Systems level investigation of the genetic basis of bovine muscle growth and development

Skeletal muscle growth is an economically and biologically important trait for livestock raised for meat production. As such, there is great interest in understanding the underlying genomic architecture influencing muscle growth and development. In spite of this, relatively little is known about the genes or biological processes regulating bovine muscle growth. In this thesis, several approaches were undertaken in order to elucidate some of the mechanisms which may be controlling bovine muscle growth and development. The first objective of this thesis was the development of a novel software tool (SNPdat) for the rapid and comprehensive annotation of SNP data for any organism with a draft sequence and annotation. SNPdat was subsequently utilised in chapters 3 and 6 to facilitate the identification of candidate genes and regions involved in bovine muscle growth. In chapter 4, a number of metrics were explored for their usefulness in assessing convergence of a Markov Chain using a Bayesian approach used in genetic prediction. The need to adequately assess convergence using multiple metrics is addressed and recommendations put forward. These recommendations were then implemented in chapter 3. In addition, three separate investigations of bovine muscle growth and development were performed. In chapter 3, a genome-wide association study was performed to identify regions of the bovine genome associated with four economically important carcass traits. This was followed by an examination of the transcriptional responses in muscle tissue of animals undergoing dietary restriction and compensatory growth (chapter 5). Finally, using high-throughput DNA sequencing, a candidate list of 200 genes was interrogated to identify genes which may be evolving at different rates, and under evolutionary selection pressure, in beef compared to dairy animals (chapter 6). A number of genes and biological pathways were found to be involved in traits related to bovine muscle growth, several of which were identified in more than one study

Antibodies against endogenous retroviruses promote lung cancer immunotherapy

B cells are frequently found in the margins of solid tumours as organized follicles in ectopic lymphoid organs called tertiary lymphoid structures (TLS). Although TLS have been found to correlate with improved patient survival and response to immune checkpoint blockade (ICB), the underlying mechanisms of this association remain elusive. Here we investigate lung-resident B cell responses in patients from the TRACERx 421 (Tracking Non-Small-Cell Lung Cancer Evolution Through Therapy) and other lung cancer cohorts, and in a recently established immunogenic mouse model for lung adenocarcinoma. We find that both human and mouse lung adenocarcinomas elicit local germinal centre responses and tumour-binding antibodies, and further identify endogenous retrovirus (ERV) envelope glycoproteins as a dominant anti-tumour antibody target. ERV-targeting B cell responses are amplified by ICB in both humans and mice, and by targeted inhibition of KRAS(G12C) in the mouse model. ERV-reactive antibodies exert anti-tumour activity that extends survival in the mouse model, and ERV expression predicts the outcome of ICB in human lung adenocarcinoma. Finally, we find that effective immunotherapy in the mouse model requires CXCL13-dependent TLS formation. Conversely, therapeutic CXCL13 treatment potentiates anti-tumour immunity and synergizes with ICB. Our findings provide a possible mechanistic basis for the association of TLS with immunotherapy response

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Systems level investigation of the genetic basis of bovine muscle growth and development

Skeletal muscle growth is an economically and biologically important trait for livestock raised for meat production. As such, there is great interest in understanding the underlying genomic architecture influencing muscle growth and development. In spite of this, relatively little is known about the genes or biological processes regulating bovine muscle growth. In this thesis, several approaches were undertaken in order to elucidate some of the mechanisms which may be controlling bovine muscle growth and development. The first objective of this thesis was the development of a novel software tool (SNPdat) for the rapid and comprehensive annotation of SNP data for any organism with a draft sequence and annotation. SNPdat was subsequently utilised in chapters 3 and 6 to facilitate the identification of candidate genes and regions involved in bovine muscle growth. In chapter 4, a number of metrics were explored for their usefulness in assessing convergence of a Markov Chain using a Bayesian approach used in genetic prediction. The need to adequately assess convergence using multiple metrics is addressed and recommendations put forward. These recommendations were then implemented in chapter 3. In addition, three separate investigations of bovine muscle growth and development were performed. In chapter 3, a genome-wide association study was performed to identify regions of the bovine genome associated with four economically important carcass traits. This was followed by an examination of the transcriptional responses in muscle tissue of animals undergoing dietary restriction and compensatory growth (chapter 5). Finally, using high-throughput DNA sequencing, a candidate list of 200 genes was interrogated to identify genes which may be evolving at different rates, and under evolutionary selection pressure, in beef compared to dairy animals (chapter 6). A number of genes and biological pathways were found to be involved in traits related to bovine muscle growth, several of which were identified in more than one study

Systems level investigation of the genetic basis of bovine muscle growth and development

Skeletal muscle growth is an economically and biologically important trait for livestock raised for meat production. As such, there is great interest in understanding the underlying genomic architecture influencing muscle growth and development. In spite of this, relatively little is known about the genes or biological processes regulating bovine muscle growth. In this thesis, several approaches were undertaken in order to elucidate some of the mechanisms which may be controlling bovine muscle growth and development. The first objective of this thesis was the development of a novel software tool (SNPdat) for the rapid and comprehensive annotation of SNP data for any organism with a draft sequence and annotation. SNPdat was subsequently utilised in chapters 3 and 6 to facilitate the identification of candidate genes and regions involved in bovine muscle growth. In chapter 4, a number of metrics were explored for their usefulness in assessing convergence of a Markov Chain using a Bayesian approach used in genetic prediction. The need to adequately assess convergence using multiple metrics is addressed and recommendations put forward. These recommendations were then implemented in chapter 3. In addition, three separate investigations of bovine muscle growth and development were performed. In chapter 3, a genome-wide association study was performed to identify regions of the bovine genome associated with four economically important carcass traits. This was followed by an examination of the transcriptional responses in muscle tissue of animals undergoing dietary restriction and compensatory growth (chapter 5). Finally, using high-throughput DNA sequencing, a candidate list of 200 genes was interrogated to identify genes which may be evolving at different rates, and under evolutionary selection pressure, in beef compared to dairy animals (chapter 6). A number of genes and biological pathways were found to be involved in traits related to bovine muscle growth, several of which were identified in more than one study

