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Informed Consent Statement | Informed consent was obtained from all subjects involved in the study. | PMC10575211 | ||
Data Availability Statement | The authors confirm that the data supporting the findings of this study are available from the authors upon reasonable request. | PMC10575211 | ||
Conflicts of Interest | D.K., M.M. and A.P. (Anna Poświata) are employees of the EGZOTech company, which designed the Luna EMG robot. | PMC10575211 | ||
References | Participant upper limb position during elbow flexion/extension strength test (source—authors’ own).Study participant flowchart.Comparison of baseline and post-rehabilitation FIM results.Comparison of baseline and post-rehabilitation FIM motor subscale results.Participants’ characteristics at baseline.BMI—body mass index; FIM—Functional Independence Measure; Berg—Berg scale; HGS—hand grip strength; Tinetti—Tinetti test; 6MWT—six-minute walking test; Barthel—Barthel Index; flexion strength—elbow flexion torque; extension strength—elbow extension torque.Repeated measures ANOVA results for all outcome measures.* Data are expressed as mean and standard deviation. BMI—body mass index; FIM—Functional Independence Measure; Berg—Berg scale; HGS—hand grip strength; Tinetti—Tinetti test; 6MWT—six-minute walking test; Barthel—Barthel Index; flexion strength—elbow flexion torque; extension strength—elbow extension torque. | PMC10575211 | ||
Background | weight loss, cardiovascular diseases | METABOLIC SYNDROME, TYPE 2 DIABETES, CARDIOVASCULAR DISEASES | Commercial smartphone apps that promote self-monitoring of weight loss are widely available. The development of disease-specific apps has begun, but there is no app for specific health guidance (SHG) to prevent metabolic syndrome, type 2 diabetes, and cardiovascular diseases in middle-aged adults in Japan. | PMC10134028 |
Objective | obesity, weight loss | OBESITY, HYPERTENSION | This study aimed to determine the efficacy of an SHG mobile health app in facilitating weight loss in Japanese adults with obesity and hypertension. | PMC10134028 |
Methods | personality traits, overweight, weight loss | OBESE | In a 12-week, statistician-blinded, randomized parallel controlled trial, 78 overweight and obese men aged 40-69 years were assigned in a 1:1 ratio to either the usual support plus KENPO-app group (intervention group) or the active control group. KENPO-app (release April 10, 2019; OMRON Healthcare Co., Ltd.) was developed by the study team and focus groups and uses behavior change techniques (ie, self-monitoring and goal-setting theory). This app was developed for SHG based on the four specific health checkups and guidance system in Japan: (1) focusing primarily on achieving the target (weight loss of ≥2 kg); (2) assessing healthy eating, exercise habits, smoking habits, relaxation, and self-weighing; (3) providing information on the results of specific health checkups; and (4) starting an intervention period of 6 months with the interim assessment at 3 months. The initial assessment explored the following: personality traits (4 types), health checkup data concerns (10 items), symptom concerns (10 items), and the aim of the intervention (weight loss, improving fitness, symptoms, laboratory data). Chatbot-supported health information on health and health behavior was selected from 392 quizzes based on app data and was provided to participants. The KENPO-app had chatbot-supported feedback and information provision combined with a self-monitoring tool (weight, steps, and blood pressure). Data on active exercise, healthy eating, and healthy lifestyle habits were obtained using a web-based self-administered questionnaire at baseline and 12 weeks. | PMC10134028 |
Results | ’s retention rate was 95% (74/78). | The trial’s retention rate was 95% (74/78). The adherence to daily self-weighing, wearing the pedometer, and blood pressure monitoring in the KENPO-app group was significantly higher than those in the active control group. Compared with the active control group, the median body weight and BMI of the intervention group significantly decreased at 3 months (–0.4, IQR –2.0 to 0.6 kg vs –1.1, IQR –2.7 to –0.5 kg; | PMC10134028 | |
Conclusions | obesity, weight loss | OBESITY | The SHG-specific KENPO-app was feasible and induced modest but significant weight loss in adults with obesity. | PMC10134028 |
Trial Registration | University Hospital Medical Information Network Center UMIN000046263; https://tinyurl.com/bderys3b | PMC10134028 | ||
Introduction | cardiovascular diseases | METABOLIC SYNDROME, TYPE 2 DIABETES, CARDIOVASCULAR DISEASES | In 2008, all health insurers in Japan were mandated to provide specific health guidance (SHG) to prevent metabolic syndrome, type 2 diabetes, and cardiovascular diseases in middle-aged adults in Japan [ | PMC10134028 |
Methods | PMC10134028 | |||
Study Design | obesity | OBESITY, MAY, HYPERTENSION | This study was a 12-week, statistician-blinded, parallel-group, randomized controlled trial (RCT) of adults with obesity and hypertension. The data were obtained between October 2021 and May 2022. | PMC10134028 |
Ethics Approval | The study protocol was approved by the institutional review board of Kyoto Medical Center (NO.21-057), and the protocol of the study was registered at the University Hospital Medical Information Network Center (UMIN000046263). | PMC10134028 | ||
Participants | RECRUITMENT | Participants were recruited from the screening panel of the Omron monitor recruitment site for product development and research in Japan. Therefore, participants may have relatively higher computer/internet literacy. We held an online information session for this trial. Inclusion criteria were as follows: age 40-64 years, BMI≥25 kg/m | PMC10134028 | |
Randomization and Masking | The independent statistician randomly allocated participants into one of two intervention arms according to sex-, age-, SBP-, and BMI-stratified block randomization (seed=1221 and block size=2). We adopted a single-blind approach; thus, the effectiveness was assessed by blinded researchers who were unaware of the randomization results. | PMC10134028 | ||
Self-monitoring Tool | Participants in both groups received a Bluetooth weighing scale (HBF-227T, OMRON Healthcare Co, Ltd), pedometer (HJA-405T, OMRON Healthcare Co, Ltd), and upper arm blood pressure (BP) monitor (HCR-7501T, OMRON Healthcare Co, Ltd). | PMC10134028 | ||
