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Changes in field perspective from pre- to post-intervention | A Bayesian repeated measures ANOVA was used for the total number of specific-field memories (across both remoteness conditions) with time (pre-and post-intervention) as a within-subjects factor, and group (LKM, colouring) as the between-subjects factor. An analysis of residuals confirmed the assumptions of linearity. Results were inconclusive regarding a main effect of time, BF10 = 1.90, and group, BF10 = 0.91, and regarding an interaction between time and group, BF10 = 0.57, contrary to our hypothesis.A further Bayesian repeated measures ANOVA was performed on the total number of specific-field memories across both remoteness conditions using valence (positive, negative, neutral, and other) and time (pre- and post-intervention) as within-subjects factors, and group (LKM, colouring) as a between-subjects factor. Results were inconclusive regarding a main effect of time, BF10 = 0.71, and group, BF10 = 0.60, while there was a significant main effect of valence, BF10 = 4.84x10 | PMC10306223 | ||
Changes in specificity mediated by changes in self-discrepancies | The current study expected LKM to reduce self-discrepancies thus LKM was expected to impact features of AM retrieval via self-discrepancies. Mediation analyses were therefore performed below. Due to the small sample size for mediation analyses, bootstrapping was used with 5,000 bootstrapping samples and 95.0% confidence intervals for all the following mediation analyses.A mediation analysis was conducted with the change in specificity as the outcome variable and change in focused self-discrepancies (from post- to post-self-discrepancy induction) as the predictor variable. Neither the LKM group, F(1, 23) = -1.52, p = 0.14, nor the colouring group, F(1, 23) = -0.63, p = 0.53 revealed significant mediation results.Another mediation analysis was conducted with the change in specificity as the outcome variable and change in experienced self-discrepancies (from post- to post-self-discrepancy induction) as the predictor variable. Neither the LKM group, F(1, 23) = -0.71, p = 0.49, nor the colouring group, F(1, 23) = -0.17, p = 0.87 revealed significant mediation results. | PMC10306223 | ||
Changes in positive memory retrieval mediated by changes in self-discrepancies | A mediation analysis was conducted with the change in positive-specific memory retrieval as the outcome variable and change in focused self-discrepancies (from post- to post-self-discrepancy induction) as the predictor variable. Neither the LKM group, F(1, 23) = 2.39, p = 0.06, nor the colouring group, F(1, 23) = -0.22, p = 0.83 revealed significant mediation results; however, a trend for significance was observed in the LKM group.Another mediation analysis was conducted with the change in positive-specific memory retrieval as the outcome variable and change in experienced self-discrepancies (from post- to post-self-discrepancy induction) as the predictor variable. Neither the LKM group, F(1, 23) = -1.87, p = 0.08, nor the colouring group, F(1, 23) = 0.96, p = 0.33 revealed significant mediation results; however, a trend for significance was observed in the LKM group. | PMC10306223 | ||
Changes in field perspective mediated by changes in self-discrepancies | A mediation analysis was conducted with the change in retrieval of specific-field memories as the outcome variable and change in focused self-discrepancies (from post- to post-self-discrepancy induction) as the predictor variable. Neither the LKM group, F(1, 23) = -0.31, p = 0.76, nor the colouring group, F(1, 23) = -1.00, p = 0.33 revealed significant mediation results.A final mediation analysis was conducted with the change in retrieval of specific-field memories as the outcome variable and change in experienced self-discrepancies (from post- to post-self-discrepancy induction) as the predictor variable. Neither the LKM group, F(1, 23) = -0.32, p = 0.75, nor the colouring group, F(1, 23) = 0.02, p = 0.98 revealed significant mediation results. | PMC10306223 | ||
Discussion | depression, depressed, depressive symptoms | EVENTS | Previous work has examined the impact of self-compassion on a variety of cognitive processes associated with depressogenic thinking. The current study extends this work to examine if a loving-kindness meditation can influence autobiographical memory patterns in remitted depression when negative thinking about the self is deliberately activated. The current study aimed to assess whether a brief LKM, in comparison to a colouring practice, would influence features of AM retrieval (specificity, remoteness, vantage perspective, valence) after inducing cognitive reactivity in remitted depression. We further aimed to identify whether baseline tendencies in a remitted depressed sample would show more remote as opposed to recent memory retrieval and whether positive-specific memories would be retrieved more remotely than recently.The effects of both interventions on depressive symptoms and characteristics were assessed. Changes in negative affect (DASS), depression (DASS depression), and self-compassion (SCS) over time were inconclusive and there were no significant group differences in changes in negative affect or depression. However, results regarding group differences in changes in self-compassion were inconclusive. Alternatively, while rumination (RRS), experienced self-discrepancies, and focused self-discrepancies did improve over time, results were inconclusive regarding differences in improvement between groups.Findings supported our hypothesis that total memory specificity would increase over time in the LKM group only. However, an anomalous finding was also observed where rumination positively correlated with specificity and both specificity and rumination improved over time. This finding might be due to the sample desiring to perform well on the AMT possibly as a result of the Covid-19 pandemic. For example, it might be that due to drastic pandemic-related changes in teaching methodology at the university, participants had higher levels of perfectionism that resulted in better performance (i.e. specificity) on the AMT while negative affect remained higher and self-compassion remained lower. While this is speculative, as measures of perfectionism were not obtained, the relationship between rumination and specificity might vary depending upon personality factors which could be a further consideration in future studies. Despite this surprising correlation, specificity at baseline was low in this sample overall, consistent with previous literature [Our hypothesis that the LKM group would retrieve more positive-specific memories over time in comparison to the colouring group was not supported given results were inconclusive. While LKM might have altered the way events were perceived, such that memories previously perceived as neutral could have been shifted to a positive valence, the colouring practice might have distracted participants from more negative memories, making positive memories more readily available. Further analyses were inconclusive regarding greater increase in recent positive-specific than remote positive-specific memories in the LKM group (free-recall condition). Although this does not support our hypothesis, given the LKM group did not show a baseline tendency to retrieve more remote positive-specific memories, this finding is not surprising.Further, results were inconclusive regarding the retrieval of more specific-field memories over time and regarding a group interaction, contrary to predictions. Moreover, it was unclear whether an increased retrieval of positive-field memories depended upon group. Given literature has demonstrated a tendency for healthy samples to use field perspective for positive memories and observer perspective for negative memories [At baseline, it was hypothesised that more remote memories would be retrieved than recent memories given a focus on self-discrepancies was activated; however, this prediction was not supported. Although cognitive reactivity was successfully induced, it might be that focused self-discrepancies were not sufficiently high to necessitate retrieval of remote memories to distance oneself from recent memories that painfully highlight current discrepancies. While the current study did not compare remoteness tendencies of the remitted depressed sample to that of a never-depressed sample, our remitted sample did reveal a similar average age of memories to that found in dysphoria [A trend in significance for self-discrepancies to mediate the changes in retrieval of positive-specific memories was revealed in the LKM group only. However, changes in self-discrepancies were not found to mediate changes in specificity or retrieval of specific-field memories in the LKM group contrary to expectations. Given the number of Bayes Factors that indicated inconclusive data however, it could be that data are too uncertain to draw conclusions about self-discrepancies mediating changes in specificity or specific-field memories. At this point, it is unclear what mechanisms of LKM influenced changes in features of AM retrieval. Thus, the next steps in line with this research would be to focus on elucidating mechanisms of change.Our findings have implications for developing treatments to alter features of AM retrieval in remitted depression and reducing a cognitive vulnerability to depression. The current study demonstrated significant improvement in specificity, valence, and vantage perspective, whereas previous treatments have largely focused on single or dual features of AM retrieval in interventions. For example, Memory Specificity Training (MEST) explicitly teaches participants in group sessions [ | PMC10306223 |
Limitations and future research | depression | There were limitations to the current study that should be considered when interpreting our results. Our sample was exclusively drawn from a university student population, decreasing the generalizability of our findings to clinical settings. However, it should be pointed out that depression is very prevalent in this population [Another limitation was the choice of procedure for the AMT. Although previous studies have successfully employed written versions of the task [A further limitation was our definition of remote memories as being over one year old. Previous literature has applied varying boundaries of remoteness from one [In conclusion, findings in the current study provide initial insights into the effects of LKM on impaired features of AM retrieval in remitted depression. LKM has been identified as a potential intervention to increase retrieval of specific, positive, and field memories in remitted depression. The current study further shows that LKM can act as a buffer for the effects of AM when cognitive reactivity is induced by a self-discrepancy task. It will be important to compare the effectiveness of LKM and MEST for example. Current models, such as MEST, train specificity with the aim that when stress is encountered, increased specificity will remain; however, MEST does not address the issue of cognitive reactivity and does not influence emotions which can generate memories. Further, future studies including fMRI would allow us to understand the neural basis of self-compassion and the neural effects of LKM on AM retrieval. Future research should also examine whether LKM can influence tryptophan as well as other biological factors, such as cortisol, and the impact of influencing these factors on features of AM retrieval. Our findings necessitate research in the field of self-compassion practices to converge with AM retrieval in current and remitted depression. | PMC10306223 | |
Consent to participate | Digital informed, written consent was obtained from all individual participants included in the study. Participants were informed that participation in the study was voluntary. | PMC10306223 | ||
Consent to publish | Participants provided informed, written consent regarding publishing their data. | PMC10306223 | ||
References | PMC10306223 | |||
Abstract | autoimmune diseases | AUTOIMMUNE DISEASES | High sodium concentration alters leukocyte activation, and in particular T‐helper (Th) lymphocyte polarization, and drives the development of autoimmune diseases in mouse studies. Similar results have been obtained with human leukocytes under The effect of habitual Western diet and salt‐reduced diet on the levels of systemic blood cytokines was analyzed in a placebo‐controlled nutritional intervention study. The results showed that reduced salt intake did not alter the concentrations of any of the analyzed 34 cytokines in blood. Our data show that marked real‐word changes in the diet can take place without any significant reflections on the systemic cytokine mileu in humans.
