Effect of Fasting Prior to Extubation on Prevalence of Empty Stomach in Enterally Fed and Mechanically Ventilated Patients.

BACKGROUND: Practice on fasting prior to extubation in critically ill patients is variable. Efficacy of fasting in reducing gastric volume has not been well established. The primary objective of this study was to assess the effect of 4 h of fasting on prevalence of empty stomach using gastric ultrasonography in critically ill subjects who are fasted for extubation. The secondary objectives were to evaluate the change in gastric volumes during 4 h of fasting and to determine factors associated with empty stomach after fasting. METHODS: This was a single-center, prospective, observational study on adult ICU subjects who were enterally fed for at least 6 h continuously and mechanically ventilated. Gastric ultrasound was performed immediately prior to commencement of fasting, after 4 h of fasting, and after nasogastric (NG) aspiration after 4 h of fasting. An empty stomach was defined as a gastric volume ≤ 1.5 mL/kg. RESULTS: Forty subjects were recruited, and 38 (95%) had images suitable for analysis. The prevalence of empty stomach increased after 4 h of fasting (25 [65.8%] vs 31 [81.6%], P = .041) and after 4 h of fasting with NG aspiration (25 [65.8%] vs 34 [89.5%], P = .008). There was a significant difference in median (interquartile range) gastric volume per body weight between before fasting and 4 h after fasting (1.0 [0.5-1.8] mL/kg vs 0.4 [0.2-1.0] mL/kg, P < .001). No patient factors were associated with higher prevalence of empty stomach after 4 h of fasting. CONCLUSIONS: Most mechanically ventilated subjects had empty stomachs prior to fasting for extubation. Fasting for 4 h further increased the prevalence of empty stomach at extubation to > 80%.

Core sepsis-related competencies for medical students: an international consensus by Delphi technique.

BACKGROUND: Sepsis is a life-threatening condition which may arise from infection in any organ system and requires early recognition and management. Healthcare professionals working in any specialty may need to manage patients with sepsis. Educating medical students about this condition may be an effective way to ensure all future doctors have sufficient ability to diagnose and treat septic patients. However, there is currently no consensus on what competencies medical students should achieve regarding sepsis recognition and treatment. This study aims to outline what sepsis-related competencies medical students should achieve by the end of their medical student training in both high or upper-middle incomes countries/regions and in low or lower-middle income countries/regions. METHODS: Two separate panels from high or upper-middle income and low or lower-middle income countries/regions participated in a Delphi method to suggest and rank sepsis competencies for medical students. Each panel consisted of 13-18 key stakeholders of medical education and doctors in specialties where sepsis is a common problem (both specialists and trainees). Panelists came from all continents, except Antarctica. RESULTS: The panels reached consensus on 38 essential sepsis competencies in low or lower-middle income countries/regions and 33 in high or upper-middle incomes countries/regions. These include competencies such as definition of sepsis and septic shock and urgency of antibiotic treatment. In the low or lower-middle income countries/regions group, consensus was also achieved for competencies ranked as very important, and was achieved in 4/5 competencies rated as moderately important. In the high or upper-middle incomes countries/regions group, consensus was achieved in 41/57 competencies rated as very important but only 6/11 competencies rated as moderately important. CONCLUSION: Medical schools should consider developing curricula to address essential competencies, as a minimum, but also consider addressing competencies rated as very or moderately important.

Association between time to surgery and hospital mortality in patients with community-acquired limb necrotizing fasciitis: an 11-year multicenter retrospective cohort analysis.

