Patients’ evaluations of patient safety in English general practices: a cross-sectional study

Background: The frequency and nature of safety problems and harm in general practices has previously relied on information supplied by health professionals, and scarce attention has been paid to experiences of patients. Aim: To examine patient-reported experiences and outcomes of patient safety in Primary Care in England. Design and Setting: Cross-sectional study in 45 general practices. Method: A postal version of the Patient Reported Experiences and Outcomes of Safety in Primary Care (PREOS-PC) questionnaire was sent to a random sample of 6,736 patients. Main outcome measures included “practice activation” (what does the practice do to create a safe environment); “patient activation” (how pro-active are patients in ensuring safe healthcare delivery); “experiences of safety events” (safety errors); “outcomes of safety” (harm); and “overall perception of safety” (how safe do patients rate their practice). Results: 1,244 patients (18.4%) returned completed questionnaires. Scores were high for “practice activation” (mean (standard error) = 80.4 out of 100 (2.0)) and low for “patient activation” (26.3 out of 100 (2.6)). A substantial proportion of patients (45%) reported having experienced at least one safety problem in the previous 12 months, mostly related to appointments (33%), diagnosis (17%), patient-provider communication (15%), and coordination between providers (14%). 221 patients (23%) reported some degree of harm in the previous 12 months. The overall assessment of the level of safety of their practices was generally high (86.0 out of 100 (16.8)). Conclusion: Priority areas for patient safety improvement in general practices in England include appointments, diagnosis, communication, coordination and patient activation

Epitope-specific antibody responses differentiate COVID-19 outcomes and variants of concern

BACKGROUND. The role of humoral immunity in COVID-19 is not fully understood, owing, in large part, to the complexity of antibodies produced in response to the SARS-CoV-2 infection. There is a pressing need for serology tests to assess patient-specific antibody response and predict clinical outcome. METHODS. Using SARS-CoV-2 proteome and peptide microarrays, we screened 146 COVID-19 patients’ plasma samples to identify antigens and epitopes. This enabled us to develop a master epitope array and an epitope-specific agglutination assay to gauge antibody responses systematically and with high resolution. RESULTS. We identified linear epitopes from the spike (S) and nucleocapsid (N) proteins and showed that the epitopes enabled higher resolution antibody profiling than the S or N protein antigen. Specifically, we found that antibody responses to the S-811–825, S-881–895, and N-156–170 epitopes negatively or positively correlated with clinical severity or patient survival. Moreover, we found that the P681H and S235F mutations associated with the coronavirus variant of concern B.1.1.7 altered the specificity of the corresponding epitopes. CONCLUSION. Epitope-resolved antibody testing not only affords a high-resolution alternative to conventional immunoassays to delineate the complex humoral immunity to SARS-CoV-2 and differentiate between neutralizing and non-neutralizing antibodies, but it also may potentially be used to predict clinical outcome. The epitope peptides can be readily modified to detect antibodies against variants of concern in both the peptide array and latex agglutination formats. FUNDING. Ontario Research Fund (ORF) COVID-19 Rapid Research Fund, Toronto COVID-19 Action Fund, Western University, Lawson Health Research Institute, London Health Sciences Foundation, and Academic Medical Organization of Southwestern Ontario (AMOSO) Innovation Fund

Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK.