| PMC10100453 |
Introduction | pro‐inflammatory | The nutritional and immune status are closely intertwined in humans [Sodium is another nutrient which not only regulates the blood pressure, but is also thought to have direct pro‐inflammatory and autoimmune disease‐inducing effects on the immune system [No study, to our knowledge, has examined the effect of salt intake on cytokine concentrations in a placebo‐controlled, intervention study setup. Therefore, our aim was to utilize unique samples available from a dietary cross‐over intervention study to assess the effect of the salt intake (and diet) on systemic cytokine concentrations under clinically relevant settings | PMC10100453 | |
Results | PMC10100453 | |||
Salt intervention in a cross‐over setup is effective | BLOOD | In this double‐blinded, placebo‐controlled study 106 participants were randomized to Habitual and Healthy Nordic (berries, vegetables and fish enriched) diets, and further to Usual Sodium and Reduced Sodium intake groups (Figure The study design. The numbers of participants included at each step of the study, the interventions (Healthy Nordic Diet vs. Habitual Diet and Usual Sodium Diet vs. Reduced Sodium Diet), and the timing of randomizations and cross‐overs are indicated on the flow chart.Baseline characteristics of participants by randomization groupAbbreviations: BMI, body mass index; BP, blood pressure; dU, daily (24‐hour) urinary.The recommended sodium intake is below 2.3 g/d, which corresponds to 5.75 g salt [Twenty‐four hours urinary sodium excretion. The estimated dietary salt (NaCl) intake (mean of the indicated group) corresponding to the measured 24 h sodium excretion rates are shown at the baseline before randomization to different Salt diets (week 4), after the first salt intervention period (week 12) and in the end of the study (week 20) in the different groups. Blood samples for the cytokine measurements were drawn at the same time points. | PMC10100453 | |
Performance of the multiplexed cytokine measurements | Out of the 45 cytokines measured, we excluded for the statistical analyses the 11 cytokines (IL‐1α, IL‐5, IL‐9, IL‐10, IL‐21, IL‐22, IL‐31, IFN‐α, TNF‐β, EGF, and VEGF‐D), in which >50% of the measurements remained under the detection limit of the multiplex assay (Table | PMC10100453 | ||
High salt intake does not alter cytokine levels | pro‐inflammatory | At the time of randomization to Healthy Nordic Diet and Habitual Diet there were no significant differences in the level of any tested cytokine between the two groups (data not shown) verifying the validity of the randomization. The cytokine measurements at the time of cross‐over and at the end of the study showed that Reduced Sodium Diet vs. Usual Sodium Diet did not have any significant effect on the circulating cytokine concentrations. Notably, the Usual Sodium Diet did not increase any of the measured signature cytokines for Th1 (IFN‐γ, IL‐12), Th2 (IL‐4, IL‐13), or Th17 (IL‐17, IL‐23) lymphocytes (Figure The effects of diet interventions on pro‐inflammatory interleukins. The effect of (The effects of diet interventions on systemic cytokine concentrations. The effect of ( | PMC10100453 | |
Similar cytokine concentrations during the different diet interventions | pro‐inflammatory | We finally determined weather berries, vegetables and fish enriched Healthy Nordic Diet would exert anti‐inflammatory effects on the cytokine levels. Analyses of the samples from the three time points (baseline, cross‐over and end of the study) showed that the Healthy Nordic Diet did not significantly affect the concentrations of Th‐signature cytokines, pro‐inflammatory cytokines, chemokines or other cytokines (Figures | PMC10100453 | |
Discussion | autoimmune disease, hypertensive | AUTOIMMUNE DISORDERS, AUTOIMMUNE DISEASE | The results from our clinical study show that the diet (fish and vegetable enriched Healthy Nordic Diet) or reduced salt intake does not change the levels of circulating cytokines in humans. We find the placebo‐controlled cross‐over study design, objective measurement of sodium excretion and relatively long duration (8+8 wk interventions) as strengths of our study. The provocative results on the salt‐induced Th2 and Th17 expansion, and their association with aggravated autoimmune reactivity in mice, thus seem not to be directly translatable into humans under physiologically relevant in vivo settings.The reasons for the discrepant results between our study and those using mouse models may include genuine species‐specific differences in electrolyte metabolism and immune cell activation. Moreover, in the in vivo mouse experiments the animals have been suddenly exposed to chow, which contains 4–5% salt [A few studies have reported salt‐induced changes in cytokine secretion in humans under in vivo settings. In a spaceflight stimulation study (an enclosed habitat) six healthy males were subjected to fixed salt intake (daily doses of 12 g, 9 g, and 6 g salt; about 50 days under each condition) in a context of a very carefully controlled diet. Analyses of plasma TNFα, IL‐6, IL‐10 and IL‐17 did not reveal statistically different changes during the different salt ingestion phases [Mediterranean diet is consistently found to lower the systemic levels of pro‐inflammatory biomarkers [Our study has several limitations. It includes a relatively small and heterogeneous group of mildly hypertensive individuals. The power calculations were done for the primary end point (blood pressure) and therefore higher number of participants would have increased the power of several cytokine analyses, although the cross‐over setup (each individual serving as her/his own control) is a clear strength in our study. Moreover, we cannot exclude the possibility that longer (or shorter) alterations in salt or diet would have altered cytokine levels. However, in other studies other types of dietary interventions have resulted in detectable alterations in cytokine levels in less than 8 weeks (e.g., [In conclusion, our data suggest that increased salt intake at the levels seen in everyday life do not affect systemic cytokine levels in humans. Therefore, salt induced changes in cytokines are unlikely to induce the differentiation of pathogenic Th2 and Th17 responses in humans. These observations have important implications in immunology and medicine, since they do not support the literature proposing that increased salt intake might precipitate the emergence of autoimmune disease or that restricting salt intake would be a therapeutic option for treating autoimmune disorders. | PMC10100453 |
Materials and methods | PMC10100453 | |||
Participants and the design of the trial | hypertensive, diabetes, gastrointestinal disease, allergies | CARDIOVASCULAR DISEASE, ALLERGIES | Previously untreated mildly hypertensive men and women (45‐77 years) living in Southwestern Finland were screened from individuals, who had earlier participated in a national FINRISK 2007 health survey [The subject could be included in the study if mean resting systolic blood pressure was 140–160 mmHg or a diastolic blood pressure was 90–100 mmHg. The participants filled in questionnaires for medical history. Individuals who were vegetarians or smoked, or with regular medication or vitamin use, cardiovascular disease, diabetes, gastrointestinal disease, fish allergies, a body mass index higher than 35 kg/mParticipants included in the study first entered a 1‐week period during which they practiced maintaining a low sodium diet with a goal of 5 grams of salt per day (Figure The study flow chart (CONSORT 2010) is given in Figure | PMC10100453 |
