The Impact of Air Pollution on Atopic Dermatitis.

PURPOSE OF REVIEW: Atopic dermatitis (AD) remains a dermatological disease that imposes a significant burden on society. Air pollution has previously been linked to both the onset and severity of atopic dermatitis. As air pollution remains a critical environmental factor impacting human health, this review seeks to provide an overview of the relationship between different air pollutants and AD. RECENT FINDINGS: AD can develop from multiple causes that can be broadly grouped into epidermal barrier dysfunction and immune dysregulation. Air pollution imposes significant health risks and includes a wide variety of pollutant types. AD has been linked to outdoor air pollutants such as particulate matter (PM), volatile organic compounds (VOC), gaseous compounds, and heavy metals. Exposure to indoor pollutants such as tobacco smoke and fungal molds has also been associated with an increased incidence of AD. While different pollutants impact distinct molecular pathways in the cell, they mostly converge on ROS product, DNA damage, and dysregulated T-cell activity and cytokine production. The presented review suggests a strengthening tie between air pollution and AD. It points to opportunities for further studies to clarify, as well as potential therapeutic opportunities that leverage the mechanistic relationships between air pollution and AD.

The Effect of Implementing Bar-Code Medication Administration in an Emergency Department on Medication Administration Errors and Nursing Satisfaction.

INTRODUCTION: Bar-code medication administration has been shown to reduce medication errors in inpatient settings with limited studies on its use in emergency departments. In addition, no studies have evaluated nursing satisfaction with implementing bar-code medication administration in an emergency department. This study was designed to determine the impact of implementing bar-code medication administration in an emergency department on medication errors and nursing satisfaction. METHODS: This is a before-and-after study, with no control group, of a bar-code medication administration intervention conducted in a community hospital emergency department. Direct observation was used to compare medication error rates before and 3 months after implementing bar-code medication administration. The Medication Administration System-Nurses Assessment of Satisfaction survey was used to assess the impact on nursing satisfaction before and 1 month after bar-code medication administration implementation. RESULTS: A total of 676 medication administrations were observed in the period before bar-code medication administration implementation and 656 after. The medication administration error rate preimplementation was 2.96% with "wrong dose" errors being the most common. After bar-code medication administration implementation, the medication administration error rate fell to 0.76%, a relative reduction of 74.2% (Fisher exact P < 0.01). The average (SD) Medication Administration System-Nurses Assessment of Satisfaction score preimplementation was 2.60 (0.75) and improved to 2.29 (0.66) (t = 2.00, P = 0.05) 1 month post implementation. DISCUSSION: Implementing bar-code medication administration in a community emergency department was associated with a decrease in medication administration errors and an improvement in Medication Administration System-Nurses Assessment of Satisfaction scores. The results of this study suggest a benefit of bar-code medication administration in reducing medication administration errors and improved nursing satisfaction in the emergency department.

Loss of Slc4a1b chloride/bicarbonate exchanger function protects mechanosensory hair cells from aminoglycoside damage in the zebrafish mutant persephone.

Mechanosensory hair cell death is a leading cause of hearing and balance disorders in the human population. Hair cells are remarkably sensitive to environmental insults such as excessive noise and exposure to some otherwise therapeutic drugs. However, individual responses to damaging agents can vary, in part due to genetic differences. We previously carried out a forward genetic screen using the zebrafish lateral line system to identify mutations that alter the response of larval hair cells to the antibiotic neomycin, one of a class of aminoglycoside compounds that cause hair cell death in humans. The persephone mutation confers resistance to aminoglycosides. 5 dpf homozygous persephone mutants are indistinguishable from wild-type siblings, but differ in their retention of lateral line hair cells upon exposure to neomycin. The mutation in persephone maps to the chloride/bicarbonate exchanger slc4a1b and introduces a single Ser-to-Phe substitution in zSlc4a1b. This mutation prevents delivery of the exchanger to the cell surface and abolishes the ability of the protein to import chloride across the plasma membrane. Loss of function of zSlc4a1b reduces hair cell death caused by exposure to the aminoglycosides neomycin, kanamycin, and gentamicin, and the chemotherapeutic drug cisplatin. Pharmacological block of anion transport with the disulfonic stilbene derivatives DIDS and SITS, or exposure to exogenous bicarbonate, also protects hair cells against damage. Both persephone mutant and DIDS-treated wild-type larvae show reduced uptake of labeled aminoglycosides. persephone mutants also show reduced FM1-43 uptake, indicating a potential impact on mechanotransduction-coupled activity in the mutant. We propose that tight regulation of the ionic environment of sensory hair cells, mediated by zSlc4a1b activity, is critical for their sensitivity to aminoglycoside antibiotics.

