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Declarations | PMC10731819 | |||
Ethics approval and consent to participate | The study protocol was approved by the Service Provider for the Education Sector (SIKT, reference 305866). Study permission was obtained from the head of the nursing study program at the Department of Health and Nursing Sciences at the University of Agder, the Faculty Ethics Committee at the University of Agder, the head of the nursing study program at the Department of Health Sciences, Norwegian University of Science and Technology. The participants were informed both in writing and orally of their rights, the study’s purpose, and that they had to provide consent to participate. The participants were given opportunity to ask questions and seek clarifications before providing their consent. Informed consent was obtained from all students participating in the study. All methods were carried out in accordance with relevant guidelines and regulations to ensure ethics and data security. | PMC10731819 | ||
Consent for publication | Not applicable. | PMC10731819 | ||
Competing interests | The authors declare no competing interests. | PMC10731819 | ||
References | PMC10731819 | |||
Subject terms | Parkinson’s disease, PD | NEURODEGENERATIVE DISORDERS | Nicotinamide adenine dinucleotide (NAD) replenishment therapy using nicotinamide riboside (NR) shows promise for Parkinson’s disease (PD) and other neurodegenerative disorders. However, the optimal dose of NR remains unknown, and doses exceeding 2000 mg daily have not been tested in humans. To evaluate the safety of high-dose NR therapy, we conducted a single-center, randomized, placebo-controlled, double-blind, phase I trial on 20 individuals with PD, randomized 1:1 on NR 1500 mg twice daily (Oral nicotinamide riboside (NR) at a dose of 3000 mg daily for 30 days is safe and associated with a pronounced systemic augmentation of the NAD metabolome, but no methyl donor depletion. | PMC10684646 |
Introduction | Parkinson’s disease, PD, neurological disorders | ADVERSE EVENTS, ADVERSE EFFECTS, MOVEMENT DISORDER, DISEASES, NEUROLOGICAL DISORDERS | Parkinson’s disease (PD) affects 1–2% of the population over 65 years, and is one of the fastest growing neurological disorders worldwideIncreasing cellular levels of nicotinamide adenine dinucleotide (NAD) has been proposed as a potential neuroprotective therapeutic strategy for neurodegenerationNAD levels decline with age, possibly due to multiple and only partially understood processes, and this has been proposed to contribute to age-related diseases, including parkinsonismsIn the NADPARK study, a recent randomized double-blind clinical trial of NAD replenishment therapy with nicotinamide riboside (NR) in PD, we showed that oral intake of 1000 mg NR daily for 30 days significantly augments cerebral NAD levelsThese findings suggested that NR may hold promise as a neuroprotective therapy for PD, which warrants further clinical investigation. An important knowledge gap in that regard is that the safety range and optimal dose of NR therapy for PD remain undetermined. In the setting of a potential neuroprotective intervention, it is critical that the given dose is sufficient to achieve the desired effects. While the NADPARK trial showed a robust neurometabolic response to NR, the effect size was variable, and not all NR-recipients respondedIn preclinical studies on rats, adverse effects appeared with doses beyond 1000 mg/kg/day, which corresponds to approximately 9700 mg/day for a 60 kg adult humanMost clinical studies with NR in adult humans to date have used up to 1000 mg dailyTo determine the safety of high-dose NR therapy, we performed a double-blind, randomized phase I trial of 3000 mg NR daily in individuals with PD. The primary outcome of the study was the incidence of treatment-associated moderate and severe adverse events (AEs). Secondary outcomes were the between-group difference in treatment-associated mild AEs, change in the clinical severity of PD, measured by the Movement Disorder Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS)We show that oral NR treatment at a dose of 3000 mg daily for a 4-week period is well tolerated without moderate or severe adverse events, induces a pronounced augmentation of the NAD metabolome, and may be associated with clinical symptomatic improvement in PD. These findings support the possibility of extending the dose range of NR up to 3000 mg in clinical trials, provided adequate safety monitoring. However, the long-term safety of this dose has not yet been established. | PMC10684646 |
Results | PMC10684646 | |||
Study population | PD | In total, 26 individuals with PD were screened, and 20 eligible participants were enrolled, all of whom completed the study (Fig. | PMC10684646 | |
High dose NR treatment augments the NAD metabolome | Next, we explored the effect of 3000 mg NR daily on the NAD metabolome in blood and urine. First, flash frozen whole blood samples were analyzed for NAD | PMC10684646 | ||
High dose NR treatment is not associated with depletion of the methyl group pool | One re-occurring concern in the literature is that NAD precursor supplementation may lead to methyl group depletion due to an increased elimination of Nam by methylation | PMC10684646 | ||
Discussion | toxicity, PD, neurological and non-neurological diseases | ADVERSE EVENTS | Our study met its primary outcome and established that orally administered NR at a dose of 3000 mg daily is well tolerated in PD over a course of 4 weeks. NR-recipients developed no moderate or severe adverse events. Furthermore, there were no mild adverse events likely attributed to NR, and no other clinical or biochemical signs of toxicity. While our data do not guarantee long-term safety, they allow future dose-optimization and efficacy studies to extend the tested dose range of NR to 3000 mg daily, provided that appropriate safety monitoring is implemented. In our opinion, adequate dose experimentation in clinical trials will be paramount, in order to adequately explore and exploit potential dose-dependent beneficial effects in PD, as well as the multitude of other neurological and non-neurological diseases, for which NR is currently being tested. Indicatively, there are 44 NR-related trials registered at NR-treatment improved clinical symptoms of PD, measured by MDS-UPDRS, while this remained unchanged in the placebo group. This improvement was driven mostly by MDS-UPDRS part III, which assesses motor function, and part I, which assesses non-motor aspects of daily living. Interestingly, a qualitatively similar but weaker effect was seen in the NADPARK trial where participants consumed 1000 mg NR dailyAt a dose of 3000 mg daily, NR treatment greatly augmented the NAD-metabolome, including a ~3.7-fold (range 1.8–5.8-fold) increase in whole blood NADIn addition to prominently elevated NADFinally, the observed increase in ADPR, a signaling molecule derived from NADNR treatment was associated with a mild but significant increase in serum HCy levels. A similar HCy increase was recently reported with escalating NR supplementation from 250 to 1000 mg over 5 months | PMC10684646 |
