UNITED KINGDOM DATABASE STUDY OF INTRAVITREAL DEXAMETHASONE IMPLANT (OZURDEX) FOR MACULAR EDEMA RELATED TO RETINAL VEIN OCCLUSION.

PURPOSE: To study the treatment patterns, visual outcomes and safety profile of intravitreal dexamethasone implant (IDI) used for the treatment of macular edema secondary to retinal vein occlusion. METHODS: Up to 2 years of routinely collected anonymized data within electronic medical record systems were remotely extracted from 16 centers. The outcome measures include visual outcome, number of injections, and safety measures, including the rate of intraocular pressure (IOP) rise, frequency of IOP-lowering medication usage, and cataract surgery rates. RESULTS: The study included 688 eyes (44.4%) with central retinal vein occlusion and 862 eyes (55.6%) with branch retinal vein occlusion; 1,250 eyes (80.6%) were treatment naive and 28% (275/989) had high IOP or were on IOP-lowering medications before IDI use. It was found that 31% (476) of eyes received two injections, and 11.7% (182) and 3.7% (58) of eyes received three and four injections, respectively. The mean baseline Snellen visual acuity improved from 20/125 to 20/40 after the first injection. The probability of cataract surgery was 15% at 24 months. The proportion of eyes with ≥10 mmHg change from baseline was higher in phakic (14.2%) compared with pseudophakic eyes (5.4%, P = 0.004). Three eyes required IOP filtering surgery (0.2%). CONCLUSION: The visual results of IDI in eyes with macular edema secondary to retinal vein occlusion in the real world are comparable to those of clinical trial setting. Increased IOP in eyes with preexisting ocular hypertension or glaucoma can be controlled with additional medical treatment. Intraocular pressure rise with IDI may be more frequent in phakic than in pseudophakic eyes.

COVID-19 and emergency department volume: The patients return but have different characteristics.

BACKGROUND: The COVID-19 pandemic has altered behaviors in the general population, as well as processes in the healthcare industry. Patients may be afraid to pursue care in the emergency department (ED) due to perceived risk of infection. The objective of this study was to determine the impact of COVID-19 on ED metrics. METHODS: At one metropolitan trauma center ED, we conducted a review of all visits from February to May in 2020 and compared findings with the same months from 2019. RESULTS: A total of 34,213 ED visits occurred during the study periods (18,471 in 2019 and 15,742 in 2020), with a decline in patient visits occurring after state emergency declarations. In 2020, patients were less likely to be female and more likely to arrive by ambulance. Diagnoses in the musculoskeletal, neurologic, and genitourinary categories occurred in lower proportions in 2020; toxicology, psychiatry, and infectious diseases occurred in higher proportions. In contrast to other insurance categories, Medicare patients comprised a larger share of ED visits in 2020 compared to 2019. DISCUSSION: Despite relatively low local prevalence of COVID-19, we report decreases in ED volume for some medical diagnosis categories. A volume rebound occurred in May 2020, but did not reach 2019 levels. Public health officials should encourage local populations to seek emergency care when concerned, and could consider programs to provide transportation. Patients should continue to protect themselves with social distancing and masks.

Float like a Butterfly, Sting like One Too.

Rash after contact with butterflies has not been previously reported in the medical literature to our knowledge. We describe potentially the first suspected case of a cutaneous reaction to the Compton tortoiseshell butterfly (Nymphalis vaualbum) in a young boy who developed urticaria after the modified hairs of the butterfly embedded within his finger. His urticaria improved through treatment with oral and topical steroids as well as systemic antihistamines. This case report expands the variety of insect species that may cause human disease and should raise awareness for this possible reaction.

Sestd1 Encodes a Developmentally Dynamic Synapse Protein That Complexes With BCR Rac1-GAP to Regulate Forebrain Dendrite, Spine and Synapse Formation.

SEC14 and Spectrin domain-1 (Sestd1) is a synapse protein that exhibits a striking shift from the presynaptic to postsynaptic space as neurons mature postnatally in the mouse hippocampus. Hippocampal pyramidal neurons from mice with global genetic deletion of Sestd1 have reduced dendrite arbors, spines, and excitatory synapses. Electrophysiologically this correlates with cell-autonomous reductions in both AMPA- and NMDA-excitatory postsynaptic currents in individual hippocampal neurons from which Sestd1 has been deleted in vivo. These neurodevelopmental and functional deficits are associated with increased activation of the Rho family GTPases Rac1 and RhoA. Co-immunoprecipitation and mass spectrometry reveal that the Breakpoint Cluster Region protein, a Rho GTPase activating protein (GAP), forms complexes with Sestd1 in brain tissue. This complements earlier findings that Sestd1 can also partner with other Rho family GAPs and guanine nucleotide exchange factors. Our findings demonstrate that Sestd1 is a developmentally dynamic synaptic regulator of Rho GTPases that contributes to dendrite and excitatory synapse formation within differentiating pyramidal neurons of the forebrain.

