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Qualitative data | Qualitative data were collected from a subset of intervention group participants (n=13) by the study research nurse (JJ) via telephone interviews at the end of the study. Feedback from the two ANPs was also taken in meeting sessions with researchers during and after the intervention period. The interview schedule was designed to explore the older adult’s perception and experience of being part of the research project. Participants were asked about their perceived challenges, strength and benefits of the assessment, care and support plan (see Additional file | PMC10463370 | ||
Deviation from protocol | Pain | There were a few deviations from the study protocol. Due to physical space limitations in most participants' homes, the gait speed test was replaced with Rockwood. Besides, the post-intervention outcome assessments were conducted by a research nurse over the phone in both study groups due to COVID-19 restrictions. Also, details of care received by the TAU were not collected due to the impact of the COVID-19 pandemic on staff time and availability in the participating GP centres. Due to the same reason, we did not hold focus group sessions with staff/practitioners to collect their views on the intervention; however, an informal discussion with ANPs reflected the findings reported in the qualitative findings section. Moreover, it was planned to assess Self-Reported Pain (e.g., Geriatric Pain Measure Short Form), however; after discussion amongst the team, it was decided not to overwhelm participants with too many outcome measure questions, and therefore it was excluded. | PMC10463370 | |
Results | PMC10463370 | |||
Participant details | The baseline demographic and study outcomes data were not significantly different between the two study groups (Tables | PMC10463370 | ||
Feasibility findings | RECRUITMENT, RECRUITMENT | The study recruitment, CGA & CSP and outcome assessments began in January 2019 and concluded in February 2020. One hundred sixty-four older adults with eFI ≥ 0.12 were identified and invited to participate; following reading the PIS, 40 (24.4%) declined to take part without stating a reason, 11 (6.1%) felt not being frail and 12 (7.3%) felt not having time to participate. The remaining Of 164 invited participants, 72 were randomised (Recruitment rate: 44.5%) to either the TAU group ( | PMC10463370 | |
Secondary outcomes | PMC10463370 | |||
Other secondary outcomes | SE | The ANPs spend on average 90.96 (95% CI: 81.66 – 100.28) minutes delivering CGA & CSP at their initial session with participants. The time spent with patients was reduced to Mean (95% CI): 68.71 (57.36 – 80.05) and 58.55 (48.36 – 68.74) minutes during the interim and final review sessions, respectively. The between-group difference in the number of 999 calls, GP/GP out-of-hours attendance, GP/GP out-of-hours calls, and A&E attendance showed a slight improvement in favour of the intervention group (Mean difference; SE: 0.37; 0.12, 0.34; 0.12, 0.30; 0.37, 0.43; 0.21 respectively); however, the between-group differences, as well as the within-group change-from-baseline, were not statistically significant for these outcomes, (see Tables Physical function, social function, and health change subscales of the SF-36 significantly deteriorated in the intervention group according to per-protocol analysis (p-values: 0.08, 0.018, 0.041 respectively; Table | PMC10463370 | |
Contents of the CGA & CSP intervention | vision | The summary of problems identified included vision problems (As part of the care and support planning, participants were asked to answer questions such as ‘What is important to me’ and ‘What makes life meaningful for me’. Most participants stated that family and friends are the most important things that make life meaningful. The importance of independent living and leisure activities were also emphasised, and therefore, being more active, in good health and being at home was what the participants wished for in the future.Referrals were made for 18 (53%) participants at the initial CGA session to GP ( | PMC10463370 | |
Qualitative findings | A total of 13 patients took part in the qualitative interviews (six and seven from each practice). These interviews lasted between 20-45 min. | PMC10463370 | ||
Theme 1: Appreciation for consistent care | There was a strong consensus that receiving the study intervention highlighted that their usual care meant they were often not able to get an appointment when needed, not able to see the same health professional or doctor each time they visited, and felt rushed in an appointment during usual care were concerns. For example, Barbara stated, | PMC10463370 | ||
Theme 2: The therapeutic relationship | The patients appreciated that they could build up a rapport with the ANPs during the CGA & CSP programme. Participants felt prioritised as the ANPs provided space for them to ask any questions about their health and therefore ANPs were more aware of their needs. For example, one participant described enjoying his visits with one of the APNs | PMC10463370 | ||
Theme 3: Connecting wider services | The ANPs were able to follow up enquiries for the patients with the surgeries, make further referrals and act as a liaison for follow-up care. For example, ‘When asked how participants would rate the quality of the care they received on a scale of 0–10, all patients gave an eight or above. | PMC10463370 | ||
Discussion | pain | SECONDARY, RECRUITMENT | The study aimed to assess the feasibility of identifying older frail adults living in the community and pilot subsequent CGA & CSP delivery by ANPs. Of 164 individuals identified at the eFI screening stage, 44.5% (The target recruitment number for this study was 160 participants; however, only 72 patients were recruited. Most patients were recruited from one of the GPs (n = 63). The low-recruiting GP centre had a period of staff shortage and did not progress according to the plan. However, the higher recruiting GP centre had one consistent administrative staff who indicated their use of communication techniques to engage and build a rapport with patients during the recruitment telephone call. This could have been key to this centre's success because frailty can carry a negative stigma associated with the end of life [Fifteen per cent of eFI-eligible individuals were not clinically eligible to enter the study. Even some of those who were diagnosed as frail and entered the study expressed in their interview that they believed they were not ‘frail’ or ‘old’ enough to take part. This contributes to the debate on the conceptual ambiguity of frailty and that when presented as a measure of true discourse, it can be problematic [Although available clinical guidelines consistently recommend