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Data analysis | pain | The data were entered into the SPSS program for Windows (v. 22.0) and were described using the measures of descriptive statistics, namely mean, standard deviation, and frequency. Groups were compared respecting participants’ demographic and clinical characteristics using the Chi-square, Fisher’s exact, and Kruskal–Wallis tests and the one-way analysis of variance. Moreover, the repeated measures analysis of variance was used for the within- and the between-subject comparisons of the variations of the mean score of CTR-associated pain across the four measurement time points. The level of significance was set at less than 0.05. | PMC10214554 | |
Ethical considerations | This study has the approval of the Ethics Committee of Rafsanjan University of Medical Sciences, Rafsanjan, Iran (code: IR.RUMS.REC.1397.174) and was registered in the Iranian Registry of Clinical Trials (code: IRCT20131228015965N18). Permissions for conducting the study were obtained from the authorities of the above-mentioned university and provided to the authorities of the study setting. The study aim was explained for all participants and informed consent was obtained from them. They were also informed about the confidentiality of their data and the voluntariness of participation. The study intervention was implemented by an experienced nurse in the study setting. Finally, study findings were provided to the authorities of the study setting. | PMC10214554 | ||
Discussion | pain | COLD | This study compared the effects of cold compress, TENS, and combined cold compress-TENS on CTR-associated pain among patients with cardiac surgery. Study findings indicated that while there was no significant difference among the groups respecting the pretest mean score of pain intensity, the variations of the mean score of pain intensity across the four measurement time points in all four groups were statistically significant. The amount of pain reduction in all three intervention groups was significantly greater than the placebo group and the combination of cold compress and TENS was more effective than both cold compress and TENS in reducing pain intensity.Findings showed that before CTR, the intensity of CTR-associated pain was mild (range: 0–0.03). This is in line with the findings of former studies [We also found that pain intensity at 15 min after CTR in the compress-TENS group was significantly less than both cold compress and TENS groups. Similarly, two former studies reported that after CTR for 15 min, CTR-associated pain in the cold compress group was significantly less than the control group (Mazloom, Demir). Contrary to our findings, a study showed that cold compress had no significant effects on CTR-associated pain [Our findings also showed that although cold compress, TENS, and combined cold compress-TENS were effective in significantly reducing CTR-associated pain, the effects of combined cold compress-TENS were significantly greater than both cold compress and TENS. Combined methods are more effective than separate methods in reducing pain [ | PMC10214554 |
Conclusion | pain | COLD | This study concludes that the combination of cold compress and TENS is more effective than both cold compress and TENS in significantly reducing CTR-associated pain among patients with CABG. As independent nursing measures, cold compression and TENS are safe, inexpensive, and easy to use methods for pain management and hence, their combination is recommended for the effective management of CTR-associated pain among patients with CABG. | PMC10214554 |
Acknowledgements | This article came from the Master’s thesis of the first author. We would like to thank the Research and Technology Administration of Rafsanjan University of Medical Sciences, Rafsanjan, Iran, for its financial support as well as the authorities of the study setting and all patients who participated in the study. | PMC10214554 | ||
Author contributions | Study design: MK, FH. Data collection and analysis: FH, PM, MK. Manuscript writing: MK, PM, SH, FH, HH. All authors read and approved the final manuscript. | PMC10214554 | ||
Funding | This study was conducted based on a master’s thesis about nursing and supported by Rafsanjan University of Medical Sciences, Rafsanjan, Iran. | PMC10214554 | ||
Availability of data and materials | The data of this study will be provided to the editor of the journal if it is needed. | PMC10214554 | ||
Declarations | PMC10214554 | |||
Ethics approval and consent to participate | This study was conducted according to the World Medical Association's Declaration of Helsinki, in which a written consent was obtained from all patients. In addition, the study protocol was approved by the Ethics Committee of Rafsanjan University of Medical Sciences (IR.RUMS.REC.1397.174). Besides, it was registered at the Iranian Registry of Clinical Trial (RCT20131228015965N18). | PMC10214554 | ||
Consent for publication | All authors declare their full consent for publishing their article in Journal of Cardiothoracic Surgery. | PMC10214554 | ||
Competing interest | The authors declare that there is no conflict of interests regarding the publication of this article. | PMC10214554 | ||
References | PMC10214554 | |||
Background | INFLAMMATION | This post-hoc analysis of the DELIGHT trial assessed effects of the SGLT2 inhibitor dapagliflozin on iron metabolism and markers of inflammation. | PMC10685512 | |
Methods | type 2 diabetes, albuminuria | TYPE 2 DIABETES | Patients with type 2 diabetes and albuminuria were randomized to dapagliflozin, dapagliflozin and saxagliptin, or placebo. We measured hemoglobin, iron markers (serum iron, transferrin saturation, and ferritin), plasma erythropoietin, and inflammatory markers (urinary MCP-1 and urinary/serum IL-6) at baseline and week 24. | PMC10685512 |
Results | 360/461 (78.1%) participants had available biosamples. Dapagliflozin and dapagliflozin-saxagliptin, compared to placebo, increased hemoglobin by 5.7 g/L (95%CI 4.0, 7.3; p < 0.001) and 4.4 g/L (2.7, 6.0; p < 0.001) and reduced ferritin by 18.6% (8.7, 27.5; p < 0.001) and 18.4% (8.7, 27.1; p < 0.001), respectively. Dapagliflozin reduced urinary MCP-1/Cr by 29.0% (14.6, 41.0; p < 0.001) and urinary IL-6/Cr by 26.6% (9.1, 40.7; p = 0.005) with no changes in other markers. | PMC10685512 | ||
Conclusions | INFLAMMATION | Dapagliflozin increased hemoglobin and reduced ferritin and urinary markers of inflammation, suggesting potentially important effects on iron metabolism and inflammation. | PMC10685512 | |
Trial registration | ClinicalTrials.gov NCT02547935. | PMC10685512 | ||
Supplementary Information | The online version contains supplementary material available at 10.1186/s12933-023-02027-8. | PMC10685512 | ||
Keywords | PMC10685512 | |||
