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E1A binding protein (p300) and CREB binding protein (CBP) are two highly homologous and multidomain histone acetyltransferases. These two proteins are involved in many cellular processes by acting as coactivators of a large number of transcription factors. Dysregulation of p300/CBP has been found in a variety of cancers and other diseases, and inhibition has been shown to decrease Myc expression. Herein, we report the identification of a series of highly potent, proline-based small-molecule p300/CBP histone acetyltransferase (HAT) inhibitors using DNA-encoded library technology in combination with high-throughput screening. The strategy of reducing ChromlogD and fluorination of metabolic soft spots was explored to improve the pharmacokinetic properties of potent p300 inhibitors. Fluorination of both cyclobutyl and proline rings of

Background Leicester was the first city in the UK to have ‘local lockdown’ measures imposed in response to high community rates of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission. As part of this response, a directive was issued by NHS England to offer testing of asymptomatic healthcare workers (HCWs) at University Hospitals of Leicester NHS Trust (UHL) for SARS-CoV-2 infection. Methods Between 20 July and 14 August 2020, we invited all HCWs at UHL to attend for SARS-CoV-2 testing by nucleic acid amplification (NAAT). We combined the result of this assay with demographic information from the electronic staff record. Results A total of 1150 staff (~8% of the workforce) volunteered. The median age was 46 years (IQR 34–55), 972 (84.5%) were female; 234 (20.4%) were of South Asian and 58 (5.0%) of Black ethnicity; 564 (49.0%) were nurses/healthcare assistants. We found no cases of asymptomatic infection. In comparison, average community test positivity rate in Leicester city was 2.6%. Conclusions Within the context of local lockdowns due to high community transmission rates, voluntary testing of asymptomatic staff has low uptake and low yield and thus its premise and cost-effectiveness should be re-considered.

Background Although evidence suggests that demographic characteristics including minority ethnicity increase the risk of infection with Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), it is unclear whether these characteristics, together with occupational factors, influence anti-SARS-CoV-2 IgG seroprevalence in hospital staff. Methods We conducted cross-sectional surveillance examining seroprevalence of anti-SARS-CoV-2 IgG amongst staff at University Hospitals of Leicester (UHL) NHS Trust. We quantified seroprevalence stratified by ethnicity, occupation and seniority of practitioner and used logistic regression to examine demographic and occupational factors associated with seropositivity. Results A total of 1148/10662 (10.8%) hospital staff members were seropositive. Compared to White staff (seroprevalence 9.1%), seroprevalence was higher in South Asian (12.3%) and Black (21.2%) staff. The occupations and department with the highest seroprevalence were nurses/healthcare assistants (13.7%) and the Emergency Department (ED)/Acute Medicine (17.5%), respectively. Seroprevalence decreased with seniority in medical/nursing practitioners. Minority ethnicity was associated with seropositivity on an adjusted analysis (South Asian: aOR 1.26; 95%CI: 1.07–1.49 and Black: 2.42; 1.90–3.09). Anaesthetics/ICU staff members were less likely to be seropositive than ED/Acute medicine staff (0.41; 0.27–0.61). Conclusions Ethnicity and occupational factors, including specialty and seniority, are associated with seropositivity for anti-SARS-Cov-2 IgG. These findings could be used to inform occupational risk assessments for front-line healthcare workers.

Background Healthcare workers (HCWs) and ethnic minority groups are at increased risk of COVID-19 infection and adverse outcomes. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination is now available for frontline UK HCWs; however, demographic/occupational associations with vaccine uptake in this cohort are unknown. We sought to establish these associations in a large UK hospital workforce. Methods and findings We conducted cross-sectional surveillance examining vaccine uptake amongst all staff at University Hospitals of Leicester NHS Trust. We examined proportions of vaccinated staff stratified by demographic factors, occupation, and previous COVID-19 test results (serology/PCR) and used logistic regression to identify predictors of vaccination status after adjustment for confounders. We included 19,044 HCWs; 12,278 (64.5%) had received SARS-CoV-2 vaccination. Compared to White HCWs (70.9% vaccinated), a significantly smaller proportion of ethnic minority HCWs were vaccinated (South Asian, 58.5%; Black, 36.8%; p < 0.001 for both). After adjustment for age, sex, ethnicity, deprivation, occupation, SARS-CoV-2 serology/PCR results, and COVID-19-related work absences, factors found to be negatively associated with vaccine uptake were younger age, female sex, increased deprivation, pregnancy, and belonging to any non-White ethnic group (Black: adjusted odds ratio [aOR] 0.30, 95% CI 0.26–0.34, p < 0.001; South Asian: aOR 0.67, 95% CI 0.62–0.72, p < 0.001). Those who had previously had confirmed COVID-19 (by PCR) were less likely to be vaccinated than those who had tested negative. Limitations include data being from a single centre, lack of data on staff vaccinated outside the hospital system, and that staff may have taken up vaccination following data extraction. Conclusions Ethnic minority HCWs and those from more deprived areas as well as younger staff and female staff are less likely to take up SARS-CoV-2 vaccination. These findings have major implications for the delivery of SARS-CoV-2 vaccination programmes, in HCWs and the wider population, and should inform the national vaccination programme to prevent the disparities of the pandemic from widening., In a cross-sectional study, Dr. Christopher A. Martin and colleagues investigate factors associated with SARS-CoV-2 vaccine uptake in a multi-ethnic healthcare workforce in UK., Author summary Why was this study done? Healthcare workers, particularly those from ethnic minority groups, are at high risk of COVID-19. There are concerns that uptake of vaccination against COVID-19 in healthcare workers may vary by ethnicity as well as other demographic, occupational, and health factors, but there is limited real-world evidence on this topic. Determining factors that are associated with a lack of vaccine uptake in healthcare workers is important as it allows for targeted interventions to improve vaccine uptake, which will protect healthcare workers and the patients under their care. What did the researchers do and find? We used routinely collected data from a hospital vaccination programme to establish which staff at a large, ethnically diverse hospital trust in the UK had accepted the offer of vaccination against COVID-19. We combined these data with data on the demographic and occupational characteristics of staff members and also with data on previous test results and work absences for COVID-19. Using this dataset, we were able to determine that 65% of staff had accepted vaccination and that vaccine uptake was significantly lower in ethnic minority groups, younger age groups, females, pregnant healthcare workers, those living in more deprived areas, and those with a history of COVID-19. What do these findings mean? Our findings indicate that there are many healthcare workers who have not accepted a vaccine against COVID-19, which has important implications for the risk of infection for the individual healthcare workers and for patients under their care. We have identified particular demographic and occupational groups that should be targeted for interventions aimed at improving vaccine uptake. To make these interventions effective, more research should be undertaken to understand what the barriers are to COVID-19 vaccination in these groups and to evaluate methods of overcoming these barriers.

