Functional genotype-phenotype associations in recessive dystrophic epidermolysis bullosa.

BACKGROUND: Genotype-phenotype associations in recessive dystrophic epidermolysis bullosa (RDEB) have been difficult to elucidate. OBJECTIVE: To investigate RDEB genotype-phenotype associations and explore a functional approach to genotype classification. METHODS: Clinical examination and genetic testing of RDEB subjects, including assessment of clinical disease by RDEB subtype and extent of blistering. Genotypes were evaluated according to each variant's effect on type VII collagen function per updated literature and subsequently categorized by degree of impact on VII collagen function as low-impact (splice/missense, missense/missense), medium-impact (premature termination codon [PTC]/missense, splice/splice), and high-impact (PTC/PTC, PTC/splice). Genotype-phenotype associations were investigated using Kruskal-Wallis and Fisher's exact tests, and age-adjusted regressions. RESULTS: Eighty-three participants were included. High-impact variants were associated with worse RDEB subtype and clinical disease, including increased prevalence of generalized blistering (55.6% for low-impact vs 72.7% medium-impact vs 90.4% high-impact variants, P = .002). In age-adjusted regressions, participants with high-impact variants had 40.8-fold greater odds of squamous cell carcinoma compared to low-impact variants (P = .02), and 5.7-fold greater odds of death compared to medium-impact variants (P = .05). LIMITATIONS: Cross-sectional design. CONCLUSION: Functional genotype categories may stratify RDEB severity; high-impact variants correlated with worse clinical outcomes. Further validation in larger cohorts is needed.

Association of Intraoperative Antibiotic Irrigation With Systemic Contact Dermatitis.

This case series describes the development of morbilliform drug eruption after breast surgery.

Long-term safety and efficacy of gene-corrected autologous keratinocyte grafts for recessive dystrophic epidermolysis bullosa.

BACKGROUND: Recessive dystrophic epidermolysis bullosa (RDEB) is a rare, devastating blistering genodermatosis caused by mutations in the COL7A1 gene, which encodes for type VII collagen and is necessary for dermal-epidermal adhesion and integrity. Disease manifestations include severe and debilitating wounds, aggressive squamous cell carcinomas, and premature death; however, there are currently no approved therapies. This Phase 1/2a, open-label study evaluated the long-term efficacy and safety of gene-corrected autologous keratinocyte grafts (EB-101) for chronic RDEB wounds. METHODS: Autologous keratinocytes were harvested from participants with severe RDEB, transduced with a retrovirus containing the full-length COL7A1 gene, and grown into 5 × 7 cm (35 cm2) sheets. Gene-corrected keratinocyte sheets were then transplanted onto chronic RDEB wounds present for ≥ 12 weeks. RESULTS: Seven adult participants with severe RDEB were grafted with six sheets each (42 total sheets) onto wounds and followed for a mean of 5.9 years (range 4-8 years). Long-term improvements in wound healing and symptoms were observed. At year five, 70% (21/30) of treated sites demonstrated ≥ 50% wound healing compared to baseline by investigator global assessment. No sites with ≥ 50% wound healing were painful or pruritic, compared to 67% (6/9) of sites with < 50% wound healing (p < 0.001) at year five. Grafts were well-tolerated throughout long-term follow-up. No serious adverse events related to treatment were reported over a mean of 5.9 years of follow-up. No persistent systemic autoimmunity against type VII collagen or replication-competent retrovirus infections were identified, and no participants developed squamous cell carcinomas related to treatment during long-term follow-up. CONCLUSIONS: Treatment with EB-101 appears safe and efficacious, and produces long-term improvements in wound healing, pain, and itch for RDEB patients. Results from the Phase 3 randomized controlled trial are forthcoming. TRIAL REGISTRATION: ClinicalTrials.gov, NCT01263379. Registered December 15, 2010. https://clinicaltrials.gov/ct2/show/NCT01263379.

