Successful transduction with AAV vectors after selective depletion of anti-AAV antibodies by immunoadsorption

Gene therapy with adeno-associated virus (AAV)-based vectors shows great promise for the gene therapeutic treatment of a broad array of diseases. In fact, the treatment of genetic diseases with AAV vectors is currently the only in vivo gene therapy approach that is approved by the US Food and Drug Administration (FDA). Unfortunately, pre-existing antibodies against AAV severely limit the patient population that can potentially benefit from AAV gene therapy, especially if the vector is delivered by intravenous injection. Here, we demonstrate that we can selectively deplete antiAAV antibodies by hemapheresis combined with AAV9 particles coupled to Sepharose beads. In rats that underwent hemapheresis and immunoadsorption, luciferase expression was dramatically increased in the hearts and fully restored in the livers of these rats. Importantly, our method can be readily adapted for the use in clinical AAV gene therapy.Fil: Orlowski, Alejandro. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani". Universidad Nacional de La Plata. Facultad de Ciencias Médicas. Centro de Investigaciones Cardiovasculares "Dr. Horacio Eugenio Cingolani"; Argentina. Icahn School of Medicine at Mount Sinai. Graduate School of Biomedical Sciences. Cardiovascular Institute; Estados UnidosFil: Katz, Michael G.. Icahn School of Medicine at Mount Sinai. Graduate School of Biomedical Sciences. Cardiovascular Institute; Estados UnidosFil: Gubara, Sarah M.. Icahn School of Medicine at Mount Sinai. Graduate School of Biomedical Sciences. Cardiovascular Institute; Estados UnidosFil: Fargnoli, Anthony S.. Icahn School of Medicine at Mount Sinai. Graduate School of Biomedical Sciences. Cardiovascular Institute; Estados UnidosFil: Fish, Kenneth M.. Icahn School of Medicine at Mount Sinai. Graduate School of Biomedical Sciences. Cardiovascular Institute; Estados UnidosFil: Weber, Thomas. Icahn School of Medicine at Mount Sinai. Graduate School of Biomedical Sciences. Cardiovascular Institute; Estados Unido

Centrifuge modelling of the behaviour of pile groups under vertical eccentric load

Annular shaped pile groups are a very common foundation layout for onshore wind turbines and other slender structures. In this study, their performance under vertical loads of moderate to high eccentricity, including moment rotation response and bearing capacity, was investigated by centrifuge testing on small scale physical models embedded in kaolin clay. To identify experimentally the capacity of the examined pile groups under different load paths, the model foundations were loaded monotonically until a clear collapse mechanism was achieved. The testing procedure and the proposed interpretation methodology can be easily adapted to load paths or pile layouts other than those considered in the current study. The experimental data can be adopted as a useful benchmark for mathematical models aimed at predicting the response of pile groups to complex load paths. The results of this testing program can also be used to assess the degree of conservatism of current methods adopted by industry for the design of piled foundations subjected to eccentric loads

Phobic Anxiety is Associated with Higher Serum Concentrations of Adipokines and Cytokines in Women with Diabetes

OBJECTIVE: Phobic anxiety has been associated with increased risk of cardiovascular disease (CVD), but the underlying mechanisms are poorly understood. We aimed to determine whether associations of phobic anxiety with several known markers of CVD might be contributors. RESEARCH DESIGN AND METHODS: We used a 16-point validated index (Crown-Crisp) measured in 1988 to categorize 984 women with type 2 diabetes from the Nurses' Health Study as having low, moderate, or high phobic anxiety. Groups were then compared for differences in adipokines (adiponectin and leptin), inflammatory markers (C-reactive protein and tumor necrosis factor [TNF]-α receptor II), and markers of endothelial function (sE-selectin, soluble intercellular adhesion molecule [sICAM]-1) measured on blood samples provided between 1989 and 1990. RESULTS: Higher levels of phobic anxiety were associated with higher BMI and lower education. Higher levels of phobic anxiety were also associated with higher leptin and soluble TNF-α receptor II in both crude analyses and after adjustment for potential confounders. sICAM and sE-selectin were higher in the highest tertile compared with the middle tertile, but there was no significant trend across tertiles. We found no association between phobic anxiety and adiponectin. CONCLUSIONS: High levels of phobic anxiety are associated with increased levels of leptin and inflammatory markers, which may in part explain the previously observed relationship between anxiety and other psychosocial disorders with CVD

