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Trial Pathway and Randomization | Once eligible patients were identified, managing physicians discussed the trial with them, and written informed consent was obtained ( | PMC10098968 | ||
Randomized Clinical Trial Algorithm | serous, infection, opacity, inadequate lung re-expansion | INFECTION, OPACITY, CAVITY | IPFT indicates intrapleural fibrinolytic therapy.Effectiveness of drainage and/or lung re-expansion was determined on protocol image 1, defined as imaging (chest radiography or chest computed tomography) the day following chest tube placement. Patients with complete pleural fluid drainage and adequate lung re-expansion were followed up with usual clinical care without randomization and were observed until discharge. Patients with incomplete drainage and/or inadequate lung re-expansion as assessed by the attending physician underwent a thoracic surgery consultation to determine surgical candidacy. Those patients deemed ineligible for surgical intervention received guideline-appropriate nonsurgical care and were observed until discharge.Those eligible for surgical management underwent randomization with a 1:1 allocation using the sealed envelope technique, generated by the research coordinator, to either IPFT or surgery. The primary intervention was required to be initiated within 48 hours. Those patients randomized to the IPFT group received 5 to 6 doses of IPFT with 10 mg of tissue plasminogen activator and 5 mg of deoxyribonuclease delivered twice a day through the chest tube, which was then clamped, allowing the IPFT to remain in the pleural cavity for 1 hour. Patients randomized to the surgical group underwent surgical decortication with either an open or a video-assisted thoracoscopic surgery (VATS) approach at the discretion of the surgeon.The morning following intervention completion (last dose of IPFT or surgery), protocol image 2 was obtained to categorize drainage as satisfactory improvement of the pleural fluid collection (>75% improvement in opacity on imaging), unsatisfactory improvement (≤75% improvement without clinical evidence of infection), or treatment failure (≤75% improvement and evidence of ongoing infection, defined below). In patients with satisfactory improvement without ongoing signs and symptoms of infection, chest tubes were removed once fluid was serous and output was less than 200 mL in 24 hours. In patients with unsatisfactory improvement without ongoing signs and symptoms of infection, and in those with treatment failure, further clinical management was at the discretion of the managing physician. | PMC10098968 |
Objectives and Outcomes | SECONDARY, RECRUITMENT, COMPLICATIONS | The primary objective was to determine the feasibility of the proposed study algorithm comparing IPFT and surgical intervention as measured by percentage of enrollment to completion of the study algorithm and percentage of multidisciplinary participation in adherence to the algorithm. There were multiple secondary objectives evaluated in an effort to maximize successful recruitment, assist with multicenter study design, and obtain preliminary information for sample size estimates. We evaluated patient identification strategies (number of and reason for inadequate screening of eligible patients and failure of screening to enrollment) and collected accrual times (time to accrual of 20 patients or number of patients accrued in 1 year, whichever occurred first). Preliminary clinical data on the proposed chest tube management algorithm were also collected, including number of chest tube and hospital days. Supplementary clinical end points (radiographic improvement, treatment failures, additional procedures, complications, and 30- and 90-day mortality) were collected to inform on the efficacy and safety of the algorithm. | PMC10098968 | |
Definitions | pleural infection, fever, infection, Comorbidity, leukocytosis, Infection | RENAL, ALEUKOCYTOSIS, PLEURAL INFECTION, INFECTION, INFECTION | Comorbidities were classified according to the Charlson Comorbidity Index.Treatment failure was defined by evidence of ongoing infection, including fever and/or leukocytosis and a persistent pleural collection still present at least 48 hours following the initial intervention. Crossover treatment, independent of treatment failure, was defined by receiving any dose of IPFT following surgery or surgery following any dose of IPFT. The RAPID (Renal, Age, Purulence, Infection Source, and Dietary Factors) score for pleural infection was calculated as a validated factor associated with mortality. | PMC10098968 |
Statistical Analysis | As this was a pilot study testing feasibility, we aimed to enroll a total of 30 patients, with the goal of randomizing 20 patients (10 in each group) and consideration for patients not randomized falling into the observation group. Groups were compared using an intention-to-treat analysis.Continuous data were reported as medians with IQRs. Categorical and count data were presented as frequencies and percentages. Characteristics between the study groups were compared using χ | PMC10098968 | ||
Results | PMC10098968 | |||
Algorithm Feasibility | A total of 26 patients were enrolled, with 10 in each treatment group and 6 in the observation group. There was 100% enrollment of patients in each treatment group to study completion. Although there were no health care professional protocol deviations in consented patients, 2 thoracic surgeons voiced a preference for surgery in 3 patients (3 of 48 exclusions [6%]) screened for inclusion. These patients were excluded prior to consent.Two amendments were made to the protocol during the trial period. The first was to drop the minimum size of the initial chest tube from 14F to 12F, as outside hospitals were referring patients with 12F chest tubes. The second was a change to the wording for protocol image 1 to “next day” instead of “within 24 to 48 hours,” as specific time restraints were restrictive for patient care. | PMC10098968 | ||
Patient Identification and Accrual | Seventy-four patients with a CPI were assessed for eligibility over the study period, and 48 (65%) were excluded ( | PMC10098968 | ||
Flow Diagram of Trial Profile | PLEURAL INFECTION | CPI indicates complicated pleural infection; IPFT, intrapleural fibrinolytic therapy. | PMC10098968 | |
Clinical Outcomes of Randomized Patients | Overall, the 20 randomized patients had a median age of 57 (IQR, 46-65) years; 15 (75%) were men and 5 (25%) were women ( | PMC10098968 | ||
Summary Statistics of Baseline Measures Overall and Stratified by Treatment Group | hemothorax, opacification, chest pain, Infection | RENAL, PLEURAL INFECTION, HEMOTHORAX, INFECTION | Abbreviations: CPI, complicated pleural infection; IPFT, intrapleural fibrinolytic therapy; RAPID, Renal, Age, Purulence, Infection Source, and Dietary Factors.Unless otherwise indicated, data are expressed as No. (%) of patients. Percentages have been rounded and may not total 100.Calculated as weight in kilograms divided by height in meters squared.In those patients randomized to IPFT, 6 (60%) had 6 doses, 2 (20%) had 5 doses, and 2 (20%) had 4 doses. One patient who received 4 doses refused further IPFT due to chest pain and requested surgery. This patient underwent crossover treatment and received a VATS decortication. The other patient who received 4 doses had a hemothorax, IPFT was stopped, and the hemothorax was monitored. The patient’s CPI ultimately resolved with no further treatment. In those patients randomized to surgery, all patients received a VATS decortication.On protocol image 2 following completion of treatment, 5 patients (50%) in the IPFT group and 3 (30%) in the surgery group had greater than 75% opacification improvement ( | PMC10098968 |
Clinical and Outcome Details Overall and Stratified by Treatment Group | death, organ dysfunction | MINOR, COMPLICATION | Abbreviations: ICU, intensive care unit; IPFT, intrapleural fibrinolytic therapy.Unless otherwise indicated, data are expressed as No. (%) of patients. Percentages have been rounded and may not total 100.Grade I indicates any complication without need for pharmacological treatment or other intervention; grade II, any complication that requires pharmacological treatment or minor intervention only; grade III, any complication that requires surgical, radiological, or endoscopic intervention or multitherapy; grade IIIa, intervention does not require general anesthesia; grade IV, any complication requiring intensive care unit management and life support; grade IVa, single organ dysfunction; grade V, any complication leading to the death of the patient. | PMC10098968 |
Major Postprocedure Complication Details, Stratified by Treatment Group | organ dysfunction | Abbreviation: IPFT, intrapleural fibrinolytic therapy.Grade IIIa indicates intervention does not require general anesthesia; grade IVa, single organ dysfunction.The median duration of chest tube use was comparable in the IPFT (5 [IQR, 4-8] days) and surgery (4 [IQR, 3-5] days) groups ( | PMC10098968 | |
