Evidence for craniofacial enhancer variation underlying nonsyndromic cleft lip and palate.

Nonsyndromic cleft lip with or without cleft palate (NSCLP) is a common birth defect for which only ~ 20% of the underlying genetic variation has been identified. Variants in noncoding regions have been increasingly suggested to contribute to the missing heritability. In this study, we investigated whether variation in craniofacial enhancers contributes to NSCLP. Candidate enhancers were identified using VISTA Enhancer Browser and previous publications. Prioritization was based on patterning defects in knockout mice, deletion/duplication of craniofacial genes in animal models and results of whole exome/whole genome sequencing studies. This resulted in 20 craniofacial enhancers to be investigated. Custom amplicon-based sequencing probes were designed and used for sequencing 380 NSCLP probands (from multiplex and simplex families of non-Hispanic white (NHW) and Hispanic ethnicities) using Illumina MiSeq. The frequencies of identified variants were compared to ethnically matched European (CEU) and Los Angeles Mexican (MXL) control genomes and used for association analyses. Variants in mm427/MSX1 and hs1582/SPRY1 showed genome-wide significant association with NSCLP (p ≤ 6.4 × 10-11). In silico analysis showed that these enhancer variants may disrupt important transcription factor binding sites. Haplotypes involving these enhancers and also mm435/ABCA4 were significantly associated with NSCLP, especially in NHW (p ≤ 6.3 × 10-7). Importantly, groupwise burden analysis showed several enhancer combinations significantly over-represented in NSCLP individuals, revealing novel NSCLP pathways and supporting a polygenic inheritance model. Our findings support the role of craniofacial enhancer sequence variation in the etiology of NSCLP.

PBX-WNT-P63-IRF6 pathway in nonsyndromic cleft lip and palate.

Nonsyndromic cleft lip and palate (NSCLP) is one of the most common craniofacial anomalies in humans, affecting more than 135,000 newborns worldwide. NSCLP has a multifactorial etiology with more than 50 genes postulated to play an etiologic role. The genetic pathway comprised of Pbx-Wnt-p63-Irf6 genes was shown to control facial morphogenesis in mice and proposed as a regulatory pathway for NSCLP. Based on these findings, we investigated whether variation in PBX1, PBX2, and TP63, and their proposed interactions were associated with NSCLP. Fourteen single nucleotide variants (SNVs) in/nearby PBX1, PBX2, and TP63 were genotyped in 780 NSCLP families of nonHispanic white (NHW) and Hispanic ethnicities. Family-based association tests were performed for individual SNVs stratified by ethnicity and family history of NSCLP. Gene-gene interactions were also tested. A significant association was found for PBX2 rs3131300 and NSCLP in combined Hispanic families (p = .003) while nominal association was found for TP63 rs9332461 in multiplex Hispanic families (p = .005). Significant haplotype associations were observed for PBX2 in NHW (p = .0002) and Hispanic families (p = .003), and for TP63 in multiplex Hispanic families (.003). An independent case-control group was used to validate findings, and significant associations were found with PBX1 rs6426870 (p = .007) and TP63 rs9332461 (p = .03). Gene-gene interactions were detected between PBX1/PBX2/TP63 with IRF6 in NHW families, and between PBX1 with WNT9B in both NHW and Hispanic families (p < .0018). This study provides the first evidence for a role of PBX1 and PBX2, additional evidence for the role of TP63, and support for the proposed PBX-WNT-TP63-IRF6 regulatory pathway in the etiology of NSCLP.

Association of IFT88 gene variants with nonsyndromic cleft lip with or without cleft palate.