Patient and physician satisfaction in an observational study with methyl aminolevulinate daylight-photodynamic therapy in the treatment of multiple actinic keratoses of the face and scalp in 6 European countries

BACKGROUND Guidelines recommend treating actinic keratoses (AKs) as they are recognized as precursors of invasive squamous cell carcinoma. OBJECTIVE The objective of this study was to collect real-world clinical data on the use of methyl aminolevulinate daylight photodynamic therapy (MAL DL-PDT) for the treatment of face and scalp AK in Europe. METHODS A prospective, multicenter, non-interventional study was conducted in six European countries in patients receiving a single treatment of MAL DL-PDT for face and/or scalp AK. Patient-reported outcomes were assessed by patient questionnaires at baseline and at 3 months after treatment, efficacy was assessed at 3 months using a 6-point global improvement scale, and adverse events (AE) were recorded at each visit. RESULTS Overall, 325 patients were enrolled from 52 investigational centres, 314 of whom attended the 3-month visit. Most patients had multiple lesions (58.4% had >10 lesions) with lesions mainly located on the scalp (60.0%) and/or forehead (54.2%). AKs were predominantly grade I (39.4%) or grade II (33.2%), and 10.5% of patients had grade III lesions. The proportions of patients and physicians that were overall satisfied to very satisfied with the MAL DL-PDT treatment were 80.4% and 90.3%, respectively. The vast majority of patients (90.0%) would consider using MAL DL-PDT again if needed. Physician-assessed efficacy at 3 months was at least much improved in 83.5% of patients, with 45.9% of patients requiring no retreatment. Related AEs were reported in 15% of patients. CONCLUSION Use of MAL DL-PDT for multiple face and/or scalp AKs resulted in high levels of patient and physician satisfaction in clinical practice in Europe, reflecting the good efficacy and high tolerability of this convenient procedure

Naturalness and theoretical constraints on the Higgs boson mass

Arbitrary regularization dependent parameters in Quantum Field Theory are usually fixed on symmetry or phenomenology grounds. We verify that the quadratically divergent behavior responsible for the lack of naturalness in the Standard Model (SM) is intrinsically arbitrary and regularization dependent. While quadratic divergences are welcome for instance in effective models of low energy QCD, they pose a problem in the SM treated as an effective theory in the Higgs sector. Being the very existence of quadratic divergences a matter of debate, a plausible scenario is to search for a symmetry requirement that could fix the arbitrary coefficient of the leading quadratic behavior to the Higgs boson mass to zero. We show that this is possible employing consistency of scale symmetry breaking by quantum corrections. Besides eliminating a fine-tuning problem and restoring validity of perturbation theory, this requirement allows to construct bounds for the Higgs boson mass in terms of $\delta m^2/m^2_H$ (where $m_H$ is the renormalized Higgs mass and $\delta m^2$ is the 1-loop Higgs mass correction). Whereas $\delta m^2/m^2_H<1$ (perturbative regime) in this scenario allows the Higgs boson mass around the current accepted value, the inclusion of the quadratic divergence demands $\delta m^2/m^2_H$ arbitrarily large to reach that experimental value.Comment: 6 pages, 4 figure

The Safe Use of Pesticides: A Risk Assessment Procedure for the Enhancement of Occupational Health and Safety (OHS) Management

The attention paid to the use of pesticides has increased notably in recent years as demonstrated by the issue of laws and regulations requiring their safe and environmentally-conscious use (e.g. Directive 2009/128/EC and Regulation (EC) no. 1272/2008). Despite the benefits that can be achieved by pursuing the targets of stricter legislative framework, the difficulties for farmers in complying with it are remarkable, especially for small-sized companies. In fact, in contrast to other occupational health and safety (OHS) contexts, in the case of pesticides even a preliminary analysis on the relationship between pesticide use and the consequent exposure risks for the workers is a complex task. In order to reduce the above-mentioned gap, the present study is focused on the development of an easy-to-use tool for carrying out occupational risk assessment of agricultural activities related to the use of pesticides. The procedure was developed by starting from the Agricultural Health Study (AHS) approach and its improvements, and continuing to the thorough development of a tool for preliminary risk assessment, providing a simplified model for its practical application by farmers. A case study concerning olive cultivation was used for its first verification. The results achieved should be considered as an initial step for the promotion of safer practices when using pesticides, providing a consistent base for their further validation

