Good Practices for the Laboratory Performance Testing of Aqueous Oral Inhaled Products (OIPs): an Assessment from the International Pharmaceutical Aerosol Consortium on Regulation and Science (IPAC-RS).

Multiple sources must be consulted to determine the most appropriate procedures for the laboratory-based performance evaluation of aqueous oral inhaled products (OIPs) for the primary measures, dose uniformity/delivery, and aerodynamic particle (droplet) size distribution (APSD). These sources have been developed at different times, mainly in Europe and North America, during the past 25 years by diverse organizations, including pharmacopeial chapter/monograph development committees, regulatory agencies, and national and international standards bodies. As a result, there is a lack of consistency across all the recommendations, with the potential to cause confusion to those developing performance test methods. We have reviewed key methodological aspects of source guidance documents identified by a survey of the pertinent literature and evaluated the underlying evidence supporting their recommendations for the evaluation of these performance measures. We have also subsequently developed a consistent series of solutions to guide those faced with the various associated challenges when developing OIP performance testing methods for oral aqueous inhaled products.

Quality of life with first-line pembrolizumab for PD-L1-positive advanced gastric/gastroesophageal junction adenocarcinoma: results from the randomised phase III KEYNOTE-062 study.

BACKGROUND: In the randomised phase III KEYNOTE-062 study, pembrolizumab was non-inferior to chemotherapy for overall survival in patients with programmed death-ligand 1 (PD-L1)-positive [combined positive score (CPS) ≥1] advanced gastric/gastroesophageal junction (GEJ) cancer. We present findings of prespecified health-related quality-of-life (HRQOL) analyses for pembrolizumab versus chemotherapy in this population. MATERIALS AND METHODS: HRQOL, a secondary endpoint, was measured in patients who received ≥1 dose of study treatment and completed ≥1 HRQOL questionnaire [European Organisation for the Research and Treatment of Cancer (EORTC) 30-question quality-of-life (QLQ-C30), EORTC 22-question quality-of-life gastric-cancer-specific module (QLQ-STO22)]. Least squares mean (LSM) change (baseline to week 18) in global health status/quality of life (GHS/QOL; EORTC QLQ-C30) and time to deterioration (TTD) in GHS/QOL, nausea/vomiting and appetite loss scores (EORTC QLQ-C30) and abdominal pain/discomfort scores (EORTC QLQ-STO22) were evaluated. RESULTS: The HRQOL population comprised 495 patients with CPS ≥1 (pembrolizumab, 252; chemotherapy, 243). Compliance rates at week 18 were similar for pembrolizumab and chemotherapy (EORTC QLQ-C30, 87.9% and 81.9%; EORTC QLQ-STO22, 87.9% and 81.3%, respectively). There was no between-arm difference in LSM score change in GHS/QOL [-0.16; 95% confidence interval (CI) -5.01 to 4.69; P = 0.948]. The LSM score change for most subscales showed comparable worsening in both arms. TTD for GHS/QOL [hazard ratio (HR), 0.96; 95% CI, 0.67-1.38; P = 0.826], appetite loss (HR, 0.83; 95% CI, 0.58-1.20; P = 0.314) and pain (HR, 1.22; 95% CI, 0.78-1.91; P = 0.381) were similar between arms. Longer TTD was observed for pembrolizumab versus chemotherapy for nausea/vomiting (HR, 0.61; 95% CI, 0.44-0.85; P = 0.003). CONCLUSIONS: HRQOL was maintained with first-line treatment with pembrolizumab in patients with PD-L1-positive advanced gastric/GEJ cancer and was similar between pembrolizumab and chemotherapy in this population.

Degeneration alters the biomechanical properties and structural composition of lateral human menisci.

