Maker Networks Fighting Covid-19: Design Guidelines for Redistributed Manufacturing (RDM) Models

Maker Networks indicate how society organizes itself to overcome significant challenges, such as the lack of Personal Protective Equipment (PPE) observed during the COVID-19 pandemic. We analyze initiatives that produced PPE for frontline health staff to propose design guidelines for implementing RDM-Maker Networks: networks of people and organizations in the Maker Movement that collaboratively produce goods or services organized in a redistributed manufacturing (RDM) model. This paper has two main results: five Maker Networks in Brazil analyzed in terms of their RDM features and the subsequent design guidelines. We selected cases through several criteria like their location and the type of one of their nodes. Those criteria also represent limitations that further works can address

Zooarchaeological Evidence for Animal Husbandry and Foodways at Sylvester Manor

Analysis of over 12,000 zooarchaeological specimens recovered from Sylvester Manor provides archaeological evidence to complement the limited historical information about stock raising and food consumption on the plantation. The analyzed collection derives from the south lawn midden deposit at the site, and contains primarily the remains of domestic sheep, cattle, and pigs. The domestic animal ages, based on tooth eruption and wear, suggest aspects of the animal husbandry system. The patterns of skeletal part representation suggest most of the bones from the midden are refuse from household consumption rather than waste from exported foodstuffs. The Sylvesters and their tenant farmers maintained a dietary emphasis on traditional European domesticates and this diet would have represented a major change for the plantation’s African and Native American occupants

Patents and Industrialisation. An Historical Overview of the British Case, 1624-1907

A Report to the Strategic Advisory Board on Intellectual Property Policy (SABIP), U

Activation of Nrf2 signaling augments Vesicular Stomatitis Virus Oncolysis via Autophagy-Driven Suppression of Antiviral Immunity

Oncolytic viruses (OVs) offer a promising therapeutic approach to treat multiple types of cancer. In this study, we show that the manipulation of the anti-oxidant network via transcription factor Nrf2 augments vesicular stomatitis virus Δ51 (VSVΔ51) replication and sensitizes cancer cells to viral oncolysis. Activation of Nrf2 signaling by the antioxidant compound sulforaphane (SFN) leads to enhanced VSVΔ51 spread in OV-resistant cancer cells and improves the therapeutic outcome in different murine syngeneic and xenograft tumor models. Furthermore, chemoresistant A549 lung cancer cells that display a constitutive dominant hyperactivation of Nrf2 signaling are particularly vulnerable to VSVΔ51 oncolysis. Mechanistically, enhanced Nrf2 signaling stimulates viral replication in cancer cells and disrupts the type I IFN response via increased autophagy. This study reveals a previously unappreciated role for Nrf2 in the regulation of autophagy and the innate antiviral response that complements the therapeutic potential of VSV-directed oncolysis against multiple types of OV-resistant or chemoresistant cancer

Aerosol Performance and Long-Term Stability of Surfactant-Associated Liposomal Ciprofloxacin Formulations with Modified Encapsulation and Release Properties

Abstract Previously, we showed that the encapsulation and release properties of a liposomal ciprofloxacin formulation could be modified post manufacture, by addition of surfactant in concert with osmotic swelling of the liposomes. This strategy may provide more flexibility and convenience than the alternative of manufacturing multiple batches of liposomes differing in composition to cover a wide range of release profiles. The goal of this study was to develop a surfactant-associated liposomal ciprofloxacin (CFI) formulation possessing good long-term stability which could be delivered as an inhaled aerosol. Preparations of 12.5 mg/ml CFI containing 0.4% polysorbate 20 were formulated between pH 4.7 and 5.5. These formulations, before and after mesh nebulization, and after refrigerated storage for up to 2 years, were characterized in terms of liposome structure by cryogenic transmission electron microscopy (cryo-TEM) imaging, vesicle size by dynamic light scattering, pH, drug encapsulation by centrifugation-filtration, and in vitro release (IVR) performance. Within the narrower pH range of 4.9 to 5.2, these formulations retained their physicochemical stability after 2-year refrigerated storage, were robust to mesh nebulization, and formed respirable aerosols with a volume mean diameter (VMD) of 3.7 μm and a geometric standard deviation (GSD) of 1.7. This study demonstrates that it may be possible to provide a range of release profiles by simple addition of surfactant to a liposomal formulation post manufacture, and that these formulations may retain their physicochemical properties after long-term refrigerated storage and following aerosolization by mesh nebulizer.</jats:p

