A systematic review and meta-analysis to compare the efficacy of acyclovir 3% ophthalmic ointment to idoxuridine in curing herpetic keratitis by Day 7 of treatment.

BACKGROUND: This objective of the review and analysis is to demonstrate that acyclovir (ACV) 3% ophthalmic ointment is superior to idoxuridine (IDU) in treating herpetic keratitis (HK) presenting as dendritic and geographic ulcer sub-types. DATA SOURCES: Publications in human subjects were identified by searching the Ovid MEDLINE database through April 2011, combining medical subject headings (MESH) "Keratitis, Herpetic/" AND "Acyclovir/" limiting by the key words "topical" OR "ointment" and also restricted to MESH "Administration, Topical/" OR "Ointments/". The results were cross checked with the references used in the Cochrane Database Syst Rev. 1:1-134, 2009 and GlaxoSmithKline clinical documents related to acyclovir. STUDY SELECTION: Randomized, double-masked studies in subjects diagnosed with HK with head to head comparator arms of ACV ophthalmic ointment and topical IDU that had actual or calculable healing rates at Day seven. DATA EXTRACTION: Data independently extracted from identified articles by two authors of this manuscript. DATA SYNTHESIS: Data from seven randomized, controlled trials (RCT) evaluating 432 subjects that met inclusion criteria (214 were treated with ACV and 218 were treated with IDU) and had Day seven healing rates calculable. All sub-classified lesions were identified as either dendritic ulcers (n = 185) or geographic ulcers (n = 35). The Cochran-Mantel-Haenszel (CMH) method in Biometrics 10:417-51, 1954 and JNCI 22:719-48, 1959, controlling for study, was performed as the primary analysis using SAS v9. Homogeneity was assessed using Breslow-Day-Tarone (BDT) test in IARC 1:1-32, 1980 and Biometrika 72:91-5, 1985. The analysis was performed with outliers removed to assess their impact. RESULTS: ACV showed statistically significant greater odds of healing HK at Day seven in all subjects (Odds Ratio 3.95, 95% CI2.60, 6.00, p < 0.0001), in dendritic ulcers (Odds Ratio 4.22, 95% CI: 2.14, 8.32; p < 0.0001) and geographic ulcers (Odds Ratio 5.31, 95% CI: 1.09, 25.93; p = 0.0244). CONCLUSION: ACV 3% ophthalmic ointment is a valuable intervention for dendritic and geographic corneal ulcers. ACV and IDU were generally well tolerated in the studies reviewed.

The emerging role of mTOR signalling in antibacterial immunity.

Mammalian target of rapamycin (mTOR) is a central regulator of cellular metabolic homeostasis that is highly conserved in evolution. Recent evidence has revealed the existence of a complex interplay between mTOR signalling and immunity. We review here the emerging role of mTOR signalling in the regulation of Toll-like receptor-dependent innate responses and in the activation of T cells and antigen-presenting cells. We also highlight the importance of amino-acid starvation-driven mTOR inhibition in the control of autophagy and intracellular bacterial clearance.

PLL-g-PEG Polymer Inhibits Antibody-Drug Conjugate Uptake into Human Corneal Epithelial Cells In Vitro.