OBJECTIVE: Because the literature relating to the influence of degeneration on the viscoelasticity and tissue composition of human lateral menisci remains contradictory or completely lacking, the aim of this study was to fill these gaps by comprehensively characterising the biomechanical properties of menisci with regard to the degree of degeneration. DESIGN: Meniscal tissue from 24 patients undergoing a total knee replacement was collected and the degeneration of each region classified according to Pauli et al. For biomechanical characterisation, compression and tensile tests were performed. Additionally, the water content was determined and infrared (IR) spectroscopy was applied to detect changes in the structural composition, particularly of the proteoglycan and collagen content. RESULTS: With an increasing degree of degeneration, a significant decrease of the equilibrium modulus was detected, while simultaneously the water content and the hydraulic permeability significantly increased. However, the tensile modulus displayed a tendency to decrease with increasing degeneration, which might be due to the significantly decreasing amount of collagen content identified by the IR measurements. CONCLUSION: The findings of the current study may contribute to the understanding of meniscus degeneration, showing that degenerative processes appear to mainly worsen viscoelastic properties of the inner circumference by disrupting the collagen integrity.

Osseointegration of titanium implants with a novel silver coating under dynamic loading.

Postoperative implant-associated infections are a severe complication in orthopaedics and trauma surgery. To address this problem, a novel implant coating was recently developed, which allows for the release of low concentrations of bactericidal silver. For an intended use on load-bearing endoprostheses, stable bone integration is required. The aim of the present study was to evaluate the biocompatibility and osseointegration of titanium implants with the novel coating in a mechanically loaded bone-defect model in sheep. Silver-coated devices were implanted into weight-bearing and non-weight-bearing tibial and femoral bone defects whereas, in the control group, uncoated titanium implants were inserted. The bony integration of the implants was assessed mechanically and histologically after 6 months. Silver concentrations were assessed in peripheral blood, liver, kidney and local draining lymph nodes as well as at the implantation site. After 6 months, shear strength at the interface and bone apposition to the implant surface were not significantly different between coated and uncoated devices. Mechanical loading reduced bony integration independently of the coating. Silver content at the implantation site was larger in the group with silver-coated implants, yet it remained below toxic levels and no cytotoxic side effects were observed. Concluding, the novel antibacterial silver coating did not negatively influence bone regeneration or implant integration under mechanically unloaded and even loaded conditions, suggesting that the silver coating might be suitable for orthopaedic load-bearing implants, including endoprostheses.

Transvaginal rectopexy using the Flex® Colorectal Drive Robotic System: a proof-of-concept approach to rectal prolapse.

BACKGROUND: The aim of this study was to demonstrate a proof-of-concept approach to rectopexy that would provide the durability of the transabdominal procedure through use of sacral rectopexy with the decreased morbidity of a perineal procedure. This was done by utilizing a transvaginal approach and developing the rectovaginal space to accommodate sacral rectopexy placement using the Flex® Colorectal Drive Robotic System by Medrobotics (Medrobotics Corp., Raynham, MA, USA). METHODS: A fresh female cadaver was acquired and placed in the high lithotomy position. The rectovaginal space was developed to accommodate the trocar of the Flex robot using blunt and sharp dissection between the posterior vaginal wall and anterior rectum. A piece of mesh was introduced into the space and using an endoscopic tacker, which was secured to the sacral promontory. The mesh was secured to the anterior rectal wall using interrupted vicryl sutures. The purse string suture was removed and the rectovaginal orifice was closed using a running vicryl suture. At the completion of the procedure, a low midline laparotomy was conducted to verify anchoring of the mesh appropriately at the sacral promontory. RESULTS: This proof-of-concept protocol is the first description of the Flex® Colorectal Drive being used successfully to perform a transvaginal rectopexy for rectal prolapse in a cadaver. This is also the first description of the Flex® Colorectal Drive robot being used transvaginally. CONCLUSIONS: This proof-of-concept approach demonstrates that transvaginal rectopexy using the Flex® Colorectal Drive is a potential surgical option to address rectal prolapse that could provide patients the durability of a transabdominal approach with the decreased morbidity of a perineal approach. While early results are promising, additional cadaveric studies are required before this procedure can be attempted in vivo.

High-sensitive multi-pass imaging interferometry of a gas/plasma jet.

