Scottish Index of Multiple Deprivation (SIMD) indicators as predictors of mortality among patients hospitalised with COVID-19 disease in the Lothian Region, Scotland during the first wave: a cohort study.

BACKGROUND: Sars-CoV-2, the causative agent of COVID-19, has led to more than 226,000 deaths in the UK and multiple risk factors for mortality including age, sex and deprivation have been identified. This study aimed to identify which individual indicators of the Scottish Index of Multiple Deprivation (SIMD), an area-based deprivation index, were predictive of mortality. METHODS: This was a prospective cohort study of anonymised electronic health records of 710 consecutive patients hospitalised with Covid-19 disease between March and June 2020 in the Lothian Region of Southeast Scotland. Data sources included automatically extracted data from national electronic platforms and manually extracted data from individual admission records. Exposure variables of interest were SIMD quintiles and 12 indicators of deprivation deemed clinically relevant selected from the SIMD. Our primary outcome was mortality. Age and sex adjusted univariable and multivariable analyses were used to determine measures of association between exposures of interest and the primary outcome. RESULTS: After adjusting for age and sex, we found an increased risk of mortality in the more deprived SIMD quintiles 1 and 3 (OR 1.75, CI 0.99-3.08, p = 0.053 and OR 2.17, CI 1.22-3.86, p = 0.009, respectively), but this association was not upheld in our multivariable model containing age, sex, Performance Status and clinical parameters of severity at admission. Of the 12 pre-selected indicators of deprivation, two were associated with greater mortality in our multivariable analysis: income deprivation rate categorised by quartile (Q4 (most deprived): 2.11 (1.20-3.77) p = 0.011)) and greater than expected hospitalisations due to alcohol per SIMD data zone (1.96 (1.28-3.00) p = 0.002)). CONCLUSIONS: SIMD as an aggregate measure of deprivation was not predictive of mortality in our cohort when other exposure measures were accounted for. However, we identified a two-fold increased risk of mortality in patients residing in areas with greater income-deprivation and/or number of hospitalisations due to alcohol. In areas where aggregate measures fail to capture pockets of deprivation, exploring the impact of specific SIMD indicators may be helpful in targeting resources to residents at risk of poorer outcomes from Covid-19.

Performance status: A key factor in predicting mortality in the first wave of COVID-19 in South-East Scotland.

BACKGROUND: COVID-19 mortality risk factors have been established in large cohort studies; long-term mortality outcomes are less documented. METHODS: We performed multivariable logistic regression to identify factors associated with in-patient mortality and intensive care unit (ICU) admission in symptomatic COVID-19 patients admitted to hospitals in South-East Scotland from 1st March to 30th June 2020. One-year mortality was reviewed. RESULTS: Of 726 patients (median age 72; interquartile range: 58-83 years, 55% male), 104 (14%) required ICU admission and 199 (27%) died in hospital. A further 64 died between discharge and 30th June 2021 (36% overall 1-year mortality). Stepwise logistic regression identified age >79 (odds ratio (OR), 4.77 (95% confidence interval (CI), 1.96-12.75)), male sex (OR, 1.83 (95% CI, 1.21-2.80)) and higher European Cooperative Oncology Group/World Health Organization performance status as associated with higher mortality risk. DISCUSSION: Poor functional baseline was the predominant independent risk factor for mortality in COVID-19. More than one-third of individuals had died by 1 year following admission.

Equity for excellence in academic institutions: a manifesto for change.

Higher academic institutions in the UK need to drive improvements in equity, diversity, and inclusion (EDI) through sustainable practical interventions. A broad view of inclusivity is based on an intersectional approach that considers race, geographical location, caring responsibilities, disability, neurodiversity, religion, and LGBTQIA+ identities. We describe the establishment of a diverse stakeholder group to develop practical grass-roots recommendations through which improvements can be advanced. We have developed a manifesto for change, comprising six domains through which academic institutions can drive progress through setting short, medium, and long-term priorities. Interventions will yield rewards in recruitment and retention of a diverse talent pool, leading to enhanced impact and output.

Diagnostic performance of the combined nasal and throat swab in patients admitted to hospital with suspected COVID-19.

