Neuroretinitis as a Complication of Cat Scratch Disease.

In this case report, a patient with neuroretinitis from a Bartonella henselae infection is described, and insights into methods to distinguish this type of case from more common etiologies of optic nerve edema are presented. A 21-year-old female with a history of right monocular vision loss due to amblyopia presented to the emergency department (ED) with occipital headache, fever, dizziness, nasal congestion, and painless blurry vision in the left eye for one day. A lumbar puncture found a slightly high opening pressure but no evidence of meningitis. The patient was diagnosed with a viral illness and discharged with outpatient follow-up. The patient, however, had persistent central vision loss and recurring headaches and returned to the ED. Subsequent ultrasound of the patient's optic nerve revealed significant optic nerve swelling. A new working diagnosis of idiopathic intracranial hypertension was made, and the patient was started on oral acetazolamide. On the next day, she was seen by ophthalmology, and recent scratches from her cat were noted on her arm. She tested positive for B. henselae and was started on doxycycline and rifampin. Nearly two weeks after the initial presentation, a macular star pattern, indicative of neuroretinitis, was noted on the fundoscopic exam. The patient had recovered her vision by three months later. In ED cases with unilateral vision loss, early use of point-of-care ultrasound and infection with B. henselae should always be considered. Early serology testing may be warranted to allow for earlier treatment since classic signs of neuroretinitis may not be apparent at the onset.

Reduction in animal abundance and oxygen availability during and after the end-Triassic mass extinction.

The end-Triassic biodiversity crisis was one of the most severe mass extinctions in the history of animal life. However, the extent to which the loss of taxonomic diversity was coupled with a reduction in organismal abundance remains to be quantified. Further, the temporal relationship between organismal abundance and local marine redox conditions is lacking in carbonate sections. To address these questions, we measured skeletal grain abundance in shallow-marine limestones by point counting 293 thin sections from four stratigraphic sections across the Triassic/Jurassic boundary in the Lombardy Basin and Apennine Platform of western Tethys. Skeletal abundance decreased abruptly across the Triassic/Jurassic boundary in all stratigraphic sections. The abundance of skeletal organisms remained low throughout the lower-middle Hettangian strata and began to rebound during the late Hettangian and early Sinemurian. A two-way ANOVA indicates that sample age (p < .01, η2  = 0.30) explains more of the variation in skeletal abundance than the depositional environment or paleobathymetry (p < .01, η2  = 0.15). Measured I/Ca ratios, a proxy for local shallow-marine redox conditions, show this same pattern with the lowest I/Ca ratios occurring in the early Hettangian. The close correspondence between oceanic water column oxygen levels and skeletal abundance indicates a connection between redox conditions and benthic organismal abundance across the Triassic/Jurassic boundary. These findings indicate that the end-Triassic mass extinction reduced not only the biodiversity but also the carrying capacity for skeletal organisms in early Hettangian ecosystems, adding to evidence that mass extinction of species generally leads to mass rarity among survivors.

Marine siliceous ecosystem decline led to sustained anomalous Early Triassic warmth.

In the wake of rapid CO2 release tied to the emplacement of the Siberian Traps, elevated temperatures were maintained for over five million years during the end-Permian biotic crisis. This protracted recovery defies our current understanding of climate regulation via the silicate weathering feedback, and hints at a fundamentally altered carbon and silica cycle. Here, we propose that the development of widespread marine anoxia and Si-rich conditions, linked to the collapse of the biological silica factory, warming, and increased weathering, was capable of trapping Earth's system within a hyperthermal by enhancing ocean-atmosphere CO2 recycling via authigenic clay formation. While solid-Earth degassing may have acted as a trigger, subsequent biotic feedbacks likely exacerbated and prolonged the environmental crisis. This refined view of the carbon-silica cycle highlights that the ecological success of siliceous organisms exerts a potentially significant influence on Earth's climate regime.

Characterisation of infections in patients with acute myeloid leukaemia receiving venetoclax and a hypomethylating agent.