Contraceptive counseling for iPLEDGE and its burden on dermatologists.

Since 2006, iPLEDGE, a risk evaluation and mitigation strategy (REMS), has attempted to prevent fetal exposures in people taking isotretinoin through contraceptive requirements and regular pregnancy testing. There has been criticism of iPLEDGE's requirements, results, and accessibility. iPLEDGE has placed significant burdens on physicians, patients, and administrative staff. Some level of burden is acceptable to prevent fetal exposures, but iPLEDGE burdens are so strenuous that physicians may choose not to prescribe isotretinoin because of them. There are several evidence-based adaptations that iPLEDGE and physicians can enact to improve the isotretinoin experience. First, physicians can practice shared-decision making in contraceptive counseling and educate patients on long-acting reversible contraceptives (LARCs) to improve the counseling process and outcomes. Second, physicians can take advantage of the reimbursed iPLEDGE contraceptive counseling sessions and refer patients accordingly. Finally, iPLEDGE should recognize the variation in efficacy among contraceptives. Specifically, LARCs and permanent surgical sterilization should be exempt from certain iPLEDGE requirements such as monthly pregnancy testing and attestations. iPLEDGE should work with dermatologists for the continual improvement of iPLEDGE. Communication, repetitive reassessment, and subsequent adaptations will result in better care for patients requiring isotretinoin.

Primary Dermal Melanoma: A Rare Subtype of Melanoma and Clinical Mimicker of Basal Cell Carcinoma.

Primary dermal melanoma (PDM) is a rare variant of melanoma. We present the case of a 76-year-old female diagnosed with PDM following initial suspicion of basal cell carcinoma, prompting extensive workup to exclude metastasis. This case demonstrates the diagnostic challenges and need for rigorous evaluation in suspected PDM cases. Current literature lacks definitive diagnostic markers for PDM, and we highlight the ongoing need for research and collaborative efforts between dermatology and oncology.

High-flow humidified oxygen as an early intervention in children with acute severe asthma: a feasibility randomised controlled trial.

Background: Treating children with acute severe asthma (ASA) who fail to respond to first-line inhaled bronchodilators is problematic: use of intravenous agents is inconsistent and side-effects are common. High-flow humidified oxygen (HiFlo) has shown promise in other respiratory conditions and is increasingly used in ASA, but with little evidence. Methods: We conducted a feasibility randomised controlled trial with deferred consent to assess early HiFlo in children aged 2-11 years with ASA not responding to "burst" therapy (high-dose inhaled salbutamol ±â€…ipratropium). Children with Paediatric Respiratory Assessment Measure (PRAM) score 5+ after "burst" were randomised to commence HiFlo or follow standard care. Candidate primary outcomes assessed were treatment failure requiring escalation, and time to meeting hospital discharge criteria. Results: The target was met despite coronavirus disease 2019 pandemic disruption: 56 children were randomised across four sites, with deferred consent received in 50 out of 56 (89%), and mean recruitment rate 1.1 per site per month. 28 were allocated early HiFlo and 22 standard care. Data collection was complete for both candidate primary outcomes. Treatment failure requiring escalation occurred in 18 of 28 children (64%) in the HiFlo arm and in 19 of 22 (86%) in the standard care arm. Median (interquartile range) time from randomisation to meeting discharge criteria was 29.3 h (21.8-43.7 h) in the HiFlo arm and 36.8 h (24.1-46.3 h) in the standard care arm. Conclusions: HiFlo in childhood ASA is a potentially promising intervention whose use is increasing despite lack of evidence. A definitive randomised controlled trial to assess its effectiveness is required and appears to be feasible.