The Active Control Group | The participants in the active control group received the usual support. The usual support was based on intensive SHG, and the participants in both groups received initial online face-to-face counseling by a health care professional (ie, a registered dietician) who had completed the established Ministry of Health, Labor and Welfare (MHLW) training course. Participants were briefed about their health condition and lifestyle through a review of their SHG results. They were instructed to set achievable personalized behavioral goals. After the initial counseling, a health care professional provided email support three times at 2, 6, and 12 weeks. Implementation points according to the MHLW in the active control group were comparable to the required points of ≥180 in the SHG. Daily recording of body weight and steps were recommended. Measurements of BP in the morning and evening were also recommended. | PMC10134028 | ||
mHealth KENPO-app | personality traits, weight loss | KENPO-app (release April 10, 2019; OMRON Healthcare Co, Ltd) was developed using behavior change techniques (ie, self-monitoring and goal-setting theory) by the study team and focus groups. This app was developed for SHG based on the four specific health checkups and guidance system in Japan: (1) focusing on achieving the primary target (weight loss of ≥2 kg); (2) assessing healthy eating, exercise habits, smoking habits, relaxation, and self-weighing; (3) providing information on the results of specific health checkups; and (4) starting an intervention period of 6 months with the interim assessment at 3 months. The initial assessment explored the following: personality traits (4 types), concerns about health checkup data (10 items), concerns about symptoms (10 items), and the aim of the intervention (weight loss, improving fitness, symptoms, laboratory data; Screenshot and initial assessment of KENPO-app system. (A) KENPO-app at APP Store; (B) KENPO-app at Google Play; (C) initial assessment items.Outline of KENPO-app system. | PMC10134028 | |
The contents of the KENPO-app study. | goals)Personality, weight loss |
Initial assessment (laboratory data, symptoms, and clinical goals)Personality traitSetting weight loss goalTargeting behavioral agenda (exercise, dietary, lifestyle habits, daily steps)
Pedometer, weight, and blood pressure, and behavioral agenda
SHG based on app data and personality trait
Pedometer, weight, and blood pressure, and behavioral agendaChatbot-supported feedback of app data and sign of weight regain
Chatbot-supported quiz on health and health behavior
Final assessment (laboratory data, symptoms, objective)Behavioral agenda (exercise, dietary, and lifestyle habits) | PMC10134028 | |
Outcome | The outcome included changes in body weight and BMI. Weight measurements were uploaded to the cloud where the data were obtained, and the 7-day average weight was calculated. Other outcomes included changes in SBP, DBP, and adherence to the device. The frequency of weight, BP, and step uploads was recorded as a measure of adherence. Data on active exercise habits (10 items), healthy eating habits (10 items), and healthy lifestyle habits (10 items) were obtained using a web-based self-administered questionnaire at baseline and 12 weeks. Quality assurance was performed through standard operating procedures and benchmarking. Adherence to the apps was defined based on the sending rate of body weight measurements, and an attrition diagram was made. | PMC10134028 | ||
Statistical Analysis | Data are expressed as the mean (SD), median (IQR), range, or number. Blinded data were analyzed using the R software version 4.0.0. (R Foundation for Statistical Computing) on an intention-to-treat basis by the statistician. Statistical analysis of quantitative data was performed using the Shapiro-Wilk test, Mann-Whitney | PMC10134028 | ||
Results | PMC10134028 | |||
Participants and Adherence | ATTRITION | After 80 participants were screened, we enrolled 78 participants and excluded 2. Of the 78 participants, the mean age was 52.0 (SD 6.5) years, and 55% (n=43) were male. Those who had full- and part-time jobs accounted for 65% (n=51) and 19% (n=15) of the sample, respectively. Participants were assigned to either the KENPO-app group (intervention group; n=39) or the active control group (n=39). There were no differences in age (mean 52.5, SD 6.6 years vs mean 51.4, SD 6.4 years; CONSORT flow diagram of KENPO-app study.Attrition diagram on self-weighing and mean changes in body weight during the study period. | PMC10134028 | |
Healthy Behavior | The percentage of participants who reported ≥8000 steps per day, slow eating speed, vegetable intake before rice, selecting a healthy menu, and relaxation in the intervention group increased after the 12-week study period, while the percentage of eating breakfast and reducing snacks in the active control group increased (Healthy lifestyle and symptoms during the study period according to the group. | PMC10134028 | ||
Discussion | PMC10134028 | |||
Principal Findings | weight loss, diabetes [ | OBESE, HYPERTENSION | This is the first study to confirm the effectiveness of the SHG-specific KENPO-app in obese adults with hypertension. The mHealth KENPO-app is feasible and can produce modest but significant weight loss. Compared with standard care, the mHealth app produced modest weight loss (–1.0 kg to –2.4 kg of body weight) in obese adults with diabetes [ | PMC10134028 |
Adherence and Weight Change | weight loss | Self-monitoring of weight was a significant predictor of weight loss [ | PMC10134028 | |
Healthy Behavior and Weight Loss | obesity | OBESITY | The current consensus states that obtaining less than 5000 steps per day is sedentary behavior, whereas obtaining >8000 steps indicates an active exercise habit [Moreover, slow eating speed, vegetable intake before rice, selection of a healthy menu, and relaxation in the intervention group increased after the intervention. Fast eating speed is positively associated with obesity [ | PMC10134028 |
Personality Traits and Weight Changes | weight loss | Personality traits are an important factor in health behaviors. Interestingly, personality traits were associated with the degree of weight change in this study. Specific aspects of personality (ie, agreeableness) are relevant to weight loss maintenance [ | PMC10134028 | |
Strength and Limitations | obesity, weight loss | OBESITY, HYPERTENSION | The strengths of this study include the SHG-specific mHealth app, objective measurement of data, and a high retention rate. Although mHealth apps for weight management are popular and widely available, many apps lack professional content expertise. Encouraging app development based on evidence-based online approaches would ensure content quality, allowing health care professionals to recommend their use [In conclusion, the SHG-specific KENPO-app was feasible and induced significant weight loss in Japanese adults with obesity and hypertension.This study was partly supported by the Japan Society for the Promotion of Science KAKENHI (grant 22K11253) and the Japan Agency for Medical Research and Development DOUKI-APP Study (grant 21ek0210124). This study was funded by OMRON Healthcare Co, Ltd.Conflicts of Interest: None declared.CONSORT-eHEALTH checklist (V 1.6.1). | PMC10134028 |