BACKGROUND: Nonsyndromic cleft lip with or without cleft palate (NSCLP) is a common birth defect with multifactorial etiology. Genetic studies have identified numerous gene variants in association with NSCLP. IFT88 (intraflagellar transport 88) has been suggested to play a major role in craniofacial development, as Ift88 mutant mice exhibit cleft palate and mutations in IFT88 were identified in individuals with NSCLP. OBJECTIVE: To investigate the association of IFT88 single nucleotide gene variants (SNVs) with NSCLP in a large family data set consisting of non-Hispanic white (NHW) and Hispanic families. METHODS: Nine SNVs in/nearby IFT88 were genotyped in 482 NHW families and 301 Hispanic NSCLP families. Genotyping was performed using TaqMan® chemistry. Single- and pairwise-SNV association analyses were performed for all families stratified by ethnicity and family history of NSCLP using the family-based association test (FBAT), and association in the presence of linkage (APL). Bonferroni correction was used to adjust for multiple testing and p values ≤.0055 were considered statistically significant. RESULTS: Significant association was found between IFT88 rs9509311 and rs2497490 and NSCLP in NHW all families (p = .004 and .005, respectively), while nominal associations were found for rs7998361 and rs9509307 (p < .05). Pairwise association analyses also showed nominal associations between NSCLP in both NHW and Hispanic data sets (p < .05). No association was found between individual variants in IFT88 and NSCLP in Hispanics. CONCLUSIONS: Our results suggest that variation in IFT88 may contribute to NSCLP risk, particularly in multiplex families from a non-Hispanic white population.

Dexmedetomidine Decreases Postoperative Pain and Narcotic Use in Children Undergoing Alveolar Bone Graft Surgery.

OBJECTIVE: Dexmedetomidine is a parenteral agent that combines the benefits of cooperative sedation, anxiolysis, and analgesia without the risks of respiratory depression. Off-label use has been reported in children. We have introduced dexmedetomidine for use in patients having undergone alveolar bone graft (ABG). The objective is to demonstrate the value and safety of postoperative dexmedetomidine infusion in a non-ICU setting following ABG. DESIGN: A retrospective review was performed on patients who underwent ABG by the senior author. Patients were divided into 2 groups: those who received postoperative dexmedetomidine and those who received patient-controlled anesthesia. MAIN OUTCOME MEASURE(S): The primary study outcome measures included patient demographics, adverse events, length of stay, pain scores, and doses of narcotics during admission were collected. RESULTS: Inclusion criteria were met by 54 patients; 39 received dexmedetomidine whereas 15 did not. There were no significant differences between groups in age, gender, and length of stay. The patients who received dexmedetomidine used oral narcotics less often ( P = .01). In addition, more patients reported no pain after surgery ( P = .05) and at the time of discharge if they received dexmedetomidine ( P < .01). There were no reported adverse effects. CONCLUSIONS: Dexmedetomidine provided superior pain control after surgery and at the time of discharge, as well as a significant decrease in the use of oral narcotics. In our institution, it has since replaced the PCA as a postoperative pain control modality. Absent the risk for respiratory depression, dexmedetomidine has demonstrated a safe option for postoperative pain control in our focused group of pediatric patients.

An Assessment of Performance Between Medicare Advantage and Stand-Alone Prescription Drug Plans on Two Quality Assurance Measures.

The purpose of our study was to compare performance between Medicare Advantage and stand-alone prescription drug plans on the two quality assurance measures of drug-disease interaction and drug-drug interaction for elderly heart failure beneficiaries. Performance on the drug-disease interaction measure appeared more problematic for stand-alone plan enrollees compared with Medicare Advantage plan enrollees. No statistical difference existed between the plans regarding drug-drug interactions. It appears there may be considerable room for more sophisticated use of disease profiling in the processing of drug claims. The provision of richer clinical data is an essential step to improving performance on the drug-disease interaction measure.

An Assessment of Three Post-Discharge Drug-Based Quality Assurance Events for Elderly Medicare Beneficiaries Enrolled in a Stand-Alone Part D Plan.

This article examines the distribution of drug-based quality assurance events (QAEs) post-discharge across five-day increments and identifies characteristics associated with post-discharge QAEs. Data were obtained through a cross-sectional study of Medicare beneficiaries age 65 and over enrolled in stand-alone Part D plans during calendar year 2010. Our findings suggest an even more compressed timeframe than previously identified in the literature for addressing medication issues among elderly beneficiaries. Specifically, medication reconciliation is needed within two to three days of discharge instead of within 14 days as the literature suggests. To decrease inadvertent readmissions, an immediate in-community medication reconciliation following hospital discharge is needed.

Applying the 2003 Beers update to elderly Medicare enrollees in the Part D program.

