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3.3. Secondary outcome: The scores of HDI and the HAMA | PMC10637508 | |||
3.3.1. The change of HDI scores. | migraine | MIGRAINE | The average scores of HDI in migraine patients were analyzed at the different treatment time points respectively. As we can see in Figure The change of HDI scores at the different treatment time points. The blue histogram represents the HDI scores of group A before and after every round treatment and the red histogram represents the HDI scores of group B. The value of | PMC10637508 |
3.3.2. The change of HAMA scores. | anxiety | The incidence of anxiety symptoms was 68.3 % (41of 60) in our samples (HAMA > 7) which was similar to the results of a study from Spanish (69 %).The change of HAMA scores at the different treatment time points. The blue histogram represents the HAMA scores of group A before and after every round treatment and the red histogram represents the HAMA scores of group B. The value of | PMC10637508 | |
4. Discussion | migraine, Headache-related disability | MIGRAINE, DISEASE, ADVERSE REACTION | In the 1930s, an osteopath named William Sutherland laid the groundwork for CST, after working extensively with patients who experienced a wide range of symptomsCST is based on the theory that the movement restriction at the cranial sutures of the skull negatively affects the rhythmic impulses transmitted from the skull to the sacrum through the cerebrospinal fluid.While the specific mechanisms of CST are still understudied, clinical trials have shown preliminary evidence for CST on improving patient-reported outcomes.Upledger believes that the sutural immobility of the skull is a contributing factor to migraine.Our center is a rehabilitation institution that develop and research craniosacral treatment and has our own professional therapists and treatment rooms for many years (Fig. All the 60 enrolled subjects completed the treatment without any fall-off, and no obvious adverse reaction report was received at the end of the treatment. The results indicated that standardized CST was both effective and safe in alleviating the migraine intensity and frequency as well as the Headache-related disability. This study provides new evidence on the effect of CST on migraine in Asians. This is important because migraine is a common disease that seriously affects people health, especially for those indoor white-collar workers. | PMC10637508 |
5. Limitations | The limitations of this study are the small sample size, and the potential differences in skills and techniques of therapists, even though we participated in 3 therapists. On the other hand, this is a single center clinical study and participants in this study were all indoor white-collar workers who had received higher education. The singularity of the subject profession and work environment is also a limitation of this study. It would be interesting to repeat this study with additional measurement tools, and it is also recommended to conduct large-scale multi-center clinical research and extend the follow-up time and the long-term effects of CST. Although this study may provide valuable results to further support clinical decision-making, further research is needed. | PMC10637508 | ||
Acknowledgments | The authors are grateful to all staff members, doctors, and all participants who were involved in this study. | PMC10637508 | ||
Abbreviations: | migraine, Disability, Anxiety | MIGRAINE | complementary light-touch sham treatmentsCraniosacral therapyHamilton Anxiety ScaleHeadache Disability inventoryHeadache Impact Test-6All data generated or analyzed during this study are included in this published article [and its supplementary information files].The authors have no funding and conflicts of interest to disclose.Clinical Trial Registration-URL: How to cite this article: Jiang G, Ma S, Zhao J, Zhang M, Li Y, Chen W, Cui L, Jia L. Assessing the efficacy and safety of Craniosacral therapy for migraine: A single center randomized controlled trial. Medicine 2023;102:45(e35431). | PMC10637508 |
References | PMC10637508 | |||
Background | knee arthroplasty, TKA | The use of poly-ether-ether-ketone (PEEK) prosthesis during total knee arthroplasty (TKA) is a relatively new concept. Several studies have suggested that the thickness of cement penetration during TKA may affect the stability of the implants. The present study aimed to compare the cement penetration and clinical performance between PEEK and traditional cobalt chromium molybdenum (CoCrMo) prosthesis during TKA. | PMC10410788 | |
Methods | This study was a randomized controlled trial with level I of evidence. A total of 48 patients were randomly assigned to either the PEEK group ( | PMC10410788 | ||
Results | According to the results of this study, the mean bone cement penetration exhibited no significant difference between PEEK and CoCrMo groups (2.49 ± 0.61 mm vs. 2.53 ± 0.68 mm, | PMC10410788 | ||
Keywords | PMC10410788 | |||
Background | knee arthroplasty, aseptic loosening of the tibial component, TKA | OSTEOARTHRITIS | Total knee arthroplasty (TKA) is commonly utilized to treat osteoarthritis, although aseptic loosening of the tibial component remains a primary concern [In order to increase the longevity of joint prostheses, researchers have explored various materials including cobalt chromium molybdenum, titanium, ceramic, and more recently, poly-ether-ether-ketone (PEEK) [The cement penetration depth is an important indicator of the quality and longevity of TKA. According to previous reports, cement penetration in well-performing TKA ranges from 2 to 4 mm [This study aimed to compare the effects of PEEK and CoCrMo knee prosthesis on cement penetration in the tibial bone and evaluate the short-term clinical outcomes and safety of PEEK TKA. | PMC10410788 |
Methods | comprehension disorders, ischemic osteonecrosis, alcoholism, neuromuscular insufficiency, traumatic arthritis, drug abuse, substance abuse | RHEUMATOID ARTHRITIS, OSTEOARTHRITIS | From June 2021 to December 2022, a prospective randomized clinical trial was conducted at Honghui Hospital affiliated to Xi'An Jiaotong University to investigate the safety and efficacy of PEEK knee prostheses for TKA. The study was approved by the local ethics committee (NO. 2021-008-001) and registered at Chinese Clinical Trial Registry (ChiCTR2100047563) in accordance with the Helsinki Declaration. All patients provided written consent prior to enrollment.Patients in the age range of 50–80 years who met the inclusion criteria and were planned for elective primary TKA were enrolled in this study. The inclusion criteria were clinical diagnosis of osteoarthritis, rheumatoid arthritis, traumatic arthritis, or ischemic osteonecrosis. The exclusion criteria were neuromuscular insufficiency, comprehension disorders, alcoholism, drug abuse, substance abuse, BMI > 35 kg/mIn this study, patients were block randomized using sealed envelopes to ensure unbiased allocation into two groups: PEEK knee implants (PEEK group) and CoCrMo knee implants (CoCrMo group). The envelopes were opened in the presence of the surgeon, just before surgery in the operating theater. The patients were kept unaware of the group to which they had been allocated, in order to avoid any potential biases. | PMC10410788 |
