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Intervention | hypoglycemic, diabetes | DIABETES, CLAP, DIABETES | All participants continued to receive standard therapy for diabetes as they received before the study began. The control group continued the standard therapy and the intervention group received the standard therapy plus the laughter yoga program. Standard therapy included taking oral hypoglycemic medications, receiving advice from the doctor in charge of dietary modifications and physical activity in accordance with the “Treatment Guide for Diabetes” in Japan (The participants in the intervention group received laughter yoga program once a week during the first 4 weeks and then every other week during the last 8 weeks. In total, eight sessions over 12 weeks were provided. The duration of laughter yoga intervention in previous studies ranged from 4 weeks to 8 weeks (Laughter yoga is a kind of exercise consisting of deep breathing and voluntary laughter in a sitting or standing position. Each laughter yoga session consisted of warm up exercises, deep-breathing exercise, laughter exercise, and calming activity. At the beginning, the participants were asked to clap their hands along with saying the phrase “Ho, Ho, Ha, Ha, Ha,” as a warm up exercises. Then, deep breathing with laughter were performed. Subsequently, the participants were asked to participate in voluntary laughing imaging in a variety of situations, including 5-min break. For example, when doing the “milkshake laughter,” participants were asked to imagine that they have a glass of milk in their right hand and a glass of their favorite fruit juice in their left hand. They pretended to pour the milk from one glass into the other and pour it back into the first glass (to mix them). Then, they pretended to drink the milkshake, with a laugh. Finally, the participants were asked to close their eyes and relax. | PMC10102335 |
Outcomes | The primary outcome was changes in HbA1c levels from the baseline to the 12-week follow-up measurement. Exploratory outcomes included changes in body weight, waist circumference, body mass index (BMI), positive affect, negative affect, subjective stress, and sleep duration from baseline to the 12-week follow-up. Physical examination and self-administered questionnaire were assessed on weeks 0 and 12.HbA1c levels were measured in capillary whole blood, collected by finger prick, using the COBAS b101 point-of-care system (Roche Diagnostics International Ltd, Rotkreuz, Switzerland). Body weights were measured using a UC-322 weighing scale (A&D Co. Ltd., Tokyo, Japan), and BMIs were calculated as follows: weight (kg)/height squared (mThe following data were obtained | PMC10102335 | ||
Sample size calculation | diabetes | DIABETES | A previous study reporting that laughter can decrease HbA1c levels in older adults without diabetes ( | PMC10102335 |
Randomization | After baseline measurements were completed, the participants were stratified according to sex and randomly allocated to either the intervention (laughter yoga program and standard therapy) or control (standard therapy only) group in a 1:1 ratio according to a computer-generated sequence. All randomization was carried out by a researcher who was not involved with participant enrollment. Participants were informed of their group assignment after consent and baseline measurements. Outcome assessors were blinded to group allocation. | PMC10102335 | ||
Statistical analysis | Data were analyzed according to an intention to treat principle, with the baseline value carried forward for missing data. The differences in baseline characteristics between the two groups were tested using independent samples | PMC10102335 | ||
Results | Forty-five eligible participants were enrolled in the study, and 42 agreed to participate in this study and underwent baseline measurements. Twenty-one participants were assigned to the laughter yoga group and 21 participants were assigned to the control group (Consolidated Standards of Reporting Trials (CONSORT) diagram of study participants.The baseline characteristics of the 42 participants stratified by groups are shown in Baseline characteristics of the participants.BMI, body mass index; HbA1c, hemoglobin A1c. Data are mean (SD) unless otherwise indicated.
Physiological and psychological changes during the intervention in the laughter yoga and control groups.BMI, body mass index; HbA1c, hemoglobin A1c; SD, standard deviation; 95% CI, 95% confidence interval.P for comparing the difference in outcomes before and after the intervention using paired-samples t test.P for unadjusted between-group difference in changes in outcomes over 12 weeks using independent samples t test.P for adjusted between-group difference (adjustment for age, BMI and each dependent variable value at baseline) using analysis of covariance.Physiological and psychological changes during the intervention in the laughter yoga and control groups using per-protocol analyses.BMI, body mass index; HbA1c, hemoglobin A1c; SD, standard deviation; 95% CI, 95% confidence interval.P for comparing the difference in outcomes before and after the intervention using paired-samples t test.P for unadjusted between-group difference in changes in outcomes over 12 weeks using independent samples t test.P for adjusted between-group difference (adjustment for age, BMI and each dependent variable value at baseline) using analysis of covariance.At baseline and 12-week follow-up, 14 (66.7%) and 19 (90.5%) individuals in the laughter yoga group, and 10 (47.6%) and 8 (38.1%) individuals in the control group reported having exercise at least twice a week, respectively. The number of individuals with exercise habits increased in the laughter yoga group but with no statistical significance. However, the adjusted between-group difference of HbA1c remained statistically significant after adding the change in exercise habits as a covariate. The mean change in HbA1c was 0% in the five participants who reported increased exercise habits and −0.32% in the 16 participants without exercise habit changes. Additionally, the number of individuals who reported eating until full and skipping breakfast was not significantly different between the two groups at baseline and 12-week follow-up (data not shown). The number of individuals who reported eating until full and skipping breakfast remained from baseline to 12-week follow-up in both groups. | PMC10102335 | ||
Discussion | diabetes-related complications, glucose intolerance, insomnia, diabetes | GLUCOSE INTOLERANCE, TYPE 2 DIABETES, DIABETES | The results of this study showed that laughter yoga program for 12 weeks decreased HbA1c levels in individuals with type 2 diabetes. Additionally, the high attendance rate suggests that the program is feasible for the participants. To the best of our knowledge, this is the first randomized controlled trial that has evaluated the long-term effects of laughter yoga on glycemic control in individuals with type 2 diabetes.The findings of the current study are consistent with previous studies demonstrating that laughter by watching a comedy show for 40 min (The mean HbA1c levels changed from 7.07% to 6.82% in the laughter yoga group. Recent study has shown that maintaining HbA1c levels at <7% over 5 years is associated with significant reductions in the odds of being diagnosed with diabetes-related complications (A meta-analysis found that, in individuals with type 2 diabetes, low-to-moderate-intensity resistance exercise reduced HbA1c levels by 0.23%, and high-intensity resistance exercise reduced HbA1c levels by 0.61% (Although the mechanisms remain unclear, there are several possibilities for the effect of laughter yoga on diabetes. First, it has been reported that laughter upregulates genes related to natural killer cell activity in individuals with type 2 diabetes, which may ameliorate glucose intolerance (It has been reported that when people experience positive affect during a specific behavior, they are more likely to continue that behavior (In this study, sleep duration tended to improve. This finding is consistent with previous studies reporting that laughter has favorable effects on sleep quality or insomnia. One study has shown that 1 h of laughter therapy once a week for 4 weeks improves insomnia and sleep quality among older individuals (Laughter yoga combines simulated laughter with yoga breathing techniques. The effects of laughter and the effects of yogic breathing are difficult to distinguish