The pharmacokinetics of nebulized nanocrystal budesonide suspension in healthy volunteers.

Nanocrystal budesonide (nanobudesonide) is a suspension for nebulization in patients with steroid-responsive pulmonary diseases such as asthma. The pharmacokinetics and safety of the product were compared to those of Pulmicort Respules. Sixteen healthy volunteers were administered nanobudesonide 0.5 and 1.0 mg, Pulmicort Respules 0.5 mg, and placebo in a four-way, randomized crossover design. All nebulized formulations were well tolerated, with no evidence of bronchospasm. Nebulization times were significantly shorter for nanobudesonide compared to Pulmicort Respules. Because of a low oral bioavailability, plasma concentration of budesonide is a good marker of lung-delivered dose. The pharmacokinetics of nanobudesonide 0.5 and 1.0 mg were approximately dose proportional with respect to Cmax, AUC(0-t), and AUC(0-infinity). Nanobudesonide 0.5 mg and Pulmicort Respules 0.5 mg exhibited similar AUCs, suggesting a similar extent of pulmonary absorption. A higher Cmax was noted with nanobudesonide 0.5 mg, and the tmax was significantly different, suggesting a more rapid rate of drug delivery of nanobudesonide 0.5 mg than Pulmicort Respules. In conclusion, nebulized nanobudesonide 0.5 mg was safe in healthy volunteers, with a similar extent of absorption as Pulmicort Respules

Analysis of peat soil organic carbon, total nitrogen, soil water content and basal respiration: Is there a ‘best’ drying temperature?

Soil needs to be dried in order to determine water content, soil organic carbon content (SOC) and total nitrogen content (N). Water content is commonly measured using standard methods that involve drying temperatures of 105–110 °C. Recommended drying temperatures differ for the determination of SOC and N. However, at moderate drying temperatures, microbial activity might lead to organic matter mineralisation and nitrification, and thus to an underestimation of SOC and N. Furthermore, low drying temperatures might not dewater soils sufficiently to correctly determine water content or bulk density. Chemical processes such as thermal decomposition and volatilisation might occur at higher temperatures. This raises the question of whether the same sample can be used to determine water content, SOC and N. Further, the effect of drying, especially at different temperatures, on basal respiration of peat soils determined by incubation experiments is so far unknown. Effects of drying temperature might be especially severe for peat soils, which have high SOC and water contents. This study systematically evaluated the effect of different drying temperatures (20, 40, 60, 80 and 105 °C) on the determination of mass loss (proxy for water content), SOC and N over a wide range of 15 different peat soils comprising amorphous, Sphagnum and sedge peat substrate. The investigated peat soils had SOC contents ranging from approximately 16.8–52.5% with different degrees of decomposition. They were thus separated into two ‘peat groups’ (amorphous and weakly decomposed). In a subsequent investigation, an incubation experiment was carried out on a subset of five peat soils to investigate the pre-treatment effect of different drying temperatures on basal respiration. The results showed that amorphous samples should be dried at 105 °C to determine water content. The weakly decomposed peat soils in the study had reliable water contents for drying temperatures above 60 °C. For temperatures below 80 °C, the determined SOC and N were biased by residual water. This could be corrected for weakly decomposed samples, but for amorphous samples only for drying temperatures ≥60 °C. Thus, mineralisation of soil organic matter is likely to take place at lower drying temperatures which are not recommendable especially for amorphous peat prone to high mineralisation rates. This is supported by the results of the incubation experiment: The effect of peat type (amorphous topsoil vs. weakly decomposed subsoil) was greater than the effect of different drying temperatures, which nonetheless affected respiration rates. The differences between all five soils were consistent, irrespective of the drying temperature. Thus, incubation experiments might be possible using peat dried at moderate temperatures. © 2021 The Author

Chiasma

Newspaper reporting on events at the Boston University School of Medicine in the 1960s

The Aromatase Gene (CYP19A1) Variants and Circulating Hepatocyte Growth Factor in Postmenopausal Women