Surgical technique | pulmonary embolism, postoperative pain, bleeding, Pain, fracture, Thrombosis, pain, DVT, cement mantle measurementsIn this study, PJI, patellar componentThe cementation, bipolar coagulation | PULMONARY EMBOLISM, BLEEDING, DELAYED WOUND HEALING, THROMBOSIS, JOINT INFECTION, EXSANGUINATION, DVT | All procedures were strictly standardized in accordance with preoperative tranexamic acid (TXA), general anesthesia, postoperative pain management, and rehabilitation regimen. Prior to surgery and immediately before skin incision, TXA (1 g) and cefuroxime (1.5 g) were administered intravenously. Following joint capsule suturing, an intra-articular injection of TXA (2 g) was given. Moreover, TXA (0.5 g) was given 3 and 6 h postoperatively, with two doses of cefuroxime (1.5 g) administered within 24 h postoperatively. Thrombosis prophylaxis was achieved using low-molecular-weight heparin calcium (40AXaIU/kg per day) during hospitalization. Both groups underwent appropriate thigh tourniquet application, limb exsanguination through elevation for 2 min, and cuff inflation to 250 mmHg just prior to skin incision.Knee implants were utilized in the experiment where the PEEK group consisted of the post-stabilized fixed-bearing knee from Suzhou SinoMed Biomaterials Co., Ltd. in Jiangsu, China (Fig. The complete peek knee system, including femoral component, tibial component, polyethylene liner, and patellar componentThe cementation was performed in two stages, with the tibia being implanted first, followed by fixation of the femoral component using another batch of cement. This approach allowed for adequate time to achieve meticulous cementation with proper pressurization. Following cementation, further pulse lavage debridement was carried out to eliminate cement debris from the wound. Upon closure of the joint capsule, the cuff was deflated and bipolar coagulation was utilized to halt bleeding in the subcutaneous vessels. Postoperative rehabilitation and pain management were standardized for both groups and adhered to a uniform protocol that included full weight-bearing.The depth of the cement penetration was assessed using the method described by Pfitzner et al. [Anteroposterior and lateral radiographs with six zone cement mantle measurementsIn this study, the postoperative knee score was assessed by the use of Knee Society Score (KSS), which includes both knee clinical score and functional score, and survivorship at 1 year after surgery. Pain intensity was measured using the visual analogue scale (VAS) on a scale ranging from 0 to 10, both pre-operatively and at 1 year postoperatively during full weight-bearing mobilization of the patients. Any incidences of postoperative delayed wound healing, periprosthetic joint infection (PJI), pulmonary embolism (PE), DVT, periprosthetic joint fracture (PJF), and radiolucent lines (RLLs) was recorded and analyzed. | PMC10410788 |
Statistical analysis | Sample size was based on earlier studies, in which the priori power analysis was undertaken for an unpaired Student’s t-test, α at 0.05 and β at 0.2, i.e., Power (1 − β) or 0.8. A difference of 0.75 mm in the mean cement penetration between each group was determined to be clinically relevant. With a two-sided test, 58 patients were required. With a one-sided test, a loss of 12 patients could be tolerated [ | PMC10410788 | ||
Results | DEEP-VEIN THROMBOSIS, COMPLICATIONS | A total of 55 patients were enrolled in the trial, with 48 (37 males and 11 females) completing the study, as depicted in Fig. Flowchart of included participantsComparison of baseline information and surgical information between the two groupsThere was no statistically significant difference in mean cement penetration on postoperative X-rays between the PEEK group (2.49 ± 0.61 mm) and the CoCrMo group (2.53 ± 0.68 mm) (Comparison of thickness of mean cement penetration between the two groupsBox and whisker plot of mean cement mantle. Whiskers represent range, boxes represent 25th and 75th percentile, line represents medianHowever, knee clinical scores, functional scores, and visual analog scale (VAS) scores at 1-year postoperative did not show any statistically significant differences between the PEEK group and CoCrMo groups (Comparison of knee clinical outcomes between the two groupsNo patient was readmitted or underwent revision surgery. Out of all patients, three in the PEEK group and 6 in the CoCrMo group were diagnosed with deep-vein thrombosis, but no statistically significant difference was found between the groups (Comparison of complications 1 year after surgery between the two groups | PMC10410788 | |
Discussion | knee arthroplasty, fatigue, TKA | COMPLICATIONS | This study showed that the application of PEEK prostheses in primary TKA produced comparable cement penetration as the traditional CoCrMo prostheses, while simultaneously offering similar short-term clinical and functional outcomes without increased complications. This indicates that PEEK knee prostheses are a safe and effective prostheses that can provide excellent patient prognosis.Between 2012 and 2021, the American Joint Replacement Registry (AJRR) collected data on 122,852 revision total knee arthroplasty (TKA) procedures, revealing that mechanical loosening of the prosthesis was the second-most common reason for knee revision surgery, accounting for 24.0% of cases [As a copolymer compound, PEEK exhibits superior properties compared to metals, including reduced allergenicity, lighter weight, greater fatigue resistance, and chemical resistance [Besides, several studies have investigated the performance of PEEK in different orthopedic implants using various testing methods and have reported positive findings regarding PEEK's mechanical properties, technical outcomes, and safety [In this study, limited research had been reviewed on PEEK knee implants that has been conducted to date. Recent studies that investigated the feasibility and mechanical performance of PEEK-based knee implants had been summarized. Du et al. [Ruiter et al. [Additionally, Cowie et al. [ | PMC10410788 |
Limitations | TKA | This study has several limitations. Firstly, this study presents a randomized controlled trial evaluating the cement penetration of the tibial component in TKA. However, the small sample size limits the analysis of the results. Secondly, only the cement penetration of the tibial component was analyzed, the femoral component cement penetration could not be assessed accurately on an anteroposterior radiograph, which is a limitation of the study. Further research is needed to investigate also the femoral component, with Roentgen Stereogrammetric Analysis potentially representing an effective tool to this aim. Thirdly, all surgeons were intraoperatively not blinded to the performed intervention. To reduce bias, the bone surface preparation, cement application, pressurization, and implantation of the components were standardized in both groups. Lastly, it should be noted that this study only evaluates cement penetration and cannot be extrapolated to TKA implant survivorship or longevity, further investigations evaluating the correlation between cement penetration and long-term outcomes of TKA implants are required. | PMC10410788 | |
Conclusions | prothesis | The PEEK knee prothesis can make a similar bone cement penetration satisfactory short-term clinical outcomes and safety compared to CoCrMo prothesis. Further studies are necessary to evaluate the potential benefits and long-term outcomes of PEEK TKA. | PMC10410788 | |
Acknowledgements | Not applicable. | PMC10410788 | ||
Author contributions | JM and SY contributed to the conceptualization and methodology. GZ and XS contributed to the validation and data curation. JW contributed to the data analyze and was a major contributor in writing the manuscript. All authors read and approved the final manuscript. | PMC10410788 | ||
Funding | Not applicable. | PMC10410788 | ||
Availability of data and materials | The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request. | PMC10410788 | ||
Declarations | PMC10410788 | |||
Ethics approval and consent to participate | The clinical and radiographic results, according to the ethical guidelines of the Helsinki Declaration, were approved by the Human Ethics Committee of Honghui hospital. Written informed consent was obtained from individual or guardian participants. | PMC10410788 | ||
Consent for publication | Not applicable. | PMC10410788 | ||
Competing interests | The authors declare that they have no competing interests. | PMC10410788 | ||