BACKGROUND: Necrotizing fasciitis (NF) is a rare but potentially life-threatening soft tissue infection. The objective of this study was to assess the association between timely surgery within 6 h and hospital mortality in patients with limb NF, and to describe the trends in patients with NF, time to surgery and standardized mortality ratio (SMR) over 11 years. METHODS: This was a multicenter, retrospective cohort study of all intensive care unit patients who had emergency surgery within 24 h of hospitalization for limb NF between April 1, 2008 and March 31, 2019 in Hong Kong. Timely surgery was defined as the first surgical treatment within 6 h of initial hospitalization. Appropriate antibiotics were achieved if the patient was given antibiotic(s) for all documented pathogens prior to or on day of culture results. The primary outcome was hospital mortality. RESULTS: There were 495 patients (median age 62 years, 349 (70.5%) males) with limb NF treated by surgery within 24 h of hospitalization over the 11 years. Appropriate antibiotic(s) were used in 392 (79.2%) patients. There were 181 (36.5%) deaths. Timely surgery was not associated with hospital mortality (Relative Risk 0.89, 95% CI: 0.73 to 1.07) but admission year, advanced age, higher severity of illness, comorbidities, renal replacement therapy, vasopressor use, and type of surgery were significant predictors in the multivariable model. There was an upward trend in NF diagnosis (1.9 cases/year, 95% CI: 0.7 to 3.1; P < 0.01; R2 = 0.60) but there was no downward trend in median time to surgery (-0.2 h/year, 95% CI: -0.4 to 0.1; P = 0.16) or SMR (-0.02/year, 95% CI: -0.06 to 0.01; P = 0.22; R2 = 0.16). CONCLUSIONS: Among patients operated within 24 h, very early surgery within 6-12 h was not associated with survival. Increasing limb NF cases were reported each year but mortality remained high despite a high rate of appropriate antibiotic use and timely surgical intervention.

Blood microbial signatures associated with mortality in patients with sepsis: A pilot study.

Sepsis is a life-threatening illness caused by the dysregulated host response to infection. Nevertheless, our current knowledge of the microbial landscape in the blood of septic patients is still limited. Next-generation sequencing (NGS) is a sensitive method to quantitatively characterize microbiomes at various sites of the human body. In this study, we analyzed the blood microbial DNA of 22 adult patients with sepsis and 3 healthy subjects. The presence of non-human DNA was identified in both healthy and septic subjects. Septic patients had a markedly altered microbial DNA profile compared to healthy subjects over α- and ß-diversity. Unexpectedly, the patients could be further divided into two subgroups (C1 and C2) based on ß-diversity analysis. C1 patients showed much higher bacteria, viruses, fungi, and archaea abundance, and a higher level of α-diversity (Chao1, Observed and Shannon index) than both C2 patients and healthy subjects. The most striking difference was seen in the case of Streptomyces violaceusniger, Phenylobacterium sp. HYN0004, Caulobacter flavus, Streptomyces sp. 11-1-2, and Phenylobacterium zucineum, the abundance of which was the highest in the C1 group. Notably, C1 patients had a significantly poorer outcome than C2 patients. Moreover, by analyzing the patterns of microbe-microbe interactions in healthy and septic subjects, we revealed that C1 and C2 patients exhibited distinct co-occurrence and co-exclusion relationships. Together, our study uncovered two distinct microbial signatures in the blood of septic patients. Compositional and ecological analysis of blood microbial DNA may thus be useful in predicting mortality of septic patients.

Quantitative and qualitative subgenomic RNA profiles of SARS-CoV-2 in respiratory samples: A comparison between Omicron BA.2 and non-VOC-D614G.

The SARS-CoV-2 Omicron variants are notorious for their transmissibility, but little is known about their subgenomic RNA (sgRNA) expression. This study applied RNA-seq to delineate the quantitative and qualitative profiles of canonical sgRNA of 118 respiratory samples collected from patients infected with Omicron BA.2 and compared with 338 patients infected with non-variant of concern (non-VOC)-D614G. A unique characteristic profile depicted by the relative abundance of 9 canonical sgRNAs was reproduced by both BA.2 and non-VOC-D614G regardless of host gender, age and presence of pneumonia. Remarkably, such profile was lost in samples with low viral load, suggesting a potential application of sgRNA pattern to indicate viral activity of individual patient at a specific time point. A characteristic qualitative profile of canonical sgRNAs was also reproduced by both BA.2 and non-VOC-D614G. The presence of a full set of canonical sgRNAs carried a coherent correlation with crude viral load (AUC â€‹= â€‹0.91, 95% CI 0.88-0.94), and sgRNA ORF7b was identified to be the best surrogate marker allowing feasible routine application in characterizing the infection status of individual patient. Further potentials in using sgRNA as a target for vaccine and antiviral development are worth pursuing.

