the same direction, crossing laterally to the main trunk of the dorsalis pedis. Conclusions Our study demonstrated high rates of branching of the dorsalis pedis artery at the level of the ankle joint. The role of these branches in pseudoaneurysm formation during anterior hindfoot surgery remains unclear.