Overview of NAD metabolism in interaction with methyl-group metabolism. | PD, SAH, SAH S-adenosyl homocysteine | The figure shows various routes of NAD biosynthesis, and examples of NAD degradation leading to Nam production. If not recycled, Nam is methylated to Me-Nam, in a reaction catalyzed by NNMT and requiring SAM as methyl-group donor. The other product of this reaction, SAH, is further converted to HCy, and subsequently regenerated to methionine in the methionine cycle. Me-Nam 1-methyl nicotinamide, NAAD Nicotinic acid adenine dinucleotide, Nam Nicotinamide, Nam N-oxide Nicotinamide N-oxide, cADPR Cyclic ADP-ribose, ADPR Adenosine diphosphate ribose, NAR Nicotinic acid ribonucleoside, NR Nicotinamide riboside, NMN, Nicotinamide mononucleotide, NA Nicotinic acid, Me-2-PY N1-methyl-2-pyridone-5-carboxamide, Me-4-PY N-methyl-4-pyridone-5-carboxamide, NAMN Nicotinic acid mononucleotide, SAM S-adenosyl methionine, SAH S-adenosyl homocysteine, NNMT Nicotinamide N-methyltransferase, MS Methionine synthase, CD38 Cluster of differentiation 38/cyclic ADP-ribose hydrolase, Methyl-THF Methyl-tetrahydrofolate, THF Tetrahydrofolate, BHMT, Betaine homocysteine methyltransferase, Di-Gly Dimethyl glycine, Bet Betaine.It has also been reported that NR treatment at lower doses, alone or in combination with pterostilbene, may be associated with a mild increase in triglycerides, total cholesterol and LDLOur study has several limitations. The results are based on a 4-week trial period and thus not informative with regard to long-term safety of 3000 mg NR daily. Therefore, until this is established, we strongly discourage the use of this dose outside of clinical studies with appropriate safety monitoring. Nevertheless, our results are sufficient to enable further testing of this dose in upcoming phase II clinical trials. The female to male ratio in our study, with only 3 and 2 females included per arm, was lower than that observed in the general PD population | PMC10684646 | |
Methods | PMC10684646 | |||
Participants and study design | idiopathic PD | This study design was a phase I, single-center, randomized, double-blinded, placebo-controlled trial, aiming to provide initial evidence of safety and tolerability for NR at a dose of 3000 mg daily. The trial was conducted at the Department of Neurology, Haukeland University Hospital, Norway, from the 29.04.22 to the 01.07.22. The first participant was enrolled on 29.04.22 and the last on 27.05.2022. Inclusion criteria were: (i) age equal to or greater than 35 years and lower than 100 years at time of enrollment, (ii) clinical diagnosis of idiopathic PD according to the MDS criteria | PMC10684646 | |
Randomization and masking | 20 participants (5 female and 15 male) were randomly allocated to receive either 1500 mg NR twice daily or placebo for 4 weeks (number of blocks: 2, block size 4, allocation: 1:1), using the electronic Case Report Form ( | PMC10684646 | ||
Primary outcome | ADVERSE EVENTS | The primary outcome was the safety of 3000 mg NR daily for 4 weeks, defined as the absence of clinically significant, NR-associated moderate or severe adverse events. | PMC10684646 | |
Secondary outcomes | PD | ADVERSE EVENTS, SECONDARY | The secondary outcomes were the incidence of treatment-associated mild adverse events, treatment-associated changes in the NAD metabolome in blood and urine, and the change in the overall clinical severity of PD, measured by total MDS-UPDRS. | PMC10684646 |
Procedures | Parkinson’s disease, movement disorder | ADVERSE EVENT, ADVERSE EVENTS, ADVERSE EVENT, MOVEMENT DISORDER, MOVEMENT DISORDER | At screening for trial entry, candidates underwent physical and neurological examination. Enrolled participants were assessed by physical visits by a movement disorder specialist at baseline (visit 1, V1), day 7 (V4), day 14 (V5), day 21 (V6) and day 28 (V7). At baseline and day 28 participants underwent additional assessment with the Movement Disorder Society Unified Parkinson’s disease Rating Scale section I-IV (MDS-UPDRS). At all physical visits an electrocardiogram (ECG), vital parameters (blood pressure, pulse, weight, height) and blood samples were obtained. Additional blood samples were taken on day 3 (V2) and day 5 (V3) to assess safety. Flash frozen whole blood samples for metabolite analyses (NADMed and LC-MS) were obtained by collecting blood in EDTA tubes, aliquoting into 250µl aliquots and snap freezing the tubes in liquid nitrogen precisely 2 min after blood was drawn. The participants were interviewed by telephone consultation by a study nurse on day 3 and day 35 to screen for additional adverse events. Participants were instructed to take their anti-Parkinson drugs as they normally would and no changes were made to anti-Parkinson drug treatment during the trial. Adverse events (AEs) were recorded by the investigating physician. These were then classified by severity according to the Common Terminology Criteria for Adverse Events v5.0 (CTCAE) | PMC10684646 |
Clinical laboratory values | Analysis of clinical laboratory values from blood samples was performed by the Department of Medical Biochemistry and Pharmacology (MBF) at Haukeland University Hospital, Bergen, Norway. | PMC10684646 | ||
NAD and glutathione metabolite analysis from frozen blood | Analysis was carried out by NADMed (Helsinki, Finland; | PMC10684646 | ||