Prognostic evaluation of quick sequential organ failure assessment score in ICU patients with sepsis across different income settings.

BACKGROUND: There is conflicting evidence on association between quick sequential organ failure assessment (qSOFA) and sepsis mortality in ICU patients. The primary aim of this study was to determine the association between qSOFA and 28-day mortality in ICU patients admitted for sepsis. Association of qSOFA with early (3-day), medium (28-day), late (90-day) mortality was assessed in low and lower middle income (LLMIC), upper middle income (UMIC) and high income (HIC) countries/regions. METHODS: This was a secondary analysis of the MOSAICS II study, an international prospective observational study on sepsis epidemiology in Asian ICUs. Associations between qSOFA at ICU admission and mortality were separately assessed in LLMIC, UMIC and HIC countries/regions. Modified Poisson regression was used to determine the adjusted relative risk (RR) of qSOFA score on mortality at 28 days with adjustments for confounders identified in the MOSAICS II study. RESULTS: Among the MOSAICS II study cohort of 4980 patients, 4826 patients from 343 ICUs and 22 countries were included in this secondary analysis. Higher qSOFA was associated with increasing 28-day mortality, but this was only observed in LLMIC (p < 0.001) and UMIC (p < 0.001) and not HIC (p = 0.220) countries/regions. Similarly, higher 90-day mortality was associated with increased qSOFA in LLMIC (p < 0.001) and UMIC (p < 0.001) only. In contrast, higher 3-day mortality with increasing qSOFA score was observed across all income countries/regions (p < 0.001). Multivariate analysis showed that qSOFA remained associated with 28-day mortality (adjusted RR 1.09 (1.00-1.18), p = 0.038) even after adjustments for covariates including APACHE II, SOFA, income country/region and administration of antibiotics within 3 h. CONCLUSIONS: qSOFA was independently associated with 28-day mortality in ICU patients admitted for sepsis. In LLMIC and UMIC countries/regions, qSOFA was associated with early to late mortality but only early mortality in HIC countries/regions.

Critical care bed capacity in Asian countries and regions before and during the COVID-19 pandemic: an observational study.

Background: The coronavirus disease 2019 (COVID-19) pandemic highlighted the importance of critical care. The aim of the current study was to compare the number of adult critical care beds in relation to population size in Asian countries and regions before (2017) and during (2022) the pandemic. Methods: This observational study collected data closest to 2022 on critical care beds (intensive care units and intermediate care units) in 12 middle-income and 7 high-income economies (using the 2022-2023 World Bank classification), through a mix of methods including government sources, national critical care societies, personal contacts, and data extrapolation. Data were compared with a prior study from 2017 of the same countries and regions. Findings: The cumulative number of critical care beds per 100,000 population increased from 3.0 in 2017 to 9.4 in 2022 (p = 0.003). The median figure for middle-income economies increased from 2.6 (interquartile range [IQR] 1.7-7.8) to 6.6 (IQR 2.2-13.3), and that for high-income economies increased from 11.4 (IQR 7.3-22.8) to 13.9 (IQR 10.7-21.7). Only 3 countries did not see a rise in bed capacity. Where data were available in 2022, 10.9% of critical care beds were in single rooms (median 5.0% in middle-income and 20.3% in high-income economies), and 5.3% had negative pressure (median 0.7% in middle-income and 18.5% in high-income economies). Interpretation: Critical care bed capacity in the studied Asian countries and regions increased close to three-fold from 2017 to 2022. Much of this increase was attributed to middle-income economies, but substantial heterogeneity exists. Funding: None.

Flattening the biological age curve by improving metabolic health: to taurine or not to taurine, that' s the question.