frailty identification, assessment and management strategies, implementing these strategies is challenging and dependent upon individual patient characteristics, circumstances and contextual factors and the level of resources and support available [Although the outcomes did not reach statistical significance to show group differences, the health service use (i.e., hospital admissions, GP/999 calls and GP/A&E attendance) was higher in the TAU group compared to the intervention group at the end of the study. The TAU group showed a deterioration in FIM total and motor and cognition subscales post-intervention, though the role limitation due to physical function and pain outcomes improved. In the intervention group, the ITT analysis revealed that the outcome measures did not differ significantly from the baseline. A sample size calculation using SPSS, acquired from the mean (SD) hospital admission of 1.06 (2.09) and 3.00 (5.83) for the intervention and TAU groups, respectively, and power (1 – β) of 0.8, revealed a total of 164 (α = 0.05) or 244 (α = 0.01) participants are needed.The qualitative findings indicate that ANPs provided consistent quality care by spending time to become more aware of the health and care needs and preferences of participants, building a strong relationship with them, signposting to wider services, and acting as a liaison for follow-up care. This would give a more accurate assessment of their needs and further follow-ups. A review of both qualitative and quantitative studies identified the essential components of implementing person-centred care for older adults, including knowing the older patient as a person, building a relationship of trust, working in an interprofessional team with and for the patient, co-creation of tailored health and care plan, and empowering the person [The post-intervention outcome assessments were conducted by a research nurse over the phone in both study groups. However, the bias attributable to the mode of data collection is considered minimal [Sufficiently powered studies with a health economic evaluation are required before the approach proposed in this study is adopted on a larger scale. The intervention was delivered to older adults with mild, moderate, or severe levels of frailty over a period of 6 months, and this may be a reason why the secondary outcomes did not demonstrate significant changes. For a further study, it is recommended to target older adults with moderate or severe levels of frailty who may benefit more from the CGA & CSP. Additionally, extending the intervention delivery time to over 12 months with a 6-month interim review could be beneficial. | PMC10463370 |
Conclusion | The study findings indicate that frailty identification and assessment in the community by nursing practitioners was feasible. This helps to target intervention to older adults living in the community who benefit most from CGA and subsequent care and support plans. CGA & CSP delivery by ANPs was acceptable to participants, and the ANPs were able to get to know the patients and therefore were more aware of their needs. The CGA & CSP might reduce health and care usage and improve functional outcomes in community-dwelling older adults with frailty. However, larger-scale studies with embedded health economic evaluation are required to assess the approach employed in this study. | PMC10463370 | ||
Acknowledgements | RECRUITMENT | We would like to thank all staff and the management team at Whitemoor Medical Centre and Riversdale Surgery. Special thanks to Sally Trent for helping with recruitment. We thank Advanced Nursing Practitioners, Mandy Miles and Veronica Hunting-Young for delivering CGA and follow-up reviews. We would also like to thank Dr Bola Owolabi and Dr Ian Lawrence for their support and advice. | PMC10463370 | |
Authors' contributions | RS, JJ | Conception and Design: RS, JJ, LB. Data collection and analysis: RS, JJ. Interpretation of data: RS, JJ, LB. Drafting the work: RS, JJ. Critically revising the work and final approval: RS, JJ, LB. | PMC10463370 | |
Funding | Funding for this study was provided by the NHS Clinical Commissioning Groups, Derbyshire, UK.Clinical Commissioning Groups, Derbyshire, UK. | PMC10463370 | ||
Availability of data and materials | The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request. | PMC10463370 | ||
Declarations | PMC10463370 | |||
Ethics approval and consent to participate | The Helsinki Declaration principles were followed during the entire design and conduct of the study. Informed consent was obtained from all participants before entering the study. Ethical approval was granted by the Yorkshire & The Humber—Leeds East Research Ethics Committee of National Health Services, UK, (IRAS Project ID: 230223; REC reference: 17/YH/0336) before the start of data collection. | PMC10463370 | ||
Consent for publication | Not applicable. | PMC10463370 | ||
Competing interests | The authors declare that they have no competing interests. | PMC10463370 | ||
References | PMC10463370 | |||
1. Introduction | inflammation, moisture loss | INFLAMMATION, SKIN CONDITION, SKIN, OXIDATIVE STRESS | Oxidative stress in the skin, induced by an unhealthy lifestyle and exposure to UVB radiation, leads to skin aging, including reduced elasticity, formation of wrinkles, moisture loss, and inflammation. In a previous study, we revealed the photoaging effects of enzyme-treated caviar extract (CV) by regulating collagen and hyaluronic acid synthase, melanogenesis, anti-oxidant mechanisms, and inflammation in a UVB irradiation-induced mice model. HPLC and MALDI-TOF were performed to determine the effect of enzyme treatment on the free amino acid contents and peptide molecular weight in supercritical caviar extract. As results of the analysis, CV is mainly composed of low-molecular-weight peptides consisting of leucine, tyrosine, and phenylalanine. Based on our in vitro and in vivo study, we conducted a clinical trial to assess the skin anti-aging efficacy of CV. In this randomized, double-blind, placebo-controlled trial, we measured indicators related to elasticity, wrinkles, and skin hydration at 4 and 8 weeks after consumption of CV. The subjects were categorized into caviar, combination, and placebo groups. After 4 weeks, skin hydration, dermal hydration, and transepidermal water loss all showed significant improvement. Furthermore, after 8 weeks, skin elasticity indexes—R2 (total elasticity), R5 (net elasticity), and R7 (ratio of elastic recovery to total deformation)—exhibited significant increases. Improvement in wrinkle indicators (Rmax, Ra, and Rz) and the whitening indicator melanin pigment was also observed. This is the first report showing that CV has significant skin anti-aging efficacy on human skin. In conclusion, our study suggests that