AR in VR: assessing surgical augmented reality visualizations in a steerable virtual reality environment

Purpose 

Augmented reality (AR) has emerged as a promising approach to support surgeries; however, its application in real world scenarios is still very limited. Besides sophisticated registration tasks that need to be solved, surgical AR visualizations have not been studied in a standardized and comparative manner. To foster the development of future AR applications, a steerable framework is urgently needed to rapidly evaluate new visualization techniques, explore their individual parameter spaces and define relevant application scenarios.

Methods 

Inspired by its beneficial usage in the automotive industry, the underlying concept of virtual reality (VR) is capable of transforming complex real environments into controllable virtual ones. We present an interactive VR framework, called Augmented Visualization Box (AVB), in which visualizations for AR can be systematically investigated without explicitly performing an error-prone registration. As use case, a virtual laparoscopic scenario with anatomical surface models was created in a computer game engine. In a study with eleven surgeons, we analyzed this VR setting under different environmental factors and its applicability for a quantitative assessment of different AR overlay concepts.

Results 

According to the surgeons, the visual impression of the VR scene is mostly influenced by 2D surface details and lighting conditions. The AR evaluation shows that, depending on the visualization used and its capability to encode depth, 37% to 91% of the experts made wrong decisions, but were convinced of their correctness. These results show that surgeons have more confidence in their decisions, although they are wrong, when supported by AR visualizations.

Conclusion 

With AVB, intraoperative situations are realistically simulated to quantitatively benchmark current AR overlay methods. Successful surgical task execution in an AR system can only be facilitated if visualizations are customized toward the surgical task.

     

Dealing with the complex drug–drug interactions: Towards mechanistic models

Unmanageable severe adverse events caused by drug‐drug interactions (DDIs), leading to market withdrawals or restrictions in the clinical usage, are increasingly avoided with the improvement in our ability to predict such DDIs quantitatively early in drug development. However, significant challenges arise in the evaluation and/or prediction of complex DDIs caused by inhibitor drugs and/or metabolites that affect not one but multiple pathways of drug clearance. This review summarizes the discussion topics at the 2013 AAPS symposium on “Dealing with the complex drug‐drug interactions: towards mechanistic models”. Physiologically based pharmacokinetic (PBPK) models, in combination with the established in vitro‐to‐in vivo extrapolations of intestinal and hepatic disposition, have been successfully applied to predict clinical pharmacokinetics and DDIs, especially for drugs with CYP‐mediated metabolism, and to explain transporter‐mediated and complex DDIs. Although continuous developments are being made towards improved mechanistic prediction of the transporter‐enzyme interplay in the hepatic and intestinal disposition and characterizing the metabolites contribution to DDIs, the prediction of DDIs involving them remains difficult. Regulatory guidelines also recommended use of PBPK modeling for the quantitative prediction and evaluation of DDIs involving multiple perpetrators and metabolites. Such mechanistic modeling approaches culminate to the consensus that modeling is helpful in predicting DDIs or quantitatively rationalizing the clinical findings in complex situations. Furthermore, they provide basis for the prediction and/or understanding the pharmacokinetics in populations like patients with renal impairment, pediatrics, or various ethnic groups where the conduct of clinical studies might not be feasible in early drug development stages and yet some guidance on management of dosage is necessary. Copyright © 2014 John Wiley & Sons, Ltd.     

A 14-Day Elemental Diet Is Highly Effective in Normalizing the Lactulose Breath Test

Treatment of small intestinal bacterial overgrowth is frustrated by the low efficacy of antibiotics. Elemental diets have been shown to reduce enteric flora. In this study, we evaluate the ability of an elemental diet to normalize the lactulose breath test (LBT) in IBS subjects with abnormal breath test findings. Consecutive subjects with IBS and abnormal LBT suggesting the presence of bacterial overgrowth underwent a 2-week exclusive elemental diet. The diet consisted of Vivonex Plus (Novartis Nutrition Corp., Minneapolis, MN) in a quantity based on individual caloric requirement. On day 15 (prior to solid food), subjects returned for a follow-up breath test and those with an abnormal LBT were continued on the diet for an additional 7 days. The ability of an elemental diet to normalize the LBT was determined for days 15 and 21. A chart review was then conducted to evaluate any clinical benefit 1 month later. Of the 93 subjects available for analysis, 74 (80%) had a normal LBT on day 15 of the elemental diet. When those who continued to day 21 were included, five additional patients normalized the breath test (85%). On chart review, subjects who successfully normalized their breath test had a 66.4 +/- 36.1% improvement in bowel symptoms, compared to 11.9 +/- 22.0% in those who failed to normalize (P < 0.001). An elemental diet is highly effective in normalizing an abnormal LBT in IBS subjects, with a concomitant improvement in clinical symptoms.     

