A Randomized Trial of Enteral Glutamine for Treatment of Burn Injuries.

BACKGROUND: Glutamine is thought to have beneficial effects on the metabolic and stress response to severe injury. Clinical trials involving patients with burns and other critically ill patients have shown conflicting results regarding the benefits and risks of glutamine supplementation. METHODS: In a double-blind, randomized, placebo-controlled trial, we assigned patients with deep second- or third-degree burns (affecting ≥10% to ≥20% of total body-surface area, depending on age) within 72 hours after hospital admission to receive 0.5 g per kilogram of body weight per day of enterally delivered glutamine or placebo. Trial agents were given every 4 hours through a feeding tube or three or four times a day by mouth until 7 days after the last skin grafting procedure, discharge from the acute care unit, or 3 months after admission, whichever came first. The primary outcome was the time to discharge alive from the hospital, with data censored at 90 days. We calculated subdistribution hazard ratios for discharge alive, which took into account death as a competing risk. RESULTS: A total of 1209 patients with severe burns (mean burn size, 33% of total body-surface area) underwent randomization, and 1200 were included in the analysis (596 patients in the glutamine group and 604 in the placebo group). The median time to discharge alive from the hospital was 40 days (interquartile range, 24 to 87) in the glutamine group and 38 days (interquartile range, 22 to 75) in the placebo group (subdistribution hazard ratio for discharge alive, 0.91; 95% confidence interval [CI], 0.80 to 1.04; P = 0.17). Mortality at 6 months was 17.2% in the glutamine group and 16.2% in the placebo group (hazard ratio for death, 1.06; 95% CI, 0.80 to 1.41). No substantial between-group differences in serious adverse events were observed. CONCLUSIONS: In patients with severe burns, supplemental glutamine did not reduce the time to discharge alive from the hospital. (Funded by the U.S. Department of Defense and the Canadian Institutes of Health Research; RE-ENERGIZE ClinicalTrials.gov number, NCT00985205.).

The effect of higher protein dosing in critically ill patients with high nutritional risk (EFFORT Protein): an international, multicentre, pragmatic, registry-based randomised trial.

BACKGROUND: On the basis of low-quality evidence, international critical care nutrition guidelines recommend a wide range of protein doses. The effect of delivering high-dose protein during critical illness is unknown. We aimed to test the hypothesis that a higher dose of protein provided to critically ill patients would improve their clinical outcomes. METHODS: This international, investigator-initiated, pragmatic, registry-based, single-blinded, randomised trial was undertaken in 85 intensive care units (ICUs) across 16 countries. We enrolled nutritionally high-risk adults (≥18 years) undergoing mechanical ventilation to compare prescribing high-dose protein (≥2·2 g/kg per day) with usual dose protein (≤1·2 g/kg per day) started within 96 h of ICU admission and continued for up to 28 days or death or transition to oral feeding. Participants were randomly allocated (1:1) to high-dose protein or usual dose protein, stratified by site. As site personnel were involved in both prescribing and delivering protein dose, it was not possible to blind clinicians, but patients were not made aware of the treatment assignment. The primary efficacy outcome was time-to-discharge-alive from hospital up to 60 days after ICU admission and the secondary outcome was 60-day morality. Patients were analysed in the group to which they were randomly assigned regardless of study compliance, although patients who dropped out of the study before receiving the study intervention were excluded. This study is registered with ClinicalTrials.gov, NCT03160547. FINDINGS: Between Jan 17, 2018, and Dec 3, 2021, 1329 patients were randomised and 1301 (97·9%) were included in the analysis (645 in the high-dose protein group and 656 in usual dose group). By 60 days after randomisation, the cumulative incidence of alive hospital discharge was 46·1% (95 CI 42·0%-50·1%) in the high-dose compared with 50·2% (46·0%-54·3%) in the usual dose protein group (hazard ratio 0·91, 95% CI 0·77-1·07; p=0·27). The 60-day mortality rate was 34·6% (222 of 642) in the high dose protein group compared with 32·1% (208 of 648) in the usual dose protein group (relative risk 1·08, 95% CI 0·92-1·26). There appeared to be a subgroup effect with higher protein provision being particularly harmful in patients with acute kidney injury and higher organ failure scores at baseline. INTERPRETATION: Delivery of higher doses of protein to mechanically ventilated critically ill patients did not improve the time-to-discharge-alive from hospital and might have worsened outcomes for patients with acute kidney injury and high organ failure scores. FUNDING: None.

Event rates and incidence of post-COVID-19 condition in hospitalised SARS-CoV-2 positive children and young people and controls across different pandemic waves: exposure-stratified prospective cohort study in Moscow (StopCOVID).

