Retinal manifestations in patients following COVID-19 infection: A consecutive case series

Purpose:To describe retinal manifestations seen in patients associated with COVID-19 infection at a multi-specialty tertiary care hospital in Southern India.Methods:In this retrospective chart review, all consecutive cases presenting to the Retina-Uveitis service from May 2020 to January 2021 with retinal manifestations associated with COVID-19 infection or its sequelae or as a result of treatment given for COVID-19 were included.Results:Of the 7 patients, 3 were female, and 4 were male. Four patients had onset of symptoms during the active phase of COVID-19 infection. Four had bilateral and three had unilateral involvement. The manifestations ranged from mild to vision threatening. Vision threatening manifestations included infections: endogenous endophthalmitis, candida retinitis and tubercular choroidal abscess and bilateral pre-foveal hemorrhages. Milder manifestations included paracentral acute middle maculopathy, central serous chorio-retinopathy and voriconazole induced visual symptoms. Final visual acuity was 6/36 or better in the four severe cases and 6/9 or better in the mild cases.Conclusion:This study highlights the retinal manifestations associated with COVID-19 infection and its sequelae. As these patients presented with an association with COVID-19 (either during or after recovery), ophthalmologists should be vigilant and screen for such entities in case of complaints of visual symptoms or in the presence of systemic sepsis. The outcomes can be good with prompt and aggressive management.     

Novel Endogenous Glycan Therapy for Retinal Diseases: Safety,In Vitro Stability,Ocular Pharmacokinetic Modeling,and Biodistribution

Asialo, tri-antennary oligosaccharide (NA3 glycan) is an endogenous compound, which supports proper folding of outer segment membranes, promotes normal ultrastructure, and maintains protein expression patterns of photoreceptors and Müller cells in the absence of retinal pigment epithelium support. It is a potential new therapeutic for atrophic age-related macular degeneration (AMD) and other retinal degenerative disorders. Herein, we evaluate the safety, in vitro stability, ocular pharmacokinetics and biodistribution of NA3. NA3 was injected into the vitreous of New Zealand white rabbits at two concentrations viz. 1 nM (minimum effective concentration (MEC)) and 100 nM (100XMEC) at three time points. Safety was evaluated using routine clinical and laboratory tests. Ocular pharmacokinetics and biodistribution of [³H]NA3 were estimated using scintillation counting in various parts of the eye, multiple peripheral organs, and plasma. Pharmacokinetic parameters were estimated by non-compartmental modeling. A 2-aminobenzamide labeling and hydrophilic interaction liquid interaction chromatography were used to assess plasma and vitreous stability. NA3 was well tolerated by the eye. The concentration of NA3 in eye tissues was in the order: vitreous > retina > sclera/choroid > aqueous humor > cornea > lens. Area under the curve (0 to infinity) (AUC∞) was the highest in the vitreous thereby providing a positive concentration gradient for NA3 to reach the retina. Half-lives in critical eye tissues ranged between 40 and 60 h. NA3 concentrations were negligible in peripheral organs. Radioactivity from [³H]NA3 was excreted via urine and feces. NA3 was stable at 37°C in vitreous over a minimum of 6 days, while it degraded rapidly in plasma. Collectively, these results document that NA3 shows a good safety profile and favorable ocular pharmacokinetics.

Electronic supplementary material

The online version of this article (doi:10.1208/s12248-014-9563-1) contains supplementary material, which is available to authorized users.Key words: age-related macular degeneration (AMD), NA3 glycan, pharmacokinetics, safety     

ClearCode34: A Prognostic Risk Predictor for Localized Clear Cell Renal Cell Carcinoma

Background

Gene expression signatures have proven to be useful tools in many cancers to identify distinct subtypes of disease based on molecular features that drive pathogenesis, and to aid in predicting clinical outcomes. However, there are no current signatures for kidney cancer that are applicable in a clinical setting.

Objective

To generate a signature biomarker for the clear cell renal cell carcinoma (ccRCC) good risk (ccA) and poor risk (ccB) subtype classification that could be readily applied to clinical samples to develop an integrated model for biologically defined risk stratification.