Background | CKD, chronic kidney disease, Anemia, kidney failure, type 2 diabetes | ANEMIA, KIDNEY FAILURE, TYPE 2 DIABETES | Anemia is common in patients with chronic kidney disease (CKD), particularly those with type 2 diabetes [Sodium glucose co-transporter 2 (SGLT2) inhibitors reduce CKD progression and the risk of kidney failure in patients with type 2 diabetes and CKD [In this post-hoc analysis of the DELIGHT trial [ | PMC10685512 |
Methods | PMC10685512 | |||
Patients and study design | non-diabetic kidney disease | MAY, TYPE 1 DIABETES | DELIGHT was a double-blind, placebo-controlled, multicenter trial that enrolled 461 patients from nine countries. The study was conducted from July 2015 to May 2018. Methods and results were previously published [Excluding criteria included a diagnosis of type 1 diabetes and non-diabetic kidney disease. Patients with hemoglobin < 9 g/dL before screening or long-term use of glucocorticoids were also excluded. All participants provided written informed consent. Participants were offered separate and optional informed consent to collect additional blood or urine samples for future biomarker research. DELIGHT trial was conducted according to the Declaration of Helsinki, registered with clinicaltrials.gov (NCT02547935), and approved by an ethics committee at each site. | PMC10685512 |
Biomarker assessment | Urine and blood samples for exploratory biomarker research were obtained at baseline and week 24. Samples were stored at -80 °C until measurement. We measured the following iron and erythropoiesis markers: serum iron, ferritin, transferrin, and plasma EPO. TSAT was calculated with iron and transferrin concentrations [ | PMC10685512 | ||
Statistical analysis | INFLAMMATION | Baseline characteristics were reported in n (%) for categorical variables and in mean (SD) or median (IQR) for continuous variables. Biomarkers were log-transformed in the following analyses. We calculated mean percentage changes (95% CI) in biomarkers from baseline to week 24 by treatment allocation. Estimations were performed with analysis of covariance adjusted for randomization strata (insulin, metformin, sulfonylurea derivatives, thiazolidinediones, or other treatment-based regimens) and baseline value. Absolute mean changes (95% CI) in hemoglobin and hematocrit over time were assessed with repeated-measures models using a restricted maximum likelihood. The model consists of randomization strata, treatment allocation, visit and treatment-by-visit interaction as fixed effects, and baseline value as a covariate and baseline-by-visit interaction.We calculated Pearson’s correlation coefficients to determine the relationship between markers of inflammation, iron metabolism and erythropoiesis at baseline. We also assessed correlations between changes in these markers by randomized treatment.We considered p-values ≤ 0.05 as statistically significant. All analyses were performed with R Statistical Software version 4.2.1 (R Foundation for Statistical Computing, Vienna, Austria). | PMC10685512 | |
Discussion | CKD, inflammation, diabetic kidney disease, anemia, Inflammation, heart failure | DIABETIC KIDNEY DISEASE, INFLAMMATION, ANEMIA, IRON DEFICIENCY, INFLAMMATION, EVENTS, HEART FAILURE, TYPE 2 DIABETES | In this post-hoc analysis of the DELIGHT trial, dapagliflozin and a combination of dapagliflozin and saxagliptin increased hemoglobin/hematocrit and reduced ferritin in patients with type 2 diabetes and CKD. Dapagliflozin reduced urinary inflammatory markers, specifically MCP-1/Cr and IL-6/Cr.The effect on iron homeostasis with SGLT2 inhibition has been assessed in patients with heart failure [Dapagliflozin with and without saxagliptin reduced urinary inflammation markers of MCP-1/Cr and IL-6/Cr. Inflammation is strongly associated with diabetic kidney disease progression as well as cardiovascular events [The current study does not support the additive effect of saxagliptin on markers of hematopoiesis, iron and inflammation when used in combination with SGLT2 inhibitors. In the current study, the reduction in HbA1c was more pronounced in the combination dapagiliflozin-saxigliptin group compared to dapagliflozin alone, suggesting that the decreases in iron and inflammation markers with dapagliflozin observed in this study are unlikely mediated by improved glycemic control.Increased systemic inflammation worsens iron availability, partly via increased hepcidin [Limitations of this study include its post-hoc nature, which may increase chance findings. Secondly, the absence of hepcidin concentration precludes our ability to test the hypothesis that SGLT2 inhibition addresses functional iron deficiency by reducing hepcidin. Third, these analyses do not account for use of iron preparation or ESA therapy during the study. Possible unbalance in anemia treatment could bias the effect estimation on hematological and iron parameters, although the short follow up duration of 6 moths reduced that risk. Finally, urinary MCP-1 and IL-6 were measured in spot urine samples and indexed to urinary creatinine. This might decrease the precision of the observed effect estimates as the concentration of urinary analytes are more variable in spot urine than 24-hour samples. However, despite the potential decrease in statistical power, we observed statistically significant reduction in urinary inflammation markers. | PMC10685512 |
Conclusions | CKD | INFLAMMATION, TYPE 2 DIABETES | In patients with type 2 diabetes and CKD, dapagliflozin increased hemoglobin/hematocrit and reduced ferritin and urinary MCP-1/Cr and IL-6/Cr, suggesting potentially important effects on iron metabolism and inflammation. | PMC10685512 |
Acknowledgements | The authors thank all investigators, trial teams, and patients for their participation in the trial. | PMC10685512 | ||
Authors’ contributions | A.K., B.L.N. and H.J.L.H. wrote the first draft of the report. A.K. and N.J. analyzed the data. C.P. and H.J.L.H. involved in data collection. All authors contributed to the interpretation of the data and revision of the paper. The first author and corresponding author take responsibility for the integrity of the data and the accuracy of the data reported. All authors reviewed and approved the final version of the report for submission. | PMC10685512 | ||
Funding | This study was funded by AstraZeneca. | PMC10685512 | ||
Data Availability | Individual de-identified participant data are not freely available because of the risk of patient re-identification, but interested parties can request access to de-identified participant data or anonymised clinical study reports through submission of a request for access via the AstraZeneca Group of Companies Data Request Portal. | PMC10685512 | ||
Declarations | PMC10685512 | |||
Ethics approval and consent to participate | Local ethics committees approved all study procedures for the DELIGHT trial and subsequent analyses. Consent was obtained from all study participants. | PMC10685512 | ||
Consent for publication | Not applicable. | PMC10685512 | ||
