Osteoblastoma of the thumb with a novel PRSS44::ALK fusion and literature review of osteoblastoma of hands and feet bones.

Osteoblastomas (OBs) are benign neoplasms constituting approximately 1% of primary bone tumors with a predilection for the spine and sacrum. We describe an OB of the proximal phalanx of the left thumb in a 38-year-old female. MRI of left hand demonstrated a 29-mm mildly expansile enhancing lesion involving the entire proximal phalanx of the first digit. Histology displayed a bone-forming tumor consisting of trabeculae of remodeled woven bone framed by plump osteoblasts in a vascularized background. Next-generation sequencing analysis identified a PRSS44::ALK fusion gene.

Synchronous Low-Grade Central Osteosarcoma and Ewing Sarcoma: A Rare Case Report.

A 23-year-old female patient presented with radicular back pain, perineal numbness, and urinary retention. The patient was diagnosed with cauda equina syndrome and magnetic resonance imaging (MRI) of the spine revealed an enhancing osseous lumbar lesion causing severe central stenosis. A core needle biopsy of the lumbar spine showed microscopic features compatible with a small round blue cell tumor. CD99 and FLI1 were positive in the tumor cells. Next-generation sequencing demonstrated a EWSR1::FLI1 fusion. Given these findings, the spine lesion was diagnosed as Ewing sarcoma. The patient underwent surgical decompression of L2. On further workup, an MRI revealed an ill-defined enhancing mass of the right distal femur. This area was biopsied, demonstrating a fibro-osseous lesion with osteoblast proliferation containing nuclear atypia, low mitotic activity, and SATB2 positivity, diagnosed as low-grade central osteosarcoma (LGCOS). The patient underwent resection, which showed a classic LGCOS by histomorphology. Although fluorescence in-situ hybridization study for MDM2 gene amplification was negative, the overall findings are most consistent with LGCOS. These neoplasms are considered to be synchronous due to the presentation of each entity within 6 months. Considering the aggregate yearly incidence of Ewing sarcoma (approximately 1 case per 750 000 per year) and LGCOS (approximately 1 case per 10 million per year), the aggregate yearly probability of developing both of these genetically unrelated tumors in a single individual is 1 per 7.5 trillion per year, and it is likely such an event has never happened in the past.

Mild Deficits in Fear Learning: Evidence from Humans and Mice with Cerebellar Cortical Degeneration.

Functional brain imaging studies in humans suggest involvement of the cerebellum in fear conditioning but do not allow conclusions about the functional significance. The main aim of the present study was to examine whether patients with cerebellar degeneration show impaired fear conditioning and whether this is accompanied by alterations in cerebellar cortical activations. To this end, a 2 d differential fear conditioning study was conducted in 20 cerebellar patients and 21 control subjects using a 7 tesla (7 T) MRI system. Fear acquisition and extinction training were performed on day 1, followed by recall on day 2. Cerebellar patients learned to differentiate between the CS+ and CS-. Acquisition and consolidation of learned fear, however, was slowed. Additionally, extinction learning appeared to be delayed. The fMRI signal was reduced in relation to the prediction of the aversive stimulus and altered in relation to its unexpected omission. Similarly, mice with cerebellar cortical degeneration (spinocerebellar ataxia type 6, SCA6) were able to learn the fear association, but retrieval of fear memory was reduced. In sum, cerebellar cortical degeneration led to mild abnormalities in the acquisition of learned fear responses in both humans and mice, particularly manifesting postacquisition training. Future research is warranted to investigate the basis of altered fMRI signals related to fear learning.

Non-neoplastic bone, joint, and soft tissue pathology: What every pathologist should know.

The diagnosis of bone and soft tissue tumors is a skill which requires experience across multiple disciplines while their incidence is small. By contrast, the numbers of patients with non-tumorous diseases of bones, soft tissues, and joints dwarfs primary tumors by several orders of magnitude. The ability to successfully diagnose non-neoplastic diseases requires a knowledge of bone development, structure, remodeling, imaging, and tissue processing. This review summarizes the alterations of bones, joints, and to a lesser extent soft tissues that are encountered in the practice of everyday surgical pathology.

Glycan-Driven Formation of Raft-Like Domains with Hierarchical Periodic Nanoarrays on Dendrimersome Synthetic Cells.

