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1.
Strategies Trauma Limb Reconstr ; 19(2): 99-103, 2024.
Article in English | MEDLINE | ID: mdl-39359365

ABSTRACT

This paper describes a modification of the traditional fascial tongue surgical approach to the distal humerus. In particular, we describe the reflection and utilisation of radial and ulnar triceps bundles to allow complete visualisation of the distal humerus. This extensile technique allows access to the entirety of the distal humerus and provides excellent visualisation to the operating surgeon. Indications for the surgical approach include open reduction with internal fixation of fractures (both intra- and extra-articular) and total elbow replacement. Whilst standard approaches to the distal humerus are well described, this modification describes a new surgical approach that improves access and visualisation of the traditional fascial tongue technique. Alternative approaches to improve visualisation include an olecranon osteotomy; the triceps bundle modification allows excellent exposure to the distal humerus whilst avoiding complications associated with an olecranon osteotomy. The surgical technique is illustrated with intra-operative photographs, which aim to aid in guiding the surgeon in undertaking critical steps of this approach. How to cite this article: Rankin IA, Dixon J, Goffin J, et al. A Modified Surgical Approach to the Distal Humerus: The Triceps Bundle Technique. Strategies Trauma Limb Reconstr 2024;19(2):99-103.

2.
Article in English | MEDLINE | ID: mdl-39112810

ABSTRACT

Harm reduction officially entered the public health lexicon in the 1980s as a response to the HIV/AIDS crisis and its spread amongst intravenous drug users, but risk prevention has been an important part of psychedelic consumption in ways that predate this formal conceptualization.We look at psychedelic drug trials in the 1950s and 1960s to consider how people-first perspectives informed those early clinical studies, and how pioneering psychedelic researchers themselves approached risk management at a time that predates the formal recognition of harm reduction. Next, we follow psychedelic drugs out of the clinic and into music scenes and festivals that proliferated during the war on the drugs, where community-based organizations stepped up to support music fans who chose to combine psychoactive substances with dancing and drugs at all-day festivals. Finally, we reflect on the longer history and traditions of the Native American Church as one specific example of how Indigenous ceremonies involving psychedelic substances combined spirituality and healing in a community setting curated to promote wellness. Ultimately, we argue that psychedelic risk management has deep historical roots in psychedelic communities representing biomedical, cultural, and Indigenous perspectives - we might heed these historical lessons as we consider how to promote sustainable risk management strategies with psychedelics going forward.

3.
Pilot Feasibility Stud ; 10(1): 117, 2024 Aug 31.
Article in English | MEDLINE | ID: mdl-39217388

ABSTRACT

BACKGROUND: Rates of disengagement from early intervention in psychosis (EIP) services are high. Care coordinators make up the largest staff group in EIP services and have the most frequent and sustained contact with service users. The quality of relationships between service users and care coordinators plays a central role in determining the effectiveness of EIP services. Care coordinators, however, are not routinely offered training in psychosocial interventions that could enhance the therapeutic impact of their role. Method of levels (MOL) is a flexible, transdiagnostic cognitive therapy with potential advantages over previously evaluated approaches. Training care coordinators in MOL could make their routine contacts with service users more helpful and improve outcomes such as recovery rates and levels of engagement. AIMS: This study aims to assess the feasibility of training care coordinators in EIP services to deliver MOL, to understand whether this approach might improve service user engagement and recovery from psychosis compared to treatment as usual, and to assess the feasibility of conducting a cluster-randomised controlled trial (C-RCT) with clustering at the level of teams. Specific feasibility outcomes relate to the recruitment and retention of participants, care coordinators' level of engagement with the MOL training and supervision programme, implementation of MOL in practice, and the acceptability of the intervention amongst participants. METHODS: A feasibility parallel group cluster-randomised controlled trial (C-RCT) designs with two arms: (1) treatment as usual (TAU) or (2) TAU plus support from a care coordinator who has received training in MOL. Randomisation will take place at the level of EIP teams with an allocation ratio of 1:2 in favour of the intervention arm. Our recruitment target is 12 EIP teams, 24 care coordinators working in participating EIP teams, and up to 96 service users working with participating care coordinators. Outcomes will be collected at baseline, 3 months, and 6 months. Qualitative methods will be used to understand participants' experiences of the study, MOL training programme, and MOL intervention. DISCUSSION: This is the first study that aims to evaluate the feasibility of training EIP care coordinators to deliver MOL in their routine practice. Training care coordinators in MOL could enhance the quality of relationships between care coordinators and service users and improve outcomes for people experiencing early psychosis. Results will be used to determine the appropriateness of progressing to a larger evaluation trial. TRIAL REGISTRATION: This study was prospectively registered with the ISRCTN Registry (14082421).

