Mutations in ASPRV1 Cause Dominantly Inherited Ichthyosis.

The discovery of genetic causes of inherited skin disorders has been pivotal to the understanding of epidermal differentiation, function, and renewal. Here we show via exome sequencing that mutations in ASPRV1 (aspartic peptidase retroviral-like 1) cause a dominant Mendelian disorder featuring palmoplantar keratoderma and lamellar ichthyosis, a phenotype that has otherwise been exclusively recessive. ASPRV1 encodes a mammalian-specific and stratified epithelia-specific protease important in processing of filaggrin, a critical component of the uppermost epidermal layer. Three different heterozygous ASPRV1 missense mutations in four unrelated ichthyosis kindreds segregate with disease and disrupt protein residues within close proximity to each other and autocatalytic cleavage sites. Expression of mutant ASPRV1 proteins demonstrates that all three mutations alter ASPRV1 auto-cleavage and filaggrin processing, a function vital to epidermal barrier integrity.

Post-zygotic ACTB mutations underlie congenital smooth muscle hamartomas.

BACKGROUND: Congenital smooth muscle hamartomas (CSMHs) are benign lesions that share clinical and histopathological features with Becker nevus, a mosaic disorder associated with post-zygotic ACTB mutations. Given the clinical and histopathological overlap between CSMH and Becker nevus, we hypothesized that post-zygotic mutations in ACTB may underlie CSMH. METHODS: Direct sequencing of ACTB gene in affected and unaffected tissue isolated from one case of hemihypertrichosis and hemihypertrophy corresponding to giant segmental CSMH and hemihypertrophy. This was followed by direct sequencing with and without enrichment assay for hotspot ACTB mutations in affected tissue from 12 samples of isolated CSMH from unrelated individuals. RESULTS: In total we identified somatic missense ACTB mutations in 9 out of 13 CSMHs (69%). Mutations were either novel or previously reported in Becker nevi and Becker nevus syndrome. CONCLUSIONS: CSMHs result from post-zygotic ACTB mutations. This study proves that CSMHs and Becker nevi are nosologically related, and expand the phenotypic spectrum of ACTB mutations.

Phenotypic expansion of POFUT1 loss of function mutations in a disorder featuring segmental dyspigmentation with eczematous and folliculo-centric lesions.

Appearance of mosaic disorders in thin Blaschko lines suggests that somatic mutations in keratinocyte precursors underlie their pathogenesis. Germline heterozygous mutations in POFUT1 gene cause Dowling-Degos disease (DDD), a skin disease that features flexural reticulated hyperpigmentation and follicular-based lesions. POFUT1 mosaicism has not been described to date. Here, we describe a 9-year-old female with segmental hyper- and hypopigmented patches with overlying eczematous plaques and follicular papules. Employing paired whole exome sequencing of saliva and keratinocytes isolated from affected skin, we found a novel germline heterozygous POFUT1 deletion causing frameshift and premature codon termination and somatic copy-neutral loss of heterozygosity on chromosome 20 encompassing POFUT1. Expression levels of POFUT1 as well as other key regulators of the notch signaling pathway-NOTCH1, NOTCH2, and HES1-were reduced in affected keratinocytes compared with normal keratinocytes. Our findings provide the first evidence of POFUT1 postzygotic mutation and a phenotypic expansion of POFUT1 loss of function mutations. We show that a recessive loss of function mutation in POFUT1 produces a distinct clinical presentation with features (e.g., dermatitis) that are absent in the generalized form of DDD. This study demonstrates how analysis of mosaic disorders can reveal unexpected phenotypes for known genes.

Complexities of Perioperative Pain Management in Orthopedic Trauma.