The aging population is an important issue around the world especially in developed countries. Although medical advances have substantially extended life span, the same cannot be said for the duration of health span. We are seeing increasing numbers of elderly people who are frail and/or have multiple chronic conditions; all of these can affect the quality of life of the elderly population as well as increase the burden on the healthcare system. Aging is mechanistically related to common medical conditions such as diabetes mellitus, ischemic heart disease, cognitive decline, and frailty. A recently accepted concept termed 'Accelerated Biological Aging' can be diagnosed when a person's biological age-as measured by biomarkers of DNA methylation-is older than their corresponding chronological age. Taurine, a conditionally essential amino acid, has received much attention in the past few years. A substantial number of animal studies have provided a strong scientific foundation suggesting that this amino acid can improve cellular and metabolic health, including blood glucose control, so much that it has been labelled one of the 'longevity amino acids'. In this review article, we propose the rationale that an adequately powered randomized-controlled-trial (RCT) is needed to confirm whether taurine can meaningfully improve metabolic and microbiome health, and biological age. This trial should incorporate certain elements in order to provide the much-needed evidence to guide doctors, and also the community at large, to determine whether this promising and inexpensive amino acid is useful in improving human metabolic health.

Population sepsis incidence, mortality, and trends in Hong Kong between 2009-2018 using clinical and administrative data.

BACKGROUND: Sepsis surveillance using electronic health record (EHR)-based data may provide more accurate epidemiologic estimates than administrative data, but experience with this approach to estimate population-level sepsis burden is lacking. METHODS: This was a retrospective cohort study including all adults admitted to publicly-funded hospitals in Hong Kong between 2009-2018. Sepsis was defined as clinical evidence of presumed infection (clinical cultures and treatment with antibiotics) and concurrent acute organ dysfunction (≥2 point increase in baseline SOFA score). Trends in incidence, mortality, and case fatality risk (CFR) were modelled by exponential regression. Performance of the EHR-based definition was compared with 4 administrative definitions using 500 medical record reviews. RESULTS: Among 13,550,168 hospital episodes during the study period, 485,057 (3.6%) had sepsis by EHR-based criteria with 21.5% CFR. In 2018, age- and sex-adjusted standardized sepsis incidence was 759 per 100,000 (relative +2.9%/year [95%CI 2.0, 3.8%] between 2009-2018) and standardized sepsis mortality was 156 per 100,000 (relative +1.9%/year [95%CI 0.9,2.9%]). Despite decreasing CFR (relative -0.5%/year [95%CI -1.0, -0.1%]), sepsis accounted for an increasing proportion of all deaths (relative +3.9%/year [95%CI 2.9, 4.9%]). Medical record reviews demonstrated that the EHR-based definition more accurately identified sepsis than administrative definitions (AUC 0.91 vs 0.52-0.55, p < 0.001). CONCLUSIONS: An objective EHR-based surveillance definition demonstrated an increase in population-level standardized sepsis incidence and mortality in Hong Kong between 2009-2018 and was much more accurate than administrative definitions. These findings demonstrate the feasibility and advantages of an EHR-based approach for widescale sepsis surveillance.

Characterization of upper airway microbiome across severity of COVID-19 during hospitalization and treatment.

Longitudinal studies on upper respiratory tract microbiome in coronavirus disease 2019 (COVID-19) without potential confounders such as antimicrobial therapy are limited. The objective of this study is to assess for longitudinal changes in the upper respiratory microbiome, its association with disease severity, and potential confounders in adult hospitalized patients with COVID-19. Serial nasopharyngeal and throat swabs (NPSTSs) were taken for 16S rRNA gene amplicon sequencing from adults hospitalized for COVID-19. Alpha and beta diversity was assessed between different groups. Principal coordinate analysis was used to assess beta diversity between groups. Linear discriminant analysis was used to identify discriminative bacterial taxa in NPSTS taken early during hospitalization on need for intensive care unit (ICU) admission. A total of 314 NPSTS samples from 197 subjects (asymptomatic = 14, mild/moderate = 106, and severe/critical = 51 patients with COVID-19; non-COVID-19 mechanically ventilated ICU patients = 11; and healthy volunteers = 15) were sequenced. Among all covariates, antibiotic treatment had the largest effect on upper airway microbiota. When samples taken after antibiotics were excluded, alpha diversity (Shannon, Simpson, richness, and evenness) was similar across severity of COVID-19, whereas beta diversity (weighted GUniFrac and Bray-Curtis distance) remained different. Thirteen bacterial genera from NPSTS taken within the first week of hospitalization were associated with a need for ICU admission (area under the receiver operating characteristic curve, 0.96; 95% CI, 0.91-0.99). Longitudinal analysis showed that the upper respiratory microbiota alpha and beta diversity was unchanged during hospitalization in the absence of antimicrobial therapy.

