Cost-effectiveness of umeclidinium/vilanterol combination therapy compared to tiotropium monotherapy among symptomatic patients with chronic obstructive pulmonary disease in the UK.

BACKGROUND: The cost-effectiveness of umeclidinium bromide-vilanterol (UMEC/VI) versus tiotropium monotherapy in the UK was assessed using a UMEC/VI treatment-specific economic model based on a chronic obstructive pulmonary disease (COPD) disease-progression model. METHODS: The model was implemented as a linked-equation model to estimate COPD progression and associated health service costs, and its impact on quality-adjusted life years (QALYs) and survival. Statistical risk equations for clinical endpoints and resource use were derived from the ECLIPSE and TORCH studies, respectively. For the selected timeframe (1-40 years) and probabilistic analysis, model outputs included disaggregated costs, total costs, exacerbations, life-years and QALYs gained, and incremental cost-effectiveness ratios (ICERs). RESULTS: Random-effects meta-analysis of tiotropium comparator trials estimated treatment effect of UMEC/VI as 92.17 mL (95 % confidence interval: 61.52, 122.82) in forced expiratory volume in 1 s. With this benefit, UMEC/VI resulted in an estimated annual exacerbation reduction of 0.04 exacerbations/patient and 0.36 life years gained compared to tiotropium over patient lifetime. With an additional 0.18 QALYs/patient and an additional lifetime cost of £372/patient at price parity, the incremental cost effectiveness ratio (ICER) of UMEC/VI compared to tiotropium was £2088/QALY. This ICER increased to £17,541/QALY when price of UMEC/VI was increased to that of indacaterol plus tiotropium in separate inhalers. The ICER improved when model duration was reduced from patient lifetime to 1 or 5 years, or when treatment effect was assumed to last for 12 months following treatment initiation. CONCLUSION: UMEC/VI can be considered a cost-effective alternative to tiotropium at a certain price.

Titanium Multi-Topology Metamaterials with Exceptional Strength.

Additively manufactured metamaterials are architectured cellular materials that can be engineered through structural innovations to achieve unusual mechanical and multifunctional properties. Among these, hollow-strut lattice (HSL) metamaterials have proven to allow outstanding structural efficiency, with a multifunctional architecture ideal for lightweight, biomedical, microfluidic, and thermal engineering. To capitalize on their structural efficiency and significantly extend their mechanical envelope, a thin-plate lattice topology is seamlessly integrated into the inner hollow space of an HSL topology. This integration serves a dual purpose: to radically enhance the resistance of the irregular HSL nodes to deformation and to uniformly distribute the applied stresses in the new topology for unparalleled strength. Fabricated in titanium alloy Ti-6Al-4V with densities of 1.0-1.8 g cm-3 , this thin-plate integrated hollow-strut lattice (TP-HSL) metamaterials achieve relative yield strength that well surpasses the empirical upper limit of all cellular metals, including HSL and solid-strut lattice (SSL) metamaterials made from various metallic alloys. Furthermore, their absolute yield strength drastically exceeds that of magnesium alloys with comparable densities while inheriting the high corrosion resistance, biocompatibility, heat resistance, and other unique attributes of Ti-6Al-4V. Titanium multi-topology metamaterials expand the boundaries of lightweight multifunctional metallic materials.

Finite element analysis of patient-specific additive-manufactured implants.

Introduction: Bone tumors, characterized by diverse locations and shapes, often necessitate surgical excision followed by custom implant placement to facilitate targeted bone reconstruction. Leveraging additive manufacturing, patient-specific implants can be precisely tailored with complex geometries and desired stiffness, enhancing their suitability for bone ingrowth. Methods: In this work, a finite element model is employed to assess patient-specific lattice implants in femur bones. Our model is validated using experimental data obtained from an animal study (n = 9). Results: The results demonstrate the accuracy of the proposed finite element model in predicting the implant mechanical behavior. The model was used to investigate the influence of reducing the elastic modulus of a solid Ti6Al4V implant by tenfold, revealing that such a reduction had no significant impact on bone behavior under maximum compression and torsion loading. This finding suggests a potential avenue for reducing the endoprosthesis modulus without compromising bone integrity. Discussion: Our research suggests that employing fully lattice implants not only facilitates bone ingrowth but also has the potential to reduce overall implant stiffness. This reduction is crucial in preventing significant bone remodeling associated with stress shielding, a challenge often associated with the high stiffness of fully solid implants. The study highlights the mechanical benefits of utilizing lattice structures in implant design for enhanced patient outcomes.

