Osteomyelitis in Late-Stage Pressure Sore Patients: A Retrospective Analysis.

BACKGROUND: Late-stage pressure sore (PS) patients are particularly susceptible to osteomyelitis (OM), as bony prominences commonly constitute the focal point of the ulcer. There are lack of data regarding the associated factors and the clinical relevance of this diagnosis in the context of PS treatment. METHODS: This retrospective analysis investigated the clinical characteristics, blood markers indicative of infection in PS patients, and development of histologically evident OM. A total of 125 patient were included from 2014 to 2019. The patient records were especially scanned for histological diagnosis of OM. RESULTS: OM was detected in 39% (37/96) of the samples taken during the index procedure. OM prevalence increased to 56% (43/77) at the second and 70% (41/59) at the third debridement. Therefore, the diagnosis of OM was acquired during treatment in 35 cases. Patients diagnosed with initial OM presented significantly higher blood markers, indicative of infection upon admission. Only patients with consistent OM (three positive biopsies) showed higher flap revision rates. CONCLUSION: This study found no compelling evidence linking OM to worse clinical outcomes in PS patients. In the absence of elevated inflammatory markers, reducing bone biopsy frequency and adopting a less aggressive bone debridement approach may help prevent OM in PS patients.

Biomarker-guided acute kidney injury risk assessment under liberal versus restrictive fluid therapy - the prospective-randomized MAYDAY-trial.

Acute kidney injury (AKI) prevalence in surgical patients is high, emphasizing the need for preventative measures. This study addresses the insufficient evidence on nephroprotective intraoperative fluid resuscitation and highlights the drawbacks of relying solely on serum creatinine/urine output to monitor kidney function. This study assessed the impact of intraoperative fluid management on AKI in female breast cancer patients undergoing autologous breast reconstruction, utilizing novel urinary biomarkers (TIMP-2 and IGFBP-7). In a monocentric prospective randomized controlled trial involving 40 patients, liberal (LFA) and restrictive (FRV) fluid management strategies were compared. TIMP-2 and IGFBP-7 biomarker levels were assessed using the NephroCheck (bioMerieux, France) test kit at preoperative, immediate postoperative, and 24-h postoperative stages. FRV showed significantly higher immediate postoperative biomarker levels, indicating renal tubular stress. FRV patients had 21% (4/19) experiencing AKI compared to 13% (2/15) in the LFA group according to KDIGO criteria (p = 0.385). Restrictive fluid resuscitation increases the risk of AKI in surgical patients significantly, emphasizing the necessity for individualized hemodynamic management. The findings underscore the importance of urinary biomarkers in early AKI detection.

Breast Lipofilling: Is the Bra Really Full? Clinical Bra Pressure Measurement and In Vitro Testing of Processed and Unprocessed Fat Cells.

BACKGROUND: Breast lipofilling, a popular cosmetic and reconstructive procedure, involves the transplantation of autologous fat to enhance breast volume and contour. Despite its widespread use, cell processing and the aftertreatment remain controversial. This study investigates the pressure applied by a compression bra and reports in vitro stress tests of processed and unprocessed fat cells. METHODS: Clinical bra pressure measurements were conducted on a cohort of 45 patients following lipofilling, reduction mammoplasties and DIEP flaps. Laboratory analysis included cell vitality testing using Resazurin assays of processed and unprocessed fat cells after exposure to mechanical or hyperbaric pressure. RESULTS: Our findings show a mean overall pressure value of the compression bra for all patients of 6.7 ± 5.7 mmHg (range 0-35). Cell processing is superior to sedimentation only regarding fat cell vitality. However, neither mechanical pressure within the specified range nor hyperbaric oxygen exposure significantly affected fat graft survival as measured by Resazurin assays. CONCLUSION: The in vitro measurements showed that it was impossible to harm fat cells with external pressure during lipofilling procedures, regardless of their processing. In the clinical context, the compression bra applied pressure values deceeding the perfusion pressure and may therefore not diminish oxygen supply nor harm the transplanted cells. Therefore, we recommend the use of a compression bra for all lipofilling procedures around the breast. LEVEL OF EVIDENCE III: This journal requires that authors assign a level of evidence to each article. For a full description of these evidence-based medicine ratings, please refer to Table of Contents or online Instructions to Authors www.springer.com/00266.

