Variation in general practice referral rate to acute medicine services and association with hospital admission. A retrospective observational study.

BACKGROUND: Variation in general practice (GP) referral rates to outpatient services is well described however variance in rates of referral to acute medical units is lacking. OBJECTIVE: To investigate variance in GP referral rate for acute medical assessment and subsequent need for hospital admission. METHODS: A retrospective cohort study of acute medical referrals from 88 GPs in Lothian, Scotland between 2017 and 2020 was performed using practice population size, age, deprivation, care home residence, and distance from hospital as explanatory variables. Patient-level analysis of demography, deprivation, comorbidity, and acuity markers was subsequently performed on referred and clinically assessed acute medical patients (n = 42,424) to examine how practice referral behaviour reflects clinical need for inpatient hospital care. RESULTS: Variance in GP referral rates for acute medical assessment was high (2.53-fold variation 1st vs. 4th quartile) and incompletely explained by increasing age and deprivation (adjusted R2 0.67, P < 0.001) such that significant variance remained after correction for confounders (2.15-fold). Patients from the highest referring quartile were significantly less likely to require hospital admission than those from the third, second, or lowest referring quartiles (adjusted odds ratio 1.28 [1.21-1.36, P < 0.001]; 1.30 [1.23-1.37, P < 0.001]; 1.53 [1.42-1.65, P < 0.001]). CONCLUSIONS: High variation in GP practice referral rate for acute medical assessment is incompletely explained by practice population socioeconomic factors and negatively associates with need for urgent inpatient care. Identifying modifiable factors influencing referral rate may provide opportunities to facilitate community-based care and reduce congestion on acute unscheduled care pathways.

Managing the populations need for urgent medical care is challenge in many healthcare systems and overcrowding of urgent medical services negatively affects patient experience and can affect timely treatment. In the United Kingdom, the primary sources of patients attending for acute medical care are self-attendance to the hospital or by way of referral by a primary care physician (general practitioner). These data for the first time demonstrate high variation in referral rates for acute medical assessment between general practices which is incompletely explained by factors such as the age, deprivation, distance to the hospital or care home residence status of the care home population. Analysis of over 40,000 of these referrals for urgent medical care was subsequently undertaken to further investigate this variation. After adjusting for important clinical factors, patients referred from "high referring" practices were over 50% less likely to require inpatient hospital care than patients from lower referring practices. This suggests that the threshold for referral varies greatly between individual primary care clinicians, practices, or practice populations and many of these patients may have been suitable for less urgent community-based care. Identification of modifiable factors that account for this unexplained variation may facilitate community-based care and improve patient experience by reducing unnecessary attendance and congestion in already busy emergency care services.

Prognostic factors in patients admitted to an urban teaching hospital with COVID-19 infection.

