Precision Drug Repurposing: A Deep Learning Toolkit for Identifying 34 Hyperpigmentation-Associated Genes and Optimizing Treatment Selection.

BACKGROUND: Hyperpigmentation is a skin disorder characterized by a localized darkening of the skin due to increased melanin production. When patients fail first line topical treatments, secondary treatments such as chemical peels and lasers are offered. However, these interventions are not devoid of risks and are associated with postinflammatory hyperpigmentation. In the quest for novel therapeutic potentials, this study aims to investigate computational methods in the identification of new targeted therapies in the treatment of hyperpigmentation. METHODS: We used a comprehensive approach, which integrated text mining, interpreting gene lists through enrichment analysis and integration of diverse biological information (GeneCodis), protein-protein association networks and functional enrichment analyses (STRING), and plug-in network centrality parameters (Cytoscape) to pinpoint genes closely associated with hyperpigmentation. Subsequently, analysis of drug-gene interactions to identify potential drugs (Cortellis) was utilized to select drugs targeting these identified genes. Lastly, we used Deep Learning Based Drug Repurposing Toolkit (DeepPurpose) to conduct drug-target interaction predictions to ultimately identify candidate drugs with the most promising binding affinities. RESULTS: Thirty-four hyperpigmentation-related genes were identified by text mining. Eight key genes were highlighted by utilizing GeneCodis, STRING, Cytoscape, gene enrichment, and protein-protein interaction analysis. Thirty-five drugs targeting hyperpigmentation-associated genes were identified by Cortellis, and 29 drugs, including 16 M2PK1 inhibitors, 11 KRAS inhibitors, and 2 BRAF inhibitors were recommended by DeepPurpose. CONCLUSIONS: The study highlights the promise of advanced computational methodology for identifying potential treatments for hyperpigmentation.

Systematic Review and Meta-Analysis of Global Neuroma Incidence in Upper Extremity Amputees.

BACKGROUND: Neuromas substantially decrease a patient's quality of life and obstruct the use of prosthetics. This systematic review and meta-analysis aimed to determine the global incidence of neuroma formation in upper extremity amputees. METHODS: A literature search was performed using 3 databases: Web of Science, MEDLINE, and Cochrane. Inclusion criteria for the systematic review were those studies investigating only upper extremity amputees and reported postamputation neuroma. A random-effects, inverse-variance analysis was conducted to determine the pooled proportion of neuromas within the upper extremity amputation population. Critical appraisal using the JBI Checklist for Studies Reporting Prevalence Data of each individual article were performed for the systematic review. RESULTS: Eleven studies met the inclusion criteria collating a total of 1931 patients across 8 countries. More than three-fourth of patients are young men (77%; age range, 19-54 years) and had an amputation due to trauma. The random-effects analysis found the pooled combined proportion of neuromas to be 13% (95% confidence interval, 8%-18%). The treatment of neuroma is highly variable, with some patients receiving no treatment. CONCLUSIONS: The pooled proportion of neuroma incidence in the 1931 patients was 13%. With the known global prevalence of upper extremity amputees, this translates to nearly 3 million amputees suffering from a neuroma globally. Increasing training in preventative surgical methods could contribute to lowering this incidence and improving the outcomes of this patient population.

Addressing Current Deficits in Patient Education Materials Through Crowdsourcing.

BACKGROUND: Patient education materials are commonly reported to be difficult to understand. OBJECTIVES: We aimed to use crowdsourcing to improve patient education materials at our institution. METHODS: This was a department-wide quality improvement project to increase organizational health literacy. There are 6 phases of this pilot study: (1) evaluating preexisting patient education materials, (2) evaluating online patient education materials at the society (the American Society of Plastic Surgeon) and government level (Medline Plus), (3) redesigning our patient education material and reevaluating the education material, (4) crowdsourcing to evaluate understandability of the new patient education material, (5) data analysis, and (6) incorporating crowdsourcing suggestions to the patient education material. RESULTS: Breast-related patient education materials are not easy to read at the institution level, the society level, and the government level. Our new implant-based breast reconstruction patient education material is easy to read as demonstrated by the crowdsourcing evaluation. More than 90% of the participants reported our material is "very easy to understand" or "easy to understand." The crowdsourcing process took 1.5 days, with 700 workers responding to the survey. The total cost was $9. After incorporating participants' feedback into the finalized material, the readability of the material is at the recommended reading level. The material also had the recommended length (between 400 and 800 words). DISCUSSION: Our study demonstrated a pathway for clinicians to efficiently obtain a large amount of feedback to improve patient education materials. Crowdsourcing is an effective tool to improve organizational health literacy.