BACKGROUND: Long-term health outcomes in children and young people (CYP) after COVID-19 infection are not well understood and studies with control groups exposed to other infections are lacking. This study aimed to investigate the incidence of post-COVID-19 condition (PCC) and incomplete recovery in CYP after hospital discharge and compare outcomes between different SARS-CoV-2 variants and non-SARS-CoV-2 infections. METHODS: A prospective exposure-stratified cohort study of individuals under 18 years old in Moscow, Russia. Exposed cohorts were paediatric patients admitted with laboratory-confirmed COVID-19 infection between April 2 and December 11, 2020 (Wuhan variant cohort) and between January 12 and February 19, 2022 (Omicron variant cohort). CYP admitted with respiratory and intestinal infections, but negative lateral flow rapid diagnostic test and PCR-test results for SARS-CoV-2, between January 12 and February 19, 2022, served as unexposed reference cohort. Comparison between the 'exposed cohorts' and 'reference cohort' was conducted using 1:1 matching by age and sex. Follow-up data were collected via telephone interviews with parents, utilising the long COVID paediatric protocol and survey developed by the International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC). The WHO case definition was used to categorise PCC. RESULTS: Of 2595 CYP with confirmed COVID-19, 1707 (65.7%) participated in follow-up interviews, with 1183/1707 (69%) included in the final 'matched' analysis. The median follow-up time post-discharge was 6.7 months. The incidence of PCC was significantly higher in the Wuhan variant cohort (89.7 cases per 1000 person-months, 95% CI 64.3-120.3) compared to post-infection sequalae in the reference cohort (12.2 cases per 1000 person-months, 95% CI 4.9-21.9), whereas the difference with the Omicron variant cohort and reference cohort was not significant. The Wuhan cohort had higher incidence rates of dermatological, fatigue, gastrointestinal, sensory, and sleep manifestations, as well as behavioural and emotional problems than the reference cohort. The only significant difference between Omicron variant cohort and reference cohort was decreased school attendance. When comparing the Wuhan and Omicron variant cohorts, higher incidence of PCC and event rates of fatigue, decreased physical activity, and deterioration of relationships was observed. The rate of incomplete recovery was also significantly higher in the Wuhan variant cohort than in both the reference and the Omicron variant cohorts. CONCLUSIONS: Wuhan variant exhibited a propensity for inducing a broad spectrum of physical symptoms and emotional behavioural changes, suggesting a pronounced impact on long-term health outcomes. Conversely, the Omicron variant resulted in fewer post-infection effects no different from common seasonal viral illnesses. This may mean that the Omicron variant and subsequent variants might not lead to the same level of long-term health consequences as earlier variants.

A Comparison of High and Usual Protein Dosing in Critically Ill Patients With Obesity: A Post Hoc Analysis of an International, Pragmatic, Single-Blinded, Randomized Clinical Trial.

OBJECTIVES: Across guidelines, protein dosing for critically ill patients with obesity varies considerably. The objective of this analysis was to evaluate whether this population would benefit from higher doses of protein. DESIGN: A post hoc subgroup analysis of the effect of higher protein dosing in critically ill patients with high nutritional risk (EFFORT Protein): an international, multicenter, pragmatic, registry-based randomized trial. SETTING: Eighty-five adult ICUs across 16 countries. PATIENTS: Patients with obesity defined as a body mass index (BMI) greater than or equal to 30 kg/m 2 ( n = 425). INTERVENTIONS: In the primary study, patients were randomized into a high-dose (≥ 2.2 g/kg/d) or usual-dose protein group (≤ 1.2 g/kg/d). MEASUREMENTS AND MAIN RESULTS: Protein intake was monitored for up to 28 days, and outcomes (time to discharge alive [TTDA], 60-d mortality, days of mechanical ventilation [MV], hospital, and ICU length of stay [LOS]) were recorded until 60 days post-randomization. Of the 1301 patients in the primary study, 425 had a BMI greater than or equal to 30 kg/m 2 . After adjusting for sites and covariates, we observed a nonsignificant slower rate of TTDA with higher protein that ruled out a clinically important benefit (hazard ratio, 0.78; 95% CI, 0.58-1.05; p = 0.10). We found no evidence of difference in TTDA between protein groups when subgroups with different classes of obesity or patients with and without various nutritional and frailty risk variables were examined, even after the removal of patients with baseline acute kidney injury. Overall, 60-day mortality rates were 31.5% and 28.2% in the high protein and usual protein groups, respectively (risk difference, 3.3%; 95% CI, -5.4 to 12.1; p = 0.46). Duration of MV and LOS in hospital and ICU were not significantly different between groups. CONCLUSIONS: In critically ill patients with obesity, higher protein doses did not improve clinical outcomes, including those with higher nutritional and frailty risk.

Engineering the cellulolytic bacterium, Clostridium thermocellum, to co-utilize hemicellulose.

Consolidated bioprocessing (CBP) of lignocellulosic biomass holds promise to realize economic production of second-generation biofuels/chemicals, and Clostridium thermocellum is a leading candidate for CBP due to it being one of the fastest degraders of crystalline cellulose and lignocellulosic biomass. However, CBP by C. thermocellum is approached with co-cultures, because C. thermocellum does not utilize hemicellulose. When compared with a single-species fermentation, the co-culture system introduces unnecessary process complexity that may compromise process robustness. In this study, we engineered C. thermocellum to co-utilize hemicellulose without the need for co-culture. By evolving our previously engineered xylose-utilizing strain in xylose, an evolved clonal isolate (KJC19-9) was obtained and showed improved specific growth rate on xylose by ∼3-fold and displayed comparable growth to a minimally engineered strain grown on the bacteria's naturally preferred substrate, cellobiose. To enable full xylan deconstruction to xylose, we recombinantly expressed three different ß-xylosidase enzymes originating from Thermoanaerobacterium saccharolyticum into KJC19-9 and demonstrated growth on xylan with one of the enzymes. This recombinant strain was capable of co-utilizing cellulose and xylan simultaneously, and we integrated the ß-xylosidase gene into the KJC19-9 genome, creating the KJCBXint strain. The strain, KJC19-9, consumed monomeric xylose but accumulated xylobiose when grown on pretreated corn stover, whereas the final KJCBXint strain showed significantly greater deconstruction of xylan and xylobiose. This is the first reported C. thermocellum strain capable of degrading and assimilating hemicellulose polysaccharide while retaining its cellulolytic capabilities, unlocking significant potential for CBP in advancing the bioeconomy.

