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BackgroundThe corpus callosum (CC) is a brain structure with a high heritability and potential role in psychiatric disorders. However, the genetic architecture of the CC and the genetic link with psychiatric disorders remains largely unclear. We investigated the genetic architectures of the volume of the CC and its subregions, and the genetic overlap with psychiatric disorders.MethodsWe applied multivariate GWAS to genetic and T1-weighted MRI data of 40,894 individuals from the UK Biobank, aiming to boost genetic discovery and to assess the pleiotropic effects across volumes of the five subregions of the CC (posterior, mid posterior, central, mid anterior and anterior) obtained by FreeSurfer 7.1. Multivariate GWAS was run combining all subregions, co-varying for relevant variables. Gene-set enrichment analyses were performed using MAGMA. Linkage disequilibrium score regression (LDSC) was used to determine SNP-based heritability of total CC volume and volumes of its subregions as well as their genetic correlations with relevant psychiatric traits.ResultsWe identified 70 independent loci with distributed effects across the five subregions of the CC (p < 5 × 10−8). Additionally, we identified 33 significant loci in the anterior subregion, 23 in the mid anterior, 29 in the central, 7 in the mid posterior and 56 in the posterior subregion. Gene-set analysis revealed 156 significant genes contributing to volume of the CC subregions (p < 2.6 × 10−6). LDSC estimated the heritability of CC to (h2SNP=0.38, SE=0.03), and subregions ranging from 0.22 (SE=0.02) to 0.37 (SE=0.03). We found significant genetic correlations of total CC volume with bipolar disorder (BD, rg=-0.09, SE=0.03; p=5.9 × 10−3) and drinks consumed per week (rg=-0.09, SE=0.02; p=4.8 × 10−4), and volume of the mid anterior subregion with BD (rg=-0.12, SE=0.02; p=2.5 × 10−4), major depressive disorder (rg=-0.12, SE=0.04; p=3.6 × 10−3), drinks consumed per week (rg=-0.13, SE=0.04; p=1.8 × 10−3) and cannabis use (rg=-0.09, SE=0.03; p=8.4 × 10−3).ConclusionsOur results demonstrate that the CC has a polygenic architecture implicating multiple genes, and show that CC subregion volumes are heritable. We found distinct genetic factors are involved in the development of anterior and posterior subregions, consistent with their divergent functional specialization. Significant genetic correlation between volumes of the CC and bipolar disorder, drinks per week, major depressive disorder and cannabis consumption subregion volumes with psychiatric traits is noteworthy and deserving of further investigation.

Coronavirus disease (COVID-19) can cause significant damage to the lungs, potentially resulting in acute respiratory distress syndrome (ARDS) (Weatherald et al. 2020). An adjunct of treatment for this is awake proning to improve oxygenation and may prevent intubation (Paul et al. 2020). This case report describes a self-ventilating 85-year-old gentleman with COVID-19 and acute hypoxemia, who experienced significant improvements in oxygenation with proning. His ceiling of care was high flow oxygen therapy (HFNC) on the ward and it was deemed clinically appropriate to commence a trial of physiotherapy led awake proning. Although the patient failed to meet the criteria outlined by the Intensive Care Society (ICS) guidelines for awake proning, after multi-disciplinary (MDT) discussion, it was felt a trial of awake proning should be piloted in the patient’s best interest. He was on 15L oxygen via non-rebreather mask for a number of days as he was acutely delirious and not tolerating HFNC. With proning, an average reduction in oxygen of nearly 20% was noted with an increase in SpO2 of 4.6%. Over a 3-week period his oxygen requirements and saturation levels improved dramatically which could be assosicated with awake proning. Our case study illustrates that awake proning can form a vital part of the COVID-19 management plan. It played a crucial role in the patient’s recovery despite not meeting the criteria set out by the ICS. This highlights that guidelines are recommendations and need to be considered on a case-to-case basis along with clinical judgement and MDT discussion.

