Search

Background: Evidence on the benefits of fiber-supplemented enteral nutrition (EN) in critically ill patients is inconsistent, and critical care nutrition guidelines lack recommendations based on high-quality evidence. This systematic review and meta-analysis (SRMA) aims to provide a current synthesis of the literature on this topic., Methods: For this SRMA of randomized controlled trials (RCT), electronic databases (MEDLINE, EMBASE, CENTRAL) were searched systematically from inception to January 2024 and updated in June 2024. Trials investigating clinical effects of fiber-supplemented EN versus placebo or usual care in adult critically ill patients were selected. Two independent reviewers extracted data and assessed the risk of bias of the included studies. Random-effect meta-analysis and trial sequential analysis (TSA) were conducted. The primary outcome was overall mortality, and one of the secondary outcomes was diarrhea incidence. Subgroup analyses were also performed for both outcomes., Results: Twenty studies with 1405 critically ill patients were included. In conventional meta-analysis, fiber-supplemented EN was associated with a significant reduction of overall mortality (RR 0.66, 95% CI 0.47, 0.92, p = 0.01, I 2  = 0%; 12 studies) and diarrhea incidence (RR 0.70, 95% CI 0.51, 0.96, p = 0.03, I 2  = 51%; 11 studies). However, both outcomes were assessed to have very serious risk of bias, and, according to TSA, a type-1 error cannot be ruled out. No subgroup differences were found for the primary outcome., Conclusion: Very low-certainty evidence suggests that fiber-supplemented EN has clinical benefits. High-quality multicenter RCTs with large sample sizes are needed to substantiate any firm recommendation for its routine use in this group of patients. PROSPERO registration number: CRD42023492829., (© 2024. The Author(s).)

Purpose: To evaluate the efficacy of the novel oXiris® membrane in critically ill adult patients., Methods: We systematically searched MEDLINE, EMBASE, and CENTRAL from inception to 01/06/2023 for relevant randomised controlled trials (RCTs) and non-randomised studies of intervention (NRSI). The primary outcome was overall mortality. Random effect meta-analyses were conducted in RevMan 5.4.1. Study quality was evaluated using Cochrane's risk of bias tool. (PROSPERO: CRD42023389198)., Results: Ten studies (2 RCTs and 8 NRSIs) with 481 patients were included. None had low risk of bias. Treatment using oXiris® was associated with reduced overall mortality (RR 0.78, 95%CI 0.62-0.98; p = 0.03; 6 NRSI). One RCT reported 28-day mortality, finding no significant difference between groups. Besides, pooled NRSIs results showed significant reductions in SOFA scores, norepinephrine dosage, and several inflammatory biomarkers (C-reactive protein [CRP], lactate, and interleukin-6 [IL-6]) post oXiris® treatment. However, other clinical outcomes (ICU and hospital length of stay, mechanical ventilation duration) were similar between groups., Conclusion: In critically ill patients, the use of oXiris® membrane was associated with reduced overall mortality, norepinephrine dosage, CRP, IL-6, lactate levels, along with improved organ function. However, the certainty of evidence was very low, necessitating high-quality RCTs to further evaluate its efficacy in this population., Competing Interests: Declaration of competing interest None., (Copyright © 2023. Published by Elsevier Inc.)

There has been increasing interest in the role of micronutrient supplementation in critical care. This narrative review summarizes the recent studies on micronutrients in critically ill patients. We searched two databases for primary randomized controlled trials that investigated the effects of micronutrient supplementation in patients with critical illness published from January 2021 to August 2023. Personal files, reference lists of included studies, and previous reviews were also screened. Twelve studies reported on vitamin C, four studies on vitamin D, three studies on thiamin, two studies on multivitamins, and one study on cobalamin. The therapeutic effects of vitamin C appear mixed, although vitamin C monotherapy appears more promising than vitamin C combination therapy. Intramuscular administration of vitamin D appeared to lower mortality, mechanical ventilation duration, and intensive care unit stay, whereas enteral administration showed limited clinical benefits. Intravenous thiamin was not associated with improved outcomes in patients with septic shock or hypophosphatemia. Preliminary evidence suggests reduced vasopressor dose with cobalamin. Decreased disease severity and hospital stay in patients with COVID-19 with vitamins A-E requires further investigation, whereas providing solely B-group vitamins did not demonstrate therapeutic effects. It is currently premature to endorse the provision of high-dose micronutrients in critical illness to improve clinical outcomes. This review may help to inform the design of future trials that will help better elucidate the optimal dosage and form of micronutrients, methods of administration, and subgroups of patients with critical illness who may most benefit., (© 2024 American Society for Parenteral and Enteral Nutrition.)

Purpose: Cardiac surgery, post-cardiotomy cardiogenic shock (PCCS), and temporary mechanical circulatory support (tMCS) provoke substantial inflammation. We therefore investigated whether a selenium-based, anti-inflammatory strategy would benefit PCCS patients treated with tMCS in a post-hoc analysis of the sustain CSX trial., Methods: Post-hoc analysis of patients receiving tMCS for PCCS in the Sustain CSX trial, which investigated the effects of high-dose selenium on postoperative organ dysfunction in cardiac surgery patients., Primary Outcome: duration of tMCS therapy., Secondary Outcomes: postoperative organ dysfunction and 30-day mortality., Results: Thirty-nine patients were treated with tMCS for PCCS. There was no difference in the median duration of tMCS between the selenium and the placebo group (3 days [IQR: 1-6] vs. 2 days [IQR: 1-7], p = 0.52). Median dialysis duration was longer in the selenium group (1.5 days [0-21.8] vs. 0 days [0-1.8], p = 0.048). There was no difference in 30-day mortality (53% vs. 41%, OR 1.44, 95% CI 0.32-6.47, p = 0.62)., Conclusion: In this explorative study, a perioperative high-dose selenium-supplementation did not show beneficial effects on organ dysfunctions and mortality rates in patients with PCCS receiving tMCS., Competing Interests: Declaration of competing interest S.O. received institutional research and study funds from Novartis Pharma GmbH and institutional research, study and educational grants, speaker fees, and advisory board fees from Abiomed outside this work. E. D. received speaker honoraria from Baxter outside this work. G.E. declares speaker honoraria from Baxter and Fresenius Kabi outside this work. B.O·B declares: British Heart Foundation for Tight K, The role of Potassium in AFACS prevention (Grant number CS/18/3/34063); National Institute for Health Research (NIHR) for Predicting AF after Cardiac Surgery - the PARADISE Scores: A Clinical Prediction Rule for AFACS (Grant number NIHR131227). All outside this work. All other authors declare no conflicts of interest., (Copyright © 2023. Published by Elsevier Inc.)

Background: Adolescent idiopathic scoliosis (AIS) corrective surgery may involve significant blood loss and blood transfusion requirements. Antifibrinolytic agents such as tranexamic acid (TXA) have been used to reduce blood loss, but its optimal dose is uncertain. The objective of this study is to determine the estimated blood loss and rate of blood transfusion between two groups of AIS patients receiving TXA as a single bolus versus bolus followed by infusion in scoliosis surgery., Methods: This was a retrospective analysis of a single bolus versus bolus followed by infusion of TXA in AIS surgery. AIS patients undergoing posterior spinal fusion (PSF) from December 2018 to September 2019 at a tertiary university hospital were identified. Inclusion criteria were patients aged between 10 and 21 years who received either a single bolus of 30 mg/kg TXA (Group A) or a single bolus of 30 mg/kg followed by continuous infusion of 10 mg/kg/h of TXA (Group B). Patient demographics, operative data, estimated blood loss, blood transfusion rate, and complications were recorded., Results: A total of 129 AIS patients were included. All operative surgeries were performed by two senior consultants. The mean age was 14.8 ± 3.4 years old, and 89.1% were female. The Cobb angle, number of fusion levels, number of screws, length of skin incision, and duration of surgery were comparable between the two groups. There was no difference in the total estimated blood loss between the two groups: 723.3 ± 279.4 mL (range: 175.0-1607.0 mL) in Group A and 819.4 ± 302.6 mL (range: 330.0-1556.0 mL) in Group B (p = 0.065). There were no complications, and none received blood transfusion., Conclusion: TXA when administered as a single bolus or bolus followed by infusion in AIS patients undergoing PSF surgery was associated with similar estimated total surgical blood loss and blood transfusion requirement., (© 2024. The Author(s).)

