Molecular Neuroscience

CADASIL with Atypical Clinical Symptoms, Magnetic Resonance Imaging, and Novel Mutations: Two Case Reports and a Review of the Literature Abstract Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a hereditary microangiopathy with adult onset caused by a missense mutation in the NOTCH3 gene in chromosome 19p13. It presents with autosomal dominant arteriopathy, subcortical infarctions, and leukoencephalopathy. Its common clinical presentations are seen as recurrent strokes, migraine or migraine-like headaches, progressive dementia, pseudobulbar paralysis, and psychiatric conditions. Two patients with CADASIL syndrome, whose diagnosis was made based on clinical course, age of onset, imaging findings, and genetic assays in the patients and family members, are presented here because of new familial polymorphisms. The first patient, with cerebellar and psychotic findings, had widespread non-confluent hyperintense lesions as well as moderate cerebellar atrophy in cranial magnetic resonance scanning. The other patient, with headache, dizziness, and forgetfulness, had gliotic lesions in both cerebral hemispheres. CADASIL gene studies revealed a new polymorphism in exon 33 in the first patient. In the other patient, the NOTCH3 gene was identified as a new variant of p.H243P (c.728A > C heterozygous). By reporting a family presenting with various clinical symptoms in the presence of new polymorphisms, we emphasize that CADASIL syndrome may present with various clinical courses and should be considered in differential diagnoses.

Impact of Auditory Integration Therapy (AIT) on the Plasma Levels of Human Glial Cell Line–Derived Neurotrophic Factor (GDNF) in Autism Spectrum Disorder Abstract Neurotrophic factors, including the glial cell line–derived neurotrophic factor (GDNF), are of importance for synaptic plasticity regulation, intended as the synapses' ability to strengthen or weaken their responses to differences in neuronal activity. Such plasticity is essential for sensory processing, which has been shown to be impaired in autism spectrum disorder (ASD). This study is the first to investigate the impact of auditory integration therapy (AIT) of sensory processing abnormalities in autism on plasma GDNF levels. Fifteen ASD children, aged between 5 and 12 years, were enrolled and underwent the present research study. AIT was performed throughout 10 days with a 30-min session twice a day. Before and after AIT, Childhood Autism Rating Scale (CARS), Social Responsiveness Scale (SRS), and Short Sensory Profile (SSP) scores were calculated, and plasma GDNF levels were assayed by an EIA test. A substantial decline in autistic behavior was observed after AIT in the scaling parameters used. Median plasma GDNF level was 52.142 pg/ml before AIT. This level greatly increased immediately after AIT to 242.05 pg/ml (P < 0.001). The levels were depressed to 154.00 pg/ml and 125.594 pg/ml 1 month and 3 months later, respectively, but they were still significantly higher compared with the levels before the treatment (P = 0.001, P = 0.01, respectively). There was an improvement in the measures of autism severity as an effect of AIT which induced the up-regulation of GDNF in plasma. Further research, on a large scale, is needed to evaluate if the cognitive improvement of ASD children after AIT is related or not connected to the up-regulation of GDNF.

Identification of Important Invasion-Related Genes in Non-functional Pituitary Adenomas Abstract Non-functioning pituitary adenomas (NFPAs) are locally invasive with high morbidity. The objective of this study was to diagnose important genes and pathways related to the invasiveness of NFPAs and gain more insights into the underlying molecular mechanisms of NFPAs. The gene expression profiles of GSE51618 were downloaded from the Gene Expression Omnibus database with 4 non-invasive NFPA samples, 3 invasive NFPA samples, and 3 normal pituitary gland samples. Differentially expressed genes (DEGs) are screened between invasive NFPA samples and normal pituitary gland samples, followed by pathway and ontology (GO) enrichment analyses. Subsequently, a protein–protein interaction (PPI) network was constructed and analyzed for these DEGs, and module analysis was performed. In addition, a target gene–miRNA network and target gene–TF (transcription factor) network were analyzed for these DEGs. A total of 879 DEGs were obtained. Among them, 439 genes were upregulated and 440 genes were downregulated. Pathway enrichment analysis indicated that the upregulated genes were significantly enriched in cysteine biosynthesis/homocysteine degradation (trans-sulfuration) and PI3K-Akt signaling pathway, while the downregulated genes were mainly associated with docosahexaenoate biosynthesis III (mammals) and chemokine signaling pathway. GO enrichment analysis indicated that the upregulated genes were significantly enriched in animal organ morphogenesis, extracellular matrix, and hormone activity, while the downregulated genes were mainly associated with leukocyte chemotaxis, dendrites, and RAGE receptor binding. Subsequently, ESR1, SOX2, TTN, GFAP, WIF1, TTR, XIST, SPAG5, PPBP, AR, IL1R2, and HIST1H1C were diagnosed as the top hub genes in the upregulated and downregulated PPI networks and modules. In addition, HS3ST1, GPC4, CCND2, and SCD were diagnosed as the top hub genes in the upregulated and downregulated target gene–miRNA networks, while CISH, ISLR, UBE2E3, and CCNG2 were diagnosed as the top hub genes in the upregulated and downregulated target gene–TF networks. The new important DEGs and pathways diagnosed in this study may serve key roles in the invasiveness of NFPAs and indicate more molecular targets for the treatment of NFPAs.

From the Editors Desk: Angela Zawacki-Downing Writing to Professor Illana Gozes, Editor-in-Chief Journal of Molecular Neuroscience—Speaking from a Mother's Heart, AD's ADNP Syndrome

Application of Single-Nucleotide Polymorphisms in the Diagnosis of Autism Spectrum Disorders: A Preliminary Study with Artificial Neural Networks Abstract Autism spectrum disorder (ASD) includes different neurodevelopmental disorders characterized by deficits in social communication, and restricted, repetitive patterns of behavior, interests or activities. Based on the importance of early diagnosis for effective therapeutic intervention, several strategies have been employed for detection of the disorder. The artificial neural network (ANN) as a type of machine learning method is a common strategy. In the current study, we extracted genomic data for 487 ASD patients and 455 healthy individuals. All individuals were genotyped in certain single-nucleotide polymorphisms within retinoic acid-related orphan receptor alpha (RORA), gamma-aminobutyric acid type A receptor beta3 subunit (GABRB3), synaptosomal-associated protein 25 (SNAP25) and metabotropic glutamate receptor 7 (GRM7) genes. Subsequently, we used the "Keras" package to create and train the ANN model. For cross-validation, samples were divided into ten folds. In the training process, initially, the first fold was preserved for validation and the other folds were used to train the model. The validation fold was then used to evaluate model performance. The k-fold cross-validation method was used to ensure model generalizability and to prevent overfitting. Local interpretable model-agnostic explanations (LIME) were applied to explain model predictions at the data sample level. The output of loss function was evaluated in the training process for each fold in the k-fold cross-validation model. Finally, the number of losses was reduced to less than 0.6 after 200 epochs (except in two cases). The accuracy, sensitivity and specificity of our model were 73.67%, 82.75% and 63.95%, respectively. The area under the curve (AUC) was 80.59. Consequently, in the current study, we propose an ANN-based method for differentiating ASD status from healthy status with adequate power.

14-3-3/Tau Interaction and Tau Amyloidogenesis Abstract The major function of microtubule-associated protein tau is to promote microtubule assembly in the central nervous system. However, aggregation of abnormally phosphorylated tau is a hallmark of tauopathies. Although the molecular mechanisms of conformational transitions and assembling of tau molecules into amyloid fibril remain largely unknown, several factors have been shown to promote tau aggregation, including mutations, polyanions, phosphorylation, and interactions with other proteins. 14-3-3 proteins are a family of highly conserved, multifunctional proteins that are mainly expressed in the central nervous system. Being a scaffolding protein, 14-3-3 proteins interact with tau and regulate tau phosphorylation by bridging tau with various protein kinases. 14-3-3 proteins also directly regulate tau aggregation via specific and non-specific interactions with tau. In this review, we summarize recent advances in characterization of tau conformation and tau/14-3-3 interaction. We discuss the connection between 14-3-3 binding and tau aggregation with a special emphasis on the regulatory role of 14-3-3 on tau conformation.

