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A reproducible and sensitive assay for melanotropic agents is described employing mouse melanoma cells in culture and measuring tyrosinase activity in terms of production of tritiated water from L-(ring-3,5-³H)-tyrosine. Molar concentrations of peptides inducing one-half maximal stimulation of tyrosinase activity were: β-MSH, 1 ± 2 × 10-9; α-MSH and βh-LPH, 1 ± 2 × 10-8; ACTHp, 1 ± 2 × 10-7. βp9-18-MSH and melanotropin potentiating factor, βs88-91-LPH exhibited no activity at concentrations as high as 10-5M. [ABSTRACT FROM AUTHOR]

STUDY DESIGN: A retrospective review of scores from the Scoliosis Research Society outcomes instrument (SRS-24 questionnaire). OBJECTIVE: To quantify the isolated effects of spinal fusion and deformity magnitude on quality of life in patients with adolescent idiopathic scoliosis (AIS). SUMMARY OF BACKGROUND DATA: Significant improvements in 2-year postoperative SRS-24 questionnaire scores have been reported despite the loss of spinal motion due to instrumentation and arthrodesis. As deformity reduction may influence patient perception, it has been difficult to isolate the effect of spinal fusion on quality of life after scoliosis surgery. METHODS: SRS-24 scores were compared between 3 cohorts of AIS patients (preoperative, postoperative, and nonoperative) using an ANOVA (P < 0.05) to determine the isolated effects of spinal fusion and deformity magnitude. Preoperative SRS-24 scores were collected from a group of patients with preoperative major Cobb angles greater than 40 degrees (n = 194). Postoperative SRS-24 scores were collected from patients with preoperative major Cobb angles greater than 40 degrees and 2-year postoperative major Cobb angles between 20 degrees and 40 degrees (n = 196). Finally, SRS-24 scores were collected from a nonoperative group of patients with major Cobb angles between 20 degrees and 40 degrees (n = 112). RESULTS: Spinal fusion was found to have a negative isolated effect on the Activity domain (-0.3) and on the Total score (-0.2) (P = 0.001) of the SRS-24 questionnaire (score range: 1-5). A smaller deformity magnitude, on the other hand, was found to have a significantly positive isolated effect on all 4 preoperative domains (P < 0.001) and on the Total score (P < 0.001). The combined effect of surgery (spinal fusion and deformity correction) was found to be significantly positive for the Total score (P < 0.001) and for the domains of Pain, Self-Image, and Function (P < 0.001). CONCLUSION: Spinal fusion has an isolated negative effect on AIS patients' quality of life (Total score) mostly due to a decrease in scores of the Activity domain. The overall positive effect of surgery depends on the individual effects of spinal fusion (slight reduction in quality of life) and deformity reduction (modest improvement in quality of life). [ABSTRACT FROM AUTHOR]

Background: Maternal health outcomes have been underresearched due to people who are pregnant being underrepresented or excluded from studies based on their status as a vulnerable study population. Based on the available evidence, Black people who are pregnant have dramatically higher maternal morbidity and mortality rates compared to other racial and ethnic groups. However, insights into prenatal care-including the use of medications, immunizations, and prenatal vitamins-are not well understood for pregnant populations, particularly those that are underrepresented in biomedical research. Medication use has been particularly understudied in people who are pregnant; even though it has been shown that up to 95% of people who are pregnant take at least 1 or more medications. Understanding gaps in use could help identify ways to reduce maternal disparities and optimize maternal health outcomes., Objective: We aimed to characterize and compare the use of prenatal vitamins, immunizations, and commonly used over-the-counter and prescription medications among people who are pregnant, those self-identifying as Black versus non-Black, and those living in rural versus urban regions in the United States., Methods: We conducted a prospective, decentralized study of 4130 pregnant study participants who answered survey questionnaires using a mobile research app that was only available on iOS (Apple Inc) devices. All people who were pregnant, living in the United States, and comfortable with reading and writing in English were eligible. The study was conducted in a decentralized fashion with the use of a research app to facilitate enrollment using an eConsent and self-reported data collection., Results: Within the study population, the use of prenatal vitamins, antiemetics, antidepressants, and pain medication varied significantly among different subpopulations underrepresented in biomedical research. Black participants reported significantly lower frequencies of prenatal vitamin use compared to non-Black participants (P<.001). The frequency of participants who were currently receiving treatment for anxiety and depression was also lower among Black and rural groups compared to their non-Black and urban counterparts, respectively. There was significantly lower use of antidepressants (P=.002) and antiemetics (P=.02) among Black compared to non-Black participants. While prenatal vitamin use was lower among participants in rural areas, the difference between rural and urban groups did not reach statistical significance (P=.08). There were no significant differences in vaccine uptake for influenza or tetanus-diphtheria-pertussis (TDaP) across race, ethnicity, rural, or urban status., Conclusions: A prospective, decentralized app-based study demonstrated significantly lower use of prenatal vitamins, antiemetics, and antidepressants among Black pregnant participants. Additionally, significantly fewer Black and rural participants reported receiving treatment for anxiety and depression during pregnancy. Future research dedicated to identifying the root mechanisms of these differences can help improve maternal health outcomes, specifically for diverse communities., (©Toluwalase Ajayi, Jeff Pawelek, Hansa Bhargava, Arij Faksh, Jennifer Radin. Originally published in JMIR Formative Research (https://formative.jmir.org), 28.11.2023.)