LC-MS analysis from whole blood and urine | Sample analysis was carried out by MS-Omics (Vedbæk, Denmark).Blood sample extraction was carried out by combining 100 µl whole blood with 900 µl ice-cold extraction solvent (Methanol/Acetonitrile/MQW – 10:6:4 fortified with stable isotope internal standards (Supplementary Data Urine sample extraction was carried out by adding 50 μl of urine into a SpinX filter and mixing it with 50 μL eluent B (10 mM ammonium acetate in 90 % acetonitrile). The filters were centrifugated at 3000 × Samples were handled during the whole extraction procedure at 4 °C, and sample analysis was started immediately after sample preparation without any intermediate storage. To ensure high-quality sample preparation, a quality control sample (QC sample) was prepared by pooling small equal aliquots from each sample for all approaches, to create a representative average of the entire set. This sample was treated and analyzed at regular intervals throughout the sequence.Polar metabolite profiling of whole blood and urine was performed using a Thermo Scientific Vanquish LC coupled to Thermo Q Exactive HF MS. An electrospray ionization interface was used as ionization source. Analysis was performed in negative and positive ionization mode. The UPLC was performed as described by Hsiao et al. Semi-polar metabolite analysis of whole blood was carried out using a Thermo Scientific Vanquish LC coupled to Orbitrap Exploris 240 MS, Thermo Fisher Scientific. An electrospray ionization interface was used as ionization source. Analysis was performed in positive and negative ionization mode under polarity switching. The UPLC was performed using a the protocol described by Doneanu et al. For urine samples only polar extraction was performed. For blood samples the applied extraction method is indicated for each reported metabolite in Supplementary Data Identification of compounds for both methods was performed at four levels; Level 1: identification by retention times (compared against in-house authentic standards), accurate mass (with an accepted deviation of 3 ppm), and MS/MS spectra; Level 2a: identification by retention times (compared against in-house authentic standards), accurate mass (with an accepted deviation of 3 ppm). Level 2b: identification by accurate mass (with an accepted deviation of 3 ppm), and MS/MS spectra, Level 3: identification by accurate mass alone (with an accepted deviation of 3 ppm). All standard metabolites used here and the annotation level of the reported metabolites are indicated in Supplementary Data | PMC10684646 | ||
Statistical analysis | Data normality was tested by the Shapiro–Wilk test. The majority of variables in the dataset were normally distributed (Supplementary Data | PMC10684646 | ||
Reporting summary | Further information on research design is available in the | PMC10684646 | ||
Supplementary information |
Peer Review FileDescription of Additional Supplementary FilesSupplementary Data 1Supplementary Data 2Supplementary Data 3Supplementary Data 4Supplementary Data 5Supplementary Data 6Supplementary Data 7Reporting Summary | PMC10684646 | ||
Supplementary information | The online version contains supplementary material available at 10.1038/s41467-023-43514-6. | PMC10684646 | ||
Acknowledgements | We are deeply grateful to the patients involved in the study. We are grateful to study coordinator Ingunn Anundskås, and thank our technical laboratory staff, Martina Castelli, Sepideh Mostafavi, Yana Mikhaleva, Hanne Linda Nakkestad, and Gry Hilde Nilsen, for excellent technical assistance. We thank Prof Mathias Ziegler and Dr Brage Brakedal for the inspiring scientific discussions. We also thank Dr Ann Cathrine Kroksveen, Biobank Haukeland, Haukeland University Hospital. We are grateful to ChromaDex (Irvine, California) for providing the NR and placebo capsules for the study. The trial was supported by grants from The Research Council of Norway (288164, C.T.), Trond Mohn Foundation (BFS2017REK05, C.T.) and the Western Norway Regional Health Authority (F-11470 CT, F-12133 CT, F-12823 H.B.). The sponsor of the study is Haukeland University Hospital, who hosted the trial and provided the required facilities and personnel. | PMC10684646 | ||
Author contributions | H.B.: participated in the study conception and design, recruited and assessed study participants, collected, analyzed and interpreted data, and drafted the manuscript. S.K., G.O.S., K.H., E.S., M.S., S.A.G.: recruited and assessed study participants, and collected and interpreted data. C.D.: participated in study conception, design, data interpretation, data generation and performed critical revision of manuscript. C.T.: conceived, designed and directed the study, contributed to data analyses and interpretation, drafted the manuscript, and acquired funding for the study. All authors have read and approved the manuscript. | PMC10684646 | ||
Peer review | PMC10684646 | |||
Funding | Open access funding provided by University of Bergen. | PMC10684646 | ||
Data availability | NADMed | The vital signs, MDS-UPDRS and NADMed analysis data required to reproduce the results presented in this manuscript have been deposited in the Neuromics Group repository | PMC10684646 | |
Code availability | The code required to reproduce the results presented in this manuscript have been deposited in the Neuromics Group repository | PMC10684646 | ||
Competing interests | Parkinson’s disease | International patent applications relating to the use of nicotinamide riboside as a treatment for Parkinson’s disease have been filed by the Technology Transfer Office “Vestlandets Innovasjonsselskap As (VIS)” on behalf of Haukeland University Hospital, Bergen, Norway, with publication authors C.T. and C.D. as inventors. The applications are pending and have the application numbers: PCT/EP2022/067408, PCT/EP2022/067412 and PCT/EP2023/060962. All other authors declare no competing interests. | PMC10684646 | |
References | PMC10684646 | |||
1. Introduction | Diabetes, vascular complications, diabetes | VASCULAR COMPLICATIONS, METABOLIC DISORDER, DISORDERS, DIABETES, OXIDATIVE STRESS, PATHOGENESIS, DIABETES | Reactive α-dicarbonyls (α-DCs), such as methylglyoxal (MGO), glyoxal (GO), and 3-deoxyglucosone (3-DG), are potent precursors in the formation of advanced glycation end products (AGEs). In particular, MGO and MGO-derived AGEs are thought to be involved in the development of vascular complications in diabetes. Experimental studies showed that citrus and pomegranate polyphenols can scavenge α-DCs. Therefore, the aim of this study was to evaluate the effect of a citrus and pomegranate complex (CPC) on the α-DCs plasma levels in a double-blind, placebo-controlled cross-over trial, where thirty-six elderly subjects were enrolled. They received either 500 mg of Despite substantial advances in diabetes treatment, vascular complications remain a significant clinical concern and are the primary cause of mortality among diabetes patients [A natural consequence of the modification of biomacromolecules by MGO is the loss of their original spatial structure. This results in a loss of physiological function, leading to various cellular disorders [Excessive MGO formation can further increase the production of reactive oxygen species and nitrogen species and consequently induce