While genome-wide association studies (GWAS) are increasingly successful in discovering genomic loci associated with complex human traits and disorders, the biological interpretation of these findings remains challenging. We developed the GSA-MiXeR analytical tool for gene-set analysis (GSA), which fits a model for gene-set heritability enrichments for complex traits, accounting for linkage disequilibrium across variants, and allowing the quantification of partitioned heritability and fold enrichment for small gene-sets. We validate the method using extensive simulations and sensitivity analyses. When applied to height and schizophrenia, GSA-MiXeR implicates gene-sets with greater biological specificity compared to standard GSA approaches, including insulin-like growth factor for height, as well as calcium channel function, GABAergic and dopaminergic signaling for schizophrenia. Such biologically relevant gene-sets, often with less than ten genes, are more likely to provide new insights into the pathobiology of complex diseases and highlight potential drug targets.

Treatment resistant schizophrenia (TRS) is characterized by repeated treatment failure with antipsychotics. A recent genome-wide association study (GWAS) of TRS showed a polygenic architecture, but no significant loci were identified. Clozapine is shown to be the superior drug in terms of clinical effect in TRS; at the same time it has a serious side effect profile, including weight gain. Here, we sought to increase power for genetic discovery and improve polygenic prediction of TRS, by leveraging genetic overlap with Body Mass Index (BMI). We analysed GWAS summary statistics for TRS and BMI applying the conditional false discovery rate (cFDR) framework. We observed cross-trait polygenic enrichment for TRS conditioned on associations with BMI. Leveraging this cross-trait enrichment, we identified 2 novel loci for TRS at cFDR MAP2K1 and ZDBF2. Further, polygenic prediction based on the cFDR analysis explained more variance in TRS when compared to the standard TRS GWAS. These findings highlight putative molecular pathways which may distinguish TRS patients from treatment responsive patients. Moreover, these findings confirm that shared genetic mechanisms influence both TRS and BMI and provide new insights into the biological underpinnings of metabolic dysfunction and antipsychotic treatment.

Recent animal work has documented a two-way interconnection between calvarial bone marrow and the brain. Bone marrow adiposity may therefore have direct implications for brain health, yet the lack of in vivo studies in humans limits our understanding of such interplay. Here, we exploit large magnetic resonance imaging (MRI) datasets to study bone marrow adiposity and its association with brain and body traits. We trained an artificial neural network to localise calvarial bone marrow in T1-weighted 3T MRI head scans. Validation in two independent samples confirmed high accuracy of our approach to semi-quantitatively measure calvarial bone marrow adiposity in vivo. Our analyses revealed sex-dimorphic age trajectories in line with earlier work from non-calvarial bone marrow. Next, we studied the genetic architecture of the calvarial bone marrow and revealed its high heritability in single-nucleotide polymorphism and twin data. We identified 41 genetic loci significantly associated with the calvarial bone marrow, including a sex-specific genetic effect of the estrogen receptor locus. By integrating mapped genes with existing bone marrow single-cell RNA sequencing data, we revealed patterns of adipogenic lineage differentiation and lipid loading. Finally, we identified significant genetic correlation with several heritable human traits, including general cognitive ability and Parkinson’s disease. Our method for quantifying calvarial bone marrow adiposity from MRI head scans enables a significant advance in our understanding of the genetic and cellular drivers of bone marrow adiposity in humans. This contributes to the groundwork needed to elucidate its function and creates an opportunity to study its effects on other organs such as bone, blood, and brain.

BACKGROUND: Schizophrenia is a complex polygenic disorder with subtle, distributed abnormalities in brain morphology. There are indications of shared genetic architecture between schizophrenia and brain measures despite low genetic correlations. Through the use of analytical methods that allow for mixed directions of effects, this overlap may be leveraged to improve our understanding of underlying mechanisms of schizophrenia and enrich polygenic risk prediction outcome.METHODS: We ran a multivariate genome-wide analysis of 175 brain morphology measures using data from 33,735 participants of the UK Biobank and analyzed the results in a conditional false discovery rate together with schizophrenia genome-wide association study summary statistics of the Psychiatric Genomics Consortium (PGC) Wave 3. We subsequently created a pleiotropy-enriched polygenic score based on the loci identified through the conditional false discovery rate approach and used this to predict schizophrenia in a nonoverlapping sample of 743 individuals with schizophrenia and 1074 healthy controls.RESULTS: We found that 20% of the loci and 50% of the genes significantly associated with schizophrenia were also associated with brain morphology. The conditional false discovery rate analysis identified 428 loci, including 267 novel loci, significantly associated with brain-linked schizophrenia risk, with functional annotation indicating high relevance for brain tissue. The pleiotropy-enriched polygenic score explained more variance in liability than conventional polygenic scores across several scenarios.CONCLUSIONS: Our results indicate strong genetic overlap between schizophrenia and brain morphology with mixed directions of effect. The results also illustrate the potential of exploiting polygenetic overlap between brain morphology and mental disorders to boost discovery of brain tissue-specific genetic variants and its use in polygenic risk frameworks.