BACKGROUND: Severe COVID-19 infection results in a systemic inflammatory response (SIRS). This SIRS response shares similarities to the changes observed during the peri-operative period that are recognised to be associated with the development of multiple organ failure. METHODS: Electronic patient records for patients who were admitted to an urban teaching hospital during the initial 7-week period of the COVID-19 pandemic in Glasgow, U.K. (17th March 2020-1st May 2020) were examined for routine clinical, laboratory and clinical outcome data. Age, sex, BMI and documented evidence of COVID-19 infection at time of discharge or death certification were considered minimal criteria for inclusion. RESULTS: Of the 224 patients who fulfilled the criteria for inclusion, 52 (23%) had died at 30-days following admission. COVID-19 related respiratory failure (75%) and multiorgan failure (12%) were the commonest causes of death recorded. Age ≥ 70 years (p < 0.001), past medical history of cognitive impairment (p ≤ 0.001), previous delirium (p < 0.001), clinical frailty score > 3 (p < 0.001), hypertension (p < 0.05), heart failure (p < 0.01), national early warning score (NEWS) > 4 (p < 0.01), positive CXR (p < 0.01), and subsequent positive COVID-19 swab (p ≤ 0.001) were associated with 30-day mortality. CRP > 80 mg/L (p < 0.05), albumin < 35 g/L (p < 0.05), peri-operative Glasgow Prognostic Score (poGPS) (p < 0.05), lymphocytes < 1.5 109/l (p < 0.05), neutrophil lymphocyte ratio (p ≤ 0.001), haematocrit (< 0.40 L/L (male)/ < 0.37 L/L (female)) (p ≤ 0.01), urea > 7.5 mmol/L (p < 0.001), creatinine > 130 mmol/L (p < 0.05) and elevated urea: albumin ratio (< 0.001) were also associated with 30-day mortality. On multivariate analysis, age ≥ 70 years (O.R. 3.9, 95% C.I. 1.4-8.2, p < 0.001), past medical history of heart failure (O.R. 3.3, 95% C.I. 1.2-19.3, p < 0.05), NEWS > 4 (O.R. 2.4, 95% C.I. 1.1-4.4, p < 0.05), positive initial CXR (O.R. 0.4, 95% C.I. 0.2-0.9, p < 0.05) and poGPS (O.R. 2.3, 95% C.I. 1.1-4.4, p < 0.05) remained independently associated with 30-day mortality. Among those patients who tested PCR COVID-19 positive (n = 122), age ≥ 70 years (O.R. 4.7, 95% C.I. 2.0-11.3, p < 0.001), past medical history of heart failure (O.R. 4.4, 95% C.I. 1.2-20.5, p < 0.05) and poGPS (O.R. 2.4, 95% C.I. 1.1-5.1, p < 0.05) remained independently associated with 30-days mortality. CONCLUSION: Age ≥ 70 years and severe systemic inflammation as measured by the peri-operative Glasgow Prognostic Score are independently associated with 30-day mortality among patients admitted to hospital with COVID-19 infection.

Comparison of Glasgow Admission Prediction Score and Amb Score in predicting need for inpatient care.

AIM: We compared the abilities of two established clinical scores to predict emergency department (ED) disposition: the Glasgow Admission Prediction Score (GAPS) and the Ambulatory Score (Ambs). METHODS: The scores were compared in a prospective, multicentre cohort study. We recruited consecutive patients attending ED triage at two UK sites: Northern General Hospital in Sheffield and Glasgow Royal Infirmary, between February and May 2016. Each had a GAPS and Ambs calculated at the time of triage, with the triage nurses and treating clinicians blinded to the scores. Patients were followed up to hospital discharge. The ability of the scores to discriminate discharge from ED and from hospital at 12 and 48 hours after arrival was compared using the area under the curve (AUC) of their receiving-operator characteristics (ROC). RESULTS: 1424 triage attendances were suitable for analysis during the study period, of which 567 (39.8%) were admitted. The AUC for predicting admission was significantly higher for GAPS at 0.807 (95% CI 0.785 to 0.830), compared with 0.743 (95% CI 0.717 to 0.769) for Ambs, P<0.00001. Similar results were seen when comparing ability to predict hospital stay of >12 hour and >48 hour. GAPS was also more accurate as a binary test, correctly predicting 1057 outcomes compared with 1004 for Ambs (74.2vs70.5%, P=0.012). CONCLUSION: The GAPS is a significantly better predictor of need for hospital admission than Ambs in an unselected ED population.

Predicting admission at triage: are nurses better than a simple objective score?

AIM: We compared two methods of predicting hospital admission from ED triage: probabilities estimated by triage nurses and probabilities calculated by the Glasgow Admission Prediction Score (GAPS). METHODS: In this single-centre prospective study, triage nurses estimated the probability of admission using a 100 mm visual analogue scale (VAS), and GAPS was generated automatically from triage data. We compared calibration using rank sum tests, discrimination using area under receiver operating characteristic curves (AUC) and accuracy with McNemar's test. RESULTS: Of 1829 attendances, 745 (40.7%) were admitted, not significantly different from GAPS' prediction of 750 (41.0%, p=0.678). In contrast, the nurses' mean VAS predicted 865 admissions (47.3%), overestimating by 6.6% (p<0.0001). GAPS discriminated between admission and discharge as well as nurses, its AUC 0.876 compared with 0.875 for VAS (p=0.93). As a binary predictor, its accuracy was 80.6%, again comparable with VAS (79.0%), p=0.18. In the minority of attendances, when nurses felt at least 95% certain of the outcome, VAS' accuracy was excellent, at 92.4%. However, in the remaining majority, GAPS significantly outperformed VAS on calibration (+1.2% vs +9.2%, p<0.0001), discrimination (AUC 0.810 vs 0.759, p=0.001) and accuracy (75.1% vs 68.9%, p=0.0009). When we used GAPS, but 'over-ruled' it when clinical certainty was ≥95%, this significantly outperformed either method, with AUC 0.891 (0.877-0.907) and accuracy 82.5% (80.7%-84.2%). CONCLUSIONS: GAPS, a simple clinical score, is a better predictor of admission than triage nurses, unless the nurse is sure about the outcome, in which case their clinical judgement should be respected.