The accurate spatial segregation into distinct phases within cell membranes coordinates vital biochemical processes and functionalities in living organisms. One of nature's strategies to localize reactivity is the formation of dynamic raft domains. Most raft models rely on liquid-ordered L0 phases in a liquid-disordered Ld phase lacking correlation and remaining static, often necessitating external agents for phase separation. Here, we introduce a synthetic system of bicomponent glycodendrimersomes coassembled from Janus dendrimers and Janus glycodendrimers (JGDs), where lactose-lactose interactions exclusively drive lateral organization. This mechanism results in modulated phases across two length scales, yielding raft-like microdomains featuring nanoarrays at the nanoscale. By varying the density of lactose and molecular architecture of JGDs, the nanoarray type and size, shape, and spacing of the domains were controlled. Our findings offer insight into the potential primordial origins of rudimentary raft domains and highlight the crucial role of glycans within the glycocalyx.

Sequencing by avidity enables high accuracy with low reagent consumption.

We present avidity sequencing, a sequencing chemistry that separately optimizes the processes of stepping along a DNA template and that of identifying each nucleotide within the template. Nucleotide identification uses multivalent nucleotide ligands on dye-labeled cores to form polymerase-polymer-nucleotide complexes bound to clonal copies of DNA targets. These polymer-nucleotide substrates, termed avidites, decrease the required concentration of reporting nucleotides from micromolar to nanomolar and yield negligible dissociation rates. Avidity sequencing achieves high accuracy, with 96.2% and 85.4% of base calls having an average of one error per 1,000 and 10,000 base pairs, respectively. We show that the average error rate of avidity sequencing remained stable following a long homopolymer.

Sclerosing epithelioid fibrosarcoma of bone with hybrid features: clinicopathologic, radiologic, and molecular analysis of three cases.

Sclerosing epithelioid fibrosarcoma (SEF) occurring as a primary bone tumor is exceptionally uncommon. Even more rare are cases of SEF that show morphologic overlap with low-grade fibromyxoid sarcoma (LGFMS). Such hybrid lesions arising within the bone have only rarely been reported in the literature. Due to their variegated histomorphology and non-specific radiologic features, these tumors may pose diagnostic difficulties. Herein we describe three molecularly confirmed primary bone cases of sclerosing epithelioid fibrosarcoma that demonstrated prominent areas showing the features of LGFMS and with areas resembling so-called hyalinizing spindle cell tumor with giant rosettes (HSCTGR). Two patients were female and one was male aged 26, 47, and 16, respectively. The tumors occurred in the femoral head, clavicle, and temporal bone. Imaging studies demonstrated relatively well-circumscribed radiolucent bone lesions with enhancement on MRI. Cortical breakthrough and soft tissue extension were present in one case. Histologically the tumors all demonstrated hyalinized areas with SEF-like morphology as well as spindled and myxoid areas with LGFMS-like morphology. Two cases demonstrated focal areas with rosette-like architecture as seen in HSCTGR. The tumors were all positive for MUC4 by immunohistochemistry and cytogenetics, fluorescence in-situ hybridization, and next-generation sequencing studies identified EWSR1 gene rearrangements confirming the diagnosis in all three cases.Hybrid SEF is exceedingly rare as a primary bone tumor and can be difficult to distinguish from other low-grade spindled and epithelioid lesions of bone. MUC4 positivity and identification of underlying EWSR1 gene rearrangements help support this diagnosis and exclude other tumor types.

Diabetic Ketoacidosis and Acute Kidney Injury Associated With Enfortumab Vedotin for Urothelial Carcinoma: A Case Report.

Enfortumab vedotin is a novel breakthrough therapy that received accelerated US Food and Drug Administration approval in 2019 for the treatment of metastatic urothelial carcinoma in patients who have failed other lines of treatment. The characteristics of its adverse effects are not well understood. Diabetic ketoacidosis has been reported in 2 postmarketing reports presented as abstracts at the 2020 American Thoracic Society Conference and the 2021 American Society of Nephrology Conference. Both cases progressed rapidly and expired in <3 days. We present a similar case of a man in his late 50s with no history of diabetes who was diagnosed with urothelial carcinoma 2 years prior. Despite several lines of treatment, including platinum-based chemotherapy and immune checkpoint inhibitors, he developed metastasis and was started on enfortumab vedotin. After his second dose of enfortumab vedotin, he was admitted to the intensive care unit for diabetic ketoacidosis with an initial A1C level of 7.7%. He was intubated for airway protection, started on pressors, and developed oliguric acute kidney injury requiring continuous venovenous hemodialysis. Despite aggressive treatment, the patient died on hospital day 2. The lethality of this aggressive diabetic ketoacidosis despite therapy suggests some other effect of enfortumab vedotin on glucose metabolism in addition to insulin resistance and the need for prior diabetes screening.

