Recent Publications by CFE Educators

BACKGROUND

The National Birth Defects Prevention Study (NBDPS) contains a wealth of information on affected and unaffected family triads, and thus provides numerous opportunities to study gene-environment interactions (G×E) in the etiology of birth defect outcomes. Depending on the research objective, several analytic options exist to estimate G×E effects that use varying combinations of individuals drawn from available triads.

METHODS

In this study, we discuss important considerations in the collection of genetic data and environmental exposures.

RESULTS

We will also present several population- and family-based approaches that can be applied to data from the NBDPS including case-control, case-only, family-based trio, and maternal versus fetal effects. For each, we describe the data requirements, applicable statistical methods, advantages, and disadvantages.

CONCLUSION

A range of approaches can be used to evaluate potentially important G×E effects in the NBDPS. Investigators should be aware of the limitations inherent to each approach when choosing a study design and interpreting results.

OBJECTIVES/HYPOTHESIS

This study aimed to characterize the common salivary gland disorders presenting in the pediatric population and to describe the diagnostic and therapeutic outcomes of sialendoscopy in this population.

STUDY DESIGN

Retrospective observational study in a tertiary care pediatric medical center.

METHODS

Medical records review of patients under 18 years of age who presented to pediatric otolaryngology with symptoms related to a salivary gland disorder from 2002 to 2014.

RESULTS

Fifty patients were identified with an average age of 7.5 years at presentation. Eighty percent (40/50) of cases were diagnosed with juvenile recurrent parotitis (JRP), and 15 underwent sialendoscopy. The other 10 (20%) patients presented with sialolithiasis. These patients had a higher average age at presentation (12.4 vs. 6.3 years), and the majority were successfully removed with sialendoscopic techniques. Juvenile recurrent parotitis patients who underwent sialendoscopy had significantly higher costs of care during the period of observation compared to those who did not have a procedure, without a statistically significant difference in outcomes.

CONCLUSIONS

Sialendoscopy is an effective tool for stone retrieval in pediatric sialolithiasis. Juvenile recurrent parotitis patients who underwent sialendoscopy had outcomes similar to those selected for conservative therapy, calling into question whether the substantially higher care costs can be justified. Further prospective studies addressing cost-effectiveness will help define the role of sialendoscopy in JRP.

LEVEL OF EVIDENCE

4.

Imprinted genes are expressed from only one parental allele and heterozygous loss involving the expressed allele is sufficient to produce complete loss of protein expression. Genetic alterations are common in tumorigenesis but the role of imprinted genes in this process is not well understood. In earlier work we mutagenized mice heterozygous for the Neurofibromatosis I tumor suppressor gene (NF1) to model radiotherapy-associated second malignant neoplasms that arise in irradiated NF1 patients. Expression analysis of tumor cell lines established from our mouse models identified Grb10 expression as widely absent. Grb10 is an imprinted gene and polymorphism analysis of cell lines and primary tumors demonstrates that the expressed allele is commonly lost in diverse Nf1 mutant tumors arising in our mouse models. We performed functional studies to test whether Grb10 restoration or loss alter fundamental features of the tumor growth. Restoring Grb10 in Nf1 mutant tumors decreases proliferation, decreases soft agar colony formation and downregulates Ras signaling. Conversely, Grb10 silencing in untransformed mouse embryo fibroblasts significantly increased cell proliferation and increased Ras-GTP levels. Expression of a constitutively activated MEK rescued tumor cells from Grb10-mediated reduction in colony formation. These studies reveal that Grb10 loss can occur during in vivo tumorigenesis, with a functional consequence in untransformed primary cells. In tumors, Grb10 loss independently promotes Ras pathway hyperactivation, which promotes hyperproliferation, an early feature of tumor development. In the context of a robust Nf1 mutant mouse model of cancer this work identifies a novel role for an imprinted gene in tumorigenesis.

