HUMANISE: Human-Inspired Smart Management, towards a Healthy and Safe Industrial Collaborative Robotics.

The workplace is evolving towards scenarios where humans are acquiring a more active and dynamic role alongside increasingly intelligent machines. Moreover, the active population is ageing and consequently emerging risks could appear due to health disorders of workers, which requires intelligent intervention both for production management and workers' support. In this sense, the innovative and smart systems oriented towards monitoring and regulating workers' well-being will become essential. This work presents HUMANISE, a novel proposal of an intelligent system for risk management, oriented to workers suffering from disease conditions. The developed support system is based on Computer Vision, Machine Learning and Intelligent Agents. Results: The system was applied to a two-arm Cobot scenario during a Learning from Demonstration task for collaborative parts transportation, where risk management is critical. In this environment with a worker suffering from a mental disorder, safety is successfully controlled by means of human/robot coordination, and risk levels are managed through the integration of human/robot behaviour models and worker's models based on the workplace model of the World Health Organization. The results show a promising real-time support tool to coordinate and monitoring these scenarios by integrating workers' health information towards a successful risk management strategy for safe industrial Cobot environments.

A Cross-Sectional, Retrospective, and Comparative Study between Delirium and Non-Delirium Psychiatric Disorders in a Psychogeriatric Inpatient Population Referred to Consultation-Liaison Psychiatry Unit.

Background and objectives: Delirium is the most prevalent psychiatric disorder in inpatient older people. Its presence is associated with higher rates of institutionalization, functional disability and mortality. This study aims to evaluate delirium in a hospitalized psychogeriatric population, focusing on which factors predict the appearance of delirium, the impact it generates and the diagnostic concordance between non-psychiatric physicians and psychiatrists. Material and methods: This is an observational, cross-sectional, retrospective, and comparative study. We obtained data from a sample of 1017 patients (≥65 years) admitted to general hospital and referred from different services to the consultation-liaison psychiatry (CLP) unit. Logistic regression was performed using delirium as the dependent variable. To estimate the concordance of the diagnoses, the Kappa coefficient was used. To assess the impact of delirium, an ordinal regression, Wilcoxon median test and Fisher's test were performed. Results: Delirium is associated with a higher number of visits, OR 3.04 (95% CI 2.38-3.88), longer length of stay and mortality, OR 2.07 (95% CI, 1.05 to 4.10). The model to predict delirium shows that being >75 years old has an OR of 2.1 (95% CI, 1.59-2.79), physical disability has an OR of 1.66 (95% CI, 1.25-2.20), history of delirium has an OR of 10.56 (95% CI, 5.26-21.18) and no use of benzodiazepines has an OR of 4.24 (95% CI, 2.92-6.14). The concordance between the referring physician's psychiatric diagnosis and the psychiatrist CLP unit showed a kappa of 0.30. When analysing depression and delirium, the concordance showed Kappa = 0.46. Conclusions: Delirium is a highly prevalent psychiatric disorder, but it is still underdiagnosed, with low diagnostic concordance between non-psychiatric doctors and psychiatrists from CLP units. There are multiple risk factors associated with the appearance of delirium, which must be managed to reduce its appearance.

Ocular related emergencies in Spain during the COVID-19 pandemic, a multicenter study.