BACKGROUND: Accurate diagnosis in patients with suspected coronavirus disease 2019 (COVID-19) is essential to guide treatment and limit spread of the virus. The combined nasal and throat swab is used widely, but its diagnostic performance is uncertain. METHODS: In a prospective, multi-centre, cohort study conducted in secondary and tertiary care hospitals in Scotland, we evaluated the combined nasal and throat swab with reverse transcriptase-polymerase chain reaction (RT-PCR) for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) in consecutive patients admitted to hospital with suspected COVID-19. Diagnostic performance of the index and serial tests was evaluated for a primary outcome of confirmed or probable COVID-19, and a secondary outcome of confirmed COVID-19 on serial testing. The diagnosis was adjudicated by a panel, who recorded clinical, laboratory and radiological features blinded to the test results. RESULTS: We enrolled 1368 consecutive patients (median age 68 [interquartile range, IQR 53-80] years, 47% women) who underwent a total of 3822 tests (median 2 [IQR 1-3] tests per patient). The primary outcome occurred in 36% (496/1368), of whom 65% (323/496) and 35% (173/496) had confirmed and probable COVID-19, respectively. The index test was positive in 255/496 (51%) patients with the primary outcome, giving a sensitivity and specificity of 51.4% (95% confidence interval [CI] 48.8 to 54.1%) and 99.5% (95% CI 99.0 to 99.8%). Sensitivity increased in those undergoing 2, 3 or 4 tests to 60.1% (95% CI 56.7 to 63.4%), 68.3% (95% CI 64.0 to 72.3%) and 77.6% (95% CI 72.7 to 81.9%), respectively. The sensitivity of the index test was 78.9% (95% CI 74.4 to 83.2%) for the secondary outcome of confirmed COVID-19 on serial testing. CONCLUSIONS: In patients admitted to hospital, a single combined nasal and throat swab with RT-PCR for SARS-CoV-2 has excellent specificity, but limited diagnostic sensitivity for COVID-19. Diagnostic performance is significantly improved by repeated testing.

A Subgroup of Patients With Hospital-acquired Pneumonia Do Not Require Broad-spectrum Gram-negative Antimicrobial Coverage.

Among 200 patients developing hospital-acquired pneumonia (HAP) outside the intensive care unit, 61% were treated empirically without broad-spectrum Gram-negative coverage, with clinical cure in 69.7%. Lower disease severity markers (systemic inflammatory response syndrome, hypoxia, tachypnoea, neutrophilia) and the absence of diabetes mellitus and prior doxycycline treatment (but not the time to HAP onset) identified patients not requiring broad-spectrum Gram-negative coverage.

The index case of SARS-CoV-2 in Scotland.

Since its identification in December 2019, SARS-CoV-2 has infected 125,048 persons globally with cases identified in 118 countries across all continents. We report on the Scottish index case of SARS-CoV-2 infection, the virus causing COVID-19.

Tractable targets for meropenem-sparing antimicrobial stewardship interventions.

BACKGROUND: As meropenem is a restricted antimicrobial, lessons learned from its real-life usage will be applicable to antimicrobial stewardship (AMS) more generally. OBJECTIVES: To retrospectively evaluate meropenem usage at our institution to identify targets for AMS interventions. METHODS: Patients receiving meropenem documented with an 'alert antimicrobial' form at two tertiary care UK hospitals were identified retrospectively. Clinical records and microbiology results were reviewed. RESULTS: A total of 107 adult inpatients receiving meropenem were identified. This was first-line in 47% and escalation therapy in 53%. Source control was required in 28% of cases after escalation, for predictable reasons. Those ultimately requiring source control had received more prior antimicrobial agents than those who did not (P = 0.03). Meropenem was rationalized in 24% of cases (after median 4 days). Positive microbiology enabled rationalization (OR 12.3, 95% CI 2.7-55.5, P = 0.001) but rates of appropriate sampling varied. In cases with positive microbiology where meropenem was not rationalized, continuation was retrospectively considered clinically and microbiologically necessary in 8/40 cases (0/17 empirical first-line usage). Rationalization was more likely when meropenem susceptibility was not released on the microbiology report (OR 5.2, 95% CI 1.3-20.2, P = 0.02). Input from an infection specialist was associated with a reduced duration of meropenem therapy (P < 0.0001). Early review by an infection specialist has the potential to further facilitate rationalization. CONCLUSIONS: In real-life clinical practice, core aspects of infection management remain tractable targets for AMS interventions: microbiological sampling, source control and infection specialist input. Further targets include supporting rationalization to less familiar carbapenem-sparing antimicrobials, restricting first-line meropenem usage and selectively reporting meropenem susceptibility.

International infectious diseases teaching to undergraduate medical students: A successful European collaborative experience.

CONTEXT: The emerging global-health paradigm requires medical teaching to be continuously redefined and updated; to this end, transnational approaches should be encouraged and medical training harmonized. Infectious diseases (ID) teaching in the current context of emerging infections, fast-increasing bacterial resistance and large-scale human migration, was chosen to develop a common international course. OBJECTIVE: We report the successful implementation of a joint European undergraduate course aiming to (i) develop a common ID core curriculum among European medical schools; (ii) promote mobility among teachers and students (iii) promote international cooperation among European teachers. METHODS: The course was built around teachers' mobility. It was delivered in English by a team of European medical educators from Paris Descartes University, Università Cattolica del Sacro Cuore in Rome and the University of Edinburgh to groups of 25-30 undergraduate medical students at each university. Partner Institutions officially recognized the course as substitutive of or additive to the regular curriculum. RESULTS: The course has been running for 3 years and received excellent satisfaction scores by students and staff as regards to scientific content, pedagogy and international exchanges. CONCLUSION: This cooperative approach demonstrates the feasibility of a harmonized European undergraduate medical education, having ID as a test experiment for future developments.

