A clinically applicable integrative molecular classification of meningiomas.

Meningiomas are the most common primary intracranial tumour in adults1. Patients with symptoms are generally treated with surgery as there are no effective medical therapies. The World Health Organization histopathological grade of the tumour and the extent of resection at surgery (Simpson grade) are associated with the recurrence of disease; however, they do not accurately reflect the clinical behaviour of all meningiomas2. Molecular classifications of meningioma that reliably reflect tumour behaviour and inform on therapies are required. Here we introduce four consensus molecular groups of meningioma by combining DNA somatic copy-number aberrations, DNA somatic point mutations, DNA methylation and messenger RNA abundance in a unified analysis. These molecular groups more accurately predicted clinical outcomes compared with existing classification schemes. Each molecular group showed distinctive and prototypical biology (immunogenic, benign NF2 wild-type, hypermetabolic and proliferative) that informed therapeutic options. Proteogenomic characterization reinforced the robustness of the newly defined molecular groups and uncovered highly abundant and group-specific protein targets that we validated using immunohistochemistry. Single-cell RNA sequencing revealed inter-individual variations in meningioma as well as variations in intrinsic expression programs in neoplastic cells that mirrored the biology of the molecular groups identified.

Characterizing Gender and Leadership Trends Among Mohs Micrographic Surgery Fellowship Directors.

BACKGROUND: Fellowship directors (FDs) play a key role in shaping Mohs micrographic surgery (MMS). Studies characterizing director trends are lacking and may provide a framework for improving gender diversity. OBJECTIVE: To explore characteristics of FDs and trends in gender of both fellows and FDs over time. MATERIALS AND METHODS: The authors compiled a comprehensive list of FDs and fellows for all Accreditation Council for Graduate Medical Education-accredited Micrographic Surgery & Dermatologic Oncology programs from 1996 to 2023. Publicly available data from various internet sources from February 1, 2023 to May 30, 2023 were used to assess characteristics of MMS FDs. RESULTS: The percentage of female FDs increased from 6% to 25% from 1996 to 2023. Female directors were more likely to select female fellows than male directors ( p = .0002) and had fewer years between fellowship completion and FD appointment (9.1 ± 4.7 years) compared with male directors (13.6 ± 8.8 years; p = .036). H-index, program type, and academic rank were similar between male and female directors. CONCLUSION: Although gender parity among MMS trainees has been achieved, discrepancies remain in the gender composition of FDs. Further studies are required to determine why women are underrepresented as FDs.

Febrile Ulceronecrotic Mucha-Habermann Disease Associated With Hemophagocytic Lymphohistiocytosis: A Case Report and Review of the Literature.

ABSTRACT: Mucha-Habermann disease (MHD) is an inflammatory skin disease characterized by polymorphous eruptions of erythematous, necrotic macules that have been reported for similarities to cutaneous T-cell lymphoma. Febrile ulceronecrotic MHD (FUMHD) represents a severe variant of MHD, marked by ulcers, hemorrhagic bullae, and systemic symptoms. Herein, we report a case of a severely atypical lymphomatoid expression of FUMHD associated with hemophagocytic lymphohistiocytosis (HLH). A previously healthy 21-year-old woman was admitted to the hospital with a rapidly progressive necrotic papular rash. Physical examination revealed right orbital swelling, bilateral hemorrhagic auricular bullae, and multiple ulcerative purpuric papulonodules on the trunk, face, and extremities. Biopsy indicated a dermal and subcutaneous infiltrate of atypical CD8 + lymphocytes with loss of CD5 and reduction in CD7 expression, along with features of lymphomatoid vasculitis. A diagnosis of a severely atypical lymphomatoid expression of FUMHD was made. The patient also met 7 of 9 HLH-2004 criteria, leading to a diagnosis of HLH. Positron emission tomography/computed tomography, flow cytometry, and rheumatologic workup were unremarkable. Treatment with an eight-week course of etoposide and dexamethasone for HLH led to rapid clinical improvement. Over time, her skin lesions regressed and eventually scabbed over to leave hyperpigmented scars, confirming the diagnosis of MHD. She has remained stable, off therapy for 4 years. Although potentially fatal, FUMHD often exhibits favorable outcomes and may resolve without recurrence, as in our patient. FUMHD should be considered in the differential diagnosis for patients presenting with cutaneous CD8 + necrotizing angiocentric lymphoproliferative disease complicated by HLH.