Assessment of x-ray efficacy for intraoperative microneedle retrieval using a cadaveric model.

INTRODUCTION: Institutional protocols often mandate the use of x-rays when a microneedle is lost intraoperatively. Although x-rays can reliably show a macroneedle, the benefit of x-rays in detecting microneedles in human tissues has not been established as available data on this topic are investigated in anthropometric models. The current study aims to evaluate whether x-rays can reliably detect retained microneedles in a human cadaveric model. We hypothesize that microneedles would be detected at a significantly lower rate than macroneedles by x-ray in human tissues. MATERIALS AND METHODS: Needles ranging from 4-0 to 10-0 were placed randomly throughout a cadaveric hand and foot. Each tissue sample was x-rayed using a Fexitron X-Ray machine, taking both anteroposterior and lateral views. A total of six x-ray images were then evaluated by 11 radiologists, independently. The radiologists circled over the area where they visualized a needle. The accuracy of detecting macroneedles (size 4-0 to 7-0) was compared with that of microneedles (size 8-0 to 10-0) using a chi-square test. RESULTS: The overall detection rate for the microneedles was significantly lower than the detection rate for macroneedles (13.5% vs 88.8%, p < .01). When subcategorized between the hand and the foot, the detection rate for microneedles was also significantly lower than the rate for macroneedles (hand: 7.6% for microneedles, 93.2% for macroneedles, p < .01; foot: 19.5% for microneedles, 84.4% for macroneedles, p < .01). The detection rate, in general, significantly decreased as the sizes of needles became smaller (7-0:70.5%, 8-0:18.2%, 9-0:16.7%, 10-0:2.3%, p < .01). CONCLUSION: X-rays, while useful in detecting macroneedles, had a significantly lower rate of detecting microneedles in a cadaveric model. The routine use of x-rays for a lost microneedle may not be beneficial. Further investigation with fresh tissue and similar intraoperative x-ray systems is warranted to corroborate and support these findings.

Optimizing Safety and Aesthetics in Facial Feminization: Laryngoscopic-Assisted Chondrolaryngoplasty (2019-2023).

INTRODUCTION: The thyroid cartilage, an androgen-sensitive structure, enlarges during puberty in individuals assigned male at birth, often resulting in a pronounced neck protuberance. This feature can exacerbate gender dysphoria in transfeminine patients. Chondrolaryngoplasty, commonly known as tracheal shave, is a procedure incorporated into facial feminization surgery (FFS) to address this issue. This study reports on the implementation of an endoscopic-assisted chondrolaryngoplasty technique, its safety, and the outcomes observed. METHODS: The authors conducted a retrospective review of chondrolaryngoplasty cases at our center, examining patient outcomes and procedural safety. The analysis included a breakdown of concurrent gender-affirming surgeries performed. An endoscopic-guided technique was utilized, and its procedural steps were documented in a video. RESULTS: In the past five years, 32 patients received chondrolaryngoplasty at our facility. Postoperative complications were minimal, with no infections, wound separations, or surgical site complications reported. Only one patient experienced temporary hoarseness, which resolved within 6 weeks without intervention. The procedure was frequently combined with other surgical interventions, with the average patient undergoing 3 additional procedures, the most common being augmentation mammaplasty, brow lifting, and frontal bone reduction. CONCLUSIONS: Tracheal shave is an effective surgical technique for alleviating gender dysphoria in transfeminine patients. Keys to its success include the accurate identification of thyroid cartilage, especially in patients with enlarged cricoid cartilages, intraoperative coordination with anesthesia for laryngoscopic vocal cord visualization, sub-perichondrial cartilage excision to minimize the risk of bleeding and damage near the vocal cords, and carefully layered closure to optimize scar healing.

Easing the Burden on Caregivers- Applications of Artificial Intelligence for Physicians and Caregivers of Children with Cleft Lip and Palate.