Design, setting, and participants

A set of 72 ccRCC sample standards was used to develop a 34-gene classifier (ClearCode34) for assigning ccRCC tumors to subtypes. The classifier was applied to RNA-sequencing data from 380 nonmetastatic ccRCC samples from the Cancer Genome Atlas (TCGA), and to 157 formalin-fixed clinical samples collected at the University of North Carolina.

Outcome measurements and statistical analysis

Kaplan-Meier analyses were performed on the individual cohorts to calculate recurrence-free survival (RFS), cancer-specific survival (CSS), and overall survival (OS). Training and test sets were randomly selected from the combined cohorts to assemble a risk prediction model for disease recurrence.

Results and limitations

The subtypes were significantly associated with RFS (p < 0.01), CSS (p < 0.01), and OS (p < 0.01). Hazard ratios for subtype classification were similar to those of stage and grade in association with recurrence risk, and remained significant in multivariate analyses. An integrated molecular/clinical model for RFS to assign patients to risk groups was able to accurately predict CSS above established, clinical risk-prediction algorithms.

Conclusions

The ClearCode34-based model provides prognostic stratification that improves upon established algorithms to assess risk for recurrence and death for nonmetastatic ccRCC patients.

Patient summary

We developed a 34-gene subtype predictor to classify clear cell renal cell carcinoma tumors according to ccA or ccB subtypes and built a subtype-inclusive model to analyze patient survival outcomes.     

Biomechanical characteristics of the horizontal mattress stitch: implication for double-row and suture-bridge rotator cuff repair

Background

We investigated the effects of bite-size horizontal mattress stitch (distance between the limbs passed through the tendon) on the biomechanical properties of the repaired tendon.

Methods

We anchored 20 bovine Achilles tendons to bone using no. 2 high-strength suture and 5-mm titanium suture anchors in a mattress–suture technique. Tendons were allocated randomly into two groups of ten each to receive stitches with a 4- or 10-mm bite. Specimens underwent cyclic loading from 5 to 30 N at 1 mm/s for 30 cycles, followed by tensile testing to failure. Gap formation, tendon strain, hysteresis, stiffness, yield load, ultimate load, energy to yield load, and energy to ultimate load were compared between groups using unpaired t tests.

Results

The 4-mm group had less (p < 0.05) gap formation and less (p < 0.05) longitudinal strain than did the 10-mm group. Ultimate load (293.6 vs. 148.9 N) and energy to ultimate load (2,563 vs. 1,472 N-mm) were greater (p < 0.001) for the 10-mm group than the 4-mm group. All tendons repaired with 4-mm suturing failed at the suture–tendon interface, with sutures pulling through the tendon, whereas the suture itself failed before the tendon did in seven of the ten specimens in the 10-mm group.

Conclusions

Whereas a 4-mm bite fixed the tendon more tightly but at the cost of decreased ultimate strength, a 10-mm bite conveyed greater ultimate strength but with increased gap and strain. These results suggest that for the conventional double-row repair, small mattress stitches provide a tighter repair, whereas large stitches are beneficial to prevent sutures from pulling through the tendon after surgery. For suture-bridge rotator cuff repair, large stitches are beneficial because the repaired tendon has a higher strength, and the slightly mobile medial knot can be tightened by lateral fixation.     

Challenges in optimizing sample preparation and LC‐MS/MS conditions for the analysis of carglumic acid,an N‐acetyl glutamate derivative in human plasma