It is not clear if mature secondary growth coniferous forests can support similar pollinator communities as old growth coniferous forests, or how active management (e.g., retention forestry) in mature secondary growth forests may affect pollinator communities. We compare the native bee community and plant-bee interaction networks of old growth, naturally regenerating and actively managed (retention forestry) mature secondary growth forests of similar stand age. Old growth forests had a higher bee species richness and Shannon's diversity index, but not Simpson's diversity index, than both actively managed and naturally regenerating mature secondary forests. Forest type (old-growth, naturally regenerating mature secondary growth, and actively managed mature secondary growth) had a significant effect on bee community composition. Redwood forest bee-plant interaction networks were small in size and had lower complexity than expected and few connector species. While studies suggest that small-scale timber harvest may increase bee biodiversity in the short-term in other coniferous forest habitats, our study suggests that there may be long-term negative effects of clear-cutting that lower bee biodiversity in mature secondary growth forests as compared to mature old-growth forests., Competing Interests: The authors have no conflicts of interest to declare., (© 2023 The Authors. Ecology and Evolution published by John Wiley & Sons Ltd.)

Electronic health record (EHR) technology has become a central digital health tool throughout health care. EHR systems are responsible for a growing number of vital functions for hospitals and providers. More recently, patient-facing EHR tools are allowing patients to interact with their EHR and connect external sources of health data, such as wearable fitness trackers, personal genomics, and outside health services, to it. As patients become more engaged with their EHR, the volume and variety of digital health information will serve an increasingly useful role in health care and health research. Particularly due to the COVID-19 pandemic, the ability for the biomedical research community to pivot to fully remote research, driven largely by EHR data capture and other digital health tools, is an exciting development that can significantly reduce burden on study participants, improve diversity in clinical research, and equip researchers with more robust clinical data. In this viewpoint, we describe how patient engagement with EHR technology is poised to advance the digital clinical trial space, an innovative research model that is uniquely accessible and inclusive for study participants., (©Jeff Pawelek, Katie Baca-Motes, Jay A Pandit, Benjamin B Berk, Edward Ramos. Originally published in JMIR Medical Informatics (https://medinform.jmir.org), 08.07.2022.)

Background: Lactic acid produced by tumors has been shown to overcome immune surveillance, by suppressing the activation and function of T cells in the tumor microenvironment. The strategies employed to impair tumor cell glycolysis could improve immunosurveillance and tumor growth regulation. Dichloroacetate (DCA) limits the tumor-derived lactic acid by altering the cancer cell metabolism. In this study, the effects of lactic acid on the activation and function of T cells, were analyzed by assessing T cell proliferation, cytokine production and the cellular redox state of T cells. We examined the redox system in T cells by analyzing the intracellular level of reactive oxygen species (ROS), superoxide and glutathione and gene expression of some proteins that have a role in the redox system. Then we co-cultured DCA-treated tumor cells with T cells to examine the effect of reduced tumor-derived lactic acid on proliferative response, cytokine secretion and viability of T cells., Result: We found that lactic acid could dampen T cell function through suppression of T cell proliferation and cytokine production as well as restrain the redox system of T cells by decreasing the production of oxidant and antioxidant molecules. DCA decreased the concentration of tumor lactic acid by manipulating glucose metabolism in tumor cells. This led to increases in T cell proliferation and cytokine production and also rescued the T cells from apoptosis., Conclusion: Taken together, our results suggest accumulation of lactic acid in the tumor microenvironment restricts T cell responses and could prevent the success of T cell therapy. DCA supports anti-tumor responses of T cells by metabolic reprogramming of tumor cells., (© 2022. The Author(s).)

In 1911 it was proposed that cancer might result from fusion and hybridization between macrophages and cancer cells. Using immunohistochemistry it was determined that essentially all solid tumors expressed macrophage-like molecules on their cell surface. More recently we have used forensic (STR) genetics that allows one to detect DNA from more than one individual in the same sample. By studying biopsies from individuals receiving allogeneic stem cell transplants and later developed solid tumor metastases, we were able to detect both donor and patient DNA sequences suggesting that hybrids were present. Previously we found hybrids in biopsies of a renal cell carcinoma, a melanoma in a brain metastasis and a melanoma in a primary tumor with lymph node metastases. Here we have traced hybrids from a primary melanoma to an axillary lymph node to a brain metastasis. This is the first time that the entire metastatic process has been documented., Competing Interests: Declaration of Competing Interest I (we) have no relevant financial interests in this manuscript., (Copyright © 2021. Published by Elsevier Inc.)

Introduction: In recent years, chimeric antigen receptor (CAR) T cell therapy has emerged as a cancer treatment. After initial therapeutic success for hematologic malignancies, this approach has been extended for the treatment of solid tumors including melanoma., Areas Covered: T cells need to be reprogramed to recognize specific antigens expressed only in tumor cells, a difficult problem since cancer cells are simply transformed normal cells. Tumor antigens, namely, CSPG4, CD70, and GD2 have been targeted by CAR-T cells for melanoma. Moreover, different co-stimulatory signaling domains need to be selected to direct T cell fate. In this review, various approaches for the treatment of melanoma and their effectiveness are comprehensively reviewed and the current status, challenges, and future perspective of CAR-T cell therapy for melanoma are discussed. Literature search was accomplished in three databases (PubMed, Google scholar, and Clinicaltrials.gov). Published papers and clinical trials were screened and relevant documents were included by checking pre-defined eligibility criteria., Expert Opinion: Despite obstacles and the risk of adverse events, CAR T cell therapy could be used for patients with treatment-resistant cancer. Clinical trials are underway to determine the efficacy of this approach for the treatment of melanoma.