A global, cross-sectional survey of patient-reported outcomes, disease burden, and quality of life in epidermolysis bullosa simplex.

BACKGROUND: Epidermolysis bullosa simplex (EBS) comprises a group of rare, blistering genodermatoses. Prior work has been limited by small sample sizes, and much remains unexplored about the disease burden and health-related quality of life (QOL) of patients with EBS. The aim of this study was to characterize the most common patient-reported clinical manifestations and the health-related impact of QOL in EBS, and to examine differences in disease burden by age. METHODS: Patients with a diagnosis of epidermolysis bullosa (EB) or their caregivers completed a one-time online survey administered by EBCare, an international online EB registry. Survey data from respondents self-reporting a diagnosis of EBS were analyzed for clinical and wound manifestations, medication use, and QOL (using Quality of Life in Epidermolysis Bullosa [QOLEB] scores). Differences across age groups were assessed using Kruskal-Wallis and Fisher's exact tests. RESULTS: There were 214 survey respondents with EBS. The mean age was 32.8 years (standard deviation = 19.2). Many respondents reported blisters (93%), recurrent wounds (89%), pain (74%), chronic wounds (59%), itch (55%), and difficulty walking (44%). Mean QOLEB score was 14.7 (standard deviation = 7.5) indicating a "moderate" impact on QOL, and 12% of respondents required regular use of opiates. Findings were consistent in subgroup analyses restricted to respondents with diagnostic confirmation via genetic testing or skin biopsy (n = 63 of 214). Age-stratified analyses revealed differences in disease burden: younger respondents were more likely to self-report severe disease (24% vs. 19% vs. 5% for respondents aged 0-9 vs. 10-17 vs. 18 + , p = 0.001), failure to thrive (9% vs. 15% vs. 3%, p = 0.02), and use of gastrostomy tubes (15% vs. 12% vs. 1%, p < 0.001) and topical antibiotics (67% vs. 69% vs. 34%, p < 0.001), while older respondents were more likely to be overweight or obese (6% vs. 0% vs. 51%, p < 0.001) and have difficulty walking (24% vs. 46% vs. 48%, p = 0.04). CONCLUSIONS: In the largest international cross-sectional survey of EBS patients conducted, respondents reported extensive disease burden including significant wounding, pain, itch, difficulty walking, and impact on QOL. Age stratified disease manifestations. These findings suggest significant unmet need, and treatment and counseling for EBS patients should consider age-specific differences.

Socioeconomic differences persist in use of permanent vs long-acting reversible contraception: An analysis of the National Survey of Family Growth, 2006 to 2010 vs 2015 to 2017.

OBJECTIVE: Permanent contraception has historically been more prevalent among non-White women with lower education and income. Given increasing popularity of long-acting reversible contraception (LARC), we examine changing sociodemographic patterns of permanent contraception and LARC. STUDY DESIGN: We performed a descriptive analysis of the National Survey of Family Growth (NSFG) from 2006 to 2017, with multivariable analyses of the 2006 to 2010 and 2015 to 2017 cohorts. Using multinomial logistic regression, we investigate predictors of contraceptive category (permanent contraception vs LARC, lower-efficacy contraception vs LARC) in reproductive-aged women. RESULTS: Total 8161 respondents were included in 2 distinct but analogous regression analyses: (1) the most recent survey cohort, 2015 to 2017 and (2) the cohort a decade prior, 2006 to 2010. Over this period, the prevalence of LARC increased nearly 3-fold (6.2%-16.7%), while permanent contraception use trended downwards (22%-18.6%). Yet, in adjusted models, we observed little change in the sociodemographic predictors of permanent contraception: from the early to recent cohort, use of permanent contraception (vs LARC) remained less likely among college graduates (multinomial odds ratio (OR) 0.45 [95% confidence interval 0.21, 0.97]) and Hispanic women (OR 0.41 [0.21, 0.82]). In addition, high income (>$74,999) and metropolitan residence came to predict less use (OR 0.33 [0.13, 0.84] and 0.47 [0.23, 0.97]). Multiparity, advanced age (over ≥35), and marital status remained strong predictors of permanent contraception. CONCLUSION: Although use of LARC nearly equals that of permanent contraception in the most recent NSFG survey, socioeconomic differences persist. Continued effort is needed to detect and address structural barriers to accessing the most effective forms of contraception for women. IMPLICATIONS: Comparing 2006-2010 to 2015-2017, reliance on female permanent contraception decreased while LARC use increased, making prevalence more similar. However, significant socioeconomic differences persist in who chooses permanent contraception, with urban, educated, higher income women more likely to use LARC. Ongoing efforts are needed to understand and reduce economic barriers to LARC.

