VEGF-A in Serum and Plasma Rich in Growth Factors (PRGF) Eye Drops.

BACKGROUND: Vascular endothelial growth factor (VEGF)-A, the most abundant subtype of the VEGF family in the eye, plays an important role in corneal homeostasis due to its ability to mediate corneal nerve repair. Repeated intravitreal anti-VEGF injections were shown to significantly reduce corneal nerve density, which might negatively affect corneal homeostasis and lead to a neuropathic dry eye disease. Currently, there are two effective modalities to treat dry eye while supplying VEGF to the ocular surface: serum eye drops (SED) and eye drops manufactured from plasma rich in growth factors (PRGF). The purpose of this study was to measure the VEGF-A concentration in SED and PRGF eye drops. MATERIAL AND METHODS: Ten healthy volunteers donated blood on two separate occasions, 2 - 8 days apart. Thus, a total of 20 blood samples were processed to obtain both SED and PRGF. Concentrations of VEGF-A were quantified by a Simple Plex platform run in triplicate. RESULTS: The VEGF-A concentration in SED and PRGF was very similar between the two blood samples drawn from one individual donor but showed substantial interindividual variability. However, in all 20 samples, VEGF concentrations were substantially higher in SED samples (mean 238.7 ± 146.6 pg/mL) compared to PRGF samples (mean 67.4 ± 46.3 pg/mL). Based upon the analysis of variance (ANOVA) model for the measured concentrations with fixed effects for specimen (SED vs. PRGF) and subject, the mean difference between the SED and PRGF concentration was 168.1 pg/mL (95% confidence interval: [142.4, 193.9], p < 0.001). CONCLUSION: Our study showed that the VEGF concentration was higher in SED than in PRGF. This is an important finding, particularly for potential treatment of dry eye disease in patients with neuropathic eye disease, especially in patients that received repeated anti-VEGF intravitreal injections, or in patients with Sjögren's disease, where the level of VEGF in tears might be pathologically decreased. Hypothetically, VEGF might be needed to restore ocular surface homeostasis. Although growing evidence has shown that VEGF-A plays an important role in corneal homeostasis, only a randomized prospective clinical trial will show whether supplying VEGF-A to the ocular surface might successfully restore the corneal homeostasis and overcome the problem of corneal neuropathy in these patients. For such a trial, based on our results, an undiluted SED should be preferred over a PRGF due to the higher content of VEGF-A.

Effect of Protective Measures on the Risk of SARS-CoV-2 Infection among Eye Clinic Staff Members.

BACKGROUND: Switzerland was strongly affected by the pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that resulted in a nationwide lockdown in March 2020. Ophthalmologists were at most risk of contracting a SARS-CoV-2 infection due to their close working distance from patients. The aim of the study is to evaluate the overall effectiveness of protective measures on the risk of SARS-CoV-2 infection among employees in a large public eye hospital. MATERIAL AND METHODS: After lifting the lockdown in April 2020, standard precaution measures were taken, such as no handshaking and the use of operating face masks and a protective plastic shield on slit lamps and diagnostic devices. Only patients with no signs of SARS-CoV-2 disease were seen during the study period. Specific anti-SARS-CoV-2 IgG antibody titers were measured in eye clinic employees at the end of April 2020 (1st test phase) and in January 2021 (2nd test phase). The prevalence of SARS-CoV-2 IgG antibody titers among employees with daily patient contact was compared to staff members with no patient contact. RESULTS: The SARS-CoV-2 prevalence in employees with daily patient contact, with 0% in the 1st phase and 7.4% in the 2nd phase, was not significantly higher than the prevalence in the control group with no patient contact (0.9% in the 1st phase, p = 0.4; and 8.6% in the 2nd phase, p = 0.8). Furthermore, physicians were not at a significantly higher risk of SARS-CoV-2 infection compared to technicians, nurses, or office staff. CONCLUSIONS: This study shows that the abovementioned precaution measurements are effective in preventing transmission of SARS-CoV-2 infection in eye hospitals and enable us to resume practicing ophthalmology in a safe manner.

The Lucerne Protocol for the Production of Autologous Serum Eyedrops.