Measurements and cytokine analyses | leukemia, tumor necrosis, TNF‐α | BLOOD, TUMOR NECROSIS, LEUKEMIA | Blood pressure, weight, and height were measured, and 12‐hour fasting blood samples were taken before randomization at the screening visit (0 weeks) and at the 4‐, 12‐ and 20‐week visits. EDTA‐plasma was separated from the blood using standard procedures. In addition, a 24‐hour urine collection was performed before the 1‐, 4‐, 12‐ and 20‐week visits. Plasma and urine samples were frozen and stored at –70°C until assayed.Daily urinary sodium excretion was determined using an ion‐selective electrode (Optima analyzer, Thermo Electron Oy, Vantaa, Finland). Based on the measured 24 h urinary sodium (U‐Na) excretion rate we calculated the estimated daily salt (sodium chloride, NaCl) intake using a formula NaCl (g/24h) = U‐Na (mmol/24h)x58.44×0.001.The concentrations of 45 cytokines were measured from previously unthawed plasma samples using antibody‐based magnetic bead kits (Procarta Plex, Thermo) for multiplexed protein quantification according to the manufacturer's instructions. The cytokines analyzed were: interleukins (IL) IL‐1α, IL‐1β, IL1‐RA (receptor antagonist), IL‐2, IL‐4, IL‐5, IL‐6, IL‐7, IL‐8, IL‐9, IL‐10, IL12p70, IL‐13, IL‐15, IL‐17A, IL18, IL‐21, IL‐22, IL‐23, IL‐27, IL‐31, interferons (IFN) IFN‐α, IFN‐γ, tumor necrosis factors TNF‐α, TNF‐β, chemokines CCL2, CCL3, CCL4, CCL5, CCL11, CXCL1, CXCL10, and CXCL12, and growth factors bNGF (nerve growth factor beta), EGF (epidermal growth factor), FGF‐2 (fibroblast growth factor‐2), HGF (hepatocyte growth factor), LIF (leukemia inhibitory factor), SCF (stem cell factor), BDNF (brain‐derived neurothrophic factor), GM‐CSF (granulocyte‐macrophage colony stimulating factor), PDGF‐BB (platelet derived growth factor‐BB), PlGF1 (placental growth factor), VEGFA (vascular endothelial growth factor A), and VEGFD.All measurements and analyses were done blinded to the intervention allocation of the subject. The baseline and follow‐up samples were always analyzed in one analytical run. | PMC10100453 |
Interventions | PMC10100453 | |||
Statistical analysis | SE | For the statistical analyses, we only included the 34 cytokines in which >50% of the measurements remained within the detection limit (Supplementary Table Baseline comparisons between the Healthy Nordic Diet and Habitual Diet groups were made with a The data are given as mean (SE) values with 95% confidence intervals for the mean changes. We used P = 0.001 as the level of significance to account for the number of cytokines (0.05 divided by 34). All statistical analyses were conducted with SAS version 9.4 (SAS Institute, Cary, NC). | PMC10100453 | |
Conflict of interest | The authors declare no commercial or financial conflict of interest. | PMC10100453 | ||
Ethics approval statement for human studies | The study was conducted according to the latest revision of the Declaration of Helsinki and was approved by the Ethical Committee of the Social Insurance Institution of Finland. This work was supported by the Emil Aaltonen Foundation [to T.N.], the Paavo Nurmi Foundation [to T.N.], the Finnish Medical Foundation [to T.N.], the Finnish Foundation for Cardiovascular research [to T.N.] and Academy of Finland [321351 to T.N.; 129479 to I.E., 141136 to S.J. and M.S.]. | PMC10100453 | ||
Patient consent statement | Informed consent was obtained from each participant of the study. | PMC10100453 | ||
Clinical trial registration | The study was registered at ClinicalTrials.gov as NCT01412346. | PMC10100453 | ||
Author contributions | I.E. and A.J. lead the intervention study. M.S. conceptualized the cytokine study. T.N., I.E., A.J., S.J., and M.S. performed investigation and data interpretation. T.N. performed statistical analyses. T.N. and M.S. wrote the manuscript. All authors have read and agreed to the published version of the manuscript. | PMC10100453 | ||
Peer review | The peer review history for this article is available at | PMC10100453 | ||
Abbreviations | necrosis | NECROSIS | C‐C chemokineC‐X‐C chemokinegrowth factorinterferoninterleukinT‐helpertumor necrosis factor | PMC10100453 |
Supporting information | Supporting InformationClick here for additional data file. | PMC10100453 | ||
Acknowledgments | The advice from Dr. Mikael Maksimow, Pauli Puukka and Tero Vahlberg and expert technical help from Ms. Teija Kanasuo are acknowledged. Companies Pakkasmarja Ltd, Raisio plc, Apetit plc and Vaasan Ltd are acknowledged for providing the foods for Healthy Nordic Diets. | PMC10100453 | ||
Data availability statement | The data that support the findings of this study are available on request from the Principal Investigators of the clinical study (A.J., I.E) pending on an application and approval by Finnish Institute for Health and Welfare. The data are not publicly available due to privacy or ethical restrictions. | PMC10100453 | ||
References | PMC10100453 | |||
Background | thalassemia, bone pain, fractures, osteoporosis | THALASSEMIA, OSTEOPOROSIS, COMPLICATIONS | Edited by: Rimesh Pal, Post Graduate Institute of Medical Education and Research (PGIMER), IndiaReviewed by: Pinaki Dutta, Post Graduate Institute of Medical Education and Research (PGIMER), India; Antonino Catalano, University of Messina, Italy†ORCID: Adisak Tantiworawit, With adequate blood transfusion and iron chelation, thalassemia patients have a longer life expectancy and experience long-term metabolic complications, including osteoporosis, fractures, and bone pain. Alendronate, an oral bisphosphonate, is currently used to treat various types of osteoporosis. However, the efficacy for the treatment of thalassemia-associated osteoporosis remains unclear. | PMC10210588 |
Methods | vertebral deformities, pain, vertebral fracture, thalassemia, osteoporosis | THALASSEMIA, SECONDARY, LOW BONE MINERAL DENSITY, OSTEOPOROSIS | We conducted a randomized controlled trial to evaluate the efficacy of alendronate for the treatment of osteoporosis in thalassemia patients. Patients were included if they were males (18–50 years) or premenopausal females with low bone mineral density (BMD) (Z-score < -2.0 SD) or positive vertebral deformities from vertebral fracture analysis (VFA). Stratified randomization was performed according to sex and transfusion status. Patients were 1:1 allocated to receive once weekly alendronate 70 mg orally or placebo for a total duration of 12 months. BMD and VFA were re-evaluated at 12 months. Markers of bone resorption (C-terminal crosslinking telopeptide of type I collagen; CTX) and bone formation (Procollagen type I N-terminal propeptide; P1NP), and pain scores were measured at baseline, 6 months, and 12 months. The primary outcome was the change of BMD. The secondary endpoints were changes in bone turnover markers (BTM) and pain scores. | PMC10210588 |
Results | A total of 51 patients received the study drug, 28 patients were assigned to receive alendronate and 23 patients to receive placebo. At 12 months, patients in the alendronate group had significant improvement of BMD at L1-L4 compared to their baseline (0.72 ± 0.11 vs 0.69 ± 0.11 g/cm | PMC10210588 | ||