because laughter also consists of mixed patterns of expiration, inspiration, and interval pauses (This study conducted a 12-week laughter yoga intervention. In a systematic review of the effects of laughter-inducing interventions, the duration of most laughter yoga interventions ranged 4 to 8 weeks and one study conducted a 12-week laughter yoga intervention (In this study, we did not assess the sustainability of the effects of the intervention after the study period. Further follow-up studies are needed to examine how long the effects of laughter yoga are maintained. A meta-analysis showed that improved physical activity through behavioral change interventions is generally not sustained after the intervention (This study has several limitations. First, the number of participants was small, and the study was conducted in a single center. Multicenter studies with larger sample sizes are needed to better understand the intervention’s efficacy and generalizability. The study participants were all Japanese living in an urban area and outpatients of the university hospital with relatively good glycemic control. Our findings may not apply to different populations, including other ethnic groups, those living in rural areas, and those with poorly controlled type 2 diabetes. Further studies are needed to evaluate the effects of laughter yoga on glycemic control in different populations. In contrast, the effects of laughter yoga on mental health have been reported worldwide (Asia, the Middle East, Australia, and United States) and in different clinical settings (In conclusion, laughter yoga for 12 weeks decreased HbA1c levels in individuals with type 2 diabetes, and the program is feasible with a high attendance rate. The importance of psychological well-being in individuals with diabetes has been gradually recognized, and positive psychological interventions have been recommended ( | PMC10102335 |
Data availability statement | The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation. | PMC10102335 | ||
Ethics statement | The studies involving human participants were reviewed and approved by Scientific Ethics Committee of Fukushima Medical University. The patients/participants provided their written informed consent to participate in this study. | PMC10102335 | ||
Author contributions | MH, HIs | MH analyzed and interpreted data, and wrote the manuscript. MH, TO, and YW conducted the study and contributed to data acquisition. TO, EE, KS, HIm, NF, HN, NK, IS, and HIs contributed to the concept and design of the study and participated in critical revision of the manuscript. HN, NK and IS recruited participants and interpreted the diabetes-related outcome measures. MH and TO are the guarantors of this work and, as such, had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. All authors contributed to the article and approved the submitted version. | PMC10102335 | |
Acknowledgments | The authors are grateful to Ms. Yoshiko Takada (chairperson of the Japanese Laughter Yoga organization), Ms. Seiko Ikegawa, and all other staff for their continuous support of the laughter yoga program. Also, we thank all participants involved and staff at Osaka University Hospital and Osaka University for their assistance with the study. | PMC10102335 | ||
Conflict of interest | The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | PMC10102335 | ||
Publisher’s note | All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. | PMC10102335 | ||
References | PMC10102335 | |||
Background | The Large-scale Assessment of the Key health-promoting Activities of two New mass drug administration regimens with Azithromycin (LAKANA) trial in Mali aims to evaluate the efficacy and safety of azithromycin (AZI) mass drug administration (MDA) to 1–11-month-old infants as well as the impact of the intervention on antimicrobial resistance (AMR) and mechanisms of action of azithromycin. To improve the transparency and quality of this clinical trial, we prepared this statistical analysis plan (SAP). | PMC10648361 | ||
Methods/design | malaria | MALARIA, SECONDARY | LAKANA is a cluster randomized trial that aims to address the mortality and health impacts of biannual and quarterly AZI MDA. AZI is given to 1–11-month-old infants in a high-mortality setting where a seasonal malaria chemoprevention (SMC) program is in place. The participating villages are randomly assigned to placebo (control), two-dose AZI (biannual azithromycin-MDA), and four-dose AZI (quarterly azithromycin-MDA) in a 3:4:2 ratio. The primary outcome of the study is mortality among the intention-to-treat population of 1–11-month-old infants. We will evaluate relative risk reduction between the study arms using a mixed-effects Poisson model with random intercepts for villages, using log link function with person-years as an offset variable. We will model outcomes related to secondary objectives of the study using generalized linear models with considerations on clustering. | PMC10648361 |
Conclusion | SECONDARY | The SAP written prior to data collection completion will help avoid reporting bias and data-driven analysis for the primary and secondary aims of the trial. If there are deviations from the analysis methods described here, they will be described and justified in the publications of the trial results. | PMC10648361 | |
Trial registration | ClinicalTrials.gov ID | PMC10648361 | ||
Keywords | Open access funding provided by Tampere University (including Tampere University Hospital). | PMC10648361 | ||
Background | infection | ADVERSE EVENTS, INFECTION, SECONDARY, INFLAMMATION | Mass drug administration (MDA) of azithromycin (AZI) is a promising strategy for improving child survival in settings with high under five mortality rates (U5MR) [LAKANA stands for Large-scale Assessment of the Key health-promoting Activities of two New mass drug administration regimens with Azithromycin. The primary aim of this trial conducted in Mali, covering 1151 villages, is to evaluate the impact on mortality of two or four annual rounds of AZI MDA delivered to 1–11-month-old infants. The study also includes a range of secondary outcomes such as efficacy outcomes related to morbidity and growth, outcomes related to the mechanism of azithromycin activity through measures of markers of infection and inflammation, safety outcomes (AMR, adverse, and serious adverse events), and outcomes related to the implementation of the intervention documenting feasibility, acceptability, and economic aspects. The LAKANA trial has been registered with ClinicalTrials.gov (NCT04424511) and its protocol (version 4.0, dated 27 June 2022) has been published [ | PMC10648361 |
Trial design | malaria | MALARIA, SECONDARY, STAGGERED | The study is a three-arm cluster randomized, placebo-controlled, double-blinded, parallel-group clinical trial. The trial was designed to estimate the impact of azithromycin on 1–11-month-old infant mortality in Mali, Western Africa, with a sample size of 1151 villages (clusters). The area is covered by a national seasonal malaria chemoprevention (SMC) program that was designed to include distribution of sulfadoxine-pyrimethamine plus amodiaquine to all l–59-month-old-children monthly during the rainy season (July to October). Details of the trial design are described in a separate protocol article [Participating study villages were randomly allocated into the three intervention groups at 3:4:2 ratio: placebo (control), two-dose AZI (azithromycin-MDA treatments given every 3 months to 1–11-month-old infants between January and June), and four-dose AZI (azithromycin-MDA treatments given every 3 months to 1–11-month-old infants). The randomization was stratified by village size: villages for which the estimated number of eligible infants was 100 or more (later referred to as “big villages”) or villages for which the estimated number of eligible infants was fewer than 100 (later referred as “small village”). The village size categorization was done based on 2018 Demographic and Health Survey [The data collection team visits the villages at quarterly intervals, eight times for MDA visits and one time for close-out visit (visit 9) during which the data collection team interviews the household representatives but do not administer study drug. A single child can receive up to four doses of study drug between the age range of 1 and 11 months, even though the villages are visited eight times at maximum. The trial may have equal stopping time for all of the villages, despite staggered starting time, if the target person-years-at risk will be reached before all the villages have had full visit cycle of nine visits. If the target person-years-at-risk requires full visits for all of the villages, there will be nine visits for all villages. The decision will be made by the Project Steering Group (PSG) after the interim analysis based on the recommendation by the Data Safety and Monitoring Board (DSMB). At minimum, all villages will be visited six times.In a subset sample of 59 villages, the study team is collecting additional biological samples and measurements to address secondary study questions about AMR, growth and nutritional status, and mechanisms of action of azithromycin. The 59 villages were chosen based on their proximity to health centers in Kita area, as well as their location in clearly rural area. The selection was based both on the possibility to deliver biological samples to a laboratory in reasonable time, as well as being rural and therefore representative of most of Mali.The trial DSMB will conduct a single interim analysis when approximately 60% of the mortality data has been collected, and based on the results of the interim analysis, a trial arm may be dropped, or the trial may be stopped early [ | PMC10648361 |