To increase the sensitivity of optical interferometry for diagnostic of gas/plasma jet density with weak refractivity, we realize several multi-pass probing setups with the visualization field. These optical setups are based on a modified Michelson interferometer with multi-pass and multi-angle propagation of the probing beam through the transparent inhomogeneity. In comparison to the standard single-pass Mach-Zehnder setup, the multi-pass interferometer allows for an increase in the measurement sensitivity of up to 8 times. This technique can be applied to a transparent axially symmetrical gas/plasma jet with low refractivity.

An update of lanreotide acetate for treatment of adults with carcinoid syndrome.

Carcinoid tumors are rare and usually slow-growing. Some patients with advanced metastatic disease however can develop symptoms of carcinoid syndrome, which results in debilitating diarrhea and flushing. Many treatments including chemotherapy were tried unsuccessfully in the past to treat this syndrome. The symptoms of carcinoid syndrome are thought to be related to the ability of the tumors to produce serotonin. The discovery that the production of this hormone can be inhibited by somatostatin led to the development of somatostatin analogues octreotide and lanreotide, which differ from native somatostatin in that they have a longer half-life. These compounds have shown dramatic responses in symptom control and reduction of serotonin metabolites including urinary 5-hydroxyindoleacetic acid (5-HIAA) levels. This review researches the origins of carcinoid tumors, the development of lanreotide as a treatment and future directions for the treatment of carcinoid syndrome.

Electromechanical vortex filaments during cardiac fibrillation.

The self-organized dynamics of vortex-like rotating waves, which are also known as scroll waves, are the basis of the formation of complex spatiotemporal patterns in many excitable chemical and biological systems. In the heart, filament-like phase singularities that are associated with three-dimensional scroll waves are considered to be the organizing centres of life-threatening cardiac arrhythmias. The mechanisms that underlie the onset, maintenance and control of electromechanical turbulence in the heart are inherently three-dimensional phenomena. However, it has not previously been possible to visualize the three-dimensional spatiotemporal dynamics of scroll waves inside cardiac tissues. Here we show that three-dimensional mechanical scroll waves and filament-like phase singularities can be observed deep inside the contracting heart wall using high-resolution four-dimensional ultrasound-based strain imaging. We found that mechanical phase singularities co-exist with electrical phase singularities during cardiac fibrillation. We investigated the dynamics of electrical and mechanical phase singularities by simultaneously measuring the membrane potential, intracellular calcium concentration and mechanical contractions of the heart. We show that cardiac fibrillation can be characterized using the three-dimensional spatiotemporal dynamics of mechanical phase singularities, which arise inside the fibrillating contracting ventricular wall. We demonstrate that electrical and mechanical phase singularities show complex interactions and we characterize their dynamics in terms of trajectories, topological charge and lifetime. We anticipate that our findings will provide novel perspectives for non-invasive diagnostic imaging and therapeutic applications.

Certainty and safe consequence responses provide additional information from multiple choice question assessments.

BACKGROUND: Clinicians making decisions require the ability to self-monitor and evaluate their certainty of being correct while being mindful of the potential consequences of alternative actions. For clinical students, this ability could be inferred from their responses to multiple-choice questions (MCQ) by recording their certainty in correctness and avoidance of options that are potentially unsafe. METHODS: Response certainty was assessed for fifth year medical students (n = 330) during a summative MCQ examination by having students indicate their certainty in each response they gave on the exam. Incorrect responses were classified as to their inherent level of safeness by an expert panel (response consequence). Analyses compared response certainty, response consequence across student performance groupings. RESULTS: As students' certainty in responses increased, the odds they answered correctly increased and the odds of giving unsafe answers decreased. However, from some ability groups the odds of an incorrect response being unsafe increased with high certainty. CONCLUSIONS: Certainty in, and safeness of, MCQ responses can provide additional information to the traditional measure of a number correct. In this sample, even students below standard demonstrated appropriate certainty. However, apart from those scoring lowest, student's incorrect responses were more likely to be unsafe when they expressed high certainty. These findings suggest that measures of certainty and consequence are somewhat independent of the number of correct responses to MCQs and could provide useful extra information particularly for those close to the pass-fail threshold.