CV can be used as skin anti-aging nutraceuticals through positive effects on skin condition in clinical trials.Caviar, the processed or salted roe of the sturgeon, is a rich source of amino acids, fatty acids, and minerals [Skin, a crucial organ comprising diverse cell types and multiple layers, functions as a physical barrier against environmental factors, regulates hydration levels, and maintains physiological balance [As shown in Consequently, the current study aims to conduct a clinical evaluation of the safety and skin anti-aging efficacy of CV based on an in vivo study. For this purpose, we conducted a randomized, placebo-controlled clinical trial involving 45 adults aged 30 to 65 years with wrinkles and dry skin. CV was prescribed to two treatment groups (10 and 500 mg) over an 8-week period to assess its skin anti-aging efficacy by measuring parameters such as hydration, elasticity, melanin content, wrinkles, and transepidermal water loss (TEWL). The safety profile of CV was evaluated through hematological, biochemical, and urine tests conducted after the 8-week trial period. Furthermore, amino acid and protein analysis was performed to determine which components of CV exhibit skin anti-aging effects. Our study is the first report verifying the exceptional skin anti-aging efficacy of CV. | PMC10780664 |
2. Materials and Methods | PMC10780664 | |||
2.1. Preparation of CV | The supercritical extract and enzyme-treated extract of Beluga (Huso Huso) caviar used in this study was sourced from Almas Caviar Inc. (Gyeonggi-do, Republic of Korea). Almas Caviar Inc. is actively engaged in environmental conservation efforts aimed at preserving sturgeon resources (a CITES-listed item), the primary source of caviar. Their commitment involves employing Sustainable Technology, specifically species conservation science, in the caviar production process. Prozyme1000L, an endopeptidase obtained from a culture of the genus Bacillus, was used for enzymatic treatment of the caviar extract, and CV was prepared as previously described [ | PMC10780664 | ||
2.2. Free Amino Acid and Peptide Analysis | dryness | HEAT | The high-performance liquid chromatography (HPLC) was used to determine free amino acid analysis of CV. Weigh 1 g of powder, add 10 times the amount of distilled water, and heat to solidify, and the solution is filtered to obtain an aqueous layer. The residue obtained by concentrating the aqueous layer to dryness under reduced pressure was dissolved in 0.2 N sodium citrate buffer (pH 2.2) and used as a sample for HPLC. Agilent LC system (Agilent Technologies, Santa Clara, CA, USA) and Capcellpak UG120 with properties of (250 mm × 4.6 mm × 5 μm) was used. The mobile phases were: A, 40 mM NaH2PO4 (pH 7.8) and B ACN:MeOH:DW (45:45:10 Peptide molecular weights of CVs were measured in linear mode using a RapifleX MALDI-TOF mass spectrometer (Bruker, Billerica, MA, USA). Sample preparation and peptide analysis were performed by modifying method Lu et al. [ | PMC10780664 |
2.4. Study Participants and Schedule | Healthy adults aged 30 to 60 years (Subjects assigned to the caviar, combination, or placebo groups consumed the sample or placebo supplement daily for eight weeks. At 0, 4, and 8 weeks, measurements of skin hydration, wrinkles, and elasticity were conducted. Unless otherwise noted, each subject washed their face, waited for 30 min under constant temperature and humidity (22–24 °C, 45–55%), and limited water intake for 1 h before skin analysis. Measurements were taken at the right-angle intersection between the corner of the eye and the tip of the nose, and the average of three measurements was calculated. | PMC10780664 | ||
2.5. Skin Hydration | SKIN | Skin hydration was measured at 0, 4, and 8 weeks using the Corneometer CM825 (Courage&Khazaka electronic GmbH). The Corneometer numerically displays skin capacitance at 30-40 μm below the stratum corneum, indicating hydration through the insulating ions remaining in the probe head (A.U.). Dermal hydration was measured using Moisturemeter D Compact (Delfin Technologies Ltd., Kuopio, Finland), which utilizes a 265 MHz high-frequency electromagnetic field to penetrate to a depth of 2 to 2.5 mm in the skin, measuring the tissue dielectric constant in terms of moisture content (%). | PMC10780664 | |
2.6. Skin Elasticity | SKIN | Skin elasticity was measured visits using the Cutometer | PMC10780664 | |
2.7. Transepidermal Water Loss (TEWL) | TEWL confirmed water loss via sweating and evaporation on the epidermis through passive diffusion processes in the stratum corneum. Limit water intake 1 h before measuring TEWL and measure it using a Vapometer | PMC10780664 | ||
2.8. Skin Melanin | At 0, 4, and 8 weeks, the skin’s melanin content was measured using Mexameter | PMC10780664 | ||
2.9. Skin Wrinkles | DMD | LENS | We took high-resolution photos through a Mark-Vu (PSIPLUS, Suwon-si, Republic of Korea) 18-megapixel lens. PRIMOSCR (GFM, Teltow, Germany), a three-dimensional wrinkle measuring device using Digital Micro Mirror Device (DMD) technology, measured crow’s feet using parameter values of Ra (arithmetic average of profile peak height within the total measurement length), Rmax (maximum peak-to-valley value Rt over the assessment length), and Rz (average maximum height of the profile). | PMC10780664 |
2.10. Safety Test and Adverse Reaction Test | renal and liver function | ADVERSE EVENTS, BLOOD | Safety was assessed by monitoring all adverse events and results from hematological tests, blood chemistry tests, and urine tests. Hematological tests measured WBC, RBC, hemoglobin, hematocrit, and platelets. Blood chemistry tests included renal and liver function indicators such as ALP, γ-GT, AST, and ALT activity, total protein, BUN, and creatine kinase concentrations, total cholesterol, and triglycerides. Indicators of renal function, albumin, total cholesterol, triglycerides, glucose, and urine tests were performed. Urine tests measured bilirubin, urobilinogen, and nitrite. | PMC10780664 |
2.11. Statistical Analysis | Statistical analyses were performed using IBM SPSS statistics 25.0. Before and after comparisons within groups were performed using Wilcoxon signed rank test. For comparison between groups, analysis of variance was performed with the Kruskal-Wallis test, followed by a post-hoc Mann-Whitney test. All analyses were performed at a significance value of 0.05. | PMC10780664 | ||
3. Results | PMC10780664 | |||
3.1. Free Amino Acid Contents and Peptide of CV | The free amino acid content for caviar and enzyme-treated caviar is presented in The peptide molecular weights of CV were determined using MALDI-TOF mass spectrometer (Bruker, Billerica, MA, USA) and are presented in | PMC10780664 | ||