Understanding the Anomalous Diffusion of Water in Aqueous Electrolytes Using Machine Learned Potentials.

The diffusivity of water in aqueous cesium iodide solutions is larger than that in neat liquid water and vice versa for sodium chloride solutions. Such peculiar ion-specific behavior, called anomalous diffusion, is not reproduced in typical force field based molecular dynamics (MD) simulations due to inadequate treatment of ion-water interactions. Herein, this hurdle is tackled by using machine learned atomic potentials (MLPs) trained on data from density functional theory calculations. MLP based atomistic MD simulations of aqueous salt solutions reproduce experimentally determined thermodynamic, structural, dynamical, and transport properties, including their varied trends in water diffusivities across salt concentration. This enables an examination of their intermolecular structure to unravel the microscopic underpinnings of the differences in their transport properties. While both ions in CsI solutions contribute to the faster diffusion of water molecules, the competition between the heavy retardation by Na ions and the slight acceleration by Cl ions in NaCl solutions reduces their water diffusivity.

Full-arch restoration with the NEXUS IOS® system: A retrospective clinical evaluation of 37 restorations after a one year of follow-up.

OBJECTIVES: Report the results with a novel workflow of digital restoration for completely edentulous patients with implant supported full arch fixed dental prostheses (ISFDP). METHODS: This multicenter retrospective clinical study was based on the evaluation from a cohort of 29 patients restored with 37 ISFDP designed and manufactured from the data captured by a direct intraoral scan, using a novel full digital system (NEXUS IOS®, Osteon Medical, a Keystone Dental Group company, Melbourne, Australia). Data was collected over a 3-year period, in six different dental centers. This study reported on the clinical parameters including: precision of marginal fit, functional and aesthetic integration of Nexus ISFDP. All patients were followed for a period of one year post delivery. Implant survival, biologic and prosthetic complications were assessed, at one year. A statistical analysis was conducted. RESULTS: All 37 ISFDP were deemed clinically acceptable on insertion. Implant survival at one year was 100 %. The biologic and prosthetic complications were minimal during the follow-up period. CONCLUSIONS: ISFDP, designed and manufactured using the NEXUS IOS® system, are clinically acceptable, with a low incidence of complications at one year. Long-term clinical studies are needed. STATEMENT OF CLINICAL RELEVANCE: Within the limitations of this study (retrospective design, small patient sample, limited follow-up) the NEXUS IOS® system seems to represent a viable solution for the restoration of completely edentulous patients with ISFDP, in a full digital workflow.

Antimicrobial Peptides (AMP) in the Cell-Free Culture Media of Xenorhabdus budapestensis and X. szentirmaii Exert Anti-Protist Activity against Eukaryotic Vertebrate Pathogens including Histomonas meleagridis and Leishmania donovani Species.

Anti-microbial peptides provide a powerful toolkit for combating multidrug resistance. Combating eukaryotic pathogens is complicated because the intracellular drug targets in the eukaryotic pathogen are frequently homologs of cellular structures of vital importance in the host organism. The entomopathogenic bacteria (EPB), symbionts of entomopathogenic-nematode species, release a series of non-ribosomal templated anti-microbial peptides. Some may be potential drug candidates. The ability of an entomopathogenic-nematode/entomopathogenic bacterium symbiotic complex to survive in a given polyxenic milieu is a coevolutionary product. This explains that those gene complexes that are responsible for the biosynthesis of different non-ribosomal templated anti-microbial protective peptides (including those that are potently capable of inactivating the protist mammalian pathogen Leishmania donovanii and the gallinaceous bird pathogen Histomonas meleagridis) are co-regulated. Our approach is based on comparative anti-microbial bioassays of the culture media of the wild-type and regulatory mutant strains. We concluded that Xenorhabdus budapestensis and X. szentirmaii are excellent sources of non-ribosomal templated anti-microbial peptides that are efficient antagonists of the mentioned pathogens. Data on selective cytotoxicity of different cell-free culture media encourage us to forecast that the recently discovered "easy-PACId" research strategy is suitable for constructing entomopathogenic-bacterium (EPB) strains producing and releasing single, harmless, non-ribosomal templated anti-microbial peptides with considerable drug, (probiotic)-candidate potential.

