Effect of High- and Low-Frequency Transcutaneous Electrical Nerve Stimulation on Angiogenesis and Myofibroblast Proliferation in Acute Excisional Wounds in Rat Skin.

OBJECTIVE: This study evaluated the effects of high- (HF) and low-frequency (LF) transcutaneous electrical nerve stimulation on angiogenesis and myofibroblast proliferation in acute excisional wounds in rat skin. DESIGN: This was an experimental controlled and randomized study. PARTICIPANTS: An excisional wound was made on the back of 90 adult male EPM1-Wistar rats using an 8-mm punch. INTERVENTIONS: The animals were randomly assigned to the HF group (80 Hz), LF group (5 Hz), or control group. Transcutaneous electrical nerve stimulation (pulse duration, 200 microseconds; current amplitude, 15 mA) was delivered (session length, 60 minutes) on 3 consecutive days. MEAN OUTCOME MEASURE: Immunohistochemistry was performed on postoperative days 3, 7, and 14 for counting blood vessels and myofibroblasts. MEAN OUTCOME RESULTS: The LF group had significantly more blood vessels than the HF group on day 3 (P = .004). The HF group had significantly less blood vessels than did the control group on days 7 (P = .002) and 14 (P = .034) and less myofibroblasts than did both the LF and control groups on day 3 (P = .004) and less than did the control group on day 7 (P = .001). CONCLUSION: There seems to be a benefit to the use of LF transcutaneous electrical nerve stimulation in the healing of acute excisional wounds, but further studies are warranted.

Effects of Lidocaine, Bupivacaine, and Ropivacaine on Calcitonin Gene-Related Peptide and Substance P Levels in the Incised Rat Skin.

OBJECTIVE: To evaluate the effect of 2% lidocaine, 0.5% bupivacaine, and 0.75% ropivacaine on the release of substance P (SP) and calcitonin gene-related peptide (CGRP) in skin wounds. DESIGN: A primary, experimental, analytical, prospective, self-controlled, blinded study. SETTING: The study is set in a university research center. INTERVENTIONS: Twenty-eight Wistar rats were randomly divided into 4 groups: lidocaine, bupivacaine, ropivacaine, and the control. After general anesthesia, a local anesthetic or 0.9% saline (control) was injected subdermally along a 2-cm line on the dorsal midline of each rat; 30 minutes later, an incision (nociceptive stimulus) was made along this line. The animals were euthanized, and skin samples were collected from the center of the incision line and sent for CGRP and SP quantification. MAIN OUTCOME MEASURES: Quantification of CGRP and SP by Western blotting. RESULTS: Substance P levels were similar in the lidocaine and ropivacaine groups but were significantly lower than those of the control group (P = .002); no significant difference in SP levels was found between the bupivacaine and control groups. Procalcitonin gene-related peptide levels were significantly lower in the experimental groups than those in control subjects (P = .009), with no significant differences among the experimental groups. No significant differences in CGRP levels were found among all groups. Lidocaine and ropivacaine inhibited SP release. All 3 local anesthetics inhibited the release of procalcitonin gene-related peptide, but not the release of CGRP in rat skin. CONCLUSIONS: Lidocaine and ropivacaine may inhibit neurogenic inflammation by biochemical pathways activated by SP, whereas bupivacaine seems to have no influence on this process.

The 975 nm Diode Laser in the Photothermal Treatment of the Aging and Sagging Face and Neck.

OBJECTIVE: The purpose of this study was to investigate the use of a 975 nm diode laser for skin tightening. BACKGROUND DATA: The photothermal effect of laser irradiation on the hypodermis causes retraction of superficial and deep skin layers by the heating of fibrous septa. New devices have been developed for repairing deformities in the cervicofacial region associated with aging and skin laxity. MATERIALS AND METHODS: This retrospective, cross-sectional study included the medical records of 17 patients who had undergone photothermal laser therapy to correct deformities in the cervicofacial region between June 2013 and February 2015. An energy dose of 3 kJ per 100 cm(2) skin area was used as a safety parameter to calculate the optimal cumulative energy for the treated areas. Four cervicofacial lines were measured preoperatively (baseline), immediately after treatment, and 3 months post-treatment with a caliper. Measurements were compared using the Wilcoxon test at a significance level of 0.05 (p < 0.05). RESULTS: A significant skin tightening was observed in all patients 3 months after the procedure. Mean length reductions found in the cervicofacial lines L1, L2, L3, and L4 at the 3-month follow-up were 0.9, 1.18, 1.32, and 1.27 cm, respectively. CONCLUSIONS: The use of a 975 nm diode laser resulted in skin tightening.