Purpose: Antibody-drug conjugates (ADCs) are a relatively recent advance in the delivery of chemotherapeutics that improve targeting of cytotoxic agents. However, despite their antitumor activity, severe ocular adverse effects, including vision loss, have been reported for several ADCs. The nonspecific uptake of ADCs into human corneal epithelial cells (HCECs) and their precursors via macropinocytosis has been proposed to be the primary mechanism of ocular toxicity. In this study, we evaluated the ability of a novel polymer, poly(l-lysine)-graft-poly(ethylene glycol) (PLL-g-PEG), to decrease the ADC rituximab-mc monomethylauristatin F (MMAF) (RIX) uptake into human corneal epithelial (HCE-T) cells. Methods: HCE-T cells were exposed to increasing concentrations of RIX to determine inhibition of cell proliferation. HCE-T cells were treated with PLL-g-PEG, the macropinocytosis inhibitor 5-(N-ethyl-N-isopropyl) amiloride (EIPA), or vehicle. After 30 min of incubation, RIX was added. ADC was detected by fluorescent anti-human immunoglobulin G and fluorescently conjugated dextran as viewed by microscopy. Results: RIX caused dose-dependent inhibition of HCE-T cell proliferation. EIPA significantly reduced RIX uptake and decreased macropinocytosis as assessed by direct quantification of RIX using a fluorescently conjugated anti-human antibody as well as quantification of macropinocytosis using fluorescently conjugated dextran. PLL-g-PEG resulted in a dose-dependent inhibition of RIX uptake with half-maximal inhibitory concentrations of 0.022%-0.023% PLL-g-PEG. Conclusion: The data show PLL-g-PEG to be a potent inhibitor of RIX uptake by corneal epithelial cells and support its use as a novel therapeutic approach for the prevention of ocular adverse events associated with ADC therapy.

Vancomycin-resistant Enterococcus sequence type 1478 spread across hospitals participating in the Canadian Nosocomial Infection Surveillance Program from 2013 to 2018.

OBJECTIVE: To analyze the spread of a novel sequence type (ST1478) of vancomycin-resistant Enterococcus faecium across Canadian hospitals. DESIGN: Retrospective chart review of patients identified as having ST1478 VRE bloodstream infection. SETTING: Canadian hospitals that participate in the Canadian Nosocomial Infection Surveillance Program (CNISP). METHODS: From 2013 to 2018, VRE bloodstream isolates collected from participating CNISP hospitals were sent to the National Microbiology Laboratory (NML). ST1478 isolates were identified using multilocus sequence typing, and whole-genome sequencing was performed. Patient characteristics and location data were collected for patients with ST1478 bloodstream infection (BSI). The sequence and patient location information were used to generate clusters of infections and assess for intrahospital and interhospital spread. RESULTS: ST1478 VRE BSI occurred predominantly in a small number of hospitals in central and western Canada. Within these hospitals, infections were clustered on certain wards, and isolates often had <20 single-nucleotide variants (SNV) differences from one another, suggesting a large component of intrahospital spread. Furthermore, some patients with bloodstream infections were identified as moving from one hospital to another, potentially having led to interhospital spread. Genomic analysis of all isolates revealed close relatedness between isolates at multiple different hospitals (<20 SNV) not predicted from our epidemiologic data. CONCLUSIONS: Both intrahospital and regional interhospital spread have contributed to the emergence of VRE ST1478 infections across Canada. Whole-genome sequencing provides evidence of spread that might be missed with epidemiologic investigation alone.

Treatment preferences of patients with relapsed or refractory multiple myeloma in the United States, United Kingdom, Italy, Germany, France, and Spain: results from a discrete choice experiment.

Introduction: Newer treatment options for relapsed/refractory multiple myeloma (RRMM) with efficacy and safety profiles that differ from traditional therapies have facilitated personalized management strategies to optimize patient outcomes. In the context of such personalized management, understanding how treatment characteristics influence patients' preferences is essential. This study assessed patients' preferences for RRMM treatment attributes and determined trade-offs between potential benefits, administration procedures, and adverse effects. Methods: Patients' preferences were evaluated using a discrete choice experiment (DCE). Patients with RRMM who reported failing two lines of anti-myeloma treatment (immunomodulatory agent and a proteasome inhibitor [PI]) or ≥ 3 lines (including ≥1 PI, immunomodulatory agent, or anti-CD38 monoclonal antibody), were recruited across the US, UK, Italy, Germany, France, and Spain. DCE attributes and levels were identified using a targeted literature review, a review of clinical data for relevant RRMM treatments, qualitative patient interviews, and input from clinical and myeloma patient experts. The DCE was administered within an online survey from February-June 2022. Preference data were analyzed using an error-component logit model and willingness to make trade-offs for potential benefits, and relative attribute importance scores were calculated. Results: Overall, 296 patients from the US (n = 100), UK (n = 49), Italy (n = 45), Germany (n = 43), France (n = 39), and Spain (n = 20) participated in the DCE. Mean (standard deviation) age was 63.8 (8.0) years, 84% had a caregiver, and patients had a median of 3 (range: 2-8) prior lines of therapy. Efficacy attributes most influenced patients' preferences, with increasing overall response rate (25-85%) and overall survival (6 months to 2 years) contributing to ~50% of treatment decision-making. Administration procedures were also considered important to patients. Avoiding individual side effects was considered relatively less important, with patients willing to tolerate increases in side effects for gains in efficacy. Patient characteristics such as rate of disease progression, sociodemographics, or clinical characteristics also influenced treatment preferences. Conclusion: Patients with RRMM were willing to tolerate increased risk of side effects for higher efficacy. Preferences and risk tolerance varied between patients, with preference patterns differing by certain patient characteristics. This highlights the importance of shared decision-making for optimal treatment selection and patient outcomes.