PURPOSE: To evaluate ophthalmological emergencies (OE) during the COVID-19 pandemic comparing them with the same period of the previous year. METHODS: Retrospective observational study of all OE visits in four tertiary hospitals in Spain comparing data from March 16th to April 30th, 2020 (COVID-19 period) and the same period of 2019 (pre-COVID-19 period). Severity of the conditions was assessed following Channa et al. publication. Data on demographics, diagnosis and treatments were collected from Electronic Medical Records. RESULTS: During lockdown, OE significantly declined by 75.18%, from 7,730 registered in the pre-COVID-19 period to 1,928 attended during the COVID-19 period (p < 0.001). In 2019, 23.86% of visits were classified as emergent, 59.50% as non-emergent, and 16.65% could not be determined. In 2020, the percentage of emergent visits increased up to 29.77%, non-emergent visits significantly decreased to 52.92% (p < 0.001), and 17.31% of the visits were classified as "could not determine". During the pandemic, people aged between 45 and 65 years old represented the largest attending group (37.89%), compared to 2019, where patients over 65 years were the majority (39.80%). In 2019, most frequent diagnosis was unspecified acute conjunctivitis (11.59%), followed by vitreous degeneration (6.47%), and punctate keratitis (5.86%). During the COVID-19 period, vitreous degeneration was the first cause for consultation (9.28%), followed by unspecified acute conjunctivitis (5.63%) and punctate keratitis (5.85%). CONCLUSIONS: OE visits dropped significantly during the pandemic in Spain (75.18%), although more than half were classified as non-urgent conditions, indicating a lack of understanding of the really emergent ocular pathologies among population.

Frequent Placental SARS-CoV-2 in Patients with COVID-19-Associated Hypertensive Disorders of Pregnancy.

INTRODUCTION: Studies described an increased frequency of hypertensive disorders of pregnancy (HDP) after a COVID-19 episode. There is limited evidence about SARS-CoV-2 viral load in placenta. This study aimed to investigate the relationship between SARS-CoV-2 viral load in the placenta and clinical development of HDP after COVID-19 throughout different periods of gestation. METHODS: This is a case-control study in women with and without gestational hypertensive disorders after SARS-CoV-2 infection diagnosed by RT-PCR during pregnancy. Patients were matched by gestational age at the moment of COVID-19 diagnosis. We performed an analysis of SARS-CoV-2 RNA levels in placenta. RESULTS: A total of 28 women were enrolled. Sixteen patients were diagnosed with COVID-19 during the third trimester and the remaining 12 patients in the other trimesters. Ten placentas (35.7%) were positive for SARS-CoV-2, 9 of them (9/14, 64.3%) belonged to the HDP group versus 1 (1/14, 7.2%) in the control group (p = 0.009). Those cases with the highest loads of viral RNA developed severe preeclampsia (PE). CONCLUSION: Among women diagnosed with COVID-19 during pregnancy, the presence of SARS-CoV-2 in the placenta was more frequent among women suffering from PE or gestational hypertension. Furthermore, the most severe cases of HDP were associated with high placental viral load, not necessarily associated with a positive nasopharyngeal RT-PCR at delivery. Our data suggest that SARS-CoV-2 infection during pregnancy could trigger gestational hypertensive disorders through persistent placental infection and resulting placental damage.

Clinical Profile and Length of Hospital Stay in a Sample of Psychogeriatric Patients Referred to Consultation Liaison Psychiatric Unit.

Background and objectives: There has been a recent increase in older patients admitted to general hospitals. A significant percentage of hospitalized older patients are ≥75 years old, which differ from the patients aged 65 to 74 years old in terms of functional status at patient discharge. This study aims to compare sociodemographic, clinical features, and factors associated with length of hospital stay in youngest-old and oldest-old populations of inpatients referred to the consultation liaison psychiatry unit. Material and methods: This is an observational, cross-sectional, retrospective, and comparative study. We obtained data from a sample of 1017 patients (≥65 years) admitted to a general hospital and referred from different services (medicine, surgery, etc.) to the consultation liaison psychiatry unit. The sample was divided into two groups of patients: youngest-old (65-74 years) and oldest-old (≥75 years). Psychiatric evaluations were performed while the patients were on wards at the hospital. Psychopharmacs were started as needed. A comparative analysis was carried out and predictive factors related to length of hospital stay were calculated. Results: The reference rate to consultation liaison psychiatry unit was 1.45% of the total older patients hospitalized. Our study demonstrates differences between the groups of older people: the oldest-old group were mainly female (p < 0.001), had more previous psychiatric diagnoses (p < 0.001), physical disabilities (p = 0.02), and neurocognitive disorders (p < 0.001), they used more antipsychotics (p < 0.001), and more frequently had a discharge disposition to a nursing home (p = 0.036). The presence of physical disability (beta = 0.07, p < 0.001) and logtime to referral to consultation liaison psychiatry unit (beta = 0.58, p < 0.001) were associated with increased length of hospital stay. Conclusions: Youngest-old and oldest-old people should be considered as two different types of patients when we consider clinical features. The time to referral to consultation liaison psychiatry unit seems to be a relevant factor associated with length of hospital stay.

