How will early onset scoliosis surgery affect my child's future as a young adult? A follow-up study using patient-reported outcome measures.

PURPOSE: Using patient-reported outcome measures (PROMs), this study was undertaken to determine how well patients with early onset scoliosis (EOS) fare in adulthood. METHODS: Among eight healthcare centers, 272 patients (≥ 18 years) surgically managed for EOS (≥ 5 years) completed the Scoliosis Research Society (SRS)-22r, Functional Assessment of Chronic Illness Therapy-10 (FACIT-Dyspnea-10), and Short Form (SF)-12. Functional and demographic data were collected. RESULTS: The response rate was 40% (108/272). EOS etiologies were congenital (45%), neuromuscular (20%), idiopathic (20%) syndromic (11%), and unknown (4%). All patients scored within normal limits on the FACIT-Dyspnea-10 pulmonary (no breathing aids, 78%; no oxygen, 92%). SF-12 physical health scores and most SRS-22r domains were significantly decreased (p < 0.05 and p < 0.001, respectively) compared with normative values. SF-12 and SRS-22r mental health scores (MHS) were lower than normative values (p < 0.05 and p < 0.02, respectively). Physical health PROMs varied between etiologies. Treatment varied by etiology. Patients with congenital EOS were half as likely to undergo definitive fusion. There was no difference between EOS etiologies in SF-12 MHS, with t scores being slightly lower than normative peers. CONCLUSION: Good long-term physical and social function and patient-reported quality of life were noted in surgically managed patients. Patients with idiopathic EOS physically outperformed those with other etiologies in objective and PROM categories but had similar MHS PROMs. Compared to normative values, EOS patients demonstrated decreased long-term physical capacity, slightly lower MHS, and preserved cardiopulmonary function. LEVEL OF EVIDENCE: Level IV Case Series.

How do implants overlying the spine influence "The Law of Diminishing Returns" in early-onset scoliosis patients?

PURPOSE: The "law of diminishing returns" (LODR) in early-onset scoliosis (EOS) is well-known. We hypothesized that previously observed variations between constructs may be related to the lateral distance that each construct lies from the spine. We therefore sought to determine whether the curve magnitude improvement and spinal length gains for distraction-based constructs in EOS are positively correlated with the collinearity of the spine and the convex-sided implant on posteroanterior radiographs. METHODS: A prospectively-collected, multicenter EOS registry was queried for all patients who underwent non-fusion, distraction-based instrumentation surgery. Post-index radiographs were graded from 1 to 5 based on amount of overlap between the convex-sided rod and the apical vertebra. Grade 1: convex rod is lateral to convex-sided pedicle; Grade 2: overlaps the convex-sided pedicle; Grade 3: lies between pedicles; Grade 4: overlaps concave-sided pedicle; Grade 5: medial to concave-sided pedicle. ANOVA assessed the correlations between post-index overlap grade and change in (a) curve magnitude and (b) T1-T12 height. Multivariable regression modeling further assessed these associations. RESULTS: 284 patients met all selection criteria and were included. On ANOVA, post-index grade was associated with curve magnitude (p <0.001) and T1-12 height (p = 0.028) change. Better curve correction and height change were associated with higher grade. On regression modeling, curve correction (R = 0.574) and T1-T12 height change (R = 0.339) remained significantly associated with grade when controlling for time, anchor locations, age, underlying diagnosis, and pre-index curve magnitude. CONCLUSION: More apical overlap by the convex rod was associated with better spinal deformity control and improved height gain. LEVEL OF EVIDENCE III: Therapeutic.

Does ventilator use status correlate with quality of life in patients with early-onset scoliosis treated with rib-based growing system implantation?

