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Conclusions | FM loss, weight loss, T2DM | In contrast with other interventions geared toward weight loss where behavioral and physiological changes in NEPA and NEAT, respectively, may be expected, a more conservative and ecological 1-year exercise intervention for individuals with T2DM had no impact on NEPA and estimated NEAT on the non-exercise days, regardless of the exercise intensity or having a clinically meaningful BW and FM loss. These results provide valuable information for those individuals with T2DM who aim to improve their body composition through an exercise intervention, where no physiological or behavioral barriers are expected to compromise their energy balance. | PMC10063485 |
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Acknowledgements | The authors are grateful to all participants for their time and effort. | PMC10063485 |
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Author’s contribution | IRC contributed to methodology, formal analysis, and writing—original draft; MHR contributed to formal analysis and writing—original draft; JPM contributed to conceptualization, methodology, formal analysis, and writing—original draft; PBJ contributed to methodology and writing—review and editing; GBR contributed to writing—review and editing; DHN contributed to writing—review and editing; AM contributed to formal analysis and writing—review and editing; IA contributed to writing—review and editing; AMS contributed to formal analysis and writing—review and editing; LBS contributed to conceptualization and writing—review and editing. All authors approved of the final manuscript version and take responsibility for the integrity of the data and the accuracy of the data analysis. All authors gave consent to submit the manuscript. | PMC10063485 |
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Funding | Open access funding provided by FCT|FCCN (b-on). This work was conducted at the Interdisciplinary Center for the Study of Human Performance (CIPER), unit I&D 447 (UIDB/00447/2020), Faculty of Human Kinetics of the University of Lisbon, and supported by the Portuguese Foundation for Science and Technology, the Portuguese Ministry of Science. IRC, JPM, and PBJ are supported by the Portuguese Foundation for Science and Technology (IRC: SFRH/BD/149394/2019; JPM: SFRH/BD/ 85742/2012; PBJ: SFRH/BPD/115977/2016; GBR: 2020.07856.BD,2020), and DHN is supported by a grant from Comité Olímpico de Portugal (doctoral scholarship—COP). | PMC10063485 |
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Data availability statement | The datasets used during the current intervention are available from the corresponding author on reasonable request. | PMC10063485 |
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Declarations | PMC10063485 |
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Conflict of interest | The authors report there are no conflicts of interest to declare. | PMC10063485 |
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Ethical standard statement | The study was approved by the Ethics Council of the Associação Protetora dos Diabéticos de Portugal (Approval Number: 07/17/2013) and conducted in accordance with the Declaration of Helsinki for Human Studies [ | PMC10063485 |
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Informed consent | Written informed consent was obtained from all participants before proceeding with any protocol-specific procedures. | PMC10063485 |
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References | PMC10063485 |
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Background: | depression, post-PCI angina, angina, anxiety | Twenty percent to 40% of patients are affected by angina after percutaneous coronary intervention (PCI), which is associated with anxiety, depression, impaired physical function, and reduced quality of life. Understanding patient and procedural factors associated with post-PCI angina may inform alternative approaches to treatment. | PMC10101135 |
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Methods: | Angina, post-PCI angina | Two hundred thirty patients undergoing PCI completed the Seattle Angina Questionnaire (SAQ-7) and European quality of life–5 dimension–5 level (EQ-5D-5L) questionnaires at baseline and 3 months post-PCI. Patients received blinded intracoronary physiology assessments before and after stenting. A post hoc analysis was performed to compare clinical and procedural characteristics among patients with and without post-PCI angina (defined by follow-up SAQ-angina frequency score <100). | PMC10101135 |
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Results: | myocardial infarction, angina | ATRIAL FIBRILLATION, MYOCARDIAL INFARCTION | Eighty-eight of 230 patients (38.3%) reported angina 3 months post-PCI and had a higher incidence of active smoking, atrial fibrillation, and history of previous myocardial infarction or PCI. Compared with patients with no angina at follow-up, they had lower baseline SAQ summary scores (69.48±24.12 versus 50.20±22.59, | PMC10101135 |
Conclusions: | angina, less angina | Larger improvements in FFR following PCI were associated with less angina and better quality of life at follow-up. In patients with stable symptoms, intracoronary physiology assessment can inform expectations of angina relief and quality of life improvement after stenting and thereby help to determine the appropriateness of PCI. | PMC10101135 |
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Registration: | URL: | PMC10101135 |
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What is Known | depression, Angina, angina, anxiety | RECURRENCE | Angina after percutaneous coronary intervention (PCI) is associated with long-term anxiety, depression, and impairment of both physical function and quality of life.Persistence or recurrence of angina after PCI may affect 20% to 40% of patients during short-to-medium-term follow-up. | PMC10101135 |
What the Study Adds | Angina, angina, anxiety, angina post-PCI.The, pre-PCI, post-PCI angina, depression | DISEASE | Patients with post-PCI angina reported more frequent angina and poorer quality of life at baseline yet had physiologically less severe disease and, accordingly, tended to achieve less improvement in coronary physiology metrics than those who were free from angina post-PCI.The degree of improvement in patient-reported outcome measures following PCI is not associated with post-PCI coronary physiology values. It relates instead to the pre-PCI value and the change from baseline. Lower pre-PCI values and larger increases in fractional flow reserve were associated with higher patient-reported outcome measures scores at follow-up.Intracoronary physiology assessment can inform expectations of angina relief and quality of life improvement after stenting and thereby help to determine the appropriateness of PCI intended to alleviate symptoms.
