A flexible access platform for robot-assisted minimally invasive surgery

Advances in Minimally Invasive Surgery (MIS) are driven by the clinical demand to reduce the invasiveness of surgical procedures so patients undergo less trauma and experience faster recoveries. These well documented benefits of MIS have been achieved through parallel advances in the technology and instrumentation used during procedures. The new and evolving field of Flexible Access Surgery (FAS), where surgeons access the operative site through a single incision or a natural orifice incision, is being promoted as the next potential step in the evolution of surgery. In order to achieve similar levels of success and adoption as MIS, technology again has its role to play in developing new instruments to solve the unmet clinical challenges of FAS. As procedures become less invasive, these instruments should not just address the challenges presented by the complex access routes of FAS, but should also build on the recent advances in pre- and intraoperative imaging techniques to provide surgeons with new diagnostic and interventional decision making capabilities. The main focus of this thesis is the development and applications of a flexible robotic device that is capable of providing controlled flexibility along curved pathways inside the body. The principal component of the device is its modular mechatronic joint design which utilises an embedded micromotor-tendon actuation scheme to provide independently addressable degrees of freedom and three internal working channels. Connecting multiple modules together allows a seven degree-of-freedom (DoF) flexible access platform to be constructed. The platform is intended for use as a research test-bed to explore engineering and surgical challenges of FAS. Navigation of the platform is realised using a handheld controller optimised for functionality and ergonomics, or in a "hands-free" manner via a gaze contingent control framework. Under this framework, the operator's gaze fixation point is used as feedback to close the servo control loop. The feasibility and potential of integrating multi-spectral imaging capabilities into flexible robotic devices is also demonstrated. A force adaptive servoing mechanism is developed to simplify the deployment, and improve the consistency of probe-based optical imaging techniques by automatically controlling the contact force between the probe tip and target tissue. The thesis concludes with the description of two FAS case studies performed with the platform during in-vivo porcine experiments. These studies demonstrate the ability of the platform to perform large area explorations within the peritoneal cavity and to provide a stable base for the deployment of interventional instruments and imaging probes

Homocysteine as a potential biochemical marker for depression in elderly stroke survivors

Background: Elderly stroke survivors have been reported to be at risk of malnutrition and depression. Vitamin B-related metabolites such as methylmalonic acid and homocysteine have been implicated in depression. Objective: We conducted a study exploring the relationship between homocysteine and post-stroke depression. Design: Three methodologies were used: Observational cohort study of elderly Swedish patients (n=149) 1.5 years post-stroke, assessed using Diagnostic and Statistical Manual of Mental Disorders, Montgomery Åsberg Depression Rating Scale and serum blood levels of methylmalonic acid and homocysteine. Results: Homocysteine significantly correlated with depressive symptomatology in stroke survivors (β = 0.18*). Individuals with abnormal levels of methylmalonic acid and homocysteine were almost twice more likely to show depressive symptomatology than those with normal levels (depressive symptoms 22%; no depressive symptoms 12%). Comparison of methylmalonic acid and homocysteine levels with literature data showed fewer stroke survivors had vitamin deficiency than did reference individuals (normal range 66%; elevated 34%). Conclusions: Homocysteine is significantly associated with depressive symptomatology in elderly Swedish stroke survivors

High resolution HLA analysis reveals independent class I haplotypes and amino-acid motifs protective for multiple sclerosis.

We investigated association between HLA class I and class II alleles and haplotypes, and KIR loci and their HLA class I ligands, with multiple sclerosis (MS) in 412 European American MS patients and 419 ethnically matched controls, using next-generation sequencing. The DRB1*15:01~DQB1*06:02 haplotype was highly predisposing (odds ratio (OR) = 3.98; 95% confidence interval (CI) = 3-5.31; p-value (p) = 2.22E-16), as was DRB1*03:01~DQB1*02:01 (OR = 1.63; CI = 1.19-2.24; p = 1.41E-03). Hardy-Weinberg (HW) analysis in MS patients revealed a significant DRB1*03:01~DQB1*02:01 homozyote excess (15 observed; 8.6 expected; p = 0.016). The OR for this genotype (5.27; CI = 1.47-28.52; p = 0.0036) suggests a recessive MS risk model. Controls displayed no HW deviations. The C*03:04~B*40:01 haplotype (OR = 0.27; CI = 0.14-0.51; p = 6.76E-06) was highly protective for MS, especially in haplotypes with A*02:01 (OR = 0.15; CI = 0.04-0.45; p = 6.51E-05). By itself, A*02:01 is moderately protective, (OR = 0.69; CI = 0.54-0.87; p = 1.46E-03), and haplotypes of A*02:01 with the HLA-B Thr80 Bw4 variant (Bw4T) more so (OR = 0.53; CI = 0.35-0.78; p = 7.55E-04). Protective associations with the Bw4 KIR ligand resulted from linkage disequilibrium (LD) with DRB1*15:01, but the Bw4T variant was protective (OR = 0.64; CI = 0.49-0.82; p = 3.37-04) independent of LD with DRB1*15:01. The Bw4I variant was not associated with MS. Overall, we find specific class I HLA polymorphisms to be protective for MS, independent of the strong predisposition conferred by DRB1*15:01

Next generation 3D pharmacophore modeling

3D pharmacophore models are three‐dimensional ensembles of chemically defined interactions of a ligand in its bioactive conformation. They represent an elegant way to decipher chemically encoded ligand information and have therefore become a valuable tool in drug design. In this review, we provide an overview on the basic concept of this method and summarize key studies for applying 3D pharmacophore models in virtual screening and mechanistic studies for protein functionality. Moreover, we discuss recent developments in the field. The combination of 3D pharmacophore models with molecular dynamics simulations could be a quantum leap forward since these approaches consider macromolecule–ligand interactions as dynamic and therefore show a physiologically relevant interaction pattern. Other trends include the efficient usage of 3D pharmacophore information in machine learning and artificial intelligence applications or freely accessible web servers for 3D pharmacophore modeling. The recent developments show that 3D pharmacophore modeling is a vibrant field with various applications in drug discovery and beyond

Air Toxics Under The Big Sky – A High School Science Teaching Tool

A project has been developed between Big Sky High School and The University of Montana (UM) which has brought together high school students and teachers, university scientists, and county environmental health officials in a multilayered research experience focusing on the collection and analysis of specific air toxics, and investigating their relationship to respiratory diseases. The Air Toxics Under the Big Sky project allows students to benefit from an independent experience linking science, research, and local environmental issues. We see this as a long term project which will be built upon and expanded by future students during each new school year and as new schools are added. This project will foster a long-term scientific collaboration between UM and Montana high schools, and establishes high school students as valuable contributors to the scientific community while educating them about environmental issues

Response to comment on "Human-specific gain of function in a developmental enhancer"

Duret and Galtier argue that human-specific sequence divergence and gain of function in the HACNS1 enhancer result from deleterious biased gene conversion (BGC) with no contribution from positive selection. We reinforce our previous conclusion by analyzing hypothesized BGC events genomewide and assessing the effect of recombination rates on human-accelerated conserved noncoding sequence ascertainment. We also provide evidence that AT → GC substitution bias can coexist with positive selection