Large-scale phenotyping of patients with long COVID post-hospitalization reveals mechanistic subtypes of disease.

One in ten severe acute respiratory syndrome coronavirus 2 infections result in prolonged symptoms termed long coronavirus disease (COVID), yet disease phenotypes and mechanisms are poorly understood1. Here we profiled 368 plasma proteins in 657 participants ≥3 months following hospitalization. Of these, 426 had at least one long COVID symptom and 233 had fully recovered. Elevated markers of myeloid inflammation and complement activation were associated with long COVID. IL-1R2, MATN2 and COLEC12 were associated with cardiorespiratory symptoms, fatigue and anxiety/depression; MATN2, CSF3 and C1QA were elevated in gastrointestinal symptoms and C1QA was elevated in cognitive impairment. Additional markers of alterations in nerve tissue repair (SPON-1 and NFASC) were elevated in those with cognitive impairment and SCG3, suggestive of brain-gut axis disturbance, was elevated in gastrointestinal symptoms. Severe acute respiratory syndrome coronavirus 2-specific immunoglobulin G (IgG) was persistently elevated in some individuals with long COVID, but virus was not detected in sputum. Analysis of inflammatory markers in nasal fluids showed no association with symptoms. Our study aimed to understand inflammatory processes that underlie long COVID and was not designed for biomarker discovery. Our findings suggest that specific inflammatory pathways related to tissue damage are implicated in subtypes of long COVID, which might be targeted in future therapeutic trials.

Changes in hospital mortality in patients with cancer during the COVID-19 pandemic (ISARIC-CCP-UK): a prospective, multicentre cohort study.

BACKGROUND: Patients with cancer are at greater risk of dying from COVID-19 than many other patient groups. However, how this risk evolved during the pandemic remains unclear. We aimed to determine, on the basis of the UK national pandemic protocol, how factors influencing hospital mortality from COVID-19 could differentially affect patients undergoing cancer treatment. We also examined changes in hospital mortality and escalation of care in patients on cancer treatment during the first 2 years of the COVID-19 pandemic in the UK. METHODS: We conducted a prospective cohort study of patients aged older than 19 years and admitted to 306 health-care facilities in the UK with confirmed SARS-CoV-2 infection, who were enrolled in the International Severe Acute Respiratory and emerging Infections Consortium (ISARIC) WHO Clinical Characterisation Protocol (CCP) across the UK from April 23, 2020, to Feb 28, 2022; this analysis included all patients in the complete dataset when the study closed. The primary outcome was 30-day in-hospital mortality, comparing patients on cancer treatment and those without cancer. The study was approved by the South Central-Oxford C Research Ethics Committee in England (Ref: 13/SC/0149) and the Scotland A Research Ethics Committee (Ref 20/SS/0028), and is registered on the ISRCTN Registry (ISRCTN66726260). FINDINGS: 177 871 eligible adult patients either with no history of cancer (n=171 303) or on cancer treatment (n=6568) were enrolled; 93 205 (52·4%) were male, 84 418 (47·5%) were female, and in 248 (13·9%) sex or gender details were not specified or data were missing. Patients were followed up for a median of 13 (IQR 6-21) days. Of the 6568 patients receiving cancer treatment, 2080 (31·7%) died at 30 days, compared with 30 901 (18·0%) of 171 303 patients without cancer. Patients aged younger than 50 years on cancer treatment had the highest age-adjusted relative risk (hazard ratio [HR] 5·2 [95% CI 4·0-6·6], p<0·0001; vs 50-69 years 2·4 [2·2-2·6], p<0·0001; 70-79 years 1·8 [1·6-2·0], p<0·0001; and >80 years 1·5 [1·3-1·6], p<0·0001) but a lower absolute risk (51 [6·7%] of 763 patients <50 years died compared with 459 [30·2%] of 1522 patients aged >80 years). In-hospital mortality decreased for all patients during the pandemic but was higher for patients on cancer treatment than for those without cancer throughout the study period. INTERPRETATION: People with cancer have a higher risk of mortality from COVID-19 than those without cancer. Patients younger than 50 years with cancer treatment have the highest relative risk of death. Continued action is needed to mitigate the poor outcomes in patients with cancer, such as through optimising vaccination, long-acting passive immunisation, and early access to therapeutics. These findings underscore the importance of the ISARIC-WHO pandemic preparedness initiative. FUNDING: National Institute for Health Research and the Medical Research Council.