References | PMC10410788 | |||
Introduction | muscle contraction | STS | The aim of this study was to compare the effects of sit-to-stand (STS) training programs with 5 Muscle power is a key factor for the health and well-being of individuals, as it not only allows them to carry out daily physical activities (Muscle power is defined as the product of muscle contraction force and velocity, and its development involves both morphological and neural factors (The muscle quality index (MQI), which is computed using the sit-to-stand test (STS) time and a formula that accounts for anthropometric variables, body mass, and gravity, has recently been utilized as a way to evaluate muscular power (It is widely acknowledged that incorporating exercise into daily life is essential for maintaining good health (An alternative training option for this situation is to use STS as a training method, where an improvement in performance, balance, and strength has been demonstrated after STS interventions (We hypothesized that STS training would increase muscle function and produce adaptations in the architecture of the vastus lateralis muscle (VL) in sedentary adults. | PMC10349562 |
Materials and Methods | PMC10349562 | |||
Study design | RECRUITMENT, -20 | This was a three-arm, parallel-group, randomized trial. The study was conducted at the Basic Sciences Laboratory, Universidad San Sebastian, Valdivia, Chile. Recruitment was conducted through social media and email during the months of June, July, and August 2022. The study protocol was approved by the Scientific Ethics Committee of the University of Granada, Spain (2380/CEIH/2021) and of the Universidad San Sebastián, Chile (55-2021-20). It has also been registered in the Protocol Registration and Results System ( | PMC10349562 | |
Allocation | The principal investigator generated a randomization sequence using an Stata 17.0 with blocks of varying sizes that were combined randomly. The allocation was performed in a one-to-one ratio, and allocation concealment was ensured by using sealed envelopes. | PMC10349562 | ||
Blinding | Neither the participants nor the providers were blinded in this study.All participants were invited to a familiarization visit in the laboratory. During this visit, the descriptive, biometric, and medical variables were assessed for each participant. We also determined whether or not the participants met the inclusion criteria and did not meet the exclusion criteria. In addition, VL muscle architecture of the dominant lower limb was assessed.Synchronous and asynchronous work sessions were conducted. All training sessions, both synchronous and asynchronous, were meticulously designed and supervised. The synchronous sessions were directly supervised by the lead investigator, ensuring that rest times and training intensity were consistently controlled. For the asynchronous sessions, participants were previously familiarized with the components of the training, enabling them to manage rest times, maintain appropriate intensity levels, and ensure safety during their workout routines. To verify that the asynchronous sessions were being correctly performed by the participants, they were asked to submit a video of the session. On average, both types of sessions had a duration of 2.7 ± 2.4 min.Rest times were monitored to ensure the protocol was executed correctly, and a Borg CR-10 scale was used to assess perceived exertion ( | PMC10349562 | ||
Design of the investigation. | PMC10349562 | |||
Participants | acute myocardial infarction, acute neuromuscular or joint injury, fracture | ACUTE MYOCARDIAL INFARCTION, HYPERTENSION, STS | Statistical software (G*Power, v3.1.9.7; Heinrich-Heine-Universität, Düsseldorf, Germany) was used to calculate the sample size. A moderate effect size of 0.95, obtained from a previous study (The participants selected for this study met the following criteria: 18 years of age or older, sedentary, and able to perform STS independently. On the other hand, participants were excluded if they were professionally involved in sports or resistance training, had untreated hypertension, acute neuromuscular or joint injury, or had suffered an acute myocardial infarction or fracture in the last six months. Informed consent forms detailing the study information, which followed the principles of the Declaration of Helsinki, were obtained written from all participants prior to the start of the interventions. | PMC10349562 |
Primary outcomes | PMC10349562 | |||
Muscle function | STS | The Muscle Quality Index (MQI) was calculated using the formula proposed by Additionally, the relative mean STS power (W·KgRelative mean STS power = 0.9 × g × Height (0.5 × Chair height)/(Five STS time × 0.1). | PMC10349562 | |
Secondary outcomes | PMC10349562 | |||
Ultrasonography | In this study, ultrasound images were used to evaluate the muscle thickness (MT), pennation angle (PA), and fascicle length (FL) in each participant’s dominant lower limb. The probe was positioned on the longitudinal axis of the VL, and a linear B-mode probe with a frequency range of 7.5 10 MHz was used at a depth of 8 cm (Sonus, DUO LCP). The probe was coated with a water-soluble gel to prevent skin pressure. Participants were seated with their knees flexed at 90° and instructed to relax their muscles at the time of measurement and avoid exercise for 48 h before the assessment. Measurements were taken at 50% of the distance between the greater trochanter and lateral condyle of the femur, and three images were captured at each site during the evaluation sessions. ImageJ software (ImageJ 1.42; National Institutes of Health, Bethesda, MD, USA,) was used to process and analyze the images, and MT was measured as the average distance between the superficial and deep aponeuroses. PA was measured as the angle between the fascicle and deep aponeurosis, and FL was calculated using the following formula: FL= sin(y+90°) × MT/sin(180°−(y+180°−PA)), where y is the angle between the superficial and deep aponeurosis, and AP is the pennation angle ( | PMC10349562 | ||
Anthropometry | stature | Body composition was assessed using bioelectrical impedance tetrapolar analysis (Rice Lake Body Composition D1000-3; Rice Lake, WI, USA). The stature was measured using a portable stadiometer (SECA, Model 213, Hamburg, Germany to 0.1 cm). Leg length was measured manually using an anthropometric measurement protocol ( | PMC10349562 | |
Sit-to-stand test | The time required for participants to complete five repetitions of the stand-and-sit exercise was established. During the evaluation, participants were advised to perform the repetitions as swiftly as possible, with their arms crossed over their chests at shoulder level. Three sets of five repetitions were timed, with a 1-min rest interval between each set. The quickest time recorded was selected for further analysis ( | PMC10349562 | ||
Sit-to-stand training program | STS | During the first 4 weeks, the 5STS and 10STS groups performed the STS exercise three times per week. The 5STS performed three sets of five repetitions, and the 10STS three sets of 10 repetitions. A rest time of 30/60 s was considered for each set. During the last 4 weeks, the number of sets increased to five to continue progressing in the training. Importantly, participants were asked to perform each set of STS movements as fast as possible and against the clock. The rest times were monitored to ensure that the protocol was performed correctly, and a Borg CR-10 scale was used to assess perceived exertion ( | PMC10349562 | |
Statistical analyses | Descriptive data are presented as mean ± standard deviation, with normality verified using the Shapiro-Wilk normality test. Additionally, the intraclass correlation coefficient (ICC), the standard error of measurement (SEM), and the minimal detectable change (MDC) were calculated ( | PMC10349562 | ||
Results | PMC10349562 | |||