Targets of antibodies against Plasmodium falciparum-infected erythrocytes in malaria immunity.

Plasmodium falciparum is the major cause of malaria globally and is transmitted by mosquitoes. During parasitic development, P. falciparum-infected erythrocytes (P. falciparum-IEs) express multiple polymorphic proteins known as variant surface antigens (VSAs), including the P. falciparum erythrocyte membrane protein 1 (PfEMP1). VSA-specific antibodies are associated with protection from symptomatic and severe malaria. However, the importance of the different VSA targets of immunity to malaria remains unclear, which has impeded an understanding of malaria immunity and vaccine development. In this study, we developed assays using transgenic P. falciparum with modified PfEMP1 expression to quantify serum antibodies to VSAs among individuals exposed to malaria. We found that the majority of the human antibody response to the IE targets PfEMP1. Furthermore, our longitudinal studies showed that individuals with PfEMP1-specific antibodies had a significantly reduced risk of developing symptomatic malaria, whereas antibodies to other surface antigens were not associated with protective immunity. Using assays that measure antibody-mediated phagocytosis of IEs, an important mechanism in parasite clearance, we identified PfEMP1 as the major target of these functional antibodies. Taken together, these data demonstrate that PfEMP1 is a key target of humoral immunity. These findings advance our understanding of the targets and mediators of human immunity to malaria and have major implications for malaria vaccine development.

Analysis of immunity to febrile malaria in children that distinguishes immunity from lack of exposure.

In studies of immunity to malaria, the absence of febrile malaria is commonly considered evidence of "protection." However, apparent "protection" may be due to a lack of exposure to infective mosquito bites or due to immunity. We studied a cohort that was given curative antimalarials before monitoring began and documented newly acquired asymptomatic parasitemia and febrile malaria episodes during 3 months of surveillance. With increasing age, there was a shift away from febrile malaria to acquiring asymptomatic parasitemia, with no change in the overall incidence of infection. Antibodies to the infected red cell surface were associated with acquiring asymptomatic infection rather than febrile malaria or remaining uninfected. Bed net use was associated with remaining uninfected rather than acquiring asymptomatic infection or febrile malaria. These observations suggest that most uninfected children were unexposed rather than "immune." Had they been immune, we would have expected the proportion of uninfected children to rise with age and that the uninfected children would have been distinguished from children with febrile malaria by the protective antibody response. We show that removing the less exposed children from conventional analyses clarifies the effects of immunity, transmission intensity, bed nets, and age. Observational studies and vaccine trials will have increased power if they differentiate between unexposed and immune children.

Acquisition of naturally occurring antibody responses to recombinant protein domains of Plasmodium falciparum erythrocyte membrane protein 1.

BACKGROUND: Antibodies targeting variant antigens expressed on the surface of Plasmodium falciparum infected erythrocytes have been associated with protection from clinical malaria. The precise target for these antibodies is unknown. The best characterized and most likely target is the erythrocyte surface-expressed variant protein family Plasmodium falciparum erythrocyte membrane protein 1 (PfEMP1). METHODS: Using recombinant proteins corresponding to five domains of the expressed A4 var gene, A4 PfEMP1, the naturally occurring antibody response was assessed, by ELISA, to each domain in serum samples obtained from individuals resident in two communities of differing malaria transmission intensity on the Kenyan coast. Using flow cytometry, the correlation in individual responses to each domain with responses to intact A4-infected erythrocytes expressing A4 PfEMP1 on their surface as well as responses to two alternative parasite clones and one clinical isolate was assessed. RESULTS: Marked variability in the prevalence of responses between each domain and between each transmission area was observed, as wasa strong correlation between age and reactivity with some but not all domains. Individual responses to each domain varied strikingly, with some individuals showing reactivity to all domains and others with no reactivity to any, this was apparent at all age groups. Evidence for possible cross-reactivity in responses to the domain DBL4gamma was found. CONCLUSION: Individuals acquire antibodies to surface expressed domains of a highly variant protein. The finding of potential cross-reactivity in responses to one of these domains is an important initial finding in the consideration of potential vaccine targets.

Clinical features and pathogenesis of severe malaria.

A major change in recent years has been the recognition that severe malaria, predominantly caused by Plasmodium falciparum, is a complex multi-system disorder presenting with a range of clinical features. It is becoming apparent that syndromes such as cerebral malaria, which were previously considered relatively clear cut, are not homogenous conditions with a single pathological correlate or pathogenic process. This creates challenges both for elucidating key mechanisms of disease and for identifying suitable targets for adjunctive therapy. The development of severe malaria probably results from a combination of parasite-specific factors, such as adhesion and sequestration in the vasculature and the release of bioactive molecules, together with host inflammatory responses. These include cytokine and chemokine production and cellular infiltrates. This review summarizes progress in several areas presented at a recent meeting.