Competing interests | Diabetes | DIABETES | A. Koshino, N. Jongs and T. Wada have no conflicts of interest.B.L. Neuen has received fees for advisory boards, scientific presentations, speaker fees, steering committee roles and travel support from the American Diabetes Association, AstraZeneca, Bayer, Boehringer and Ingelheim, Cambridge Healthcare Research, Janssen and Medscape, with all honoraria paid to his institution. C. Pollock has served on the steering committee for CREDENCE trial of canagliflozin (sponsored by Janssen Cilag) and is an advisory board member and speaker for Astra Zeneca, and a speaker for Eli Lilly and Boehringer Ingelheim. P.J. Greasley, E.-M. Anderson, A. Hammarstedt, C. Karlsson and A.M. Langkilde are employees and shareholder of AstraZeneca.H.J.L. Heerspink is supported by a VIDI (917.15.306) grant from the Netherlands Organisation for Scientific Research and has served as a consultant for AbbVie, Astellas, AstraZeneca, Bayer, Boehringer Ingelheim, Chinook, CSL Pharma, Fresenius, Gilead, Janssen, Merck, Mundipharma, Mitsubishi Tanabe, and Retrophin; and has received grant support from AbbVie, AstraZeneca, Boehringer Ingelheim, and Janssen. | PMC10685512 |
Abbreviations | Chronic kidney diseaseErythropoietinDipeptidyl | Chronic kidney diseaseErythropoietinDipeptidyl peptidase-4Interleukin-6Monocyte chemoattractant protein-1Sodium glucose co-transporter 2Transferrin saturationUrinary albumin-creatinine ratio | PMC10685512 | |
References | PMC10685512 | |||
Keywords | HIV however | Cash transfers are increasingly used to motivate adherence to HIV care. However, evidence on cash transfers and intimate partner violence (IPV) is mixed and little is known about their safety for women living with HIV. We conducted in-depth interviews with women living with HIV who participated in a randomized trial providing 6 months of cash transfers (~$4.5 or $11 USD) conditional on HIV clinic attendance in Shinyanga, Tanzania to assess how receiving cash affects IPV and relationship dynamics. Eligible participants were 18–49 years, received cash transfers, and in a partnership at baseline. Data were analyzed in Dedoose using a combined inductive-deductive coding approach. 25 interviews were conducted between November 2019-February 2020. Women’s employment was found to be a source of household tension and violence. None of the participants reported physical or sexual IPV in relation to cash transfers, however, some women experienced controlling behaviors or emotional violence including accusations and withholding of money, particularly those who were unemployed. Cash transfers were predominantly used for small household expenses and were not viewed as being substantial enough to shift the financial dynamic or balance of power within relationships. Our findings suggest that small, short-term cash transfers do not increase physical or sexual IPV for women living with HIV however can exacerbate controlling behaviors or emotional violence. Modest incentives used as a behavioral nudge to improve health outcomes may affect women differently than employment or larger cash transfers. Nonetheless, consultations with beneficiaries should be prioritized to protect women from potential IPV risks. | PMC10338570 | |
Introduction | Economic interventions including cash transfers have been used to address poor engagement and retention in HIV care and support the UNAIDS 95-95-95 targets [Cash transfers are commonly used as a strategy to combat IPV, hypothesized to reduce poverty-related household stress and improve women’s bargaining power in relationships [In addition to the heterogeneity in the existing literature, there is a paucity of evidence examining how cash transfers affect IPV among women living with HIV. IPV is pervasive among women living with HIV in sub-Saharan Africa [Given the mixed findings on cash transfers and IPV in the general population and the scale and scope of interventions under consideration to improve HIV outcomes, it is critical to determine whether this approach is safe and beneficial for women living with HIV, who comprise a large population. Most prior studies have investigated cash transfer safety using quantitative approaches and there is limited understanding of how women perceive their risk of IPV to be influenced when receiving financial incentives. To address this gap, we conducted a qualitative study with women living with HIV who participated in a cash transfer trial in Shinyanga Region, Tanzania to explore beneficiary perspectives on cash transfers. The main objective of our study was to understand how cash transfers affect relationship safety and IPV. We also aimed to understand the extent to which women experience their partners interfering with their access and ability to remain in HIV care. | PMC10338570 | ||
Methods | PMC10338570 | |||
Study Population and Setting | This qualitative study was conducted with participants from a three-arm randomized trial investigating the effect of cash transfers on viral suppression (Participants in the trial were enrolled from April-December 2018 and randomized in a 1:1:1 ratio to receive six months of cash transfers of 10,000 TZS (~ 4.5 USD) or 22,500 TZS (~ 11 USD) per month via mobile money, conditional on HIV clinic attendance, or standard HIV services (n = 530). The goal of the cash transfer was to motivate engagement in HIV care, with cash amounts designed to subsidize the cost of food, clinic transportation, or lost wages for time spent at the clinic (e.g., 10,000 TZS ≈ roundtrip transportation for 3 clinic visits, 22,500 ≈ roundtrip transportation for 6 clinic visits). The intervention period was completed between October 2018-June 2019 (six months after enrollment), with a maximum of 27–60 USD (total) disbursed to each cash transfer participant depending on their randomization assignment. At six-months, the trial found that those in the cash arms of the trial were significantly more likely to be virally suppressed at 6 months [We used purposive sampling to recruit female participants aged 18–49 years who were randomized to either of the cash arms and in a relationship at baseline of the trial. Participants were recruited from HIV clinics where they initiated care from November 2019-February 2020, up to eight months after the intervention period, until theme saturation was reached (no new insights emerged from interviewees) [ | PMC10338570 | ||
Theoretical Framework | HIV [ | This study was informed by the Theory on Gender and Power and its extension to HIV [ | PMC10338570 | |
Data Collection | A list of all potentially eligible participants and their upcoming HIV clinic appointment dates was generated from baseline trial data. Potential participants attending clinic visits were approached discreetly in the waiting room by female interviewers to present the qualitative study. Upon conducting a final eligibility screening and receiving informed consent, interviews were conducted in Kiswahili by two female interviewers trained in qualitative and gender-based violence (GBV) research ethics [ | PMC10338570 | ||