An Evaluation of the Repeatability of Visual Function Following Surgical Repair of Macula-Off Rhegmatogenous Retinal Detachment.

Purpose: To evaluate the reliability and reproducibility of visual function assessments for patients with macula-off rhegmatogenous retinal detachment (RRD). Methods: This prospective study included patients with unilateral macula-off RRD of <10-day duration successfully treated with a single, uncomplicated surgery at least 1 year following repair. Visual function assessments were performed at time of enrollment and 1 month later. Testing included Early Treatment Diabetic Retinopathy Study (ETDRS) best-corrected visual acuity (BCVA), low-luminance visual acuity (LLVA), low-contrast visual acuity (VA) 2.5% and 5%, contrast sensitivity assessment with Mars and Gabor patches, reading speed (acuity, speed, and critical print size), color vision testing (protan, deutan, and tritan), and microperimetry. Spectral-domain ocular coherence tomography (SD-OCT) was performed. Paired t-statistics were used to compare values between visits and between the study and fellow eyes. Results: Fourteen patients (9 male, 5 female) with a mean age of 69 years at time of surgery were evaluated. Correlation coefficients across the two visits were highest for ETDRS BCVA (0.97), tritan color vision testing (0.96), and low-contrast VA 5% (0.96), while the average t-statistic was largest for low-luminance deficit (4.2), ETDRS BCVA (4.1), and reading speed critical print size (3.7). ETDRS BCVA did not correlate with SD-OCT findings. Conclusions: ETDRS BCVA can be considered a highly reliable and reproducible outcome measure. LLVA, protan color discrimination, contrast sensitivity, and reading speed may be useful secondary outcome measures. Translational Relevance: This study provides guidance on the selection of visual function outcome measures for clinical trials of patients with macula-off RRD.

Patient-Reported Outcomes With Belantamab Mafodotin Treatment in Patients With Triple-Class Refractory Multiple Myeloma.

In the randomized phase II DREAMM-2 study, single-agent belantamab mafodotin demonstrated deep and durable responses and a manageable safety profile in triple-class refractory relapsed/refractory multiple myeloma (RRMM). We present patient-reported outcomes (PROs) from this study for patients treated with the approved dose of belantamab mafodotin (2.5 mg/kg q3w). Disease and treatment-related symptoms, health-related quality of life (HRQOL), functioning, and patient-reported ocular changes were assessed using questionnaires (European Organisation for Research and Treatment of Cancer Quality of Life questionnaires EORTC-QLQ-C30 and EORTC-QLQ-MY20, Ocular Surface Disease Index [OSDI], and the National Eye Institute Visual Functioning Questionnaire 25 [NEI VFQ-25]) at baseline, during treatment (every 3 or 6 weeks), and at the end of treatment (EOT). Eye examinations were conducted at baseline, prior to each treatment cycle, and at EOT. Patients reported ocular symptoms in the OSDI and NEI VFQ-25 questionnaires, with the median time to worst severity of 45 to 64 days depending on symptoms considered. Some limitations in driving and reading were reported. Ocular symptoms were improved and median time to recovery was 23.5 to 44.0 days. EORTC-QLQ-C30 data suggest core MM symptoms (including fatigue and pain), overall HRQOL, and patient functioning were maintained while patients continued belantamab mafodotin treatment, even if meaningful worsening of vision-related symptoms occurred. These PRO results, together with the clinical efficacy of belantamab mafodotin, support its use in patients with RRMM and further evaluation of its use at earlier lines of therapy.