Conclusion | thalassemia, pain | THALASSEMIA, OSTEOPOROSIS | Alendronate 70 mg orally once weekly for 12 months effectively improves BMD at L-spine, reduces serum BTMs, and alleviates back pain in thalassemia patients with osteoporosis. The treatment was well tolerated and had a good safety profile. | PMC10210588 |
Introduction | osteoporosis, anemia, Thalassemia | OSTEOPOROSIS, ANEMIA, THALASSEMIA | Thalassemia is a common cause of inherited anemia in Thailand with estimated 3,000 new cases each year (Alendronate is an oral bisphosphonate which is convenient, safe, and widely available. Alendronate is currently used for the treatment of postmenopausal, glucocorticoid-induced, and male osteoporosis ( | PMC10210588 |
Materials and methods | PMC10210588 | |||
Study design and participants | thalassemia, vertebral fracture, osteoporosis | OTHER HEMOGLOBINOPATHIES, SYNDROME, TAO, THALASSEMIA, OSTEOPOROSIS | We conducted a double-blind, randomized controlled trial to evaluate the efficacy of alendronate, compared with placebo, in patients with TAO. Eligible participants were ambulatory thalassemia patients aged 18–50 years (males) or more than 18 years (premenopausal females). Other hemoglobinopathies were allowed in case of compound heterozygosity with α- or β-thalassemia leading to clinically significant thalassemia syndrome. Patients had to be diagnosed with thalassemia-associated osteoporosis as defined by one of the following criteria, (i) a bone mineral density (BMD) Z-score of less than -2.0 SD at either the L1-L4 spine or the femoral neck on either side, measured by dual-energy X-ray absorptiometry (DXA; Hologic Discovery A, Hologic Company, Marlborough, MA, USA); or (ii) presence of vertebral deformity detected by vertebral fracture analysis (VFA; obtained in the supine position from T4 to L4 using the same machine as DXA). Key exclusion criteria were an estimated glomerular filtration rate of less than 30 ml per minute per 1.73 m | PMC10210588 |
Procedures | NTDT, diabetes mellitus | CHRONIC VIRAL HEPATITIS, HYPOGONADISM, DIABETES MELLITUS, HUMAN IMMUNODEFICIENCY VIRUS INFECTION, HEPATITIS C, HYPOTHYROIDISM | Eligible patients were 1:1 randomized to receive either alendronate at a dose of 70 mg orally once weekly or a placebo in the morning on an empty stomach for 12 months. Computer-generated block randomization was performed according to sex and dependency of red cells transfusion (TDT or NTDT), with a block size of 4. The details of the randomization list were only known and kept by a department’s research officer. Calcium carbonate (with elemental calcium of 600 mg per day, taken after lunch or dinner) and vitamin D2 20,000 IU per week supplementations were given to all participants.Patients were evaluated at baseline and every 3 months thereafter. At baseline, complete blood count and biochemical profile were measured, including calcium, phosphate, and vitamin D (as 25-hydroxy vitamin D) levels. Iron profile, in the form of serum ferritin, was measured. Patients were tested for chronic viral hepatitis B, hepatitis C, and human immunodeficiency virus infection. Tests for hypogonadism, hypothyroidism, abnormal parathyroid hormone, low insulin-like growth factor-1 (IGF-1) level, and diabetes mellitus were performed at baseline. Low IGF-1 was defined as less than the lower limit of normal IGF-1 level of that age and sex. Hormone replacement therapy was allowed during the study period. | PMC10210588 |
Outcomes | Pain, bone pain, pain, vertebral fracture, vertebral deformity | SECONDARY, VITAMIN D DEFICIENCY, TAO | Two bone turnover markers (BTMs), a marker of bone resorption (C-terminal crosslinking telopeptide of type I collagen; CTX) and a marker of bone formation (Procollagen type I N-terminal propeptide; P1NP) were measured at baseline, 6 months, and 12 months. Pain scores at back and bone were evaluated using the numeric rating scale (0 point = no pain; 10 points = worst pain possible) at baseline, 6 months, and 12 months. Bone pain referred to generalized bone pain. DXA with VFA was re-evaluated at 12 months to determine the changes in BMD and degree of vertebral deformity.The primary endpoint was the change of BMD at 12 months. Key secondary endpoints were the change of serum BTMs, back pain, and bone pain score at 12 months. The least significant change (LSC) was defined as more than 25% reduction of serum BTMs compared to baseline. The safety profile of the study drug was evaluated. Other outcomes were the prevalence of vertebral fracture and vitamin D deficiency among patients with TAO. | PMC10210588 |
Statistical analysis | We planned to recruit at least a total of 48 patients in order to detect the difference in mean BMD of 0.091 g/cmThe study was conducted with approval from the Institutional Research Ethics Committee at the Faculty of Medicine, Chiang Mai University (Ref. number 045/2018). This study was registered with the Thai Clinical Trial Registry, number TCTR20180219004. This study was supported by research grants from the Faculty of Medicine, Chiang Mai University (Grant number 026/2562), and the Thai Society of Hematology. | PMC10210588 | ||
Results | PMC10210588 | |||
Patients | fracture, hypogonadism, fractures, vertebral fracture, thalassemia, NTDT, osteoporosis | THALASSEMIA, EVENT, HYPOGONADISM, OSTEOPOROSIS | From a total of 106 thalassemia patients with osteoporosis in the Chiang Mai University Hematology outpatient clinic between January 2018 and September 2018, 60 patients were eligible and underwent randomization. Thirty-three patients were assigned to receive alendronate, while 27 were assigned to receive placebo. Six and four patients from the alendronate and placebo groups withdrew their consent, respectively. At 12 months, 27 patients in the alendronate group and 20 patients in the placebo group completed the follow-up visit and were included in the analysis (Study population flow.The baseline characteristics of patients were well-balanced (Patient characteristics.BMD, bone mineral density; BMI, body mass index; CBC, complete blood count; CTX, C-terminal crosslinking telopeptide of type I collagen; DFO, deferoxamine; DFP, deferiprone; DFX, deferasirox; HRT, hormone replacement therapy; IGF-1, insulin-like growth factor 1; IQR, interquartile range; P1NP, procollagen type I N-terminal propeptide; PRC, packed red cells; RBC, red blood cell; SD, standard deviation; VFA, vertebral fracture analysis; WBC, white blood cell.The mean serum vitamin D level was 30.2 ± 8.9 ng/ml, and 54.9% of patients had low serum vitamin D. Patients in the placebo group tended to have more hypogonadism but not statistically significant (14.8% vs 30.4%, p = 0.18). Low IGF-1 level was common among thalassemia patients with osteoporosis (54.9%).About 40% of patients had a history of trauma-related fracture, with a median age of 21 years (IQR 11 – 25) when they had the first fracture event. The prevalence of vertebral fractures among thalassemia patients with osteoporosis was 35.3%. Most patients were asymptomatic (11 of 18, 61.1%).Prespecified analysis comparing the characteristics between TDT and NTDT patients revealed that the TDT group had more patients with low IGF-1 level (73.5% vs 17.6%, p <0.001) compared to the NTDT group. In addition, patients in the TDT group had higher mean serum ferritin level (2,122 ± 1,310 vs 994 ± 502 μg/L, p < 0.001). TDT patients tended to have more hypogonadism than NTDT group (29.4% vs 11.8%, p=0.161). However, the mean BMD Z-score, levels of BTMs, and history of fractures were not statistically different between groups. | PMC10210588 |
