Is Article Methodological Quality Associated With Conflicts of Interest?: An Analysis of the Plastic Surgery Literature.

PURPOSE: Conflicts of interest (COI) are an emerging area of discussion within the field of plastic surgery. Recently, several reports have found that research studies that disclose COI are associated with publication of positive outcomes. We hypothesize that this association is driven by higher-quality studies receiving industry funding. This study aimed to investigate the association between industry support and study methodological quality. METHODS: We reviewed all entries in Plastic and Reconstructive Surgery, Annals of Plastic Surgery, and Journal of Plastic, Reconstructive, and Aesthetic Surgery within a 1-year period encompassing 2013. All clinical research articles were analyzed. Studies were evaluated blindly for methodology quality based on a validated scoring system. An ordinal logistic regression model was used to examine the association between methodology score and COI. RESULTS: A total of 1474 articles were reviewed, of which 483 met our inclusion criteria. These articles underwent methodological quality scoring. Conflicts of interest were reported in 28 (5.8%) of these articles. After adjusting for article characteristics in the ordinal logistic regression analysis, there was no significant association between articles with COI and higher methodological scores (P = 0.7636). CONCLUSIONS: Plastic surgery studies that disclose COI are not associated with higher methodological quality when compared with studies that do not disclose COI. These findings suggest that although the presence of COI is associated with positive findings, the association is not shown to be driven by higher-quality studies.

The Impact of Financial Conflicts of Interest in Plastic Surgery: Are They All Created Equal?

BACKGROUND: Recently, several studies have demonstrated that articles that disclose conflicts of interests (COI) are associated with publication of positive results. The purpose of this study was to learn more about the different types of COI as they relate to the general topic of COI in plastic surgery. Specifically, we aimed to examine whether different types of COI are more likely than others to be associated with the presentation of positive findings. METHODS: We reviewed all original articles in Annals of Plastic Surgery, Journal of Plastic, Reconstructive, and Aesthetic Surgery, and Plastic & Reconstructive Surgery from January 1, 2012, to December 31, 2013. All scientific articles were analyzed, and several article characteristics were extracted. Disclosed COI were categorized into the following categories: consultant/employee, royalties/stock options, and research support. The findings reported in each article abstract were blindly graded as reporting a positive, negative, neutral, or not applicable result. A multivariable analysis was performed to determine whether an association existed between certain types of COI and publication of positive conclusions. RESULTS: A total of 3124 articles were identified of which 1185 fulfilled the inclusion criteria. Financial COI were reported in 153 studies (12.9%). The most common type of COI was "research support" (7.3%), whereas the least common was "royalties/stock options" (1.2%). Rates of different types of COI varied significantly by plastic surgery subspecialty field (P < 0.001). In the multivariable analysis, authors who disclosed COI related to research support, consultant/employee, and royalties/stock options were 1.31, 6.62, and 8.72 times more likely, respectively, to publish positive findings when compared with authors that disclosed no COI after correcting for potential confounding factors. However, consultancy/employee status was the only COI category statistically associated with publication of positive results (P < 0.001). CONCLUSIONS: Self-reported COI are uncommon in plastic surgery research. Our results provide evidence that certain types of financial COI are more likely than others to be associated with the presentation of positive findings. This analysis suggests that certain investigators may be more biased, consciously or unconsciously, by the type of financial benefit offered by industry.

A GCH1 haplotype confers sex-specific susceptibility to pain crises and altered endothelial function in adults with sickle cell anemia.

GTP cyclohydrolase (GCH1) is rate limiting for tetrahydrobiopterin (BH4) synthesis, where BH4 is a cofactor for nitric oxide (NO) synthases and aromatic hydroxylases. GCH1 polymorphisms are implicated in the pathophysiology of pain, but have not been investigated in African populations. We examined GCH1 and pain in sickle cell anemia where GCH1 rs8007267 was a risk factor for pain crises in discovery (n = 228; odds ratio [OR] 2.26; P = 0.009) and replication (n = 513; OR 2.23; P = 0.004) cohorts. In vitro, cells from sickle cell anemia subjects homozygous for the risk allele produced higher BH4. In vivo physiological studies of traits likely to be modulated by GCH1 showed rs8007267 is associated with altered endothelial dependent blood flow in females with SCA (8.42% of variation; P = 0.002). The GCH1 pain association is attributable to an African haplotype with where its sickle cell anemia pain association is limited to females (OR 2.69; 95% CI 1.21-5.94; P = 0.01) and has the opposite directional association described in Europeans independent of global admixture. The presence of a GCH1 haplotype with high BH4 in populations of African ancestry could explain the association of rs8007267 with sickle cell anemia pain crises. The vascular effects of GCH1 and BH4 may also have broader implications for cardiovascular disease in populations of African ancestry.