Scientific collaboration has been a critical aspect of the development of all fields of science, particularly clinical medicine. It is well understood that myriads of benefits can be yielded by interdisciplinary and international collaboration. For instance, our rapidly growing knowledge on COVID-19 and vaccine development could not be attained without expanded collaborative activities. However, achieving fruitful results requires mastering specific tactics in collaborative efforts. These activities can enhance our knowledge, which ultimately benefits society. In addition to tackling the issue of the invisible border between different countries, institutes, and disciplines, the border between the scientific community and society needs to be addressed as well. International and transdisciplinary approaches can potentially be the best solution for bridging science and society. The Universal Scientific Education and Research Network (USERN) is a non-governmental, non-profit organization and network to promote professional, scientific research and education worldwide. The fifth annual congress of USERN was held in Tehran, Iran, in a hybrid manner on November 7-10, 2020, with key aims of bridging science to society and facilitating borderless science. Among speakers of the congress, a group of top scientists unanimously agreed on The USERN 2020 consensus, which is drafted with the goal of connecting society with scientific scholars and facilitating international and interdisciplinary scientific activities in all fields, including clinical medicine., Competing Interests: Conflict of InterestThe authors declare no competing interests., (© The Author(s), under exclusive licence to Springer Nature Switzerland AG 2021.)

Background: Children with spinal muscular atrophy (SMA) sustain a progressive reduction in pulmonary function (PF) related to both muscular weakness and the concomitant effects of spinal deformity on the thorax. Growth-friendly instrumentation is commonly utilized for younger patients with scoliosis and SMA to halt the progression of spinal curvature, but its effect on PF in these patients has not previously been investigated. Using the change in Early Onset Scoliosis 24-Item Questionnaire (EOSQ-24) PF subdomain scores, the authors will investigate whether PF improves in patients with SMA after a growth-friendly intervention., Methods: This was a multicenter retrospective cohort study from 2 international registries of patients with SMA undergoing spinal deformity surgery from 2005 to 2015. Data collected were age, sex, degree of major coronal curve, type of growth-friendly construct, forced vital capacity (FVC), and EOSQ-24 scores at the patient's preoperative, 1-year postoperative, and 2-year postoperative visits. Differences in EOSQ-24 PF scores and FVC between baseline and postoperative assessment were examined by paired tests., Results: A total of 74 patients were identified (mean age, 7.6±2.3 y, major curve 68.1±22.4 degrees, 51.4% female individuals). The mean EOSQ-24 PF scores improved significantly from 70.6 preoperatively to 83.6 at 1 year (P=0.092) and 86.5 at 2 years postoperatively (P=0.020). The scores in patients with rib-based constructs showed steeper increases at 1-year assessments than those in patients with spine-based constructs. The mean paired FVC value decreased from 63.9% predicted preoperatively, to 57.6% predicted at 1 year postoperatively (P=0.035), and 61.9% predicted preoperatively, to 56.3% predicted at 2 years postoperatively (P=0.178)., Conclusions: Patients with SMA who received growth-friendly instrumentation did experience improvements in PF as measured by EOSQ-24 assessing the caregivers' perception. Given the uncertain reliability of PFTs in this young population, EOSQ-24 is an important tool for measuring improvements in health-related quality of life., Level of Evidence: Level III-retrospective study.

Aims: Spinal fusion remains the gold standard in the treatment of idiopathic scoliosis. However, anterior vertebral body tethering (AVBT) is gaining widespread interest, despite the limited data on its efficacy. The aim of our study was to determine the clinical efficacy of AVBT in skeletally immature patients with idiopathic scoliosis., Methods: All consecutive skeletally immature patients with idiopathic scoliosis treated with AVBT enrolled in a longitudinal, multicentre, prospective database between 2013 and 2016 were analyzed. All patients were treated by one of two surgeons working at two independent centres. Data were collected prospectively in a multicentre database and supplemented retrospectively where necessary. Patients with a minimum follow-up of two years were included in the analysis. Clinical success was set a priori as a major coronal Cobb angle of < 35° at the most recent follow-up., Results: A total of 57 patients were included in the study. Their mean age was 12.7 years (SD 1.5; 8.2 to 16.7), with 95% being female. The mean preoperative Sanders score and Risser grade was 3.3 (SD 1.2), and 0.05 (0 to 3), respectively. The majority were thoracic tethers (96.5%) and the mean follow-up was 40.4 months (SD 9.3). The mean preoperative major curve of 51° (SD 10.9°; 31° to 81°) was significantly improved to a mean of 24.6° (SD 11.8°; 0° to 57°) at the first postoperative visit (45.6% (SD 17.6%; 7% to 107%); p < 0.001)) with further significant correction to a mean of 16.3° (SD 12.8°; -12 to 55; p < 0.001) at one year and a significant correction to a mean of 23° (SD 15.4°; -18° to 57°) at the final follow-up (42.9% (-16% to 147%); p < 0.001). Clinical success was achieved in 44 patients (77%). Most patients reached skeletal maturity, with a mean Risser score of 4.3 (SD 1.02), at final follow-up. The complication rate was 28.1% with a 15.8% rate of unplanned revision procedures., Conclusion: AVBT is associated with satisfactory correction of deformity and an acceptable complication rate when used in skeletally immature patients with idiopathic scoliosis. Improved patient selection and better implant technology may improve the 15.8% rate of revision surgery in these patients. Further scrutiny of the true effectiveness and long-term risks of this technique remains critical. Cite this article: Bone Joint J 2020;102-B(12):1703-1708.