Background: Systematic reviews and data synthesis of randomised clinical trials play a crucial role in clinical practice, research, and health policy. Trial sequential analysis can be used in systematic reviews to control type I and type II errors, but methodological errors including lack of protocols and transparency are cause for concern. We assessed the reporting of trial sequential analysis., Methods: We searched Medline and the Cochrane Database of Systematic Reviews from 1 January 2018 to 31 December 2021 for systematic reviews and meta-analysis reports that include a trial sequential analysis. Only studies with at least two randomised clinical trials analysed in a forest plot and a trial sequential analysis were included. Two independent investigators assessed the studies. We evaluated protocolisation, reporting, and interpretation of the analyses, including their effect on any GRADE evaluation of imprecision., Results: We included 270 systematic reviews and 274 meta-analysis reports and extracted data from 624 trial sequential analyses. Only 134/270 (50%) systematic reviews planned the trial sequential analysis in the protocol. For analyses on dichotomous outcomes, the proportion of events in the control group was missing in 181/439 (41%), relative risk reduction in 105/439 (24%), alpha in 30/439 (7%), beta in 128/439 (29%), and heterogeneity in 232/439 (53%). For analyses on continuous outcomes, the minimally relevant difference was missing in 125/185 (68%), variance (or standard deviation) in 144/185 (78%), alpha in 23/185 (12%), beta in 63/185 (34%), and heterogeneity in 105/185 (57%). Graphical illustration of the trial sequential analysis was present in 93% of the analyses, however, the Z-curve was wrongly displayed in 135/624 (22%) and 227/624 (36%) did not include futility boundaries. The overall transparency of all 624 analyses was very poor in 236 (38%) and poor in 173 (28%)., Conclusions: The majority of trial sequential analyses are not transparent when preparing or presenting the required parameters, partly due to missing or poorly conducted protocols. This hampers interpretation, reproducibility, and validity., Study Registration: PROSPERO CRD42021273811., (© 2024. The Author(s).)

Membrane trafficking within the Golgi apparatus plays a pivotal role in the intracellular transportation of lipids and proteins. Dysregulation of this process can give rise to various pathological manifestations, including cancer. Exploiting Golgi defects, cancer cells capitalise on aberrant membrane trafficking to facilitate signal transduction, proliferation, invasion, immune modulation, angiogenesis, and metastasis. Despite the identification of several molecular signalling pathways associated with Golgi abnormalities, there remains a lack of approved drugs specifically targeting cancer cells through the manipulation of the Golgi apparatus. In the initial section of this comprehensive review, the focus is directed towards delineating the abnormal Golgi genes and proteins implicated in carcinogenesis. Subsequently, a thorough examination is conducted on the impact of these variations on Golgi function, encompassing aspects such as vesicular trafficking, glycosylation, autophagy, oxidative mechanisms, and pH alterations. Lastly, the review provides a current update on promising Golgi apparatus-targeted inhibitors undergoing preclinical and/or clinical trials, offering insights into their potential as therapeutic interventions. Significantly more effort is required to advance these potential inhibitors to benefit patients in clinical settings., Competing Interests: Declaration of competing interest The authors declare no competing financial interest and personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Aim: The cardiac surgery-related ischemia-reperfusion-related oxidative stress triggers the release of cytotoxic reactive oxygen and nitrogen species, contributing to organ failure and ultimately influencing patients' short- and long-term outcomes. Selenium is an essential co-factor for various antioxidant enzymes, thereby contributing to the patients' endogenous antioxidant and anti-inflammatory defense mechanisms. Given these selenium's pleiotropic functions, we investigated the effect of a high-dose selenium-based anti-inflammatory perioperative strategy on functional recovery after cardiac surgery., Materials and Methods: This prospective study constituted a nested sub-study of the SUSTAIN CSX trial, a double-blinded, randomized, placebo-controlled multicenter trial to investigate the impact of high-dose selenium supplementation on high-risk cardiac surgery patients' postoperative recovery. Functional recovery was assessed by 6-min walk distance, Short Form-36 (SF-36) and Barthel Index questionnaires., Key Findings: 174 patients were included in this sub-study. The mean age (SD) was 67.3 (8.9) years, and 78.7 % of the patients were male. The mean (SD) predicted 30-day mortality by the European System for Cardiac Operative Risk Evaluation II score was 12.6 % (9.4 %). There was no difference at hospital discharge and after three months in the 6-min walk distance between the selenium and placebo groups (131 m [IQR: not performed - 269] vs. 160 m [IQR: not performed - 252], p = 0.80 and 400 m [IQR: 299-461] vs. 375 m [IQR: 65-441], p = 0.48). The SF-36 and Barthel Index assessments also revealed no clinically meaningful differences between the selenium and placebo groups., Significance: A perioperative anti-inflammatory strategy with high-dose selenium supplementation did not improve functional recovery in high-risk cardiac surgery patients., Competing Interests: Declaration of competing interest Dr. Ott received institutional research and study funds from Novartis Pharma GmbH and institutional research, study and educational grants, speaker fees and advisory board fees from Abiomed. Dr. Stoppe reported grants and nonfinancial support from Biosyn Arzneimittel Gmbh and grants from Hecht Foundation during the conduct of the study and consultant fees from B. Braun, Baxter, and Fresenius Kabi and speaker fees from Biosyn Arzneimittel Gmbh outside the submitted work. Dr. Fremes was a site investigator of the SUSTAIN study and received fees for per-patient enrollment to their institution during the conduct of the study; received grants from Medtronic and Boston Scientific as a site co-investigator for SURTAVI and Low Risk trials and received fees for per-patient enrollment to their institution; received grants from Boston Scientific as a site co–principal investigator for the NeoAccurate IDE trial and received fees for per-patient enrollment to their institution; and received grants from the Canadian Institutes of Health Research as the nominated principal investigator of the ROMA trial outside the submitted work. Dr. Heyland reported nonfinancial support from Biosyn Arzneimittel Gmbh during the conduct of the study. No other disclosures were reported. Dr. O'Brien received research funding from the British Heart Foundation and the National Institute for Health Science Research and funding for work as a consultant for Teleflex. The other authors declare no conflicts of interest related to this manuscript., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Patient complaints are a perennial challenge faced by health care institutions globally, requiring extensive time and effort from health care workers. Despite these efforts, patient dissatisfaction remains high. Recent studies on the use of large language models (LLMs) such as the GPT models developed by OpenAI in the health care sector have shown great promise, with the ability to provide more detailed and empathetic responses as compared to physicians. LLMs could potentially be used in responding to patient complaints to improve patient satisfaction and complaint response time., Objective: This study aims to evaluate the performance of LLMs in addressing patient complaints received by a tertiary health care institution, with the goal of enhancing patient satisfaction., Methods: Anonymized patient complaint emails and associated responses from the patient relations department were obtained. ChatGPT-4.0 (OpenAI, Inc) was provided with the same complaint email and tasked to generate a response. The complaints and the respective responses were uploaded onto a web-based questionnaire. Respondents were asked to rate both responses on a 10-point Likert scale for 4 items: appropriateness, completeness, empathy, and satisfaction. Participants were also asked to choose a preferred response at the end of each scenario., Results: There was a total of 188 respondents, of which 115 (61.2%) were health care workers. A majority of the respondents, including both health care and non-health care workers, preferred replies from ChatGPT (n=164, 87.2% to n=183, 97.3%). GPT-4.0 responses were rated higher in all 4 assessed items with all median scores of 8 (IQR 7-9) compared to human responses (appropriateness 5, IQR 3-7; empathy 4, IQR 3-6; quality 5, IQR 3-6; satisfaction 5, IQR 3-6; P<.001) and had higher average word counts as compared to human responses (238 vs 76 words). Regression analyses showed that a higher word count was a statistically significant predictor of higher score in all 4 items, with every 1-word increment resulting in an increase in scores of between 0.015 and 0.019 (all P<.001). However, on subgroup analysis by authorship, this only held true for responses written by patient relations department staff and not those generated by ChatGPT which received consistently high scores irrespective of response length., Conclusions: This study provides significant evidence supporting the effectiveness of LLMs in resolution of patient complaints. ChatGPT demonstrated superiority in terms of response appropriateness, empathy, quality, and overall satisfaction when compared against actual human responses to patient complaints. Future research can be done to measure the degree of improvement that artificial intelligence generated responses can bring in terms of time savings, cost-effectiveness, patient satisfaction, and stress reduction for the health care system., (©Lorraine Pei Xian Yong, Joshua Yi Min Tung, Zi Yao Lee, Win Sen Kuan, Mui Teng Chua. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 09.08.2024.)

