Preoperative Fasting and the Gut Microbiome Before Hip Replacement (PreFAST-Hip)
Preoperative Metabolic Optimization: Influence of Intermittent and Buchinger-Type Fasting on the Gut Microbiome, Immune Profile, and Postoperative Complications in Patients Undergoing Primary Total Hip Arthroplasty - A Randomized Controlled Trial
Postoperative complications occur in 5-15% of patients undergoing elective primary total hip arthroplasty (THA), including periprosthetic joint infection (PJI), thrombosis, wound healing disorders, and metabolic dysregulation. The gut microbiome and the systemic immune profile have both been implicated as modifiable contributors to perioperative complication risk. Preoperative therapeutic fasting has been shown to remodel the gut microbiome, lower proinflammatory cytokines, and improve metabolic parameters.
This single-center, prospective, randomized, two-arm controlled trial at Charité - Universitätsmedizin Berlin investigates whether a structured 20-day preoperative fasting intervention (alternating cycles of the Buchinger Fastenbox and intermittent fasting) modulates two co-primary endpoints - plasma IL-8 (a central proinflammatory marker) and gut microbial alpha-diversity (Shannon index) - compared with standard preoperative care. Secondary endpoints include further immune markers (TNFα, IL-10, T-/B-/NK-cell subsets, activation/exhaustion markers, monocyte HLA-DR), microbiome composition and function, continuous glucose-monitoring and daily metabolic measures, patient-reported outcomes (HOOS, PROMIS-33, infection self-report), and clinical outcomes (postoperative complications per EBJIS criteria, length of stay).
Adults aged 18-75 undergoing elective primary THA are stratified by metabolic status (metabolically healthy vs. metabolically unhealthy according to harmonized metabolic-syndrome criteria) and randomized 1:1 to the fasting intervention versus standard care. Stool and whole-blood samples are collected at baseline (Day -21), and at Day +7 post-operatively for shotgun-metagenomic sequencing and multiparameter flow cytometry, with additional cytokine blood samples at Day -1 and 6 h / 24 h / 72 h post-operatively. Continuous glucose monitoring is performed in all participants from Day -21 until surgery. Planned enrollment is 130 participants.
調査の概要
状態
詳細な説明
Background. Periprosthetic joint infection (PJI) and other postoperative complications after THA carry substantial clinical and economic costs. Recent evidence links the gut microbiome and systemic immune homeostasis to perioperative complication risk, and preoperative caloric restriction has been shown to lower proinflammatory cytokines and shift gut microbial composition toward a less inflammatory profile.
Hypotheses. Primary: A structured 20-day preoperative fasting intervention reduces plasma IL-8 and increases gut microbial alpha-diversity (Shannon index) at Day +7 post-operatively compared with standard preoperative care.
Secondary (exploratory): Fasting modulates broader immune (TNFα, IL-10, immune-cell subsets, activation/exhaustion markers, HLA-DR) and microbiome (taxonomic, functional) parameters, improves metabolic indicators captured by continuous glucose monitoring and daily measures, and reduces postoperative complications, patient-reported infection symptoms, and length of stay.
Design. Single-center, prospective, two-arm, parallel-group, randomized, open-label controlled trial. Randomization is stratified by metabolic status (metabolically healthy vs. metabolically unhealthy per harmonized metabolic-syndrome criteria, Alberti et al. 2009). Planned enrollment: n = 130 (65 per arm; balanced across metabolic strata).
Intervention (Fasting arm). Structured 20-day preoperative fasting schedule self-administered at home with study-team supervision:
- Day -20 to Day -16 (5 days): Buchinger Fastenbox - ready-to-use organic vegetable broths, low carbohydrate, designed to facilitate ketogenic metabolic switch.
- Day -15 to Day -11 (5 days): Intermittent fasting (time-restricted feeding).
- Day -10 to Day -6 (5 days): Buchinger Fastenbox (second cycle).
