Multi-ancestry genome-wide association study of major depression aids locus discovery, fine mapping, gene prioritization and causal inference.

Most genome-wide association studies (GWAS) of major depression (MD) have been conducted in samples of European ancestry. Here we report a multi-ancestry GWAS of MD, adding data from 21 cohorts with 88,316 MD cases and 902,757 controls to previously reported data. This analysis used a range of measures to define MD and included samples of African (36% of effective sample size), East Asian (26%) and South Asian (6%) ancestry and Hispanic/Latin American participants (32%). The multi-ancestry GWAS identified 53 significantly associated novel loci. For loci from GWAS in European ancestry samples, fewer than expected were transferable to other ancestry groups. Fine mapping benefited from additional sample diversity. A transcriptome-wide association study identified 205 significantly associated novel genes. These findings suggest that, for MD, increasing ancestral and global diversity in genetic studies may be particularly important to ensure discovery of core genes and inform about transferability of findings.

Meta-Analyses of Genome-Wide Association Studies for Postpartum Depression.

OBJECTIVE: Postpartum depression (PPD) is a common subtype of major depressive disorder (MDD) that is more heritable, yet is understudied in psychiatric genetics. The authors conducted meta-analyses of genome-wide association studies (GWASs) to investigate the genetic architecture of PPD. METHOD: Meta-analyses were conducted on 18 cohorts of European ancestry (17,339 PPD cases and 53,426 controls), one cohort of East Asian ancestry (975 cases and 3,780 controls), and one cohort of African ancestry (456 cases and 1,255 controls), totaling 18,770 PPD cases and 58,461 controls. Post-GWAS analyses included 1) single-nucleotide polymorphism (SNP)-based heritability ([Formula: see text]), 2) genetic correlations between PPD and other phenotypes, and 3) enrichment of the PPD GWAS findings in 27 human tissues and 265 cell types from the mouse central and peripheral nervous system. RESULTS: No SNP achieved genome-wide significance in the European or the trans-ancestry meta-analyses. The [Formula: see text] of PPD was 0.14 (SE=0.02). Significant genetic correlations were estimated for PPD with MDD, bipolar disorder, anxiety disorders, posttraumatic stress disorder, insomnia, age at menarche, and polycystic ovary syndrome. Cell-type enrichment analyses implicate inhibitory neurons in the thalamus and cholinergic neurons within septal nuclei of the hypothalamus, a pattern that differs from MDD. CONCLUSIONS: While more samples are needed to reach genome-wide levels of significance, the results presented confirm PPD as a polygenic and heritable phenotype. There is also evidence that despite a high correlation with MDD, PPD may have unique genetic components. Cell enrichment results suggest GABAergic neurons, which converge on a common mechanism with the only medication approved by the U.S. Food and Drug Administration for PPD (brexanolone).

Distributed genetic effects of the corpus callosum subregions suggest links to neuropsychiatric disorders and related traits.

BACKGROUND: The corpus callosum (CC) is a brain structure with a high heritability and potential role in psychiatric disorders. However, the genetic architecture of the CC and the genetic link with psychiatric disorders remain largely unclear. We investigated the genetic architectures of the volume of the CC and its subregions and the genetic overlap with psychiatric disorders. METHODS: We applied multivariate genome-wide association study (GWAS) to genetic and T1-weighted magnetic resonance imaging (MRI) data of 40,894 individuals from the UK Biobank, aiming to boost genetic discovery and to assess the pleiotropic effects across volumes of the five subregions of the CC (posterior, mid-posterior, central, mid-anterior and anterior) obtained by FreeSurfer 7.1. Multivariate GWAS was run combining all subregions, co-varying for relevant variables. Gene-set enrichment analyses were performed using MAGMA. Linkage disequilibrium score regression (LDSC) was used to determine Single nucleotide polymorphism (SNP)-based heritability of total CC volume and volumes of its subregions as well as their genetic correlations with relevant psychiatric traits. RESULTS: We identified 70 independent loci with distributed effects across the five subregions of the CC (p < 5 × 10-8). Additionally, we identified 33 significant loci in the anterior subregion, 23 in the mid-anterior, 29 in the central, 7 in the mid-posterior and 56 in the posterior subregion. Gene-set analysis revealed 156 significant genes contributing to volume of the CC subregions (p < 2.6 × 10-6). LDSC estimated the heritability of CC to (h2SNP = 0.38, SE = 0.03) and subregions ranging from 0.22 (SE = 0.02) to 0.37 (SE = 0.03). We found significant genetic correlations of total CC volume with bipolar disorder (BD, rg = -0.09, SE = 0.03; p = 5.9 × 10-3) and drinks consumed per week (rg = -0.09, SE = 0.02; p = 4.8 × 10-4), and volume of the mid-anterior subregion with BD (rg = -0.12, SE = 0.02; p = 2.5 × 10-4), major depressive disorder (MDD) (rg = -0.12, SE = 0.04; p = 3.6 × 10-3), drinks consumed per week (rg = -0.13, SE = 0.04; p = 1.8 × 10-3) and cannabis use (rg = -0.09, SE = 0.03; p = 8.4 × 10-3). CONCLUSIONS: Our results demonstrate that the CC has a polygenic architecture implicating multiple genes and show that CC subregion volumes are heritable. We found that distinct genetic factors are involved in the development of anterior and posterior subregions, consistent with their divergent functional specialisation. Significant genetic correlation between volumes of the CC and BD, drinks per week, MDD and cannabis consumption subregion volumes with psychiatric traits is noteworthy and deserving of further investigation.