Optimization of Diabetic Macular Edema Management in the Real World: A Model of Excellence in Retina Units: The EMUREX Initiative.

PURPOSE: To define and develop a model of excellence for the clinical management of diabetic macular edema (DME) patients in a real-world setting. METHODS: A multidisciplinary joint commission (5 ophthalmologists, 1 nurse, and 1 pharmaceutic) established a series of preliminary recommendations based on clinical guidelines and DME activity results from 8 Pilot Hospitals (PH). These were validated by members of each PH and a group of DME patients in discussion workshops. Thus, the validated guideline (VG) took into consideration different aspects, namely, main core points (ranging 0-100), criteria, and indicators. Finally, each PH own setting was compared to the VG in order to settle down a starting point to clinical excellence. RESULTS: Mean PH score was 51.5 (range 30-65). As compared to their maximum, main points that showed best scores were Clinical Guidelines and Protocols (78%) and Portfolio of Services (73%). Topics reaching close to 50% scoring included Resources (55%), Innovation (54%), Care Process (53%), Organization (52%), and Leadership (50%). Lowest scores were observed in the Strategic Alliances (46%) and Staff (37%) points. CONCLUSIONS: Analysis of each PH by the VG delivered a global vision of the starting situation, especially focused in the identification of the different improvement areas. In order to further extend this model into the Public Health System, the effect of implementing it in different hospitals should be assessed to analyze its impact on daily clinical practice and health economics.

Relationship between vascular densities of choriocapillaris and the whole choroid using OCTA.

PURPOSE: To study the vascular density (VD) of choriocapillaris and the whole choroid using optical coherence tomography-angiography (OCTA). METHODS: Cross-sectional study enrolling healthy individuals between 18 and 35 years old and with an axial length (AL) lower than 26 mm, who were examined with swept-source OCTA Triton DRI (Topcon). Color pictures of both VD were obtained from a fovea-centered 6 × 6 mm macular exam, which were divided into 900 squares and codified into numbers. RESULTS: A total of 50 patients (100 eyes) with a mean age of 27.29 ± 3.90 years and a mean AL of 23.67 ± 0.74 mm were analyzed. The highest choroidal VD was found in juxtapapillary macula, being followed by the most temporal macula and fovea. The lowest was found in superior and inferior perifoveal areas. The highest VD in choriocapillaris was in the fovea. VD in this layer was uniform, with a decrease from temporal toward nasal. Both VD differed and but correlated, especially in the fovea and in inferior-temporal macula. CONCLUSION: VD of choriocapillaris and the whole choroid are not similar. The former is maximal in the fovea, and the latter is maximal in the juxtapapillary macula. In general lines, choroidal VD is higher than that of choriocapillaris. Both VD are directly correlated.

REPEATABILITY OF CHOROIDAL THICKNESS MEASUREMENTS ASSESSED WITH SWEPT-SOURCE OPTICAL COHERENCE TOMOGRAPHY IN HEALTHY AND DIABETIC INDIVIDUALS.

