Gender equity in academic dermatology: Problems aplenty, yet paths ahead.

Efforts to achieve gender equity of health professionals should be a priority in all fields of medicine, including academic dermatology. This review aimed, first, to summarize available evidence about the status of gender equity in various domains of academic dermatology-headship positions, salary, editor and editorial board appointments, publications, conference presentations, receipt of research grants and academic prizes-second, to identify challenges to achieving gender equity and, third, to articulate the components of a multifaceted strategy for gender parity. A variety of databases were searched. Manual searching of reference lists and searching of grey literature were also undertaken. It was found that, despite improvements in some domains, the gender inequity persists in all of the above-mentioned areas of academic dermatology. Challenges to achieve gender parity include time in pregnancy, disproportionate participation in childrearing and domestic tasks compared with men, suboptimal legislation in many jurisdictions for parenting and childcare leave, and unconscious biases about women. Elements of a multipronged approach include strengthening women's dermatology societies that advocate for women in academia; celebrating the careers of distinguished female academic dermatologists; mentoring; promoting leadership courses; striving for a greater representation of women among editors-in-chief, authors, and conference presenters, among others; seeking better pay, leave conditions and other work entitlements; conducting high-quality research about gender inequity in academic dermatology; imposing sanctions for violations of gender equity; supporting dermatologists' health; and learning from the experience of other fields of academic medicine.

Mepolizumab decreases tissue eosinophils while increasing type-2 cytokines in eosinophilic chronic rhinosinusitis.

BACKGROUND: Eosinophilic chronic rhinosinusitis is an often treatment-resistant inflammatory disease mediated by type-2 cytokines, including interleukin (IL)-5. Mepolizumab, a monoclonal antibody drug targeting IL-5, has demonstrated efficacy and safety in inflammatory airway disease, but there is negligible evidence on direct tissue response. The study's aim was to determine the local effect of mepolizumab on inflammatory biomarkers in sinonasal tissue of eosinophilic chronic rhinosinusitis patients. METHODS: Adult patients with eosinophilic chronic rhinosinusitis received 100mg mepolizumab subcutaneously at four-weekly intervals for 24 weeks in this prospective phase 2 clinical trial. Tissue eosinophil counts, eosinophil degranulation (assessed as submucosal eosinophil peroxidase deposition by immunohistochemistry) and cytokine levels (measured in homogenates by immunoassay) were evaluated in ethmoid sinus tissue biopsies collected at baseline and at weeks 4, 8, 16 and 24. RESULTS: Twenty patients (47.7 ± 11.7 years, 50% female) were included. Sinonasal tissue eosinophil counts decreased after 24 weeks of treatment with mepolizumab (101.64 ± 93.80 vs 41.74 ± 53.76 cells per 0.1 mm2 ; p = .035), eosinophil degranulation remained unchanged (5.79 ± 2.08 vs 6.07 ± 1.20, p = .662), and type-2 cytokine levels increased in sinonasal tissue for IL-5 (10.84 ± 18.65 vs 63.98 ± 50.66, p = .001), IL-4 (4.48 ± 3.77 vs 9.38 ± 7.56, p = .004), IL-13 (4.02 ± 2.57 vs 6.46 ± 3.99, p = .024) and GM-CSF (1.51 ± 1.74 vs 4.50 ± 2.97, p = .001). CONCLUSION: Mepolizumab reduced eosinophils in sinonasal tissue, demonstrating that antagonism of IL-5 suppresses eosinophil trafficking. With reduced tissue eosinophils, a local type-2 inflammatory feedback loop may occur. The study exposes mechanistic factors which may explain incomplete treatment response.

Kv3.1 and Kv3.3 subunits differentially contribute to Kv3 channels and action potential repolarization in principal neurons of the auditory brainstem.