Evidence-Based Approaches to Anticoagulation in Reconstructive Microsurgery-A Systematic Literature Review.

This systematic review addresses the crucial role of anticoagulation in microsurgical procedures, focusing on free flap reconstruction and replantation surgeries. The objective was to balance the prevention of thrombotic complications commonly leading to flap failure, with the risk of increased bleeding complications associated with anticoagulant use. A meticulous PubMed literature search following Evidence-Based-Practice principles yielded 79 relevant articles, including both clinical and animal studies. The full-texts were carefully reviewed and evaluated by the modified Coleman methodology score. Clinical studies revealed diverse perioperative regimens, primarily based on aspirin, heparin, and dextran. Meta-analyses demonstrated similar flap loss rates with heparin or aspirin. High doses of dalteparin or heparin, however, correlated with higher flap loss rates than low dose administration. Use of dextran is not recommended due to severe systemic complications. In animal studies, systemic heparin administration showed predominantly favorable results, while topical application and intraluminal irrigation consistently exhibited significant benefits in flap survival. The insights from this conducted systematic review serve as a foundational pillar towards the establishment of evidence-based guidelines for anticoagulation in microsurgery. An average Coleman score of 55 (maximum 103), indicating low overall study quality, however, emphasizes the need for large multi-institutional, randomized-clinical trials as the next vital step.

Patient characteristics may affect the lymphatic staining ability of Indocyanine green and Patent blue during lymphaticovenous anastomosis.

BACKGROUND: The use of dyes like Indocyanine green (ICG) and Patent blue facilitates the identification of lymphatic vessels during lymphaticovenous anastomosis (LVA) surgery. However, some patients experience "staining failure". In these cases, no stained lymphatic vessels can be detected, making supermicrosurgical LVA even more complex. OBJECTIVE: This study aims to investigate patient-related factors that may interfere with lymphatic vessel staining during LVA. METHODS: A retrospective study was conducted on 30 patient charts, focusing on patient characteristics and the staining quality of ICG and Patent blue dye. Statistical analyses were performed to identify correlations between variables. RESULTS: Significant correlations were found between higher age and secondary lymphedema, longer duration of lymphedema in male patients until surgery and reoccurring cellulitis and Patent blue staining. Notably, recurrent infections to the lymphatic system resulted in inferior staining ability during LVA surgery. CONCLUSIONS: Due to staining failure the detection of functional lymphatic vessels remains challenging in LVA surgery. A more extensive preoperative workup is recommended for patients with recurrent cellulitis to optimize surgical feasibility and procedure quality in LVA treatment for lymphedema.

The masseteric nerve for facial reanimation: Macroscopic and histomorphometric characteristics in 106 human cadavers and comparison of axonal ratio with recipient nerves.

Peripheral facial palsy causes severe impairments. Sufficient axonal load is critical for adequate functional outcomes in reanimation procedures. The aim of our study was to attain a better understanding of the anatomy of the masseteric nerve as a donor, in order to optimize neurotization procedures. Biopsies were obtained from 106 hemifaces of fresh frozen human cadavers. Histological cross-sections were fixed, stained with PPD, and digitized. Histomorphometry and a validated software-based axon quantification were conducted. Of the 154 evaluated branches, 74 specimens were of the main trunk (MT), 40 of the anterior branch (AB), and 38 of the descending branch (DB), while two halves of one cadaver featured an additional branch. The MT showed a diameter of 1.4 ± 0.41 mm (n = 74) with 2213 ± 957 axons (n = 55). The AB diameter was 0.9 ± 0.33 mm (n = 40) with 725 ± 714 axons (n = 30). The DB diameter was 1.15 ± 0.34 mm (n = 380) with 1562 ± 926 axons (n = 30). The DB demonstrated a high axonal capacity - valuable for nerve transfers or muscle transplants. Our findings should facilitate a balanced selection of axonal load, and are potentially helpful in achieving more predictable results while preserving masseter muscle function.

Histomorphometry of the Sural Nerve for Use as a CFNG in Facial Reanimation Procedures.