The Mechanism of Rap1 Regulates N-cadherin to Control Neuronal Migration Abstract Rap1 and N-cadherin regulate glia-independent translocation of cortical neurons. It remains unclear how Rap1 regulates N-cadherin-mediated neuronal migration. Here, we overexpressed Rap1gap in mouse brains (embryonic day 16) to inactivate Rap1, and observed that neurons did not migrate to the outer layer. We confirmed that Rap1 was involved in the regulation of late neurons in vivo. Rap1gap overexpression and Rap1 suppression in CHO cells decreased the expression of cytoskeletal proteins such as tubulin. Changes in the expression of cell morphology regulators, such as N-cadherin and β-catenin, were also observed. Inhibition of N-cadherin in mouse brains prevented neuronal migration to the outer layer. The morphology of CHO cells was changed after overexpression of Rap1gap. We propose that Rap1 regulates the expression of N-cadherin during embryonic development, which affects β-catenin expression. Beta-catenin in turn regulates cytoskeletal protein expression, ultimately affecting neuronal morphology and migration.

Adult-Onset Hypothyroidism Alters the Metaplastic Properties of Dentate Granule Cells by Decreasing Akt Phosphorylation Abstract The expression of homosynaptic long-term depression (LTD) governs the subsequent induction of long-term potentiation (LTP) at hippocampal synapses. This process, called metaplasticity, is associated with a transient increase in the levels of several kinases, such as extracellular signal-regulated protein kinases 1/2 (ERK1/2), c-Jun N-terminal kinase (JNK), and Akt kinase. It has been increasingly realized that the chemical changes in the hippocampus caused by hypothyroidism may be the key underlying causes of the learning deficits, memory loss, and impaired LTP associated with this disease. However, the functional role of thyroid hormones in the "plasticity of synaptic plasticity" has only begun to be elucidated. To address this issue, we sought to determine whether the administration of 6-n-propyl-2-thiouracil (PTU) alters the relationship between priming and the induction of subsequent LTP and related signaling molecules. The activation of ERK1/2, JNK, and Akt was measured in the hippocampus at least 95 min after priming onset. We found that priming stimulation at 5 Hz for 3 s negatively impacted the induction of LTP by subsequent tetanic stimulation in hypothyroid animals, as manifested by a more rapid decrease in the fEPSP slope and population spike amplitude. This phenomenon was accompanied by lower levels of phosphorylated Akt in the surgically removed hippocampus of the hypothyroid rats compared to the euthyroid rats. The metaplastic response and the expression of these proteins in the 1-Hz-primed hippocampus were not different between the two groups. These observations suggest that decreased PI3K/Akt signaling may be involved in the compromised metaplastic regulation of LTP observed in hypothyroidism, which may account for the learning difficulties/cognitive impairments associated with this condition.

TP53 Polymorphism Contributes to the Susceptibility to Bipolar Disorder but Not to Schizophrenia in the Chinese Han Population Abstract TP53 has been reported to be involved in diverse neurological processes related to the pathogenesis of psychosis. In this study, we aim to determine the association of TP53 polymorphisms, rs1042522 and rs17879353, with the susceptibility to schizophrenia (SCZ) or bipolar disorder (BD) in Chinese Han population. A total of 548 SCZ patients, 512 BD patients, and 598 healthy controls were recruited. Genotyping was conducted through Sequenom MassARRAY technology platform. The quantitative real-time polymerase chain reaction (qRT-PCR) was used to detect TP53 expression level. Results revealed that the allele frequency and genotype distribution of rs1042522 within BD patients were significantly different from those of the controls. Rs1042522 was significantly associated with BD risk under diverse genetic models. However, no significant association was found for rs17879353 and BD risk and for rs1042522 and rs17879353 and SCZ risk. TP53 expression was significantly increased in SCZ patients and BD patients compared with that in the controls but was significantly decreased in BD patients with CC genotype of rs1042522 compared with that in other BD patients with either CG or GG genotype. In summary, we observed for the first time that rs1042522 is significantly associated with BD risk in the Chinese Han population. The increased TP53 expression might affect the occurrence of BD and SCZ, and rs1042522 might affect the progress of BD by disturbing gene expression.

Myeloid-Related Protein 8/14 Participates in the Progression of Experimental Pneumococcal Meningitis by Augmentation of Inflammation Abstract It has been reported that myeloid-related protein 8/14 (MRP8/14) participates in the progression of inflammation after release from neutrophils and monocytes. This study aimed to clarify the mechanism(s) of the MRP8/14-augmented inflammatory response in mice with pneumococcal meningitis. Streptococcus pneumoniae (SP) meningitis was established by intracerebral injection of SP suspension. Balb/c mice were randomly divided into four groups and received the following injections: phosphate-buffer saline (PBS), MRP8/14 alone, SP alone, and SP plus MRP8/14. At 6 h, 24 h and 48 h postinfection, the clinical disease status was measured by the modified neurological severity score test, body weight loss and degree of cerebral edema; mice were anaesthetized, blood samples and brain samples were collected and brain inflammation was detected by haematoxylin and eosin (HE) staining; tumour necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), C-reactive protein (CRP) and monocyte chemoattractant protein-1 (MCP-1) levels in serum and brain homogenates were assessed by an enzyme-linked immunosorbent assay (ELISA), and the mRNA levels of the above cytokines in brain homogenates were measured by polymerase chain reaction (PCR); and the expression of nuclear factor-kappa B (NF-κB) p65 in brain tissues was determined by immunohistochemical assay. In this study, we identified that MRP8/14 substantially augmented the SP-stimulated inflammatory response, aggravated clinical disease status and exacerbated SP-induced brain edema in a murine model of pneumococcal meningitis. Exogenous administration of MRP8/14 significantly enhanced mRNA and protein expression of the proinflammatory cytokines and chemokines TNF-α, CRP, IL-6 and MCP-1 in brain homogenates and serum from mice with pneumococcal meningitis, which may be related to the NF-κB signalling pathway. We further found that MRP8/14 strongly augmented SP-induced phosphorylation of NF-κB p65 in brain tissue slices from the same model. In conclusion, our results indicated that MRP8/14 augmented the inflammatory response in mice with pneumococcal meningitis and contributed to the development of disease, which was probably through NF-κB signalling pathway activation.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Osteoporosis

What information can the lay public find about osteoporosis treatment? A descriptive study coding the content and quality of bisphosphonate information on the internet Abstract Summary Despite its effectiveness, bisphosphonate use for osteoporosis is low. We assessed bisphosphonate information on the internet and found the most commonly listed benefits/risks were bone density loss, gastrointestinal issues, and jaw necrosis, that risk quantification was rare, and information quality varied. Findings underscore the importance of clinical communication about bisphosphonates. Introduction The US Preventative Services Task Force recommends osteoporosis screening and treatment with bisphosphonates in high-risk populations. However, bisphosphonate use among individuals with osteoporosis remains low. The content and quality of information from outside sources may influence individuals' bisphosphonate decisions. Therefore, we sought to assess the content and quality of osteoporosis treatment information available to the public by conducting an internet search and coding available bisphosphonate information. Methods Eleven search terms about osteoporosis and bisphosphonates were entered into four search engines. Two raters assessed websites for information about bisphosphonates, whether and how benefits and side effects were described and quantified, contraindications, and dosing instructions. Coders also assessed website interface and slant/balance of information. Results One thousand four hundred seventy-three websites were identified. Two hundred twenty-seven websites met inclusion criteria and were coded. The most common bisphosphonate benefit described was prevention of bone density loss (77.1% of websites). The most common side effects described were gastrointestinal problems (66.1%) and jaw osteonecrosis (58.6%). Most websites did not quantify bisphosphonate benefits (78.0%) or side effects (82.4%). Complementary/integrative health websites (p < .001) and pharmaceutical litigation websites (p < .001) were more often slanted against taking bisphosphonates, compared to all websites coded. General medical knowledge websites were more balanced than other websites (p = .023). Conclusions The quality of bisphosphonate information on the internet varies substantially. Providers counseling patients about osteoporosis treatment should inquire about patients' baseline bisphosphonate knowledge. Providers can complement accurate information and address potential bisphosphonate misconceptions.