Angina after percutaneous coronary intervention (PCI) is associated with long-term anxiety, depression, impaired physical function, and quality of life. | PMC10101135 |
Methods | The data that support the findings of this study are available from the corresponding author upon reasonable request. The rationale, study design, and primary outcome of the TARGET-FFR controlled trial have been published previously. | PMC10101135 |
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Definition of Angina | angina | The presence of angina post-PCI was defined by a patient-reported follow-up SAQ-angina frequency (SAQ-AF) score of <100. Patients with a follow-up of SAQ-AF score=100 were classified as having no angina. | PMC10101135 |
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Clinical Outcomes | vessel failure, vessel myocardial infarction, cardiovascular death | Clinical outcomes at a median of 3 years post-PCI were assessed by electronic health record linkage. The primary clinical outcome was target vessel failure, a composite end point comprising cardiovascular death, target vessel myocardial infarction, and target vessel revascularization. | PMC10101135 |
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Statistical Analysis | Continuous variables are presented as mean±SD and categorical data as counts and percentages. A 2-sample | PMC10101135 |
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Results | angina, post-PCI angina | Of 260 participants, 230 (88.5%) provided follow-up SAQ-AF scores 3 months (median [interquartile range], 105 [31] days) post-PCI. For the purposes of this analysis, patients were stratified by the presence of post-PCI angina. Eighty-eight (38.3%) of 230 patients had post-PCI angina as determined by a follow-up SAQ-AF score <100. Expanded subgroup analyses with additional stratification by the presence of angina at baseline are included in the ( | PMC10101135 |
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Baseline Demographics | Clinical characteristics at baseline are presented in Table Baseline Clinical Characteristics Stratified by Presence of Angina 3 Months Post-PCI | PMC10101135 |
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Procedural Outcomes | Procedural and coronary physiology characteristics are presented in Table Procedural and Coronary Physiology Characteristics Stratified by Presence of Angina 3 Months Post-PCI | PMC10101135 |
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Predictors of Post-PCI Angina | Post-PCI Angina, post-PCI angina | Univariate and multivariate analysis of predictors of post-PCI angina are presented in Table Predictors of Post-PCI Angina | PMC10101135 |
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Clinical Outcomes | vessel failure, post-PCI angina | The rate of target vessel failure at a median (interquartile range) follow-up of 3 (0.9) years was 1.7% (4/230) with no significant difference between groups (no angina, 0.7% versus post-PCI angina, 3.4%; | PMC10101135 |
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Discussion | chest tightness, angina, physician-adjudicated angina, dyspnea, chest pain, post-PCI angina, atrial fibrillation, heart failure | MYOCARDIAL INFARCTION, ANGINAL ATTACKS, ATRIAL FIBRILLATION, HEART FAILURE, HYPERTENSION | One in 3 patients in the TARGET-FFR randomized trial reported angina 3 months after undergoing PCI which, while a substantial proportion, is not unprecedented. In the ABSORB IV trial, 39% (494/1265) of patients in the drug-eluting stent arm had physician-adjudicated angina or angina-equivalent symptoms at 1-year follow-up.As the impact of anginal symptoms is inherently subjective, we concluded that attempting to define a level of post-PCI angina that might be acceptable to patients or represent a clinically meaningful improvement would be arbitrary and ultimately futile. Improved but persistent symptoms may be considered a success by some patients yet be completely unacceptable to others, so we therefore, determined a complete absence of patient-reported angina after PCI to represent the gold standard. The SAQ-AF domain asks patients to report the frequency of “chest pain, chest tightness, or anginal attacks” over the preceding 4 weeks with a score <100 indicating at least one anginal episode within that period. Accordingly, we adopted a follow-up SAQ-AF score of <100 as the definition of post-PCI.Approximately 6% of participants reporting angina after stenting did not have symptoms prior to their intervention which highlights the importance of ascertaining the indication for and appropriateness of PCI with patients prior to embarking upon the procedure, particularly for those who are asymptomatic.Patients reporting post-PCI angina had a higher burden of cardiovascular risk factors, including cigarette smoking, prior myocardial infarction, and atrial fibrillation at baseline. The higher rates of oral anticoagulants and concomitant lower rate of antiplatelets prescribed at baseline among patients reporting post-PCI angina are likely just commensurate with the higher incidence of atrial fibrillation in this group. As there was no difference in the incidence of the heart failure or hypertension, the higher rate of diuretic therapy may relate to prescriptions for dyspnea thought to represent an angina-equivalent symptom.Patients with post-PCI angina had more severe symptoms at baseline (higher incidence of both CCS class 2 and 3 angina and self-reported rates of daily and weekly angina) and were prescribed more antianginal agents with greater use of oral and sublingual nitrates than those who were angina-free postprocedure. Patients experiencing any angina post-PCI reported effectively no improvement in quality of life as assessed by the mean change in their EQ-5D-5L weighted health index score ( | PMC10101135 |
Procedural and Intracoronary Physiology Characteristics | Angioplasty, angina, pre-PCI, Coronary microvascular dysfunction, Post-PCI, post-PCI angina, coronary artery disease | STABLE ANGINA, CORONARY ARTERY DISEASE, CORONARY MICROVASCULAR DYSFUNCTION | There were no significant differences between groups in angiography-based parameters of coronary artery disease severity either pre- or post-PCI. Counterintuitively, patients with post-PCI angina had a higher burden of angina at baseline yet physiologically less severe lesions (significantly higher pre-PCI FFR and CFR values and faster hyperemic transit times) than those who were angina-free at follow-up. There were no differences in absolute post-PCI physiology values between groups, and among patients with angina at baseline, there was no correlation between post-PCI values and patient-reported outcome measures at follow-up. Coronary microvascular dysfunction has been proposed as a potential mechanism for persistent angina post-PCI.A physiology-stratified analysis of the ORBITA trial (Objective Randomised Blinded Investigation With Optimal Medical Therapy of Angioplasty in Stable Angina) assessed paired SAQ and EQ-5D-5L data from 189 patients and found that pre-PCI FFR and the instantaneous wave-free ratio (iFR) did not predict the effect of placebo-controlled PCI on anginal symptoms or quality of life.In the present analysis, among patients who had angina at baseline (CCS class I and above), pre-PCI, absolute and percentage delta FFR values had significant correlations with patient-reported outcome measures at follow-up. Post-PCI values had no correlation with angina or quality of life at follow-up indicating that, as demonstrated in the Figure and | PMC10101135 |