CONSORT diagram of eligibility and inclusion of participants. | PMC10349562 | |||
Characteristics of the participants. |
Values are shown as mean ± standard deviation. | PMC10349562 | ||
Muscle function | STS | The study revealed significant time and group interactions for the MQI and relative STS power after 8 weeks of intervention. Specifically, both the 5STS and 10STS groups showed significant improvements in these parameters, with no notable differences between them.When comparing the pre- and post-measurements for each group, all groups demonstrated an improvement in MQI. However, the improvements were more pronounced and significant in the 5STS and 10STS groups compared to the control group.In terms of relative STS mean power, both the 5STS and 10STS groups exhibited a significant increase at the end of the study period, while the control group did not show significant changes ( | PMC10349562 | |
Changes in muscle function. |
MQI, muscle quality index.= Significant change = Significant change | PMC10349562 | ||
Individual changes in functional performance. | PMC10349562 | |||
Muscle architecture | At the beginning of the study, no significant differences were detected among the 5STS, 10STS, and CG in any of the muscle architecture variables. Following the intervention, significant time × group interactions were observed for both MT and PA, but not for FL.When comparing the pre- and post-intervention measurements in each group, significant increases in MT were detected in both the 5STS and 10STS groups. Similarly, only the 5STS group showed a significant increase in PA. Conversely, in the 10STS group, while an increase in PA was observed, it was not significant. In all groups, a slight decrease in FL was noted, being more pronounced in the intervention groups, although these changes were not significant.As for the CG, no significant changes were recorded in any of the studied muscle architecture variables: MT, PA, and FL ( | PMC10349562 | ||
Changes in muscle architecture of VL. |
MT, muscle thickness; PA, pennation angle. FL, fascicle length; VL, vastus lateralis.= Significant change = Significant change | PMC10349562 | ||
Individual changes in VL muscle architecture. | MT, muscle thickness; PA, pennation angle; FL, fascicle length. | PMC10349562 | ||
Discussion | CONTRACTION, STS | The objective of this research was to compare the effects of five and 10 repetitions of STS training programs on muscle function and muscle architecture in sedentary adults. The main findings of the study were that both the five and 10 repetitions of STS programs over an 8-week period resulted in significant increases in the MQI and relative STS mean power. Additionally, adaptations in muscle architecture parameters were observed, including an increase in MT and PA. However, the increase in PA was significant only in the 5STS group. These findings suggest that STS, as a low-cost exercise, can improve the muscle function of sedentary individuals and promote adaptations in muscle architecture. It is important to note that this training program is also characterized by its time efficiency. These findings support the implementation of STS programs as a viable and efficient strategy to improve function and muscle architecture in sedentary adults.There are several methods to evaluate muscle quality (There was a significant increase in PA (5STS) and a slight, non-significant decrease in the FL intervention group. Previous studies found an increase in PA in response to concentric contraction training (Another parameter evaluated in this intervention was the adaptation of the VL in the MT, which increased significantly in both the intervention groups. This situation has been observed in response to different types of interventions. MT has been described as a valuable predictor of muscle strength during knee extension (In recent years, various interventions have been tested to examine their effects on health outcomes from low-energy cost routines. Data suggests that low-volume, high-load training can enhance strength (Exercise routines have been tested that interrupt sedentary time and improve insulin and glucose levels. (A limitation of the present study was the heterogeneity in the age of the population. Additionally, to complement the effectiveness of the intervention, additional measurements, such as dynamometric devices to assess strength and velocity, are needed. Another limitation of the study is the absence of an evaluator during the training sessions, which resulted in participants not receiving real-time feedback while performing the exercises to encourage them to complete each repetition at maximum speed. Furthermore, despite being a controlled trial, it was not blinded, as both participants and evaluators were aware of the study conditions and their assigned groups. This lack of blinding may have introduced biases in the data collection and analysis, as expectations and preconceptions could have influenced the results and their interpretation. Additionally, it is worth noting that the measurements of muscular architecture and subsequent analysis were conducted by the same evaluator. Therefore, caution is necessary when generalizing the findings of this study, and these limitations should be considered when interpreting the results. | PMC10349562 | |
Conclusions | STS | In conclusion, the results of this study suggest that STS training effectively improves muscle quality and generates adaptations in the AP and MT muscles. These findings are important to understand that although a low volume of training was used, the results were positive in the study population. This finding indicates the importance of encouraging the general population to engage in exercise, even with a seemingly low volume. However, further research is required to determine the ideal training volume. Additionally, it is essential to study its effects on functional variables that support improvement in daily activities and promote independence in the elderly population. | PMC10349562 | |
Supplemental Information | PMC10349562 | |||
Reporting checklist for randomised trial. | Click here for additional data file. | PMC10349562 | ||
Categorical Data. | Click here for additional data file. | PMC10349562 | ||
Study Data. | Pre and post intervention variables.Click here for additional data file.This article will be part of the Rodrigo Lizama-Pérez Doctoral thesis conducted in the Biomedicine Doctorate Program of the University of Granada, Spain. | PMC10349562 | ||
Additional Information and Declarations | PMC10349562 | |||
Competing Interests | The authors declare that they have no competing interests. | PMC10349562 | ||
Human Ethics | -20 | The following information was supplied relating to ethical approvals (The study protocol was approved by the Scientific Ethics Committee of the University of Granada, Spain (2380/CEIH/2021) and of the Universidad San Sebastián, Chile (55-2021-20). | PMC10349562 | |
Clinical Trial Ethics | -20 | The following information was supplied relating to ethical approvals (The study was conducted at the Basic Sciences Laboratory, Universidad San Sebastian, Valdivia, Chile. The study protocol was approved by the Scientific Ethics Committee of the University of Granada, Spain (2380/CEIH/2021) and of the Universidad San Sebastián, Chile (55-2021-20). | PMC10349562 | |
Data Availability | The following information was supplied regarding data availability:The raw measurements are available in the | PMC10349562 | ||
References | PMC10349562 | |||
Abstract | HIV exhibit immune dysfunction | CHRONIC INFLAMMATION | The anti‐diabetic drug metformin may promote healthy aging. However, few clinical trials of metformin assessing biomarkers of aging have been completed. In this communication, we retrospectively examined the effect of metformin on epigenetic age using principal component (PC)‐based epigenetic clocks, mitotic clocks, and pace of aging in peripheral monocytes and CD8People living with HIV exhibit immune dysfunction, chronic inflammation, and heightened signs of biological aging captured by epigenetic clocks. Here, we performed a post hoc cell‐type specific epigenetic age analysis of monocytes and CD8