- Day -5 to Day -1 (5 days): Intermittent fasting (second cycle). No fasting is performed post-operatively.
Control arm. Standard preoperative care per institutional protocol; no fasting and no probiotic, prebiotic, or symbiotic supplementation as part of the study.
Specimen collection and assessments.
- Day -21 (baseline / T0): stool + whole-blood sampling for shotgun-metagenomic sequencing, FACS immunophenotyping, and cytokine panel. Start of continuous glucose monitoring (CGM, all participants). Baseline questionnaires: DEGS1 food frequency questionnaire, HOOS, PROMIS-33, and a study-specific infection-baseline questionnaire.
- Day -20 onward (fasting arm only): daily self-monitored urinary or capillary ketones.
- Day -20 to surgery (all participants): daily body weight, waist circumference, blood pressure.
- Day -1 (immediately pre-op): blood sample for cytokine panel.
- 6 h, 24 h, and 72 h post-operatively: blood samples for cytokine panel.
- Day +7 post-operatively: stool + whole-blood sampling for shotgun metagenomics, FACS immunophenotyping, and cytokine panel (primary endpoint readout).
- Weekly to Week 6 post-operatively: study-specific patient-reported infection questionnaire.
- Week 6, Month 3, Month 6 post-operatively: HOOS, PROMIS-33, body weight.
Analyses. Stool: shotgun metagenomic sequencing (Illumina NovaSeq 6000) with bioinformatic processing (Trimmomatic, DIAMOND, QIIME, Centrifuge, MetaPhlAn/HUMAnN, LEfSe). Blood: multiparameter flow cytometry (CD3, CD4, CD8, CD16/56, CD19, plus CD28, CD57, HLA-DR, PD-1) and standard inflammatory chemistry (CRP, IL-6, IL-8, IL-10, TNFα).
Statistics. Two co-primary endpoints (IL-8, alpha-diversity) tested with a fixed-sequence (gatekeeping) procedure: IL-8 first at α=0.05 two-sided; if significant, alpha-diversity is then tested at α=0.05. Linear mixed models or generalized estimating equations are used to model time × group interactions for repeated measures. Microbiome differential abundance: ANCOM/DESeq2 with covariate adjustment (BMI, age, sex). Multiple testing controlled with FDR. Clinical secondary endpoints are analyzed descriptively.
研究の種類
入学 (推定)
段階
- 適用できない
連絡先と場所
研究連絡先
- 名前：Nele Wagener, Dr. med.
- 電話番号：+49 30 450 615076
- メール：nele.wagener@charite.de
研究場所
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State of Berlin
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Berlin、State of Berlin、ドイツ、10117
- 募集
- Centrum für Muskuloskeletale Chirurgie (CMSC), Charité - Universitätsmedizin Berlin
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コンタクト：
- Nele Wagener, Dr. med.
- 電話番号：+49 30 450 615076
- メール：nele.wagener@charite.de
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-
参加基準
適格基準
就学可能な年齢
- 大人
- 高齢者
健康ボランティアの受け入れ
説明
Inclusion Criteria:
- Adults aged 18-75 years (inclusive)
- Scheduled for elective primary total hip arthroplasty (THA)
- Able and willing to provide written informed consent
- Able to follow the 20-day preoperative fasting protocol independently at home (if randomized to the fasting arm) or willing to be randomized to either arm
Exclusion Criteria:
- Resorption disorder due to bowel disease (e.g. inflammatory bowel disease, short-bowel syndrome, active celiac disease)
- Antibiotic therapy within the last 2 months before baseline (T0)
- Probiotic, prebiotic, or symbiotic supplementation within the last 2 months before baseline (T0)
- Inability or unwillingness to provide informed consent
- Severe comorbidity precluding fasting (e.g. ASA ≥ IV, advanced renal/hepatic impairment, eating disorder)
- BMI < 18.5 kg/m² (underweight)
- Concurrent participation in another interventional drug or device trial
- Pregnancy or breastfeeding
研究計画
研究はどのように設計されていますか？
デザインの詳細
- 主な目的：防止
- 割り当て：ランダム化
- 介入モデル：並列代入
- マスキング：なし（オープンラベル）
武器と介入
参加者グループ / アーム |
介入・治療 |
|---|---|
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実験的：Preoperative Fasting (20 days; Buchinger Fastenbox + intermittent fasting)
Adults aged 18-75 scheduled for elective primary total hip arthroplasty follow a structured 20-day preoperative fasting schedule self-administered at home with study-team supervision.