Abbreviations | blood pressurediastolic blood pressureinformation and communications technologymobile healthMinistry of Health, Labor and Welfarerandomized controlled trialsystolic blood pressurespecific health guidance | PMC10134028 | ||
Materials and methods | PMC10426956 | |||
Overview | OSF | Prior to beginning our study, we secured approval to carry out our research through the Grand Valley State University institutional review board (Protocol 21-248-H, written consent obtained via online survey). Data and materials for our research are available via OSF at Participants were asked to complete the reference check for “the employee you least like to work with in your primary job.” We chose these instructions for several reasons. First, although applicants are asked to list preferred sources for reference checks, employers often ask for references from individuals not provided by the applicant, what the Society for Human Resource Management (SHRM) refers to as backdoor references [Second, we wanted to minimize demand characteristics insofar as we did not want to directly inform participants that our research interest (in part) was in their perceptions of an employee’s incivility, which we believed would occur if we had directly focused participant’s attention on an uncivil employee. We nonetheless reasoned that uncivil behavior would influence who participants decided to reflect upon; in addition to perceptions of competence, perceptions of warmth–to which uncivil behavior directly relate [ | PMC10426956 | |
Participants | Responses were received from 436 individuals in supervisory positions. Prior to data analysis, we screened for insufficient effort responding (IER) [ | PMC10426956 | ||
Procedure | Participants were asked to reflect upon the employee they least like to work with in their primary job, after which they were presented with the following instructions, which were inspired by instructions used by König and colleagues [Imagine that the employee you’ve been asked to think about had to leave their job for private reasons.Your former employee–Now imagine that you have been asked to After these instructions, participants began the reference check with three questions informed by Taylor and colleagues’ [ | PMC10426956 | ||
Measures | The following focal measures were completed by participants after the aforementioned instructions, and they were presented in random order. Additional questions commonly found in reference checks were included to enhance the realism of the reference check (e.g., “Would you rehire the applicant?”), although they were not the focus of our research questions. | PMC10426956 | ||
Fear of adverse consequences | Although researchers have studied fear of adverse consequences in performance management contexts [Items measuring fear of legal consequences included: “Worried about being sued for defamation of character by the applicant because of the reference check”, “Concerned that the applicant might file a lawsuit against me because of the reference check”, and “Fearful of legal concerns with the applicant because of the reference check”. Items measuring fear of interpersonal consequences included: “Worried about getting into a disagreement with the applicant because of the reference check”, “Concerned about having an argument with the applicant because of the reference check,” and “Fearful about getting into a fight with the applicant because of the reference check”. Responses were on a “1” ( | PMC10426956 | ||
Applicant workplace incivility | Blau and Andersson’s [ | PMC10426956 | ||
Manipulation checks | We used factual manipulation checks to assess their effectiveness [ | PMC10426956 | ||
Interaction between applicant consent and qualified privilege reminders in relation to fear of adverse legal consequences. | PMC10426956 | |||
Interaction between confidentiality and qualified privilege reminders in relation to applicant workplace incivility. | PMC10426956 | |||
Discussion | We sought to apply signaling theory to experimentally test whether three signals (reminders) sent to reference providers could decrease their fear and increase their reporting of applicant workplace incivility. Below we summarize the theoretical implications and limitations of our study, as well as the practical implications of our research for hiring organizations. | PMC10426956 | ||
Implications for theory, research, and practice | SAID | Our study offers implications for the literature on reference checks. First, it is important to note that the signals and their interactions explained only a small amount of variability in reference provider’s fear of adverse consequences and reports of applicant workplace incivility. We found no evidence for direct effects of the signals we studied. Thus, although researchers and practitioners encourage hiring organizations to employ the practices we studied and remind reference providers if the practices are in effect, findings from our study suggests that they have a limited impact on fear of adverse consequences and reports of applicant workplace incivility when used in isolation. This observation is pertinent as we seek to move toward evidence-based practice [With that said, we did observe some evidence for interactions among the signals that were sent to reference providers, each of which explained a small proportion of the variability in the outcomes that we studied. In both of the observed interactions, the reminder of qualified privilege appeared to slightly modify the impact of another reminder: the effect of confidentiality for reports of applicant incivility, and the effect of applicant consent for fear of adverse legal consequences. For reports of applicant workplace incivility, it is intriguing to note that a reminder of confidentiality alone, without qualified privilege, led to the lowest reports of incivility. This suggests that confidentiality alone is not entirely reassuring for reference providers, a finding which stands in contrast with prior research [Our research also offers implications for signaling theory. Specifically, our research provides additional evidence that signals can interact to influence receiver (e.g., reference provider) behavior [We also contribute to research on potential ways to improve the effectiveness of reference checks. With the exception of confidentiality [We encourage additional research into ways to improve the utility of reference checks, and we envision several possibilities to that end. For instance, in our control conditions, no reminders of applicant consent, confidentiality, or qualified privilege were sent. In future studies, researchers may find value in studying the implications for fear and reports of incivility of signaling to reference providers that they do We believe that several practical implications extend from our study. Reference checks are among the most widely used selection methods [Second, fear of adverse legal consequences was lowest and reports of applicant incivility were highest when providers were reminded of qualified privilege and confidentiality (for incivility) or applicant consent (for fear). Thus, we encourage hiring organizations and reference checking vendors to include all three reminders in instructions prior to gathering data from reference checks, assuming qualified privilege applies in their locale [Finally, given the small effects that we observed, and our limited ability to influence reference provider fear and reports of incivility via the manipulations we studied, we ultimately encourage hiring organizations to use | PMC10426956 | |