Changes in respiratory symptoms during 48 weeks treatment with ARD-3150 (inhaled liposomal ciprofloxacin) in bronchiectasis:results from the ORBIT-3 and -4 studies

Introduction: It is not known if inhaled antibiotics improve respiratory symptoms in patients with bronchiectasis. In the recent phase-3 ORBIT trials, 48-weeks treatment with ARD-3150 (inhaled liposomal ciprofloxacin) did not significantly improve symptoms using the prespecified method of analysis comparing baseline symptoms to those after 48 weeks, when patients had been off treatment for 28 days. This method of analysis does not take account of possible improvements in symptoms while on active treatment.Methods: A post-hoc analysis of 2 identical randomised trials of ARD-3150 (ORBIT-3 and -4) administered 28-days on and 28 days off in patients with bronchiectasis and chronic Pseudomonas aeruginosa infection. The quality of life bronchiectasis respiratory symptom scale (QOL-B-RSS), which has a 1-week recall period, was administered every 28-days. We examined whether respiratory symptoms improved during on-treatment periods and the relationship of changes in QOL-B-RSS to changes in bacterial load using a mixed model repeated measures approach.Results: ARD-3150 treatment resulted in a significant improvement in respiratory symptoms during the on-treatment periods with concordant results between ORBIT-3 (estimate 1.4 points, standard error (se) 0.49, p=0.004) and ORBIT-4 (estimate 1.1 point, SE0.41, p=0.006). The proportion of patients achieving a symptom improvement above the minimum clinically important difference was higher with ARD-3150 compared to placebo during on-treatment cycles (p=0.024). Changes in respiratory symptoms were correlated with changes in bacterial load in the treatment group (r=-0.89, p&lt;0.0001). Individual estimates for decrements in the QOL-B RSS during exacerbation were -9.4 points (se 0.91) in ORBIT-3 and -10.8 points (0.74) in ORBIT-4 (both p&lt;0.0001).Conclusion: Inhaled ARD-3150 resulted in significant improvements in respiratory symptoms during the on-treatment periods which were lost during off-treatment periods. These results supports the concept that reducing bacterial load can improve respiratory symptoms in patients with bronchiectasis.</p

Dipeptidyl peptidase-1 inhibition with brensocatib reduces the activity of all major neutrophil serine proteases in patients with bronchiectasis:results from the WILLOW trial

Background: Brensocatib is an oral, selective, reversible inhibitor of dipeptidyl peptidase-1 (DPP-1), responsible for activating neutrophil serine proteases (NSPs) including neutrophil elastase (NE), proteinase 3 (PR3), and cathepsin G (CatG). In chronic inflammatory lung diseases such as non-cystic fibrosis bronchiectasis (NCFBE), neutrophils accumulate in the airways resulting in excess active NSPs that cause damaging inflammation and lung destruction.Methods: The 24-week WILLOW trial (NCT03218917) was a randomized, double-blind, placebo-controlled, parallel-group trial in patients with NCFBE conducted at 116 sites across 14 countries. In this trial, treatment with brensocatib was associated with improvements in clinical outcomes including time to first exacerbation, reduction in exacerbation frequency and a reduction in NE activity in sputum. An exploratory analysis of NE activity in white blood cell (WBC) extracts and NE, PR3 and CatG activity in sputum was conducted to further characterize brensocatib's effect and identify potential correlated effects.Results: NE, PR3 and CatG activities were reduced in sputum and NE activity was reduced in WBC extracts in a dose-dependent manner after four weeks of brensocatib treatment, with a return to baseline four weeks after the end of treatment. Brensocatib produced the greatest reduction in the sputum activity of CatG, followed by NE and then PR3. Positive correlations among the sputum NSPs were observed both at baseline and in response to treatment, with the strongest correlation among the sputum NSPs for NE and CatG.Conclusions: These results suggest a broad anti-inflammatory effect of brensocatib underlying its clinical efficacy observed in NCFBE patients.Trial registration: The study was approved by the corresponding ethical review boards of all participating centers. The trial was approved by the Food and Drug Administration and registered at clinicaltrials.gov (NCT03218917) on July 17, 2017 and approved by the European Medicines Agency and registered at the European Union Clinical trials Register (EudraCT No. 2017-002533-32). An independent, external data and safety monitoring committee (comprising physicians with pulmonary expertise, a statistician experienced in the evaluation of clinical safety, and experts in periodontal disease and dermatology) reviewed all adverse events.</p

