Real-time active constraint generation and enforcement for surgical tools using 3D detection and localisation network.

Introduction: Collaborative robots, designed to work alongside humans for manipulating end-effectors, greatly benefit from the implementation of active constraints. This process comprises the definition of a boundary, followed by the enforcement of some control algorithm when the robot tooltip interacts with the generated boundary. Contact with the constraint boundary is communicated to the human operator through various potential forms of feedback. In fields like surgical robotics, where patient safety is paramount, implementing active constraints can prevent the robot from interacting with portions of the patient anatomy that shouldn't be operated on. Despite improvements in orthopaedic surgical robots, however, there exists a gap between bulky systems with haptic feedback capabilities and miniaturised systems that only allow for boundary control, where interaction with the active constraint boundary interrupts robot functions. Generally, active constraint generation relies on optical tracking systems and preoperative imaging techniques. Methods: This paper presents a refined version of the Signature Robot, a three degrees-of-freedom, hands-on collaborative system for orthopaedic surgery. Additionally, it presents a method for generating and enforcing active constraints "on-the-fly" using our previously introduced monocular, RGB, camera-based network, SimPS-Net. The network was deployed in real-time for the purpose of boundary definition. This boundary was subsequently used for constraint enforcement testing. The robot was utilised to test two different active constraints: a safe region and a restricted region. Results: The network success rate, defined as the ratio of correct over total object localisation results, was calculated to be 54.7% ± 5.2%. In the safe region case, haptic feedback resisted tooltip manipulation beyond the active constraint boundary, with a mean distance from the boundary of 2.70 mm ± 0.37 mm and a mean exit duration of 0.76 s ± 0.11 s. For the restricted-zone constraint, the operator was successfully prevented from penetrating the boundary in 100% of attempts. Discussion: This paper showcases the viability of the proposed robotic platform and presents promising results of a versatile constraint generation and enforcement pipeline.

Exploring various measures of the area under the curve for the assessment of dose-proportionality and estimation of bioavailability.

OBJECTIVE: In pharmacokinetics, the area under the concentration versus time curve (AUC) extrapolated to infinity (AUC0-∞) is the preferred metric but it is not always possible to have a reliable estimate of the terminal phase half-life. Here we sought to explore the accuracy of three different area measures to accurately identify dose proportionality and bioavailability. METHODS: One to three compartment model simulations with different doses for dose-proportionality or different rates and/or extents of bioavailability. Area measures evaluated were AUC0-∞, to the last quantifiable concentration (AUCtlast), and to a common time value (AUCt'). RESULTS: Under linear pharmacokinetics, AUCt' provided the most accurate measure of dose proportionality. Except for the one compartment model where AUC0-∞ provided the best predictor of the true measure, there was no clear advantage to the use of either of the three measures of AUC. CONCLUSION: With uncertainty about the terminal phase half-life, the use of AUCt' can be a very useful and even the preferred measure of exposure for use in assessing proportionality in exposure between doses. The choice of AUC measure in bioavailability is less clear and may depend on compartmental nature of the drug, and study parameters including assay sensitivity and sampling protocols.

Fetal ascites in cloacal malformations-a red flag.

INTRODUCTION: Cloacal malformation is a rare anomaly that remains a diagnostic challenge prenatally, despite the current advances in ultrasonography and MRI. This condition can in some, present with isolated ascites or with other findings, such as a pelvic cyst or upper urinary tract dilatation. In a minority, the ascites may be progressive, questioning the role of antenatal intervention. METHODS: We report on ten patients that have been identified from our Cloaca database between 2010 and 2022. RESULTS: The presence of ascites was associated with extensive bowel adhesions and matting, leading to a challenging initial laparotomy and peri-operative course. CONCLUSIONS: Antenatal finding of ascites in newborns with cloacal malformations should raise a red flag. The surgeon and anaesthetist should be prepared for the operative difficulties secondary to bowel adhesions and the higher risk of haemodynamic instability at the initial surgery. An experienced team at initial laparotomy in such patients is vital. LEVEL OF EVIDENCE: II.

A systematic review of the effectiveness of dust control measures adopted to reduce workplace exposure.