Limitations | vessel failure | TARGET-FFR was a single-center study with a relatively homogeneous PCI practice, including high rates of lesion predilatation and high-pressure stent postdilatation. A larger multicenter trial incorporating a wider range of PCI strategies and techniques may have had a different outcome. The study was not powered for clinical outcomes and the incidence of target vessel failure at a median follow-up of 3 years remained low. | PMC10101135 |
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Conclusions | angina, post-PCI angina | The magnitude of FFR improvement following PCI correlated with angina status and quality of life at follow-up and was an independent predictor of the presence of post-PCI angina. In patients with stable symptoms, intracoronary physiology assessment can aid prediction of angina relief and quality of life improvement after stenting and thereby help to determine the appropriateness of PCI. | PMC10101135 |
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Article Information | PMC10101135 |
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Sources of Funding | HEART | Endowment funds at the Golden Jubilee National Hospital (NHS Golden Jubilee), Glasgow, United Kingdom, with support from the British Heart Foundation (Research Excellence Award RE/18/6/34217). | PMC10101135 |
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Disclosures | MAY, COLLET | Dr Collison received consultancy fees from Abbott. Dr Mizukami received consultancy fees from Zeon Medical Inc; research grants from Boston Scientific; speaker fees from Abbott, Cathworks, Boston Scientific. Dr Collet received research grants from Biosensors, Coroventis Research, Medis Medical Imaging, Pie Medical Imaging, CathWorks, Boston Scientific, Siemens, HeartFlow, Abbott; consultancies HeartFlow, OpSens, Abbott, Philips Volcano. Dr Ford received consulting fees from BioExcel; honoraria from Abbott, Boehringer, Novartis. Dr Watkins received honoraria from Abbott, AstraZeneca, Biosensors, Boston Scientific, Daiichi Sankyo, GE Healthcare, ShockWave Medical. Dr Robertson received honoraria from AstraZeneca, Abbott. Dr O’Boyle received honoraria from AstraZeneca, Boston Scientific, Novartis. Dr McEntegart received consulting fees from Abbott, Boston Scientific, ShockWave Medical; honoraria from International Medical Device Solutions, Medtronic. Prof Berry received institutional grants/contracts from Abbott, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, HeartFlow, Novartis, Siemens Healthcare; consulting fees from Abbott, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, HeartFlow, Menarini, Novartis; honoraria from Abbott, AstraZeneca, Boehringer Ingelheim, GlaxoSmithKline, HeartFlow, Philips, Valo Health. Prof Oldroyd received honoraria from Abbott, Biosensors International, Boston Scientific; institutional research grant from Boston Scientific which supported the present manuscript; full-time employee of Biosensors International since May 2020. The other authors report no conflicts. | PMC10101135 |
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Supplemental Material | Supplemental MethodsFigure S1Tables S1–S13 | PMC10101135 |
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Supplementary Material | PMC10101135 |
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Nonstandard Abbreviations and Acronyms | Canadian Cardiovascular Societycoronary flow reserveEuropean quality of life-5 dimension-5 level questionnairefractional flow reservepercutaneous coronary interventionSeattle Angina QuestionnaireSeattle Angina Questionnaire-angina frequencyFor Sources of Funding and Disclosures, see page 164.Supplemental Material is available at | PMC10101135 |
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References | PMC10101135 |
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Background | Hypertension | HYPERTENSION | Clinical trials commonly use multiple endpoints to measure the impact of an intervention. While this improves the comprehensiveness of outcomes, it can make trial results difficult to interpret. We examined the impact of integrating patient weights into a composite endpoint on the interpretation of Control of Hypertension in Pregnancy Study (CHIPS) Trial results. | PMC9906819 |
Methods | PREGNANCY HYPERTENSION | Outcome weights were extracted from a previous patient preferences study in pregnancy hypertension (Outcome weights from the preference subgroups were integrated with CHIPS data for the seven outcomes identified in the preference study. A weighted composite score was derived for each participant by multiplying the preference weight for each outcome by the binary outcome if it occurred. Analyses considered equal weights and those from the preference subgroups. The mean composite scores were compared between trial arms ( | PMC9906819 |
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Results | Composite scores were similar between trial arms with the use of equal weights or those of subgroup (1) (95% confidence intervals [CIs]: − 0.03, 0.02; | PMC9906819 |
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Conclusions | Evidence-based recommendations for ‘tight’ control are consistent with most women’s preferences, but for a sixth of women, ‘less-tight’ control is more preference consistent. Depending on patient preferences, a single trial may support different interventions. Future trials should specify component weights to improve interpretation. | PMC9906819 |
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Trial registration | ClinicalTrials.gov NCT01192412 | PMC9906819 |
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Supplementary Information | The online version contains supplementary material available at 10.1186/s13063-023-07118-1. | PMC9906819 |
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Keywords | PMC9906819 |