A randomized, dose-escalation study of subconjunctival and intravitreal injections of sirolimus in patients with diabetic macular edema.

OBJECTIVE: To evaluate the safety and tolerability of a single subconjunctival (SCJ) or intravitreal (IVT) injection of an ophthalmic sirolimus formulation in eyes with diabetic macular edema (DME). DESIGN: Randomized, open-label, dose-escalating phase I study. PARTICIPANTS: Fifty eyes among 50 patients with DME, retinal thickness ≥ 300 microns and best-corrected visual acuity (BCVA) 20/40 to 20/200. METHODS: A single dose of sirolimus administered SCJ (220, 440, 880, 1320, or 1760 µg) or IVT (44, 110, 176, 264, or 352 µg) on day 0; observation through day 90. MAIN OUTCOME MEASURES: Primary end points were the frequency and severity of ocular and systemic adverse events. Secondary end points were changes in BCVA and retinal thickness. RESULTS: No dose-limiting toxicities were observed and ocular adverse events were mostly mild and transient. Conjunctival hyperemia, hemorrhage, and edema were common after the SCJ injection procedure and conjunctival hemorrhage was common after the IVT injection procedure. Three patients experienced ocular adverse events considered possibly related to study drug: Conjunctival edema and reduced visual acuity were reported in 1 SCJ patient each and iritis was reported in 1 IVT patient. No serious ocular adverse events were reported. No nonocular adverse events were considered related to study drug. Systemic exposure to sirolimus was low, with blood concentrations below levels necessary for systemic immunosuppression. For the SCJ group (n = 25), a median increase in BCVA started at day 7 (5.0 letters) and was 3.0, 4.0, and 4.0 letters at days 14, 45 and 90, respectively. At day 45, median decrease in retinal thickness was -23.7 µm. For the IVT group (n = 25), the median increase in BCVA was 2.0 letters at day 7; at days 14, 45, and 90, the median increase was maintained (4.0 letters); the median decrease in retinal thickness was -52.0 µm at day 45. CONCLUSIONS: Locally administered sirolimus was well-tolerated with minimal systemic exposure at all doses tested in this small phase I population. These findings support advancing the present sirolimus formulation into phase II studies. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found after the references.

Infectious endophthalmitis in adult eyes receiving Boston type I keratoprosthesis.

PURPOSE: To report the clinical characteristics of infectious endophthalmitis after Boston type I keratoprosthesis (K-Pro) implantation. DESIGN: Retrospective study. PARTICIPANTS: One hundred forty-one adult eyes receiving a K-Pro at a single institution from May 2004 through July 2008. METHODS: A retrospective chart review was performed of all adult eyes receiving a K-Pro at the University of Rochester from May 2004 through July 2008. Those patients identified as having been treated for exogenous bacterial endophthalmitis were reviewed for demographic data, indication for K-Pro, bandage contact lens use, prophylactic antibiotic use, timing and clinical presentation of endophthalmitis, gram stain and culture results of intraocular fluid, timing and presentation of any subsequent episodes of endophthalmitis (recurrent endophthalmitis), and preoperative and postoperative visual acuity through August 2010. MAIN OUTCOME MEASURES: Incidence of endophthalmitis, time to occurrence, recurrence rates, visual outcomes, and risk factors associated with K-Pro endophthalmitis. RESULTS: Ten (7.1%) of 141 eyes of 130 adult patients were diagnosed and treated for bacterial endophthalmitis. Average time to endophthalmitis developing after K-Pro was 9.8 months (standard deviation [SD], 6.2 months; range, 2-25 months). Coagulase-negative staphylococci were identified in 7 eyes. In 7 of the 10 eyes, recurrent endophthalmitis developed that occurred at a mean of 4 months (SD, 3.9 months; range, 1-13 months) after resolution of the initial episode. At each episode of endophthalmitis, no eye was receiving vancomycin ophthalmic drops and most eyes were receiving only fluoroquinolone ophthalmic drops for prophylaxis. CONCLUSIONS: Infectious endophthalmitis after K-Pro implantation has a higher incidence, delayed onset, and high risk for recurrence compared with postoperative endophthalmitis associated with more common intraocular procedures such as cataract surgery. The concurrent use of topical vancomycin is recommended because it seems to be important in reducing the incidence and recurrence of endophthalmitis and because fluoroquinolone ophthalmic drops do not seem to be sufficient prophylaxis in these eyes.