Aim: Despite the superiority of regional citrate anticoagulation (RCA) in continuous renal replacement therapy (CRRT), its application is limited in resource-limited settings. We aim to explore the cost and safety of RCA for CRRT in critically ill patients, compared to usual care., Methods: This prospective observational study included patients requiring CRRT in a tertiary intensive care unit (ICU) from February 2022 to January 2023. They were classified to either the RCA or usual care groups based on the anticoagulation technique chosen by the treating physician, considering contraindications. The CRRT prescription follows the institutional protocol. All relevant data were obtained from the ICU CRRT-RCA charts and electronic medical records. A cost analysis was performed., Results: A total of 54 patients (27 per group) were included, with no demographic differences. Sequential Organ Failure Assessment score and lactate levels were significantly higher in the usual care group. The number of filters used were comparable (p = .108). The median filter duration in the RCA group was numerically longer (35.00 [15.50-56.00] vs. 23.00 [17.00-29.00] h), but not statistically significant (p = .253). The duration of mechanical ventilation, vasopressor requirement, and mortality were similar, but the RCA group had a significantly longer ICU stay. The rate of adverse events was similar, with four severe metabolic alkalosis cases in the RCA group. The RCA group had higher total cost per patient per day (USD 611 vs. 408; p = .013)., Conclusion: In this resource-limited setting, RCA for CRRT appeared safe and had clinically longer filter lifespan compared with usual care, albeit the increased cost., (© 2024 Asian Pacific Society of Nephrology.)

Background: There is controversy over the optimal early protein delivery in critically ill patients with acute kidney injury (AKI). This study aims to evaluate whether the association between early protein delivery and 28-day mortality was impacted by the presence of AKI in critically ill patients., Methods: This is a post hoc analysis of data from a multicenter cluster-randomised controlled trial enrolling newly admitted critically ill patients (n = 2772). Participants without chronic kidney disease and with complete data concerning baseline renal function were included in this study. The primary outcome was 28-day mortality. Cox proportional hazards models were used to analyze the association between early protein delivery, reflected by mean protein delivery from day 3-5 after enrollment, 28-day mortality and whether baseline AKI stages interacted with this association., Results: Overall, 2552 patients were included, among whom 567 (22.2%) had AKI at enrollment (111 stage I, 87 stage II, 369 stage III). Mean early protein delivery was 0.60 ± 0.38 g/kg/day among the study patients. In the overall study cohort, each 0.1 g/kg/day increase in protein delivery was associated with a 5% reduction in 28-day mortality[hazard ratio (HR) = 0.95; 95% confidence interval (CI) 0.92-0.98, p  < 0.001]. The association between early protein delivery and 28-day mortality significantly interacted with baseline AKI stages (adjusted interaction p  = 0.028). Each 0.1 g/kg/day increase in early protein delivery was associated with a 4% reduction in 28-day mortality (HR = 0.96; 95%CI 0.92-0.99, p  = 0.011) among patients without AKI and 9% (HR = 0.91; 95%CI 0.84-0.99, p  = 0.021) among those with AKI stage III. However, such associations cannot be observed among patients with AKI stages I and II., Conclusions: Increased early protein delivery (up to close to the guideline recommendation) was associated with reduced 28-day mortality in critically ill patients without AKI and with AKI stage III, but not in those with AKI stage I or II., Competing Interests: ARHvZ reports receiving honoraria for advisory board meetings, lectures and research, and travel expenses from Abbott, AOP Pharma, Baxter, Cardinal Health, Danone-Nutricia, DIM3, Fresenius Kabi, GE Healthcare, InBody, Mermaid, Nestle, PAION, Rousselot and Lyric. LK reports grants from Nutricia Pharmaceutical (Wuxi) Co., Ltd China, and personal fees from SciClone Pharmaceuticals. The remaining authors declare no conflict of interest., (© The Author(s) 2024. Published by Oxford University Press.)

The generation of lung epithelial cells through the directed differentiation of human pluripotent stem cells (hPSCs) in vitro provides a platform to model both embryonic lung development and adult airway disease. Here, we describe a robust differentiation protocol that closely recapitulates human embryonic lung development. Differentiating cells progress through obligate intermediate stages, beginning with definitive endoderm formation and then patterning into anterior foregut endoderm that yields lung progenitors (LPs) with extended culture. These LPs can be purified using the cell surface marker CD166 (also known as ALCAM), and further matured into proximal airway epithelial cells including basal cells, secretory cells and multiciliated cells using either an organoid platform or culture at the air-liquid interface (ALI). We additionally demonstrate that these hPSC-derived airway epithelial cells can be used to model Influenza A infection. Collectively, our results underscore the utility of CD166 expression for the efficient enrichment of LPs from heterogenous differentiation cultures and the ability of these isolated cells to mature into more specialized, physiologically relevant proximal lung cell types., Competing Interests: Competing interests The authors declare no competing or financial interests., (© 2024. Published by The Company of Biologists Ltd.)

Background: Preexisting malnutrition in critically ill patients is associated with adverse clinical outcomes. Malnutrition can be diagnosed with the Global Leadership Initiative on Malnutrition using parameters such as weight loss, muscle wasting, and BMI. International critical care nutrition guidelines recommend high protein treatment to improve clinical outcomes in critically ill patients diagnosed with preexisting malnutrition. However, this recommendation is based on expert opinion., Research Question: In critically ill patients, what is the association between preexisting malnutrition and time to discharge alive (TTDA), and does high protein treatment modify this association?, Study Design and Methods: This multicenter randomized controlled trial involving 16 countries was designed to investigate the effects of high vs usual protein treatment in 1,301 critically ill patients. The primary outcome was TTDA. Multivariable regression was used to identify if preexisting malnutrition was associated with TTDA and if protein delivery modified their association., Results: The prevalence of preexisting malnutrition was 43.8%, and the cumulative incidence of live hospital discharge by day 60 was 41.2% vs 52.9% in the groups with and without preexisting malnutrition, respectively. The average protein delivery in the high vs usual treatment groups was 1.6 g/kg per day vs 0.9 g/kg per day. Preexisting malnutrition was independently associated with slower TTDA (adjusted hazard ratio, 0.81; 95% CI, 0.67-0.98). However, high protein treatment in patients with and without preexisting malnutrition was not associated with TTDA (adjusted hazard ratios of 0.84 [95% CI, 0.63-1.11] and 0.97 [95% CI, 0.77-1.21]). Furthermore, no effect modification was observed (ratio of adjusted hazard ratio, 0.84; 95% CI, 0.58-1.20)., Interpretation: Malnutrition was associated with slower TTDA, but high protein treatment did not modify the association. These findings challenge current international critical care nutrition guidelines., Clinical Trial Registration: ClinicalTrials.gov; No.: NCT03160547; URL: www., Clinicaltrials: gov., Competing Interests: Financial/Nonfinancial Disclosures The authors have reported to CHEST the following: D. B. received funding from Baxter Healthcare (advisory board and speaker fees), Avanos (advisor board fees), and Cardinal Health (speaker fees). None declared (C. C. H. L., Z.-Y. L., A. G. D., X. J., G. L. J., P. Y. N., L. T., A. P., D. K. H., C. C.)., (Copyright © 2024 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