"Your Skin Tells You" Campaign for Keratinocyte Cancers: When Individuals' Selection Makes the Difference

Background: Prevention campaigns for skin cancers have focused primarily on melanoma, and over time there has been increasing awareness of the need to select the population to be screened to maximize program effectiveness. Objectives: The objective of the study was to report the results of a free dermatological initiative, as part of an awareness campaign dedicated to keratinocyte cancers, targeting individuals pre-selected through a short questionnaire. Methods: One day of dermatological consultations was held at 15 dermato-oncology referral centers during May 22-June 30, 2021. For selection, individuals answered a telephone interview consisting of 7 yes/no questions on risk factors. Demographics, clinical characteristics of suspicious tumors, and histopathologic diagnosis of excised lesions were collected. Suspicion rate, detection rate, and positive predictive values (PPVs) for any skin cancer, basal cell carcinoma (BCC), cutaneous squamous cell carcinoma (cSCC), and melanoma were calculated. Results: A total of 320 individuals (56.9% males; 43.1% females) with a median age of 69.6 (range 21-91) years qualified for the screening initiative. Overall, skin cancers and precancerous lesions were diagnosed in 65.9% of the patients. Suspicion rate was 28.7% for any skin cancer (92/320), 22.8% for BCC (73/320), 4.7% for cSCC (15/320), and 1.2% for melanoma (4/320). Detection rate was 23.4% for any skin cancer (PPV 93.7%), 18.1% for BCC (PPV 95.1%), 4.4% for cSCC (PPV 93.3%), and 0.9% for melanoma (PPV 75%). Conclusions: Selection of individuals at high risk is a cost-effective approach for early detection campaigns for keratinocyte cancers

Melanocortin-1 Receptor, Skin Cancer and Phenotypic Characteristics (M-SKIP) Project: Study Design and Methods for Pooling Results of Genetic Epidemiological Studies

Background: For complex diseases like cancer, pooled-analysis of individual data represents a powerful tool to investigate the joint contribution of genetic, phenotypic and environmental factors to the development of a disease. Pooled-analysis of epidemiological studies has many advantages over meta-analysis, and preliminary results may be obtained faster and with lower costs than with prospective consortia. Design and methods: Based on our experience with the study design of the Melanocortin-1 receptor (MC1R) gene, SKin cancer and Phenotypic characteristics (M-SKIP) project, we describe the most important steps in planning and conducting a pooled-analysis of genetic epidemiological studies. We then present the statistical analysis plan that we are going to apply, giving particular attention to methods of analysis recently proposed to account for between-study heterogeneity and to explore the joint contribution of genetic, phenotypic and environmental factors in the development of a disease. Within the M-SKIP project, data on 10,959 skin cancer cases and 14,785 controls from 31 international investigators were checked for quality and recoded for standardization. We first proposed to fit the aggregated data with random-effects logistic regression models. However, for the M-SKIP project, a two-stage analysis will be preferred to overcome the problem regarding the availability of different study covariates. The joint contribution of MC1R variants and phenotypic characteristics to skin cancer development will be studied via logic regression modeling. Discussion: Methodological guidelines to correctly design and conduct pooled-analyses are needed to facilitate application of such methods, thus providing a better summary of the actual findings on specific fields

A 48-week update of a multicentre real-life experience of dupilumab in adult patients with moderate-to-severe atopic dermatitis

The long-term efficacy and safety of dupilumab has been demonstrated in clinical trials and only in few real-world studies. We conducted an extension analysis from a previous 16-week study on 109 adult patients affected by moderate-to-severe atopic dermatitis treated with dupilumab. Eczema-Area-and-Severity-Index (EASI), itch numerical-rating-score (itch-NRS), Dermatology-Life-Quality-Index (DLQI) scores, drug survival rate and occurrence of adverse events after 24 and 48 weeks of dupilumab treatment were retrospectively collected. Dupilumab demonstrated sustained improvement of disease severity, pruritus, and quality of life in our series with an increasing percentage of patients gaining EASI75 and EASI90 response during the study period. Few patients interrupted treatment resulting in a very high drug survival rate. We also confirmed the favorable safety profile of the drug with absence of serious adverse events and serious infections throughout the 48-week period. The prevalence of conjunctivitis was low and mainly occurred in the mid-term with resolution of the majority of cases at 48 weeks