Incidence of corneal adverse events in patients with multiple myeloma and their clinical and economic impact: A real-world retrospective cohort study.

AIMS: Ocular toxicities are common adverse events (AEs) associated with anticancer agents. There is a paucity of data documenting their impact on patient care. This study assessed the clinical and economic burden of corneal AEs and related symptoms (collectively termed corneal AEs) in patients receiving multiple myeloma (MM) treatment. MATERIALS AND METHODS: Adults with a newly diagnosed MM (MM cohort) were identified from PharMetrics Plus, a US insurance claims database. Incidence, outpatient (OP) care, emergency department (ED) visits, hospitalizations, and costs were assessed for corneal AEs of interest: keratopathy/keratitis, blurred vision/decreased acuity, dry eye, eye pain, and photophobia. Incidence of new corneal AEs, healthcare resource utilization (HCRU), corneal AE-related HCRU, and costs were assessed and benchmarked against a hematology cohort of patients. RESULTS: The MM cohort included 2,120 patients with a median follow-up of 734.5 days. Overall, 11.7% of patients in the MM cohort and 7.4% in the hematology cohort had ≥1 corneal AE of interest. In the MM cohort, dry eye (6.1%), blurred vision/decreased acuity (3.4%), and keratopathy/keratitis (2.5%) were the most frequent. The overall median corneal AE-related per-patient-per-month (PPPM) cost was $27, predominantly contributed by OP care (median $19 PPPM). During follow-up, 4.8% of patients visited the ED, 3.6% were hospitalized, and 42.5% of patients visited an ophthalmologist/optometrist (∼1.69 visits/year). Costs of these visits were negligible (median PPPM $19) compared to total all-cause costs (median PPPM $17,286). LIMITATIONS: The results can only be generalized to commercially insured and Medicare Advantage patients. Claims-based diagnosis of corneal AEs may underestimate true incidences. CONCLUSIONS: Corneal AEs were observed in ∼12% of patients in the MM cohort, the most common were keratopathy/keratitis, dry eye, and blurred vision. Most of them required only OP care. The clinical and economic burden for treating corneal AEs was low when compared with total all-cause or MM-related PPPM costs.

Quantitative Comparison of Fundus Images by 2 Ultra-Widefield Fundus Cameras.

