In Vivo Applications of Dendrimers: A Step toward the Future of Nanoparticle-Mediated Therapeutics.

Over the last few years, the development of nanotechnology has allowed for the synthesis of many different nanostructures with controlled sizes, shapes, and chemical properties, with dendrimers being the best-characterized of them. In this review, we present a succinct view of the structure and the synthetic procedures used for dendrimer synthesis, as well as the cellular uptake mechanisms used by these nanoparticles to gain access to the cell. In addition, the manuscript reviews the reported in vivo applications of dendrimers as drug carriers for drugs used in the treatment of cancer, neurodegenerative diseases, infections, and ocular diseases. The dendrimer-based formulations that have reached different phases of clinical trials, including safety and pharmacokinetic studies, or as delivery agents for therapeutic compounds are also presented. The continuous development of nanotechnology which makes it possible to produce increasingly sophisticated and complex dendrimers indicates that this fascinating family of nanoparticles has a wide potential in the pharmaceutical industry, especially for applications in drug delivery systems, and that the number of dendrimer-based compounds entering clinical trials will markedly increase during the coming years.

Ellipsoid Zone recovery in Macular Telangiectasia Type 2 (MacTel).

PURPOSE: To describe imaging features of Macular Telangiectasia Type 2 (MacTel) eyes experiencing ellipsoid zone (EZ) recovery. METHODS: MacTel patients with EZ-recovery were identified from the Natural History and Observational Registry Study and underwent retinal imaging including optical coherence tomography (OCT) and fundus photography. Eyes were graded according to the classification system by Gass and Blodi, the EZ-loss area was measured and OCT parameters were assessed by two independent readers. Parameters were analysed for their presence prior to EZ-recovery. RESULTS: Twenty-four eyes of 21 patients (12 female, 57.12%; mean age 68 ± 8.54 years) were included in this study and followed for 21.25 ± 12.79 months. At baseline, mean EZ-loss area was 0.036 ± 0.028 mm2 and 0.01 ± 0.013 mm2 at follow-up (p<0.001). A persisting external limiting membrane overlaying the EZ-loss was detected in 16 cases (66%) and hyperreflective changes in the outer retina were present in 18 cases (75%). Best corrected visual acuity was 0.23 (20/32) ± 0.33 logMar at baseline and 0.34 (20/40) ± 0.34 logMar at follow up (p=0.3). CONCLUSION: Distinct OCT features precede ellipsoid zone recovery in MacTel and warrant further studies investigating implications for patient care and clinical trial interpretation.

Mathematical modelling of the waning of anti-RBD IgG SARS-CoV-2 antibody titers after a two-dose BNT162b2 mRNA vaccination.

Background: After exposure to SARS-CoV-2 and/or vaccination there is an increase in serum antibody titers followed by a non-linear waning. Our aim was to find out if this waning of antibody titers would fit to a mathematical model. Methods: We analyzed anti-RBD (receptor binding domain) IgG antibody titers and the breakthrough infections over a ten-month period following the second dose of the mRNA BNT162b2 (Pfizer-BioNtech.) vaccine, in a cohort of 54 health-care workers (HCWs) who were either never infected with SARS-CoV-2 (naïve, nHCW group, n=27) or previously infected with the virus (experienced, eHCW group, n=27). Two mathematical models, exponential and power law, were used to quantify antibody waning kinetics, and we compared the relative quality of the goodness of fit to the data between both models was compared using the Akaik Information Criterion. Results: We found that the waning slopes were significantly more pronounced for the naïve when compared to the experienced HCWs in exponential (p-value: 1.801E-9) and power law (p-value: 9.399E-13) models. The waning of anti-RBD IgG antibody levels fitted significantly to both exponential (average-R2: 0.957 for nHCW and 0.954 for eHCW) and power law (average-R2: 0.991 for nHCW and 0.988 for eHCW) models, with a better fit to the power law model. In the nHCW group, titers would descend below an arbitrary 1000-units threshold at a median of 210.6 days (IQ range: 74.2). For the eHCW group, the same risk threshold would be reached at 440.0 days (IQ range: 135.2) post-vaccination. Conclusion: Two parsimonious models can explain the anti-RBD IgG antibody titer waning after vaccination. Regardless of the model used, eHCWs have lower waning slopes and longer persistence of antibody titers than nHCWs. Consequently, personalized vaccination booster schedules should be implemented according to the individual persistence of antibody levels.