Preoperative nutrition therapy in people undergoing gastrointestinal surgery.

BACKGROUND: Poor preoperative nutritional status has been consistently linked to an increase in postoperative complications and worse surgical outcomes. We updated a review first published in 2012. OBJECTIVES: To assess the effects of preoperative nutritional therapy compared to usual care in people undergoing gastrointestinal surgery. SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials, MEDLINE, Embase, three other databases and two trial registries on 28 March 2023. We searched reference lists of included studies. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of people undergoing gastrointestinal surgery and receiving preoperative nutritional therapy, including parenteral nutrition, enteral nutrition or oral nutrition supplements, compared to usual care. We only included nutritional therapy that contained macronutrients (protein, carbohydrate and fat) and micronutrients, and excluded studies that evaluated single nutrients. We included studies regardless of the nutritional status of participants, that is, well-nourished participants, participants at risk of malnutrition, or mixed populations. We excluded studies in people undergoing pancreatic and liver surgery. Our primary outcomes were non-infectious complications, infectious complications and length of hospital stay. Our secondary outcomes were nutritional aspects, quality of life, change in macronutrient intake, biochemical parameters, 30-day perioperative mortality and adverse effects. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodology. We assessed risk of bias using the RoB 1 tool and applied the GRADE criteria to assess the certainty of evidence. MAIN RESULTS: We included 16 RCTs reporting 19 comparisons (2164 participants). Seven studies were new for this update. Participants' ages ranged from 21 to 79 years, and 62% were men. Three RCTs used parenteral nutrition, two used enteral nutrition, eight used immune-enhancing nutrition and six used standard oral nutrition supplements. All studies included mixed groups of well-nourished and malnourished participants; they used different methods to identify malnutrition and reported this in different ways. Not all the included studies were conducted within an Enhanced Recovery After Surgery (ERAS) programme, which is now current clinical practice in most hospitals undertaking GI surgery. We were concerned about risk of bias in all the studies and 14 studies were at high risk of bias due to lack of blinding. We are uncertain if parenteral nutrition has any effect on the number of participants who had a non-infectious complication (risk ratio (RR) 0.61, 95% confidence interval (CI) 0.36 to 1.02; 3 RCTs, 260 participants; very low-certainty evidence); infectious complication (RR 0.98, 95% CI 0.53 to 1.80; 3 RCTs, 260 participants; very low-certainty evidence) or length of hospital stay (mean difference (MD) 5.49 days, 95% CI 0.02 to 10.96; 2 RCTs, 135 participants; very low-certainty evidence). None of the enteral nutrition studies reported non-infectious complications as an outcome. The evidence is very uncertain about the effect of enteral nutrition on the number of participants with infectious complications after surgery (RR 0.90, 95% CI 0.59 to 1.38; 2 RCTs, 126 participants; very low-certainty evidence) or length of hospital stay (MD 5.10 days, 95% CI -1.03 to 11.23; 2 RCTs, 126 participants; very low-certainty evidence). Immune-enhancing nutrition compared to controls may result in little to no effect on the number of participants experiencing a non-infectious complication (RR 0.79, 95% CI 0.62 to 1.00; 8 RCTs, 1020 participants; low-certainty evidence), infectious complications (RR 0.74, 95% CI 0.53 to 1.04; 7 RCTs, 925 participants; low-certainty evidence) or length of hospital stay (MD -1.22 days, 95% CI -2.80 to 0.35; 6 RCTs, 688 participants; low-certainty evidence). Standard oral nutrition supplements may result in little to no effect on number of participants with a non-infectious complication (RR 0.90, 95% CI 0.67 to 1.20; 5 RCTs, 473 participants; low-certainty evidence) or the length of hospital stay (MD -0.65 days, 95% CI -2.33 to 1.03; 3 RCTs, 299 participants; low-certainty evidence). The evidence is very uncertain about the effect of oral nutrition supplements on the number of participants with an infectious complication (RR 0.88, 95% CI 0.60 to 1.27; 5 RCTs, 473 participants; very low-certainty evidence). Sensitivity analysis based on malnourished and weight-losing participants found oral nutrition supplements may result in a slight reduction in infections (RR 0.58, 95% CI 0.40 to 0.85; 2 RCTs, 184 participants). Studies reported some secondary outcomes, but not consistently. Complications associated with central venous catheters occurred in RCTs involving parenteral nutrition. Adverse events in the enteral nutrition, immune-enhancing nutrition and standard oral nutrition supplements RCTs included nausea, vomiting, diarrhoea and abdominal pain. AUTHORS' CONCLUSIONS: We were unable to determine if parenteral nutrition, enteral nutrition, immune-enhancing nutrition or standard oral nutrition supplements have any effect on the clinical outcomes due to very low-certainty evidence. There is some evidence that standard oral nutrition supplements may have no effect on complications. Sensitivity analysis showed standard oral nutrition supplements probably reduced infections in weight-losing or malnourished participants. Further high-quality multicentre research considering the ERAS programme is required and further research in low- and middle-income countries is needed.