A simple tool to predict admission at the time of triage.

AIM: To create and validate a simple clinical score to estimate the probability of admission at the time of triage. METHODS: This was a multicentre, retrospective, cross-sectional study of triage records for all unscheduled adult attendances in North Glasgow over 2 years. Clinical variables that had significant associations with admission on logistic regression were entered into a mixed-effects multiple logistic model. This provided weightings for the score, which was then simplified and tested on a separate validation group by receiving operator characteristic (ROC) analysis and goodness-of-fit tests. RESULTS: 215 231 presentations were used for model derivation and 107 615 for validation. Variables in the final model showing clinically and statistically significant associations with admission were: triage category, age, National Early Warning Score (NEWS), arrival by ambulance, referral source and admission within the last year. The resulting 6-variable score showed excellent admission/discharge discrimination (area under ROC curve 0.8774, 95% CI 0.8752 to 0.8796). Higher scores also predicted early returns for those who were discharged: the odds of subsequent admission within 28 days doubled for every 7-point increase (log odds=+0.0933 per point, p<0.0001). CONCLUSIONS: This simple, 6-variable score accurately estimates the probability of admission purely from triage information. Most patients could accurately be assigned to 'admission likely', 'admission unlikely', 'admission very unlikely' etc., by setting appropriate cut-offs. This could have uses in patient streaming, bed management and decision support. It also has the potential to control for demographics when comparing performance over time or between departments.

Analysis and modelling of cholesterol and high-density lipoprotein cholesterol changes across the range of C-reactive protein levels in clinical practice as an aid to better understanding of inflammation-lipid interactions.

OBJECTIVES: Raised total cholesterol (TC) and reduced high-density lipoprotein (HDL) cholesterol levels are established cardiovascular disease (CVD) risk factors. However, in autoimmune conditions the lipid-CVD association appears paradoxical, with inflammation as a potential confounding factor. We therefore sought to model the relationship between systemic inflammatory illness and lipid levels using C-reactive protein (CRP) as the prototypical marker of inflammation. Our hypothesis was that there would be an inverse association between raised CRP levels and both TC and HDL-cholesterol levels. METHODS: Results from samples analysed simultaneously for CRP and lipids in a 6-month period were collected retrospectively from a large city hospital laboratory database that collates results from both primary and secondary care. The relationships between CRP and lipids were determined using graphical techniques and empirical, non-parametric, best fit models. RESULTS: A total of 11 437 blood samples was included. We identified a significant (p<0.001) biphasic relationship between TC and CRP: TC increased within the healthy CRP range of less than 5 mg/l, but decreased with CRP levels above 10 mg/l. The two effects approximately cancelled each other out in the intermediate CRP range of 5-10 mg/l. There was an inverse relationship between HDL-cholesterol and CRP. CONCLUSIONS: Lipid levels change significantly during inflammatory illness in a population with both acute and chronic conditions. These results provide a strong epidemiological basis for the better understanding of lipid changes in inflammatory conditions and with anti-inflammatory therapies.

Alpha-B-Crystallin overexpression is sufficient to promote tumorigenesis and metastasis in mice.