BACKGROUND: There are a variety of protocols for manufacturing autologous serum (AS) eye drops. The Lucerne protocol for the production of AS eye drops uses a slightly reduced gravitational (g)-force and time for the centrifugation process (2500 × g for 10 minutes), compared to previously published optimised protocols, to obtain high levels of epitheliotropic growth factors (3000 × g for 15 minutes). The goal of this study was to compare the concentrations of growth factors, albumin and lysozyme in autologous serum eye drops manufactured with these protocols. MATERIAL AND METHODS: Blood from 5 healthy volunteers was placed in plastic tubes without an anticoagulant. Tubes from each donor were left in a vertical position for 2 hours at room temperature to facilitate coagulation, followed by centrifugation at either 2500 × g for 10 minutes or at 3000 × g for 15 minutes at room temperature. The serum levels of beta nerve growth factor (ß-NGF), transforming growth factor ß1 (TGF-ß1), epidermal growth factor (EGF), hepatocyte growth factor (HGF), platelet-derived growth factor BB (PDGF-BB) and vascular endothelial growth factor A (VEGF-A) were measured in triplicate with a multi-analyte Simple Plex platform. The Simple Plex cartridge allows each sample to be run in triplicate for each analyte and prevents any interaction between the antibody components for each biomarker. The serum level of albumin was measured by turbidimetric immunoassay Tina-quant and of lysozyme by single radial immunodiffusion assay. RESULTS: For all analytes, the reduced g-force and centrifugation time did not result in a significant difference in serum levels. CONCLUSIONS: The Lucerne protocol for the production of autologous serum eye drops with reduced g-force and a shorter centrifugation time does not affect the concentrations of the main epitheliotropic growth factors, albumin and lysozyme, in AS eye drops.

Measurement of long-term iron absorption and loss during iron supplementation using a stable isotope of iron (57 Fe).

We report the first measurements of long-term iron absorption and loss during iron supplementation in African children using a stable isotope of iron (57 Fe). After uniform labelling of body iron with 57 Fe, iron absorption is proportional to the rate of decrease in the 57 Fe tracer concentration, while iron loss is proportional to the rate of decrease in the 57 Fe tracer amount. Anaemic Gambian toddlers were given 2 mg 57 Fe orally to equilibrate with total body iron over 8-11 months. After assignment to the positive control arm of the HIGH study, 22 toddlers consumed a micronutrient powder containing 12 mg iron for 12 weeks followed by 12 weeks without iron supplementation. Their daily iron absorption increased 3·8-fold during the iron supplementation period compared to the control period [median (interquartile range, IQR): 1·00 (0·82; 1·28) mg/day vs. 0·26 (0·22; 0·35) mg/day; P = 0·001]. Unexpectedly, during the supplementation period, daily iron loss also increased by 3·4-fold [0·75 (0·55; 0·87) mg/day vs. 0·22 (0·19; 0·29) mg/day; P = 0·005]. Consequently, most (~72%) of the absorbed iron was lost during supplementation. Long-term studies of iron absorption and loss are a promising and accurate method for assessing and quantifying long-term iron balance and may provide a reference method for evaluating iron intervention programs in vulnerable population groups. This study was registered as ISRCTN 0720906.

A novel biomarker-based prognostic score in acute ischemic stroke: The CoRisk score.

OBJECTIVES: To derive and externally validate a copeptin-based parsimonious score to predict unfavorable outcome 3 months after an acute ischemic stroke (AIS). METHODS: The derivation cohort consisted of patients with AIS enrolled prospectively at the University Hospital Basel, Switzerland. The validation cohort was prospectively enrolled after the derivation cohort at the University Hospital of Bern and University Hospital Basel, Switzerland, as well as Frankfurt a.M., Germany. The score components were copeptin levels, age, NIH Stroke Scale, and recanalization therapy (CoRisk score). Copeptin levels were measured in plasma drawn within 24 hours of AIS and before any recanalization therapy. The primary outcome of disability and death at 3 months was defined as modified Rankin Scale score of 3 to 6. RESULTS: Overall, 1,102 patients were included in the analysis; the derivation cohort contributed 319 patients, and the validation cohort contributed 783. An unfavorable outcome was observed among 436 patients (40%). For the 3-month prediction of disability and death, the CoRisk score was well calibrated in the validation cohort, for which the area under the receiver operating characteristic curve was 0.819 (95% confidence interval [CI] 0.787-0.849). The calibrated CoRisk score correctly classified 75% of patients (95% CI 72-78). The net reclassification index between the calibrated CoRisk scores with and without copeptin was 46% (95% CI 32-60). CONCLUSIONS: The biomarker-based CoRisk score for the prediction of disability and death was externally validated, was well calibrated, and performed better than the same score without copeptin. CLINICALTRIALSGOV IDENTIFIER: NCT00390962 (derivation cohort) and NCT00878813 (validation cohort).