oxidative stress, which further contributes to the development and progression of vascular complications in diabetes [Preventing diabetes vascular complications necessitates a multidirectional therapeutic approach, as simply targeting risk factors, like glycemic control and a healthy lifestyle, may not be sufficient. Diabetes is a complex metabolic disorder, and the pathogenesis of its vascular complications involves multiple interlinked biochemical, molecular, and physiological processes and, therefore, requires multidirectional therapy. Lowering systemic levels of MGO, GO, and 3-DG may delay the formation of AGEs, particularly crucial in patients experiencing pathophysiological increases in α-DCs (dicarbonyl stress) due to diabetes.To date, several agents have been studied and proposed to be useful as an anti-MGO therapy. Among them are experimental compounds, such as aminoguanidine [Plant-derived dietary supplements and nutraceuticals are becoming increasingly popular all over the world as a result of growing customer awareness regarding their potential health benefits [Several experimental in vitro studies have proved that citrus and pomegranate polyphenols can scavenge reactive α-dicarbonyls and prevent the formation of AGEs [Despite experimental evidence, controlled human studies on the effects of orange and pomegranate actives on α-DCs levels are lacking. Therefore, this post hoc analysis of a double-blind, randomized, cross-over clinical trial in apparently healthy elderly participants examines the impact of a combination of citrus extract and pomegranate concentrate (CPC) on α-DCs levels. The results may shed light on potential therapeutic approaches to inhibit hyperglycemia-induced vascular endothelial damage. | PMC10488144 |
3. Materials and Methods | PMC10488144 | |||
3.1. Study Population and Design | The study was conducted from June 2018 to January 2019 and was approved by the local Medical Ethics Committee of the Maastricht University Medical Centre + and performed in accordance with the Declaration of Helsinki of 1975, as amended in 2013, and with the Dutch Regulations on Medical Research involving Human Subjects from 1998. All participants gave written informed consent before data collection. The study was registered at clinicaltrials.gov as NCT03781999. The detailed design of this research containing CONSORT flow diagram of the study participants was previously described by Ahles et al. [ | PMC10488144 | ||
3.2. Treatment and Placebo | The treatment was 500 mg | PMC10488144 | ||
3.3. Measurement of α-Dicarbonyls in Plasma | Fasting blood samples were collected into Heparin S-Monovette tubes (Sarstedt, Nümbrecht, Germany). Before analysis, all plasma samples stored at −80 °C were thawed and mixed thoroughly. The concentration of α-dicarbonyls in plasma samples was measured with ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS) according to the method proposed by Scheijen et al. [ | PMC10488144 | ||
3.4. Instrumentation | A Waters Acquity I-class system combined with a Xevo TQ-XS mass spectrometer (Waters, Milford, MA, USA) equipped with a reversed-phase C18 column (Acquity UPLC HSS T3, 50 × 2.1 mm, 1.8 μm) was employed for the determination of α-dicarbonyl concentrations. | PMC10488144 | ||
3.5. Statistical Analysis | Statistical analyses were carried out according to a method previously described by Dower et al. [ | PMC10488144 | ||
Author Contributions | Conceptualization, C.G.S.; data curation, J.L.J.M.S. and K.B.; formal analysis, J.L.J.M.S. and K.B.; methodology, C.G.S. and S.A.; supervision, C.G.S., J.L.J.M.S. and I.F.; visualization, K.B., J.L.J.M.S. and I.F.; writing—original draft, K.B.; writing—review and editing, J.L.J.M.S., C.G.S., P.V., S.A. and I.F. All authors have read and agreed to the published version of the manuscript. | PMC10488144 | ||
Institutional Review Board Statement | The study was conducted in accordance with the Declaration of Helsinki and approved by the Ethics Committee of the Maastricht University Medical Centre+ (protocol code NCT03781999 approved by EC on 14 February 2018). | PMC10488144 | ||
Informed Consent Statement | Informed consent was obtained from all subjects involved in the study. | PMC10488144 | ||
Data Availability Statement | The data presented in this study are available on request from the corresponding author. | PMC10488144 | ||
Conflicts of Interest | S.A. receives a salary from BioActor BV. The other authors declare no conflict of interest. | PMC10488144 | ||
Abbreviations | PMC10488144 | |||
1. Introduction | brachial plexus block, nausea and vomiting, postoperative pain | ADVERSE EFFECTS, MINOR, POSTOPERATIVE COMPLICATIONS | To explore the early clinical value of enhanced recovery after surgery (ERAS) with interscalene brachial plexus block (ISB) for arthroscopic rotator cuff repair (ARCR). We enrolled 240 patients who underwent arthroscopic rotator cuff repair, randomly divided into 3 groups (n = 80 each). Groups A, B, and C underwent only surgery, surgery + ERAS, and ISB + surgery + ERAS, respectively. We analyzed the clinical data and postoperative indicators for the 3 patient groups. Group comparisons of clinical data and postoperative indicators revealed no significant differences in clinical characteristics (The rotator cuff is composed of the supraspinatus, infraspinatus, subscapularis, and teres minor muscles, and is primarily responsible for rotational movements of the shoulder joint and maintaining shoulder stability. The prevalence of rotator cuff injuries can reach 30% to 50% in individuals over age 50.Interscalene brachial plexus block (ISB) provides effective analgesia by blocking conduction of painful stimuli, reducing dosage of intraoperative and postoperative analgesics, and consequently reducing the incidence of adverse effects, such as nausea and vomiting.Therefore, the present study was conducted to answer the following questions: How effective are ERAS with ISB and ERAS alone compared to conventional treatment for control of early postoperative pain? Are there differences in the length of hospital stay (LOS) and early functional outcomes? Are there differences in the incidence of postoperative complications? Answers to these questions will provide valuable evidence for future clinical treatments. | PMC10637507 |
2. Materials and methods | PMC10637507 | |||