PURPOSE: To compare the relative number of retinal pixels and retinal area imaged using the Optos P200DTx (Optos PLC) and Zeiss Clarus 500 (Carl Zeiss Meditec AG) ultra-widefield (UWF) fundus cameras. DESIGN: Single-center retrospective cross-sectional analysis. PARTICIPANTS: Seventy-eight eyes of 46 patients. METHODS: Eyes were imaged with Optos P200DTx, single-capture, and Zeiss Clarus 500, 2 capture montages when possible, UWF fundus cameras. Relative number of pixels encompassing all foveal-centered retinal quadrants were measured. Retinal area was measured with Zeiss Clarus 500 images that were registered to the Optos P200DTx images. Patients and technicians were asked for preferences between the machines. Imaging session times were recorded. MAIN OUTCOME MEASURES: Relative number of retinal pixels and retina area captured by each fundus camera. RESULTS: Optos P200DTx consistently captured more relative pixels compared with Zeiss Clarus 500: 510.4 versus 355.6 (P < 0.001) in total with a similarly statistically significant trend in all 4 quadrants (P < 0.001 for each). For area calculation, 70 of the 78 images achieved successful registration. Optos captured a larger total retinal area: 765.6 versus 566.5 mm2 (P < 0.001) with a similarly statistically significant trend in all 4 quadrants. In the subset of 52 of 70 registered and montaged Zeiss Clarus 500 images, similar results were found. For peripheral pathologic features, Optos P200DTx captured unique findings in 28 images, and Zeiss Clarus 500 captured unique findings 1 image (P < 0.001). Among the 48 imaging sessions in which technicians preferred Optos P200DTx for 28 sessions (58%) and Zeiss Clarus 500 for 20 (42%; P = 0.15). Among patients who responded with a preference, 24 preferred Optos P200DTx and 20 preferred Zeiss Clarus 500 (P = 0.52). Average imaging session time was 4.6 minutes (standard deviation, 3.0 minutes) for Optos P200DTx and 5.2 minutes (standard deviation, 3.0 minutes) for Zeiss Clarus 500 (P = 0.17). CONCLUSIONS: In the current study, the Optos P200DTx captured statistically significantly more retinal area in all 4 quadrants compared with the Zeiss Clarus 500. No statistically significant difference was found in patient or technician preference or image acquisition time between devices.

Rapamycin inhibits VEGF-induced microvascular hyperpermeability in vivo.

OBJECTIVE: To test the hypothesis that rapamycin inhibits induced microvascular hyperpermeability directly in vivo. METHODS: Male golden Syrian hamsters (80-120 g) were treated with either rapamycin (at 0.1, 0.5, 2, and 10 mg/kg i.p.) or vehicle at 24 hours and at 1 hour prior to preparation of the cheek pouch. Caveolin-1 scaffolding (1 mg/kg; positive inhibitory control) was injected i.p. 24 hours prior to the experiment. 10(-8) M vascular endothelial growth factor (VEGF) or 10(-7) M platelet-activating factor (PAF) were topically applied to the cheek pouch. Microvascular permeability and arteriolar diameter were assessed using integrated optical intensity (IOI) and vascular wall imaging, respectively. RESULTS: Rapamycin at 0.1 and 0.5 mg/kg significantly reduced VEGF-stimulated mean IOI from 63.0 +/- 4.2 to 9.7 +/- 5.0 (85% reduction, P < 0.001) and 3.6 +/- 2.7 (95% reduction, P < 0.001), respectively. Rapamycin at 2 mg/kg also lowered VEGF-stimulated hyperpermeability (40% reduction, P < 0.05). However, 10 mg/kg rapamycin increased VEGF-induced microvascular hyperpermeability. Rapamycin at 0.5 mg/kg attenuated VEGF-induced vasodilation and PAF-induced hyperpermeability, but did not inhibit PAF-induced vasoconstriction. CONCLUSIONS: At therapeutically relevant concentrations, rapamycin inhibits VEGF- and PAF-induced microvascular permeability. This inhibition is (i) a direct effect on the endothelial barrier, and (ii) independent of arteriolar vasodilation. Rapamycin at 10 mg/kg stimulates effectors that increase microvascular permeability.

Bartonella quintana infective endocarditis in northern Alberta: A case report.

We present a case of Bartonella quintana infective endocarditis requiring valvular surgery in an Indigenous patient from northern Alberta that was identified months after initial presentation to hospital with undifferentiated laboratory abnormalities. Syndromes caused by B. quintana are often challenging to diagnose due to their non-specific presentation and the difficulty in detecting this organism using traditional culture methods. Additionally, risk factors for B. quintana include marginal housing and alcohol use disorder, which often impede access to health care. Indigenous patients in northern Canada often face worse health outcomes compared with other regions owing to poor economic conditions, substandard housing, and limited access to health care resources. Given that risk factors for B. quintana are prevalent throughout northern Canada and that this infection is difficult to diagnose, we surmise that the prevalence of B. quintana infection is underestimated in northern Canada.