Correction to: Secondary prevention of osteoporotic fractures: evaluation of the Lille University Hospital's Fracture Liaison Service between January 2016 and January 2018 The original version of this article, published on 5 June 2019, an author's name was misspelled.

Multiple vertebral compression fractures after sleeve gastrectomy and a subsequent pregnancy: a case report Abstract We report that a 33-year-old woman developed multiple compression fractures several years after a sleeve gastrectomy followed by pregnancy. Despite normal areal BMD values assessed by dual-energy X-ray absorptiometry and no family history of osteoporosis, the patient demonstrated low lumbar spine trabecular bone score, as well as low peripheral trabecular volumetric BMD and deterioration of trabecular microarchitecture assessed by high-resolution peripheral quantitative computed tomography. Women of reproductive age should be provided with lifestyle management targeting bone health following bariatric surgery.

Association between serum uric acid and bone health in adolescents Abstract Summary Previous studies are suggestive of the protective role of uric acid on bone in the middle-aged and elderly. Whether this association exists in younger individuals has not been examined. This investigation showed a significant positive association between serum uric acid and bone parameters among Iranian adolescents. Introduction Uric acid (UA) might be linked to bone health, but it is unclear whether its effects on bone are limited to certain population subgroups. This study is aimed at investigating the correlation between serum uric acid levels and bone mineral density (BMD) in Iranian adolescents. Methods This cross-sectional study was conducted on 413 (221 girls and 192 boys) Iranian adolescents aged 9–19 years. An analysis of anthropometric, biochemical parameters and bone density was performed on the participants. Measurements included serum uric acid, calcium, phosphorus, alkaline phosphatase, albumin, and vitamin D. They were divided according to their serum UA into the low UA group who had UA ≤ 6 mg/dL and the high UA group with UA > 6 mg/dL. BMD and bone mineral content (BMC) were measured in the total body, lumbar spine, and left femoral neck, using dual energy X-ray absorptiometry (DXA), and bone mineral apparent density (BMAD) was calculated. Results A Pearson correlation analysis revealed a significant correlation between UA and bone parameters. In multiple regression analyses adjusted for potential confounders, serum UA was proven to be associated with BMD and BMC at all sites. There was no association between UA, serum calcium, and vitamin D concentrations. Conclusion Our study, as the first research on adolescents, demonstrated a higher bone density in those who had higher UA levels.

History of cardiovascular disease and cardiovascular biomarkers are associated with 30-day mortality in patients with hip fracture Abstract Summary Hip fractures are associated with increased mortality and it is important to identify risk factors. This study demonstrates that preexisting cardiovascular disease as well as cardiovascular biomarkers that are associated with increased 30-day mortality. These findings can be used to identify high-risk patients who might benefit from specialized care. Introduction This study investigates the association between cardiovascular disease (CVD), cardiovascular biomarkers, and 30-day mortality following a hip fracture. Methods The Danish National Patient Registry was used to investigate the association between CVD and mortality following hip fracture in a nationwide population-based cohort study. In a subset of the included patients (n = 355), blood samples were available from a local biobank. These samples were used for analyzing the association between specific biochemical markers and mortality. The primary outcome was 30-day mortality. Results A total of 113,211 patients were included in the population-based cohort study. Among these, heart failure was present in 9.4%, ischemic heart disease in 15.9%, and ischemic stroke in 12.0%. Within 30 days after the hip fracture, 11,488 patients died, resulting in an overall 30-day mortality of 10.1%. The 30-day mortality was significantly increased in individuals with preexisting CVD with multivariably adjusted odds ratios of 1.69 (95% confidence interval, 1.60–1.78) for heart failure, 1.23 (1.17–1.29) for ischemic heart disease, and 1.06 (1.00–1.12) for ischemic stroke. In the local database including 355 patients, 41 (11.5%) died within 30 days. The multivariably adjusted odds ratio for 30-day mortality increased with increasing NT-proBNP (2.36 [1.53–3.64] per quartile) and decreased with increasing HDL cholesterol (0.58 [0.41–0.82] per quartile). On this basis, we established a model for predicting the probability of death based on the biochemical markers. Conclusion Preexisting CVD was associated with increased 30-day mortality after a hip fracture. Furthermore, high levels of NT-proBNP and low levels of HDL cholesterol were associated with increased 30-day mortality.

Cost-effectiveness of pharmacological fracture prevention for osteoporosis as prescribed in clinical practice in France, Germany, Italy, Spain, and the United Kingdom Abstract Summary This study estimated the cost-effectiveness of pharmacological fracture prevention as prescribed in the five largest European countries (EU5) using the IOF reference cost-effectiveness model. Pharmacological fracture prevention as prescribed in clinical practice was cost-saving (provided more QALYs at lower costs) compared to no treatment in each of the EU5. Purpose To estimate the real-world cost-effectiveness of pharmacological fracture prevention as prescribed in the five largest European countries by population size: France, Germany, Italy, Spain, and the United Kingdom (UK) (collectively EU5). Materials and methods We analyzed sales data on osteoporosis drugs in each of the EU5 to derive a hypothetical intervention that corresponds to the mix of osteoporosis medication prescribed in clinical practice. The costs for this treatment mix were obtained directly from the sales data, and the efficacy of the treatment mix was estimated by weighing the treatment-specific fracture risk reductions from a published meta-analysis. Subsequently, we estimated the cost-effectiveness using costs per quality adjusted life year (QALY) of the intervention compared to no treatment in each of the EU5 using the International Osteoporosis Foundation (IOF) reference cost-effectiveness model. The model population comprised postmenopausal women, mean age 72 years with established osteoporosis (T-score ≤ − 2.5) among whom 23.6% had a prevalent vertebral fracture. The model was populated with country-specific data from the literature. Results Pharmacological fracture prevention as prescribed in clinical practice was cost-saving (provided more QALYs at lower costs) compared to no treatment in each country. The findings were robust in scenario analyses. Conclusions Pharmacological fracture prevention as prescribed in clinical practice is cost-saving in each of the EU5. Because of the under-diagnosis and under-treatment of post-menopausal osteoporosis, from a health economic perspective, further cost-savings may be reached by expanding treatment to those at increased risk of fracture currently not receiving any treatment.

A population-based study of postfracture care in Manitoba, Canada 2000/2001–2014/2015 Abstract Summary We previously found that population-based postfracture notification, which informed primary care physicians of their patient's recent fracture and suggested assessment for osteoporosis, led to an improvement in postfracture care in the context of a randomized controlled trial (ClinicalTrials.gov identifier NCT00594789, fractures from late 2007 to mid-2010). Since June 2010, a province-wide postfracture notification program was implemented. This study was to (1) determine whether this program has resulted in sustained improvement in postfracture care and (2) test factors associated with receiving osteoporosis care. Methods A retrospective matched cohort study was performed using population-based health administrative data in Manitoba, Canada. We selected individuals aged 50+ years with an incident major osteoporosis fracture (MOF; N = 18,541) in fiscal years 2000/2001 to 2013/2014 and controls without a MOF (N = 92,705) matched (5:1) on age, sex, and residential area. The Cochran-Armitage test tested for a linear trend in osteoporosis care outcomes for cases and controls. Logistic regressions were used to test characteristics associated with the likelihood of receiving osteoporosis care. Results The percentage of individuals receiving DXA testing and/or osteoporosis medication increased in fracture cases (p < 0.001), but decreased in controls (p < 0.001). Odds ratios for osteoporosis care in years following the postfracture notification program were approximately double of those prior to the clinical trial. In addition to prior MOF (OR 9.03, 95% CI 8.60–9.48), factors associated with osteoporosis care included lower income (OR   0.72, 95% CI 0.67–0.78), glucocorticoid use (OR   4.37, 95% CI 3.72–5.14), diabetes diagnosis (OR =  0.74, 95% CI 0.68–0.80), and Charlson Comorbidity Index (indexes 1–2: OR 1.27, 95% CI 1.20–1.34; indexes 3–5: OR 1.26, 95% CI 1.13–1.40). Conclusions Adopting a population-based postfracture notification program led to sustained improvements in postfracture care.