Elucidating the native sources of an invasive tree species, Acacia pycnantha, reveals unexpected native range diversity and structure.

BACKGROUND AND AIMS: Understanding the introduction history of invasive plant species is important for their management and identifying effective host-specific biological control agents. However, uncertain taxonomy, intra- and interspecific hybridization, and cryptic speciation may obscure introduction histories, making it difficult to identify native regions to explore for host-specific agents. The overall aim of this study was to identify the native source populations of Acacia pycnantha, a tree native to south-eastern Australia and invasive in South Africa, Western Australia and Portugal. Using a phylogeographical approach also allowed an exploration of the historical processes that have shaped the genetic structure of A. pycnantha in its native range. METHODS: Nuclear (nDNA) and plastid DNA sequence data were used in network and tree-building analyses to reconstruct phylogeographical relationships between native and invasive A. pycnantha populations. In addition, mismatch distributions, relative rates and Bayesian analyses were used to infer recent demographic processes and timing of events in Australia that led to population structure and diversification. KEY RESULTS: The plastid network indicated that Australian populations of A. pycnantha are geographically structured into two informally recognized lineages, the wetland and dryland forms, whereas the nuclear phylogeny showed little geographical structure between these two forms. Moreover, the dryland form of A. pycnantha showed close genetic similarity to the wetland form based on nDNA sequence data. Hybrid zones may explain these findings, supported here by incongruent phylogenetic placement of some of these taxa between nuclear and plastid genealogies. CONCLUSIONS: It is hypothesized that habitat fragmentation due to cycles of aridity inter-dispersed with periods of abundant rainfall during the Pleistocene (approx. 100 kya) probably gave rise to native dryland and wetland forms of A. pycnantha. Although the different lineages were confined to different ecological regions, we also found evidence for intraspecific hybridization in Victoria. The invasive populations in Portugal and South Africa represent wetland forms, whereas some South African populations resemble the Victorian dryland form. The success of the biological control programme for A. pycnantha in South Africa may therefore be attributed to the fact that the gall-forming wasp Trichilogaster signiventris was sourced from South Australian populations, which closely match most of the invasive populations in South Africa.

Automated elaborate resection planning for bone tumor surgery.

PURPOSE: Planning for bone tumor resection surgery is a technically demanding and time-consuming task, reliant on manual positioning of planar cuts in a virtual space. More elaborate cutting approaches may be possible through the use of surgical robots or patient-specific instruments; however, methods for preparing such a resection plan must be developed. METHODS: This work describes an automated approach for generating conformal bone tumor resection plans, where the resection geometry is defined by the convex hull of the tumor, and a focal point. The resection geometry is optimized using particle swarm, where the volume of healthy bone collaterally resected with the tumor is minimized. The approach was compared to manually prepared planar resection plans from an experienced surgeon for 20 tumor cases. RESULTS: It was found that algorithm-generated hull-type resections greatly reduced the volume of collaterally resected healthy bone. The hull-type resections resulted in statistically significant improvements compared to the manual approach (paired t test, p < 0.001). CONCLUSIONS: The described approach has potential to improve patient outcomes by reducing the volume of healthy bone collaterally resected with the tumor and preserving nearby critical anatomy.

Robot-assisted implantation of additively manufactured patient-specific orthopaedic implants: evaluation in a sheep model.