Les auteurs présentent un cas d'endocardite infectieuse à Bartonella quintana exigeant une chirurgie valvulaire chez un patient autochtone du nord de l'Alberta, dépisté des mois après la première consultation à l'hôpital, alors que les anomalies de laboratoires étaient indifférenciées. Les syndromes causés par le Bartonella quintana sont souvent difficiles à diagnostiquer à cause de leur présentation non spécifique et de la difficulté à déceler cet organisme au moyen des méthodes de culture classiques. De plus, les facteurs de risque de Bartonella quintana incluent des logements inférieurs aux normes et des troubles de l'usage de l'alcool, qui nuisent souvent à l'accès aux soins. Les patients autochtones du nord du Canada présentent souvent des résultats cliniques pires que ceux d'autres régions à cause des mauvaises conditions économiques, des logements inférieurs aux normes et de l'accès limité aux ressources de santé. Puisque les facteurs de risque de Bartonella quintana prévalent dans tout le nord du Canada et que cette infection est difficile à diagnostiquer, les auteurs postulent que la prévalence d'infection à Bartonella quintana est sous-estimée dans cette région.

On the Identification of Noise Covariances and Adaptive Kalman Filtering: A New Look at a 50 Year-Old Problem.

The Kalman filter requires knowledge of the noise statistics; however, the noise covariances are generally unknown. Although this problem has a long history, reliable algorithms for their estimation are scant, and necessary and sufficient conditions for identifiability of the covariances are in dispute. We address both of these issues in this paper. We first present the necessary and sufficient condition for unknown noise covariance estimation; these conditions are related to the rank of a matrix involving the auto and cross-covariances of a weighted sum of innovations, where the weights are the coefficients of the minimal polynomial of the closed-loop system transition matrix of a stable, but not necessarily optimal, Kalman filter. We present an optimization criterion and a novel six-step approach based on a successive approximation, coupled with a gradient algorithm with adaptive step sizes, to estimate the steady-state Kalman filter gain, the unknown noise covariance matrices, as well as the state prediction (and updated) error covariance matrix. Our approach enforces the structural assumptions on unknown noise covariances and ensures symmetry and positive definiteness of the estimated covariance matrices. We provide several approaches to estimate the unknown measurement noise covariance R via post-fit residuals, an approach not yet exploited in the literature. The validation of the proposed method on five different test cases from the literature demonstrates that the proposed method significantly outperforms previous state-of-the-art methods. It also offers a number of novel machine learning motivated approaches, such as sequential (one sample at a time) and mini-batch-based methods, to speed up the computations.

Baseline Visual Acuity at Wet AMD Diagnosis Predicts Long-Term Vision Outcomes: An Analysis of the IRIS Registry.

BACKGROUND AND OBJECTIVE: Clinical trials in neovascular age-related macular degeneration (nAMD) demonstrate that high visual acuity (VA) can be maintained, and low VA can be improved with anti-vascular endothelial growth factor (VEGF) treatment. Few real-world data investigating the relationship between baseline VA and long-term outcomes exist. This study compares VA at diagnosis and after treatment using data from a large patient registry. PATIENTS AND METHODS: Retrospective study of IRIS Registry patients diagnosed with nAMD in one or both eyes between January 2013 and June 2017. Patients received at least two anti-VEGF injections in the study eye(s) less than 45 days apart during the study period. Primary outcomes were the percentage of eyes with 20/40 VA or better at diagnosis and association of VA at diagnosis with longer-term visual outcomes. RESULTS: The study included 162,902 eyes. Among all included eyes, 34.3% presented with 20/40 VA or better at diagnosis. Patients with 20/40 vision or better at baseline maintained a mean VA of 20/40 or better for 2 years after treatment initiation. CONCLUSIONS: Baseline VA at nAMD diagnosis predicts long-term VA outcomes. Early diagnosis before VA is adversely affected is a key factor in preserving vision in patients with nAMD. [Ophthalmic Surg Lasers Imaging Retina. 2020;51:633-639.].