Patients with Abrasion or Ecchymosis Seat Belt Sign Have High Risk for Abdominal Injury, but Initial Computed Tomography is 100% Sensitive.

BACKGROUND: Trauma providers seek to accurately assess the risk of patients with abdominal seat belt sign (ASBS). As hospital costs continue to rise, identification of strategies to safely discharge emergency department (ED) patients has become crucial. OBJECTIVES: The purpose of this study is to 1) describe a large cohort of patients by type of ASBS and 2) determine the value of computed tomography (CT) of the abdomen and pelvis as a screening tool to rule out intra-abdominal injury (IAI) and support discharge of stable patients. METHODS: We conducted a retrospective case series of all patients presenting to our urban, Level I trauma center from 2013-2015. We studied motor vehicle collision patients who presented with ASBS. We further classified individuals into ASBS groups: Abrasion, Ecchymosis, Abrasion + Ecchymosis, or Unknown ASBS to examine differences between groups. RESULTS: In one of the largest described cohorts, the ASBS remained associated with IAI, most commonly, solid organ injury. Of 425 patients, 36.1% had some IAI on CT, but only 13.6% required laparotomy. Categorizing the type of skin injury in ASBS, we found that both abrasion and ecchymosis were associated with IAI. Initial CT performed with 100% sensitivity. CONCLUSIONS: This study shows that ED trauma patients with significant seat belt abrasion or contusion can have IAI. With the very high sensitivity of modern abdominal CT scanners, clinicians could consider safe ED discharge of stable ASBS patients while providing strong return precautions. Our large cohort strengthens the evidence on decision-making in ASBS patients to ensure outcomes and use of health care resources.

Meiotic onset is reliant on spatial distribution but independent of germ cell number in the mouse ovary.

Mouse ovarian germ cells enter meiosis in a wave that propagates from anterior to posterior, but little is known about contribution of germ cells to initiation or propagation of meiosis. In a Ror2 mutant with diminished germ cell number and migration, we find that overall timing of meiotic initiation is delayed at the population level. We use chemotherapeutic depletion to exclude a profoundly reduced number of germ cells as a cause for meiotic delay. We rule out sex reversal or failure to specify somatic support cells as contributors to the meiotic phenotype. Instead, we find that anomalies in the distribution of germ cells as well as gonad shape in mutants contribute to aberrant initiation of meiosis. Our analysis supports a model of meiotic initiation via diffusible signal(s), excludes a role for germ cells in commencing the meiotic wave and furnishes the first phenotypic demonstration of the wave of meiotic entry. Finally, our studies underscore the importance of considering germ cell migration defects while studying meiosis to discern secondary effects resulting from positioning versus primary meiotic entry phenotypes.

Bevacizumab for treatment of choroidal neovascularization secondary to candida chorioretinitis.

PURPOSE: To report a case of juxtafoveal choroidal neovascularization in a patient with candida chorioretinitis successfully treated with intravitreal bevacizumab. METHODS: Case report. RESULTS: A 45-year-old woman previously treated for candida chorioretinitis was presented with reduced vision in the left eye. The patient was investigated with ophthalmoscopy, fluorescein angiography, and optical coherence tomography (OCT). Following initial treatment, fundus examination, fluorescein angiography, and OCT of the right eye revealed a secondary juxtafoveal classic choroidal neovascularization. Following a single intravitreal injection of bevacizumab, the patient had excellent visual recovery, with absence of subretinal or intraretinal fluid in the OCT. CONCLUSIONS: Bevacizumab was effective in treatment of choroidal neovascularization associated with candida chorioretinitis.

Comparison of Weight-Based Dose vs. Standard Dose Diltiazem in Patients with Atrial Fibrillation Presenting to the Emergency Department.

