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Abstract Background Three-dimensional (3D) multivariate Fourier Transform Infrared (FTIR) image maps of tissue sections are presented. A villoglandular adenocarcinoma from a cervical biopsy with a number of interesting anatomical features was used as a model system to demonstrate the efficacy of the technique. Methods Four FTIR images recorded using a focal plane array detector of adjacent tissue sections were stitched together using a MATLAB® routine and placed in a single data matrix for multivariate analysis using Cytospec™. Unsupervised Hierarchical Cluster Analysis (UHCA) was performed simultaneously on all 4 sections and 4 clusters plotted. The four UHCA maps were then stacked together and interpolated with a box function using SCIRun software. Results The resultant 3D-images can be rotated in three-dimensions, sliced and made semi-transparent to view the internal structure of the tissue block. A number of anatomical and histopathological features including connective tissue, red blood cells, inflammatory exudate and glandular cells could be identified in the cluster maps and correlated with Hematoxylin & Eosin stained sections. The mean extracted spectra from individual clusters provide macromolecular information on tissue components. Conclusion 3D-multivariate imaging provides a new avenue to study the shape and penetration of important anatomical and histopathological features based on the underlying macromolecular chemistry and therefore has clear potential in biology and medicine.

Acute aortic occlusion is an infrequent clinical event with high morbidity and mortality. Management is determined by the cause of the occlusion, with thromboembolectomy used for embolic events and bypass for thrombotic events. After bypass, recanalization of a total aortic occlusion has been sparsely reported. We present a case of a total occlusion of an infrarenal abdominal aorta that was managed surgically with a left axillary-bifemoral bypass. Imaging performed 6 months postoperatively revealed a spontaneously recanalized aorta and occluded bypass graft.

Despite the annual vaccination of livestock against foot and mouth disease (FMD) in the United Arab Emirates (UAE), outbreaks of the disease continue to be reported. The effective control of field outbreaks by vaccination requires that the vaccines used are antigenically matched to circulating field FMD viruses. In this study, a vaccine matching analysis was performed using the two-dimensional virus neutralization test (VNT) for three field isolates belonging to the O/ME-SA/PanAsia-2/ANT-10 and O/ME-SA/SA-2018 lineages collected from different FMD outbreaks that occurred within the Abu Dhabi Emirate in 2021 affecting Arabian oryx ( Oryx leucoryx ), goat, and sheep. In addition, post-vaccination antibodies in sheep and goats were measured using solid-phase competitive ELISA (SPCE) for FMDV serotypes A and O at five months after a single vaccine dose and a further 28 days later after a second dose of the FMD vaccine. An analysis of vaccine matching revealed that five out of the six vaccine strains tested were antigenically matched to the UAE field isolates, with r 1 -values ranging between 0.32 and 0.75. These results suggest that the vaccine strains (O-3039 and O1 Manisa) included in the FMD vaccine used in the Abu Dhabi Emirate are likely to provide protection against outbreaks caused by the circulating O/ME-SA/PanAsia-2/ANT-10 and O/ME-SA/SA-2018 lineages. All critical residues at site 1 and site 3 of VP1 were conserved in all isolates, although an analysis of the VP1-encoding sequences revealed 14-16 amino acid substitutions compared to the sequence of the O1 Manisa vaccine strain. This study also reports on the results of post-vaccination monitoring where the immunization coverage rates against FMDV serotypes A and O were 47% and 69% five months after the first dose of the FMD vaccine, and they were increased to 81 and 88%, respectively, 28 days after the second dose of the vaccine. These results reinforce the importance of using a second booster dose to maximize the impact of vaccination. In conclusion, the vaccine strains currently used in Abu Dhabi are antigenically matched to circulating field isolates from two serotype O clades (O/ME-SA/PanAsia-2/ANT-10 sublineage and O/ME-SA/SA-2018 lineage). The bi-annual vaccination schedule for FMD in the Abu Dhabi Emirate has the potential to establish a sufficient herd immunity, especially when complemented by additional biosecurity measures for comprehensive FMD control. These findings are pivotal for the successful implementation of the region's vaccination-based FMD control policy, showing that high vaccination coverage and the wide-spread use of booster doses in susceptible herds is required to achieve a high level of FMDV-specific antibodies in vaccinated animals.

Abstract: We present the case of a 61-year-old male patient with a history of intracranial IDH-wildtype glioblastoma with an isolated cutaneous metastasis within the previous surgical site scar. The cytomorphology of the cutaneous deposits was reminiscent of metastatic melanoma, which is a differential diagnostic pitfall. The tumor molecular characteristics are described, as these have become essential diagnostic criteria for many central nervous system tumors, along with a discussion of the role of immunohistochemical markers and potential pitfalls in the differential diagnosis of melanoma and poorly differentiated carcinoma. We discuss the biology of metastatic glioblastoma and provide a focused literature review of previous glioblastomas with tumor cell seeding within prior surgical scars., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