Analysis | Interviewers produced field notes in English after each interview. Emergent themes from field notes were reviewed and discussed weekly by the study team; this included dialogue around social and cultural expectations of partnered women in Tanzania, reflection on our individual beliefs about women’s finances and position in the household, and consideration of how our differing beliefs, cultures, and personal experiences may influence the interview process or interpretations of the data.Audio recordings were transcribed and translated from Kiswahili into English. The English transcripts were coded independently in Dedoose version 8.3.17 [A matrix of codes was created to identify patterns in the data, and distill and describe key concepts and themes. Views and experiences were summarized overall and tabulated by key socio-demographic characteristics, cash arm, participation in the labor force, reported IPV experiences (ever), and whether IPV was related to the money received from the trial. Findings and interpretations were discussed and validated with the local study team. | PMC10338570 | ||
Ethics | Human subjects research approval was obtained from the Institutional Review Boards at the University of California, Berkeley [CPHS 2017-12-10558] and National Institute for Medical Research in Tanzania (NIMR/HQ/R.8a/Vol. IX/2677). The study conforms to the principles embodied in the Declaration of Helsinki. | PMC10338570 | ||
Acknowledgements | The authors would like to acknowledge and thank the local research team at Health for a Prosperous Nation and the study participants for their time participating in this research study. | PMC10338570 | ||
Funding | Funding for the parent trial discussed in this study was supported by the National Institute of Mental Health under award number R01MH112432. | PMC10338570 | ||
Data Availability | Data provided upon official request. | PMC10338570 | ||
Code Availability | Not applicable. | PMC10338570 | ||
Declarations | PMC10338570 | |||
Competing Interests | There are no conflicts of interest to declare. | PMC10338570 | ||
Ethics Approvals | Human subjects research approval was obtained from the Institutional Review Boards at the University of California, Berkeley [CPHS 2017-12-10558] and National Institute for Medical Research in Tanzania (NIMR/HQ/R.8a/Vol. IX/2677). | PMC10338570 | ||
Consent to Participate | All study participants provided written informed consent during study enrollment. | PMC10338570 | ||
Consent for Publication | Not applicable. | PMC10338570 | ||
References | PMC10338570 | |||
Background | In recent years, ambulatory lower limb exoskeletons are being gradually introduced into the clinical practice to complement walking rehabilitation programs. However, the clinical evidence of the outcomes attained with these devices is still limited and nonconclusive. Furthermore, the user-to-robot adaptation mechanisms responsible for functional improvement are still not adequately unveiled. This study aimed to (1) assess the safety and feasibility of using the HANK exoskeleton for walking rehabilitation, and (2) investigate the effects on walking function after a training program with it. | PMC10039497 | ||
Methods | LEMS, fatigue, pain | ADVERSE EVENTS, SPINAL CORD | A randomized controlled trial was conducted including a cohort of 23 patients with less than 1 year since injury, neurological level of injury (C2-L4) and severity (American Spinal Cord Injury Association Impairment Scale [AIS] C or D). The intervention was comprised of 15 one-hour gait training sessions with lower limb exoskeleton HANK. Safety was assessed through monitoring of adverse events, and pain and fatigue through a Visual Analogue Scale. LEMS, WISCI-II, and SCIM-III scales were assessed, along with the 10MWT, 6MWT, and the TUG walking tests (see text for acronyms). | PMC10039497 |
Results | fatigue, pain | ADVERSE EVENTS | No major adverse events were reported. Participants in the intervention group (IG) reported 1.8 cm (SD 1.0) for pain and 3.8 (SD 1.7) for fatigue using the VAS. Statistically significant differences were observed for the WISCI-II for both the “group” factor (F = 16.75, p < 0.001) and “group-time” interactions (F = 8.87; p < 0.01). A post-hoc analysis revealed a statistically significant increase of 3.54 points (SD 2.65, p < 0.0001) after intervention for the IG but not in the CG (0.7 points, SD 1.49, p = 0.285). No statistical differences were observed between groups for the remaining variables. | PMC10039497 |
Conclusions | The use of HANK exoskeleton in clinical settings is safe and well-tolerated by the patients. Patients receiving treatment with the exoskeleton improved their walking independence as measured by the WISCI-II after the treatment. | PMC10039497 | ||
Keywords | PMC10039497 | |||
Background | cord injury | PARTIAL PARALYSIS, STILL | One of the most limiting consequences of spinal cord injury (SCI) is the complete or partial paralysis of the lower limbs. Still, independent from the severity of the spinal injury, the time after lesion, or age at the time of injury, the restoration of walking is given high priority by subjects with SCI [Functional walking rehabilitation has therefore to be intensive and task-oriented. Robotic devices were developed more than 20 years ago to allow for intensive, weight-bearing, stepping training with precise movement control [In this sense, ambulatory robotic exoskeletons have been proposed in the last decade to provide task-specific, ambulatory overground walking training, mainly in incomplete SCI patients that have improvement prognosis. In contrast to robotic trainers, robotic exoskeletons may optimally challenge the patient in the domains of balance and physical exercise, while providing walking-consistent visual and functional feedback. The safety and comfort of robotic exoskeletons as a rehabilitation tool have been previously assessed in patients with acute and chronic SCI [While some studies have reported improvements in some functional and spatial–temporal variables of walking (i.e. gait speed), the literature concerning the walking outcomes due after a rehabilitation program with robotic exoskeletons is nowadays limited and nonconclusive. One of the main rationales is related to the differences in interventions (robot type and control, treatment time, and the number of sessions), which makes it difficult to obtain a clinically reliable conclusion [Currently, one of the main issues to be addressed is whether walking training with robotic exoskeletons generates improvements in the person’s walking ability, and what device-related rationales are responsible for the outcomes. In this article, we present the results of a prospective, randomized, and comparative study conducted to assess the clinical efficacy of a novel robotic lower-limb robotic exoskeleton named HANK. While the main features of this exoskeleton are similar to others available on the market or tested in similar studies, there are slight differences that justify the present study. We also provide evidence on the impact of delivering walking training with this kind of technology in incomplete SCI patients, contributing to answering the fundamental question related to the outcomes of robotic walking rehabilitation conveyed with exoskeletons [ | PMC10039497 |