PURPOSE OF REVIEW: This review discusses both obvious and hidden barriers in trauma patient access to pain management specialists and provides some suggestions focusing on outcome optimization in the perioperative period. RECENT FINDINGS: Orthopedic trauma surgeons strive to provide patients the best possible perioperative pain management, while balancing against potential risks of opioid abuse and addiction. Surgeons often find they are ill-prepared to effectively manage postoperative pain in patients returning several months following trauma surgery, many times still dependent on opioids for pain control. Some individuals from this trauma patient population may also require the care of pain management specialists and/or consultation with drug addiction specialists. As the US opioid epidemic continues to worsen, orthopedic trauma surgeons can find it difficult to obtain access to pain management specialists for those patients requiring complex pain medication management and substance abuse counseling. The current state of perioperative pain management for orthopedic trauma patients remains troubling due to reliance on only opioid analgesics, society-associated risks of opioid medication addiction, an "underground" prescription drug marketplace, and an uncertain legal atmosphere related to opioid pain medication management that can deter pain management physicians from accepting narcotic-addicted patients and discourage future physicians from pursuing advanced training in the specialty of pain management. Additionally, barriers continue to exist among Medicaid patients that deter this patient population from access to pain medicine subspecialty care, diminishing medication management reimbursement rates make it increasingly difficult for trauma patients to receive proper opioid analgesic pain medication management, and a lack of proper opioid analgesic medication management training among PCPs and orthopedic trauma surgeons further contributes to an environment ill-prepared to provide effective perioperative pain management for orthopedic trauma patients.

A p.478I>T KRT1 mutation in a case of annular epidermolytic ichthyosis.

Annular epidermolytic ichthyosis (AEI; Online Mendelian Inheritance in Man [OMIM]# 607602) is a rare subtype of epidermolytic ichthyosis that is characterized by polycyclic, migratory erythematous and scaly plaques. It typically results from dominant mutations in the keratin 1 or keratin 10 genes. We present the case of a 5-year-old girl who developed intermittent eruptions of pink, round, scaly, migratory plaques with palmoplantar keratoderma and was originally diagnosed with erythrokeratodermia variabilis et progressiva (EKVP). Genetic analysis revealed a c.1436T>C transition mutation in the keratin 1 gene, and histopathology showed epidermolysis and hyperkeratosis, confirming the diagnosis of AEI.

Preclinical endoscopic training using a part-task simulator: learning curve assessment and determination of threshold score for advancement to clinical endoscopy.

BACKGROUND: Preclinical simulator training has the potential to decrease endoscopic procedure time and patient discomfort. This study aims to characterize the learning curve of endoscopic novices in a part-task simulator and propose a threshold score for advancement to initial clinical cases. METHODS: Twenty novices with no prior endoscopic experience underwent repeated endoscopic simulator sessions using the part-task simulator. Simulator scores were collected; their inverse was averaged and fit to an exponential curve. The incremental improvement after each session was calculated. Plateau was defined as the session after which incremental improvement in simulator score model was less than 5%. Additionally, all participants filled out questionnaires regarding simulator experience after sessions 1, 5, 10, 15, and 20. A visual analog scale and NASA task load index were used to assess levels of comfort and demand. RESULTS: Twenty novices underwent 400 simulator sessions. Mean simulator scores at sessions 1, 5, 10, 15, and 20 were 78.5 ± 5.95, 176.5 ± 17.7, 275.55 ± 23.56, 347 ± 26.49, and 441.11 ± 38.14. The best fit exponential model was [time/score] = 26.1 × [session #]-0.615; r 2 = 0.99. This corresponded to an incremental improvement in score of 35% after the first session, 22% after the second, 16% after the third and so on. Incremental improvement dropped below 5% after the 12th session corresponding to the predicted score of 265. Simulator training was related to higher comfort maneuvering an endoscope and increased readiness for supervised clinical endoscopy, both plateauing between sessions 10 and 15. Mental demand, physical demand, and frustration levels decreased with increased simulator training. CONCLUSION: Preclinical training using an endoscopic part-task simulator appears to increase comfort level and decrease mental and physical demand associated with endoscopy. Based on a rigorous model, we recommend that novices complete a minimum of 12 training sessions and obtain a simulator score of at least 265 to be best prepared for clinical endoscopy.

The Genomic and Phenotypic Landscape of Ichthyosis: An Analysis of 1000 Kindreds.