PURPOSE: Pulmonary function and quality of life (QOL) are important outcome measures for patients with early-onset scoliosis (EOS) undergoing rib-based growing system (RBGS) implantation. The Assisted Ventilation Rating (AVR) measures ventilator requirements in this population. A higher, more severe, score implies negative changes in QOL. The EOS Questionnaire (EOSQ) is a validated outcome measure. Paired measurements for both ratings were compared to clarify correlation between ventilator status and QOL. Secondary analysis aimed at defining QOL between more broad subgroups defined by ventilator use. METHODS: AVR and EOSQ scores were extracted from the Pediatric Spine Study Group database for patients 10 years of age and under. Instances were excluded if the time between AVR and EOSQ assessment was greater than 6 months. Scores were compared using Spearman correlation coefficient. Subgroup analysis included control for age, gender, and etiology. Secondary analysis was performed for broad functional grouping using ranked analysis of variance for repeated measures using median scores. RESULTS: Two thousand five hundred and forty-two instances of paired EOSQ and AVR in 329 patients were analyzed. A statistically significant weak correlation between AVR and EOSQ was identified in Child's Health Related QOL and Family Impact sections, in nine subsets. Subgroup analysis showed little variation, except increased correlation in female patients to near moderate level. Analysis of variance for demonstrated decreased medians for all subdomains when comparing those mechanically ventilated to patients who did not require ventilation. CONCLUSION: Ventilator status tracks with QOL were measured by EOSQ. A more severe AVR is negatively correlated with most domains of the EOSQ for patients with EOS who have undergone RBGS implantation. The strength of this correlation is weak, and so AVR alone may be insufficient to precisely determine QOL in this population. LEVEL OF EVIDENCE: Level-III, Retrospective.

The Role of Attachment Style, Adverse Childhood Experiences and Dissociation in Migraine.

Migraine and chronic migraine are caused by a combination of modifiable and non-modifiable genetic, social, behavioral and environmental risk factors. Further research of possible modifiable risk factors for this headache disorder is merited, given its role as one of the leading causes of years lived with disability per year. The first aim of this online cross-sectional study was to investigate the psychosocial risk factors that predicted chronic migraine and severe migraine-related disability in 507 Irish and UK participants, focusing specifically on childhood maltreatment, attachment and tendency to dissociate, or experience depressed mood and/or anxiety. Additionally, this study aimed to examine variables that mediated the relationships between these psychosocial risk factors and migraine chronicity or severe migraine-related disability. Adjusted binary logistic regression revealed that shutdown dissociation (Odds Ratio [OR] 4.57, 95% Confidence Interval [CI] 2.66-7.85) and severe physical abuse (OR 4.30, 95% CI 1.44-12.83 had significant odds of predicting migraine chronicity, while depression (OR 3.28, 95% CI 1.86-5.77) significantly predicted severe migraine-related disability. Mediation analyses indicated that shutdown dissociation mediated the relationship between seven predictor variables and both chronicity and severe disability including possible predisposing factors emotional abuse, physical neglect, avoidant attachment and anxious attachment. These findings suggest that early life stressors (such as childhood trauma and avoidant attachment style), shutdown dissociation and depression may impact on migraine trajectory. To investigate whether these psychosocial factors are risk factors for migraine chronicity or disability, prospective research should be conducted in this area to account for fluctuations in migraine chronicity over time.

Instant Gelation System as Self-Healable and Printable 3D Cell Culture Bioink Based on Dynamic Covalent Chemistry.

The rapid development of additive manufacturing techniques in the field of tissue regeneration offers unprecedented success for artificial tissue and organ fabrication. However, some limitations still remain for current bioinks, such as the compromised cell viability after printing, the low cross-linking efficiency leading to poor printing resolution and speed due to the relatively slow gelation rate, and the requirement of external stimuli for gelation. To address these problems, herein, a biocompatible and printable instant gelation hydrogel system has been developed based on a designed hyperbranched poly(ethylene glycol) (PEG)-based multihydrazide macro-cross-linker (HB-PEG-HDZ) and an aldehyde-functionalized hyaluronic acid (HA-CHO). HB-PEG-HDZ is prepared by the postfunctionalization of hyperbranched PEG-based multivinyl macromer via thiol-ene chemistry. Owing to the high functional group density of HB-PEG-HDZ, the hydrogel can be formed instantly upon mixing the solutions of two components. The reversible cross-linking mechanism between the hydrazide and aldehyde groups endows the hydrogel with shear-thinning and self-healing properties. The minimally toxic components and cross-linking chemistry allow the resulting hydrogel to be a biocompatible niche. Moreover, the fast sol-to-gel transition of the hydrogel, combining all of the advanced characteristics of this platform, protects the cells during the printing procedure, avoids their damage during extrusion, and improves the transplanted cell survival.

Hypoxia Alters Epigenetic and N-Glycosylation Profiles of Ovarian and Breast Cancer Cell Lines in-vitro.