Comparison of COVID-19 with influenza A in the ICU: a territory-wide, retrospective, propensity matched cohort on mortality and length of stay.

OBJECTIVES: Direct comparisons between COVID-19 and influenza A in the critical care setting are limited. The objective of this study was to compare their outcomes and identify risk factors for hospital mortality. DESIGN AND SETTING: This was a territory-wide, retrospective study on all adult (≥18 years old) patients admitted to public hospital intensive care units in Hong Kong. We compared COVID-19 patients admitted between 27 January 2020 and 26 January 2021 with a propensity-matched historical cohort of influenza A patients admitted between 27 January 2015 and 26 January 2020. We reported outcomes of hospital mortality and time to death or discharge. Multivariate analysis using Poisson regression and relative risk (RR) was used to identify risk factors for hospital mortality. RESULTS: After propensity matching, 373 COVID-19 and 373 influenza A patients were evenly matched for baseline characteristics. COVID-19 patients had higher unadjusted hospital mortality than influenza A patients (17.5% vs 7.5%, p<0.001). The Acute Physiology and Chronic Health Evaluation IV (APACHE IV) adjusted standardised mortality ratio was also higher for COVID-19 than influenza A patients ((0.79 (95% CI 0.61 to 1.00) vs 0.42 (95% CI 0.28 to 0.60)), p<0.001). Adjusting for age, PaO2/FiO2, Charlson Comorbidity Index and APACHE IV, COVID-19 (adjusted RR 2.26 (95% CI 1.52 to 3.36)) and early bacterial-viral coinfection (adjusted RR 1.66 (95% CI 1.17 to 2.37)) were directly associated with hospital mortality. CONCLUSIONS: Critically ill patients with COVID-19 had substantially higher hospital mortality when compared with propensity-matched patients with influenza A.

Effectiveness of mRNA and inactivated COVID-19 vaccines: A test-negative study in an infection-naïve Hong Kong population.

OBJECTIVE: Assess real-world effectiveness of vaccines against COVID-19. METHODS: A test-negative study was conducted in January-May 2022 during an Omicron BA.2 wave in Hong Kong. COVID-19 was identified by RT-PCR. 1-1 case-control matching was based on propensity score with vaccine effectiveness adjusted for confounders. RESULTS: Altogether, 1781 cases and 1737 controls aged 3-105 years were analysed. The mean lag time from the last dose of vaccination to testing for SARS-CoV-2 was 133.9 (SD: 84.4) days. Two doses of either vaccine within 180 days offered a low effectiveness against COVID-19 of all severity combined (VEadj [95% CI] for BNT162b2: 27.0% [4.2-44.5], CoronaVac: 22.9% [1.3-39.7]), and further decreased after 180 days. Two doses of CoronaVac were poorly protective 39.5% [4.9-62.5] against severe diseases for age ≥ 60 years, but the effectiveness increased substantially after the third dose (79.1% [25.7-96.7]). Two doses of BNT162b2 protected age ≥ 60 years against severe diseases (79.3% [47.2, 93.9]); however, the uptake was not high enough to assess three doses. CONCLUSIONS: The current real-world analysis indicates a high vaccine effectiveness of three doses of inactivated virus (CoronaVac) vaccines against Omicron variant, whereas the effectiveness of two doses is suboptimal.

GWAS and meta-analysis identifies 49 genetic variants underlying critical COVID-19.