3.2. Effects of CV on Skin Hydration | After eight weeks of sample capsule intake, skin hydration changed from 43.091 ± 5.209 A.U. to 45.980 ± 5.008 A.U. in the caviar group, from 46.398 ± 1.484 A.U. to 47.438 ± 1.433 A.U. in the combination group, and from 44.940 ± 2.631 A.U. to 45.513 ± 2.514 A.U. in the placebo group. A significant difference was observed between the caviar and combination groups before and after sample intake, with both groups showing a significant difference compared to the placebo group.Dermal hydration after eight weeks changed from 52.156 ± 4.580 A.U. to 53.844 ± 4.538 A.U. in the caviar group, from 52.156 ± 4.580 A.U. to 53.844 ± 4.538 A.U. in the combination group, and from 51.069 ± 3.105 A.U. to 51.860 ± 3.189 A.U. in the placebo group. A significant difference was noted between the two experimental groups before and after sample intake, but only the caviar group exhibited a significant difference compared to the placebo group after treatment (The effects of CV on TEWL are depicted in | PMC10780664 | ||
3.3. Skin Elasticity | Results for skin elasticity are illustrated in After eight weeks of sample intake, the R5 value in the placebo group decreased from 0.474 ± 0.075 to 0.512 ± 0.068, while in the caviar and combination groups, it increased from 0.457 ± 0.064 to 0.547 ± 0.095 and from 0.458 ± 0.080 to 0.514 ± 0.075, respectively. Caviar showed a significant increase at eight weeks compared to the placebo group (After eight weeks of sample intake, the R7 value in the placebo group decreased from 0.387 ± 0.066 to 0.407 ± 0.060, the combination group increased from 0.375 ± 0.069 to 0.417 ± 0.064, and the caviar group increased from 0.375 ± 0.053 to 0.447 ± 0.084. After eight weeks, the R7 value significantly improved in all groups, and the change in R7 value significantly increased in both treatment groups compared to the placebo group ( | PMC10780664 | ||
3.4. Effects of CV on Skin Melanin Index and Wrinkles | To assess the whitening effect of CV, the melanin index measurement results are shown in Wrinkles were measured using PRIMOSCR (GFM, Teltow, Germany) at the right-angle intersection of the nose and the tip of the eye. Wrinkle parameters included Ra (average roughness), Rmax (maximum peak to valley distance over the assessment length), and Rz (average maximum profile height). After eight weeks of sample intake, the Ra value in the combination group decreased from 21.093 ± 2.620 μm to 19.869 ± 2.851 μm, that of the caviar group decreased from 23.347 ± 5.647 μm to 22.007 ± 4.823 μm, and that of the placebo group decreased from 18.862 ± 3.360 μm to 19.005 ± 2.934 μm. The change in Ra value was significantly improved in both treatment groups (The Rmax value decreased from 244.442 ± 46.975 μm to 234.957 ± 36.421 μm in the combination group and from 249.927 ± 61.225 μm to 235.144 ± 61.048 μm in the caviar group, while it increased from 224.223 ± 36.487 μm to 226.752 ± 27.608 μm in the placebo group. There was a significant improvement only in the caviar group compared to the placebo group (The Rz value of the combination group decreased from 114.493 ± 14.097 μm to 107.556 ± 15.006 μm, that of the caviar group decreased from 124.783 ± 29.388 μm to 116.770 ± 24.634 μm, and that of the placebo group increased from 103.663 ± 17.749 μm to 104.239 ± 14.970 μm. The change in Rz value was significantly improved in both treatment groups compared to the placebo group ( | PMC10780664 | ||
4. Discussion | premature senescence | DNA DAMAGE, PATHOLOGY, ASH, SKIN CONDITION | Caviar, internationally acclaimed as a highly esteemed seafood, is prized for its abundance of protein and fat, establishing it as an exceptional source of high-quality protein in food [Previous studies have demonstrated that the protein, carbohydrate, and ASH content of caviar increased more in supercritical COIn the clinical trial, a caviar group was formulated to assess the effects of caviar extract alone, while a combination group was included as an example of a finished product, containing well-known ingredients recognized for their positive impact on skin elasticity, hydration, and wrinkle improvement, such as fish collagen, hyaluronic acid, and ascorbic acid [Type 1 collagen induces collagen synthesis in human dermal fibroblasts, while MMPs degrade collagen [UVB radiation induces ROS, causing DNA damage, premature senescence, and melanin production within melanocytes, along with tyrosinase (TYR) [Clinical pathology tests, including hematological, biochemical, and urine tests, were conducted to ensure the safety of CV. To ensure safety, clinical pathology tests such as blood tests, biochemical tests, and urine tests were conducted. Safety evaluations revealed that almost all values exhibited no significant differences within or between groups. Some clinical hematological test results or biochemical test items showed significant differences between groups; however, these variations were within the clinical laboratory reference values, making it challenging to assign clinical significance. Based on the confirmed data, CV can be considered an effective food ingredient for improving skin conditions. | PMC10780664 |
5. Conclusions | ADVERSE REACTIONS | In conclusion, this study unequivocally established the skin anti-aging efficacy and safety of CV through a randomized, placebo-controlled, and double-blind clinical trial. Over an 8-week period, CV administration resulted in a significant improvement in skin parameters, including hydration, elasticity, whitening, and wrinkles, when compared to the placebo group. Notably, there were no clinically significant adverse reactions or noteworthy findings in the safety evaluation factors observed. As a result, CV improves factors such as skin hydration, elasticity, and wrinkles due to high free amino acids and low molecular weight peptides. This study demonstrates caviar’s potential as a functional food for skin anti-aging. | PMC10780664 | |
Supplementary Materials | The following supporting information can be downloaded at: Click here for additional data file. | PMC10780664 | ||
Author Contributions | Conceptualization, Y.K.K.; methodology, Y.K.K. and G.H.N.; Formal analysis, Y.K.K. and G.H.N.; Resources, S.H.H. and J.H.; Data curation, Y.K.K., S.K. and G.H.N.; Writing original draft preparation, Y.K.K., S.K. and G.H.N.; Investigation, Y.K.K. and G.H.N.; Writing review and editing, H.M.J., Y.K.K. and S.K.; Visualization, G.H.N.; Supervision, H.M.J.; Project administration, H.M.J., Y.K.K. and G.H.N.; Funding acquisition, H.M.J. All authors have read and agreed to the published version of the manuscript. | PMC10780664 | ||