Identification of modulators of hair cell regeneration in the zebrafish lateral line.

The external location of the zebrafish lateral line makes it a powerful model for studying mechanosensory hair cell regeneration. We have developed a chemical screen to identify FDA-approved drugs and biologically active compounds that modulate hair cell regeneration in zebrafish. Of the 1680 compounds evaluated, we identified two enhancers and six inhibitors of regeneration. The two enhancers, dexamethasone and prednisolone, are synthetic glucocorticoids that potentiated hair cell numbers during regeneration and also induced hair cell addition in the absence of damage. BrdU analysis confirmed that the extra hair cells arose from mitotic activity. We found that dexamethasone and prednisolone, like other glucocorticoids, suppress zebrafish caudal fin regeneration, indicating that hair cell regeneration occurs by a distinctly different process. Further analyses of the regeneration inhibitors revealed that two of the six, flubendazole and topotecan, significantly suppress hair cell regeneration by preventing proliferation of hair cell precursors. Flubendazole halted support cell division in M-phase, possibly by interfering with normal microtubule activity. Topotecan, a topoisomerase inhibitor, killed both hair cells and proliferating hair cell precursors. A third inhibitor, fulvestrant, moderately delayed hair cell regeneration by reducing support cell proliferation. Our observation that hair cells do not regenerate when support cell proliferation is impeded confirms previous observations that cell division is the primary route for hair cell regeneration after neomycin treatment in zebrafish.

Experiences of genetic counselors in referring young and metastatic breast cancer patients to support services: A needs assessment.

OBJECTIVE: Conduct a needs assessment to explore the experiences, barriers, and needs of genetic counselors (GCs), who counsel and refer young and metastatic breast cancer (BC) patients to support services, in order to develop resources to address any noticeable gaps. METHODS: GCs providing care to BC patients were eligible to complete the survey. Support services were defined as resources to address patient-centered healthcare, emotional, and quality-of-life needs. RESULTS: Most participants (n = 117) reported familiarity with cancer prevention services (93%); fewer were familiar with services secondary to a BC diagnosis (e.g., fatigue=16% and sexual health=24%). The volume of GCs indicating familiarity with support services increased significantly as work experience increased for seven services. Many (>50%) never referred patients to most (9/12) support services, excluding cancer prevention, mental health, and financial issues. Open-ended responses highlighted that GCs considered referrals to be outside their scope of practice or that healthcare systems prevent GCs from making referrals. CONCLUSION: GCs may benefit from curated resources and materials, especially for support services secondary to a BC diagnosis, to better support their patients. PRACTICAL IMPLICATIONS: Collaboration of GCs with other health professionals through integrative care programs may decrease burdens to accessing support services.

CC2D2A is mutated in Joubert syndrome and interacts with the ciliopathy-associated basal body protein CEP290.