KEY POINTS: Kv3.1 and Kv3.3 subunits are highly expressed in the auditory brainstem, with little or no mRNA for Kv3.2 or Kv3.4. Changes in Kv3 currents and action potential (AP) firing were analysed from wild-type, Kv3.1 and Kv3.3 knockout (KO) mice. Both Kv3.1 and Kv3.3 immunostaining was present and western blots confirmed loss of subunit protein in the respective KO. Medial nucleus of the trapezoid body (MNTB) AP repolarization utilized Kv3.1 and/or Kv3.3; while in the lateral superior olive (LSO) Kv3.3 was essential. Voltage-gated calcium currents were unchanged between the genotypes. But APs evoked higher [Ca2+ ]i in LSO than MNTB neurons; and were highest in the Kv3.3KO, consistent with longer AP durations. High frequency stimulation increased AP failure rates and AP latency in LSO neurons from the Kv3.3KO, underlining the physiological consequences for binaural integration. LSO neurons require Kv3.3 for functional Kv3 channels, while MNTB neurons can utilize either Kv3.1 or Kv3.3 subunits. ABSTRACT: Kv3 voltage-gated potassium channels mediate action potential (AP) repolarization. The relative importance of Kv3.1 and Kv3.3 subunits for assembly of functional channels in neurons of the auditory brainstem was examined from the physiological perspective that speed and precision of AP firing are crucial for sound source localization. High levels of Kv3.1 and Kv3.3 mRNA and protein were measured, with no evidence of compensation by Kv3.2 or Kv3.4 in the respective knockout (KO) mouse. Using the KOs, composition of Kv3 channels was constrained to either Kv3.1 or Kv3.3 subunits in principal neurons of the medial nucleus of the trapezoid body (MNTB) and lateral superior olive (LSO); while TEA (1 mm) was employed to block Kv3-mediated outward potassium currents in voltage- and current clamp experiments. MNTB neuron APs (half-width 0.31 ± 0.08 ms, n = 25) were fast, reliable, and showed no distinction between channels assembled from Kv3.1 or Kv3.3 subunits (in the respective KO). LSO AP half-widths were also fast, but absolutely required Kv3.3 subunits for fast repolarization (half-widths: 0.25 ± 0.08 ms, n = 19 wild-type, 0.60 ± 0.17 ms, n = 21 Kv3.3KO, p = 0.0001). The longer AP duration increased LSO calcium influx and AP failure rates, and increased AP latency and jitter during high frequency repetitive firing. Both Kv3.1 and Kv3.3 subunits contribute to Kv3 channels in the MNTB (and compensate for each other in each KO); in contrast, LSO neurons require Kv3.3 subunits for fast repolarization and to sustain AP firing during high frequency stimulation. In conclusion, Kv3 channels exhibit both redundancy and Kv3.3 dominance between the brainstem nuclei involved in sound localization.

Effect of monoclonal antibody drug therapy on mucosal biomarkers in airway disease: A systematic review.

BACKGROUND: Monoclonal antibody therapies have a growing role in treating refractory airway disease. OBJECTIVE: The review aimed to summarize the response of respiratory mucosa to monoclonal antibody treatments in inflammatory airway conditions. DESIGN: We conducted a systematic review including risk of bias assessment. DATA SOURCES: MEDLINE, EMBASE and PubMed from 1 January 2000 to 16 November 2019 were searched. ELIGIBILITY CRITERIA: Eligible studies assessed the immunological and histological response of airway mucosa to monoclonal antibody therapy compared with baseline or a comparison group in patients with respiratory diseases (asthma, chronic rhinosinusitis and allergic rhinitis). Any prospective interventional studies, including randomized controlled trials (RCTs) and single-arm trials, were eligible. RESULTS: There were 4195 articles screened, and full-text analysis produced n = 11 studies with extractable data. Nine were RCTs, and two were single-arm trials. These studies focused on asthma (n = 9 articles), chronic rhinosinusitis (n = 1) and allergic rhinitis (n = 1). Five monoclonal antibody drugs were assessed (omalizumab, mepolizumab, dupilumab, benralizumab and tralokinumab). Risk of bias was low (n = 6) or unclear (n = 3) in the RCTs and moderate in the single-arm trials. Omalizumab reduced the mucosal concentration of its target, IgE. Dupilumab reduced the concentration of one of its targets, IL-13, but not IL-4. Omalizumab, mepolizumab and benralizumab reduced tissue eosinophil cell density. Dupilumab decreased mucosal eosinophil granule proteins. Tralokinumab did not affect airway mucosa. CONCLUSIONS: Knowledge of the expected biological response of monoclonal antibody therapy on biomarkers in disease tissue provides an important supplement to data about clinical outcomes. An understanding of the biological effect is essential to identify likely responders, reasons for treatment failure and necessary adjustments to monoclonal antibody treatment. Further investigation into the effect of monoclonal antibody therapy on disease mucosa and more precise endotyping are required to move closer to achieving personalized medicine.

Diagnostic Yield and Outcomes of Computed Tomography of the Head in Critically Ill Nontrauma Patients.

