Two New Polymorphic Cocrystals of Zafirlukast: Preparation, Crystal Structure, and Stability Relations

Two new cocrystals of zafirlukast with piperazine, existing in five different solid forms, have been discovered during a cocrystal screening. The crystal structure of one of these forms has been determined by single crystal X-ray diffraction, and the stability landscape of the crystalline forms of the new cocrystal has been studied. In the present article, we extend the knowledge about the solid state of this important pharmaceutical drug for the treatment of asthma by reporting the crystal structures of two new solvates (acetonitrile and butanol) and the elusive anhydrous Form X, which have been solved by single crystal X-ray diffraction

Personalisation of warfarin therapy using thermal ink-jet printing

Warfarin is a widely used anticoagulant that is critical in reducing patient morbidity and mortality associated with thromboembolic disorders. However, its narrow therapeutic index and large inter-individual variability can lead to complex dosage regimes. Formulating warfarin as an orodispersible film (ODF) using thermal ink-jet (TIJ) printing could enable personalisation of therapy to simplify administration. Commercial TIJ printers are currently unsuitable for printing the milligram dosages, typically required for warfarin therapy. As such, this study aimed to modify a commercial TIJ printing system to formulate personalised warfarin ODFs containing therapeutic dosages. A TIJ printer was modified successfully with the printer functionality intact; the substrate (paper) rolling mechanism of the printer was replaced by printing onto a stationary stage. Free film substrates were composed of hydroxypropyl methylcellulose (20%w/w) and glycerol (3%w/w). The resulting ODFs were characterised for morphology, disintegration, solid-state properties and drug content. Printed film stability was assessed at 40 °C/75% relative humidity for 30 days. Therapeutic warfarin doses (1.25 and 2.5 mg) were successfully printed onto the film substrates. Excellent linearity was observed between the theoretical and measured dose by changing the warfarin feed concentration (R2 = 0.9999) and length of the print objective, i.e. the Y-value, (R2 = 0.9998). Rapid disintegration of the ODFs was achieved. As such, this study successfully formulated personalised warfarin ODFs using a modified TIJ printer, widening the range of applications for TIJ printing to formulate narrow therapeutic index drugs

Printing T3 and T4 oral drug combinations as a novel strategy for hypothyroidism

Hypothyroidism is a chronic and debilitating disease that is estimated to affect 3% of the general population. Clinical experience has highlighted the synergistic value of combining triiodothyronine (T3) and thyroxine (T4) for persistent or recurrent symptoms. However, thus far a platform that enables the simultaneous and independent dosing of more than one drug for oral administration has not been developed. Thermal inkjet (TIJ) printing is a potential solution to enable the dual deposition of T3 and T4 onto orodispersible films (ODFs) for therapy personalisation. In this study, a two-cartridge TIJ printer was modified such that it could print separate solutions of T3 and T4. Dose adjustments were achieved by printing solutions adjacent to each other, enabling therapeutic T3 (15-50 μg) and T4 dosages (60-180 μg) to be successfully printed. Excellent linearity was observed between the theoretical and measured dose for both T3 and T4 (R2 = 0.982 and 0.985, respectively) by changing the length of the print objective (Y-value). Rapid disintegration of the ODFs was achieved (< 45 seconds). As such, this study for the first time demonstrates the ability to produce personalised dose combinations by TIJ printing T3 and T4 onto the same substrate for oral administration

Impact of physical distancing due to novel coronavirus (SARS-CoV-2) on daily travel for work during transition to lockdown

The outbreak of COVID-19 pandemic has resulted in change in both commute and personal travel patterns. Though, in India, lockdown was implemented from 25th March 2020, due to self-awareness and pandemic risk perception, change in commuter behavior was observed from the beginning of March 2020. The period from 15th to 24th March 2020 is considered as the transition phase of COVID-19 outbreak in India (i.e., between no lockdown and lockdown period). This study attempts to use a decision tree approach to investigate the modal preference of 1542 commuters in association with socio-economic and travel characteristics, and safety perceptions with respect to public and private modes during transition to lockdown due to COVID-19 in India. About 41% of commuters stopped traveling during the transition to lockdown phase, 51.3% were using the same mode of transport and 5.3% of commuters shifted from public to private mode. The study findings reported different interactions of factors influencing the decision to use public or private modes of transport for daily commuting during pandemic situations like COVID-19. Interestingly, safety perceptions (associated with personal health) of commuters did not play a significant role in their mode choice behavior during the transition phase. Though people perceived public transportation as unsafe over personal vehicle use, the actual commute patterns did not validate this due to a possible reason that commuters do not have enough alternative modes. Given the uncertainties in the decision making of the commuters regarding their travel behavior due to physical distancing, the insights from this study are important to policymakers and local transport authorities to understand the change in travel patterns. © 202

