Identification and management of preoperative anaemia in adults: A British Society for Haematology Guideline update.

This updated British Society for Haematology guideline provides an up-to-date literature review and recommendations regarding the identification and management of preoperative anaemia. This includes guidance on thresholds for the diagnosis of anaemia and the diagnosis and management of iron deficiency in the preoperative context. Guidance on the appropriate use of erythropoiesis-stimulating agents and preoperative transfusion is also provided.

Urinary Ferritin as a Noninvasive Means of Assessing Iron Status in Young Children.

BACKGROUND: Iron deficiency (ID) is the most common nutritional deficiency affecting young children. Serum ferritin concentration is the preferred biomarker for measuring iron status because it reflects iron stores; however, blood collection can be distressing for young children and can be logistically difficult. A noninvasive means to measure iron status would be attractive to either diagnose or screen for ID in young children. OBJECTIVES: This study aimed to determine the correlation between urinary and serum ferritin concentrations in young children; to determine whether correcting urinary ferritin for creatinine and specific gravity improves the correlation; and to determine a urine ferritin cut point to predict ID. METHODS: Validation study was conducted using paired serum and urine collected from 3-y-old children (n = 142) participating in a longitudinal birth cohort study: the ORIGINS project in Perth, Western Australia. We calculated the sensitivity, specificity, positive, and negative predictive values of urinary ferritin amount in identifying those with ID at the clinical cut point used by the World Health Organization (serum ferritin concentration of <12 ng/mL). RESULTS: Urine ferritin, corrected for creatinine, correlated moderately with serum ferritin [r = 0.53 (0.40-0.64)] and performed well in predicting those with ID (area under the curve: 0.85; 95% confidence interval: 0.75, 0.94). Urine ferritin <2.28 ng/mg creatinine was sensitive (86%) and specific (77%) in predicting ID and had a high negative predictive value of 97%; however, the positive predictive value was low (40%) owing to the low prevalence of ID in the sample (16%). CONCLUSIONS: Urine ferritin shows good diagnostic performance for ID. This noninvasive biomarker maybe a useful screening tool to exclude ID in healthy young children; however, further research is needed in other populations.

Associations Between Nonanemic Iron Deficiency and Postoperative Outcomes in Cardiac Surgery: A Systematic Review and Meta-Analysis.

BACKGROUND: Preoperative screening for iron deficiency is a part of patient blood management protocols. This systematic review, meta-analysis, and meta-regression reviews the association between nonanemic iron deficiency and postoperative outcomes in patients undergoing cardiac surgery. We aimed to determine whether preoperative screening for nonanemic iron deficiency should be recommended in patients undergoing cardiac surgery. METHODS: Electronic databases MEDLINE (Ovid), Embase (Ovid), and Scopus were searched from inception until December 9, 2022. Studies were considered for inclusion if they (1) used an observational study design; (2) enrolled adult patients undergoing cardiac surgery; and (3) included an iron-deficient and iron-replete group, defined using serum ferritin and/or transferrin saturation. The primary outcome was the length of acute hospital stay. Secondary outcomes included length of intensive care unit stay, requirement for allogeneic red blood cell transfusion, number of red blood cell units transfused, days alive and at home at postoperative days 30 and 90, all-cause postoperative complications, postoperative infection, mortality, and hospital readmission. Meta-regression was performed to assess the effects of study and patient-level factors on the associations between nonanemic iron deficiency and specific outcomes. Individual study quality was assessed using the Risk of Bias in Non-Randomized Studies of Exposures (ROBINS-E) tool. The Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) framework was used to determine the quality of evidence for each outcome. RESULTS: Eight studies (2683 patients) were included. No significant association was observed between nonanemic iron deficiency and any of the primary or secondary outcomes except for an increased requirement for allogeneic red blood cell transfusion (odds ratio [OR], 1.39 [95% confidence interval, CI, 1.16-1.68; P < .001; I2 2.8%]). Meta-regression did not identify any potential sources of heterogeneity to explain variation in individual study results. The quality of evidence was rated as "low" or "very low" for all outcomes. CONCLUSIONS: Few high-quality studies are available to assess associations between nonanemic iron deficiency and outcomes after cardiac surgery. Acknowledging these limitations, the presence of preoperative nonanemic iron deficiency was not associated with a change in the primary outcome of length of hospital stay, or any patient-centered secondary outcome compared to those without iron deficiency. There was an association with increased requirement for allogeneic red blood cell transfusion, but this did not impact the reported patient-centered outcomes.

Associations between postoperative anaemia and unplanned readmission to hospital after major surgery: a retrospective cohort study†.