Efficacy | PMC10210588 | |||
Bone mineral density and vertebral deformity | After 12 months of alendronate, there was a significant improvement in mean BMD at L1-L4 compared to baseline (0.72 ± 0.11 vs 0.69 ± 0.11 g/cmChanges in bone mineral density at 12 months.Data were presented as mean±SD; BMC, bone mineral content; BMD, bone mineral density. | PMC10210588 | ||
Bone turnover markers | After 12 months of the study drug, patients receiving alendronate had a significant reduction in serum CTX compared to baseline (0.32 ± 0.22 vs 0.57 ± 0.52 ng/ml, p = 0.002) (Changes in bone turnover markers; | PMC10210588 | ||
Pain scores | pain | The mean score of back pain was significantly reduced when compared to baseline in both groups (p = 0.003); however, there was no significant difference between groups (p = 0.222) (Changes in pain score; | PMC10210588 | |
Safety | bisphosphonate-related, fatigue, femur fracture | HYPOCALCEMIA, ADVERSE EFFECTS, SIDE EFFECTS, OSTEONECROSIS OF THE JAW | Side effects were rarely found. There was one patient who experienced grade 3 fatigue after administrating a single dose of alendronate, which led to drug discontinuation. No bisphosphonate-related adverse effects were found during the study period, including hypocalcemia, gastrointestinal side effects, osteonecrosis of the jaw, or atypical femur fracture. | PMC10210588 |
Discussion | fracture, hypogonadism, pain, fractures, vertebral fracture, thalassemia, beta-thalassemia, osteoporosis | HYPOGONADISM, OSTEOPOROSIS, ADVERSE EVENT, THALASSEMIA, BETA-THALASSEMIA, TAO | Currently, bisphosphonates are the mainstay of treatment of TAO, particularly the intravenous forms (Alendronate 10 mg once daily for 24 months has been shown to improve BMD only at femoral neck in 9 beta-thalassemia patients with hypogonadism who received hormone replacement therapy (HRT) (In addition to mean BMD improvement, fewer patients in the alendronate group had declined BMD at L1-L4 from their baseline (33.3% vs 50%). This suggests that although alendronate did not improve BMD in all patients, it helped slow the rate of BMD reduction. Since one-third of patients did not adequately respond to 12 months of alendronate, the longer treatment duration, switching to more potent anti-resorptive agents such as zoledronate (The efficacy of alendronate in the reduction of the risk of fracture has been shown regardless of the improvement in BMD among postmenopausal women (LSC was defined as the least significant change in bone marker level that results in clinical significance. It has been proposed that the LSC was approximately 25% for serum CTX and P1NP levels (The most commonly reported adverse event of alendronate is upper gastrointestinal tract side effects found in 41–47% among postmenopausal osteoporotic patients (Another important endpoint is back pain, which may affect patients’ quality of life. In previous studies, zoledronate significantly reduced bone pain in thalassemia with osteoporosis (Not all thalassemia patients with low BMD need pharmacological treatment. According to The ISCD 2013 Pediatric Official Positions (There were some limitations of this study. First, since the follow-up period is relatively short, it was unable to measure fracture rate as an important clinical outcome. Therefore, we also measured BTMs, which may correlate with fractures among patients receiving alendronate from the previous report. In addition, VFA after the study drug was also performed and no new vertebral fracture was found during the study period. Second, the number of patients in the study was relatively small. However, we recruited more than the expected sample size, and there was a low rate of incomplete follow-up (7.8%). Last, we did not collect the data on diet and physical activity of the participants which may affect the study outcomes. However, we prescribed calcium and vitamin D supplements to all participants to ensure the adequacy of these daily requirements while taking study drug. | PMC10210588 |
Conclusion | thalassemia, pain | THALASSEMIA, OSTEOPOROSIS | Alendronate 70 mg orally once weekly for 12 months is effective in improving BMD at L-spine, reducing serum BTMs, and alleviating back pain in thalassemia patients with osteoporosis. The treatment was well tolerated and had a rather good safety profile. | PMC10210588 |
Data availability statement | The data analyzed in this study is subject to the following licenses/restrictions: The data that support the findings of this study are available from the corresponding author, AT, | PMC10210588 | ||
Ethics statement | The studies involving human participants were reviewed and approved by the Institutional Research Ethics Committee at the Faculty of Medicine, Chiang Mai University (Ref. number 045/2018). The patients/participants provided their written informed consent to participate in this study. | PMC10210588 | ||
Author contributions | MP | Conceptualization, PP and AT. Methodology, PP, MP, WT and SS. Validation, PP and AT. Formal Analysis, PP and AT. Investigation, PP and AT. Data Curation, PP. Writing-Original Draft Preparation, PP and AT. Writing-Review & Editing, TR, SH, CC, ER, LN, KF, PC. Supervision, AT. Funding Acquisition, AT. All authors contributed to the article and approved the submitted version. | PMC10210588 | |
Acknowledgments | Antika | Authors would like to thank Ms. Antika Wongthanee, Former Head of Analytical & Statistical data unit, Research Institute for Health Sciences, Chiang Mai University for her suggestions regarding the statistical analysis in this study. | PMC10210588 | |
Conflict of interest | The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. | PMC10210588 | ||
Publisher’s note | All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher. | PMC10210588 | ||
References | PMC10210588 | |||
Glossary | PMC10210588 | |||
Abstract | PMC9838778 | |||
Background | SKIN | Medical Adhesive Related Skin Injuries can arise from topically applied medical devices, especially in those with fragile skin, including the elderly and premature infants. The purpose of this study was to compare gentleness and reapplication of two pulse oximetry sensors (OxySoftN and MaxN, Medtronic, Boulder, CO). | PMC9838778 | |
Materials and methods | water loss | Eighteen healthy subjects aged 65 years and older were enrolled in the gentleness trial, and 20 healthy subjects (18–69 years) were enrolled in the reapplication trial. For the gentleness trial, trans‐epidermal water loss (TEWL) measurements were made at five sites on each forearm at three time points (baseline [T0], 4‐h postinitial wear [T1], 4‐h postsecond wear [T2]). Total amount of protein adhered to each device was also determined. For the reapplication trial, a series of 180° peel tests were performed to observe the forces required to detach the sensor from the skin. | PMC9838778 | |
Results | TEWL rates in the tail region were significantly greater with MaxN compared to OxySoftN at T1 ( | PMC9838778 | ||
Conclusion | ADHESION | The OxySoftN sensor appears to be gentle, even on fragile skin, based on reduced strain on the skin during removal. Further, it demonstrated the ability to withstand several reapplications without functional loss in adhesion.