BACKGROUND: Despite evidence-based recommended weight-based (WB) dosing of diltiazem for the initial treatment of atrial fibrillation (AF) with rapid ventricular response (RVR), many providers utilize lower initial doses of diltiazem. OBJECTIVE: We sought to determine whether a low, standard dose of diltiazem is noninferior to WB diltiazem as an initial bolus dose in the treatment of AF with RVR. METHODS: This retrospective review included patients who presented to the emergency department (ED) of an urban, academic tertiary medical center experiencing AF with RVR from November 2010 to August 2014. Adult patients were categorized by the dose of diltiazem received; 10 mg standard dose or 0.2-0.3 mg/kg WB dose. The primary outcome of successful treatment was defined as a composite of the following parameters 15 min after the initial bolus dose: heart rate (HR) < 100 beats/min, reduction of HR ≥ 20%, or a conversion to normal sinus rhythm. RESULTS: Four hundred and fifty-six patients who received diltiazem were included for study evaluation (standard dose: n = 255 patients, WB: n = 201 patients). Baseline characteristics, medical history, and medication use before ED presentation were similar between the groups. Significant differences at baseline between the groups included weight and HR at presentation. The primary outcome of successful treatment was attained in 60.8% of the standard dose patients and 68.7% of the WB patients (p = 0.082). CONCLUSIONS: In patients presenting to the ED, we found that standard dose diltiazem was noninferior to WB dosing in the initial treatment of AF with RVR.

Michaelis-like complex of mouse ketohexokinase isoform C.

Over the past forty years there has been a drastic increase in fructose-related diseases, including obesity, heart disease and diabetes. Ketohexokinase (KHK), the first enzyme in the liver fructolysis pathway, catalyzes the ATP-dependent phosphorylation of fructose to fructose 1-phosphate. Understanding the role of KHK in disease-related processes is crucial for the management and prevention of this growing epidemic. Molecular insight into the structure-function relationship in ligand binding and catalysis by KHK is needed for the design of therapeutic inhibitory ligands. Ketohexokinase has two isoforms: ketohexokinase A (KHK-A) is produced ubiquitously at low levels, whereas ketohexokinase C (KHK-C) is found at much higher levels, specifically in the liver, kidneys and intestines. Structures of the unliganded and liganded human isoforms KHK-A and KHK-C are known, as well as structures of unliganded and inhibitor-bound mouse KHK-C (mKHK-C), which shares 90% sequence identity with human KHK-C. Here, a high-resolution X-ray crystal structure of mKHK-C refined to 1.79 Šresolution is presented. The structure was determined in a complex with both the substrate fructose and the product of catalysis, ADP, providing a view of the Michaelis-like complex of the mouse ortholog. Comparison to unliganded structures suggests that KHK undergoes a conformational change upon binding of substrates that places the enzyme in a catalytically competent form in which the ß-sheet domain from one subunit rotates by 16.2°, acting as a lid for the opposing active site. Similar kinetic parameters were calculated for the mouse and human enzymes and indicate that mice may be a suitable animal model for the study of fructose-related diseases. Knowledge of the similarity between the mouse and human enzymes is important for understanding preclinical efforts towards targeting this enzyme, and this ground-state, Michaelis-like complex suggests that a conformational change plays a role in the catalytic function of KHK-C.

Altered gene expression patterns in muscle ring finger 1 null mice during denervation- and dexamethasone-induced muscle atrophy.

Muscle atrophy can result from inactivity or unloading on one hand or the induction of a catabolic state on the other. Muscle-specific ring finger 1 (MuRF1), a member of the tripartite motif family of E3 ubiquitin ligases, is an essential mediator of multiple conditions inducing muscle atrophy. While most studies have focused on the role of MuRF1 in protein degradation, the protein may have other roles in regulating skeletal muscle mass and metabolism. We therefore systematically evaluated the effect of MuRF1 on gene expression during denervation and dexamethasone-induced atrophy. We find that the lack of MuRF1 leads to few differences in control animals, but there were several significant differences in specific sets of genes upon denervation- and dexamethasone-induced atrophy. For example, during denervation, MuRF1 knockout mice showed delayed repression of metabolic and structural genes and blunted induction of genes associated with the neuromuscular junction. In the latter case, this pattern correlates with blunted HDAC4 and myogenin upregulation. Lack of MuRF1 caused fewer changes in the dexamethasone-induced atrophy program, but certain genes involved in fat metabolism and intracellular signaling were affected. Our results demonstrate a new role for MuRF1 in influencing gene expression in two important models of muscle atrophy.

Aligning an emergency department hepatitis C and human immunodeficiency virus testing quality improvement initiative with universal screening recommendations.