Artificial intelligence in surgery.

Artificial intelligence (AI) is rapidly emerging in healthcare, yet applications in surgery remain relatively nascent. Here we review the integration of AI in the field of surgery, centering our discussion on multifaceted improvements in surgical care in the preoperative, intraoperative and postoperative space. The emergence of foundation model architectures, wearable technologies and improving surgical data infrastructures is enabling rapid advances in AI interventions and utility. We discuss how maturing AI methods hold the potential to improve patient outcomes, facilitate surgical education and optimize surgical care. We review the current applications of deep learning approaches and outline a vision for future advances through multimodal foundation models.

A comprehensive benchmark for COVID-19 predictive modeling using electronic health records in intensive care.

The COVID-19 pandemic highlighted the need for predictive deep-learning models in health care. However, practical prediction task design, fair comparison, and model selection for clinical applications remain a challenge. To address this, we introduce and evaluate two new prediction tasks-outcome-specific length-of-stay and early-mortality prediction for COVID-19 patients in intensive care-which better reflect clinical realities. We developed evaluation metrics, model adaptation designs, and open-source data preprocessing pipelines for these tasks while also evaluating 18 predictive models, including clinical scoring methods and traditional machine-learning, basic deep-learning, and advanced deep-learning models, tailored for electronic health record (EHR) data. Benchmarking results from two real-world COVID-19 EHR datasets are provided, and all results and trained models have been released on an online platform for use by clinicians and researchers. Our efforts contribute to the advancement of deep-learning and machine-learning research in pandemic predictive modeling.

Effect of recipient age on prioritisation for liver transplantation in the UK: a population-based modelling study.