| PMC9838778 | |
INTRODUCTION | MARSI, skin injuries | SKIN | It is generally recognized that Medical Adhesive Related Skin Injuries (MARSI) are very common and can occur with any medical device that adheres to the skin. Elderly and premature infants are at particular risk for skin injuries based on their fragile skin.Pulse oximetry is a standard of care that is routinely used in the NICU on premature infants.Measurement of gentleness of an adhesive is based on measuring the disruption of the skin barrier. A consensus group of key opinion leaders recommends both trans‐epidermal water loss (TEWL) and the amount of protein removed as highly objective measures to clinically assess and document MARSI.The purpose of the current study was to compare the gentleness and reapplication of two pulse oximetry sensors, OxySoftN and MaxN (Medtronic, Boulder, CO). OxySoftN uses a new silicone‐based skin‐contacting adhesive, whereas MaxN uses an acrylic adhesive in the optical region and synthetic rubber adhesive in the tail region. The ability to reapply the sensor is characterized through peel force measurements on skin. The gentleness is characterized through TEWL and protein removal. Significant benefits were observed with the silicone‐based patient‐side adhesive. | PMC9838778 |
MATERIALS AND METHODS | Two studies comparing different attributes of OxySoftN and MaxN in a pair‐wise fashion were carried out on healthy volunteers and performed in accordance with the Declaration of Helsinki under protocols that were duly approved by an independent review board (Integreview IRB, Austin, TX).All volunteers were fully informed about the purpose of the study in which they were participating and the associated instrumental methods. Upon signing an informed consent document, they were instructed to stop the use of all potentially moisturizing products (lotions, sunscreens, insect repellants, etc.) on their arms for the 3 days prior to the study day. Upon arrival at the clinic, any hair within the test sites, which could interfere with the procedures, was removed using a gentle surgical prep clipper. Both volar forearms were then wiped with an alcohol swab and allowed to dry for at least 2 min before mapping out the test sites using a nontoxic marker. | PMC9838778 | ||
Participants | Eighteen (18) healthy subjects (five males and 13 females) were enrolled in the gentleness study. All were aged 65 years or older, with the assumption being that they might be more likely to have more fragile skin than those below age 65 years. | PMC9838778 | ||
Investigational products | The test products for both studies were provided by Medtronic (Boulder, CO). Both devices are pulse oximetry sensors that are very similar in design, consisting of an optical region that houses the sensor and an associated fabric tail, as shown in Figure Image of optical (outlined in orange) and tail (outlined in blue) regions on the OxySoftN sensor. OxySoftN uses a silicone‐based skin‐contacting adhesive. | PMC9838778 | ||
Procedures for gentleness study | Nelson | NELSON, CORTEX | This was a 1‐day study in which subjects remained at the clinic for approximately 10 h.TEWL measurements were made using a recently calibrated cyberDERM RG1 Evaporimeter System (Broomall, PA) with dual TEWL Probes that were manufactured by Cortex Technology (Hadsund, Denmark) and available in the US through cyberDERM, Inc. (Media, PA). All the measurements were performed in an environmentally controlled room with temperature at 20–22°C and relative humidity at 40%–60%. Measurements were taken after a 30‐min acclimatization period, with the test areas on the volar forearm fully exposed. The TEWL rate was calculated as the average value over a 20 s period after steady‐state conditions had been reached.Measurements were made on the five (5) sites that have been mapped out on each arm as labeled in Figure Physical location of the 10 labeled measurement sites with their specific designations. The red circles represent footprint of the paired trans‐epidermal water loss (TEWL) probes within each measurement area.TEWL measurements were taken at the following time points:
T0: Baseline (prior to the first application)T1: After 4 h of wear (1st application of devices)T2: After 4 h of wear (2nd application of devices)At T1, after the devices had been worn for approximately 4 h, the devices were manually removed and retained for reapplication for the second wear period. After the 30‐min post‐removal TEWL measurements were completed, the same devices were reapplied to the same sites as at the baseline visit. Approximately 25% of the MaxN sensors showed some signs of lifting while this never was a problem with the OxySoftN sensors. In a few cases, there were concerns that the MaxN device may become detached completely, and these sensors were replaced during the second wear period. At T2, the devices were again manually removed and then sent to Nelson Labs (Salt Lake City, UT), where the total amount of protein adhered to each device was determined using the Micro BCA | PMC9838778 |
Procedures for reapplication study | ADHESION, BENDING, BEND | This was a 1‐day study in which the subjects remained at the clinic for approximately 2 h.The computerized cyberDERM 180° peel tester (Figure The computerized cyberDERM 180° peel tester uses a stepper motor attached to uniaxial lead screw to pull the stressing clamp at a constant rate of 5.0 + 0.2 mm/s. A calibrated Imada Digital Force Gauge records the resulting tension at least one sample per mm tape peeled.The OxySoftN and MaxN devices were run in a pairwise fashion, with one being assigned to the lateral side and the other to the medial side of the forearm according to the randomized treatment map, with the optical sensor region always positioned toward the wrist as shown in Figure Devices were tested in a pairwise fashion, with random assignment to lateral or medial location of the forearm. The optical sensor region was always positioned toward the wrist. Peel tests alternated between right and left forearms, with the first peel test always starting on the lateral site of the right forearm, until 18 peels tests were completed.A nontoxic marker was used to place fiducial marks on the subject's skin to ensure the device was placed parallel to the major axis of the forearm. The subject's arm was then positioned within the Peel Test Apparatus such that the test site surface was in plane with the horizontal path that the clamp would take during the run. A micro projector attached to the apparatus overlaid an image of the peel traverse to ensure proper alignment. Extreme care was also taken to have the subject always have his fingers properly placed and arm fully extended so that the tension across the skin surface remained reasonably constant during the entire series of peels for that individual.One caveat with the 180° peel test is that observed forces arise not only from detaching the adhesive device from the skin but also from the device bending back upon itself. Since both test devices consist of a flexible lead strip and a stiffer section with electrodes, the observed plot, as shown in Figure An example plot of the differences in the amount of force required to remove the tail and optical regions of the device during the 180° peel test, due to differences in stiffness along the deviceAs the adhesive under the optical region is the same as the adhesive on the tail for both devices, the increase in values seen in the optical region is not an increase in adhesion but rather an increase in force of removal due to the work required to bend the stiff components. Nevertheless, we do want to analyze this portion of the peel test because the effectiveness of the device depends upon the optical sensors being firmly attached to the skin. Thus, in addition to confirming visually that the sensor is still firmly attached to the skin, we also determined the work required to remove the optical region by using the Riemann left sum as an approximation of the area under the curve within the optical region. | PMC9838778 | |
Statistical analysis | ADHESION | The data were processed using GraphPad statistical software. A two‐sided For the TEWL results, the appropriate values were pooled by individual subject to provide a mean value for the optical region and tail regions of the two sensors and the corresponding control for each time point. A repeated measure ANOVA with Tukey‐Kramer Multiple Comparisons Test was then run on the net change from baseline to determine the degree of significance at T1 and T2.For protein adhered to each device, a paired For the Peel Test, the appropriate values for the optical and tail regions were calculated from profiles obtained from both devices for each of the 18 serial cycles of removal and reattachment from each subject. These were then compiled, and the mean values plotted as a function of cycle number. The resulting trendlines, which show the dynamics of decreasing adhesion with increased number of reapplications, were analyzed for goodness of fit using the MS Excel toolbox. | PMC9838778 | |
RESULTS | PMC9838778 | |||