Limitations and future research directions | Our study has several limitations that should be considered by readers as they interpret our findings. First, our study involved a hypothetical reference check. We believe this approach was necessary for the ethical reasons we described earlier; namely, that manipulating the reference checking process for actual job applicants could influence their ability to secure employment. In addition, our instructions did induce a moderate level of fear of adverse legal and interpersonal consequences and reports of applicant workplace incivility compared to a pilot sample. However, future research may attempt to study these variables in an actual high-stakes selection context, if such a possibility became available. Researchers may find that the effects we observed may become stronger if studied in a high-stakes context wherein a job applicant’s future employment depends on the input of the reference provider.Second, although we investigated the impacts of three reminders that may be sent to reference providers on their reports of applicant workplace incivility, our study is limited insofar as we did not account for any additional explanations for the uncivil behavior of the applicant, as perceived by the prospective reference provider. Research suggests that people engage in instigated incivility as a result of various situational and personal explanations [Third, because our data were collected via an online survey, all participants essentially completed a web-based reference check. Web-based reference checking is commonly used [Fourth, our analysis of the effectiveness of our manipulation checks suggested that participants who were sent the reminders of applicant consent, confidentiality, and qualified privilege tended to receive the reminders, which attests to their observability as signals [Fifth, the composition of our sample also represents a potential limitation of our research. In particular, our sample was comprised primarily of white female supervisors. We acknowledge the possibility that our results may not generalize to more diverse samples. Future research should seek to gather data from more demographically diverse groups in order to investigate the generalizability of our findings.Sixth, our data were cross-sectional. We believe that this approach is justifiable as it represents the way reference checks are actually conducted, such that providers respond at a single time, and it is consistent with prior research on reference checks [One such possibility is a potential causal relation between reference provider’s fear of adverse consequences and their reports of applicant workplace incivility, because the direction of that relation is unclear. Interestingly, fear of adverse legal and interpersonal consequences and applicant incivility as reported by reference providers were positively correlated in our study. Research shows that fearful individuals attempt to minimize risk in their decision making [ | PMC10426956 | ||
Supporting information | PMC10426956 | |||
STROBE statement—checklist of items that should be included in reports of observational studies. | (DOCX)Click here for additional data file. | PMC10426956 | ||
References | PMC10426956 | |||
Subject terms | pain | Symptomatic, partial-thickness rotator cuff tears (sPTRCT) are problematic. This study tested the hypothesis that management of sPTRCT with injection of fresh, uncultured, unmodified, autologous, adipose-derived regenerative cells (UA-ADRCs) is safe and more effective than injection of corticosteroid even in the long run. To this end, subjects who had completed a former randomized controlled trial were enrolled in the present study. At baseline these subjects had not responded to physical therapy treatments for at least 6 weeks, and were randomly assigned to receive respectively a single injection of UA-ADRCs (n = 11) or a single injection of methylprednisolone (n = 5). Efficacy was assessed using the ASES Total score, pain visual analogue scale (VAS), RAND Short Form-36 Health Survey and range of motion at 33.2 ± 1.0 (mean ± SD) and 40.6 ± 1.9 months post-treatment. Proton density, fat-saturated, T2-weighted MRI of the index shoulder was performed at both study visits. There were no greater risks connected with injection of UA-ADRCs than those connected with injection of corticosteroid. The subjects in the UA-ADRCs group showed statistically significantly higher mean ASES Total scores than the subjects in the corticosteroid group. The MRI scans at 6 months post-treatment allowed to “watch the UA-ADRCs at work”. | PMC10630470 | |
Introduction | shoulder pain | OXIDATIVE STRESS | Symptomatic, partial-thickness rotator cuff tear (sPTRCT) is a common cause of shoulder pain, loss of function and occupational disabilityCurrent non-surgical and surgical treatment options to address sPTRCT do not offer the potential to naturally replace damaged tendon tissue and often do not improve clinical results. Subacromial injection of corticosteroids, among the most widely used nonoperative treatment options for sPTRCTA recent, first-in-human RCTUnlike most other cell preparations currently under investigation for use in regenerative medicine (including cultured adipose derived stem cells (ADSCs), induced pluripotent stem cells, etc.) UA-ADRCs are not expanded in culture, and are therefore not exposed to potential, culture-related mechanic and oxidative stress that could affect their safety as a medicinal productIn the former study | PMC10630470 |
Methods | PMC10630470 | |||
Study design | The present study was a long term follow-up study of a first-in-human, two center, prospective, open-label, randomized controlled trialFigure Flow of subjects in the present and the former studies | PMC10630470 | ||