BACKGROUND: Anaemia following major surgery may be associated with unplanned readmission to hospital. However, the severity-response relationship between the degree of anaemia at discharge and the risk of unplanned readmission is poorly defined. We aimed to describe the severity-response relationship between haemoglobin concentration at the time of discharge and the risk of unplanned readmission in a cohort of patients undergoing different types of major surgery. METHODS: We performed a retrospective cohort study in a single tertiary health service, including all patients who underwent major surgery (orthopaedic, abdominal, cardiac or thoracic) between 1 May 2011 and 1 February 2022. The primary outcome was unplanned readmission to hospital in the 90 days following discharge after the index surgical procedure. These complex, non-linear relationships were modelled with restricted cubic splines. RESULTS: We identified 22,134 patients and included 14,635 in the primary analysis, of whom 1804 (12%) experienced at least one unplanned readmission. The odds of unplanned readmission rose when the discharge haemoglobin concentration was < 100 g.l-1 (p < 0.001). On subgroup analysis, the haemoglobin threshold below which odds of readmission began to increase appeared to be higher in patients undergoing emergency surgery (110 g.l-1; p < 0.001) compared with elective surgery. Declining discharge haemoglobin concentration was associated with increased odds ratios (95%CI) of unplanned readmission in patients undergoing orthopaedic (1.08 (1.01-1.15), p = 0.03), abdominal (1.13 (1.07-1.19), p < 0.001) and thoracic (1.12 (1.01-1.24), p = 0.03) procedures, but not cardiac surgery (1.09 (0.99-1.19), p = 0.07). CONCLUSIONS: Our findings suggest that a haemoglobin concentration < 100 g.l-1 following elective procedures and < 110 g.l-1 following emergency procedures, at the time of hospital discharge after major surgery, was associated with unplanned readmission. Future interventional trials that aim to treat postoperative anaemia and reduce unplanned readmission should include patients with discharge haemoglobin below these thresholds.

The relationship between heavy menstrual bleeding, iron deficiency, and iron deficiency anemia.

For reproductive-aged women, the symptom of heavy menstrual bleeding is highly prevalent and a major contributor to iron deficiency and its most severe manifestation, iron deficiency anemia. It is recognized that these 2 clinical entities are not only highly prevalent, but their interrelationship is poorly appreciated and frequently normalized by society, healthcare providers, and affected girls and women themselves. Both heavy menstrual bleeding and iron deficiency, with or without anemia, adversely impact quality of life-heavy menstrual bleeding during the episodes of bleeding and iron deficiency on a daily basis. These combined issues adversely affect the lives of reproductive-aged girls and women of all ages, from menarche to menopause, and their often-insidious nature frequently leads to normalization. The effects on cognitive function and the related work and school absenteeism and presenteeism can undermine the efforts and function of women in all walks of life, be they students, educators, employers, or employees. There is also an increasing body of evidence that suggests that iron deficiency, even in early pregnancy, may adversely impact fetal neurodevelopment with enduring effects on a spectrum of cognitive and psychological disorders, critically important evidence that begs the normalization of iron stores in reproductive-aged women. The authors seek to raise individual, societal, and professional awareness of this underappreciated situation in a fashion that leads to meaningful and evidence-based changes in clinical guidance and healthcare policy directed at preventing, screening, diagnosing, and appropriately managing both disorders. This manuscript provides evidence supporting the need for action and describes the elements necessary to address this pervasive set of conditions that not only affect reproductive-aged girls and women but also the lives of children everywhere.

The Impact of Pre-Operative Anaemia on One Year Amputation Free Survival and Re-Admissions in Patients Undergoing Vascular Surgery for Peripheral Arterial Disease: a National Vascular Registry Study.

OBJECTIVE: Anaemia is common among patients undergoing surgery, but its association with post-operative outcomes in patients with peripheral arterial disease (PAD) is unclear. The aim of this observational population based study was to examine the association between pre-operative anaemia and one year outcomes after surgical revascularisation for PAD. METHODS: This study used data from the National Vascular Registry, linked with an administrative database (Hospital Episode Statistics), to identify patients who underwent open surgical lower limb revascularisation for PAD in English NHS hospitals between January 2016 and December 2019. The primary outcome was one year amputation free survival. Secondary outcomes were one year re-admission rate, 30 day re-intervention rate, 30 day ipsilateral major amputation rate and 30 day death. Flexible parametric survival analysis and generalised linear regression were performed to assess the effect of anaemia on one year outcomes. RESULTS: The analysis included 13 641 patients, 57.9% of whom had no anaemia, 23.8% mild, and 18.3% moderate or severe anaemia. At one year follow up, 80.6% of patients were alive and amputation free. The risk of one year amputation or death was elevated in patients with mild anaemia (adjusted HR 1.3; 95% CI 1.15 - 1.41) and moderate or severe anaemia (aHR 1.5; 1.33 - 1.67). Patients with moderate or severe anaemia experienced more re-admissions over one year (adjusted IRR 1.31; 1.26 - 1.37) and had higher odds of 30 day re-interventions (aOR 1.22; 1.04 - 1.45), 30 day ipsilateral major amputation (aOR 1.53; 1.17 - 2.01), and 30 day death (aOR 1.39; 1.03 - 1.88) compared with patients with no anaemia. CONCLUSION: Pre-operative anaemia is associated with lower one year amputation free survival and higher one year re-admission rates following surgical revascularisation in patients with PAD. Research is required to evaluate whether interventions to correct anaemia improve outcomes after lower limb revascularisation.