BACKGROUND: Following the introduction of an algorithm aiming to maximise life-years gained from liver transplantation in the UK (the transplant benefit score [TBS]), donor livers were redirected from younger to older patients, mortality rate equalised across the age range and short-term waiting list mortality reduced. Understanding age-related prioritisation has been challenging, especially for younger patients and clinicians allocating non-TBS-directed livers. We aimed to assess age-related prioritisation within the TBS algorithm by modelling liver transplantation prioritisation based on data from a UK transplant unit and comparing these data with other regions. METHODS: In this population-based modelling study, serum parameters and age at liver transplantation assessment of patients attending the Scottish Liver Transplant Unit, Edinburgh, UK, between December, 2002, and November, 2023, were combined with representative synthetic data to model TBS survival predictions, which were compared according to age group (25-49 years vs ≥60 years), chronic liver disease severity, and disease cause. Models for end-stage liver disease (UKELD [UK], MELD [Eurotransplant region], and MELD 3.0 [USA]) were used as validated comparators of liver disease severity. FINDINGS: Of 2093 patients with chronic liver disease, 1808 (86%) had complete datasets and liver disease parameters consistent with eligibility for the liver transplant waiting list in the UK (UKELD ≥49). Disease severity as assessed by UKELD, MELD, and MELD 3.0 did not differ by age (median UKELD scores of 56 for patients aged ≥60 years vs 56 for patients aged 25-49 years; MELD scores of 16 vs 16; and MELD 3.0 scores of 18 vs 18). TBS increased with advancing age (R=0·45, p<0·0001). TBS predicted that transplantation in patients aged 60 years or older would provide a two-fold greater net benefit at 5 years than in patients aged 25-49 years (median TBS 1317 [IQR 1116-1436] in older patients vs 706 [411-1095] in younger patients; p<0·0001). Older patients were predicted to have shorter survival without transplantation than younger patients (263 days [IQR 144-473] in older patients vs 861 days [448-1164] in younger patients; p<0·0001) but similar survival after transplantation (1599 days [1563-1628] vs 1573 days [1525-1614]; p<0·0001). Older patients could reach a TBS for which a liver offer was likely below minimum criteria for transplantation (UKELD <49), whereas many younger patients were required to have high-urgent disease (UKELD >60). US and Eurotransplant programmes did not prioritise according to age. INTERPRETATION: The UK liver allocation algorithm prioritises older patients for transplantation by predicting that advancing age increases the benefit from liver transplantation. Restricted follow-up and biases in waiting list data might limit the accuracy of these benefit predictions. Measures beyond overall waiting list mortality are required to fully capture the benefits of liver transplantation. FUNDING: None.

Barriers and Facilitators to Collecting Surgical Outcome Data in Low- and Middle-Income Countries: An International Survey.

Background: Perioperative data are essential to improve the safety of surgical care. However, surgical outcome research (SOR) from low- and middle-income countries (LMICs) is disproportionately sparse. We aimed to assess practices, barriers, facilitators, and perceptions influencing the collection and use of surgical outcome data (SOD) in LMICs. Methods: An internet-based survey was developed and disseminated to stakeholders involved in the care of surgical patients in LMICs. The Performance of Routine Information Systems Management framework was used to explore the frequency and relative importance of organizational, technical, and behavioral barriers. Associations were determined using χ 2 and ANOVA analyses. Results: Final analysis included 229 surgeons, anesthesia providers, nurses, and administrators from 36 separate LMICs. A total of 58.1% of individuals reported that their institution had experience with collection of SOD and 73% of these reported a positive impact on patient care. Mentorship and research training was available in <50% of respondent's institutions; however, those who had these were more likely to publish SOD (P = 0.02). Sixteen barriers met the threshold for significance of which the top 3 were the burden of clinical responsibility, research costs, and accuracy of medical documentation. The most frequently proposed solutions were the availability of an electronic data collection platform (95.3%), dedicated research personnel (93.2%), and access to research training (93.2%). Conclusions: There are several barriers and facilitators to collection of SOD that are common across LMICs. Most of these can be addressed through targeted interventions and are highlighted in this study. We provide a path towards advancing SOR in LMICs.

Post-acute COVID-19 neuropsychiatric symptoms are not associated with ongoing nervous system injury.

