CD4 T-Cell Suppression by Cells from Toxoplasma gondii-Infected Retinas Is Mediated by Surface Protein PD-L1

In the inflamed retina, CD4(+) T cells can cause retinal damage when they are not properly regulated. Since tissue expression of major histocompatibility complex (MHC) class II and costimulatory molecules is a key mechanism for regulating effector T cells, we tested the hypothesis that upregulation of these proteins in the retina contributes to the regulation of CD4 T cells. Here we report that in retinas infected with the protozoan parasite Toxoplasma gondii, MHC class II is upregulated on infiltrating leukocytes as well as on resident retinal cells, including photoreceptors. Flow cytometric analysis indicated that B7 costimulatory family members (CD80, CD86, ICOS-L, and programmed death ligand 2 [PD-L2]) were not expressed on class II(+) cells. In contrast, PD-L1 (also named B7-H1 or CD274) was expressed on the majority of both hematopoietic and resident retinal MHC class II-expressing cells. Retinal cells from Toxoplasma-infected animals were able to suppress T-cell activation in a PD-L1-dependent manner. Finally, we demonstrate that the expression of MHC class II and PD-L1 was critically dependent on gamma interferon (IFN-gamma) expression. These data suggest that retinal MHC class II and PD-L1 expression is a novel mechanism by which the retina protects itself from CD4 T-cell-mediated immune damage in ocular toxoplasmosis and other types of retinal immune responses

A retrospective study of cochlear implant outcomes in children with residual hearing

BACKGROUND: There has been increasing demand for the cochlear implantation of children who demonstrate some auditory capacity with conventional hearing aids. The purpose of this study was to examine speech recognition outcomes in a group of children who were regarded as borderline candidates for cochlear implantation as their residual hearing and/or auditory functioning levels exceeded typical audiologic candidacy criteria. METHODS: A retrospective chart review was undertaken at one Canadian cochlear implant centre to identify children implanted at age 4 or older with a pure-tone-average of 90 dB or better and speech recognition of 30% or greater. Pre-implant and post-implant open-set word and sentence test scores were analyzed. RESULTS: Eleven children of 195 paediatric cochlear implant recipients met the inclusion criteria for this study. Speech recognition results for the10 English-speaking children indicated significant gains in both open-set word and sentence understanding within the first 6 to 12 months of implant use. Seven of 9 children achieved 80% open-set sentence recognition within 12 months post-surgery. CONCLUSION: Children with several years of experience using conventional amplification demonstrated rapid progress in auditory skills following cochlear implantation. These findings suggest that cochlear implantation may be an appropriate intervention for selected children with severe hearing losses and/or auditory capacity outside current candidacy criteria

Living risk prediction algorithm (QCOVID) for risk of hospital admission and mortality from coronavirus 19 in adults: national derivation and validation cohort study.

OBJECTIVE: To derive and validate a risk prediction algorithm to estimate hospital admission and mortality outcomes from coronavirus disease 2019 (covid-19) in adults. DESIGN: Population based cohort study. SETTING AND PARTICIPANTS: QResearch database, comprising 1205 general practices in England with linkage to covid-19 test results, Hospital Episode Statistics, and death registry data. 6.08 million adults aged 19-100 years were included in the derivation dataset and 2.17 million in the validation dataset. The derivation and first validation cohort period was 24 January 2020 to 30 April 2020. The second temporal validation cohort covered the period 1 May 2020 to 30 June 2020. MAIN OUTCOME MEASURES: The primary outcome was time to death from covid-19, defined as death due to confirmed or suspected covid-19 as per the death certification or death occurring in a person with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in the period 24 January to 30 April 2020. The secondary outcome was time to hospital admission with confirmed SARS-CoV-2 infection. Models were fitted in the derivation cohort to derive risk equations using a range of predictor variables. Performance, including measures of discrimination and calibration, was evaluated in each validation time period. RESULTS: 4384 deaths from covid-19 occurred in the derivation cohort during follow-up and 1722 in the first validation cohort period and 621 in the second validation cohort period. The final risk algorithms included age, ethnicity, deprivation, body mass index, and a range of comorbidities. The algorithm had good calibration in the first validation cohort. For deaths from covid-19 in men, it explained 73.1% (95% confidence interval 71.9% to 74.3%) of the variation in time to death (R2); the D statistic was 3.37 (95% confidence interval 3.27 to 3.47), and Harrell's C was 0.928 (0.919 to 0.938). Similar results were obtained for women, for both outcomes, and in both time periods. In the top 5% of patients with the highest predicted risks of death, the sensitivity for identifying deaths within 97 days was 75.7%. People in the top 20% of predicted risk of death accounted for 94% of all deaths from covid-19. CONCLUSION: The QCOVID population based risk algorithm performed well, showing very high levels of discrimination for deaths and hospital admissions due to covid-19. The absolute risks presented, however, will change over time in line with the prevailing SARS-C0V-2 infection rate and the extent of social distancing measures in place, so they should be interpreted with caution. The model can be recalibrated for different time periods, however, and has the potential to be dynamically updated as the pandemic evolves