IMPORTANCE: Ichthyoses are clinically and genetically heterogeneous disorders characterized by scaly skin. Despite decades of investigation identifying pathogenic variants in more than 50 genes, clear genotype-phenotype associations have been difficult to establish. OBJECTIVE: To expand the genotypic and phenotypic spectra of ichthyosis and delineate genotype-phenotype associations. DESIGN, SETTING, AND PARTICIPANTS: This cohort study recruited an international group of individuals with ichthyosis and describes characteristic and distinguishing features of common genotypes, including genotype-phenotype associations, during a 10-year period from June 2011 to July 2021. Participants of all ages, races, and ethnicities were included and were enrolled worldwide from referral centers and patient advocacy groups. A questionnaire to assess clinical manifestations was completed by those with a genetic diagnosis. MAIN OUTCOMES AND MEASURES: Genetic analysis of saliva or blood DNA, a phenotyping questionnaire, and standardized clinical photographs. Descriptive statistics, such as frequency counts, were used to describe the cases in the cohort. Fisher exact tests identified significant genotype-phenotype associations. RESULTS: Results were reported for 1000 unrelated individuals enrolled from around the world (mean [SD] age, 50.0 [34.0] years; 524 [52.4%] were female, 427 [42.7%] were male, and 49 [4.9%] were not classified); 75% were from the US, 12% from Latin America, 4% from Canada, 3% from Europe, 3% from Asia, 2% from Africa, 1% from the Middle East, and 1% from Australia and New Zealand. A total of 266 novel disease-associated variants in 32 genes were identified among 869 kindreds. Of these, 241 (91%) pathogenic variants were found through multiplex amplicon sequencing and 25 (9%) through exome sequencing. Among the 869 participants with a genetic diagnosis, 304 participants (35%) completed the phenotyping questionnaire. Analysis of clinical manifestations in these 304 individuals revealed that pruritus, hypohydrosis, skin pain, eye problems, skin odor, and skin infections were the most prevalent self-reported features. Genotype-phenotype association analysis revealed that the presence of a collodion membrane at birth (odds ratio [OR], 6.7; 95% CI, 3.0-16.7; P < .001), skin odor (OR, 2.8; 95% CI, 1.1-6.8; P = .02), hearing problems (OR, 2.9; 95% CI, 1.6-5.5; P < .001), eye problems (OR, 3.0; 95% CI, 1.5-6.0; P < .001), and alopecia (OR, 4.6; 95% CI, 2.4-9.0; P < .001) were significantly associated with TGM1 variants compared with other ichthyosis genotypes studied. Skin pain (OR, 6.8; 95% CI, 1.6-61.2; P = .002), odor (OR, 5.7; 95% CI, 2.0-19.7; P < .001), and infections (OR, 3.1; 95% CI, 1.4-7.7; P = .03) were significantly associated with KRT10 pathogenic variants compared with disease-associated variants in other genes that cause ichthyosis. Pathogenic variants were identified in 869 (86.9%) participants. Most of the remaining individuals had unique phenotypes, enabling further genetic discovery. CONCLUSIONS AND RELEVANCE: This cohort study expands the genotypic and phenotypic spectrum of ichthyosis, establishing associations between clinical manifestations and genotypes. Collectively, the findings may help improve clinical assessment, assist with developing customized management plans, and improve clinical course prognostication.

Clusters of Injuries From Motorcycle Collisions: Exploratory Factor Analysis of a Single Institution Trauma Registry.

Objective With the goal of guiding acute management of associated injuries motorcycle trauma patients, this study aims to identify patterns of associated injuries after motorcycle collisions using exploratory factor analysis. Methods We conducted a retrospective review at a Level 1 trauma center of all patients who presented after motorcycle collisions resulting in trauma system activations between July 2, 2002 and December 31, 2013. We performed exploratory factor analysis on this dataset to identify sets of injuries that cluster together. Results We identified 1,050 patients who presented for trauma after a motorcycle collision. These patients had 3,101 injuries, including 1,694 fractures. Using exploratory factor analysis, we developed a model with four latent factors that explained approximately half of the variance in injuries. These factors were defined by: head and cervical spine injuries; extremity injuries; abdomen, pelvis and upper extremity injuries; and shoulder girdle and thorax injuries. We also found a novel injury pattern relationship between forearm shaft/wrist and lower extremity injuries. Conclusions Motorcycle trauma results in distinct clusters of associated injuries likely due to common motorcycle collision patterns, most notably a novel relationship between forearm shaft/wrist and lower extremity injuries that merits further exploration, and could play a role during secondary survey.

High-risk motor vehicle drivers engage in more risk behaviors than motorcyclists.