Alcohol use disorder (AUD) is a pervasive and devastating mental illness with high comorbidity rates with other mental disorders. We aimed to characterize the sharedvs. unique polygenicity of AUD, alcohol consumption (AC) and mood instability (MOOD), a relevant transdiagnostic factor, using large genome-wide association studies (GWASs) data. We hypothesize that cross-analyzing these phenotypes would shed light on their unique and shared polygenicity, increase our knowledge regarding the genetic basis of the comorbidity between AUD and mood disorders, and boost discovery for jointly-associated loci. Summary statistics for MOOD, AC and AUD GWASs (Ns =363,705; 200,680 and 200,004; respectively) were analysed to characterize the cross-phenotype associations between MOOD and AC, MOOD and AUD and AC and AUD, respectively. To do so, we used a newly-established pipeline that combines (i) the bivariate causal mixture model (MiXeR) to quantify the cross-phenotype polygenic overlap and (ii) the conjunctional false discovery rate (conjFDR) to discover specific jointly-associated genomic loci. These loci were functionally characterized and mapped to genes and biological functions. We also performed validation in independent samples and phenotypic analyses. MOOD was highly polygenic (10,400 single nucleotide polymorphisms, SNPs) compared to AC and AUD (4,900 SNPs, SD =600 and 4,300 SNPs, SD =2,000; respectively). The polygenic overlap of MOOD and AC was much larger than that of MOOD and AUD (98%vs. 49%) and genetic correlation was opposite (−0.2vs. 0.23), which was confirmed in independent samples. MOOD&AUD causal SNPs were significantly enriched for brain genes, conversely to MOOD&AC. Among 38 loci identified in the joint analysis, sixteen were novel for MOOD, AC and AUD. Similarly distinct patterns were evidenced for SNP localization, function and previous GWAS associations outside of the phenotypes that were currently studied. MOOD, AC and AUD were also strongly associated at the phenotypic level. Overall, using multilevel polygenic quantification, joint loci discovery and functional annotation methods, we evidenced that the polygenic overlap between MOOD and AC/AUD implicated shared biological underpinnings but clearly distinct functional patterns between MOOD&AC and MOOD&AUD. Using the MOOD endophenotype, the current study suggests new mechanisms for the comorbidity of AUD with mood disorders.

The oilfield is in many ways the backbone of the world economy. Historically economic recessions and booms were linked directly or indirectly to the oil price, itself governed by supply and demand. Since the start of this industry, it has experienced multiple scandals and major accidents that have affected its path to date. In 2001 the Enron scandal of poor accounting practices shook the entire stock market, and it contributed to the complete recession in the same year. Not too long after, a supermajor revealed in 2004 a reserves accounting error that surprised the world. In 2010 the Deepwater Horizon blow out known as the "Macondo Incident" caused serious damage to the environment and significant fines to be paid in compensation due to poor engineering practice. Incidents like these arise concurrent with times of high demand and are instructive as we study their causes and effects on the oil industry and therefore the global economy. Areas of study for this paper include reserves/production estimation as well as ethical considerations for the oil industry at large. Our study is based on the review of uncertainty in both the subsurface and surface parts of oil and gas production. We refer to the previous classifications of uncertainty for the subsurface part and focus on the uncertainty currently existing within the surface production system. Current surface production monitoring methods are discussed. We propose a more automated process to reduce the current uncertainty about hydrocarbon production. Artificial intelligence applicability in the surface production system is investigated. Additionally, in this paper we review the previously mentioned poor practices and accidents briefly and use them to guide our suggestions about preventive actions to avoid future wrongdoing and incidents. We attempt to provide an objective for oilfield ethics and advocate for a unified oilfield industry code of ethics. However due to the large diversity that exists in the wide range of oilfield disciplines, a single code of ethics may not be applicable. Accordingly, we propose a guideline that may be used by different parts of the oilfield industry to develop an application-specific code of ethics. It is hoped that this guideline will guard against the gaps that may foster errors that affect the oilfield industry and global markets.