2.1. Patient selection and general information | epilepsy, shoulder fracture, peripheral neurological diseases | GROUP B, EPILEPSY | This study enrolled patients with rotor cuff repair, treated in our joint and sports medicine department between April 2022 and April 2023. The study was conducted in accordance with the Declaration of Helsinki and approved by the Institutional Review Board of Li Huili Hospital affiliated with Ningbo University (KY2023SL004-01).The inclusion criteria were as follows: obvious shoulder symptoms with restricted motion and no improvement of symptoms after 2 months of conservative treatment; confirmation of rotator cuff tear on magnetic resonance imaging; first-time unilateral ARCR; American Society of Anesthesiologists classification I–II; and patients and family members being aware of the study treatment plan and providing written informed consent.The exclusion criteria were as follows: history of shoulder fracture or prior surgical treatment; rotator cuff tear size >3 cm; presence of central or peripheral neurological diseases, such as epilepsy; and incomplete medical records or refusal to participate in the experimental study till completion.In total, 240 patients met the above criteria. Patients were divided into Groups A, B, and C using the random number table method, with 80 cases in each group. Group A included 26 men and 54 women aged 57.60 ± 12.09 years (range: 22–78 years) treated with ARCR alone. Group B included 31 men and 49 women aged 56.85 ± 8.32 years (range: 35–70 years) and treated with ERAS + ARCR. Group C included 30 men and 50 women aged 55.90 ± 11.98 years (range: 26–80 years) and treated with ERAS + ISB + ARCR. No significant differences were observed in age, sex, body mass index, and duration of surgery among the 3 groups (all Patient demographics and clinical indicators (n, BMI = body mass index. | PMC10637507 |
2.2. Treatment modalities | PMC10637507 | |||
2.2.1. Surgery. | All ARCR surgeries were performed by a senior chief physician. After achieving anesthesia, thorough disinfection, and draping, the affected limb was abducted and flexed in the anterior direction in preparation for suspension traction using the standard posterior approach for routine repair. | PMC10637507 | ||
2.2.2. Routine perioperative management. | pain | Before the operation, patients were routinely instructed not to take pain medications, to fast for 8 hours, and to not drink water for 6 hours prior to surgery in order to ensure accuracy of the experimental study. The lavage fluid was maintained at room temperature, and the volume was not controlled. Interventions were performed for patients with blood pressure over 140/90 mm Hg. No drain placement was performed at the end of the procedure, and patients were allowed to eat food 6 hours postoperatively. After the operation, patients were placed in a shoulder brace and administered nonsteroidal anti-inflammatory drugs daily for pain management. Patients were instructed to perform functional rehabilitation exercises under the supervision of a rehabilitation physician. | PMC10637507 | |
2.2.3. ERAS perioperative management. | diabetes, blood glucose, insomnia, anxiety, pain | HYPERTENSION, CAVITY, COLD, POSTOPERATIVE COMPLICATIONS | Prior to the operation, the attending physician, anesthesiologist, rehabilitation physician, and the nurse-in-charge communicated with each patient in detail. This team comprehensively assessed physiological, psychological, mental, and nutritional status, and informed the patient about measures specific to ERAS, postoperative complications, and the rehabilitation plan. Based on the patient’s condition, targeted health education was provided, and an individualized ERAS plan was formulated. Patients were provided psychological counseling to alleviate adverse emotions, such as tension and anxiety. For patients with hypertension, short-acting antihypertensive drugs were administered on the day of surgery to control blood pressure. For patients with diabetes, blood glucose was strictly controlled. Patients with insomnia were treated with oral zolpidem tartrate tablets. Patients were instructed to avoid taking pain medication for as long as possible prior to surgery. During the operation, heating pads were used to maintain body temperature. The temperature of the operating room was controlled to 23°C, and the temperature of the irrigation fluid in the joint cavity was controlled to 36°C. The patient’s blood pressure was controlled and lowered as necessary, the levels of perioperative fluid input and perfusion were limited, and no drainage tubes were placed at the end of the operation. Patients were placed in the same shoulder brace as after operation, nonsteroidal anti-inflammatory drugs were administered for pain management, and hot and cold wet compresses were applied intermittently. Patients were instructed to perform the same functional rehabilitation exercises under the supervision of a rehabilitation physician. In addition, psychological guidance and distraction techniques were provided.Although some of the perioperative interventions differed between groups, all postoperative rehabilitation measures were the same and were therefore treated as constants in the present study. In order to elucidate the effects of ERAS and ISB interventions, the remaining interventions had to be as consistent as possible to minimize errors in the study results. Other than the application of ISB, the perioperative management of patients in Group C was identical to that of Group B. | PMC10637507 |
2.2.4. Interscalene brachial plexus block. | ISB was performed under ultrasound guidance. After the puncture needle reached the target location under ultrasound guidance, 0.5 µg/kg dexmedetomidine compounded with 0.5% ropivacaine 15 to 20 mL was injected. The efficacy of the block was tested, and general anesthesia was induced after successful completion of the block. | PMC10637507 | ||
2.3. Outcome indicators | postoperative joint stiffness, pain | SECONDARY, HAND SWELLING | The primary outcome was pain intensity, measured using the VAS score, measured at 0–6, 6–24, and 24–48 hours postoperatively. LOS, 1- and 3-month Constant-Murley shoulder scores (CMS), University of California-Los Angeles (UCLA) shoulder scores, and incidence of postoperative joint stiffness and swelling in the 3 groups were collected as secondary outcomes. | PMC10637507 |
2.4. Statistical analysis | Data were analyzed using SPSS v. 25.0 (IBM, Armonk, NY). Continuous variables were expressed as the mean ± standard deviation and categorical variables were expressed as number of cases. After determining whether the data conformed to a normal distribution, normally distributed continuous variables were analyzed by one-way analysis of variance with post hoc tests. The Kruskal–Wallis test was performed for multiple sets of continuous variables not conforming to normal distribution. Categorical variables were compared using the chi-square test or Fisher’s exact test. | PMC10637507 | ||