Current status of trial | Enrollment for LAKANA began on October 15, 2020, and ended in December 2022. Data collection is ongoing and the last follow-up for the final participants is currently planned to take place in the second half of 2024. We estimate the interim analysis to take place in August 2023. | PMC10648361 | ||
Study objectives | PMC10648361 | |||
Main objective | The main objective of this trial is to determine the impact of a public health intervention program of two-dose (given twice a year, between January and June) or four-dose (given every 3 months) AZI MDA to 1–11-month-old infants on their mortality, when provided in a context of a national SMC program. | PMC10648361 | ||
Secondary objectives | acute infection symptoms, weight gain, malaria | MALARIA, SECONDARY, INTESTINAL INFLAMMATION, MALNUTRITION | In addition to the primary aim, the trial has secondary aims in assessing other health effects of AZI on the treated population. The secondary aims are as follows:To evaluate the effect of receiving two-dose and four-dose AZI MDA on AMR.To evaluate the impact of AZI MDA to 1–11-month-old infants on their period prevalence of acute infection symptoms.To evaluate the impact of AZI MDA to 1–11-month-old infant on their linear growth, weight gain, and prevalence of malnutrition.To investigate mechanisms of AZI action by testing hypotheses onwhether or not AZI MDA eliminates malaria parasitaemia.whether or not AZI MDA increases mean blood hemoglobin concentration.whether or not AZI MDA reduces systemic or intestinal inflammation in asymptomatic children.Also, an integrated LAKANA feasibility study aims to provide comprehensive policy advice to decision makers on possible strategies to implement an AZI intervention as a national program should the trial yield positive clinical results. Feasibility study is not described in this SAP due to many aspects of the study being conditional on the trial results. | PMC10648361 |
Outcomes | PMC10648361 | |||
Primary outcome | death | The primary outcome of the trial will be 1–14-month-old mortality following the 3-month interval after the village has received the AZI MDA or placebo. We record the vital status of village residents as categorical variable with four options: “alive”, “dead”, “moved”, and “unknown”. In the mortality analysis, the numerator will be binary (alive/dead). For participants whose information on vital status at the end of a 3-month interval, we cannot obtain or infer based on subsequent visits, the interval will be excluded. The denominator, follow-up time, is calculated by subtracting date of first treatment from date of the last vital status or date of death, whichever is earlier. The obtained difference in days is divided by 365.25 to obtain person-years-at-risk (PYR). If the date of death is not obtained for any reason, we will use the mid-point between previous visit and date when death is reported as an approximation.The treatment variable is a three-level categorical variable:Control: category for infants in villages that receive placebo at every visitTwo-dose AZI: category for infants in villages that receive azithromycin two times in a yearFour-dose AZI: category for infants in villages that receive azithromycin at every visit | PMC10648361 | |
Secondary outcomes | PMC10648361 | |||
Antimicrobial resistance | We will express AMR as the proportion of The nasopharyngeal and rectal samples will be collected from 4–14-month-old and 49–59-month-old children at the first visit to the village, at 12 months (MDA 5), at 24 months (visit 9), and at 36 months, i.e., 1 year after the last MDA for the villages. We will primarily calculate the proportion of R/I isolates from all isolates and secondarily the proportion of children with R/I isolate in their sample.We will test a sample of 1350 children aged 4–14 months at 24 months and aged 49–59 months at 36 months. At the three other time points, we will test 450 children (taken randomly from approximately 20 clusters/arm) from 4–14 months old and 49–59 months old, respectively. In total, this will mean 5400 AMR-analyses for We hypothesize the prevalence of AMR will exhibit an initial increase among 4–14-month-old individuals, followed by a subsequent decrease after cessation of the MDA intervention. In comparison, we anticipate that AMR prevalence will remain stationary among 49–59-month-old individuals across all three study arms throughout the course of the MDA cycles, as well as following the cessation of the intervention (Fig. The assumptions of AMR prevalence at baseline and follow-up visits in the 4–14-month-old and 49–59-month-old children. Graph is generated with hypothetical data for illustration of what the study team hypothesizesWe will employ probability weighting to account for the stratified sampling procedure used to select individuals from the village-age strata. The weights are calculated as the inverse of the selection probability for each individual in the sample, which enables weighted analysis of the dataset. | PMC10648361 | ||
Growth and nutritional status | Length-for-age Z-score (LAZ), weight-for-age Z-score (WAZ), weight-for-length Z-score (WLZ), and mid-upper arm circumference Z-score (MUAC-Z) will be calculated using the WHO Child Growth Standards [ | PMC10648361 | ||
Morbidity | malaria, ARI, diarrhea, fever | MALARIA, ACUTE RESPIRATORY INFECTION | Fourteen-day period prevalence of fever with acute respiratory infection (ARI), fever without respiratory symptoms (potential sign of malaria), and diarrhea prior to the visit in children aged 4–14 months will be assessed in each participating cluster (village) from the 59-village subset on each MDA. | PMC10648361 |
Hypotheses | PMC10648361 | |||
Mortality effect | deaths | The hypotheses in terms of mortality effect are as follows:There are fewer deaths per 1000 PYRs among 4–14-month-old infants in clusters where 1–11-month-old-infants are treated with two-dose AZI MDA than in villages where 1–11-month infants are treated with respective placebo.There are fewer deaths per 1000 PYRs among 4–14-month-old infants in clusters where 1–11-month-old-infants are treated with four-dose AZI MDA than in villages where 1–11-month infants are treated with respective placebo.There are fewer deaths per 1000 PYRs among 4–14-month-old infants in clusters where 1–11-month-old-infants are treated with four-dose AZI MDA than in villages where 1–11-month infants are treated with two-dose AZI MDA.In addition to the aforementioned, we will conduct exploratory analyses to assess mortality among children who were 12–59 months old when the latest AZI MDA took place in their village of residence and who had not been eligible to receive azithromycin on previous MDA visits.For hypothesis generating purposes, we will carry out exploratory analysis to investigate whether the following selected variables modified the effect of the MDA intervention on the mortality and growth outcomes:◦ Age at the time of MDA◦ Sex of the child◦ LAZ◦ WAZ◦ WLZ◦ Seasonality: rainy season vs non-rainy season◦ SMC given in village◦ Cluster level coverage of SMC (in %)◦ Cluster level baseline mortality (established at MDA 1)◦ Cluster level coverage of AZI MDA◦ Individual level coverage and the number of administered AZI doses◦ District of residence◦ Distance from the nearest health facility (in km)◦ Household asset index◦ Water, sanitation, and hygiene (WASH) indexThe household asset index and WASH index will be developed by principal component analysis. The component that explains the largest proportion of variance from household assets and WASH questionnaires will be used as the indices [ | PMC10648361 | |
