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In 2012, the United Nations (UN), identified chlorhexidine as a Life-saving Commodity and called for the development of a chlorhexidine product suitable for the prevention of omphalitis (umbilical cord infection) in developing countries. In response, GlaxoSmithKline (GSK) set out to develop a chlorhexidine digluconate 7.1% w/w gel, in partnership with Save the Children. The vision was to develop a gel which could pass a stringent regulatory review thereby assuring a safe, effective, and quality product. Review under the European Medicines Agency’s (EMA) Article 58 pathway was pursued, with accelerated assessment granted. The regulatory dossier compiled literature-based evidence for clinical efficacy and safety, supplemented by GSK-generated in-vitro studies and a full CMC data package to support the quality. No new clinical trial data or in vivo non-clinical study data were submitted. A positive opinion from the EMA was received in 2016. The time from the initial UN call to EMA Positive Opinion was 3 years and 7 months.

Ceramides were isolated from the pig stratum corneum (SC) and mixed in varying molar ratios with either cholesterol or with cholesterol and free fatty acids. The phase behavior of the mixtures was studied by small-(SAXD) and wide-angle (WAXD) X-ray diffraction. Ceramides alone did not exhibit a long range ordering. Upon addition of cholesterol to ceramides, lamellar phases were formed and a hexagonal lateral packing was detected similar to that seen in intact SC. At a cholesterol/ceramide molar ratio of 0.1, only one reflection at 5.9 nm was observed. At a cholesterol/ceramide molar ratio of 0.2, three reflections corresponding to 12.3, 5.56, and 4.26 nm appeared. The reflections were based on two phases. Increasing the cholesterol/ceramide ratio to 0.4, the peak positions were slightly shifted. The diffraction pattern revealed the presence of two lamellar phases with periodicities of 12.2 and 5.2 nm, respectively. The positions of the peaks remained unchanged when the cholesterol/ceramide ratio was increased up to 1.0. At a cholesterol/ceramide molar ratio of 2.0, the intensity of various peaks based on the 12.2 nm phase decreased in intensity. The phase behavior of the cholesterol/ceramide mixtures in a ratio between 0.4 and 1.0 was very similar to that found in intact pig SC in which two lamellar phases with periodicities of 6.0 and 13.2 nm are present. Our data further indicate that the formation of the 5.2 nm lamellar phase requires a higher cholesterol content than the formation of the 12.2 nm lamellar phase. Furthermore, when the relative amount of cholesterol is very high, the 5.2 nm phase is the most pronounced one. Addition of free fatty acids increased the solubility of cholesterol, indicating the role free fatty acids may play for the skin barrier function. The phase behavior of cholesterol/ceramide/fatty acid mixtures was found to be dependent on the chain length of fatty acids used. Namely, addition of short-chain free fatty acids (C14-C18) did not change the periodicity of the 12.2 and 5.2 nm phases, but induced the formation of an additional 4.2 nm phase. In the presence of long-chain free fatty acids (C16-C26), the periodicity of the lamellar phases was slightly increased (to 13.0 and 5.3 nm, respectively) but no additional 4.2 nm phase was formed. These results indicate that the lipid phase behavior of the cholesterol/ceramide/free fatty acid mixtures closely mimics that of the intact stratum corneum only in the presence of long-chain free fatty acids.

In-silico studies are an ideal medium to model and improve our understanding of the mechanisms underlying gastric motility in health and disease. In this study, a workflow to create computational models of the stomach was developed using SPARC scaffolds. Three anatomically based finite element method (FEM) models of the rat stomach incorporating experimental measurements of muscle layer thickness and fiber orientations across the stomach were developed: (i) 2D (surface) FEM model with no thickness, (ii) 3D (volume) FEM model with a fixed thickness across the longitudinal and circular muscle layers, and (iii) 3D (volume) FEM model with varying thickness across the longitudinal and circular muscle layers. The three FEM models were subsequently used in whole-organ slow wave simulations and the impact of anatomical details on the simulation outcomes was investigated. The 3D FEM model with varying thickness was the most computationally expensive, while the 2D FEM model provided the fastest solution (a 200 s simulation took 8 min vs. 38 h to solve). The spatiotemporal profiles of the slow wave activation and propagation in the three FEM models were in good agreement. The largest temporal difference of 1 s in cellular activation was observed between the 2D FEM model and the varying thickness 3D FEM model in the most distal-stomach regions. These FEM models and developed workflow will be used in in-silico studies to improve our understanding of the structure-function relationship in the stomach and identify the optimal parameters of electrical therapies, an alternative treatment for the motility disorders in the stomach. In addition, the developed workflow can be readily used to generate computational models of other organs using SPARC scaffolds.