3. Results | PMC10637507 | |||
3.1. Primary outcome | VAS scores were compared as the primary outcome. Results at 0–6 and 6–24 hours postoperatively exhibited differences between the 3 groups (Comparison of VAS scores among the 3 groups at different time points. VAS = Visual Analog Scale. | PMC10637507 | ||
3.2. Secondary outcomes | PMC10637507 | |||
3.2.1. Length of hospital stay. | A significant difference in the LOS was found among the 3 groups (Comparison of LOS among the 3 groups. LOS = length of hospital stay. | PMC10637507 | ||
3.2.2. CMS and UCLA scores. | The preoperative shoulder function scores did not significantly differ among the 3 groups. However, at 6 weeks and 3 months postoperatively, the scores of Groups B and C were better than those of Group A (Comparison of CMS among the 3 groups at different time points. CMS = Constant-Murley shoulder score.Comparison of UCLA scores among the 3 groups at different time points. UCLA = University of California-Los Angeles. | PMC10637507 | ||
3.2.3. Postoperative complications. | postoperative stiffness | POSTOPERATIVE COMPLICATIONS | The incidence of postoperative stiffness did not significantly differ among the 3 groups (Comparison of incidence of postoperative complications among the 3 groups. | PMC10637507 |
4. Discussion | Postoperative pain, shoulder stiffness, Shoulder swelling, pain | COMPLICATIONS | Shoulder surgery involves multiple muscles and ligaments. Patients undergoing ARCR experience more pain after surgery than those who undergo other shoulder arthroscopy procedures.The concept of perioperative ERAS was introduced by Danish surgeon Henrik Kehlet in 1990.Nerve block techniques modify the generation of responses to stress by modulating or inhibiting the transmission of noxious afferent signals during surgery.The results of the current study show that group A had the longest LOS whereas group C had the shortest LOS, which is consistent with previous findings.Postoperative pain induces the stress response in the body and delays postoperative recovery, thus affecting functional recovery. However, Tirefort et alThe CMS score was adopted by the European Society for Surgery of the Shoulder and the Elbow as a standardized scale for the assessment of shoulder function and is now used worldwide.Shoulder swelling and stiffness are common complications in the early postoperative periodPrevention of shoulder stiffness requires early and standardized rehabilitation.This study has some limitations. Firstly, it had a small sample size and was conducted at a single center, which may have introduced bias. Further studies should be conducted at multiple centers in order to facilitate more scientific and accurate conclusions. Furthermore, the length of the follow-up period was short; the longest follow-up period was only 3 months. In the future, the follow-up period should be extended to facilitate observation of long-term efficacy. | PMC10637507 |
5. Conclusion | postoperative shoulder swelling, pain | We found that the combination of ERAS and ISB eliminates pain in the early postoperative period following ARCR, reduces LOS, and decreases the incidence of postoperative shoulder swelling. However, the effect on early postoperative functional recovery is similar. | PMC10637507 | |
Acknowledgments | We would like to thank Editage ( | PMC10637507 | ||
Abbreviations: | arthroscopic rotator cuff repairConstant-Murley shoulder scoreenhanced recovery after surgerygeneral anesthesiainterscalene brachial plexus blocklength of hospital stayUniversity of California-Los Angeles scoresVisual Analog ScaleThe study was conducted in accordance with the Declaration of Helsinki, and approved by the Ningbo Medical Center Li Huili Hospital review board (KY2023SL004-01).Informed consent was obtained from all subjects involved in the study.The authors have no funding and conflicts of interest to disclose.The datasets generated during and/or analyzed during the current study are not publicly available, but are available from the corresponding author on reasonable request.How to cite this article: Li X, Jiang H-y, Zhao Y-j, Liu S-z, Pan L-x. Early clinical efficacy analysis of enhanced recovery following surgery combined with interscalene brachial plexus block for arthroscopic rotator cuff repair. Medicine 2023;102:45(e35943). | PMC10637507 | ||
References | PMC10637507 | |||
Abstract | PMC10626224 | |||
Background | As the outcome of immunotherapy can be improved when concurrently or sequentially combined with cytotoxic chemotherapy or radiotherapy, we investigated the efficacy of immunotherapy maintenance following platinum‐based chemotherapy in epidermal growth factor receptor ( | PMC10626224 | ||
Methods | In this prospective, open‐label, single arm phase 2 trial, we enrolled patients aged 18 years or older with | PMC10626224 | ||
Results | tumor | MAY, DISEASE, TUMOR | We enrolled 26 patients between May 2020 and July 2021. The median PFS was 1.7 months (95% CI: 0.401–2.999 months). The median OS was 21.4 months (95% CI: 18.790–24.010 months) with 6‐ and 12‐month OS rates of 96.2% and 76.9%, respectively. The objective response rate was 7.7% (2/26) and disease control rate, 11.5% (3/26). The tumor mutational burden by next‐generation sequencing in blood was not related to the treatment outcomes. Grade 3–4 treatment‐related AEs occurred in four (15.4%) patients; the most frequent AE was increased alanine aminotransferase (7.7%). | PMC10626224 |
Conclusion | Nivolumab maintenance following platinum‐based chemotherapy did not show clinical benefits after EGFR‐TKI failure in patients with Immunotherapy in patients with
| PMC10626224 | ||
INTRODUCTION | cancer death, Lung cancer | LUNG CANCER | Lung cancer is the leading cause of cancer death worldwide,Several studies have shown that the response rate can be improved when immunotherapy is administered concurrently or sequentially with cytotoxic chemotherapy or radiotherapy.Recently, we encountered some
| PMC10626224 |
METHODS | PMC10626224 | |||
Study design and participants | This was a prospective, open‐label, single center, single‐arm, phase 2 trial performed at Asan Medical Center, Seoul, Republic of Korea. Eligible patients were aged at least 18 years with a pathologically proven diagnosis of The study was conducted in accordance with the principles of the Declaration of Helsinki and the International Conference on Harmonization guidelines for Good Clinical Practice. The study protocol was approved by the institutional review boards of Asan Medical Center (IRB no.: 2019‐1493). All of the patients provided written informed consent. | PMC10626224 | ||