PURPOSE: To assess the intrasession repeatability of choroidal thickness measurements obtained using swept-source optical coherence tomography in Type 2 diabetic (T2D) patients and healthy controls. METHODS: This was a single-center, prospective, observational, cross-sectional study with consecutive inclusion of 33 healthy subjects and 43 T2D patients. Subjects underwent three consecutive swept-source optical coherence tomography scans in a single session. After automatic delineation of the choroid, subfoveal choroidal thickness, and thickness at 500-µm intervals up to 2,500 µm nasal and temporal from the fovea were measured using the software caliper by the same operator. Intraclass correlation coefficients (ICCs), coefficients of variation, and test-retest variability were calculated. RESULTS: Mean subfoveal choroidal thickness in healthy subjects and in T2D patients was 229.97 ± 79.9 and 192.67 ± 74.3 µm, respectively (P = 0.013). All intrasession intraclass correlation coefficients were higher than 0.95 and 0.99, respectively. Coefficients of variations were less than 4.4% and 1.8%, respectively. Test-retest variability ranged from 0.76 µm to 11.12 µm and 0.64 µm to 6.29 µm, respectively. No significant differences were found in the intrasession repeatability of any choroidal measurement between healthy subjects and T2D patients. CONCLUSION: Swept-source optical coherence tomography provided excellent intrasession repeatability of choroidal thickness measurements in healthy subjects and T2D patients.

OCULAR ADVERSE EVENTS ASSOCIATED WITH MEK INHIBITORS.

PURPOSE: Mitogen-activates protein kinase (MAPK) inhibitors, particularly MEK inhibitors, have shifted the treatment paradigm for metastatic BRAF-mutant cutaneous melanoma; however, oncologists, ophthalmologists, and patients have noticed different toxicities of variable importance. This review aims to provide an update of the ocular adverse events (OAEs), especially retinal toxicity, associated with the use of MEK inhibitors. METHODS: We conducted a scientific literature search using the PubMed database up to July 2018 with the terms "MEK inhibitors" with a "review" filter and "MEK inhibitors" with a "clinical trials" filter. Phase I-III experimental studies and reviews were selected. Current principles and techniques for diagnosing and managing MEK inhibitor retinopathy and other OAEs are discussed. RESULTS: In patients treated with MEK inhibitors, including asymptomatic patients, OAEs occur with an incidence of up to 90%. Mild to severe ophthalmic toxicities are described, including visual disturbances, a 2-line decrease in Snellen visual acuity, dry eye symptoms, ocular adnexal abnormalities, visual field defects, panuveitis, and retinal toxicities, such as different degrees of MEK-associated retinopathy, vascular injury, and retinal vein occlusion. CONCLUSION: MEK inhibitors can lead to different degrees of retinal, uveal, and adnexal OAE, causing visual disturbances or discomfort. One of the most relevant OAE of MEK therapy is MEK inhibitor-associated retinopathy (MEKAR), which is usually mild, self-limited, and may subside after continuous use of the drug for weeks or months, or discontinuation, thereby restoring the normal visual function of the retina, with some exceptions. Ocular adverse events are often associated with other systemic adverse effects that can modify the dosage of treatment, so the communication with the oncologist is fundamental.

EFFECT OF AN INTRAVITREAL DEXAMETHASONE IMPLANT ON DIABETIC MACULAR EDEMA AFTER CATARACT SURGERY.

PURPOSE: To analyze the effects of a dexamethasone intravitreal implant (DEX; Ozurdex 700 µg; Allergan) administered immediately after cataract surgery in diabetic patients. METHODS: This prospective, single-arm, open label study (NCT01748487 at ClinicalTrials.gov) involved Type 2 diabetic patients with at least mild diabetic retinopathy (DR) who underwent cataract surgery and DEX insertion after phacoemulsification, and intraocular lens implantation were enrolled. Best-corrected visual acuity and central retinal thickness (CRT) measured by spectral-domain optical coherence tomography were recorded at 1 week preoperatively, and 1 week, 1 month, and 3 months after surgery. Adverse events were also recorded. RESULTS: Twenty-four eyes of 24 patients (17 [70.8%] men; mean age 63.7 ± 8.7 years) with mild nonproliferative DR (41.7%), moderate nonproliferative DR (33.3%), severe nonproliferative DR (16.7%), or treated proliferative DR (8.3%) were selected. After DEX treatment, mean CRT changed from 241.1 µm (95% confidence interval, 227.5-254.6 µm) at baseline to 236.9 µm (95% confidence interval, 223.9-249.9 µm) at 1 week (P = 0.09), 238.9 µm (95% confidence interval, 225.5-252.3 µm) at 1 month (P = 0.44), and 248 µm (95% confidence interval, 232.4-260.8 µm) at 3 months (P = 0.15). No eyes showed a postoperative increase >50 µm in the CRT at any visit. A 10% increase in CRT was found in 8.3% of eyes. Mean best-corrected visual acuity significantly improved from 0.37 (20/50) at baseline to 0.19 (20/30) at 1 week, 0.12 (20/25) at 1 month, and 0.12 (20/25) at 3 months (P < 0.001 for each comparison). Mean intraocular pressure before surgery was 13.8 mmHg, and none of the patients developed an intraocular pressure ≥22 mmHg at any visit. None of the patients developed any serious adverse events during the follow-up. CONCLUSION: These short-term results suggest that a single DEX injection intraoperatively after phacoemulsification could avoid an increase in CRT after cataract surgery in diabetic patients.