Controlling the controls: what is negative pressure wound therapy compared to in clinical trials?

AIM: Surgical site infections (SSIs) are common following colorectal operations. Clinical trials suggest that closed incision negative pressure wound therapy (ciNPWT) may reduce SSIs compared to a 'standard of care' group. However, wound management in the standard of care group may vary. The aim of this review was to assess the control arms in trials of ciNPWT for potential confounding variables that could influence the rates of SSI and therefore the trial outcomes. METHODS: A mapping review of the PubMed database was undertaken in the English language for randomized controlled trials that assessed, in closed surgical wounds, the use of ciNPWT compared to standard of care with SSI as an outcome. Data regarding wound care to assess potential confounding factors that may influence SSI rates were compared between the ciNPWT and standard of care groups. Included were the method of wound closure, control dressing type, frequency of dressing changes and postoperative wound care (washing). RESULTS: Twenty-seven trials were included in the mapping review. There was heterogeneity in ciNPWT duration. There was little control in the comparator standard of care groups with a variety of wound closure techniques and different control dressings used. Overall standard of care dressings were changed more frequently than the ciNPWT dressing and there was no control over wound care or washing. No standard for 'standard of care' was apparent. CONCLUSION: In randomized trials assessing the intervention of ciNPWT compared to standard of care there was considerable heterogeneity in the comparator groups and no standard of care was apparent. Heterogeneity in dressing protocols for standard of care groups could introduce potential confounders impacting SSI rates. There is a need to standardize care in ciNPWT trials to assess potential meaningful differences in SSI prevention.

Impact of closed-incision negative pressure wound dressings on surgical site infection following groin incisions in vascular surgery; a single-centre experience.

OBJECTIVES: Surgical site infection (SSI) is a common complication in vascular surgery, and is associated with increased patient morbidity, readmission and reintervention. The aim of this study was to assess the impact of closed-incision negative pressure wound therapy (CiNPWT) upon rate of SSI and length of hospital stay. METHODS: This study was reported in line with the STROBE guidelines. We assessed the baseline incidence of SSI from a 12-month retrospective cohort and, following a change in practice intervention with CiNPWT, compared to a 6-month prospective cohort. The primary endpoint was incidence of SSI (according to CDC-NHSN guidelines) while secondary endpoints included length of hospital stay, readmission, reintervention and Days Alive and Out of Hospital (DAOH) to 90-days. RESULTS: A total of 127 groin incisions were performed: 76 (65 patients) within the retrospective analysis and 51 (42 patients) within the prospective analysis (of whom 69% received CiNPWT). The primary endpoint of SSI was seen in 21.1% of the retrospective cohort and 9.8% of the prospective cohort (p = .099). Readmission was found to be significantly associated with the retrospective cohort (p = .016) while total admission (inclusive of re-admission) was significantly longer in those in the retrospective cohort (p = .013). DAOH-90 was 83 days (77-85) following introduction of the CiNPWT protocol as compared to the retrospective cohort (77 days (64-83), p = .04). CONCLUSION: Introduction of CiNPWT was associated with a reduced length of hospital stay and improved DAOH-90. Further trials on CINPWT should include patient-centred outcomes and healthcare cost analysis.

ESAIC focused guideline for the use of cardiac biomarkers in perioperative risk evaluation.

BACKGROUND: In recent years, there has been increasing focus on the use of cardiac biomarkers in patients undergoing noncardiac surgery. AIMS: The aim of this focused guideline was to provide updated guidance regarding the pre-, post- and combined pre-and postoperative use of cardiac troponin and B-type natriuretic peptides in adult patients undergoing noncardiac surgery. METHODS: The guidelines were prepared using Grading of Recommendations Assessment Development and Evaluation (GRADE) methodology. This included the definition of critical outcomes, a systematic literature search, appraisal of certainty of evidence, evaluation of biomarker measurement in terms of the balance of desirable and undesirable effects including clinical outcomes, resource use, health inequality, stakeholder acceptance, and implementation. The panel differentiated between three different scopes of applications: cardiac biomarkers as prognostic factors, as tools for risk prediction, and for biomarker-enhanced management strategies. RESULTS: In a modified Delphi process, the task force defined 12 critical outcomes. The systematic literature search resulted in over 25,000 hits, of which 115 full-text articles formed the body of evidence for recommendations. The evidence appraisal indicated heterogeneity in the certainty of evidence across critical outcomes. Further, there was relevant gradient in the certainty of evidence across the three scopes of application. Recommendations were issued and if this was not possible due to limited evidence, clinical practice statements were produced. CONCLUSION: The ESAIC focused guidelines provide guidance on the perioperative use of cardiac troponin and B-type natriuretic peptides in patients undergoing noncardiac surgery, for three different scopes of application.