Schedule: Day -20 to -16 - Buchinger Fastenbox (5 days); Day -15 to -11 - intermittent fasting (5 days); Day -10 to -6 - Buchinger Fastenbox (5 days); Day -5 to -1 - intermittent fasting (5 days).
No fasting is performed post-operatively.
Daily self-monitored ketones, weight, waist circumference, and blood pressure are recorded throughout the fasting window.
All other perioperative care follows the standard institutional protocol.
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Two 5-day cycles of the Buchinger Wilhelmi Fastenbox (hypocaloric, low-carbohydrate, plant-based vegetable broths) alternating with two 5-day cycles of intermittent fasting (time-restricted feeding), totaling 20 days immediately preceding surgery.
Self-administered at home; participants receive structured instructions, daily symptom and metabolic logs, and contact options with the study team for the duration of each cycle.
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介入なし：Standard Preoperative Care
Adults aged 18-75 scheduled for elective primary total hip arthroplasty receive routine preoperative care according to the institutional standard at Charité Centrum für Muskuloskeletale Chirurgie.
No fasting protocol is provided as part of the study.
Continuous glucose monitoring and daily weight, waist circumference, and blood pressure are recorded during the same pre-operative window as the fasting arm.
Stool and blood samples are collected at the same study time points as the fasting arm.
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この研究は何を測定していますか？
主要な結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
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Change in plasma interleukin-8 (IL-8) concentration from baseline to Day +7 post-operatively
時間枠：Baseline (Day -21, before start of intervention) and Day +7 post-operatively
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IL-8 plasma concentration (pg/mL), measured by validated immunoassay
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Baseline (Day -21, before start of intervention) and Day +7 post-operatively
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Change in gut microbial alpha-diversity (Shannon index) from baseline to Day +7 post-operatively
時間枠：Baseline (Day -21, before start of intervention) and Day +7 post-operatively
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Shannon diversity index from shotgun-metagenomic stool sequencing
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Baseline (Day -21, before start of intervention) and Day +7 post-operatively
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二次結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
|---|---|---|
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Perioperative kinetics of plasma cytokines (TNFα, IL-10, IL-6, IL-8)
時間枠：Baseline (Day -21), Day -1 pre-op, and 6 h, 24 h, 72 h, and Day +7 post-operatively
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Serial plasma concentrations of TNFα, IL-10, IL-6, and IL-8 measured by validated immunoassays.
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Baseline (Day -21), Day -1 pre-op, and 6 h, 24 h, 72 h, and Day +7 post-operatively
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Serum C-reactive protein (CRP)
時間枠：Baseline (Day -21) and Day +7 post-operatively
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Serum CRP concentration (mg/L).
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Baseline (Day -21) and Day +7 post-operatively
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T-cell subsets (CD3+, CD4+, CD8+) by flow cytometry
時間枠：Baseline (Day -21) and Day +7 post-operatively
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Absolute and relative frequencies of CD3+, CD4+, and CD8+ T cells in whole blood.
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Baseline (Day -21) and Day +7 post-operatively
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B-cell frequency (CD19+)
時間枠：Baseline (Day -21) and Day +7 post-operatively
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Frequency of CD19+ B cells.