We investigated the incidence of invasive fungal infections (IFIs) and other infectious complications in patients receiving venetoclax and hypomethylating agent therapy for acute myeloid leukaemia (AML). This retrospective, multicentre cohort study included adult patients with AML who received at least one cycle of venetoclax and either azacitidine or decitabine between January 2016 and August 2020. The primary outcome was the incidence of probable or confirmed IFI. Secondary outcomes included antifungal prophylaxis prescribing patterns, incidence of bacterial infections, and incidence of neutropenic fever hospital admissions. Among 235 patients, the incidence of probable or confirmed IFI was 5.1%. IFI incidence did not differ significantly according to age, antifungal prophylaxis use, or disease status. In the subgroup of patients with probable or confirmed IFIs, six (50%) were receiving antifungal prophylaxis at the time of infection. The overall incidence of developing at least one bacterial infection was 33.6% and 127 (54%) patients had at least one hospital admission for febrile neutropenia. This study demonstrated an overall low risk of developing probable or confirmed IFI as well as a notable percentage of documented bacterial infections and hospital admissions due to neutropenic fever.

Characterization of relapse patterns in patients with acute lymphoblastic leukemia treated with blinatumomab.

INTRODUCTION: Blinatumomab is a CD19/CD3 bispecific T-cell engager (BiTE) antibody that simultaneously binds CD19 on the surface of B-cells and CD3 on the surface of T-cells, resulting in tumor cell lysis. It is approved for the treatment of patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL) and in patients with minimal residual disease after intensive induction chemotherapy. Relapse patterns after treatment with blinatumomab have not been well characterized. METHODS: We reviewed patients treated with blinatumomab with relapsed, refractory or minimal residual disease-positive B-ALL from 1 December 2014 to 31 December 2018 at a single academic medical center. Patient demographics, blast percentage prior to blinatumomab initiation, prior lines of therapy, blinatumomab treatment duration, sites of relapse, progression free survival, and overall survival were collected. RESULTS: A total of 20 patients were identified. Four (20%) patients developed extramedullary relapse following blinatumomab. The median time from treatment initiation to extramedullary relapse was 179 days (range 47-241). Sites of extramedullary relapse included the pancreas, adrenal gland, kidneys, liver, parotid gland, and brain. CONCLUSION: Extramedullary relapse occurs frequently following treatment of B-ALL with blinatumomab. Further studies aimed at preventing extramedullary relapse following blinatumomab treatment are warranted.

IRX3/5 regulate mitotic chromatid segregation and limb bud shape.

Pattern formation is influenced by transcriptional regulation as well as by morphogenetic mechanisms that shape organ primordia, although factors that link these processes remain under-appreciated. Here we show that, apart from their established transcriptional roles in pattern formation, IRX3/5 help to shape the limb bud primordium by promoting the separation and intercalation of dividing mesodermal cells. Surprisingly, IRX3/5 are required for appropriate cell cycle progression and chromatid segregation during mitosis, possibly in a nontranscriptional manner. IRX3/5 associate with, promote the abundance of, and share overlapping functions with co-regulators of cell division such as the cohesin subunits SMC1, SMC3, NIPBL and CUX1. The findings imply that IRX3/5 coordinate early limb bud morphogenesis with skeletal pattern formation.

Evaluation of pharmacist interventions in a head and neck medical oncology clinic.

INTRODUCTION: Head and neck cancers (HNC) are a complex and heterogeneous group of cancers, often necessitating a multidisciplinary approach across the care continuum. Oncology pharmacists are uniquely qualified to play a vital role on a multidisciplinary team and provide specialized care to optimize medication therapy. METHODS: This was a retrospective chart review evaluating the role of a board-certified oncology pharmacist in the head and neck oncology clinic at an academic, comprehensive cancer center from April 2017 through March 2018. The primary objective of the study was to describe the types of interventions made by the oncology pharmacists. Secondary objectives included quantifying time spent on patient education and number of prescriptions sent to pharmacies. RESULTS: The pharmacist had 873 encounters with 151 patients, resulting in 2080 interventions. Approximately 57% of the interventions were performed in the clinic. Patient education (58%), facilitation of new prescriptions or refill requests (49.9%), and supportive care management (32.6%) were the most frequent interventions. The oncology pharmacist spent 154.1 h on patient education and sent 811 prescriptions to pharmacies, with 63.6% of prescriptions sent to the institution's cancer center pharmacy. CONCLUSION: The incorporation of an oncology pharmacist in the HNC team optimized patient care through comprehensive and timely interventions across the care continuum. Our study is the first to highlight the vital role oncology pharmacists have in improving the overall quality of care of HNC patients. Future directions include exploring the impact of oncology pharmacist interventions on select Quality Oncology Practice Initiative measures by the American Society of Clinical Oncology.