Why Dissolving Salt in Water Decreases Its Dielectric Permittivity.

The dielectric permittivity of salt water decreases on dissolving more salt. For nearly a century, this phenomenon has been explained by invoking saturation in the dielectric response of the solvent water molecules. Herein, we employ an advanced deep neural network (DNN), built using data from density functional theory, to study the dielectric permittivity of sodium chloride solutions. Notably, the decrease in the dielectric permittivity as a function of concentration, computed using the DNN approach, agrees well with experiments. Detailed analysis of the computations reveals that the dominant effect, caused by the intrusion of ionic hydration shells into the solvent hydrogen-bond network, is the disruption of dipolar correlations among water molecules. Accordingly, the observed decrease in the dielectric permittivity is mostly due to increasing suppression of the collective response of solvent waters.

Risk mitigation measures for pesticide runoff: How effective are they?

BACKGROUND: One of the most important sources of pesticide pollution of surface waters is runoff and erosion from agricultural fields after rainfall. This study analyses the efficacy of different risk mitigation measures to reduce pesticide runoff and erosion inputs into surface waters from arable land excluding rice fields. RESULTS: Three groups of risk mitigation measures were quantitatively analyzed: vegetative filter strips, micro-dams in row crops and soil conservation measures. Their effectiveness was evaluated based on a meta-analysis of available experimental data using statistical methods such as classification and regression trees, and exploratory data analysis. Results confirmed the effectiveness of vegetative filter strips and micro-dams. Contrary to common assumption, the width of vegetative filter strips alone is not sufficient to predict their effectiveness. The effectiveness of soil conservation measures (especially mulch-tillage) varied widely. This was in part due to the heterogeneity of the available experimental data, probably resulting from the inconsistent implementation and the inadequate definitions of these measures. CONCLUSION: Both vegetative filter strips and micro-dams are effective and suitable, and can therefore be recommended for quantitative assessment of environmental pesticide exposure in surface waters. However, the processes of infiltration and sedimentation in vegetative filter strips should be simulated with a mechanistic model like Vegetative Filter Strip Modeling System, VFSMOD. The reduction effect of micro-dams can be modelled by reducing the runoff curve number, e.g., in the pesticide root zone model, PRZM. Soil conservation measures are in principle promising, but further well-documented data are needed to determine under which conditions they are effective. © 2023 The Authors. Pest Management Science published by John Wiley & Sons Ltd on behalf of Society of Chemical Industry.

Ventricular Arrhythmias Associated With Over-the-Counter and Recreational Opioids.

BACKGROUND: Epidemic increases in opioid deaths prompted policies limiting access to prescription opioids in North America. Consequently, the over-the-counter opioids loperamide (Imodium A-D) and mitragynine, the herbal ingredient in kratom, are increasingly used to avert withdrawal or induce euphoria. Arrhythmia events related to these nonscheduled drugs have not been systematically studied. OBJECTIVES: In this study, we sought to explore opioid-associated arrhythmia reporting in North America. METHODS: The U.S. Food and Drug Administration Adverse Event Reporting System (FAERS), Center for Food Safety and Applied Nutrition Adverse Event Reporting System (CAERS), and Canada Vigilance Adverse Reaction (CVAR) databases were searched (2015-2021). Reports involving nonprescription drugs (loperamide, mitragynine) and diphenoxylate/atropine (Lomotil) were identified. Methadone, a prescription opioid (full agonist), served as a positive control owing to its established arrhythmia risk. Buprenorphine (partial agonist) and naltrexone (pure antagonist), served as negative controls. Reports were classified according to Medical Dictionary for Regulatory Activities terminology. Significant disproportionate reporting required a proportional reporting ratio (PRR) of ≥2, ≥3 cases, and chi-square ≥4. Primary analysis used FAERS data, whereas CAERS and CVAR data were confirmatory. RESULTS: Methadone was disproportionately associated with ventricular arrhythmia reports (PRR: 6.6; 95% CI: 6.2-7.0; n = 1,163; chi-square = 5,456), including 852 (73%) fatalities. Loperamide was also significantly associated with arrhythmia (PRR: 3.2; 95% CI: 3.0-3.4; n = 1,008; chi-square = 1,537), including 371 (37%) deaths. Mitragynine demonstrated the highest signal (PRR: 8.9; 95% CI: 6.7-11.7; n = 46; chi-square = 315), with 42 (91%) deaths. Buprenorphine, diphenoxylate, and naltrexone were not associated with arrhythmia. Signals were similar in CVAR and CAERS. CONCLUSIONS: The nonprescription drugs loperamide and mitragynine are associated with disproportionate reports of life-threatening ventricular arrhythmia in North America.