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Baseline (Day -21) and Day +7 post-operatively
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NK-cell frequency (CD16+/CD56+)
時間枠：Baseline (Day -21) and Day +7 post-operatively
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Frequency of CD16+/CD56+ natural killer cells.
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Baseline (Day -21) and Day +7 post-operatively
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T-cell activation / exhaustion markers (CD28, CD57, HLA-DR, PD-1)
時間枠：Baseline (Day -21) and Day +7 post-operatively
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Frequencies of CD28-, CD57+, HLA-DR+, and PD-1+ T-cell subpopulations.
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Baseline (Day -21) and Day +7 post-operatively
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Monocyte HLA-DR expression (mHLA-DR)
時間枠：Baseline (Day -21) and Day +7 post-operatively
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Median fluorescence intensity of HLA-DR on circulating monocytes.
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Baseline (Day -21) and Day +7 post-operatively
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Neutrophil-to-lymphocyte ratio (NLR)
時間枠：Baseline (Day -21) and Day +7 post-operatively
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NLR derived from differential blood count.
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Baseline (Day -21) and Day +7 post-operatively
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Gut microbial beta-diversity
時間枠：Baseline (Day -21) and Day +7 post-operatively
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Bray-Curtis and weighted UniFrac dissimilarity between time points, analyzed with PERMANOVA.
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Baseline (Day -21) and Day +7 post-operatively
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Differential microbial abundance
時間枠：Baseline (Day -21) and Day +7 post-operatively
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Differential abundance of bacterial taxa at genus and species level between arms (ANCOM/DESeq2 with covariate adjustment).
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Baseline (Day -21) and Day +7 post-operatively
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Microbial functional gene profile
時間枠：Baseline (Day -21) and Day +7 post-operatively
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Functional gene profiling (HUMAnN) including CAZyme abundance and SCFA-related pathways.
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Baseline (Day -21) and Day +7 post-operatively
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Continuous glucose monitoring (CGM) metrics
時間枠：Day -21 to day of surgery (continuous)
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Mean interstitial glucose, glucose variability (SD, CV), time-in-range (70-180 mg/dL) derived from a continuous glucose monitor worn from Day -21 until surgery, compared between arms.
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Day -21 to day of surgery (continuous)
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Daily self-monitored ketones (fasting arm)
時間枠：Day -20 to day of surgery
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Daily urinary or capillary ketone measurements during the 20-day fasting window.
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Day -20 to day of surgery
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Daily body weight
時間枠：Day -20 to day of surgery, then Week 6, Month 3, Month 6 post-operatively
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Daily self-measured body weight (kg) during the preoperative window, and at follow-up (Week 6, Month 3, Month 6).
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Day -20 to day of surgery, then Week 6, Month 3, Month 6 post-operatively
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Daily waist circumference
時間枠：Day -20 to day of surgery
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Daily self-measured waist circumference (cm) during the preoperative window.
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Day -20 to day of surgery
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Daily blood pressure
時間枠：Day -20 to day of surgery
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Daily self-measured systolic and diastolic blood pressure (mmHg) during the preoperative window.
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Day -20 to day of surgery
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Dietary intake (DEGS1 food frequency questionnaire)
時間枠：Baseline (Day -21)
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Habitual dietary intake captured at baseline using the DEGS1 food-frequency questionnaire.
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Baseline (Day -21)
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Patient-reported postoperative infection symptoms (study-specific questionnaire)
時間枠：Weekly from Day +1 to Week 6 post-operatively
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Study-specific questionnaire on infection-relevant signs and symptoms, completed weekly by the patient during the first 6 weeks post-operatively.
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Weekly from Day +1 to Week 6 post-operatively
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Postoperative infectious complications (EBJIS)
時間枠：Day 0 to Day 90 after surgery
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Incidence of periprosthetic joint infection per EBJIS criteria within 90 days post-operatively.