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., Competing Interests: Dr. Bear received funding from Baxter Healthcare (advisory board and speaker fees), Avanos (advisor board fees), and Cardinal Health (speaker fees). Dr. León received funding from B Braun Sharing Expertise. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Background: The PRECISe trial is a pragmatic, multicenter randomized controlled trial that evaluates the effect of high versus standard enteral protein provision on functional recovery in adult, mechanically ventilated critically ill patients. The current protocol presents the rationale and analysis plan for an evaluation of the primary and secondary outcomes under the Bayesian framework, with an emphasis on clinically important effect sizes., Methods: This protocol was drafted in agreement with the ROBUST-statement, and is submitted for publication before database lock and primary data analysis. The primary outcome is health-related quality of life as measured by the EQ-5D-5L health utility score and is longitudinally assessed. Secondary outcomes comprise the 6-min walking test and handgrip strength over the entire follow-up period (longitudinal analyses), and 60-day mortality, duration of mechanical ventilation, and EQ-5D-5L health utility scores at 30, 90 and 180 days (cross-sectional). All analyses will primarily be performed under weakly informative priors. When available, informative priors elicited from contemporary literature will also be incorporated under alternative scenarios. In all other cases, objectively formulated skeptical and enthusiastic priors will be defined to assess the robustness of our results. Relevant identified subgroups were: patients with acute kidney injury, severe multi-organ failure and patients with or without sepsis. Results will be presented as absolute risk differences, mean differences, and odds ratios, with accompanying 95% credible intervals. Posterior probabilities will be estimated for clinically important benefit and harm., Discussion: The proposed secondary, pre-planned Bayesian analysis of the PRECISe trial will provide additional information on the effects of high protein on functional and clinical outcomes in critically ill patients, such as probabilistic interpretation, probabilities of clinically important effect sizes, and the integration of prior evidence. As such, it will complement the interpretation of the primary outcome as well as several secondary and subgroup analyses., Competing Interests: Declaration of competing interest MvdP received travel and speaker fees from Nutricia and research funding from Nestle Health Science and Fresenius-Kabi, not related to this research. EDW received research grants, travel and speakers fees from the Belgian Government Health, KCE (Belgian Health Care), Baxter Healthcare, Fresenius, Nestlé and Art Medical., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background and Aims: Exclusive enteral nutrition (EN) is often observed during the first week of ICU admission because of the extra costs and safety considerations for early parenteral nutrition. This study aimed to assess the association between nutrition intake and 28-day mortality in critically ill patients receiving exclusive EN., Methods: This is a post hoc analysis of a cluster-randomized clinical trial that assesses the effect of implementing a feeding protocol on mortality in critically ill patients. Patients who stayed in the ICUs for at least 7 days and received exclusive EN were included in this analysis. Multivariable Cox hazard regression models and restricted cubic spline models were used to assess the relationship between the different doses of EN delivery and 28-day mortality. Subgroups with varying lactate levels at enrollment were additionally analyzed to address the potential confounding effect brought in by the presence of shock-related hypoperfusion., Results: Overall, 1322 patients were included in the analysis. The median (interquartile range) daily energy and protein delivery during the first week of enrollment were 14.6 (10.3-19.6) kcal/kg and 0.6 (0.4-0.8) g/kg, respectively. An increase of 5 kcal/kg energy delivery was associated with a significant reduction (approximately 14%) in 28-day mortality (adjusted hazard ratio [HR] = 0.865, 95% confidence interval [CI]: 0.768-0.974, P = 0.016). For protein intake, a 0.2 g/kg increase was associated with a similar mortality reduction with an adjusted HR of 0.868 (95% CI 0.770-0.979). However, the benefits associated with enhanced nutrition delivery could be observed in patients with lactate concentration ≤ 2 mmol/L (adjusted HR = 0.804 (95% CI 0.674-0.960) for energy delivery and adjusted HR = 0.804 (95% CI 0.672-0.962) for protein delivery, respectively), but not in those > 2 mmol/L., Conclusions: During the first week of critical illness, enhanced nutrition delivery is associated with reduced mortality in critically ill patients receiving exclusive EN, only for those with lactate concentration ≤ 2 mmol/L., Trial Registration: ISRCTN12233792, registered on November 24, 2017., (© 2024. The Author(s).)

Background: A recent large multicentre trial found no difference in clinical outcomes but identified a possibility of increased mortality rates in patients with acute kidney injury (AKI) receiving higher protein. These alarming findings highlighted the urgent need to conduct an updated systematic review and meta-analysis to inform clinical practice., Methods: From personal files, citation searching, and three databases searched up to 29-5-2023, we included randomized controlled trials (RCTs) of adult critically ill patients that compared higher vs lower protein delivery with similar energy delivery between groups and reported clinical and/or patient-centred outcomes. We conducted random-effect meta-analyses and subsequently trial sequential analyses (TSA) to control for type-1 and type-2 errors. The main subgroup analysis investigated studies with and without combined early physical rehabilitation intervention. A subgroup analysis of AKI vs no/not known AKI was also conducted., Results: Twenty-three RCTs (n = 3303) with protein delivery of 1.49 ± 0.48 vs 0.92 ± 0.30 g/kg/d were included. Higher protein delivery was not associated with overall mortality (risk ratio [RR]: 0.99, 95% confidence interval [CI] 0.88-1.11; I 2  = 0%; 21 studies; low certainty) and other clinical outcomes. In 2 small studies, higher protein combined with early physical rehabilitation showed a trend towards improved self-reported quality-of-life physical function measurements at day-90 (standardized mean difference 0.40, 95% CI - 0.04 to 0.84; I 2  = 30%). In the AKI subgroup, higher protein delivery significantly increased mortality (RR 1.42, 95% CI 1.11-1.82; I 2  = 0%; 3 studies; confirmed by TSA with high certainty, and the number needed to harm is 7). Higher protein delivery also significantly increased serum urea (mean difference 2.31 mmol/L, 95% CI 1.64-2.97; I 2  = 0%; 7 studies)., Conclusion: Higher, compared with lower protein delivery, does not appear to affect clinical outcomes in general critically ill patients but may increase mortality rates in patients with AKI. Further investigation of the combined early physical rehabilitation intervention in non-AKI patients is warranted., Prospero Id: CRD42023441059., (© 2024. The Author(s).)

Purpose: This study aimed to compare cognitive, non-cognitive, and overall learning outcomes for sepsis and trauma resuscitation skills in novices with virtual patient simulation (VPS) versus in-person simulation (IPS)., Methods: A randomized controlled trial was conducted on junior doctors in 1 emergency department from January to December 2022, comparing 70 minutes of VPS (n=19) versus IPS (n=21) in sepsis and trauma resuscitation. Using the nominal group technique, we created skills assessment checklists and determined Bloom’s taxonomy domains for each checklist item. Two blinded raters observed participants leading 1 sepsis and 1 trauma resuscitation simulation. Satisfaction was measured using the Student Satisfaction with Learning Scale (SSLS). The SSLS and checklist scores were analyzed using the Wilcoxon rank sum test and 2-tailed t-test respectively., Results: For sepsis, there was no significant difference between VPS and IPS in overall scores (2.0; 95% confidence interval [CI], -1.4 to 5.4; Cohen’s d=0.38), as well as in items that were cognitive (1.1; 95% CI, -1.5 to 3.7) and not only cognitive (0.9; 95% CI, -0.4 to 2.2). Likewise, for trauma, there was no significant difference in overall scores (-0.9; 95% CI, -4.1 to 2.3; Cohen’s d=0.19), as well as in items that were cognitive (-0.3; 95% CI, -2.8 to 2.1) and not only cognitive (-0.6; 95% CI, -2.4 to 1.3). The median SSLS scores were lower with VPS than with IPS (-3.0; 95% CI, -1.0 to -5.0)., Conclusion: For novices, there were no major differences in overall and non-cognitive learning outcomes for sepsis and trauma resuscitation between VPS and IPS. Learners were more satisfied with IPS than with VPS (clinicaltrials.gov identifier: NCT05201950).