The body proportions of extant animals help inform inferences about the behaviors of their extinct relatives, but relationships between body proportions, behavior, and phylogeny in extant primates remain unclear. Advances in behavioral data, molecular phylogenies, and multivariate analytical tools make it an opportune time to perform comprehensive comparative analyses of primate traditional limb length proportions (e.g., intermembral, humerofemoral, brachial, and crural indices), body size-adjusted long bone proportions, and principal components. In this study we used a mix of newly-collected and published data to investigate whether and how the limb length proportions of a diverse sample of primates, including monkeys, apes, and modern humans, are influenced by behavior and phylogeny. We reconfirm that the intermembral index, followed by the first principal component of traditional limb length proportions, is the single most effective variable distinguishing hominoids and other anthropoids. Combined limb length proportions and positional behaviors are strongly correlated in extant anthropoid groups, but phylogeny is a better predictor of limb length proportion variation than of behavior. We confirm convergences between members of the Atelidae and extant apes (especially Pan), members of the Hylobatidae and Pongo, and a potential divergence of Presbytis limb proportions from some other cercopithecoids, which correlate with adaptations for forelimb-dominated behaviors in some colobines. Collectively, these results substantiate hypotheses indicating that extinct hominins and other hominoid taxa can be distinguished by analyzing combinations of their limb length proportions at different taxonomic levels. From these results, we hypothesize that fossil skeletons characterized by notably disparate limb length proportions are unlikely to have exhibited similar behavioral patterns., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The terms 'Bowen disease' and 'intraepidermal squamous cell carcinoma' are sometimes considered synonymous. In this paper we present historical, clinical, histological and molecular evidence that this is incorrect. The term Bowen disease should be reserved for a subset of intraepidermal squamous cell carcinoma with a distinctive and reproducible morphological pattern, described in detail by Bowen in 1912. One other common subset of intraepidermal squamous cell carcinoma represents progression of actinic keratosis. In some cases the separation of these two common patterns of intraepidermal squamous cell carcinoma can be challenging and there are patterns of intraepidermal squamous cell carcinoma which appear to represent other distinct pathways. However, there is emerging biological evidence to support this distinction and reason to suspect that the types of invasive squamous cell carcinoma which arise from these different pathways may show important clinical and biological differences, particularly in the era of targeted and immunomodulatory therapy for advanced disease., (Copyright © 2024 Royal College of Pathologists of Australasia. Published by Elsevier B.V. All rights reserved.)

Abstract: The distinction between digital papillary adenocarcinoma (DPAC) and benign cutaneous adnexal tumors is clinically important and can be challenging. Poroid hidradenoma frequently occurs at acral sites and can show a number of histological features, which overlap with digital papillary adenocarcinoma. Recent work has shown that YAP1-NUTM1 fusions are frequent in poroid hidradenoma and are associated with nuclear protein in testis (NUT) expression by immunohistochemistry. We evaluated the expression of NUT-1 by immunohistochemistry in 4 cases of DPAC and 4 cases of poroid hidradenoma. Three of 4 cases of poroid hidradenoma showed strong NUT-1 expression, with no staining in any of the cases of DPAC. These results suggest that NUT-1 immunohistochemistry may be a useful additional tool in evaluating this differential diagnosis., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Morphological overlap exists between cutaneous granular cell tumours (GCT) and malignant melanoma, with the melanocyte-specific markers HMB45 and Melan-A commonly used to support the diagnosis of melanoma. We recently encountered several cases of GCT in our practice showing strong expression of Melan-A. The aim of this study was to establish the prevalence of positive immunohistochemical staining for Melan-A and HMB45 in a series of unequivocal GCTs. We also aimed to assess the prevalence of staining for PRAME (PReferentially expressed Antigen in MElanoma), a marker expressed in >80% of primary melanomas as well as many non-melanocytic tumours. A total of 20 cutaneous/subcutaneous GCTs were evaluated using Melan-A, HMB45 and PRAME immunohistochemistry. Staining for Melan-A and HMB45 was scored using a semiquantitative scale from 0 (absent) to 3+ (staining present in >50% of tumour cells). PRAME expression was recorded as either positive (>75% of cell nuclei staining) or negative. Melan-A expression was observed in four GCTs (20%), with strong and diffuse (3+) staining seen in two cases (10%), both from anogenital areas. Weak patchy nuclear PRAME expression was seen in every case, interpreted to be negative. HMB45 was also negative in all cases (100%). Our study demonstrates that Melan-A expression can be strong and diffuse in a subset of otherwise unequivocal cutaneous GCTs, which may cause diagnostic confusion with malignant melanoma. HMB45 and PRAME did not stain any of the GCTs in our series., (Copyright © 2023 Royal College of Pathologists of Australasia. All rights reserved.)

Background: Cutaneous squamous cell carcinoma is a significant cause of morbidity for immunosuppressed patients such as organ transplant recipients; however, histological parameters which predict the likelihood of tumor progression are typically based on general population studies in which immunosuppressed patients represent only a small fraction of cases., Objectives: To determine the histological parameters which have independent prognostic value for cutaneous squamous cell carcinoma arising in renal transplant recipients., Methods: Case-control study incorporating a retrospective blinded histological review of 70 archived specimens of cutaneous squamous cell carcinoma diagnosed in renal transplant recipients, comprising 10 cases where the tumor had progressed and 60 controls., Results: Progression was significantly associated with head and neck location, size, depth, poor histological grade, perineural invasion (including small caliber perineural invasion), lymphovascular invasion, and a desmoplastic growth pattern., Limitations: The retrospective nature and the low number of cases compared to controls., Conclusion: In immunosuppressed patients both small caliber perineural invasion and a desmoplastic growth pattern may also have prognostic significance in addition to other histological parameters already recognized in formal staging schemes., Competing Interests: None disclosed., (© 2024 by the American Academy of Dermatology, Inc. Published by Elsevier Inc.)