BLINDNESS RELATED TO PRESUMED RETINAL TOXICITY AFTER USING PERFLUOROCARBON LIQUID DURING VITREORETINAL SURGERY.

PURPOSE: To describe the presumed retinal toxicity after using specific batches of perfluorocarbon liquid ALA OCTA (Alamedics, Dornstadt, Germany) in pars plana vitrectomy. METHODS: This is an observational retrospective consecutive case series analyses of patients operated on pars plana vitrectomy for retinal detachment or intraocular lens subluxation, using the 150141 or 200114 batches of perfluorocarbon liquid ALA OCTA as assistance during the surgery in a single center. Patients were included in this report if they manifested retinal toxicity signs throughout the follow-up, such as retinal and retinal pigment epithelium atrophy, disk paleness, and intensive macular fibrosis. Spectral domain optical coherence tomography (Spectralis; Heidelberg Engineering, Heidelberg, Germany) and Ultra-Wide Field 200° retinal camera (Optos P200Tx; Optos, Scotland, United Kingdom) images, electrophysiological tests, and visual fields were performed to analyze the retinal structure and functionality. RESULTS: Seven of 80 patients showed all the described signs of toxicity, after a mean follow-up of 34.29 days (range: 10-87) since surgery. Four patients needed a second pars plana vitrectomy because of tractional retinal detachment and proliferative vitreoretinopathy, and two of them underwent a third surgery because of redetachment. All patients experienced amaurosis or central scotoma, with a final best-corrected visual acuity ranging from 20/200 to light perception. CONCLUSION: Presumed toxic batches of perfluorocarbon liquid may cause massive retinal toxicity. A rapid suspicion, a correct traceability of surgical products, and informing health authorities are fundamental to prevent further cases of toxicity.

Improved pharmacokinetic profile of lipophilic anti-cancer drugs using ανß3-targeted polyurethane-polyurea nanoparticles.

Glutathione degradable polyurethane-polyurea nanoparticles (PUUa NP) with a disulfide-rich multiwalled structure and a cyclic RGD peptide as a targeting moiety were synthesized, incorporating a very lipophilic chemotherapeutic drug named Plitidepsin. In vitro studies indicated that encapsulated drug maintained and even improved its cytotoxic activity while in vivo toxicity studies revealed that the maximum tolerated dose (MTD) of Plitidepsin could be increased three-fold after encapsulation. We also found that pharmacokinetic parameters such as maximum concentration (Cmax), area under the curve (AUC) and plasma half-life were significantly improved for Plitidepsin loaded in PUUa NP. Moreover, biodistribution assays in mice showed that RGD-decorated PUUa NP accumulate less in spleen and liver than non-targeted conjugates, suggesting that RGD-decorated nanoparticles avoid sequestration by macrophages from the reticuloendothelial system. Overall, our results indicate that polyurethane-polyurea nanoparticles represent a very valuable nanoplatform for the delivery of lipophilic drugs by improving their toxicological, pharmacokinetic and whole-body biodistribution profiles.

Automatic Analysis of Archimedes' Spiral for Characterization of Genetic Essential Tremor Based on Shannon's Entropy and Fractal Dimension.