Does dexamethasone act in neuropeptides SP and CGRP in neurogenic inflammation of the skin? An experimental study.

PURPOSE: To investigate the neuropeptides substance P (SP) and calcitonin gene-related peptide (CGRP) after subcutaneous injection of dexamethasone prior to skin incision in rats. METHODS: Twenty seven Wistar-EPM-1 rats were randomly divided into three groups. The sham group (SG) of rats was injected with 0.9 % saline. The second group (Dexa) was injected with 1.0 mg/kg dexamethasone, and the third group (Dexa+) was injected with 10.0 mg/kg dexamethasone. In all groups, the three subcutaneous injections were performed 30 minutes prior to the surgical skin incision and tissue collection. SP and CGRP (15 kDa pro-CGRP and 5 kDa CGRP) were quantified by Western Blotting. RESULTS: No statistically significant differences (p>0.05) were found in pro-CGRP, CGRP and SP values in all three groups. CONCLUSION: The anti-inflammatory effect of dexamethasone did not occur when the substance P and calcitonin gene-related peptide levels were altered during the neurogenic inflammation process of skin wound healing in rats.

Photographs for anthropometric measurements of the breast region. Are there limitations?

PURPOSE: To determine the limitations of the photographs used to obtain the anthropometric measurements of the breast region. METHODS: Five women, between the ages of 18 to 60 years, were evaluated. Photographs of the frontal and left and right profile views of their breasts were taken. Based on the current literature, the most commonly used anthropometric and anatomic landmarks for breast measurement were marked in their different positions. The different points were used to evaluate if the direct anthropometry was possible in a standardized way and determine how the points and the positions can to be used in any breast measurements. RESULTS: There were some limitations to the use of defining points of the breast fold, as well as of its lower portion and lateral extension positions in both profiles. CONCLUSION: The defining points of the breast fold and the profile photographs have some limitations and we suggested how the points and positions can be used for breasts measurements.

Does dexamethasone act in neuropeptides SP and CGRP in neurogenic inflammation of the skin? An experimental study

PURPOSE: To investigate the neuropeptides substance P (SP) and calcitonin gene-related peptide (CGRP) after subcutaneous injection of dexamethasone prior to skin incision in rats.METHODS:Twenty seven Wistar-EPM-1 rats were randomly divided into three groups. The sham group (SG) of rats was injected with 0.9 % saline. The second group (Dexa) was injected with 1.0 mg/kg dexamethasone, and the third group (Dexa+) was injected with 10.0 mg/kg dexamethasone. In all groups, the three subcutaneous injections were performed 30 minutes prior to the surgical skin incision and tissue collection. SP and CGRP (15 kDa pro-CGRP and 5 kDa CGRP) were quantified by Western Blotting.RESULTS: No statistically significant differences (p>0.05) were found in pro-CGRP, CGRP and SP values in all three groups.CONCLUSION:The anti-inflammatory effect of dexamethasone did not occur when the substance P and calcitonin gene-related peptide levels were altered during the neurogenic inflammation process of skin wound healing in rats.

Photographs for anthropometric measurements of the breast region. Are there limitations?

PURPOSE: To determine the limitations of the photographs used to obtain the anthropometric measurements of the breast region. METHODS: Five women, between the ages of 18 to 60 years, were evaluated. Photographs of the frontal and left and right profile views of their breasts were taken. Based on the current literature, the most commonly used anthropometric and anatomic landmarks for breast measurement were marked in their different positions. The different points were used to evaluate if the direct anthropometry was possible in a standardized way and determine how the points and the positions can to be used in any breast measurements. RESULTS: There were some limitations to the use of defining points of the breast fold, as well as of its lower portion and lateral extension positions in both profiles. CONCLUSION: The defining points of the breast fold and the profile photographs have some limitations and we suggested how the points and positions can be used for breasts measurements. .