One-year survival of patients admitted for sepsis to intensive care units in Colombia.

BACKGROUND: Sepsis is a frequent cause of admission to intensive care units (ICUs). High mortality rates are estimated globally, and in our country, few studies have reported one-year survival. The objective of this study is to determine one-year survival in patients with sepsis admitted to the ICU in Colombia, compared with the survival of patients admitted for other conditions. METHODS: Retrospective cohort study using administrative databases from the Ministry of Health of Colombia. One-year survival and the adjusted hazard ratio for survival, adjusted for comorbidities included in the Charlson Index, were determined using a Cox proportional hazards model for patients admitted for other causes as well as for those admitted for sepsis. This was then compared with an inverse propensity score weighting model. RESULTS: A total of 116.407 patients were initially admitted to the ICUs, with 12.056 (10.36%) diagnosed with sepsis. Within the first year, 4.428 (36.73%) patients died due to sepsis. Age and male gender were associated with an increased risk of death from sepsis, and the covariates associated with one-year mortality were as follows: age over 80 years with HR 9.91 (95% CI: 9.22-10.65), renal disease with HR 3.16 (95% CI: 3.03-3.29), primary tumoral disease with HR 2.07 (95% CI: 1.92-2.23), liver disease with HR 2.27 (95% CI: 2.07-2.50), and metastatic solid tumor with HR 2.03 (95% CI: 1.92-2.15). CONCLUSION: This study revealed a high one-year sepsis mortality rate in the population, associated with variables such as age over 80 years, the presence of renal disease, liver disease, connective tissue diseases, and cancer. Men exhibited higher mortality compared to women.

Adherence to key recommendations for design and analysis of stepped-wedge cluster randomized trials: A review of trials published 2016-2022.

BACKGROUND/AIMS: The stepped-wedge cluster randomized trial (SW-CRT), in which clusters are randomized to a time at which they will transition to the intervention condition - rather than a trial arm - is a relatively new design. SW-CRTs have additional design and analytical considerations compared to conventional parallel arm trials. To inform future methodological development, including guidance for trialists and the selection of parameters for statistical simulation studies, we conducted a review of recently published SW-CRTs. Specific objectives were to describe (1) the types of designs used in practice, (2) adherence to key requirements for statistical analysis, and (3) practices around covariate adjustment. We also examined changes in adherence over time and by journal impact factor. METHODS: We used electronic searches to identify primary reports of SW-CRTs published 2016-2022. Two reviewers extracted information from each trial report and its protocol, if available, and resolved disagreements through discussion. RESULTS: We identified 160 eligible trials, randomizing a median (Q1-Q3) of 11 (8-18) clusters to 5 (4-7) sequences. The majority (122, 76%) were cross-sectional (almost all with continuous recruitment), 23 (14%) were closed cohorts and 15 (9%) open cohorts. Many trials had complex design features such as multiple or multivariate primary outcomes (50, 31%) or time-dependent repeated measures (27, 22%). The most common type of primary outcome was binary (51%); continuous outcomes were less common (26%). The most frequently used method of analysis was a generalized linear mixed model (112, 70%); generalized estimating equations were used less frequently (12, 8%). Among 142 trials with fewer than 40 clusters, only 9 (6%) reported using methods appropriate for a small number of clusters. Statistical analyses clearly adjusted for time effects in 119 (74%), for within-cluster correlations in 132 (83%), and for distinct between-period correlations in 13 (8%). Covariates were included in the primary analysis of the primary outcome in 82 (51%) and were most often individual-level covariates; however, clear and complete pre-specification of covariates was uncommon. Adherence to some key methodological requirements (adjusting for time effects, accounting for within-period correlation) was higher among trials published in higher versus lower impact factor journals. Substantial improvements over time were not observed although a slight improvement was observed in the proportion accounting for a distinct between-period correlation. CONCLUSIONS: Future methods development should prioritize methods for SW-CRTs with binary or time-to-event outcomes, small numbers of clusters, continuous recruitment designs, multivariate outcomes, or time-dependent repeated measures. Trialists, journal editors, and peer reviewers should be aware that SW-CRTs have additional methodological requirements over parallel arm designs including the need to account for period effects as well as complex intracluster correlations.

Performance of risk scores in predicting mortality at 3, 6, and 12 months in patients diagnosed with community-acquired pneumonia.