Developments in management and treatment of myeloma have extended survival rates in the myeloma population (Kumar et al, 2008) resulting in older patients living with the effects of myeloma and treatments and also the concurrent problems of ageing. The myeloma multidisciplinary team (MDT) in Leicester UK introduced frailty assessment for newly diagnosed patients over 65 years using QIP methodology as a Clinical Nurse Specialist (CNS) led initiative. The aim being to improve MDT decision making and documentation about treatment attenuation and furthermore to proactively identify frailty to enable enhanced support for frailer patients. This was aimed to be the initial development of an older person’s pathway of care. The International Myeloma Working Group (IMWG) frailty score (Palumbo et al 2015) and Clinical Frailty Score (Rockwood et al, 2005) were used as assessment tools, the latter being widely used throughout UK healthcare settings. Following initial audit and project planning, stakeholder engagement was undertaken using questionnaires, experience surveys and presentations. Interventions were planned using the Plan-Do-Study-Act (PDSA) method. Data was collected via audit of a number of team documentation sources and via patient feedback questionnaires. The aim of the project was surpassed and in both PDSA 2 and 3, 100% of newly diagnosed patients were frailty assessed, results being discussed in MDT, documented and communicated to primary care. The quality of information about patient frailty and function assisted MDT decision-making processes and improved over the QIP. This enabled clear rationales for MDT decisions to be documented in relation to individualised patient treatment options. There were no extra demands on CNS time, in fact consultation time decreased. Patient experience was maintained. The MDT recognised during the project that frailty scores need to be used with caution taking into consideration myeloma burden and presenting complications to avoid the risk of under-treatment (American Society of Haematology, 2019). Frailty scoring is now embedded into practice and assessment.

In recent years, social media has become one of the most popular mediums with widespread linkages from traditional media formats to social media. The expected advertising spend in this area is $14 billion by 2018 (Hoelzel ,The social media advertising report: Growth forecasts, market trends and the rise of the mobile. Retrieved January 1, 2015 from http://www.businessinsider.com/social-media-advertising-spending-growth-2014-9, 2014). In fact, the marketers are using more than one advertising channel to reach a target audience (Romaniuk, Beal, & Uncles, Journal of Advertising Research, 53:221–230, 2014). A common example of cross-channel advertising is the usage of social media links on magazine advertising. This descriptive study explores the determinants of the usage of social media links on print magazine advertisements, with a focus on reference group theory, demographics, and product-related dimensions. We believe that advertisers must consider using social media links in their advertising campaigns if they target female consumers, younger consumers, and ethnic consumers. Moreover, we propose that for nonnecessity, visible products, social marketing campaigns, and social events, these links are essential.

SUMMARY. Various models of functional communication offer help in formulating curriculum content for pupils at the pre-one word and one word production level. However, for teachers of children with severe learning difficulties, these are often limited in practical application. One particular aspect of communication development is Teaching First Meanings, which in this article has been related directly to functional application and classroom practice.