A research design for the quantification of the neuropeptides substance p and calcitonin gene-related Peptide in rat skin using Western blot analysis.

OBJECTIVE: To describe and standardize a protocol that overcomes the technical limitations of Western blot (WB) analysis in the quantification of the neuropeptides substance P (SP) and calcitonin gene-related peptide (CGRP) following nociceptive stimuli in rat skin. DESIGN: Male Wistar rats (Rattus norvegicus albinus) weighing 250 to 350 g were used in this study. Elements of WB analysis were adapted by using specific manipulation of samples, repeated cycles of freezing and thawing, more thorough maceration, and a more potent homogenizer; increasing lytic reagents; promoting greater inhibition of protease activity; and using polyvinylidene fluoride membranes as transfer means for skin-specific protein. Other changes were also made to adapt the WB analysis to a rat model. SETTING: University research center. MAIN OUTCOME MEASURE: Western blot analysis adapted to a rat model. RESULTS: This research design has proven effective in collecting and preparing skin samples to quantify SP and CGRP using WB analysis in rat skin. CONCLUSION: This study described a research design that uses WB analysis as a reproducible, technically accessible, and cost-effective method for the quantification of SP and CGRP in rat skin that overcomes technical biases.

Laser lipolysis: skin tightening in lipoplasty using a diode laser.

BACKGROUND: New devices have been developed for surgical repair of deformities caused by localized fat deposits associated with skin laxity. The use of these devices requires the adoption of safety parameters. The aim of this study was to investigate skin tightening by laser lipolysis, using a dual-wavelength diode laser. METHODS: This prospective, cross-sectional study was conducted between June of 2008 and July of 2010 with 41 consecutive patients who underwent laser lipolysis to correct contour deformities. Laser lipolysis was performed with a diode laser operating at two wavelengths (924 and 975 nm) controlled independently, and using three different tip lengths, allowing treatment of small, medium, and large areas of adipose tissue. The procedure was performed under local anesthesia in a surgical setting. To calculate the optimal cumulative energy, a total energy dose of 5 kJ/10 × 10-cm skin area was used as a safety parameter to prevent treatment complications. The circumferences of body regions were measured preoperatively, immediately after surgery, and 90 days later. Measurements were compared using the Wilcoxon test at a significance level of 0.05 (p < 0.05). RESULTS: A significant skin tightening was observed in all patients, regardless of the body site involved (i.e., face, breast, arms, or waist regions), and no complications occurred. CONCLUSION: Laser lipolysis results in progressive skin tightening over time. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, IV.

Does ear keloid formation depend on the type of earrings or piercing jewellery?

The ear is one of the most common sites of keloid formation, usually associated with the wearing of earrings. However, although this is a small perforating lesion that is equal on both sides, keloids are bigger and more prevalent on the posterior surface. In this study, 141 keloids were evaluated, most of which were located on the posterior surface of the earlobe and caused by the piercing of the ear. Most of the earrings and piercing jewellery used had metallic backs. The more frequent occurrence of earlobe keloids on the posterior surface of the ear therefore may be associated with the exacerbation of local neurogenic inflammation caused by the metallic backs.

New approach to the understanding of keloid: psychoneuroimmune-endocrine aspects.

The skin is a dynamic and complex organ that relies on the interrelation among different cell types, macromolecules, and signaling pathways. Further, the skin has interactions with its own appendages and other organs such as the sebaceous glands and hair follicles, the kidney, and adrenal glands; systems such as the central nervous system; and axes such as the hypothalamic-pituitary-adrenal axis. These continuous connections give the skin its versatility, and when an injury is caused, some triggers start a cascade of events designed to restore its integrity. Nowadays, it is known that this psychoneuroimmune-endocrine intercommunication modulates both the homeostatic condition and the healing process. In this sense, the skin conditions before a trauma, whether of endogenous (acne) or exogenous origin (injury or surgical incision), could regulate the process of tissue repair. Most skin diseases such as psoriasis and atopic dermatitis, among others, have in their pathophysiology a psychogenic component that triggers integrated actions in the nervous, immune, and endocrine systems. However, fibroproliferative disorders of wound healing, such as hypertrophic scar and keloid, are not yet included in this listing, despite showing correlation with stress, especially with the psychosocial character. This review, by understanding the "brain-skin connection", presents evidence that allows us to understand the keloid as a psychomediated disease.