Foot-and-mouth disease (FMD) is endemic in many Asian countries, with outbreaks occurring regularly due to viruses from serotypes O, A, and Asia1 that co-circulate in the region. The ability to rapidly characterize new virus occurrences provides critical information to understand the epidemiology and risks associated with field outbreaks, and helps in the selection of appropriate vaccines to control the disease. FMD lineage-specific characterization is usually determined through sequencing; however, this capacity is not always readily available. In this study, we provide a panel of real-time RT-PCR (rRT-PCR) assays to allow differentiation of the FMD virus (FMDV) lineages known to have been co-circulating in Asia during 2020. This panel included five new rRT-PCR assays designed to detect lineages O/ME-SA/PanAsia-PanAsia-2, O/ME-SA/Ind-2001, O/SEA/Mya-98, O/CATHAY, and A/ASIA/Sea-97, along with three published rRT-PCR assays for A/ASIA/Iran-05, A/ASIA/G-VII, and Asia1 serotypes. Samples of known FMD lineage ( n = 85) were tested in parallel with all eight lineage-specific assays and an established 3D pan-FMD rRT-PCR assay, and comparative limit of detection (LOD) experiments were conducted for the five newly developed assays. All samples (85/85) were assigned to the correct serotype, and the correct lineage was assigned for 70 out of 85 samples where amplification only occurred with the homologous assay. For 13 out of 85 of the samples, there was amplification in two assays; however, the correct lineage could be designated based on the strongest Ct values for 12 out of 13 samples. An incorrect lineage was assigned for 3 out of 85 samples. The amplification efficiencies for the five new rRT-PCR assays ranged between 79.7 and 100.5%, with nucleic acid dilution experiments demonstrating broadly equivalent limits of detection when compared to the 3D pan-FMD rRT-PCR assay. These new tests, together with other published lineage-specific rRT-PCR assays, constitute a panel of assays (or molecular toolbox) that can be selected for use in FMD endemic countries (individually or a subset of the assays depending on region/lineages known to be circulating) for rapid characterization of the FMDV lineages circulating in Asia at a relatively low cost. This molecular toolbox will enhance the ability of national laboratories in endemic settings to accurately characterize circulating FMDV strains and facilitate prompt implementation of control strategies, and may be particularly useful in settings where it is difficult to access sequencing capability., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Saduakassova, Wood, Henry, Gray, Mioulet, Sultanov, Wadsworth, Knowles, Di Nardo, King and Bachanek-Bankowska.)

Sebaceous carcinoma is a rare cutaneous malignancy which is typically regarded as relatively aggressive and has traditionally been subdivided into periorbital or extraorbital tumours. We conducted a retrospective review of all cases of sebaceous carcinoma reported to the Western Australian Cancer Registry between 1987 and May 2019. The incidence of sebaceous carcinoma in Western Australia has increased over the last three decades, with extraorbital tumours being much more common than periorbital tumours. Very few sebaceous carcinomas have led directly to the death of patients; however, adverse outcomes were more likely with periorbital tumours, in particular local recurrence and the need for major surgical intervention., (© 2023 The Authors. Australasian Journal of Dermatology published by John Wiley & Sons Australia, Ltd on behalf of Australasian College of Dermatologists.)

Dysregulation of metabolic functions in the liver impacts the development of diabetes and metabolic disorders. Normal liver function can be compromised by increased inflammation via the activation of signaling such as nuclear factor (NF)-κB signaling. Notably, we have previously identified lysine demethylase 2A (KDM2A)-as a critical negative regulator of NF-κB. However, there are no studies demonstrating the effect of KDM2A on liver function. Here, we established a novel liver-specific Kdm2a knockout mouse model to evaluate KDM2A's role in liver functions. An inducible hepatic deletion of Kdm2a, Alb-Cre-Kdm2a fl/fl ( Kdm2a KO), was generated by crossing the Kdm2a floxed mice ( Kdm2a fl/fl ) we established with commercial albumin-Cre transgenic mice (B6.Cg-Tg(Alb-cre)21Mgn/J). We show that under a normal diet, Kdm2a KO mice exhibited increased serum alanine aminotransferase (ALT) activity, L-type triglycerides (TG) levels, and liver glycogen levels vs. WT ( Kdm2a fl/fl ) animals. These changes were further enhanced in Kdm2a liver KO mice in high-fat diet (HFD) conditions. We also observed a significant increase in NF-κB target gene expression in Kdm2a liver KO mice under HFD conditions. Similarly, the KO mice exhibited increased immune cell infiltration. Collectively, these data suggest liver-specific KDM2A deficiency may enhance inflammation in the liver, potentially through NF-κB activation, and lead to liver dysfunction. Our study also suggests that the established Kdm2a fl/fl mouse model may serve as a powerful tool for studying liver-related metabolic diseases.

Competing Interests: The author declares no conflicts of interest.