Background: Estrogen and androgen have been linked to the regulation of circulating hepatocyte growth factor (HGF), an adipose tissue-derived cytokine. It is possible that the CYP19A1 gene which alters sex hormones production may influence HGF levels. We examined the association between the CYP19A1 gene variants and plasma HGF concentrations. Design We evaluated 45 common and putative functional variants of CYP19A1 and circulating levels of HGF among 260 postmenopausal women who later developed colorectal cancer from the Women's Health Initiative Observational Cohort. As the distribution of HGF levels was highly skewed, we transformed HGF concentrations for all women into a log-, ranked-, or normal score-scale value. Multiple linear regression with adjustment for age was used to evaluate the associations. Results: We observed an association between the rs7172156, rs1008805, rs6493494, rs749292, and rs11636639 variants and HGF levels in ranked and normal score scales (corrected p values ≤0.02), although the association of these 5 SNPs with log-scale HGF was not significant (corrected p values ≥0.16). The associations remained unchanged after additional adjustment for hormone therapy use and estradiol levels. These 5 SNPs, which were in linkage disequilibrium (pairwise D′≥97%, r2≥56%), constituted a block with 2 common haplotypes accounting for 82% frequency. The most common haplotype, TCCCA, was associated with lower ranked- or normal score-transformed HGF levels (corrected p values ≤0.001), whereas the second most common haplotype, CTTCA, was associated with higher ranked- or normal score-transformed HGF levels (corrected p values ≤0.02). Conclusion: Our findings of a potential association between the CYP19A1 variants and circulating HGF levels warrant confirmation in studies with larger sample size

Approaches and challenges to optimising primary care teams’ electronic health record usage

Background Although the presence of an electronic health record (EHR) alone does not ensure high quality, efficient care, few studies have focused on the work of those charged with optimising use of existing EHR functionality.Objective To examine the approaches used and challenges perceived by analysts supporting the optimisation of primary care teams’ EHR use at a large U.S. academic health care system.Methods A qualitative study was conducted. Optimisation analysts and their supervisor were interviewed and data were analysed for themes.Results Analysts needed to reconcile the tension created by organisational mandates focused on the standardisation of EHR processes with the primary care teams’ demand for EHR customisation. They gained an understanding of health information technology (HIT) leadership’s and primary care team’s goals through attending meetings, reading meeting minutes and visiting with clinical teams. Within what was organisationally possible, EHR education could then be tailored to fit team needs. Major challenges were related to organisational attempts to standardise EHR use despite varied clinic contexts, personnel readiness and technical issues with the EHR platform. Forcing standardisation upon clinical needs that current EHR functionality could not satisfy was difficult.Conclusions Dedicated optimisation analysts can add value to health systems through playing a mediating role between HIT leadership and care teams. Our findings imply that EHR optimisation should be performed with an in-depth understanding of the workflow, cognitive and interactional activities in primary care

Structure of CD20 in complex with the therapeutic monoclonal antibody rituximab.

Cluster of differentiation 20 (CD20) is a B cell membrane protein that is targeted by monoclonal antibodies for the treatment of malignancies and autoimmune disorders but whose structure and function are unknown. Rituximab (RTX) has been in clinical use for two decades, but how it activates complement to kill B cells remains poorly understood. We obtained a structure of CD20 in complex with RTX, revealing CD20 as a compact double-barrel dimer bound by two RTX antigen-binding fragments (Fabs), each of which engages a composite epitope and an extensive homotypic Fab:Fab interface. Our data suggest that RTX cross-links CD20 into circular assemblies and lead to a structural model for complement recruitment. Our results further highlight the potential relevance of homotypic Fab:Fab interactions in targeting oligomeric cell-surface markers

Human Herpesvirus 6 (HHV-6) Causes Severe Thymocyte Depletion in SCID-hu Thy/Liv Mice

Human herpesvirus 6 (HHV-6) is a potentially immunosuppressive agent that may act as a cofactor in the progression of AIDS. Here, we describe the first small animal model of HHV-6 infection. HHV-6 subgroup A, strain GS, efficiently infected the human thymic tissue implanted in SCID-hu Thy/Liv mice, leading to the destruction of the graft. Viral DNA was detected in Thy/Liv implants by quantitative polymerase chain reaction (PCR) as early as 4 d after inoculation and peaked at day 14. The productive nature of the infection was confirmed by electron microscopy and immunohistochemical staining. Atypical thymocytes with prominent nuclear inclusions were detected by histopathology. HHV-6 replication was associated with severe, progressive thymocyte depletion involving all major cellular subsets. However, intrathymic T progenitor cells (ITTPs) appeared to be more severely depleted than the other subpopulations, and a preferred tropism of HHV-6 for ITTPs was demonstrated by quantitative PCR on purified thymocyte subsets. These findings suggest that thymocyte depletion by HHV-6 may be due to infection and destruction of these immature T cell precursors. Similar results were obtained with strain PL-1, a primary isolate belonging to subgroup B. The severity of the lesions observed in this animal model underscores the possibility that HHV-6 may indeed be immunosuppressive in humans