PURPOSE: Bone tumours must be surgically excised in one piece with a margin of healthy tissue. The unique nature of each bone tumour case is well suited to the use of patient-specific implants, with additive manufacturing allowing production of highly complex geometries. This work represents the first assessment of the combination of surgical robotics and patient-specific additively manufactured implants. METHODS: The development and evaluation of a robotic system for bone tumour excision, capable of milling complex osteotomy paths, is described. The developed system was evaluated as part of an animal trial on 24 adult male sheep, in which robotic bone excision of the distal femur was followed by placement of patient-specific implants with operative time evaluated. Assessment of implant placement accuracy was completed based on post-operative CT scans. RESULTS: A mean overall implant position error of 1.05 ± 0.53 mm was achieved, in combination with a mean orientation error of 2.38 ± 0.98°. A mean procedure time (from access to implantation, excluding opening and closing) of 89.3 ± 25.25 min was observed, with recorded surgical time between 58 and 133 min, with this approximately evenly divided between robotic (43.9 ± 15.32) and implant-based (45.4 ± 18.97) tasks. CONCLUSIONS: This work demonstrates the ability for robotics to achieve repeatable and precise removal of complex bone volumes of the type that would allow en bloc removal of a bone tumour. These robotically created volumes can be precisely filled with additively manufactured patient-specific implants, with minimal gap between cut surface and implant interface.

Reducing the prosthesis modulus by inclusion of an open space lattice improves osteogenic response in a sheep model of extraarticular defect.

Introduction: Stress shielding is a common complication following endoprosthetic reconstruction surgery. The resulting periprosthetic osteopenia often manifests as catastrophic fractures and can significantly limit future treatment options. It has been long known that bone plates with lower elastic moduli are key to reducing the risk of stress shielding in orthopedics. Inclusion of open space lattices in metal endoprostheses is believed to reduce the prosthesis modulus potentially improving stress shielding. However, no in vivo data is currently available to support this assumption in long bone reconstruction. This manuscript aims to address this hypothesis using a sheep model of extraarticular bone defect. Methods: Initially, CT was used to create a virtual resection plan of the distal femoral metaphyses and to custom design endoprostheses specific to each femur. The endoprostheses comprised additively manufactured Ti6Al4V-ELI modules that either had a solid core with a modulus of ∼120 GPa (solid implant group) or an open space lattice core with unit cells that had a modulus of 3-6 GPa (lattice implant group). Osteotomies were performed using computer-assisted navigation followed by implantations. The periprosthetic, interfacial and interstitial regions of interest were evaluated by a combination of micro-CT, back-scattered scanning electron microscopy (BSEM), as well as epifluorescence and brightfield microscopy. Results: In the periprosthetic region, mean pixel intensity (a proxy for tissue mineral density in BSEM) in the caudal cortex was found to be higher in the lattice implant group. This was complemented by BSEM derived porosity being lower in the lattice implant group in both caudal and cranial cortices. In the interfacial and interstitial regions, most pronounced differences were observed in the axial interfacial perimeter where the solid implant group had greater bone coverage. In contrast, the lattice group had a greater coverage in the cranial interfacial region. Conclusion: Our findings suggest that reducing the prosthesis modulus by inclusion of an open-space lattice in its design has a positive effect on bone material and morphological parameters particularly within the periprosthetic regions. Improved mechanics appears to also have a measurable effect on the interfacial osteogenic response and osteointegration.

A customizable anthropomorphic phantom for dosimetric verification of 3D-printed lung, tissue, and bone density materials.