OBJECTIVE: Many caregivers of children with cleft lip and palate experience a high level of anxiety throughout their child's medical and surgical care. We aim to evaluate artificial intelligence (AI) as a tool to mitigate these feelings and can aid clinicians in the development of robust pediatric educational materials for caregivers and families. DESIGN: Thirteen of the most common postoperative questions following cleft lip and/or palate repair were developed by an expert panel of senior Pediatric Plastic Surgeons and were posed to ChatGPT. Professional answers from the expert panel were provided and compared to responses from ChatGPT. A literature review was also conducted to generate a new support model for caregivers with children undergoing a surgical procedure. SETTING: Department of Pediatric Plastic Surgery at a metropolitan Children's Hospital. PARTICIPANTS: Senior Pediatric Plastic Surgeons at a metropolitan Children's Hospital. INTERVENTIONS: None. MAIN OUTCOME MEASURE: The primary outcome was to determine the ability of ChatGPT to respond to common postoperative questions and to develop a model for AI assistance in family-centered perioperative care. RESULTS: ChatGPT had a postoperative question response accuracy rate of 69% when compared with subject matter expert responses, with its greatest errors being information errors. An extensive literature search revealed that AI can assist in multiple traditional perioperative strategies to reduce caregivers and patient anxiety. CONCLUSIONS: Artificial Intelligence can help to reduce the burden of generating patient education materials as well as support caregivers in multiple aspects and perioperative care.

Complications and Risks Associated with the Different Types of Abdominoplasties: An Analysis of 55,956 Patients.

BACKGROUND: Different types of abdominoplasties have been developed to address individual patient characteristics. However, complication rates and risk factors for complications between different types of abdominoplasties has yet to be reported. OBJECTIVES: The aim of this study was to evaluate the complication rates and risks associated with each type of abdominoplasty. METHODS: Using the CosmetAssure database, patients undergoing an abdominoplasty from 2015 to 2022 were identified. Demographic factors and major complications were recorded and analyzed using a chi-square test or ANOVA. A logistic regression was performed to identify the risk associated with each type of abdominoplasty for developing complications. RESULTS: A total of 55,596 patients underwent an abdominoplasty procedure by any method. The overall complication rate was 2.1%. There was a significant difference in the overall complication rate between all seven types of abdominoplasties (p<0.05), with Fleur-de-lis abdominoplasty having the highest complication rate. The year of surgery, being underweight or morbidly obese, diabetes, and being male placed patients at a significantly higher risk for developing a post-operative complication. Over 15,000 patients (27.2%) had concurrent procedures related to breast surgery, other body contouring, liposuction, or facial surgery. When accounting for various risk factors in a regression model, there was no significant added risk for major complications after a combination procedure with an abdominoplasty compared to abdominoplasty alone. CONCLUSIONS: Among the different types of abdominoplasties, a Fleur-de-lis abdominoplasty has the highest complication rate. Concurrent cosmetic procedures in addition to an abdominoplasty showed no added risk for major complications compared to abdominoplasty alone.

Three siblings with variable degrees of neuromuscular involvement and congenital sideroblastic anemia: A peculiar phenotype and a surprise genotypic explanation.

INTRODUCTION: Congenital sideroblastic anemias (CSAs) are a group of inherited bone-marrow disorders manifesting with erythroid hyperplasia and ineffective erythropoiesis. METHODS: We describe a detailed clinical and genetic characterization of three siblings with CSA. RESULTS: Two of them had limb-girdle myopathy and global developmental delay. The two elder siblings performed allogenic hematopoietic stem-cell transplantation 5 and 3 years prior with stabilization of the hematological features. Exome sequencing in the non-transplanted sibling revealed a novel homozygous nonsense variant in SLC25A38 gene NM_017875.2:c.559C > T; p.(Arg187*) causing autosomal-recessive sideroblastic anemia type-2, and a second homozygous pathogenic previously reported variant in GMPPB gene NM_013334.3:c.458C > T; p.(Thr153Ile) causing autosomal-recessive muscular dystrophy-dystroglycanopathy type B14. With the established diagnosis, hematopoietic stem cell transplantation is now being scheduled for the youngest sibling, and a trial therapy with acetylcholine esterase inhibitors was started for the two neurologically affected patients with partial clinical improvement. CONCLUSION: This family emphasizes the importance of whole-exome sequencing for familial cases with complex phenotypes and vague neurological manifestations.