Abstract: The combination of lichenoid and granulomatous inflammation is uncommon in vulval biopsies. We present a series of 5 patients with lichenoid and granulomatous vulvitis, presenting with clinical changes resembling lichen sclerosus. Despite detailed clinicopathological investigation and follow-up, there was no apparent association with an underlying recognized cause. All 5 cases occurred in postmenopausal women and displayed a distinctive histological pattern of superficial band-like inflammation with granulomas "anchored" to the dermoepidermal junction. There was no evidence of deeper granulomatous inflammation. Despite repeated biopsies over 2 years in 2 patients, neither developed typical histological features of lichen sclerosus. We postulate that idiopathic lichenoid and granulomatous vulvitis may represent a distinct clinicopathologically defined vulvar dermatosis., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Body mass is a critical variable in many hominin evolutionary studies, with implications for reconstructing relative brain size, diet, locomotion, subsistence strategy, and social organization. We review methods that have been proposed for estimating body mass from true and trace fossils, consider their applicability in different contexts, and the appropriateness of different modern reference samples. Recently developed techniques based on a wider range of modern populations hold promise for providing more accurate estimates in earlier hominins, although uncertainties remain, particularly in non-Homo taxa. When these methods are applied to almost 300 Late Miocene through Late Pleistocene specimens, the resulting body mass estimates fall within a 25-60 kg range for early non-Homo taxa, increase in early Homo to about 50-90 kg, then remain constant until the Terminal Pleistocene, when they decline., (© 2023 The Authors. Evolutionary Anthropology published by Wiley Periodicals LLC.)

Objective: To identify areas of agreement and variation in clinical guidance documents (protocols, policies, or guidelines) that direct water birth care., Design: Qualitative descriptive., Setting: The clinical guidance documents studied covered water birth in home and hospital settings., Sample: The sample included 22 water birth guidance documents in English from six countries. The documents were obtained by request and resulting snowball sampling., Measurements: The framework method was adapted as an analytic tool, and a structured matrix output was used to organize and support the method of qualitative content analysis using a general inductive approach. Areas of general agreement and variations in practice guidelines for water birth were identified., Results: Criteria for a term, singleton, and cephalic presentation with reassuring maternal and fetal status were the most consistent for inclusion. The reliance on "low-risk" status was strongly present but without a uniform definition. A history of previous cesarean birth, body mass index, use of opioid pain medication, adequate labor progress, and vaginal bleeding were found to vary in directed care, and scarce supporting evidence was offered. Meconium-stained fluid variably excluded water birth in most documents, but this was not supported by evidence. The inconsistent findings from this study are cohesive in the evidence they provide for needed research in areas that affect access to water birth. The findings also provide nurses and birth providers with evidence-based guidelines for water birth care., Conclusion: There was variation across guidance documents, demonstrating that water immersion is a flexible intervention that can be implemented in different settings and locations while following individual facility protocols for processes for care. An identified area of concern comes from examples of overly restrictive policies for water birth based on opinion or perceived risk rather than evidence from research., (Copyright © 2023 AWHONN. Published by Elsevier Inc. All rights reserved.)

Ontogeny provides critical information about the evolutionary history of early hominin adult morphology. We describe fossils from the southern African sites of Kromdraai and Drimolen that provide insights into early craniofacial development in the Pleistocene robust australopith Paranthropus robustus . We show that while most distinctive robust craniofacial features appear relatively late in ontogeny, a few do not. We also find unexpected evidence of independence in the growth of the premaxillary and maxillary regions. Differential growth results in a proportionately larger and more postero-inferiorly rotated cerebral fossa in P. robustus infants than in the developmentally older Australopithecus africanus juvenile from Taung. The accumulated evidence from these fossils suggests that the iconic SK 54 juvenile calvaria is more likely early Homo than Paranthropus. It is also consistent with the hypothesis that P. robustus is more closely related to Homo than to A. africanus .

Purpose: To evaluate the efficacy of ketamine in total knee and hip arthroplasty., Design: Evidence-based review., Methods: Following the guidelines outlined in the PRISMA statement, a comprehensive search was conducted using Google Scholar, PubMed, CINAHL, Cochrane Collaboration, and other grey literature. Only randomized controlled studies and pre-appraised evidence such as systematic review and meta-analysis examining the effects of ketamine in total knee and hip arthroplasty were included. The quality appraisal of the literature was conducted using the proposed algorithm described in the Johns Hopkins Nursing Evidence-Based Practice Evidence Level and Quality Guide., Findings: Three systematic reviews and meta-analyses and 2 randomized controlled trials involving 1284 patients were included in this review. The use of ketamine reduced pain scores within the 24 hours after surgery. In addition, evidence suggests that patients who were treated with ketamine consumed fewer opioids 24 and 48 hours after surgery. Furthermore, ketamine reduced the incidence of postoperative nausea and vomiting with no effects on the incidence of hallucinations and central nervous system side effects. All studies included in the review were categorized as Level I and rated Grade A implying strong confidence in the true effects of ketamine in all outcome measures in the review., Conclusions: The current evidence demonstrates the viability of ketamine as a safe and effective alternative to opioids in the perioperative setting with major total joint arthroplasty surgery. Decreased pain scores and opioid consumption up to 48 hours into the postoperative period were observed in a number of the appraised articles., (Copyright © 2022 American Society of PeriAnesthesia Nurses. Published by Elsevier Inc. All rights reserved.)