Background: Mutations in the TP53 gene are the most common among genetic alterations in human cancers, resulting in the formation of mutant p53 protein (mutp53). Mutp53 promotes proliferation, migration, invasion, and metastasis in cancer cells. Not only does the initiation of oncogenesis ensue due to mutp53, but resistance towards chemotherapy and radiotherapy in cancer cells also occurs. This review aims to summarise and discuss the oncogenesis of mutant p53 in cancer cells and introduce the various mutant p53 inhibitors currently being evaluated at the pre-clinical and clinical stages. Compounds that induce the wild-type conformation on the targeted p53 missense mutation, restore or enhance the DNA binding of mutant p53, and inhibit cancer cells' growth are highlighted. In addition, the progression and development of the mutant p53 inhibitors in clinical trials are updated., Conclusion: The progress of developing a cancer treatment that may successfully and efficiently target mutant p53 is on the verge of development. Mutant p53 proteins not only initiate oncogenesis but also cause resistance in cancer cells to certain chemo or radiotherapies, further endorse cancer cell survival and promote migration as well as metastasis of cancerous cells. With this regard, many mutant p53 inhibitors have been developed, some of which are currently being evaluated at the pre-clinical level and have been identified and discussed. To date, APR-246 is the most prominent one that has progressed to the Phase III clinical trial., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Background: Recent data from the randomized SUSTAIN CSX trial could not confirm clinical benefits from perioperative selenium treatment in high-risk cardiac surgery patients. Underlying reasons may involve inadequate biosynthesis of glutathione peroxidase (GPx3), which is a key mediator of selenium's antioxidant effects. This secondary analysis aimed to identify patients with an increase in GPx3 activity following selenium treatment. We hypothesize that these responders might benefit from perioperative selenium treatment., Methods: Patients were selected based on the availability of selenium biomarker information. Four subgroups were defined according to the patient's baseline status, including those with normal kidney function, reduced kidney function, selenium deficiency, and submaximal GPx3 activity., Results: Two hundred and forty-four patients were included in this analysis. Overall, higher serum concentrations of selenium, selenoprotein P (SELENOP) and GPx3 were correlated with less organ injury. GPx3 activity at baseline was predictive of 6-month survival (AUC 0.73; p = 0.03). While selenium treatment elevated serum selenium and SELENOP concentrations but not GPx3 activity in the full patient cohort, subgroup analyses revealed that GPx3 activity increased in patients with reduced kidney function, selenium deficiency and low to moderate GPx3 activity. Clinical outcomes did not vary between selenium treatment and placebo in any of these subgroups, though the study was not powered to conclusively detect differences in outcomes., Conclusions: The identification of GPx3 responders encourages further refined investigations into the treatment effects of selenium in high-risk cardiac surgery patients., (© 2023. The Author(s).)

This study aimed to investigate the feasibility of ultrasound (US)-guidance in reducing adverse event (AE) rates when using Angioseal device during antegrade lower limb angioplasty via common femoral artery access. From December 2016 to November 2022, 1,322 patients were identified, including 1,131 (85.6%) patients who underwent US-guided closure and 191 (14.4%) who underwent non-US-guided closure. Moderate AEs were encountered in 10 (5.2%) patients in the non-US-guided closure group compared to 38 (3.4%) patients in the US-guided closure group (P = .208). Severe AEs were encountered in 4 (2.1%) patients in the non-US-guided closure group compared to 3 (0.3%) patients in the US-guided closure group (P = .010). Overall AEs occurred in 14 (7.3%) patients in the non-US-guided closure group compared to 41 (3.6%) patients in the US-guided closure group (P = .029). Binary logistic regression showed that only non-US guidance was an independent risk factor for the occurrence of severe AEs (P = .008)., (Copyright © 2023. Published by Elsevier Inc.)

Background: CONCISE is an internationally agreed minimum set of outcomes for use in nutritional and metabolic clinical research in critically ill adults. Clinicians and researchers need to be aware of the clinimetric properties of these instruments and understand any limitations to ensure valid and reliable research. This systematic review and meta-analysis were undertaken to evaluate the clinimetric properties of the measurement instruments identified in CONCISE., Methods: Four electronic databases were searched from inception to December 2022 (MEDLINE via Ovid, EMBASE via Ovid, CINAHL via Healthcare Databases Advanced Search, CENTRAL via Cochrane). Studies were included if they examined at least one clinimetric property of a CONCISE measurement instrument or recognised variation in adults ≥ 18 years with critical illness or recovering from critical illness in any language. The COnsensus-based Standards for the selection of health Measurement INstruments (COSMIN) checklist for systematic reviews of Patient-Reported Outcome Measures was used. The Preferred Reporting Items for Systematic Reviews and Meta-Analyses were used in line with COSMIN guidance. The COSMIN checklist was used to evaluate the risk of bias and the quality of clinimetric properties. Overall certainty of the evidence was rated using a modified Grading of Recommendations, Assessment, Development and Evaluation approach. Narrative synthesis was performed and where possible, meta-analysis was conducted., Results: A total of 4316 studies were screened. Forty-seven were included in the review, reporting data for 12308 participants. The Short Form-36 Questionnaire (Physical Component Score and Physical Functioning), sit-to-stand test, 6-m walk test and Barthel Index had the strongest clinimetric properties and certainty of evidence. The Short Physical Performance Battery, Katz Index and handgrip strength had less favourable results. There was limited data for Lawson Instrumental Activities of Daily Living and the Global Leadership Initiative on Malnutrition criteria. The risk of bias ranged from inadequate to very good. The certainty of the evidence ranged from very low to high., Conclusions: Variable evidence exists to support the clinimetric properties of the CONCISE measurement instruments. We suggest using this review alongside CONCISE to guide outcome selection for future trials of nutrition and metabolic interventions in critical illness., Trial Registration: PROSPERO (CRD42023438187). Registered 21/06/2023., (© 2023. The Author(s).)

Recent successes in deep learning have inspired researchers to apply deep neural networks to Acoustic Event Classification (AEC). While deep learning methods can train effective AEC models, they are susceptible to overfitting due to the models' high complexity. In this paper, we introduce EnViTSA, an innovative approach that tackles key challenges in AEC. EnViTSA combines an ensemble of Vision Transformers with SpecAugment, a novel data augmentation technique, to significantly enhance AEC performance. Raw acoustic signals are transformed into Log Mel-spectrograms using Short-Time Fourier Transform, resulting in a fixed-size spectrogram representation. To address data scarcity and overfitting issues, we employ SpecAugment to generate additional training samples through time masking and frequency masking. The core of EnViTSA resides in its ensemble of pre-trained Vision Transformers, harnessing the unique strengths of the Vision Transformer architecture. This ensemble approach not only reduces inductive biases but also effectively mitigates overfitting. In this study, we evaluate the EnViTSA method on three benchmark datasets: ESC-10, ESC-50, and UrbanSound8K. The experimental results underscore the efficacy of our approach, achieving impressive accuracy scores of 93.50%, 85.85%, and 83.20% on ESC-10, ESC-50, and UrbanSound8K, respectively. EnViTSA represents a substantial advancement in AEC, demonstrating the potential of Vision Transformers and SpecAugment in the acoustic domain.