Baricitinib improves respiratory function in patients treated with corticosteroids for SARS-CoV-2 pneumonia: an observational cohort study.

OBJECTIVES: The Janus kinase (JAK) inhibitor baricitinib may block viral entry into pneumocytes and prevent cytokine storm in patients with SARS-CoV-2 pneumonia. We aimed to assess whether baricitinib improved pulmonary function in patients treated with high-dose corticosteroids for moderate to severe SARS-CoV-2 pneumonia. METHODS: This observational study enrolled patients with moderate to severe SARS-CoV-2 pneumonia [arterial oxygen partial pressure (PaO2)/fraction of inspired oxygen (FiO2) <200 mmHg] who received lopinavir/ritonavir and HCQ plus either corticosteroids (CS group, n = 50) or corticosteroids and baricitinib (BCT-CS group, n = 62). The primary end point was the change in oxygen saturation as measured by pulse oximetry (SpO2)/FiO2 from hospitalization to discharge. Secondary end points included the proportion of patients requiring supplemental oxygen at discharge and 1 month later. Statistics were adjusted by the inverse propensity score weighting (IPSW). RESULTS: A greater improvement in SpO2/FiO2 from hospitalization to discharge was observed in the BCT-CS vs CS group (mean differences adjusted for IPSW, 49; 95% CI: 22, 77; P < 0.001). A higher proportion of patients required supplemental oxygen both at discharge (62.0% vs 25.8%; reduction of the risk by 82%, OR adjusted for IPSW, 0.18; 95% CI: 0.08, 0.43; P < 0.001) and 1 month later (28.0% vs 12.9%, reduction of the risk by 69%, OR adjusted for IPSW, 0.31; 95% CI: 0.11, 0.86; P = 0.024) in the CS vs BCT-CS group. CONCLUSIONS: . In patients with moderate to severe SARS-CoV-2 pneumonia a combination of baricitinib with corticosteroids was associated with greater improvement in pulmonary function when compared with corticosteroids alone. TRIAL REGISTRATION: European Network of Centres for Pharmacoepidemiology and Pharmacovigilance, ENCEPP (EUPAS34966, http://www.encepp.eu/encepp/viewResource.htm? id = 34967).

Closing the Serological Gap in the Antiphospholipid Syndrome: The Value of "Non-criteria" Antiphospholipid Antibodies.

OBJECTIVE: Most clinicians use the 2006 Sydney classification criteria to evaluate patients suspected of having antiphospholipid syndrome (APS). Although sensitive and specific for APS, many patients fulfilling clinical criteria for the syndrome are persistently negative for the specific serological tests ("laboratory criteria"). These "seronegative APS" (SN-APS) patients can go undiagnosed and untreated until they experience serious clinical events. This study's objective was to describe antibody profiles of SN-APS patients using non-criteria markers, assess the clinical utility of these markers separately and in combination, and suggest incorporation into guidelines for patients suspected of APS. METHODS: We categorized 175 consecutive patients suspected of APS into 2 subgroups: 107 fulfilling Sydney APS classification for seropositive APS (SP-APS) and 68 with clinical manifestations suggestive of APS but having negative serology, on 2 occasions, for criteria markers (SN-APS). On study inclusion, samples were retested for criteria and 11 non-criteria markers, including antiphosphatidylserine/prothrombin antibodies. RESULTS: Using 4 of 11 non-criteria tests, a cumulative 30.9% of SN-APS patients were detected. Combining results of all 11 non-criteria tests, 25 SN-APS (36.8%) and 89 SP-APS (83.2%) were positive for 1 or more non-criteria antibodies. CONCLUSION: Failure to diagnose APS can result in severe clinical consequences. Patients displaying clinical features of APS, but negative for conventional criteria markers, should undergo additional testing for non-criteria biomarkers. In our cohort, around one-third of SN-APS patients showed reactivity to 1 or more non-criteria markers. An update to the current classification criteria incorporating new serological markers should be considered to identify and stratify patients with APS for more effective treatment and management.