Image analysis software versus direct anthropometry for breast measurements.

PURPOSE: To compare breast measurements performed using the software packages ImageTool(r), AutoCAD(r) and Adobe Photoshop(r) with direct anthropometric measurements. METHODS: Points were marked on the breasts and arms of 40 volunteer women aged between 18 and 60 years. When connecting the points, seven linear segments and one angular measurement on each half of the body, and one medial segment common to both body halves were defined. The volunteers were photographed in a standardized manner. Photogrammetric measurements were performed by three independent observers using the three software packages and compared to direct anthropometric measurements made with calipers and a protractor. RESULTS: Measurements obtained with AutoCAD(r) were the most reproducible and those made with ImageTool(r) were the most similar to direct anthropometry, while measurements with Adobe Photoshop(r) showed the largest differences. Except for angular measurements, significant differences were found between measurements of line segments made using the three software packages and those obtained by direct anthropometry. CONCLUSION: AutoCAD(r) provided the highest precision and intermediate accuracy; ImageTool(r) had the highest accuracy and lowest precision; and Adobe Photoshop(r) showed intermediate precision and the worst accuracy among the three software packages.

Image analysis software versus direct anthropometry for breast measurements

PURPOSE: To compare breast measurements performed using the software packages ImageTool(r), AutoCAD(r) and Adobe Photoshop(r) with direct anthropometric measurements. METHODS: Points were marked on the breasts and arms of 40 volunteer women aged between 18 and 60 years. When connecting the points, seven linear segments and one angular measurement on each half of the body, and one medial segment common to both body halves were defined. The volunteers were photographed in a standardized manner. Photogrammetric measurements were performed by three independent observers using the three software packages and compared to direct anthropometric measurements made with calipers and a protractor. RESULTS: Measurements obtained with AutoCAD(r) were the most reproducible and those made with ImageTool(r) were the most similar to direct anthropometry, while measurements with Adobe Photoshop(r) showed the largest differences. Except for angular measurements, significant differences were found between measurements of line segments made using the three software packages and those obtained by direct anthropometry. CONCLUSION: AutoCAD(r) provided the highest precision and intermediate accuracy; ImageTool(r) had the highest accuracy and lowest precision; and Adobe Photoshop(r) showed intermediate precision and the worst accuracy among the three software packages. .

Perioperative corticosteroids for preventing complications following facial plastic surgery

BACKGROUND: Early recovery is an important factor for people undergoing facial plastic. However, the normal inflammatory processes that are a consequence of surgery commonly cause oedema (swelling) and ecchymosis (bruising), which are undesirable complications. Severe oedema and ecchymosis delay full recovery, and may make patients dissatisfied with procedures. Perioperative corticosteroids have been used in facial plastic surgery with the aim of preventing oedema and ecchymosis. OBJECTIVES: To determine the effects, including safety, of perioperative administration of corticosteroids for preventing complications following facial plastic surgery in adults. METHODS: Search strategy: In January 2014, we searched the following electronic databases: the Cochrane Wounds Group Specialised Register; the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library); Ovid MEDLINE; Ovid MEDLINE (In-Process & Other Non-Indexed Citations); Ovid Embase; EBSCO CINAHL; and Literatura Latino-Americana e do Caribe em Ciências da Saúde (LILACS). There were no restrictions on the basis of date or language of publication. Selection criteria: We included RCTs that compared the administration of perioperative systemic corticosteroids with another intervention, no intervention or placebo in facial plastic surgery. ata collection and analysis: Two review authors independently screened the trials for inclusion in the review, appraised trial quality and extracted data. MAIN RESULTS: We included 10 trials, with a total of 422 participants, that addressed two of the outcomes of interest to this review: swelling (oedema) and bruising (ecchymosis). Nine studies on rhinoplasty used a variety of different types, and doses, of corticosteroids. Overall, the results of the included studies showed that there is some evidence that perioperative administration of corticosteroids decreases formation of oedema over the first two postoperative ...

Perioperative corticosteroids for preventing complications following facial plastic surgery.