Copeptin for the prediction of recurrent cerebrovascular events after transient ischemic attack: results from the CoRisk study.

BACKGROUND AND PURPOSE: Copeptin has been associated with recurrent cerebrovascular events after transient ischemic attack (TIA). In an independent cohort, we evaluated copeptin for the prediction of recurrent cerebrovascular events within 3 months after TIA and assessed the incremental value of copeptin compared with the ABCD2 (age, blood, clinical features of TIA, duration of symptoms, presence of diabetes mellitus) and ABCD3-I (ABCD2, dual TIA [the presence of ≥2 TIA symptoms within 7 days], imaging [the presence of abnormal findings on neuroimaging]) scores. METHODS: This prospective, multicenter cohort study was conducted at 3 tertiary Stroke Centers in Switzerland and Germany. RESULTS: From March 2009 through April 2011, we included 302 patients with TIA admitted within 24 hours from symptom onset. Of 28 patients with a recurrent cerebrovascular event within 3 months (stroke or TIA), 11 patients had a stroke. Although the association of copeptin with recurrent cerebrovascular events was not significant, the association with stroke alone as end point was significant. After adjusting for the ABCD2 score, a 10-fold increase in copeptin levels was associated with an odds ratio for stroke of 3.39 (95% confidence interval, 1.28-8.96; P=0.01). After addition of copeptin to the ABCD2 score, the area under the curve of the ABCD2 score improved from 0.60 (95% confidence interval, 0.46-0.74) to 0.74 (95% confidence interval, 0.60-0.88, P=0.02). In patients with MRI (n=223), the area under the curve of the ABCD3-I score increased in similar magnitude, although not significantly. Based on copeptin, 31.2% of patients were correctly reclassified across the risk categories of the ABCD2 score (net reclassification improvement; P=0.17). CONCLUSIONS: Copeptin improved the prognostic value of the ABCD2 score for the prediction of stroke but not TIA, and it may help clinicians in refining risk stratification for patients with TIA. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00878813.

Copeptin adds prognostic information after ischemic stroke: results from the CoRisk study.

OBJECTIVE: To evaluate and validate the incremental value of copeptin in the prediction of outcome and complications as compared with established clinical variables. METHODS: In this prospective, multicenter, cohort study, we measured copeptin in the emergency room within 24 hours from symptom onset in 783 patients with acute ischemic stroke. The 2 primary end points were unfavorable functional outcome (modified Rankin Scale score 3-6) and mortality within 90 days. Secondary end points were any of 5 prespecified complications during hospitalization. RESULTS: In multivariate analysis, higher copeptin independently predicted unfavorable outcome (adjusted odds ratio 2.17 for any 10-fold copeptin increase [95% confidence interval {CI}, 1.46-3.22], p < 0.001), mortality (adjusted hazard ratio 2.40 for any 10-fold copeptin increase [95% CI, 1.60-3.60], p < 0.001), and complications (adjusted odds ratio 1.93 for any 10-fold copeptin increase [95% CI, 1.33-2.80], p = 0.001). The discriminatory accuracy, calculated with the area under the receiver operating characteristic curve, improved significantly for all end points when adding copeptin to the NIH Stroke Scale score and the multivariate models. Moreover, the combination of copeptin with a validated score encompassing both the NIH Stroke Scale and age led to a net reclassification improvement of 11.8% for functional outcome and of 37.2% for mortality. CONCLUSIONS: In patients with ischemic stroke, copeptin is a validated blood marker that adds predictive information for functional outcome and mortality at 3 months beyond stroke severity and age. Copeptin seems to be a promising new blood marker for prediction of in-hospital complications.

Copeptin and risk stratification in patients with ischemic stroke and transient ischemic attack: the CoRisk study.

RATIONALE: Copeptin independently predicts functional outcome and mortality at 90 days and one-year after ischemic stroke. In patients with transient ischemic attack, elevated copeptin values indicate an increased risk of further cerebrovascular events. AIMS: The Copeptin Risk Stratification (CoRisk) study aims to validate the predictive value of copeptin in patients with ischemic stroke and transient ischemic attack. In patients with ischemic stroke, the CoRisk study aims to further explore the effect of treatment (i.e. thrombolysis) on the predictive value of copeptin. DESIGN: Prospective observational multicenter study analyzing three groups of patients, i.e. patients with ischemic stroke treated with and without thrombolysis and patients with transient ischemic attack. OUTCOMES: Primary end-point: In patients with ischemic stroke, the primary end-point includes disability (modified Rankin scale from 3 to 5) and mortality (modified Rankin scale 6) at three-months after stroke. In patients with transient ischemic attack, the primary end-point is a recurrent ischemic cerebrovascular event (i.e. ischemic stroke or recurrent transient ischemic attack). Secondary end-point: In patients with ischemic stroke, the secondary end-points include in-house complications (i.e. symptomatic intracerebral hemorrhage, malignant edema, aspiration pneumonia or seizures during hospitalization, and in-house mortality).