Background: We aimed to analyze and confirm the clinical features of patients with non-lateralized tinnitus and to identify clues that can be used in their management., Methods: Data from 469 patients who visited a university hospital complaining of tinnitus between March 2020 and December 2021 were reviewed. The patients' medical histories, Tinnitus Handicap Inventory, Beck Depression Inventory, and numerical rating scale scores on tinnitus awareness, annoyance, loudness, and effect on life, audiological profiles, and quantitative electroencephalography findings were documented., Results: Forty-nine (10.4%) patients had non-lateralized tinnitus. They were older and had a shorter duration of symptoms (13.91 ± 34.16 months) than patients with bilateral tinnitus (duration: 39.15 ± 80.82 months) (P -lt; .05). The accompanying symptoms, Tinnitus Handicap Inventory scores, and numerical rating scale scores were not significantly different between the 2 groups (P -gt; .05). Patients with non-lateralized tinnitus had worse hearing at 12 kHz on the left side than those with unilateral tinnitus. Hearing asymmetry was least common in non-lateralized tinnitus (n=11/49, 10.4%), followed by bilateral tinnitus (n=54/198, 42.2%) and unilateral tinnitus (n=97/222, 47.3%) (P-lt; .001). Regarding quantitative electroencephalography, there were significant differences in the absolute power of the theta, alpha, beta, gamma, and total frequency bands based on tinnitus lateralization (P -lt; .001)., Conclusion: Non-lateralized tinnitus can be perceived in elderly patients with symmetric and extended high-frequency hearing loss before habituation is achieved at an early stage of tinnitus. However, there was no difference in the questionnaire scores and accompanying symptoms; therefore, it may not be worth managing non-lateralized tinnitus separately from tinnitus in the ear.

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., (© 2023. BioMed Central Ltd., part of Springer Nature.)

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., Competing Interests: Dr. Hill received funding from Fresenius Kabi; she disclosed that she is currently supported by the Medical Faculty Rheinisch-Westfälische Technische Hochschule Aachen University (“Habilitationsstipendium”). Dr. Jeschke received support for article research from the National Institutes of Health. Dr. Cancio disclosed government work. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2023 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)

Background: Transcranial random noise stimulation has previously been used to manage tinnitus. This study assessed the feasibility of adjuvant transcranial random noise stimulation with conventional steroid treatment for idiopathic sudden sensorineural hearing loss with or without tinnitus., Methods: Prospective, randomized, single-blind study was conducted in Eulji University hospital. Twenty-four patients with idiopathic sudden sensorineural hearing loss were admitted for treatment between March 2019 and February 2020. The study group received 4 sessions of adjuvant transcranial random noise stimulation (frequency band: 0.1-100 Hz; target, T7/T8; duration: 20 minutes), while the control group received only conventional treatment. Hearing levels at admission, discharge day (day 7), and 4 weeks later and clinical characteristics were assessed. The primary outcome measure was hearing improvement at 4 weeks after neuromodulation. The secondary outcome measure was the presence of tinnitus at 4 weeks., Results: The mean hearing thresholds improved significantly over time (P < .05). Although initial hearing levels did not differ between the 2 groups, the study group had a significantly better hearing at 4 weeks after discharge (P > .05). A significant interaction was also observed between the mean hearing thresholds at various timepoints and transcranial random noise stimulation (P=.001). However, the persistence of tinnitus after treatment did not differ irrespective of the allocation groups., Conclusion: Adjuvant transcranial random noise stimulation seems to be a potential treatment option for hearing restoration in patients with idiopathic sudden sensorineural hearing loss without serious complications. However, transcranial random noise stimulation does not seem to alleviate tinnitus.

Terminal acceptor atoms and side-chain functionalization play a vital role in the construction of efficient nonfullerene small-molecule acceptors (NF-SMAs) for AM1.5G/indoor organic photovoltaic (OPV) applications. In this work, we report three dithienosilicon-bridged carbazole-based (DTSiC) ladder-type (A-DD'D-A) NF-SMAs for AM1.5G/indoor OPVs. First, we synthesize DTSiC-4F and DTSiC-2M, which are composed of a fused DTSiC-based central core with difluorinated 1,1-dicyanomethylene-3-indanone (2F-IC) and methylated IC (M-IC) end groups, respectively. Then, alkoxy chains are introduced in the fused carbazole backbone of DTSiC-4F to form DTSiCODe-4F. From solution to film absorption, DTSiC-4F exhibits a bathochromic shift with strong π-π interactions, which improves the short-circuit current density ( J sc ) and the fill factor (FF). On the other hand, DTSiC-2M and DTSiCODe-4F display up-shifting lowest unoccupied molecular orbital (LUMO) energy levels, which enhances the open-circuit voltage ( V oc ). As a result, under both AM1.5G/indoor conditions, the devices based on PM7:DTSiC-4F, PM7:DTSiC-2M, and PM7:DTSiCOCe-4F show power conversion efficiencies (PCEs) of 13.13/21.80%, 8.62/20.02, and 9.41/20.56%, respectively. Furthermore, the addition of a third component to the active layer of binary devices is also a simple and efficient strategy to achieve higher photovoltaic efficiencies. Therefore, the conjugated polymer donor PTO2 is introduced into the PM7:DTSiC-4F active layer because of the hypsochromically shifted complementary absorption, deep highest occupied molecular orbital (HOMO) energy level, good miscibility with PM7 and DTSiC-4F, and optimal film morphology. The resulting ternary OSC device based on PTO2:PM7:DTSiC-4F can improve exciton generation, phase separation, charge transport, and charge extraction. As a consequence, the PTO2:PM7:DTSiC-4F-based ternary device achieves an outstanding PCE of 13.33/25.70% under AM1.5G/indoor conditions. As far as we know, the obtained PCE results under indoor conditions are one of the best binary/ternary-based systems processed from eco-friendly solvents.

Background: The liberal use of remifentanil in spine surgery has been associated with an increased incidence of postoperative hyperalgesia. Nevertheless, controversies remain as the existing evidence is inconclusive to determine the relationship between remifentanil use and the development of opioid-induced hyperalgesia. We hypothesized that intraoperative infusion of higher dose remifentanil during scoliosis surgery is associated with postoperative hyperalgesia, manifesting clinically as greater postoperative morphine consumption and pain scores., Methods: Ninety-seven patients with adolescent idiopathic scoliosis (AIS) who underwent posterior spinal fusion surgery at a single tertiary institution from March 2019 until June 2020 were enrolled in this retrospective study. Anesthesia was maintained using a target-controlled infusion of remifentanil combined with volatile anesthetic desflurane in 92 patients, while five patients received it as part of total intravenous anesthesia. Intravenous ketamine, paracetamol, and fentanyl were administered as multimodal analgesia. All patients received patient-controlled analgesia (PCA) morphine postoperatively. Pain scores at rest and on movement, assessed using the numerical rating scale, and the cumulative PCA morphine consumption were collected at a six-hourly interval for up to 48 h. According to the median intraoperative remifentanil dose usage of 0.215 µg/kg/min, patients were divided into two groups: low dose and high dose group., Results: There were no significant differences in the pain score and cumulative PCA morphine consumption between the low and high dose remifentanil group. The mean duration of remifentanil infusion was 134.9 ± 22.0 and 123.4 ± 23.7 min, respectively., Conclusion: Intraoperative use of remifentanil as an adjuvant in AIS patients undergoing posterior spinal fusion surgery was not associated with postoperative hyperalgesia., (© 2023. The Author(s).)

Tubulin glutamylation is a reversible modification of the microtubules that regulates cilia stability and function. The addition of glutamates to the microtubule is catalyzed by members of the TTLL family of enzymes, while the removal is carried out by a family of cytosolic carboxypeptidase (CCP) enzymes. C. elegans has two deglutamylating enzymes, CCPP-1 and CCPP-6 . CCPP-1 is required for ciliary stability and function in the worm, however CCPP-6 is dispensable for cilia integrity. To investigate redundancy between the two deglutamylating enzymes we made a ccpp-1 ( ok1821 ); ccpp-6 ( ok382 ) double mutant. The double mutant shows normal viability, and the dye-filling phenotypes are not worse than the ccpp-1 single mutant, suggesting that CCPP-1 and CCPP-6 do not function redundantly in C. elegans cilia ., Competing Interests: The authors declare that there are no conflicts of interest present., (Copyright: © 2023 by the authors.)