AMR | To evaluate the effect of different MDA frequencies on AMR, we will test 12 hypotheses:Among 4–14-month-old children, the prevalence of AZI-resistant Among 4–14-month-old children, the prevalence of AZI-resistant Among 4–14-month-old children, the prevalence of AZI-resistant Among 4–14-month-old children, the proportion of infants carrying AZI-resistant pneumococci in their nasopharynx or AZI-resistant Among 4–14-month-old children, the proportion of infants carrying azithromycin-resistant pneumococci in their nasopharynx or AZI-resistant Among 4–14-month-old children, the proportion of infants carrying AZI-resistant pneumococci in their nasopharynx or AZI resistant We will also investigate older children (49–59 months old) for reference:Among children who are 49–59 month olds at the end of the trial, and who live in villages where MDA has been given to 1–11-month infants, but who have themselves not received any MDA, the proportion carrying AZI-resistant pneumococci in their nasopharynx after eight MDA rounds have been completed in the previous 2 years is not higher in villages that receive two- or four-dose AZI regimen than in villages that receive respective placebo regimen during the same time frame. | PMC10648361 | ||
Morbidity | cough, diarrhea, fever | The specific hypotheses regarding morbidity are the following:Four to 14-month-old children in villages receiving two- or four-dose AZI regimen have lower prevalence of diarrhea within the last 14 days before MDA than same-aged children living in villages receiving placebo.Four to 14-month-old children in villages receiving two- or four-dose AZI regimen have lower prevalence of fever without cough within the last 14 days before MDA than same-aged children living in villages receiving placebo.Four to 14-month-old children in villages receiving two- or four-dose AZI regimen have lower prevalence of respiratory symptoms within the last 14 days before MDA than same-aged children living in villages receiving placebo.Children in villages receiving two- or four-dose AZI regimen have lower prevalence of any morbidity symptoms within the last 14 days before MDA than same-aged children living in villages receiving placebo. | PMC10648361 | |
Growth and nutritional status | MUAC-Z | The specific hypotheses regarding growth and nutritional status are as follows:Mean LAZ, WAZ, WLZ, and MUAC-Z measured at 15, 18, 21, and 24 months after village enrollment are higher among 6–8- and 12–14-month-old children in villages that receive two-dose AZI regimen than among same-aged children in villages that receive placebo.Mean LAZ, WAZ, WLZ, and MUAC-Z measured at 15, 18, 21, and 24 months after village enrollment are higher in 6–8- and 12–14-month-old infants in villages that receive four-dose AZI regimen than among same-aged children in villages that receive placebo.Proportion of children with LAZ, WAZ, WLZ, or MUAC-Z below − 2 at 15, 18, 21, and 24 months after village enrollment is higher in 6–8- and 12–14-month-old infants in villages that receive two-dose AZI regimen than among same-aged children in villages that receive placebo.Proportion of children with LAZ, WAZ, WLZ, or MUAC-Z below − 2 at 15, 18, 21, and 24 months after village enrollment is higher in 6–8- and 12–14-month-old infants in villages that receive four-dose AZI regimen than among same-aged children in villages that receive placebo. | PMC10648361 | |
Mechanisms | malaria, PCR-diagnosed malaria infections | MALARIA | As the investigation into the mechanisms of action of azithromycin centers on the dose-dependent impact at an individual level, specifically the underlying mechanisms of azithromycin’s function following administration, the two treatment arms may be consolidated for analysis. The mechanisms of azithromycin’s action shall be investigated through testing the following hypotheses:Reduction in the prevalence of PCR-diagnosed malaria infections between day 0 and day 14 is greater in infants in villages receiving two-dose or four-dose AZI MDA regimen than in infants in villages receiving placebo MDA regimen.Among those who test positive on day 0, the proportion of positive PCR test for malaria on day 14 is lower among infants who receive AZI MDA than among children who receive respective placebo.Reduction of intensity of subclinical malaria (expressed in parasite density) between day 0 and day 14 is greater in infants in villages receiving two-dose or four-dose AZI MDA regimen than in infants in villages receiving placebo MDA regimen.Increase in mean blood hemoglobin concentration between day 0 and day 14 is greater in infants in villages receiving two-dose or four-dose AZI MDA regimen than in infants in villages receiving placebo MDA regimen.Reduction in mean CRP concentration between day 0 and day 14 is greater in infants in villages receiving two-dose or four-dose AZI MDA regimen than in infants in villages receiving placebo MDA regimen.Among infants with elevated CRP concentration (CRP > 5 μg/mL) at day 0, reduction in the prevalence of elevated CRP concentration is greater among infants who receive AZI MDA than among children who receive respective placebo.Reduction in mean AAT, mean NEO, mean MPO concentrations, and EE score, between day 0 and day 14 is greater in infants in villages receiving two-dose or four-dose AZI MDA regimen than in infants in villages receiving placebo MDA regimen.Among infants with elevated AAT/MPO/NEO concentration (AAT > 270 µg/g; MPO > 2000 ng/L; NEO > 70 nmol/L) at day 0, reduction in the prevalence of elevated AAT/MPO/NEO concentration is greater among infants who receive AZI MDA than among children who receive respective placebo. | PMC10648361 |
Statistical methods | PMC10648361 | |||
General principles | SECONDARY | We will analyze the mortality outcome data by the intention-to-treat (ITT) principle, where the ITT population will include all infants of the eligible age at the time of the MDA visit from all the randomized villages according to the treatment the villages were randomized to receive. That is, if the household gives consent on participating to the study, the study team will offer to treat the child. Even if the child is not treated, their survival information will be analyzed. For the secondary outcome data from the subset of 59 villages, we will analyze the treated population, which only includes the infants who received at least one dose of the treatment drug.Unless otherwise specified, we will use mixed-effects modeling approach to account for clustering, all the hypothesis testing will be at 5% two-sided significance level, and all confidence intervals will be 95% and two-sided, calculated by using robust standard errors. For calculating robust standard errors, we will use sandwich estimator of variance for clustered data. For the primary aim of the estimation of the effect of azithromycin treatment on 1–11-month-old mortality and for the secondary aims, we will carry out adjustment for multiple comparisons between groups by closed-testing procedure [We conduct blind-review on the data during data collection and prior to any formal analysis. That is, we conduct exploratory analysis to check for errors and inconsistencies, without knowing the intervention group identities. Based on the blind-review of the data as well as previous literature, we will apply natural log transformation on the following biomarker variables: CRP, AAT, NEO, MPO, and parasite density [ | PMC10648361 | |
Analysis of the primary outcome | PMC10648361 | |||