BACKGROUND: Inappropriate prescribing of certain medications known as Beers drugs may be harmful to the elderly, because the potential risk for an adverse outcome outweighs the potential benefit. OBJECTIVES: (1) To assess Beers drug use in dual enrollees compared to non-duals; (2) to explore the association between dual enrollment status and Beers use, controlling for the effects of age, gender, race/ethnicity, census region, and health status; (3) to assess which medication therapeutic category had the highest Beers use. DESIGN: Cross sectional retrospective review of 2007 Centers for Medicare & Medicaid Service Part D data. Potentially inappropriate medication use was assessed, independent of diagnosis, using the 2003 update by Fick et al. FINDINGS: The likelihood of Beers drug use among duals approximates that of non-duals (OR 1.023, 95% CI 1.020-1.026). Characteristics associated with the receipt of a Beers medication include Hispanic origin, younger age, female gender, poor health status, and residence outside of the U.S.' Northeast region. Genitourinary products had the highest Beers use within medication therapeutic categories among both dual and non-dual enrollees (21.1% and 19.9%, respectively). CONCLUSIONS: Part D data can be successfully used to monitor Beers drug use. With adjustments for several important and easily measured demographic, health, and prescription drug use covariates, Beers drug use appears to be as common among non-dual enrollees as it is among dual enrollees in the Part D program. New Part D drug utilization policies that apply to all beneficiaries may need to be enacted to reduce Beers drug use.

National study of prescription poisoning with psychoactive and nonpsychoactive medications in Medicare/Medicaid dual enrollees age 65 or over.

The purpose of this study is to assess prescription medication poisoning among psychoactive and nonpsychoactive medications used by elderly (65 years or older) Medicare & Medicaid dual enrollees as well as examine contextual components associated with poisoning. Our primary research goal was to compare medication poisonings among psychoactive medications to nonpsychoactive medications. Our second research goal was to identify components influencing medication poisonings and how they interrelate. The approach used a cross-sectional retrospective review of calendar year 2003 Centers for Medicare & Medicaid Service's Medicaid Pharmacy claims data for elderly dual enrollees. Poisonings were identified based on ICD-9-CM categorizations. Poisonings associated with the psychoactive medications were proportionally over twice as high as compared to nonpsychoactive medications (14.3 per 100,000 enrollees and 6.6 per 100,000 enrollees, respectively). Additionally, the two contextual components of (a) use of many drugs and (b) familiarity with the medication have a direct, but competing impact on poisoning. The reasons behind unintentional poisoning in the elderly have been somewhat a mystery. This study is among the first to attempt to distinguish between poisoning events associated with psychoactive medications versus nonpsychoactive medications as well as assess the impact of differing contextual components on medication poisoning.

Endocrine therapy use among elderly hormone receptor-positive breast cancer patients enrolled in Medicare Part D.

BACKGROUND: Clinical guidelines recommend that women with hormone-receptor positive breast cancer receive endocrine therapy (selective estrogen receptor modulators [SERMs] or aromatase inhibitors [AIs]) for five years following diagnosis. OBJECTIVE: To examine utilization and adherence to therapy for SERMs and AIs in Medicare Part D prescription drug plans. DATA: Linked Surveillance, Epidemiology, and End Results (SEER)-Medicare data. STUDY DESIGN: We identified 15,542 elderly women diagnosed with hormone-receptor positive breast cancer in years 2003-2005 (the latest SEER data at the time of the study) and enrolled in a Part D plan in 2006 or 2007 (the initial years of Part D). This permitted us to compare utilization and adherence to therapy at various points within the recommended five-year timeframe for endocrine therapy. SERM and AI use was measured from claim records. Non-adherence to therapy was defined as a medication possession ratio of less than 80 percent. PRINCIPAL FINDINGS: Between May 2006 and December 2007, 22 percent of beneficiaries received SERM, 52 percent AI, and 26 percent received neither. The percent receiving any endocrine therapy decreased with time from diagnosis. Among SERM and AI users, 20-30 percent were non-adherent to therapy; out-of-pocket costs were higher for AI than SERM and were strongly associated with non-adherence. For AI users without a low income subsidy, adherence to therapy deteriorated after reaching the Part D coverage gap. CONCLUSIONS: Many elderly breast cancer patients were not receiving therapy for the recommended five years following diagnosis. Choosing a Part D plan that minimizes out-of-pocket costs is critical to ensuring beneficiary access to essential medications.

Noncompliance in the use of cardiovascular medications in the Medicare Part D population.