Genetic determinants of haemolysis in sickle cell anaemia.

Haemolytic anaemia is variable among patients with sickle cell anaemia and can be estimated by reticulocyte count, lactate dehydrogenase, aspartate aminotransferase and bilirubin levels. Using principal component analysis of these measurements we computed a haemolytic score that we used as a subphenotype in a genome-wide association study. We identified in one cohort and replicated in two additional cohorts the association of a single nucleotide polymorphism in NPRL3 (rs7203560; chr16p13·3) (P = 6·04 × 10(-07) ). This association was validated by targeted genotyping in a fourth independent cohort. The HBA1/HBA2 regulatory elements, hypersensitive sites (HS)-33, HS-40 and HS-48 are located in introns of NPRL3. Rs7203560 was in perfect linkage disequilibrium (LD) with rs9926112 (r(2)  = 1) and in strong LD with rs7197554 (r(2)  = 0·75) and rs13336641 (r(2)  = 0·77); the latter is located between HS-33 and HS-40 sites and next to a CTCF binding site. The minor allele for rs7203560 was associated with the -∝(3·7) thalassaemia gene deletion. When adjusting for HbF and ∝ thalassaemia, the association of NPRL3 with the haemolytic score was significant (P = 0·00375) and remained significant when examining only cases without gene deletion∝ thalassaemia (P = 0·02463). Perhaps by independently down-regulating expression of the HBA1/HBA2 genes, variants of the HBA1/HBA2 gene regulatory loci, tagged by rs7203560, reduce haemolysis in sickle cell anaemia.

Fetal hemoglobin in sickle cell anemia: genome-wide association studies suggest a regulatory region in the 5' olfactory receptor gene cluster.

In a genome-wide association study of 848 blacks with sickle cell anemia, we identified single nucleotide polymorphisms (SNPs) associated with fetal hemoglobin concentration. The most significant SNPs in a discovery sample were tested in a replication set of 305 blacks with sickle cell anemia and in subjects with hemoglobin E or beta thalassemia trait from Thailand and Hong Kong. A novel region on chromosome 11 containing olfactory receptor genes OR51B5 and OR51B6 was identified by 6 SNPs (lowest P = 4.7E-08) and validated in the replication set. An additional olfactory receptor gene, OR51B2, was identified by a novel SNP set enrichment analysis. Genome-wide association studies also validated a previously identified SNP (rs766432) in BCL11A, a gene known to affect fetal hemoglobin levels (P = 2.6E-21) and in Thailand and Hong Kong subjects. Elements within the olfactory receptor gene cluster might play a regulatory role in gamma-globin gene expression.

Gene expression profiles in a rabbit model of systemic lupus erythematosus autoantibody production.

We previously reported the establishment of a rabbit (Oryctolagus cuniculus) model in which peptide immunization led to production of lupus-like autoantibodies including anti-Sm, -RNP, -SS-A, -SS-B, and -dsDNA characteristic of those produced in systemic lupus erythematosus (SLE) patients. Some neurologic symptoms in the form of seizures and nystagmus were observed. The animals used in the previous and in the current study were from a National Institute of Allergy and Infectious Diseases colony of rabbits that were pedigreed, Ig-allotype defined, but not inbred. Their genetic heterogeneity may correspond to that found among patients of a given ethnicity. We extended the information about this rabbit model by microarray-based expression profiling. We first demonstrated that human expression arrays could be used with rabbit RNA to yield information on molecular pathways. We then designed a study evaluating gene expression profiles in eight groups of control and treated rabbits (47 rabbits in total). Genes significantly upregulated in treated rabbits were associated with NK cytotoxicity, Ag presentation, leukocyte migration, cytokine activity, protein kinases, RNA spliceosomal ribonucleoproteins, intracellular signaling cascades, and glutamate receptor activity. These results link increased immune activation with upregulation of components associated with neurologic and anti-RNP responses, demonstrating the utility of the rabbit model to uncover biological pathways related to SLE-induced clinical symptoms, including neuropsychiatric lupus. Our finding of distinct gene expression patterns in rabbits that made anti-dsDNA compared with those that only made other anti-nuclear Abs should be further investigated in subsets of SLE patients with different autoantibody profiles.

