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Even less is known regarding the applicability of vaccine use for testing (in vitro/vivo) to ascertain pathogenesis or predict reactivity risk. Expedient and thorough research-based evaluation of patients who have suffered anaphylactic vaccine reactions and prospective clinical trials in putative at-risk individuals are needed to address these concerns during a public health crisis.Biologics, like peptides, proteins and nucleic acids, have proven to be promising drugs for the treatment of numerous diseases. However, besides the off label use of the monoclonal antibody bevacizumab for the treatment of corneal neovascularization, to date no other biologics for corneal diseases have reached the market. Indeed, delivering biologics in the eye remains a challenge, especially at the level of the cornea. While it appears to be a rather accessible tissue for the administration of drugs, the cornea in fact presents several anatomical barriers to delivery. In addition, also intracellular delivery barriers need to be overcome to achieve a promising therapeutic outcome with biologics. This review outlines efforts that have been reported to successfully deliver biologics into the cornea. Biochemical and physical methods for achieving delivery of biologics in the cornea are discussed, with a critical view on their efficacy in overcoming corneal barriers.Increasing emphasis is being placed on using in vitro permeation test (IVPT) results for topical products as a surrogate for their in vivo behaviour. This study sought to relate in vivo plasma concentration - time pharmacokinetic (PK) profiles after topical application of drug products to IVPT findings with mechanistic diffusion and compartment models that are now widely used to describe permeation of solutes across the main skin transport barrier, the stratum corneum. Novel in vivo forms of the diffusion and compartment-in-series models were developed by combining their IVPT model forms with appropriate in vivo disposition functions. Available in vivo and IVPT data were then used with the models in data analyses, including the estimation of prediction intervals for in vivo plasma concentrations derived from IVPT data. The resulting predicted in vivo plasma concentration - time profiles for the full models corresponded closely with the observed results for both nitroglycerin and rivastigmine at all times. learn more In contrast, reduced forms of these in vivo models led to discrepancies between model predictions and observed results at early times. A two-stage deconvolution procedure was also used to estimate the in vivo cumulative amount absorbed and shown to be linearly related to that from IVPT, with an acceptable prediction error. External predictability was also shown using a separate set of in vitro and in vivo data for different nitroglycerin patches. This work suggests that mechanistic and physiologically based pharmacokinetic models can be used to predict in vivo behaviour from IVPT data for topical products.Glycogen storage disease type IV (GSD IV) is caused by mutations in the glycogen branching enzyme gene (GBE1) that lead to the accumulation of aberrant glycogen in affected tissues, mostly in the liver. To determine whether dysfunctional glycogen metabolism in GSD IV affects other components of cellular bioenergetics, we studied mitochondrial function in heterozygous Gbe1 knockout (Gbe1+/-) mice. Mitochondria isolated from the livers of Gbe1+/- mice showed elevated respiratory complex I activity and increased reactive oxygen species production, particularly by respiratory chain complex III. These observations indicate that GBE1 deficiency leads to broader rearrangements in energy metabolism and that the mechanisms underlying GSD IV pathogenesis may include more than merely mechanical cell damage caused by the presence of glycogen aggregates.The purpose of this study was to examine the associations of cardiorespiratory fitness, general adiposity, and central adiposity with incident intermediate hyperglycemia (IH) in women. We conducted a prospective cohort study of 1534 women aged 20-79 years old who had an annual health check-up with no history of major chronic diseases. At baseline, fitness was assessed by a Balke graded exercise test, and the estimated metabolic equivalents were used to create quartile groups. Women were also grouped based on their body mass index ( less then 25 kg/m2, 25-29.9 kg/m2, and ≥ 30 kg/m2) and waist-to-height ratio (≥0.50 or less then 0.50). Cox proportional hazards models were conducted to assess the association of fitness and fatness variables with incident IH defined as fasting glucose of 5.6-6.9 mmol/L. Overall, 18.1% (n = 277) of the women developed IH during an average follow-up of 5.06 years. Fitness, body mass index, and waist-to-height ratio at baseline were the independent predictors of the IH incidence in separate age-adjusted models; yet when all three variables were included in the same model along with confounding variables, only fitness remained significant and demonstrated a clear inverse association with incident IH (P-for-trend less then 0.001). Health promotion efforts should focus on improving fitness for the prevention of IH in women.Provider communication can be critically important to families as they consider HPV vaccination. We sought to characterize the association of provider communication and HPV vaccine uptake, and when communication better motivates vaccination. We searched four databases for studies published between 2006 and 2019. Eligible studies examined health care provider communication (defined as recommendation or discussion) and HPV vaccine uptake (defined as initiation, completion, or follow-through) in the US. Two coders independently identified eligible studies and coded effect sizes and study characteristics. We pooled effect sizes using random-effects meta-analysis. We identified 59 eligible studies of 265,083 patients. Receiving a provider recommendation was associated with higher HPV vaccine initiation (pooled OR = 10.1, 95% CI 7.6-13.4). HPV vaccine initiation was 24% for patients without and 60% for patients with a provider recommendation. The pooled effect size for provider recommendation and initiation was smaller for probability samples, clinical records, and NIS-Teen (all p less then 0.
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