Histologic grading schemes for canine inflammatory conditions are sparse, and in the case of the canine pancreas, have not been previously described. In a previous study, we determined that histologic lesions of the exocrine pancreas occurred much more frequently than gross lesions. The intention of the current study was to develop a histologic grading scheme for nonneoplastic lesions following extensive assessment of the exocrine pancreas from dogs presented for necropsy examination. The parameters of the proposed scheme include neutrophilic inflammation, lymphocytic inflammation, pancreatic necrosis, pancreatic fat necrosis, edema, fibrosis, atrophy, and hyperplastic nodules. In this case series, the most common lesion was pancreatic hyperplastic nodules (80.2%), followed by lymphocytic inflammation (52.5%), fibrosis (49.5%), atrophy (46.5%), neutrophilic inflammation (31.7%), pancreatic fat necrosis (25.7%), pancreatic necrosis (16.8%), and edema (9.9%). Only 8 of the 101 animals had no evidence of any of the lesions in any of the sections examined. Fibrosis, atrophy, and/or lymphocytic infiltration most commonly accompanied nodules. Neutrophilic inflammation, when present, was often associated with necrosis (pancreatic necrosis, pancreatic fat necrosis, or both) and occasionally with hyperplastic nodules. The utilization of a grading scheme for exocrine pancreatic lesions will be useful in advancing the classification of exocrine pancreatic disease in the dog, which may lead to multicenter studies of exocrine pancreatic disorders in the dog and in other species.

The purpose of this study was to determine the prevalence of pancreatic nodular hyperplasia (NH) and its relation to age in the dog. A total of 101 dogs were enrolled. The pancreas was evaluated by histology and hyperplastic lesions were detected and scored. Age was recorded from the medical records. Correlation of age with inflammation and presence of hyperplastic lesions was evaluated. Of the 101 dogs, 81 (80.2%) had evidence of NH. Twenty-five of the 101 dogs did not have evidence of pancreatic inflammation, necrosis, and/or fibrosis, 17 (68.0%) of which had evidence of NH. Mean ± SD age in dogs with NH was significantly higher compared with dogs without NH (9.5 ± 3.4 years versus 3.4 ± 3.3; p-value < 0.0001). We conclude that NH is a common pathologic lesion in dogs and shows a positive correlation with age regardless of the presence or absence of pancreatic inflammation, necrosis, or fibrosis.

The contribution of respiratory muscle fatigue to the development of ventilatory failure has been the subject of considerable interest and has stimulated much research. Experimental studies in dogs have shown respiratory muscle fatigue to be a cause of ventilatory failure in both cardiogenic and septic shock models. In clinical conditions resulting in acute or chronic hypercapnia, respiratory muscle fatigue is believed to occur; however, the specific role of fatigue has been difficult to prove.

Pancreatitis is recognized as an important and common problem in dogs, but diagnosis can be challenging. Recently, new assays for the measurement of trypsin-a1-proteinase inhibitor complexes and canine pancreatic lipase immunoreactivity (cPLI and Spec cPL) have been developed and analytically validated. This is the first report of a direct comparison of the sensitivity of these and other more traditional serum markers for the diagnosis of canine pancreatitis in a subset of dogs with this disease (i.e., dogs with both macroscopic and microscopic changes characteristic of pancreatitis). Serum cPLI and Spec cPL concentrations showed the highest sensitivity for the diagnosis of pancreatitis in this group of patients. Further studies will be required to compare the specificity of these serum markers and thus determine their overall clinical utility.

Few studies of the prevalence of histologic lesions of the exocrine pancreas in dogs have been reported, and none of them systematically evaluate the localization of these lesions. The purpose of this study was to describe the anatomic localization of pancreatic inflammation, necrosis, and fibrosis in dogs presented for postmortem examination. Seventy-three pancreata from dogs presented for postmortem examination were evaluated and investigated for the presence of suppurative inflammation (SI), pancreatic necrosis (PN), and lymphocytic inflammation (LI). Sections that showed evidence of SI, PN, or LI also were evaluated for pancreatic fibrosis (F). The tendency for a preferred localization for SI, PN, and LI was evaluated by chi-square analysis. A total of 47 pancreata with histologic evidence of pancreatitis (SI, PN, or LI; F alone was not considered evidence of pancreatitis) were identified. Twenty-four (51.1%) had SI, 23 (48.9%) had PN, and 34 (72.3%) had LI. Of the 47 dogs with SI, PN, or LI, 28 (59.6%) had F. The distribution of SI, PN, and LI between the right and the left limb of the pancreas and among the 5 anatomic regions was random, based on a goodness-of-fit test. We conclude that pancreatic inflammation tends to occur in discrete areas within the pancreas rather than diffusely throughout the whole organ. These findings suggest that a single biopsy is insufficient to exclude subclinical pancreatitis and that there is no preferred site for pancreatic biopsy collection unless gross lesions are apparent.

With the advancement of veterinary critical care medicine, an increasing number of veterinary patients are being supported with positive-pressure ventilation. Animals with potentially reversible ventilatory failure (PaCO260 mmHg) caused by neuromuscular disease or pulmonary parenchymal disease or with pulmonary parenchymal disease causing hypoxemia (PaO260) despite supplemental oxygen are candidates for ventilatory support. The equation of motion for the respiratory system is defined and is used to describe the potential interactions between the patient and the ventilator. Commonly used modes of ventilation are described in terms of control and phase variables. The intent of this report is to aid clinicians in choosing an optimal ventilatory strategy for each patient that will best achieve the desired physiologic goals with minimal detrimental side effects.