Neoadjuvant Therapy in Melanoma: Where Are We Now?

PURPOSEOF REVIEW: This review summarizes the current state of neoadjuvant immunotherapy and targeted therapy for locoregionally advanced melanoma. RECENT FINDINGS: Melanoma systemic therapy has witnessed major advances with the development of immune checkpoint inhibitors and molecularly targeted therapy that have been translated into the neoadjuvant setting in managing locoregionally advanced disease. PD1 blockade as monotherapy and combined with CTLA4 blockade or LAG3 inhibition has demonstrated major improvements in reducing the risk of relapse and death that were associated with high pathologic response rates. Similar results were reported with BRAF-MEK inhibition for BRAF mutant melanoma with high pathologic response rates that appear to be less durable compared to immunotherapy. More importantly, in a recent randomized trial, event-free survival was significantly improved with neoadjuvant pembrolizumab compared to standard surgery and adjuvant therapy. Neoadjuvant therapy has become the standard of care for locoregionally advanced melanoma. Ongoing studies will define the most optimal combination regimens.

Comparison of Patient Education Materials Generated by Chat Generative Pre-Trained Transformer Versus Experts: An Innovative Way to Increase Readability of Patient Education Materials.

INTRODUCTION: Improving patient education materials may improve patient outcomes. This study aims to explore the possibility of generating patient education materials with the assistance of a large language model, Chat Generative Pre-Trained Transformer (ChatGPT). In addition, we compare the accuracy and readability of ChatGPT-generated materials versus expert-generated materials. METHODS: Patient education materials in implant-based breast reconstruction were generated by experts and ChatGPT independently. Readability and accuracy of the materials are the main outcomes. Readability of the materials was compared using Flesch-Kincaid score. Accuracy of the materials generated by ChatGPT was evaluated by 2 independent reviewers. Content errors are categorized into information errors, statistical errors, and multiple errors (errors more than 2 types). RESULTS: The content generated by experts had higher readability. The Flesch-Kincaid score is at the 7.5 grade for expert-generated materials, whereas the content generated by ChatGPT is at the 10.5 grade (despite ChatGPT being asked to generate content at the seventh grade level). The accuracy of ChatGPT-generated content is 50%, with most errors being information errors. ChatGPT often provides information about breast reduction or breast augmentation, despite being asked specifically about breast reconstruction. Despite its limitation, ChatGPT significantly reduced the time required to generate patient education materials. Although it takes experts 1 month to generate patient education materials, ChatGPT generates materials within 30 minutes. CONCLUSIONS: ChatGPT can be a powerful starting tool to generate patient education materials. However, its readability and accuracy still require improvements.

Examination of Outcome Disparities in Reports of Prepectoral and Subpectoral Direct-to-Implant Reconstruction: A Systematic Review and Meta-analysis.

BACKGROUND: There are mixed results in surgical complications regarding the usage of prepectoral versus subpectoral implant placement in direct-to-implant breast reconstruction. This study aimed to provide a comprehensive synthesis of surgical complications between the subpectoral and prepectoral reconstructive method. METHODS: PubMed, Embase, and Cochrane were searched for literature published up until December 2022. Studies that compared subpectoral and prepectoral breast reconstruction and reported at least one postoperative complication were included. The following 8 major outcomes were included: revision and reoperation, capsular contracture, explantation, seroma, hematoma, infection, skin necrosis, and animation deformity. Systematic review and meta-analysis were performed to compare outcomes of the 2 techniques. Subgroup analysis was performed to compare whether practice differences in different countries may have an impact on outcomes. RESULTS: A total of 18 studies were identified in our literature search. Two thousand three hundred sixty patients were included, representing a total of 3135 breasts. Our analysis demonstrated that prepectoral reconstruction had significantly lower odds of developing postoperative hematoma [odds ratio (OR), 0.62; P = 0.05], seroma (OR, 0.67; P = 0.01), infection (OR, 0.64; P = 0.03), revision and reoperation (OR, 0.44; P < 0.00001), and animation deformity (OR, 0.01; P < 0.00001), compared with the subpectoral method. Subgroup analysis showed that differences between 3 countries (United States, Korea, Italy) are low (all subgroup heterogeneity test P > 0.1). CONCLUSIONS: While both subpectoral and prepectoral are safe methods for breast reconstruction, the prepectoral technique may lead to lower odds of developing multiple major postoperative complications.