Dual Approach to Talar Dome Increases Access for Fracture Care Without Osteotomy.

BACKGROUND: There is no consensus surgical treatment algorithm for talar body fractures, with authors recommending both soft tissue-only and osteotomy-based approaches. This study evaluates talar dome access via dual approaches to the talar dome through anterolateral transligamentous (ATL) and modified posteromedial (mPM) approaches. METHODS: Ten cadaveric legs (5 matched pairs) were included. An mPM approach, between flexor hallucis longus and Achilles tendon, and an ATL approach, utilizing the anterolateral interval with transection of anterior talofibular ligament and calcaneofibular ligament, were performed on each specimen. Order of approach was alternated within each pair. Accessible dome surface area (DSA) was outlined by drilling with a 1.6-mm Kirschner wire at the visualized talar dome margin both with and without 4 mm of tibiotalar distraction using an external fixator. Specimens were analyzed by computed tomography (CT). Primary outcome was accessible DSA. Student t tests compared DSA accessed by different exposure methods. RESULTS: An initial mPM approach exposed 25.6% and 33.6% of DSA without and with distraction (P = .002). An initial ATL approach accessed 47.0% and 58.1% of DSA without and with distraction, respectively (P = .003). Accessibility via dual approaches was 71.7% and 93% of DSA without and with distraction with an initial ATL approach and 71.3% and 87.5% of DSA without and with distraction with an initial mPM approach (P = .96 and .37, respectively). The central talar dome was inaccessible in an almond-shaped area, tapered at the medial and lateral ends. Anterior, lateral, and posterior articular margins were able to be fully exposed, often with overlapping exposure between posterior and anterior approaches, with distraction reliably improving lateral visualization. CONCLUSION: Dual approaches provided access to greater than 70% and 85% of talar DSA without and with distraction, respectively. Order of approach did not significantly affect exposure and thus should be determined by surgeon discretion. These results may promote soft tissue-only treatment strategies in talar body fracture care with an extensile exposure of the talar dome surface. Careful preoperative planning optimizes the advantages of this approach. LEVEL OF EVIDENCE: Level IV, case series.

Development and Validation of a Health-Related Quality-of-Life Measure in Older Children and Adolescents with Early-Onset Scoliosis: Early-Onset Scoliosis Self-Report Questionnaire (EOSQ-SELF).

BACKGROUND: The 24-question Early-Onset Scoliosis Questionnaire (EOSQ-24) is a proxy measure assessing health-related quality of life (HRQoL) among patients with early-onset scoliosis (EOS). There exists an increasing need to assess HRQoL through a child's own perspective, particularly for older children and adolescents with EOS. The purpose of this study was to develop and validate a self-reported questionnaire, the Early-Onset Scoliosis Self-Report Questionnaire (EOSQ-SELF), to assess HRQoL in older children and adolescents with EOS. METHODS: A literature review, an expert focus group, and patient interviews were used to generate a preliminary survey of appropriate domains and question items. This survey was provided to English-speaking patients with EOS who were 8 to 18 years of age and capable of answering survey questions. Content validity was assessed for clarity and relevance of questions. Confirmatory factors analysis was performed to reduce the number of items and determine domains that fit items. Reliability was evaluated by measuring the internal consistency of items and test-retest reliability. Construct validity was evaluated by convergent, discriminant, and known-group validity. RESULTS: The literature review, expert focus group, and patient interviews identified 59 questions in 14 domains. Psychometric analysis reduced these to 30 questions across 12 domains: General Health, Pain/Discomfort, Pulmonary Function, Transfer, Physical Function/Daily Living, Participation, Fatigue/Energy Level, Sleep, Appearance, Relationships, Emotion, and Satisfaction. The final questionnaire was found to have good content and construct validity and adequate reliability. CONCLUSIONS: The EOSQ-SELF is a valid and reliable instrument for measuring self-reported HRQoL among older children and adolescents with EOS (ages 8 to 18 years). This will serve as an important research outcome measure and enhance clinical care by providing a better understanding of HRQoL for these patients. LEVEL OF EVIDENCE: Diagnostic Level II . See Instructions for Authors for a complete description of levels of evidence.