Critical illness in COVID-19 is an extreme and clinically homogeneous disease phenotype that we have previously shown1 to be highly efficient for discovery of genetic associations2. Despite the advanced stage of illness at presentation, we have shown that host genetics in patients who are critically ill with COVID-19 can identify immunomodulatory therapies with strong beneficial effects in this group3. Here we analyse 24,202 cases of COVID-19 with critical illness comprising a combination of microarray genotype and whole-genome sequencing data from cases of critical illness in the international GenOMICC (11,440 cases) study, combined with other studies recruiting hospitalized patients with a strong focus on severe and critical disease: ISARIC4C (676 cases) and the SCOURGE consortium (5,934 cases). To put these results in the context of existing work, we conduct a meta-analysis of the new GenOMICC genome-wide association study (GWAS) results with previously published data. We find 49 genome-wide significant associations, of which 16 have not been reported previously. To investigate the therapeutic implications of these findings, we infer the structural consequences of protein-coding variants, and combine our GWAS results with gene expression data using a monocyte transcriptome-wide association study (TWAS) model, as well as gene and protein expression using Mendelian randomization. We identify potentially druggable targets in multiple systems, including inflammatory signalling (JAK1), monocyte-macrophage activation and endothelial permeability (PDE4A), immunometabolism (SLC2A5 and AK5), and host factors required for viral entry and replication (TMPRSS2 and RAB2A).

Therapeutic drug monitoring of carbapenem antibiotics in critically ill patients: an overview of principles, recommended dosing regimens, and clinical outcomes.

INTRODUCTION: The importance of antibiotic treatment for sepsis in critically ill septic patients is well established. Consistently achieving the dose of antibiotics required to optimally kill bacteria, minimize the development of resistance, and avoid toxicity is challenging. The increasing understanding of the pharmacokinetic and pharmacodynamic (PK/PD) characteristics of antibiotics, and the effects of critical illness on key PK/PD parameters, is gradually re-shaping how antibiotics are dosed in critically ill patients. AREAS COVERED: The PK/PD characteristics of commonly used carbapenem antibiotics, the principles of the application of therapeutic drug monitoring (TDM), and current as well as future methods of utilizing TDM to optimally devise dosing regimens will be reviewed. The limitations and evidence-base supporting the use of carbapenem TDM to improve outcomes in critically ill patients will be examined. EXPERT OPINION: It is important to understand the principles of TDM in order to correctly inform dosing regimens. Although the concept of TDM is attractive, and the ability to utilize PK software to optimize dosing in the near future is expected to rapidly increase clinicians' ability to meet pre-defined PK/PD targets more accurately, current evidence provides only limited support for the use of TDM to guide carbapenem dosing in critically ill patients.

Characterization of METRNß as a novel biomarker of Coronavirus disease 2019 severity and prognosis.

Introduction: Coronavirus disease 2019 (COVID-19) is increasing worldwide, with complications due to frequent viral mutations, an intricate pathophysiology, and variable host immune responses. Biomarkers with predictive and prognostic value are crucial but lacking. Methods: Serum samples from authentic and D614G variant (non-Omicron), and Omicron-SARS-CoV-2 infected patients were collected for METRNß detection and longitudinal cytokine/chemokine analysis. Correlation analyses were performed to compare the relationships between serum METRNß levels and cytokines/chemokines, laboratory parameters, and disease severity. Receiver operating characteristic (ROC) curves and Kaplan-Meier survival curves were used to evaluate the predictive value of METRNß in COVID-19. Results: The serum level of METRNß was highly elevated in non-Omicron-SARS-CoV-2 infected patients compared to healthy individuals, and the non-survivor displayed higher METRNß levels than survivors among the critical ones. METRNß concentration showed positive correlation with viral load in NAPS. ROC curve showed that a baseline METRNß level of 1886.89 pg/ml distinguished COVID-19 patients from non-infected individuals with an AUC of 0.830. Longitudinal analysis of cytokine/chemokine profiles revealed a positive correlation between METRNß and pro-inflammatory cytokines such as IL6, and an inverse correlation with soluble CD40L (sCD40L). Higher METRNß was associated with increased mortality. These findings were validated in a second and third cohort of COVID-19 patients identified in a subsequent wave. Discussion: Our study uncovered the precise role of METRNß in predicting the severity of COVID-19, thus providing a scientific basis for further evaluation of the role of METRNß in triage therapeutic strategies.