Observation Patients | pleural infection, fever, empyema, deaths, leukocytosis | PLEURAL EFFUSION, ALEUKOCYTOSIS, PLEURAL INFECTION, DENTAL ABSCESS, COMPLICATION, PARAPNEUMONIC EFFUSION, EMPYEMA, ACUTE HYPOXIC RESPIRATORY FAILURE | There were 6 patients in the observation group. Their median RAPID score was 3 (IQR, 2-4), and 4 (67%) had a complicated pleural infection vs 2 (33%) who had an empyema. During observation, 2 patients (33%) were given additional treatment for radiographic persistent pleural fluid collections; neither had a fever or leukocytosis at the time of additional treatment. Both patients received IPFT; one patient had a single dose and the other had 3 doses. Protocol image 1 for both of these patients was chest radiography.Only 1 patient (17%) had a complication (grade II): a dental abscess. The median duration of chest tube use was 4 (IQR, 3-6) days, and the median hospital length of stay was 10 (IQR, 7-13) days. One patient (17%) who required additional treatment was readmitted within 30 days with a persistent parapneumonic effusion, a new contralateral pleural effusion, and acute hypoxic respiratory failure. The patient underwent chest tube placement and 3 doses of IPFT. There were no 30- or 90-day deaths in the observation group. | PMC10098968 |
Discussion | In this pilot randomized clinical trial, we identified the study algorithm comparing IPFT with surgical management of a CPI to be feasible with 100% patient enrollment to study completion and excellent multidisciplinary protocol adherence following randomization. Patient identification and accrual was adequate, with all eligible patients screened, no screening to enrollment failures, and approximately 9 patients enrolled annually. Clinical characteristics and outcomes were similar to those in previous reports, confirming safety and efficacy of the algorithm. We also conclude that our standardized chest tube removal criteria were effective, as no additional procedures were required in randomized patients following chest tube removal. We believe these findings provide evidence that the proposed algorithm can move forward to a large, multicenter randomized clinical trial.Previous studiesSupporting the primary outcome, we identified the study algorithm to be feasible, safe, and efficacious. As with any randomized trial, equipoise in physician screening of patients and in discussion of the trial with patients is critical to study the algorithm feasibility and implementation. With the proposed algorithm, there were 3 instances of the physician choosing surgery instead of randomization, and these patients were excluded prior to enrollment. This may be prevented in the future by including sites where physicians commit to the algorithm. At the study summation meeting of investigators, all participants voiced support for the study algorithm and to proceed with a multicenter trial.A potential challenge to accrual, which should not affect future trials, was the emergence of the COVID-19 pandemic. Study enrollment was paused briefly in 2020, and while this may have prolonged the overall duration of patient enrollment, enrollment was similar in 2020 and 2021 compared with 2019. Patient clinical follow-up was likely affected, as we noticed patients were not routinely available.This study was not powered to identify differences in clinical outcomes; therefore, the small population size warrants some hesitation in interpretation. However, with that caveat, our outcomes appear relatively similar to the previously published retrospective data.This pilot trial is notable as it is one of the first to assess the feasibility, safety, and efficacy of a study algorithm comparing IPFT with surgical decortication for the management of a CPI. Ongoing trials across the globe | PMC10098968 | ||
Limitations | hemothorax | HEMOTHORAX, MINOR, COMPLICATION, COMPLICATIONS | This study has some limitations. We identified chest tube duration as a clinically useful primary outcome that is both easy to quantify and standardize; therefore, we intend to use chest tube duration as the primary outcome in the future multicenter trial. Due to the small sample size and skewed mean values in this pilot study, the power calculation will have to be based on cumulative historical data. Another limitation of this study is the use of the Ottawa classification of thoracic morbidity and mortality for categorizing complications. This classification was designed for postoperative thoracic surgery complications, and it is also based on the severity of the complication being proportional to the effort to treat it. We would consider a hemothorax due to IPFT to be a significant complication; however, since IPFT was stopped and there was no further treatment, this complication is categorized as minor. We used this classification in an attempt to standardize categorization of complications for comparison purposes. | PMC10098968 |
Conclusions | pleural infections | PLEURAL INFECTION | In this pilot randomized clinical trial, we identified an algorithm comparing tissue plasminogen activator plus deoxyribonuclease therapy with surgical decortication to be feasible with 100% enrollment to completion, with excellent multidisciplinary participation and adherence. These findings show that the studied algorithm is safe and efficacious for patients with complicated pleural infections, with a strong feasibility for appropriate enrollment within a reasonable time frame for a multicenter study. | PMC10098968 |
1. Introduction | T2DM | TYPE 2 DIABETES MELLITUS | Aronia melanocarpa berries are rich in antioxidants and possess a high antioxidant capacity. Aronia berries have shown potential in type 2 diabetes mellitus (T2DM) treatment, and previous studies indicate improvements in glycemia after supplementation. Unfortunately, the effectiveness of aronia berries is limited by the low bioavailability of aronia, which fermentation could potentially overcome. The objective of this study was to compare the effects of fermented or non-fermented aronia pulp with placebo in subjects with T2DM. This study was a triple-blinded, triple-crossover study with eight-week intervention periods with fermented aronia extract (FAE), non-fermented aronia extract (AE), and placebo. Extracts were incorporated in snack bars with 37% aronia (FAE or AE) or wheat bran (placebo) and 63% raisins and coconut oil. Pre- and post-treatment period, we did fasting blood samples, including hemoglobin A1c, fructosamine, insulin, glucose, glucagon-like peptide-1, glucose-dependent insulinotropic peptide (GIP) and glucagon, oral glucose tolerance tests, and anthropometric measurements. Of 36 randomized participants, 23 completed the trial. Aside from a higher increase in GIP after FAE supplementation compared to after placebo supplementation, aronia extracts had no effect. The increase in GIP levels after FAE supplementation may hold potential benefits, but the overall clinical impact remains unclear.Aronia melanocarpa is a garden shrub that is convenient to cultivate and requires low maintenance [Aronia berries have attained great interest in relation to their high antioxidant capacity [It has been reported that the polyphenols from aronia berries are poorly absorbed, which may limit their health-promoting effects [Therefore, we wanted to further clarify the role of aronia in the treatment of T2DM. At present, no clinical studies have examined the effect of aronia in a blinded setting or investigated the effect of aronia on glucose metabolism and on circulating levels of glucagon, incretin, and insulin. Thus, the objective of the present study was to compare the effects of eight weeks of administration of fermented or non-fermented aronia pulp with a placebo in a blinded setting in subjects with T2DM. We hypothesized that both aronia extracts would improve glucose metabolism, however, the fermented more than the unfermented product, in comparison to placebo, with AUC and iAUC during OGTT being the primary endpoint. Secondary outcomes include computations of glucose metabolism and measurements of circulating levels of glucagon, incretin, and insulin. | PMC10574687 |
2. Materials and Methods | PMC10574687 | |||
2.1. Study Design | RECRUITMENT | The trial was a triple-blinded, triple-crossover study with intervention periods of eight weeks duration. Between each intervention period, there was a wash-out period lasting at least three weeks. Each participant received fermented aronia extract (FAE), aronia extract (AE), or placebo in a random order. The dietary supplements were consumed twice daily, once in the morning, before breakfast and once in the evening, before dinner. The participants were randomly assigned to the treatment order using block randomization based on random sequence generation in Excel. A person not related to the study generated the codes and put them in sealed envelopes. Participants were recruited through advertisements in local newspapers, at a dedicated website for recruitment of participants (“forsoegsperson.dk”), and on social media platforms. The study candidates received study information orally and in writing and were given one week for consideration. If the candidate was interested in participating, a written consent was obtained. Participants had the right to withdraw their participation at any time.All tests and examinations were performed before and after each of the three intervention periods, e.g., a total of six repeats. Tests and examinations included fasting blood samples, oral glucose tolerance tests, and measurements of weight and waist circumference. The study was conducted at the Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Denmark from December 2020 to April 2022. The trial was performed in accordance with the Declaration of Helsinki and approved by The Danish Ethics Committee (Journal no. 1-10-72-102-19). The trial was registered at ClinicalTrials.gov under NCT04647175. | PMC10574687 | |