Gentleness | ± | Mean TEWL rates are summarized in Figure Mean trans‐epidermal water loss (TEWL) rates for the respective optical and tail regions of the OxySoftN and MaxN sensors at baseline and after the first 4‐h wear period (T1) or the second 4‐h wear period (T2)In comparing results from the optical region of the OxySoftN and MaxN sensors, it was found that at both T1 and T2, TEWL rates were significantly elevated with both devices compared to the control sites. However, no significant differences were found to exist between the two sensors at either time point.In comparing the results from the tail region of the OxySoftN and MaxN sensors, it was found that at T1, TEWL rates were significantly elevated for both the OxySoftN and MaxN sensors when compared to the control (In comparing the results obtained at T2 from the tail region, it was found that TEWL rates were significantly elevated only for the MaxN sensors when compared to the control (Further, the amount of protein removed was significantly less with the OxySoftN sensor compared to the MaxN sensor (1.3 ± 0.4 ug/ml vs. 10.1 ± 2.9 μg/ml, Interval plot comparing amount of protein adhered to the removed device. Samples for subject #16 were not suitable for measurement. The detection limit of the test was 1.2 μg/cm | PMC9838778 | |
Reapplication | ADHESION, DECAY, BEND | Successful completion of all 18 reapplication trials was seen with the OxySoftN sensor. However, in 60% of cases, the MaxN sensor lost adhesion prior to the 18th trial. To gain a better insight into this observation, we compiled the calculated values for the 18 sequential runs sorted by code for the 20 individuals who participated in this study. The group averages for each device obtained from the tail and optical regions were then plotted as a function of the sequential run number (Figures Mean peel force (g), as measured at the tail region, required to remove OxySoftN and MaxN sensors during the 180° peel test at each test run. The black solid line represents the mean peel force for each test run of the OxySoftN sensor. The dotted black line represents the decay trendline for the OxySoftN sensor. The gray solid line represents the mean peel force for each test run of the MaxN sensor. The dotted gray line represents the decay trendline for the MaxN sensor.Work required, as measured at the optical region, to remove OxySoftN and MaxN sensors during the 180° peel test at each test run based on area under the curve. The black solid line represents mean work for each test run of the OxySoftN sensor. The dotted black line represents the decay trendline for the OxySoftN sensor. The gray solid line represents mean work for each test run of the MaxN sensor. The dotted gray line represents the decay trendline for the MaxN sensor.It should be appreciated that interpreting the data obtained from the optical region is complicated, as factors other than the adhesion can impact the work required to remove the device from the skin. Chief among these is that this region contains the sensors, causing it to be stiffer, and thus more work is required to bend the region back on itself to achieve the 180° pull. Nevertheless, we feel that it is the loss of adhesion that is primarily responsible for the observed behavior. | PMC9838778 | |
DISCUSSION | ADHESION, DECAY | The silicone‐based adhesive of the OxySoftN sensor does not appear to disrupt the skin barrier function, as evidenced by the TEWL results. Although TEWL rates were significantly elevated in those sites to which either the OxySoftN or MaxN sensors were attached compared to the intact skin of the control sites, it is important to understand that the degree of change, although statistically significant, is clinically very modest and iin‐line with previous findings.The protein removal results also demonstrated that the OxySoftN sensor removes much less skin than the MaxN. The amount of protein removal was significantly different, and the real difference is probably even larger, as the OxySoftN fell below the detection limit of the test. Lower dilution ratios than those used here would increase the concentration of protein in the assay, potentially allowing for a lower detection limit of protein on future adhesives. The results from the protein assay demonstrate that the OxySoftN adhesive removed less skin than the MaxN sensor, corroborating the difference in TEWL seen between the two devices in the sensor region.Peel force testing demonstrated that the adhesive on the OxySoftN sensor far outlasts the MaxN sensor. The OxySoftN adhesive was able to reposition up to 18 times, whereas the MaxN lost adhesion more quickly. The decay rate of adhesion can be estimated through the fitted parameters. The adhesion of OxySoftN decayed by 1.1% per reposition for both the tail and optical region. The typical lifetime of an adhesive is 1–3 days. Assuming the sensor is removed and placed at a new site every 4 h, 18 reapplications would not be uncommon. Here, OxySoftN retained adhesion over 18 removals and, on average, decreased by approximately 20%. This would also suggest that limit for re‐adhering the OxySoftN sensor was not achieved, even at 18 repositions.The reapplication testing was completed in rapid succession and therefore did not have a 4‐h dwell time, as would be expected in the NICU. However, increasing the dwell time would likely not impact the results for OxySoftN but increase the decay rate for the MaxN. Traditional adhesives, such as the MaxN, exhibit increased peel forces and reduced reapplication with longer dwell times as the adhesive can flow and fully wet the skin.Skin‐contacting adhesives form physical bonds with the skin, which requires the adhesive to be in close contact with the skin. | PMC9838778 | |
Limitations | DECAY | The study was designed as an initial investigation into the benefits of a new silicone‐based patient‐side adhesive for pulse oximetry sensors. Gentleness of the adhesive was assessed on an elderly population with the intent to target fragile skin. However, no screening was performed on subjects to characterize fragile skin, and no age restrictions were used for the reapplication study. Further, pediatric patients were not included in the study population. The protein assay results for the silicone‐based adhesive were at the detection limit. Hence, the expected amount of protein removed by the silicone‐based adhesive would be lower than what was measured.The 180° peel test was used to assess reapplication. This testing assumes that stiffness is the same throughout the device backing. Although the stiffness between the optical and tail regions did differ, as seen in the bimodal peel profile, the adhesive coverage was uniform across the respective devices. Further, the decay curves for the tail and optical regions demonstrated the same dynamics.The sensor dwell time during the gentleness study was 4 h, timing that may be seen in the clinical setting. However, due to the time restraints of completing 18 reapplication trials, the dwell time of the sensors during this testing was only a few minutes. Clear differences between the two sensors were seen at six reapplications, demonstrating the superiority of the OxySoftN to MaxN in terms of reapplications. | PMC9838778 | |
CONCLUSION | DECAY | Silicone adhesive can be a good solution for strong, yet gentle adhesives that are repositionable. The current study demonstrates that the OxySoftN sensor made of silicone had greater repositionability and less skin removal compared to the traditional MaxN sensor with acrylic and synthetic rubber adhesives. TEWL shows that there was not damage to the skin barrier function during removal of the device. Protein removal results show that they are more sensitive to changes in adhesives than TEWL and that OxySoftN removes a significantly less amount of skin compared to MaxN. Reapplication results show that the decay curves of the adhesives are markedly different and that the OxySoftN can withstand 18 repositions to skin, potentially more. These three metrics combined show that the new adhesive is gentler, as well as having the ability to stay adhered to the patient for a larger number of repositions. | PMC9838778 | |
CONFLICT OF INTEREST | Jacob Dove and Derek Moody are employees of Medtronic. Other authors have no conflict of interest. | PMC9838778 | ||
ACKNOWLEDGMENTS | The authors thank Jonn Damia and Mary Louise Grove from cyberDERM for their support and efforts throughout study execution. Medical writing support was provided by Hanan Zavala of Medtronic (Minneapolis, MN) in accordance with Good Publication Practice (GPP3) guidelines. This study was funded by Medtronic. | PMC9838778 | ||
DATA AVAILABILITY STATEMENT | The data that support the findings of this study are available from the corresponding author upon reasonable request. | PMC9838778 | ||
REFERENCES | PMC9838778 | |||