BACKGROUND: Computed tomography of the head (HCT) is a widely used diagnostic tool, especially for emergency and trauma patients. However, the diagnostic yield and outcomes of HCT for patients on medical intensive care units (MICUs) are largely unknown. METHODS: We retrospectively evaluated all head CTs from patients admitted to a single-center MICU during a 5-year period for CT indications, diagnostic yield, and therapeutic consequences. Uni- and multivariate analyses for the evaluation of risk factors for positive head CT were conducted. RESULTS: Six hundred ninety (18.8%) of all patients during a 5-year period underwent HCT; 78.7% had negative CT results, while 21.3% of all patients had at least 1 new pathological finding. The main indication for acquiring CT scan of the head was an altered mental state (AMS) in 23.5%, followed by a new focal neurology in 20.7% and an inadequate wake up after stopping sedation in 14.9% of all patients. The most common new finding was intracerebral bleeding in 6.4%. In 6.7%, the CT scan itself led to a change of therapy of any kind. Admission after resuscitation or a new focal neurology were independent predictors of a positive CT. Psychic alteration and AMS were both independent predictors of a higher chance of a negative head CT. Positive HCT during MICU is an independent predictor of lower survival. CONCLUSIONS: New onset of focal neurologic deficit seems to be a good predictor for a positive CT, while AMS and psychic alterations seem to be very poor predictors. A positive head CT is an independent predictor of death for MICU patients.

Dresden to "Down Under": The Career of German Dermatologist Erwin Oppenheim.

Erwin Oppenheim (1893-1975) was a successful dermatologist in Dresden, Germany. He with his family fled the country in 1939 because of National Socialism and settled in Melbourne in the Australian state of Victoria. The regulations of Australian universities and medical boards of that era in relation to refugee medicos hindered Oppenheim's registration as a medical practitioner. He was permitted to treat skin conditions, but not allowed to prescribe medications other than some topical preparations. In spite of these restrictions, Oppenheim soon established a busy private practice. He also contributed to dermatology by providing guidance to "Ego Pharmaceuticals," a large company formed by Oppenheim's son and daughter-in-law in 1953 that produces a range of skin and other healthcare products for Australian and global markets.

"KYDS": an innovative service addressing the health needs of youth and families in an Australian community.

OBJECTIVE: To describe the evolution of KYDS Youth Development Service ("KYDS"), a pioneering youth service in Sydney, Australia, its range of programs and the challenges that it has faced. CONCLUSIONS: KYDS emerged in the context of the escalating presentation of mental health and other problems affecting young people, and the desire of a local community to provide a service for its youth. The service has expanded since opening in 2005 and now includes, among other elements, therapy for referred clients, parent educational forums, and group programs such as a young women's program and a program for teenagers with parents affected by mental illness. The challenges for the service include financial pressures, service expansion, and how to best complement other services in the public and private sector.

European Jewish dermatologists who came to New South Wales, Australia, as a consequence of National Socialism: Challenges and contributions.

The period of National Socialism (1933-1945) had a seismic impact on the medical profession in Europe and beyond. This study aimed to identify Jewish dermatologists who fled Europe as a result of National Socialism and migrated to the Australian state of New South Wales (NSW), to document their struggles, and to describe their contributions to dermatology. Five dermatologists who survived the horrors of Nazism and migrated to NSW were identified. Frederik Goldschlag (1893-1973), Richard Kantor (1886-1954), Isidor Knossew (1898-1965), Emil Milder (1902-1973), and Emery Kocsard (1912-2005) arrived in NSW during the period of 1938 to 1951. Myriad contributions were made to dermatology. The challenges confronted by refugee dermatologists did not cease with the end of National Socialism. On reaching Australia, university and medical board barriers and the country's strong British affiliation posed further difficulties for many refugee doctors from the European continent. The study complements previous research on the exodus of dermatologists from Europe to countries other than Australia as a result of National Socialism. The study also prompts sober reflection about the losses suffered by dermatology, alongside other branches of medicine, through Nazism and the Holocaust.

Comparison of Sinonasal Histopathological Changes in Biological Treatment of Eosinophilic Chronic Rhinosinusitis.