Procedures | EGFR‐TKI failure, tumor, Tumor, Cancer | DISEASE PROGRESSION, ADVERSE EVENT, TUMOR, TUMOR, BLOOD, CANCER | The patients received platinum‐based chemotherapy followed by nivolumab maintenance therapy after EGFR‐TKI failure (Figure Imaging assessments, including computed tomography or magnetic resonance imaging, of the brain were performed every 6 weeks (±7 days) for 6 months, and then every 12 weeks (±14 days) until disease progression. Tumor response and progression were evaluated as per protocol until disease progression according to RECIST version 1.1.AEs were graded as per the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 and monitored throughout the study for 30 days after the last dose of nivolumab or until a new treatment was started, whichever occurred first.Blood samples were collected to assess the blood TMB before the first dosing of nivolumab and at the first tumor assessment. More than 10 mutations per mega‐base was defined as high TMB. | PMC10626224 |
Outcomes | death | TUMOR PROGRESSION | The primary endpoint was progression‐free survival (PFS), which was defined as the time from the day nivolumab was initiated until objective tumor progression or death. Secondary endpoints were the objective response rate (ORR) and overall survival (OS), which were also calculated from the initiation of nivolumab. The safety profile was assessed during the study period after the administration of nivolumab. Exploratory objectives included the assessment of blood TMB, which could affect the treatment response of this therapy. | PMC10626224 |
Statistical analysis | tumor | DISEASE, TUMOR | Continuous variables are described in mean (standard deviation) and median (IQR) values. Categorical variables are described as frequencies using counts and percentages. We used the Kaplan–Meier method to estimate PFS and OS and corresponding 95% CIs. For PFS, patients whose disease condition did not progress were censored at the date of their final tumor evaluation. For OS, patients who were still alive were censored at data cutoff. The statistical analysis was performed using SPSS version 28. | PMC10626224 |
RESULTS | PMC10626224 | |||
Patient characteristics | death, tumor | ONCOLOGY, TUMOR, DISEASE CHARACTERISTIC | We enrolled 26 patients between January 2020 and December 2021, of whom one withdrew their consent during the study. The patient demographics and characteristics are shown in Table Baseline patient demographics and disease characteristics.Abbreviations: CCRT, concurrent chemoradiation therapy; ECOG PS, Eastern Cooperative Oncology Group performance state; EGFR, epidermal growth factor receptor; EGFR‐TKI, epidermal growth factor receptor tyrosine kinase inhibitor; PD‐L1, programmed death ligand 1; TMB, tumor mutation burden.More than half (76.9%, 20/26) of the patients received gefitinib as the first‐line EGFR‐TKI treatment, and 12 (46.2%) received osimertinib as the second‐line treatment before platinum‐based chemotherapy. | PMC10626224 |
Efficacy | death, SD, tumor | LUNG CANCER, DISEASE, SOLID TUMORS, TUMOR | The median follow‐up duration was 1.9 months (range, 1.3–4.3 months). According to the investigator assessment, partial response (PR) was achieved in two patients (7.7%), and stable disease (SD) was exhibited in one (3.8%), with no complete response (Table Overall efficacy of nivolumab maintenance therapy following platinum‐based chemotherapy.Abbreviations: CI, confidence interval; OS, overall survival; PFS, progression‐free survival; RECIST, response criteria in solid tumors.Waterfall plot of best change from baseline in 26 non‐small cell lung cancer patients.Progression‐free survival and overall survival of Kaplan–Meier curves of platinum‐based chemotherapy followed by nivolumab maintenance. (a) Progression‐free survival. (b) Overall survival.Comparison of baseline characteristics between patients in the responder and nonresponder groups in nivolumab maintenance therapy.Abbreviations: EGFR, epidermal growth factor receptor; PD‐L1, programmed death ligand 1; TMB, tumor mutation burden. | PMC10626224 |
Safety | ADVERSE EVENTS | AEs were reported by 13 (50.0%) patients. Treatment‐related AEs were mainly grade 1 or 2. Five (19.2%) patients had grade 3–4 AEs and two (7.7%), serious AEs (SAEs). The most common grade 3–4 AEs were laboratory abnormalities, especially increased alanine aminotransferase (7.7%) (Table Treatment‐related adverse events of nivolumab maintenance therapy. | PMC10626224 | |
DISCUSSION | nonsquamous NSCLC | ADVERSE EVENTS | It is well‐known that immunotherapy in Despite the negative impact of However, this phase 2 study failed to show any improvement in outcomes compared with previous studies on second‐line cytotoxic chemotherapy following EGFR‐TKI. In an open‐label phase 3 study called CheckMate‐057, patients with nonsquamous NSCLC that had progressed during or after platinum‐based doublet chemotherapy received nivolumab. The study reported a median PFS of 2.3 months and a median OS of 12.2 months.Some studies have suggested that a high TMB may predict a good clinical response in the treatment with immune check point inhibitors.The safety profile of nivolumab in this study was consistent with that in previous studies.There has been ongoing research focused on evaluating the efficacy of combining immunotherapy with chemotherapy in In conclusion, nivolumab maintenance following platinum‐based chemotherapy was well‐tolerated and showed no new unexpected adverse events. However, it failed to show clinical benefits after EGFR‐TKI failure in patients with | PMC10626224 |
AUTHOR CONTRIBUTIONS | Conceptualization: Chang‐Min Choi, Wonjun Ji, Jae Cheol Lee. Data curation: Jiwon Kim, Chang‐Min Choi, Wonjun Ji, Jae Cheol Lee. Formal analysis: Jiwon Kim, Wonjun Ji. Funding acquisition: Jae Cheol Lee. Investigation: Chang‐Min Choi, Wonjun Ji, Jae Cheol Lee. Methodology: Wonjun Ji, Jae Cheol Lee. Validation: Chang‐Min Choi, Wonjun Ji, Jae Cheol Lee. Visualization: Jiwon Kim, Wonjun Ji. Writing ‐ original draft: Jiwon Kim, Wonjun Ji. Writing ‐ review & editing: Chang‐Min Choi, Wonjun Ji, Jae Cheol Lee. | PMC10626224 | ||
CONFLICT OF INTEREST STATEMENT | The authors have no conflicts of interest to declare. The funders had no role in the design of this study, data collection, data analyses, data interpretation, writing of the manuscript, or the decision to publish the results. | PMC10626224 | ||
Supporting information |
Click here for additional data file.
Click here for additional data file.