1. Introduction | cardiometabolic diseases, cardiometabolic disease, autonomic dysfunction | DISEASE, HYPERGLYCEMIA, AUTONOMIC DYSFUNCTION, AUTONOMIC DYSFUNCTION, HEART | Heart rate variability (HRV) provides a simple method to evaluate autonomic function in health and disease. A reduction in HRV may indicate autonomic dysfunction and is strongly associated with aspects of cardiometabolic disease, including hyperglycemia. Reduced nitric oxide (NO) bioavailability is also implicated in the development of cardiometabolic disease and autonomic dysfunction. Watermelons are natural sources of L-arginine and L-citrulline, substrates used for NO synthesis. Watermelon consumption can improve NO bioavailability. We conducted a randomized, double-blind, placebo-controlled crossover trial to test the effects of 2 weeks of daily watermelon juice (WMJ) supplementation on HRV in response to an oral glucose challenge (OGC) in healthy young adults. We also performed indirect calorimetry to assess if our intervention altered the metabolic response to the OGC. WMJ supplementation preserved high-frequency power (HF) (treatment effect, Autonomic dysfunction is an emerging mechanism in the development of cardiometabolic disease [Deficits in energy expenditure and substrate utilization are also aspects of autonomic dysfunction that characterize cardiometabolic diseases. During meal feeding or insulin stimulation, hormonal and sympathovagal coordination regulates blood flow and metabolic flux. In healthy men, postprandial energy expenditure correlates with sympathetic nervous system activity [An oral glucose challenge (OGC) has been shown to reduce HRV in diverse patient populations [The loss of NO bioavailability and reduction in HRV during an OGC suggests that these phenomena may be causally linked. To date, no studies have explored the protective effects of NO donor therapy on hyperglycemia-induced autonomic dysfunction and metabolic function. In a randomized, double-blind, placebo-controlled crossover trial, we studied the effects of two weeks of WMJ supplementation on HRV and metabolic control during an oral glucose challenge (OGC). We hypothesized that increased NO bioavailability via WMJ supplementation would attenuate the decline in HRV during brief, transient hyperglycemia. We also sought to evaluate our intervention’s impact on metabolic parameters (energy expenditure and substrate oxidation) using indirect calorimetry. | PMC9967111 |
2. Materials and Methods | PMC9967111 | |||
2.1. Participants and Study Design | Before enrollment, eligible participants provided written and informed consent. Our participation criteria were based on age (18–40 years of age) with a BMI between 18 and 29.9 kg/m | PMC9967111 | ||
2.2. Oral Glucose Challenge (OGC) | glucose beverage | BLOOD | Participants arrived in the morning at approximately 6:30 AM in the fasted state and abstained from alcohol, exercise, and caffeine at least 48 h before the study visit. A baseline (0-min) blood sample was collected from a flexible intravenous catheter inserted into the antecubital vein of the left arm. After participants drank a 75 g glucose beverage (Glucola, Mercedes Scientific), blood samples were collected at 15, 30, 60, 90, and 120 min. Blood was collected for the catheter at each time point in an EDTA tube and centrifuged. Plasma glucose was then measured (Analox GL5, Analox Instruments Ltd., Stourbridge, United Kingdom). | PMC9967111 |
2.3. Heart Rate Variability (HRV) | A Zephyr BioHarness strap and BioModule sensor (Medtronic, Boulder, CO) were used to continuously monitor electrographic (ECG) and respiratory data at a sampling frequency of 1000 Hz. All participants were supine with free breathing for a stationary assessment of heart rate for 5 min. From this, the RR intervals were quantified, and HRV was determined (Kubios HRV, Version 3.4.1, Kuopio, Finland).HRV was analyzed in time and frequency domain measures [ | PMC9967111 | ||
2.4. Indirect Calorimetry | In conjunction with the oral glucose challenge, indirect calorimetry was performed using a ventilated hood (ParvoMedics, Inc., Sandy, UT) to determine the expired volume of oxygen (VO2) and carbon dioxide (VCO2). Briefly, participants arrived in a fasted state and were instructed to rest supine for 30 min with the lights dimmed to ensure a rested state. Then a ventilated hood was placed over the participant’s head and shoulders. Exhaled air was continuously measured for the 30 min preceding glucose ingestion (0 min) to measure resting energy expenditure (REE) and substrate oxidation. We repeated these measurements at the 60 min and 120 min time points. REE, RER, carbohydrate, and fat oxidation were calculated according to previously published equations [ | PMC9967111 | ||
2.5. Statistical Analysis | ± | REGRESSION | Distribution and normality were assessed by a Shapiro–Wilk test. A linear mixed model was used to assess differences between treatment, time points (0, 60-, and 120-min), and visit order (fixed effects). Subject ID was treated as a random effect. Time points, treatment, and interactions were adjusted for visit order and tested using a linear mixed effects model. Post hoc differences were determined by a Student’s t-test. A linear regression was performed to calculate Pearson’s correlation coefficient. Data are reported as means ± SD. Statistical significance was determined as a | PMC9967111 |
3. Results | PMC9967111 | |||
3.2. HRV | There were no significant treatment effects of glucose across time points ( | PMC9967111 | ||
4. Discussion | Hyperglycemia | HYPERGLYCEMIA, HYPERGLYCEMIA, DISEASE | Hyperglycemia attenuates HRV by reducing parasympathetic tone and/or increasing sympathetic nervous system activity [We confirm that in healthy young participants, an OGC reduces HRV, as evidenced by the reduction in SDNN, RMSSD, LF, HF, and TP (The OGC is also a metabolic perturbation that causes an increase in REE and a shift in substrate oxidation. In the fasted state, fat is the primary substrate utilized. In the postprandial state, increased plasma glucose and insulin are cues for metabolism to shift from fat to carbohydrate oxidation. In response to a meal challenge or insulin stimulation, REE and RER are positively associated with sympathetic activity [A major limitation of our study is our inability to directly link improved NO bioavailability to the preservation of HRV during the OGC. Several studies have documented the importance of NO to autonomic function in health and disease [In conclusion, we show that the autonomic system is susceptible to a hyperglycemic episode. Furthermore, using a rigorous study design, we show the efficacy of a naturally rich source of amino acids, L-citrulline, and L-arginine, to preserve HRV during a hyperglycemic episode. These findings build on our previous work that shows WMJ supplementation protects vascular function during hyperglycemia. NO bioavailability is potentially a link between these two integrated physiological systems, but more work is required to develop a mechanistic understanding of this relationship. | PMC9967111 |
Author Contributions | The author’s responsibilities were as follows: T.D.A. designed the research and was responsible for the final contents; T.D.A., R.M. and K.S.E. analyzed the data and wrote the manuscript. C.M.V. conducted the experiments and reviewed manuscript drafts. G.S., J.L. and B.A.I. provided essential materials and reviewed and edited manuscript drafts. All authors have read and agreed to the published version of the manuscript. | PMC9967111 | ||
Institutional Review Board Statement | The study was conducted in accordance with the Declaration of Helsinki and approved by the Institutional Review Board (or Ethics Committee) of Pennington Biomedical Research Center (approved 6 June 2019). | PMC9967111 | ||
Informed Consent Statement | Informed consent was obtained from all subjects involved in the study. | PMC9967111 | ||
Data Availability Statement | The data contained in the manuscript are available upon request to the corresponding author. | PMC9967111 | ||
Conflicts of Interest | The authors declare no conflict of interest. | PMC9967111 | ||
References | (Metabolic responses comparison between PLA versus WMJ treatment during the OGC. (Baseline participant characteristics.Values are means ± SD.Heart rate variability response during the oral glucose challenge.SDNN, standard deviation of NN intervals; RMSSD, root mean square of successive RR interval differences; pNN50, percentage of successive differences that differ by more than 50 ms; LF, low-frequency power; HF, high-frequency power; TP, total power; LF/HF, ratio of LF-to-HF power. Values are means ± SDs. * HRV and metabolic parameter correlations.SDNN, standard deviation of NN intervals; RMSSD, root mean square of successive RR interval differences; pNN50, percentage of successive differences that differ by more than 50 ms; LF, low-frequency power; HF, high-frequency power; TP, total power; LF/HF, ratio of LF-to-HF power. Values are means ± SDs. * | PMC9967111 | ||
Rationale | Behavioral economic drug purchase tasks quantify the reinforcing value of a drug (i.e., demand). Although widely used to assess demand, drug expectancies are rarely accounted for and may introduce variability across participants given diverse drug experiences. | PMC10006272 | ||
Objectives | Three experiments validated and extended previous hypothetical purchase tasks by using blinded drug dose as a reinforcing stimulus, and determined hypothetical demand for experienced effects while controlling for drug expectancies. | PMC10006272 |
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