World Congress on Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (WCO-IOF-ESCEO 2019): Posters Abstracts

WORLD CONGRESS ON OSTEOPOROSIS, OSTEOARTHRITIS AND MUSCULOSKELETAL DISEASES

World Congress on Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (WCO-IOF-ESCEO 2019): ESCEO-IOF USA Symposium Abstracts

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

General Internal Medicine

Capsule Commentary on Jetelina et al., Patient-Reported Barriers to Completing a Diagnostic Colonoscopy Following Abnormal Fecal Immunochemical Test among Uninsured Patients

How Do We Address the Influence of Social Determinants on Health?

Practicing Clinicians' Recommendations to Reduce Burden from the Electronic Health Record Inbox: a Mixed-Methods Study Abstract Background Workload from electronic health record (EHR) inbox notifications leads to information overload and contributes to job dissatisfaction and physician burnout. Better understanding of physicians' inbox requirements and workflows could optimize inbox designs, enhance efficiency, and reduce safety risks from information overload. Design We conducted a mixed-methods study to identify strategies to enhance EHR inbox design and workflow. First, we performed a secondary analysis of national survey data of all Department of Veterans Affairs (VA) primary care practitioners (PCP) to identify major themes in responses to a free-text question soliciting suggestions to improve EHR inbox design and workflows. We then conducted expert interviews of clinicians at five health care systems (1 VA and 4 non-VA settings using 4 different EHRs) to understand existing optimal strategies to improve efficiency and situational awareness related to EHR inbox use. Themes from survey data were cross-validated with interview findings. Results We analyzed responses from 2104 PCPs who completed the free-text inbox question (of 5001 PCPs who responded to survey) and used an inductive approach to identify five themes: (1) Inbox notification content should be actionable for patient care and relevant to recipient clinician, (2) Inboxes should reduce risk of losing messages, (3) Inbox functionality should be optimized to improve efficiency of processing notifications, (4) Team support should be leveraged to help with EHR inbox notification burden, (5) Sufficient time should be provided to all clinicians to process EHR inbox notifications. We subsequently interviewed 15 VA and non-VA clinicians and identified 11 unique strategies, each corresponding directly with one of these five themes. Conclusion Feedback from practicing end-user clinicians provides robust evidence to improve content and design of the EHR inbox and related clinical workflows and organizational policies. Several strategies we identified could improve clinicians' EHR efficiency and satisfaction as well as empower them to work with their local administrators, health IT personnel, and EHR developers to improve these systems.

Strengthening the Medical Error "Meme Pool" Abstract The exact number of patients in the USA who die from preventable medical errors each year is highly debated. Despite uncertainty in the underlying science, two very large estimates have spread rapidly through both the academic and popular media. We utilize Richard Dawkins' concept of the "meme" to explore why these imprecise estimates remain so compelling, and examine what potential harms can occur from their dissemination. We conclude by suggesting that instead of simply providing more precise estimates, physicians should encourage nuance in public medical error discussions, and strive to provide narrative context about the reality of the complex biological and social systems in which we practice medicine.

Physicians Interrupting Patients

Capsule Commentary on Gordon et al., The Impact of Medicaid Expansion on Continuous Enrollment: a Two-State Analysis

Veteran Satisfaction with Early Experiences of Health Care Through the Veterans Choice Program: a Concurrent Mixed Methods Study Abstract Background The 2014 Veterans Access, Choice and Accountability Act (i.e., "Choice") allows eligible Veterans to receive covered health care outside the Veterans Affairs (VA) Healthcare System. The initial implementation of Choice was challenging, and use was limited in the first year. Objective To assess satisfaction with Choice, and identify reasons for satisfaction and dissatisfaction during its early implementation. Design and Participants Semi-structured telephone interviews from July to September 2015 with Choice-eligible Veterans from 25 VA facilities across the USA. Main Measures Satisfaction was assessed with 5-point Likert scales and open-ended questions. We compared ratings of satisfaction with Choice and VA health care, and identified reasons for satisfaction/dissatisfaction with Choice in a thematic analysis of open-ended qualitative data. Results Of 195 participants, 35 had not attempted to use Choice; 43 attempted but had not received Choice care (i.e., attempted only); and 117 attempted and received Choice care. Among those who attempted only, a smaller percentage were somewhat/very satisfied with Choice than with VA health care (17.9% and 71.8%, p < 0.001); among participants who received Choice, similar percentages were somewhat/very satisfied with Choice and VA health care (66.6% and 71.1%, p = 0.45). When asked what contributed to Choice ratings, participants who attempted but did not receive Choice care reported poor access (50%), scheduling problems (20%), and care coordination issues (10%); participants who received Choice care reported improved access (27%), good quality of care (19%), and good distance to Choice provider (16%). Regardless of receipt of Choice care, most participants expressed interest in using Choice in the future (70–82%). Conclusions Access and scheduling barriers contributed to dissatisfaction for Veterans unsuccessfully attempting to use Choice during its initial implementation, whereas improved access and good care contributed to satisfaction for those receiving Choice care. With Veterans' continued interest in using services outside VA facilities, subsequent policy changes should address Veterans' barriers to care.

Capsule Commentary on Homoya et al., Uncertainty as a Key Influence in the Decision to Admit Patients with Transient Ischemic Attack

Capsule Commentary on Bond et al., Real-time Feedback in Pay-for-Performance: Does More Information Lead to Improvement?

Capsule Commentary on Zhang et al., Combined healthy lifestyle behaviors and disability-free survival: the Ohsaki Cohort 2006 Study

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Medicine

Symptomatic posterior fossa and supratentorial subdural hygromas as a rare complication following transarticular screw fixation with posterior wiring for atlantoaxial instability: A case report Rationale: Atlantoaxial transarticular screw fixation has been an effective and appealing method for inducing fusion of the C1-C2 complex. This technique is usually performed with Gallie fusion. In performing Gallie fusion using sublaminar wiring, a major concern is the risk of dural tear associated with passing sublaminar wires through the epidural space. We present the first report on symptomatic symptomatic subdural hygroma (SDH) due to transarticular screw fixation with posterior wiring. Patients concerns: A 50-year-old man had sustained dens fracture 20 years ago and presented with severe neck pain following a recent traffic accident. The images showed atlantoaxial instability due to nonunion of the dens fracture and the patient underwent transarticular screw fixation with posterior sublaminar wiring using Gallie technique. When the U-shaped wire was passed under the arch of C1 from inferior to superior, a dural tear and cerebrospinal fluid (CSF) leak occurred. The site of dural tear was repaired by direct application of sutures. The patient was discharged in good condition. Fifteen day after surgery, the patient was readmitted with a history of a progressive headache associated with vomiting and vertigo. Diagnonsis: Brain CT and MRI showed bilateral posterior fossa and a right-sided supratentorial SDH. Interventions: The patient underwent right occipital burr hole and evacuation of posterior fossa SDH due to deteriorating neurological status. Outcomes: The patient's condition gradually improved after the operation and became asymptomatic at 3-year follow-up. Lessons: Posterior fossa and supratentorial SDH could occur resulting from any intraoperative dural tear and CSF leakage during posterior cervical spinal surgery. Symptomatic SDH after posterior cervical spinal surgery should be cautiously assessed and treated. Level of Evidence: 5

Diagnostic and prognostic role of HE4 expression in multiple carcinomas: A protocol for systematic review and meta-analysis Background: Human epididymis protein 4 (HE4) protein has garnered a great degree of interest as a complementary biomarker to carbohydrate antigen 125 (CA125), or even as an independent biomarker for monitoring, diagnosis, and prognostication of ovarian cancer. Its use is currently limited to ovarian cancer. Recent studies have suggested that it could also be used in other types of cancers. Methods: The Preferred Reporting Items for Systematic Review and Meta-Analysis Protocols (PRISMA-P) guidelines was used to design this meta-analysis protocol. The final study will also be conducted under the PRISMA guidelines for systematic reviews and meta-analyses. The core bibliographic database search will be carried out by 2 reviewers working individually, with each conducting an initial screening based on titles and abstracts. The shortlisted articles will be selected for review and statistical analysis based on predefined inclusion and exclusion criteria. Study characteristics, relevant clinicopathological characteristics and statistical data required for meta-analysis (hazard ratios [HRs] and 95% confidence interval [CIs) will be extracted and compiled into a MS Excel datasheet. Meta-analysis will be performed, using a random-effects model, and the results (pooled HR and 95% CI) will be presented in the form of a forest plot. Publication bias will also be assessed by use of Egger bias indicator test and funnel plot symmetry. If data are insufficient, a narrative line of review will be pursued. Discussion: HE4 protein has been shown to have great potential for clinical use as a diagnostic and prognostic marker in epithelial ovarian cancer (EOC). However, HE4 is not only limited to expression in ovarian cancer, but is also overexpressed in lung and endometrial cancers. The effectiveness of HE4 as a biomarker in cancers (other than EOC) has not yet been studied in the form of a comprehensive systematic review and meta-analysis. The results of this study should allow for expanded use of HE4 as a multiutility biomarker in multiple cancer types, thereby, elevating HE4's value as a cancer biomarker. PROSPERO registration: CRD42019120326.