Study Design: Retrospective., Objectives: To assess final outcomes in patients with early-onset scoliosis (EOS) who underwent growth-preserving instrumentation (GPI). Various types of growth-preserving instrumentation (GPI) are frequently employed, but until recently had not been utilized long enough to assess final outcomes., Methods: GPI "graduates" with multi-level congenital curves were identified. Graduation was defined as a final fusion or 5 years of follow-up without planned future surgeries. Outcomes included radiographic parameters and complications., Results: 26 patients were included. 11 had associated diagnoses; eight had fused ribs. 17 were treated with traditional growing rods, seven with vertically expandable prosthetic ribs, and two with Shilla procedures. The mean GPI spanned 12.3 levels including 10.7 motion segments, age at index surgery was 5.5 years, treatment spanned 7.5 years, and follow-up was 9.2 years. 24 patients underwent final fusion. Mean major curve decreased from 73° to 49° with index surgery (p < 0.01) and remained unchanged through a final follow-up. Final major curve was < 40° in 9 patients (35%), 40°-60° in 11 patients (42%), and > 60° in 6 patients (23%). None worsened throughout treatment. Mean T1-T12 height increased 2.4 cm with index surgery (p = 0.02) and 5.4 cm total (p < 0.01). T1-T12 height increased in all patients and was ultimately < 18 cm in 10 patients (38%), 18-22 cm in 10 patients (38%), and > 22 cm in 6 patients (23%). On average, there were 2.6 complications per patient, including 1.7 implant failures. 12 patients (46%) experienced ≥ 3 complications; four patients (15%) experienced none., Conclusion: We observed successful prevention of deformity progression but substantial residual deformity among GPI graduates with multi-level congenital EOS. Most coronal curve correction was attained during GPI implantation; thoracic height improved throughout treatment. While some favorable results were found, treatment strategies allowing improved deformity correction would be valuable for this challenging population., Level of Evidence: Therapeutic-III.

Background: Growth-friendly treatment of early-onset scoliosis (EOS) has changed with the development and evolution of multiple devices. This study was designed to characterize changes in the use of growth-friendly implants for EOS from 2007 to 2017., Methods: We queried the Pediatric Spine Study Group database for patients who underwent index surgery with growth-friendly implants from July 2007 to June 2017. In 1298 patients, we assessed causes of EOS; preoperative curve magnitude; age at first surgery; patient sex; construct type; lengthening interval; incidence of "final" fusion for definitive treatment; and age at definitive treatment. α=0.05., Results: From 2007 to 2017, the annual proportion of patients with idiopathic EOS increased from 12% to 33% (R=0.58, P=0.006). Neuromuscular EOS was the most common type at all time points (range, 33% to 44%). By year, mean preoperative curve magnitude ranged from 67 to 77 degrees, with no significant temporal changes. Mean (±SD) age at first surgery increased from 6.1±2.9 years in 2007 to 7.8±2.5 years in 2017 (R=0.78, P<0.001). As a proportion of new implants, magnetically controlled growing rods increased from <5% during the first 2 years to 83% in the last 2 years of the study. Vertically expandable prosthetic titanium ribs decreased from a peak of 48% to 6%; growth-guidance devices decreased from 10% to 3%. No change was seen in mean surgical lengthening intervals (range, 6 to 9 mo) for the 614 patients with recorded lengthenings. Final fusion was performed in 88% of patients who had undergone definitive treatment, occurring at a mean age of 13.4±2.4 years., Conclusions: From 2007 to 2017, neuromuscular EOS was the most common diagnosis for patients treated with growth-friendly implants. Patient age at first surgery and the use of magnetically controlled growing rods increased during this time. Preoperative curve magnitude, traditional growing rod lengthening intervals, and rates of final fusion did not change., Level of Evidence: Level II.

Established criteria for reporting safety and efficacy have not yet been defined in growing rod surgery for early onset scoliosis. A systematic literature review revealed a high degree of variability in how authors stratified complications and patient outcomes as a means to define safety and efficacy for this challenging patient population., Introduction: Several publications have reported the safety and efficacy of traditional growing rods (TGR) and magnetically controlled growing rods (MCGR) using various parameters. Radiographic parameters are most commonly used to measure efficacy, while incidence and type of complications are used to assess safety. A systematic review of peer-reviewed articles was performed to identify whether a consensus exists in how safety and efficacy parameters are reported in EOS patients treated with TGR and MCGR., Hypothesis: There is no consensus on the parameters used for reporting safety and efficacy in growing rod treatment for early onset scoliosis., Study Design: Systematic literature review., Methods: Four databases were searched on November 10, 2016 to identify all qualified peer-reviewed articles using specific keyword searches. All peer-reviewed articles published in English language reporting any data related to safety and efficacy of the TGR and/or MCGR surgical technique were included. Articles that met the inclusion criteria were scored by modified Downs and Black scoring system (J Epidemiol Community Health 52(6):377-384, 1998) for non-randomized studies. All reported safety and efficacy data were extracted and analyzed., Results: Search of the databases resulted in 111 unique citations including: PubMed (50), Embase (68 with 21 duplicates), Web of Science (29 with 15 duplicates), and CINAHL (15; all duplicates). Fifty-six of 111 citations were excluded during the review of the titles and abstracts. In addition, 16 citations were excluded at the time of full manuscript review. The remaining 39 articles included 23 TGR (2007-2016) and 16 MCGR papers (2012-2016). The overall Downs and Black score was 63.9 for TGR papers vs. 64.0 for MCGR papers (p = 0.97). Efficacy measures were not consistently reported among the publications. The only consistently reported efficacy parameter in majority (> 90%) of papers was curve size. Complication reporting was highly variable., Conclusion: Major curve size was the only consistent parameter to report efficacy in peer-reviewed TGR and MCGR publications. Since complications were not consistently reported, assessing safety of either treatment was infeasible. Establishing standardized safety and efficacy parameters in growing rod surgery for EOS would improve the quality of future studies and makes comparison of different treatment modalities possible. Indeed, other clinically relevant parameters such as health-related quality of life, pulmonary function, nutritional status, and psychiatric and developmental health should also be considered to improve the future safety and efficacy reporting.