Purpose. To determine whether flexion contracture continues to improve up to 5 years after total knee arthroplasty (TKA). Methods. Records of 200 women and 123 men (mean age, 72 years) with osteoarthritis and preoperative flexion contracture were reviewed. 155 (48%) involved the left knee and 168 (52%) the right knee. Patients were assessed clinically before TKA and one and 5 years later, by a single researcher using a goniometer to measure flexion contracture, range of movement, maximum flexion, and the Knee Society Score. In all patients the same prosthesis design was used. The surgical technique was standard and involved a medial parapatellar approach with bone resection. Results. All variables improved significantly from pre-TKA to one-year post-TKA and from one-year post-TKA to 5-year post-TKA; respectively the mean flexion contracture decreased from 11° to 3° to 2°; the mean knee range of movement increased from 90° to 103° to 107°; the mean maximum flexion increased from 101° to 106° to 109°; and the mean Knee Society Scores increased from 39 to 87 to 90. Conclusion. Functional outcome and flexion contracture may continue to improve up to 5 years after TKA.

Abstract Lung cancer has been the most common cancer worldwide for several decades. The outcomes of patients with locally advanced lung cancer remain dismal, and only a minority of patients survive more than 5 years. However, tumor therapeutic resistance mechanisms are poorly studied. Identification of therapeutic resistance pathways in lung cancer in order to increase the sensitivity of lung tumor cells to therapeutic agents is a crucial but challenging need. To identify novel genes that modulate the response to platinum-based therapy, we performed a genome-wide high-throughput ribonucleic acid interference (RNAi) screen via transfection of human lung cancer (PC9) cells with a viral short hairpin RNA (shRNA) library. We further validated a potential target via 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and clonogenic survival assays on PC9 and A549 lung tumor cells transfected with small interfering RNAs (siRNAs) to successfully downregulate protein expression and then treated with increasing doses of cisplatin or X-ray radiation. We determined protein expression by immunohistochemistry (IHC) after chemoradiotherapy and analyzed gene expression-based survival outcomes in two cohorts of human non-small-cell lung cancer (NSCLC) patients. The screen identified several targets involved in epithelial-to-mesenchymal transition (EMT), including Smurf1, Smurf2, YAP1, and CEBPZ, and glycolytic pathway proteins, including PFKFB3. Furthermore, we found that the small molecule proteasome inhibitor bortezomib significantly downregulated Smurf2 in lung cancer cells. The addition of bortezomib in combination with cisplatin and radiation therapy in PC9 and A549 cells led to an increase in deoxyribonucleic acid (DNA) double-strand breaks with increased numbers of γ-H2AX-positive cells and upregulation of apoptosis. Finally, we found that Smurf2 protein expression was upregulated in situ after treatment with cisplatin and radiation therapy in a relevant cohort of patients with stage III NSCLC. Additionally, Smurf2 gene expression was the strongest predictor of survival in patients with squamous NSCLC after chemotherapy or chemoradiotherapy. We successfully identified and validated Smurf2 as both a common modulator of resistance and an actionable target in lung cancer. These results suggest the urgent need to investigate clinical Smurf2 inhibition via bortezomib in combination with cisplatin and radiation for patients with locally advanced NSCLC.

The nerves in the skin surface of the foot are comprised of unmyelinated smaller somatic nerves and larger myelinated sensory nerves. Current diagnostic methods are unable to evaluate combined nerve conduction velocity (NCV) from both unmyelinated smaller somatic nerve (USSN) and myelinated larger nerves (MLN) respectively. Computational models may provide an alternative tool to determine the NCV of the combined nerve. Therefore, a combined functional dorsal nerve model (CFDNM) of the various dorsal nerves along with its associated nerve ending of the human foot is proposed and constructed. The combined dorsal nerve model consists of synthetic USSN (SUSSN) and dorsal MLN of the foot. The unmyelinated as well as myelinated electrophysiological nerve models were used to simulate selected SUSSN and MLN of the foot by injecting an external stimulus at the most distal part of SUSSN of the foot through the use of bidomain model. Results from our work demonstrated that the action potential propagated from the most distal part to proximal part of distinct dorsal nerves of the foot, e.g., the simulated NCV of the combined intermediate dorsal cutaneous nerve (IDCN) of the foot was 28.4 m s-1. The CFDNM will provide a vital tool for diagnosis initially small fibre neuropathy (SFN) by computing NCV in the prospective studies.

Taiwan is located in subtropical monsoon area and Pacific Ring of Fire. Both the rate of crustal uplift and annual rainfall are among the highest in the world. Earthquakes and heavy rainfall have led to massive landslides and debris flow. Frequent disasters and the high rate of surface erosion have caused drastic changes in river topography and catchment areas, and, consequently, have impacted the safety of human lives. To mitigate the losses, better simulation and prediction of landslides are critical. Existing landslide prediction research works employed terrain, geology, rainfall, earthquakes and human activities as landslide triggering factors in the predicting model. In addition to aforementioned environmental conditions, this study would like to explore the use of SAR differential interferometry (InSAR) information to help observe characteristics of the slope movement behavior, which is also an important factor. Factors are analyzed and quantified on the basis of slope units. To confirm the applicability of selected factors to landslide, factors are firstly analyzed with Spearman correlation, and then those with higher correlations are incorporated into the prediction model. Machine learning based techniques are then employed to establish the prediction model. The experiment result demonstrates that InSAR information can improve the accuracy by more than 5% in landslide prediction.