Severe sickle cell anemia is associated with increased plasma levels of TNF-R1 and VCAM-1.

Sickle cell anemia (SCA, HBB glu6val) is characterized by multiple complications and a high degree of phenotypic variability: some subjects have only sporadic pain crises and few acute hospitalizations, while others experience multiple serious complications, high levels of morbidity, and accelerated mortality [1]. The tumor necrosis factor-α (TNF-α) signaling pathway plays important roles in inflammation and the immune response; variation in this pathway might be expected to modify the overall severity of SCA through the pathway's effects on the vascular endothelium [2,3]. We examined plasma biomarkers of TNF-α activity and endothelial cell activation for associations with SCA severity in 24 adults (12 mild, 12 severe). Two biomarkers, tumor necrosis factor-α receptor-1 (TNF-R1) and vascular cell adhesion molecule-1 (VCAM-1) were significantly higher in subjects with severe SCA. Along with these biomarker differences, we also examined data from a genome-wide association study (GWAS) using SCA severity as a disease phenotype, and found evidence of genetic association between disease severity and a single nucleotide polymorphism (SNP) in VCAM1, which codes for VCAM-1, and several SNPs in ARFGEF2, a gene involved in TNF-R1 release [4].

Genetic modifiers of the severity of sickle cell anemia identified through a genome-wide association study.

We conducted a genome-wide association study (GWAS) to discover single nucleotide polymorphisms (SNPs) associated with the severity of sickle cell anemia in 1,265 patients with either "severe" or "mild" disease based on a network model of disease severity. We analyzed data using single SNP analysis and a novel SNP set enrichment analysis (SSEA) developed to discover clusters of associated SNPs. Single SNP analysis discovered 40 SNPs that were strongly associated with sickle cell severity (odds for association >1,000); of the 32 that we could analyze in an independent set of 163 patients, five replicated, eight showed consistent effects although failed to reach statistical significance, whereas 19 did not show any convincing association. Among the replicated associations are SNPs in KCNK6 a K(+) channel gene. SSEA identified 27 genes with a strong enrichment of significant SNPs (P < 10(-6)); 20 were replicated with varying degrees of confidence. Among the novel findings identified by SSEA is the telomere length regulator gene TNKS. These studies are the first to use GWAS to understand the genetic diversity that accounts the phenotypic heterogeneity sickle cell anemia as estimated by an integrated model of severity. Additional validation, resequencing, and functional studies to understand the biology and reveal mechanisms by which candidate genes might have their effects are the future goals of this work.

Pediatric Nasoorbitoethmoid Fractures: Cause, Classification, and Management.

BACKGROUND: Currently, there is a paucity of information on the presentation and proper management of pediatric nasoorbitoethmoid fractures. The purpose of this study was to examine the incidence, cause, associated injuries, and management of these fractures. Furthermore, the authors sought to assess outcomes after transnasal wiring or suture canthopexy for type III nasoorbitoethmoid fractures. METHODS: A retrospective cohort review was performed of all patients with nasoorbitoethmoid fractures who presented to a Level I trauma center from 1990 to 2010. Charts and computed tomographic imaging were reviewed, and nasoorbitoethmoid fractures were labeled based on the Markowitz-Manson classification system. Patient fracture patterns, demographics, characteristics, and outcomes were recorded. Univariate and multivariate methods were used to compare groups. RESULTS: A total of 63 pediatric patients were identified in the study period. The sample's mean age was 8.78 ± 4.08 years, and 28.6 percent were girls. The sample included 18 type I injuries, 28 type II injuries, and 17 type III injuries. No significant demographic differences were found between patients with type I, II, and III fractures (p > 0.05). Operative intervention was pursued in 16.7, 46.4, and 82.4 percent of type I, II, and III nasoorbitoethmoid fractures, respectively. In patients with type III nasoorbitoethmoid fractures, no patients with transnasal wiring developed telecanthus. CONCLUSIONS: Pediatric nasoorbitoethmoid fractures are uncommon injuries. Type I fracture can often be treated with close observation. However, type II and III injury patterns should be evaluated for operative intervention. Transnasal wiring is an effective method to prevent traumatic telecanthus deformity in type III fracture patterns.