BACKGROUND: A safe and efficacious vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), if deployed with high coverage, could contribute to the control of the COVID-19 pandemic. We evaluated the safety and efficacy of the ChAdOx1 nCoV-19 vaccine in a pooled interim analysis of four trials. METHODS: This analysis includes data from four ongoing blinded, randomised, controlled trials done across the UK, Brazil, and South Africa. Participants aged 18 years and older were randomly assigned (1:1) to ChAdOx1 nCoV-19 vaccine or control (meningococcal group A, C, W, and Y conjugate vaccine or saline). Participants in the ChAdOx1 nCoV-19 group received two doses containing 5 × 1010 viral particles (standard dose; SD/SD cohort); a subset in the UK trial received a half dose as their first dose (low dose) and a standard dose as their second dose (LD/SD cohort). The primary efficacy analysis included symptomatic COVID-19 in seronegative participants with a nucleic acid amplification test-positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to treatment received, with data cutoff on Nov 4, 2020. Vaccine efficacy was calculated as 1 - relative risk derived from a robust Poisson regression model adjusted for age. Studies are registered at ISRCTN89951424 and ClinicalTrials.gov, NCT04324606, NCT04400838, and NCT04444674. FINDINGS: Between April 23 and Nov 4, 2020, 23 848 participants were enrolled and 11 636 participants (7548 in the UK, 4088 in Brazil) were included in the interim primary efficacy analysis. In participants who received two standard doses, vaccine efficacy was 62·1% (95% CI 41·0-75·7; 27 [0·6%] of 4440 in the ChAdOx1 nCoV-19 group vs71 [1·6%] of 4455 in the control group) and in participants who received a low dose followed by a standard dose, efficacy was 90·0% (67·4-97·0; three [0·2%] of 1367 vs 30 [2·2%] of 1374; pinteraction=0·010). Overall vaccine efficacy across both groups was 70·4% (95·8% CI 54·8-80·6; 30 [0·5%] of 5807 vs 101 [1·7%] of 5829). From 21 days after the first dose, there were ten cases hospitalised for COVID-19, all in the control arm; two were classified as severe COVID-19, including one death. There were 74 341 person-months of safety follow-up (median 3·4 months, IQR 1·3-4·8): 175 severe adverse events occurred in 168 participants, 84 events in the ChAdOx1 nCoV-19 group and 91 in the control group. Three events were classified as possibly related to a vaccine: one in the ChAdOx1 nCoV-19 group, one in the control group, and one in a participant who remains masked to group allocation. INTERPRETATION: ChAdOx1 nCoV-19 has an acceptable safety profile and has been found to be efficacious against symptomatic COVID-19 in this interim analysis of ongoing clinical trials. FUNDING: UK Research and Innovation, National Institutes for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, Bill & Melinda Gates Foundation, Lemann Foundation, Rede D'Or, Brava and Telles Foundation, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and AstraZeneca

Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK

Background A safe and efficacious vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), if deployed with high coverage, could contribute to the control of the COVID-19 pandemic. We evaluated the safety and efficacy of the ChAdOx1 nCoV-19 vaccine in a pooled interim analysis of four trials. Methods This analysis includes data from four ongoing blinded, randomised, controlled trials done across the UK, Brazil, and South Africa. Participants aged 18 years and older were randomly assigned (1:1) to ChAdOx1 nCoV-19 vaccine or control (meningococcal group A, C, W, and Y conjugate vaccine or saline). Participants in the ChAdOx1 nCoV-19 group received two doses containing 5 × 1010 viral particles (standard dose; SD/SD cohort); a subset in the UK trial received a half dose as their first dose (low dose) and a standard dose as their second dose (LD/SD cohort). The primary efficacy analysis included symptomatic COVID-19 in seronegative participants with a nucleic acid amplification test-positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to treatment received, with data cutoff on Nov 4, 2020. Vaccine efficacy was calculated as 1 - relative risk derived from a robust Poisson regression model adjusted for age. Studies are registered at ISRCTN89951424 and ClinicalTrials.gov, NCT04324606, NCT04400838, and NCT04444674. Findings Between April 23 and Nov 4, 2020, 23 848 participants were enrolled and 11 636 participants (7548 in the UK, 4088 in Brazil) were included in the interim primary efficacy analysis. In participants who received two standard doses, vaccine efficacy was 62·1% (95% CI 41·0–75·7; 27 [0·6%] of 4440 in the ChAdOx1 nCoV-19 group vs71 [1·6%] of 4455 in the control group) and in participants who received a low dose followed by a standard dose, efficacy was 90·0% (67·4–97·0; three [0·2%] of 1367 vs 30 [2·2%] of 1374; pinteraction=0·010). Overall vaccine efficacy across both groups was 70·4% (95·8% CI 54·8–80·6; 30 [0·5%] of 5807 vs 101 [1·7%] of 5829). From 21 days after the first dose, there were ten cases hospitalised for COVID-19, all in the control arm; two were classified as severe COVID-19, including one death. There were 74 341 person-months of safety follow-up (median 3·4 months, IQR 1·3–4·8): 175 severe adverse events occurred in 168 participants, 84 events in the ChAdOx1 nCoV-19 group and 91 in the control group. Three events were classified as possibly related to a vaccine: one in the ChAdOx1 nCoV-19 group, one in the control group, and one in a participant who remains masked to group allocation. Interpretation ChAdOx1 nCoV-19 has an acceptable safety profile and has been found to be efficacious against symptomatic COVID-19 in this interim analysis of ongoing clinical trials

