Development of a multivariable prediction model for severe COVID-19 disease: a population-based study from Hong Kong

Recent studies have reported numerous predictors for adverse outcomes in COVID-19 disease. However, there have been few simple clinical risk scores available for prompt risk stratification. The objective is to develop a simple risk score for predicting severe COVID-19 disease using territory-wide data based on simple clinical and laboratory variables. Consecutive patients admitted to Hong Kong’s public hospitals between 1 January and 22 August 2020 and diagnosed with COVID-19, as confirmed by RT-PCR, were included. The primary outcome was composite intensive care unit admission, need for intubation or death with follow-up until 8 September 2020. An external independent cohort from Wuhan was used for model validation. COVID-19 testing was performed in 237,493 patients and 4442 patients (median age 44.8 years old, 95% confidence interval (CI): [28.9, 60.8]); 50% males) were tested positive. Of these, 209 patients (4.8%) met the primary outcome. A risk score including the following components was derived from Cox regression: gender, age, diabetes mellitus, hypertension, atrial fibrillation, heart failure, ischemic heart disease, peripheral vascular disease, stroke, dementia, liver diseases, gastrointestinal bleeding, cancer, increases in neutrophil count, potassium, urea, creatinine, aspartate transaminase, alanine transaminase, bilirubin, D-dimer, high sensitive troponin-I, lactate dehydrogenase, activated partial thromboplastin time, prothrombin time, and C-reactive protein, as well as decreases in lymphocyte count, platelet, hematocrit, albumin, sodium, low-density lipoprotein, high-density lipoprotein, cholesterol, glucose, and base excess. The model based on test results taken on the day of admission demonstrated an excellent predictive value. Incorporation of test results on successive time points did not further improve risk prediction. The derived score system was evaluated with out-of-sample five-cross-validation (AUC: 0.86, 95% CI: 0.82–0.91) and external validation (N = 202, AUC: 0.89, 95% CI: 0.85–0.93). A simple clinical score accurately predicted severe COVID-19 disease, even without including symptoms, blood pressure or oxygen status on presentation, or chest radiograph results

Extremely strong tubular stacking of aromatic oligoamide macrocycles

As the third-generation rigid macrocycles evolved from progenitor 1, cyclic aromatic oligoamides 3, with a backbone of reduced constraint, exhibit extremely strong stacking with an astoundingly high affinity (estimated lower limit of Kdimer \u3e 1013 M–1 in CHCl3), which leads to dispersed tubular stacks that undergo further assembly in solution. Computational study reveals a very large binding energy (–49.77 kcal mol–1) and indicates highly cooperative local dipole interactions that account for the observed strength and directionality for the stacking of 3. In the solid-state, X-ray diffraction (XRD) confirms that the aggregation of 3 results in well-aligned tubular stacks. The persistent tubular assemblies of 3, with their non-deformable sub-nm pore, are expected to possess many interesting functions. One such function, transmembrane ion transport, is observed for 3. Includes supplemental material

Extremely strong tubular stacking of aromatic oligoamide macrocycles

As the third-generation rigid macrocycles evolved from progenitor 1, cyclic aromatic oligoamides 3, with a backbone of reduced constraint, exhibit extremely strong stacking with an astoundingly high affinity (estimated lower limit of Kdimer \u3e 1013 M–1 in CHCl3), which leads to dispersed tubular stacks that undergo further assembly in solution. Computational study reveals a very large binding energy (–49.77 kcal mol–1) and indicates highly cooperative local dipole interactions that account for the observed strength and directionality for the stacking of 3. In the solid-state, X-ray diffraction (XRD) confirms that the aggregation of 3 results in well-aligned tubular stacks. The persistent tubular assemblies of 3, with their non-deformable sub-nm pore, are expected to possess many interesting functions. One such function, transmembrane ion transport, is observed for 3. Includes supplemental material

Single-gene association between GATA-2 and autoimmune hepatitis:a novel genetic insight highlighting immunologic pathways to disease