Summary Background Awake prone positioning has been reported to improve oxygenation for patients with COVID-19 in retrospective and observational studies, but whether it improves patient-centred outcomes is unknown. We aimed to evaluate the efficacy of awake prone positioning to prevent intubation or death in patients with severe COVID-19 in a large-scale randomised trial. Methods In this prospective, a priori set up and defined, collaborative meta-trial of six randomised controlled open-label superiority trials, adults who required respiratory support with high-flow nasal cannula for acute hypoxaemic respiratory failure due to COVID-19 were randomly assigned to awake prone positioning or standard care. Hospitals from six countries were involved: Canada, France, Ireland, Mexico, USA, Spain. Patients or their care providers were not masked to allocated treatment. The primary composite outcome was treatment failure, defined as the proportion of patients intubated or dying within 28 days of enrolment. The six trials are registered with ClinicalTrials.gov , NCT04325906 , NCT04347941 , NCT04358939 , NCT04395144 , NCT04391140 , and NCT04477655 . Findings Between April 2, 2020 and Jan 26, 2021, 1126 patients were enrolled and randomly assigned to awake prone positioning (n=567) or standard care (n=559). 1121 patients (excluding five who withdrew from the study) were included in the intention-to-treat analysis. Treatment failure occurred in 223 (40%) of 564 patients assigned to awake prone positioning and in 257 (46%) of 557 patients assigned to standard care (relative risk 0·86 [95% CI 0·75−0·98]). The hazard ratio (HR) for intubation was 0·75 (0·62−0·91), and the HR for mortality was 0·87 (0·68−1·11) with awake prone positioning compared with standard care within 28 days of enrolment. The incidence of prespecified adverse events was low and similar in both groups. Interpretation Awake prone positioning of patients with hypoxaemic respiratory failure due to COVID-19 reduces the incidence of treatment failure and the need for intubation without any signal of harm. These results support routine awake prone positioning of patients with COVID-19 who require support with high-flow nasal cannula. Funding Open AI inc, Rice Foundation, Projet Hospitalier de Recherche Clinique Interregional, Appel d'Offre 2020, Groupement Interregional de Recherche Clinique et d'Innovation Grand Ouest, Association pour la Promotion a Tours de la Reanimation Medicale, Fond de dotation du CHRU de Tours, Fisher & Paykel Healthcare Ltd.

Nucleoprotein (N) is an immunodominant antigen in many enveloped virus infections. While the diagnostic value of anti‐N antibodies is clear, their role in immunity is not. This is because while they are non‐neutralising, they somehow clear infection by coronavirus, influenza and LCMV in vivo. Here, we show that anti‐N immune protection is mediated by the cytosolic Fc receptor and E3 ubiquitin ligase TRIM21. Exploiting LCMV as a model system, we demonstrate that TRIM21 uses anti‐N antibodies to target N for cytosolic degradation and generate cytotoxic T cells (CTLs) against N peptide. These CTLs rapidly eliminate N‐peptide‐displaying cells and drive efficient viral clearance. These results reveal a new mechanism of immune synergy between antibodies and T cells and highlights N as an important vaccine target., Cytosolic antibody receptor and ubiquitin ligase TRIM21 promotes antigen presentation and T cell activation by targeting immune complexes for efficient proteasomal degradation.