Joubert syndrome and related disorders (JSRD) are primarily autosomal-recessive conditions characterized by hypotonia, ataxia, abnormal eye movements, and intellectual disability with a distinctive mid-hindbrain malformation. Variable features include retinal dystrophy, cystic kidney disease, and liver fibrosis. JSRD are included in the rapidly expanding group of disorders called ciliopathies, because all six gene products implicated in JSRD (NPHP1, AHI1, CEP290, RPGRIP1L, TMEM67, and ARL13B) function in the primary cilium/basal body organelle. By using homozygosity mapping in consanguineous families, we identify loss-of-function mutations in CC2D2A in JSRD patients with and without retinal, kidney, and liver disease. CC2D2A is expressed in all fetal and adult tissues tested. In ciliated cells, we observe localization of recombinant CC2D2A at the basal body and colocalization with CEP290, whose cognate gene is mutated in multiple hereditary ciliopathies. In addition, the proteins can physically interact in vitro, as shown by yeast two-hybrid and GST pull-down experiments. A nonsense mutation in the zebrafish CC2D2A ortholog (sentinel) results in pronephric cysts, a hallmark of ciliary dysfunction analogous to human cystic kidney disease. Knockdown of cep290 function in sentinel fish results in a synergistic pronephric cyst phenotype, revealing a genetic interaction between CC2D2A and CEP290 and implicating CC2D2A in cilium/basal body function. These observations extend the genetic spectrum of JSRD and provide a model system for studying extragenic modifiers in JSRD and other ciliopathies.

Identification of genetic and chemical modulators of zebrafish mechanosensory hair cell death.

Inner ear sensory hair cell death is observed in the majority of hearing and balance disorders, affecting the health of more than 600 million people worldwide. While normal aging is the single greatest contributor, exposure to environmental toxins and therapeutic drugs such as aminoglycoside antibiotics and antineoplastic agents are significant contributors. Genetic variation contributes markedly to differences in normal disease progression during aging and in susceptibility to ototoxic agents. Using the lateral line system of larval zebrafish, we developed an in vivo drug toxicity interaction screen to uncover genetic modulators of antibiotic-induced hair cell death and to identify compounds that confer protection. We have identified 5 mutations that modulate aminoglycoside susceptibility. Further characterization and identification of one protective mutant, sentinel (snl), revealed a novel conserved vertebrate gene. A similar screen identified a new class of drug-like small molecules, benzothiophene carboxamides, that prevent aminoglycoside-induced hair cell death in zebrafish and in mammals. Testing for interaction with the sentinel mutation suggests that the gene and compounds may operate in different pathways. The combination of chemical screening with traditional genetic approaches is a new strategy for identifying drugs and drug targets to attenuate hearing and balance disorders.

Phenotypic Optimization of Urea-Thiophene Carboxamides To Yield Potent, Well Tolerated, and Orally Active Protective Agents against Aminoglycoside-Induced Hearing Loss.

Hearing loss is a major public health concern with no pharmaceutical intervention for hearing protection or restoration. Using zebrafish neuromast hair cells, a robust model for mammalian auditory and vestibular hair cells, we identified a urea-thiophene carboxamide, 1 (ORC-001), as protective against aminoglycoside antibiotic (AGA)-induced hair cell death. The 50% protection (HC50) concentration conferred by 1 is 3.2 µM with protection against 200 µM neomycin approaching 100%. Compound 1 was sufficiently safe and drug-like to validate otoprotection in an in vivo rat hearing loss model. We explored the structure-activity relationship (SAR) of this compound series to improve otoprotective potency, improve pharmacokinetic properties and eliminate off-target activity. We present the optimization of 1 to yield 90 (ORC-13661). Compound 90 protects mechanosensory hair cells with HC50 of 120 nM and demonstrates 100% protection in the zebrafish assay and superior physiochemical, pharmacokinetic, and toxicologic properties, as well as complete in vivo protection in rats.

Ultrastructural analysis of aminoglycoside-induced hair cell death in the zebrafish lateral line reveals an early mitochondrial response.

Loss of the mechanosensory hair cells in the auditory and vestibular organs leads to hearing and balance deficits. To investigate initial, in vivo events in aminoglycoside-induced hair cell damage, we examined hair cells from the lateral line of the zebrafish, Danio rerio. The mechanosensory lateral line is located externally on the animal and therefore allows direct manipulation and observation of hair cells. Labeling with vital dyes revealed a rapid response of hair cells to the aminoglycoside neomycin. Similarly, ultrastructural analysis revealed structural alteration among hair cells within 15 minutes of neomycin exposure. Animals exposed to a low, 25-microM concentration of neomycin exhibited hair cells with swollen mitochondria, but little other damage. Animals treated with higher concentrations of neomycin (50-200 microM) had more severe and heterogeneous cellular changes, as well as fewer hair cells. Both necrotic-like and apoptotic-like cellular damage were observed. Quantitation of the types of alterations observed indicated that mitochondrial defects appear earlier and more predominantly than other structural alterations. In vivo monitoring demonstrated that mitochondrial potential decreased following neomycin treatment. These results indicate that perturbation of the mitochondrion is an early, central event in aminoglycoside-induced damage.