Rationale: In the United States, Black women are disproportionately affected by HIV, accounting for most new HIV infections diagnosed among women. Socio-structural barriers to HIV testing include stigma and discrimination but may be mitigated by resilience., Objective: We aimed to examine the effect of discrimination and resilience on HIV testing behaviors among Black women., Methods: Between 2016 and 2018, we conducted The ESSENCE Project, a retrospective cohort study on the role of physiological and environmental factors on the association between sexual assault and HIV risk among Black women in Baltimore, Maryland, USA. Black women aged 18-44 were recruited from public health STD clinics and completed an audio-computer-assisted self-interview survey. Hierarchical multiple negative binomial regression models were used to examine the associations of everyday discrimination (subtle and overt) and resilience on HIV testing frequency; resilience and its subscales (relational maintenance, personal fortitude, positive coping, independence and insight) were also examined as moderators., Results: Among 236 Black women reporting HIV testing history, the median number of lifetime HIV tests was 4 (IQR = 2, 6). Mean everyday discrimination was 2.3 (SD = 1.2). Mean resilience was 5.3 (SD = 0.8). Everyday discrimination and its subscales (overt and subtle) were negatively associated with lifetime HIV testing frequency, while overall resilience was not associated with lifetime HIV testing frequency. Accounting for demographics, overall resilience moderated the association of subtle discrimination and lifetime HIV testing frequency. For the resilience subscales, more specifically: (1) associations of subtle discrimination and HIV testing frequency were significant at the lowest relational maintenance and lowest positive coping resilience; and (2) the association of subtle discrimination and HIV testing frequency was significant at the highest resilience for all four subscales., Conclusions: These findings highlight the need for provider- and community-level interventions addressing the deleterious effects of everyday discrimination and more specifically subtle everyday discrimination to encourage HIV testing., (Copyright © 2022. Published by Elsevier Ltd.)

Accurate and complete pathology reports are critical for the optimal management of cancer patients. Protocols for the pathologic reporting of Merkel cell carcinoma (MCC) have been developed independently by the Royal College of Pathologists (UK) and the College of American Pathologists. In this study, data elements for pathologic reporting of MCC were analyzed by an international panel of pathologists and clinicians with the aim of developing a common, internationally agreed upon dataset useful for clinical practice. The International Collaboration on Cancer Reporting expert review panel developed a protocol containing "core" (required) and "noncore" (recommended) elements. Core elements were defined as those that had evidentiary support and were unanimously agreed upon by the review panel as essential for the clinical management, staging, and/or assessment of prognosis in patients with MCC. Noncore elements were those considered to be clinical of interest, but with lesser degrees of supportive evidence or nonactionable implications. Ten core data elements for pathology reports on primary MCC were defined. Development and agreement on this evidence-based protocol at an international level was accomplished in a timely and efficient manner. The template developed for melanoma reporting was used as a structural base for this initiative. It is applicable to, and may facilitate the development of, protocols for other tumor types. Widespread utilization of an internationally agreed upon structured pathology dataset for MCC can be expected to lead to improved patient management. It should also facilitate collaborative clinical research., Competing Interests: Conflicts of Interest and Source of Funding: R.A.S. is supported by an NHMRC Practitioner Fellowship (APP1141295). Support from Deborah McMurtrie and John McMurtrie AM is also gratefully acknowledged. R.A.S. has received fees for professional services from F. Hoffmann-La Roche Ltd, Evaxion, Provectus Biopharmaceuticals Australia, Qbiotics, Novartis, Merck Sharp & Dohme, NeraCare, AMGEN Inc., Bristol-Myers Squibb, Myriad Genetics, GlaxoSmithKline. For the remaining authors none were declared., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Abstract: Merkel cell carcinoma with a sarcomatous component is very rare, with only 12 cases reported in the literature, often with overtly malignant myoid differentiation. We report a case of metastatic Merkel cell carcinosarcoma presenting in a lymph node 6 months after a diagnosis of cutaneous Merkel cell carcinoma with conventional histologic features. The metastatic lesion showed a unique biphasic appearance with admixed populations of neuroendocrine epithelial cells and fascicles of mitotically active spindle cells with mild cytological atypia. In addition to the immunomorphological features, a common molecular profile between the epithelial and mesenchymal components further supported the notion of carcinosarcoma in this case. To the best of our knowledge, a bland sarcomatous component has not been previously described in Merkel cell carcinosarcoma, which can be easily overlooked as a reactive stromal reaction microscopically., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Abstract: The aim of this study was to review the dermatopathological findings in skin biopsy specimens from pediatric oncology and hematopoietic stem cell transplantation patients over a 20-year period. Three hundred fifty-two skin biopsies from 240 patients were reviewed, and the findings were grouped into 6 categories: index neoplasms, nonindex neoplasms, infections, graft-versus-host disease, other treatment complications, and others. Among the index neoplasms identified on skin biopsy, the most common conditions were Langerhans cell histiocytosis (14 patients) and melanoma (7 patients), with other hematological malignancies and an array of soft-tissue tumors accounting for the bulk of the remainder. Neoplastic conditions common in general dermatopathological practice such as basal cell carcinoma and squamous cell carcinoma were uncommon, each being identified in only 1 patient younger than the age of 18, although basal cell carcinomas developing subsequently in young adult life were identified in 7 patients. Infections were common, with infectious agents or viral cytopathic effects (not including human papillomavirus) identified in 34 biopsies. A significant proportion (74%) represented invasive fungal infections, which are of very significant clinical importance. Biopsies performed for a clinical suspicion of graft-versus-host seldom showed histological features to suggest an alternative diagnosis, with only a single case suggesting a diagnosis of toxic erythema of chemotherapy identified., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Abstract: Deep penetrating nevus (DPN) is a pigmented melanocytic tumor which typically displays a wedge-shaped deep penetrating architecture. Some cases show a coexisting component resembling conventional melanocytic nevus. These morphological attributes are correlated with the acquisition of genomic alterations in the Wnt pathway on a background of underlying activating MAPK pathway mutations. Lesions with features of DPN, but displaying expansile architecture, sheet-like arrangement of cells, cytological atypia, and/or more than rare mitotic activity have been described as "atypical deep penetrating nevus" or "deep penetrating melanocytoma." The molecular correlates of these atypical morphological features are not well-established. In this case report, we describe a tumor in an 8-year-old boy with histological features of atypical DPN showing somatic BRAFV600E , beta catenin , and IDH1R132C mutations. The combination of abnormalities in MAPK and Wnt pathways with IDH1 mutations seems to be a reproducible feature in a subset of atypical DPNs. Whether this "three-hit" combination is associated with a significant risk of adverse outcome remains to be established., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2022 Wolters Kluwer Health, Inc. All rights reserved.)