Prognostic significance of polyvascular disease in heart failure with preserved left ventricular ejection fraction The prognostic significance of systemic atherothrombosis in heart failure (HF) with preserved ejection fraction (HFpEF) remains unclear. This study aimed to investigate the relation between the presence of polyvascular disease (PVD) and cardiovascular outcomes in HFpEF patients. A total of 510 consecutive HFpEF patients were prospectively observed for up to 1500 days or until occurrence of cardiovascular events. PVD was defined as ≥2 coexistence of coronary artery disease, peripheral arterial disease, and cerebrovascular disease. Overall, 124 cardiovascular events were observed during follow-up (median: 1430 days). Kaplan–Meier curve showed HFpEF with PVD (n = 84) experienced more cardiovascular events than did those without PVD patients (44.0% vs 20.4%, log-rank: P < .001). Multivariable Cox proportional hazards analysis with significant factors from univariate analysis showed the presence of PVD (hazard ratio [HR]: 2.875, 95% [CI]: 1.894–4.365, P < .001), previous HF hospitalization (HR: 1.578, 95% CI: 1.031–2.414, P = .036), hemoglobin (HR: 0.889, 95% CI: 0.805–0.983, P = .021), serum sodium (HR: 0.946, 95% CI 0.896–1.000, P = .048), ln-BNP (per 1.0, HR: 1.255, 95% CI: 1.055–1.494, P = .010), and E/e' (HR: 1.047, 95% CI: 1.020–1.075, P < .001) significantly predicted future cardiovascular events. Multivariable Cox hazard analysis with 4 established factors (age, BNP, diabetes mellitus, and previous HF hospitalization) from the I-PRESERVE (Irbesartan in HFpEF) study showed PVD was independently associated with cardiovascular events in HFpEF patients (HR: 2.562, 95% CI: 1.715–3.827, P < .001). The presence of PVD is significantly associated with cardiovascular events in HFpEF, suggesting the importance of screening PVD in HFpEF.

Disappearance of the blood supply to a giant uterine myoma due to childbirth: A CARE-compliant article Rationale: Giant uterine myomas may be life-threatening due to pressure effects on the lungs and other contiguous organs. Patient concerns: A 32-year-old pregnant Asian woman was admitted to our hospital early in her pregnancy with a pre-pregnancy history of multiple uterine myomas. Diagnosis: She was diagnosed with multiple giant uterine myomas in pregnancy. Interventions: No intervention was performed on the woman. Outcomes: A reduction in tumor size and disappearance of tumor blood supply were seen on conventional and contrast-enhanced ultrasounds (CEUS) on postpartum day 34. Mass volume gradually decreased and no blood flow signals were seen on CEUS during postpartum follow-up. Lessons: Childbirth can block the blood supply of giant uterine myomas and reduce mass size. In such cases, childbirth may be considered therapeutic.

Effect and safety of LCZ696 in the treatment of hypertension: A meta-analysis of 9 RCT studies Background: LCZ696 has been introduced in patients with hypertension in several trials. Here, we performed a meta-analysis to evaluate the effect and safety of LCZ696 in hypertensive patients. Methods: PubMed, Embase, the Cochrane Library and ClinicalTrials.gov databases were searched to identify the available randomized controlled trials (RCTs) investigating the effect and safety of LCZ696 in hypertension patients. The last search date was October 31, 2018. Results: Nine RCTs with 6765 subjects were finally included, in which 8 trials compared the effect and safety between LCZ696 and angiotensin receptor antagonists (ARBs). Evidences showed LCZ696, compared with ARBs, achieved a better blood pressure control rate (OR 1.24, 95% CI: 1.14–1.35), specifically, LCZ696 were better at reducing systolic blood pressure [WMD −4.11 mmHg, 95% CI: (−5.13, −3.08) mmHg], diastolic blood pressure [WMD −1.79 mmHg, 95% CI: (−2.22, −1.37) mmHg], mean 24-hour ambulatory systolic blood pressure [WMD −3.24 mmHg, 95% CI: (−4.48, −1.99) mmHg] and mean 24-hour ambulatory diastolic blood pressure [WMD −1.25 mmHg, 95% CI: (−1.81, −0.69) mmHg]. There was no difference in the events of adverse events (risk ratio [RR] 1.01, 95% CI: 0.39–1.09), serious adverse events (RR 0.80, 95% CI: 0.52–1.22) and discontinuation of treatment for any adverse events (RR 0.79, 95% CI: 0.56–1.11) between LCZ696 group and ARB/placebo group, except LCZ696 reduced the rate of headaches (RR 0.69, 95% CI: 0.48-0.99) while increased cough (RR 2.12, 95% CI: 1.11–4.04; P = .02; I2 = 25%). Conclusion: Our finding provides evidence that LCZ 696 was more effective than ARB on blood pressure control and was safe enough in patients with hypertension.

Association between tongue coating thickness and ultraviolet fluorescence in patients with functional dyspepsia: A prospective observational study The aim of this study was to examine the correlation between the tongue coating thickness (TCT) and ultraviolet (UV) fluorescence and propose a new method for the estimation of TCT using a computerized tongue image acquisition system (CTIS). In this prospective and observational single-center study, we acquired tongue images under visible light and near-UV light for 60 patients with functional dyspepsia. Tongue images were acquired twice within a 30-minute interval to assess the reliability of CTIS. Then, the tongue coating was scraped and weighed to derive the wet weight of the tongue coating (WWTC). The percentage of the tongue coating area was calculated from the tongue images acquired under visible light. Mean color values (mCVs) for the UV fluorescence of the dorsal surface of the tongue were also computed. The reliabilities of the derived mCVs and percentage of the tongue coating area were acceptable (intraclass correlation coefficients, 0.907–0.947). The mCVs were more strongly correlated with WWTC than with the area, with mCV of modified lightness showing the strongest association (r = 0.785, P < .01). Finally, we suggested an estimation model for TCT based on the results. The results of this study suggest that both UV fluorescence of the dorsal tongue and the distribution area of tongue coating are useful parameters for the quantitative assessment of tongue coating. We believe that these findings will contribute to the development of a clinically useful CTIS.

A network meta-analysis protocol of adjuvant chemotherapy for unresectable patients with advanced gastric cancer Background: The treatment methods about surgery, chemotherapy, and radiation therapy were recommended for gastric cancer (GC) patients by National Comprehensive Cancer Network (NCCN) guidelines. However, for the advanced gastric cancer patients or with metastatic lesions who have lost their chance of surgery, the current adjuvant chemotherapy treatments are still controversial. Therefore, this network meta-analysis is mainly to assess the relative efficacy of different adjuvant chemotherapy regimens for advanced gastric cancer (AGC). Methods: In order to compare the relative efficacy among different adjuvant chemotherapy regimens for AGC patients, randomized controlled trials (RCTs) and non-RCTs were systematic searched in PubMed, Web of Science, Clinical Trials, Cochrane Library and Embase database. R-3.4.1 software will be used for data analysis. The risk of bias in RCTs and non-RCTs will be evaluated through the risk of bias tool from the Cochrane Handbook version 5.1.0 and non-randomized studies of interventions (ROBINS-I), respectively. Results and conclusion: The results of this network meta-analysis will evaluate the relative effectiveness and rank the interventions among all chemotherapy methods for unresectable AGC patients, and provide more evidence-based guidance in clinical practice. Protocol registration number: CRD42018111835.