Facial palsy (FP) is a debilitating nerve pathology. Cross Face Nerve Grafting (CFNG) describes a surgical technique that uses nerve grafts to reanimate the paralyzed face. The sural nerve has been shown to be a reliable nerve graft with little donor side morbidity. Therefore, we aimed to investigate the microanatomy of the sural nerve. Biopsies were obtained from 15 FP patients who underwent CFNG using sural nerve grafts. Histological cross-sections were fixated, stained with PPD, and digitized. Histomorphometry and a validated software-based axon quantification were conducted. The median age of the operated patients was 37 years (5-62 years). There was a significant difference in axonal capacity decrease towards the periphery when comparing proximal vs. distal biopsies (p = 0.047), while the side of nerve harvest showed no significant differences in nerve caliber (proximal p = 0.253, distal p = 0.506) and axonal capacity for proximal and distal biopsies (proximal p = 0.414, distal p = 0.922). Age did not correlate with axonal capacity (proximal: R = -0.201, p = 0.603; distal: R = 0.317, p = 0.292). These novel insights into the microanatomy of the sural nerve may help refine CFNG techniques and individualize FP patient treatment plans, ultimately improving overall patient outcomes.

Precise Monitoring of Returning Sensation in Digital-Nerve Lesions by Three-Dimensional Imaging: A Proof-of-Concept Study.

SUMMARY: Digital-nerve lesions result in a loss of tactile sensation reflected by an anesthetic area (AA) at the radial or ulnar aspect of the respective digit. Available tools to monitor the recovery of tactile sense have been criticized for their lack of validity. Precise quantification of AA dynamics by three-dimensional (3D) imaging could serve as an accurate surrogate to monitor recovery after digital-nerve repair. For validation, AAs were marked on digits of healthy volunteers to simulate the AA of an impaired cutaneous innervation. The 3D models were composed from raw images that had been acquired with a 3D camera to precisely quantify relative AA for each digit (3D models, n = 80). Operator properties varied with regard to individual experience in 3D imaging and image processing. In addition, the concept was applied in a clinical case study. Results showed that images taken by experienced photographers were rated as better quality ( P < 0.001) and needed less processing time ( P = 0.020). Quantification of the relative AA was not altered significantly, regardless of experience level of the photographer ( P = 0.425) or image assembler ( P = 0.749). The proposed concept allows precise and reliable surface quantification of digits and can be performed consistently without relevant distortion by lack of examiner experience. Routine 3D imaging of the AA has the great potential to provide visual evidence of various returning states of sensation and to convert sensory nerve recovery into a metric variable with high responsiveness to temporal progress.

Technical Aspects of High-Resolution Color-Coded Duplex Sonography for the Design of Perforator Flaps.

BACKGROUND: Technical aspects are of utmost significance for an efficient execution in designing perforator flaps with high-resolution color-coded Duplex sonography (CCDS). The following study evaluates decisive factors for a successful microvessel examination conducted by the microsurgeon. METHODS: Technical knowledge presented in this study was based on a series of more than 200 perforator flaps planned with CCDS. Flap reconstructions were performed at the University Hospital Regensburg, Germany, from July 2013 to January 2021. Standard high-resolution ultrasound (US) devices with linear multifrequency transducers of 4 to 18 MHz were used. Modes and device settings were evaluated regarding applicability by microsurgeons. Key steps for safe perforator identification and further optional steps for additional assessment should be discriminated. RESULTS: Different US modes including brightness mode (B-mode), color flow (CF), power Doppler (PD), pulse wave (PW), and blood flow (B-Flow) were used. Transducers from 15 MHz and up were favorable to detect microvessels. Knobology of a standard US device regarding buttons, switches, and specific onscreen options with relevance for perforator mapping was subcategorized in four different groups. For qualitative and quantitative evaluation of microvessels, different US modes were tested with respect to their usefulness.Vital elements of the CCDS exam are disaggregated into three key steps for safe perforator identification and three optional steps for further perforator characterization. A standardized protocol for the CCDS exams was applied. Downregulation of pulse-repetition frequency/scale to adapt device sensitivity to slow-flow velocities represented the most important criterion to visualize microvessels.Qualitative microvessel evaluation was performed in B-mode, CCDS, PD mode, and B-Flow mode. Quantitative assessment was executed using PW-mode and CCDS measuring the microvessels' diameter (mm) and flow characteristics. Quantitative information may be obtained using PW-mode and the distance-measuring tool in CF-mode. CONCLUSION: Technical aspects with respect to proper device trimming and application decisively impact CCDS-guided perforator vessel identification and evaluation.