Ethics | The present study received Investigational Device Exemption (IDE) from the U.S. Food and Drug Administration (FDA) on 13/05/2019 (no. 16956), received Institutional Review Board (IRB) approval from WIRB Copernicus Group, Inc. (Olympia, WA, USA) on 23/07/2019 for study site Sanford USD Medical Center, Sioux Falls, SD, USA (IRB Tracking Number: 20191931; Study Number: 1263181) and on 29/09/2019 for study site Sanford Orthopedic Sports Medicine Clinic, Fargo, ND, USA (IRB Tracking Number: 20191931; Study Number: 1266705), and was registered at Clinicaltrials.gov on 04/09/2019 (NCT04077190). The first subject was enrolled in the present study on 21/11/2019, and the last subject on 20/03/2020. The present study was closed on 05/05/2022 at study site Sanford Orthopedic Sports Medicine Clinic, Fargo, ND, USA, and on 09/05/2022 at study site Sanford USD Medical Center, Sioux Falls, SD, USA.Written, informed consent to participate was obtained from all subjects.The former study | PMC10630470 | ||
Outcome measurements and assessments | pain | ADVERSE EVENTS, EVENTS | According to the study protocol the primary endpoints of the present study were long-term safety as indicated through the rate of treatment emergent adverse events (TEAEs), and long-term efficacy of pain and function through American Shoulder and Elbow Surgeons Standardized Shoulder Assessment FormAdverse events in the present and the former studiesIn the former studyIn the present study, the aforementioned endpoints were assessed at 33.2 ± 1.0 (mean ± standard deviation) months post-treatment (range, 30.7–34.7) (first study visit; FSV) and at 40.6 ± 1.9 months post-treatment (range, 36.5–44.7) (second study visit; SSV). | PMC10630470 |
Analysis of MRI scans | PD | Next to the determination of the partial-thickness tear size (calculated as ellipsoid volume), the proton density weighted, fat saturated, T2-weighted (PD FS T2) coronal MRI scans of all subjects who were enrolled in the present study were transferred in digital and fully anonymized form (compliant with the HIPAA regulation) | PMC10630470 | |
Estimand strategies for handling intercurrent events | EVENTS | In line with the new In short, in case of treatment failures (comprising all intercurrent events that required additional injections of corticosteroid into the index shoulder or surgery of the index shoulder that were definitely, probably or possibly related to the study treatments, including development of a full-thickness rotator cuff tear) subjects' data were handled using a combination of the While-on-Treatment StrategyIn contrast, intercurrent events that required additional injections of corticosteroid into the index shoulder or surgery of the index shoulder that were unlikely related or unrelated to the study treatments (e.g., accidents that affected the index shoulder) were handled using a combination of the While-on-Treatment Strategy and a Hyopthetical StrategyIn line with recommendations in the literature | PMC10630470 | |
Statistical analysis | TEAEs, pain | Statistical analysis of the safety data included group-specific comparisons of the following variables: (i) total number of TEAEs, (ii) number of TEAEs experienced per subject, (iii) number of TEAEs classified as {mild/moderate/severe}, (iv) relationship of TEAEs to treatment classified as {not related/unlikely/possible/probable/definite} and (v) number of TEAEs classified as {mild and unlikely to be related to the investigated treatment/mild and possibly related to the investigated treatment/moderate and unlikely to be related to the investigated treatment/moderate and possibly related to the investigated treatment}. According to the protocol of the present study these comparisons were performed for the following time periods: from BL to W24 post-treatment (considering only data of the former studyStatistical analysis of the efficacy data included calculation of the group specific mean, standard error of the mean and median as well as group-specific comparisons of the following variables: (i) ASES Total score, (ii) SF-36 Total score, (iii) VAS pain score, (iv) active and passive ROM and (v) tear volume measured on MRIs. According to the protocol of the present study these comparisons were performed at BL and at W24 and W52 post-treatment (data of the former studyIn all analyses, a p value < 0.05 was considered statistically significant. Calculations were performed using GraphPad Prism (Version 9.4.1 for Windows; GraphPad Software, San Diego, CA, USA). | PMC10630470 | |
Results | PMC10630470 | |||
Long-term safety of treating sPTRCT with injection of either UA-ADRCs or corticosteroid | TEAEs | The subjects in the UA-ADRCs group reported a total number of 58 TEAEs (35 TEAEs during the former studyNo TEAE that occurred during the present and the former studiesAll subjects reported experiencing at least one TEAE. The number of subjects who experienced 1/2/3/4/6/7/8/10/12 TEAEs in the present and the former studiesThe number of TEAEs classified as {mild/moderate/severe} in the present and the former studiesThe relationship of TEAEs to treatment classified as {not related/unlikely/possible/probable/definite} in the present and the former studiesThe number of TEAEs classified as {mild and unlikely to be related to the investigated treatment/mild and possibly related to the investigated treatment/moderate and unlikely to be related to the investigated treatment/moderate and possibly related to the investigated treatment} in the present and the former studiesThe four severe TEAEs that occurred in the UA-ADRCs group during the present and the former studies | PMC10630470 | |
Long-term efficacy of treating sPTRCT with injection of either UA-ADRCs or corticosteroid | Pain, pain | Four of the 11 subjects (36.4%) in the UA-ADRCs group and three of the five subjects (60.0%) in the corticosteroid group developed additional pathologies of the index shoulder (next to sPTRCT) and/or received additional injections into or surgery of the index shoulder (next to injection of either UA-ADRCs or corticosteroid) during the present and the former studiesThe individual ASES Total scores, SF-36 Total scores and VAS pain scores as a function of time post-treatment are shown in Supplementary Figs. Statistical analysis demonstrated that compared with the subjects in the corticosteroid group, the subjects in the UA-ADRCs group had (i) a significantly higher mean ASES Total score at W24 and W52 post-treatment as well as at SSV (i.e., at 40.6 ± 1.9 months post-treatment), (ii) a significantly higher mean SF-36 Total score at W24 post-treatment, and (iii) a significantly higher mean VAS Pain score at W24 and W52 post-treatment (Fig. Tukey boxplots of (Tukey boxplots of ( | PMC10630470 | |