2.2. Participants | substance abuse, T2DM, fasting blood glucose ≤, diabetes | RENAL DISEASES, DIABETES | Inclusion criteria were diagnosis of T2DM, age of 30 to 80 years, fasting blood glucose ≤ 12 mmol/L, and HbA1c > 6.1% and <10% (>43 and <86 mmol/mol) if participants were in medical diabetes treatment OR HbA1c > 6.5% and <10% (>48 and <86 mmol/mol) if participants were treated with lifestyle only. Any treatment modality was accepted, including GLP-1 agonists and insulin therapy. Exclusion criteria were changes in diabetes medication within the last 3 months, serious comorbidities, including cardiovascular, neurological, psychological, and/or renal diseases, alcohol or substance abuse, and pregnant or planned pregnancy. To make an overall health assessment of the participants before enrolment, various other blood tests were performed. The participants should abstain from aronia consumption three weeks prior to trial initiation. During the trial, they were not allowed to consume other aronia products than the test supplements. | PMC10574687 |
2.3. Test Products | DECAY | The test products are made on leftover aronia pulp from juice production and kindly provided by the company Elkærholm (Egtved, Denmark). To reduce variations in the test products’ antioxidant potential due to differences in cultivation conditions, all test products were based on berries harvested at the same time and location. In order to make the aronia pulp extract edible, snack bars consisting of aronia, raisins, and coconut oil were produced. For FAE and AE, a daily dose was composed of 34 g of either fermented or non-fermented aronia, 55 g of raisins, and 3 g of coconut oil. In the placebo bars, aronia pulp was substituted with 17 g of wheat bran and 5 g of liquid (water and colorants). The anthocyanin concentration in both fermented and non-fermented aronia was assessed by Elkærholm using HPLC, which measured the combined concentrations of cyanidin-3-galactoside, cyanidin-3-arabinoside, and cyanidin-3-glucoside. A daily dose of 34 g of fermented aronia contained 893 mg of anthocyanins, while the same quantity of non-fermented aronia provided 533 mg of anthocyanins.HPLC measurements were made on berries harvested in 2018, whereas berries from 2019 were used for the test products. The pH differential method was used to determine the relative cyanidin-3-glucoside concentration in both fermented and non-fermented aronia made from berries harvested in both 2018 and 2019. The cyanidin-3-glucoside equivalent anthocyanin concentration was higher in the aronia pulp extract from berries from 2019 than in 2018, by 3.3 and 2.12 times for non-fermented and fermented aronia, respectively. It should be emphasized that natural decay during storage undoubtedly contributed to this difference.Energy contents of the test products were measured by Eurofins Steins Laboratorium (Vejen, Denmark). The nutritional composition of the three test products was comparable as outlined in | PMC10574687 | |
2.4. Compliance | Each daily dose of test product (2 bars) was individually packed in plastic bags. In order to assess compliance, the participants handed in empty plastic bags after each 8-week intervention period, which were then counted by blinded personnel. | PMC10574687 | ||
2.5. Oral Glucose Tolerance Test | BLOOD | The last supplement was consumed the evening before the OGTT allowing for an eight-hour fast prior to the OGTT. At the OGTT, the participants consumed 75 g of glucose dissolved in 150 mL of water within 5 min. Blood was sampled from a peripheral venous catheter placed at the antecubital fossa at time points −10, 0, 30, 60, 90, 120, and 240 min. | PMC10574687 | |
2.6. Anthropometric Measurements | Body weight measurements were determined using a calibrated SECA scale. For each participant, the same scale was used at all visits. Waist circumference was determined using a measuring tape. The same investigator undertook all measurements. | PMC10574687 | ||
2.7. Blood Analyses | BLOOD | Blood was collected from participants after an eight-hour fast. HbA1c was measured in whole blood immediately after collection. Baseline values were also measured immediately. Remaining samples were centrifuged at 4 °C and 3989 RPM for 10 min after which plasma was stored at −80 °C until analysis. | PMC10574687 | |
2.7.1. Baseline Measurements, HbA1c and Lipids | Baseline measurements and HbA1c concentrations were measured by Department of Clinical Biochemistry at Aarhus University Hospital, Denmark (DS/EN ISO 15189:2013 approved). | PMC10574687 | ||
2.7.2. Glucose (Complete Cases) | For participants that completed the trial, glucose was quantified on Cobas c111-system using a commercially available enzymatic colorimetric kit (#11491253 216, Roche Diagnostics, Basel, Sitzerland) that employs a glucose oxidase–peroxidase method. Intra-assay and inter-assay coefficients of variability (CV) were between 1.25–2.18% and 2.29–2.40%, respectively. For incomplete cases, glucose concentrations were measured as described below. | PMC10574687 | ||
2.7.3. Fructosamine and Glucose (Incomplete Cases) | The Indiko analyzer was used with commercially available kits to determine blood concentrations of fructosamine (#FR4030, Randox Laboratories Ltd., Malling, Denmark) for all participants and glucose (#981779, ThermoFisher Scientific, Roskilde, Denmark) for the non-completers. | PMC10574687 | ||
2.7.4. Insulin, Glucagon, GIP, and GLP-1 | Commercially available ELISA kits were used to determine the concentrations of insulin (#10-1113-01, MERCODIA), glucagon (#10-1271-01, MERCODIA), GIP (#10-1258-01, MERCODIA) and GLP-1 (#10-1278-01, MERCODIA). The concentration of glucagon was below the lower limit of detection in 11 samples. These values were dispersed across all groups. Seven values were below the lower limit of detection for GIP; again, values were dispersed across all groups. | PMC10574687 | ||
2.8. Power Calculation | T2DM | The power calculation was performed for our primary endpoint, which was a 240 min incremental area under the curve (iAUC) for glucose during an OGTT. In a previous study investigating the effect of stevioside in T2DM, we identified a minimally relevant difference for a 240 min iAUC for a test meal of 18% (iAUC 638 ± 55 versus 522 ± 64 mmol/L × 240 min (control versus stevioside); | PMC10574687 | |
2.9. Statistics and Calculations | INSULIN RESISTANCE, INSULIN SENSITIVITY | For baseline data, normality was assessed visually by histograms and by Shapiro–Wilk test using RStudio (version 2023.06.1). Normally distributed data are presented as mean ± standard deviation (SD) and non-normally distributed data are presented as median (interquartile range (IQR)). Total area under the curve (AUC) and iAUC for glucose and insulin during the OGTT were calculated with GraphPad Prism (Version 9). In order to assess insulin sensitivity, homeostasis model assessment for insulin resistance (HOMA-IR) [Normality was evaluated using quantile–quantile plots of residuals, fitted values versus residuals plots, and histograms of residuals. The RStudio package emmeans was used to obtain estimated marginal means, which will be referred to as mean throughout the article, and to compare means. Normally distributed data are presented as the difference between pre- and post-values with standard error. Not normally distributed data were log-transformed, and they are presented as ratio and confidence intervals, e.g., 1.02 indicates a 2% increase from pre to post, whereas 0.98 indicates a 2% decrease.In cases where blood analyses revealed concentrations below the lower level of detection for the various assays, the values were computed as half of the lower level of detection. | PMC10574687 | |
3. Results | PMC10574687 | |||
3.1. Baseline Characteristics | Forty-four persons were screened for the trial, of which thirty-six were randomized. The remaining eight did not fulfill the inclusion criteria. A total of 23 participants completed the trial, of which 15 were men and 8 were women. A CONSORT flow diagram, including reasons for exclusion and reasons for discontinuation of the intervention, is presented in | PMC10574687 | ||