Institutional Review Board Statement | DISEASE | The study was conducted according to the guidelines of the Declaration of Helsinki, approved by the Institutional Review Board of Global Medical Research Center (Protocol No.: GMRC-22415-HK, 29 April 2022) for studies involving humans. The study was registered with registered with the Clinical Research Information Service (CRIS, no. KCT0008242) in the Korea Disease Control and Prevention Agency supported by the Ministry of Health and Welfare. | PMC10780664 | |
Informed Consent Statement | Informed consent was obtained from all subjects involved in the study. | PMC10780664 | ||
Data Availability Statement | Data supporting the study results can be provided followed by request sent to the corresponding author’s e-mail. | PMC10780664 | ||
Conflicts of Interest | The authors declare no conflicts of interest. | PMC10780664 | ||
Abbreviations | tumor necrosis | TUMOR NECROSIS | SOD, Superoxide dismutase; GPx, glutathione peroxidase; MAPK, mitogen-activated protein kinase; JNK, c-Jun N-terminal kinase; NF-κB, nuclear factor-κB; JNK, Jun NH2-terminal kinas; TNF-α, tumor necrosis factor α; IL, interleukin; SPT, serine palmitoyltransferase; CerS, ceramide synthase; Des, dihydroceramide desaturases; TRP, tyrosinase-related protein; cAMP, cyclic adenosine monophosphate; PKA, cAMP-protein kinase A; MITF, microphthalmia-associated transcription factor; HAS, Hyaluronic Acid Synthases. | PMC10780664 |
Background | sepsis, death, organ dysfunction | SEPSIS | The LOVIT trial examined the effect of vitamin C on sepsis patients, and concluded that in adults with sepsis receiving vasopressor therapy in the ICU, those who received 4-day intravenous vitamin C had a higher risk of death or persistent organ dysfunction at 28 days than those who received placebo. The aim of this study was to determine whether the abrupt termination of vitamin C administration could explain the increased mortality in the vitamin C group. | PMC10115628 |
Methods | deaths | REGRESSION | We used Cox regression with two time periods to model the distribution of deaths over the first 11 days in the LOVIT trial. | PMC10115628 |
Results | Compared with a uniform difference between vitamin C and placebo groups over the 11-day follow-up period, addition of a separate vitamin C effect starting from day 5 improved the fit of the Cox model ( | PMC10115628 | ||
Conclusion | critically ill | CRITICALLY ILL | The increased mortality in the vitamin C group in the LOVIT trial is not explained by ongoing vitamin C administration, but by the abrupt termination of vitamin C. The LOVIT trial findings should not be interpreted as evidence against vitamin C therapy for critically ill patients.
| PMC10115628 |
Subject terms | PMC10115628 | |||
Introduction | sepsis, critically ill | SEPSIS, CRITICAL ILLNESS, CRITICALLY ILL | There is evidence from randomized trials that vitamin C may be beneficial for critically ill patients. Oral and intravenous vitamin C shortened the length of ICU stay on average by 7.8% in a meta-analysis of 12 trials with 1766 patients [The potential benefits of vitamin C for sepsis have been reviewed [Two randomized trials found that vitamin C decreased mortality due to sepsis [The recent LOVIT trial also examined the effect of vitamin C on sepsis patients [We hypothesized that the harm in the vitamin C group may be explained by the rebound effect, by abrupt termination of treatment during the period of critical illness. Furthermore, our earlier analysis showed modification of the vitamin C effect by the termination of the vitamin [ | PMC10115628 |
Methods | Deaths | REGRESSION | The methods of the randomized double-blind LOVIT trial have been described in other papers [Deaths in the LOVIT trial over the first 11 days.Vitamin C was administered for 4 days, thus, from day 5 forward, the vitamin C group did not get additional vitamin C. See the We used Cox regression to estimate the mortality rate in the vitamin C group compared with the placebo group, using the Improvement of the Cox model by allowing two separate vitamin C effects in the LOVIT trial.The improvement in the Cox regression model over the reference model (uniform effect) was tested by the likelihood ratio test. The reference model estimates that vitamin C decreased mortality uniformly over the 11 days by RR = 1.32 (95% CI 0.99–1.76; | PMC10115628 |
Results | In the LOVIT trial, there were 429 participants in the vitamin C group and 433 in the placebo group [Since the focus of our analysis is the effect of abrupt termination of vitamin C, we restricted the time period of the analysis to the first 11 days, such that participants were followed for 1 week after the 4-day vitamin C administration (Table | PMC10115628 | ||
Survival curves for the LOVIT trial. | deaths | The original survival curves were published with a scale up to 180 days, but such a wide scale makes it difficult to see the divergence of the vitamin C and placebo group curves after the termination of the 4-day vitamin C administration. See the We tested the uniformity of the vitamin C effect by allowing separate effects of vitamin C for the early and late periods of the 11-day follow-up (Table During the first 4 days, there were 49 deaths in the vitamin C group, and 51 deaths in the placebo group, with RR = 0.97 (95% CI 0.65–1.44). Thus, there is no evidence of harm from vitamin C During the week after the termination of vitamin C, there were 57 deaths in the vitamin C group, but only 32 deaths in the placebo group, with RR = 1.9 (95% CI 1.2–2.9; Over days 5–7, there were 33 deaths in the vitamin C group, and 15 deaths in the placebo group, with RR = 2.28 (95% CI 1.24–4.2; | PMC10115628 | |
Discussion | PMC10115628 | |||
Harm after abrupt termination of vitamin C | death, critically ill, organ dysfunction, sepsis, diabetes | PHYSIOLOGICAL STRESS, CRITICALLY ILL, EVENTS, SEPSIS, DIABETES | The LOVIT authors concluded that “in adults with sepsis receiving vasopressor therapy in the ICU, those who received intravenous vitamin C had a higher risk of death or persistent organ dysfunction at 28 days than those who received placebo” [This conclusion is misleading as it implies that it was the “receiving” of intravenous vitamin C that explains the increased risk of death by day 28 in the participants randomized to vitamin C. We demonstrate that there is no evidence of difference in mortality between the trial groups The published survival curves comparing the vitamin C and placebo groups of the LOVIT trial cover a period of 180 days [Similar time-modification was previously observed in the CITRIS-ALI trial, which also examined the effect of 4-day vitamin C on sepsis. The groups differed significantly during the 4-day vitamin C administration, but not thereafter [Some medical treatments are events at a point in time, or within a narrow time period, such as vaccination and surgery. In such cases we expect long-term benefits from the short treatment and the effects can be estimated over a long follow-up period. On the other