The effect of magnesium sulfate on surgical field during endoscopic sinus surgery: A meta-analysis of randomized controlled trials Introduction: The benefits of magnesium sulfate for surgical field during endoscopic sinus surgery remain controversial. We conduct a systematic review and meta-analysis to explore the influence of magnesium sulfate versus placebo on surgical field during endoscopic sinus surgery. Methods: We search PubMed, EMbase, Web of science, EBSCO, and Cochrane library databases through November 2018 for randomized controlled trials (RCTs) assessing the effect of magnesium sulfate versus placebo on surgical field during endoscopic sinus surgery. This meta-analysis is performed using the random-effect model. Results: Four RCTs and 404 patients are included in the meta-analysis. Overall, compared with control group endoscopic sinus surgery, magnesium sulfate has remarkably positive impact on surgical field scores (MD = −1.76; 95% CI = −2.33 to −1.18; P < .00001), and intraoperative blood loss (MD = −89.09; 95% CI = −163.20 to −14.97; P = .02), but shows no markedly effect on surgery duration (MD = −7.08; 95% CI = −21.38 to 7.22; P = .33), fentanyl (MD = −0.64; 95% CI = −1.97 to 0.70; P = .35), and vecuronium (MD = −3.64; 95% CI = −10.99 to 3.70; P = .33). Conclusions: Magnesium sulfate exerts positive impact on surgical field and blood loss reduction for endoscopic sinus surgery.

Uniport video assisted thoracoscopic surgery (U-VATS) exhibits increased feasibility, non-inferior tolerance, and equal efficiency compared with multiport VATS and open thoracotomy in the elderly non-small cell lung cancer patients at early stage This study aimed to compare the feasibility, efficacy and safety among uniport video assisted thoracoscopic surgery (U-VATS), multiport VATS (M-TATS), and open thoracotomy in elderly non-small cell lung cancer (NSCLC) patients at early stage. One hundred ninety-one elderly NSCLC patients at early stage underwent U-VATS (N = 73), M-VATS (N = 56) or open thoracotomy (N = 62) were included. Perioperative parameters, short-term outcomes, postoperative complications, and overall survival (OS) were assessed. Three-group analysis disclosed that operational duration, blood loss, drainage duration, hospital stay, pain score on the first day (D1) and D3, patients' global assessment (PGA), lasing air leak, infection, arrhythmia, and cardio-cerebrovascular events incidences were different among U-VATS, M-VATS, and open thoracotomy groups. Subsequently, 2-group analysis revealed that: Pain score on D1 and D3 and PGA score were decreased in U-VATS group compared with M-VATS group;The operational duration was longer, blood loss, drainage duration, hospital stay, pain score on D1 and D3, PGA score, lasing air leak, infection, arrhythmia, and cardio-cerebrovascular events were decreased in U-VATS group than open thoracotomy group;The operational duration was longer, blood loss, drainage duration, hospital stay, pain score on D1 and D3, lasing air leak, infection, and arrhythmia were reduced in M-VATS group than open thoracotomy group. In addition, there was no difference of OS among 3 groups, nor between any of the 2 groups. U-VATS presents with elevated feasibility, non-inferior tolerance, and similar efficacy compared with M-VATS and open thoracotomy in the elderly NSCLC patients at early stage.

The mediating and moderating roles of self-acceptance and self-reported health in the relationship between self-worth and subjective well-being among elderly Chinese rural empty-nester: An observational study This study aims to test the moderation and mediation effects of self-acceptance and self-reported health on self-worth's impact on subjective well-being among elderly Chinese rural empty-nester elderly, and confirm whether self-report health is a moderating variable between self-worth and subjective well-being. This cross-sectional study was performed from May 2017 to April 2018; the participants were 365 empty-nest elderly adults from rural areas of Chifeng City in Inner Mongolia. Data were collected with the General information questionnaire, Self-worth questionnaire for adults, Self-acceptance Questionnaire, and Memorial University of New Found land Scale of Happiness. For the analyses, correlations, regressions, and structural equation models were used. Bootstrapping was performed to confirm the mediation effect. Multiple regression analysis was performed to confirm the moderation effect. Self-worth showed significant correlations with self-acceptance and subjective well-being (all P < .01). Bootstrapping indicated that the mediating role of self-acceptance was statistically significant. And self-reported health moderated the self-worth and subjective well-being association. Self-acceptance partially mediated the relationship between self-worth and subjective well-being of the rural empty-nest elderly and self-reported health moderated self-worth and subjective well-being association. Consequently, to improve the subjective well-being of the rural empty-nest elderly, self-acceptance and personal health should be the focus.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com

Pediatric Orthopaedics

Timing of Pavlik Harness Initiation: Can We Wait? Background: Developmental dysplasia of the hip is effectively treated with a Pavlik harness (PH) within the first 6 months of life. Over 80% of unstable hips in the newborn period will naturally stabilize by 2 months of age. If there is no difference in the effectiveness of initiating PH treatment at 1 week compared with 4 weeks of age, waiting may allow the hips to naturally stabilize and avoid treatment. The purpose of this study is to evaluate whether the timing of PH implementation influences its effectiveness in the treatment of developmental dysplasia of the hip. Methods: A retrospective review was conducted between 2004 and 2010. Patients were included if PH therapy was prescribed for hip instability or dislocation at or before 6 months of age. PH failure was defined as requiring any operative procedure for definitive management. Groups were divided based on the age at which the PH was initiated—group1=<30 days, group 2=30 to 60 days, group 3=>60 days. Results: A total of 176 children were included with 38 (21.6%) failing PH treatment. The mean age at PH initiation was 1.3 months (SD=1.3) in the successfully treated children and 1.4 months (SD=1.2) in the failures (P=0.77). There was no difference in the failure rates by age with group 1=19.1% (18/94), group 2=22.5% (9/40), and group 3=26.2% (11/42) (P=0.87). There was no statistical difference with respect to sex or breech positioning in the success or failure groups; however, there was a higher percentage of bilateral involvement in the failure group (P=0.04). Conclusions: Patients who had PH initiation before 30 days of age were no more or less likely to fail than when PH was initiated after 30 days of age. Parents can be counseled that waiting until after 30 days of age is appropriate before PH implementation. By avoiding swaddling during this period, the hips may stabilize without treatment and allow for more parental-infant bonding before implementation of PH. Level of Evidence: Level III—therapeutic, case control study.

Safe Transportation in-Spica Following Surgical Treatment of Infantile DDH: Solutions and Threats Background: Government regulations mandate appropriate vehicular restraints for children under 4 years of age. Patients treated for infantile developmental dysplasia of the hip (DDH) with spica casts often require special accommodations. Previous work suggests that car seat loaner programs may help achieve these goals while avoiding the need for costly ambulance transportation. The purpose of this study was to evaluate our center's experience with postdischarge transportation in a large population of DDH infants and identify future threats to our program. Methods: We performed a retrospective review of patients 4 years or younger of age who underwent closed or open reduction for DDH at our center between 2011 and 2018. Only the initial surgery of staged procedures was included. Patient demographic factors were recorded, as were procedure type, final restraint used for postdischarge transportation, and any potential discharge delays secondary to transportation issues. Costs were compared amongst transportation options. Results: Our cohort consisted of 130 patients (mean age, 1.4±0.9 y; 98 females) treated for DDH. In total 41 children (31.5%) underwent closed reduction procedures, whereas 89 patients (68.5%) underwent open reductions. After reduction, 62 (47.7%) received 2-legged spica casts and 68 (52.3%) received 1.5-legged casts. The most common restraint was a hospital-loaned Hippo car seat (73, 55.8%) followed by family-owned car seats (27, 20.8%). Eight patients (6.2%) experienced delays in discharge while waiting for adequate restraints, 6 patients (4.6%) were transported by ambulance, and 4 patients (3.1%) left against medical advice with inadequate restraints. Conclusions: Following surgical treatment of DDH, over 50% of patients with a spica cast were discharged using our center's car seat loaner program. However, availability and cost can present barriers for patients, with 4.6% of patients still being transported home by ambulance and 3.1% with inadequate restraints against medical advice. Costs of car seats are significant both for patients' families intending to purchase them, as well as for hospitals maintaining loaner programs and replacing used/lost seats. Moving forward, the recent cessation of production of the most common "spica car seat" threatens the longevity of existing loaner programs and calls renewed attention to the issue of safe transportation in-spica from providers and car-seat manufacturers alike. Level of Evidence: Level III.