BACKGROUND: αB-Crystallin is a heat shock chaperone protein which binds to misfolded proteins to prevent their aggregation. It is overexpressed in a wide-variety of cancers. Previous studies using human cancer cell lines and human xenograft models have suggested potential tumor promoter (oncogene) roles for αB-Crystallin in a wide-spectrum of cancers. METHODS: To determine the causal relationship between CRYAB overexpression and cancer, we generated a Cryab overexpression knock-in mouse model and monitor them for development of spontaneous and carcinogen (DMBA)-induced tumorigenesis. In order to investigate the mechanism of malignancies observed in this model multiple techniques were used such as immunohistochemical characterizations of tumors, bioinformatics analysis of publically available human tumor datasets, and generation of mouse embryonic fibroblasts (MEFs) for in vitro assays (clonogenic survival and migration assays and proteome analysis by mass-spectrometry). RESULTS: This model revealed that constitutive overexpression of Cryab results in the formation of a variety of lethal spontaneous primary and metastatic tumors in mice. In vivo, the overexpression of Cryab correlated with the upregulation of epithelial-to-mesenchymal (EMT) markers, angiogenesis and some oncogenic proteins including Basigin. In vitro, using E1A/Ras transformed MEFs, we observed that the overexpression of Cryab led to the promotion of cell survival via upregulation of Akt signaling and downregulation of pro-apoptotic pathway mediator JNK, with subsequent attenuation of apoptosis as assessed by cleaved caspase-3 and Annexin V staining. CONCLUSIONS: Overall, through the generation and characterization of Cryab overexpression model, we provide evidence supporting the role of αB-Crystallin as an oncogene, where its upregulation is sufficient to induce tumors, promote cell survival and inhibit apoptosis.

The systemic inflammatory response and clinicopathological characteristics in patients admitted to hospital with COVID-19 infection: Comparison of 2 consecutive cohorts.

BACKGROUND: In order to manage the COVID-19 systemic inflammatory response, it is important to identify clinicopathological characteristics across multiple cohorts. METHODS: The aim of the present study was to compare the 4C mortality score, other measures of the systemic inflammatory response and clinicopathological characteristics in two consecutive cohorts of patients on admission with COVID-19. Electronic patient records for 2 consecutive cohorts of patients admitted to two urban teaching hospitals with COVID-19 during two 7-week periods of the COVID-19 pandemic in Glasgow, U.K. (cohort 1: 17/3/2020-1/5/2020) and (cohort 2: 18/5/2020-6/7/2020) were examined for routine clinical, laboratory and clinical outcome data. RESULTS: Compared with cohort 1, cohort 2 were older (p<0.001), more likely to be female (p<0.05) and have less independent living circumstances (p<0.001). More patients in cohort 2 were PCR positive, CXR negative (both p<0.001) and had low serum albumin concentrations (p<0.001). 30-day mortality was similar between both cohorts (23% and 22%). In cohort 2, age >70 (p<0.05), male gender (p<0.05), COPD (p<0.05), cognitive impairment (p<0.05), frailty (p<0.001), delirium (p = 0.001), CRP>150mg/L (p<0.05), albumin <30 g/L (p<0.01), elevated perioperative Glasgow Prognostic Score (p<0.05), elevated neutrophil-lymphocyte ratio (p<0.001), low haematocrit (p<0.01), elevated PT (p<0.05), sodium <133 mmol/L (p<0.01) elevated urea (p<0.001), creatinine (p<0.001), glucose (p<0.05) and lactate (p<0.001) and the 4C score (p<0.001) were associated with 30-day mortality. In multivariate analysis, greater frailty (CFS>3) (OR 11.3, 95% C.I. 2.3-96.7, p<0.05), low albumin (<30g/L) (OR 2.5, 95% C.I. 1.0-6.2, p<0.05), high NLR (≥3) (OR 2.2, 95% C.I. 1.5-4.5, p<0.05) and the 4C score (OR 2.4, 95% C.I. 1.0-5.6, p<0.05) remained independently associated with 30-day mortality. CONCLUSION: In addition to the 4C mortality score, frailty score and a low albumin were strongly independently associated with 30-day mortality in two consecutive cohorts of patients admitted to hospital with COVID-19. TRIAL REGISTRATION: clinicaltrials.gov: NCT04484545.

Formulation and manufacturing of lymphatic targeting liposomes using microfluidics.