AbstractBackground & AimsAutoimmune hepatitis (AIH), an immune-mediated liver disease, originates as a consequence of interacting genetic and environmental risk factors. Treatment remains non-specific and prone to side effects. Deficiencies in regulatory T cell (Treg) function are hypothesized to contribute to the pathogenesis of AIH.MethodsWe describe an adult patient who presented with AIH in the context of monocytopenia. The patient was characterized by GATA2 gene sequencing, flow cytometry of peripheral blood for leucocyte subsets, ELISA for serum Flt-3 ligand, and immunohistochemistry of liver biopsy tissue.ResultsSequencing confirmed a GATA2 mutation. Peripheral Treg were absent in the context of a preserved total T cell count. Immunostaining for the Treg transcription factor FOXP3 was reduced in liver tissue as compared to a control AIH specimen. There were marked deficiencies in multiple antigen-presenting cell subsets and Flt-3 ligand was elevated. These findings are consistent with previous reports of GATA2 dysfunction.ConclusionsThe association of a GATA2 mutation with AIH is previously unrecognized. GATA2 encodes a hematopoietic cell transcription factor, and mutations may manifest as monocytopenia, dendritic and B cell deficiencies, myelodysplasia, and immunodeficiency. Tregs may be depleted as in this case. Our findings provide support for the role of Tregs in AIH, complement reports of other deficiencies in T cell regulation causing AIH-like syndromes, and support the rationale of attempting to modulate the Treg axis for the therapeutic benefit of AIH patients

Increased Risk of Vascular Events in Emergency Room Patients Discharged Home with Diagnosis of Dizziness or Vertigo: A 3-Year Follow-Up Study

BACKGROUND: Dizziness and vertigo symptoms are commonly seen in emergency room (ER). However, these patients are often discharged without a definite diagnosis. Conflicting data regarding the vascular event risk among the dizziness or vertigo patients have been reported. This study aims to determine the risk of developing stroke or cardiovascular events in ER patients discharged home with a diagnosis of dizziness or vertigo. METHODOLOGY: A total of 25,757 subjects with at least one ER visit in 2004 were identified. Of those, 1,118 patients were discharged home with a diagnosis of vertigo or dizziness. A Cox proportional hazard model was performed to compare the three-year vascular event-free survival rates between the dizziness/vertigo patients and those without dizziness/vertigo after adjusting for confounding and risk factors. RESULTS: We identified 52 (4.7%) vascular events in patients with dizziness/vertigo and 454 (1.8%) vascular events in patients without dizziness/vertigo. ER patients discharged home with a diagnosis of vertigo or dizziness had 2-fold (95% confidence interval [CI], 1.35-2.96; p<0.001) higher risk of stroke or cardiovascular events after adjusting for patient characteristics, co-morbidities, urbanization level of residence, individual socio-economic status, and initially taking medications after the onset of dizziness or vertigo during the first year. CONCLUSIONS: ER patients discharged home with a diagnosis of dizziness or vertigo were at a increased risk of developing subsequent vascular events than those without dizziness/vertigo after the onset of dizziness or vertigo. Further studies are warranted for developing better diagnostic and follow-up strategies in increased risk patients

Concomitant Hepatorenal Dysfunction and Malnutrition in Valvular Heart Surgery:Long-Term Prognostic Implications for Death and Heart Failure

BACKGROUND: Strategies to improve long-term prediction of heart failure and death in valvular surgery are urgently needed because of an increasing number of procedures globally. This study sought to report the prevalence, changes, and prognostic implications of concomitant hepatorenal dysfunction and malnutrition in valvular surgery. METHODS AND RESULTS: In 909 patients undergoing valvular surgery, 3 groups were defined based on hepatorenal function (the modified model for end-stage liver disease excluding international normalized ratio score) and nutritional status (Controlling Nutritional Status score): normal hepatorenal function and nutrition (normal), hepatorenal dysfunction or malnutrition alone (mild), and concomitant hepatorenal dysfunction and malnutrition (severe). Overall, 32%, 46%, and 19% of patients were classified into normal, mild, and severe groups, respectively. Over a 4.1-year median follow-up, mild and severe groups in-curred a higher risk of mortality (hazard ratio [HR], 3.17 [95% CI, 1.40–7.17] and HR, 9.30 [95% CI, 4.09– 21.16], respectively), cardiovascular death (subdistribution HR, 3.29 [95% CI, 1.14– 9.52] and subdistribution HR, 9.29 [95% CI, 3.09– 27.99]), heart failure hospitalization (subdistribution HR, 2.11 [95% CI, 1.25– 3.55] and subdistribution HR, 3.55 [95% CI, 2.04– 6.16]), and adverse outcomes (HR, 2.11 [95% CI, 1.25– 3.55] and HR, 3.55 [95% CI, 2.04– 6.16]). Modified model for end-stage liver disease excluding international normalized ratio and controlling nutritional status scores improved the predictive ability of European System for Cardiac Operative Risk Evaluation (area under the curve: 0.80 versus 0.73, P<0.001) and Society of Thoracic Surgeons score (area under the curve: 0.79 versus 0.72, P=0.004) for all-cause mortality. One year following surgery (n=707), patients with persistent concomitant hepatorenal dysfunction and malnutrition (severe) experienced worse outcomes than those without.  CONCLUSIONS: Concomitant hepatorenal dysfunction and malnutrition was frequent and strongly linked to heart failure and mortality in valvular surgery