Background: Glycosylation is one of the most fundamental post-translational modifications. Importantly, glycosylation is altered in many cancers. These alterations have been proven to impact on tumor progression and to promote tumor cell survival. From the literature, it is known that there is a clear link between chemoresistance and hypoxia, hypoxia and epigenetics and more recently glycosylation and epigenetics. Methods and Results: Our objective was to investigate these differential parameters, in an in vitro model of ovarian and breast cancer. Ovarian (A2780, A2780cis, PEO1, PEO4) and triple negative breast cancer (TNBC) (MDA-MB-231 and MDA-MB-436) cells were exposed to differential hypoxic conditions (0.5-2% O2) and compared to normoxia (21% O2). Results demonstrated that in hypoxic conditions some significant changes in glycosylation on the secreted N-glycans from the ovarian and breast cancer cell lines were observed. These included, alterations in oligomannosylated, bisected glycans, glycans with polylactosamine extensions, in branching, galactosylation and sialylation in all cell lines except for PEO1. In general, hypoxia exposed ovarian and TNBC cells also displayed increased epithelial to mesenchymal transition (EMT) and migration, with a greater effect seen in the 0.5% hypoxia exposed samples compared to 1 and 2% hypoxia (p ≤ 0.05). SiRNA transient knock down of GATA2/3 transcription factors resulted in a decrease in the expression of glycosyltransferases ST3GAL4 and MGAT5, which are responsible for sialylation and branching, respectively. Conclusions: These glycan changes are known to be integral to cancer cell survival and metastases, suggesting a possible mechanism of action, linking GATA2 and 3, and invasiveness of both ovarian and TNBC cells in vitro.

Green Synthetic Approach for Photo-Cross-Linkable Methacryloyl Hyaluronic Acid with a Tailored Substitution Degree.

The conventional synthesis of methacryloyl hyaluronic acid (HA-MA) requires an extremely high amount of modification reagents, the organic solvents, and strenuous purification steps. Herein, a new green synthetic approach for the methacryloyl hyaluronic acid preparation with a tailorable substitution degree (SD) is reported, in which methacryloyl hydrazide is used as a more reactive reagent and only water is used as the solvent. The new method significantly reduces the amount of functionalization reagents (as low as only 0.3 equiv) and avoids the use of any organic solvents. The substitution degree can be tailored from 26% to 86% in a facile controllable manner. The new HA-MA (termed as HA-MA-H) can be UV-cross-linked to form a biocompatible hydrogel.

The identification of needs and development of best practice guidance for the psychological support of frontline healthcare workers during and after COVID-19: A protocol for the FLoWS project.

Recent estimates suggest that up to 34% of frontline workers in healthcare (FLWs) at the forefront of the COVID-19 pandemic response are reporting elevated symptoms of psychological distress due to resource constraints, ineffective treatments, and concerns about self-contamination. However, little systematic research has been carried out to assess the mental health needs of FLWs in Europe, or the extent of psychological suffering in FLWs within different European countries of varying outbreak severity. Accordingly, this project will employ a mixed-methods approach over three work packages to develop best-practice guidelines for alleviating psychological distress in FLWs during the different phases of the pandemic. Work package 1 will identify the point and long-term prevalence of psychological distress symptoms in a sample of Irish and Italian FLWs, and the predictors of these symptoms. Work package 2 will perform a qualitative needs assessment on a sample of Irish and Italian FLWs to identify sources of stress and resilience, barriers to psychological care, and optimal strategies for alleviating psychological distress in relation to the COVID-19 pandemic. Work package 3 will synthesise the findings from the preceding work packages to draft best practice guidelines, which will be co-created by a multidisciplinary panel of experts using the Delphi method. The guidelines will provide clinicians with a framework for alleviating psychological distress in FLWs, with particular relevance to the COVID-19 pandemic, but may also have relevance for future pandemics and other public health emergencies.

The relative effectiveness of psychotherapeutic techniques and delivery modalities for chronic pain: a protocol for a systematic review and network meta-analysis.