The lymphatics are a target for a range of therapeutic purposes, including cancer therapy and vaccination, and both vesicle size and charge have been considered as factors controlling lymphatic targeting. Within this work, a range of liposomal formulations were investigated to develop a liposomal lymphatic targeting system. Initial screening of formulations considered the effect of charge, with neutral, cationic and anionic liposomes being investigated. Biodistribution studies demonstrated that after intramuscular injection, anionic liposomes offered the most rapid clearance to the draining lymphatics with cationic liposomes forming a depot at the injection site. Anionic liposomes containing phosphatidylserine showed higher clearance to the lymphatics and this may result form preferential uptake by macrophages. In terms of vesicle size, smaller unilamellar vesicles gave high lymphatic targeting and a 10-fold increase in concentration was achieved in dose escalation studies. Given that effective trafficking to the lymphatics was achieved, the next step was to enhance retention of the liposomes within the lymphatics, therefore the liposome formulation was combined with an avidin/biotin complex mechanism. The affinity of avidin for biotin allows biotinylated liposomes to complex in the presence of avidin. By pre-dosing with avidin, the biotin-avidin complex can be exploited to promote longer retention of the liposomes at the draining lymphatics. To load these small, biotinylated liposomes with protein, microfluidics manufacturing was used. Using microfluidics, protein could easily be incorporated in these small (~90nm) biotinylated liposomes. Both liposome and protein retention at the local draining lymph nodes was demonstrated with the liposome-biotin-avidin system. These results demonstrate that microfluidics can be used to prepare protein-loaded liposomes that offer enhanced lymphatic targeting and retention of both the liposomes and entrapped antigen.

Multicentre, prospective observational study of the correlation between the Glasgow Admission Prediction Score and adverse outcomes.

OBJECTIVES: To assess whether the Glasgow Admission Prediction Score (GAPS) is correlated with hospital length of stay, 6-month hospital readmission and 6-month all-cause mortality. This study represents a 6-month follow-up of patients who were included in an external validation of the GAPS' ability to predict admission at the point of triage. SETTING: Sampling was conducted between February and May 2016 at two separate emergency departments (EDs) in Sheffield and Glasgow. PARTICIPANTS: Data were collected prospectively at triage for consecutive adult patients who presented to the ED within sampling times. Any patients who avoided formal triage were excluded from the study. In total, 1420 patients were recruited. PRIMARY OUTCOMES: GAPS was calculated following triage and did not influence patient management. Length of hospital stay, hospital readmission and mortality against GAPS were modelled using survival analysis at 6 months. RESULTS: Of the 1420 patients recruited, 39.6% of these patients were initially admitted to hospital. At 6 months, 30.6% of patients had been readmitted and 5.6% of patients had died. For those admitted at first presentation, the chance of being discharged fell by 4.3% (95% CI 3.2% to 5.3%) per GAPS point increase. Cox regression indicated a 9.2% (95% CI 7.3% to 11.1%) increase in the chance of 6-month hospital readmission per point increase in GAPS. An association between GAPS and 6-month mortality was demonstrated, with a hazard increase of 9.0% (95% CI 6.9% to 11.2%) for every point increase in GAPS. CONCLUSION: A higher GAPS is associated with increased hospital length of stay, 6-month hospital readmission and 6-month all-cause mortality. While GAPS's primary application may be to predict admission and support clinical decision making, GAPS may provide valuable insight into inpatient resource allocation and bed planning.

Outpatient management of low-risk patients with upper gastrointestinal bleeding: can we safely extend the Glasgow Blatchford Score in clinical practice?

BACKGROUND AND AIM: The Glasgow Blatchford Score (GBS) is a validated prognostic score for patients presenting with upper gastrointestinal (GI) bleeding (UGIB). The score predicts the need for therapeutic intervention or death, and studies have suggested that outpatient management is safe for patients with a GBS of zero. Our aim was to assess whether we could safely extend the threshold for outpatient management to patients with GBS≤1. METHODS: Following assessment of our historical data, our UGIB protocol was changed to recommend outpatient management for patients with a GBS≤1, unless required for other reasons. Data on all patients presenting with UGIB over the following 12 months were prospectively recorded, including GBS and clinical Rockall scores. Adverse outcomes were defined by a 30-day combined endpoint of death, endotherapy, interventional radiology, surgery or transfusion. Negative predictive value (NPV) of GBS≤1 for adverse outcomes in UGIB was calculated. RESULTS: A total of 514 patients presented with UGIB in the 12 month study period. Of the patients, 183 (35.6%) had GBS≤1 (111, GBS=0; 72, GBS=1). Of these, 88 (48.1%) were managed as outpatients, and none had an adverse outcome. Of the 95 (51.9%) patients with GBS≤1 managed as inpatients, 80 (84.2%) had comorbidities requiring inpatient care. Within this admitted group with GBS≤1, one patient required transfusion and one died from a nongastrointestinal malignancy. GBS≤1 had an NPV of 99.45% (95% confidence interval 95.53-99.97%) in predicting adverse outcomes within 30 days. CONCLUSION: GBS≤1 has a high NPV for adverse outcomes in UGIB. This suggests outpatient management of patients with UGIB and that GBS≤1 is safe in our population.