| PMC10776116 |
INTRODUCTION | diabetes | DIABETES | Metformin is an FDA‐approved diabetes drug impacting aging biology (Barzilai et al., | PMC10776116 |
RESULTS AND DISCUSSION | First, we examined epigenetic clocks of monocyte cells from a 24‐week clinical trial of 12 participants (time since HIV diagnosis ranged from 13 to 29 years) that were randomized 1:1 to receive either adjunctive metformin (500 mg extended release increasing to 1000 mg at Week 4 until 24 weeks) or observation. The study design of the retrospective analysis of a 24 week adjunctive metformin clinical trial is shown in Figure Epigenetic clock estimates in monocytes (a) Overview of 24 week clinical trial (b, c) Monocyte subsets did not significantly differ in participants in the metformin and observation arms. (d) PCGrimAge was significantly decreased in the metformin arm, We observed no significant differences in the percent of total monocytes, classical CD14Next, we utilized the DNAm dataset to examine whether metformin impacted monocytes DNAm mitotic clocks constructed from CpGs that map to gene promoters marked by the polycomb repressive complex 2 (PRC2) in human embryonic stem cells that estimate the relative stem cell division rate (Beerman et al., We next retrospectively examined epigenetic age of CD8Epigenetic clock estimates in CD8Observational epigenetic clock studies have reported conflicting metformin results on reducing epigenetic aging estimates (Li et al., In summary, this brief report suggests adjunctive metformin in PLWH reduces mortality‐based epigenetic clocks in monocyte cells, potentially impacting accelerated and or accentuated aging—a major concern for PLWH due to increased age‐related comorbidities. It is crucial to further investigate metformin's cell‐type specific effects on monocytes through clinical trials. This report's limitations include a small sample size and the absence of follow‐up after metformin therapy to assess the durability of epigenetic clock changes in short‐lived monocyte cells. Our findings highlight the importance of pursuing more geroscience interventions that target biological aging in PLWH who stand to gain the most benefits and incorporating epigenetic clocks in clinical trials of metformin for aging to provide valuable insights into assessing treatment effects, understanding mechanisms, and longitudinal monitoring. | PMC10776116 | ||
AUTHOR CONTRIBUTIONS | Michael J. Corley and Lishomwa C. Ndhlovu conceived, designed and carried out experiments. Alina PS Pang contributed to data analysis and interpretation. Cecilia M Shikuma contributed biological specimens and clinical data. Michael J. Corley and Lishomwa C. Ndhlovu drafted the manuscript. All authors critically reviewed and edited the final version of the manuscript. | PMC10776116 | ||
FUNDING INFORMATION | L. C. N. and M.J.C. were supported during the draft of the manuscript in part by the National Institutes of Health (NIH) grant number UM1AI164559. | PMC10776116 | ||
CONFLICT OF INTEREST STATEMENT | L.C.N. reports grants from the NIH and has received consulting fees from work as a scientific advisor for AbbVie, ViiV Healthcare, and Cytodyn and for service on the Board of Directors of CytoDyn and has financial interests in Ledidi AS, all for work outside of the submitted work. All other authors declare no competing interests. | PMC10776116 | ||
Supporting information |
Figure S1:
Click here for additional data file. | PMC10776116 | ||
ACKNOWLEDGMENTS | AIDS | AIDS | We gratefully acknowledge the study participants and the Hawaii Center for AIDS (HICFA) clinical study staff who made this work possible. We acknowledge support from Annette Jones at the UH Cancer Center for DNA methylation profiling of all samples. | PMC10776116 |
DATA AVAILABILITY STATEMENT | The data from this study was submitted to the NCBI Gene Expression Omnibus (GEO) | PMC10776116 | ||
REFERENCES | PMC10776116 | |||
Methods | RESPIRATORY FAILURE | In an open-label, single site randomized controlled trial (RCT), hospitalized COVID-19 patients were assigned to adjunctive Aggrenox (Dipyridamole ER 200mg/ Aspirin 25mg orally/enterally) with standard of care treatment compared to standard of care treatment alone. Primary endpoint was illness severity according to changes on the eight-point COVID ordinal scale, with levels of 1 to 8 where higher scores represent worse illness. Secondary endpoints included all-cause mortality and respiratory failure. Outcomes were measured through days 14, 28, and/or hospital discharge. | PMC9886260 | |
Results | Respiratory failure | RESPIRATORY FAILURE | From October 1, 2020 to April 30, 2021, a total of 98 patients, who had a median [IQR] age of 57 [47, 62] years and were 53.1% (n = 52) female, were randomized equally between study groups (n = 49 Aggrenox plus standard of care versus n = 49 standard of care alone). No clinically significant differences were found between those who received adjunctive Aggrenox and the control group in terms of illness severity (COVID ordinal scale) at days 14 and 28. The overall mortality through day 28 was 6.1% (3 patients, n = 49) in the Aggrenox group and 10.2% (5 patients, n = 49) in the control group (OR [95% CI]: 0.40 [0.04, 4.01], p = 0.44). Respiratory failure through day 28 occurred in 4 (8.3%, n = 48) patients in the Aggrenox group and 7 (14.6%, n = 48) patients in the standard of care group (OR [95% CI]: 0.21 [0.02, 2.56], p = 0.22). A larger decrease in the platelet count and blood glucose levels, and larger increase in creatinine and sodium levels within the first 7 days of hospital admission were each independent predictors of 28-day mortality (p < 0.05). | PMC9886260 |
Conclusion | respiratory failure, COVID illness | RESPIRATORY FAILURE | In this study of hospitalized patients with COVID-19, while the outcomes of COVID illness severity, odds of mortality, and chance of respiratory failure were better in the Aggrenox group compared to standard of care alone, the data did not reach statistical significance to support the standard use of adjuvant Aggrenox in such patients. | PMC9886260 |
Data Availability | All relevant data are within the paper and its | PMC9886260 | ||
1 Introduction | deaths | VIRUS, INFLAMMATION, ADHESION, CORONAVIRUS, SEVERE ACUTE RESPIRATORY SYNDROME | A novel coronavirus was first reported in December 2019 and declared an international pandemic by the World Health Organization (WHO) on March 11, 2020. Approximately, 18–19 months later, more than 250 million cases have been confirmed resulting in over 5 million deaths [COVID-19 is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a single-stranded, positive-sense RNA virus belonging to a group of Antiplatelet therapy has provided another avenue of great interest to reduce platelet adhesion and aggregation, which is a major consequence of COVID-19 induced renin-angiotension system (RAS) activation [Utilization of a therapy that can simultaneously intervene along multiple pathways (i.e: viral replication, inflammation, vasoconstriction, and coagulation) may provide an important mechanism to improve patient outcomes. One particular agent, Thus, we hypothesized that | PMC9886260 |
2 Methods | PMC9886260 | |||