3.2. Compliance | Based on the number of empty plastic bags the participants handed in, EMM for compliance was 99% ± 1%, 97% ± 1%, and 95% ± 1% for intervention with FAE, AE, and placebo, respectively. The 3% difference in compliance between FAE and placebo was statistically significant at | PMC10574687 | ||
3.3. Anthropometric Measurements | In regard to anthropometric measurements, as outlined in | PMC10574687 | ||
3.4. Blood Analyses | HbA1c and fructosamine measurements were applied to evaluate the effect of the interventions on blood glucose over the preceding period of approximately 3 months and 2 weeks, respectively [ | PMC10574687 | ||
4. Discussion | fasting blood glucose, mean fasting blood glucose, taste and sensory, T2DM, glucometabolic | DISEASE, MINOR, INSULIN SENSITIVITY | In this study, we investigated the effect of an 8-week supplementation regimen with two different formulations of aronia extract, i.e., fermented and non-fermented formulations, and compared with placebo on glucometabolic parameters in subjects with T2DM. We hypothesized that both aronia extracts would improve glucose metabolism in comparison to placebo, with AUC and iAUC during OGTT being the primary endpoint. We found no significant impact on waist circumference, BMI, HbA1c, fructosamine, or fasting values of insulin, glucose, GLP-1, or glucagon. Additionally, we detected no impact on the AUC of glucose or insulin or influence on insulin sensitivity. However, we did observe a minor increase in body weight and an elevation of the fasting level of GIP in the FAE group. Notably, the increase in GIP was significantly higher after intervention with FAE compared to placebo, whereas no intergroup differences were observed in relation to body weight.Regarding incretins, it is well-established that GLP-1 analogs improve disease outcomes for individuals with T2DM [We chose to incorporate the aronia extracts in snack bars as we expected higher compliance in comparison to, e.g., pills or capsules. Indeed, we observed an excellent compliance of above 95% for those who completed the trial. Nevertheless, it is possible that the nutritional composition of the bars contributed to the observed slight increases in weight, BMI, and waist circumference after supplementation with FAE and AE. The test products were high in sugar, as raisins were used to make the aronia pulp eatable and improve taste and sensory acceptance. Since it has been demonstrated that the consumption of raisins only produces a minor increase in postprandial blood glucose [Additionally, we found no significant differences in fasting and long-term blood glucose control, glucose tolerance, or insulin concentrations following any of the interventions. This is in contrast to results from in vitro and in vivo animal models of T2DM that have reported positive effects on the aforementioned parameters [It is worth mentioning that overall, the participants in our study were rather well-regulated with fasting blood glucose of ~8.4 mol/L and HbA1c of ~54 mmol/mol. Consequently, it could be questioned whether our participants were too well controlled regarding risk markers to demonstrate any improvements after supplementation. In contrast, Simeonov et al. reported a pre-intervention mean fasting glucose of ~13.3 mmol/L and a mean HbA1c of ~79 mmol/mol, which were subsequently reduced to a level similar to our baseline values after supplementation, resulting in a mean fasting blood glucose of ~9.1 mol/L and HbA1c of ~58 mmol/mol.One notable strength of our study is the high amount of anthocyanins provided. In comparison, the studies included in our aforementioned systematic review generally employed aronia supplements that typically provided between 300 mg and a maximum of 600 mg polyphenols per day [We hypothesized that FAE would deliver an increased amount of bioavailable polyphenols, potentially resulting in improved efficacy. It should be considered that fermentation might have the opposite effect and make the polyphenols more susceptible to degradation [ | PMC10574687 |
5. Conclusions | T2DM | INSULIN SENSITIVITY | In conclusion, our study demonstrated that supplementation with either fermented or non-fermented aronia extract did not affect waist circumference, insulin sensitivity, or fasting levels of glucose, insulin, or glucagon in subjects with T2DM. To our knowledge, this study is the first examination of dietary supplementation with aronia extracts on glucose metabolism in subjects with T2DM. Our research contributes to the expanding body of knowledge on aronia supplementation on human health. However, there is a need for further investigations, particularly on the effect of longer intervention periods as well as a need for studies with a larger sample size. | PMC10574687 |
Author Contributions | Conceptualization, C.B.C., P.B.J., K.H. and S.G.; validation, C.B.C., P.B.J., K.H. and S.G.; formal analysis, C.B.C.; investigation, C.B.C.; data curation, C.B.C.; writing—original draft preparation, C.B.C.; writing—review and editing, P.B.J., K.H. and S.G.; supervision, P.B.J., K.H. and S.G.; project administration, C.B.C., P.B.J., K.H. and S.G.; funding acquisition, C.B.C., P.B.J., K.H. and S.G. All authors have read and agreed to the published version of the manuscript. | PMC10574687 | ||
Institutional Review Board Statement | The study was conducted in accordance with the Declaration of Helsinki, and approved by the Institutional Review Board (or Ethics Committee) of The Central Denmark Region Committees on Health Research Ethics (Journal no. 1-10-72-102-19, 12 August 2019). | PMC10574687 | ||
Informed Consent Statement | Informed consent was obtained from all subjects involved in the study. | PMC10574687 | ||
Data Availability Statement | Data supporting reported results can obtained by contacting the corresponding author. | PMC10574687 | ||
Conflicts of Interest | The authors declare no conflict of interest. | PMC10574687 | ||
References | INSULIN RESISTANCE | CONSORT flow diagram outlining inclusions, exclusions, and reasons for discontinuation.Nutritional composition of test products containing aronia extract or placebo. Values are for one daily dose (2 bars). For macronutrients, we also provide energy in percentage in square brackets, which are calculated by assigning 4 kcal/g of carbohydrate or protein and 9 kcal/g of fat and dividing that value by the energy content.Abbreviations: FAE: fermented aronia extract, AE: aronia extract.Baseline values for participants that have completed the trial. Abbreviations: SD: standard deviation, IQR: interquartile range, W: women, M: men.Abbreviations: SD: standard deviation, IQR: interquartile range, W: women, M: men.Overview of participants’ medications.Mean pre- and post-values as well as mean difference (Δ-mean) for anthropometric measurements and blood analyses. Normally distributed data are presented as the mean difference between pre- and post-values ± standard error (Δ-mean). Not normally distributed data are written in italics and presented as ratio (confidence levels), e.g., 1.02 indicates a 2% increase from pre to post, whereas 0.98 indicates a 2% decrease. Means for pre- and post-values are all presented on original scale ± standard error. Abbreviations: FAE: fermented aronia extract, AE: aronia extract, HbA1c: hemoglobin A1c, AUC: area under the curve, iAUC: incremental area under the curve, HOMA-IR: homeostasis model assessment for insulin resistance, GLP-1: glucagon-like-peptide-1, GIP: glucose-dependent insulinotropic polypeptide. | PMC10574687 | |
1. Introduction | embolus, death, Strokes, stroke, hemorrhagic, physical disability, psychiatric, musculoskeletal pathologies, disability, strokes | STROKES, STROKE, PHYSICAL DISABILITY, ISCHEMIC STROKE, CEREBROVASCULAR ACCIDENT, CEREBRAL INFARCTION, STROKES | A stroke is a neurological condition with a high impact in terms of physical disability in the adult population, requiring specific and effective rehabilitative approaches. Virtual reality (VR), a technological approach in constant evolution, has great applicability in many fields of rehabilitation, including strokes. The aim of this study was to analyze the effects of a traditional neurological physiotherapy-based approach combined with the implementation of a specific VR-based program in the treatment of patients following rehabilitation after a stroke. Participants (A stroke, also known as a cerebrovascular accident (CVA), is one of the main causes of physical disability in adults [A stroke can be either ischemic or hemorrhagic. An ischemic stroke, which is the most frequent type, is caused by a significant decrease in the blood flow to a part of the brain. This lack of blood supply produces a cerebral infarction, generated by an embolus, leading to the death of neurons due to a lack of oxygen supply and nutrients in the blood [Strokes are currently the second leading cause of death and the leading cause of disability in Europe [Neurorehabilitation is a therapeutical approach which mainly focuses on neurological care and the early application of rehabilitative treatment, with a wide range of therapeutic applications [Virtual reality (VR) is the creation of an artificial scenario adapted to the real world, in