BACKGROUND: Early recovery is an important factor for people undergoing facial plastic surgery. However, the normal inflammatory processes that are a consequence of surgery commonly cause oedema (swelling) and ecchymosis (bruising), which are undesirable complications. Severe oedema and ecchymosis delay full recovery, and may make patients dissatisfied with procedures. Perioperative corticosteroids have been used in facial plastic surgery with the aim of preventing oedema and ecchymosis. OBJECTIVES: To determine the effects, including safety, of perioperative administration of corticosteroids for preventing complications following facial plastic surgery in adults. SEARCH METHODS: In January 2014, we searched the following electronic databases: the Cochrane Wounds Group Specialised Register; the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library); Ovid MEDLINE; Ovid MEDLINE (In-Process & Other Non-Indexed Citations); Ovid Embase; EBSCO CINAHL; and Literatura Latino-Americana e do Caribe em Ciências da Saúde (LILACS). There were no restrictions on the basis of date or language of publication. SELECTION CRITERIA: We included RCTs that compared the administration of perioperative systemic corticosteroids with another intervention, no intervention or placebo in facial plastic surgery. DATA COLLECTION AND ANALYSIS: Two review authors independently screened the trials for inclusion in the review, appraised trial quality and extracted data. MAIN RESULTS: We included 10 trials, with a total of 422 participants, that addressed two of the outcomes of interest to this review: swelling (oedema) and bruising (ecchymosis). Nine studies on rhinoplasty used a variety of different types, and doses, of corticosteroids. Overall, the results of the included studies showed that there is some evidence that perioperative administration of corticosteroids decreases formation of oedema over the first two postoperative days. Meta-analysis was only possible for two studies, with a total of 60 participants, and showed that a single perioperative dose of 10 mg dexamethasone decreased oedema formation in the first two days after surgery (SMD = -1.16, 95% CI: -1.71 to -0.61, low quality evidence). The evidence for ecchymosis was less consistent across the studies, with some contradictory results, but overall there was some evidence that perioperatively administered corticosteroids decreased ecchymosis formation over the first two days after surgery (SMD = -1.06, 95% CI:-1.47 to -0.65, two studies, 60 participants, low quality evidence ). The difference was not maintained after this initial period. One study, with 40 participants, showed that high doses of methylprednisolone (over 250 mg) decreased both ecchymosis and oedema between the first and seventh postoperative days. The only study that assessed facelift surgery identified no positive effect on oedema with preoperative administration of corticosteroids. Five trials did not report on harmful (adverse) effects; four trials reported that there were no adverse effects; and one trial reported adverse effects in two participants treated with corticosteroids as well as in four participants treated with placebo. None of the studies reported recovery time, patient satisfaction or quality of life. The studies included were all at an unclear risk of selection bias and at low risk of bias for other domains. AUTHORS' CONCLUSIONS: There is limited evidence for rhinoplasty that a single perioperative dose of corticosteroids decreases oedema and ecchymosis formation over the first two postoperative days, but the difference is not maintained after this period. There is also limited evidence that high doses of corticosteroids decrease both ecchymosis and oedema between the first and seventh postoperative days. The clinical significance of this decrease is unknown and there is little evidence available regarding the safety of this intervention. More studies are needed because at present the available evidence does not support the use of corticosteroids for prevention of complications following facial plastic surgery.

Cost-utility of reduction mammaplasty assessed for the Brazilian public health system.

BACKGROUND: Economic evaluation is important for making decisions about resource allocation. Few cost-utility or cost-effectiveness studies on breast hypertrophy have been reported in the medical literature. OBJECTIVES: The authors sought to determine the cost-utility of reduction mammaplasty in the Brazilian national health care system. METHODS: This randomized controlled study was conducted in a university-affiliated hospital. Sixty patients with breast hypertrophy were enrolled prospectively and were assigned randomly to either the control group (n = 30 patients who received follow-up for 6 months) or the treatment group (n = 30 patients who underwent reduction mammaplasty). Direct costs were recorded, and the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) was administered to both groups at the beginning of the study (preoperatively for the treatment group) and 3 and 6 months postoperatively. Utility was determined with Instrument 6D of the Brazilian version of the Short-Form Health Survey (SF-6D), from the SF-36 data. RESULTS: At the 6-month follow-up, the treatment group showed an improvement in utility, with an average direct cost of approximately £104. CONCLUSIONS: Reduction mammaplasty performed in the Brazilian national health care system provides a cost-utility ratio equivalent to approximately £142 per 1 quality-adjusted life year.