COVID-19 vaccine hesitancy in rural and metropolitan Western Australia: A mid-rollout cross-sectional analysis of why it exists and potential solutions.

INTRODUCTION: Vaccine hesitancy represents a state of uncertainty before a decision about vaccination is made. It can lead to limited vaccine uptake despite adequate supply and an efficacious product. Western Australia (WA) presents a unique challenge with a population widely spread across metropolitan and rural sites and diverse opinions regarding vaccination. OBJECTIVE: To elicit and compare the common COVID-19 vaccine concerns in rural and metropolitan WA, and to identify proposed solutions to vaccine hesitancy. DESIGN: A voluntary online survey was distributed via social media over a 2-week period in August 2021 during Phase 2A of the National COVID-19 Vaccine Rollout Strategy. General practitioners and members of the public living in rural and metropolitan WA over the age of 18 were surveyed regarding COVID-19 vaccine concerns (blood clots; long- and short-term side effects; lack of testing; and other concerns) and suggested methods to address vaccine hesitancy. Data were analysed with a sequential mixed methods and thematic analysis approach. FINDINGS: There were 468 general population respondents to our survey, of whom 19.0% (n = 89) lived rurally. A majority (52.6% [n = 246]) of general respondents expressed concerns about COVID-19 vaccine safety. The commonest concerns were long- and short-term side effects, blood clots and inadequate testing. There was a positive correlation between rurality and vaccine concerns; an inverse relationship between rurality and vaccine uptake; and an inverse relationship between vaccine concerns and uptake. Improved media coverage was the commonest solution suggested to address COVID-19 vaccine hesitancy. DISCUSSION: A significant proportion of respondents had concerns about vaccine safety; concerns were more common in rural respondents. Rural communities may benefit from location-targeted media campaigns with a focus on breaking down barriers specific to these members of the population. Vaccine access is more challenging, and consistent messaging from trusted sources is of utmost importance to improve uptake. CONCLUSION: COVID-19 vaccine hesitancy is more common in rural populations. Targeted media-based education regarding vaccine safety may improve COVID-19 vaccine uptake.

Revacept, an Inhibitor of Platelet Adhesion in Symptomatic Carotid Stenosis: A Multicenter Randomized Phase II Trial.

BACKGROUND: Patients with symptomatic internal carotid artery (ICA) stenosis are at high risk of recurrent ischemic stroke and require early interventional treatment and antiplatelet therapy. Increased bleeding rates might counterbalance the periprocedural efficacy of intensified platelet inhibition. We aim to investigate, whether Revacept, a competitive antagonist of glycoprotein VI, adjunct to standard antiplatelet therapy reduces the occurrence of ischemic lesions in patients with symptomatic ICA stenosis. METHODS: International, multicenter (16 sites), 3-arm, randomized (1:1:1), double-blind, and placebo-controlled study with parallel groups, including patients with symptomatic ICA stenosis. A single infusion over 20 minutes of either placebo, 40 mg or 120 mg Revacept in addition to guideline-conform antiplatelet therapy was evaluated with regard to the exploratory efficacy end point: Number of new ischemic lesions on diffusion-weighted magnetic resonance imaging after treatment initiation. Main clinical outcome was the combined safety and efficacy end point including any stroke or death, transient ischemic attack, myocardial infarction, coronary intervention, and bleeding complications during follow-up. RESULTS: Out of 160 randomized patients, 158 patients (68±10.1 years, 24% female) received study medication (51 patients placebo, 54 patients 40 mg Revacept and 53 patients 120 mg Revacept) and were followed for 11.2±2.3 months. A total of 1.16 (95% CI, 0.88-1.53)/1.05 (95% CI, 0.78-1.42; P=0.629)/0.63 (95% CI, 0.43-0.93) new diffusion-weighted magnetic resonance imaging lesions per patient were detected in the placebo/40 mg/120 mg Revacept groups, without statistical evidence of a difference. A reduction of the combined safety and efficacy end point during the study period was observed in patients who received 120 mg (HR, 0.46 [95% CI, 0.21-0.99]; P=0.047), but not 40 mg Revacept compared with placebo (HR, 0.72 [95% CI, 0.37-1.42]; P=0.343). CONCLUSIONS: Revacept 120 mg reduced the combined safety and efficacy end point in patients with symptomatic ICA stenosis. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique Identifier: NCT01645306.