which it is possible to interact, navigate and immerse in a three-dimensional space by applying different sensory stimuli. Thus, it implies a full-immersion process of the person or the patient in a virtual scenario as close as possible to the real world [VR can be used in the clinical field as a non-invasive technological therapy that allows the patient to interact with a computer-created environment. The use of VR and video games in the health sector increasingly requires more evidence of their efficacy in combination with conventional treatments. This efficacy is explained by their numerous applications and beneficial effects in patients affected by neurological, psychiatric or musculoskeletal pathologies [One of the physiological explanations for these physical improvements is the action of mirror neurons. According to Rizzolatti (discoverer of mirror neurons), the essence of this “mirror” mechanism is the following: each time individuals observe an action performed by another person, a set of neurons that encode that action is activated in the motor system of the observers. If the patient observes a certain action in the VR environment, they will be “activated” at a motor level by the functioning of their mirror neurons [The aim of the current study is to analyze the effects of a traditional neurological physiotherapy-based approach combined with the implementation of a specific VR-based program in the treatment of patients following rehabilitation after a stroke. | PMC10049060 |
2. Materials and Methods | RECRUITMENT | A description of the methods followed for the recruitment of participants, the design of the interventions, the process of data collection and the overview of the statistical analyses are provided in the current section. | PMC10049060 | |
2.1. Participants | stroke, hemorrhagic, neurodegenerative diseases, Alzheimer’s and, Parkinson’s | STROKE, NEURODEGENERATIVE DISEASES | The current study corresponds to a pilot randomized clinical trial involving 26 patients from the outpatient clinical setting “Casaverde” in Murcia (Spain).The inclusion criteria were patients receiving neurological physical therapy treatments, patients having suffered a stroke (hemorrhagic or ischemic) in the last 6 months, an 18- to 80-year age range, ability to have active mobility in at least one upper limb, ability to understand simple instructions and ability to keep a standing position. The exclusion criteria concerned patients with neurodegenerative diseases such as Alzheimer’s and Parkinson’s, having undergone surgery on the limbs assessed or having scars which limit mobility.The corresponding informed consent, signed by all the participants or their legal caregivers, was collected prior to the onset of the study.Participants who met the inclusion criteria received a code and were subsequently included in one of the two groups. Assignment to the groups was randomized by numerical codes using the “Random Group Generator” tool of “RecursosTic.net”. The physical therapist who applied the VR treatment was not blinded to the use of both VR and neurological physical therapy treatment in each patient. The blinding itself corresponded to the assessors, since they were not aware of the assignment of any of the patients evaluated, neither at the baseline nor at the post-test measurement (after six weeks).A total of 26 subjects were initially recruited. Two subjects dropped out of the study for the following reasons: (i) considering the videogame and VR approach a waste of time and (ii) nonattendance to the clinical setting for 2 weeks. Therefore, 24 patients participated in the study and were randomly assigned to either a control group (CG, 12 subjects) or an experimental group (EG, 12 subjects). The study adhered to the Declaration of Helsinki, it was approved by the Ethics Committee of the University of Murcia under the code JVP-2022-01 and it was registered in the U.S. National Library of Medicine Clinical Trials.Gov with the identifier NCT05278403. | PMC10049060 |
2.2. Intervention | dizziness, headache | This study lasted 6 weeks. Both groups received a 1-h neurological physiotherapy session 5 times a week, but the EG additionally received 3 sessions of VR per week. This pattern of 3 VR sessions per week was previously described and used by Cho et al. [The neurological physiotherapy sessions consisted of upper and lower limb strengthening exercises, resistance exercises, active and active-assisted kinesitherapy, anti-resistance exercises, aerobic exercises, simple and obstacle parallel bar gait, jumping gait, skill circuits with different tasks and different surfaces, stable and unstable, work on trellises, fine motor skill exercises in both limbs and weight transfer exercises to improve balance and postural stability. The exercises were performed in different positions, including standing, sedentary, quadrupedia, supine and prone depending on the condition of each patient.The VR program applied was an immersive VR by means of VR glasses (Oculus Quest 2), a computer (with the software), a camera (Kinect 360 v1) used as a sensor of the patient’s movements and a router that acted as a connection point between the glasses and the computer (For the generation of the virtual environment, a specific software called “Blexer “ was used, which was created with the idea of being a rehabilitation tool for physiotherapists [“Phiby’s Adventure” has two different modes according to each patient’s laterality. The patient, thus, by means of their left or right arm, will have to direct the green character, called “Phiby”, to one of the following mini games: Chop the Wood (chopping movement), Row the Boat (performing rowing movements) or Climb the Tree (simulating the movement of climbing up a tree) (To complete all the mini games, patients had to achieve a target of logs cut, meters rowed or meters climbed within a time limit. An interesting aspect of this software is that both the objectives and the time limit can be set according to the criteria of the physiotherapist prior to the exercise, depending on the ability of each patient, so that it is not the patient who adapts to the game: it is the game that adapts to each patient’s situation.Initially, a first contact session is carried out, with a time limit set at 180 s and a target of 40 logs cut, 40 m rowed and 40 m climbed, so that the patient has time to delve into the environment and perform the test.Both the calibration and the use of the mini games were performed in a standing position, with the physiotherapist behind the patient giving positive reinforcement and assisting the patient, if necessary, in each mini game. A chair was placed next to the patient as a safety measure, in case the patient suffers a headache, dizziness or needs to rest.The VR therapy was always applied after the neurological physiotherapy treatment. | PMC10049060 | |
2.3. Data Collection | shoulder extensors, elbow extensors, shoulder abduction, knee extensors, elbow flexion, wrist extensors, knee flexors, hip extensors, Spasticity | All researchers involved in data collection were trained in and practiced the standardized data collection and measurement procedures.Initially, sociodemographic data (gender and age) were collected.Measurements of the different clinical variables were taken at baseline (pre-treatment or baseline) and at the end of treatment (post-treatment) after the corresponding six weeks of treatment. The different clinical variables were:Muscle strength, measured through the Daniels and Worthingham Scale. The following muscles were assessed: shoulder flexors, elbow flexors, wrist flexors, hip flexors, knee flexors, ankle flexors, shoulder extensors, elbow extensors, wrist extensors, hip extensors, knee extensors and ankle extensors.Spasticity, measured by means of the Modified Ashworth Scale on shoulder flexors, elbow flexors, wrist flexors, hip and knee flexors, ankle and foot flexors, shoulder extensors, elbow extensors, wrist extensors, hip and knee extensors, ankle and foot extensors.Functionality was assessed through the Motricity Index. Arms and legs were tested: pinch grip, elbow flexion, shoulder abduction, ankle dorsiflexion, knee extension and hip flexion.Trunk control was assessed through the following movements: rolling to weak side, rolling to strong side, sitting up from lying down and balance in the sitting position.Balance and gait were evaluated through the Tinetti Balance Scale.Balance was assessed by means of the Berg Balance Scale.The Functional Ambulation Classification of the Hospital of Sagunto (CFMHS) was used for the assessment of the functional level of gait. | PMC10049060 | |