BACKGROUND: Risk scores (RS) evaluate the likelihood of short-term mortality in patients diagnosed with community-acquired pneumonia (CAP). However, there is a scarcity of evidence to determine the risk of long-term mortality. This article aims to compare the effectiveness of 16 scores in predicting mortality at three, six, and twelve months in adult patients with CAP. METHODS: A retrospective cohort study on individuals diagnosed with CAP was conducted across two hospitals in Colombia. Receiver Operating Characteristic (ROC) curves were constructed at 3, 6, and 12 months to assess the predictive ability of death for the following scoring systems: CURB-65, CRB-65, SCAP, CORB, ADROP, NEWS, Pneumonia Shock, REA-ICU, PSI, SMART-COP, SMRT-CO, SOAR, qSOFA, SIRS, CAPSI, and Charlson Comorbidity Index (CCI). RESULTS: A total of 3688 patients were included in the final analysis. Mortality at 3, 6, and 12 months was 5.2%, 8.3%, and 16.3% respectively. At 3 months, PSI, CCI, and CRB-65 scores showed ROC curves of 0.74 (95% CI: 0.71-0.77), 0.71 (95% CI: 0.67-0.74), and 0.70 (95% CI: 0.66-0.74). At 6 months, PSI and CCI scores showed performances of 0.74 (95% CI: 0.72-0.77) and 0.72 (95% CI: 0.69-0.74), respectively. Finally at 12 months, all evaluated scores showed poor discriminatory capacity, including PSI, which decreased from acceptable to poor with an ROC curve of 0.64 (95% CI: 0.61-0.66). CONCLUSION: When predicting mortality in patients with CAP, at 3 months, PSI, CCI, and CRB-65 showed acceptable predictive performances. At 6 months, only PSI and CCI maintained acceptable levels of accuracy. For the 12-month period, all evaluated scores exhibited very limited discriminatory ability, ranging from poor to almost negligible.

Complications of the Superior Eyelid Endoscopic Transorbital Approach to the Skull Base: Preliminary Experience With Specific Focus on Orbital Outcome.

BACKGROUND: The endoscopic superior eyelid approach is a relatively novel mini-invasive technique that is currently investigating for skull base cancers. However, questions remain regarding specific approach-related complications when treating different skull base tumors. This study aims to analyze any surgical complications that occurred in our preliminary consecutive experience, with specific focus on orbital outcome. METHODS: A retrospective and consecutive cohort of patients treated via a superior eyelid endoscopic transorbital approach at the Division of Neurosurgery of the Hospital Clinic in Barcelona was analyzed. Patients features were described in detail. Complications were divided into 2 groups to analyze separately the approach-related complications, and those resulting from tumor removal. The ocular complications were subdivided into early ocular status (<3 weeks), late ocular status (3-8 weeks), and persistent ocular complications. The "Park questionnaire" was used to determine patient's satisfaction related to the transorbital approach. RESULTS: A total of 20 patients (5 spheno-orbital meningiomas, 1 intradiploic Meningioma, 2 intraconal lesions, 1 temporal pole lesion, 2 trigeminal schwannoma, 3 cavernous sinus lesions, and 6 petroclival lesions) were included in the period 2017-2022. Regarding early ocular status, upper eyelid edema was detected in all cases (100%) associated with diplopia in the lateral gaze in 30% of cases, and periorbital edema in 15% of cases. These aspects tend to resolve at late ocular follow-up (3-8 weeks) in most cases. Regarding persistent ocular complications, in one case of intraconal lesion, a limitation of eye abduction was detected (5%). In another patient with intraconal lesion, an ocular neuropathic pain was reported (5%). In 2 cases of petroclival menigioma, who were also treated with a ventriculo-peritoneal shunt, slight enophthalmus was observed as a persistent complication (10%). According to the Park questionnaire, no cosmetic complaints, no head pain, no palpable cranial irregularities, and no limited mouth opening were reported, and an average of 89% of general satisfaction was encountered. CONCLUSIONS: The superior eyelid endoscopic transorbital approach is a safe and satisfactory technique for a diversity of skull base tumors. At late follow-up, upper eyelid edema, diplopia, and periorbital edema tend to resolve. Persistent ocular complications are more frequent after treating intraconal lesions. Enophthalmus may occur in patients with associated ventriculo-peritoneal shunt. According to patient's satisfaction, fairly acceptable results are attained.

PaCO2 Association with Outcomes of Patients with Traumatic Brain Injury at High Altitude: A Prospective Single-Center Cohort Study.