Evaluation and Selection of the Inhaler Device for Treprostinil Palmitil Inhalation Powder

Treprostinil palmitil (TP) is a prodrug of treprostinil that has been formulated as an inhaled powder, termed TPIP, for evaluation in patients with pulmonary arterial hypertension. In these characterization studies we investigated the aerosol performance of TPIP in response to changes in capsule fill, device resistance, and inspiratory flow rate to enable selection of an inhaler for clinical use. Capsules containing 8, 16 or 32 mg of TPIP (80, 160, or 320 μg TP, respectively) were evaluated using four commercially-available, breath-actuated RS01 devices (Plastiape, S. p.A., Osnago, Italy) with low, medium, high or ultra-high inspiratory resistances, creating 12 different capsule and device configurations for evaluation. Aerosol characterization was performed using the next generation impactor at compendial conditions of 23°C and 35% relative humidity and a flow rate corresponding to a 4 kPa pressure drop. The aerosol mass median aerodynamic diameter, geometric standard deviation, fine particle fraction, emitted dose and fine particle dose (FPD) were calculated from the in vitro impactor data. The TP emitted dose at 4 kPa exceeded 75% for all 12 capsule and device configurations. The FPD, an estimate of the respirable dose, varied between 61.0 and 70.6% of the loaded TP dose for all four devices with the 8 and 16 mg TPIP capsule dose. For the 32 mg TPIP capsule dose, the FPD remained above 61.0% for the high and ultra-high resistance devices but decreased to 48.5 and 52.6% for the low and medium resistance devices, respectively. Based on this initial data, the high resistance device was selected for additional characterization studies at 40 and 80 L/min corresponding to pressure drops of 1.4 and 5.4 kPa. The FPD was relatively insensitive to changes in flow rate, providing an expectation of a consistent total lung dose of TP under scenarios simulating variability in how the device is used. Based on these findings, the high resistance device was chosen for further development in human clinical trials

Quantitative immunomorphological analysis of heat shock proteins in thyroid follicular adenoma and carcinoma tissues reveals their potential for differential diagnosis and points to a role in carcinogenesis

Hsp27, Hsp60, Hsp70, and Hsp90 are chaperones that play a crucial role in cellular homeostasis and differentiation, but they may be implicated in carcinogenesis. Follicular neoplasms of the thyroid include follicular adenoma and follicular carcinoma. The former is a very frequent benign encapsulated nodule, whereas the other is a nodule that infiltrates the capsule, blood vessels and the adjacent parenchyma, with a tendency to metastasize. The main objective was to assess the potential of the Hsps in differential diagnosis and carcinogenesis. We quantified by immunohistochemistry Hsp27, Hsp60, Hsp70, and Hsp90 on thin sections of human thyroid tissue with follicular adenoma or follicular carcinoma, comparing the tumor with the adjacent peritumoral tissue. Hsp60, Hsp70, and Hsp90 were increased in follicular carcinoma compared to follicular adenoma, while Hsp27 showed no difference. Histochemical quantification of Hsp60, Hsp70, and Hsp90 allows diagnostic distinction between follicular adenoma and carcinoma, and between tumor and adjacent non-tumoral tissue. The quantitative variations of these chaperones in follicular carcinoma suggest their involvement in tumorigenesis, for instance in processes such as invasion of thyroid parenchyma and metastasization