Methods | A prospective, randomized, comparative study was carried out (Fig. CONSORT flow diagram | PMC10039497 | ||
HANK exoskeleton | stroke, Exo-H2 | STROKE | The HANK exoskeleton (Gogoa Mobility Robots SA, Spain) is an updated version of Exo-H2 exoskeleton, previously described and studied in patients with stroke [HANK exoskeleton; | PMC10039497 |
Participants | injuy, brachial muscle, spasticity, contracture, arthrodesis, lower extremity fracture | RECRUITMENT, ULCERS, SPINAL CORD | This clinical study focused on individuals with incomplete SCI less than 1 year since injuy. The cohort was recruited at the National Hospital for Paraplegics (Toledo, Spain) and the eligibility criteria were: age between 16 and 70 years old; C2-L4 level of injury; severity (American Spinal Cord Injury Association Impairment Scale [AIS] C or D); time since injury less than 12 months; enough strength in the upper limbs necessary to handle a walker or crutches (triceps brachial muscle balance ≥ 3); the capacity to tolerate standing; spasticity in lower limb muscles ≤ 2 according to the Modified Ashworth scale; and signing of informed consent. Participants were excluded if they were pregnant or had: any other neurological condition apart from SCI; a recent lower extremity fracture (less than 1 year); irreducible contracture or arthrodesis in the lower limb joints; ulcers sores at the contact points with the exoskeleton. Although to facilitate recruitment, the age range of the inclusion criteria was very wide, most of the subjects were between 33 and 59 years old except 4 who were 19, 23, 64 and 71 bearing the heterogeneity of the cohort. | PMC10039497 |
Intervention procedures | The IG training protocol consisted of 15 robotic ambulatory gait training sessions, each session lasting 30 min. Three sessions were performed on non-consecutive days each week for 5 consecutive weeks. The total duration of each session was about 1 h, which included 20 min to put on and remove the exoskeleton, 30 min for the walking training, 5 min of rest and 5 min to register the variables assessed. The training was conducted indoors on a smooth level surface in the physiotherapy room. External support was always used depending on the participant’s functional status, preferences, and ability: parallel bars, walker or two crutches. Besides, a researcher -physiotherapist- provide contact guarding, and another -engineer- was in charge of the exoskeleton control. Feedback was provided to patients of the IG during the sessions, were instructed on maintaining their walking pace. After the sessions, we provided feedback regarding the distance walked. The CG rehabilitation program was comprised of 15 sessions, 30 min. long, of a traditional gait training program (analytical mobilization, strengthening exercises for the lower limbs and gait re-education when possible using parallels), distributed similarly as in the IG: 3 sessions each week for 5 weeks. Neither the participants in the IG group nor those in the CG group modified their usual medications or the rehabilitation programs during the study. In other words, both the IG and the CG groups received additional walking treatment due to their participation in the study. | PMC10039497 | ||
Outcome variables | pain | PRESSURE ULCER, SPINAL CORD, PRESSURE ULCER, ADVERSE EVENT, SKIN LESIONS | Safety was closely monitored during the study. It was assessed by registering and analyzing any adverse event, particularly those related to skin lesions, falls and pain. The participants’ skin was inspected before and after each session based on the US National Pressure Ulcer Advisory Panel and European Pressure Ulcer Advisory Panel pressure ulcer classification system [Clinical and functional data were measured at baseline and end of the training period (post-intervention), without the exoskeleton by another physiotherapist than those who conducted the treatment. The severity and level of SCI were determined through neurological examination according to the International Standards for Neurological Classification of Spinal Cord Injury (ISNCSCI) [ | PMC10039497 |
Statistical analysis | LEMS | Statistical analyses were performed using the commercial IMB SPSS v22 software package (IBM Corporation, Armonk, NY).The sample size was calculated based on the LEMS score as the main variable, considering a mean difference of 8.2 and a standard deviation of 10 that was obtained from a pilot study [ | PMC10039497 | |
Results | LEMS | RECRUITMENT, SPINAL CORD | The eligibility criteria were met by 23 participants with incomplete SCI within the recruitment period: 12 out of the 23 were randomly allocated to the IG and 11 of the 23 to the CG. We experienced a slow recruitment rate due to different but common reasons [Patients´ baseline characteristicsVariables are expressed as mean (SD). (n), number of participants able to finish the studyAIS: American Spinal Injury Association Impairment Scale; LEMS: Lower Extremity Motor Scale; WISCI-II: Walking Index for Spinal Cord Injury II. *p ≥ 0.05 | PMC10039497 |
Safety, feasibility, pain and fatigue | muscle pain, skin erythema, fatigue, pain | AIDS, SKIN ERYTHEMA | No participants experienced a fall during the study, yet two IG participants suffered mild skin erythema in the tibia contact zone during the first session that was related to the strap. This issue was resolved by adding padding to the specific zones and the lesions disappeared within one day. In addition, mild neck and shoulder muscle pain was reported 24 h after the training session in 6 IG patients, which was probably related to the use of walking aids. Concerning the pain and fatigue perceived after each IG session, the participants rated the pain as 1.8 (SD 1.0) cm and the fatigue as 3.8 (SD1.7) cm in a VAS (0–10 cm). | PMC10039497 |
Effects on LEMS | ηLower extermity motor score, LEMS | The two-way ANOVA showed significant differences for the “time” factor in LEMS (F = 19.9, p < 0.001) but not for the “group” factor (F = 0.16, p = 0.69) and for the “time-group” interaction (F = 0.5, p = 0.4). A post-hoc pairwise comparison with Bonferroni correction showed a significant increase in the LEMS score after the intervention of 4.4 (SD 5.4) points in the IG (p = 0.003, ηLower extermity motor score (LEMS) assessmentCG: control group; IG: intervention group; *significant differences (p < 0.05). η | PMC10039497 | |