Azithromycin treatment effect on mortality among 1–11-month-old infants | IRD | We will tabulate the mortality (deaths/1000 PYR and absolute numbers) per arm and per 3-month intervals preceding the second to ninth visit. To investigate if azithromycin treatment reduces mortality among 1–11-month-old infants, we will estimate incidence rate ratio (IRR) and its 95% CI to compare the treatment regimens. We will use mixed-effects Poisson model to estimate intervention effects between treatment groups, with random intercepts for clusters (villages), using log link function with person-years as an offset variable. At maximum, an infant can receive the treatment at four MDAs, thus provide up to 1 year of follow-up time to the study data.The main analysis hypothesis testing will be conducted as one-sided, that is, we hypothesize there to be lower mortality in the treatment groups. The decision to use one-sided test was based on the existing evidence of AZI having a potentially beneficial effect on early childhood mortality in previous trials [In the main analyses, we will adjust for stratification factor in the randomization scheme (village size category) as a fixed effect. The main analysis will not make additional adjustments for covariates.The mixed-effects model with log link function for the primary aim on intervention effect on mortality will provide the IRR. To understand the population importance of the intervention, we will use non-linear combinations of the parameter estimates from the same mixed-effects model to obtain average estimates of incidence rate difference (IRD) [ | PMC10648361 | |
Analysis of the secondary outcomes | PMC10648361 | |||
The effect of MDA regimes on AMR | We will present the proportions of children with resistant isolates in at baseline (i.e., MDA 1) and at visit 9 for all the trial arms. We will also produce a table with proportions of resistant isolates from all isolates in the same manner as for children with resistant isolates. To estimate the impact of two- or four-dose AZI regimen on the prevalence of phenotypic AZI resistance among If the entire 95% CI for the time point at 1 year after the last MDA in the treatment arms is below a predefined non-inferiority margin of + 10 percent points as compared to the control arm, the sample findings will be considered supportive of the hypothesis of no clinically significant increase in AMR prevalence. The procedure will be same for 49–59-month-old children. | PMC10648361 | ||
The effect of MDA regimens on morbidity | ARI, diarrhea, fever | REGRESSION | For morbidity analyses, we will calculate the 14-day period prevalence of fever with ARI, fever without respiratory symptoms, and diarrhea in the three intervention arms and perform a three-group comparison using likelihood ratio tests. The latter will be obtained from mixed-effects logistic regression models, with random intercepts for clusters and children to allow within-cluster correlation in clusters and timepoints. If the global test of null hypothesis shows a statistically significant difference ( | PMC10648361 |
The effect of MDA regimens on growth and nutritional status | stunting or wasting, wasting, MUAC-Z, stunting | REGRESSION, WASTED, WASTING | We will tabulate the descriptive summaries (mean, SD, min, max) on LAZ, WAZ, WHZ, and MUAC-Z score for each treatment arm. We will analyze the impact of AZI MDA on growth and nutritional status using mixed-effects regression model with identity link and random intercepts for clusters and for children.In addition, we will perform analyses on dichotomous outcome variables, including moderate-to-severe and severe stunting (LAZ < − 2/LAZ < − 3), moderate-to-severe and severe underweight (WAZ < − 2/WAZ < − 3), and moderate-to-severe and severe wasting (WLZ < − 2/WLZ < − 3). We will tabulate the proportions of stunted, underweight, and wasted per treatment arm and age group (6–8 months, 12–14 months, respectively) and calculate their differences (95% CI). We will test a hypothesis that there is no difference between the treatment arms with respect to the prevalence of stunting or wasting by using a mixed-effects logistic regression model with random intercepts for clusters and for children. The marginal risk ratios will be predicted from the obtained model coefficients. | PMC10648361 |
The effect of MDA regimens on mechanisms of action of azithromycin | malaria, inflammation, parasitemia, parasitaemia, intestinal inflammation | MALARIA, INFLAMMATION, PARASITEMIA, INTESTINAL INFLAMMATION, REGRESSION | Outcomes related to study questions on mechanisms of action of azithromycin are measured twice: at day 0, i.e., before the treatment on the day of fourth MDA visit (9 months after village enrolment), and 14 days after. The two intervention groups will be combined in the analysis. For each endpoint in the mechanistic study, mixed-effects regression model with random intercepts for clusters will be estimated, including intervention (versus control) and the day 0 measure as the independent variables and the day 14 measure as the dependent variables.To investigate the impact of AZI MDA on malaria parasitaemia prevalence, the prevalence of elevated CRP concentration (CRP > 5 µg/mL), prevalence of elevated AAT concentration (AAT > 270 µg/g), MPO concentration (MPO > 2000 ng/L), and NEO concentration (NEO > 70 nmol/L), we will use the binary variables as dependent outcome variables in mixed-effects logistic regression models with random intercepts for clusters and for children. The marginal risk ratios will be predicted from the obtained model coefficients. Risk ratios and their 95% CIs will be reported.We will model the impact of AZI MDA on the intensity of subclinical malaria by using the natural logarithm transformed values from the parasite density variable as the dependent outcome variable in a mixed-effects model with random intercepts for clustering and identity link function. We will use the same modeling approach on modeling the impact of AZI MDA on general inflammation and intestinal inflammation (that is, CRP concentration, AAT concentration, MPO concentration, and NEO concentration, respectively). We will report the exponentiated value of the regression coefficient (geometric mean) and their 95% CI. We will conduct the same analysis with the blood hemoglobin concentration as the dependent outcome variable but report regression coefficients and their 95% CIs without exponentiation.We will also produce tabulations on the descriptive summaries (means, medians, standard deviations, minimum, maximum) of the variables and report proportions and absolute numbers on positive and negative malaria parasitemia prevalences, as well as proportions and absolute numbers on elevated CRP/AAT/MPO/NEO concentration levels. The tabulations will be done respectively for day 0 and day 14. | PMC10648361 |
Subgroup analyses | To examine the effect modification, we will construct different models to test for interaction with pre-defined set of baseline variables. Hypothesis test of difference between groups within each stratum will be performed only if the interaction test gives statistically significant results ( | PMC10648361 | ||
Loss to follow-up and missing data | A participant will be deemed lost to follow-up, if vital status cannot be ascertained in any of the subsequent MDAs. We will present the numbers of loss to follow-up between the three trial arms in the trial flow diagram (Fig. Trial profile | PMC10648361 | ||
Interim analysis | An interim analysis will be conducted when approximately 60% of the target PYR is available. This interim analysis will focus on mortality and SAEs. For this analysis, statistical significance is defined as two-sided If the interim analysis reveals statistically significant mortality difference between the quarterly azithromycin-MDA group and the placebo group and between the biannual azithromycin-MDA group and the placebo group but not between the two azithromycin groups, the placebo arm will be discontinued, and the trial will continue with two arms only. In this scenario, the villages with remaining MDA rounds in the placebo arm will be re-randomized to either of the treatment arms. If there is evidence of a mortality benefit in one or both azithromycin groups and also a statistically significant difference between the two azithromycin groups, the trial will be stopped, and the team will offer to work with Malian Ministry of Health to provide AZI MDA in the trial site and elsewhere in the regions of Mali, choosing the MDA regimen (quarterly or biannual) based on the trial data [ | PMC10648361 | ||
Safety analysis | Written reports of any SAEs will be prepared during the duration of the trial and AEs will be reported as part of the data collection. Types, severity, and relatedness to intervention of the SAEs will be reported. We will not conduct formal group comparisons or statistical inference for the SAEs. | PMC10648361 | ||
Sample size considerations | PMC10648361 | |||