The relationship between skin color and skin cancer is well established: the less melanin in one's skin the greater the risk for developing skin cancer. This review is in two parts. First, we summarize the current understanding of the cutaneous pigmentary system and trace melanin from its synthesis in the pigment cell melanosomes through its transfer to keratinocytes. We also present new methods for reducing melanin content in hyper-pigmented areas of skin such as solar lentigenes, melasma, and post-inflammatory hyperpigmentation. Second, we present evidence that at least one mechanism for the development of metastatic melanoma and other solid tumors is fusion and hybridization of leucocytes such as macrophages with primary tumor cells. In this scenario, hybrid cells express both the chemotactic motility of the leucocyte and the de-regulated cell division of the tumor cell, causing the cells to migrate a deadly journey to lymph nodes, distant organs, and tissues., (Copyright ©2020, Yale Journal of Biology and Medicine.)

Cell-cell fusion is a normal biological process playing essential roles in organ formation and tissue differentiation, repair and regeneration. Through cell fusion somatic cells undergo rapid nuclear reprogramming and epigenetic modifications to form hybrid cells with new genetic and phenotypic properties at a rate exceeding that achievable by random mutations. Factors that stimulate cell fusion are inflammation and hypoxia. Fusion of cancer cells with non-neoplastic cells facilitates several malignancy-related cell phenotypes, e.g ., reprogramming of somatic cell into induced pluripotent stem cells and epithelial to mesenchymal transition. There is now considerable in vitro, in vivo and clinical evidence that fusion of cancer cells with motile leucocytes such as macrophages plays a major role in cancer metastasis. Of the many changes in cancer cells after hybridizing with leucocytes, it is notable that hybrids acquire resistance to chemo- and radiation therapy. One phenomenon that has been largely overlooked yet plays a role in these processes is polyploidization. Regardless of the mechanism of polyploid cell formation, it happens in response to genotoxic stresses and enhances a cancer cell's ability to survive. Here we summarize the recent progress in research of cell fusion and with a focus on an important role for polyploid cells in cancer metastasis. In addition, we discuss the clinical evidence and the importance of cell fusion and polyploidization in solid tumors., Competing Interests: Conflict-of-interest statement: Dr. Tim Spary received salary (not related to the submitted work) from Novintum Bioscience Ltd, London, England. The other authors have no conflict of interest., (©The Author(s) 2019. Published by Baishideng Publishing Group Inc. All rights reserved.)

Study Design: Retrospective review of prospective registries., Objectives: We hypothesized that patients with congenitally fused ribs who underwent thoracostomy upon implantation of rib-based distraction devices would achieve improved spine growth compared with those who did not undergo thoracostomy., Summary of Background Data: Patients with fused ribs may develop thoracic insufficiency syndrome. Treatment for severe early-onset spinal deformity with rib fusions often includes the placement of rib-based expansion devices with surgical division of the fused ribs (thoracostomy). The effect of thoracostomy on spinal growth has not been fully examined., Methods: Two multicenter registries of primarily prospectively collected data were searched. Patients with fused ribs and implantation of a rib-based device were identified. A total of 151 patients with rib fusions treated with rib-based constructs and minimum two-year follow-up were included. Among those, 103 patients were treated with expansion thoracostomy at the time of implantation, whereas 48 patients received device implantation alone. We evaluated change in T1-T12 and T1-S1 height, coronal Cobb angle, kyphosis, and number of surgeries. Preoperative deformity was similar between the two groups. Only 19% of patient underwent final fusion, with similar numbers fused in each group., Results: At latest follow-up, the expansion thoracostomy group had a greater total improvement in T1-S1 height (7.2 cm vs. 4.8 cm, p = .004). There was no difference between the two groups for change in spinal height at each lengthening procedure. Interestingly, thoracostomy patients also underwent more total surgeries (11.5 vs. 9.6, p = .031) and more lengthening procedures (8.3 vs. 6.6, p = .017) than the comparison group despite similar length of follow-up., Conclusions: Patients who underwent expansion thoracostomy at the time of rib expansion device implantation achieved greater improvement in T1-S1 height than those who underwent implantation of rib expansion device alone. Further work is needed to evaluate whether expansion thoracostomy impacts pulmonary function., (Copyright © 2019 Scoliosis Research Society. Published by Elsevier Inc. All rights reserved.)

The process of melanin biosynthesis and its distribution throughout the skin is regulated by complex processes involving several enzymes in melanocytes. Recently, Diwakar et al. demonstrated that cytidine-a sialyltransferase inhibitor, 6'-sialyllactose (6'-SL) and 3'-sialyllactose (3'-SL) inhibited melanogenesis and melanosome transfer process. In this study, we have furthered this research, considering cytidine as a commercially viable and safe option over 6'-SL and 3'-SL. The efficacy of 2% w/v cytidine was studied in MelanoDerm™ skin equivalents in comparison with the positive control 1% w/v kojic acid and the vehicle control. Both the positive control and cytidine demonstrated a significant reduction in melanin content relative to the vehicle control. These experiments conclude that cytidine can effectively reduce melanin content in a skin equivalence assay and suggests that cytidine may be a good candidate for a skin lightening agent for human skin.