Outcomes related to intravenous fluid administration in sickle cell patients during vaso-occlusive crisis.

While fluid replacement therapy is a primary treatment modality used in vaso-occlusive crises for sickle cell disease, data is limited on its safety, efficacy, and variability. We performed a retrospective analysis on 157 unique patient encounters from 49 sickle cell patients hospitalized with a vaso-occlusive episode at our institution from 2013 to 2017. The median length of hospital stay was 4 days (IQR 2-7). The mean total amount of intravenous fluid administered during the hospitalization was 7.4 L (Std 9.6). The mean total amount of fluid intake including intravenous fluids, blood transfusions, and oral fluids was 14.2 L (Std 18.2). Multivariate analyses revealed significant associations between the development of any adverse event (including a new oxygen requirement, acute chest syndrome, aspiration event, other hospital-acquired infection, acute kidney injury, and intensive care unit transfer) and the following variables: intravenous fluid administered in the first 24 h (p = 0.001, OR 1.899, 95% CI 1.319-2.733), total amount of intravenous fluid administered (p = 0.005, OR 1.081, 95% CI 1.023-1.141), and total amount of fluid intake including oral fluids, blood transfusions, and intravenous fluids (p = 0.009, OR 1.046, 95% CI 1.011-1.081). Other factors found to be significantly associated with any adverse event were dialysis dependence prior to admission (p < 0.001, OR 12.984, 95% CI 3.660-46.056) and admission to an inpatient service versus an emergency room or observation unit (p = 0.008, OR 3.201, 95% CI 1.346-7.612). While fluid administration may theoretically slow the sickling process, this data suggests that fluid administration during a vaso-occlusive episode, and especially total volume given in the first 24 h, may also lead to adverse events.

Isavuconazole treatment for rare fungal diseases and for invasive aspergillosis in patients with renal impairment: Challenges and lessons of the VITAL trial.

Invasive fungal disease (IFD) confers a substantial risk for morbidity and mortality to immunocompromised patients. Invasive aspergillosis (IA) is the most common IFD caused by moulds but the prevalence of other rare mould diseases, such as mucormycosis, hyalohyphomycosis and phaeohyphomycosis, may be increasing. Treatments are available for IA, but evidence to support efficacy and safety of antifungal agents for rare IFDs, or for IFDs in special patient populations, is limited or lacking. The VITAL trial was conducted to assess the efficacy and safety of isavuconazole for the treatment of patients with IA and renal impairment, or with IFDs caused by rare moulds, yeasts or dimorphic fungi. These patients stand to benefit most from a new treatment option but are unlikely to be included in a randomised, controlled trial. In this article, we review the challenges faced in the design and conduct of the VITAL trial. We also review the findings of VITAL, which included evidence of the efficacy and safety of isavuconazole. Finally, we consider the importance of trials such as VITAL to inform therapeutic decision making for clinicians faced with the challenge of treating patients with rare IFDs and as one paradigm of how to determine efficacy and safety of new drugs for rare and resistant infections without a suitable comparator.

SIRCLE: a randomised controlled cost comparison of self-administered short-course isoniazid and rifapentine for cost-effective latent tuberculosis eradication.

BACKGROUND: Currently, treatment of latent tuberculosis infection (LTBI) in Australia consists most commonly of a 9-month course of isoniazid (9H). A 3-month course of weekly isoniazid and rifapentine (3HP) has been shown to be as effective as 9 months of daily isoniazid, and associated with less hepatotoxicity; however, rifapentine is not currently available in Australia. Introduction of this regimen would have apparent advantages for people with LTBI in Victoria by safely shortening duration of LTBI therapy. However, the cost benefit of this new therapeutic approach is uncertain. AIM: Cost-analysis of standard and short-course therapy for LTBI in an Australian context. METHODS: Single-centre randomised controlled trial conducted between December 2013-March 2016. Participants underwent 1:1 randomisation to either a 9-month course of daily isoniazid or a 12-week course of weekly isoniazid and rifapentine. The primary outcome measure was total healthcare system costs (in Australian dollars; AUD) per completed course of LTBI therapy. Secondary cost analyses were performed to consider varying assumptions regarding commercial cost of rifapentine. RESULTS: Overall, 34 of 40 (85%) participants in the 9H group and 36/40 (90%) in the 3HR group completed therapy. One patient in the 3HP group was hospitalised for a febrile illness; no hospitalisations were recorded in the 9H group. The cost per completed course of 9H was 601 AUD, while that of 3HP was significantly lower at 511 AUD (P < 0.01). CONCLUSIONS: This study provides cost analysis evidence to support the use of 3HP for the treatment of LTBI in Australia.