Background: A recent landmark randomized controlled trial (RCT) in septic patients demonstrated an increased risk of death and persistent organ dysfunction with intravenous Vitamin C (IVVC) monotherapy, which represents a disparate result from previous systematic reviews and meta-analyses (SRMA). We performed an updated SRMA of IVVC monotherapy to summarize and explore heterogeneity across current trials and conduct trial sequential analysis (TSA) to guard against type-I or type-II statistical errors., Methods: RCTs evaluating IVVC in adult critically ill patients were included. Four databases were searched from inception to 22 June 2022 without language restrictions. The primary outcome was overall mortality. Random effect meta-analysis was performed to estimate the pooled risk ratio. TSA for mortality was performed using the DerSimonian-Laird random effect model, alpha 5%, beta 10%, and relative risk reduction (RRR) of 30%, 25%, and 20%., Results: We included 16 RCTs (n = 2130). IVVC monotherapy is associated with significant reduction in overall mortality [risk ratio (RR) 0.73, 95% confidence interval (CI) 0.60-0.89; p = 0.002; I 2  = 42%]. This finding is supported by TSA using RRR of 30% and 25%, and sensitivity analysis using fixed-effect meta-analysis. However, the certainty of our mortality finding was rated low using GRADE due to the serious risk of bias and inconsistency. In a priori subgroup analyses, we found no differences between single vs multicenter, higher (≥ 10,000 mg/day) vs lower dose and sepsis vs non-sepsis trials. Post-hoc, we found no differences in subgroup analysis of earlier (< 24 h) vs delayed treatment, longer (> 4 days) vs shorter treatment duration, and low vs other risk of bias studies. IVVC may have the greatest benefit in trials that enrolled patients above (i.e., > 37.5%; RR 0.65, 95% CI 0.54-0.79) vs below (i.e., ≤ 37.5%; RR 0.89, 95% CI 0.68-1.16) median control group mortality (test for subgroup differences: p = 0.06), and TSA supported this., Conclusions: IVVC monotherapy may be associated with mortality benefits in critically ill patients, particularly in patients with a high risk of dying. Given the low certainty of evidence, this potentially life-saving therapy warrants further studies to identify the optimal timing, dosage, treatment duration, and patient population that will benefit most from IVVC monotherapy. PROSPERO Registration ID: CRD42022323880. Registered 7th May 2022., (© 2023. The Author(s).)

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., Competing Interests: Declaration of interests The UK sites received support in the form of protein supplement supply from Nutrinovo (prosource tube feed [TF]) and Stanningly Pharma (Renapro Shot), and CA$20 000 from Nutricia to cover insurance and project management costs locally. Those that provided financial and product support for the trial had no role in designing the protocol, conducting the trial, or analysing the data, and did not have access to the data nor influence the content of the publication. We declare no competing interests., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

In 1747, an important milestone in the history of clinical research was set, as the Scottish surgeon James Lind conducted the first randomized controlled trial. Lind was interested in scurvy, a severe vitamin C deficiency which caused the death of thousands of British seamen. He found that a dietary intervention with oranges and lemons, which are rich in vitamin C by nature, was effective to recover from scurvy. Because of its antioxidative properties and involvement in many biochemical processes, the essential micronutrient vitamin C plays a key role in the human biology. Moreover, the use of vitamin C in critical illness-a condition also resulting in death of thousands in the 21st century-has gained increasing interest, as it may restore vascular responsiveness to vasoactive agents, ameliorate microcirculatory blood flow, preserve endothelial barriers, augment bacterial defense, and prevent apoptosis. Because of its redox potential and powerful antioxidant capacity, vitamin C represents an inexpensive and safe antioxidant, with the potential to modify the inflammatory cascade and improve clinical outcomes of critically ill patients. This narrative review aims to update and provide an overview on the role of vitamin C in the human biology and in critically ill patients, and to summarize current evidence on the use of vitamin C in diverse populations of critically ill patients, in specific focusing on patients with sepsis and coronavirus disease 2019., (© 2022 The Authors. Nutrition in Clinical Practice published by Wiley Periodicals LLC on behalf of American Society for Parenteral and Enteral Nutrition.)

Introduction: This study was performed to assess identifiable abnormalities in tinnitus patients with normal hearing., Methods: The medical records of subjective non-pulsatile tinnitus patients with normal hearing confirmed by conventional pure-tone audiometry who visited our tinnitus clinic between March 2020 and May 2022 were reviewed. The loudness discomfort level (LDL), extended high-frequency hearing loss (EHFHL), summating potential (SP)/action potential (AP) ratio, distortion product otoacoustic emission (DPOAE), thresholds of auditory brainstem response (ABR) wave V, somatic modulation, and psychiatric symptoms, such as anxiety, depression, and stress were evaluated by questionnaires., Results: Decreased LDL ( n = 48, 59.8%) was the most frequent finding, followed by EHFHL ( n = 29, 35.4%), increased SP/AP ratio ( n = 27, 32.9%), psychiatric symptoms ( n = 24, 29.3%), decreased DPOAE ( n = 17, 20.7%), somatic modulation ( n = 8, 9.8%), and increased ABR threshold ( n = 3, 3.7%); 75.6% of patients had one or more of these findings. The presence of psychiatric symptoms was independently associated with the Tinnitus Handicap Inventory (THI) score., Conclusion: Tinnitus in patients with normal hearing may be accompanied by a combination of various subclinical abnormal audiological findings. However, the presence of psychiatric symptoms alone was independently associated with tinnitus distress., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Park, Shin, Byun, Lee and Lee.)

Cortisol is an endogenous steroid hormone essential for the natural resolution of inflammation. Synthetic glucocorticoids (GCs) were developed and are currently amongst the most widely prescribed anti-inflammatory drugs in our modern clinical landscape owing to their potent anti-inflammatory activity. However, the extent of GC's effects has yet to be fully elucidated. Indeed, GCs modulate a broad spectrum of cellular activity, from their classical regulation of gene expression to acute non-genomic mechanisms of action. Furthermore, tissue specific effects, disease specific conditions, and dose-dependent responses complicate their use, with side-effects potentially plaguing their use. It is thus vital to outline and consolidate the effects of GCs, to demystify and maximize their therapeutic potential while avoiding pitfalls that would otherwise render them obsolete., Competing Interests: Conflict of interest statement The authors declare no conflicts of interest. All data reported in the present review are from the public scientific literature., (Copyright © 2023. Published by Elsevier Inc.)

Competing Interests: The authors have disclosed that they do not have any potential conflicts of interest.

This study was designed to evaluate paraffin wax as a potential controlled release matrix for spray congealing and its impact on drug release and stability of the microparticles. Paraffin wax can form a hydrophobic barrier to moisture and reduce drug degradation besides retarding drug release in the gastrointestinal tract. More hydrophilic lipid-based additives can be incorporated to modulate the drug release through the paraffin wax barrier. This study reports the findings of lipid-wax formulations at preserving the stability of moisture-sensitive drugs in spray-congealed microparticles. Aspirin-loaded microparticles formulated with different drug loads, lipid additives, and lipid:wax ratios were produced by spray congealing. Stearic acid (SA), cetyl alcohol (CA), and cetyl ester (CE) were the lipid additives studied. The microparticles were evaluated for yield, encapsulation efficiency, particle size, drug stability, and release. CE exhibited the greatest effect on increasing drug release, followed by CA and SA. Dissolution profiles showed the best fit to Weibull kinetic model. The degree of drug degradation was low, with CA imparting the least protective effect, followed by SA and CE. Paraffin wax is useful for preserving the stability of moisture-sensitive aspirin and retarding its release from spray-congealed microparticles. The addition of lipid additives modulated drug release without compromising drug stability.