Rotavirus is a major cause of gastroenteritis in children, with infection typically inducing high levels of protective antibodies. Antibodies targeting the middle capsid protein VP6 are particularly abundant, and as VP6 is only exposed inside cells, neutralisation must be post-entry. However, while a system of poly immune globulin receptor (pIgR) transcytosis has been proposed for anti-VP6 IgAs, the mechanism by which VP6-specific IgG mediates protection remains less clear. We have developed an intracellular neutralisation assay to examine how antibodies neutralise rotavirus inside cells, enabling comparison between IgG and IgA isotypes. Unexpectedly we found that neutralisation by VP6-specific IgG was much more efficient than by VP6-specific IgA. This observation was highly dependent on the activity of the cytosolic antibody receptor TRIM21 and was confirmed using an in vivo model of murine rotavirus infection. Furthermore, mice deficient in only IgG and not other antibody isotypes had a serious deficit in intracellular antibody-mediated protection. The finding that VP6-specific IgG protect mice against rotavirus infection has important implications for rotavirus vaccination. Current assays determine protection in humans predominantly by measuring rotavirus-specific IgA titres. Measurements of VP6-specific IgG may add to existing mechanistic correlates of protection., Author summary Rotavirus is the leading cause of gastroenteritis in children worldwide. Effective rotavirus vaccines have been available for over a decade, but detailed understanding of the immune response to rotavirus infection is essential for further improvement of vaccines. High levels of antibodies are made in response to infection, especially antibodies targeting the inner capsid protein VP6, but while both IgA and IgG isotypes are produced, previous work has focused predominantly on VP6-specific IgA. In this study we sought to evaluate the importance of VP6-specific IgG in rotavirus protection. As VP6-specific antibodies target incomplete rotavirus particles inside cells, we developed a new assay to examine how antibodies neutralise rotavirus intracellularly. We showed that neutralisation by VP6-specific IgG was much more efficient than VP6-specific IgA, due to the activity of the cytosolic antibody receptor TRIM21. This was confirmed using a mouse model of rotavirus infection. Furthermore, mice with normal IgA levels but deficient in IgG had a serious deficit in intracellular antibody-mediated protection. Our finding that VP6-specific IgG protect mice against rotavirus infection may be valuable for predicting whether new rotavirus vaccines will work. Current assays to determine protection in humans focus on measuring rotavirus-specific IgA titres. We propose that including measurements of VP6-specific IgG may improve knowledge on correlates of protection.

The benefits of using autonomous nodes in a desert environment to efficiently achieve very high trace density seismic surveys with reduced HSSE risk and improved operational efficiency are increasingly being recognised by the industry. ADNOC, in partnership with BP, Rosneft and WesternGeco recently deployed 50,000 newly-developed ultra-light nodes (Manning et al, 2018) with simultaneous vibroseis source technology to acquire the densest ever seismic survey on land. The survey covered an area of 81km2 containing significant surface infrastructure and sand dunes. The field trial had two main goals: first demonstrate the readiness of this new nodal system to acquire high quality seismic at full scale in a production-like setting; and second, to compare the data recorded by this new system to legacy data acquired by a conventional array geophone system and demonstrate the benefits of the former in terms of safety, operational efficiency and ability to image fine stratigraphic details at the reservoir.

The complement system is vital for anti-microbial defense. In the classical pathway, pathogen-bound antibody recruits the C1 complex (C1qC1r2C1s2) that initiates a cleavage cascade involving C2, C3, C4, and C5 and triggering microbial clearance. We demonstrate a C4-dependent antiviral mechanism that is independent of downstream complement components. C4 inhibits human adenovirus infection by directly inactivating the virus capsid. Rapid C4 activation and capsid deposition of cleaved C4b are catalyzed by antibodies via the classical pathway. Capsid-deposited C4b neutralizes infection independent of C2 and C3 but requires C1q antibody engagement. C4b inhibits capsid disassembly, preventing endosomal escape and cytosolic access. C4-deficient mice exhibit heightened viral burdens. Additionally, complement synergizes with the Fc receptor TRIM21 to block transduction by an adenovirus gene therapy vector but is partially restored by Fab virus shielding. These results suggest that the complement system could be altered to prevent virus infection and enhance virus gene therapy efficacy.

Distributed vibration sensing (DVS), also known as distributed acoustic sensing (DAS), is a relatively new method for recording seismic data using a standard fiber-optic cable as the sensor. Although the dynamic range and noise floor of DVS systems are currently below those of industry-standard seismic sensors, usable seismic data can be obtained in downhole configurations, as this is the source and receiver configuration at which DVS is most sensitive. The use of DVS for more conventional land and marine seismic acquisition is still some way off. However, the potential benefits of simple, lightweight fiber-optic cables, with fine spatial sampling and the ability to instrument all offsets of any spread, suggest it is worth pursuing these new applications. Permanent reservoir monitoring, particularly for marine environments, represents another application where the simplicity of fiber-optic sensors is attractive. Advances in laser interrogation techniques and signal processing continue to improve the quality of DVS data, increasing its potential applications across the seismic industry.