Partial thickness rotator cuff tear size as a function of time after treatment with injection of either UA-ADRCs or corticosteroid | The individual tear size as a function of time post-treatment is shown in Supplementary Fig. | PMC10630470 | ||
Detection of hyperintense structures on PD FS T2 coronal MRI scans of the index shoulder at the position of the supraspinatus tendon after injection of UA-ADRCs, but not after injection of corticosteroid, at 24 weeks post-treatment but not at baseline | The PD FS T2 coronal MRI scans of the index shoulder of 10 of 11 subjects (90.9%) in the UA-ADRCs group and none of the subjects (0%) in the corticosteroid group showed hyperintense structures at the position of the supraspinatus tendon at W24 post-treatment but not at baseline. A representative example is shown in Fig. Proton density weighted, fat saturated, T2-weighted, coronal MRI scans of the index shoulder of Subject A4 (injection of UA-ADRCs), showing hyperintense structures at the position of the supraspinatus tendon at 24 weeks post-treatment (arrows) but not at baseline. | PMC10630470 | ||
No relationship between treatment outcome and baseline data | Supplementary Figs. | PMC10630470 | ||
Conclusions | The present investigation further supports treatment of sPTRCT with injection of UA-ADRCs. Once this therapy is approved in the US, clinicians should consider injection of UA-ADRCs instead of injection of corticosteroids. In the long run treatment of sPTRCT with injection of UA-ADRCs may delay or even prevent surgical treatment of sPTRCT. | PMC10630470 | ||
Supplementary Information | The online version contains supplementary material available at 10.1038/s41598-023-46653-4. | PMC10630470 | ||
Acknowledgements | We thank the personell at Sanford Orthopedics and Sports Medicine Fargo (Fargo, ND, USA), Sanford Orthopedics and Sports Medicine Sioux Falls (Sioux Falls, SD, USA) and Sanford Radiology Clinic (Sioux Falls, SD, USA) for skillful assistance in this study. | PMC10630470 | ||
Author contributions | N.M. | M.L. screened and treated subjects, and edited the manuscript. J.H. screened and treated subjects, and edited the manuscript. M.H. analyzed MRI scans and edited the manuscript. M.H. analyzed MRI scans and edited the manuscript. T.R.F. participated in conceptualization and data curation, and edited the manuscript. J.P.F. assisted with data interpretation, and edited the manuscript. N.M. assisted with data interpretation, and edited the manuscript. C.A. participated in conceptualization and data curation, provided resources, assisted with data interpretation, and edited the manuscript. E.U.A. participated in conceptualization and data curation, provided resources, supervision and project administration, assisted with data interpretation, and edited the manuscript. C.S. analyzed MRI scans, performed the statistical analysis, assisted with data interpretation, and wrote the manuscript. D.A.P. participated in conceptualization and data curation, performed funding acquisition, provided resources and supervision, assisted with data interpretation, and edited the manuscript. All authors have read and approved the final version of the manuscript, and agree with the order of presentation of the authors. | PMC10630470 | |
Data availability | The datasets used and analyzed during the current study are available from the corresponding author on reasonable request, taking into account any confidentiality. | PMC10630470 | ||
Competing interests | C.A. is Director of Medical and Scientific Affairs of InGeneron, Inc. (Houston, TX, USA). E.U.A. is Executive Chair of InGeneron. C.S. is Advisory Medical Director of InGeneron. However, InGeneron had no role in study design, data collection and analysis, interpretation of the data, and no role in the decision to publish and write this manuscript. No other potential conflicts of interest relevant to this article were reported. | PMC10630470 | ||
References | PMC10630470 | |||
Subject terms | inflammation | INFLAMMATION, DISEASE | Inflammatory response in COVID-19 contributes greatly to disease severity. Mesenchymal Stem Cells (MSCs) have the potential to alleviate inflammation and reduce mortality and length of stay in COVID-19 patients. We investigated the safety and effectiveness of normoxic-allogenic umbilical cord (NA-UC)-MSCs as an adjunctive treatment in severe COVID-19 patients. A double-blind, multicentric, randomized, placebo-controlled trial involving severe COVID-19 patients was performed from January to June 2021 in three major hospitals across Java, Indonesia. Eligible participants (n = 42) were randomly assigned to two groups (1:1), namely the intervention (n = 21) and control (n = 21) groups. UC-MSCs dose was 1 × 10 | PMC10397314 |
Introduction | DISEASE, CORONAVIRUS DISEASE 2019, INFLAMMATORY RESPONSE | The emergence of the Coronavirus disease 2019 (COVID-19) pandemic has highlighted the need for streamlined drug development and validation within a condensed timeframeThe severity of the disease is not determined by the SARS-CoV-2 viral load but rather by the inflammatory response, which may be quantified in plasma samplesAs no approved pharmaceuticals have been demonstrated to reduce viral load, all therapy in COVID-19 is directed towards improving symptoms and immune responseBesides these potentials, one notable aspect of allogenic MSCs application is its economic efficiency. Firstly, they are prepared by extracting cord blood or cutting up Wharton's Jelly (WJ), readily available in virtually all hospitals with maternity wards, and culturing them inside flasks | PMC10397314 | |
Results | PMC10397314 | |||
Recruitment | RECRUITMENT, RECRUITMENT | Recruitment patients using both the Indonesian Ministry of Health guidelines on COVID-19 and Wu Z, McGoogan JM criteria were consulted for severe COVID-19 categorisationParticipant recruitment process. | PMC10397314 | |
General subject characteristics | The general comparison between the NA-UC-MSCs and the placebo groups was summarised in Table General Characteristics of Participants.Note: NA-UC-MSCs (normoxic-allogenic umbilical cord mesenchymal stem cells). | PMC10397314 | ||
Duration of hospitalisation | The average hospital stay in subjects who received NA-UC-MSCs was 20.81 ± 12.25 days compared to control subjects, who were treated for 16.81 ± 5.63 days as shown in Table Duration of Hospitalisation (Days) Since Admission.* Normal distribution, | PMC10397314 | ||
Radiographical severity (Brixia score) | Table Brixia score between groups.Variables were presented as median (IQR). *Mean Brixia scores at days 0, 15, and 22 of treatment. | PMC10397314 | ||
MMRC dyspnoea scale, PEF, and 6 MW test | dyspnoea | Table MMRC dyspnoea scale over time across groups.Note: NA-UC-MSCs (normoxic-allogenic umbilical cord mesenchymal stem cells).* MMRC dyspnoea scale in the intervention and control groups.PEF and 6 MW distance (m) between two groups.Variables were presented as median (IQR). *Significant values are in [bold].PEF and 6 MW distance across both treatment groups. | PMC10397314 | |