Effects on the functional scales | SPINAL CORD | The functional outcomes at baseline and post-intervention were assessed (Table Functional outcomes following exoskeleton training or convectional training, and comparison among times and interventions WISCI-II(0–20) SCIM-III(0–100) WISCI-II(0–20) SCIM-III(0–100)CG: control group; IG: intervention group; *significant differences (p < 0.05). ηSignificant differences in the WISCI-II were also observed for the “group” factor (F = 16.75, p < 0.001) and “group-time” interaction (F = 8.87; p = 0.01). Indeed, the post-hoc analysis revealed a significant increase of 3.5 (SD 2.65) points after intervention in the IG (p < 0.0001) but not in the CG when compared to the CG (0.7, SD 1.5 points; p = 0.285). WISCI-II details are shown in Table WISCI II outcomes and technical aid used in functional gait test (10MWT, TUG, 6MinWT) at baseline and post-intervention timeCG: control group; IG: intervention group; *change of assistive device from pre- to post-intervention10MWT: 10 Meters Walking Test; TUG: Test Up and Go; 6MWT: 6 Minutes Walking Test; WISCI-II: Walking Index Spinal Cord Injury- II | PMC10039497 | |
Discussion | stroke, fatigue, Exo-H2, pain | ADVERSE EVENTS, ADVERSE EFFECTS, STROKE | This article reports the results of a prospective, randomized, comparative clinical study, blinded to the evaluators conducted in a sample of individuals with incomplete SCI less than 1 year since injury to: (1) assess the safety and adherence to the robotic-assisted walking training as provided with of the device HANK exoskeleton by individuals with incomplete SCI; and (2) assess the changes in walking function after a training program with the robotic exoskeleton compared to traditional walking therapy. We hypothesized that the treatment with the exoskeleton would provide better functional walking outcomes than traditional overground gait therapy. To our knowledge, we present the first results of the effects on walking outcomes after training with robotic exoskeletons in SCI individuals less than 1 year since injury.Although we estimated 24 individuals per group, we managed to recruit 23 and analyze 21 subjects. However, we present the available data, and our interpretation is unlikely to introduce bias because we did not conduct any interim analysis [No serious adverse effects were found. Only a small number of skin issues were registered, and no participants withdrew from the study due to the use of the exoskeleton. All the clinical and functional variables assessed improved after treatment in both groups, although the WISCI-II improvement was greater in participants trained with the robotic exoskeleton. As it will be discussed below, this result has an important implication regarding the improvement mechanisms underlying the use of ambulatory robotic exoskeletons.The HANK exoskeleton introduces some improvements with respect to the preceding Exo-H2 exoskeleton, the latter proved its feasibility to provide walking assistance in a sample of stroke individuals with preserved walking ability [Here, we also demonstrate the feasibility of HANK to provide walking therapy in light of the changes in walking function in a sample of incomplete SCI individuals. The inclusion criteria focused on individuals with SCI less than 12 months since injury, not least because changes in the neurological situation can be expected and the effect of any therapy may be enhanced. In fact most of the patients were less than 6 months post injury. This supports the idea that the exoskeleton can be used to achieve better results in early gait rehabilitation. The optimal timing of treatment with exoskeletons, the duration and the protocols have yet to be defined. A recent study using an exoskeleton for gait training on acute SCI was yet focusing more on safety and feasibility than on neurological changes [All of the participants except 2 completed the 15 training sessions, and these two withdrawals were not related to the intervention. In terms of the feasibility and adverse events, our results were similar to other studies [The overall pain and fatigue perceived here were recorded during robotic gait training through a VAS scale [As in previous studies [ | PMC10039497 |
Study limitations | RECRUITMENT | There were some limitations to the present study. Firstly, we did not set guidance force and step initiation detection specifically for each patient. Adapting robot guidance to the actual walking capacity of the patient, in other words to the patient’s movement as needed (Assist-as-Needed, AAN [The sample size was not adequate since we estimated 24. Besides, no stratification based on the time since the injury or the level of injury could be made. The IG appears to be younger with a shorter injury duration, which could potentially favor more change. However, differences for demographic variables did not reach statistical significance. This could also be attributable to the limited study size. Another limitation, no follow-up evaluation after 6 months was registered. Furthermore, the recruitment period and the number of training sessions were limited due to logistics and time constraints. Likewise, it was not possible to carry out a multi-center study as the exoskeleton is not available at other centers. Finally, we also acknowledge that the intervention could not be blinded to the patient, therefore risking a placebo effect. | PMC10039497 | |
Conclusion | The results of a prospective, randomized, comparative study of walking training with the lower limb robotic ambulatory exoskeleton HANK, are presented. This study provides evidence of its safety and feasibility for gait training in patients with SCI less than 1 year since injury. We found that both the IG and CG subjects were able to walk faster and longer after the training programs, yet the IG patients needed less external assistance. In the light of these data, the mechanisms responsible for the improvements in exoskeleton-driven interventions should be confirmed in future multi-center efficacy trials with larger sample sizes. | PMC10039497 | ||
Acknowledgements | We acknowledge Mark Shefton for the revision of the English version. | PMC10039497 | ||
Author contributions | Study conception and design: AJA and AG. Coordination: JLP. Experimental procedure: AM, VL. Data extraction: NC, IS. Statistical analysis of the results: AMG. Writing manuscript: AG, AM, AJA. Review manuscript: all authors. All authors read and approved the final manuscript. | PMC10039497 | ||
Funding | This work was partially supported by the Institute of Health Carlos III (Spain) and co-funded by FEDER (PI15/01437), as well as the Spanish Ministerio de Ciencia, Innovación y Universidades, under the Programa Estatal de Investigación, Desarrollo e Innovación Orientada a los Retos de la Sociedad (Ref.: RTI2018-097290-B-C31). | PMC10039497 | ||
Availability of data and materials | The dataset analyzed during the current study are available from the corresponding author on reasonable request. | PMC10039497 | ||
Declarations | PMC10039497 | |||