OBJECTIVES: (1) to assess non-compliance among Medicare Part D recipients for the cardiovascular medication classes; (2) to identify the probability of noncompliance for each medication class when controlling for the potential risk factors of age, gender, race/ethnic origin, census region, disease burden, dual eligibility enrollment status, Part D plan status, relative out-of-pocket (OOP) non-class costs, and relative OOP daily class costs. DESIGN: Cross sectional retrospective review of 2007 Centers for Medicare & Medicaid Services (CMS) Part D data. All drugs within a drug class were used to conduct the assessment. FINDINGS: Non-compliance was found to be lower than previously reported. Patients who are male, age 65 to 74, Black, or residing in the South are associated with higher noncompliance for cardiovascular medications among the therapeutic classes we studied. Dual eligibility enrollment is typically associated with improved compliance; enrollment in a Medicare Advantage Prescription Drug (MAPD) plan may or may not improve compliance dependent on the therapeutic class under study. Increased disease burden is associated with lower compliance. OOP non-class costs had an opposing effect on compliance as compared to OOP daily costs; higher OOP non-class costs were associated with better compliance. CONCLUSION: Identifying patient characteristics that may contribute positively or negatively to medication compliance is an essential step to improved therapy. As a strategy to improve compliance, the proper selection of therapy that fits a particular patient is paramount.

Characterization of the nasal, sublingual, and oropharyngeal mucosa microbiota in cleft lip and palate individuals before and after surgical repair.

OBJECTIVE: To delineate inherent differences in the microbial milieu in cleft palate patients compared with cleft lip patients and to document changes in microbial flora before and after cleft lip and palate repair. DESIGN: A prospective study of preoperative and postoperative culture results from the nasal, sublingual, and oropharyngeal surfaces of patients undergoing primary cleft lip repair and palate closure. SETTING: Shriners Hospitals for Children, Galveston, Texas, and University of Texas Medical Branch, Galveston, Texas. PATIENTS: Seventy-nine patients were included in a 3-year period. Ten patients with isolated cleft lip underwent primary lip repair. Twenty-five patients with cleft lip and palate underwent primary lip repair, and 44 patients underwent palatoplasty. RESULTS: Cleft palate patients had a significantly higher rate of colonization by staphylococcal species, but not methicillin-resistant Staphylococcus aureus , when compared to cleft lip patients (p=.0298; chi-square test). Closure of the palatal cleft coincided with significant decline in the prevalence of Klebsiella and Enterobacter species (p<.05; McNemar test). The only major complication, palatal dehiscence, was believed to be directly related to infection with group A beta-hemolytic streptococci. CONCLUSIONS: Despite a high prevalence of potential pathogenic and enteric flora preoperatively in primary palate repair, postoperative wound infection is rare in the prospective study population. However, the presence of beta-hemolytic streptococci was associated with a higher risk of repair dehiscence; therefore, screening for Streptococci prior to surgery should be performed routinely.

National study of medications associated with injury in elderly Medicare/Medicaid dual enrollees during 2003.

OBJECTIVES: To address the association between inappropriate prescribing for the elderly and adverse outcomes and to identify the magnitude of the cost of medication-associated injury in this population. DESIGN: Cross sectional. SETTING: United States, 2003. PATIENTS: 5,412,678 dually eligible Medicare/Medicaid enrollees aged 65 years or older. INTERVENTION: Beers and non-Beers medications with potential central nervous system adverse effects of dizziness/vertigo, drowsiness, and/or fainting were assessed. Emergency department (ED) visits with admitting diagnoses pertaining to injuries for elderly enrollees dually eligible for Medicare and Medicaid during the calendar year were linked to prescriptions filled during the 90 days preceding the visit. MAIN OUTCOME MEASURE: For each drug, the proportion of ED-related fills and the Medicare average revenue charge per injury-related ED visit were calculated. RESULTS: Several drugs not currently on the Beers list were found to be associated with high proportions of ED-related fills: methadone had the highest proportion of any of the drugs studied (12.3 per 1,000 fills), and bethanechol (7.8 per 1,000 fills) had the highest proportion among genitourinary products. Regarding narcotic analgesics, propoxyphene (7.7 per 1,000 fills) had a higher association with injury than morphine (6.6 per 1,000 fills) or tramadol (6.5 per 1,000 fills). For cardiovascular agents, clonidine (4.7 per 1,000 fills) and doxazosin (3.6 per 1,000 fills) had higher associations with injury than nifedipine (3.3 per 1,000 fills). Fentanyl, a non-Beers medication, was associated with the most expensive injury-related ED visits ($1,263 average revenue charge). CONCLUSION: Beers medications are associated with high injury-related ED visit rates for the elderly, and a number of drugs not currently on the Beers list also pose an apparent risk for injury-related visits.