Purpose: We aimed to assess the characteristics of patients with concurrent tinnitus and hyperacusis, determine the best audiological criteria for predicting hyperacusis, and confirm whether objective evidence of changes in the brain exists., Materials and Methods: The medical records of patients with tinnitus who visited the hospital between March 2020 and December 2021 were reviewed. Data on accompanying hyperacusis, audiological profiles, and questionnaires including the Tinnitus Handicap Inventory (THI), Beck Depression Inventory, and numerical rating scale were analyzed. Resting-state quantitative electroencephalography (qEEG) using power spectral density (PSD) and event-related spectral perturbation (ERSP) were performed to objectively quantify changes in the brain., Results: A total of 194 patients were analyzed. Among them, 51 (26.3%) reported combined subjective hyperacusis with tinnitus. However, the proportions widely varied from 7.4% to 68.4% based on three audiological criteria for assessment. A higher score on the THI questionnaire was independently associated with the co-occurrence of tinnitus and hyperacusis. Fair agreement was observed between subjective hyperacusis and the audiological criterion based on a loudness discomfort level (LDL) of ≤90 dB at two or more frequencies for the diagnosis of hyperacusis. An increased beta-PSD and decreased levels of gamma-PSD, all-ERSP, and delta-ERSP were observed in patients with hyperacusis ( p <0.05)., Conclusion: Patients with co-occurring tinnitus and hyperacusis had more severe tinnitus distress. An LDL of ≤90 dB at two or more frequencies may be applicable to predict accompanying hyperacusis in subjects with tinnitus, and qEEG also provides more objective information., Competing Interests: The authors have no potential conflicts of interest to disclose., (© Copyright: Yonsei University College of Medicine 2022.)

A urease-producing Gram-stain-positive actinobacterium, designated strain T5 T , was isolated from a soil sample collected at a highway hillslope in Selangor, Malaysia. The strain was found to produce pale yellowish-pink aerial mycelia with smooth long chain spores and extensively branched light yellowish-pink substrate mycelia on oatmeal agar. Strain T5 T grew at 15-37 °C, pH 6-11, and tolerated up to 9 % (w/v) NaCl, with optimal growth occurring at 28 °C, pH 6-9 and without NaCl. The whole-cell sugar hydrolysate of strain T5 T contained galactose, glucose and ribose. The ll-diaminopimelic acid isomer was detected in the cell wall. Diphosphatidylglycerol, phosphatidylcholine, phosphatidylethanolamine, phosphatidylglycerol and phosphatidylinositol were found to be the predominant polar lipids. The main fatty acids were anteiso-C 17 : 0 , iso-C 16 : 0 , anteiso-C 15 : 0 and iso-C 14 : 0 . Comparative analysis of the 16S rRNA gene sequences indicated that strain T5 T belonged to Streptomyces of the family Streptomycetaceae with the highest 16S rRNA gene sequence similarity to Streptomyces lichenis LCR6-01 T (99.0 %). The overall genome relatedness indices revealed that the closest related species was S. lichenis LCR6-01 T with 89.4 % average nucleotide identity and 33.7 % digital DNA-DNA hybridization. Phylogeny analyses showed that strain T5 T was closely related to Streptomyces fradiae , Streptomyces lavendofoliae , Streptomyces lichenis , Streptomyces roseolilacinus and Streptomyces somaliensis . Based on these polyphasic data, strain T5 T represents a novel species, for which the name Streptomyces solincola sp. nov. is proposed. The type strain is T5 T (=TBRC 5137 T = DSM 42166 T ).

Introduction: There is a lack of guidelines or formal systematic synthesis of evidence for nutrition therapy in older critically ill patients. This study is a scoping review to explore the state of evidence in this population., Method: MEDLINE and Embase were searched from inception until 9 February 2022 for studies that enrolled critically ill patients aged ≥60 years and investigated any area of nutrition therapy. No language or study design restrictions were applied., Results: Thirty-two studies (5 randomised controlled trials) with 6 topics were identified: (1) nutrition screening and assessments, (2) muscle mass assessment, (3) route or timing of nutrition therapy, (4) determination of energy and protein requirements, (5) energy and protein intake, and (6) pharmaconutrition. Topics (1), (3) and (6) had similar findings among general adult intensive care unit (ICU) patients. Skeletal muscle mass at ICU admission was significantly lower in older versus young patients. Among older ICU patients, low muscularity at ICU admission increased the risk of adverse outcomes. Predicted energy requirements using weight-based equations significantly deviated from indirect calorimetry measurements in older vs younger patients. Older ICU patients required higher protein intake (>1.5g/kg/day) than younger patients to achieve nitrogen balance. However, at similar protein intake, older patients had a higher risk of azotaemia., Conclusion: Based on limited evidence, assessment of muscle mass, indirect calorimetry and careful monitoring of urea level may be important to guide nutrition therapy in older ICU patients. Other nutrition recommendations for general ICU patients may be used for older patients with sound clinical discretion.

Background: The clinical significance of vitamin D administration in critically ill patients remains inconclusive. The purpose of this systematic review with meta-analysis was to investigate the effect of vitamin D and its metabolites on major clinical outcomes in critically ill patients, including a subgroup analysis based on vitamin D status and route of vitamin D administration., Methods: Major databases were searched through February 9, 2022. Randomized controlled trials of adult critically ill patients with an intervention group receiving vitamin D or its metabolites were included. Random-effect meta-analyses were performed to estimate the pooled risk ratio (dichotomized outcomes) or mean difference (continuous outcomes). Risk of bias assessment included the Cochrane tool for assessing risk of bias in randomized trials., Results: Sixteen randomized clinical trials with 2449 patients were included. Vitamin D administration was associated with lower overall mortality (16 studies: risk ratio 0.78, 95% confidence interval 0.62-0.97, p = 0.03; I 2  = 30%), reduced intensive care unit length of stay (12 studies: mean difference - 3.13 days, 95% CI - 5.36 to - 0.89, n = 1250, p = 0.006; I 2  = 70%), and shorter duration of mechanical ventilation (9 studies: mean difference - 5.07 days, 95% CI - 7.42 to - 2.73, n = 572, p < 0.0001; I 2  = 54%). Parenteral administration was associated with a greater effect on overall mortality than enteral administration (test of subgroup differences, p = 0.04), whereas studies of parenteral subgroups had lower quality. There were no subgroup differences based on baseline vitamin D levels., Conclusions: Vitamin D supplementation in critically ill patients may reduce mortality. Parenteral administration might be associated with a greater impact on mortality. Heterogeneity and assessed certainty among the studies limits the generalizability of the results., Trial Registration: PROSPERO international prospective database of systematic reviews (CRD42021256939-05 July 2021)., (© 2022. The Author(s).)

Objectives: Concise definitive review of how to read and critically appraise a systematic review., Data Sources: None., Study Selection: Current literature describing the conduct, reporting, and appraisal of systematic reviews and meta-analyses., Data Extraction: Best practices for conducting, reporting, and appraising systematic review were summarized., Data Synthesis: A systematic review is a review of a clearly formulated question that uses systematic and explicit methods to identify, select, and critically appraise relevant original research, and to collect and analyze data from the studies that are included in the review. Critical appraisal methods address both the credibility (quality of conduct) and rate the confidence in the quality of summarized evidence from a systematic review. The A Measurement Tool to Assess Systematic Reviews-2 tool is a widely used practical tool to appraise the conduct of a systematic review. Confidence in estimates of effect is determined by assessing for risk of bias, inconsistency of results, imprecision, indirectness of evidence, and publication bias., Conclusions: Systematic reviews are transparent and reproducible summaries of research and conclusions drawn from them are only as credible and reliable as their development process and the studies which form the systematic review. Applying evidence from a systematic review to patient care considers whether the results can be directly applied, whether all important outcomes have been considered, and if the benefits are worth potential harms and costs., Competing Interests: Dr. Hill’s institution received funding from Fresenius Kabi and the Medical Faculty Rheinisch-Westfälische Technische Hochschule Aachen; she received funding from Fresenius Kabi. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2022 by the Society of Critical Care Medicine and Wolters Kluwer Health, Inc. All Rights Reserved.)