hand, many treatments require compliance over a long period of time. For example, antihypertensive and diabetes drugs are taken regularly for years before effects are seen on clinically relevant outcomes. Similarly, when vitamin C is administered for critically ill patients, it should be administered over a long period for benefits to be seen.There is evidence that vitamin C is depleted during severe physiological stress, indicated by decreases in vitamin C levels, and parallel increases in the oxidized forms of the vitamin, i.e., dehydroascorbate and ascorbate free radical [For decades, there has been concern about the possibility of a rebound effect from abrupt termination of vitamin C [In the LOVIT trial, the median length of ICU stay was 6 days, that is, 2 days longer than the 4-day vitamin C administration. Furthermore, 25% of patients stayed in ICU for ≥12 days, that is ≥8 days beyond the termination of vitamin C. The LOVIT trial reported baseline vitamin C levels, but not levels thereafter. Excess mortality was pronounced in patients with the lowest baseline vitamin C levels [ | PMC10115628 |
Lack of benefit during vitamin C administration | sepsis, Urgency, organ dysfunction | SEPSIS | The motivation for our paper was to challenge the LOVIT authors’ conclusion that it was the intravenous vitamin C that caused the higher risk of mortality or persistent organ dysfunction in the vitamin group [In a recent retrospective cohort study conducted in Korea using propensity score matching, vitamin C administration was associated with lower mortality in sepsis patients who were treated for ≥5 days, but it was ineffective when treatment was shorter [Another potentially relevant issue is the delay of vitamin C initiation. Urgency is important in the treatment of sepsis [Finally, mortality is not the only important outcome in the ICU context. In our view, the 862 patient LOVIT trial does not refute the significant effect of vitamin C on the length of stay in ICU found in the meta-analysis which combined 12 trials with 1766 participants [ | PMC10115628 |
Ethical concerns with not treating overt vitamin C deficiency | dyspnea, fatigue, scurvy, edema, chest pain, irritability | VITAMIN C DEFICIENCY, SCURVY, SCURVY, EDEMA, DISEASE | A particular ethical concern with the LOVIT trial is that patients with severe vitamin C deficiency were not treated. In the trial protocol [Scurvy is usually associated with vitamin C levels below 0.2 mg/dl, which is 11 µM in current units. However, 11 µM should not be interpreted as a definitive level below which scurvy symptoms start to appear. For example, Hodges commented in the report of an empirical scurvy trial that “a distressing feature is the lack of precision of serum ascorbic acid levels. According to most authorities, deficiency appears after the serum level has fallen below 0.2 mg/100 ml, yet several men in these studies had obvious scurvy at a time when their serum levels were above this value” [Emergence of scurvy symptoms has a much closer correlation with the total body pool of vitamin C than with plasma vitamin C level. Hodges stated that “… a comparison between plasma levels of ascorbate and pool sizes showed a very poor correlation… it is fair to say that scurvy appeared when the [vitamin C] body pool size fell below 300 mg” [A more recent study on vitamin C deprivation found that at the lowest point of depletion, with vitamin C levels of about 10 µM, mild but consistent feelings of fatigue and/or irritability were elicited [Experimental vitamin C deprivation in healthy volunteers has led to dyspnea, chest pain, edema, fatigue and reduced autonomic reflexes [In the LOVIT trial, 25% of patients had baseline vitamin C levels less than 5.37 µM (figure 3 in [Given that scurvy is a serious and potentially life-threatening disease it seems ethically inappropriate to randomize half the patients who have vitamin C levels <5.37 µM to a placebo group which is not administered vitamin C. There is no discussion in the LOVIT trial protocol or trial report [ | PMC10115628 |
Conclusions | critically ill, scurvy | CRITICALLY ILL, VITAMIN C DEFICIENCY, SCURVY | Since the publication of the results of the LOVIT trial, we are concerned about the ongoing possibility of some patients with vitamin C deficiency not being administered the vitamin on the basis that “receiving” intravenous vitamin C caused the observed harm in those randomized to the vitamin C group [Further research on the role of vitamin C for critically ill patients is needed and should not be discouraged by the increased mortality caused by the abrupt termination of vitamin C in the LOVIT trial. However, any future research should give thorough consideration to the ethical issues associated with randomizing patients with very low vitamin C levels (such as <11 µM) and symptoms consistent with scurvy to a placebo group, instead of treating them for vitamin C deficiency. | PMC10115628 |
Supplementary information | The online version contains supplementary material available at 10.1038/s41430-022-01254-8. | PMC10115628 | ||
Acknowledgements | We are grateful to Dr. John Hoffer and Dr. Pekka Louhiala for critical reading of the manuscript. | PMC10115628 | ||
Author contributions | HH planned the study, measured the published survival curve [ | PMC10115628 | ||
Funding | Open Access funding provided by University of Helsinki including Helsinki University Central Hospital. | PMC10115628 | ||
Data availability | Data analyzed in the paper are available in the | PMC10115628 | ||
Competing interests | The authors declare no competing interests. | PMC10115628 | ||
References | PMC10115628 | |||
Background | ESOPHAGEAL CANCER | This study aims to investigate the outcomes of patients who received early fiberoptic bronchoscopic sputum aspiration and lavage after thoracoscopic and laparoscopic esophagectomy due to esophageal cancer. | PMC10552382 | |
Methods | esophageal cancer, atelectasis, anastomotic, respiratory dysfunction | OESOPHAGEAL CANCER, POSTOPERATIVE COMPLICATIONS, ATELECTASIS, PULMONARY INFECTION, LEAKAGE | A prospective randomized clinical trial was performed between March 2020 and June 2022. Patients who were scheduled for thoracoscopic and laparoscopic esophagectomy due to esophageal cancer were enrolled. Then, these patients were assigned to the control group (traditional postoperative care) and study group (traditional postoperative care with early bronchoscopic sputum aspiration and lavage). The outcomes, which included the length of hospital stay and medical expenses, and postoperative complications, which included pulmonary infection, atelectasis, respiratory dysfunction and anastomotic leakage, were compared between these two groups. | PMC10552382 |