Ethics approval and consent to participate | The present study was approved by the local Ethical Committee in Hospital Virgen de la Salud (Ref. No. 39; 07/02/2007). We certify that all applicable institutional and governmental regulations concerning the ethical use of human volunteers. | PMC10039497 | ||
Consent for publication | Participants give their consent for publication of their image if require. | PMC10039497 | ||
Competing interests | José L. Pons, Angel Gil-Agudo and Antonio J. del-Ama are founding partners of Gogoa Mobility Robots S.A. | PMC10039497 | ||
References | PMC10039497 | |||
Introduction | LUTZ | Edited by: Luca Roncati, University of Modena and Reggio Emilia, ItalyReviewed by: Elizabeth De Gaspari, Adolfo Lutz Institute, Brazil; Srinivasa Reddy Bonam, University of Texas Medical Branch at Galveston, United StatesInterim analysis of phase I and phase II clinical trials of personalized vaccines made from autologous monocyte-derived dendritic cells (DCs) incubated with S-protein of SARS-CoV-2 show that this vaccine is safe and well tolerated. Our previous report also indicates that this vaccine can induce specific T-cell and B cell responses against SARS-CoV-2. Herein, we report the final analysis after 1 year of follow-up regarding its safety and efficacy in subjects of phase I and phase II clinical trials. | PMC10315914 | |
Methods | ADVERSE EVENTS, VIRUS DISEASE | Adult subjects (>18 years old) were given autologous DCs derived from peripheral blood monocytes, which were incubated with the S-protein of SARS-CoV-2. The primary outcome is safety in phase I clinical trials. Meanwhile, optimal antigen dosage is determined in phase II clinical trials. Corona Virus Disease 2019 (COVID-19) and Non-COVID-19 adverse events (AEs) were observed for 1 year. | PMC10315914 | |
Results | A total of 28 subjects in the phase I clinical trial were randomly assigned to nine groups based on antigen and Granulocyte-Macrophage Colony Stimulating Factor (GM-CSF) dosage. In the phase II clinical trial, 145 subjects were randomly grouped into three groups based on antigen dosage. During the 1-year follow-up period, 35.71% of subjects in phase I and 16.54% in phase II had non-COVID AEs. No subjects in phase I experienced moderate–severe COVID-19. Meanwhile, 4.31% of subjects in phase II had moderate–severe COVID-19. There is no difference in both COVID and non-COVID-19 AEs between groups. | PMC10315914 | ||
Conclusions | After 1 year of follow-up, this vaccine is proven safe and effective for preventing COVID-19. A phase III clinical trial involving more subjects should be conducted to establish its efficacy and see other possible side effects. | PMC10315914 | ||
Introduction | deaths | ADVERSE EVENT | Since being designated by the WHO as a pandemic in March 2019, SARS-CoV-2 has infected more than 540 million people and was responsible for 6 million deaths in June 2022 (The development of dendritic cell (DC)–based vaccines is an innovative vaccine that can overcome existing problems. DC–based vaccines utilize the ability of DCs as antigen-presenting cells (APCs) to induce a human immune system oriented to T-cell immunity (In previous studies, both preclinical and interim analysis results of phase I and II clinical trials found that this vaccine has good potential. In short-term observations (3 months), no serious adverse event (SAE) was found in the subjects of phase I and II clinical trials. In addition, autologous DC–based vaccines loaded with SARS CoV-2 S-protein (AV-COVID-19 or Nusantara vaccine) can induce adequate T-cell immunity well. The vaccine can also form an antibody response ( | PMC10315914 |
Methods | PMC10315914 | |||
Study oversight and outcomes | MAY | The study was randomized and double-blinded phase 1 and 2 clinical trials. The phase I clinical trial was carried out at Dr. Kariadi Hospital Semarang, Faculty of Medicine, Diponegoro University, from December 2020 to December 2021. The phase II clinical trial was carried out at Gatot Subroto Hospital from April 2021 to May 2022. The research protocol follows the Helsinki declaration and has received ethical approval. Data security is reviewed by an independent Data Safety Monitoring Board (DSMB). The main objective of phase I clinical trials is to determine the safety of AV-COVID-19 vaccines, whereas phase II clinical trials aim to determine the optimal dose of SARS-CoV-2 antigens used in forming immunogenicity. Then, the safety and efficacy of the vaccine was also analyzed based on the immune response to the SARS CoV-2 protein. This study is registered in the US National Library of Medicine ClinicalTrials.gov under identifier NCT05007496. This research was sponsored by PT. Aivita Biomedika Indonesia. | PMC10315914 | |
Participants, randomization, and blinding | obesity, autoimmune laboratory abnormalities, immunodeficiency diseases, thromboembolic, physical/mental disabilities, Hepatitis C | OBESITY, UNCONTROLLED HYPERTENSION, HIV INFECTION, INVASIVE CANCER, COVID-19 INFECTION, IMMUNODEFICIENCY DISEASE, HEPATITIS B, HEPATITIS C | In phase I, as many as 106 prospective subjects were screened, and 33 subjects met the criteria and received the vaccine. Meanwhile, in phase II, as many as 227 prospective subjects were screened, and 145 subjects met the criteria and received the vaccine. The subjects included in this study were over 18 years old, generally healthy, not pregnant or planning to get pregnant for productive women, willing to comply with research protocols, and provided informed consent in writing. While the exclusion criteria consist of subjects with symptoms of active COVID-19 infection, positive PCR test results infected with SARS-CoV-2 less than 3 months, rapid examination of reactive SARS-CoV-2 IgG antibodies, having received other COVID-19 vaccines, positive pregnant, subjects with immunodeficiency diseases (HIV infection, Hepatitis C, and Hepatitis B), taking immunosuppressive drugs and corticosteroids for a long time, conditions that require oxygen supplementation, diagnosed with invasive cancer and receiving anticancer therapy, a history of thromboembolism/genetic predisposition of thromboembolic events/in antithromboembolic treatment other than low-dose aspirin, physical/mental disabilities that make a person unable to carry out daily activities, obesity (BMI > 40), uncontrolled hypertension (cystole > 180, diastole > 100), and unwilling to sign written consent. In phase I, in addition to the above conditions, subjects with uncontrolled, autoimmune laboratory abnormalities based on the Food and Drug Administration was excluded, as well as a history of obtaining blood products within 3 months.All subjects that met the criteria were then randomized. In phase I, the subjects were divided into nine groups based on three antigen dose groups (0.1, 0.33, and 1.0 mcg) and three GM-CSF groups administered (0, 250, and 500 mcg). In phase II, subjects were divided into three different dose groups (0.1, 0.33, and 1.0 mcg). Neither the researchers nor the subjects knew the doses of antigens and GM-CSF. | PMC10315914 |