The recent increase in silicosis cases in several countries casts doubt on dust control practices and their effectiveness in preventing respirable crystalline silica (RCS) exposure. Apart from silicosis, RCS may lead to other illnesses, health-related quality of life losses for workers and their families, and economic losses for companies. Thus, this systematic literature review examined the effectiveness of interventions employed to prevent exposure to RCS and increase the use of dust control measures. The review used keywords related to dust control interventions to search seven databases. Search results were screened and extracted for synthesis. The narrative synthesis showed the extent of research investment in China. In several designs and combinations, the interventions utilized water, surfactant, foam, and air currents to reduce dust exposure. These interventions offer varying degrees of dust control effectiveness against RCS and respirable dust. Although evidence indicates that interventions significantly decrease dust concentration levels, the control measures in place may not effectively prevent workplace overexposure to RCS. The review found that education and training interventions are employed to improve dust controls and respiratory protective equipment (RPE) use. Also, marketing strategies promote the use of RPE. These interventions can increase the frequency of use of RPE and the adoption of best practice dust control measures. Interventions increase knowledge, awareness, and attitudes about RPE usage and generate positive perceptions while reducing misconceptions. However, the benefits obtained from an intervention may diminish after its implementation, indicating that the interventions may not continually motivate workers to adopt control measures or use RPE.

End-of-Shift Monitoring of Respirable Crystalline Silica: A Critical Review of Measurement Techniques and Factors Influencing Accurate Measurements.

This article presents the findings of a systematic literature review focusing on the impact of interferences in host materials on Respirable Crystalline Silica (RCS) measurement, and the development of a validated method of calibration for RCS instrumentation for in-field use. The impact of interferences in host materials on RCS measurement has been shown to be critical information required for in-field use of portable RCS devices. Portable RCS instruments such as FTIR and XRD have been established to have good sensitivity for measurement but relatively low specificity due to interference in host materials. It has been shown that correction factors are needed to be applied to account for known interferences, especially when calibrating portable RCS instrumentation in-field. The potential to obtain reliable and repeatable results from RCS analysis instrumentation has also been demonstrated. There was significant evidence that interference materials could be present in host materials, and they influence RCS measurement. There is the potential and possibility of using portable RCS instrument for in-field measurement however the challenge is the calibration of such instrumentation in the field to account for changing host materials and thus potential interferences.

µRALP and Beyond: Micro-Technologies and Systems for Robot-Assisted Endoscopic Laser Microsurgery.

Laser microsurgery is the current gold standard surgical technique for the treatment of selected diseases in delicate organs such as the larynx. However, the operations require large surgical expertise and dexterity, and face significant limitations imposed by available technology, such as the requirement for direct line of sight to the surgical field, restricted access, and direct manual control of the surgical instruments. To change this status quo, the European project µRALP pioneered research towards a complete redesign of current laser microsurgery systems, focusing on the development of robotic micro-technologies to enable endoscopic operations. This has fostered awareness and interest in this field, which presents a unique set of needs, requirements and constraints, leading to research and technological developments beyond µRALP and its research consortium. This paper reviews the achievements and key contributions of such research, providing an overview of the current state of the art in robot-assisted endoscopic laser microsurgery. The primary target application considered is phonomicrosurgery, which is a representative use case involving highly challenging microsurgical techniques for the treatment of glottic diseases. The paper starts by presenting the motivations and rationale for endoscopic laser microsurgery, which leads to the introduction of robotics as an enabling technology for improved surgical field accessibility, visualization and management. Then, research goals, achievements, and current state of different technologies that can build-up to an effective robotic system for endoscopic laser microsurgery are presented. This includes research in micro-robotic laser steering, flexible robotic endoscopes, augmented imaging, assistive surgeon-robot interfaces, and cognitive surgical systems. Innovations in each of these areas are shown to provide sizable progress towards more precise, safer and higher quality endoscopic laser microsurgeries. Yet, major impact is really expected from the full integration of such individual contributions into a complete clinical surgical robotic system, as illustrated in the end of this paper with a description of preliminary cadaver trials conducted with the integrated µRALP system. Overall, the contribution of this paper lays in outlining the current state of the art and open challenges in the area of robot-assisted endoscopic laser microsurgery, which has important clinical applications even beyond laryngology.

Quantitative skin exposure assessment of metals: A case study.

This article provides guidance into the quantitative risk assessment of skin exposures to metals. The use of wipe sampling methodologies has been shown to be standardised and effective for skin exposure assessment to metals. However, there is a lack of guidance documents and frameworks available to evaluate the level of health risk to workers from skin exposures to metals. Adverse health effects from exposures to metals have been described in the literature (Fernández-Nieto et al. 2006; Herman et al. 2006; Kreiss et al. 1996). Monitoring of workplace exposures typically focuses on the assessment of respiratory exposures. To provide a safe workplace there is a need to ensure all routes of exposure are risk assessed and controlled. The goal of this article was to develop skin (surface) exposure limits to metals, using the construction industry as a test environment, to quantitatively assess worker health risk of skin exposures to metals. This research concluded it was not feasible to establish single quantitative skin exposure limits to metals due to the many assumptions surrounding dermal exposures. A range of acceptable exposure limits are presented.

Bro1 stimulates Vps4 to promote intralumenal vesicle formation during multivesicular body biogenesis.