Cilia-Associated Genes Play Differing Roles in Aminoglycoside-Induced Hair Cell Death in Zebrafish.

Hair cells possess a single primary cilium, called the kinocilium, early in development. While the kinocilium is lost in auditory hair cells of most species it is maintained in vestibular hair cells. It has generally been believed that the primary role of the kinocilium and cilia-associated genes in hair cells is in the establishment of the polarity of actin-based stereocilia, the hair cell mechanotransduction apparatus. Through genetic screening and testing of candidate genes in zebrafish (Danio rerio) we have found that mutations in multiple cilia genes implicated in intraflagellar transport (dync2h1, wdr35, ift88, and traf3ip), and the ciliary transition zone (cc2d2a, mks1, and cep290) lead to resistance to aminoglycoside-induced hair cell death. These genes appear to have differing roles in hair cells, as mutations in intraflagellar transport genes, but not transition zone genes, lead to defects in kinocilia formation and processes dependent upon hair cell mechanotransduction activity. These mutants highlight a novel role of cilia-associated genes in hair cells, and provide powerful tools for further study.

Symphysis pubis dysfunction--a cause of significant obstetric morbidity.

OBJECTIVES: To investigate the prevalence and severity of symphysis pubis dysfunction (SPD) in pregnancy and the postnatal period. DESIGN: A postnatal questionnaire was sent to 248 women who had been referred to the Obstetric Physiotherapy Department in 1997 and 1998 with symptoms of pubic pain either during pregnancy or soon after delivery. SETTING: A north of England teaching hospital, The Clarendon Wing, Leeds General Infirmary. PARTICIPANTS: Questionnaires were sent to 248 women. One hundred and forty-one were returned (response rate 57%). RESULTS: The condition is associated with much unrecognised obstetric morbidity. The prevalence in our unit over the 2-year study period was 1/36 women. Many medical and midwifery staff have little knowledge of SPD. Patients often felt ignored when they complained of pain. One out of four of the respondents were still symptomatic 6 months later. CONCLUSION: Further research is needed to identify the best practice in the antenatal care provided, including the provision of support belts, the most appropriate mode of delivery and postnatal treatment.

The zebrafish merovingian mutant reveals a role for pH regulation in hair cell toxicity and function.

Control of the extracellular environment of inner ear hair cells by ionic transporters is crucial for hair cell function. In addition to inner ear hair cells, aquatic vertebrates have hair cells on the surface of their body in the lateral line system. The ionic environment of these cells also appears to be regulated, although the mechanisms of this regulation are less understood than those of the mammalian inner ear. We identified the merovingian mutant through genetic screening in zebrafish for genes involved in drug-induced hair cell death. Mutants show complete resistance to neomycin-induced hair cell death and partial resistance to cisplatin-induced hair cell death. This resistance is probably due to impaired drug uptake as a result of reduced mechanotransduction ability, suggesting that the mutants have defects in hair cell function independent of drug treatment. Through genetic mapping we found that merovingian mutants contain a mutation in the transcription factor gcm2. This gene is important for the production of ionocytes, which are cells crucial for whole body pH regulation in fish. We found that merovingian mutants showed an acidified extracellular environment in the vicinity of both inner ear and lateral line hair cells. We believe that this acidified extracellular environment is responsible for the defects seen in hair cells of merovingian mutants, and that these mutants would serve as a valuable model for further study of the role of pH in hair cell function.