Objectively measured physical activity and sedentary behaviour and ankle brachial index: Cross-sectional and longitudinal associations in older men

AbstractBackgroundAssociations between bouts of physical activity (PA), sedentary behaviour (SB) and cardiovascular disease, and their mutual independence are not well defined. A low ankle brachial index (ABI ≤0.9) indicates peripheral arterial disease (PAD) and is predictive of cardiovascular events and functional impairment. We investigated the independence of PA and SB and the importance of bout duration in relation to ABI using objective measures.Methods945 men from the British Regional Heart Study, mean age 78.4 y, had concurrent measurements of ABI (Vicorder) and physical activity (Actigraph GT3X accelerometer); 427 men also had accelerometer measurements one year previously and contributed data to longitudinal analyses.Results and conclusionIn cross-sectional analyses, after adjusting for covariates each extra 10 min of moderate and vigorous PA per day was associated with an OR of 0.81 (95% CI 0.72, 0.91) for a low ABI, a stronger association than for light PA (OR 0.85, 95% CI 0.75, 0.98). Each extra 30 min of SB was associated with an OR of 1.19 (95% CI 1.07, 1.33) for a low ABI. Associations between moderate and vigorous PA and ABI persisted after adjustment for light PA or SB. Bout lengths for PA and SB were not associated with a low ABI. One year changes in PA or SB were not associated with low ABI.All physical activity and lower levels of SB, regardless of bout duration were inversely associated with ABI; more intense PA showed a stronger association. No associations between changes in PA and ABI were observed, but power may have been limited

Objectively measured physical activity, sedentary time and subclinical vascular disease: Cross-sectional study in older British men.

Low physical activity (PA) and high levels of sedentary time (ST) are associated with higher cardiovascular disease (CVD) risk among older people. However, their independent contribution and importance of duration of PA and ST bouts remain unclear. We investigated associations between objectively measured PA, ST and non-invasive vascular measures, markers of CVD risk. Cross-sectional study of 1216 men from the British Regional Heart Study, mean age 78.5years, measured in 2010-2012. Carotid intima thickness (CIMT), distensibility coefficient (DC) and plaque presence were measured using ultrasound; pulse wave velocity (cfPWV) and augmentation index (AIx) using a Vicorder. PA and ST were measured using hip-worn ActiGraph GT3X accelerometers. After adjusting for covariates, each additional 1000 steps per day was associated with a 0.038m/s lower cfPWV (95% CI=-0.076, 0.0003), 0.095 10(-3) kPa(-1) higher DC (95% CI=0.006, 0.185), 0.26% lower AIx (95% CI=-0.40, -0.12) and a 0.005mm lower CIMT (95% CI=-0.008, -0.001). Moderate and vigorous PA (MVPA) was associated with lower AIx and CIMT, light PA (LPA) with lower cfPWV and CIMT and ST with higher cfPWV, AIx and CIMT and lower DC. LPA and ST were highly correlated (r=-0.62). The independence of MVPA and ST or MVPA and LPA was inconsistent across vascular measures. Bout lengths for both PA and ST were not associated with vascular measures. In our cross-sectional study of older men, all PA regardless of intensity or bout duration was beneficially associated with vascular measures, as was lower ST. LPA was particularly relevant for cfPWV and CIMT

One year outcomes of a mentoring scheme for female academics: a pilot study at the Institute of Psychiatry, King's College London