According to estimates from the International Agency for Research on Cancer, by the year 2030 there will be 22 million new cancer cases and 13 million deaths per year. The main cause of cancer mortality is not the primary tumor itself but metastasis to distant organs and tissues, yet the mechanisms of this process remain poorly understood. Leukocyte⁻cancer cell fusion and hybrid formation as an initiator of metastasis was proposed more than a century ago by the German pathologist Prof. Otto Aichel. This proposal has since been confirmed in more than 50 animal models and more recently in one patient with renal cell carcinoma and two patients with malignant melanoma. Leukocyte⁻tumor cell fusion provides a unifying explanation for metastasis. While primary tumors arise in a wide variety of tissues representing not a single disease but many different diseases, metastatic cancer may be only one disease arising from a common, nonmutational event: Fusion of primary tumor cells with leukocytes. From the findings to date, it would appear that such hybrid formation is a major pathway for metastasis. Studies on the mechanisms involved could uncover new targets for therapeutic intervention.

Background: Melanocytes, which reside in the basal layer of the epidermis, produce the pigment melanin in cytoplasmic organelles known as melanosomes. Melanosomes are transferred to keratinocytes which provide the color in our skin. Recently, Diwakar et  al reported the crucial roles of protein glycosylation in both melanogenesis and melanosome transfer to keratinocytes, and each was inhibited by the nucleotide cytidine., Objective: The main objective of this study was to determine the clinical effects of topical application of cytidine to the hyperpigmented regions of the face in a group of human volunteers., Methods: A randomized, vehicle-controlled study was conducted for 12 weeks on healthy Korean female subjects. Cytidine was formulated into the lotion at concentrations of 2%, 3%, and 4% (w/w) and compared to the vehicle control formulation. The clinical outcomes were evaluated by performing visual assessment grading, measuring melanin index, skin brightness, and skin color parameters. In vitro skin penetration studies were conducted using Franz cell chambers for the 2% cytidine test formulation., Results: The test group showed significant improvements in the visual assessment scores, melanin index, skin brightness, and skin color compared to the control group. Although significant dose-dependent improvements were seen in the clinical study, the in vitro Franz cell studies indicated that the clinical efficacy and potency of cytidine might be further enhanced by formulating a better topical delivery system, which will be the goal of our future studies., Conclusions: This randomized, double-blind, 12-week clinical study successfully demonstrated the efficacy of cytidine on skin depigmentation in a dose-dependent manner., (© 2018 Wiley Periodicals, Inc.)

Study Design: Retrospective review of prospectively collected data., Objective: To compare the use of spine-based versus rib-based implants for the treatment of early-onset scoliosis (EOS) in the setting of rib fusions., Summary of Background Data: Treatment for severe early-onset spinal deformity with rib fusions includes growing spine devices with proximal rib or spine anchors. The results of treatment, however, have not been compared between spine-based versus rib-based proximal anchors., Methods: 169 patients with rib fusions treated with rib-based or spine-based constructs and minimum two-year follow-up were included. Sixteen patients were treated with proximal spine-based anchors and 153 with proximal rib-based devices (VEPTRs). Overall, 104 of the patients with rib-based fixation underwent thoracoplasty at the index surgery. We evaluated change in T1-T12 and T1-S1 height, coronal Cobb angle, kyphosis, and number of lengthening/revision surgeries., Results: Kyphosis increased a mean of 7° in the rib-based group and decreased a mean of 20 degrees in the spine-based group (p = .002). Major Cobb angle decreased in both groups (p < .0001); however, the spine-based group had greater Cobb angle improvement (24 vs. 11 degrees, p = .04). From implant and lengthening of distraction devices, there was a mean 3.3-cm (22%) increase in T1-T12 height and a mean of 8.0 lengthenings in the rib-based group compared with a 5.7-cm increase and 6.3 lengthening surgeries in the spine-based group. Patients with rib-based constructs had a mean of 11 total procedures, whereas spine-based patients had a mean of 8., Conclusions: Patients underwent a mean of eight lengthening surgeries before final fusion or cessation of lengthening with a modest 2.3-cm increase in T1-T12 height. Compared with proximal rib anchors, proximal spine anchors controlled kyphosis and improved Cobb angle correction for early-onset scoliosis with rib fusions., (Copyright © 2018 Scoliosis Research Society. Published by Elsevier Inc. All rights reserved.)