Comparison of Surgical Outcomes Between a Triplane Proximal Femoral Osteotomy and the Modified Dunn Procedure for Stable, Moderate to Severe Slipped Capital Femoral Epiphysis Background: Recent studies have demonstrated the intra-articular cartilage and labral damage that can occur from the proximal femoral cam-like deformity of a moderate to severe slipped capital femoral epiphysis (SCFE). The approach to treating this deformity in a symptomatic Loder stable hip is controversial. The purpose of this study was to compare radiographic outcomes, complication rates, and revision rates between Imhauser type triplane proximal femoral osteotomy (TPFO) and the modified Dunn procedure (MDP). Methods: Twenty-six subjects with minimum 1-year follow-up were included (12 treated with a TPFO, and 14 treated with the MDP). A chart review was performed to capture data related to complications, revision procedures, surgical time, and body mass index. Radiographs were measured preoperatively and at final follow-up to evaluate epiphyseal-slip angle, neck-shaft angle, articular surface to trochanter distance, and medial proximal femoral angle. Results: Surgical time was shorter for the TPFO group (150.0±57.4 min) compared with the MDP group (203.8±30 min) (P=0.005). All preoperative and postoperative radiographic measures were similar between the 2 groups except postoperative neck-shaft angle, which was significantly less in the TPFO group (129.7±8.6 vs. 140.9±9.4 degrees) (P=0.005). There were no cases of femoral head avascular necrosis (AVN) in the TPFO group. The modified Dunn group had a 29% AVN rate (P=0.1). The overall complication rate was similar between the TPFO (33%) and modified Dunn (36%) groups (P=1.0) and the reoperation rate was slightly greater in the TPFO group (33%) as compared with the modified Dunn group (21%) (P=0.67). Conclusions: The complex 3-dimensional proximal femoral deformity of a moderate to severe SCFE can be difficult to treat with relatively high complication/reoperation rates observed in both TPFO and MDP groups. All 4 instances of AVN in this study of stable slips, however, were in the MDP group. As this can be a devastating complication leading to early total hip arthroplasty, we advise against the MDP in stable SCFE patients. Level of Evidence: Level III—retrospective comparative study.

Wash, Rinse, Repeat: Which Patients Undergo Serial Joint Irrigation in Pediatric Septic Hip Arthritis? Background: The purpose of this study is to identify risk factors associated with repeat surgical irrigation in pediatric septic hip arthritis. Methods: A single center retrospective case-control study was performed. Patients who underwent ≥2 washouts (cases) were compared with those who had only 1 washout (controls). Demographic, clinical, laboratory, microbial, and magnetic resonance imaging data were compared between cases and controls and a prediction model was developed using logistic regression. A risk score was then constructed by counting the number of risk factors from the model that were present in each patient. Results: We identified 26 patients between 1994 and 2015 who underwent ≥2 washouts for septic hip arthritis, and 63 control patients who had only a single washout. Twenty-two patients had 2 washouts, 3 had 4 washouts, 1 had 5 washouts. Median number of days between first and second washout was 5 (interquartile range, 4 to 8). The most common reason for repeat washout was persistent fever (N=21), followed by persistently elevated laboratory values (N=13), abnormal magnetic resonance imaging findings (N=12), and continued pain (N=12). Repeat washout cases demonstrated higher temperature preoperatively (P<0.001), had more frequent initial misdiagnosis (P=0.002), and had a longer time from symptom onset to surgery (P=0.02). Laboratory values in these cases showed higher C-reactive protein (P=0.003), and more frequent left shift (P=0.03) at presentation, with a greater proportion of positive cultures (P<0.001). Postoperatively, repeat washout cases had higher temperatures (P<0.001), more frequent wound drainage (P=0.02), and complications (P=0.001). A risk score for predicting the likelihood of undergoing repeat washout was constructed by counting the number of the following factors present: presence of left shift in CBC, positive blood or synovial fluid cultures, and postoperative temperature over 39°C. Seventy percent of cases had ≥2 of these risk factors and 80% of controls had ≤1 risk factor. Conclusions: Cases of pediatric septic arthritis which undergo repeat washout are associated with left shift, high postoperative temperatures, and positive cultures. They have more frequent misdiagnosis leading to delayed treatment and subsequent medical complications. Level of Evidence: Level III.

Idiopathic Genu Valgum and Its Association With Obesity in Children and Adolescents Background: Obesity as a cause of lower extremity deformity in children has been well established. This deformity is most often seen as tibia vara, however, at our institution we have observed more obese children and adolescents over age 7 years with excessive or progressive idiopathic genu valgum. Our hypothesis is that children with idiopathic genu valgum have high rates of obesity which impact the severity of their disease. Methods: Retrospective review of existing data was performed on 66 consecutive children/112 limbs over age 7 years with idiopathic genu valgum, seen from 2010 to 2013. Children with known metabolic or skeletal disease were excluded. Genu valgum was defined as mechanical axis in zone II or III and mechanical tibiofemoral angle ≥4 degrees on standing anteroposterior radiograph of the lower extremities. Body mass index (BMI) was calculated and classified by Center for Disease Control percentiles. Skeletal maturation was rated by closure of pelvic and peri-genu physes. Severity of genu valgum was also assessed by femoral and tibial mechanical axes and the mechanical axis deviation. Results: Mean patient age was 12.2±2.2 years. 47% of patients had BMI≥30 and 71% were categorized as obese (>95th percentile). No sex differences were identified. Skeletal maturation explained 25% of the variance in the mechanical axis deviation and 22% of the mechanical tibiofemoral angle. BMI predicted 9.8% of the tibial valgus. Because of its skewed distribution, BMI percentile was a less useful parameter for assessment. Conclusions: The 71% obesity rate found in our children with idiopathic genu valgum is significantly higher than the normal population. Higher BMI is associated with more tibial valgum but skeletal maturation was the main predictor of overall valgus severity. This suggests that obesity may play a role in the etiology of idiopathic genu valgum which progresses with skeletal maturation, thereby increasing the risk of osteoarthritis in adulthood. Level of Evidence: Level III.

Concomitant Anterior Cruciate Ligament Reconstruction and Temporary Hemiepiphysiodesis in the Skeletally Immature: A Combined Technique Background: Young athletes with an anterior cruciate ligament (ACL) disruption and limb malalignment pose a treatment dilemma. Little has been published regarding limb malalignment in this population. Our aim is to review the results of combined treatment of an ACL deficient knee and genu valgum in skeletally immature patients. Methods: A retrospective review of skeletally immature patients who underwent transphyseal ACL reconstruction and concomitant hemiepiphysiodesis between 2004 and 2015 by 1 surgeon at a single institution was performed. Included patients had at least a year of growth remaining and were followed to skeletal maturity. Patients with a diagnosis of a connective tissue disorder were excluded. Knee stability, rate of retear, the rate of mechanical axis correction, and time to full correction were determined. Results: Ninety skeletally immature patients underwent transphyseal ACL reconstruction, 8 of which met inclusion criteria. Mean time to correction of the valgus deformity was 13 months (0.4 degree/mo). No patient required additional surgeries for malalignment. All patients had improvement in knee stability. One patient had a retear of their ACL reconstruction, for a failure rate of 13%. Preoperative mechanical lateral distal femoral angle and mechanical axis deviation corrected to near-neutral alignment for all treated limbs and were significantly different (P=0.001) than those measured preoperatively. Conclusions: Promising results were seen for simultaneous correction of genu valgum and transphyseal ACL reconstruction. Treatment of both pathologies in a concomitant surgery can be considered in the appropriate population, with expected results comparable to each procedure in isolation. Level of Evidence: Level IV—case series.