Results | esophageal cancer | OESOPHAGEAL CANCER | A total of 106 patients were enrolled for the present study, and 53 patients were assigned for the control and study groups. There were no statistically significant differences in gender, age, and location of the esophageal cancer between the two groups. Furthermore, the length of hospital stay was statistically significantly shorter and the medical expenses were lower during hospitalization in the study group, when compared to the control group (12.3 ± 1.2 vs. 18.8 ± 1.3 days, 5.5 ± 0.9 vs. 7.2 ± 1.2 Chinese Yuan, respectively; all, | PMC10552382 |
Conclusions | ESOPHAGEAL CANCER, POSTOPERATIVE COMPLICATIONS | For patients with esophageal cancer, early fiberoptic bronchoscopic sputum aspiration and lavage after thoracoscopic and laparoscopic esophagectomy can shorten the length of hospital stay, and lower the medical expense and incidence of postoperative complications. | PMC10552382 | |
Keywords | PMC10552382 | |||
Background | Esophageal cancer, malignancy, respiratory muscle, pain | ESOPHAGEAL CANCER | Esophageal cancer has been reported as the 7th most common malignancy in the world [It has been reported that different strategies, including adequate pain control, respiratory muscle training, nebulizer treatment, fluid balance control, and corticosteroid administration, can be employed to decrease pulmonary secretions after esophagectomy, with variable efficacies [The present study conducted a randomized clinical trial, and compared the postoperative outcomes of patients with or without fiberoptic bronchoscopic sputum aspiration and lavage after minimally invasive thoracoscopic and laparoscopic esophagectomy, with the purpose of improving the recovery and prognosis of these patients. | PMC10552382 |
Methods | PMC10552382 | |||
Study design and participants | esophageal cancer, psychiatric, coagulation dysfunction | DISORDER, OESOPHAGEAL CANCER | A prospective randomized clinical trial was performed at the Affiliated Hospital of Putian University, Putian, Fujian, China, between March 2020 and June 2022. The study protocol was approved by the hospital ethics committee. All study participants provided a signed informed consent.The participant inclusion criteria were, as follows: (1) patients between 44 and 76 years old; (2) esophageal cancer patients who were scheduled for thoracoscopic and laparoscopic esophagectomy; (3) patients with normal preoperative cardiopulmonary, hepatic and renal function evaluations. The exclusion criteria were, as follows: (1) patients with a previous history of psychiatric disorder, (2) patients with coagulation dysfunction, and (3) patients with previous thoracic surgical operations. | PMC10552382 |
Study protocol | bradycardia, bacterial infection, diabetes, alcohol abuse, hypotension, COPD, flushing | ESOPHAGEAL CANCER, BACTERIAL INFECTION, PULMONARY INFECTION, CHRONIC OBSTRUCTIVE PULMONARY DISEASE, COPD, CAVITY, DIABETES | The baseline characteristics, including the demographics, history of smoking, alcohol abuse, diabetes, chronic obstructive pulmonary disease (COPD), neoadjuvant therapy, and location and stage of the esophageal cancer, were recorded. The patients were randomized to the control and study groups using the random ball method. After the thoracoscopic and laparoscopic esophagectomy, patients in the control group received traditional treatment, while patients in the study group received fiberoptic bronchoscopic lavage and sputum aspiration, in addition to traditional treatment.The thoracoscopic and laparoscopic esophagectomy was performed according to the standard method [The fiberoptic bronchoscopic sputum aspiration and lavage was performed according to the following steps: (1) the fiberoptic bronchoscope, adequate light source system, negative pressure suction, oxygen saturation monitor, oxygen supply, and cardiac monitor were prepared in advance; (2) the patient was laid flat, and high-flow oxygen (6–8 L/min) was provided for 20 min before the procedure; (3) the nasal cavity was cleaned, and topical 2% lidocaine was applied for local anesthesia; (4) a fiberoptic bronchoscope was inserted through one nostril, and high-flow oxygen was provided through the other nostril to maintain an oxygen saturation of > 90% throughout the procedure; (5) a bronchoscope was entered into the left and right bronchus, respectively, and the sputum was aspirated with a constant negative pressure of 150 mmHg (if the patient had thick sputum, 10–20 ml of saline was used for repeated flushing and aspiration, and the lavage fluid was sent for culture and sensitivity analysis; if there was a laboratory positive result for confirmed bacterial infection and pulmonary infection, alveolar lavage was performed with the relevant sensitive antibiotics); (6) the fiberoptic bronchoscope was withdrawn. The whole procedure was performed for approximately 15 min. The procedure was terminated when the patient had bradycardia, hypotension, or an oxygen saturation of < 85%. | PMC10552382 |
Outcome and postoperative complication measurements | Pulmonary dysfunction, pneumonia, Atelectasis, laryngeal sphincter adduction, cord injury, pulmonary dysfunction, atelectasis, reduced cardiac output, fistula, anastomotic, abduction | VOCAL CORD PARALYSIS, PNEUMONIA, ATELECTASIS, POSTOPERATIVE COMPLICATION, ATELECTASIS, COLLAPSE, VOCAL CORD PARALYSIS, LEAKAGE | The outcomes were the entire length of hospital stay and the medical expenses during hospitalization. Postoperative complications, including pneumonia, atelectasis, pulmonary dysfunction, vocal cord paralysis, and anastomotic leakage, were documented. Atelectasis was defined as the partial or complete collapse of one side, lobe, or segment of the lungs. Pulmonary dysfunction was defined as an arterial blood oxygen partial pressure of < 60 mmHg in the resting position in room air, with or without a carbon dioxide partial pressure of > 50 mmHg, after excluding interventricular shunt and reduced cardiac output. Vocal cord paralysis refers to the loss of adduction, abduction, and normal tone of the vocal cords, resulting in voice change, protective laryngeal sphincter adduction, or difficult breathing. It was diagnosed by the fiberoptic bronchoscopic examination in patients with clinical symptoms suspected to have vocal cord injury. Anastomotic leakage is defined as the formation of a fistula due to an unsealed or poorly healed anastomosis between the esophagus and stomach. | PMC10552382 |
Statistical analysis | Continuous data were presented as mean ± standard deviation, and compared using Student | PMC10552382 | ||
Results | PMC10552382 | |||
Patient enrollment and comparison of baseline characteristics | CHRONIC OBSTRUCTIVE PULMONARY DISEASE | A total of 106 patients were enrolled and completed the study. Then, 53 patients were assigned to the control and study groups (Fig.