OBJECTIVE: The purpose of this study was to characterize and compare risk behaviors between motorcyclists and motor vehicle drivers who were involved in accidents and required hospitalization. The study focused on patients who were recently involved in motorcycle collisions (MCCs) and motor vehicle collisions (MVCs). METHODS: We identified 63 patients involved in MCCs and 39 patients involved in MVCs who were admitted to our level-1 trauma center from April 2014 to September 2015. These 102 patients completed a questionnaire designed to evaluate risky driving behaviors. Pearson's chi-squared tests and unpaired two-tailed t-tests were used to evaluate categorical and normally distributed continuous variables, respectively. Multivariable linear regression was used to analyze predictors of risk behavior. Significance was set at p < 0.05. RESULTS: When compared to patients involved in an MCC, patients involved in MVCs were more likely to be female (p = 0.007), drive more frequently (p < 0.001), and never perceive the risk of an accident (p = 0.036). MVC patients were more likely to have admitted to substance use on the day of the accident (p = 0.030), historically drive under the influence of drugs (p = 0.031), drive while tired (p < 0.001), drive while text messaging (p < 0.001), and speed while overtaking vehicles (p = 0.011). Overall, MVC patients engaged in more risk behaviors (3.3 ± 1.3 vs. 2.0 ± 1.5; p < 0.001) and were more likely to engage in multiple risk behaviors (p < 0.001). MVCs were associated with increased risk behavior, even after controlling for protective behaviors, driving history, and demographics (p = 0.045). CONCLUSIONS: Within our cohort of trauma patients at our institution, motor vehicle drivers were more likely than motorcyclists to engage in any one risk behavior and engage in a higher number of risk behaviors. In addition, motor vehicle drivers perceived their risk of a potential accident as lower than riding a motorcycle. Education initiatives should focus on motor vehicle driver safety interventions that reduce risk behaviors.

A review of common motorcycle collision mechanisms of injury.

Injuries sustained in motorcycle collisions can be organized into distinct patterns to improve recognition and treatment.Lowside, highside, topside, and collision are the four main categories of motorcycle crash types.Within those four crash types, mechanisms of injury include head-leading collisions, direct vertical impact, motorcycle radius, motorcycle thumb, fuel tank injures, limb entrapment, tyre-spoke injury, and crash modifying manoeuvre. Cite this article: EFORT Open Rev 2020;5:544-548. DOI: 10.1302/2058-5241.5.190090.

Clues to primary vismodegib resistance lie in histology and genetics.

Basal cell carcinoma (BCC) is the most common human malignant neoplasm. However, there are multiple BCC subtypes that share clinical features while demanding different management. We present a case of a woman with hundreds of BCCs throughout her body that were resistant to vismodegib and without other features of basal cell nevus syndrome. Histological results of biopsies taken from various sites revealed three lesions characteristic of infundibulocystic BCCs (IBCCs) and two BCCs. Paired whole-exome sequencing performed using DNA isolated from blood and one of her IBCCs uncovered a germline heterozygous SUFU (Suppressor of Fused) mutation. The downstream location of SUFU in the hedgehog pathway explains why its mutation results in IBCCs that will not respond to any therapeutics that target upstream components of SUFU These results capture the significance of histological and genetic analysis in directing treatment.

Recent advances in understanding inherited disorders of keratinization.

The ichthyoses are a heterogeneous group of skin diseases characterized by localized or generalized scaling or both. Other common manifestations include palmoplantar keratoderma, erythroderma, recurrent infections, and hypohidrosis. Abnormal barrier function is a cardinal feature of the ichthyoses, which results in compensatory hyperproliferation and transepidermal water loss. Barrier function is maintained primarily by the stratum corneum, which is composed of cornified cells surrounded by a corneocyte lipid envelope and intercellular lipid layers. The lipid components are composed primarily of ceramides. Human genetics has advanced our understanding of the role of the epidermal lipid barrier, and a series of discoveries in animals and humans revealed mutations in novel genes causing disorders of keratinization. Recently, next-generation sequencing has further expanded our knowledge, identifying novel mutations that disrupt the ceramide pathway and result in disorders of keratinization. This review focuses on new findings in ichthyoses caused by mutations involving lipid synthesis or function or both.

The effect of insurance type on trauma patient access to psychiatric care under the Affordable Care Act.