Clinical manifestations of antiphospholipid syndrome (APS) with and without antiphospholipid antibodies (the so-called 'seronegative APS').

OBJECTIVES: Although the medical literature currently provides a growing number of isolated case reports of patients with clinically well-defined antiphospholipid syndrome (APS) and persistently negative antiphospholipid antibodies (aPL), there are no studies including a series of patients addressing the clinical features of this condition. METHODS: The authors assessed clinical manifestations of APS in 154 patients: 87 patients with seropositive APS and 67 patients with thrombosis and/or pregnancy morbidity persistently negative for aPL and presenting with at least two additional non-criteria manifestations of APS (the so-called 'seronegative APS', SN-APS). Patients were interviewed at the time of recruitment, and a retrospective file review was carried out. RESULTS: There were no significant differences in the frequency of thrombotic events or obstetric morbidity in patients with SN-APS versus patients with seropositive APS: deep vein thrombosis (31.4% vs 31.0%), pulmonary embolism (23.8% vs 28.7%), stroke (14.9% vs 17.2%), transient ischaemic attack (11.9% vs 10.3%), early spontaneous abortions (67.1% vs 52.1%), stillbirths (62.5% vs 59.4%), prematurity (28.1% vs 21.7%) or pre-eclampsia (28.1% vs 23.1%). CONCLUSIONS: Classic and SN-APS patients show similar clinical profiles. The results suggest that clinical management in patients with APS should not be based only on the presence of conventional aPL.

Metástasis pulmonares de un carcinoma papilar de tiroides / Lung metastases in papillary thyroid carcinoma

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Significance of elevated blood pressure and its management on the short-term outcome of patients with acute ischemic stroke.

BACKGROUND: The objectives of this study were to characterize blood pressure (BP) in acute ischemic stroke and to determine its relationship with short-term functional outcome. METHODS: We examined 24-h BP recordings in 434 patients with ischemic stroke (lacunar stroke [LS], n = 205; non-lacunar stroke [NLS], n = 229) and in 178 normotensive subjects. Stroke severity was evaluated by the National Institutes of Health Stroke Scale (NIHSS). Patients found to be hypertensive on BP recordings on day 1 were given captopril or amlodipine. The primary outcome was both moderate-to-severe disability (Rankin scale scores 4 to 6) on day 7 or death during hospital stay. RESULTS: Patients with LS and NLS had significantly higher systolic BP (SBP) and diastolic BP levels than control subjects. On day 1, patients with NLS showed significantly higher NIHSS scores, SBP, and heart rate (HR) levels than LS patients. In the multivariate analysis, combined death or dependency was associated with NIHSS score (odds ratio [OR] = 1.08 per 1-point increase, 95% confidence interval [CI] = 1.04 to 1.13), 24-h SBP >160 mm Hg (OR = 2.35, 95% CI = 1.10 to 5.52), and plasma glucose levels >125 mg/dL on admission (OR = 1.88, 95% CI =1.03 to 3.57), whereas a decrease in SBP on day 7 (OR = 0.46, 95% CI = 0.24 to 0.88) was associated with better short-term outcome. CONCLUSIONS: At presentation, NLS patients showed higher BP levels than LS patients. Moderate reductions in BP during the first week after admission were associated with short-term functional improvement in patients with acute ischemic stroke.