PCT, ESR, and CRP markers | PCT | Table Oxygen index, duration oxygenation, and O2 saturation across group.Oxygen index, and OSignificant values are in [bold].Oxygenation index and oxygen saturation across both treatment groups.Table PCT, ESR and CRP level across groups.Variables were presented as median (IQR). *Significant values are in [bold].Evolution of PCT, ESR, and CRP levels on days 15 and 22 post-intervention. A marked reduction in CRP levels was seen in both groups.Differences in Mean Changes in PCT between groups.Note: MSCs (mesenchymal stem cells), Con (control).Significant values are in [bold]. | PMC10397314 | |
Survival | A total of 14 subjects (33.3%) were deceased during the course of therapy. Among those who died, seven (16.7%) were in the NA-UC-MSCs group, and the other seven (16.7%) were from the control group. These subjects were then classified as "early terminated" patients. | PMC10397314 | ||
Discussion | inflammation, bacterial co-infection, pneumonia, dyspnoea | PNEUMONIA, PCT, INFLAMMATION, DISEASE, RESPIRATORY FAILURE, SKIN BACTERIAL INFECTION | The intravenous administration of NA-UC-MSCs did not affect the duration of hospitalization in severe COVID-19 patients. This study, however, confirmed the safety of NA-UC-MSCs therapy in these subjects. We choose the duration of stay in the hospital as the primary outcome since we want to clarify previously study that was found the length of hospitalization and ICU stays were shorter in the experimental group, when compared to the control group. However, most of the differences were not statistically significantThe Brixia score is a new, potent inventory in determining the current condition and prognosis of pneumonia in COVID-19 patients. It was invented by Borghesi et al.Oxygen saturation, dyspnoea, and oxygen therapy are crucial inventories in managing COVID-19 patients. The former and the middle has been entrenched as an indicator of a patient’s survivalWe also tracked the levels of three key inflammatory markers: PCT, ESR, and CRP. Out of the three, only CRP showed a significant reduction in both groups. This suggested no difference in bacterial co-infection between groups since PCT is a powerful biomarker for inflammation of bacterial originAdditionally, we found that on the day 22 of the intervention, the treatment group had a significantly smaller increase in PCT value compared to the control group. Procalcitonin is a commonly used diagnostic marker in bacterial infection. However, previous studies showed that in COVID-19, procalcitonin is a biomarker for disease severity rather than bacterial co-infection. High procalcitonin level has been shown to be associated with disease severity, increased intensive unit admission, and mortality in patients with COVID-19. A decrease in PCT level has also been shown as an indication of recovery from COVID-19Clinically, COVID-19 cases may be classified as asymptomatic, mild, moderate, or severe with respiratory failure, with the lattermost frequently leading to deathThe two primary limitations of our study were the relatively small number of participants and the absence of a window period to recruit them. A greater number of subjects would allow a finer distinction between truly significant associations and those that occurred by chance. Complementarily, due to the hospitals' hierarchical status being the highest in each respective region, potential eligible subjects may be screened before receiving referral patients. If a window period had been properly defined (i.e., days 0–3 since positive PCR confirmation) and implemented, more pronounced response to MSCs therapy can be expectedThe two other crucial limitations were the choice of inflammatory markers and a single delivery route. In numerous other studies, cytokines (e.g., IL-6, TNF-α) and VEGF were quantified in addition to ESR and CRPThe route of MSCs delivery may also be varied to better quantify the patient's response to each. It has been established that intramuscular or intra-organ delivery of MSCs provides a more robust response compared to the systemic intravenous route | PMC10397314 |
Methodology | PMC10397314 | |||
Study design | This study was a multicentric, double-blinded, randomized, placebo-controlled trial to evaluate NA-UC-MSCs as a complementary treatment in severe COVID-19 patients (clinicaltrials.gov registration number NCT05132972 24/11/2021). This study approved by Health Research Ethics Committee, National Institute of Health Research and Development (HREC-NIHRD); ethical clearance number LB.02.01/2/KE.573/2020 extended no. LB.02.01/2/KE.582/2021. All experiments were conducted in accordance with the relevant guidelines and regulations. | PMC10397314 | ||
Participants | ovarian cancer, shock, breast cancer, organ failure, tumors | OVARIAN CANCER, RECRUITMENT, SHOCK, BREAST CANCER, TUMORS, COMPLICATIONS | Subjects were picked via stratified random sampling, then randomized via a computerized random number generator. The total number of subjects was 42, divided into 21 subjects in the NA-UC-MSCs group and 21 in the placebo (NaCl) group. They hail from three major hospitals across the island of Java: Dr. Hasan Sadikin General Hospital in Bandung, Dr. Moewardi General Hospital in Surakarta, and Dr. Sardjito General Hospital in Yogyakarta. Recruitment was done from 30 January to 24 June 2021.All subjects who participated in this trial had satisfied the inclusion and exclusion criteria. The inclusion criteria were: (1) Subjects 18–75 years old, who had been positively diagnosed with COVID-19 based on real-time reverse-transcriptase polymerase chain reaction (RT-PCR) assay of either pharyngeal, sputum, or broncho-alveolar lavage swab specimen; (2) Subjects are classified as severe COVID-19 patients; (3) Not mechanically ventilated upon admission; (4) No other adjunctive treatments were administered; (5) Agreed to participate and signed the informed consent. Meanwhile, the exclusion criteria were: (1) Pregnant, lactating women, or women on a contraceptive program; (2) a history or diagnosis of tumors or a history of breast cancer or ovarian cancer in the mother or sister; (3) SGPT/ALT value five times the upper limit of the normal value; (4) eGFR value < 30 mL/min; (5) requires invasive ventilation; (6) shock; (7) complications of organ failure; (8) had enrolled in other clinical trials within the last 3 months. | PMC10397314 |