Introduction: There is increasing evidence for the use of psychotherapies, including cognitive behavioural therapy, acceptance and commitment therapy, and mindfulness based stress reduction therapy, as an approach to management of chronic pain. Similarly, online psychotherapeutic interventions have been shown to be efficacious, and to arguably overcome practical barriers associated with traditional face-to-face treatment for chronic pain. This is a protocol for a systematic review and network meta-analysis aiming to evaluate and rank psychotherapies (delivered in person and online) for chronic pain patients. Methods/ design: Four databases, namely the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and PsycINFO will be searched from inception. Randomised controlled trials that have evaluated psychological interventions for pain management delivered online or in person will be included in the review. Data will be independently extracted in duplicate and the Cochrane Collaboration Risk of Bias Tool will be used to assess study quality. Measures of pain interference will be extracted as the primary outcome and measures of psychological distress will be extracted as the secondary outcome. A network meta-analysis will generate indirect comparisons of psychotherapies across treatment trials. Rankings of psychotherapies for chronic pain will be made available.   Discussion: A variety of psychotherapies, delivered both online and in person, have been used in an attempt to help manage chronic pain. Although occasional head to head trials have been conducted, little evidence exists to help identify which psychotherapy is most effective in reducing pain interference. The current review will address this gap in the literature and compare the psychotherapies used for internet delivered and in person interventions for chronic pain in relation to the reduction of pain interference and psychological distress. Results will provide a guide for clinicians when determining treatment course and will inform future research into psychotherapies for chronic pain. PROSPERO registration: CRD42016048518 01/11/16.

Manipulation of Transgene Expression in Fibroblast Cells by a Multifunctional Linear-Branched Hybrid Poly(ß-Amino Ester) Synthesized through an Oligomer Combination Approach.

Delivery of functional genetic materials into fibroblast cells to manipulate the transgene expression is of great significance in skin gene therapy. Despite numerous polymeric gene delivery systems having been developed, highly safe and efficient fibroblast gene transfection has not yet been achieved. Here, through a new linear oligomer combination strategy, linear poly(ß-amino ester) oligomers are connected by the branching units, forming a new type of poly(ß-amino ester). This new multifunctional linear-branched hybrid poly(ß-amino ester) (LBPAE) shows high-performance fibroblast gene transfection. In human primary dermal fibroblasts (HPDFs) and mouse embryo fibroblasts (3T3s), ultrahigh transgene expression is achieved by LBPAE: up to 3292-fold enhancement in Gaussia luciferase (Gluc) expression and nearly 100% of green fluorescence protein expression are detected. Concurrently, LBPAE is of high in vitro biocompatibility. In depth mechanistic studies reveal that versatile LBPAE can navigate multiple extra- and intracellular barriers involved in the fibroblast gene transfection. More importantly, LBPAE can effectively deliver minicircle DNA encoding  COL7A1 gene (a large and functional gene construct) to substantially upregulate the expression of type VII collagen (C7) in HPDFs, demonstrating its great potential in the treatment of C7-deficiency related genodermatoses such as recessive dystrophic epidermolysis bullosa.

Versatile Hyperbranched Poly(ß-hydrazide ester) Macromers as Injectable Antioxidative Hydrogels.

Synthetic reactive oxygen species (ROS)-responsive biomaterials have emerged as a useful platform for regulating critical aspects of ROS-induced pathologies and can improve such hostile microenvironments. Here, we report a series of new hyperbranched poly(ß-hydrazide ester) macromers (HB-PBHEs) with disulfide moieties synthesized via an "A2 + B4" Michael addition approach. The three-dimensional structure of HB-PBHEs with multiacrylate end groups endows the macromers with rapid gelation capabilities to form (1) injectable hydrogels via cross-linking with thiolated hyaluronic acid and (2) robust UV-cross-linked hydrogels. The disulfide-containing macromers and hydrogels exhibit H2O2-responsive degradation compared with the counterparts synthesized by a dihydrazide monomer without disulfide moieties. The cell viability under a high ROS environment can be well-maintained under the protection of the disulfide containing hydrogels.

A hybrid injectable hydrogel from hyperbranched PEG macromer as a stem cell delivery and retention platform for diabetic wound healing.