True antiglide fixation of Danis-Weber B fibula fractures has lower rates of removal of hardware.

INTRODUCTION: Plating of unstable OTA/AO 44-B2 equivalent lateral malleolus (Danis-Weber B) fractures has been associated with pain, peroneal irritation, and the need for subsequent hardware removal (ROH). The purpose of this study is to retrospectively compare the rates of ROH in unstable Weber B fractures fixed with a posterior, true antiglide plate with no screws in the distal segment versus those that were fixed with a similarly placed posterior, neutralization construct that included screws in the distal fragment. Thus, evaluating the role of the distal screws in rates of ROH. METHODS: Skeletally mature patients that were treated for an unstable, isolated Weber B fracture at a single level-1 trauma center over a ten-year period were reviewed. Fractures treated with a single posterior plate with at least six months of follow-up were included and those fixed with a direct lateral plate were excluded. The primary outcome of this study was hardware removal defined as entire plate removal; isolated syndesmotic screw removal was not included. RESULTS: Ninety-six patients were included in the study with average age of 46 years (range 17-83) and mean length of follow-up of 24.5 months (range 6.1-140.3). There were 33 patients in the antiglide group (mean follow-up 25.5 months) and 63 in the neutralization plate group (mean follow-up 24 months, p=0.81). Fractures fixed with or without distal screws had equivalent excellent results related to bony union and alignment. However, there was a statistically significant decrease in ROH rates in the antiglide group (antiglide ROH rate 15.2%; neutralization ROH rate 38.1%; p=0.02). Relative risk of ROH with antiglide plate was 0.4 (95% CI 0.17 - 0.95; p=0.04). CONCLUSIONS: Antiglide plating shows a significant risk reduction in the rate of ROH when compared to posterior based neutralization plating. A true antiglide plating construct should be considered as a safe and effective way of managing Weber B fractures with a lower relative risk of a second operation for hardware removal. LEVEL OF EVIDENCE: Therapeutic level III. See Instructions for Authors for a complete description of levels of evidence.

Risk Factors Associated with Surgical Site Infection in Pediatric Patients Undergoing Spinal Deformity Surgery: A Systematic Review and Meta-Analysis.

BACKGROUND: Considerable variation exists in surgical site infection (SSI) prevention practices for pediatric patients undergoing spinal deformity surgery, but the incidence of SSI has been reported to remain high in the United States. The literature reports various risk factors associated with SSI but findings are inconsistent. The purpose of this systematic review and meta-analysis was to assess the published literature investigating associations between various risk factors and SSI in pediatric patients undergoing spinal surgery. METHODS: The systematic review and the meta-analysis were conducted according to Preferred Reporting Items for Systematic review and Meta-Analysis Protocols (PRISMA-P) guidelines among peer-reviewed journals published in English between January 2000 and April 2019. Studies that involved pediatric patients with spinal deformity undergoing surgical procedures in North America and assessed risk factors for SSI were included. The quality of individual studies was assessed, and weighted risk ratios and mean differences were calculated for each risk factor. RESULTS: Of 763 potential articles identified, 13 met inclusion criteria; 7 studies were rated as average and 6, as poor quality based on the quality checklist. The meta-analysis demonstrated that the SSI risk increased by the following factors: 2.53 (95% confidence interval [CI], 1.26 to 5.10) for overweight to obese patients compared with patients with normal weight, 2.84 (95% CI, 1.67 to 4.81) for patients with a neuromuscular etiology compared with non-neuromuscular etiology, 1.69 (95% CI, 1.41 to 2.02) for patients with a gastrostomy tube (G-tube) compared with those without, 3.45 (95% CI, 2.08 to 5.72) for nonambulatory patients compared with ambulators, and 3.39 (95% CI, 2.38 to 4.83) for patients with pelvic instrumentation compared with those without. Patients who developed SSI also had 158.38 mL (95% CI, 46.78 to 269.97 mL) greater estimated blood loss compared with those who did not. CONCLUSIONS: Despite the limited quality of the available studies and wide variety of populations and outcome definitions, evidence suggests that overweight to obese status, neuromuscular etiology, use of a G-tube, nonambulatory status, instrumentation to the pelvis, and greater estimated blood loss are risk factors for SSI. The use of a common SSI definition and strong methodology are warranted for future studies. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete list of levels of evidence.

Establishing Consensus on the Best Practice Guidelines for Use of Halo Gravity Traction for Pediatric Spinal Deformity.