Power-by-simulation approach | STAGGERED | Simulations were conducted to determine the appropriate sample size to achieve target level of power for the main objectives as well as to confirm that the procedures related to the interim analysis will not compromise type I error rate [Mortality among 1–11-month-(29–364 days)-old children in control group of 20 deaths/1000 PYR.Justification for the baseline mortality estimate and respective assumptions on reduction in mortality had been described in separate protocol article [Mortality in the two-dose AZI intervention group 16/1000 (20% relative reduction)Mortality in the four-dose AZI intervention group 12/1000 (40% lower than control, 25% lower than two-dose AZI)Two-year intervention with eight quarterly cycles of MDA for 50% of clusters, seven rounds for 30%, and six rounds for 20%, due to staggered entry but equal stopping calendar date.Coefficient of variation (k = sd/mean) (CV) of 0.1 in mortality among clusters.According to our estimate of 20 deaths/1000 PYR, the intra-cluster correlation (ICC) is estimated to be 0.0001 according to the findings of Gulliford et al. [Unequal number of infants per cluster: on average, 22 infants in a small village and 70 in a big village. Average for number of infants in a village being 31.Average number of infants in small and big villages (respectively) was simulated with Poisson process. Based on prior information from local census data, we inferred the mean size to be 22 for small villages and 70 for big villages.From the same data, we inferred the proportions for big and small villages to be 18% and 82%, respectively.Sample size of 1150 villagesUnequal ratio of clusters. Control vs AZI-biannual vs AZI-quarterly = 3: 4: 2One interim analysis when 60% of the planned 3-month time intervals have been completed.One-sided 2.5% type 1 error, controlling of multiple pairwise comparisons by the closed-testing procedureClosed-testing procedure will be carried out by calculating a As per the Peto’s rule, significance level is set to 0.001 at interim analysis leading to either continuing the study to second phase, dropping the control arm, or stopping the trial early.Simulations were run with 2000 iterations using aforementioned values for parameters. The simulations show that by specifying the aforementioned inputs, the study has approximately 89% power for testing the hypothesis that biannual AZI MDA will reduce mortality, > 99% power for testing the hypothesis that quarterly AZI MDA will reduce mortality, and 80% power for testing the hypothesis that quarterly AZI MDA will reduce mortality more than biannual AZI MDA. The simulations also showed that with the chosen analytical approach familywise type I error rate is controlled at the target level despite multiple pairwise comparison and interim analysis. | PMC10648361 | |
AMR | The following assumptions were used for the AMR sub-sample size calculations:The AMR sub-sample size is based on the following assumptions.95% AMR prevalence of 12% in the control group for Non-inferiority margin of 10 percent-points in AMR prevalence.80% power, one-sided 2.5% type 1 error rate for each pairwise comparison against placebo control.Coefficient of variation of 0.3 in AMR among clusters. | PMC10648361 | ||
Statistical software | The analyses will be conducted using Stata statistical software. R programming language will be used for data pre-processing and other analyses if necessary. The used packages and version numbers will be included in the final report. | PMC10648361 | ||
Data management | Data management is described in detail in separate standardized operating procedure (SOP) document as mentioned in the protocol article [ | PMC10648361 | ||
Conclusion | LAKANA will provide valuable information on effect of different MDA strategies on 1–11-month-old mortality and health outcomes in Mali. This article provides details of the statistical analysis strategies planned for the trial data, aiming to reduce the risk of data driven results, as well as reporting bias. Large cluster randomized study design aims to evaluate the effect of azithromycin treatment on infant mortality by adding in dimensions that have not been addressed in previous studies. Cluster randomized design also simulates how the potential intervention rollout could be applied, should there be a nationwide implementation program. | PMC10648361 | ||
Acknowledgements | The LAKANA Trial team would like to thank all national and local leaders in Mali who are facilitating trial activities and the children and their families who have participated in the trial to date. The authors gratefully acknowledge the work and dedication of all study staff at all participating sites. The authors thank Pfizer Inc. for donating azithromycin and placebo. The authors appreciate the support and guidance of the DSMB members, Dr. Robert Black (chair), Dr. Julia Bielicki, Dr. Alassane Dicko, Dr. Queen Dube, and Dr. Paul Milligan. The authors would like to thank the TAG members, Dr. Tom Lietman (chair), Dr. Anthony Solomon, and Dr. Karen Kotloff, for their guidance on trial implementation. | PMC10648361 | ||
Authors’ contributions | All authors adhere to the authorship guidelines of Trials. All authors have agreed to publication. | PMC10648361 | ||
Funding | subawards | Open access funding provided by Tampere University (including Tampere University Hospital). Tampere University has received funding for the proposed trial from the Bill & Melinda Gates Foundation (Seattle, WA, USA). For implementation, Tampere University will issue subawards to CVD-Mali, UCL, and Tro Da Ltd. | PMC10648361 | |
Availability of data and materials | Not applicable. Upon completion of the trial, de-identified data will be made publicly available per the funder, the Bill and Melinda Gates Foundation, policy. | PMC10648361 | ||
Declarations | PMC10648361 | |||
Ethics approval and consent to participate | The trial is conducted in accordance with the International Conference on Harmonization Good Clinical Practice (ICH-GCP) and adheres to the principles of the Helsinki declaration and regulatory guidelines in Mali. LAKANA has received approval from the Mali IRB, the Comité d'Éthique de la Faculté de Médecine, de Pharmacie et d’Odonto-Stomatologie (FMPOS), Université des Sciences, des Techniques et des Technologies de Bamako. An ethics committee in Finland has no legal mandate to authorize trials abroad, but the LAKANA trial has received a favorable opinion from the Ethics Committee of the Pirkanmaa Hospital District for Tampere University researchers to participate in the project. | PMC10648361 | ||
Consent for publication | Not applicable. | PMC10648361 | ||
Competing interests | The authors declare that they have no competing interests. | PMC10648361 | ||
References | PMC10648361 | |||
Background: | traumas, high disability | DISEASES | Severe multiple traumas are one of the most common diseases and carry a significant financial burden with high disability and mortality. There are no effective drugs in the clinical management of severe multiple traumas, and there is an absence of evidence-based medicine concerning the treatment of severe multiple traumas. | PMC9935977 |
Methods: | traumas, infection, UTIs, trauma | MULTIPLE ORGAN DYSFUNCTION SYNDROME, ADVERSE EFFECTS, INFECTION, UTI, INFLAMMATORY RESPONSE | The present study explored whether ulinastatin (UTI) can improve the outcome of severe multiple traumas. The present research included patients who were hospitalized in intensive care units after being diagnosed with severe multiple trauma. Patients received UTIs (400,000 IU) or placebos utilizing computer-based random sequencing (in a 1:1 ratio). The primary outcome measures were 30-day mortality, multiple organ dysfunction syndrome, inflammatory response, coagulation function, infection, liver function, renal function, and drug-related adverse effects. | PMC9935977 |
Results: | coagulation dysfunction, infection, UTI, multiple organ dysfunction syndrome, hyperinflammation | INFECTION, MULTIPLE ORGAN DYSFUNCTION SYNDROME, UTI | A total of 239 individuals were classified into 2 groups, namely, the placebo group (n = 120) and the UTI group (n = 119). There were no statistically significant differences in baseline clinical data between the 2 groups. The 30-day mortality and multiple organ dysfunction syndrome in the UTI group were remarkably improved compared with those in the placebo group. UTI can protect against hyperinflammation and improve coagulation dysfunction, infection, liver function, and renal function. UTI patients had markedly decreased hospitalization expenditures compared with the placebo group. | PMC9935977 |