Your Automated Implantable Cardioverter Defibrillator Is Not a Bulletproof Vest but It Might Save Your Life.

A 43-year-old male was brought to the emergency department as the highest level trauma activation with complaints of chest and arm pain after sustaining gunshot wounds (GSW). Initial workup was notable for superficial GSWs to the left chest and upper extremity with direct impact to the patient's automated implantable cardioverter defibrillator. The patient underwent replacement of the device without rewiring and was discharged home without complications.

MYC Drives Pten/Trp53-Deficient Proliferation and Metastasis due to IL6 Secretion and AKT Suppression via PHLPP2.

UNLABELLED: We have recently recapitulated metastasis of human PTEN/TP53-mutant prostate cancer in the mouse using the RapidCaP system. Surprisingly, we found that this metastasis is driven by MYC, and not AKT, activation. Here, we show that cell-cell communication by IL6 drives the AKT-MYC switch through activation of the AKT-suppressing phosphatase PHLPP2, when PTEN and p53 are lost together, but not separately. IL6 then communicates a downstream program of STAT3-mediated MYC activation, which drives cell proliferation. Similarly, in tissues, peak proliferation in Pten/Trp53-mutant primary and metastatic prostate cancer does not correlate with activated AKT, but with STAT3/MYC activation instead. Mechanistically, MYC strongly activates the AKT phosphatase PHLPP2 in primary cells and prostate cancer metastasis. We show genetically that Phlpp2 is essential for dictating the proliferation of MYC-mediated AKT suppression. Collectively, our data reveal competition between two proto-oncogenes, MYC and AKT, which ensnarls the Phlpp2 gene to facilitate MYC-driven prostate cancer metastasis after loss of Pten and Trp53. SIGNIFICANCE: Our data identify IL6 detection as a potential causal biomarker for MYC-driven metastasis after loss of PTEN and p53. Second, our finding that MYC then must supersede AKT to drive cell proliferation points to MYC inhibition as a critical part of PI3K pathway therapy in lethal prostate cancer.

Retinopathy in sickle cell trait: does it exist?

BACKGROUND: Patients with sickle cell trait and concomitant systemic disease are known to be at risk for proliferative retinopathy. However, there are reports of retinopathy in patients with sickle cell trait without systemic disease. There are no population-based studies addressing the risk of sickle cell retinopathy in this group. We performed a study to clarify the relation between sickle cell trait and retinopathy in healthy subjects. METHODS: We reviewed the medical records of 100 children with sickle cell disease who attended the Sickle Cell Clinic at the Hospital for Sick Children, Toronto. We then contacted 200 parents with sickle cell trait, of whom 32 agreed to participate in the study. All participants were proven to have hemoglobin AS status with prior hemoglobin electrophoresis. An ophthalmologic history was obtained, and a complete ophthalmologic examination was performed. We defined sickle cell retinopathy as any salmon patch hemorrhages, iridescent spots, black sunbursts, retinal neovascularization or retinal detachment. The evaluation also included attempts to identify the more subtle signs of sickle cell retinopathy, such as optic nerve head vascular changes, vascular tortuosity, macular changes (e.g., microaneurysms and vascular loops) and peripheral arteriovenous anastamoses. Blood samples were obtained for complete blood count, reticulocyte count and smear. RESULTS: We found no cases of sickle cell retinopathy among the 32 subjects. Ten of 30 subjects had a high reticulocyte count (greater than 120 x 10(9)/L); however, there were no associated eye findings in this subgroup. INTERPRETATION: Our results indicate that there is no increased risk of retinopathy in healthy people with sickle cell trait.