Comparison of Complication Rates Between Subpectoral vs Prepectoral Techniques in Prosthetic Breast Reconstruction.

BACKGROUND: The location of tissue expanders in implant-based breast reconstruction remains controversial due to variation in surgical techniques and devices. OBJECTIVES: The aim of this study was to provide a comprehensive assessment of early and late complication rates between prepectoral and subpectoral placement of tissue expanders. METHODS: A retrospective cohort study was conducted of all adult female patients who had undergone 2-stage implant-based breast reconstruction between 2013 and 2019 in our institution. Early complication was defined as complications that occurred within 30 days after surgery. Time-to-event analyses were performed and Cox proportional hazard models were used to adjust for confounders. RESULTS: In total, 854 patients were included; 76% of patients underwent a subpectoral tissue expander placement. After the first-stage procedure, the early complication rate was 34% and the late complication rate was 36.4%. After the second-stage procedure, the early complication rate was 16.3% and the late complication rate was 16.1%. Location of the tissue expander did not predict either overall early or late complication rates, regardless of the stages of reconstruction, after adjusting for confounders. Tissue expanders placed in prepectoral plane were associated with a higher hazard ratio (HR) for developing early and late infection after the first stage of reconstruction (HR, 2.1 and 2.4, respectively) as well as late infection after the second stage of reconstruction (HR, 5.3; all P < .05). CONCLUSIONS: Location of tissue expanders did not predict risk of complication. However, the prepectoral group was associated with an increased risk of developing infection.

Enhanced immune activation within the tumor microenvironment and circulation of female high-risk melanoma patients and improved survival with adjuvant CTLA4 blockade compared to males.

BACKGROUND: We hypothesized that a gender difference in clinical response may exist to adjuvant CTLA4 blockade with ipilimumab versus high-dose IFNα (HDI). We investigated differences in candidate immune biomarkers in the circulation and tumor microenvironment (TME). PATIENTS AND METHODS: This gender-based analysis was nested within the E1609 trial that tested adjuvant therapy with ipilimumab 3 mg/kg (ipi3) and 10 mg/kg (ipi10) versus HDI in high risk resected melanoma. We investigated gender differences in treatment efficacy with ipi3 and ipi10 versus HDI while adjusting for age, stage, ECOG performance (PS), ulceration, primary tumor status and lymph node number. Forest plots were created to compare overall survival (OS) and relapse free survival (RFS) between ipi and HDI. Gene expression profiling (GEP) was performed on tumors of 718 (454 male, 264 female) patients. Similarly, serum and peripheral blood mononuclear cells (PBMC) samples were tested for soluble and cellular biomarkers (N = 321 patients; 109 female and 212 male). RESULTS: The subgroups of female, stage IIIC, PS = 1, ulcerated primary, in-transit metastasis demonstrated significant improvement in RFS and/or OS with ipi3 versus HDI. Female gender was significant for both OS and RFS and was further explored. In the RFS comparison, a multivariate Cox regression model including significant variables indicated a significant interaction between gender and treatment (P = 0.024). In peripheral blood, percentages of CD3+ T cells (P = 0.024) and CD3+ CD4+ helper T cells (P = 0.0001) were higher in females compared to males. Trends toward higher circulating levels of IL1ß (P = 0.07) and IL6 (P = 0.06) were also found in females. Males had higher percentages of monocytes (P = 0.03) with trends toward higher percentages of regulatory T cells (T-reg). Tumor GEP analysis supported enhanced infiltration with immune cells including gammadelta T cells (P = 0.005), NK cells (P = 0.01), dendritic cells (P = 0.01), CD4+ T cells (P = 0.03), CD8+ T cells (P = 0.03) and T-reg (P = 0.008) in the tumors of females compared to males and a higher T-effector and IFNγ gene signature score (P = 0.0244). CONCLUSION: Female gender was associated with adjuvant CTLA4 blockade clinical benefits and female patients were more likely to have evidence of type1 immune activation within the TME and the circulation. Trial registration ClinicalTrials.gov NCT01274338. Registered 11 January 2011, https://www. CLINICALTRIALS: gov/ct2/show/NCT01274338.