Artificially Induced Pluripotent Stem Cell-Derived Whole-Brain Organoid for Modelling the Pathophysiology of Metachromatic Leukodystrophy and Drug Repurposing

Metachromatic leukodystrophy (MLD) is a rare neurodegenerative disease that results from a deficiency of the lysosomal enzyme arylsulfatase A (ARSA). Worldwide, there are between one in 40,000 and one in 160,000 people living with the disease. While there are currently no effective treatments for MLD, induced pluripotent stem cell-derived brain organoids have the potential to provide a better understanding of MLD pathogenesis. However, developing brain organoid models is expensive, time consuming and may not accurately reflect disease progression. Using accurate and inexpensive computer simulations of human brain organoids could overcome the current limitations. Artificially induced whole-brain organoids (aiWBO) have the potential to greatly expand our ability to model MLD and guide future wet lab research. In this study, we have upgraded and validated our artificially induced whole-brain organoid platform (NEUBOrg) using our previously validated machine learning platform, DeepNEU (v6.2). Using this upgraded NEUBorg, we have generated aiWBO simulations of MLD and provided a novel approach to evaluate factors associated with MLD pathogenesis, disease progression and new potential therapeutic options

Elucidating the Molecular Mechanisms Involved in Assembly/Folding and Targeting V-ATPase a-subunit Isoforms to their Functional Destinations

Vacuolar H+-ATPases (V-ATPases) are proton pumps distributed across membranes of specialized cells and luminal compartments. V-ATPases in the plasma membrane of osteoclasts are responsible for acidifying the surface of bone, essential for bone resorption. V-ATPases in the plasma membrane of metastatic cells acidify the extracellular space to facilitate invasion. The V-ATPase a subunit has four isoforms (a1-a4) that localize to distinct compartments. In invasive cancer, plasma membrane expression of a3 and a4 are required for metastasis while a3 is specific for the plasma membrane of osteoclasts. Thus, both isoforms are potential therapeutic targets. Sequences of a isoforms reveal putative N-glycosylation sites within extracellular loop II (ELII). Upon PNGase F and Endo H treatment, all a isoforms showed faster mobility on SDS-PAGE indicating the presence of N-linked oligosaccharide. Using site-directed mutagenesis, I showed that deglycosylated a1â a4 had shorter half-lifes, more rapid proteasomal degradation, endoplasmic reticulum (ER) retention, defective Golgi trafficking, and an inability to associate with ER assembly factor, VMA21. In addition, deglycosylated a4 showed defective cell-surface expression and assembly. Cutis laxa type II, osteopetrosis and distal renal tubular acidosis (dRTA) result from mutations within the a2, a3 and a4 subunits, respectively. To further map critical domains essential for V-ATPase structure and function, I studied human disease-causing missense mutations that affect conserved residues of a isoforms, specifically: a2P405L, a4R449H and a4G820R. a4R449H and a2P405L were unstable and degraded by the proteasomal pathway. The data also indicated that a2-P405 is required for Golgi trafficking while a4-R449 is essential for ER exit and cell-surface expression. a4R449H shows increased association with the assembly factor, VMA21. Molecular modeling of a4 predicts a4G820R would interfere with proton translocation through the cytoplasmic half channel formed by the a subunit. This work enhances our knowledge of a isoforms structure and informs possible therapeutic interventions against cancer metastasis and lytic bone diseases.Ph.D