Objective: The interactions among hepatitis C virus (HCV), human immunodeficiency virus (HIV), and the ongoing injection drug epidemic have created a syndemic that significantly affects the Appalachian region of the United States. The purpose of this work is to describe a successful Kentucky program that aimed to increase HCV and HIV testing for people visiting an urban emergency department (ED) who were screened, diagnosed, and linked to care after diagnosis with special consideration for substance use disorder. Methods: The Plan-Do-Study-Act model for quality improvement was used to create a streamlined process for testing, reporting results, and linking people to care. The program was refined and expanded across 3 phases. Results: Across all phases, a total of 25,685 patients were eligible for testing and did not opt out. Of those, 17,090 had HCV antibody (Ab) testing; 3460 (20.2%) had HCV Ab; 1750 (50.8%) had HCV RNA, and an average of 31% of patients were linked to care within 30 days. The program found 54 new cases of HIV infection. Conclusions: Universal HCV and HIV testing and linkage to care is possible within an ED. In areas affected by the syndemic, EDs may serve as a public health safety net to identify affected individuals and ensure they receive follow-up care. Testing in this center uncovered an exceptionally high prevalence of HCV infection and new HIV case identification.

Review and update of central serous chorioretinopathy.

PURPOSE OF REVIEW: Greater understanding of central serous chorioretinopathy (CSCR) has changed initial beliefs that CSCR is a benign condition affecting young men with almost complete resolution. CSCR has a spectrum of presentations with more diffuse retinal dysfunction and variations between races. CSCR can affect older individuals and in a subset of patients may lead to significant ocular morbidity. RECENT FINDINGS: Advances in imaging, particularly in indocyanine green angiography and optical coherence tomography, have led to a greater understanding of the pathophysiology of this condition. Treatments for CSCR are still evolving, in particular photodynamic dynamic therapy using lower doses and reduced fluence showing promising results. More research is required on ideal dosage. Anti-vascular endothelial growth factor treatment offers a new medical treatment modality with promising results. SUMMARY: There have been recent imaging developments in addition to therapeutic advances for refractory CSCR.

Management of upper eyelid cicatricial entropion.

PURPOSE: There is a paucity of published data on the management of upper eyelid cicatricial entropion. We report on our results using such techniques as lamella repositioning, recession or augmentation and terminal tarsal rotation. DESIGN: Observational retrospective case series. PARTICIPANTS: Consecutive cases of upper eyelid cicatricial entropion of two specialist oculoplastic centres (Corneoplastic Unit, East Grinstead, UK and South Australian Institute of Ophthalmology, Adelaide, Australia) were reviewed over a 7-year period. METHODS: All patients underwent anterior lamellar repositioning or terminal tarsal rotation. MAIN OUTCOME MEASURES: Success was defined by two definitions: anatomical success was defined where the lid margin was restored to its normal position. Complete success was defined where there were no eyelashes touching the globe. Gain or loss (≤ or ≥2 Snellen lines) in best corrected visual acuity using a Snellen chart and resolution of any corneal epitheliopathy at final follow-up were also recorded (as graded by experienced oculoplastic consultants). RESULTS: Fifty-two procedures were performed on 41 patients (11 bilateral). All patients underwent either an anterior lamellar repositioning or a terminal tarsal rotation. Trachoma, previous upper lid surgery, Stevens-Johnson syndrome and meibomian gland dysfunction were the commonest underlying diagnoses. Ninety-eight per cent of the group had a normal anatomical lid position at follow-up. Nine eyelids (17%) of the group had recurrence of trichiasis. CONCLUSION: This large case series demonstrates that upper eyelid cicatricial entropion is managed effectively utilizing procedures that involve recession and reposition. We recommend that excision of tissue is avoided, especially in pathology that has a progressive immunological cicatricial drive.

Pseudohyperkalemia and the Need for Imperative Caution With the Newly Introduced Potent Potassium Binders: Two Cases.

Pseudohyperkalemia was first reported in 1955 by Hartmann and Mellinkoff, as a marked elevation of serum potassium in the absence of clinical evidence of electrolyte imbalance - simultaneous serum potassium exceeds plasma potassium by >0.4 mmol/L. We describe two patients with pseudohyperkalemia who inadvertently received inappropriate potassium binder therapy for weeks to months before the diagnosis of pseudohyperkalemia was entertained and subsequently confirmed. Potassium binders ultimately were promptly discontinued once the diagnosis of pseudohyperkalemia was confirmed. Physicians' attention must be drawn to the availability of the new potent oral potassium binders, patiromer and sodium zirconium cyclosilicate. We strongly advocate for imperative caution with these new binders. Iatrogenic life-threatening hypokalemia remains a real concern and must be avoided. Our patients highlighted the importance of caution in the use of the newer potent potassium binders to mitigate against the causation of iatrogenic hypokalemia. Also as important is the observation that in the same patient, with changing clinical scenarios, a patient might exhibit true hyperkalemia that alternated with pseudohyperkalemia, the first of such a report.