BACKGROUND: Biologic therapies such as mepolizumab and benralizumab are currently utilised in the treatment of eosinophilic asthma, and are emerging in the management of eosinophilic chronic rhinosinusitis (eCRS). These biologics inhibit the interaction of IL-5 with its receptor, thus impairing cytokine signalling and eosinophil inflammation. Mepolizumab does so by targeting IL-5, whereas benralizumab targets the α chain of the IL-5 receptor. This study compares the sinonasal tissue response to anti-IL-5 biologic therapies in patients with eCRS. METHODS: A cross-sectional study of adult eCRS patients who had completed at least 2 cycles of biologic therapy and underwent endoscopic sinus surgery as part of their management were included. Sinonasal mucosal tissue biopsies were obtained intraoperatively and assessed with structured histopathological examination. Comparisons of tissue histopathology outcomes following treatment with mepolizumab or benralizumab were performed. RESULTS: 18 patients (age 49.6 ± 14.2 years, 47% female, 100% co-morbid asthma) were included in this study, comprising 10 patients managed with mepolizumab and 8 patients managed with benralizumab. Even after mepolizumab, the tissue had predominantly eosinophilic inflammation compared to benralizumab (90% v 0%, p < 0.01), which demonstrated a greater lymphoplasmacytic inflammation (10% v 75%, χ2(2) = 14.53, p < 0.01). Compared with benralizumab, mepolizumab had increased tissue eosinophil count (100% v 37.5% >10 eosinophils/HPF, τb = -8.47, p < 0.001) and more severe subepithelial oedema (80% v 37.5% severe, τb = -2.37, p = 0.02). CONCLUSION: Tissue histopathologic outcomes reflect the differing mechanism of action of mepolizumab and benralizumab in eCRS. Further analysis at the tissue level will provide further information to guide application of mAbs in type 2 inflammatory diseases.

Anti-embolism stockings and proximal indentation.

The authors of this study noticed that the elastic garters of below knee anti-embolism stockings (AES) were indenting the proximal calves of patients after application and feared this might be interrupting venous return. This was lower on one ward which had a rigorous standardized protocol for sizing and checking stockings. Hypotheses were that proximal indentation caused higher proximal than distal pressures (reverse gradients) and that by adopting the standardized protocol throughout the unit, proximal indentation could be reduced. Fifty-seven patients were recruited after total hip replacement (THR) or total knee replacement (TKR) in a regional orthopaedic centre. The authors implemented the standardized protocol for sizing stockings and measured the pressures under them. After implementation of the standardized protocol, proximal indentation fell from 53% to 19% (p<0.05), incorrectly sized stockings from 74% to 34% (p<0.05) and removal of stockings by patients from 32% to 0% (p<0.05). In total, 21% of patients had reverse gradients which occurred in 41% of legs with proximal indentation and 8% without. When reverse gradients or proximal indentation exist, AES may not be as effective and may be counterproductive. A standardized protocol of nursing practice is critical to optimizing AES after THR and TKR. More in-vivo research is needed on AES after hip and knee replacement.

Eosinophilic chronic rhinosinusitis and concurrent Kimura's disease treated with mepolizumab.

Kimura's disease is a rare, benign, chronic inflammatory disorder characterised by its eosinophilic infiltrate. Patients often present with one or more progressively enlarging subcutaneous lymph nodes in the head and neck region or enlarging salivary glands. We describe the case of a 26-year-old man presenting with severe peripheral eosinophilia and upper airway inflammatory symptoms, who later developed cervical lymphadenopathy and formally diagnosed with Kimura's disease. Based on our English-language MEDLINE literature search, to our knowledge this is the first case report describing treatment of Kimura's disease with mepolizumab.

Incidence of Parkinson's disease in a large patient cohort with idiopathic smell and taste loss.

INTRODUCTION: Patients with idiopathic smell loss constitute an at-risk population for the development of Parkinson's disease (PD). The study aimed to follow up a large number of patients with idiopathic smell and/or taste loss to define the incidence of PD in this population and, further, to assess characteristics of both olfactory and gustatory function and their possible association with PD development. METHODS: In this prospective case-control study, 833 patients diagnosed with an idiopathic smell disorder at our Smell and Taste Center during the last 15 years were contacted for a telephone interview. In 474 patients, a complete data set containing of demographic data, clinical information, retrospective smell and taste testing results, and telephone assessment was obtained. RESULTS: Out of 474 patients with idiopathic smell loss 45 (9.8%) had been diagnosed with PD, since they received the diagnosis of idiopathic smell and/or taste loss (mean 10.9 years after olfactory loss onset). Thus, with respect to the classification into olfactory/gustatory disorders, 28.6% of the patients with a combined olfactory and gustatory disorder developed PD, whereas in 9.9% of those with a pure olfactory disorder and in 3.8% of those with a pure gustatory disorder, PD was diagnosed. No association emerged between qualitative smell or taste loss and PD development. CONCLUSION: This large patient cohort study extends the previous literature, indicating that risk stratification might be considerably improved by correct diagnostic allocation and emphasizes the need for an exhaustive olfactory and gustatory assessment in specialized centers.