Decreased intracellular calcium mediates the histamine H3-receptor-induced attenuation of norepinephrine exocytosis from cardiac sympathetic nerve endings

Activation of presynatic histamine H(3) receptors (H(3)R) down-regulates norepinephrine exocytosis from cardiac sympathetic nerve terminals, in both normal and ischemic conditions. Analogous to the effects of alpha(2)-adrenoceptors, which also act prejunctionally to inhibit norepinephrine release, H(3)R-mediated antiexocytotic effects could result from a decreased Ca(2+) influx into nerve endings. We tested this hypothesis in sympathetic nerve terminals isolated from guinea pig heart (cardiac synaptosomes) and in a model human neuronal cell line (SH-SY5Y), which we stably transfected with human H(3)R cDNA (SH-SY5Y-H(3)). We found that reducing Ca(2+) influx in response to membrane depolarization by inhibiting N-type Ca(2+) channels with omega-conotoxin (omega-CTX) greatly attenuated the exocytosis of [(3)H]norepinephrine from both SH-SY5Y and SH-SY5Y-H(3) cells, as well as the exocytosis of endogenous norepinephrine from cardiac synaptosomes. Similar to omega-CTX, activation of H(3)R with the selective H(3)R-agonist imetit also reduced both the rise in intracellular Ca(2+) concentration (Ca(i)) and norepinephrine exocytosis in response to membrane depolarization. The selective H(3)R antagonist thioperamide prevented this effect of imetit. In the parent SH-SY5Y cells lacking H(3)R, imetit affected neither the rise in Ca(i) nor [(3)H]norepinephrine exocytosis, demonstrating that the presence of H(3)R is a prerequisite for a decrease in Ca(i) in response to imetit and that H(3)R activation modulates norepinephrine exocytosis by limiting the magnitude of the increase in Ca(i). Inasmuch as excessive norepinephrine exocytosis is a leading cause of cardiac dysfunction and arrhythmias during acute myocardial ischemia, attenuation of norepinephrine release by H(3)R agonists may offer a novel therapeutic approach to this condition.     

A marked decrease in l‐selectin expression by leucocytes in infants with Bordetella pertussis infection: leucocytosis explained?

OBJECTIVE: Infants with Bordetella pertussis infection (whooping cough) have an unexplained lymphocytosis and leucocytosis characterized by an increase in small lymphocytes with convoluted and cleaved nuclei. To characterize these cells immunophenotyping using multiparameter flow cytometry was performed on leucocytes from a group of 11 infants aged 3-6 months with proven pertussis and from uninfected control subjects. METHODOLOGY: The panel of monoclonal antibodies used to elucidate leucocyte subtypes included activation, adhesion, costimulatory, memory, T-helper (Th) 1 and Th2 markers. RESULTS: Patients with pertussis showed an increase in absolute numbers of neutrophils, monocytes, T lymphocytes (both CD4 and CD8), B lymphocytes (including CD10+/CD19+ haematogones) and natural killer (NK) cells. All leucocyte subgroups showed a marked decrease in L-selectin (CD62L) expression. The expression of other adhesion molecules CD11a, CD44 and CD54 on all leucocyte subgroups was unchanged. Expression of costimulatory molecules, CD49D and CD28 on T cells and CD80 and CD86 on monocytes, was unchanged. Lymphocyte activation markers CD69, CD25 and HLA-DR were unchanged. There was an increase in CD45RA+/CD45RO+/CD4+ cells (activated) and CD62L-/CD45RO+/CD4+ cells (Th1-like) but no increase in CD7-/CD4+ T cells (Th2-like). CONCLUSIONS: L-Selectin expression mediates extravasation of leucocytes into tissues and is important for homing of peripheral blood lymphocytes to lymph nodes. The significant down-regulation of L-selectin on leucocytes in pertussis infection may prevent leucocyte migration to areas of infection and homing and adhesion of T and B cells to peripheral lymphoid tissues. The increase in lymphocytes with Th1 phenotype may be required for effective immune response to the infective organism. These data provide a possible explanation for the absolute leucocytosis observed in this disease.