"A-PePSI LIGhT" Assessment Score to Predict Pressure Sore Impaired Healing Late Recurrence, Immobility, Greater Surface, Inhibited Thrombocytes.

BACKGROUND: Complication rates of up to 46 percent are reported following pressure sore surgery. Pressure sore patients often exhibit ineffective postoperative wound healing despite tension-free flap coverage, necessitating surgical revision and prolonged hospitalization. Rather than pressure sore recurrence, such impaired healing reflects a failed progress through the physiologic stages of the normal wound-healing cascade. The principal objective of the study reported here was to elucidate potentially modifiable inherent variables that predict predisposition to impaired healing and to provide a tool for identifying cases at risk for complicated early postoperative recovery following pressure sore reconstruction. METHODS: A retrospective chart review of late-stage (stage 3 or higher) sacral and ischial pressure sore patients who underwent flap reconstruction from 2014 to 2019 was performed. A multivariable logistic regression model was used to identify key patient and operative factors predictive of impaired healing. Furthermore, the Assessment Score to Predict Pressure Sore Impaired Healing (A-PePSI) was established based on the identified risk factors. RESULTS: In a cohort of 121 patients, 36 percent exhibited impaired healing. Of these, 34 patients suffered from dehiscences, necessitating surgical revision. Statistically significant risk factors comprising late recurrence (OR, 3.8), immobility (OR, 12.4), greater surface (>5 cm diameter; OR, 7.3), and inhibited thrombocytes (aspirin monotherapy; OR, 5.7) were combined to formulate a prognostic scoring system (A-PePSI LIGhT). CONCLUSIONS: The A-PePSI LIGhT score serves as a prognostic instrument for assessing individual risk for impaired healing in pressure sore patients. Preoperative risk stratification supports rational decision-making regarding operative candidacy, allows evidence-based patient counseling, and supports the implementation of individualized treatment protocols. . CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, III.

Microanatomy of the Frontal Branch of the Facial Nerve: The Role of Nerve Caliber and Axonal Capacity.

BACKGROUND: A commonly seen issue in facial palsy patients is brow ptosis caused by paralysis of the frontalis muscle powered by the frontal branch of the facial nerve. Predominantly, static methods are used for correction. Functional restoration concepts include the transfer of the deep temporal branch of the trigeminal nerve and cross-facial nerve grafts. Both techniques can neurotize the original mimic muscles in early cases or power muscle transplants in late cases. Because axonal capacity is particularly important in cross-facial nerve graft procedures, the authors investigated the microanatomical features of the frontal branch to provide the basis for its potential use and to ease intraoperative donor nerve selection. METHODS: Nerve biopsy specimens from 106 fresh-frozen cadaver facial halves were obtained. Histologic processing and digitalization were followed by nerve morphometric analysis and semiautomated axon quantification. RESULTS: The frontal branch showed a median of three fascicles (n = 100; range, one to nine fascicles). A mean axonal capacity of 1191 ± 668 axons (range, 186 to 3539 axons; n = 88) and an average cross-sectional diameter of 1.01 ± 0.26 mm (range, 0.43 to 1.74 mm; n = 67) were noted. In the linear regression model, diameter and axonal capacity demonstrated a positive relation (n = 57; r2 = 0.32; p < 0.001). Based on that equation, a nerve measuring 1 mm is expected to carry 1339 axons. CONCLUSION: The authors' analysis on the microanatomy of the frontal branch could promote clinical use of cross-facial nerve graft procedures in frontalis muscle neurotization and free muscle transplantations.

Facial Rejuvenation with Concentrated Lipograft-A 12 Month Follow-Up Study.