Characteristics, symptoms, and outcome of severe dysnatremias present on hospital admission.

OBJECTIVE: Dysnatremias are common in critically ill patients and associated with adverse outcomes, but their incidence, nature, and treatment rarely have been studied systematically in the population presenting to the emergency department. We conducted a study in patients presenting to the emergency department of the University of Bern. METHODS: In this retrospective case series at a university hospital in Switzerland, 77,847 patients admitted to the emergency department between April 1, 2008, and March 31, 2011, were included. Serum sodium was measured in 43,911 of these patients. Severe hyponatremia was defined as less than 121 mmol/L, and severe hypernatremia was defined as less than 149 mmol/L. RESULTS: Hypernatremia (sodium>145 mmol/L) was present in 2% of patients, and hyponatremia (sodium<135 mmol/L) was present in 10% of patients. A total of 74 patients had severe hypernatremia, and 168 patients had severe hyponatremia. Some 38% of patients with severe hypernatremia and 64% of patients with hyponatremia had neurologic symptoms. The occurrence of symptoms was related to the absolute elevation of serum sodium. Somnolence and disorientation were the leading symptoms in hypernatremic patients, and nausea, falls, and weakness were the leading symptoms in hyponatremic patients. The rate of correction did not differ between symptomatic and asymptomatic patients. Patients with symptomatic hypernatremia showed a further increase in serum sodium concentration during the first 24 hours after admission. Corrective measures were not taken in 18% of hypernatremic patients and 4% of hyponatremic patients. CONCLUSIONS: Dysnatremias are common in the emergency department. Hyponatremia and hypernatremia have different symptoms. Contrary to recommendations, serum sodium is not corrected more rapidly in symptomatic patients.

Dysnatraemias in the emergency room: Undetected, untreated, unknown?

BACKGROUND: Hypo- and hypernatraemia are the most common electrolyte disorders in hospitalized patients and have been associated with increased mortality. However, data on the prevalence of dysnatraemias in the emergency room and the characteristics of patients presenting with them are rare. METHODS: In this retrospective study, we analyzed data from patients who presented to the emergency department of a large tertiary university hospital between September 1st 2010 and November 30th 2010 and who received measurement of serum sodium. RESULTS: 3,182 patients received measurement of serum sodium during the three-month study period. 124 patients (4%) presented with hyponatraemia on admission to the emergency department while 400 patients (13%) presented with hypernatraemia. While there was no difference in age between patients with hypernatraemia and those who were normonatraemic, patients with hyponatraemia were significantly older. CONCLUSION: Dysnatraemias are present in almost 1 in 5 patients who presented to the emergency department. Contrarily to patients who are already hospitalized, hypernatraemia was by far more common than hyponatraemia in patients at the emergency department. Surprisingly, patients with hyponatraemia were significantly older than normonatraemic patients while there was no age difference in hypernatraemic patients. Dysnatraemias are common in the emergency room and further studies are indicated to evaluate the causes and the impact on outcome of patients.

Antibiotic prophylaxis in rhinosurgery.

BACKGROUND: This study investigated the in vivo efficacy of nasal packing containing an antibiotic substance after septal and turbinate surgery on the potentially infectious nasal flora (Staphylococcus aureus, etc.) without systemic administration of antibiotics. METHODS: The study was designed as an exploratory randomized trial. Three types of packings were used on 110 patients because of septoplasty and/or turbinate surgery. Packings were distributed randomly among three groups. The first and second groups received an antibiotic-free sample (polyvinyl acetate sponge and cotton gauze strips with sea-salt ointment) and the third group received an antibiotic one (cotton gauze strips with polymyxin-B-sulfate and oxytetracycline ointment). The nasal flora was determined by microscopy and cultures, both preoperatively and after elimination of the packing. RESULTS: Significantly less growth of the potentially infectious nasalflora overall and of S. aureus in particular was found in the group with the antibiotic packing. CONCLUSION: Antibiotic-containing nasal packing effectively inhibits potentially infectious germs (including S. aureus) in the nasal flora and secondarily may diminish the incidence of postoperative infections.