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Introduction | Hypertension | SECONDARY, HYPERTENSION | Clinical trials in cardiovascular medicine routinely use primary, secondary, and other endpoints to capture the breadth of an intervention’s effects. However, this can make the interpretation of trial results challenging, as an intervention’s effects can vary by outcome, including benefits and harms [The international Control of Hypertension in Pregnancy Study (CHIPS; ClinicalTrials.gov NCT01192412) [In a secondary analysis of CHIPS Trial data, we explored whether weighting outcomes to reflect patient preferences would change the interpretation of trial results. | PMC9906819 |
Discussion | BWS | PRETERM BIRTH, PREGNANCY HYPERTENSION | This re-analysis of CHIPS trial outcomes incorporated patient views and demonstrated that integrating patient preferences for outcomes and their associated weights into trial analyses is feasible and can identify different management approaches based on the results of a single trial. Our findings suggest that while almost two-thirds of women prioritize adverse outcomes equally, as assumed in the primary CHIPS analyses, about one-quarter prioritize very preterm birth that clearly favours ‘tight’ control. A distinct minority prioritize minimizing antihypertensive medication above other adverse outcomes, making ‘less-tight’ control the most value-congruent BP management for them.Recent clinical practice guidelines have recommended ‘tight’ control of pregnancy hypertension [While integrating preferences into composites has been considered in cardiology [Limitations of our work include the use of preference weights that reflect women’s values in Canada; despite its multiethnic population, values may differ elsewhere. Preferences were identified after CHIPS was completed; consequently, different composite components may have been identified a priori. However, CHIPS evaluated the standard obstetric outcomes that cover most of the subsequently published relevant core outcome set. These results are statistically significant at the group level, but clinical significance likely depends on individual preferences. Additionally, our method of preference elicitation may have been too cognitively burdensome for some participants. BWS was chosen because it can provide cardinal importance values on an additive scale. As a result, weights can be directly compared to one another and the magnitude of the difference in the importance of outcomes is known. Alternative methods of analysis which use ranks, rather than weights, to incorporate the importance of composite components were considered [ | PMC9906819 |
Conclusions | This study illustrates that integrating patient values into trial analyses can change the interpretation of trial results for clinical decision-making. Future trials with composite or multiple outcomes should seek patient preference weights to improve the interpretation of trial results and support patient-centred care. | PMC9906819 |
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Acknowledgements | We would like to acknowledge the time and contributions of the 981 participants in the CHIPS trial and the 183 participants in the preferences study that made this work possible, as well as the members of the CHIPS Study Group (Additional file | PMC9906819 |
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Authors’ contributions | MH, NB | All authors contributed to the conceptualization and design of the study, have approved the submitted final version and have agreed to be accountable for their own contributions and the work as a whole. In addition, RKM contributed to the acquisition, analysis, and interpretation of the data and drafted the initial manuscript. MH, JS, and TL contributed to the analysis and interpretation of the data and provided feedback on the manuscript drafts. ML contributed to the acquisition and interpretation of the data. PvD and LAM contributed to the acquisition and interpretation of the data and provided feedback on the manuscript drafts. NB contributed to the acquisition, analysis, and interpretation of the data and contributed to the initial draft manuscript. | PMC9906819 |
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Funding | This study was funded by peer-reviewed grants from two government entities: the Canadian Institutes of Health Research (MCT 87522) and the BC SUPPORT Unit (RWCT-001). Funders had no involvement in the design of the study; the collection, analysis and interpretation of the data; or the presentation of findings. | PMC9906819 |
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Availability of data and materials | APPENDIX | The datasets used and/or analysed during the current study are not publicly posted as participant consent was not obtained for the open distribution of data. However, data are available from the corresponding author upon reasonable request. Aggregate data are available as part of the Supplementary Appendix of the initial publication of the CHIPS trial results (10.1056/NEJMoa1404595). | PMC9906819 |
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Declarations | PMC9906819 |
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Ethics approval and consent to participate | This study was reviewed and approved by the Behavioural Research Ethics Board (H17-01194) at the University of British Columbia. | PMC9906819 |
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Consent for publication | Not applicable | PMC9906819 |
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Competing interests | The authors declare that they have no competing interests. | PMC9906819 |
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References | PMC9906819 |
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Background | Residual neuromuscular block | COMPLICATION | Residual neuromuscular block after using neuromuscular blocking agents is a common and potentially harmful complication of general anesthesia. Neostigmine is a widely used antagonist, but its optimal dose for elderly patients is unclear. | PMC10413529 |
Objectives | cisatracurium-induced neuromuscular block | To compare the optimal dosage and safety of neostigmine for reversing shallow residual block in elderly patients after cisatracurium-induced neuromuscular block. | PMC10413529 |
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Methods | A randomized controlled trial was conducted in 196 elderly patients undergoing non-cardiac surgery under general anesthesia with cisatracurium. Patients were assigned to receive either no neostigmine (control group) or neostigmine at 20 µg/kg, 40 µg/kg or 50 µg/kg when train-of-four (TOF) ratio reached 0.2 at the end of surgery. The primary outcome was the time to reach TOF ratio of 0.9 after administration. Secondary outcomes included TOF ratio at 10 min after administration, postoperative nausea and vomiting, postoperative cognitive impairment and post-anesthesia care unit (PACU) stay time. | PMC10413529 |
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Results | The time to reach TOF ratio of 0.9 in the 20 µg/kg, 40 µg/kg and 50 µg/kg groups was significantly shorter than the control group (H = 104.257, | PMC10413529 |