Lipofilling is a popular technique to treat volume loss in aging patients. The isolated adipose tissue is composed of adipocytes and stromal vascular fraction cells, which include adipose-derived stem cells (ASC). We hypothesize that the patient's wrinkle severity scale (WSS) and patient's satisfaction on the global aesthetic improvement scale (GAIS) can be improved after using concentrated lipoaspirate. Fourteen patients (54 years ± 11.09 years) with volume loss in the midface area underwent waterjet-assisted liposuction (Human Med AG, Schwerin, Germany). Fat was centrifuged in an ACP Double Syringe (Arthrex GmbH, Munich, Germany) using Rotofix 32A centrifuge (Andreas Hettich, GmbH & Co.KG, Tuttlingen, Germany). Homogenization was performed using the double syringe and a 1.4 mm female-female luerlock connector. After a second centrifugation, patients received periorbital (PO) and nasolabial (NL) lipografting. ASC count was performed after enzymatical digestion. Vitality of cells was assessed using a resazurin assay. During long-term follow up (12 months, n = 10), we found a high patient's satisfaction (GAIS 1+/-0.52) and a good improvement of the WSS during short- and long-term follow-up. The ASC count of processed lipoaspirate was 2.1-fold higher than of unprocessed lipoaspirate (p < 0.001). The difference of ASC in sedimented and simply centrifuged lipoaspirate was also significant (p < 0.05). Facial rejuvenation with concentrated fat graft offers good results concerning objective aesthetic outcome and patient's satisfaction.

Local Triamcinolone Treatment Affects Inflammatory Response in Seroma Exudate of Abdominoplasty Patients: A Randomized Controlled Trial.

BACKGROUND: As the leading complication of abdominoplasty, seroma formation might represent an inflammatory process in response to surgical trauma. This prospective randomized trial investigated whether local administration of the antiinflammatory agent triamcinolone could prevent seroma accumulation. METHODS: Weekly and cumulative seroma volumes were compared between the study groups A, B, and C over a 4-week follow-up (group A, with drain, without triamcinolone; group B, without drain, without triamcinolone; group C, without drain, with triamcinolone). Aspirated seroma samples were analyzed by enzyme-linked immunosorbent assay for selective inflammatory mediators. RESULTS: Triamcinolone significantly reduced cumulative seroma volume (n = 60; mA 845 ± SDA 578 ml, mC 236 ± SDC 381 ml, p = 0.001). The most accentuated suppressive effect of triamcinolone was observed shortly after the treatment (week 1) (mA1 616 ± SDA1 457 ml, mB1 153 ± SDB1 161 ml, mC1 22 ± SDC1 44 ml, pA1/C1 < 0.001, pB1/C1 = 0.014). Local triamcinolone administration resulted in a differential concentration of interleukin-6 (IL-6) and matrix metalloproteinase-9 (MMP-9 (week 1) in seroma exudate as measured by enzyme-linked immunosorbent assay (mIL-6A1 1239 ± SDA1 59 pg/ml, mIL-6C1 848 ± SDC1 80 pg/ml, p < 0.001; mMMP-9A1 2343 ± SDA1 484 pg/ml, mMMP-9C1 376 ± SDC1 120 pg/ml, p = 0.001). CONCLUSIONS: Local administration of 80 mg of triamcinolone reduced postabdominoplasty seroma accumulation significantly. Under triamcinolone treatment, suppressed levels of IL-6 and MMP-9 in seroma fluid were observed. Notably, inflammatory marker suppression correlated clinically with a decrease in seroma accumulation. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, II.

Effects of electrostimulation therapy in facial nerve palsy.

Facial palsy (FP) is a functional disorder of the facial nerve involving paralysis of the mimic muscles. According to the principle "time is muscle," early surgical treatment is tremendously important for preserving the mimic musculature if there are no signs of nerve function recovery. In a 49-year-old female patient, even 19 months after onset of FP, successful neurotization was still possible by a V-to-VII nerve transfer and cross-face nerve grafting. Our patient suffered from complete FP after vestibular schwannoma surgery. With continuous application of electrostimulation (ES) therapy, the patient was able to bridge the period between the first onset of FP and neurotization surgery. The significance of ES for mimic musculature preservation in FP patients has not yet been fully clarified. More attention should be paid to this form of therapy in order to preserve the facial musculature, and its benefits should be evaluated in further prospective clinical studies.

Clinical Impact of DIEP Flap Perforator Characteristics - A Prospective Indocyanine Green Fluorescence Imaging Study.