Conclusion: | traumas, UTIs | ADVERSE REACTIONS | The findings from the present research indicated that UTIs can improve the clinical outcomes of patients with severe multiple traumas and have fewer adverse reactions. | PMC9935977 |
1. Introduction | death, traumatic brain injury, traumas, posttraumatic hyperinflammation, trauma | UTI | Injuries caused by trauma remain one of the most common causes of death in the world, especially emergency severe multiple traumas combined with traumatic brain injury.Ulinastatin (UTI) is a serine protease inhibitor with a molecular weight of 67,000 that is purified from human urine. The primary pharmacological activities of this compound were anti-inflammatory, immunoregulatory, and organ protection.However, because of the unique nature of emergency severe multiple trauma patients and the lack of evidence-based medical studies with large sample sizes, the efficacy of UTI treatment remains unclear. Thus, the present study aimed to test the hypothesis that the administration of UTI would improve the outcome and alleviate posttraumatic hyperinflammation after severe multiple traumas. | PMC9935977 |
2. Methods | PMC9935977 | |||
2.1. Study design | A placebo-controlled, parallel-arm, randomized experiment was carried out in Jiangsu from January 2019 to December 2021. A total of 267 patients were screened over this period, and 239 of these were initially enrolled in the study to form the intention-to-treat population. To determine if the intervention is superior, the present research was conducted. The Clinical Research Ethics Committees of the 904Study design. | PMC9935977 | ||
2.2. Patients enrolled in the study and sample selection procedures | allergic, organ dysfunction | MALIGNANT TUMORS, UTI | Patients were included in the present research in the emergency intensive care unit. The following were the criteria for inclusion: patients aged 25 to 70 years; >2 anatomical sites injured and injury severity score ≥ 16; time from injury to hospitalization <12 hours; estimated posttraumatic survival time >72 hours; and randomly assigned to receive either UTI or a placebo. The exclusion criteria were as follows: patients who were unlikely to be salvaged upon admission; allergic to UTI; received anticoagulant medication within 48 hours before hospitalization; pregnant women and patients with malignant tumors; treatment with immunosuppressive drugs; multiple organ dysfunction; and other explanations were discovered by researchers. | PMC9935977 |
2.3. Randomization and concealment | EVENT, ACUTE HEPATIC FAILURE | With the aid of SPSS software (version: 14.0) (SPSS Institute, Anhui Medical University, Hefei, China), permuted-block randomization was carried out based on a computer system that used an allotment list to produce random numbers (in a 1-to-1 ratio). This was carried out by a statistician who was not a member of the research team to maintain the integrity and blinding of the research. The outcomes of the random sampling process were enclosed in prenumbered envelopes and kept at the location of the research until the study’s conclusion was reached. The study medicines were delivered by a research nurse following the random assignment sequence. Both the research participants and the patients were unaware of which medicine was being applied in the trial. In the event of an emergency, such as acute hepatic failure, 2 experts might recommend that the treatment allotment be unmasked and that the study medicine be adjusted or discontinued if needed, according to the protocol. All of the occurrences were recorded in detail. Then, we acquired information on the patient’s demographics, medical histories, and pertinent investigation findings. | PMC9935977 | |
2.4. Outcome assessment | MODS, tumor necrosis, infection | MODS, SECONDARY, TUMOR NECROSIS, INFECTION | All clinical and imaging data and treatment were subjected to assessment by a masked independent diagnostic and assessment committee. This committee included 2 researchers who were trained before the start of the present research and did not engage in the clinical care of patients. The primary endpoint of this study was 30-day mortality. The secondary endpoints included the incidence of MODS; inflammatory cytokine levels (pretherapy and posttreatment), such as serum tumor necrosis factor-α and interleukin-6; coagulation function, such as the plasma prothrombin time, activated partial thromboplastin time and fibrinogen (FIB) levels, was measured using an automatic coagulation analyzer; serum infection index levels, such as white blood cell count, C-reactive protein, and procalcitonin; liver function index levels, such as alanine aminotransferase and aspartate aminotransferase; and renal function index levels, such as creatinine and urea nitrogen. | PMC9935977 |
2.5. Safety evaluation and complications | diarrhea, Abnormal liver enzymes, vomiting, abnormal liver, granulocytopenia, allergies, UTIs | ADVERSE EFFECTS, ALLERGIES, COMPLICATIONS, GRANULOCYTOPENIA | We kept track of the length of time spent in the intensive care unit, and the most prevalent adverse effects of UTIs included granulocytopenia and abnormal liver enzymes. Other rare complications include diarrhea, vomiting, and allergies. All complications were confirmed and recorded by physical examination after 2 doctors and nurses; granulocytopenia was diagnosed by routine blood level detection. Abnormal liver enzymes were diagnosed by liver function tests. Finally, we check the related index every 2 days over the first 14 days. | PMC9935977 |
2.6. Postoperative hospital stays and hospitalization costs | traumas | As previously reported, severe multiple traumas or critical care patients have remarkably longer hospital stays and higher hospitalization expenses. Thus, the present research examined the difference in the overall duration of hospital stay and healthcare costs among patients belonging to the 2 groups. | PMC9935977 | |
2.7. Sample size estimates | In a previous study, | PMC9935977 | ||
2.8. Statistical analysis | Data from the baseline as well as outcome assessments were input into the database by a research nurse. The information was gathered on handwritten forms and stored in a digital database that was password secured. All continuous variables are presented as the mean ± SD. SPSS 19.0 statistical software (SPSS, Inc., Chicago, IL, USA) was used for the statistical analyses. Measurement data with a nonnormal distribution are represented by M (Q1, Q3). Independent-samples | PMC9935977 | ||
3. Results | blindness | BLINDNESS, UTI | A total of 267 patients were evaluated between January 2019 and December 2021, and 239 of these were initially enrolled in the study to form the intention-to-treat population, which was given UTI (n = 120) or placebo (n = 119) treatment in a random manner. There were no cases of open blindness observed throughout the research period. Furthermore, no statistically significant differences were discovered in terms of the baseline data between the 2 subgroups (Table Comparison of baseline data.BMI = body mass index, ISS = injury severity score, SD = standard deviation, UTI = ulinastatin.Trial profile. | PMC9935977 |
3.1. The primary endpoint and risk of MODS | MODS | MODS, MULTIPLE ORGAN DYSFUNCTION SYNDROME, UTI | After treatment, the total 30-day mortality was 16.74% (40/239), according to the findings. The 30-day mortality was 15.38% (14/120) in the UTI group and 28.89% (26/119) in the placebo control group. As opposed to the UTI group, the placebo group exhibited a remarkably greater 30-day mortality rate, with a significant difference (Comparison of 7-day mortality and clinical efficacy.MODS = multiple organ dysfunction syndrome, UTI = ulinastatin. | PMC9935977 |
3.2. The secondary endpoints | infection, tumor necrosis | PCT, TUMOR NECROSIS, INFECTION, SECONDARY, UTI | Before UTI or placebo treatment, there was no significant difference in the inflammatory cytokine levels, coagulation function, serum infection index levels, liver function index levels, or renal function index levels between the 2 groups (Comparison of the secondary end-points.ALT = alanine aminotransferase, APTT = activated partial thromboplastin time, AST = aspartate aminotransferase, BUN = urea nitrogen, CRP = C-reactive protein, D-D = d-dimer, FIB = fibrinogen, IL-6 = interleukin-6, PCT = procalcitonin, PT = prothrombin time, SCr = serum creatinine, SD = standard deviation, TNF-α = tumor necrosis factor-α, UTI = ulinastatin, WBC = white blood cell. | PMC9935977 |