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Conclusions | Timely use of neostigmine after general anesthesia in elderly patients can significantly shorten time of TOF value reaching 0.9, among which 40 µg/kg dosage may be a more optimized choice. | PMC10413529 |
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Trial registration | this study was registered on chictr.org.cn (ChiCTR2100054685, 24/12/2021). | PMC10413529 |
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Keywords | PMC10413529 |
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Background | MUSCLE RELAXATION, POSTOPERATIVE COMPLICATIONS | Neuromuscular blocking agents (NMBAs) are widely used to provide muscle relaxation for endotracheal intubation, certain modes of mechanical ventilation and surgical procedures. However, with the widespread application of neuromuscular blocking agents in general anesthesia, the residual effects have become one of the important factors of postoperative complications [Previous studies have shown that the optimal dose of neostigmine for reversal of minimal NMB (TOFr = 0.5) in adults is 40 µg/kg [ | PMC10413529 |
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Methods | PMC10413529 |
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Study design and patient selection | Neuromuscular block | NEUROMUSCULAR BLOCK | This study was approved by the Ethics Committee of the Third Xiangya Hospital. Written informed consent was obtained from all patients. Inclusion criteria were: aged 60 to 85 years, American Society of Anesthesiology (ASA) physical status 1 to 3, and scheduled for elective surgery under general anesthesia with cisatracurium for tracheal intubation. Exclusion criteria were: BMI < 18.5 kg/mPatients were randomly assigned into four groups according to the dose of neostigmine used, using a computer generated list of random numbers. Neuromuscular block was induced with cisatracurium and neostigmine 0 µg/kg (Normal Saline, NS), 20 µg/kg, 40 µg/kg or 50 µg/kg was administered at a TOF ratio of 0.2 to reverse the block. Anaesthesia nurses who were not involved in the care of the patients helped prepare the study drug according to randomisation. | PMC10413529 |
Procedure | nausea and vomiting, normocapnia, postoperative pain, tetanic | MUSCLE RELAXATION | On arrival at the operating room, an intravenous cannula was inserted in the forearm vein of the patient, and standard anesthesia monitoring (noninvasive blood pressure, electrocardiogram, and oxygen saturation) were established and anesthesia depth was monitored using Bispectral Index (BIS, Medtronic, Minneapolis, MN, USA). Anesthesia was induced with sufentanil (0.5 µg/kg) and etomidate (0.2–0.3 mg/kg), cisatracurium (0.15–0.2 mg/kg). Anaesthesia was maintained by a continuous inhalation of 1% sevoflurane and infusion of propofol (3–4 mg/kg/h) and remifentanil (0.5-1.0 µg/kg/min); the infusion speed was adjusted to maintain the BIS between 40 and 60. Cisatracurium was added as required to facilitate the completion of the surgery. After tracheal intubation, ventilation was controlled to maintain arterial oxygen saturation at 96% or higher and normocapnia. Body temperature was maintained at 36.0 °C or higher. Sevoflurane was stopped about 1 h before the end of the surgery and the flow of fresh gas was increased to ensure no residual of inhalational anesthetics at the end of the surgery. Ondansetron 4 mg was administered intravenously 0.5 h before the end of the surgery to prevent nausea and vomiting. An additional 10–15 µg of sufentanil was administered at the end of surgery for postoperative pain management.Neuromuscular function was evaluated by TOF-Watch SX acceleration muscle relaxation monitor (Organon, Dublin, Ireland). After the skin had been cleaned carefully, two surface skin electrodes were attached over the ulnar nerve proximal to the wrist at a distance of 3–6 cm. After immobilising the forearm, the acceleration transducer was fixed firmly to the volar side of the distal phalanx of the thumb on a small elastic hand adapter (TOF-Watch Handadapter; Schering-Plough, Swords, Ireland). The monitoring was initiated after induction, but before cisatracurium administration. The device was calibrated automatically after a 50-Hz tetanic stimulation for 5 s and a stable baseline (< 5% change in TOF ratio) was recorded. Normalized TOF values were calculated and recorded according to baseline TOF values. TOF stimulus was applied every 60 s until a TOF ratio greater than or equal to 0.9. When a TOF ratio of 0.2 was reached two times consecutively, a pre-determined dose of neostigmine provided by Sine Jinzhu Pharmaceutical company (Shanghai, China) was administered according to the patient group (NS, 20 µg/kg, 40 µg/kg or 50 µg/kg), accompanied by glycopyrrolate in an 1:5 ratio. The time from the administration of neostigmine to a TOF ratio of 0.9 was recorded. The proportion of patients with TOF value ≥ 0.9 10 min after neostigmine administration; the incidence of nausea and vomiting in patients on postoperative day 1-day 3; the proportion of patients with Mini-Mental State Examination (MMSE) score decrease ≥ 3 points on postoperative day 3; and PACU stay time after neostigmine administration were followed up. | PMC10413529 |
Statistical analysis | A sample size was calculated based on the primary outcome variable (the time from the administration of neostigmine to a TOF ratio of 0.9). To achieve a power of 0.8 with an alpha level of 0.05 and an effect size of f = 0.25, and considering a 10% drop out rate, a total sample size of N = 200 was needed. SPSS 22.0 software was used for statistical analysis. Count data were expressed as composition ratio; normally distributed measures were expressed as mean ± standard deviation, and t-test was used for comparison between two groups and one-way ANOVA for comparison between multiple groups; non-normally distributed measures were expressed as median (interquartile range), and Kruskal-Wallis H rank sum test was used for comparison between multiple groups; while categorical data were expressed as numbers with percentages and were compared using the Chi-square test. | PMC10413529 |
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Results | allergies | ALLERGIES | From January 2022 to November 2022, 240 ASA I-III patients aged from 60 to 85 who were scheduled for elective non-cardiac surgery under general anesthesia were enrolled, of which 40 patients were excluded due to contraindications (n = 18), allergies (n = 12) or declined to participate (n = 10). 200 patients completed randomization and participated in the study. 4 patients were excluded due to protocol violation (3 in NS group and 1 in 20 µg/kg group B). The number of patients included in the final statistical analysis was 196 (Fig.