Antimicrobial use in Australian hospitals: how much and how appropriate?

Antimicrobial agents play a central role in modern health care, especially in the hospital setting. This article describes the currently available information on the volumes of antimicrobial use in Australian hospitals, the appropriateness of that use, and the levels of compliance with nationally or locally endorsed prescribing guidelines. The data presented here come from the 2014 National Antimicrobial Utilisation Surveillance Program report and the 2013 and 2014 National Antimicrobial Prescribing Survey reports and are based on voluntary participation in the two programs. While the results can be considered indicative only, they show that Australia has high volumes of prescribing in hospitals, and that in certain circumstances and conditions these are inappropriate and/or not compliant with national or local prescribing guidelines. In 2014, the national aggregate use rate for antimicrobials was 936 defined daily doses per 1000 occupied bed days. In the same year, the overall rate of appropriate prescribing was 72%, and compliance with guidelines was 74% where this was assessable. The rate of surgical antimicrobial prophylaxis exceeding the benchmark of 24 hours was high (36%), as was the inappropriate prescribing for infective exacerbations of chronic obstructive pulmonary disease (38%). The findings indicate that there is room for improvement in antimicrobial prescribing in Australian hospitals, and provides insights into where the efforts for improvement might be directed.

Mass spectrometric analyses of phospholipids in the S334ter-3 rat model of retinal degeneration.

PURPOSE: The purpose of this study was to profile the endogenous phospholipid species in the retinal tissue of the S334ter-3 rat model of retinal degeneration. Retinal tissue was collected from S334ter-3 rats at postnatal day (P) 20, P30, and P60, while control retinal samples were collected from Sprague-Dawley (SD) rats at the same time points for comparison. METHODS: Lipids were extracted using the Bligh and Dyer method, and resuspended in an acetonitrile/isopropanol (1:1) solution. For lipid analyses, a positive ion-mode precursor ion scan (PIS) was used for phosphatidylcholine (PC; product m/z of 184), a negative ion-mode neutral loss scan (NLS) was used for phosphatidylserine (PS; product m/z of 87.1), and a negative ion-mode PIS was used for phosphatidylinositol (PI; product m/z of 241) and phosphatidylethanolamine (PE; product m/z of 196); the analyses were carried out using a TSQ Quantum Access Max mass spectrometer. The samples were directly infused with a Triversa Nanomate using 1.6 kV and 0.4 psi of pressure for the positive ion mode, and 1.3 kV and 0.6 psi of pressure for the negative ion mode, and scanned for 2 min between 200 m/z and 1000 m/z. Ratiometric quantification was performed using quantitative standards for each lipid class. RESULTS: The comparative profiles of PC, PE, PS, and PI between S334ter-3 and control rats showed that there were several lipid species common to both groups, as well as several that were unique to the S334ter-3 group and vice versa. CONCLUSIONS: It was found that the proportions of PC and PS were higher in the control retina compared to S334ter-3, and that the proportions of PE and PI were higher in the S334ter-3 retina compared to control.

Modeling ion sensing in molecular electronics.