Roadmaps to Utopia: Tales of the Smart City

Notions of the Smart City are pervasive in urban development discourses. Various frameworks for the development of smart cities, often conceptualized as roadmaps, make a number of implicit claims about how smart city projects proceed but the legitimacy of those claims is unclear. This paper begins to address this gap in knowledge. We explore the development of a smart transport application, MotionMap, in the context of a £16M smart city programme taking place in Milton Keynes, UK. We examine how the idealized smart city narrative was locally inflected, and discuss the differences between the narrative and the processes and outcomes observed in Milton Keynes. The research shows that the vision of data-driven efficiency outlined in the roadmaps is not universally compelling, and that different approaches to the sensing and optimization of urban flows have potential for empowering or disempowering different actors. Roadmaps tend to emphasize the importance of delivering quick practical results. However, the benefits observed in Milton Keynes did not come from quick technical fixes but from a smart city narrative that reinforced existing city branding, mobilizing a growing network of actors towards the development of a smart region. Further research is needed to investigate this and other smart city developments, the significance of different smart city narratives, and how power relationships are reinforced and constructed through them

Thermomechanical modelling of laser surface glazing for H13 tool steel

A two-dimensional thermomechanical finite element (FE) model of laser surface glazing (LSG) has been developed for H13 tool steel. The direct coupling technique of ANSYS 17.2 (APDL) has been utilised to solve the transient thermomechanical process. A H13 tool steel cylindrical cross-section has been modelled for laser power 200 W and 300 W at constant 0.2 mm beam width and 0.15 ms residence time. The model can predict temperature distribution, stress–strain increments in elastic and plastic region with time and space. The crack formation tendency also can be assumed by analysing the von Mises stress in the heat-concentrated zone. Isotropic and kinematic hardening models have been applied separately to predict the after-yield phenomena. At 200 W laser power, the peak surface temperature achieved is 1520 K which is below the melting point (1727 K) of H13 tool steel. For laser power 300 W, the peak surface temperature is 2523 K. Tensile residual stresses on surface have been found after cooling, which are in agreement with literature. Isotropic model shows higher residual stress that increases with laser power. Conversely, kinematic model gives lower residual stress which decreases with laser power. Therefore, both plasticity models could work in LSG for H13 tool steel

Measurement and Reproducibility of Preserved Ellipsoid Zone Area and Preserved Retinal Pigment Epithelium Area in Eyes With Choroideremia

PURPOSE: To identify valid and reproducible methods for quantifying anatomic outcome measures for eyes with choroideremia (CHM) in clinical trials. DESIGN: Reliability analysis study. METHODS: In this multicenter study, patients with confirmed genetic diagnosis of CHM were enrolled. All cases underwent spectral-domain optical coherence tomography (SDOCT) and fundus autofluorescence (FAF) imaging. Two graders independently delineated boundaries of preserved autofluorescence (PAF) and pre-served ellipsoid zone (EZ) on FAF and OCT images, respectively. The results of the 2 independent gradings of both FAF and OCT images were compared to assess the reproducibility of the grading methods. RESULTS: A total of 148 eyes from 75 cases were included. In 21% of eyes PAF and in 43% of eyes preserved EZ had extended beyond the image capture area. After exclusion of these eyes and low-quality images, 114 FAF and 77 OCT images were graded. The mean PAF areas from 2 independent gradings were 3.720 +/- 3.340 mm(2) and 3.692 +/- 3.253 mm2, respectively. Intraclass correlation coefficient (ICC) for these gradings was 0.996. The mean preserved EZ areas from 2 independent gradings were 2.746 +/- 2.319 mm2 and 2.858 2.446 mm2, respectively. ICC for these gradings was 0.991. CONCLUSIONS: Quantifying preserved retinal pigment epithelium and EZ areas on FAF and OCT images, respectively, in CHM patients is highly reproducible. These variables would be potential anatomic outcome measures for CHM clinical trials and could be studied and tracked longitudinally in choroideremia. (C) 2017 Elsevier Inc. All rights reserved.Peer reviewe

The PTPN22 C1858T gene variant is associated with proinsulin in new-onset type 1 diabetes

<p>Abstract</p> <p>Background</p> <p>The protein tyrosine phosphatase nonreceptor type 2 (<it>PTPN22</it>) has been established as a type 1 diabetes susceptibility gene. A recent study found the C1858T variant of this gene to be associated with lower residual fasting C-peptide levels and poorer glycemic control in patients with type 1 diabetes. We investigated the association of the C1858T variant with residual beta-cell function (as assessed by stimulated C-peptide, proinsulin and insulin dose-adjusted HbA_1c), glycemic control, daily insulin requirements, diabetic ketoacidosis (DKA) and diabetes-related autoantibodies (IA-2A, GADA, ICA, ZnT8Ab) in children during the first year after diagnosis of type 1 diabetes.</p> <p>Methods</p> <p>The C1858T variant was genotyped in an international cohort of children (n = 257 patients) with newly diagnosed type 1 diabetes during 12 months after onset. We investigated the association of this variant with liquid-meal stimulated beta-cell function (proinsulin and C-peptide) and antibody status 1, 6 and 12 months after onset. In addition HbA_1cand daily insulin requirements were determined 1, 3, 6, 9 and 12 months after diagnosis. DKA was defined at disease onset.</p> <p>Results</p> <p>A repeated measurement model of all time points showed the stimulated proinsulin level is significantly higher (22%, p = 0.03) for the T allele carriers the first year after onset. We also found a significant positive association between proinsulin and IA levels (est.: 1.12, p = 0.002), which did not influence the association between <it>PTPN22 </it>and proinsulin (est.: 1.28, p = 0.03).</p> <p>Conclusions</p> <p>The T allele of the C1858T variant is positively associated with proinsulin levels during the first 12 months in newly diagnosed type 1 diabetes children.</p