Rebound Deformity After Growth Modulation in Patients With Coronal Plane Angular Deformities About the Knee: Who Gets It and How Much? Background: With observed success and increased popularity of growth modulation techniques, there has been a trend toward use in progressively younger patients. Younger age at growth modulation increases the likelihood of complete deformity correction and need for implant removal before skeletal maturity introducing the risk of rebound deformity. The purpose of this study was to quantify magnitude and identify risk factors for rebound deformity after growth modulation. Methods: We performed a retrospective review of all patients undergoing growth modulation with a tension band plate for coronal plane deformity about the knee with subsequent implant removal. Exclusion criteria included completion epiphysiodesis or osteotomy at implant removal, ongoing growth modulation, and <1 year radiographic follow-up without rebound deformity. Mechanical lateral distal femoral angle, mechanical medial proximal tibial angle, hip-knee-ankle angle (HKA), and mechanical axis station were measured before growth modulation, before implant removal, and at final follow-up. Results: In total, 67 limbs in 45 patients met the inclusion criteria. Mean age at growth modulation was 9.8 years (range, 3.4 to 15.4 y) and mean age at implant removal was 11.4 years (range, 5.3 to 16.4 y). Mean change in HKA after implant removal was 6.9 degrees (range, 0 to 23 degrees). In total, 52% of patients had >5 degrees rebound and 30% had >10 degrees rebound in HKA after implant removal. Females below 10 years and males below 12 years at time of growth modulation had greater mean change in HKA after implant removal compared with older patients (8.4 vs. 4.7 degrees, P=0.012). Patients with initial deformity >20 degrees had an increased frequency of rebound >10 degrees compared with patients with less severe initial deformity (78% vs. 22%, P=0.002). Conclusions: Rebound deformity after growth modulation is common. Growth modulation at a young age and large initial deformity increases risk of rebound. However, rebound does not occur in all at risk patients, therefore, we recommend against routine overcorrection. Level of Evidence: Level IV—retrospective study.

Growth-Friendly Spine Surgery in Escobar Syndrome Background: The aims of this study were to characterize the spinal deformity of patients with Escobar syndrome, describe results of growth-friendly treatments, and compare these results with those of an idiopathic early-onset scoliosis (EOS) cohort to determine whether the axial stiffness in Escobar syndrome limited correction. Methods: We used 2 multicenter databases to review the records of 8 patients with EOS associated with Escobar syndrome who had at least 2-year follow-up after initiation of growth-friendly treatment from 1990 to 2016. An idiopathic EOS cohort of 16 patients matched for age at surgery (±1 y), postoperative follow-up (±1 y), and initial curve magnitude (±10 degrees) was identified. A randomized 1:2 matching algorithm was applied (α=0.05). Results: In the Escobar group, spinal deformity involved 7 to 13 vertebrae and ranged from no vertebral anomalies in 3 patients to multiple segmentation defects in 6 patients. Mean age at first surgery was 5 years (range, 1.4 to 7.8 y) with a mean follow-up of 7.5 years (range, 4.0 to 10 y). Mean major curve improved from 76 degrees at initial presentation, to 43 degrees at first instrumentation, to 37 degrees at final follow-up (both P<0.001). Mean pelvic obliquity improved from 16 degrees (range, 5 to 31 degrees) preoperatively to 4 degrees (range, 0 to 8 degrees) at final follow-up (P=0.005). There were no differences in the mean percentage of major curve correction between the idiopathic EOS and Escobar groups at the immediate postoperative visit (P=0.743) or final follow-up (P=0.511). There were no differences between the cohorts in T1-S1 height at initial presentation (P=0.129) or in growth per month (P=0.211). Conclusions: Multiple congenital fusions and spinal curve deformity are common in Escobar syndrome. Despite large areas of congenital fusion, growth-friendly constructs facilitate spinal growth and improve curve correction. These results are comparable to those in idiopathic EOS. Level of Evidence: Level III—case-control study.

Common Elements in Surgical Site Infection Care Bundles for Adolescent Idiopathic Scoliosis at North American Pediatric Institutions: A Survey of POSNA QSVI Challenge Participants Background: Surgical site infection (SSI) following posterior spinal fusion for idiopathic scoliosis is a difficult complication, with little information published regarding the best preventative comprehensive care plan. The Spine Subgroup of the Quality, Safety, Value Initiative (QSVI) committee of the Pediatric Orthopaedic Society of North America undertook a survey to generate an overview of bundle elements in comprehensive SSI care bundles across institutions in North America. The purpose of this study was to develop a toolkit of SSI care bundle elements that could be used in developing future SSI care bundles. Methods: A survey email was sent to pediatric orthopaedic surgeons requesting a copy of the SSI prevention care bundle used in their practice. Surgeons were included if they had participated in the 2016 POSNA QSVI challenge, indicated they performed pediatric spine surgery, and had a spine SSI bundle. These bundles were evaluated by the QSVI committee and divided into preoperative, intraoperative, and postoperative elements with the frequency of use of each element recorded. A follow-up qualitative questionnaire was sent assessing the implementation and development of these SSI bundles. Results: In total, 16 care bundles from 15 different institutions were included for review. The response rate for this survey was 44% of individuals (50/113 QSVI challenge participants) and 43% (15/35) of unique institutions. The most common elements included: use of preoperative antibiotics, use of preoperative chlorhexidine wipes, use of wound irrigation intraoperatively, and a standardized prescription for the length of postoperative antibiotic. Each of these elements was included in ≥75% of the SSI bundles evaluated. Conclusions: SSI care bundles are increasingly being used by pediatric institutions to lower the risk of SSI following pediatric spinal surgery. This study provides an overview of various care elements used in established SSI care bundles across multiple institutions in North America. It is hoped this data will provide institutions interested in developing their own SSI care bundle with useful information for beginning this process. Level of Evidence: Level V—Decision Analysis.

The Role of Computed Tomography and Magnetic Resonance Imaging in the Diagnosis of Pediatric Thoracolumbar Compression Fractures Background: Because of concerns about radiation exposure, some centers consider magnetic resonance imaging (MRIs) the preferred imaging modality for pediatric thoracic and/or lumbar compression fractures. The purpose of this study was to evaluate the sensitivity of computed tomography (CT) and MRI in diagnosing thoracolumbar compression fractures and the utility of MRI in their management. Methods: Retrospective review identified 52 patients aged 0 to 18 years with 191 thoracic and/or lumbar compression fractures who had both CT and MRI during the initial trauma evaluation. The decision to perform CT and/or MRI was made by the attending pediatric spine surgeon. In all cases the CT scan was performed before the MRI. All imaging studies were reviewed by a board-certified pediatric radiologist and attending pediatric spine surgeon. Results: Only 10 patients (19%) had a single-level injury. Of 42 with multiple compression fractures, 34 (81%) had fractures in contiguous levels, and 8 had noncontiguous injuries. Comparing CT and MRI, there was complete agreement in the number and distribution of fractures in 23 patients (44%). MRI identified additional levels of fracture in 15 patients (29%); 14 (27%) had fewer levels fractured on MRI than CT. Only one patient (2%) had fractures seen on MRI after a normal CT scan. Complete correlation between CT and MRI was seen in 59% (17/29) of patients aged 11 to 18 years, compared with 26% (6/23) of patients younger than 11. Conclusions: In pediatric patients with mild thoracic or lumbar compression fracture(s), CT scan demonstrates a high sensitivity in determining the presence or absence of a fracture compared with MRI. Although some variability exists between the 2 modalities in the exact number of spinal levels involved, the definitive treatment and outcome were not changed by the addition of MRI. The information that may be obtained from an MRI must be weighed against the increased time and expense of the study, as well as the risks associated with sedation when necessary. Level of Evidence: Level II—diagnostic study.

Alexandros Sfakianakis
Anapafseos 5 . Agios Nikolaos
Crete.Greece.72100
2841026182

6948891480

alsfakia@gmail.com