No Evidence for Long Term Blood Pressure Differences Between Eversion and Conventional Carotid Endarterectomy in Two Independent Study Cohorts.

OBJECTIVE: Blood pressure (BP) management is a vital aspect of stroke prevention and post-stroke care. Different surgical carotid endarterectomy (CEA) techniques may impact on BP control post-operatively. Specifically, the carotid sinus nerve, which innervates the carotid baroreceptors and carotid body, is commonly left intact during conventional CEA but is routinely transected as part of eversion CEA. The aim of this study was to assess long term BP control after eversion and conventional CEA. METHODS: Patients from the International Carotid Stenting Study (ICSS cohort) and a personal series of patients from the Stroke Clinical Trials Unit at University College London (UCL cohort) were separately analysed and divided into eversion and conventional CEA groups. Mixed effect linear models were fitted and adjusted for baseline demographic data and antihypertensive treatment to test for changes in BP from baseline over a three year follow up period after the respective procedures. RESULTS: There were no differences in changes in baseline BP readings and follow up readings between eversion and conventional CEA in the ICSS or UCL cohorts. In the ICSS cohort a mild but significant systolic (-8.6 mmHg; 95% confidence interval [CI] -10.6 - -6.6) and diastolic (-4.9 mmHg; 95% CI -6.0 - -3.8) BP lowering effect was evident at discharge in the conventional group but not in the eversion CEA group. BP monitoring during follow up did not reveal any consistent BP changes with either conventional or eversion CEA vs. baseline levels. CONCLUSION: Neither conventional nor eversion CEA seem to result in clinically significant long term BP changes. Potential concerns related to either short or long term alterations in BP levels with transection of the carotid sinus nerve during eversion CEA could not be substantiated.

Hospital costs and factors associated with days alive and at home after surgery (DAH30 ).

OBJECTIVE: To assess the relationships of patient and surgical factors and hospital costs with the number of days alive and at home during the 30 days following surgery (DAH30 ). DESIGN: Retrospective cohort study; analysis of Medibank Private health insurance hospital claims data, Australia, 1 January 2016 - 31 December 2017. SETTING, PARTICIPANTS: Admissions of adults (18 years or older) to hospitals for elective or emergency inpatient surgery with anaesthesia covered by private health insurance, Australia, 1 January 2016 - 31 December 2017. MAIN OUTCOME MEASURES: Associations between DAH30 and total hospital costs, and between DAH30 and surgery risk factors. RESULTS: Complete data were available for 126 788 of 181 281 eligible patients (69.9%); their median age was 62 years (IQR, 47-73 years), 72 872 were women (57%), and 115 117 had undergone elective surgery (91%). The median DAH30 was 27.1 days (IQR, 24.2-28.8 days), the median hospital cost per patient was $10 358 (IQR, $6624-20 174). The association between DAH30 and total hospital costs was moderate (Spearman ρ = -0.60; P < 0.001). Median DAH30 declined with age, comorbidity score, ASA physical status score, and surgical severity and duration, and was also lower for women. CONCLUSIONS: DAH30 is a validated, patient-centred outcome measure of post-surgical outcomes; higher values reflect shorter hospital stays and fewer serious complications, re-admissions, and deaths. DAH30 can be used to benchmark quality of surgical care and to monitor quality improvement programs for reducing the costs of surgical and other peri-operative care.

Postoperative anaemia and patient-centred outcomes after major abdominal surgery: a retrospective cohort study.

BACKGROUND: Compared with anaemia before surgery, the underlying pathogenesis and implications of postoperative anaemia are largely unknown. METHODS: This retrospective cohort study analysed prospective data obtained from 2983 adult patients across 47 centres enrolled in a clinical trial evaluating restrictive and liberal intravenous fluids. The primary endpoint was persistent disability or death up to 90 days after surgery. Secondary endpoints included major septic complications, hospital stay, and patient quality of recovery using a 15-item quality of recovery (QoR-15) score, hospital re-admissions, and disability-free survival up to 12 months after surgery. Anaemia and disability were defined according to the WHO definitions. Multivariable regression was used to adjust for baseline risk and surgery. RESULTS: A total of 2983 patients met inclusion criteria for this study, of which 78.5% (95% confidence interval [CI], 76.7-80.1%) had postoperative anaemia. Patients with postoperative anaemia had a higher adjusted risk of death or disability up to 90 days after surgery when compared with those without anaemia: 18.2% vs 9.2% (risk ratio [RR]=1.51; 95% CI, 1.10-2.07, P=0.011); lower QoR-15 scores on Day 3 and Day 30, 105 (95% CI, 87-119) vs 114 (95% CI, 99-128; P<0.001), and 130 (95% CI, 112-140) vs 139 (95% CI, 121-144; P<0.011), respectively; higher adjusted risk of a composite of mortality/septic complications, 2.01 (95% CI, 1.55-42.67; P<0.001); unplanned admission to ICU (RR=2.65; 95% CI, 1.65-4.23; P<0.001); and longer median (inter-quartile range [IQR]) hospital stays, 6.6 (4.4-12.4) vs 3.7 (2.5-6.5) days (P<0.001). CONCLUSIONS: Postoperative anaemia is common and is independently associated with poor outcomes after surgery. Optimal prevention and treatment strategies need to be investigated. CLINICAL TRIAL REGISTRATION: NCT04978285 (ClinicalTrials.gov).