We examine the ability of molecules to sense ions by measuring the change in molecular conductance in the presence of such charged species. The detection of protons (H(+)), alkali metal cations (M(+)), calcium ions (Ca(2+)), and hydronium ions (H3O(+)) is considered. Density functional theory (DFT) is used within the Keldysh non-equilibrium Green's function framework (NEGF) to model electron transport properties of quinolinedithiol (QDT, C9H7NS2), bridging Al electrodes. The geometry of the transport region is relaxed with DFT. The transport properties of the device are modeled with NEGF-DFT to determine if this device can distinguish among the M(+) + QDT species containing monovalent cations, where M(+) = H(+), Li(+), Na(+), or K(+). Because of the asymmetry of QDT in between the two electrodes, both positive and negative biases are considered. The electron transmission function and conductance properties are simulated for electrode biases in the range from -0.5 V to 0.5 V at increments of 0.1 V. Scattering state analysis is used to determine the molecular orbitals that are the main contributors to the peaks in the transmission function near the Fermi level of the electrodes, and current-voltage relationships are obtained. The results show that QDT can be used as a proton detector by measuring transport through it and can conceivably act as a pH sensor in solutions. In addition, QDT may be able to distinguish among different monovalent species. This work suggests an approach to design modern molecular electronic conductance sensors with high sensitivity and specificity using well-established quantum chemistry.

Gammopathic dermopathy: characterization of cutaneous MGUS.

Monoclonal Gammopathy of Undetermined Significance (MGUS) is a clonal plasma cell disorder that is considered preneoplastic, asymptomatic, and only requiring observation. However, MGUS may result in cutaneous complications, which are poorly understood, causing treatment delays and patient suffering. We present 30 patients with cutaneous findings associated with MGUS, characterizing clinical presentations, isoforms, treatments, and outcomes. These included: MGUS-associated 'rashes' (pruritic eczematous rashes), reactive and mucin-depositional conditions (pyoderma gangrenosum, scleromyxedema), M-protein-related deposition disorders (POEMS syndrome, Waldenstrom macroglobulinemia), and cutaneous lymphomas. Twelve of 30 (40%) patients received multiple myeloma drugs (MMDs). Eleven (92%) patients improved, and those not receiving MMDs rarely improved, suggesting that MMDs have efficacy for cutaneous manifestations of MGUS. Therefore, trialing MMDs may be warranted for patients with MGUS not responding to other therapies. Moreover, evaluation for monoclonal gammopathy in elderly patients with intractable pruritus or other chronic skin conditions that are non-responsive to skin-directed therapies should be considered.

Current status of artificial intelligence methods for skin cancer survival analysis: a scoping review.

Skin cancer mortality rates continue to rise, and survival analysis is increasingly needed to understand who is at risk and what interventions improve outcomes. However, current statistical methods are limited by inability to synthesize multiple data types, such as patient genetics, clinical history, demographics, and pathology and reveal significant multimodal relationships through predictive algorithms. Advances in computing power and data science enabled the rise of artificial intelligence (AI), which synthesizes vast amounts of data and applies algorithms that enable personalized diagnostic approaches. Here, we analyze AI methods used in skin cancer survival analysis, focusing on supervised learning, unsupervised learning, deep learning, and natural language processing. We illustrate strengths and weaknesses of these approaches with examples. Our PubMed search yielded 14 publications meeting inclusion criteria for this scoping review. Most publications focused on melanoma, particularly histopathologic interpretation with deep learning. Such concentration on a single type of skin cancer amid increasing focus on deep learning highlight growing areas for innovation; however, it also demonstrates opportunity for additional analysis that addresses other types of cutaneous malignancies and expands the scope of prognostication to combine both genetic, histopathologic, and clinical data. Moreover, researchers may leverage multiple AI methods for enhanced benefit in analyses. Expanding AI to this arena may enable improved survival analysis, targeted treatments, and outcomes.

Aminoglycosides: how should we use them in the 21st century?

PURPOSE OF REVIEW: Aminoglycoside antibiotics (AGAs) have proved an invaluable part of our antimicrobial armamentarium since their introduction into practice over 60 years ago. This review summarizes recent developments, defining their role in the context of the current global epidemic of antibiotic resistance, raising awareness of their toxicity profile, and highlighting current data on their utility as synergistic agents. RECENT FINDINGS: Clinicians are facing an unprecedented threat from antibiotic resistance, resulting in an increased reliance on the addition of an AGA to provide adequate empirical cover in cases of severe sepsis. Concurrently, an increased awareness of the potential for severe disability, particularly from vestibular toxicity, has restrained directed therapy of AGAs to situations in which there are no appropriate alternatives. Their role as synergistic agents in the treatment of enterococcal endocarditis is currently under reevaluation, and new data have emerged on combination therapy for Pseudomonas aeruginosa bacteremia. AGAs are themselves coming under increasing threat from resistance, predominately from aminoglycoside modifying enzymes (mediating selective resistance) and 16S rRNA methyltransferases (conferring class-wide resistance). New agents and the development of alternate ways to circumvent resistance are likely to have important roles in future clinical care. SUMMARY: Aminoglycosides retain an invaluable but well defined role, and will remain important agents into the foreseeable future.