Targeted therapy (BRAF inhibitor plus MEK inhibitor) is now among the possible treatment options for patients with BRAF mutation-positive stage III or stage IV melanoma. This makes prompt BRAF mutation testing an important step in the management of patients diagnosed with stage III or IV melanoma; one that can help better ensure that the optimal choice of systemic treatment is initiated with minimal delay. This article offers guidance about when and how BRAF mutation testing should be conducted when patients are diagnosed with melanoma in Australia. Notably, it recommends that pathologists reflexively order BRAF mutation testing whenever a patient is found to have American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) stage III or IV melanoma (i.e., any metastatic spread beyond the primary tumour) and that patient's BRAF mutation status is hitherto unknown, even if BRAF mutation testing has not been specifically requested by the treating clinician (in Australia, Medicare-subsidised BRAF V600 mutation testing does not need to be requested by the treating clinician). When performed in centres with appropriate expertise and experience, immunohistochemistry (IHC) using the anti-BRAF V600E monoclonal antibody (VE1) can be a highly sensitive and specific means of detecting BRAF V600E mutations, and may be used as a rapid and relatively inexpensive initial screening test. However, VE1 immunostaining can be technically challenging and difficult to interpret, particularly in heavily pigmented tumours; melanomas with weak, moderate or focal BRAF V600E immunostaining should be regarded as equivocal. It must also be remembered that other activating BRAF V600 mutations (including BRAF V600K ), which account for ∼10-20% of BRAF V600 mutations, are not detected with currently available IHC antibodies. For these reasons, if available and practicable, we recommend that DNA-based BRAF mutation testing always be performed, regardless of whether IHC-based testing is also conducted. Advice about tissue/specimen selection for BRAF mutation testing of patients diagnosed with stage III or IV melanoma is also offered in this article; and potential pitfalls when interpreting BRAF mutation tests are highlighted., (Copyright © 2021 Royal College of Pathologists of Australasia. Published by Elsevier B.V. All rights reserved.)

Abstract: We present the case of a prepubescent man of African descent who developed a spitzoid melanocytic proliferation showing evidence of a novel promoter hijacking ALK-C2orf42 rearrangement, with atypical histology, clinically apparent metastatic disease, and abnormal cytogenetic findings, representing a rare genuine case of "Spitz melanoma of childhood." As our understanding of the distinct molecular biology of different tumors traditionally grouped as spitzoid melanocytic lesions evolves, it is becoming increasingly apparent that this group encompasses morphologically and genetically distinct entities. Accurate classification with detailed molecular analysis and prolonged clinical follow-up is essential to allow meaningful conclusions regarding prognostication and prediction of response to therapy., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Abstract: Preferentially expressed antigen in melanoma (PRAME) is a tumor-associated repressor of retinoic acid signaling which is expressed in melanoma and has emerged as a potential biomarker for malignant behavior in melanocytic neoplasms. Although ancillary molecular techniques such as fluorescence in situ hybridization (FISH) are established techniques in the diagnosis of problematic cutaneous melanocytic proliferations, they are expensive, time-consuming, and require appropriate infrastructure, which places them out of reach of some laboratories. The advent of readily available commercial antibodies to PRAME has the potential to provide a more accessible alternative. The aim of this study was to determine whether immunohistochemistry for PRAME could serve as a surrogate for FISH analysis in a subgroup of challenging superficial melanocytic proliferations. Cases which had previously been submitted for FISH analysis were stained for PRAME and interpreted by a panel of at least 3 dermatopathologists is a blinded fashion. Of a study set of 55 cases, 42 (76%) showed a pattern of PRAME immunostaining which was concordant with the cytogenetic interpretation, with an unweighted kappa of 0.42 (representing mild-to-moderate agreement). Thus, although there was a correlation between positive immunohistochemistry for PRAME and abnormal findings on FISH analysis, in our view, the concordance was not sufficient to enable PRAME immunohistochemistry to act as a surrogate for FISH testing. Our findings reiterate the principle that interpretation of problematic superficial melanocytic proliferations requires a synthesis of all the available data, including clinical scenario, morphological features, immunohistochemistry, and ancillary molecular investigations., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Tumor heterogeneity is a major obstacle to the success of cancer treatment. An accurate understanding and recognition of tumor heterogeneity is critical in the clinical management of cancer patients. Here, we utilized single-cell RNA sequencing (scRNA-seq) to uncover the intra- and intertumoral heterogeneity of liver metastases from a patient with metastatic uveal melanoma. The two metastases analyzed were largely infiltrated by noncancerous cells with significant variability in the proportion of different cell types. Analysis of copy-number variations (CNVs) showed gain of 8q and loss of 6q in both tumors, but loss of Chromosome 3 was only detected in one of the tumors. Single-nucleotide polymorphism (SNP) array revealed a uniparental isodisomy 3 in the tumor with two copies of Chromosome 3, indicating a regain of Chromosome 3 during the development of the metastatic disease. In addition, both tumors harbored subclones with additional CNVs. Pathway enrichment analysis of differentially expressed genes revealed that cancer cells in the metastasis with isodisomy 3 showed up-regulation in epithelial-mesenchymal transition and myogenesis related genes. In contrast, up-regulation in interferon signaling was observed in the metastasis with monosomy 3 and increased T-cell infiltrate. This study highlights the complexity and heterogeneity of different metastases within an individual case of uveal melanoma., (© 2021 Lin et al.; Published by Cold Spring Harbor Laboratory Press.)