Brain mass estimation by head circumference and body mass methods in neonatal glycaemic modelling and control.

INTRODUCTION: Hyperglycaemia is a common complication of stress and prematurity in extremely low-birth-weight infants. Model-based insulin therapy protocols have the ability to safely improve glycaemic control for this group. Estimating non-insulin-mediated brain glucose uptake by the central nervous system in these models is typically done using population-based body weight models, which may not be ideal. METHOD: A head circumference-based model that separately treats small-for-gestational-age (SGA) and appropriate-for-gestational-age (AGA) infants is compared to a body weight model in a retrospective analysis of 48 patients with a median birth weight of 750g and median gestational age of 25 weeks. Estimated brain mass, model-based insulin sensitivity (SI) profiles, and projected glycaemic control outcomes are investigated. SGA infants (5) are also analyzed as a separate cohort. RESULTS: Across the entire cohort, estimated brain mass deviated by a median 10% between models, with a per-patient median difference in SI of 3.5%. For the SGA group, brain mass deviation was 42%, and per-patient SI deviation 13.7%. In virtual trials, 87-93% of recommended insulin rates were equal or slightly reduced (Δ<0.16mU/h) under the head circumference method, while glycaemic control outcomes showed little change. CONCLUSION: The results suggest that body weight methods are not as accurate as head circumference methods. Head circumference-based estimates may offer improved modelling accuracy and a small reduction in insulin administration, particularly for SGA infants.

A clinical scoring system in undifferentiated chest pain predicting undetectable troponin concentration.

BACKGROUND: Chest pain is the most common reason for emergency admission to hospital, but the majority of these are due to non-cardiac pain. We sought to determine which combination of clinical features is more likely to predict an undetectable troponin level in patients presenting with chest pain. METHODS: We collected data over a two-month period on consecutive patients presenting acutely to hospital with chest pain and who had a troponin I measured. We recorded basic demographics, risk factors, pain distribution, associated symptoms, physical findings and ECG changes. The parameters significantly associated with troponin positivity were entered into a stepwise logistic regression analysis and the resulting model's coefficients were used to construct a simple clinical score to categorise patients into low, medium or high probability of having a positive troponin. RESULTS: 26 of 157 (16.6%) patients had a positive troponin. The variables retained in the regression model were: age >65, heart rate >80, previous myocardial infarction, diabetes and pain radiating to either arm. The model showed good discrimination (area under ROC curve 0.869, 95% CI 0.806 - 0.917). Using the regression model's coefficients, patients were grouped into low, intermediate or high probability groups. Being in the low probability group had a negative predictive value of 97.8% and being in the high probability group had a positive predictive value of 65.2%. The majority (73.9%) of patients could be categorised as either low or high probability. DISCUSSION: This simple scoring system, if prospectively validated, may be useful in identifying low risk patients with chest pain who are unlikely to have elevation of serum troponin concentration.

Spontaneous subcapsular hematoma of liver in pregnancy of unknown etiology--conservative management: a case report.

Mrs. AB, a 40-year-old woman, in her second pregnancy had a spontaneous hematoma of liver of unknown etiology that was managed successfully conservatively under the umbrella of the multidisciplinary care. The subcapsular hematoma was diagnosed at 31 weeks gestational age while she was being investigated because of sudden and gross drop of hemoglobin from 12.8 to 8 g/dl in 2 weeks duration. The dilemma remains as how to manage her future pregnancies and what are the risks of recurrence.