Adenovirus has enormous potential as a gene-therapy vector, but preexisting immunity limits its widespread application. What is responsible for this immune block is unclear because antibodies potently inhibit transgene expression without impeding gene transfer into target cells. Here we show that antibody prevention of adenoviral gene delivery in vivo is mediated by the cytosolic antibody receptor TRIM21. Genetic KO of TRIM21 or a single-antibody point mutation is sufficient to restore transgene expression to near-naïve immune levels. TRIM21 is also responsible for blocking cytotoxic T cell induction by vaccine vectors, preventing a protective response against subsequent influenza infection and an engrafted tumor. Furthermore, adenoviral preexisting immunity can lead to an augmented immune response upon i.v. administration of the vector. Transcriptomic analysis of vector-transduced tissue reveals that TRIM21 is responsible for the specific up-regulation of hundreds of immune genes, the majority of which are components of the intrinsic or innate response. Together, these data define a major mechanism underlying the preimmune block to adenovirus gene therapy and demonstrate that TRIM21 efficiently blocks gene delivery in vivo while simultaneously inducing a rapid program of immune transcription.

(2013). A review of nodal land seismic acquisition systems. Preview: Vol. 2013, No. 164, pp. 34-39.

Genetic factors have been shown to associate with various exercise-related phenotypes, including exercise performance, adaptation to training and sports injuries. The genes implicated in the pathogenesis of musculoskeletal soft-tissue injuries all code for either structural components or regulatory components of the extracellular matrix. It has been hypothesized that these genetic associations with injuries are due to genetically regulated changes in mechanical properties of musculoskeletal soft tissue. Thus, the objective of this review is to highlight the research which has advanced our understanding of how genetic variation within these structural genes affects the properties of our connective tissue. The genetics of various exercise-related phenotypes, such as range of motion, endurance performance and exercise-associated muscle cramps, are reviewed. Lastly, a model is presented where genetic variations within a collagen-encoding gene result in a continuum of phenotype ranging from a normal tissue to a seriously deleterious or lethal disorder.

Performance improvement is the continual effort to objectively assess current performance and then restructure the practices that support it to more closely achieve desired performance. A plan for performance improvement, unlike other approaches to correcting problems in job fulfillment, is a systematic method used to first find the root causes of areas of concern and then apply corrections to remedy those deficits. Implementing a performance improvement plan that can be easily adapted to ensure compliance with evolving and increasingly complex state and federal regulations is crucial to a successful compounding practice. In this article, we discuss the need for performance improvement in 503A compounding pharmacies, list the steps necessary to develop such a plan, and present three case reports of performance improvement plans in differing compounding settings.

The provision of safe and reliable means to afford protection against electric shock in the built environment is deemed one of the most important design elements for electrical services engineers who design low voltage electrical installations to conform to BS7671: 2008 (17th edition IEE Wiring Regulations) and ET 101:2008. The fact that, domestic properties rank as one of the leading locations for electrical injury and death, and domestic electrical installations lack routine inspection and scheduled maintenance in a European environment where an ageing housing stock exists in many countries, highlights the growing concerns for domestic electrical safety. However, by performing a value-engineering design through the implementation of residual current devices and a ‘low touch voltage’ design, a higher level of domestic electrical safety can be attained. Practical application: The ‘touch voltage simulator’ Excel application presented is a powerful tool for designers and installers of low voltage electrical installations to test and evaluate the resulting touch voltage for various design parameters. It can also be used to identify the sensitivity of resulting touch voltages to any variations in the four main design parameters U OC, Ze, R1 and R2. The ‘interactive touch voltage charts’ can plot interactive graphs, which can be used as visual aids for engineers to ascertain how the touch voltage could fluctuate with variations in the major design parameters at the design stage.

Electricity is one of the most convenient forms of energy that is used in every building today. However, it causes a number of fatalities every year and has the potential to cause harm to anyone exposed to it. This article, investigates the cause and effects of electrical accidents in domestic properties over a 3-year period (2000—2002) in the UK based on the 24th Report of the Home and Leisure Accident Surveillance System (HASS/LASS). The electrical accident data from this database was analysed to establish electrical injury trends for various categories and groups. This highlighted the high-risk activities, which led to receiving an electric shock in a domestic property and identified at-risk groups that could most benefit from electrical safety interventions. In order to enhance electrical safety and to aid in the formulation of the relevant national wiring regulations, it is imperative that the narrative reports and statistics presented in the HASS/LASS document and this article are considered by regulators, manufacturers, educators, safety officers and engineers so that the whole of society can benefit. Based on the evidence and analysis presented in this article, it was concluded that there are a number of recommended protective measures designers, installers and regulators could consider implementing to advance electrical safety in the home. Practical application: Engineers, educators, manufacturers and regulators can use the information highlighted in this article to improve electrical safety in the built environment.