2.4. Statistical Analyses | Means between sex and age groups were analyzed and significant differences were sought between the groups. Data were assessed for normality through the Shapiro–Wilk test due to the small sample size (In relation to the required sample size, a calculation using the G* Power software (ver. 3.1.9.7; Heinrich-Heine-Universität Düsseldorf, Düsseldorf, Germany) was performed using the following parameters: one tail, medium effect size d = 0.3, alpha = 0.05, statistical power = 0.80 and a 1:1 allocation ratio. The total sample size would consist of 64 subjects (i.e., 32 individuals per group); our study therefore corresponds to a pilot study, since a total of 24 individuals completed the study (EG = 12; SG = 12). The perception that pilot trials are simply a casual prelude to a larger trial may somehow threaten the rigor with which they are implemented, and such an approach to pilot trial design and implementation runs the risk of providing misleading results, as stated by Arnold et al. [All analyses were performed using the statistical package SPSS v.24 (Statistical Package for the Social Sciences, IBM Corp, Armonk, NY, USA). An alpha value of 0.05 was set across all the analyses performed. | PMC10049060 | ||
3. Results | ±, stroke, spasticity | STROKE | This study involved 24 stroke patients. The CG had seven males and five females, with a mean age of 59.58 ± 15.97 years (Median: 65 years; age range: 18 to 75 years of age). The EG encompassed nine males and three females, with a mean age of 51.91 ± 18.58 (Median: 58 years; age range: 18 to 71 years of age). No statistically significant differences were found between the two groups, neither for gender distribution (Concerning the post-test assessment (after six weeks of treatment), muscle strength revealed no differences between both groups for any of the muscular groups assessed, with p-values ranging from 0.154 (wrist-extensors) to 0.897 (elbow-flexors). Likewise, spasticity did not experience significantly different changes between both groups across the different muscle groups assessed, with a Data on functionality, assessed through the Motricity Index, revealed the existence of statistically significant differences in the Trunk Control Test, Tinetti, Berg Scale and the CFMHS variables in the EG, but not in the CG. Data on the aforementioned results are displayed in | PMC10049060 |
4. Discussion | stroke, reduction of motor deficit, spasticity | STROKE | According to the results obtained, the use of neurological physiotherapy in combination with VR and video games is more effective for the treatment of patients following a stroke than neurological physiotherapy alone. This 6-week pilot randomized clinical trialhas shown significant improvements in the Motricity Index, Trunk Control Test, Tinetti Balance Scale, Berg Balance Scale and Functional Ambulation Classification of the Hospital of Sagunto. Thus, the experimental therapeutic approach used in the rehabilitation of stroke patients is an effective and efficient tool for improving the values of balance, gait, functional level of gait, trunk control and reduction of motor deficit. With regards to the evidence collected on strength (Daniels and Worthingham Scale) and spasticity (Modified Ashworth Scale), no significant improvements were found in any of the groups.Compared to the results of other studies [To understand the incidence of our study at a brain-processing level, some authors [Focusing on strength, unlike in our study, some authors [Another important factor to highlight in the comparison with some of the studies previously developed [Our study should be interpreted in the light of its potential methodological limitations. First, a possible limitation of this study may be that the sample is not very large, although the review of other studies [ | PMC10049060 |
5. Conclusions and Future Work | stroke, post-stroke-related disability, spasticity | STROKE | The use of VR alongside a traditional physiotherapy approach in the treatment of patients following a stroke provided significant improvements in terms of balance, gait, trunk control and functional level of gait, while no significant differences were found in strength or spasticity. The results stemming from our study highlight the efficacy of the use of VR and video games in the rehabilitation of stroke patients.The treatment of neurological physiotherapy in combination with the use of VR and video games in the rehabilitation of stroke patients is a useful strategy. Further research should focus on larger samples, alongside establishing the most effective VR strategy and tailored interventions based on the individuals’ specific needs and deficits. Virtual reality emerges as an efficient therapeutic approach for the treatment of post-stroke-related disability, and future research may explore cheaper, safer and more accessible devices that will enable and enhance at-home rehabilitation. | PMC10049060 |
6. Patents | The game and the Blexer environment led to several registrations of intellectual property for software with the following entry numbers: Blexer-med web platform 16/2019/1687; Middleware Chiro 16/2019/1576; and Phiby’s Adventures 16/2019/871.The Blexer environment was loaned by the Universidad Politécnica de Madrid to the Universidad de Murcia for research and teaching purposes. | PMC10049060 | ||
Author Contributions | Conceptualization, Á.M.-C. and F.-J.P.-V.; methodology, Á.M.-C. and M.G.-S.; software, M.E.; validation, F.-J.P.-V., Á.M.-C., M.E. and M.G.-S.; formal analysis, M.G.-S.; investigation, Á.M.-C. and F.-J.P.-V.; data curation, F.-J.P.-V.; writing—original draft preparation, F.-J.P.-V. and Á.M.-C.; writing—review and editing, Á.M.-C. and M.G.-S. All authors have read and agreed to the published version of the manuscript. | PMC10049060 | ||
Institutional Review Board Statement | The study was conducted according to the guidelines of the Declaration of Helsinki and approved by the Ethics Committee of the University of Murcia: protocol code: JVP-2022-01 (25.03.2022) and registered in the U.S. National Library of Medicine Clinical Trials.Gov with the identifier: NCT05278403. | PMC10049060 | ||
Informed Consent Statement | Informed consent was obtained from all subjects (or their legal representatives) involved in the study. | PMC10049060 | ||
Data Availability Statement | The data presented in this study are available on request from the corresponding author. The data are not publicly available due to privacy issues. | PMC10049060 | ||
Conflicts of Interest | The authors declare no conflict of interest. All authors have read and approved the paper and it has not been published previously nor is it being considered by any other peer-reviewed journal. | PMC10049060 | ||
References | Flowchart of the study.VR equipment used. 1. Kinect 360 2. Computer with the software. 3. VR glasses (oculus Quest 2) 4. Router.Patient during a VR session.Two different screens of Phiby’s Adventure.Patient playing “Chop the Wood”, “Row the Boat” and “Climb the Tree”, respectively.Results of Clinical Variables (Mean ± SD).CG: Control Group; EG: Experimental Group; Pre: Baseline measurement; Post: Follow-up measurement. | PMC10049060 | ||
Objective | pulmonary hypertension | BRONCHOPULMONARY DYSPLASIA, PULMONARY HYPERTENSION | Information is needed to guide the design of randomized controlled trials (RCTs) evaluating L-citrulline therapy for premature infants with pulmonary hypertension associated with bronchopulmonary dysplasia (BPD-PH). Based on our single-dose pharmacokinetic study, we evaluated the ability of a multi-dose enteral L-citrulline strategy to achieve a target trough steady-state L-citrulline plasma concentration and its tolerability in premature infants. | PMC10844094 |
Study Design | Plasma L-citrulline concentrations were measured in six premature infants receiving 60 mg/kg L-citrulline every 6 h for 72 h before the first and last L-citrulline doses. L-citrulline concentrations were compared to concentration-time profiles from our previous study. | PMC10844094 | ||
Results | ADVERSE EVENTS | Target trough plasma L-citrulline concentrations were achieved in 2/6 subjects. No serious adverse events occurred. | PMC10844094 | |
Conclusions | Multi-dose L-citrulline was well tolerated. These results will assist in the design of phase II RCTs evaluating L-citrulline dosage strategies to achieve target plasma L-citrulline concentrations in infants at risk for BPD-PH. Clinical trials.gov ID: NCT03542812 | PMC10844094 | ||
Subject terms | PMC10844094 | |||
Introduction | BRONCHOPULMONARY DYSPLASIA (BPD), CHRONIC LUNG DISEASE OF PREMATURITY, PULMONARY HYPERTENSION, PREMATURE, PULMONARY HYPERTENSION | Premature infants with chronic lung disease of prematurity, bronchopulmonary dysplasia (BPD), are at risk of developing pulmonary hypertension (PH) [Research efforts are needed to develop and evaluate therapies to improve outcomes for infants with BPD-PH. In 2022, the Pediatric Pulmonary Hypertension Network (PPHNet) noted the remarkable contribution of BPD-PH to the spectrum of pediatric PH and highlighted the need for focused research and randomized clinical trials (RCTs) in this understudied group of patients [Nitric oxide (NO) is a potent pulmonary vasodilator that can be administered exogenously as inhaled NO (iNO) gas. Oral/enteral supplementation with the NO-L-arginine precursor, L-citrulline, provides a way to increase endogenous NO as a potential treatment for PH [Our overarching goal is to evaluate orally/enterally administered L-citrulline as a potential treatment for BPD-PH. As a first step, we recently published data from a phase I study that characterized the PK profile of a single dose of enterally administered L-citrulline in premature infants at risk of developing BPD-PH to derive optimal dosage strategies using simulation-based methodology [ | PMC10844094 | |