BACKGROUND: Partial pressure of carbon dioxide (PaCO2) is generally known to influence outcome in patients with traumatic brain injury (TBI) at normal altitudes. Less is known about specific relationships of PaCO2 levels and clinical outcomes at high altitudes. METHODS: This is a prospective single-center cohort of consecutive patients with TBI admitted to a trauma center located at 2600 m above sea level. An unfavorable outcome was defined as a Glasgow Outcome Scale-Extended (GOSE) score < 4 at the 6-month follow-up. RESULTS: We had a total of 81 patients with complete data, 80% (65/81) were men, and the median (interquartile range) age was 36 (25-50) years. Median Glasgow Coma Scale (GCS) score on admission was 9 (6-14); 49% (40/81) of patients had severe TBI (GCS 3-8), 32% (26/81) had moderate TBI (GCS 12-9), and 18% (15/81) had mild TBI (GCS 13-15). The median (interquartile range) Abbreviated Injury Score of the head (AISh) was 3 (2-4). The frequency of an unfavorable outcome (GOSE < 4) was 30% (25/81), the median GOSE was 4 (2-5), and the median 6-month mortality rate was 24% (20/81). Comparison between patients with favorable and unfavorable outcomes revealed that those with unfavorable outcome were older, (median age 49 [30-72] vs. 29 [22-41] years, P < 0.01), had lower admission GCS scores (6 [4-8] vs. 13 [8-15], P < 0.01), had higher AISh scores (4 [4-4] vs. 3 [2-4], P < 0.01), had higher Acute Physiology and Chronic Health disease Classification System II scores (17 [15-23] vs. 10 [6-14], P < 0.01), had higher Charlson scores (0 [0-2] vs. 0 [0-0], P < 0.01), and had higher PaCO2 levels (mean 35 ± 8 vs. 32 ± 6 mm Hg, P < 0.01). In a multivariate analysis, age (odds ratio [OR] 1.14, 95% confidence interval [CI] 1.1-1.30, P < 0.01), AISh (OR 4.7, 95% CI 1.55-21.0, P < 0.05), and PaCO2 levels (OR 1.23, 95% CI 1.10-1.53, P < 0.05) were significantly associated with the unfavorable outcomes. When applying the same analysis to the subgroup on mechanical ventilation, AISh (OR 5.4, 95% CI 1.61-28.5, P = 0.017) and PaCO2 levels (OR 1.36, 95% CI 1.13-1.78, P = 0.015) remained significantly associated with the unfavorable outcome. CONCLUSIONS: Higher PaCO2 levels are associated with an unfavorable outcome in ventilated patients with TBI. These results underscore the importance of PaCO2 levels in patients with TBI and whether it should be adjusted for populations living at higher altitudes.

The Efficacy of Glutamine Supplementation in Severe Adult Burn Patients: A Systematic Review With Trial Sequential Meta-Analysis.

OBJECTIVES: Evidence supporting glutamine supplementation in severe adult burn patients has created a state of uncertainty due to the variability in the treatment effect reported across small and large randomized controlled trials (RCTs). We aimed to systematically review the effect of glutamine supplementation on mortality in severe adult burn patients. DATA SOURCES: MEDLINE, Embase, CINAHL, and Cochrane Central were searched from inception to February 10, 2023. STUDY SELECTION: RCTs evaluating the effect of enteral or IV glutamine supplementation alone in severe adult burn patients were included. DATA EXTRACTION: Two reviewers independently extracted data on study characteristics, burn injury characteristics, description of the intervention between groups, adverse events, and clinical outcomes. DATA SYNTHESIS: Random effects meta-analyses were performed to estimate the pooled risk ratio (RR). Trial sequential analyses (TSA) for mortality and infectious complications were performed. Ten RCTs (1,577 patients) were included. We observed no significant effect of glutamine supplementation on overall mortality (RR, 0.65, 95% CI, 0.33-1.28; p = 0.21), infectious complications (RR, 0.83; 95% CI, 0.63-1.09; p = 0.18), or other secondary outcomes. In subgroup analyses, we observed no significant effects based on administration route or burn severity. We did observe a significant subgroup effect between single and multicenter RCTs in which glutamine significantly reduced mortality and infectious complications in singe-center RCTs but not in multicenter RCTs. However, TSA showed that the pooled results of single-center RCTs were type 1 errors and further trials would be futile. CONCLUSIONS: Glutamine supplementation, regardless of administration, does not appear to improve clinical outcomes in severely adult burned patients.

Effectiveness of prolonged versus standard-course of oseltamivir in critically ill patients with severe influenza infection: A multicentre cohort study.

The aim of this study is to investigate the effectiveness of prolonged versus standard course oseltamivir treatment among critically ill patients with severe influenza. A retrospective study of a prospectively collected database including adults with influenza infection admitted to 184 intensive care units (ICUs) in Spain from 2009 to 2018. Prolonged oseltamivir was defined if patients received the treatment beyond 5 days, whereas the standard-course group received oseltamivir for 5 days. The primary outcome was all-cause ICU mortality. Propensity score matching (PSM) was constructed, and the outcome was investigated through Cox regression and RCSs. Two thousand three hundred and ninety-seven subjects were included, of whom 1943 (81.1%) received prolonged oseltamivir and 454 (18.9%) received standard treatment. An optimal full matching algorithm was performed by matching 2171 patients, 1750 treated in the prolonged oseltamivir group and 421 controls in the standard oseltamivir group. After PSM, 387 (22.1%) patients in the prolonged oseltamivir and 119 (28.3%) patients in the standard group died (p = 0.009). After adjusting confounding factors, prolonged oseltamivir significantly reduced ICU mortality (odds ratio [OR]: 0.53, 95% confidence interval [CI]: 0.40-0.69). Prolonged oseltamivir may have protective effects on survival at Day 10 compared with a standard treatment course. Sensitivity analysis confirmed these findings. Compared with standard treatment, prolonged oseltamivir was associated with reduced ICU mortality in critically ill patients with severe influenza. Clinicians should consider extending the oseltamivir treatment duration to 10 days, particularly in higher-risk groups of prolonged viral shedding. Further randomized controlled trials are warranted to confirm these findings.

Comparison of systemic inflammatory profiles in COVID-19 and community-acquired pneumonia patients: a prospective cohort study.