PURPOSE: To design and manufacture a customized thoracic phantom slab utilizing the 3D printing process, also known as additive manufacturing, consisting of different tissue density materials. Here, we demonstrate the 3D-printed phantom's clinical feasibility for imaging and dosimetric verification of volumetric modulated arc radiotherapy (VMAT) plans for lung and spine stereotactic ablative body radiotherapy (SABR) through end-to-end dosimetric verification. METHODS: A customizable anthropomorphic phantom slab was designed using the CT dataset of a commercial phantom (adult female ATOM dosimetry phantom, CIRS Inc.). Material extrusion 3D printing was utilized to manufacture the phantom slab consisting of acrylonitrile butadiene styrene material for the lung and the associated lesion, polylactic acid (PLA) material for soft tissue and spinal cord, and both PLA and iron-reinforced PLA materials for bone. CT images were acquired for both the commercial phantom and 3D-printed phantom for HU comparison. VMAT plans were generated for spine and lung SABR scenarios and were delivered as per departmental SABR protocols using a Varian TrueBeam STx linear accelerator. End-to-end dosimetry was implemented with radiochromic films, analyzed with gamma criteria of 5% dose difference, and a distance-to-agreement of 1 mm, at a 10% low-dose threshold by comparing with calculated dose using the Acuros algorithm of the Eclipse treatment planning system (v15.6). RESULTS: 3D-printed phantom inserts were observed to produce HU ranging from -750 to 2100. The 3D-printed phantom slab was observed to achieve a similar range of HU from the commercial phantom including a mean HU of -760 for lung tissue, a mean HU of 50 for soft tissue, and a mean HU of 220 and 630 for low- and high-density bone, respectively. Film dosimetry results show 2D-gamma passing rates for lung SABR (internal and superior) and spine SABR (inferior and superior) over 98% and 90%, respectively. CONCLUSIONS: The end-to-end testing of VMAT plans for spine and lung SABR suggests the clinical feasibility of the 3D-printed phantom, consisting of different tissue density materials that emulate lung, soft tissue, and bone in kV imaging and megavoltage photon dosimetry. Further investigation of the proposed 3D printing techniques for manufacturability and reproducibility will enable the development of clinical 3D-printed phantoms in radiotherapy.

Automated resection planning for bone tumor surgery.

Planning for bone tumor resection surgery is a technically demanding and time-consuming task, reliant on manual positioning of cutting planes (CPs). This work describes an automated approach for generating bone tumor resection plans, where the volume of healthy bone collaterally resected with the tumor is minimized through optimized placement of CPs. Particle swarm optimization calculates the optimal position and orientation of the CPs by introducing a single new CP to an existing resection, then optimizing all CPs to find the global minima. The bone bounded by all CPs is collaterally resected with the tumor. The approach was compared to manual resection plans from an experienced surgeon for 20 tumor cases. It was found that a greater number of CPs reduce the collaterally resected healthy bone, with diminishing returns on this improvement after five CPs. The algorithm-generated resection plan with equivalent number of CPs resulted in a statistically significant improvement over manual plans (paired t-test, p < 0.001). The described approach has potential to improve patient outcomes by reducing loss of healthy bone in tumor surgery while offering a surgeon multiple resection plan options.

Image-Based Geometrical Characterization of Nodes in Additively Manufactured Lattice Structures.

Additive manufacturing (AM) enables the fabrication of lattice structures with optimal mechanical, fluid, and thermal properties. However, during the AM fabrication process, defects are produced in the strut and node elements, which comprise the lattice structure. This leads to discrepancies between the AM fabricated lattice and its idealized computer-aided design (CAD) model, negatively affecting the ability to predict the mechanical behavior of the fabricated lattice via numerical models. Current research is focused on quantification of geometric uncertainties in the strut elements of the lattice; as-manufactured node geometries remain relatively unexplored on an individual scale, despite their criticality to the mechanical response of the structure. Understanding the geometrical properties of as-manufactured nodes relative to CAD idealizations can be used to improve lattice designs and numerical models. In this research, X-ray microcomputed tomography (µCT) is used to analyze and quantify the as-manufactured nodal geometry, found in face-centered cubic and face-centered cubic with axial struts lattices fabricated via selective laser melting. A custom tool is developed that enables auto-isolation and classification of nodal joints from µCT-derived cross-sectional slices. Geometrical properties are extracted from the isolated nodal cross sections and compared with their idealized CAD model counterpart. Quantification of geometrical defects provides insight into how nodes within an AM lattice structure differ from each other and their idealized design. Overall, this research is an initial step toward developing accurate and efficient numerical models, as well as better node design for AM.