3.3. Safety evaluation | abnormal liver enzymes, abnormal liver, granulocytopenia | ADVERSE EFFECTS, GRANULOCYTOPENIA, UTI | The most prevalent adverse effects of UTI include granulocytopenia and abnormal liver enzymes. We found that 10 (8.33%) patients experienced granulocytopenia in the UTI group, while 6 (5.04%) patients experienced granulocytopenia in the placebo group, with no significant difference between the 2 groups. There were 21 (17.65%) cases of abnormal liver enzymes in the control group, while there were 39 (32.50%) cases of abnormal liver enzymes in the UTI group, which was significantly higher than the placebo group (Comparison of safety evaluation, and postoperative hospital stays and costs.CNY = Chinese Yuan, SD = standard deviation, UTI = ulinastatin. | PMC9935977 |
3.4. Postoperative hospital stays and hospitalization costs | UTI | In the UTI group, the average duration of stay was 28.64 days, whereas the value for the placebo group was 29.41 days, with no statistically significant difference ( | PMC9935977 | |
4. Discussion | MODS, toxic shock, coagulation dysfunction, abnormal liver, infection, allergies, hyperinflammation, sepsis, trauma | TOXIC SHOCK, INFLAMMATORY DISORDER, MODS, INFECTION, ADVERSE EFFECTS, HEMORRHAGIC SHOCK, UTI, ALLERGIES, SEPSIS | According to the findings of the current investigation, UTI may greatly reduce the incidence of total 30-day mortality and MODS in emergency severe multiple trauma patients. Additionally, we also found that UTI can protect against hyperinflammation and improve coagulation dysfunction, infection, liver function, and renal function. It also did not significantly increase the incidence rate of severe adverse effects other than allergies and abnormal liver enzymes, and this should be considered because the synergistic effect after the combined application of other drugs in some patients may lead to an increase in the proportion of patients with allergies. Moreover, it can also decrease the expenditure on hospitalization.According to the findings, the total 30-day mortality was 16.74%, which was consistent with earlier reports.UTI is a 67 kDa glycoprotein purified from the urine of healthy humans that is a nonspecific protease inhibitor and a urinary trypsin inhibitor that is used to treat acute inflammatory disorders, sepsis, toxic shock, and hemorrhagic shock. | PMC9935977 |
5. Conclusion | MODS, traumas, coagulation dysfunction, infection, hyperinflammation, UTIs, trauma | MODS, INFECTION, UTI | The findings of the present research suggest that UTI treatment may help to minimize the risk of mortality and MODS against hyperinflammation and improve coagulation dysfunction, infection, liver function, and renal function following severe multiple traumas. Furthermore, it resulted in a considerable reduction in hospitalization expenditures. To completely grasp the prospective application of UTIs in multiple trauma patients, more studies with individuals who receive varied dosages are needed. | PMC9935977 |
Acknowledgments | We hereby express our gratitude to Jiangsu Brilliant Biological Technology Co., Ltd. for providing technical and linguistic help. | PMC9935977 | ||
Abbreviations: | fibrinogenmultiple organ dysfunction, trauma | fibrinogenmultiple organ dysfunction syndromemultiorgan failureulinastatinThe authors have no funding to disclose.The authors have no conflicts of interest to disclose.The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.How to cite this article: Xu H, Jiao W, Zhang Y, Deng X, Dai R, Chen L. Effects of ulinastatin therapy in emergency severe multiple trauma: A single-center randomized controlled trial. Medicine 2023;102:7(e32905). | PMC9935977 | |
References | PMC9935977 | |||
Supplementary Information | cardiovascular arrythmias | Plasma potassium (p-K) in the high-normal range has been suggested to reduce risk of cardiovascular arrythmias and mortality through electrophysiological and mechanical effects on the myocardium. In this study, it was to investigated if increasing p-K to high-normal levels improves systolic- and diastolic myocardial function in patients with low-normal to moderately reduced left ventricular ejection fraction (LVEF). The study included 50 patients (mean age 58 years (SD 14), 81% men), with a mean p-K 3.95 mmol/l (SD 0.19), mean LVEF 48% (SD 7), and mean Global Longitudinal Strain (GLS) -14.6% (SD 3.1) patients with LVEF 35–55% from “The online version contains supplementary material available at 10.1007/s10554-023-02914-x. | PMC10673982 | |
Keywords | Open access funding provided by Royal Library, Copenhagen University Library | PMC10673982 | ||
Introduction | heart failure, systolic dysfunction | HEART FAILURE, SYSTOLIC DYSFUNCTION | Low as well as high plasma-potassium (p-K) levels have been shown to be associated with reduced survival [Myocardial function at low p-K levels has been studied experimentally in dogs (n = 27) and in healthy human volunteers (n = 10) [2D-speckle tracking echocardiography has been demonstrated to be a sensitive and robust method for detection of subtle systolic dysfunction as in preclinical heart failure [ | PMC10673982 |
Materials and methods | PMC10673982 | |||
Population | heart failure | MAY, EVENTS, HEART FAILURE | The current substudy was prespecified in the protocol for the For the present study, 50 consecutive patients from the POTCAST trial with LVEF between 35 and 55% were included between June 1, 2020 and May 31, 2021. Patients were excluded from the final analysis if any of the following criteria were present: echocardiographic image quality too poor for 2D-speckle tracking criteria, acute coronary events during follow-up, any changes in heart failure medication during follow-up unrelated to the study, and difference in rhythm at baseline and follow-up echocardiographies. | PMC10673982 |
Ethics | The study was performed according to the declaration of Helsinki. All patients provided informed consent. The study was approved by regional Danish committee of health research ethics (Regional Videnskabsetisk komité) — Protocol approval no. H-18,044,908 and by the Danish Data Protection Agency — approval no. VD-2018-453. | PMC10673982 | ||
Intervention | Patients in the control group continued standard medical treatment. In addition to the standard treatment patients in the intervention group were educated in intake of a potassium rich diet and commenced oral potassium supplement and/or MRA (spironolactone or eplerenone) according to the POTCAST protocol [ | PMC10673982 | ||
Screening and follow-up | Transthoracic echocardiography was performed at enrollment after measurements of p-K | PMC10673982 | ||
Echocardiography | All echocardiographies were performed by a single investigator using the same ultrasound system (Vivid E9, GE healthcare), the same probe (M5S-D, GE) and the same analyzing software (EchoPac, version 203.66). Cine loops from 3 standard apical views (2-chamber, 4-chamber, and apical long-axis) were recorded using gray-scale harmonic imaging and saved in raw data format. Images were obtained at an acquisition rate of 50 to 90 frames per second. Left ventricular end-diastolic and end-systolic volumes and left ventricular ejection fraction (LVEF) were obtained using Simpson’s biplane method. For 2D-speckle tracking analysis, the inner endocardial borders were traced in the end-systolic frame in images from the three standard apical views. Speckles were tracked frame by-frame throughout the left ventricular wall during the cardiac cycle and basal-, mid-, and apical regions of interest were drawn (Fig. Off-line image analyses were independently performed by two investigators blinded to randomization allocation, clinical data and blood test results to reduce the risk of bias.
Measurement of Global Longitudinal Strain (A) and Mechanical Dispersion (B) from 2D-Speckle-Tracking software | PMC10673982 | ||
Outcomes | The predefined outcomes were differences in changes from baseline to follow-up between the two groups in 2D-speckle tracking derived indices of systolic function: GLS, MD and for assessment of diastolic function: E/A, e´ and E/e´. | PMC10673982 | ||
Sensitivity analysis | A subgroup analysis was performed on patients in the intervention group that only received dietary guidance and potassium as a supplement to reach target p-K levels to test if the effects of increasing potassium levels on myocardial function was independent of the effects of MRA on loading conditions. | PMC10673982 |
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