Determinants of SARS-CoV-2 receptor gene expression in upper and lower airways.

The recent outbreak of the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), which causes coronavirus disease 2019 (COVID-19), has led to a worldwide pandemic. One week after initial symptoms develop, a subset of patients progresses to severe disease, with high mortality and limited treatment options. To design novel interventions aimed at preventing spread of the virus and reducing progression to severe disease, detailed knowledge of the cell types and regulating factors driving cellular entry is urgently needed. Here we assess the expression patterns in genes required for COVID-19 entry into cells and replication, and their regulation by genetic, epigenetic and environmental factors, throughout the respiratory tract using samples collected from the upper (nasal) and lower airways (bronchi). Matched samples from the upper and lower airways show a clear increased expression of these genes in the nose compared to the bronchi and parenchyma. Cellular deconvolution indicates a clear association of these genes with the proportion of secretory epithelial cells. Smoking status was found to increase the majority of COVID-19 related genes including ACE2 and TMPRSS2 but only in the lower airways, which was associated with a significant increase in the predicted proportion of goblet cells in bronchial samples of current smokers. Both acute and second hand smoke were found to increase ACE2 expression in the bronchus. Inhaled corticosteroids decrease ACE2 expression in the lower airways. No significant effect of genetics on ACE2 expression was observed, but a strong association of DNA- methylation with ACE2 and TMPRSS2- mRNA expression was identified in the bronchus.

In vivo models and decision trees for formulation development in early drug development: A review of current practices and recommendations for biopharmaceutical development.

The ability to predict new chemical entity performance using in vivo animal models has been under investigation for more than two decades. Pharmaceutical companies use their own strategies to make decisions on the most appropriate formulation starting early in development. In this paper the biopharmaceutical decision trees available in four EFPIA partners (Bayer, Boehringer Ingelheim, Bristol Meyers Squibb and Janssen) were discussed by 7 companies of which 4 had no decision tree currently defined. The strengths, weaknesses and opportunities for improvement are discussed for each decision tree. Both pharmacokineticists and preformulation scientists at the drug discovery & development interface responsible for lead optimization and candidate selection contributed to an overall picture of how formulation decisions are progressed. A small data set containing compound information from the database designed for the IMI funded OrBiTo project is examined for interrelationships between measured physicochemical, dissolution and relative bioavailability parameters. In vivo behavior of the drug substance and its formulation in First in human (FIH) studies cannot always be well predicted from in vitro and/or in silico tools alone at the time of selection of a new chemical entity (NCE). Early identification of the risks, challenges and strategies to prepare for formulations that provide sufficient preclinical exposure in animal toxicology studies and in FIH clinical trials is needed and represents an essential part of the IMI funded OrBiTo project. This article offers a perspective on the use of in vivo models and biopharmaceutical decision trees in the development of new oral drug products.

Fistula Isolation and the Use of Negative Pressure to Promote Wound Healing: A Case Study.

BACKGROUND: A 54-year-old morbidly obese woman with a small bowel obstruction and large ventral hernia was admitted to hospital. She underwent an exploratory laparotomy, lysis of adhesions, and ventral hernia repair with mesh placement. She subsequently developed an enteroatmospheric fistula; several months of hospital care was required to effectively manage the wound and contain effluent from the fistula. METHODS: Several approaches were used to manage output from the fistula during her hospital course. She was initially discharged to a skilled nursing facility where a fistula management pouch was used for several months to encompass the wound and contain effluent, but this method ultimately proved ineffective. The fistula was then isolated using a collapsible enteroatmospheric fistula isolation device and an ostomy appliance to contain effluent. CONCLUSION: The application of the collapsible enteroatmospheric fistula isolation and effluent containment devices in conjunction with negative-pressure wound therapy produced positive patient outcomes; it improved patient satisfaction with fistula management, promoted wound healing, and diminished cost.

Physicochemical characterisation of fluids and soft foods frequently mixed with oral drug formulations prior to administration to children.