Among neural disorders related to movement, essential tremor has the highest prevalence; in fact, it is twenty times more common than Parkinson's disease. The drawing of the Archimedes' spiral is the gold standard test to distinguish between both pathologies. The aim of this paper is to select non-linear biomarkers based on the analysis of digital drawings. It belongs to a larger cross study for early diagnosis of essential tremor that also includes genetic information. The proposed automatic analysis system consists in a hybrid solution: Machine Learning paradigms and automatic selection of features based on statistical tests using medical criteria. Moreover, the selected biomarkers comprise not only commonly used linear features (static and dynamic), but also other non-linear ones: Shannon entropy and Fractal Dimension. The results are hopeful, and the developed tool can easily be adapted to users; and taking into account social and economic points of view, it could be very helpful in real complex environments.

Threatened preterm labor is a risk factor for impaired cognitive development in early childhood.

BACKGROUND: Threatened preterm labor is a leading cause of hospital admission during pregnancy. Patients with an episode of threatened preterm labor who deliver at term are considered to have false preterm labor. However, threatened preterm labor has been proposed as a pathologic insult that is not always sufficient to induce irreversible spontaneous preterm birth but that could alter the normal course of pregnancy. OBJECTIVE: The aim of this study was to evaluate threatened preterm labor during pregnancy as a risk factor of neurodevelopmental deficits of children at 2 years of age. STUDY DESIGN: Two-year-old children who were born late preterm (n=22) or at term after threatened preterm labor (n=23) were compared with at-term control children (n=42). Neurodevelopment was evaluated at a corrected age of 24-29 months with the use of the Merrill-Palmer-Revised Scales of Development. RESULTS: Children who were born at term after threatened preterm labor had lower scores than control children on global cognitive index (95.4 vs 104.2; P=.011), cognition (95.1 vs 103.1; P=.021), fine motor (95.2 vs 103.4; P=.003), gross motor (84.7 vs 99.8; P=.001), memory (92.9 vs 100.4; P=.015), receptive language (93.9 vs 102.9; P=.03), speed of processing (105.7 vs 113.3; P=.011), and visual motor coordination (98.8 vs 106.7; P=.003) subtests. Children born at term after threatened preterm labor had an increased risk of mild neurodevelopmental delay compared with control children (odds ratio for global cognitive index, 2.06; 95% confidence interval, 1.09-3.88; P=.033). There were no significant differences in any cognitive domain between children who were born late preterm and children who were born at term after threatened preterm labor. CONCLUSIONS: Threatened preterm labor is a risk factor for impaired cognitive development at 2 years of age, even if birth occurred at term.

Assessment of the retinal nerve fiber layer in individuals with obstructive sleep apnea.

BACKGROUND: The effect of obstructive sleep apnea (OSA) syndrome in the peripapillary retinal nerve fiber layer (RNFL) thicknesses remains unclear. The purpose of this study was to assess RNFL measurements acquired using scanning laser polarimetry (SLP) and optical coherence tomography (OCT) in patients with OSA. METHODS: The sample of this cross-sectional study included 40 OSA patients and 45 age-matched controls, consecutively and prospectively selected. All participants underwent at least one reliable standard automated perimetry (SAP) test, while RNFL measurements were obtained using the SLP and OCT. The OSA group was divided into 3 sub-groups based on the apnea/hypopnea index (AHI): mild, moderate, or severe OSA. SAP, SLP, and OCT outcomes were compared between the control and OSA groups. The relationship between AHI and RNFL parameters was also evaluated. RESULTS: Age was not different between both groups. Mean deviation of SAP was -0.47 ± 0.9 dB and -1.43 ± 2.3 dB in the control and OSA groups, respectively (p = 0.01). RNFL thickness measured with OCT was similar between groups. OSA patients showed increased nerve fiber indicator (NFI; 20.9 ± 7.9 versus 16.42 ± 7.82; p = 0.01) and decreased superior average (59.74 ± 10.35 versus 63.73 ± 6.58; p = 0.03) obtained with SLP compared with healthy individuals. In the total sample, NFI and AHI were moderately correlated (r = 0.358; p = 0.001). In severe OSA subjects (n = 22), NFI and AHI had a Spearman correlation coefficient of 0.44 (p = 0.04). CONCLUSION: RNFL thickness measured with OCT did not differ significantly between groups. Severe OSA was related to a reduction of the RNFL thickness assessed by SLP.