2.1 Study design and participants | myocardial infarction, SARS-CoV-2 infection, angina, fever, shock, sub-valvular aortic stenosis, cough, hypoxemia | MYOCARDIAL INFARCTION, SARS-COV-2 INFECTION, SHOCK, ASYMPTOMATIC SARS-COV-2 INFECTION, BILATERAL PULMONARY INFILTRATES, GASTRIC OR DUODENAL ULCER, BLEEDING DISORDER, S; HEMOGLOBIN, G6PD DEFICIENCY | This study was a two-arm, open-label, single site randomized controlled trial (RCT) conducted in an urban academic medical center in New Jersey, United States of America. FDA-approval was obtained for exemption from Investigational New Drug Application (IND) to conduct a clinical investigation with the drug Aggrenox (Dipyridamole ER 200mg/ Aspirin 25mg). A placebo group was not included in the current study given the ethical concerns of the authors for not providing treatment for COVID-19 hospitalized patients especially when FDA approved drugs existed at the time of study [All the patients included in this trial were admitted to the hospital during the 2Adult patients (aged ≥18 years) who were hospitalized for suspected symptomatic SARS-CoV-2 infection with a high clinical suspicion for COVID-19 (fever and cough for ≤ 7 days, bilateral pulmonary infiltrates on imaging or new hypoxemia with spO2 ≤94% on room air or no alternative explanation for respiratory symptoms) were eligible for inclusion in the study. Patients required a positive laboratory test for SARS-CoV-2 infection within 3 days of hospitalization. Patients were then excluded based on the following criteria: pregnancy; history of G6PD deficiency; antiplatelet agents including inhibitor of P2Y12 ADP platelet receptors, phosphodiesterase inhibitors, and glycoprotein IIB/IIIA inhibitors; therapeutic anticoagulation with coumadin, unfractionated or low molecular weight heparin, and direct oral anticoagulants; vasodilatory shock; known ongoing angina, recent myocardial infarction and sub-valvular aortic stenosis; active gastric or duodenal ulcer or any bleeding disorder or creatinine clearance < 10; hemoglobin <9 mg/dL, platelet count of <30,000 /mm | PMC9886260 |
Randomization and masking | CRF | CRF | Participants were randomly assigned to receive either adjunctive Aggrenox treatment along with standard of care (SOC) (Aggrenox group) or SOC (control group) alone in a 1:1 ratio using random permuted blocks. The randomization sequence was concealed from study staff and was integrated into the REDCap electronic data capture system built to record the study’s patient data by the study biostatistician. Patients were assessed daily while hospitalized and outcomes were examined through days 14, 28, and/or discharge. A COVID-19 baseline electronic case report form (eCRF; as available on the WHO website for COVID-related studies) was completed at admission and the daily core CRF were completed on subsequent days for the duration of hospitalization. Patients and health care providers were not masked to study group assignment. | PMC9886260 |
Procedures | Patients in the Aggrenox group received Aggrenox (dipyridamole ER 200mg and aspirin 25mg), 2 times daily for a total of 2 weeks along with the SOC treatment. Standard of care treatment consisted of an intravenous Remidesivir 200 mg loading dose and then 100 mg daily for a total of 4 days for non-intubated patients and 10 days for intubated patients, intravenous/oral decadron 6 mg daily for 10 days and prophylactic subcutaneous LMWH daily, started on the day of enrollment and for the duration of hospitalization. If the patients were discharged before 10 days, they were prescribed oral decadron 6 mg daily to complete the course of 10 days. Patients in the control group only received SOC treatment as described above. No patients enrolled in this study received other experimental antivirals or immunomodulators used for COVID-19. Thus, regardless of randomization, all patients were treated according to the SOC protocol at the time of the study for COVID-19 according to the state of New Jersey.Follow-up visits were completed through phone-calls on day 14 | PMC9886260 | ||
Outcomes | death, CPD, HTN, respiratory failure, CVD, Respiratory failure, diabetes | CVD, RESPIRATORY FAILURE, HTN, SECONDARY, RESPIRATORY FAILURE, DIABETES | The primary study outcome was change in composite COVID-ordinal scale (S1 Table in The secondary study outcomes included all-cause mortality and/or respiratory failure through days 14, 28, or final follow-up, compared between the study groups. Respiratory failure was defined as those requiring high-flow oxygen therapy, noninvasive ventilation, invasive ventilation, and/or death (levels 5–8 on COVID ordinal scale) per prior published studies [Laboratory markers including hemoglobin, WBC, lymphocytes, neutrophils, hematocrit, platelets, ALT/SGPT, bilirubin, AST/SGOT, glucose, BUN, creatinine, sodium, potassium, CRP, d-dimer, ferritin, lactate dehydrogenase, and other independent risk factors (CPD, diabetes, CVD, HTN, Aids/HIV, Smoking status) were also assessed and compared between study groups. | PMC9886260 |
2.2 Statistical analysis | ±, respiratory failure | REGRESSION, RESPIRATORY FAILURE, SECONDARY, EVENT | A sample size of 132 patients (66 patients per arm) was estimated to provide 90% power, while a sample size of 100 patients (50 patients per arm) was estimated to provide 80% power, to detect a relative between-group difference of 20% reduction in composite ordinal scale (from baseline to day 14) with an assumption of a mean ± standard deviation composite ordinal scale value of 4.5 ± 1.6 at baseline and two-sided alpha value of 0.05.All baseline patient demographics, presenting symptomology, comorbidities, recent medication usage, and clinical outcome risk factors were summarized using range, mean and standard deviation (SD), and median with interquartile range (IQR) for continuous measures, or as frequencies with percentages for categorical measures. In order to compare these measures between the two treatment groups, Pearson Chi-Square and Fisher Exact tests were used for categorical measures, while independent student t-tests were used for normally distributed continuous measures, and Wilcoxon Rank Sum tests were used for ordinal and non-normally distributed continuous measures. Normality was assessed using Shapiro-Wilk and Kolmogorov–Smirnov testing along with visual inspection of quantile-quantile plots. Patient discharge measures, laboratory values, and primary and secondary outcomes were analyzed in the same way prior to any multivariable analyses.To further assess the primary and secondary outcomes, multivariable regression models were used. In order to examine the change in the composite COVID ordinal scale from baseline to day 14 and day 28, multivariable linear regression was used. For the patients’ raw COVID ordinal scale measure at day 14 and day 28, ordinal multivariable logistic regression was used. However, due to the small number of patients who belonged to most of the levels at both time points, the proportional odds assumption was violated. Therefore, these models were built using an unequal slopes assumption (for non-proportional odds), and results were summarized as odds ratios with 95% confidence by cumulative scale level. Additionally, due to low event rates, multivariable logistic regression with Firth’s penalized likelihood was used to model both all-cause mortality and respiratory failure at days 14 and 28, and results were summarized as odds ratios with 95% confidence intervals [In addition, Kaplan Meier curves were used to plot all-cause mortality at day 14, day 28, and overall. Log Rank tests were used to determine whether there were significant differences between the curves for the two treatment groups. All statistical analyses were completed using SAS software version 9.4 (SAS Institute Inc., Cary, NC, USA) and R version 4.1.1 (R Foundation for Statistical Computing, Vienna, Austria), where a two-sided p-value < 0.05 was considered statistically significant. | PMC9886260 |
3 Results | PMC9886260 | |||
3.1 Demographics and presenting symptoms | From October 1, 2020 to April 30, 2021, a total of 98 patients with RT-PCR confirmed COVID-19 were enrolled and randomized equally between study groups (n = 49 per group). See consort flow diagram for details on enrollment and analysis ( | PMC9886260 | ||
Consort 2010 flow diagram. | PMC9886260 | |||