Ankylosing spondylitis (AS) is a common, highly heritable, inflammatory arthritis for which HLA-B*27 is the major genetic risk factor, although its role in the aetiology of AS remains elusive. To better understand the genetic basis of the MHC susceptibility loci, we genotyped 7,264 MHC SNPs in 22,647 AS cases and controls of European descent. We impute SNPs, classical HLA alleles and amino-acid residues within HLA proteins, and tested these for association to AS status. Here we show that in addition to effects due to HLA-B*27 alleles, several other HLA-B alleles also affect susceptibility. After controlling for the associated haplotypes in HLA-B, we observe independent associations with variants in the HLA-A, HLA-DPB1 and HLA-DRB1 loci. We also demonstrate that the ERAP1 SNP rs30187 association is not restricted only to carriers of HLA-B*27 but also found in HLA-B*40:01 carriers independently of HLA-B*27 genotype.

OBJECTIVE

Surgical site infections (SSIs) are a leading cause of morbidity and mortality among women undergoing cesarean section (C-section), a common procedure in North America. While risk factors for SSI are often modifiable, wide variation in clinical practice exists. With this review, we provide a comprehensive overview of the results and quality of systematic reviews and meta-analyses on interventions to reduce surgical site infections among women undergoing C-section.

METHODS

We searched PubMed and the Cochrane Database of Systematic Reviews for systematic reviews and meta-analyses published between January 2000 and May 2014 on interventions to reduce the occurrence of SSIs (incisional infections and endometritis), among women undergoing C-section. We extracted data on the interventions, outcomes, and strength of evidence as determined by the original article authors, and assessed the quality of each article based on a modified Assessment of Multiple Systematic Reviews tool.

RESULTS

A total of 30 review articles met inclusion criteria and were reviewed. Among these articles, 77 distinct interventions were evaluated: 29% were supported with strong evidence as assessed by the original article authors, and 83% of the reviews articles were classified as good quality based on our assessment. Ten interventions were classified as being effective in reducing SSI with strong evidence in a good-quality article, including preoperative vaginal cleansing, the use of perioperative antibiotic prophylaxis, and several surgical techniques.

CONCLUSION

Efforts to reduce SSI rates among women undergoing C-section should include interventions such as preoperative vaginal cleansing and the use of perioperative antibiotics because compelling evidence exists to support their effectiveness.

BACKGROUND

A better understanding of case management practices is required to improve inpatient pediatric care in resource-limited settings. Here we utilize data from a unique health facility-based surveillance system at six Ugandan hospitals to evaluate the quality of pediatric case management and the factors associated with appropriate care.

METHODS

All children up to the age of 14 years admitted to six district or regional hospitals over 15 months were included in the study. Four case management categories were defined for analysis: suspected malaria, selected illnesses requiring antibiotics, suspected anemia, and diarrhea. The quality of case management for each category was determined by comparing recorded treatments with evidence-based best practices as defined in national guidelines. Associations between variables of interest and the receipt of appropriate case management were estimated using multivariable logistic regression.

RESULTS

A total of 30,351 admissions were screened for inclusion in the analysis. Ninety-two percent of children met criteria for suspected malaria and 81% received appropriate case management. Thirty-two percent of children had selected illnesses requiring antibiotics and 89% received appropriate antibiotics. Thirty percent of children met criteria for suspected anemia and 38% received appropriate case management. Twelve percent of children had diarrhea and 18% received appropriate case management. Multivariable logistic regression revealed large differences in the quality of care between health facilities. There was also a strong association between a positive malaria diagnostic test result and the odds of receiving appropriate case management for comorbid non-malarial illnesses - children with a positive malaria test were more likely to receive appropriate care for anemia and less likely for illnesses requiring antibiotics and diarrhea.

CONCLUSIONS

Appropriate management of suspected anemia and diarrhea occurred infrequently. Pediatric quality improvement initiatives should target deficiencies in care unique to each health facility, and interventions should focus on the simultaneous management of multiple diagnoses.

OBJECTIVES

Our survey aimed to characterize the practice of inducing fetal demise before pregnancy termination among abortion providers, including its technical aspects and why providers have chosen to adopt it.

STUDY DESIGN

We conducted a survey of Family Planning Fellowship-trained or Fellowship-affiliated Family Planning (FP) subspecialists about their practice of inducing fetal demise, including questions regarding the circumstances in which they would induce demise, techniques used and rationales for choosing whether to adopt this practice.