The injectable hydrogel with desirable biocompatibility and tunable properties can improve the efficacy of stem cell-based therapy. However, the development of injectable hydrogel remains a great challenge due to the restriction of crosslinking efficiency, mechanical properties, and potential toxicity. Here, we report that a new injectable hydrogel system was fabricated from hyperbranched multi-acrylated poly(ethylene glycol) macromers (HP-PEGs) and thiolated hyaluronic acid (HA-SH) and used as a stem cell delivery and retention platform. The new HP-PEGs were synthesized via in situ reversible addition fragmentation chain transfer (RAFT) polymerization using an FDA approved anti-alcoholic drug-Disulfiram (DS) as the RAFT agent precursor. HP-PEGs can form injectable hydrogels with HA-SH rapidly via thiol-ene click reaction under physiological conditions. The hydrogels exhibited stable mechanical properties, non-swelling and anti-fouling properties. Hydrogels encapsulating adipose-derived stem cells (ADSCs) have demonstrated promising regenerative capabilities such as the maintenance of ADSCs' stemness and secretion abilities. The ADSCs embedded hydrogels were tested on the treatment of diabetic wound in a diabetic murine animal model, showing enhanced wound healing. STATEMENT OF SIGNIFICANCE: Diabetic wounds, which are a severe type of diabetes, have become one of the most serious clinical problems. There is a great promise in the delivery of adipose stem cells into wound sites using injectable hydrogels that can improve diabetic wound healing. Due to the biocompatibility of poly(ethylene glycol) diacrylate (PEGDA), we developed an in situ RAFT polymerization approach using anti-alcoholic drug-Disulfiram (DS) as a RAFT agent precursor to achieve hyperbranched PEGDA (HP-PEG). HP-PEG can form an injectable hydrogel by crosslinking with thiolated hyaluronic acid (HA-SH). ADSCs can maintain their regenerative ability and be delivered into the wound sites. Hence, diabetic wound healing process was remarkably promoted, including inhibition of inflammation, enhanced angiogenesis and re-epithelialization. Taken together, the ADSCs-seeded injectable hydrogel may be a promising candidate for diabetic wound treatment.

Injectable hyperbranched poly(ß-amino ester) hydrogels with on-demand degradation profiles to match wound healing processes.

Adjusting biomaterial degradation profiles to match tissue regeneration is a challenging issue. Herein, biodegradable hyperbranched poly(ß-amino ester)s (HP-PBAEs) were designed and synthesized via "A2 + B4" Michael addition polymerization, and displayed fast gelation with thiolated hyaluronic acid (HA-SH) via a "click" thiol-ene reaction. HP-PBAE/HA-SH hydrogels showed tunable degradation profiles both in vitro and in vivo using diamines with different alkyl chain lengths and poly(ethylene glycol) diacrylates with varied PEG spacers. The hydrogels with optimized degradation profiles encapsulating ADSCs were used as injectable hydrogels to treat two different types of humanized excisional wounds - acute wounds with faster healing rates and diabetic wounds with slower healing and neo-tissue formation. The fast-degrading hydrogel showed accelerated wound closure in acute wounds, while the slow-degrading hydrogel showed better wound healing for diabetic wounds. The results demonstrate that the new HP-PBAE-based hydrogel in combination with ADSCs can be used as a well-controlled biodegradable skin substitute, which demonstrates a promising approach in the treatment of various types of skin wounds.

Double-Cross-Linked Hydrogel Strengthened by UV Irradiation from a Hyperbranched PEG-Based Trifunctional Polymer.

Conventional wound healing materials suffer from low efficiency, poor mechanical strength, and nontunable properties. Responsive hydrogels are appealing candidates for tissue engineering. Herein, we developed a double-cross-linked hydrogel system composed of hyperbranched PEG-based polymer, comprising pre-cross-linked acetal structure and numerous terminal acrylate groups, which can form hydrogels in situ and can be further strengthened by UV irradiation. The hyperbranched glycidyl methacrylate-co-poly(ethylene glycol) diacrylate polymers (HB-GMA-PEGs) were first synthesized via in situ deactivation enhanced atom transfer radical polymerization (DE-ATRP). A series of pre-cross-linked materials were achieved after postfunctionalization. The material can absorb a high amount of water to form hydrogels, and the gel stiffness was evaluated in detail before and after UV irradiation. The in vitro cytotoxicity experiments were conducted with the resulting materials and have demonstrated their good biocompatibility. The results indicate that this type of hydrogel with high water uptake capacity has appealing potential as a responsive biomaterial for wound closure.