This paper describes a systematic approach to overcoming challenges in developing a robust and selective liquid chromatography‐tandem mass spectrometry (LC‐MS/MS) method for reliable and precise determination of carglumic acid in human plasma. Sample extraction was tested on several reversed‐phase solid‐phase extraction (SPE) sorbents with different chemistries, such as hydrophobic C18, hydrophilic‐lipophilic balance, and mixed‐mode cation and anion exchange. The best recovery under the optimized extraction conditions was obtained with Oasis MAX (30 mg, 1cc) mixed‐mode anion exchange (~ 50%) cartridge, compared to other sorbents from 100 μL plasma sample. Complete analytical separation of carglumic acid and carglumic acid‐13C5 15N as an internal standard (IS) from endogenous plasma components was achieved on ACE 5CN (150 × 4.6 mm, 5 µm) column under isocratic conditions using acetonitrile:methanol (50:50, v/v) ? 0.1% acetic acid in water [80:20, v/v] as the mobile phase. The deprotonated precursor → product ion transitions for carglumic acid (189/146) and IS (195/152) were monitored in the negative ionization mode on a triple quadrupole mass spectrometer. The regression curves were linear over a concentration range of 6.00‐6000 ng/mL (r² ≥ 0.9987). Matrix effect was evaluated in terms of IS‐normalized matrix factors, which ranged from 0.95 to 1.01 across four quality control levels. Intra‐ and inter‐batch accuracy and precision, and the stability of carglumic acid in spiked plasma samples were assessed under different conditions. The method was applied to assess the pharmacokinetics of 100 mg/kg body weight carglumic acid in a healthy Indian subject. Copyright © 2015 John Wiley & Sons, Ltd.     

Perioperative complications of robotic sacrocolpopexy for post-hysterectomy vaginal vault prolapse

Introduction and hypothesis

Open abdominal sacrocolpopexy has been the preferred treatment for post-hysterectomy vaginal vault prolapse. In light of the rise in popularity of less invasive robotic sacrocolpopexy, our objective was to compare perioperative complications of robotic vs open sacrocolpopexy.

Methods

This was a single-institution, retrospective cohort study of robotic and open sacrocolpopexies. Robotic sacrocolpopexies performed between 1 January 2007 and 31 December 2009 were compared with open cases performed between 1 January 2002 and 31 December 2006. Baseline and intraoperative variables of the groups were compared. Complications were compared univariately and in a multivariable logistic regression model to adjust for prior transabdominal surgery.

Results

A total of 50 robotic and 87 open sacrocolpopexies were analyzed. Baseline characteristics were similar, but patients in the open group had more prior transabdominal surgeries. The robotically assisted group had decreased estimated blood loss (median, 100 mL vs 150 mL; P?=?0.002) and hospital stay (median, 2 days vs 3 days; P?P?P?=?0.02), and vaginotomy (24.0 % [12 out of 50] vs 5.7 % [5 out of 87]; P?=?0.003). Two patients in the robotically assisted group had postoperative hernia. There were no differences in rates of ureteral or bowel injury, urinary tract infection, ileus, bowel obstruction, or overall complications.

Conclusions

Overall complication rates of robotic and open sacrocolpopexy were not significantly different. The robotically assisted group experienced shorter hospital stay but increased operative times and increased incidence of cystotomy and vaginotomy, possibly reflecting the learning curve of robotic sacrocolpopexy.     

Monocyte major histocompatibility complex class II expression in term and preterm labor

OBJECTIVE: To investigate how term and preterm labor (PTL) influence the balance between maternal proinflammatory and antiinflammatory responses as measured by expression of major histocompatibility complex (MHC) Class II on maternal monocytes and tumor necrosis factor-alpha (TNF-alpha) production by in vitro stimulation of whole blood by lipopolysaccharide (LPS). METHODS: Blood was taken from the following women (n=118): term elective cesarean delivery or in spontaneous labor, in premature labor, or with preterm premature rupture of the membranes (PROM) at less than 32 weeks, and gestation-matched reference group. Monocyte MHC Class II expression was measured by flow cytometry using a dual-staining technique. Plasma cytokine levels were assayed using a cytometric bead array system. In vitro whole blood stimulation with LPS was also performed, and cytokine production was measured. RESULTS: Term labor was associated with a fall in the percentage of monocytes expressing MHC Class II, compared with third trimester of pregnancy, P<.05 and a reduction in LPS-stimulated TNF-alpha production. This fall in MHC Class II was even more pronounced in PTL and preterm PROM groups compared with the reference group, P<.01. CONCLUSION: There was evidence of reduced expression of monocyte MHC Class II and LPS-stimulated TNF-alpha in term and preterm labor. This pattern of reduced MHC Class II expression and reduced TNF-alpha production is known as monocyte hyporesponsiveness or immune paresis. Detection of this state may provide insights into the maternal inflammatory status and be of use in the management of women with threatened PTL or preterm PROM. LEVEL OF EVIDENCE: II.