Evaluation of Microdissection Testicular Sperm Extraction (mTESE), Outcomes and Predictive Factors in Ireland: The Gold Standard for Men with Non-Obstructive Azoospermia.

BACKGROUND: Microdissection testicular sperm extraction (mTESE) is the gold standard approach in sperm retrieval in men with non-obstructive azoospermia (NOA). The purpose of the study was to assess the outcomes for Irish men who have undergone mTESE with a single surgeon. METHODS: This is a retrospective, single cohort study. Thirty-four patients underwent mTESE between September 2015 and June 2019. A p<0.05 was considered statistically significant. RESULTS: In this study, sperm retrieval rate (SRR) was 47.06%. (16/34). The mean age in those who had retrieved sperm at mTESE was 37.9±2.6 years. Johnson Score (JS) and FSH were statistically different between successful and unsuccessful mTESE groups (p=0.017*10-5 and p=0.004, respectively). Optimal cutoff values for FSH, T and JS were 15 IU/L, 13 nmol/L and 5, respectively. The pregnancy rate was 63.64% (7/11) among men who went on to use mTESE sperm in an ICSI cycle. CONCLUSION: The combination of mTESE/Intracytoplasmic sperm injection (ICSI) is the best option available for men with NOA who prefer to achieve paternity using their own DNA. Given the overall SRRs in mTESE, it is imperative to continue research for a predictive model to better counsel azoospermic men regarding the use of mTESE. For this purpose, large, multicenter, randomized controlled trials are needed.

Metallic additive manufacturing for bone-interfacing implants.

This review investigates the available metallic powder bed additive manufacturing technologies with respect to their basic principles and capabilities in terms of developing orthopedic implants. Detailed descriptions of commonly used metallic alloys employed for orthopedic applications are also presented. The relationship between implant surface properties and cellular attachment and the formation of bacterial colonies are also discussed. Accordingly, we show how different surface modification techniques have been applied to improve both the biointerface of metallic implants for enhanced osseointegration and to control the formation of biofilm to protect against implant infection. In addition, the future direction of metallic additive manufacturing in the case of improving bone interface has been discussed. This review aids in the design of bone-interfacing metallic implants fabricated by additive manufacturing processes, specifically accommodating enhanced biointerfaces for the next generation patient-specific orthopedic implants.

Robots and Tools for Remodeling Bone.

The field of robotic surgery has progressed from small teams of researchers repurposing industrial robots, to a competitive and highly innovative subsection of the medical device industry. Surgical robots allow surgeons to perform tasks with greater ease, accuracy, or safety, and fall under one of four levels of autonomy; active, semi-active, passive, and remote manipulator. The increased accuracy afforded by surgical robots has allowed for cementless hip arthroplasty, improved postoperative alignment following knee arthroplasty, and reduced duration of intraoperative fluoroscopy among other benefits. Cutting of bone has historically used tools such as hand saws and drills, with other elaborate cutting tools now used routinely to remodel bone. Improvements in cutting accuracy and additional options for safety and monitoring during surgery give robotic surgeries some advantages over conventional techniques. This article aims to provide an overview of current robots and tools with a common target tissue of bone, proposes a new process for defining the level of autonomy for a surgical robot, and examines future directions in robotic surgery.

A Systematic Review on 3D-Printed Imaging and Dosimetry Phantoms in Radiation Therapy.