Pegaspargase-induced hypertriglyceridemia in a patient with acute lymphoblastic leukemia.

Pegaspargase, a long acting formulation of L-asparaginase, is an asparagine specific enzyme that selectively kills leukemic cells by depleting plasma asparagine. Pegaspargase is FDA approved for the first-line treatment of adult acute lymphoblastic leukemia and is a critical component of numerous multi-chemotherapeutic regimens. Pegaspargase is associated with well-described toxicities including hypersensitivity reactions, hepatotoxicity, and thrombosis. However, hypertriglyceridemia is a much rarer complication of pegaspargase and has only been described in a limited number of reports. We present a case of severe hypertriglyceridemia after a single dose of pegaspargase. The patient was re-challenged with pegaspargase and again developed hypertriglyceridemia which was complicated by pancreatitis. Here, we summarize published reports and a literature review describing the incidence of pegaspargase-induced hypertriglyceridemia in common acute lymphoblastic leukemia protocols.

Outcomes of Inpatient Administration of Restricted Antineoplastic Medications at a Large Academic Medical Institution.

BACKGROUND: Restricting oncology and hematology medications to outpatient infusion centers may be considered when infrequent administration is required, a low risk of serious adverse effects exists, or when prompt amelioration of a condition is not expected. At the University of California, San Diego (UCSD), we created a new formulary status for medications designated "formulary, outpatient-restricted use only." This designation could optimize payer reimbursement, as well as improve patient comfort, by negating the need for inpatient admission. When the inpatient administration of a restricted medication is requested at UCSD, there ensues a loosely defined review process involving an informal conversation between the requesting prescriber and the oncology pharmacy and therapeutics (P&T) chair. Patient outcomes associated with this formulary status and informal request process are limited. The purpose of this study is to describe the use of formulary, outpatient-restricted oncology and hematology medications in the inpatient setting at a single-center, academic, and comprehensive cancer center. METHODS: A retrospective chart review was conducted between January 1, 2015 and May 1, 2017. The primary outcome was to determine the percentage of formulary, outpatient-restricted oncology or hematology medications that were administered in the inpatient setting and continued to the outpatient setting. Secondary outcomes included overall survival, hospice enrollment, disease progression status, level of evidence supporting the medication usage, and cost. RESULTS: Twenty-three patients and 24 outpatient-restricted medications met the inclusion criteria. Thirteen (54%) medications were continued upon discharge and eight (33%) were not continued in the outpatient setting. Five of those eight medications were discontinued as a result of patient death. CONCLUSION: In this single-center study, approximately one-third of the outpatient-restricted medications were not continued upon discharge. The findings suggest that our informal approval process could result in the suboptimal use of formulary outpatient-restricted medications for oncology and hematology indications. A more formalized request process might lead to the more effective utilization of these medications.

Oscillatory cortical forces promote three dimensional cell intercalations that shape the murine mandibular arch.

Multiple vertebrate embryonic structures such as organ primordia are composed of confluent cells. Although mechanisms that shape tissue sheets are increasingly understood, those which shape a volume of cells remain obscure. Here we show that 3D mesenchymal cell intercalations are essential to shape the mandibular arch of the mouse embryo. Using a genetically encoded vinculin tension sensor that we knock-in to the mouse genome, we show that cortical force oscillations promote these intercalations. Genetic loss- and gain-of-function approaches show that Wnt5a functions as a spatial cue to coordinate cell polarity and cytoskeletal oscillation. These processes diminish tissue rigidity and help cells to overcome the energy barrier to intercalation. YAP/TAZ and PIEZO1 serve as downstream effectors of Wnt5a-mediated actomyosin polarity and cytosolic calcium transients that orient and drive mesenchymal cell intercalations. These findings advance our understanding of how developmental pathways regulate biophysical properties and forces to shape a solid organ primordium.

Isotopic Fingerprint of Uranium Accumulation and Redox Cycling in Floodplains of the Upper Colorado River Basin.