Low Volume in Vitro Diagnostic Proton NMR Spectroscopy of Human Blood Plasma for Lipoprotein and Metabolite Analysis: Application to SARS-CoV-2 Biomarkers.

The utility of low sample volume in vitro diagnostic (IVDr) proton nuclear magnetic resonance (1H NMR) spectroscopic experiments on blood plasma for information recovery from limited availability or high value samples was exemplified using plasma from patients with SARS-CoV-2 infection and normal controls. 1H NMR spectra were obtained using solvent-suppressed 1D, spin-echo (CPMG), and 2-dimensional J-resolved (JRES) spectroscopy using both 3 mm outer diameter SampleJet NMR tubes (100 µL plasma) and 5 mm SampleJet NMR tubes (300 µL plasma) under in vitro diagnostic conditions. We noted near identical diagnostic models in both standard and low volume IVDr lipoprotein analysis (measuring 112 lipoprotein parameters) with a comparison of the two tubes yielding R2 values ranging between 0.82 and 0.99 for the 40 paired lipoprotein parameters samples. Lipoprotein measurements for the 3 mm tubes were achieved without time penalty over the 5 mm tubes as defined by biomarker recovery for SARS-CoV-2. Overall, biomarker pattern recovery for the lipoproteins was extremely similar, but there were some small positive offsets in the linear equations for several variables due to small shimming artifacts, but there was minimal degradation of the biological information. For the standard untargeted 1D, CPMG, and JRES NMR experiments on the same samples, the reduced signal-to-noise was more constraining and required greater scanning times to achieve similar differential diagnostic performance (15 min per sample per experiment for 3 mm 1D and CPMG, compared to 4 min for the 5 mm tubes). We conclude that the 3 mm IVDr method is fit-for-purpose for quantitative lipoprotein measurements, allowing the preparation of smaller volumes for high value or limited volume samples that is common in clinical studies. If there are no analytical time constraints, the lower volume experiments are equally informative for untargeted profiling.

NMR Spectroscopic Windows on the Systemic Effects of SARS-CoV-2 Infection on Plasma Lipoproteins and Metabolites in Relation to Circulating Cytokines.

To investigate the systemic metabolic effects of SARS-CoV-2 infection, we analyzed 1H NMR spectroscopic data on human blood plasma and co-modeled with multiple plasma cytokines and chemokines (measured in parallel). Thus, 600 MHz 1H solvent-suppressed single-pulse, spin-echo, and 2D J-resolved spectra were collected on plasma recorded from SARS-CoV-2 rRT-PCR-positive patients (n = 15, with multiple sampling timepoints) and age-matched healthy controls (n = 34, confirmed rRT-PCR negative), together with patients with COVID-19/influenza-like clinical symptoms who tested SARS-CoV-2 negative (n = 35). We compared the single-pulse NMR spectral data with in vitro diagnostic research (IVDr) information on quantitative lipoprotein profiles (112 parameters) extracted from the raw 1D NMR data. All NMR methods gave highly significant discrimination of SARS-CoV-2 positive patients from controls and SARS-CoV-2 negative patients with individual NMR methods, giving different diagnostic information windows on disease-induced phenoconversion. Longitudinal trajectory analysis in selected patients indicated that metabolic recovery was incomplete in individuals without detectable virus in the recovery phase. We observed four plasma cytokine clusters that expressed complex differential statistical relationships with multiple lipoproteins and metabolites. These included the following: cluster 1, comprising MIP-1ß, SDF-1α, IL-22, and IL-1α, which correlated with multiple increased LDL and VLDL subfractions; cluster 2, including IL-10 and IL-17A, which was only weakly linked to the lipoprotein profile; cluster 3, which included IL-8 and MCP-1 and were inversely correlated with multiple lipoproteins. IL-18, IL-6, and IFN-γ together with IP-10 and RANTES exhibited strong positive correlations with LDL1-4 subfractions and negative correlations with multiple HDL subfractions. Collectively, these data show a distinct pattern indicative of a multilevel cellular immune response to SARS CoV-2 infection interacting with the plasma lipoproteome giving a strong and characteristic immunometabolic phenotype of the disease. We observed that some patients in the respiratory recovery phase and testing virus-free were still metabolically highly abnormal, which indicates a new role for these technologies in assessing full systemic recovery.