3.2 Primary outcome | CPD, HTN, CVD, diabetes | CVD, REGRESSION, HTN, DIABETES | Based on univariate analyses, both groups demonstrated statistically similar mean (SD) changes on the 8-point COVID ordinal scale of increasing illness severity through day 14 (Aggrenox: 2.3 (1.8) vs control: 2.1 (2.0); p = 0.74) and day 28 (Aggrenox: 2.5 (1.7) vs control: 2.0 (2.2), p = 0.24). More specifically, the majority of patients (82.7%) in both study groups improved from days 1 to 14 (Aggrenox: 41 vs control: 40), more patients in the control group got worse (Aggrenox: 4 vs control: 6), and all other patients showed no change (n = 7, 7.1%). Similar trends were demonstrated when analyzing data through day 28, where 85.7% of patients improved from baseline (Aggrenox: 44 vs control: 40) and 10.2% of patients got worse (Aggrenox: 4 vs control: 6), while 2 patients (4.1%) in the control showed no change and 1 patient in each group (2.0%) was removed due to missing data. These data are presented in S2 Table in After controlling for other potential risk factors including: comorbidities (CPD, diabetes, CVD, HTN, Aids/HIV, Smoking status), DBP at baseline, recent use of NSAIDS and oral steroids, and baseline lab values (hemoglobin, WBC, lymphocytes, neutrophils, hematocrit, platelets, ALT/SGPT, bilirubin, AST/SGOT, glucose, BUN, creatinine, sodium, potassium, CRP, d-dimer, and ferritin, lactate dehydrogenase) there was no significant difference in the change in the composite COVID ordinal scale from baseline to day 14 and day 28 based on the treatment group (p = 0.32 and p = 0.31, respectively). After removing the lab value predictors which caused a large drop in sample size due to missing data, treatment group was still not a significant predictor of change in the composite COVID ordinal scale from baseline to day 14 (p = 0.23). However, for the day 28 linear regression model without lab values, treatment group was marginally significant in the full model (β = 0.86, p = 0.07) (S4 Table in Again, the multivariable ordinal logistic models for patients’ raw COVID ordinal scale measure at days 14 and 28 showed no significant differences between the treatment groups for all cumulative COVID scale levels (all p = 1.0); however, the models failed to fully converge even after allowing for uneven slopes (non-proportional odds). After applying both an uneven slopes assumption and stepwise selection methods to pair the model down to only treatment group, plus any remaining significant factors, only treatment group remained in both the day 14 and day 28 outcome models. When comparing those who received Aggrenox versus the control group in terms of illness severity at day 14, there were no significant differences for those who recovered and could resume normal activities versus everyone else (OR [95% CI]: 0.46 [0.14, 1.43], p = 0.18); those who were discharged versus those who were not (OR [95% CI]: 0.33 [0.08, 1.32], p = 0.12); those who were discharged or were still in the hospital without requiring oxygen versus those who required therapies or died (OR [95% CI]: 0.29 [0.06, 1.49], p = 0.14); those who were discharged or were still in hospital with or without oxygen only versus those who required more involved therapies or died (OR [95% CI]: 0.21 [0.02, 1.87], p = 0.16); those who were discharged or were still in hospital with or without only noninvasive therapy versus those who required invasive therapies or died (OR not estimable, p = 0.99); those who were discharged or were still in hospital with or without pulmonary therapy only versus those who required additional organ support or died (OR not estimable, p = 1.0). However, when comparing all surviving patients versus those who died, there was a significant difference (OR [95% CI]: 11.75 [1.29, 107.10], p = 0.03), suggesting that patients on Aggrenox have significantly higher odds of being alive versus dead on day 14. No significant differences were found between those who received Aggrenox and the control group in in terms of illness severity at day 28 (OR [95% CI]: 1.62 [0.52, 4.96], p = 0.40; 1.88 [0.51, 6.89], p = 0.34; 1.74 [0.39, 7.75], p = 0.47) when comparing those who recovered and could resume normal activities versus everyone else, those who were discharged versus those who were not, and all surviving patients versus those who died, respectively. | PMC9886260 |
3.3 Secondary outcomes | death | The overall mortality rate was 11.2% (n = 11). Univariate analyses suggested non-significant differences between study groups for the outcome of all-cause mortality, although less patients in the Aggrenox group died compared to the control group (Aggrenox: 4 vs control: 7; p = 0.34). Furthermore, while not statistically significant, Kaplan-Meier analyses visually suggest an increasing trend of later death in the control group as day 28 was approached ( | PMC9886260 | |
Overall K-M Mortality (a), day 14 (b) and day 28 (c). | obesity, death, respiratory failure, CVD, CPD, diabetes | OBESITY, CVD, RESPIRATORY FAILURE, REGRESSIONS, DIABETES | A total of 11 (11.2%) patients experienced respiratory failure, defined as those requiring high-flow oxygen therapy, noninvasive ventilation, invasive ventilation, and/or death (levels 5–8 on COVID ordinal scale). Most of the patients who experienced respiratory failure were in the control group (Aggrenox: 4 vs control: 7), but these data failed to reach statistical significance on univariate analyses (p = 0.34). When controlling for possible risk factors including age, sex, obesity status, and comorbidities (CVD, CPD, diabetes, smoking status), multivariate analyses demonstrated non-significant differences between Aggrenox and the control group on the outcome of respiratory failure through day 14 (OR [95% CI]: 0.49 [0.07, 3.51], p = 0.48) and through day 28 (OR [95% CI]: 0.21 [0.02, 2.57], p = 0.22). Multivariate regressions for mortality and respiratory failure are shown in S3 Table in | PMC9886260 |
3.4 COVID-19 related complications | acute renal injury, liver dysfunction, Disseminated intravascular coagulation | COMPLICATIONS, DISSEMINATED INTRAVASCULAR COAGULATION | The median [IQR] duration of hospital stay was 6 [4, 9] days, which was similar between groups (p = 0.45). A total of 12 patients were admitted to the ICU or high dependency unit (Aggrenox: 5 vs control: 7, p = 0.88), which lasted a median of 2 [1, 5] days. All patients required some form of oxygen therapy, which lasted a median of 5 [4, 9] days and was similarly represented between study groups (p = 0.82). The oxygen therapy mostly consisted of non-invasive ventilation in 26.5% of patients (Aggrenox: 12 vs control: 14, p = 0.15) compared to invasive ventilation in 9.2% of patients (Aggrenox: 4 vs control: 5, p = 1.00). All other patients (64.3%) received oxygen therapy with nasal cannula only. The maximum oxygen flow volume received in patients was statistically similar between study groups (p = 0.36).The most common complications included liver dysfunction among 21.4% of patients (Aggrenox: 9 vs control: 12, p = 0.54) and acute renal injury among 14.3% of patients (Aggrenox: 5 vs control: 9, p = 0.71). Disseminated intravascular coagulation occurred in only 3 patients, all of which were in the control group (6.1%). Additional antibiotics were required in a total of 17.3% of patients (Aggrenox: 5 vs control: 12, p = 0.14). These data are presented in S4 Table in | PMC9886260 |
3.5 Study drug-related adverse and SAEs | ADVERSE EVENTS, SECONDARY | No adverse or serious adverse events secondary to the study drug were seen in patients in the experimental treatment group. | PMC9886260 | |