Primary prophylaxis of invasive fungal diseases in patients with haematological malignancies: 2022 update of the recommendations of the Infectious Diseases Working Party (AGIHO) of the German Society for Haematology and Medical Oncology (DGHO).

Patients with haematological malignancies (HM) are at high risk of developing invasive fungal disease (IFD) with high morbidity and attributable mortality. We reviewed data published until September 2021 to update the 2017 antifungal prophylaxis recommendations of the German Society of Haematology and Medical Oncology (DGHO). The strong recommendation to administer antifungal prophylaxis in patients with HM with long-lasting neutropenia, i.e. <500 cells/µL for >7 days remains unchanged. Posaconazole remains the drug of choice for mould-active prophylaxis in these patients. Novel treatment options in HM, such as CAR-T-cell treatment or novel targeted therapies for acute myeloid leukaemia (AML) were considered, however, data are insufficient to give general recommendations for routine antifungal prophylaxis in these patients. Major changes regarding specific recommendations compared to the 2017 edition are the now moderate instead of mild support for the recommendations of isavuconazole and voriconazole. Furthermore, published evidence on micafungin allows recommending it at moderate strength for its use in HM. For the first time we included recommendations for non-pharmaceutical measures regarding IFD, comprising the use of high-efficiency particulate air (HEPA) filters, smoking, measures during construction work and neutropenic diets. We reviewed the impact of antifungal prophylaxis with triazoles on drug-drug interactions with novel targeted therapies that are metabolized via cytochrome p450 where triazoles inhibit CYP3A4/5. The working group recommends reducing the dose of venetoclax when used concomitantly with strong CYP3A4 inhibiting antifungals. Furthermore, we reviewed data on the prophylactic use of novel antifungal agents. Currently there is no evidence to support their use in a prophylactic setting in clinical practice.

Ultra-rare complement factor 8 coding variants in families with age-related macular degeneration.

Genome-wide association studies have uncovered 52 independent common and rare variants across 34 genetic loci, which influence susceptibility to age related macular degeneration (AMD). Of the 5 AMD-associated complement genes, complement factor H (CFH) and CFI exhibit a significant rare variant burden implicating a major contribution of the complement pathway to disease pathology. However, the efforts for developing AMD therapy have been challenging as of yet. Here, we report the identification of ultra-rare variants in complement factors 8A and 8B, two components of the terminal complement membrane attack complex (MAC), by whole exome sequencing of a cohort of AMD families. The identified C8 variants impact local interactions among proteins of C8 triplex in vitro, indicating their effect on MAC stability. Our results suggest that MAC, and not the early steps of the complement pathway, might be a more effective target for designing treatments for AMD.

Immediate Implant Placement, Immediate Load With Same-Day Fully Digital Fabrication of a Screw-Retained Provisional Implant Prosthesis.

This article describes the use of technology capable of converting a failed dentition to a full-arch screw-retained implant-supported provisional restoration in one day using a fully digital restorative protocol. With this expedited digital treatment, the transition to a restored dentition is completed without the need for any physical impressions. Predicated on facially driven virtual smile designs, sophisticated engineering designs, complex algorithms, artificial intelligence, and novel laboratory and clinical workflows, the protocol allows for streamlined, same-day digital delivery of an in-house 3D-printed provisional prosthesis after implant placement surgery.