An investigation of genetic and epigenetic factors in the regulation of gene expression in schizophrenia: insights into pathways involved in pathogenesis

Schizophrenia is a common psychiatric disorder with a complex aetiology that has a strong genetic component as well as a major contribution from non-genetic factors. Whilst GWAS studies have not yielded substantial evidence of DNA variants linked to schizophrenia, microarray expression studies, which reflect both genetic and environmental factors, have provided evidence of candidate genes whose expression changes significantly in schizophrenia. The present thesis is based on a prospective microarray study carried out on two brain regions implicated in schizophrenia: frontal cortex and superior temporal cortex (Maycox et al., 2009; Barnes et al., 2011). SNP variants in six of these genes were genotyped and allele, genotype and haplotype analysis carried out initially to investigate associations with levels of expression found in these microarray studies. Subsequently SNP associations with disease were investigated in an extended case-control cohort from the East UK region. The selected candidates genes, highlighted from microarray studies, reflected two main functional categories: synaptic plasticity and the Wnt signalling pathway. Initial ANOVA revealed a significant interaction of disease status with genotype/haplotype in ZnT3 with respect to levels of expression. Significant effects of specific genotypes and haplotypes in CACNA1E and FRZB on expression were also observed. Furthermore, ZnT3 was the gene for which the strongest evidence of association with schizophrenia was obtained in the East UK cohort, with four SNPs associated at the allelic and genotypic level. Significant associations of a number of haplotypes of ZnT3 with disease status were also identified. In addition, modest evidence of statistical epistasis between genes within both functional groups was identified. Finally, a method for analysis of CpG island methylation was developed based on bisulphite sequencing and methylation specific PCR (MSP) using previously validated primers for DKK3 (Yue et al., 2008). Although DKK3 showed a low density of methylation, the application of this method may prove useful for other candidate genes

Impact of COVID-19 on cardiovascular testing in the United States versus the rest of the world

Objectives: This study sought to quantify and compare the decline in volumes of cardiovascular procedures between the United States and non-US institutions during the early phase of the coronavirus disease-2019 (COVID-19) pandemic. Background: The COVID-19 pandemic has disrupted the care of many non-COVID-19 illnesses. Reductions in diagnostic cardiovascular testing around the world have led to concerns over the implications of reduced testing for cardiovascular disease (CVD) morbidity and mortality. Methods: Data were submitted to the INCAPS-COVID (International Atomic Energy Agency Non-Invasive Cardiology Protocols Study of COVID-19), a multinational registry comprising 909 institutions in 108 countries (including 155 facilities in 40 U.S. states), assessing the impact of the COVID-19 pandemic on volumes of diagnostic cardiovascular procedures. Data were obtained for April 2020 and compared with volumes of baseline procedures from March 2019. We compared laboratory characteristics, practices, and procedure volumes between U.S. and non-U.S. facilities and between U.S. geographic regions and identified factors associated with volume reduction in the United States. Results: Reductions in the volumes of procedures in the United States were similar to those in non-U.S. facilities (68% vs. 63%, respectively; p = 0.237), although U.S. facilities reported greater reductions in invasive coronary angiography (69% vs. 53%, respectively; p < 0.001). Significantly more U.S. facilities reported increased use of telehealth and patient screening measures than non-U.S. facilities, such as temperature checks, symptom screenings, and COVID-19 testing. Reductions in volumes of procedures differed between U.S. regions, with larger declines observed in the Northeast (76%) and Midwest (74%) than in the South (62%) and West (44%). Prevalence of COVID-19, staff redeployments, outpatient centers, and urban centers were associated with greater reductions in volume in U.S. facilities in a multivariable analysis. Conclusions: We observed marked reductions in U.S. cardiovascular testing in the early phase of the pandemic and significant variability between U.S. regions. The association between reductions of volumes and COVID-19 prevalence in the United States highlighted the need for proactive efforts to maintain access to cardiovascular testing in areas most affected by outbreaks of COVID-19 infection

An investigation of genetic and epigenetic factors in the regulation of gene expression in schizophrenia : insights into pathways involved in pathogenesis

Schizophrenia is a common psychiatric disorder with a complex aetiology that has a strong genetic component as well as a major contribution from non-genetic factors. Whilst GWAS studies have not yielded substantial evidence of DNA variants linked to schizophrenia, microarray expression studies, which reflect both genetic and environmental factors, have provided evidence of candidate genes whose expression changes significantly in schizophrenia. The present thesis is based on a prospective microarray study carried out on two brain regions implicated in schizophrenia: frontal cortex and superior temporal cortex (Maycox et al., 2009; Barnes et al., 2011). SNP variants in six of these genes were genotyped and allele, genotype and haplotype analysis carried out initially to investigate associations with levels of expression found in these microarray studies. Subsequently SNP associations with disease were investigated in an extended case-control cohort from the East UK region. The selected candidates genes, highlighted from microarray studies, reflected two main functional categories: synaptic plasticity and the Wnt signalling pathway. Initial ANOVA revealed a significant interaction of disease status with genotype/haplotype in ZnT3 with respect to levels of expression. Significant effects of specific genotypes and haplotypes in CACNA1E and FRZB on expression were also observed. Furthermore, ZnT3 was the gene for which the strongest evidence of association with schizophrenia was obtained in the East UK cohort, with four SNPs associated at the allelic and genotypic level. Significant associations of a number of haplotypes of ZnT3 with disease status were also identified. In addition, modest evidence of statistical epistasis between genes within both functional groups was identified. Finally, a method for analysis of CpG island methylation was developed based on bisulphite sequencing and methylation specific PCR (MSP) using previously validated primers for DKK3 (Yue et al., 2008). Although DKK3 showed a low density of methylation, the application of this method may prove useful for other candidate genes.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