Development of a multivariable prediction model for severe COVID-19 disease: a population-based study from Hong Kong

Recent studies have reported numerous predictors for adverse outcomes in COVID-19 disease. However, there have been few simple clinical risk scores available for prompt risk stratification. The objective is to develop a simple risk score for predicting severe COVID-19 disease using territory-wide data based on simple clinical and laboratory variables. Consecutive patients admitted to Hong Kong’s public hospitals between 1 January and 22 August 2020 and diagnosed with COVID-19, as confirmed by RT-PCR, were included. The primary outcome was composite intensive care unit admission, need for intubation or death with follow-up until 8 September 2020. An external independent cohort from Wuhan was used for model validation. COVID-19 testing was performed in 237,493 patients and 4442 patients (median age 44.8 years old, 95% confidence interval (CI): [28.9, 60.8]); 50% males) were tested positive. Of these, 209 patients (4.8%) met the primary outcome. A risk score including the following components was derived from Cox regression: gender, age, diabetes mellitus, hypertension, atrial fibrillation, heart failure, ischemic heart disease, peripheral vascular disease, stroke, dementia, liver diseases, gastrointestinal bleeding, cancer, increases in neutrophil count, potassium, urea, creatinine, aspartate transaminase, alanine transaminase, bilirubin, D-dimer, high sensitive troponin-I, lactate dehydrogenase, activated partial thromboplastin time, prothrombin time, and C-reactive protein, as well as decreases in lymphocyte count, platelet, hematocrit, albumin, sodium, low-density lipoprotein, high-density lipoprotein, cholesterol, glucose, and base excess. The model based on test results taken on the day of admission demonstrated an excellent predictive value. Incorporation of test results on successive time points did not further improve risk prediction. The derived score system was evaluated with out-of-sample five-cross-validation (AUC: 0.86, 95% CI: 0.82–0.91) and external validation (N = 202, AUC: 0.89, 95% CI: 0.85–0.93). A simple clinical score accurately predicted severe COVID-19 disease, even without including symptoms, blood pressure or oxygen status on presentation, or chest radiograph results

Antimicrobial resistance among migrants in Europe: a systematic review and meta-analysis

BACKGROUND: Rates of antimicrobial resistance (AMR) are rising globally and there is concern that increased migration is contributing to the burden of antibiotic resistance in Europe. However, the effect of migration on the burden of AMR in Europe has not yet been comprehensively examined. Therefore, we did a systematic review and meta-analysis to identify and synthesise data for AMR carriage or infection in migrants to Europe to examine differences in patterns of AMR across migrant groups and in different settings. METHODS: For this systematic review and meta-analysis, we searched MEDLINE, Embase, PubMed, and Scopus with no language restrictions from Jan 1, 2000, to Jan 18, 2017, for primary data from observational studies reporting antibacterial resistance in common bacterial pathogens among migrants to 21 European Union-15 and European Economic Area countries. To be eligible for inclusion, studies had to report data on carriage or infection with laboratory-confirmed antibiotic-resistant organisms in migrant populations. We extracted data from eligible studies and assessed quality using piloted, standardised forms. We did not examine drug resistance in tuberculosis and excluded articles solely reporting on this parameter. We also excluded articles in which migrant status was determined by ethnicity, country of birth of participants' parents, or was not defined, and articles in which data were not disaggregated by migrant status. Outcomes were carriage of or infection with antibiotic-resistant organisms. We used random-effects models to calculate the pooled prevalence of each outcome. The study protocol is registered with PROSPERO, number CRD42016043681. FINDINGS: We identified 2274 articles, of which 23 observational studies reporting on antibiotic resistance in 2319 migrants were included. The pooled prevalence of any AMR carriage or AMR infection in migrants was 25·4% (95% CI 19·1-31·8; I2 =98%), including meticillin-resistant Staphylococcus aureus (7·8%, 4·8-10·7; I2 =92%) and antibiotic-resistant Gram-negative bacteria (27·2%, 17·6-36·8; I2 =94%). The pooled prevalence of any AMR carriage or infection was higher in refugees and asylum seekers (33·0%, 18·3-47·6; I2 =98%) than in other migrant groups (6·6%, 1·8-11·3; I2 =92%). The pooled prevalence of antibiotic-resistant organisms was slightly higher in high-migrant community settings (33·1%, 11·1-55·1; I2 =96%) than in migrants in hospitals (24·3%, 16·1-32·6; I2 =98%). We did not find evidence of high rates of transmission of AMR from migrant to host populations. INTERPRETATION: Migrants are exposed to conditions favouring the emergence of drug resistance during transit and in host countries in Europe. Increased antibiotic resistance among refugees and asylum seekers and in high-migrant community settings (such as refugee camps and detention facilities) highlights the need for improved living conditions, access to health care, and initiatives to facilitate detection of and appropriate high-quality treatment for antibiotic-resistant infections during transit and in host countries. Protocols for the prevention and control of infection and for antibiotic surveillance need to be integrated in all aspects of health care, which should be accessible for all migrant groups, and should target determinants of AMR before, during, and after migration. FUNDING: UK National Institute for Health Research Imperial Biomedical Research Centre, Imperial College Healthcare Charity, the Wellcome Trust, and UK National Institute for Health Research Health Protection Research Unit in Healthcare-associated Infections and Antimictobial Resistance at Imperial College London