Systems level investigation of the genetic basis of bovine muscle growth and development

Skeletal muscle growth is an economically and biologically important trait for livestock raised for meat production. As such, there is great interest in understanding the underlying genomic architecture influencing muscle growth and development. In spite of this, relatively little is known about the genes or biological processes regulating bovine muscle growth. In this thesis, several approaches were undertaken in order to elucidate some of the mechanisms which may be controlling bovine muscle growth and development. The first objective of this thesis was the development of a novel software tool (SNPdat) for the rapid and comprehensive annotation of SNP data for any organism with a draft sequence and annotation. SNPdat was subsequently utilised in chapters 3 and 6 to facilitate the identification of candidate genes and regions involved in bovine muscle growth. In chapter 4, a number of metrics were explored for their usefulness in assessing convergence of a Markov Chain using a Bayesian approach used in genetic prediction. The need to adequately assess convergence using multiple metrics is addressed and recommendations put forward. These recommendations were then implemented in chapter 3. In addition, three separate investigations of bovine muscle growth and development were performed. In chapter 3, a genome-wide association study was performed to identify regions of the bovine genome associated with four economically important carcass traits. This was followed by an examination of the transcriptional responses in muscle tissue of animals undergoing dietary restriction and compensatory growth (chapter 5). Finally, using high-throughput DNA sequencing, a candidate list of 200 genes was interrogated to identify genes which may be evolving at different rates, and under evolutionary selection pressure, in beef compared to dairy animals (chapter 6). A number of genes and biological pathways were found to be involved in traits related to bovine muscle growth, several of which were identified in more than one study

Systems level investigation of the genetic basis of bovine muscle growth and development

Skeletal muscle growth is an economically and biologically important trait for livestock raised for meat production. As such, there is great interest in understanding the underlying genomic architecture influencing muscle growth and development. In spite of this, relatively little is known about the genes or biological processes regulating bovine muscle growth. In this thesis, several approaches were undertaken in order to elucidate some of the mechanisms which may be controlling bovine muscle growth and development. The first objective of this thesis was the development of a novel software tool (SNPdat) for the rapid and comprehensive annotation of SNP data for any organism with a draft sequence and annotation. SNPdat was subsequently utilised in chapters 3 and 6 to facilitate the identification of candidate genes and regions involved in bovine muscle growth. In chapter 4, a number of metrics were explored for their usefulness in assessing convergence of a Markov Chain using a Bayesian approach used in genetic prediction. The need to adequately assess convergence using multiple metrics is addressed and recommendations put forward. These recommendations were then implemented in chapter 3. In addition, three separate investigations of bovine muscle growth and development were performed. In chapter 3, a genome-wide association study was performed to identify regions of the bovine genome associated with four economically important carcass traits. This was followed by an examination of the transcriptional responses in muscle tissue of animals undergoing dietary restriction and compensatory growth (chapter 5). Finally, using high-throughput DNA sequencing, a candidate list of 200 genes was interrogated to identify genes which may be evolving at different rates, and under evolutionary selection pressure, in beef compared to dairy animals (chapter 6). A number of genes and biological pathways were found to be involved in traits related to bovine muscle growth, several of which were identified in more than one study

Cluster randomized trial in the general practice research database: 2. Secondary prevention after first stroke (eCRT study): study protocol for a randomized controlled trial.

BACKGROUND: The purpose of this research is to develop and evaluate methods for conducting pragmatic cluster randomized trials in a primary care electronic database. The proposal describes one application, in a less frequent chronic condition of public health importance, secondary prevention of stroke. A related protocol in antibiotic prescribing was reported previously. METHODS/DESIGN: The study aims to implement a cluster randomized trial (CRT) using the electronic patient records of the General Practice Research Database (GPRD) as a sampling frame and data source. The specific objective of the trial is to evaluate the effectiveness of a computer-delivered intervention at enhancing the delivery of stroke secondary prevention in primary care. GPRD family practices will be allocated to the intervention or usual care. The intervention promotes the use of electronic prompts to support adherence with the recommendations of the UK Intercollegiate Stroke Working Party and NICE guidelines for the secondary prevention of stroke in primary care. Primary outcome measure will be the difference in systolic blood pressure between intervention and control trial arms at 12-month follow-up. Secondary outcomes will be differences in serum cholesterol, prescribing of antihypertensive drugs, statins, and antiplatelet therapy. The intervention will continue for 12 months. Information on the utilization of the decision-support tools will also be analyzed. DISCUSSION: The CRT will investigate the effectiveness of using a computer-delivered intervention to reduce the risk of stroke recurrence following a first stroke event. The study will provide methodological guidance on the implementation of CRTs in electronic databases in primary care. TRIAL REGISTRATION: Current Controlled Trials ISRCTN35701810