Click here for additional data file. | PMC10626224 | ||
ACKNOWLEDGMENTS | This research was supported by the Ono pharmaceutical company. | PMC10626224 | ||
REFERENCES | PMC10626224 | |||
1. Introduction | oral cancer, Cancer | CANCER, ORAL CANCER, ORAL SQUAMOUS CELL CARCINOMA | Background: Areca nut and betel quid (ANBQ) chewing is a widespread carcinogenic habit. The BENIT (ClinicalTrials—NCT02942745) is the first known randomized trial designed for ANBQ chewers. Methods: We compared the intensive behavioral treatment intervention condition (IC) with the control condition (CC) in the BENIT and included a 5-stage early stopping rule. We report the primary analysis at stage 3. English-literate adults in Guam and Saipan who self-identified as ANBQ chewers with tobacco were enrolled between August 2016 and August 2020. IC participants (Areca nut (AN), the drupe fruit of the Areca palm (In 2004, compelling evidence suggested strong associations between AN chewing and an increased risk of developing oral cancer (particularly oral squamous cell carcinoma), leading to the classification of AN chewing both with and without tobacco as carcinogenic to humans by the International Agency for Research on Cancer [Despite the global prominence of AN and BQ (ANBQ) and the devastating health burdens associated with their use, ANBQ remains an understudied research topic and an unappreciated global public health issue [One largely overlooked topic within ANBQ research is randomized trials of ANBQ cessation directed specifically at chewers who are ready to make a serious attempt to quit. However, there have been a few recent studies relevant to this issue. Lee et al. [ | PMC10454381 |
2. Materials and Methods | PMC10454381 | |||
2.1. Study Design | The study design of BENIT was described in detail previously [ | PMC10454381 | ||
2.2. Target Population, Inclusion/Exclusion Criteria, and Recruitment | Cancer | EVENTS, RECRUITMENT, CANCER | BENIT was conducted exclusively with Class 2 chewers residing in Guam and Saipan. Thus, all participants added tobacco to their BQ. This inclusion criterion was due to: (1) previous research that revealed a preponderance of Class 2 chewers in these locations [Inclusion criteria were: (1) self-identified chewer of ANBQ with tobacco for at least one year with a minimum thrice weekly frequency; (2) at least 18 years of age; (3) willingness to attempt to quit chewing ANBQ during the intervention; (4) willingness to participate in five hour-long intervention sessions to take place over approximately 22 days; and (5) English literacy. Pregnant women were excluded from participating.Recruitment was conducted using a variety of methods. Some participants were identified from previous ANBQ-related studies conducted under the National Cancer Institute-sponsored University of Guam/University of Hawaii Cancer Center Partnership to Advance Cancer Health Equity, while others were recruited through local community activities, health coalitions and associations, dental clinics, community health centers, village mayoral offices, radio announcements and interviews, religious organizations, on-campus university events, and print and social media advertising. | PMC10454381 |
2.3. Sample Size and Early Termination Plan | The target sample size for BENIT was 324, which was based on a difference of 13 percentage points between intervention and control for ANBQ chewing cessation prevalence at 22 days with α = 0.05 (2-sided) and β = 0.20. However, an early termination plan was developed to accommodate the possibility of stronger-than-expected intervention effects. The specific plan employed the O’Brien-Fleming procedure for interim analysis to maintain the nominal type I error probability of 0.05. This procedure has been described previously [ | PMC10454381 | ||
2.4. Randomization | BENIT participants were randomized to each treatment condition within each island [ | PMC10454381 | ||
2.5. Control Condition Procedures | Participants in the control condition received a single booklet created specifically for BENIT and designed to encourage and facilitate ANBQ cessation. The booklet, entitled “Quitting Betel Nut”, included information about the health risks associated with ANBQ chewing as well as advice and strategies for quitting and maintaining ANBQ abstinence. Participants assigned to the control condition met with study staff three times: baseline, 22-day follow-up, and six-month follow-up. At baseline, participants were provided with the ANBQ cessation booklet, completed a baseline survey assessment, and provided a saliva sample. Participants also completed survey assessments and provided saliva samples at the 22-day and six-month follow-up sessions. Control condition participants received compensation for their time and specimen donation. | PMC10454381 | ||
2.6. Intervention Condition Procedures | SESSION | The BENIT intervention followed the general framework of intensive cognitive-behavioral therapy [The intervention was comprised of five in-person sessions over a 22-day period. The BENIT program’s structure was such that participants were expected to attempt to quit chewing ANBQ at Session 3 (Day 15). Thus, Sessions 1 and 2 were intended to prepare participants for a quit attempt, whereas Sessions 3, 4, and 5 focused on relapse prevention. Saliva samples and survey assessments were collected at baseline (Session 1), at Session 5 (Day 22), and at 6-month follow-up (see | PMC10454381 | |
2.7. Baseline Assessments | Baseline survey assessments included questions on demographics, current chewing behavior, chewing history, ANBQ dependence measured by the Betel Quid Dependence Scale (BQDS) [ | PMC10454381 | ||
2.8. Follow-Up Assessments | Betel quid chewer” | SESSION | The first follow-up assessment was administered at the final intervention session (Session 5). This assessment was scheduled for approximately 22 days after the first intervention session. Participants in this assessment provided data regarding their experience with the BENIT program and their chewing and quitting behaviors during the program. This follow-up assessment was identical for both intervention and control condition participants, except that control condition participants were not asked about the intervention program. The current analyses employed an outcome measure for the ANBQ that was a composite of two survey items. The first survey item read: “Which of the following do you consider yourself to be right now?” Response options were “Betel quid chewer” and “Ex-betel quid chewer”. The second survey item read: “Are you trying to quit chewing right now?” Response options were: “I already quit chewing”, “Yes, chewing but trying to quit”, and “No, chewing but not trying to quit”. For the current analyses, participants were coded as ex-chewers (quitters) if they responded “Ex-betel quid chewer” to the first survey item and “I already quit chewing” to the second survey item. We employed this composite variable to cross-verify self-reported cessation using two items with disparate wordings and response options. If the item responses provided a mixed (contradictory) response, the participant was categorized as a chewer. This composite outcome variable was employed for both intervention and control participants. | PMC10454381 |
2.9. Statistical Analysis | REGRESSION | Participant characteristics were compared between randomization groups. A proportional hazards regression model of the time until cessation was fit using the randomization group as the independent variable, with and without adjustment for factors found to be out of balance between groups. The Wald test using a robust variance estimator accounting for the clustered (i.e., group) structure of the randomization was the test of the hypothesis. | PMC10454381 |
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