Endosomal sorting complexes required for transport (ESCRT-0, -I, -II, -III) execute cargo sorting and intralumenal vesicle (ILV) formation during conversion of endosomes to multivesicular bodies (MVBs). The AAA-ATPase Vps4 regulates the ESCRT-III polymer to facilitate membrane remodeling and ILV scission during MVB biogenesis. Here, we show that the conserved V domain of ESCRT-associated protein Bro1 (the yeast homologue of mammalian proteins ALIX and HD-PTP) directly stimulates Vps4. This activity is required for MVB cargo sorting. Furthermore, the Bro1 V domain alone supports Vps4/ESCRT-driven ILV formation in vivo without efficient MVB cargo sorting. These results reveal a novel activity of the V domains of Bro1 homologues in licensing ESCRT-III-dependent ILV formation and suggest a role in coordinating cargo sorting with membrane remodeling during MVB sorting. Moreover, ubiquitin binding enhances V domain stimulation of Vps4 to promote ILV formation via the Bro1-Vps4-ESCRT-III axis, uncovering a novel role for ubiquitin during MVB biogenesis in addition to facilitating cargo recognition.

Ciliopathy protein HYLS1 coordinates the biogenesis and signaling of primary cilia by activating the ciliary lipid kinase PIPKIγ.

Mutation of ciliopathy protein HYLS1 causes the perinatal lethal hydrolethalus syndrome (HLS), yet the underlying molecular etiology and pathogenesis remain elusive. Here, we reveal unexpected mechanistic insights into the role of mammalian HYLS1 in regulating primary cilia. HYLS1 is recruited to the ciliary base via a direct interaction with the type Iγ phosphatidylinositol 4-phosphate [PI(4)P] 5-kinase (PIPKIγ). HYLS1 activates PIPKIγ by interrupting the autoinhibitory dimerization of PIPKIγ, which thereby expedites depletion of centrosomal PI(4)P to allow axoneme nucleation. HYLS1 deficiency interrupts the assembly of ciliary NPHP module and agonist-induced ciliary exit of ß-arrestin, which, in turn, disturbs the removal of ciliary Gpr161 and activation of hedgehog (Hh) signaling. Consistent with this model of pathogenesis, the HLS mutant HYLS1D211G supports ciliogenesis but not activation of Hh signaling. These results implicate mammalian HYLS1 as a multitasking protein that facilitates ciliogenesis and ciliary signaling by coordinating with the ciliary lipid kinase PIPKIγ.

Polarized human cholangiocytes release distinct populations of apical and basolateral small extracellular vesicles.

Intercellular communication is critical for organismal homeostasis, and defects can contribute to human disease states. Polarized epithelial cells execute distinct signaling agendas via apical and basolateral surfaces to communicate with different cell types. Small extracellular vesicles (sEVs), including exosomes and small microvesicles, represent an understudied form of intercellular communication in polarized cells. Human cholangiocytes, epithelial cells lining bile ducts, were cultured as polarized epithelia in a Transwell system as a model with which to study polarized sEV communication. Characterization of isolated apically and basolaterally released EVs revealed enrichment in sEVs. However, differences in apical and basolateral sEV composition and numbers were observed. Genetic or pharmacological perturbation of cellular machinery involved in the biogenesis of intralumenal vesicles at endosomes (the source of exosomes) revealed general and domain-specific effects on sEV biogenesis/release. Additionally, analyses of signaling revealed distinct profiles of activation depending on sEV population, target cell, and the function of the endosomal sorting complex required for transport (ESCRT)-associated factor ALG-2-interacting protein X (ALIX) within the donor cells. These results support the conclusion that polarized cholangiocytes release distinct sEV pools to mediate communication via their apical and basolateral domains and suggest that defective ESCRT function may contribute to disease states through altered sEV signaling.

Quantitative skin exposure assessment of metals: a systematic literature review of current approaches for risk assessment using the construction industry as an exposure scenario.

PURPOSE: This article summarises a systematic literature review of skin exposure assessment methods and concepts for deriving skin (dermal) exposure limits for metals, using the construction industry, where there is a high prevalence of occupational skin exposures as a test environment. METHODS: A systematic literature review was undertaken across ten databases key to Occupational Health and Safety. Articles were considered for inclusion if they evaluated skin or surface exposure to metals or discussed the feasibility of establishing skin or surface exposure limits in an occupational setting. Only full text, peer-reviewed articles were retrieved. All publications up to 30/06/2019 were considered. The quality of evidence was evaluated based on methodology. RESULTS: A total of 71 studies were selected for inclusion in the review with 49 on skin exposure assessment methods for metals and 22 relating to the derivation of skin exposure limits. The use of wipe sampling methodologies was shown to be standardised and effective for sampling skin exposures to metals. In contrast, there was no scientific consensus on the concept of quantitative skin exposure limits. CONCLUSION: There was greater strength of evidence that wipe methods for the measurement of metals would work well. A research gap with respect to the development of health-based skin exposure limits for metals was identified. Frameworks currently proposed for devising quantitative skin exposure limits are provided. These approaches could be adapted to improve the risk assessment of skin exposures to surface metal contaminants.