Patient Experiences of Integrated Care in Medicare Accountable Care Organizations and Medicare Advantage Versus Traditional Fee-for-Service.

BACKGROUND: Health insurance design can influence the extent to which clinical care is well-coordinated. Through alternative payment models, Medicare Advantage (MA) and Accountable Care Organizations (ACOs) have the potential to improve integration relative to traditional fee-for-service (FFS) Medicare. OBJECTIVE: To characterize patient experiences of integrated care within Medicare and identify whether MA or ACO beneficiaries perceive greater integration than FFS beneficiaries. DESIGN: Retrospective cross-sectional analysis of the 2015 Medicare Current Beneficiary Survey. SUBJECTS: Nationally representative sample of 11,978 Medicare beneficiaries. MEASURES: Main outcomes included 8 previously derived domains of patient-perceived integrated care (PPIC), measured on a scale of 1-4. RESULTS: The final sample was 55% female with a mean (SD) age of 71.1 (11.3). In unadjusted analyses, we observed considerable variation across PPIC domains in the full sample, but little variation across subsamples defined by coverage type within a given PPIC domain. In linear models adjusting for a rich set of patient characteristics, we observe no significant benefits of ACOs nor MA relative to FFS, a finding which is robust to alternative specifications and adjustment for multiple comparisons. We similarly observed no benefits in subgroup analyses restricted to states with relatively high market penetration of ACOs or MA. CONCLUSIONS: Despite characteristics of ACOs and MA that theoretically promote integrated care, we find that PPIC is largely similar across coverage types in Medicare.

Nonmydriatic Photographic Screening for Diabetic Retinopathy in Pregnant Patients with Pre-Existing Diabetes in a Safety Net Population: 1 Year Results from the Diabetic Retinopathy in Pregnant Patients Study.

Background: Pregnant patients with pre-existing diabetes mellitus (DM) are at increased risk for development or progression of existing diabetic retinopathy (DR). A quality improvement project was initiated to improve DR screening during pregnancy at a safety net hospital. This article highlights the utility and generalizability of our telemedicine-based screening model. Materials and Methods: In April 2018, we implemented a photographic retinal screening system in the Maternal Fetal Medicine (MFM) clinic at Santa Clara Valley Medical Center in San Jose, CA. The system is intended to screen all pregnant patients with pre-existing diabetes (type 1 and 2). Retinal images are automatically uploaded to a secure server and interpreted by a retina specialist (C.K.P.). Results: A total of 71 pregnant patients with pre-existing DM were seen in the MFM clinic during the study period. Sixty-six of 71 patients (93.0%) were screened compared with 69.1% in the year prior. Of the 64 patients screened with readable images 11 (17.2%) had DR, whereas 53 did not. Forty-nine of the 64 (74.2%) patients screened underwent screening using the new nonmydriatic system in the MFM clinic. Only 7 out of 47 (14.9%) patients with readable images in the MFM clinic required referral to the ophthalmology clinic. Conclusion: Our model for DR screening in pregnant patients in safety net hospitals is effective in improving screening rates and expediting evaluation and treatment for those in need. This system can prevent irreversible vision loss in pregnant patients and provides an effective framework for ophthalmic care in a safety net hospital system.