BACKGROUND: Inflammatory responses contribute to tissue damage in COVID-19 and community-acquired pneumonia (CAP). Although predictive values of different inflammatory biomarkers have been reported in both, similarities and differences of inflammatory profiles between these conditions remain uncertain. Therefore, we aimed to determine the similarities and differences of the inflammatory profiles between COVID-19 and CAP, and their association with clinical outcomes. METHODS: We report a prospective observational cohort study; conducted in a reference hospital in Latin America. Patients with confirmed COVID-19 pneumonia and CAP were included. Multiplex (Luminex) cytokine assays were used to measure the plasma concentration of 14 cytokines at hospital admission. After comparing similarities and differences in the inflammatory profile between COVID-19 and CAP patients, an unsupervised classification method (i.e., hierarchical clustering) was used to identify subpopulations within COVID-19 and CAP patients. RESULTS: A total of 160 patients were included, 62.5% were diagnosed with COVID-19 (100/160), and 37.5% with CAP (60/160). Using the hierarchical clustering, COVID-19 and CAP patients were divided based on its inflammatory profile: pauci, moderate, and hyper-inflammatory immune response. COVID-19 hyper-inflammatory subpopulation had the highest mortality. COVID-19 hyper-inflammatory subpopulation, compared to pauci-inflammatory, had higher levels of IL-10 (median [IQR] 61.4 [42.0-109.4] vs 13.0 [5.0-24.9], P: < 0.001), IL-6 (48.1 [22.3-82.6] vs 9.1 [0.1-30.4], P: < 0.001), among others. Hyper-inflammatory vs pauci-inflammatory CAP patients were characterized by elevation of IFN2 (48.8 [29.7-110.5] vs 3.0 [1.7-10.3], P: < 0.001), TNFα (36.3 [24.8-53.4] vs 13.1 [11.3-16.9], P: < 0.001), among others. Hyper-inflammatory subpopulations in COVID-19 and CAP compared to the corresponding pauci-inflammatory subpopulations had higher MCP-1. CONCLUSIONS: Our data highlights three distinct subpopulations in COVID-19 and CAP, with differences in inflammatory marker profiles and risks of adverse clinical outcomes. TRIAL REGISTRATION: This is a prospective study, therefore no health care intervention were applied to participants and trial registration is not applicable.

Major adverse cardiovascular events are associated with necroptosis during severe COVID-19.

BACKGROUND: The mechanisms used by SARS-CoV-2 to induce major adverse cardiac events (MACE) are unknown. Thus, we aimed to determine if SARS-CoV-2 can induce necrotic cell death to promote MACE in patients with severe COVID-19. METHODS: This observational prospective cohort study includes experiments with hamsters and human samples from patients with severe COVID-19. Cytokines and serum biomarkers were analysed in human serum. Cardiac transcriptome analyses were performed in hamsters' hearts. RESULTS: From a cohort of 70 patients, MACE was documented in 26% (18/70). Those who developed MACE had higher Log copies/mL of SARS-CoV-2, troponin-I, and pro-BNP in serum. Also, the elevation of IP-10 and a major decrease in levels of IL-17ɑ, IL-6, and IL-1rɑ were observed. No differences were found in the ability of serum antibodies to neutralise viral spike proteins in pseudoviruses from variants of concern. In hamster models, we found a stark increase in viral titters in the hearts 4 days post-infection. The cardiac transcriptome evaluation resulted in the differential expression of ~ 9% of the total transcripts. Analysis of transcriptional changes in the effectors of necroptosis (mixed lineage kinase domain-like, MLKL) and pyroptosis (gasdermin D) showed necroptosis, but not pyroptosis, to be elevated. An active form of MLKL (phosphorylated MLKL, pMLKL) was elevated in hamster hearts and, most importantly, in the serum of MACE patients. CONCLUSION: SARS-CoV-2 identification in the systemic circulation is associated with MACE and necroptosis activity. The increased pMLKL and Troponin-I indicated the occurrence of necroptosis in the heart and suggested necroptosis effectors could serve as biomarkers and/or therapeutic targets. Trial registration Not applicable.

Impact of macrolide treatment on long-term mortality in patients admitted to the ICU due to CAP: a targeted maximum likelihood estimation and survival analysis.

INTRODUCTION: Patients with community-acquired pneumonia (CAP) admitted to the intensive care unit (ICU) have high mortality rates during the acute infection and up to ten years thereafter. Recommendations from international CAP guidelines include macrolide-based treatment. However, there is no data on the long-term outcomes of this recommendation. Therefore, we aimed to determine the impact of macrolide-based therapy on long-term mortality in this population. METHODS: Registered patients in the MIMIC-IV database 16 years or older and admitted to the ICU due to CAP were included. Multivariate analysis, targeted maximum likelihood estimation (TMLE) to simulate a randomised controlled trial, and survival analyses were conducted to test the effect of macrolide-based treatment on mortality six-month (6 m) and twelve-month (12 m) after hospital admission. A sensitivity analysis was performed excluding patients with Pseudomonas aeruginosa or MRSA pneumonia to control for Healthcare-Associated Pneumonia (HCAP). RESULTS: 3775 patients were included, and 1154 were treated with a macrolide-based treatment. The non-macrolide-based group had worse long-term clinical outcomes, represented by 6 m [31.5 (363/1154) vs 39.5 (1035/2621), p < 0.001] and 12 m mortality [39.0 (450/1154) vs 45.7 (1198/2621), p < 0.001]. The main risk factors associated with long-term mortality were Charlson comorbidity index, SAPS II, septic shock, and respiratory failure. Macrolide-based treatment reduced the risk of dying at 6 m [HR (95% CI) 0.69 (0.60, 0.78), p < 0.001] and 12 m [0.72 (0.64, 0.81), p < 0.001]. After TMLE, the protective effect continued with an additive effect estimate of - 0.069. CONCLUSION: Macrolide-based treatment reduced the hazard risk of long-term mortality by almost one-third. This effect remains after simulating an RCT with TMLE and the sensitivity analysis for the HCAP classification.