CONSORT 2010 flow diagram. (adapted from | PMC10413529 |
Comparison of general data and perioperative data between the groups | Table
Analysis of baseline characteristicsBMI: Body Mass Index | PMC10413529 |
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Comparison of results of postoperative muscle relaxation monitoring | Postoperative nausea and vomiting | MUSCLE RELAXATION | As listed in Table Similar to the results of time to reach TOF value of 0.9, TOF value at 10 min after administration in 20 µg, 40 and 50 µg groups was significantly increased compared with that in control group (H = 93.351, In addition, we evaluated the postoperative outcomes of each group. As shown in the Table
Analysis of postoperative muscle relaxation monitoring and patient recovery*MMSE: Mini-Mental State Examination; PONV: Postoperative nausea and vomiting
Analysis of time of TOF ≥ 90% after neostigmine (min). Time of 20 µg, 40 and 50 µg groups was significantly shorter than that in NS group after administration of neostigmine (all
Analysis of TOF value 10 min after neostigmine (%). TOF value of 20 µg, 40 and 50 µg groups was significantly higher than that in NS group after administration of neostigmine ( | PMC10413529 |
Discussion | postoperative cognitive impairment, muscle blockade | DEGENERATION, MUSCLE RELAXATION, NEUROMUSCULAR BLOCKADE, POSTOPERATIVE COMPLICATIONS, COMPLICATION | This study explored the optimal dose of neostigmine in elderly patients to reverse the TOF value to 0.9. The results indicated that the dose of 40 µg/kg may be an optimized choice and did not increase the incidence of postoperative cognitive impairment or PONV.Incomplete neuromuscular recovery after general anesthesia is a common complication in patients after general anesthesia, with an incidence ranging from 31 to 64% [Elderly patients are prone to residual muscle relaxation due to organ function degeneration and physiological changes that lead to slow metabolism of neuromuscular blockers [The results of this study show that neostigmine was used for antagonism at the end of surgery, and even a small dose (20 µg/kg) can significantly accelerate muscle function recovery; but 40 µg/kg can achieve the purpose of rapid reversal of muscle blockade effect, further increasing the dose (50 µg/kg) cannot significantly shorten the time for muscle recovery. It suggested that a dose of 40 µg/kg of neostigmine may be an optimized choice to reverse the effects of muscle relaxants quickly, without increasing postoperative complications.Previous studies have explored the dose of neostigmine required for reversal of neuromuscular blockade. Preault A et al.[Additionally, our study found that the use of neostigmine to antagonize muscle relaxation at the end of surgery did not significantly shorten the postoperative PACU stay time of patients, which may be affected by confounding factors such as surgical type, analgesic sedative drugs and wound drainage at the end of surgery. Subsequent further trials should limit and standardize trial conditions, reduce related confounding factors and increase sample size to clarify the role of neostigmine in shortening PACU stay. | PMC10413529 |
Author contributions | Yan Liao and Jianbin Tong designed the study and collected the data. Mengya Cao, Yangwen Ou analyzed the data and Huifan Huang, Yan Liao drafted the manuscript. Mengya Cao and Jianbin Tong provided critical feedback on the study design, data analysis, and manuscript revisions.All authors have read and approved the final manuscript. | PMC10413529 |
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Funding | Not applicable. | PMC10413529 |
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Availability of data and materials | The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. | PMC10413529 |
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Declarations | PMC10413529 |
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Ethics approval and consent to participate | The study was approved by the ethics committee of the Ethics Committee of the Third Xiangya Hospital (reference number [R22008]) and written informed consent was obtained from all participants. The authors declare that all experiments were performed in accordance with relevant guidelines and regulations (such as the Declaration of Helsinki). | PMC10413529 |
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Consent for publication | Not applicable. | PMC10413529 |
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Competing interests | The authors declare that they have no competing interests. | PMC10413529 |
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References | PMC10413529 |
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Background | DEL | Edited by: Mario Clerici, University of Milan, ItalyReviewed by: Camilla Tincati, University of Milan, Italy; Julian Olalla, Hospital Costa del Sol, SpainThe aim of this randomized clinical trial (RCT) was to compare immunological changes in virally suppressed people living with HIV (PLWH) switching from a three-drug regimen (3DR) to a two-drug regimen (2DR). | PMC10613634 |
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Methods | BLOOD, SECONDARY | An open-label, prospective RCT enrolling PLWH receiving a 3DR who switched to bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) or dolutegravir/lamivudine (DTG/3TC) was performed. Blood was taken at baseline and months 6 and 12. The primary outcome was the change in CD4+ or CD8+ T-cell counts and CD4/CD8 ratio over time points. The secondary outcomes were the changes in immunological and inflammatory parameters. Parametric mixed-linear models with random intercepts and slopes were fitted separately for each marker after controlling for potential confounders. | PMC10613634 |
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Results | Between the two arms (33 PLWH each), there was no difference in CD4+ or CD8+ T cells, CD4/CD8 ratio, and IL-6 trajectories. PLWH switching to DTG/3TC had increased levels of both transitional memory and terminally differentiated CD4+ T cells (arm–time interaction p-value = 0.02) and to a lesser extent for the corresponding CD8+ T-cell subsets (p = 0.09). Significantly lower levels of non-classical monocytes were detected in the B/F/TAF arm at T6 (diff = −6.7 cells/mm | PMC10613634 |
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Conclusion | No evidence for a difference in absolute CD4+ and CD8+ T-cell counts, CD4/CD8 ratio, and IL-6 trajectories by study arm over 12 months was found. PLWH on DTG/3TC showed higher levels of terminally differentiated and exhausted CD4+ and CD8+ T lymphocytes and non-classical monocytes at T6. Further studies are warranted to better understand the clinical impact of our results. | PMC10613634 |
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Clinical Trial Registration | PMC10613634 |
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Introduction | HIV-1 infection, viremia, virological failure | HIV-1 INFECTION, CHRONIC INFLAMMATION, VIREMIA | Bictegravir/emtricitabine/tenofovir alafenamide (B/F/TAF) is a guideline-recommended regimen for the treatment of HIV-1 infection in both naïve and experienced patients that demonstrated high efficacy and barrier to resistance without occurrence of incident resistance among individuals experiencing virological failure (Despite the lack of evidence for a difference in rates of virological suppression, whether levels of chronic inflammation differ after effective treatment with 2DR Concerning viral replication, DTG/3TC in either naïve or experienced patients was shown to be non-inferior to 3DRs for the outcomes of target not detectable viremia or viral blips (Concerning chronic inflammation, the TANGO randomized trial, comparing PLWH switching to DTG/3TC to those remaining on a 3DR, has shown a statistically significant 16% increase in interleukin (IL)-6 plasma levels at 48 weeks in the first group (The aim of this randomized clinical trial was to compare the immunophenotype and inflammatory biomarkers in PLWH with viral load ≤50 copies/mL switching from a 3DR to B/F/TAF | PMC10613634 |