BACKGROUND: Although halo gravity traction (HGT) has been used to treat children with severe spinal deformity for decades, there is a distinct lack of high-quality evidence to speak to its merits or to dictate ideal manner of implementation. In addition, no guidelines exist to drive research or assist surgeons in their practice. The aim of this study was to establish best practice guidelines (BPG) using formal techniques of consensus building among a group of experienced pediatric spinal deformity surgeons to determine ideal indications and implementation of HGT for pediatric spinal deformity. METHODS: The Delphi process and nominal group technique were used to formally derive consensus among leaders in pediatric spine surgery. Initial work identified significant areas of variability in practice for which we sought to garner consensus. After review of the literature, 3 iterative surveys were administered from February through April 2018 to nationwide experts in pediatric spinal deformity. Surveys assessed anonymous opinions on ideal practices for indications, preoperative evaluation, protocols, and complications, with agreement of 80% or higher considered consensus. Final determination of consensus items and equipoise were established using the Nominal group technique in a facilitated meeting. RESULTS: Of the 42 surgeons invited, responses were received from 32, 40, and 31 surgeons for each survey, respectively. The final meeting included 14 experts with an average 10.5 years in practice and average 88 annual spinal deformity cases. Experts reached consensus on 67 items [indications (17), goals (1), preoperative evaluations (5), protocols (36), complications (8)]; these were consolidated to create final BPG in all categories, including statements to help dictate practice such as using at least 6 to 8 pins under 4 to 8 lbs of torque, with a small, tolerable starting weight and reaching goal weight of 50% TBW in ∼2 weeks. Nine items remained items of equipoise for the purposes of guiding future research. CONCLUSIONS: We developed consensus-based BPG for the use and implementation of HGT for pediatric spinal deformity. This can serve as a measure to help drive future research as well as give new surgeons a place to begin their practice of HGT. LEVEL OF EVIDENCE: Level V-expert opinion.

Functional outcomes of an integrated Parkinson's Disease Wellbeing Program.

INTRODUCTION: There is growing evidence that exercise provides benefit in treating motor and non-motor symptoms in Parkinson's disease (PD). OBJECTIVES: The aims of this study were to determine (a) whether a 5-week PD-specific program resulted in sustained physical and psychosocial benefits, and (b) the relationship between patient characteristics, exercise, falls and physical and psychosocial parameters. DESIGN: Single-centre prospective observational study. METHODS: A total of 135 consecutive patients with mild-to-moderate PD underwent a 5-week PD-specific education and exercise program from August 2013 to March 2015. Gait, mobility and psychosocial measures were compared at baseline, 6 weeks and 12 months. RESULTS: Significant improvements in physical (walking distance in 2 minutes, number of "Sit To Stands" in 30 seconds, time in seconds taken to "Timed Up and Go," fast gait velocity over 10 m, Berg Balance Scale [BBS]) and psychosocial (quality of life (QoL) [PDQ-39], depression and anxiety [DASS-21], and fatigue [PSF-16]) measures were seen at 6 weeks (all P < .01) with physical improvements sustained at 12 months (all P < .001). The number of patients at 12 months with ≥1 fall reduced from 66% to 33%, and the number not exercising reduced from 42% to 21%. A lack of exercise correlated with ≥1 fall at 12 months (OR 3.39, 95% CI 1.36-8.39, P = .009). It was also associated with poorer balance and psychosocial parameters at 12 months (all P < .05). CONCLUSIONS: Patients recruited into a 5-week Parkinson's disease education and exercise program achieved significant 12-month benefits in physical but not psychosocial measures. Patients with ≥1 fall post-treatment were less likely to have been exercising at 12-month follow-up.

Reconstruction with Custom Unicondylar Hemiarthroplasty following Tumor Resection: A Case Series and Review of the Literature.

For patients with tumors of the distal femur, options for limb salvage include tumor resection followed by reconstruction. While reconstruction commonly involves a distal femoral replacement, careful selection of patients with tumor involvement limited to a single condyle may be candidates for reconstruction with distal femur hemiarthroplasty. In these procedures, resection spares considerably more native anatomy. Three consecutive patients who underwent resection and reconstruction at the distal femur with custom unicondylar hemiarthroplasty are presented in this case series at a mean follow-up of 45 months (range, 26-78). In two cases, prostheses were utilized as a secondary procedure after failure of initial reconstruction. In one case, the custom prosthesis was utilized as the primary method of reconstruction. Mean Musculoskeletal Tumor Society disease-specific scores were 26.7 (range, 25-28). All patients achieved a return to full weight bearing, activities of daily living, and functional range of motion. In appropriately selected patients with tumors of the distal femur, reconstruction with custom unicondylar hemiarthroplasty provides benefits including optimal function postoperatively via preservation of tumor-free bone and ligamentous structures. Additionally, maintenance of greater bone stock may confer benefits to patients with pathology at a high likelihood for recurrence and need for subsequent procedures.