Macular Retinal Ganglion Cell Layer Thickness Is Not Reduced in Patients with Obstructive Sleep Apnea.

PURPOSE: To evaluate macular ganglion cell layer (GCL) and ganglion cell-inner plexiform layer (GCIPL) thicknesses in patients with obstructive sleep apnea (OSA) syndrome. METHODS: 73 OSA patients and 67 age-matched controls were consecutively and prospectively enrolled. All participants underwent at least one reliable standard automated perimetry (SAP) and were imaged with spectral-domain optical coherence tomography (OCT) using two different devices. The OCT parameters were compared between groups, and Pearson correlations between main indices of SAP and OCT parameters were calculated. RESULTS: The pattern standard deviation of SAP was higher in the OSA group (p = 0.001). Mean GCIPL thickness was 82.99 ± 10.30 and 80.78 ± 12.15 µm in the control and OSA groups, respectively (p = 0.25), and GCL thickness was 44.93 ± 11.42 µm in the control group and 48.81 ± 10.85 µm in OSA individuals (p = 0.47). Pearson correlations between the GCIPL-GCL measurements and the main indices of SAP were not significant. CONCLUSIONS: Neither GCIPL nor GCL thickness were reduced in OSA subjects compared with healthy individuals. Retinal sensitivity evaluated with SAP was however decreased in OSA patients.

Nano-encapsulation of plitidepsin: in vivo pharmacokinetics, biodistribution, and efficacy in a renal xenograft tumor model.

PURPOSE: Plitidepsin is an antineoplasic currently in clinical evaluation in a phase III trial in multiple myeloma (ADMYRE). Presently, the hydrophobic drug plitidepsin is formulated using Cremophor®, an adjuvant associated with unwanted hypersensitivity reactions. In search of alternatives, we developed and tested two nanoparticle-based formulations of plitidepsin, aiming to modify/improve drug biodistribution and efficacy. METHODS: Using nanoprecipitation, plitidepsin was loaded in polymer nanoparticles made of amphiphilic block copolymers (i.e. PEG-b-PBLG or PTMC-b-PGA). The pharmacokinetics, biodistribution and therapeutic efficacy was assessed using a xenograft renal cancer mouse model (MRI-H-121 xenograft) upon administration of the different plitidepsin formulations at maximum tolerated multiple doses (0.20 and 0.25 mg/kg for Cremophor® and copolymer formulations, respectively). RESULTS: High plitidepsin loading efficiencies were obtained for both copolymer formulations. Considering pharmacokinetics, PEG-b-PBLG formulation showed lower plasma clearance, associated with higher AUC and Cmax than Cremophor® or PTMC-b-PGA formulations. Additionally, the PEG-b-PBLG formulation presented lower liver and kidney accumulation compared with the other two formulations, associated with an equivalent tumor distribution. Regarding the anticancer activity, all formulations elicited similar efficacy profiles, as compared to the Cremophor® formulation, successfully reducing tumor growth rate. CONCLUSIONS: Although the nanoparticle formulations present equivalent anticancer activity, compared to the Cremophor® formulation, they show improved biodistribution profiles, presenting novel tools for future plitidepsin-based therapies.

Structure-Function Relationship between Frequency-Doubling Technology Perimetry and Optical Coherence Tomography in Glaucoma.