3.6 Inflammatory markers for illness severity | respiratory failure | RESPIRATORY FAILURE, DECREASED LYMPHOCYTES | Inflammatory markers at patient presentation (day 1) which correlated with increased mortality through day 28 include decreased lymphocytes and platelets, as well as increased D-dimer, creatinine, C-reactive protein (CRP), urea, troponin, potassium, lactate dehydrogenase (LDH), and blood glucose levels. Patients that had a higher risk of 28-day mortality had a greater magnitude of change from day 1 to day 7 in decreased platelets, decreased blood glucose, increased creatinine, and increased sodium. Further values are represented in the S6 Table in Inflammatory markers at patient admission (day 1) which correlated with increased respiratory failure through day 28 included: decreased lymphocytes and platelets, as well as increased D-dimer, white blood cell counts, blood glucose, urea, lactate, creatinine, procalcitonin, CRP, LDH, and troponin. Patients that had a higher risk of 28-day respiratory failure had a greater magnitude of change from day 1 to day 7 in decreased platelets, increased total bilirubin, and increased potassium levels. Further values are represented in the S7 Table in There were no statistically significant differences in any inflammatory markers between the Aggrenox and control groups on univariate analyses (S8 Table in | PMC9886260 |
4 Discussion | death, critically ill, respiratory failure, stroke, venous thromboembolism, reduced overall illness, platelet aggregation | PERIPHERAL ARTERIAL DISEASE, CRITICALLY ILL, RESPIRATORY FAILURE, STROKE, DISEASE, COVID-19 INFECTION, ADHESION, EVENTS, COMPLICATIONS, INFLUENZA | In this RCT involving 98 hospitalized patients with confirmed COVID-19, an FDA-approved standard therapeutic-dose of Aggrenox in addition to the SOC treatment did not result in significantly reduced overall illness severity on the COVID ordinal scale, all-cause mortality, or respiratory failure as compared to the patients only receiving SOC treatment. Our results refute our hypothesis that use of Aggrenox as an adjunctive therapy improves outcomes for hospitalized SARS-CoV-2 infected patients at standard dose compared with SOC treatment alone. However, as fewer instances of these outcomes occurred in patients taking Aggrenox, additional studies utilizing adenosine augmenting therapies appear warranted in the treatment of COVID-19 moving forward.Our overall hypothesis is primarily based on the scientific premise that dipyridamole (DIP) increases extracellular adenosine, a potent immunoregulatory nucleoside that interferes with inflammatory processes by modulating the biosynthesis and release of proinflammatory cytokines, slowing down the oxidative activity, preventing platelet aggregation, and reducing neutrophils adhesion and degranulation. Specifically, DIP blocks intracellular uptake of extracellularly- generated adenosine thereby increasing extracellular adenosine. This results in the up-regulation of adenosine A2A receptors (A2AR) signaling which exerts anti-inflammatory and anti-thrombotic effects through cAMP [COVID-19 induces venous and arterial micro- and macrothrombotic events resulting in complications such as venous thromboembolism, peripheral arterial disease and stroke [ATTAC-19 is the first RCT to investigate the role of Aggrenox in improving patient outcomes after COVID-19. Our results showed that in patients hospitalized with COVID-19, Aggrenox was not associated with statistically significant reductions in 28-day mortality or in the risk of progressing to invasive mechanical ventilation or death. Therefore, results from the current trial do not justify the additional use of Aggrenox on top of SOC practice for hospitalized COVID-19 patients.A number of potential hypotheses may explain our results. First, despite the controversial results demonstrated in the recent literature on in-hospital aspirin, earlier use of anti-inflammatory and anti-platelet drugs, such as Aggrenox at the beginning of symptoms may be more beneficial for moderately to critically ill patients. Preexisting aspirin prescription among COVID-19-positive veterans was found to result in a statistically and clinically significant decreases in overall mortality at 14-days (OR [95% CI]: 0.38 [0.32,0.46] and at 30-days (OR [95% CI]: 0.38 [0.33, 0.45]) [Secondly, although DIP has demonstrated the ability to indirectly reduce many of the pathogenic mechanisms of COVID-19 in other settings, such as influenza [Currently, improving vaccination rates remains the most effective method of preventing widespread viral dissemination and global morbidity and mortality due to COVID-19 infection. However, emerging data demonstrates waning immunity just 6 months after vaccination, illustrating the importance of continuing to identify prognostic markers of disease severity for earlier interventions and resource allocation as well as further examination of possible drug therapies [ | PMC9886260 |
4.1 Limitations | respiratory failure, deaths | RESPIRATORY FAILURE | The ATTAC-19 trial is not without its limitations. It is important to mention the current trial did identify a decrease in respiratory failure and all-cause mortality for the Aggrenox group compared to SOC alone, despite these data not reaching statistical significance. For instance, Aggrenox resulted in nearly half the number of deaths compared to the control group (n = 4 vs 7). Unfortunately, one patient could not be contacted in the Aggrenox group despite repeated efforts. It is possible that with additional patients, this difference would become statistically significant. The sample size for the current study was acquired with the goal to detect a relative between-group difference of 20% reduction on the COVID-19 ordinal scale discussed above. Twenty percent reduction was chosen to determine the sample size as we included only hospitalized patients ranging from COVID-ordinal scale 4 to 7 and we considered that a 1-point change in patient’s COVID-ordinal scale would be a significant improvement in hospitalized patient’s clinical status, such as improving from invasive ventilation to non-invasive ventilation. Previous larger studies have varied in their methods to plan an appropriate sample size which could detect a meaningful intervention effect, and there has been a lack of standard methods across trials especially given the lack of historical data for COVID-19 treatments which could inform these analyses. Other trials also examining ordinal scale outcomes have include larger percent reductions between groups (eg, 40%) [The current study was an open-label, single site design and thus is inherently subject to ascertainment bias on the outcome of respiratory failure and also a possible selection bias. While we believe that it was clinically evident which patients indeed required high flow oxygen or some form of non-invasive/invasive ventilation therapy, and therefore did not likely interfere with our results, it is possible that our sample represented a different group of patients compared to that of the general population. Other studies have reported much higher mortality rates during similar study periods [ | PMC9886260 |
5 Conclusion | RESPIRATORY FAILURE | Adjuvant Aggrenox therapy was not associated with significantly reduced illness severity, respiratory failure, or all-cause mortality in hospitalized COVID-19 patients as compared with standard of care treatment alone. While these outcomes were numerically reduced in patients on both Aggrenox and SOC treatment, there is currently insufficient evidence to justify the standard use of adjuvant Aggrenox treatment in hospitalized patients with COVID-19. | PMC9886260 | |
Supporting information | Yesenia | (DOCX)Click here for additional data file.(PDF)Click here for additional data file.We thank Roxanne Nagurka, Randall Teeter, Nancy Reilly, Olga Kovalenko and Yesenia Sanchez from the clinical research unit to help coordinate different research activities. We also thank Roxanne Nagurka and Yesenia Sanchez to help gather the data along with the authors. Their help was critical in the successful completion of this project. | PMC9886260 | |
References | PMC9886260 |
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