Oral drug administration to children poses specific pharmaceutical challenges that are often not seen to the same extent in adults, and whose occurrence may also be age dependent. When an age-appropriate dosage form is not available, manipulation of adult dosage forms (e.g., splitting and crushing of tablets or opening of capsules) has been reported as a means to facilitate administration to children. To enhance swallowability and/or mask an unpleasant taste of the dosage form to be administered, crushed/split tablets or the contents of capsules are often mixed with food or drinks or suspended in a vehicle prior to administration. However, it seems that the risks and benefits of an approach whereby the dosage form is modified prior to administration in this manner are everything but clear. The aim of the present study was to gain an overview of the physicochemical properties of a number of fluids, soft foods and suspension vehicles that are commonly reported to be mixed with oral medications before administration to children to improve patient acceptability. For this purpose, physicochemical parameters of 15 different fluids, soft foods and suspension vehicles were measured. These included pH, buffer capacity, osmolality, surface tension and viscosity. Results of the study clearly show the differences in physicochemical properties of the test candidates. It is thus obvious that the type of fluid/food mixed with a drug product before administration may have a significant impact on bioavailability of the drug administered. Therefore, a risk-based assessment of such practices considering API properties, formulation features and physicochemical properties of the fluids and foods intended to be co-administered with the dosage form, in conjunction with the anatomical and physiological maturity of the gastro-intestinal tract in the intended paediatric population, should be an essential part of paediatric oral formulation development.

Vesta's shape and morphology.

Vesta's surface is characterized by abundant impact craters, some with preserved ejecta blankets, large troughs extending around the equatorial region, enigmatic dark material, and widespread mass wasting, but as yet an absence of volcanic features. Abundant steep slopes indicate that impact-generated surface regolith is underlain by bedrock. Dawn observations confirm the large impact basin (Rheasilvia) at Vesta's south pole and reveal evidence for an earlier, underlying large basin (Veneneia). Vesta's geology displays morphological features characteristic of the Moon and terrestrial planets as well as those of other asteroids, underscoring Vesta's unique role as a transitional solar system body.

Pilot study: The effect of reducing treatment on exercise induced bronchoconstriction.

UNLABELLED: SUMMARY RATIONALE: Asthma therapy should be stepped up or stepped down in response to changes in asthma control. However, there is little evidence available on the optimal timing, sequence, and degree of medication reductions. In this study we analyzed clinically stable asthmatic children who underwent a medication reduction from a combination preparation consisting of an inhaled corticosteroid (ICS) and long acting beta2-agonist (LABA) to monotherapy with the same dose of the ICS. We hypothesized that the extent of exercise-induced bronchoconstriction (EIB) would not increase after the cessation of the LABA. METHODS: Nineteen children, aged 8-16 years, with clinically stable asthma, receiving LABA/ICS combination therapy, were analyzed in this open-label pilot study. Children performed an exercise challenge at baseline and 3 weeks after the medication reduction. Best values of spirometric measurements of the forced expiratory volume in 1 sec (FEV(1)) were used for statistical calculations. RESULTS: Maximum percent fall in FEV(1) was significantly lower after 3 weeks of ICS monotherapy (P = 0.03). Eight of 19 children had a >or=15% fall in FEV(1) after exercise at the initial exercise challenge. In this subgroup, maximum percent fall in FEV(1) after the medication reduction was significantly lower (P < 0.01), and in six children it decreased to <15%, indicating they no longer had EIB. CONCLUSION: In clinically stable asthmatic children on LABA/ICS combination therapy, the cessation of the LABA can reduce and in most cases abolish EIB.

Bringing staff on board: creating an outcomes project tied to continuous quality improvement in an adult community residential service.

This article describes the establishment of the ServiceNet, Inc. Residential Division Outcomes Project. Combining the need to respond to the emerging managed care funding environment and the commitment to having direct care staff engage in activities aimed at continuous quality improvement, the ServiceNet, Inc. Residential Division initiated a model for assessing the outcomes of the clinical curriculum. The article describes an outcomes model designed to bring the staff of a community mental health program into the measurement process. It describes how an outcomes program helped staff enhance the treatment they provide by improving quality of care.