Materials/subjects and methods | PMC10844094 | |||
Patient population | death, congenital heart disease, fever, diarrhea, liver failure, ventricular septal defect, fetal anomalies, vomiting or, patent ductus arteriosus, BPD, atrial septal defect | LIVER FAILURE, PREMATURE, NECROTIZING ENTEROCOLITIS, ANEUPLOIDY | This study was the multiple-dose steady state arm of a phase I study NCT03542812 (PK of L-citrulline in infants at substantial risk of developing PH associated with BPD). The single-dose PK arm of the study has been previously published [We enrolled participants from two Newborn Intensive Care Units (NICUs) in Salt Lake City, UT, the University of Utah Hospital NICU and the Intermountain Medical Center NICU. The institutional review board for human subjects committee at each hospital approved the study protocol. Informed consent was obtained from the legal guardians of all subjects.Premature neonates born at ≤ 28 weeks gestation were eligible to be enrolled in the study if they required invasive mechanical ventilation or non-invasive positive pressure support (nasal continuous positive airway pressure or high flow nasal cannula ≥ 1 liter per minute) at 32 ± 1 week’s postmenstrual age. Other criteria included (1) the ability to tolerate at least one-half of full-volume oral/gavage tube feedings, using 120 ml/kg/d as full-volume oral/gavage tube feedings, (2) a need for some form of continuous respiratory support for the prior 14 days, and (3) a hemoglobin ≥ 10 mg/dl.Multiple births and infants with anticipated death prior to hospital discharge were excluded from the study. Also excluded were patients with any known major fetal anomalies, chromosomal aneuploidy, or clinical evidence of congenital heart disease, except for patent ductus arteriosus, atrial septal defect, or ventricular septal defect. Additional exclusion criteria were the presence of any acute illness as defined by a fever >100.4°, vomiting or diarrhea, a urine output < 1 ml/kg/hr., significant feeding intolerance beyond the first week of life, or a history of or known to have liver failure or necrotizing enterocolitis. | PMC10844094 |
Patient monitoring | diarrhea, vomiting, hypotension, sepsis, gastro-intestinal disturbances | NECROTIZING ENTEROCOLITIS, ADVERSE EVENT, GASTROINTESTINAL BLEEDING, ADVERSE EVENT, SEPSIS | Vital signs (heart rate, respiratory rate, temperature, blood pressure, and oxygen saturation) and respiratory support (FiOL-citrulline administration carries a theoretical risk of systemic hypotension. An adverse drop in blood pressure was defined as a decrease in mean arterial blood pressure of more than 25% of baseline blood pressure. Enterally administered medications carry the risk of causing gastro-intestinal disturbances, such as vomiting and diarrhea. Therefore, participants were monitored for clinical evidence of feeding intolerance (including vomiting and diarrhea), necrotizing enterocolitis, and gastrointestinal bleeding. Participants were also monitored for clinical evidence of sepsis. Adverse events were recorded during treatment and within 48 h at the end of treatment. The Principal Investigator determined any potential relationship to L-citrulline treatment. In addition, a data safety monitoring committee reviewed each adverse event and its relationship to L-citrulline. An interim safety analysis was undertaken after the first 3 participants were enrolled and after a total of 6 participants were enrolled. | PMC10844094 |
Drug dosing and sample collection | STERILE | Each patient received 12 doses of 60 mg/kg enteral L-citrulline. The L-citrulline was donated by Askeplion Pharmaceuticals, Baltimore, MD, and was provided in a powder form that was solubilized in sterile water to achieve 50 mg/ml concentration. Each participant received 1.2 ml/kg (60 mg/kg) of the solubilized L-citrulline every 6 h ± 30 min (4 times a day) for 72 h. The total daily volume of solubilized L-citrulline was 4.8 ml/kg/d for a total daily L-citrulline dose of 240 mg/kg/d. Each dose of L-citrulline was delivered via an indwelling nasogastric feeding tube thirty minutes prior to a feeding.Two (0.3–0.5 mL) blood samples were collected into EDTA microtainers by heel stick methodology from each infant. The first sample was a pre-dose blood sample collected between 10 min and 6 h before administering the first dose of enteral L-citrulline. The second sample was collected 10 to 30 min before the last (12th) dose of enteral L-citrulline. These sampling times were designed to assess baseline and steady-state trough L-citrulline plasma concentrations.For each infant, we also collected two urine samples via cotton balls placed in their diapers. The first urine sample was collected the day before administering the first enteral dose of L-citrulline. The second sample was collected between 4 and 8 h following the last (12 | PMC10844094 | |
Sample processing and analyses | All blood samples were centrifuged at 1500 g for 5 min at 4 °C. The plasma was separated and stored at −80 °C for later determination of concentrations of the amino acids, L-citrulline (μmol/L) and L-arginine (μmol/L). All amino acid analyses were performed by ARUP Laboratories (Salt Lake City, UT) via Liquid Chromatograph-Tandem Mass Spectrometry (LC-MS/MS) using the Sciex aTRAQEach urine sample was aliquoted into two separate tubes (minimum 0.5 ml urine per tube), then stored at −80 °C. One of the aliquoted urine samples was used to determine urine creatinine (Cr). Urine Cr analysis was performed by either ARUP Laboratories (Salt Lake City, UT) or the Central Laboratory at the University of Utah Health Hospital (Salt Lake City, UT).The second aliquoted urine sample was used to determine urine nitric oxide metabolites, nitrites/nitrates (NOx). For urine NOx analysis, using methods as previously described [ | PMC10844094 | ||
Pharmacokinetic analysis | Dosing regimen (using median dose) for the current study was used to obtain simulated concentration-time data and corresponding profiles of L-citrulline using R (version 4.1.0) via package “linpk”. Parameter values for clearance, volume of distribution and absorption rate constant were obtained from a previous study and were fixed at 0.6 L/h, 0.9 L and 0.95, respectively [ | PMC10844094 | ||
Statistical analyses | Wilcoxon’s signed rank test was used to compare plasma concentrations of L-citrulline and arginine obtained at baseline to plasma concentrations obtained prior to the 12 | PMC10844094 | ||
Results | PMC10844094 | |||
Subject characteristics | sepsis, congenital anomalies, liver disease | SEPSIS, NECROTIZING ENTEROCOLITIS, LIVER DISEASE | A total of 91 infants born ≤ 28 weeks were screened for eligibility. 62 were ineligible for the following reasons: multiple gestations (n = 27), feeding problems or necrotizing enterocolitis (n = 14), lack of consent form in parent’s language (n = 4), respiratory support below eligibility criteria (n = 4), congenital anomalies (n = 4), sepsis or instability (n = 3), possible liver disease (n = 3), staff unavailable to perform study (n = 2), attending request (n = 1). A total of 6 premature infants were enrolled in this study. The original enrollment target was 18 infants. Slow enrollment and budgetary limitations, which precluded updating the Certificate of Analysis on the L-citrulline product used in this study, necessitated the termination of the study after the sixth study patient was enrolled. The median birth weight was 1050 grams (range 769–1430 g) and the weight at the time of study was 1487.5 grams (range 1330–1880 g) (Table Patient Characteristics.Values presented are counts (%) for categorical variables or median (min,max) for continuous variables. | PMC10844094 |
Plasma amino acid and urine NOx data | Basal plasma concentrations were obtained between 30 min to 5 ½ hours prior to administering the first dose of L-citrulline, and a second plasma concentration was obtained between 18–27 min prior to the last, 12 | PMC10844094 | ||
Observed/predicted plasma L-citrulline concentration (μmol/L) time profiles. | Solid black lines represent predicted plasma L-citrulline concentrations. Dotted black lines represent 50 μmol/L and 80 μmol/L concentrations and reflect the target trough plasma concentrations. Black dots are the observed L-citrulline concentrations (μmol/L) collected at study time points (i.e. at baseline and trough prior to the 12Five of the six premature infants enrolled in this study provided two urine NOx/Cr levels. The first urine sample from these five subjects was collected before administering the first dose of L-citrulline or shortly after the first dose of L-citrulline was given. The first urine sample collected from one patient was lost. All six premature infants enrolled in this study provided urine NOx/Cr levels from urine collected between 6 ¼ and 7 ½ hours after administering the last study dose of L-citrulline. There was no difference between the urine NOx/Cr levels (median 25.8, IQR 22–44) obtained as a baseline and the urine NOx/Cr levels obtained after the last dose of L-citrulline (median 36, IQR 27–46.6) for the combined group of 5 subjects that provided two samples (p = 0.89). When considering values for each of the individual subjects, as shown in Fig. | PMC10844094 | ||