Introduction: In addition to patient characteristics, consideration of length of construct to number of anchored levels ratio and rod diameter should be a part of preoperative planning to minimize implant-related complications (IRCs). IRCs including rod breakage, anchor dislodgement, and pullout are among the most common adverse events in traditional growing rods (TGRs). The current study hypothesized that anchor type and configuration are associated with IRC., Methods: Patients with (1) age ≤10 years at surgery; (2) spine-based dual TGR; (3) minimum 2-year follow-up; and (4) available imaging. Cephalad and caudal foundations were grouped based on the number of instrumented levels and anchor type. All radiographs were reviewed. Based on the results, a "construct levels / anchored levels" (CL/AL) ratio was calculated, which is the number of levels spanned by instrumentation divided by the number of levels with bone-anchor fixation. Receiver operating characteristic curve was used to define the CL/AL threshold., Results: 274 patients divided into patients with complications (IRC+, n = 140) and without complications (IRC-, n = 134) groups. Mean follow-up was 6.3 years (2.1-18.0 years). No significant differences in age, gender, body mass index, ambulatory status, etiology, primary curve size, T1-S1 height, coronal and sagittal balance, and rod material were observed between the two groups. Comparative analysis showed that connector type, presence and location of crosslinks, number of levels instrumented, number and type of anchors, presence of pelvic fixation, and mirroring of cephalad and caudal foundations were not different. However, maximum kyphosis and rod diameter were significantly different. The CL/AL ratio threshold was 3.5. Multivariate analysis of kyphosis, rod diameter, and CL/AL ratio showed a significant association with IRC (p < .05)., Discussion and Conclusion: Although patient characteristics like kyphosis have been proven to be associated with instrumentation failure, it is a combination of characteristics that include rod diameter and CL/AL ratio that showed significant correlation with IRC. Validation of the CL/AL ratio is recommended., (Copyright © 2017 Scoliosis Research Society. Published by Elsevier Inc. All rights reserved.)

Study Design: Surgeon survey., Objectives: To determine if magnetic resonance imaging (MRI) following implantation of magnetically controlled growing rods (MCGRs) is associated with any adverse events., Summary of Background Data: Magnetically controlled growing rods have been shown to reduce the need for repeated surgical procedures and improve costs when compared to traditional growing rods, but concerns about MRI compatibility exist. MRIs are often clinically indicated in the EOS population., Methods: Pediatric spine surgeons who are members of the Growing Spine Study Group, Children's Spine Study Group, and early international users of this technology were surveyed regarding MRI use after performing MCGR surgery., Results: A total of 118 surgeons were surveyed. Four surgeons reported that 10 patients had an MRI with an implanted MCGR. Loss of fixation (0%, 0/10), movement of implants (0%, 0/10), unintended lengthening/shortening (0%, 0/10), or noticeable heating of MCGR (0%, 0/10) were not observed. No problems were observed with function of the MCGR following MRI, and a mean of 2.1 mm was obtained at the next lengthening (range, 0.5-3.0 mm). Two patients had brain MRIs, both of which could be interpreted. All cervical spine MRIs could be interpreted without excessive artifact (100%, 7/7). Six patients had MRIs of the thoracic or lumbar spine, but these were considered uninterpretable as a result of artifact from the MCGR device (0%, 0/6)., Conclusion: These are the first reported cases of MRI use in humans with MCGR. There were no adverse events observed. MCGR rods lengthened as expected following MRI. MRIs of the brain and cervical spine were able to be interpreted, but MRIs of the thoracolumbar spine could not be interpreted because of MCGR artifact. MRIs can be safely performed in patients with MCGRs; however, MRIs of thoracic and thoracolumbar spine may be of limited clinical benefit because of artifact., Level of Evidence: Level IV, case series., (Copyright © 2017 Scoliosis Research Society. Published by Elsevier Inc. All rights reserved.)

Study Design: Comparative cohort study., Objective: To compare coronal deformity control, lengthening efficacy, and sagittal alignment between distraction-based growing rod constructs utilizing tandem versus wedding band connectors., Summary of Background Data: Different construct designs exist for growing rod treatment of early-onset scoliosis. All use a version of a rod connector, with the two main types being tandem and wedding band. Little data exist to quantify the impact of connector choice on radiographic outcomes of treatment., Methods: A multicenter database of prospectively and retrospectively collected data on early-onset scoliosis patients was reviewed. Patients of any thoracic or thoracolumbar coronal plane deformity whose initial growing rod treatment was initiated before age 10 years and underwent at least 3 years of dual growing rod treatment with either tandem or wedding band connectors were included. Preoperative, immediate postoperative, and prefinal radiographs were reviewed and compared in regard to major curve magnitude, T1-T12 and T1-S1 spinal length, length of instrumentation, and sagittal plane measures., Results: A total of 209 patients were included. The overall percent change from preoperative to prefinal in all radiographic parameters was not different between the two groups indicating similar efficacy in treatment. After controlling for institutional variation, the improvement of the major coronal Cobb angle from preoperative to prefinal was statistically improved for the tandem group (34° vs. 29°, p = .002) and the difference in T5-T12 kyphosis from preoperative to prefinal was significantly different between the groups (-6° vs. +1.3°, p = .008)., Conclusion: We identified little difference in the effects of connector type on radiographic outcomes of patients treated with traditional growing rod, which indicates that both wedding band and tandem connectors function similarly. The small differences detected suggest that tandem connectors may improve major Cobb correction, and wedding band connectors may maintain thoracic kyphosis over time., Level of Evidence: Level III., (Copyright © 2017 Scoliosis Research Society. Published by Elsevier Inc. All rights reserved.)