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Day 0 to Day 90 after surgery
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Wound healing disorders
時間枠：Day 0 to Day 90 after surgery
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Incidence of any wound healing disorder requiring intervention within 90 days post-operatively.
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Day 0 to Day 90 after surgery
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Reoperation rate
時間枠：Day 0 to Day 90 after surgery
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Incidence of reoperation related to the index joint within 90 days post-operatively.
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Day 0 to Day 90 after surgery
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Length of hospital stay (LOS)
時間枠：From day of surgery to day of discharge (assessed up to 30 days)
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Length of inpatient stay for the index admission, in days.
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From day of surgery to day of discharge (assessed up to 30 days)
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Metabolic complications
時間枠：Day 0 to Day 30 after surgery
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Incidence of postoperative metabolic complications (hyper-/hypoglycemia, electrolyte imbalance, sarcopenia risk markers).
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Day 0 to Day 30 after surgery
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Hip disability and Osteoarthritis Outcome Score (HOOS)
時間枠：Baseline (Day -21), Week 6, Month 3, Month 6 post-operatively
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Validated patient-reported hip-specific outcome score; change from baseline to each follow-up time point.
HOOS subscale scores range from 0 to 100, with 0 indicating extreme hip symptoms/worst outcome and 100 indicating no hip symptoms/best outcome.
Higher scores indicate a better outcome.
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Baseline (Day -21), Week 6, Month 3, Month 6 post-operatively
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Patient-Reported Outcomes Measurement Information System 33-item Profile (PROMIS-33)
時間枠：Baseline (Day -21), Week 6, Month 3, Month 6 post-operatively
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Validated multi-domain patient-reported outcomes (PROMIS-33); change from baseline to each follow-up time point.
ROMIS-33 is reported as domain-specific T-scores plus a pain intensity item.
Domain T-score ranges are: Physical Function 22.5-57.0;
Anxiety 40.3-81.6;
Depression 41.0-79.4;
Fatigue 33.7-75.8;
Sleep Disturbance 32.0-73.3;
Ability to Participate in Social Roles and Activities 27.5-64.2;
Pain Interference 41.6-75.6;
Cognitive Function 25.0-61.1.
Pain Intensity ranges from 0 to 10. Higher scores indicate a better outcome for Physical Function, Ability to Participate in Social Roles and Activities, and Cognitive Function, and a worse outcome for Anxiety, Depression, Fatigue, Sleep Disturbance, Pain Interference, and Pain Intensity.
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Baseline (Day -21), Week 6, Month 3, Month 6 post-operatively
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協力者と研究者
出版物と役立つリンク
一般刊行物
- Alberti KG, Eckel RH, Grundy SM, Zimmet PZ, Cleeman JI, Donato KA, Fruchart JC, James WP, Loria CM, Smith SC Jr; International Diabetes Federation Task Force on Epidemiology and Prevention; Hational Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; International Association for the Study of Obesity. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation. 2009 Oct 20;120(16):1640-5. doi: 10.1161/CIRCULATIONAHA.109.192644. Epub 2009 Oct 5.
- Cella D, Riley W, Stone A, Rothrock N, Reeve B, Yount S, Amtmann D, Bode R, Buysse D, Choi S, Cook K, Devellis R, DeWalt D, Fries JF, Gershon R, Hahn EA, Lai JS, Pilkonis P, Revicki D, Rose M, Weinfurt K, Hays R; PROMIS Cooperative Group. The Patient-Reported Outcomes Measurement Information System (PROMIS) developed and tested its first wave of adult self-reported health outcome item banks: 2005-2008. J Clin Epidemiol. 2010 Nov;63(11):1179-94. doi: 10.1016/j.jclinepi.2010.04.011. Epub 2010 Aug 4.
- Nilsdotter AK, Lohmander LS, Klassbo M, Roos EM. Hip disability and osteoarthritis outcome score (HOOS)--validity and responsiveness in total hip replacement. BMC Musculoskelet Disord. 2003 May 30;4:10. doi: 10.1186/1471-2474-4-10. Epub 2003 May 30.