Purpose: To assess the relationship between the retinal nerve fibre layer (RNFL) thickness and the frequency-doubling technology perimetry (FDT) outcome. Methods: Sixty-two healthy individuals and 72 glaucoma patients were prospectively selected. All participants underwent a reliable FDT and optical coherence tomography (OCT). Pearson correlations were calculated between the unlogged threshold values of FDT and RNFL thicknesses measured by OCT. Results: Mild to moderate correlations were found between a few points from FDT and RNFL thicknesses in the vertical axis. The nasal superior area of FDT and the RNFL thickness at the 7-o'clock position had the strongest correlation (0.434, p < 0.001). Conclusions: The poor agreement between FDT and OCT parameters suggests that both instruments assess different characteristics of glaucomatous optic neuropathy. The map obtained validates previously reported clinical findings and contributes to a better understanding of the structure-function relationship in glaucoma. © 2014 S. Karger AG, Basel.

Burden of Disease Study of Patients with Neovascular Age-Related Macular Degeneration in Spain.

INTRODUCTION: Neovascular age-related macular degeneration (nAMD) is a progressive retinal disease that causes severe and irreversible vision loss. The disease can therefore have a significant impact on the life of patients' and their families. The aim of this study was to evaluate the socio-economic burden of nAMD in Spain. METHODS: The annual cost per patient with nAMD was estimated for the first, second, and third year (or beyond) of treatment since diagnosis. Several cost categories were considered including direct healthcare costs (DHC), direct non-healthcare costs (DNHC), labor productivity losses (LPL), and intangible costs (IC) related to loss of quality of life. The average annual cost per patient was estimated by assigning a unit price or financial proxy to the resources consumed per patient. Reference year of costs was 2021. RESULTS: The mean annual cost of nAMD was estimated at €17,265, €15,403, and €14,465 per patient in the first, second, and third year of treatment after diagnosis. There was an additional one-off cost of €744 associated with the diagnosis of nAMD. DHC accounted for most of the total annual cost per patient independent of the year of treatment since diagnosis (48% in year 1; 42% in year 2; 39% in year 3). Similarly, DNHC had an important contribution to the total costs (32% in year 1; 35% in year 2; 37% in year 3), followed by IC (20% in year 1; 23% in year 2; 24% in year 3), while the contribution of patients' LPL was minimal. CONCLUSION: This study estimated a high economic burden associated with nAMD for patients and their families, the healthcare system, and society at large. There is a need to improve the management of these patients to reduce the impact of nAMD disease progression.

Burden of Disease Study of Patients with Diabetic Macular Oedema in Spain.

INTRODUCTION: Diabetic macular oedema (DMO) is a complication of diabetic retinopathy that can result in vision loss. The disease can impact different spheres of a patient's life, including physical and psychological health, work, and activities of daily living, entailing an important use of healthcare and non-healthcare resources. This study aimed to estimate the socio-economic burden of DMO in Spain. METHODS: The burden of DMO was estimated from a societal perspective, per patient, year of treatment since diagnosis, and type of treatment. Four categories were considered: direct healthcare costs (DHC), direct non-healthcare costs (DNHC), labour productivity losses (LPL), and intangible costs (IC) associated with loss of quality of life. Average annual costs were calculated by multiplying the resources used per patient by their corresponding unit price (or financial proxy). For a more accurate estimation, differences in resource use between treatments (intravitreal anti-vascular endothelial growth factor injections of ranibizumab or aflibercept, and intravitreal dexamethasone implants) and year since diagnosis (first, second, and third year or beyond) were considered and presented separately. The reference year for costs was 2021. RESULTS: The average annual costs of DMO in the first year of treatment after diagnosis was estimated at €18,774, €17,512, and €16,188 per patient treated with ranibizumab, aflibercept, and dexamethasone, respectively. This burden would be reduced to €15,783, €15,701, and €12,233 in the second year, and to €15,119, €15,043, and €12,790 in the third year, respectively. Diagnosis of DMO entails an additional one-off cost of €485. DHC accounted for the greatest proportion of total annual costs per patient, independent of the year, with LPL also making an important contribution to total costs. CONCLUSIONS: The socio-economic impact of DMO on patients, the healthcare system, and society at large is substantial. The constant increase in its prevalence accentuates the need for planning and implementation of healthcare strategies to prevent vision loss and reduce the socio-economic burden of the disease.