Preoperative Opioid Use Predicts Poorer Outcomes of Total Ankle Arthroplasty and Hindfoot Fusions.

BACKGROUND: This study aimed to determine the impact of preoperative opioid use on outcomes of patients undergoing ankle or hindfoot arthrodesis, or total ankle arthroplasty (TAA). METHODS: We conducted a retrospective review of 190 patients undergoing an ankle or hindfoot arthrodesis (n=122) or TAA (n=68) between December 2015 and September 2020 with a single fellowship-trained orthopaedic foot and ankle surgeon at an academic medical center. Data collected included demographics, medical comorbidities, treatment history, complications and reoperation rates, patient-reported outcome measures (PROMs) (eg, Foot and Ankle Outcome Score [FAOS]), and opioid use. RESULTS: Patients with preoperative opioid use were more likely to continue usage at 90 (r = 0.931, P < .001) and 180 (r = 0.940, P < .001) days postoperatively. For the entire cohort, complication and reoperation rates were 48.9% and 13.2%, respectively. While preoperative opioid use groups did not differ in the overall complication rate, users had significantly more infections (user = 12.5%, nonuser = 3.3%; P = .036) and reoperations (user = 22.5%, nonuser = 10.7%; P = .049). When analyzing postoperative opioid prescriptions, there were many significant correlations with preoperative PROMs, mainly FAOS, such that increased postoperative opioid use was associated with worse subjective outcomes. CONCLUSION: Preoperative opioid users are more likely to continue postoperative opioid use, experience infections, and undergo reoperations. LEVEL OF EVIDENCE: Level III: Retrospective cohort study.

Clusters, crop dusters, and myth busters: a scoping review of environmental exposures and cutaneous T-cell lymphoma.

INTRODUCTION: Cutaneous T-cell lymphoma (CTCL) is a heterogenous group of non-Hodgkin lymphomas. Similar presentation to benign conditions, significant genetic variation, and lack of definitive biomarkers contributes to diagnostic delay. The etiology of CTCL is unknown, and environmental exposures, such as geographic, occupational, chemicals, sunlight, and insects have been investigated. EVIDENCE ACQUISITION: Review of the literature for CTCL and exposures was performed in PubMed and Google Scholar in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) Extension for Scoping Reviews. This search yielded 193 total results, which were initially screened with defined inclusion and exclusion criteria. The 45 remaining articles were reviewed and classified by exposure type. EVIDENCE SYNTHESIS: The most frequently investigated CTCL exposure type was geographic (13/45 articles, 29%). Chemical exposures were commonly discussed (10/45 articles, 22%), along with occupational (10/45 articles, 22%). Insect exposures (6/45, 13%) and sun exposure (3/45, 7%) were also reviewed, along with articles describing multiple exposure types (3/45, 7%). Article types ranged from cases to systematic reviews and case-control studies. Evidence linking CTCL and these exposures was mixed. Limitations of this investigation include reliance on patient reporting and frequent speculation on disease association versus causality. CONCLUSIONS: This investigation synthesizes the current literature on exposures potentially implicated in the pathogenesis of CTCL, while offering guidance on patient history-taking to ensure potential exposures are captured. Awareness of these possible associations may improve understanding of disease pathogenesis and diagnosis. Moreover, these insights may help with public health decision-making and disease mitigation.

Trends in Orthopaedic Foot and Ankle Publications.