A proportion of patients infected with severe acute respiratory syndrome coronavirus 2 experience a range of neuropsychiatric symptoms months after infection, including cognitive deficits, depression and anxiety. The mechanisms underpinning such symptoms remain elusive. Recent research has demonstrated that nervous system injury can occur during COVID-19. Whether ongoing neural injury in the months after COVID-19 accounts for the ongoing or emergent neuropsychiatric symptoms is unclear. Within a large prospective cohort study of adult survivors who were hospitalized for severe acute respiratory syndrome coronavirus 2 infection, we analysed plasma markers of nervous system injury and astrocytic activation, measured 6 months post-infection: neurofilament light, glial fibrillary acidic protein and total tau protein. We assessed whether these markers were associated with the severity of the acute COVID-19 illness and with post-acute neuropsychiatric symptoms (as measured by the Patient Health Questionnaire for depression, the General Anxiety Disorder assessment for anxiety, the Montreal Cognitive Assessment for objective cognitive deficit and the cognitive items of the Patient Symptom Questionnaire for subjective cognitive deficit) at 6 months and 1 year post-hospital discharge from COVID-19. No robust associations were found between markers of nervous system injury and severity of acute COVID-19 (except for an association of small effect size between duration of admission and neurofilament light) nor with post-acute neuropsychiatric symptoms. These results suggest that ongoing neuropsychiatric symptoms are not due to ongoing neural injury.

Long-term impact of COVID-19 hospitalisation among individuals with pre-existing airway diseases in the UK: a multicentre, longitudinal cohort study - PHOSP-COVID.

Background: The long-term outcomes of COVID-19 hospitalisation in individuals with pre-existing airway diseases are unknown. Methods: Adult participants hospitalised for confirmed or clinically suspected COVID-19 and discharged between 5 March 2020 and 31 March 2021 were recruited to the Post-hospitalisation COVID-19 (PHOSP-COVID) study. Participants attended research visits at 5 months and 1 year post discharge. Clinical characteristics, perceived recovery, burden of symptoms and health-related quality of life (HRQoL) of individuals with pre-existing airway disease (i.e., asthma, COPD or bronchiectasis) were compared to the non-airways group. Results: A total of 615 out of 2697 (22.8%) participants had a history of pre-existing airway diseases (72.0% diagnosed with asthma, 22.9% COPD and 5.1% bronchiectasis). At 1 year, the airways group participants were less likely to feel fully recovered (20.4% versus 33.2%, p<0.001), had higher burden of anxiety (29.1% versus 22.0%, p=0.002), depression (31.2% versus 24.7%, p=0.006), higher percentage of impaired mobility using short physical performance battery ≤10 (57.4% versus 45.2%, p<0.001) and 27% had a new disability (assessed by the Washington Group Short Set on Functioning) versus 16.6%, p=0.014. HRQoL assessed using EQ-5D-5L Utility Index was lower in the airways group (mean±SD 0.64±0.27 versus 0.73±0.25, p<0.001). Burden of breathlessness, fatigue and cough measured using a study-specific tool was higher in the airways group. Conclusion: Individuals with pre-existing airway diseases hospitalised due to COVID-19 were less likely to feel fully recovered, had lower physiological performance measurements, more burden of symptoms and reduced HRQoL up to 1 year post-hospital discharge.

Cognitive and psychiatric symptom trajectories 2-3 years after hospital admission for COVID-19: a longitudinal, prospective cohort study in the UK.