Genetic contributions to the autoantibody profile in a rabbit model of Systemic Lupus Erythematosus (SLE).

For the development of rabbit models of Systemic Lupus Erythematosus (SLE), immunoglobulin allotype-defined pedigreed rabbits from the National Institute of Allergy and Infectious Diseases rabbit resource more closely approximate human populations due to their non-inbred pedigreed structure. In an initial study from this laboratory, peptides (SM and GR) from the spliceosomal Smith (Sm) and the NMDA glutamate receptor NR2b, on branched polylysine backbones (BB) elicited antinuclear and anti-dsDNA autoantibodies typical of SLE, as well as seizures and nystagmus sometimes observed as neurological manifestations in SLE patients. This suggested the feasibility of further selective breeding to develop a more reproducible rabbit model for investigations of SLE. Here we report the results of GR-MAP-8 and control BB immunization on autoantibody responses in a group of 24 rabbits specifically bred and developed from parents and ancestors tested for autoantibody responses. The changes in hematological profile and blood chemistry in the experimental rabbits were evaluated along with autoantibody responses. Elevations of total white blood cell (WBC), monocyte, eosinophil and basophil counts that developed following immunizations were moderately influenced by litter and presence of the antibody heavy chain allotype VH1a1. Autoantibody development followed a sequential pattern with anti-nuclear antibodies (ANA) followed by anti-dsDNA and subsequently anti-Sm and anti-RNP similar to SLE patients. High autoantibody levels to one autoantigen were not always associated with antibody response to another. Female rabbits had higher prevalence and levels of autoantibodies similar to human SLE. Higher autoantibody levels of anti-dsDNA and -ANA were observed among some full sibs and the presence of high responder ancestors in the pedigree was associated the augmented responses. We observed significant association between highest antibody responses to GR-MAP-8 and highest anti-dsDNA levels. Naturally occurring autoantibodies were found in some pre-immune sera and some unique ANA fluorescent staining patterns within the experimental group were observed. Background immunofluorescence in pre-immune sera, distinct patterns of programmed autoantibody responses unique among individual rabbits may have been modulated by genetic constitution, gender and environmental factors including exposure to antigens. The high incidence and intensity of autoantibody responses among descendants of high responders suggest that there may be an additive mode of inheritance with high heritability. It is conceivable that further rigorous pedigree selection for autoantibody responses could lead to development of rabbit models with spontaneous occurrence of SLE like serology and disease phenotypes.

Plastic Surgeons' Perceptions of Financial Conflicts of Interest and the Sunshine Act.

BACKGROUND: It is unknown whether recent legislation known as the Physician Payments Sunshine Act has affected plastic surgeons' views of conflicts of interest (COI). The purpose of this study was to evaluate plastic surgeons' beliefs about COI and their comprehension of the government-mandated Sunshine Act. METHODS: Plastic surgeon members of the American Society of Plastic Surgeons were invited to complete an electronic survey. The survey contained 27 questions that assessed respondents' past and future receipt of financial gifts from industry, awareness of the Sunshine Act, and beliefs surrounding the influence of COI on surgical practice. RESULTS: A total of 322 individuals completed the survey. A majority had previously accepted gifts from industry (n = 236; 75%) and would accept future gifts (n = 181; 58%). Most respondents believed that COI would affect their colleagues' medical practice (n = 190; 61%) but not their own (n = 165; 51%). A majority was aware of the Sunshine Act (n = 272; 89%) and supported data collection on surgeon COI (n = 224; 73%). A larger proportion of young surgeons believed patients would benefit from knowing their surgeon's COI (P = 0.0366). Surgeons who did not expect COI in the future believed financial COI could affect their own clinical practice (P = 0.0221). CONCLUSIONS: Most plastic surgeons have a history of accepting industry gifts but refute their influence on personal clinical practice. Surgeon age and anticipation of future COI affected beliefs about the benefits of COI disclosure to patients and the influence of COI on surgical practice.