Study Design: Expert consensus building using combined Delphi method and Nominal group technique., Objectives: To identify the current state of equipoise surrounding the use of magnetically controlled growing rods (MCGRs) and to determine consensus for planning a randomized controlled trial (RCT) with MCGRs., Background: The use of MCGRs for the treatment of early-onset scoliosis (EOS) is a new technology. Optimal use has not been thoroughly investigated and much uncertainty exists. Areas of uncertainty include construct architecture, timing of lengthenings, and amount of distraction per lengthening. Expert discussion and consensus is useful at this early juncture and necessary when designing an RCT., Methods: Two rounds of surveys were administered to a group of experienced pediatric spine surgeons, followed by a 2-hour, face-to-face meeting in November 2015 and a 1-hour, face-to-face meeting in February 2016. The first survey used example cases to establish agreement around the proper use of MCGRs and identified areas of equipoise and disagreement. The second survey again used example cases-this time selected for their equipoise status-to solicit trial arms for a potential RCT of MCGRs and identified important open questions in the use of MCGRs. Lastly, the face-to-face meetings employed iterative voting to preliminarily plan an RCT of MCGRs., Results: Following the Delphi survey rounds and the two Nominal face-to-face meetings, the group of experts decided on an MCGR RCT design that standardized all patients to bidirectional constructs, and randomized to a lengthening interval of 6 versus 16 weeks with a standardized equation for calculating the total yearly lengthening that approximates normal spine growth., Conclusion: This endeavor indicates expert support for the use of MCGR in children older than 6 years, with curves greater than 60°. The uncertainty surrounding frequency of lengthening justifies an RCT of MCGRs., Level of Evidence: Level V., (Copyright © 2017 Scoliosis Research Society. Published by Elsevier Inc. All rights reserved.)

Background: Traditional growing rods have a reported wound and implant complication rate as high as 58%. It is unclear whether the use of magnetically controlled growing rods (MCGR) will affect this rate. This study was performed to characterize surgical complications following MCGR in early onset scoliosis., Methods: A multicenter retrospective review of MCGR cases was performed. Inclusion criteria were: (1) diagnosis of early onset scoliosis of any etiology; (2) 10 years and younger at time of index surgery; (3) preoperative major curve size >30 degrees; (4) preoperative thoracic spine height <22 cm. Complications were categorized as wound related and instrumentation related. Complications were also classified as early (<6 mo from index surgery) versus late (>6 mo). Distraction technique and interval of distraction was surgeon preference without standardization across sites., Results: Fifty-four MCGR patients met inclusion criteria. There were 30 primary and 24 conversion procedures. Mean age at initial surgery was 7.3 years (range, 2.4 to 11 y), and mean duration of follow-up 19.4 months. Twenty-one (38.8%) of 54 patients had at least 1 complication. Fifteen (27.8%) had at least 1 revision surgery. Six (11.1%) had broken rods (2 to 4.5 and 4 to 5.5 mm rods); two 5.5 mm rods failed early (4 mo) and 4 late (mean=14.5 mo). Six (11.1%) patients experienced 1 episode of lack or loss of lengthening, of which 4 patients subsequently lengthened. Seven patients (13.0%) had either proximal or distal fixation-related complication at average of 8.4 months. Two patients (3.7%) had infections requiring incision and drainage; 1 early (2 wk) with wound drainage and 1 late (8 mo). The late case required removal of one of the dual rods., Conclusions: This study shows that compared with traditional growing rods, MCGR has a lower infection rate (3.7% vs. 11.1%). MCGR does not appear to prevent common implant-related complications such as rod or foundation failure. The long-term implication remains to be determined., Level of Evidence: Level IV.

Introduction of magnetically controlled growing rods (MCGR) for early onset scoliosis treatment was anticipated to improve quality of life for patients and their families. A cohort of patients converted from traditional growing rods to MCGR may be best suited to detect this improvement and have not previously been examined. Using the validated EOSQ-24, no HRQoL differences were detected between TGR, MCGR, or converted patient cohorts.

Despite having lower HRQoL domain scores pre-operatively, EOS patients treated with magnetically-controlled growing (MCGR) had similar EOSQ-24 domain scores after two years of treatment compared to patients treated with traditional growing rods (TGR).

EOS treated with VCR were predominantly congenital or myelomeningocele with 84% performed at index surgery and 70% definitive fusion. Correction of major curve was 69% and increases in spinal and thoracic height. Complication rate was 33% with 57% being IONM/neuro related.

Measuring the true spine growth during growing rod (GR) lengthening is limited with 2D radiographs. With 3D imaging, this study demonstrates that during GR lengthening the spine lengthens and vertebra increase in size suggesting spinal growth that matches the relative increase in rod length during the distraction period.

A study of 119 early onset scoliosis (EOS) who underwent magnetically controlled growing rod (MCGR) treatment suggests that more than 4 distractions per year yields greater rates of rod lengthening but no significant differences in spine length gain compared to less than 4 distractions per year.

Established criteria for reporting safety and efficacy have not yet been defined in growing rod surgery for early-onset scoliosis. A systematic literature review revealed a high degree of variability in how authors stratified complications and patient outcomes as a means to define safety and efficacy for this challenging patient population.

In a series of 748 traditional growing rod patients the overall rate of post-op neurological deficit was 0.45%, and the rate of permanent deficit was 0.05%. Neurological events occurred in all types of procedures including routine lengthenings. It is recommended IOM be utilised as a default for all distraction-based surgeries including lengthenings.

Use of IOM in treating EOS with a VCR was found to be effective in 100% of the patients; despite 7/33 having a preop neuro deficit. 12/33 with an IOM change, with 42% having a post-op deficit.

179 patients with congenital rib fusions treated with rib-based or spine-based constructs and minimum 2-year follow-up were reviewed. 19 patients were treated with proximal spine-based and 160 with proximal rib-based devices. Patients treated with growing rods achieved equivalent SAL to those treated with rib-based devices, while also achieving greater improvement to their spine deformity, as measured by postoperative kyphosis, and Cobb angle.

Treatment of complex congenital scoliosis with growth friendly instrumentation led to only modest correction of major curves, residual imbalance, minimal gain in spine and thoracic height and a high incidence of complications. It is unknown whether this treatment improves upon the natural history or early fusion.