Individual subject mean BP measurements. | The mean BP measurements (mm Hg) of individual subjects recorded at baseline (dose 0) and with each of the 12 doses of L-citrulline administration. | PMC10844094 | ||
Acknowledgements | We thank Asklepion Pharmaceuticals for the generous gift of the oral L-citrulline used in this study. We also thank the Newborn Clinical Research Nurse Coordinators at the University of Utah and Intermountain Medical Center for their help in enrolling patients and performing the study. | PMC10844094 | ||
Author contributions | CDF, JLA, and CMS contributed to the conception and design of the study. Data collection was performed by CDF. Formal data analysis was performed by CDF, AKB, CA, and CMS. CDF wrote the first draft of the abstract. All authors reviewed and edited drafts of the manuscript and approved the final manuscript. | PMC10844094 | ||
Funding | BLOOD, HEART, LUNG | This work was supported by National Heart, Lung, and Blood Institute Grant R34-HL-142995 (CDF). | PMC10844094 | |
Data availability | The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request. | PMC10844094 | ||
Competing interests | BRONCHOPULMONARY DYSPLASIA | CDF and JLA are inventors on a patent at Vanderbilt University Medical Center that has been licensed to Asklepion Pharmaceuticals for the “Therapeutic treatment of bronchopulmonary dysplasia.” | PMC10844094 | |
Ethics approval | All procedures performed in this study involving human participants were in accordance with the 1964 Helsinki Declaration and its later amendments. The study design was approved by the institutional review boards of The University of Utah and Intermountain Healthcare. All participants or legal guardians of participants in the clinical trial included in these analyses provided written informed consent. | PMC10844094 | ||
References | PMC10844094 | |||
Objective | sarcopenia, femoral fracture | SARCOPENIA | Academic Editor: Xiaolong Chen To study the clinical efficacy of nutritional intervention combined with muscle exercise on sarcopenia patients with femoral fracture. | PMC9937758 |
Methods | fracture, pain, sarcopenia, femoral fracture | SARCOPENIA | From January 2019 to January 2021, a total of 100 sarcopenia patients with femoral fracture were included in this study and were divided into a control group (routine postoperative care) and a research group (nutritional intervention and muscle exercise), 50 cases in each group. Primary clinical outcomes included sarcopenia-related indicators and functional independence assessed by activities of daily living scale (ADL). Secondary clinical outcomes included time of fracture healing and hospital stay, pain score as assessed by visual analogue scale (VAS), and nursing satisfaction. | PMC9937758 |
Results | sarcopenia | SARCOPENIA | Before the intervention, there was no significant difference in the indicators of sarcopenia and the indicators of functional independence assessed by ADL between the two groups ( | PMC9937758 |
Conclusion | fracture, sarcopenia, sarcopenic femoral fractures | SARCOPENIA | Nutritional intervention combined with muscle exercise can help improve sarcopenia symptoms and promote fracture recovery in patients with sarcopenic femoral fractures. | PMC9937758 |
1. Introduction | loss of skeletal muscle mass, muscle strength loss, swelling, muscle reduction, fracture, pain, fractures, Femoral fracture, Sarcopenia, muscle loss, osteoporosis, femoral fracture | LOSS OF SKELETAL MUSCLE MASS, SYNDROME, SARCOPENIA, DISEASES, OSTEOPOROSIS | Sarcopenia is a syndrome of persistent loss of skeletal muscle mass, strength, and function and characterized by a marked age-dependent onset. Previous studies have found that skeletal muscle begins to age from about 40 years, with an average annual decrease in quantity and quality of about 8%, and muscle loss doubles after the age of 70 [Importantly, fracture patients need to stay in bed for a long time, and long-term bed rest is more prone to muscle strength loss caused by muscle reduction, and the probability of falling when getting out of bed is very likely to increase, thereby increasing the risk of femoral fracture again [Femoral fracture is one of the common diseases in clinical surgery, characterized by severe pain, swelling, and distortion, which have a serious impact on the patient's ability to live. Sarcopenia and osteoporosis are two major risk factors for fractures in patients, especially elderly patients [ | PMC9937758 |
2. Material and Methods | PMC9937758 | |||
2.1. Patients and Ethics Statement | impaired cognitive function, death, sarcopenia, malignant disease, cardiopulmonary insufficiency, renal insufficiency, neuropsychiatric disorders, sarcopenic femoral fractures, femoral fracture | SARCOPENIA, INFECTIOUS DISEASE, RENAL INSUFFICIENCY, DISEASES, MALIGNANT DISEASE | A total of 100 patients with sarcopenic femoral fractures were included in this study from January 2019 to January 2021 (age from 57 to 74 years old, 53 males and 47 females). The following are the inclusion criteria: (1) femoral fracture and received artificial joint replacement; (2) combined with sarcopenia; (3) aged 40-75 years; (4) mentally stable, able to communicate normally and to move independently, and voluntarily cooperate with this study. The following are the exclusion criteria: (1) complicated with severe cardiopulmonary insufficiency; (2) severe neuropsychiatric disorders; (3) inability to stand up independently; (4) impaired cognitive function; (5) severe renal insufficiency requires protein intake to be restricted; (6) patients with malignant disease or infectious disease; and (7) lost in the middle of the study, suffering from other diseases or death. All patients were informed about the study and signed the informed consent to join the study voluntarily. In addition, this study was a prospective study; the present study was approved and supervised by The Third Affiliated Hospital of Chongqing Medical University Hospital Ethics Committee. | PMC9937758 |
2.2. Intervention Protocol | Patients in the control group were received routine care such as primary care and symptomatic care. Patients in the research group received nutritional interventions and muscle exercises in addition to routine care. Nutritional intervention and muscle exercise duration is from 10 days postoperatively to 3 months plus 10 days postoperatively. The following are the nutritional interventions: daily supplementation of 400 kcal of whole nutritional formula powder and 0.6-1.0 g/kg of whey protein powder. The following are the muscle exercises: do 30 minutes of aerobic and resistance exercise each time, 5 times a week, including brisk walking and slow walking. Muscle exercises are guided by medical staff, mainly targeting the leg muscles, with video instruction which is given once a week. | PMC9937758 | ||
2.3. Data Collection and Follow-Up | diabetes | HYPERTENSION, CARDIOPULMONARY DISEASE, DIABETES | Baseline data were collected for all patients recruited in this study, including gender, age, education, comorbidities (hypertension, diabetes, and cardiopulmonary disease), drinking, and smoking. All patients received a 4-month follow-up after surgery, including telephone follow-up every 2 weeks and unscheduled hospital admissions. | PMC9937758 |
2.4. Primary Clinical Outcome | Primary clinical outcomes included sarcopenia-related indicators and functional independence assessed by activities of daily living scale (ADL) [ | PMC9937758 | ||
2.5. Secondary Clinical Outcome | fracture, pain | Secondary clinical outcomes included the time of fracture healing and hospital stay, pain as assessed by visual analogue scale (VAS) at different times, and patient satisfaction with care. In detail, we used VAS to assess pain before intervention, 1 week, 2 weeks, 1 month, and 3 months after intervention. The VAS scoring standard is divided into 10 equal parts using a ruler, 0 is no pain, 1-3 is mild pain, 4-6 is moderate pain, and 7-10 is severe pain. | PMC9937758 | |
2.6. Statistical Analysis | Data in the present study were analyzed by SPSS 20.0 software (SPSS Inc., Chicago, USA). Qualitative data are presented as counts (%), and | PMC9937758 | ||
3. Results | PMC9937758 | |||
3.1. Baseline Data | 167 patients were enrolled in the beginning, and 67 were excluded, and no patient lose to follow-up. 100 eligible patients were randomly divided into two groups, control group and research group. There were no significant differences between the two groups in baseline data ( | PMC9937758 |
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