The impact of higher protein dosing on outcomes in critically ill patients with acute kidney injury: a post hoc analysis of the EFFORT protein trial.

BACKGROUND: Based on low-quality evidence, current nutrition guidelines recommend the delivery of high-dose protein in critically ill patients. The EFFORT Protein trial showed that higher protein dose is not associated with improved outcomes, whereas the effects in critically ill patients who developed acute kidney injury (AKI) need further evaluation. The overall aim is to evaluate the effects of high-dose protein in critically ill patients who developed different stages of AKI. METHODS: In this post hoc analysis of the EFFORT Protein trial, we investigated the effect of high versus usual protein dose (≥ 2.2 vs. ≤ 1.2 g/kg body weight/day) on time-to-discharge alive from the hospital (TTDA) and 60-day mortality and in different subgroups in critically ill patients with AKI as defined by the Kidney Disease Improving Global Outcomes (KDIGO) criteria within 7 days of ICU admission. The associations of protein dose with incidence and duration of kidney replacement therapy (KRT) were also investigated. RESULTS: Of the 1329 randomized patients, 312 developed AKI and were included in this analysis (163 in the high and 149 in the usual protein dose group). High protein was associated with a slower time-to-discharge alive from the hospital (TTDA) (hazard ratio 0.5, 95% CI 0.4-0.8) and higher 60-day mortality (relative risk 1.4 (95% CI 1.1-1.8). Effect modification was not statistically significant for any subgroup, and no subgroups suggested a beneficial effect of higher protein, although the harmful effect of higher protein target appeared to disappear in patients who received kidney replacement therapy (KRT). Protein dose was not significantly associated with the incidence of AKI and KRT or duration of KRT. CONCLUSIONS: In critically ill patients with AKI, high protein may be associated with worse outcomes in all AKI stages. Recommendation of higher protein dosing in AKI patients should be carefully re-evaluated to avoid potential harmful effects especially in patients who were not treated with KRT. TRIAL REGISTRATION: This study is registered at ClinicalTrials.gov (NCT03160547) on May 17th 2017.

Anti-hepatitis B virus activity of food nutrients and potential mechanisms of action.

Hepatitis B virus (HBV) is endemic in many parts of the world and is a significant cause of chronic liver damage and hepatocellular carcinoma. HBV therapeutics vary according to the disease stage. The best therapeutic option for patients with end-stage liver disease is liver transplantation, while for chronic patients, HBV infection is commonly managed using antivirals (nucleos(t)ides analogs or interferons). However, due to the accessibility issues and the high cost of antivirals, most HBV patients do not have access to treatment. These complications have led researchers to reconsider treatment approaches, such as nutritional therapy. This review summarizes the nutrients reported to have antiviral activity against HBV and their possible mechanism of action. Recent studies suggest resveratrol, vitamin E, lactoferrin, selenium, curcumin, luteolin-7-O-glucoside, moringa extracts, chlorogenic acid, and epigallocatechin-3-gallate may be beneficial for patients with hepatitis B. The anti-HBV effect of most of these nutrients has been analyzed in vitro and in animal models. Different antiviral and hepatoprotective mechanisms have been proposed for these nutrients, such as the activation of antioxidant and anti-inflammatory pathways, regulation of metabolic homeostasis, epigenetic control, activation of the p53 gene, inhibition of oncogenes, inhibition of virus entry, and induction of autophagosomes. In conclusion, scientific evidence indicates that HBV replication, transcription, and expression of viral antigens can be affected directly by nutrients. In the future, these nutrients may be considered to develop appropriate nutritional management for patients with hepatitis B.

Medications and traffic accidents involving older drivers: do Spanish primary healthcare physicians know enough?