Protection against electric shock in our homes and work places is one of the most important priorities for electrical services engineers who are now designing electrical installations to conform to the requirements of the 17th edition IEE Wiring Regulations (BS7671: 2008). Now Chapter 41 of BS7671: 2008 requires that additional protection by means of a 30 mA 40 ms residual current protection device be provided for final circuits supplying general purpose socket outlets that are intended for use by ‘Ordinary persons’. However, there are few publications and little information available on the theory describing how touch voltage of a dangerous magnitude could be transferred from a faulty circuit onto the exposed-conductive-parts of Class 1 equipment of another healthy circuit. This paper summarises the theory of transfer touch voltage calculations and expands on it to show how to carry out a sensitivity analysis in relation to the design parameters that are being used by designers and installers. Based on the results of a real case study, it appears that there is sufficient evidence to show that it may not be sufficiently safe to use the nominal external earth fault loop impedance quoted by the electricity utility companies for adopting a low touch voltage design. Practical application: The touch voltage sensitivity equation derived in this paper is a powerful tool for designers and installers of electrical installations to investigate and identify the sensitivity of resulting touch voltages of any electrical circuits.

Stimulation of different T-cell subsets during antigen presentation influences the antibody isotype response to an antigen. Salmonella infection and Salmonella bacterin vaccination are likely to stimulate different T-cell subtypes. The objective of this study was to determine whether there are differences in the isotype response of cattle to Salmonella antigens following Salmonella infection and Salmonella bacterin vaccination. Sera from Salmonella bacterin-vaccinated, experimentally infected, and chronically infected (carrier) adult cattle collected during previous studies was used to evaluate the IgG1, IgG2, and IgM isotype responses of cows to Salmonella serotype Dublin lipopolysaccharide (LPS) and porin. Following vaccination and experimental oral infection, IgG1 titers to LPS and porin rose more quickly and persisted longer than did IgG2 titers. In contrast to Salmonella infection, bacterin vaccination stimulated a weak response to Salmonella porin. Salmonella in- fection also induced a higher IgG2:IgG1 titer ratio to LPS than did bacterin vaccination. Chronic Salmonella infection induced the highest LPS and porin IgG2:IgG1 titer ratios and the highest correlation between LPS and porin titers. Response operating characteristic curves for each isotype-specific enzyme-linked immunosorbent assay (ELISA) were determined to evaluate the effect of isotype on the sensitivity and specificity of Salmonella ELISA serology for distinguishing sera of Salmonella carriers from those of vaccinated and acutely infected cows. IgG2 titers to LPS and porin provide a more specific indicator of chronic Salmonella infection status than do IgG1 titers to the same antigens with little to no loss in sensitivity. The prevalence of Salmonella in intensive food pro- ducing industries and the link of infected foodstuffs to human outbreaks of salmonellosis has focused public health attention and political pressure on livestock in- dustries to control Salmonella infections. Estimates of the prevalence of Salmonella on dairy farms in Cali- fornia range from 16% to 73%. 14,15,18 Livestock mor- tality, increased therapeutic costs, reduced production, discarded milk, and reduced consumer confidence all contribute to the cost of Salmonella infections to cattle industries. Persistence of Salmonella in herds is associated with repetitive contamination of salable milk even in the absence of continued clinical disease. 4 Farms with en- demic Salmonella infections often report a cyclic pat- tern of clinical cases, possibly reflecting introduction of new serotypes, fluctuations in herd immunity, en- vironmental stress, or changes in herd management or bacterial virulence. Reservoirs of Salmonella in in- fected herds include contaminated environments, ro- dents, birds, and chronically infected carrier cows. 13,17

Host species have evolved mechanisms that can inhibit pathogen replication even after a cell has been successfully invaded. Here we show that tripartite-motif protein 21 (TRIM21), a ubiquitously expressed E3 ubiquitin ligase that targets viruses inside the cytosol, protects mice against fatal viral infection. Upon infection with mouse adenovirus-1, naive mice lacking TRIM21 succumb to encephalomyelitis within 7 d. In contrast, wild-type mice rapidly up-regulate TRIM21 and control viremia. Trim21 heterozygous mice have a haploinsufficiency phenotype in which reduced TRIM21 expression leads to a viral load that is higher than wild types but lower than knockouts. TRIM21 is a high-affinity antibody receptor that allows antibodies to operate inside an infected cell. In passive transfer experiments at high viral dose, antisera that fully protects wild-type mice fails to protect most Trim21 knockout animals. These results demonstrate that TRIM21 provides potent antiviral protection and forms an important part of the humoral immune response.