Vaccine | The vaccine consists of DCs and lymphocytes obtained from the blood of the peripheral autologous. First, 40 cc of blood was taken and then incubated with GM-CSF and IL-4 for 5 days to differentiate monocytes into DCs. Then, DCs and lymphocytes were incubated with recombinant SARS-CoV-2 S protein for 2 days. S protein is manufactured by LakePharma Biological (San Carlos, USA). The antigen is SARS-CoV-2 spike (S) protein pre-fusion stabilized ectodomain, C-terminus His tag, with the furin cleavage site removed and trimerization stabilized. The sequence is based on SARS-CoV-2 wild type. The amount of S protein given differs according to the dose group, namely, 0.1, 0.33, and 1.0 mcg. The vaccine composition consists of 10% DCs and 90% lymphocytes. In phase I clinical trials, a DC vaccine was given an additional GM-CSF of 250 or 500 mcg, while in phase II clinical trials, it was not given additionally. The formed DC vaccine is dissolved in the subject’s plasma before injection. Vaccines are produced following the requirements of a Good Manufacturing Product. | PMC10315914 | ||
Procedure | CRF | EVENTS, DIABETES MELLITUS, CRF | Screening of all potential subjects by medical staff was carried out. In the phase I clinical trial, eligible subjects were randomly divided into nine groups based on dose and GM-CSF addition, while in the phase II clinical trial, the subjects were divided into three groups. Then, 40 cc peripheral blood were drawn from subjects, which was processed into a DC vaccine. Seven days after the blood draw, the subject came back. If there are no signs of being infected with COVID-19, 6 cc of blood is taken again to evaluate baseline conditions before vaccination for hematology, BUN, creatinine, sodium, potassium, chloride, phosphorus, calcium, lipid profile, SGOT, SGPT, total protein, albumin, globulin, alkaline phosphatase, total bilirubin, direct bilirubin, and lipase. In patients with diabetes mellitus, fasting blood sugar and HbA1c tests are carried out, while in non-diabetic patients, only blood sugar is carried out. The vaccine was injected subcutaneously, and subjects were monitored for 30 min to assess any unintended reactions or events after vaccine administration. Then, the subjects were asked to report the local and systemic reactions they experienced within 7 days post-vaccination using a recall card. Safety evaluations were conducted again on the 7th- and 28th-day visits. The subject was then monitored again in the 3rd, 6th, 9th, and 12th months for monitoring of unwanted events. In phase II, an Enzyme-linked immunosorbent spot (ELISPOT) examination is carried out at week 2 and 4 to determine the immunogenicity of the vaccine. All data are stored in a manual and electronic Case Report Form (CRF). | PMC10315914 |
Safety assessment | meanwhile non-fasting blood glucose | EVENTS, DIABETES MELLITUS | Safety assessments are carried out by evaluating local and systemic reactions experienced by post-vaccination subjects. Subjects were monitored for 30 min post-vaccination to assess the immediate effects of the vaccine. On the 7th and 28th days after vaccination, we conducted a safety laboratory examination consisting of haematology, blood urea nitrogen (BUN), creatinine, sodium, potassium, chloride, phosphorus, calcium, lipid profile, SGOT, SGPT, total protein, albumin, globulin, alkaline phosphatase, total bilirubin, direct bilirubin and lipase. Fasting blood glucose were examined in subjects with diabetes mellitus, meanwhile non-fasting blood glucose were examined in non-diabetic subjects. Patients are continuously monitored to assess unwanted events that occurred in the 3rd, 6th, 9th, and 12th months after vaccination. | PMC10315914 |
Immunogenicity and effective dose assessment | In phase II, the determination of an effective dose is assessed based on the immunogenicity of the vaccine. The doses of the SARS-CoV-2 S protein composition tested were 0.10, 0.33, and 1.00 mcg. The immune response to detect specific memory T cells against SARS-CoV-2 was assessed by performing an ELISPOT examination measuring interferon-gamma. | PMC10315914 | ||
Efficacy assessment | The efficacy assessment was assessed by looking at the immunogenicity of the vaccine through the results of the ELISPOT examination at weeks 2 and 4. In addition, clinical trial subjects were followed for up to 1 year and incidence rates of COVID-19 that occurred were recorded. Efficacy is assessed by the vaccine’s protective ability to prevent hospitalization due to COVID-19. | PMC10315914 | ||
Statistical analysis | EVENTS | In phase, I and phase II, vaccine safety and efficacy analysis for up to 1 year were performed on all vaccinated subjects (intention-to-treat). Vaccine safety is presented descriptively by showing the proportion of unintended events in each dose group. The efficacy of the vaccine for up to 1 year was presented descriptively by showing the proportion of COVID-19 incidence in each dose group. If you meet the requirements (the number of expected counts <5 does not exceed 20%), then the difference in proportion is tested using chi-square. However, if it does not meet the requirements, the proportion difference test is carried out using Fisher’s exact test. | PMC10315914 | |
Result | PMC10315914 | |||
Subject characteristics | In the phase, I clinical trial, a total of 28 subjects received the vaccine and were grouped into nine groups. A total of 16 subjects (57.14%) were men, and 12 (42.83%) were women. The subjects of the study were in the age range of 18–61 years for men and 23–60 years for women. In the phase II clinical trial, a total of 145 subjects received the vaccine and were grouped into three groups (Demographic characteristics of phase II clinical trial subjects. | PMC10315914 | ||
Safety | ADVERSE EVENT, ALLERGIC REACTIONS | AEs occurring up to 28 days post-vaccination in phase I and phase II clinical trial subjects have been previously reported where there were no acute allergic reactions, SAE, or AE of degree 3 or 4[8]. In phase, I, subjects who experienced AE degrees 1 and 2 to 28 days were 64.5%. Meanwhile, in phase II, which experienced AE degrees 1 and 2, it was 53.6%. The incidence of AE did not differ significantly between the three antigen dose groups, except that the proportion without AE was significantly higher in the 0.10 μg group when compared to the 1.00 μg group.Observations of the presence of AE occurred were made on all subjects of phase I and phase II clinical trials for up to 1 year. In addition to the incidence of COVID-19, 10 AEs that happened were not related to vaccine administration in phase I clinical trial subjects (Adverse event (AE) phase I clinical trials during a follow-up period of 1–12 months post-vaccination.AE phase II clinical trials during a follow-up period of 1–12 months post-vaccination.The meaning of bold values are the result from our study. | PMC10315914 |
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