Reduction of cardiac imaging tests during the COVID-19 pandemic: The case of Italy. Findings from the IAEA Non-invasive Cardiology Protocol Survey on COVID-19 (INCAPS COVID)

Background: In early 2020, COVID-19 massively hit Italy, earlier and harder than any other European country. This caused a series of strict containment measures, aimed at blocking the spread of the pandemic. Healthcare delivery was also affected when resources were diverted towards care of COVID-19 patients, including intensive care wards. Aim of the study: The aim is assessing the impact of COVID-19 on cardiac imaging in Italy, compare to the Rest of Europe (RoE) and the World (RoW). Methods: A global survey was conducted in May–June 2020 worldwide, through a questionnaire distributed online. The survey covered three periods: March and April 2020, and March 2019. Data from 52 Italian centres, a subset of the 909 participating centres from 108 countries, were analyzed. Results: In Italy, volumes decreased by 67% in March 2020, compared to March 2019, as opposed to a significantly lower decrease (p &lt; 0.001) in RoE and RoW (41% and 40%, respectively). A further decrease from March 2020 to April 2020 summed up to 76% for the North, 77% for the Centre and 86% for the South. When compared to the RoE and RoW, this further decrease from March 2020 to April 2020 in Italy was significantly less (p = 0.005), most likely reflecting the earlier effects of the containment measures in Italy, taken earlier than anywhere else in the West. Conclusions: The COVID-19 pandemic massively hit Italy and caused a disruption of healthcare services, including cardiac imaging studies. This raises concern about the medium- and long-term consequences for the high number of patients who were denied timely diagnoses and the subsequent lifesaving therapies and procedures

Impact of COVID-19 on Diagnostic Cardiac Procedural Volume in Oceania: The IAEA Non-Invasive Cardiology Protocol Survey on COVID-19 (INCAPS COVID)

Objectives: The INCAPS COVID Oceania study aimed to assess the impact caused by the COVID-19 pandemic on cardiac procedure volume provided in the Oceania region. Methods: A retrospective survey was performed comparing procedure volumes within March 2019 (pre-COVID-19) with April 2020 (during first wave of COVID-19 pandemic). Sixty-three (63) health care facilities within Oceania that perform cardiac diagnostic procedures were surveyed, including a mixture of metropolitan and regional, hospital and outpatient, public and private sites, and 846 facilities outside of Oceania. The percentage change in procedure volume was measured between March 2019 and April 2020, compared by test type and by facility. Results: In Oceania, the total cardiac diagnostic procedure volume was reduced by 52.2% from March 2019 to April 2020, compared to a reduction of 75.9% seen in the rest of the world (p&lt;0.001). Within Oceania sites, this reduction varied significantly between procedure types, but not between types of health care facility. All procedure types (other than stress cardiac magnetic resonance [CMR] and positron emission tomography [PET]) saw significant reductions in volume over this time period (p&lt;0.001). In Oceania, transthoracic echocardiography (TTE) decreased by 51.6%, transoesophageal echocardiography (TOE) by 74.0%, and stress tests by 65% overall, which was more pronounced for stress electrocardiograph (ECG) (81.8%) and stress echocardiography (76.7%) compared to stress single-photon emission computerised tomography (SPECT) (44.3%). Invasive coronary angiography decreased by 36.7% in Oceania. Conclusion: A significant reduction in cardiac diagnostic procedure volume was seen across all facility types in Oceania and was likely a function of recommendations from cardiac societies and directives from government to minimise spread of COVID-19 amongst patients and staff. Longer term evaluation is important to assess for negative patient outcomes which may relate to deferral of usual models of care within cardiology

International Impact of COVID-19 on the Diagnosis of Heart Disease

Background: The coronavirus disease 2019 (COVID-19) pandemic has adversely affected diagnosis and treatment of noncommunicable diseases. Its effects on delivery of diagnostic care for cardiovascular disease, which remains the leading cause of death worldwide, have not been quantified. Objectives: The study sought to assess COVID-19's impact on global cardiovascular diagnostic procedural volumes and safety practices. Methods: The International Atomic Energy Agency conducted a worldwide survey assessing alterations in cardiovascular procedure volumes and safety practices resulting from COVID-19. Noninvasive and invasive cardiac testing volumes were obtained from participating sites for March and April 2020 and compared with those from March 2019. Availability of personal protective equipment and pandemic-related testing practice changes were ascertained. Results: Surveys were submitted from 909 inpatient and outpatient centers performing cardiac diagnostic procedures, in 108 countries. Procedure volumes decreased 42% from March 2019 to March 2020, and 64% from March 2019 to April 2020. Transthoracic echocardiography decreased by 59%, transesophageal echocardiography 76%, and stress tests 78%, which varied between stress modalities. Coronary angiography (invasive or computed tomography) decreased 55% (p &lt; 0.001 for each procedure). In multivariable regression, significantly greater reduction in procedures occurred for centers in countries with lower gross domestic product. Location in a low-income and lower–middle-income country was associated with an additional 22% reduction in cardiac procedures and less availability of personal protective equipment and telehealth. Conclusions: COVID-19 was associated with a significant and abrupt reduction in cardiovascular diagnostic testing across the globe, especially affecting the world's economically challenged. Further study of cardiovascular outcomes and COVID-19–related changes in care delivery is warranted