RESULTS

Of the 169 FP subspecialists we surveyed, 105 (62%) responded. About half (52%) of respondents indicated that they routinely induced fetal demise before terminations in the second trimester. Providers' practices varied in the gestations at which they started inducing demise as well as the techniques used. Respondents provided legal, technical and psychological reasons for their decisions to induce demise.

CONCLUSION

Inducing fetal demise before second-trimester abortions is common among US FP specialists for multiple reasons. The absence of professional guidelines or robust data may contribute to the variance in the current practice patterns of inducing demise.

IMPLICATIONS

Our study documents the widespread practice of inducing fetal demise before second-trimester abortion and further describes wide variation in providers' methods and rationales for inducing demise. It is important for abortion providers as a professional group to come to a formal consensus on the appropriate use of these techniques and to determine whether such practices should be encouraged, tolerated or even permitted.

BACKGROUND

Calcification of the thoracic aorta is a risk factor for cardiovascular disease and peripheral arterial disease but has not been well studied in diabetics. In addition, many studies consider aortic calcium as a single anatomic entity, whereas calcification of the ascending and descending portions of the thoracic aorta may represent separate phenotypes. We sought to characterize the prevalence of ascending and descending aortic calcium among diabetics and to assess their associations with cardiovascular risk factors, coronary artery calcium, and peripheral arterial disease.

METHODS

Within the Penn Diabetes Heart Study, a cross-sectional study of subjects with type 2 diabetes mellitus but without coronary or renal disease, we quantified Agatston scores of the ascending and descending thoracic aorta in 1739 subjects (63% male, 61% Caucasian). Multivariate logistic and Tobit regressions were used to assess associations with cardiovascular risk factors, coronary calcium, and peripheral arterial disease.

RESULTS

Of all subjects, 54% had thoracic aortic calcium; of these, 37% had calcium solely in the ascending thoracic aorta and 20% solely in the descending thoracic aorta. In multivariate regression, age, Caucasian race, systolic blood pressure, low-density lipoprotein cholesterol, smoking, and diabetes duration were independently associated with calcium of both the ascending and descending thoracic aorta (P .001 for all). Ascending and descending aortic calcium were each independently associated with coronary calcium in multivariate regression, but only calcification of the descending thoracic aortic was associated with low ankle-brachial index.

CONCLUSION

Ascending and descending thoracic aortic calcium have similar associations with traditional cardiovascular risk factors in diabetics and are independently associated with coronary artery calcium. Only calcium in the descending aorta is associated with peripheral arterial disease. Delineation of both phenotypes may provide information about the individualized vascular disease and risk profile of patients with type 2 diabetes mellitus.

OBJECTIVE

We report the clinical features, comorbidities, and outcome of 22 newly identified patients with antibodies to the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR).

METHODS

This was a retrospective review of patients diagnosed between May 2009 and March 2014. Immunologic techniques have been reported previously.

RESULTS

Patients' median age was 62 years (range 23-81; 14 female). Four syndromes were identified: 12 (55%) patients presented with distinctive limbic encephalitis (LE), 8 (36%) with limbic dysfunction along with multifocal/diffuse encephalopathy, one with LE preceded by motor deficits, and one with psychosis with bipolar features. Fourteen patients (64%) had a tumor demonstrated pathologically (5 lung, 4 thymoma, 2 breast, 2 ovarian teratoma) or radiologically (1 lung). Additional antibodies occurred in 7 patients (3 onconeuronal, 1 tumor-related, 2 cell surface, and 1 tumor-related and cell surface), all with neurologic symptoms or tumor reflecting the concurrent autoimmunity. Treatment and outcome were available from 21 patients (median follow-up 72 weeks, range 5-266): 5 had good response to immunotherapy and tumor therapy, 10 partial response, and 6 did not improve. Eventually 5 patients died; all had a tumor or additional paraneoplastic symptoms related to onconeuronal antibodies. Coexistence of onconeuronal antibodies predicted a poor outcome (p = 0.009).

CONCLUSION

Anti-AMPAR encephalitis usually manifests as LE, can present with other symptoms or psychosis, and is paraneoplastic in 64% of cases. Complete and impressive neurologic improvement can occur, but most patients have partial recovery. Screening for a tumor and onconeuronal antibodies is important because their detection influences outcome.