Randomization and masking | All eligible subjects (n = 42) were randomly assigned into two groups (1:1 ratio) to either the intervention group, who were to receive NA-UC-MSCs (n = 21), or the placebo group, who were administered with NaCl (n = 21). Randomization was performed using blocks (block size = 4), and subjects were assigned to both groups with randomization software (sealedenvelope.com) by an independent statistician. The trial was prepared by a third party with no responsibility for patient care and data collection. All subjects, investigators, and treating physicians were blinded. | PMC10397314 | ||
NA-UC-MSCs preparation | Bifarma, infectious disease, HIV, Hepatitis B | INFECTIOUS DISEASE, SYPHILIS, HEPATITIS C | Human umbilical cords were obtained from the cesarean section in the maternity ward of a hospital in Jakarta from a qualified donor that passed donor screening and testing of infectious disease (HIV, Hepatitis B, Hepatitis C, Syphilis, CMV IgM) and karyotyping. The human umbilical cord was subsequently processed to yield MSCs in Regenic Laboratory PT. Bifarma Adiluhung, Jakarta, Indonesia, with GMP standard. The MSCs were isolated with Alpha MEM (+ GlutaMAX) + Human Serum + Growth Factors and Vitamin + Antibiotic Antimicotic 1% and then passaged to passage 7 with Alpha MEM (+ GlutaMAX) + Human Platelet Lysate. To positively identify MSCs, the markers CD105, CD73, CD90 (> 95%) and CD45, CD34 CD14, CD19 and HLA-DR (< 2%) were used; and also Adipogenic, Osteogenic, Chondrogenic Differentiation were tested. | PMC10397314 |
Intervention | dyspnea | PCT | Before the administration of either MSCs or placebo, history-taking and physical examination [including the Modified Medical Research Council (mMRC) dyspnea scale], routine hematological testing, inflammatory marker testing [procalcitonin (PCT), erythrocyte sedimentation rate (ESR), C-reactive protein (CRP)], chest X-ray, respiratory testing [peripheral oxygen saturation (SpO | PMC10397314 |
Outcomes | PMC10397314 | |||
Primary outcome | The primary outcome of this trial was the subjects' duration of hospitalization. | PMC10397314 | ||
Secondary outcome | Dyspnea | ADVERSE EVENTS, SECONDARY, PCT | The secondary outcomes of this trial were radiological and clinical indicators on baseline (day 0–2), 15 (± 2), and 22 (± 2) days: (1) Brixia score for radiographic severity; (2) mMRC Dyspnea scale; (3) oxygenation index; (4) duration of oxygen therapy (days); (5) peripheral oxygen saturation; (6) 6 MW test; (7) PEF; (8) PCT; (9) ESR; and (10) CRP levels. In addition, adverse events (AE) and serious adverse events (SAE) were recorded until day 91 (± 2) since randomization. | PMC10397314 |
Sample collection | Peripheral venous blood samples | BLOOD, SECONDARY, PCT | Peripheral venous blood samples were collected for PCT, ESR, and CRP level assessment. Blood was collected on days 0–2 (baseline), 15 (± 2), and 22 (± 2) after the intervention. Following extraction, sample tubes were secured into primary (zip-lock bag), secondary (insulated bottles), and tertiary packs (insulated box with cooler packs), before being ultimately transported. | PMC10397314 |
Statistical analysis | All data in this trial were analyzed with the software SPSS V.22 (IBM). For categorical variables, analyses were computed using the χ-square or Fisher's exact test. For unpaired continuous quantities, either an independent-sample T-test (normal distribution) or an independent-sample Mann–Whitney U test (non-normal distribution) was used. In addition, the paired T-test (normal distribution) or Wilcoxon test (non-normal distribution) were performed for continuous variables. | PMC10397314 | ||
Conclusion | DISEASES, PCT | Although we have failed to demonstrate the reduction in the length of stay of severe COVID-19 patients with NA-UC-MSCs therapy, we have established that it is a very safe adjunct that yielded no AE, including serious ones, for at least 91 days after the first dose. NA-UC-MSCs therapy also did not reduce the Brixia score to values below that of the control group. However, NA-UC-MSCs improved the patients' oxygen saturation by day 22 compared to placebo, in addition to having a significantly smaller increase in PCT value compared to the control group. Thus, we are confident that MSCs-based therapies are beneficial in COVID-19 and related diseases but need fine-tuning to reach their pinnacle potential. We aim to expand this study in the near future by introducing novel delivery routes and incorporating MSCs products (i.e., secretome, extracellular vesicles (EV)). | PMC10397314 | |
Supplementary Information | The online version contains supplementary material available at 10.1038/s41598-023-39268-2. | PMC10397314 | ||
Acknowledgements | Bifarma | This study was supported by the Grants-in-Aid from The National Research and Innovation Agency (BRIN) Indonesia and PT. Bifarma Adiluhung, Jakarta, Indonesia. | PMC10397314 | |
Author contributions | B.S., R.G.M., A.N. and A.F. designed the study. B.S. as national coordinator; R.G.M., A.N. and A.F. as PI for each center; R.G.M., J.A.T. and A.F. performed statistical analyses and drafted the manuscript. B.S. and A.N. team in Solo site are Pur., A.A., B.R.A.S., and W.S.; R.G.M. team in Yogyakarta site are Sum., Sud., J.A.T., E.H.H., I.T. and N.R.A.; A.F team in Bandung site are R.W., A.Y.S., T.W.M. and R.W.S. All sites team at least consist of internist, pulmonologist, anesthesiologist, radiologist and clinical pathologist. All sites maintained the study database and contributed to the data analysis. B.S., R.G.M. and A.F. made critical revisions to the manuscript. All sites obtained their own funding of the study. All authors read and approved the final manuscript. All authors are a Member of Indonesian Medical Doctor Association for Tissue Engineering and Cell Therapy (REJASELINDO). | PMC10397314 | ||
Funding | Bifarma | Badan Riset dan Inovasi Nasional, No. 94/FI/P-KCOVID-19.2B3/IX/2020, No. 94/FI/P-KCOVID-19.2B3/IX/2020, No. 94/FI/P-KCOVID-19.2B3/IX/2020, No. 94/FI/P-KCOVID-19.2B3/IX/2020, No. 94/FI/P-KCOVID-19.2B3/IX/2020, No. 94/FI/P-KCOVID-19.2B3/IX/2020, No. 94/FI/P-KCOVID-19.2B3/IX/2020, No. 94/FI/P-KCOVID-19.2B3/IX/2020, No. 94/FI/P-KCOVID-19.2B3/IX/2020, No. 94/FI/P-KCOVID-19.2B3/IX/2020, No. 94/FI/P-KCOVID-19.2B3/IX/2020, No. 94/FI/P-KCOVID-19.2B3/IX/2020, No. 94/FI/P-KCOVID-19.2B3/IX/2020, No. 94/FI/P-KCOVID-19.2B3/IX/2020, No. 94/FI/P-KCOVID-19.2B3/IX/2020, No. 94/FI/P-KCOVID-19.2B3/IX/2020, No. 94/FI/P-KCOVID-19.2B3/IX/2020, No. 94/FI/P-KCOVID-19.2B3/IX/2020, PT. Bifarma Adiluhung, Jakarta, Indonesia. | PMC10397314 | |
Data availability | The datasets generated during and/or analysed during the current study are not publicly available due to confidential data of the patients but are available from the corresponding author on reasonable request. | PMC10397314 | ||
Competing interests | The authors declare no competing interests. | PMC10397314 | ||
References | PMC10397314 |
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