Caenorhabditis elegans has often been used as a model system in studies of early developmental processes. The transparency of the embryos, the genetic resources, and the relative ease of transformation are qualities that make C. elegans an excellent model for early embryogenesis. Laser-based confocal microscopy and fluorescently labeled tags allow researchers to follow specific cellular structures and proteins in the developing embryo. For example, one can follow specific organelles, such as lysosomes or mitochondria, using fluorescently labeled dyes. These dyes can be delivered to the early embryo by means of microinjection into the adult gonad. Also, the localization of specific proteins can be followed using fluorescent protein tags. Examples are presented here demonstrating the use of a fluorescent lysosomal dye as well as fluorescently tagged histone and ubiquitin proteins. The labeled histone is used to visualize the DNA and thus identify the stage of the cell cycle. GFP-tagged ubiquitin reveals the dynamics of ubiquitinated vesicles in the early embryo. Observations of labeled lysosomes and GFP:: ubiquitin can be used to determine if there is colocalization between ubiquitinated vesicles and lysosomes. A technique for the microinjection of the lysosomal dye is presented. Techniques for generating transgenenic strains are presented elsewhere (1, 2). For imaging, embryos are cut out of adult hermaphrodite nematodes and mounted onto 2% agarose pads followed by time-lapse microscopy on a standard laser scanning confocal microscope or a spinning disk confocal microscope. This methodology provides for the high resolution visualization of early embryogenesis.

Background Hamstring injury is one of the most common injuries affecting gaelic footballers, similar to other field sports. Research in other sports on whether residual hamstring weakness is present after hamstring injury is inconsistent, and no study has examined this factor in irish gaelic footballers. The aim of this study was to examine whether significant knee muscle weakness is present in male Irish gaelic footballers who have returned to full activity after hamstring injury. Methods The concentric isokinetic knee flexion and extension strength of 44 members of a university gaelic football team was assessed at 60, 180 and 300 degrees per second using a Contrex dynamometer. Results Fifteen players (34%) reported a history of hamstring strain, with 68% of injuries affecting the dominant (kicking) limb. The hamstrings were significantly stronger (p < 0.05) on the dominant limb in all uninjured subjects. The previously injured limbs had a significantly lower (p < 0.05) hamstrings to quadriceps (HQ) strength ratio than all other non-injured limbs, but neither their hamstrings nor quadriceps were significantly weaker (p > 0.05) using this comparison. The previously unilaterally injured hamstrings were significantly weaker (p < 0.05) than uninjured limbs however, when matched for dominance. The hamstring to opposite hamstring (H:oppH) strength ratio of the previously injured players was also found to be significantly lower (p < 0.05) than that of the uninjured players. Conclusion Hamstring muscle weakness was observed in male Irish gaelic footballers with a history of hamstring injury. This weakness is most evident when comparisons are made to multiple control populations, both within and between subjects. The increased strength of the dominant limb should be considered as a potential confounding variable in future trials. The study design does not allow interpretation of whether these changes in strength were present before or after injury.

Maev O’Connell was born in Cork, Ireland, the youngest of 11 children, five of whom died in infancy. She owed her early education to her father, who was a founding member of the Irish teachers’ union. She subsequently attended the St Louis School in Monaghan, where all subjects were …

The poet Gerard Manley Hopkins (1844-89) pursued music intermittently throughout his short life. He was not only a composer but also an ad hoc theorist. Hopkins’s compositions, like his poems, remained almost entirely unknown during his lifetime. His theories about music and his compositions were distributed in the same way as the poems, as apercus in his letters to friends, with the manuscript scores enclosed. The purpose of this essay is to attempt a composite picture of Hopkins the musician.