Health economics and health preference concepts to orthopedics practitioners.

The aim of this study was to describe concepts of health economics in order to update and provide the orthopedic practitioner decision making parameters based on preferences. Four basic types of studies of economical evaluation were presented (cost minimization analysis, cost-benefit, cost-effectiveness and cost-utility), as well as the origin, the concept, advantages and disadvantages of using QALY and utility. It was discussed the importance of costs and of SF-6D, an instrument able to get through the utility data from the Medical Outcomes Study 36-item Short Form Health Survey (SF-36). Physicians, especially orthopedic practitioners, are increasingly using technologies which are progressively expensive, thus, they should be able to understand health economics concepts, the importance of utility in clinical decision making process and economic analysis in health.09+

Effects of subcutaneous carbon dioxide on calcitonin gene related peptide and substance P secretion in rat skin.

PURPOSE: To investigate the subcutaneous injection of carbon dioxide (CO2) on neuropeptides Calcitonin Gene-Related Peptide (CGRP) and Substance P (SP) secretion in rat skin. METHODS: Fifty-six Wistar-EPM rats were distributed in two groups: one for CGRP analysis, the other for SP analysis. Each group was subdivided into four subgroups: control (Cont), control with needle (ContNd), CO2 injection (CO2Inj) and atmospheric air injection (AirInj) - with seven animals each. Sample analyses of partial skin were conducted by Western Blotting (WB). RESULTS: In SP group, there was a decrease in the amount of neuropeptides in subgroups CO2Inj and AirInj. Similarly, in CGRP group, there was a decrease in the amount of pro-CGRP neuropeptides (15 kDa) in subgroups CO2Inj and AirInj; Nevertheless, there was no decrease in the amount of CGRP (5 kDa) in any subgroups. CONCLUSION: Subcutaneous injection of CO2 and atmospheric air decreased the amount of Substance P and pro-Calcitonin Gene-Related Peptide (15 kDa) neuropeptides in rat skin.

Effects of subcutaneous carbon dioxide on calcitonin gene related peptide and substance P secretion in rat skin

To investigate the subcutaneous injection of carbon dioxide (CO2) on neuropeptides Calcitonin Gene-Related Peptide (CGRP) and Substance P (SP) secretion in rat skin. Fifty-six Wistar-EPM rats were distributed in two groups: one for CGRP analysis, the other for SP analysis. Each group was subdivided into four subgroups: control (Cont), control with needle (ContNd), CO2 injection (CO2Inj) and atmospheric air injection (AirInj) - with seven animals each. Sample analyses of partial skin were conducted by Western Blotting (WB). RESULTS: In SP group, there was a decrease in the amount of neuropeptides in subgroups CO2Inj and AirInj. Similarly, in CGRP group, there was a decrease in the amount of pro-CGRP neuropeptides (15 kDa) in subgroups CO2Inj and AirInj; Nevertheless, there was no decrease in the amount of CGRP (5 kDa) in any subgroups. Subcutaneous injection of CO2 and atmospheric air decreased the amount of Substance P and pro-Calcitonin Gene-Related Peptide (15 kDa) neuropeptides in rat skin.

Anthropometry of the breast region: how to measure?

BACKGROUND: Breast region measurements are important for research, but they may also become significant in the legal field as a quantitative tool for preoperative and postoperative evaluation. Direct anthropometric measurements can be taken in clinical practice. The aim of this study was to compare direct breast anthropometric measurements taken with a tape measure and a compass. METHODS: Forty women, aged 18-60 years, were evaluated. They had 14 anatomical landmarks marked on the breast region and arms. The union of these points formed eight linear segments and one angle for each side of the body. The volunteers were evaluated by direct anthropometry in a standardized way, using a tape measure and a compass. RESULTS: Differences were found between the tape measure and the compass measurements for all segments analyzed (p>0.05). CONCLUSION: Measurements obtained by tape measure and compass are not identical. Therefore, once the measurement tool is chosen, it should be used for the pre- and postoperative measurements in a standardized way. 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 .