Systemic Perturbations in Amine and Kynurenine Metabolism Associated with Acute SARS-CoV-2 Infection and Inflammatory Cytokine Responses.

We performed quantitative metabolic phenotyping of blood plasma in parallel with cytokine/chemokine analysis from participants who were either SARS-CoV-2 (+) (n = 10) or SARS-CoV-2 (-) (n = 49). SARS-CoV-2 positivity was associated with a unique metabolic phenotype and demonstrated a complex systemic response to infection, including severe perturbations in amino acid and kynurenine metabolic pathways. Nine metabolites were elevated in plasma and strongly associated with infection (quinolinic acid, glutamic acid, nicotinic acid, aspartic acid, neopterin, kynurenine, phenylalanine, 3-hydroxykynurenine, and taurine; p < 0.05), while four metabolites were lower in infection (tryptophan, histidine, indole-3-acetic acid, and citrulline; p < 0.05). This signature supports a systemic metabolic phenoconversion following infection, indicating possible neurotoxicity and neurological disruption (elevations of 3-hydroxykynurenine and quinolinic acid) and liver dysfunction (reduction in Fischer's ratio and elevation of taurine). Finally, we report correlations between the key metabolite changes observed in the disease with concentrations of proinflammatory cytokines and chemokines showing strong immunometabolic disorder in response to SARS-CoV-2 infection.

Incomplete Systemic Recovery and Metabolic Phenoreversion in Post-Acute-Phase Nonhospitalized COVID-19 Patients: Implications for Assessment of Post-Acute COVID-19 Syndrome.

We present a multivariate metabotyping approach to assess the functional recovery of nonhospitalized COVID-19 patients and the possible biochemical sequelae of "Post-Acute COVID-19 Syndrome", colloquially known as long-COVID. Blood samples were taken from patients ca. 3 months after acute COVID-19 infection with further assessment of symptoms at 6 months. Some 57% of the patients had one or more persistent symptoms including respiratory-related symptoms like cough, dyspnea, and rhinorrhea or other nonrespiratory symptoms including chronic fatigue, anosmia, myalgia, or joint pain. Plasma samples were quantitatively analyzed for lipoproteins, glycoproteins, amino acids, biogenic amines, and tryptophan pathway intermediates using Nuclear Magnetic Resonance (NMR) spectroscopy and mass spectrometry. Metabolic data for the follow-up patients (n = 27) were compared with controls (n = 41) and hospitalized severe acute respiratory syndrome SARS-CoV-2 positive patients (n = 18, with multiple time-points). Univariate and multivariate statistics revealed variable patterns of functional recovery with many patients exhibiting residual COVID-19 biomarker signatures. Several parameters were persistently perturbed, e.g., elevated taurine (p = 3.6 × 10-3 versus controls) and reduced glutamine/glutamate ratio (p = 6.95 × 10-8 versus controls), indicative of possible liver and muscle damage and a high energy demand linked to more generalized tissue repair or immune function. Some parameters showed near-complete normalization, e.g., the plasma apolipoprotein B100/A1 ratio was similar to that of healthy controls but significantly lower (p = 4.2 × 10-3) than post-acute COVID-19 patients, reflecting partial reversion of the metabolic phenotype (phenoreversion) toward the healthy metabolic state. Plasma neopterin was normalized in all follow-up patients, indicative of a reduction in the adaptive immune activity that has been previously detected in active SARS-CoV-2 infection. Other systemic inflammatory biomarkers such as GlycA and the kynurenine/tryptophan ratio remained elevated in some, but not all, patients. Correlation analysis, principal component analysis (PCA), and orthogonal-partial least-squares discriminant analysis (O-PLS-DA) showed that the follow-up patients were, as a group, metabolically distinct from controls and partially comapped with the acute-phase patients. Significant systematic metabolic differences between asymptomatic and symptomatic follow-up patients were also observed for multiple metabolites. The overall metabolic variance of the symptomatic patients was significantly greater than that of nonsymptomatic patients for multiple parameters (χ2p = 0.014). Thus, asymptomatic follow-up patients including those with post-acute COVID-19 Syndrome displayed a spectrum of multiple persistent biochemical pathophysiology, suggesting that the metabolic phenotyping approach may be deployed for multisystem functional assessment of individual post-acute COVID-19 patients.

Preoperative intravenous iron to treat anaemia before major abdominal surgery (PREVENTT): a randomised, double-blind, controlled trial.