Methods | INFECTIOUS DISEASE | This is an open-label, prospective, single-center, randomized trial enrolling PLWH seen for care at the Infectious Disease Clinic of Azienda Ospedaliero-Universitaria Policlinico of Modena, Italy. The study, with EudraCT Number 2018-003458-26, was approved by the local Ethical Committee with Authorization Number AOU 0010923/19 on April 4, 2019, and AIFA Authorization Number AIFA/SC/P/33830 on March 25, 2019.Participants who had a suppressed HIV-RNA ≤50 copies/mL on a 3DR ART regimen for >12 months without any previous failure (previous switches to any other 3DRs with HIV-RNA ≤50 copies/mL were allowed), after providing written informed consent, were randomized 1:1 by means of simple randomization either to switch to B/F/TAF or DTG/3TC and were subsequently followed up for 48 weeks. Concealment of allocation was guaranteed using opaque envelopes so that random assignment was not revealed to the recruiters until participants had passed all screening tests and were deemed to be eligible. Participants have been enrolled over a period of 18 months. Other key inclusion criteria were as follows: i) age ≥18 years; ii) the ability to understand and sign a written informed consent form, which must be obtained prior to initiation of study procedures; and iii) no history of viral blips or virological failure prior to enrolment. Virological failure after randomization was defined as a confirmed virological rebound of HIV-1 RNA ≥ 50 copies/mL at two consecutive visits. Since at the time of enrollment there were still concerns about dolutegravir safety in pregnancy, female participants who were pregnant or planning pregnancy were excluded. More details about inclusion and exclusion criteria are included in Supplementary Annex 1. | PMC10613634 |
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Outcomes | inflammation | INFLAMMATION, SECONDARY | The primary outcome of the trial was the change in CD4+ or CD8+ T-cell counts and CD4/CD8 ratio from enrolment to week 48.The secondary outcomes were the changes in inflammation and other immune characteristics (phenotype of T cells, proportion of cells belonging to different CD4+ and CD8+ T-cell subsets, monocytes, and plasma levels of IL-6) from enrolment to week 48. | PMC10613634 |
Immunological analyses | Immunological analyses are described in detail in Supplementary Annex 2 ( | PMC10613634 |
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Statistical analyses | AIDS | AIDS | Participants’ characteristics by study arm were described and reported as the number of participants with relative frequencies for categorical factors and as the median and interquartile range (IQR) for continuous variables.Repeated measurements of all biomarkers were available at the three fixed time points (T0 = baseline, T6 = 6 months after randomization, and T12 = 12 months after randomization) of the trial overall, and the description was broken down by study arm. Box plots were used to describe the distribution of the raw data at the three time points (the graphs display values below Q1 and Q3 as outliers). We then performed unadjusted and adjusted parametric mixed-linear models with random intercepts and slopes including the main effects (study arm and time) as well as the interaction term. The adjusted model also included the key baseline confounders age, nationality, AIDS, duration of HIV, duration of viral load (VL) suppression, and CD4 count nadir. We fitted separate models for each of the outcome variables in the log scale and estimated at each time point the mean levels and difference by study arm with the corresponding 95% CI using the model predictions.Two symmetric analyses were conducted: the first using as the main outcome the absolute parameters values and the second analysis using the changes from T0 as an alternative outcome. Although the two approaches and the related statistical tests partially overlap statistically, this second analysis allows the estimation of the parameter changes from T1 by study arm. Specific contrasts (i.e., the mean CD4 count difference by study arm at T6) were considered only when there was an overall type 3 significant p-value (<0.05) for the global test for interaction between study arm and time. All participants stayed on the randomization treatment until the end of the study. Although a total of 10 parameters (CD4, CD8, ratio, CD4 TM, CD4 EMRA, CD8 TM, CD8 EMRA, two classes of monocytes, and IL-6) were fitted, these analyses were conceived | PMC10613634 |
Sample size calculations | We based the sample size calculations on the primary outcome change in CD8 count from T0 to T12. At the time of writing the trial protocol, we hypothesized that switching to DTG/3TC could be associated with a higher CD8 activation compared to switching to B/F/TAF. In particular, on the basis of data previously published in the literature available at the time of the protocol, we assumed that CD8 count could increase by 20 cells/mm | PMC10613634 |
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Results | AIDS, high-density lipoprotein | INFECTIOUS DISEASES, AIDS | Between September 2020 and January 2021, 66 patients attending the Clinic of Infectious Diseases of the Azienda Ospedaliero-Universitaria Policlinico of Modena were enrolled in the trial. Epidemiological characteristics are described in Main characteristics of target population by study arm.IQR, interquartile range; MSM, men who have sex with men; PWID, people who inject drugs; LDL, low-density lipoprotein; HDL, high-density lipoprotein; eGFR, estimated glomerular filtration rate.At baseline, patients were randomized to switch either to DTG/3TC (n = 33) or to B/F/TAF (n = 33). Despite randomization, the two groups differed in the proportion of those who were previously diagnosed with AIDS (18.2% DTG/3TC n = 6 | PMC10613634 |
Primary outcomes: CD4+ or CD8+ T-cell count and CD4/CD8 ratio | Concerning the primary endpoint of absolute values and change in CD4+ or CD8+ T lymphocyte count and in CD4/CD8 ratio, no evidence for a difference by study arm was found either at 6 (T6) or at 12 months (T12) after the switch (T0). All these three main immunological parameters tended to remain stable over time in both arms (Primary endpoints by study arm—adjusted analysis.RCT, randomized clinical trial; VL, viral load.
Primary endpoints (change) by study arm—adjusted analysis.RCT, randomized clinical trial; VL, viral load.
| PMC10613634 |
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CD4+ T-cell subsets | In contrast, when we looked at the proportion of CD4+ T-cell subsets, significant differences in trends by arm were detected for both TM and EMRA (arm–time interaction p-value = 0.02 in the adjusted analysis). The significance was likely to be driven by the trends at T6, the time at which values of both TM (−4.6 cells/mmCD4 subsets by study arm—adjusted analysis.RCT, randomized clinical trial; VL, viral load.