Telepsychiatry evaluation in the north-west of England: preliminary results of a qualitative study

A telepsychiatry referral service for patients suffering from anxiety and depression was evaluated from a user perspective. Low-cost video-phones linked a psychiatrist to two general practices in the north-west of England. Quantitative data were collected using a semistructured interview schedule. Twenty-two patients and 13 doctors were interviewed after a video-link consultation. Some users were very positive about the service and recognized its potential benefits, while others were more ambivalent. Patients saw the service as a means of obtaining additional expert' advice. General practitioners felt that the service might adversely affect the doctor-patient relationship in psychiatry. Both patients and clinicians recognized that the video-link modified normal interaction. Users need to adapt to this form of communication. An induction session is recommended for both patients and clinicians. <br/

Rates of turnover among general practitioners: a retrospective study of all English general practices between 2007 and 2019.

From PubMed via Jisc Publications RouterPublication status: epublishTo quantify general practitioners' (GPs') turnover in England between 2007 and 2019, describe trends over time, regional differences and associations with social deprivation or other practice characteristics. A retrospective study of annual cross-sectional data. All general practices in England (8085 in 2007, 6598 in 2019). We calculated turnover rates, defined as the proportion of GPs leaving a practice. Rates and their median, 25th and 75th percentiles were calculated by year and region. The proportion of practices with persistent high turnover (>10%) over consecutive years were also calculated. A negative binomial regression model assessed the association between turnover and social deprivation or other practice characteristics. Turnover rates increased over time. The 75th percentile in 2009 was 11%, but increased to 14% in 2019. The highest turnover rate was observed in 2013-2014, corresponding to the 75th percentile of 18.2%. Over time, regions experienced increases in turnover rates, although it varied across English regions. The proportion of practices with high (10% to 40%) turnover within a year almost doubled from 14% in 2009 to 27% in 2019. A rise in the number of practices with persistent high turnover (>10%) for at least three consecutive years was also observed, from 2.7% (2.3%-3.1%) in 2007 to 6.3% (5.7%-6.9%) in 2017. The statistical analyses revealed that practice-area deprivation was moderately associated with turnover rate, with practices in the most deprived area having higher turnover rates compared with practices in the least deprived areas (incidence rate ratios 1.09; 95% CI 1.06 to 1.13). GP turnover has increased in the last decade nationally, with regional variability. Greater attention to GP turnover is needed, in the most deprived areas in particular, where GPs often need to deal with more complex health needs. There is a large cost associated with GP turnover and practices with very high persistent turnover need to be further researched, and the causes behind this identified, to allow support strategies and policies to be developed. [Abstract copyright: © Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

Patient satisfaction with store-and-forward teledermatology

We assessed patient satisfaction with a nurse-led store-and-forward teledermatology service in Manchester. A teledermatology nurse obtained the patient's history, took digital photographs of the patient's skin lesion and then sent the information to a hospital dermatologist, who responded with management advice the following week. Of 141 patients who attended their teledermatology appointment, 123 (50 male, 73 female) completed the study questionnaire (87%). The average age of respondents was 42 years (SD 17, range 18-90 years). Ninety-three per cent reported that they were happy with the teleconsultation while 86% reported that it was more convenient than going to the outpatient clinic. Forty per cent agreed that they would feel more comfortable seeing the dermatologist in person while only 58% were comfortable with not speaking to the dermatologist about their skin condition. The absence of interaction with the dermatologist and the delay in receiving management advice may have contributed to the somewhat low satisfaction rates