Uranium (U) groundwater contamination is a major concern at numerous former mining and milling sites across the Upper Colorado River Basin (UCRB), USA, where U(IV)-bearing solids have accumulated within naturally reduced zones (NRZs). Understanding the processes governing U reduction and oxidation within NRZs is critical for assessing the persistence of U in groundwater. To evaluate the redox cycling of uranium, we measured the U concentrations and isotopic compositions (δ238U) of sediments and pore waters from four study sites across the UCRB that span a gradient in sediment texture and composition. We observe that U accumulation occurs primarily within fine-grained (low-permeability) NRZs that show active redox variations. Low-permeability NRZs display high accumulation and low export of U, with internal redox cycling of U. In contrast, within high-permeability NRZs, U is remobilized under oxidative conditions, possibly without any fractionation, and transported outside the NRZs. The low δ238U of sediments outside of defined NRZs suggests that these reduced zones act as additional U sources. Collectively, our results indicate that fine-grained NRZs have a greater potential to retain uranium, whereas NRZs with higher permeability may constitute a more-persistent but dilute U source.

Bacterio- and Isobacteriodilactones by Stepwise or Direct Oxidations of meso-Tetrakis(pentafluorophenyl)porphyrin.

Porpholactones are porphyrinoids in which one or more ß,ß'-bonds of the parent chromophore were replaced by lactone moieties. Accessible to varying degrees by direct and nonselective oxidations of porphyrins, the rational syntheses of all five dilactone isomers along stepwise, controlled, and high-yielding routes via porphyrin → tetrahydroxyisobacteriochlorin metal complexes → isobacteriochlorindilactone metal complexes or porphyrin → tetrahydroxybacteriochlorin → bacteriochlorindilactone (and related) pathways, respectively, are described. A major benefit of these complementary routes over established methods is the simplicity of the isolation of the dilactones because of the reduced number of side products formed. In an alternative approach we report the direct and selective conversion of free base meso-tetrakis(pentafluorophenyl)porphyrin to all isomers of free base isobacteriodilactones using the oxidant cetyltrimethylN+MnO4-. The solid-state structures of some of the isomers and their precursors are reported, providing data on the conformational modulation induced by the derivatizations. We also rationalize computationally their differing thermodynamic stability and electronic properties. In making new efficient routes toward these dilactone isomers available, we enable the further study of this diverse class of porphyrinoids.

The Iroquois homeobox proteins IRX3 and IRX5 have distinct roles in Wilms tumour development and human nephrogenesis.

Wilms tumour is a paediatric malignancy with features of halted kidney development. Here, we demonstrate that the Iroquois homeobox genes IRX3 and IRX5 are essential for mammalian nephrogenesis and govern the differentiation of Wilms tumour. Knock-out Irx3- /Irx5- mice showed a strongly reduced embryonic nephron formation. In human foetal kidney and Wilms tumour, IRX5 expression was already activated in early proliferative blastema, whereas IRX3 protein levels peaked at tubular differentiation. Accordingly, an orthotopic xenograft mouse model of Wilms tumour showed that IRX3-/- cells formed bulky renal tumours dominated by immature mesenchyme and active canonical WNT/ß-catenin-signalling. In contrast, IRX5-/- cells displayed activation of Hippo and non-canonical WNT-signalling and generated small tumours with abundant tubulogenesis. Our findings suggest that promotion of IRX3 signalling or inhibition of IRX5 signalling could be a route towards differentiation therapy for Wilms tumour, in which WNT5A is a candidate molecule for enforced tubular maturation. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

Mechanical stability of the cell nucleus - roles played by the cytoskeleton in nuclear deformation and strain recovery.

Extracellular forces transmitted through the cytoskeleton can deform the cell nucleus. Large nuclear deformations increase the risk of disrupting the integrity of the nuclear envelope and causing DNA damage. The mechanical stability of the nucleus defines its capability to maintain nuclear shape by minimizing nuclear deformation and allowing strain to be minimized when deformed. Understanding the deformation and recovery behavior of the nucleus requires characterization of nuclear viscoelastic properties. Here, we quantified the decoupled viscoelastic parameters of the cell membrane, cytoskeleton, and the nucleus. The results indicate that the cytoskeleton enhances nuclear mechanical stability by lowering the effective deformability of the nucleus while maintaining nuclear sensitivity to mechanical stimuli. Additionally, the cytoskeleton decreases the strain energy release rate of the nucleus and might thus prevent shape change-induced structural damage to chromatin.

Genetic interaction between Gli3 and Ezh2 during limb pattern formation.