The reliability of saliva for the detection of SARS-CoV-2 in symptomatic and asymptomatic patients: Insights on the diagnostic performance and utility for COVID-19 screening.

Current literature has focused on testing saliva in symptomatic patients, and little information is available regarding saliva performance in asymptomatic severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection. We compared paired saliva and nasopharyngeal swabs (NPS) collected from 33 symptomatic and 12 asymptomatic known SARS-CoV-2-positive patients. Saliva had an overall sensitivity of 59%, a specificity of 95%, and a negative predictive value of 98%. Saliva demonstrated higher sensitivity in symptomatic (80%) vs. asymptomatic individuals (36%) (P = 0.006), and in high-risk (symptomatic, febrile and/or with comorbidities) (82%) vs. low-risk (asymptomatic, afebrile, and no comorbidities) (22%) patients (P = 0.0002). Cycle threshold (Ct) values in NPS specimens were higher in saliva-negative vs. saliva-positive cases (P = 0.02 and <0.001). Overall, these findings show that despite saliva's low sensitivity in asymptomatic SARS-CoV-2 infections, it can detect infections with lower Ct values and a potentially higher chance of viral transmission. Additional studies are warranted to fully evaluate saliva as a screening test for coronavirus disease-2019.

Systemic corticosteroid use in UK Uveitis practice: results from the ocular inflammation steroid toxicity risk (OSTRICH) study.

OBJECTIVES: To ascertain adherence to an international consensus target of ≤7.5 mg/day of prednisolone for maintenance systemic corticosteroid (CS) prescribing in uveitis and report the frequency of courses of high-dose systemic CS in the UK. METHODS: We conducted a national, multicentre audit of systemic CS prescribing for uveitis at 11 UK sites between November 2018 and March 2019. High-dose CS was defined as (1) maintenance >7.5 mg prednisolone for >3 consecutive months, or (2) >1 course ≥40 mg oral CS or ≥500 mg intravenous (IV) methylprednisolone in the past 12 months. Case notes of patients exceeding threshold CS doses were reviewed by an independent uveitis specialist and judged as avoidable or not, based upon a scoring matrix. RESULTS: Of 667 eligible patients, 285 (42.7%) were treated with oral or IV CS over the preceding 12 months; 96 (33.7%) of these exceeded the threshold for high-dose CS. Twenty-five percent of prescribing in patients on excess CS was judged avoidable; attributed to either prescribing long-term CS without evidence of consideration of alternative strategies, prescribing error or miscommunication. More patients received immunomodulatory therapy (IMT) in the group treated with CS above threshold than below threshold (p < 0.001) but there was no significant difference in doses of IMT. CONCLUSION: 33% of patients had been prescribed excessive corticosteroid when compared to the reference standard. An analysis of decision-making suggests there may be opportunity to reduce excess CS prescribing in 25% of these patients.

Oncogenic N-Ras Mitigates Oxidative Stress-Induced Apoptosis of Hematopoietic Stem Cells.

Leukemic relapse is believed to be driven by transformed hematopoietic stem cells (HSC) that harbor oncogenic mutations or have lost tumor suppressor function. Recent comprehensive sequencing studies have shown that mutations predicted to activate Ras signaling are highly prevalent in hematologic malignancies and, notably, in refractory and relapsed cases. To better understand what drives this clinical phenomenon, we expressed oncogenic NrasG12D within the hematopoietic system in mice and interrogated its effects on HSC survival. N-RasG12D conferred a survival benefit to HSCs and progenitors following metabolic and genotoxic stress. This effect was limited to HSCs and early progenitors and was independent of autophagy and cell proliferation. N-RasG12D-mediated HSC survival was not affected by inhibition of canonical Ras effectors such as MEK and PI3K. However, inhibition of the noncanonical Ras effector pathway protein kinase C (PKC) ameliorated the protective effects of N-RasG12D. Mechanistically, N-RasG12D lowered levels of reactive oxygen species (ROS), which correlated with reduced mitochondrial membrane potential and ATP levels. Inhibition of PKC restored the levels of ROS to that of control HSCs and abrogated the protective effects granted by N-RasG12D. Thus, N-RasG12D activation within HSCs promotes cell survival through the mitigation of ROS, and targeting this mechanism may represent a viable strategy to induce apoptosis during malignant transformation of HSCs. SIGNIFICANCE: Targeting oncogenic N-Ras-mediated reduction of ROS in hematopoietic stem cells through inhibition of the noncanonical Ras effector PKC may serve as a novel strategy for treatment of leukemia and other Ras-mutated cancers.