Fragment Ends of Circulating Microbial DNA as Signatures for Pathogen Detection in Sepsis.

BACKGROUND: Nuclear-derived cell-free DNA (cfDNA) molecules in blood plasma are nonrandomly fragmented, bearing a wealth of information related to tissues of origin. DNASE1L3 (deoxyribonuclease 1 like 3) is an important player in shaping the fragmentation of nuclear-derived cfDNA molecules, preferentially generating molecules with 5 CC dinucleotide termini (i.e., 5 CC-end motif). However, the fragment end properties of microbial cfDNA and its clinical implication remain to be explored. METHODS: We performed end motif analysis on microbial cfDNA fragments in plasma samples from patients with sepsis. A sequence context-based normalization method was used to minimize the potential biases for end motif analysis. RESULTS: The end motif profiles of microbial cfDNA appeared to resemble that of nuclear cfDNA (Spearman correlation coefficient: 0.82, P value 0.001). The CC-end motif was the most preferred end motif in microbial cfDNA, suggesting that DNASE1L3 might also play a role in the fragmentation of microbe-derived cfDNA in plasma. Of note, differential end motifs were present between microbial cfDNA originating from infection-causing pathogens (enriched at the CC-end) and contaminating microbial DNA potentially derived from reagents or the environment (nearly random). The use of fragment end signatures allowed differentiation between confirmed pathogens and contaminating microbes, with an area under the receiver operating characteristic curve of 0.99. The performance appeared to be superior to conventional analysis based on microbial cfDNA abundance alone. CONCLUSIONS: The use of fragmentomic features could facilitate the differentiation of underlying contaminating microbes from true pathogens in sepsis. This work demonstrates the potential usefulness of microbial cfDNA fragmentomics in metagenomics analysis.

Restrictive and liberal transfusion strategies in extracorporeal membrane oxygenation: A retrospective observational study.

BACKGROUND: To compare the outcomes of patients requiring extracorporeal membrane oxygenation (ECMO) support who had a restrictive transfusion strategy with those who had a liberal strategy. STUDY DESIGN AND METHODS: We retrospectively reviewed all adult patients from 2010 to 2019 who received a minimum of one packed red blood cell (pRBC) during ECMO. Hemoglobin values before each transfusion were retrieved. Restrictive transfusion strategy was defined as a transfusion threshold ≤8.5 g/dl in all transfusion episodes for a single patient, while liberal transfusion strategy was defined as a transfusion threshold >8.5 g/dl in any transfusion episode. RESULTS: The analysis included 763 patients, with 138 (18.1%) patients in the restrictive and 625 (81.9%) in the liberal transfusion strategy group. The median hemoglobin level, taking into account all measured hemoglobin values, during ECMO support was 8.3 and 9.9 g/dl, and the average units of pRBC received per day were 0.7 (0.3-1.8) and 1.2 (0.6-2.3), respectively. There were no significant differences in intensive care unit (ICU) mortality (adjusted odds ratio (OR), 0.86; 95% CI 0.56-1.30; p = .47), hospital mortality (adjusted OR, 0.79; 95% CI 0.52-1.21; p = .28), and 90-day mortality (adjusted OR, 0.84; 95% CI 0.55-1.28; p = .42) between the two groups. Among subgroup analyses, a restrictive transfusion strategy was associated with decreased risk of ICU mortality in patients on veno-venous ECMO (adjusted OR, 0.36; 95% CI 0.17-0.73; p = .005). There was no heterogeneity on outcomes across patients stratified by age, APACHE IV score, or need for large volume transfusion. DISCUSSION: Our data suggested it may be safe to adopt a restrictive red cell transfusion threshold of 8.5 g/dl in patients on ECMO, and highlighted the need for prospective trials in this heavily-transfused population.

Population study on diagnosis, treatment and outcomes of critically ill patients with tuberculosis (2008-2018).