The Accuracy of Conflict-of-Interest Disclosures Reported by Plastic Surgeons and Industry.

BACKGROUND: The purpose of this study was to analyze the frequency and nature of self-reported conflict-of-interest disclosures in the plastic surgery literature and to compare these findings to the Physician Payments Sunshine Act database. METHODS: All articles published from August of 2013 through December of 2013 in four major plastic surgery journals were analyzed. For every publication, the conflict-of-interest disclosure statement for each investigator was reviewed. These statements were then compared to transactions of value for each investigator as reported by biomedical companies in the Sunshine Act database. An analysis was performed to identify and characterize specific factors associated with conflict-of-interest disclosures. RESULTS: A total of 1002 independent investigators/authors were identified. Of these, 90 investigators (9 percent) self-reported a conflict of interest. In contrast, a total of 428 authors (42.7 percent) were found to have received transactions of value from a biomedical company according to the Sunshine Act database. Conversely, a total of 22 authors (2.2 percent) self-reported a conflict of interest but were not found to have received transactions of value in the Sunshine Act database. Our analysis found that (1) academic investigators, (2) transactions of value in excess of $500, and (3) publishing articles related to the sponsoring biomedical company were all statistically associated with reporting conflicts of interest (p < 0.0001). CONCLUSIONS: Discordance exists between investigator/authors self-reporting in scientific journals and the government-mandated reporting of conflicts of interest by industry. Factors associated with conflict-of-interest disclosure include academic status, transaction amount, and article content related to the sponsoring biomedical company.

Citation Rate Predictors in the Plastic Surgery Literature.

BACKGROUND: The purpose of this study is to determine and characterize the scientific and nonscientific factors that influence the rate of article citation in the field of plastic surgery. DESIGN: Cross-sectional study. SETTING: We reviewed all entries in Annals of Plastic Surgery and Journal of Plastic, Reconstructive, and Aesthetic Surgery from January 1, 2007 to December 31, 2007; and Plastic and Reconstructive Surgery from January 1, 2007 to December 31, 2008. All scientific articles were analyzed and several article characteristics were extracted. The number of citations at 5 years was collected as the outcome variable. A multivariable analysis was performed to determine which variables were associated with higher citations rates. RESULTS: A total of 2456 articles were identified of which only 908 fulfilled the inclusion criteria. Most studies were publications in the fields of reconstructive (26.3%) or pediatric/craniofacial (17.6%) surgery. The median number of citations 5 years from publication was 8. In the multivariable analysis, factors associated with higher citations rates were subspecialty field (p = 0.0003), disclosed conflict of interest (p = 0.04), number of authors (p = 0.04), and journal (p = 0.02). CONCLUSION: We have found that higher level of evidence (or other study methodology factors) is not associated with higher citation rates. Instead, conflict of interest, subspecialty topic, journal, and number of authors are strong predictors of high citation rates in plastic surgery.

Ear biometrics for patient identification in global health: a cross-sectional study to test the feasibility of a simplified algorithm.

BACKGROUND: One of the greatest public health challenges in low- and middle-income countries (LMICs) is identifying people over time and space. Recent years have seen an explosion of interest in developing electronic approaches to addressing this problem, with mobile technology at the forefront of these efforts. We investigate the possibility of biometrics as a simple, cost-efficient, and portable solution. Common biometrics approaches include fingerprinting, iris scanning and facial recognition, but all are less than ideal due to complexity, infringement on privacy, cost, or portability. Ear biometrics, however, proved to be a unique and viable solution. METHODS: We developed an identification algorithm then conducted a cross sectional study in which we photographed left and right ears from 25 consenting adults. We then conducted re-identification and statistical analyses to identify the accuracy and replicability of our approach. RESULTS: Through principal component analysis, we found the curve of the ear helix to be the most reliable anatomical structure and the basis for re-identification. Although an individual ear allowed for high re-identification rate (88.3%), when both left and right ears were paired together, our rate of re-identification amidst the pool of potential matches was 100%. CONCLUSIONS: The results of this study have implications on future efforts towards building a biometrics solution for patient identification in LMICs. We provide a conceptual platform for further investigation into the development of an ear biometrics identification mobile application.