- Wilhelmi de Toledo F, Grundler F, Bergouignan A, Drinda S, Michalsen A. Safety, health improvement and well-being during a 4 to 21-day fasting period in an observational study including 1422 subjects. PLoS One. 2019 Jan 2;14(1):e0209353. doi: 10.1371/journal.pone.0209353. eCollection 2019.
- Mesnage R, Grundler F, Schwiertz A, Le Maho Y, Wilhelmi de Toledo F. Changes in human gut microbiota composition are linked to the energy metabolic switch during 10 d of Buchinger fasting. J Nutr Sci. 2019 Nov 12;8:e36. doi: 10.1017/jns.2019.33. eCollection 2019.
- Delconte RB, Owyong M, Santosa EK, Srpan K, Sheppard S, McGuire TJ, Abbasi A, Diaz-Salazar C, Chun J, Rogatsky I, Hsu KC, Jordan S, Merad M, Sun JC. Fasting reshapes tissue-specific niches to improve NK cell-mediated anti-tumor immunity. Immunity. 2024 Aug 13;57(8):1923-1938.e7. doi: 10.1016/j.immuni.2024.05.021. Epub 2024 Jun 14.
- Kong L, Cao J, Zhang Y, Ding W, Shen Y. Risk factors for periprosthetic joint infection following primary total hip or knee arthroplasty: a meta-analysis. Int Wound J. 2017 Jun;14(3):529-536. doi: 10.1111/iwj.12640. Epub 2016 Jul 10.
- Casals-Pascual C, Gonzalez A, Vazquez-Baeza Y, Song SJ, Jiang L, Knight R. Microbial Diversity in Clinical Microbiome Studies: Sample Size and Statistical Power Considerations. Gastroenterology. 2020 May;158(6):1524-1528. doi: 10.1053/j.gastro.2019.11.305. Epub 2020 Jan 10. No abstract available.
- Valtetsiotis K, Di Martino A, Brunello M, Tassinari L, D'Agostino C, Traina F, Faldini C. The Potential Role of Gut Bacteriome Dysbiosis as a Leading Cause of Periprosthetic Infection: A Comprehensive Literature Review. Microorganisms. 2023 Jul 9;11(7):1778. doi: 10.3390/microorganisms11071778.
- Salimi M, Karam JA, Willman M, Willman J, Lucke-Wold B, Khanzadeh S, Mirghaderi P, Parvizi J. Neutrophil to Lymphocyte Ratio and Periprosthetic Joint Infection: A Systematic Review and Meta-Analysis. J Arthroplasty. 2024 Mar;39(3):831-838. doi: 10.1016/j.arth.2023.08.067. Epub 2023 Aug 24.
- McNally M, Sousa R, Wouthuyzen-Bakker M, Chen AF, Soriano A, Vogely HC, Clauss M, Higuera CA, Trebse R. The EBJIS definition of periprosthetic joint infection. Bone Joint J. 2021 Jan;103-B(1):18-25. doi: 10.1302/0301-620X.103B1.BJJ-2020-1381.R1.
研究記録日
主要日程の研究
研究開始 (実際)
一次修了 (推定)
研究の完了 (推定)
試験登録日
最初に提出
QC基準を満たした最初の提出物
最初の投稿 (実際)
学習記録の更新
投稿された最後の更新 (実際)
QC基準を満たした最後の更新が送信されました
最終確認日
詳しくは
本研究に関する用語
キーワード
追加の関連 MeSH 用語
その他の研究ID番号
- EA1/279/24
個々の参加者データ (IPD) の計画
個々の参加者データ (IPD) を共有する予定はありますか?
IPD プランの説明
医薬品およびデバイス情報、研究文書
米国FDA規制医薬品の研究
米国FDA規制機器製品の研究
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