Robust estimation of bacterial cell count from optical density

Optical density (OD) is widely used to estimate the density of cells in liquid culture, but cannot be compared between instruments without a standardized calibration protocol and is challenging to relate to actual cell count. We address this with an interlaboratory study comparing three simple, low-cost, and highly accessible OD calibration protocols across 244 laboratories, applied to eight strains of constitutive GFP-expressing E. coli. Based on our results, we recommend calibrating OD to estimated cell count using serial dilution of silica microspheres, which produces highly precise calibration (95.5% of residuals &lt;1.2-fold), is easily assessed for quality control, also assesses instrument effective linear range, and can be combined with fluorescence calibration to obtain units of Molecules of Equivalent Fluorescein (MEFL) per cell, allowing direct comparison and data fusion with flow cytometry measurements: in our study, fluorescence per cell measurements showed only a 1.07-fold mean difference between plate reader and flow cytometry data

Surgical site infection after gastrointestinal surgery in high-income, middle-income, and low-income countries: a prospective, international, multicentre cohort study

Background: Surgical site infection (SSI) is one of the most common infections associated with health care, but its importance as a global health priority is not fully understood. We quantified the burden of SSI after gastrointestinal surgery in countries in all parts of the world. Methods: This international, prospective, multicentre cohort study included consecutive patients undergoing elective or emergency gastrointestinal resection within 2-week time periods at any health-care facility in any country. Countries with participating centres were stratified into high-income, middle-income, and low-income groups according to the UN's Human Development Index (HDI). Data variables from the GlobalSurg 1 study and other studies that have been found to affect the likelihood of SSI were entered into risk adjustment models. The primary outcome measure was the 30-day SSI incidence (defined by US Centers for Disease Control and Prevention criteria for superficial and deep incisional SSI). Relationships with explanatory variables were examined using Bayesian multilevel logistic regression models. This trial is registered with ClinicalTrials.gov, number NCT02662231. Findings: Between Jan 4, 2016, and July 31, 2016, 13 265 records were submitted for analysis. 12 539 patients from 343 hospitals in 66 countries were included. 7339 (58·5%) patient were from high-HDI countries (193 hospitals in 30 countries), 3918 (31·2%) patients were from middle-HDI countries (82 hospitals in 18 countries), and 1282 (10·2%) patients were from low-HDI countries (68 hospitals in 18 countries). In total, 1538 (12·3%) patients had SSI within 30 days of surgery. The incidence of SSI varied between countries with high (691 [9·4%] of 7339 patients), middle (549 [14·0%] of 3918 patients), and low (298 [23·2%] of 1282) HDI (p < 0·001). The highest SSI incidence in each HDI group was after dirty surgery (102 [17·8%] of 574 patients in high-HDI countries; 74 [31·4%] of 236 patients in middle-HDI countries; 72 [39·8%] of 181 patients in low-HDI countries). Following risk factor adjustment, patients in low-HDI countries were at greatest risk of SSI (adjusted odds ratio 1·60, 95% credible interval 1·05–2·37; p=0·030). 132 (21·6%) of 610 patients with an SSI and a microbiology culture result had an infection that was resistant to the prophylactic antibiotic used. Resistant infections were detected in 49 (16·6%) of 295 patients in high-HDI countries, in 37 (19·8%) of 187 patients in middle-HDI countries, and in 46 (35·9%) of 128 patients in low-HDI countries (p < 0·001). Interpretation: Countries with a low HDI carry a disproportionately greater burden of SSI than countries with a middle or high HDI and might have higher rates of antibiotic resistance. In view of WHO recommendations on SSI prevention that highlight the absence of high-quality interventional research, urgent, pragmatic, randomised trials based in LMICs are needed to assess measures aiming to reduce this preventable complication