Background: Scientific publication and original articles remain the primary method of sharing scientific findings and advancing the knowledge base of that subject. Despite the value of these publications, little research has surveyed what topics are being published. This study aims to identify and characterize the most common topics in current foot and ankle literature. Methods: We reviewed all 1514 published articles in a 5.5-year period (January 2014-June 2019) in 2 foot and ankle-specific journals: Foot & Ankle International (FAI) and Foot and Ankle Surgery (FAS). The articles were sorted into different topic domains to identify the 3 most common categories of publication. The top 3 domains were further characterized by level of evidence (LOE) as well as citations. Results: The 3 most published topics in foot and ankle literature were hallux valgus (8.3%), total ankle arthroplasty (TAA) (8.3%), and ankle fracture (6.6%). These 3 subjects accounted for 351 articles (23.2%). Other common topics were patient-reported outcomes (5.0%), osteochondritis dissecans (3.9%), syndesmotic injury (3.8%), ankle instability (3.7%), hallux rigidus (3.0%), and anatomy (2.8%). The average LOE for articles on hallux valgus, TAA, and ankle fracture was 3.27 from FAI, and the average number of annual citations for a given article in both journals was 3.05. Based on our study, there is no correlation between LOE and number of overall citations, but there is a significant, negative linear correlation in ankle fracture data. We also found that articles on TAA had the highest impact factor and that articles from FAI were cited more often than articles from FAS. Conclusion: The 3 most published topics in foot and ankle literature comprise only 23.2% of all articles. This finding is indicative of the wide variety of cases performed by orthopaedic foot and ankle surgeons. High-quality data are still needed in all topics. Level of Evidence: Level III, retrospective cohort study.

Unilateral Loss of Maxillary Molars in Young Mice Leads to Bilateral Condylar Adaptation and Degenerative Disease.

The adaptive response of the mandible and temporomandibular joint (TMJ) to altered occlusion in juvenile patients is presently unclear. To address this question, we established a mouse model in which all molars were extracted from the maxillary right quadrant in prepubertal, 3-week-old mice and analyzed morphological, tissue, cellular, and molecular changes in the mandible and condyle 3 weeks later. Unilateral loss of maxillary molars led to significant, robust, bilateral changes, primarily in condylar morphology, including anteroposterior narrowing of the condylar head and neck and increased convexity at the condylar surface, as determined by geometric morphometric analysis. Furthermore, both condyles in experimental mice exhibited a degenerative phenotype, which included decreased bone volume and increased mineral density near the condylar head surface compared to control mice. Changes in condylar morphology and mineralized tissue composition were associated with alterations in the cellular architecture of the mandibular condylar cartilage, including increased expression of markers for mature (Col2a1) and hypertrophic (Col10a1) chondrocytes, suggesting a shift toward differentiating chondrocytes. Our results show significant bilateral condylar morphological changes, alterations in tissue composition, cellular organization, and molecular expression, as well as degenerative disease, in response to the unilateral loss of teeth. Our study provides a relatively simple, tractable mouse tooth extraction system that will be of utility in uncovering the cellular and molecular mechanisms of condylar and mandibular adaptation in response to altered occlusion. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

The feasibility and generalizability of assessing the appropriateness of antimicrobial prescribing in hospitals: a review of the Australian National Antimicrobial Prescribing Survey.

The National Antimicrobial Prescribing Survey (NAPS) is a web-based qualitative auditing platform that provides a standardized and validated tool to assist hospitals in assessing the appropriateness of antimicrobial prescribing practices. Since its release in 2013, the NAPS has been adopted by all hospital types within Australia, including public and private facilities, and supports them in meeting the national standards for accreditation. Hospitals can generate real-time reports to assist with local antimicrobial stewardship (AMS) activities and interventions. De-identified aggregate data from the NAPS are also submitted to the Antimicrobial Use and Resistance in Australia surveillance system, for national reporting purposes, and to strengthen national AMS strategies. With the successful implementation of the programme within Australia, the NAPS has now been adopted by countries with both well-resourced and resource-limited healthcare systems. We provide here a narrative review describing the experience of users utilizing the NAPS programme in Canada, Malaysia and Bhutan. We highlight the key barriers and facilitators to implementation and demonstrate that the NAPS methodology is feasible, generalizable and translatable to various settings and able to assist in initiatives to optimize the use of antimicrobials.