CONSORT flow diagram
Comparison of baseline characteristics between the two groupsCOPD, chronic obstructive pulmonary disease | PMC10552382 | |
Comparison of outcomes between the two groups | Compared to patients in the control group, patients in the study group had a shorter length of hospital stay, and lower medical expenses during hospitalization (Table
Comparison of outcomes between the two groupsRMB, Renminbi (Chinese Yuan, CNY). All data were presented in mean ± standard deviation | PMC10552382 | ||
Comparison of postoperative complications between the two groups | pneumonia, vocal cord paralysis | PNEUMONIA, VOCAL CORD PARALYSIS, POSTOPERATIVE COMPLICATIONS, CHRONIC OBSTRUCTIVE PULMONARY DISEASE, COMPLICATIONS | Compared to patients in the control group, patients in the study group had lower overall incidences of complications (45.2% vs. 20.7% for the control and study groups, respectively; Table
Comparison of postoperative complications between the two groups
Comparison of pneumonia incidences in patients with vocal cord paralysis or chronic obstructive pulmonary disease between the two groupsCOPD, chronic obstructive pulmonary disease | PMC10552382 |
Discussion | respiratory complications, respiratory complication, expectoration | ESOPHAGEAL CANCER, POSTOPERATIVE COMPLICATIONS, COMPLICATIONS, RESPIRATORY COMPLICATIONS, RESPIRATORY COMPLICATION | The minimally invasive approach to thoracoscopic and laparoscopic esophagectomy has been applied for patients with esophageal cancer. The successful management of respiratory secretion can decrease postoperative complications and improve patient outcomes. The present study performed early fiberoptic bronchoscopic sputum aspiration and lavage after thoracoscopic and laparoscopic esophagectomy. The present study results revealed that patients had a shorter length of hospital stay, and lower medical expenses and incidences of postoperative complications. Early fiberoptic bronchoscopic sputum aspiration and lavage can be used after thoracoscopic and laparoscopic esophagectomy to improve patient outcomes.For patients with esophageal cancer, thoracoscopic and laparoscopic radical esophagectomy can preserve the latissimus dorsi and intercostal muscles, in order to maintain respiratory function and facilitate postoperative recovery [The traditional postoperative care to facilitate sputum expectoration include oral or nasal suction, nebulizer treatment, breathing exercise, back clapping, and corticosteroid administration [In the present study, patients in the study group had a shorter length of hospital stay, when compared to patients in the control group. Furthermore, patients in the study group incurred lower medical expenses. All these were attributed to the successful sputum removal and pulmonary lavage through the early fiberoptic bronchoscopic procedure. In addition, antibiotics were locally injected for these patients to reach a high topic concentration of antibiotics in the pulmonary tissues. All these can shorten the length of hospital stay and reduce medical expenses, ultimately improving patient outcomes.The incidence of postoperative complications was also investigated in the present study. The results revealed that the incidence of overall complications was 45.2% and the incidence of respiratory complications was 28.3% in the control group. The respiratory complication was lower than that reported by a previous study (40% respiratory complication) [The limitations of the present study include the single-center nature of the study, and the small sample size. Furthermore, the performance of the fiberoptic bronchoscopy and sputum removal was influenced by the skill of the operator. The present study results need to be confirmed through future large-scale studies. | PMC10552382 |
Acknowledgements | None. | PMC10552382 | ||
Authors’ contributions | WW, JX, TY, SH, BC were responsible for the study design, data collection, and analysis. WW wrote and revised the manuscript. The final manuscript has been read and approved by all authors. | PMC10552382 | ||
Funding | The study was funded by the Science and Technology Project of Putian, Fujian, China (2018S3F019). | PMC10552382 | ||
Data Availability | The datasets used and/or analyzed during the study are available from the corresponding author on reasonable request. | PMC10552382 | ||
Declarations | PMC10552382 | |||
Ethics approval and consent to participate | The study was approved by the Ethics Committee of the Affiliated Hospital of Putian University (No. 202304), and conducted in accordance with the Declaration of Helsinki (2013). All patients provided a written consent prior to enrollment. | PMC10552382 | ||
Consent for publication | Not applicable. | PMC10552382 | ||
Competing interests | The authors declare that they have no competing interests. | PMC10552382 | ||
Abbreviations | Not applicable. | PMC10552382 | ||
References | PMC10552382 | |||
Abstract | PMC10042092 | |||
Objective | To describe a tobacco cessation intervention using personalized mobile phone text messages based on behaviour change theory and to assess why the intervention was effective. | PMC10042092 | ||
Methods | We conducted a two-arm, double-blind, randomized controlled trial in five cities in China from April to July 2021. We recruited daily or weekly smokers aged 18 years or older. The 90-day intervention was delivered using a mobile phone chat application. At different stages of quitting, intervention group participants received personalized text messages based on analyses of the strength of their intention to quit, their motivation to quit and their self-reported success at quitting. Control group participants received non-personalized text messages. The primary outcome was the biochemically verified 6-month abstinence rate. Secondary outcomes were changes in scores on the components of protection motivation theory. All analyses were by intention to treat. | PMC10042092 | ||
Findings | We randomly assigned 722 participants to intervention or control groups. Biochemically verified continuous abstinence at 6 months was 6.9% (25/360) in the intervention group and 3.0% (11/362) in the control group. Smokers who received the personalized intervention had lower scores on intrinsic rewards of smoking and response costs of quitting in the protection motivation theory analysis. These two variables were also determinants of sustained abstinence, thus explaining why the intervention group had a higher quitting rate. | PMC10042092 |
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