INTRODUCTION: Additive manufacturing or 3-dimensional printing has become a widespread technology with many applications in medicine. We have conducted a systematic review of its application in radiation oncology with a particular emphasis on the creation of phantoms for image quality assessment and radiation dosimetry. Traditionally used phantoms for quality assurance in radiotherapy are often constraint by simplified geometry and homogenous nature to perform imaging analysis or pretreatment dosimetric verification. Such phantoms are limited due to their ability in only representing the average human body, not only in proportion and radiation properties but also do not accommodate pathological features. These limiting factors restrict the patient-specific quality assurance process to verify image-guided positioning accuracy and/or dose accuracy in "water-like" condition. METHODS AND RESULTS: English speaking manuscripts published since 2008 were searched in 5 databases (Google Scholar, Scopus, PubMed, IEEE Xplore, and Web of Science). A significant increase in publications over the 10 years was observed with imaging and dosimetry phantoms about the same total number (52 vs 50). Key features of additive manufacturing are the customization with creation of realistic pathology as well as the ability to vary density and as such contrast. Commonly used printing materials, such as polylactic acid, acrylonitrile butadiene styrene, high-impact polystyrene and many more, are utilized to achieve a wide range of achievable X-ray attenuation values from -1000 HU to 500 HU and higher. Not surprisingly, multimaterial printing using the polymer jetting technology is emerging as an important printing process with its ability to create heterogeneous phantoms for dosimetry in radiotherapy. CONCLUSION: Given the flexibility and increasing availability and low cost of additive manufacturing, it can be expected that its applications for radiation medicine will continue to increase.

Seawater softening of suture zones inhibits fracture propagation in Antarctic ice shelves.

Suture zones are abundant on Antarctic ice shelves and widely observed to impede fracture propagation, greatly enhancing ice-shelf stability. Using seismic and radar observations on the Larsen C Ice Shelf of the Antarctic Peninsula, we confirm that such zones are highly heterogeneous, consisting of multiple meteoric and marine ice bodies of diverse provenance fused together. Here we demonstrate that fracture detainment is predominantly controlled by enhanced seawater content in suture zones, rather than by enhanced temperature as previously thought. We show that interstitial seawater can reduce fracture-driving stress by orders of magnitude, promoting both viscous relaxation and the development of micro cracks, the incidence of which scales inversely with stress intensity. We show how simple analysis of viscous buckles in ice-penetrating radar data can quantify the seawater content of suture zones and their modification of the ice-shelf's stress regime. By limiting fracture, enhancing stability and restraining continental ice discharge into the ocean, suture zones act as vital regulators of Antarctic mass balance.

Topological design and additive manufacturing of porous metals for bone scaffolds and orthopaedic implants: A review.

One of the critical issues in orthopaedic regenerative medicine is the design of bone scaffolds and implants that replicate the biomechanical properties of the host bones. Porous metals have found themselves to be suitable candidates for repairing or replacing the damaged bones since their stiffness and porosity can be adjusted on demands. Another advantage of porous metals lies in their open space for the in-growth of bone tissue, hence accelerating the osseointegration process. The fabrication of porous metals has been extensively explored over decades, however only limited controls over the internal architecture can be achieved by the conventional processes. Recent advances in additive manufacturing have provided unprecedented opportunities for producing complex structures to meet the increasing demands for implants with customized mechanical performance. At the same time, topology optimization techniques have been developed to enable the internal architecture of porous metals to be designed to achieve specified mechanical properties at will. Thus implants designed via the topology optimization approach and produced by additive manufacturing are of great interest. This paper reviews the state-of-the-art of topological design and manufacturing processes of various types of porous metals, in particular for titanium alloys, biodegradable metals and shape memory alloys. This review also identifies the limitations of current techniques and addresses the directions for future investigations.

Massive subsurface ice formed by refreezing of ice-shelf melt ponds.

Surface melt ponds form intermittently on several Antarctic ice shelves. Although implicated in ice-shelf break up, the consequences of such ponding for ice formation and ice-shelf structure have not been evaluated. Here we report the discovery of a massive subsurface ice layer, at least 16 km across, several kilometres long and tens of metres deep, located in an area of intense melting and intermittent ponding on Larsen C Ice Shelf, Antarctica. We combine borehole optical televiewer logging and radar measurements with remote sensing and firn modelling to investigate the layer, found to be ∼10 °C warmer and ∼170 kg m(-3) denser than anticipated in the absence of ponding and hitherto used in models of ice-shelf fracture and flow. Surface ponding and ice layers such as the one we report are likely to form on a wider range of Antarctic ice shelves in response to climatic warming in forthcoming decades.