BACKGROUND: Our aim was to evaluate Spanish family doctors' knowledge about medications that increase the risk of traffic accidents involving older drivers, and to obtain data about the involvement of family doctors in accident prevention activities and the associations between these factors and their demographic and workplace characteristics. METHODS: A cross-sectional study of 1888 family doctors throughout Spain was carried out from 2016 to 2018. Participants completed a previously validated self-administered questionnaire that explored whether family doctors distinguished between medications associated with a high or low risk of involvement in a traffic accident, investigated the appropriateness of advice given to older patients, and physicians' involvement in preventive activities. Multiple regression models were used to estimate the adjusted association of these variables with each other and with characteristics of family doctors in the sample. RESULTS: On a scale of 1 (never or hardly ever) to 4 (always), the indexes constructed to evaluate how often family doctors believed they should oversee the use of high-risk and low-risk medications yielded values of 3.38 for the former and 2.61 for the latter (p < 0.001). Only 24% responded correctly to all three items that inquired about the appropriateness of the advice they gave to older patients. On a scale of 1 to 4, the frequency at which family doctors gave older patients advice about preventive measures was 2.85, and only 43% reported allocating time during appointments to provide this advice. These latter two variables were directly associated with appropriate values for the index used to evaluate physicians' oversight of medications associated with a high risk. The perception of risk associated with medications and involvement in preventive activities were both greater among female participants. CONCLUSIONS: Family doctors correctly identified medications according to their risk of playing a role in traffic accidents, although the recommendations they gave to their patients were not always appropriate. These findings, along with physicians' infrequent involvement in preventive activities, suggest a need to improve family doctors' competencies and increase the resources available to them so that they can provide their older patients with advice on ways to prevent involvement in traffic accidents.

Long-term (180-Day) Outcomes in Critically Ill Patients With COVID-19 in the REMAP-CAP Randomized Clinical Trial.

Importance: The longer-term effects of therapies for the treatment of critically ill patients with COVID-19 are unknown. Objective: To determine the effect of multiple interventions for critically ill adults with COVID-19 on longer-term outcomes. Design, Setting, and Participants: Prespecified secondary analysis of an ongoing adaptive platform trial (REMAP-CAP) testing interventions within multiple therapeutic domains in which 4869 critically ill adult patients with COVID-19 were enrolled between March 9, 2020, and June 22, 2021, from 197 sites in 14 countries. The final 180-day follow-up was completed on March 2, 2022. Interventions: Patients were randomized to receive 1 or more interventions within 6 treatment domains: immune modulators (n = 2274), convalescent plasma (n = 2011), antiplatelet therapy (n = 1557), anticoagulation (n = 1033), antivirals (n = 726), and corticosteroids (n = 401). Main Outcomes and Measures: The main outcome was survival through day 180, analyzed using a bayesian piecewise exponential model. A hazard ratio (HR) less than 1 represented improved survival (superiority), while an HR greater than 1 represented worsened survival (harm); futility was represented by a relative improvement less than 20% in outcome, shown by an HR greater than 0.83. Results: Among 4869 randomized patients (mean age, 59.3 years; 1537 [32.1%] women), 4107 (84.3%) had known vital status and 2590 (63.1%) were alive at day 180. IL-6 receptor antagonists had a greater than 99.9% probability of improving 6-month survival (adjusted HR, 0.74 [95% credible interval {CrI}, 0.61-0.90]) and antiplatelet agents had a 95% probability of improving 6-month survival (adjusted HR, 0.85 [95% CrI, 0.71-1.03]) compared with the control, while the probability of trial-defined statistical futility (HR >0.83) was high for therapeutic anticoagulation (99.9%; HR, 1.13 [95% CrI, 0.93-1.42]), convalescent plasma (99.2%; HR, 0.99 [95% CrI, 0.86-1.14]), and lopinavir-ritonavir (96.6%; HR, 1.06 [95% CrI, 0.82-1.38]) and the probabilities of harm from hydroxychloroquine (96.9%; HR, 1.51 [95% CrI, 0.98-2.29]) and the combination of lopinavir-ritonavir and hydroxychloroquine (96.8%; HR, 1.61 [95% CrI, 0.97-2.67]) were high. The corticosteroid domain was stopped early prior to reaching a predefined statistical trigger; there was a 57.1% to 61.6% probability of improving 6-month survival across varying hydrocortisone dosing strategies. Conclusions and Relevance: Among critically ill patients with COVID-19 randomized to receive 1 or more therapeutic interventions, treatment with an IL-6 receptor antagonist had a greater than 99.9% probability of improved 180-day mortality compared with patients randomized to the control, and treatment with an antiplatelet had a 95.0% probability of improved 180-day mortality compared with patients randomized to the control. Overall, when considered with previously reported short-term results, the findings indicate that initial in-hospital treatment effects were consistent for most therapies through 6 months.

Studying the post-COVID-19 condition: research challenges, strategies, and importance of Core Outcome Set development.

BACKGROUND: A substantial portion of people with COVID-19 subsequently experience lasting symptoms including fatigue, shortness of breath, and neurological complaints such as cognitive dysfunction many months after acute infection. Emerging evidence suggests that this condition, commonly referred to as long COVID but also known as post-acute sequelae of SARS-CoV-2 infection (PASC) or post-COVID-19 condition, could become a significant global health burden. MAIN TEXT: While the number of studies investigating the post-COVID-19 condition is increasing, there is no agreement on how this new disease should be defined and diagnosed in clinical practice and what relevant outcomes to measure. There is an urgent need to optimise and standardise outcome measures for this important patient group both for clinical services and for research and to allow comparing and pooling of data. CONCLUSIONS: A Core Outcome Set for post-COVID-19 condition should be developed in the shortest time frame possible, for improvement in data quality, harmonisation, and comparability between different geographical locations. We call for a global initiative, involving all relevant partners, including, but not limited to, healthcare professionals, researchers, methodologists, patients, and caregivers. We urge coordinated actions aiming to develop a Core Outcome Set (COS) for post-COVID-19 condition in both the adult and paediatric populations.