Wound complications of vertical expandable prosthetic titanium rib incisions.

STUDY DESIGN: Multicenter retrospective review. OBJECTIVE: To compare the incidence of infection between vertical expandable prosthetic titanium rib (VEPTR) incision locations and determine if the infection risk increases in relation to presence of previous incisions and/or increased number of times incisions are opened. SUMMARY OF BACKGROUND DATA: Patients undergoing treatment for chest and spine deformity with VEPTR require multiple incisions that are opened repeatedly during expansion procedures. METHODS: A prospective database (7 sites) and institutional database (2 sites), were queried to identify their 20 most recent patients with VEPTR with a minimum of 4 expansions for inclusion. A total of 103 patients were identified. Clinical and operative reports were reviewed to determine incision locations, number, and infection complications. RESULTS: Twenty-five of 103 patients (24%) developed an infection during treatment. Six had multiple infections (range, 2-4), providing a total of 34 infection events. Patients averaged 6.4 expansion procedures and 13 total incisions. Infection rate at each incision site was not significantly different, in the range from 1% to 5%: paramedian (6 infections/23 patients with total 185 incisions, 3%), proximal midline (12/39; 224, 5%), thoracotomy (6/61; 455, 1%), iliac (5/37; 143, 4%), and distal midline (5/58; 148, 3%). Infection events occurred after an average of 3 times a particular incision was opened (95% confidence interval: 2.2-3.8). There was a trend toward higher infection rate with increased number of times a particular incision was opened. There was no increased infection rate in patients with surgical incisions prior to VEPTR (26%; 6/23) compared with patients not having prior incisions (24%; 19/80). CONCLUSION: The incidence of infection in patients with 4 or more VEPTR lengthenings was 24% and did not differ across the various incision locations. Presence of prior surgical incisions was not a risk factor for infection. Surgeons should use the most appropriate incision in relation to their patient's pathology when using VEPTR while remaining vigilant for infection. LEVEL OF EVIDENCE: 3.

Fusionless procedures for the management of early-onset spine deformities in 2011: what do we know?

While attempts to understand them better and treat them more effectively, early-onset deformities have gained great pace in the past few years. Large patient series with long follow-ups that would provide high levels of evidence are still almost non-existent. That there is no safe treatment algorithm defined and agreed upon for this patient population continues to pose a challenge for pediatric spine surgeons. In this review, authors who are well known for their research and experience in the treatment of early-onset scoliosis (EOS) have come together in order to answer those questions which are most frequently asked by other surgeons. The most basic eight questions in this field have been answered succinctly by these authors and a current overview is provided.

The use of traction in the treatment of severe spinal deformity.

STUDY DESIGN: Multicenter, retrospective, nonrandomized comparison group study of patients with severe scoliosis and kyphosis treated after 1995 with halo-gravity traction and without halo-gravity traction before definitive fusion. OBJECTIVE: Compare surgical correction of severe spine deformity with preoperative halo traction and without preoperative traction. SUMMARY OF BACKGROUND DATA: Prior studies have demonstrated that halo traction is a safe, well-tolerated method of applying gradual, sustained traction to maximize operative correction in patients with severe idiopathic scoliosis (IS) and kyphosis. However, these studies lack a comparison control group and study only a relatively small number of patients with IS. METHODS: Fifty-three patients with severe scoliosis or kyphosis were studied using hospital records, standing preoperative, traction, postoperative, and final radiographs. Thirty were treated with traction and 23 were treated without traction. Patients within each group were analyzed based on demographics, diagnosis, perioperative, and radiographic data. In addition, patients were evaluated based on diagnosis, specifically whether patients had adolescent idiopathic scoliosis. RESULTS: Within the entire study population, there was no statistically significant difference in main coronal curve correction (62% vs. 59%), operative time, blood loss, and total complication rate (27% vs. 52%). However, the nontraction group underwent vertebral column resection more often (30% vs. 3%, P = 0.015). The traction group had a statistically significant increase in average hospital stay (36 vs. 14 days) (P = 0.011). Analysis of the 23 patients with adolescent idiopathic scoliosis also showed no statistically significant differences in curve correction, blood loss, or complications. CONCLUSION: Our study shows that patients with halo traction less frequently had a vertebral body resection, but achieved comparable deformity correction.