BACKGROUND: COVID-19 is known to be associated with increased risks of cognitive and psychiatric outcomes after the acute phase of disease. We aimed to assess whether these symptoms can emerge or persist more than 1 year after hospitalisation for COVID-19, to identify which early aspects of COVID-19 illness predict longer-term symptoms, and to establish how these symptoms relate to occupational functioning. METHODS: The Post-hospitalisation COVID-19 study (PHOSP-COVID) is a prospective, longitudinal cohort study of adults (aged ≥18 years) who were hospitalised with a clinical diagnosis of COVID-19 at participating National Health Service hospitals across the UK. In the C-Fog study, a subset of PHOSP-COVID participants who consented to be recontacted for other research were invited to complete a computerised cognitive assessment and clinical scales between 2 years and 3 years after hospital admission. Participants completed eight cognitive tasks, covering eight cognitive domains, from the Cognitron battery, in addition to the 9-item Patient Health Questionnaire for depression, the Generalised Anxiety Disorder 7-item scale, the Functional Assessment of Chronic Illness Therapy Fatigue Scale, and the 20-item Cognitive Change Index (CCI-20) questionnaire to assess subjective cognitive decline. We evaluated how the absolute risks of symptoms evolved between follow-ups at 6 months, 12 months, and 2-3 years, and whether symptoms at 2-3 years were predicted by earlier aspects of COVID-19 illness. Participants completed an occupation change questionnaire to establish whether their occupation or working status had changed and, if so, why. We assessed which symptoms at 2-3 years were associated with occupation change. People with lived experience were involved in the study. FINDINGS: 2469 PHOSP-COVID participants were invited to participate in the C-Fog study, and 475 participants (191 [40·2%] females and 284 [59·8%] males; mean age 58·26 [SD 11·13] years) who were discharged from one of 83 hospitals provided data at the 2-3-year follow-up. Participants had worse cognitive scores than would be expected on the basis of their sociodemographic characteristics across all cognitive domains tested (average score 0·71 SD below the mean [IQR 0·16-1·04]; p<0·0001). Most participants reported at least mild depression (263 [74·5%] of 353), anxiety (189 [53·5%] of 353), fatigue (220 [62·3%] of 353), or subjective cognitive decline (184 [52·1%] of 353), and more than a fifth reported severe depression (79 [22·4%] of 353), fatigue (87 [24·6%] of 353), or subjective cognitive decline (88 [24·9%] of 353). Depression, anxiety, and fatigue were worse at 2-3 years than at 6 months or 12 months, with evidence of both worsening of existing symptoms and emergence of new symptoms. Symptoms at 2-3 years were not predicted by the severity of acute COVID-19 illness, but were strongly predicted by the degree of recovery at 6 months (explaining 35·0-48·8% of the variance in anxiety, depression, fatigue, and subjective cognitive decline); by a biocognitive profile linking acutely raised D-dimer relative to C-reactive protein with subjective cognitive deficits at 6 months (explaining 7·0-17·2% of the variance in anxiety, depression, fatigue, and subjective cognitive decline); and by anxiety, depression, fatigue, and subjective cognitive deficit at 6 months. Objective cognitive deficits at 2-3 years were not predicted by any of the factors tested, except for cognitive deficits at 6 months, explaining 10·6% of their variance. 95 of 353 participants (26·9% [95% CI 22·6-31·8]) reported occupational change, with poor health being the most common reason for this change. Occupation change was strongly and specifically associated with objective cognitive deficits (odds ratio [OR] 1·51 [95% CI 1·04-2·22] for every SD decrease in overall cognitive score) and subjective cognitive decline (OR 1·54 [1·21-1·98] for every point increase in CCI-20). INTERPRETATION: Psychiatric and cognitive symptoms appear to increase over the first 2-3 years post-hospitalisation due to both worsening of symptoms already present at 6 months and emergence of new symptoms. New symptoms occur mostly in people with other symptoms already present at 6 months. Early identification and management of symptoms might therefore be an effective strategy to prevent later onset of a complex syndrome. Occupation change is common and associated mainly with objective and subjective cognitive deficits. Interventions to promote cognitive recovery or to prevent cognitive decline are therefore needed to limit the functional and economic impacts of COVID-19. FUNDING: National Institute for Health and Care Research Oxford Health Biomedical Research Centre, Wolfson Foundation, MQ Mental Health Research, MRC-UK Research and Innovation, and National Institute for Health and Care Research.