Cross-chest lipoplasty and surgical excision for gynecomastia: a 10-year experience.

BACKGROUND: Gynocomastia is a relatively common condition in men, with a reported overall incidence of 32% to 36% and as high as 65% among adolescent males in some series. OBJECTIVE: We reviewed the senior surgeon's experience over the past decade in the surgical treatment of gynecomastia using suction-assisted lipoplasty (SAL) with a cross-chest tunneling technique, performed alone or in combination with direct excision. METHODS: Thirty-four patients with gynecomastia were evaluated and treated surgically at the University of Texas Medical Branch in the past 10 years. Twelve were treated with cross-chest SAL alone, 16 with cross-chest SAL and direct excision, and 6 with direct excision. Infusion of wetting solution was performed with the use of a 2.0-mm cannula, through an access site at the medial border of the contralateral nipple-areolar complex. Next, a 4.0-mm Mercedes-tip (Byron/Mentor Corp., Santa Barbara, CA) cannula was tunneled across the sternum to liposuction the contralateral prepectoral fatty breast. Patients with composite fatty and glandular tissue first underwent SAL, then direct excision through a periareolar incision; those with only retroareolar glandular tissue underwent direct excision alone. RESULTS: All patients who underwent SAL alone or SAL combined with excision had satisfactory aesthetic results and no reported postoperative complications. In one patient who underwent excision alone, a hematoma developed. CONCLUSIONS: Despite newer technologies, traditional SAL performed with a cross-chest technique and direct excision as indicated is a valuable approach that yields predictable success. This approach avoids scarring and offers a sculpted reduction of the retroareolar glandular and fatty elements, resulting in a natural, smooth breast contour.

Facial fracture approaches with landmark ratios to predict the location of the infraorbital and supraorbital nerves: an anatomic study.

In exposing facial fractures for reduction and fixation with coronal, subciliary, subtarsal, and upper buccal sulcus approaches, the supraorbital and infraorbital nerves are susceptible to injury. The location of the supraorbital and infraorbital nerves can be predicted by palpating for the supraorbital notch. Significant edema as seen with facial fractures can make these prominent bony landmarks difficult to palpate, however. The purpose of this study was to determine a method to predict the location of the supraorbital and infraorbital nerves in the face of frontal and periorbital edema when the supraorbital and infraorbital nerves are not palpable. The supraorbital and infraorbital nerves were identified in 14 cadaver heads. The orbital width from the medial to lateral canthus was measured. The distance of the vertical vector of the supraorbital and infraorbital nerves from the medial canthus was measured along this horizontal vector of the orbit. The distance of the infraorbital nerve from the infraorbital rim was measured. The orbital width measured 42.2 +/- 1.6 mm from the medial to lateral canthus. The vertical vector of the supraorbital nerve measured 15.9 +/- 1.1 mm from the medial canthus along the horizontal vector of the orbit. The vertical vector of the infraorbital verve measured 16.8 +/- 1.4 mm from the medial canthus along the horizontal vector of the orbit. The infraorbital nerve measured 9.8 +/- 1.0 mm inferior to the infraorbital rim. The medial one third of the orbit measured 14.1 mm. Therefore, the supraorbital and infraorbital nerves are located approximately along the medial third of the orbit, with the upper bound of 95% confidence at 3.1 mm. The location of the supraorbital and infraorbital nerves can be predicted by the previous landmark ratio to within 3 mm.

Anatomic basis of notch deformity in open rhinoplasty.

Notch deformity at the columella after the stairstep incision is an unsightly sequel that fuels negativism for open rhinoplasty critics. Obvious causes cited include surgical misadventures involving division of the foot of the medial crus and poor healing. The authors offer yet an additional etiology based on the contraction distortion caused by the depressor septi nasi muscle. The purpose of this study is to investigate the anatomic basis for notch deformity after stairstep technique in open rhinoplasty. For this anatomic study, 10 fresh cadavers were used. Dissections were performed, exposing the columellar components. The macroscopic and microscopic photo documentation gathered supports the authors' theory that depressor septi nasi action causes skin-edge deformation that leads to closure malalignment and notch deformity. Pre-incision landmark defining tattoo or sutures will assure proper alignment at closure.