Insights into potential differences among the bony labyrinths of Plio-Pleistocene hominins may inform their evolutionary histories and sensory ecologies. We use four recently-discovered bony labyrinths from the site of Kromdraai to significantly expand the sample for Paranthropus robustus. Diffeomorphometry, which provides detailed information about cochlear shape, reveals size-independent differences in cochlear shape between P. robustus and Australopithecus africanus that exceed those among modern humans and the African apes. The cochlea of P. robustus is distinctive and relatively invariant, whereas cochlear shape in A. africanus is more variable, resembles that of early Homo, and shows a degree of morphological polymorphism comparable to that evinced by modern species. The curvature of the P. robustus cochlea is uniquely derived and is consistent with enhanced sensitivity to low-frequency sounds. Combined with evidence for selection, our findings suggest that sound perception shaped distinct ecological adaptations among southern African early hominins., (© 2021. The Author(s).)

The LFBK-α v β 6 cell line is highly sensitive for the isolation of foot-and-mouth disease virus (FMDV) and porcinophilic vesicular viruses. However, LFBK-α v β 6 cells are contaminated with a non-cytopathic bovine viral diarrhea virus (BVDV), which complicates handling procedures in areas where other cell lines are maintained, as well downstream use of viral isolates. In this study, we used an aromatic cationic compound (DB772) to treat LFBK-α v β 6 cells using an approach that has been previously used to eliminate persistent BVDV from fetal fibroblast cell lines. After three cell passages with 4 μM DB772, BVDV could no longer be detected in unclarified cell suspensions using a pan-pestivirus real-time RT-PCR assay, and remained undetectable after treatment was stopped (nine passages) for an additional 28 passages. The analytical sensitivity of the DB772-treated LFBK-α v β 6 cultures (renamed WRL-LFBK-α v β 6 ) to titrations of FMDV and other vesicular virus isolates was comparable to untreated LFBK-α v β 6 cells. These new BVDV-free cells can be handled without the risk of cross-contaminating other cells lines or reagents, and used for routine diagnostics, in vivo studies and/or preparation of new vaccine strains., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Gray, Wood, Henry, King and Mioulet.)

Background: In the United States, racial and ethnic minorities are disproportionately affected by COVID-19, with persistent social and structural factors contributing to these disparities. At the intersection of race/ethnicity and gender, women of color may be disadvantaged in terms of COVID-19 outcomes due to their role as essential workers, their higher prevalence of pre-existing conditions, their increased stress and anxiety from the loss of wages and caregiving, and domestic violence., Objective: The purpose of this study is to examine racial and ethnic differences in the prevalence of COVID-19 outcomes, stressors, fear, and prevention behaviors among adult women residing in the United States., Methods: Between May and June 2020, women were recruited into the Capturing Women's Experiences in Outbreak and Pandemic Environments (COPE) Study, a web-based cross-sectional study, using advertisements on Facebook; 491 eligible women completed a self-administered internet-based cross-sectional survey. Descriptive statistics were used to examine racial and ethnic differences (White; Asian; Native Hawaiian or other Pacific Islander; Black; Hispanic, Latina, or Spanish Origin; American Indian or Alaskan Native; multiracial or some other race, ethnicity, or origin) on COVID-19 outcomes, stressors, fear, and prevention behaviors., Results: Among our sample of women, 16% (73/470) reported COVID-19 symptoms, 22% (18/82) were concerned about possible exposure from the people they knew who tested positive for COVID-19, and 51.4% (227/442) knew where to get tested; yet, only 5.8% (27/469) had been tested. Racial/ethnic differences were observed, with racial/ethnic minority women being less likely to know where to get tested. Significant differences in race/ethnicity were observed for select stressors (food insecurity, not enough money, homeschooling children, unable to have a doctor or telemedicine appointment) and prevention behaviors (handwashing with soap, self-isolation if sick, public glove use, not leaving home for any activities). Although no racial/ethnic differences emerged from the Fear of COVID-19 Scale, significant racial/ethnic differences were observed for some of the individual scale items (eg, being afraid of getting COVID-19, sleep loss, and heart racing due to worrying about COVID-19)., Conclusions: The low prevalence of COVID-19 testing and knowledge of where to get tested indicate a critical need to expand testing for women in the United States, particularly among racial/ethnic minority women. Although the overall prevalence of engagement in prevention behaviors was high, targeted education and promotion of prevention activities are warranted in communities of color, particularly with consideration for stressors and adverse mental health., (©Jamila K Stockman, Brittany A Wood, Katherine M Anderson. Originally published in the Journal of Medical Internet Research (https://www.jmir.org), 12.07.2021.)