<p>Abstract</p> <p>Background</p> <p>The professional development of under-represented faculty may be enhanced by mentorship, but we understand very little about the mechanisms by which mentoring brings about change. Our study posed the research question, what are the mechanisms by which mentoring may support professional development in under-represented groups?</p> <p>The study aims to: (i) to pilot a mentoring scheme for female academics; (ii) to compare various health-related and attitudinal measures in mentees at baseline, 6 months, and 1 year into the mentoring relationship and, (iii) to compare pre-mentoring expectations to outcomes at 6 months and 1 year follow-up for mentees and mentors.</p> <p>Methods</p> <p>Female academic mentees were matched 1:1 or 2:1 with more senior academic mentors. Online surveys were conducted to compare health-related and attitudinal measures and expectations of mentoring at baseline with outcomes at 6 months and 1 year using paired t-tests and McNemar's test for matched cohort data.</p> <p>Results</p> <p>N = 46 mentoring pairs, 44 (96%) mentees completed the pre-mentoring survey, 37 (80%) at 6 months and 30 (65%) at 1 year. Job-related well-being (anxiety-contentment), self-esteem and self-efficacy all improved significantly and work-family conflict diminished at 1 year. Highest expectations were career progression (39; 89%), increased confidence (38; 87%), development of networking skills (33; 75%), better time-management (29; 66%) and better work-life balance (28; 64%). For mentees, expectations at baseline were higher than perceived achievements at 6 months or 1 year follow-up.</p> <p>For mentors (N = 39), 36 (92%) completed the pre-mentoring survey, 32 (82%) at 6 months and 28 (72%) at 1 year. Mentors' highest expectations were of satisfaction in seeing people progress (26; 69%), seeing junior staff develop and grow (19; 53%), helping solve problems (18; 50%), helping women advance their careers (18; 50%) and helping remove career obstacles (13; 36%). Overall, gains at 6 months and 1 year exceeded pre-mentoring expectations.</p> <p>Conclusions</p> <p>This uncontrolled pilot study suggests that mentoring can improve aspects of job-related well-being, self-esteem and self-efficacy over 6 months, with further improvements seen after 1 year for female academics. Work-family conflict can also diminish. Despite these gains, mentees' prior expectations were shown to be unrealistically high, but mentors' expectations were exceeded.</p

An interdisciplinary team communication framework and its application to healthcare 'e-teams' systems design

<p>Abstract</p> <p>Background</p> <p>There are few studies that examine the processes that interdisciplinary teams engage in and how we can design health information systems (HIS) to support those team processes. This was an exploratory study with two purposes: (1) To develop a framework for interdisciplinary team communication based on structures, processes and outcomes that were identified as having occurred during weekly team meetings. (2) To use the framework to guide 'e-teams' HIS design to support interdisciplinary team meeting communication.</p> <p>Methods</p> <p>An ethnographic approach was used to collect data on two interdisciplinary teams. Qualitative content analysis was used to analyze the data according to structures, processes and outcomes.</p> <p>Results</p> <p>We present details for team meta-concepts of structures, processes and outcomes and the concepts and sub concepts within each meta-concept. We also provide an exploratory framework for interdisciplinary team communication and describe how the framework can guide HIS design to support 'e-teams'.</p> <p>Conclusion</p> <p>The structures, processes and outcomes that describe interdisciplinary teams are complex and often occur in a non-linear fashion. Electronic data support, process facilitation and team video conferencing are three HIS tools that can enhance team function.</p

A multicenter assessment of interreader reliability of LI-RADS version 2018 for MRI and CT

Background: Various limitations have impacted research evaluating reader agreement for Liver Imaging-Reporting and Data System (LI-RADS). Purpose: To assess reader agreement of LI-RADS in an international multi-center, multireader setting using scrollable images. Materials and Methods: This retrospective study used de-identified clinical multiphase CT and MRI examinations and reports with at least one untreated observation from six institutions and three countries; only qualifying examinations were submitted. Examination dates were October 2017 – August 2018 at the coordinating center. One untreated observation per examination was randomly selected using observation identifiers, and its clinically assigned features were extracted from the report. The corresponding LI-RADS v2018 category was computed as a re-scored clinical read. Each examination was randomly assigned to two of 43 research readers who independently scored the observation. Agreement for an ordinal modified four-category LI-RADS scale (LR-1/2, LR-3, LR-4, LR-5/M/tumor in vein) was computed using intra-class correlation coefficients (ICC). Agreement was also computed for dichotomized malignancy (LR-4/LR5/LR-M/LR-tumor in vein), LR-5, and LR-M. Agreement was compared between researchversus-research reads and research-versus-clinical reads. Results: 484 patients (mean age, 62 years ±10 [SD]; 156 women; 93 CT, 391 MRI) were included. ICCs for ordinal LI-RADS, dichotomized malignancy, LR-5, and LR-M were 0.68 (95% CI: 0.62, 0.74), 0.63 (95% CI: 0.56, 0.71), 0.58 (95% CI: 0.50, 0.66), and 0.46 (95% CI: 0.31, 0.61) respectively. Research-versus-research reader agreement was higher than research-versus-clinical agreement for modified four-category LI-RADS (ICC, 0.68 vs. 0.62, P = .03) and for dichotomized malignancy (ICC, 0.63 vs. 0.53, P = .005), but not for LR-5 (P = .14) or LR-M (P = .94). Conclusion: There was moderate agreement for Liver Imaging-Reporting and Data System v2018 overall. For some comparisons, research-versus-research reader agreement was higher than research-versus-clinical reader agreement, indicating differences between the clinical and research environments that warrant further study