Anteroposterior polarity of the early limb bud is essential for proper skeletal pattern formation. In order to establish anterior identity, hedgehog signalling needs to be repressed by GLI3 repressor activity, although the mechanism of repression is not well defined. Here we describe genetic interaction between Gli3 and Enhancer of Zeste 2 (Ezh2) that encodes the histone methyltransferase subunit of Polycomb Repressive Complex 2. Loss of anterior limb identity was evident in both Gli3 and conditional Ezh2 single mutant embryos. This phenotype was enhanced in Ezh2;Gli3 double mutant embryos, but more closely resembled that of Ezh2 single mutants. Absent anterior skeletal elements in the Ezh2 mutant background were not rescued by either reduction of Gli activator or forced expression of Gli repressor. The data imply that Ezh2 is epistatic to Gli3 and suggest the possibility that hedghehog activation is repressed by the recruitment of polycomb repressive complex 2.

Multiple episodes of extensive marine anoxia linked to global warming and continental weathering following the latest Permian mass extinction.

Explaining the ~5-million-year delay in marine biotic recovery following the latest Permian mass extinction, the largest biotic crisis of the Phanerozoic, is a fundamental challenge for both geological and biological sciences. Ocean redox perturbations may have played a critical role in this delayed recovery. However, the lack of quantitative constraints on the details of Early Triassic oceanic anoxia (for example, time, duration, and extent) leaves the links between oceanic conditions and the delayed biotic recovery ambiguous. We report high-resolution U-isotope (δ238U) data from carbonates of the uppermost Permian to lowermost Middle Triassic Zal section (Iran) to characterize the timing and global extent of ocean redox variation during the Early Triassic. Our δ238U record reveals multiple negative shifts during the Early Triassic. Isotope mass-balance modeling suggests that the global area of anoxic seafloor expanded substantially in the Early Triassic, peaking during the latest Permian to mid-Griesbachian, the late Griesbachian to mid-Dienerian, the Smithian-Spathian transition, and the Early/Middle Triassic transition. Comparisons of the U-, C-, and Sr-isotope records with a modeled seawater PO43- concentration curve for the Early Triassic suggest that elevated marine productivity and enhanced oceanic stratification were likely the immediate causes of expanded oceanic anoxia. The patterns of redox variation documented by the U-isotope record show a good first-order correspondence to peaks in ammonoid extinctions during the Early Triassic. Our results indicate that multiple oscillations in oceanic anoxia modulated the recovery of marine ecosystems following the latest Permian mass extinction.

Early Earth and the rise of complex life.

The history of life on Earth progressed in parallel with the evolving oxygen state of the atmosphere and oceans, but the details of that relationship remain poorly known and debated. There is, however, general agreement that the first appreciable and persistent accumulation of oxygen in the oceans and atmosphere occurred around 2.3 to 2.4 billion years ago. Following this Great Oxidation Event, biospheric oxygen remained at relatively stable intermediate levels for more than a billion years. Much current research focuses on the transition from the intermediate conditions of this middle chapter in Earth history to the more oxygenated periods that followed - often emphasizing whether increasing and perhaps episodic oxygenation drove fundamental steps in the evolution of complex life and, if so, when. These relationships among early organisms and their environments are the thematic threads that stitch together the papers in this collection. Expert authors bring a mix of methods and opinions to their leading-edge reviews of the earliest proliferation and ecological impacts of eukaryotic life, the subsequent emergence and ecological divergence of animals, and the corresponding causes and consequences of environmental change.

Cell and Tissue Scale Forces Coregulate Fgfr2-Dependent Tetrads and Rosettes in the Mouse Embryo.

What motivates animal cells to intercalate is a longstanding question that is fundamental to morphogenesis. A basic mode of cell rearrangement involves dynamic multicellular structures called tetrads and rosettes. The contribution of cell-intrinsic and tissue-scale forces to the formation and resolution of these structures remains unclear, especially in vertebrates. Here, we show that Fgfr2 regulates both the formation and resolution of tetrads and rosettes in the mouse embryo, possibly in part by spatially restricting atypical protein kinase C, a negative regulator of non-muscle myosin IIB. We employ micropipette aspiration to show that anisotropic tension is sufficient to rescue the resolution, but not the formation, of tetrads and rosettes in Fgfr2 mutant limb-bud ectoderm. The findings underscore the importance of cell contractility and tissue stress to multicellular vertex formation and resolution, respectively.