BACKGROUND: Tuberculosis (TB) is a preventable and curable disease, but mortality remains high among those who develop sepsis and critical illness from TB. METHODS: This was a population-based, multicentre retrospective cohort study of patients admitted to all 15 publicly funded Hong Kong adult intensive care units (ICUs) between 1 April 2008 and 31 March 2019. 940 adult critically ill patients with at least one positive Mycobacterium tuberculosis (MTB) culture were identified out of 133 858 ICU admissions. Generalised linear modelling was used to determine the impact of delay in TB treatment on hospital mortality. Trend of annual Acute Physiology and Chronic Health Evaluation (APACHE) IV-adjusted standardised mortality ratio (SMR) over the 11-year period was analysed by Mann-Kendall's trend test. RESULTS: ICU and hospital mortality were 24.7% (232/940) and 41.1% (386/940), respectively. Of those who died in the ICU, 22.8% (53/232) never received antituberculosis drugs. SMR for ICU patients with TB remained unchanged over the study period (Kendall's τb=0.37, p=0.876). After adjustment for age, Charlson comorbidity index, APACHE IV, albumin, vasopressors, mechanical ventilation and renal replacement therapy, delayed TB treatment was directly associated with hospital mortality. In 302/940 (32.1%) of patients, TB could only be established from MTB cultures alone as Ziehl-Neelsen staining or PCR was either not performed or negative. Among this group, only 31.1% (94/302) had concurrent MTB PCR performed. CONCLUSIONS: Survival of ICU patients with TB has not improved over the last decade and mortality remains high. Delay in TB treatment was associated with higher hospital mortality. Use of MTB PCR may improve diagnostic yield and facilitate early treatment.

Interferon response and profiling of interferon response genes in peripheral blood of vaccine-naive COVID-19 patients.

Introduction: There is insufficient understanding on systemic interferon (IFN) responses during COVID-19 infection. Early reports indicated that interferon responses were suppressed by the coronavirus (SARS-CoV-2) and clinical trials of administration of various kinds of interferons had been disappointing. Expression of interferon-stimulated genes (ISGs) in peripheral blood (better known as interferon score) has been a well-established bioassay marker of systemic IFN responses in autoimmune diseases. Therefore, with archival samples of a cohort of COVID-19 patients collected before the availability of vaccination, we aimed to better understand this innate immune response by studying the IFN score and related ISGs expression in bulk and single cell RNAs sequencing expression datasets. Methods: In this study, we recruited 105 patients with COVID-19 and 30 healthy controls in Hong Kong. Clinical risk factors, disease course, and blood sampling times were recovered. Based on a set of five commonly used ISGs (IFIT1, IFIT2, IFI27, SIGLEC1, IFI44L), the IFN score was determined in blood leukocytes collected within 10 days after onset. The analysis was confined to those blood samples collected within 10 days after disease onset. Additional public datasets of bulk gene and single cell RNA sequencing of blood samples were used for the validation of IFN score results. Results: Compared to the healthy controls, we showed that ISGs expression and IFN score were significantly increased during the first 10 days after COVID infection in majority of patients (71%). Among those low IFN responders, they were more commonly asymptomatic patients (71% vs 25%). 22 patients did not mount an overall significant IFN response and were classified as low IFN responders (IFN score < 1). However, early IFN score or ISGs level was not a prognostic biomarker and could not predict subsequent disease severity. Both IFI27 and SIGLEC1 were monocyte-predominant expressing ISGs and IFI27 were activated even among those low IFN responders as defined by IFN score. In conclusion, a substantial IFN response was documented in this cohort of COVID-19 patients who experience a natural infection before the vaccination era. Like innate immunity towards other virus, the ISGs activation was observed largely during the early course of infection (before day 10). Single-cell RNA sequencing data suggested monocytes were the cell-type that primarily accounted for the activation of two highly responsive ISGs (IFI44L and IFI27). Discussion: As sampling time and age were two major confounders of ISG expression, they may account for contradicting observations among previous studies. On the other hand, the IFN score was not associated with the severity of the disease.