Abstract: The distinction between nevoid melanoma and a mitotically active nevus can be challenging at the microscopic level. In this study, we performed cytogenetic testing on a cohort of 25 mitotically active melanocytic proliferations resembling common melanocytic nevus from 25 patients. Based on cytogenetic findings, the lesions were classified as "nevoid melanoma" (n = 13) or "mitotically active nevus" (n = 12). Subsequently, we compared the clinicopathological features between these 2 groups. Nevoid melanomas occurred in older patients (P = 0.007); however, there were no significant differences in gender, size, or anatomical distribution between the 2 groups. Histologically, deep/marginal mitoses (P = 0.006), lack of maturation with depth (P = 0.036), and pseudo-maturation (P = 0.006) were significantly more common in nevoid melanomas. Immunohistochemically, complete loss of p16 was an important divisive feature (P = 0.0004), seen in 70% of nevoid melanomas, and highly correlated with loss of CDKN2A gene (chromosome 9p21). Our findings suggest that such reproducible immunomorphological differences can be of value in distinguishing nevoid melanoma from mitotically active nevus. Nevoid melanomas demonstrated a spectrum of chromosomal aberrations similar to those seen in common subtypes of melanoma, which can serve as a powerful adjunct diagnostic tool in morphologically challenging lesions., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Hypoglycemia can be a common occurrence in hospitalized patients, both those with and without diabetes. Hypoglycemia poses significant risks to hospitalized patients, including increased mortality., Objectives: This was a retrospective pre-post study of hypoglycemic patients in an academic medical center of an intervention to improve timely staff nurse adherence to a hypoglycemia protocol. The number of mild and severe hypoglycemia events pre- and postintervention, timeliness of adherence to the hypoglycemia protocol, the number of treatment interventions, and time to return patients to euglycemia were analyzed., Methods: Data from hospitalizations of patients who experienced hypoglycemia (<70 mg/dl) and met inclusion criteria 1 year prior to intervention and 3 years postintervention were extracted, including demographics, glycemic control medications, diagnostic-related group, length of stay, and Charlson comorbidity index. For clarity and to determine if any significant change was sustained, the analysis compared data from 1 year prior to intervention to the second-year postintervention., Results: A total of 7,895 unique hypoglycemic events in 3,819 patients experiencing 20,094 hypoglycemic measures were included in the analysis. Patients were primarily adult, female, and White. Only 58.7% of the sample had diabetes; the median Charlson comorbidity index was 6. Results demonstrated improvement postintervention to registered nurse hypoglycemia protocol adherence regardless of age category or hypoglycemia severity. There was a significant reduction in median time from the first hypoglycemia measure to the second measure. In addition, there was a significant difference in the number of treatment interventions and reduction in time from the first hypoglycemia measure to return of patient to a blood glucose of ≥70 mg/dl., Discussion: These study results support that the use of a standardized hypoglycemia protocol and appropriate nurse workflows enables nurses to manage hypoglycemia promptly and effectively in most acute and critically ill hospitalized patients. Results also supported a differentiation in nurse workflow for patients with mild versus severe hypoglycemia. Implementing these interventions may result in avoidance or mitigation of the potential consequences of severe and/or sustained hypoglycemia.

Supportive school and community resources are associated with reduced risk of suicidality among lesbian, gay, bisexual, transgender, and queer/questioning (LGBTQ +) adolescents as well as their cisgender, heterosexual peers. This study examined whether adolescents attending schools and living in communities with more versus fewer LGBTQ +-supportive resources were at lower risk of a past-year suicide attempt. Data on sexual orientation and past-year suicide attempt were obtained from student surveys administered in 30 Massachusetts public high schools between 2014 and 2017 ( N = 20,790). Data on school resources were obtained from a questionnaire administered to school officials, and community resources were assessed through internet searching. Modified Poisson generalized estimating equations tested associations between school and community LGBTQ +-supports and suicide attempt separately by sex/gender, adjusting for student, school, and community covariates. Several school resources and the availability of community-wide LGBTQ +-supportive resources were associated with lower risk of a suicide attempt among several subgroups of students, even after controlling for the presence of multiple school and community resources and covariates. For example, the risk of a suicide attempt among gay, bisexual and questioning boys in schools with a gender-neutral restroom was approximately half compared to gay, bisexual and questioning boys in schools without this resource. Past year suicide attempts were also significantly lower among questioning, RR = 0.56, CI [0.37-0.86], and heterosexual, RR = 0.59, CI [0.50-0.68], girls living in communities with more supportive resources compared to those in communities with fewer resources. LGBTQ +-supportive resources in schools and communities may be beneficial for all adolescents regardless of sexual orientation. (PsycInfo Database Record (c) 2021 APA, all rights reserved).