Box plots of CD4 and CD8 count subsets and adjusted prediction with 95% CI from fitting the mixed-linear model. | PMC10613634 |
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CD8+ T-cell subsets | The results for the CD8+ T-cell subsets were similar to those seen for the corresponding CD4+ T cells shown above, although none of the statistical interaction tests reached statistical significance (p = 0.09 for TM and p = 0.19 for EMRA in the adjusted analysis, CD8 subsets by study arm—adjusted analysis.
RCT, randomized clinical trial; VL, viral load.
| PMC10613634 |
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Monocytes | We then investigated trend in monocytes, specifically by distinguishing between classical and non-classical subsets (note that non-classical monocytes also included a small proportion of intermediate monocytes). Although no statistical significance was detected for the classical monocyte subsets (interaction p-value=0.50), for the non-classical monocytes we detected a strong association by arm and time (interaction p-value=0.03 in the adjusted model). Also in this analysis, the significance was likely driven by the difference at T6 when non-classical monocytes were significantly lower in B/F/TAF vs the DTG/3TC arm (diff =-6.7 cells/mm3, 95% CI; -16;+2.6). The difference was again attenuated at T12 (Monocytes by study arm—adjusted analysis.RCT, randomized clinical trial. | PMC10613634 |
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Inflammation: IL-6 | inflammation | INFLAMMATION | We finally analyzed the trend in IL-6, chosen as the most important cytokine related to onset and maintenance of inflammation. Because of the trend seen with the CD4+ and CD8+ TM/EMRA T cell subsets (large difference by study arm at T6 followed by an attenuation of the difference at T12), we hypothesized that this might have been caused by a return to normal in the overall level of inflammation at T6. However, the data carried no evidence of a difference in the trajectories of IL-6 over T0-T12 by study arm, and especially the difference by arm in IL-6 tended to remain small and stable over T6-T12 (IL-6 by study arm—adjusted analysis.
RCT, randomized clinical trial; VL, viral load.
| PMC10613634 |
Discussion | inflammation, atherosclerosis, HIV infection, non-AIDS | HIV INFECTION, INFLAMMATION, DYSFUNCTION, EVENTS, ATHEROSCLEROSIS, PERSISTENT INFLAMMATION, ENDOTHELIAL DYSFUNCTION | Our randomized study shows no evidence for a difference in absolute CD4+ and CD8+ T-cell counts and in CD4/CD8 ratio trajectories over 12 months of follow-up by study arm (DTG/3TC However, importantly, our data provide additional insights concerning immunological changes after switching from 3DR treatment to DTG/3TC or B/F/TAF. First, the increase in CD4+ and to a lesser extent in CD8+ activated T cells, coupled with an increase in transitional memory and terminally differentiated cells, especially at 6 months after switching to DTG/3TC, but not after switching to B/F/TAF, could indicate an effect of DTG/3TC, which goes beyond reaching an undetectable plasma viral load. Second, in order to synthesize soluble or plasma membrane molecules that provide signals to the cells of interest, monocytes have to receive stimulatory signals that activate them. The analysis of the changes in monocyte subpopulations reveals a significant difference by arm at 6 months in non-classical monocytes, including intermediate cells that have inflammatory properties.The balance between monocyte subsets is disrupted after HIV infection, and the number and function of these cells are not completely restored even after long-term ART (As for T-cell activation, inflammation in response to a phenomenon could be only transient since the immune system tries to reach a new balance, which could explain, at least in part, the changes in monocyte populations that were observed at time 6, but to a less extent at time 12 in the DTG/3TC group. Thus, during HIV infection as well as in its treatment, proportions of monocyte subgroups (classical, intermediate, and non-classical) can provide information regarding the level of residual immune dysfunction and associated risk of serious non-AIDS events (Concerning cardiovascular risk, persistent inflammation and immune activation have been hypothesized to promote atherosclerosis in PLWH (Concerning IL-6 trajectories, our results are consistent with those of a recent meta-analysis of all published data (including both real-world and randomized studies) showing inconclusive results regarding the level of inflammation after switching to DTG/3TC compared to those seen with 3DRs (In a real-world study evaluating inflammatory biomarkers, median sCD14 significantly decreased 48 weeks post-switch to DTG/3TC, while other biomarkers remained stable (Our study has several limitations. First of all, as in most small trials, despite randomization (However, this analysis has several strengths. First of all, our analysis confirms that in the rigorous context of a randomized comparison in PLWH with ≤50 copies/mL, after 1 year of therapy, there is little evidence for a difference in immune response when comparing DTG/3TC with B/F/TAF. In addition to randomization, there is the fact that although this study was open-label, all laboratory analyses were conducted without knowing the treatment received by the patients. Moreover, our data could provide a glimpse of what is happening in the lymphoid tissues. Indeed, we observed changes in different blood cell populations that play a key role in triggering or maintaining the immune response, including inflammation. There are two main aspects to consider about this. First, the number of cells in blood represents just a small proportion (approximately 2%) of those belonging to innate or acquired immunity. Thus, even a minimal change in this compartment could be a signal for a much larger change at the level of a number of immune tissues.In conclusion, our study showed no evidence for a difference in absolute CD4 and CD8 T-cell counts and CD4/CD8 ratio trajectories over 12 months between DTG/3TC and B/F/TAF after the switch. However, the switch to DTG/3TC was associated after 6 months with statistically higher levels both in CD4+ and CD8+ T lymphocytes with markers related to terminal differentiation and exhaustion and in non-classical monocytes, a population of cells that has been recently associated with endothelial dysfunction. Further studies investigating a wider range of dual antiretroviral combinations, longer follow-up, and the power to detect differences in harder clinical outcomes are needed to confirm the clinical impact of our findings. | PMC10613634 |
Author’s note | Preliminary results were presented at the 30th HIV Glasgow, October 23–26, 2022. Abstract n. P099 published in | PMC10613634 |
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Data availability statement | The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation. | PMC10613634 |
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