OBJECTIVE: The objective of the study was to assess the effect of insurance type (Medicaid, Medicare, private insurance or cash pay) on patients' access to psychiatrists for a new patient consultation. METHOD: 240 psychiatrists identified as interested in treating patients with PTSD were called across 8 states. The caller requested an appointment for her fictitious boyfriend who had been in a car accident to be evaluated for PTSD. Each office was called four times to assess the responses for each payment type. From each call, whether an appointment was offered and barriers to an appointment were recorded. RESULTS: 21% of psychiatrists would see new patients. 15% of offices scheduled an appointment for a patient with Medicaid, compared to 34% for Medicare, 54% for BlueCross and 93% for cash pay (p<0.001). Medicaid patients confronted more barriers to receiving appointments and had more trouble scheduling appointments in states with expanded Medicaid eligibility. The overall number of Medicaid patients who would be able to theoretically schedule an appointment in states with versus states without expanded Medicaid eligibility was approximately equivalent. Psychiatry practice characteristics, such as whether the practice was academic, were not significantly associated with acceptance of Medicaid. CONCLUSIONS: Access to a psychiatrist for a new patient consultation is challenging. Despite expansion of the Affordable Care Act, substantial barriers remain for Medicaid patients in accessing psychiatric care compared to patients with Medicare, private insurance or those who pay cash.

The Effect of Insurance Type on Fragility Fracture Patient Access to Endocrinology Under the Affordable Care Act.

OBJECTIVES: To assess the effect of insurance type (Medicaid, Medicare, and private insurance) on fragility fracture patients' access to endocrinology specialists in the postoperative period. MATERIALS AND METHODS: The research team called 247 board-certified endocrinologists in 8 representative states. The caller requested an appointment for her fictitious mother to be evaluated for osteoporosis after suffering a hip fracture that required surgery. The caller stated that her mother had an abnormal level of parathyroid hormone and her mother's orthopedic surgeon believed she needed to see an endocrinologist. Each office was called 3 times to assess the responses for each insurance type. For each call, we documented whether the patient was able to receive an appointment and the barriers the patient confronted to receiving an appointment. RESULTS: About 15.8% of offices scheduled an appointment for a patient with Medicaid, compared to 48.6% for Medicare and 54.3% for BlueCross (P < .0001). Medicaid patients confronted more barriers to receiving appointments. There was no statistically significant difference in access for Medicaid patients in states that had expanded Medicaid versus states that had not expanded Medicaid. Medicaid reimbursement for a new level 3 patient visit did not significantly correlate with appointment success rates or wait times. CONCLUSION: Despite the passage of the Affordable Care Act, Medicaid patients have reduced access to endocrinologists and more complex barriers to receiving appointments. A more robust strategy for increasing access to care for Medicaid patients would be more equitable.

Influence of Medical Insurance Under the Affordable Care Act on Access to Pain Management of the Trauma Patient.

BACKGROUND AND OBJECTIVES: The Affordable Care Act intended to "extend affordable coverage" and "ensure access" for vulnerable patient populations. This investigation examined whether the type of insurance (Medicaid, Medicare, Blue Cross, cash pay) carried by trauma patients influences access to pain management specialty care. METHODS: Investigators phoned 443 board-certified pain specialists, securing office visits with 235 pain physicians from 8 different states. Appointments for pain management were for a patient who sustained an ankle fracture requiring surgery and experiencing difficulty weaning off opioids. Offices were phoned 4 times assessing responses to the 4 different payment methodologies. RESULTS: Fifty-three percent of pain specialists contacted (235 of 443) were willing to see new patients to manage pain medication. Within the 53% of positive responses, 7.2% of physicians scheduled appointments for Medicaid patients, compared with 26.8% for cash-paying patients, 39.6% for those with Medicare, and 41.3% with Blue Cross (P < 0.0001). There were no differences in appointment access between states that had expanded Medicaid eligibility for low-income adults versus states that had not expanded Medicaid eligibility. Neither Medicaid nor Medicare reimbursement levels for new patient visits correlated with ability to schedule an appointment or influenced wait times. CONCLUSIONS: Access to pain specialists for management of pain medication in the postoperative trauma patient proved challenging. Despite the Affordable Care Act, Medicaid patients still experienced curtailed access to pain specialists and confronted the highest incidence of barriers to receiving appointments.