Power-Assisted Liposculpture in Male Patients: A Spectrum of Definitions.

BACKGROUND: Liposculpture procedures have gained popularity over the last 2 decades with the evolution of surgeons' skills and technological advancement. According to the 2018 The Aesthetic Society report, liposuction is the second-most popular aesthetic procedure in the United States. OBJECTIVES: The authors aimed to demonstrate that a spectrum of liposculpture definitions can be achieved utilizing power-assisted liposuction (PAL). Also, the authors sought to describe the satisfaction and complication rates in mild-, moderate-, and high-definition groups utilizing the PAL technology. METHODS: The authors designed a single-center retrospective study, including male patients who underwent PAL liposculpture of the chest, abdomen, back, and arms. Inclusion criteria were male patients >18 years of age and body mass index <30 kg/m2. Measured outcomes included extent of definition, complication rates, and levels of satisfaction. RESULTS: Fifty male patients were included in this study between January 2018 and November 2019. The average age was 37.34 years (range = 25-56 years). The average body mass index was 26.4 kg/m2 (range = 24-30 years). A total of 54.3% of patients opted for high definition (HD), 36.4% for moderate definition, and 9.2% for mild definition. There were no major complications. The HD subgroup registered the highest incidence of minor complications (21%). Patient satisfaction levels were high in all 3 subgroups, with the highest scores in the HD subgroup (9.3/10). CONCLUSIONS: A spectrum of definitions can be safely achieved utilizing the PAL technology, with high patient satisfaction in mild-, moderate-, and high-definition liposculpture subgroups and low complication rates.

Deletion of oxyR in Legionella pneumophila causes growth defect on agar.

The intracellular pathogen Legionella pneumophila (Lp) is a strict aerobe, surviving and replicating in environments where it frequently encounters reactive oxygen species (ROS), such as the nutrient-poor water environment and its replicative niche inside host cells. In many proteobacteria, the LysR-type regulator OxyR controls the oxidative stress response; however, the importance of the OxyR homologue in Lp is still unclear. Therefore, we undertook the characterization of phenotypes associated with the deletion of oxyR in Lp. Contrary to the wild type, the oxyR deletion mutant exhibits a severe growth defect on charcoal - yeast extract (CYE) agar lacking α-ketoglutarate supplementation. Growth in AYE broth (CYE without agar and charcoal), in amoeba and in human cultured macrophages, and survival in water is unaffected by the deletion. Supplementing CYE agar with antioxidants that neutralize ROS or introducing the oxyR gene in trans rescues the observed growth defect. Moreover, the mutant grows as well as the wild type on CYE plates made with agarose instead of agar, suggesting that a compound present in the latter is responsible for the growth defect phenotype.

Ethnic Rhinoplasty in Female Patients: The Neoclassical Canons Revisited.

BACKGROUND: Despite the substantial amount of research devoted to objectively defining facial attractiveness, the canons have remained a paradigm of aesthetic facial analysis, yet their omnipresence in clinical assessments revealed their limitations outside of a subset of North American Caucasians, leading to criticism about their validity as a standard of facial beauty. In an effort to introduce more objective treatment planning into ethnic rhinoplasty, we compared neoclassical canons and other current standards pertaining to nasal proportions to anatomic proportions of attractive individuals from seven different ethnic backgrounds. METHODS: Beauty pageant winners (Miss Universe and Miss World nominees) between 2005 and 2015 were selected and assigned to one of seven regionally defined ethnic groups. Anteroposterior and lateral images were obtained through Google, Wikipedia, Miss Universe, and Miss World Web sites. Anthropometry of facial features was performed via Adobe Photoshop TM. Individual facial measurements were then standardized to proportions and compared to the neoclassical canons. RESULTS: Our data reflected an ethnic-dependent preference for the multiple fitness model. Wide-set eyes, larger mouth widths, and smaller noses were significantly relevant in Eastern Mediterranean and European ethnic groups. Exceptions lied within East African and Asian groups. CONCLUSION: As in the attractive face, the concept of the ideal nasal anatomy varies between different ethnicities. Using objective criteria and proportions of beauty to plan and execute rhinoplasty in different ethnicities can help the surgeon plan and deliver results that are in harmony with patients' individual background and facial anatomy. 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 .