BACKGROUND: The question to what extent perfusion in deep inferior epigastric perforator (DIEP) flaps depends on specific perforator characteristics has been raised. Anatomical studies and previous clinical trials focussing on DIEP flap perfusion resulted in discrepancies. This prospective study investigates how perforator row, number and diameter affect DIEP flap microperfusion via Indocyanine Green (ICG) fluorescence angiography. METHODS: The fractional weight of insufficiently perfused flap tissue in Zone 4 related to the total DIEP flap weight was measured based on ICG fluorescence angiography and defined as Zone 4 %. As a surrogate for overall DIEP flap perfusion, Zone 4 % was assessed according to the row, number and diameter of perforators included in the flap. RESULTS: In 42 unilateral DIEP flap breast reconstructions, neither medial (33.6 ± 14.2 %)/lateral perforator row (29.9 ± 7.5 %, p = 0.683) nor the parameter perforator number (single perforator 31.5 ± 14.4 %, two perforators 30.2 ± 10.2 %, p = 0.727) had a statistically significant effect on flap tissue availability as measured via Zone 4 %. A negative correlative trend between perforator diameter and Zone 4 % (r = -0.096, p = 0.588) was observed. CONCLUSION: Zone 4 % provides a novel method for an objective assessment of DIEP flap perfusion. Medial/lateral row selection and other perforator properties (number, diameter) within the standard ranges, did not affect Zone 4 % as indicated by ICG fluorescence angiography.

A Novel Method of Outcome Assessment in Breast Reconstruction Surgery: Comparison of Autologous and Alloplastic Techniques Using Three-Dimensional Surface Imaging.

BACKGROUND: Breast reconstruction is an important coping tool for patients undergoing a mastectomy. There are numerous surgical techniques in breast reconstruction surgery (BRS). Regardless of the technique used, creating a symmetric outcome is crucial for patients and plastic surgeons. Three-dimensional surface imaging enables surgeons and patients to assess the outcome's symmetry in BRS. To discriminate between autologous and alloplastic techniques, we analyzed both techniques using objective optical computerized symmetry analysis. Software was developed that enables clinicians to assess optical breast symmetry using three-dimensional surface imaging. METHODS: Twenty-seven patients who had undergone autologous (n = 12) or alloplastic (n = 15) BRS received three-dimensional surface imaging. Anthropomorphic data were collected digitally using semiautomatic measurements and automatic measurements. Automatic measurements were taken using the newly developed software. To quantify symmetry, a Symmetry Index is proposed. RESULTS: Statistical analysis revealed that there is no difference in the outcome symmetry between the two groups (t test for independent samples; p = 0.48, two-tailed). CONCLUSION: This study's findings provide a foundation for qualitative symmetry assessment in BRS using automatized digital anthropometry. In the present trial, no difference in the outcomes' optical symmetry was detected between autologous and alloplastic approaches. Level of evidence Level IV. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Adipose Tissue in Multiple Symmetric Lipomatosis Shows Features of Brown/Beige Fat.

INTRODUCTION: Multiple symmetric lipomatosis (MSL) (syn.: Launois-Bensaude Syndrome, benign symmetric lipomatosis) is a rare disease of fatty tissue. The pathophysiology of MSL still remains unclear, although several approaches have been described in order to understand it. Beside morphological characteristics and some molecular cell biological approaches, little is known about the histological and immunohistochemical characterization of adipose tissue from patients with MSL. METHODS: From the 45 patients with MSL in our database, 10 were included in the study. Fat tissue samples were collected from affected and unaffected areas. The forearm served as a control area as this area is not affected in MSL. The specimens were analyzed after selected stainings were taken (hematoxylin-eosin = HE, Elastica van Gieson, Ladewig, CD200, CIDEA, myf5, p107, Prdm16, Sca-1, syndecan, UCP1, MAC387, Glut4). RESULTS: In patients suffering from MSL, no macroscopic or microscopic morphological difference could be found between affected and unaffected adipose tissue in HE stainings. The majority of samples showed positivity for UCP1 (9/10 clinically affected tissues, 7/10 clinically unaffected tissues) and CD200. CONCLUSION: Marker profiles support the hypothesis that affected adipose tissue derives from brown or beige adipose tissue rather than from white fat. LEVEL OF EVIDENCE IV: This journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266.