Development and evaluation of low-volume tests to detect and characterize antibodies to SARS-CoV-2

Low-volume antibody assays can be used to track SARS-CoV-2 infection rates in settings where active testing for virus is limited and remote sampling is optimal. We developed 12 ELISAs detecting total or antibody isotypes to SARS-CoV-2 nucleocapsid, spike protein or its receptor binding domain (RBD), 3 anti-RBD isotype specific luciferase immunoprecipitation system (LIPS) assays and a novel Spike-RBD bridging LIPS total-antibody assay. We utilized pre-pandemic (n=984) and confirmed/suspected recent COVID-19 sera taken pre-vaccination rollout in 2020 (n=269). Assays measuring total antibody discriminated best between pre-pandemic and COVID-19 sera and were selected for diagnostic evaluation. In the blind evaluation, two of these assays (Spike Pan ELISA and Spike-RBD Bridging LIPS assay) demonstrated >97% specificity and >92% sensitivity for samples from COVID-19 patients taken >21 days post symptom onset or PCR test. These assays offered better sensitivity for the detection of COVID-19 cases than a commercial assay which requires 100-fold larger serum volumes. This study demonstrates that low-volume in-house antibody assays can provide good diagnostic performance, and highlights the importance of using well-characterized samples and controls for all stages of assay development and evaluation. These cost-effective assays may be particularly useful for seroprevalence studies in low and middle-income countries

The QICKD study protocol: a cluster randomised trial to compare quality improvement interventions to lower systolic BP in chronic kidney disease (CKD) in primary care

BACKGROUND: Chronic kidney disease (CKD) is a relatively newly recognised but common long-term condition affecting 5 to 10% of the population. Effective management of CKD, with emphasis on strict blood pressure (BP) control, reduces cardiovascular risk and slows the progression of CKD. There is currently an unprecedented rise in referral to specialist renal services, which are often located in tertiary centres, inconvenient for patients, and wasteful of resources. National and international CKD guidelines include quality targets for primary care. However, there have been no rigorous evaluations of strategies to implement these guidelines. This study aims to test whether quality improvement interventions improve primary care management of elevated BP in CKD, reduce cardiovascular risk, and slow renal disease progression DESIGN: Cluster randomised controlled trial (CRT) METHODS: This three-armed CRT compares two well-established quality improvement interventions with usual practice. The two interventions comprise: provision of clinical practice guidelines with prompts and audit-based education. The study population will be all individuals with CKD from general practices in eight localities across England. Randomisation will take place at the level of the general practices. The intended sample (three arms of 25 practices) powers the study to detect a 3 mmHg difference in systolic BP between the different quality improvement interventions. An additional 10 practices per arm will receive a questionnaire to measure any change in confidence in managing CKD. Follow up will take place over two years. Outcomes will be measured using anonymised routinely collected data extracted from practice computer systems. Our primary outcome measure will be reduction of systolic BP in people with CKD and hypertension at two years. Secondary outcomes will include biomedical outcomes and markers of quality, including practitioner confidence in managing CKD. A small group of practices (n = 4) will take part in an in-depth process evaluation. We will use time series data to examine the natural history of CKD in the community. Finally, we will conduct an economic evaluation based on a comparison of the cost effectiveness of each intervention. CLINICAL TRIALS REGISTRATION: ISRCTN56023731. ClinicalTrials.gov identifier