FoxM1 insufficiency hyperactivates Ect2-RhoA-mDia1 signaling to drive cancer.

FoxM1 activates genes that regulate S-G2-M cell-cycle progression and, when overexpressed, is associated with poor clinical outcome in multiple cancers. Here we identify FoxM1 as a tumor suppressor in mice that, through its N-terminal domain, binds to and inhibits Ect2 to limit the activity of RhoA GTPase and its effector mDia1, a catalyst of cortical actin nucleation. FoxM1 insufficiency impedes centrosome movement through excessive cortical actin polymerization, thereby causing the formation of non-perpendicular mitotic spindles that missegregate chromosomes and drive tumorigenesis in mice. Importantly, low FOXM1 expression correlates with RhoA GTPase hyperactivity in multiple human cancer types, indicating that suppression of the newly discovered Ect2-RhoAmDia1 oncogenic axis by FoxM1 is clinically relevant. Furthermore, by dissecting the domain requirements through which FoxM1 inhibits Ect2 GEF activity, we provide mechanistic insight for the development of pharmacological approaches that target protumorigenic RhoA activity.

Mosaic-variegated aneuploidy syndrome mutation or haploinsufficiency in Cep57 impairs tumor suppression.

A homozygous truncating frameshift mutation in CEP57 (CEP57T/T) has been identified in a subset of mosaic-variegated aneuploidy (MVA) patients; however, the physiological roles of the centrosome-associated protein CEP57 that contribute to disease are unknown. To investigate these, we have generated a mouse model mimicking this disease mutation. Cep57T/T mice died within 24 hours after birth with short, curly tails and severely impaired vertebral ossification. Osteoblasts in lumbosacral vertebrae of Cep57T/T mice were deficient for Fgf2, a Cep57 binding partner implicated in diverse biological processes, including bone formation. Furthermore, a broad spectrum of tissues of Cep57T/T mice had severe aneuploidy at birth, consistent with the MVA patient phenotype. Cep57T/T mouse embryonic fibroblasts and patient-derived skin fibroblasts failed to undergo centrosome maturation in G2 phase, causing premature centriole disjunction, centrosome amplification, aberrant spindle formation, and high rates of chromosome missegregation. Mice heterozygous for the truncating frameshift mutation or a Cep57-null allele were overtly indistinguishable from WT mice despite reduced Cep57 protein levels, yet prone to aneuploidization and cancer, with tumors lacking evidence for loss of heterozygosity. This study identifies Cep57 as a haploinsufficient tumor suppressor with biologically diverse roles in centrosome maturation and Fgf2-mediated bone formation.

A New Venous Entry Detection Method Based on Electrical Bio-impedance Sensing.

Peripheral intravenous catheterization (PIVC) is frequently required for various medical treatments. Over 1 billion PIVC operations are performed per year in the United States alone. However, this operation is characterized by a very low success rate, especially amongst pediatric patients. Statistics show that only 53% of first PIVC attempts are successful in pediatric patients. Since their veins are small and readily rupture, multiple attempts are commonly required before successfully inserting the catheter into the vein. This article presents and evaluates a novel venous entry detection method based on measuring the electrical bio-impedance of the contacting tissue at the tip of a concentric electrode needle (CEN). This detection method is then implemented in the design of a clinical device called smart venous entry indicator (SVEI), which lights up a LED to indicate the venous entry when the measured value is within the range of blood. To verify this detection method, two experiments are conducted. In the first experiment, we measured the bio-impedance during the insertion of a CEN into a rat's tail vein with different excitation frequencies. Then three classifiers are tested to discriminate blood from surrounding tissues. The experimental results indicate that with 100 kHz excitation frequency the blood bio-impedance can be identified with accuracy nearly 100%, demonstrating the feasibility and reliability of the proposed method for venous entry detection. The second experiment aims to assess the impact of SVEI on PIVC performance. Ten naive subjects were invited to catheterize a realistic baby arm phantom. The subjects are equally divided into two groups, where one group does PIVC with SVEI and the other group uses an ordinary IV catheter. The results show that subjects using SVEI can achieve much higher success rates (86%) than those performing PIVC in a conventional way (12%). Also, all subjects assisted by SVEI succeeded in their first trials while no one succeed in their first attempt using the conventional unassisted system. These results demonstrate the proposed detection method has great potential to improve pediatric PIVC performance, especially for non-expert clinicians. This supports further investment towards clinical validation of the technology.