BACKGROUND: Preoperative anaemia affects a high proportion of patients undergoing major elective surgery and is associated with poor outcomes. We aimed to test the hypothesis that intravenous iron given to anaemic patients before major open elective abdominal surgery would correct anaemia, reduce the need for blood transfusions, and improve patient outcomes. METHODS: In a double-blind, parallel-group randomised trial, we recruited adult participants identified with anaemia at preoperative hospital visits before elective major open abdominal surgery at 46 UK tertiary care centres. Anaemia was defined as haemoglobin less than 130 g/L for men and 120 g/L for women. We randomly allocated participants (1:1) via a secure web-based service to receive intravenous iron or placebo 10-42 days before surgery. Intravenous iron was administered as a single 1000 mg dose of ferric carboxymaltose in 100 mL normal saline, and placebo was 100 mL normal saline, both given as an infusion over 15 min. Unblinded study personnel prepared and administered the study drug; participants and other clinical and research staff were blinded to treatment allocation. Coprimary endpoints were risk of the composite outcome of blood transfusion or death, and number of blood transfusions from randomisation to 30 days postoperatively. The primary analysis included all randomly assigned patients with data available for the primary endpoints; safety analysis included all randomly assigned patients according to the treatment received. This study is registered, ISRCTN67322816, and is closed to new participants. FINDINGS: Of 487 participants randomly assigned to placebo (n=243) or intravenous iron (n=244) between Jan 6, 2014, and Sept 28, 2018, complete data for the primary endpoints were available for 474 (97%) individuals. Death or blood transfusion occurred in 67 (28%) of the 237 patients in the placebo group and 69 (29%) of the 237 patients in the intravenous iron group (risk ratio 1·03, 95% CI 0·78-1·37; p=0·84). There were 111 blood transfusions in the placebo group and 105 in the intravenous iron group (rate ratio 0·98, 95% CI 0·68-1·43; p=0·93). There were no significant differences between the two groups for any of the prespecified safety endpoints. INTERPRETATION: Preoperative intravenous iron was not superior to placebo to reduce need for blood transfusion when administered to patients with anaemia 10-42 days before elective major abdominal surgery. FUNDING: UK National Institute of Health Research Health Technology Assessment Program.

Diffusion and Relaxation Edited Proton NMR Spectroscopy of Plasma Reveals a High-Fidelity Supramolecular Biomarker Signature of SARS-CoV-2 Infection.

We have applied nuclear magnetic resonance spectroscopy based plasma phenotyping to reveal diagnostic molecular signatures of SARS-CoV-2 infection via combined diffusional and relaxation editing (DIRE). We compared plasma from healthy age-matched controls (n = 26) with SARS-CoV-2 negative non-hospitalized respiratory patients and hospitalized respiratory patients (n = 23 and 11 respectively) with SARS-CoV-2 rRT-PCR positive respiratory patients (n = 17, with longitudinal sampling time-points). DIRE data were modelled using principal component analysis and orthogonal projections to latent structures discriminant analysis (O-PLS-DA), with statistical cross-validation indices indicating excellent model generalization for the classification of SARS-CoV-2 positivity for all comparator groups (area under the receiver operator characteristic curve = 1). DIRE spectra show biomarker signal combinations conferred by differential concentrations of metabolites with selected molecular mobility properties. These comprise the following: (a) composite N-acetyl signals from α-1-acid glycoprotein and other glycoproteins (designated GlycA and GlycB) that were elevated in SARS-CoV-2 positive patients [p = 2.52 × 10-10 (GlycA) and 1.25 × 10-9 (GlycB) vs controls], (b) two diagnostic supramolecular phospholipid composite signals that were identified (SPC-A and SPC-B) from the -+N-(CH3)3 choline headgroups of lysophosphatidylcholines carried on plasma glycoproteins and from phospholipids in high-density lipoprotein subfractions (SPC-A) together with a phospholipid component of low-density lipoprotein (SPC-B). The integrals of the summed SPC signals (SPCtotal) were reduced in SARS-CoV-2 positive patients relative to both controls (p = 1.40 × 10-7) and SARS-CoV-2 negative patients (p = 4.52 × 10-8) but were not significantly different between controls and SARS-CoV-2 negative patients. The identity of the SPC signal components was determined using one and two dimensional diffusional, relaxation, and statistical spectroscopic experiments. The SPCtotal/GlycA ratios were also significantly different for control versus SARS-CoV-2 positive patients (p = 1.23 × 10-10) and for SARS-CoV-2 negatives versus positives (p = 1.60 × 10-9). Thus, plasma SPCtotal and SPCtotal/GlycA are proposed as sensitive molecular markers for SARS-CoV-2 positivity that could effectively augment current COVID-19 diagnostics and may have value in functional assessment of the disease recovery process in patients with long-term symptoms.