4.
J Orthop Case Rep ; 14(7): 154-158, 2024 Jul.
Article in English | MEDLINE | ID: mdl-39035382

ABSTRACT

Introduction: Simultaneous bilateral anterior cruciate ligament (ACL) ruptures are rare, especially in the pediatric population, with very limited evidence. We aimed to review the current literature and present a case study of an adolescent patient who underwent bilateral reconstruction with hamstrings autograft in a single-stage with a partial transphyseal "all-inside" technique. Literature Review: The limited evidence reports that the incidence of growth disturbance following ACL reconstruction in the skeletally immature is 2.6% with no significant difference between a partial transphyseal and an all-epiphyseal technique. Regarding graft choice in the skeletally immature, no significant difference has been found in function using hamstrings versus bone-to-bone patella autograft. The all-inside technique has shown good outcomes in the skeletally immature with no cases of growth disturbance observed in the literature reviewed. Patients spend less days in hospital and return to sport sooner following simultaneous reconstruction versus staged. Case Report: A 15-year-old male footballer underwent simultaneous reconstruction of bilateral ACL ruptures through a partial transphyseal "all-inside" technique with hamstrings autografts. He began physiotherapy according to local protocol and was discharged from hospital on Day 4 post-operative. He returned to competitive sports 11 months postoperatively with no intraoperative or post-operative complications. Conclusion: This case suggests that bilateral simultaneous ACL reconstruction is a safe management strategy in the rare case of bilateral ruptures in the skeletally immature, which adds to the evidence base. The number of required hospital stays was reduced and there was return to sport in a comparative time frame to unilateral ACL reconstruction rehabilitation.

5.
Arch Bone Jt Surg ; 12(5): 361-364, 2024.
Article in English | MEDLINE | ID: mdl-38817417

ABSTRACT

Here we present a novel adaptation of the previously described fibula pro-tibial fixation in a case requiring salvage fixation of a bimalleolar ankle fracture in an osteoporotic patient. Unstable osteoporotic ankle fractures are a challenging injury to manage and typically occur in a frail and comorbid subgroup of patients. Various techniques have been described in the evolution of managing these injuries, e.g. hindfoot nailing and anatomical locking plates, however in this uniquely challenging case a novel strategy was required to mitigate bone loss in the distal fibular fracture fragment. There is some evidence to suggest fibular protibial fixation offers a lower complication profile to its alternatives. The novel use of distal fibula pro-tibial screws offers a new alternative to hindfoot nailing of bimalleolar ankle fracture in osteoporotic bone with compromised distal fibular fragment bone purchase. Further research is required to investigate the compatibility of this technique with early weightbearing.

6.
Arch Orthop Trauma Surg ; 144(5): 2413-2420, 2024 May.
Article in English | MEDLINE | ID: mdl-38578310

ABSTRACT

INTRODUCTION: The aim of this study was to evaluate noise exposure to the operating room staff consisting of the surgeon, assistant, anaesthetist and Mako Product Specialist (MPS) during Mako robotic-arm assisted total knee arthroplasty (TKA) and total hip arthroplasty (THA). We aimed to determine whether employees were exposed to noise at or above a lower exposure action value (LEAV) set out by the Noise at Work Regulations 2005, Health and Safety Executive (HSE), UK. MATERIALS AND METHODS: We prospectively recorded intra-operative noise levels in Mako robotic-arm assisted TKA and THA over a period of two months using the MicW i436 connected to an iOS device (Apple), using the Sound Level Meter App (iOS) by the National Institute for Occupation Safety and Health (NIOSH). Data obtained was then used to calculate "worst case" daily exposure value to assess if sound levels were compliant with UK guidelines. Comparison between operating room staff groups was performed with ANOVA testing. RESULTS: A total of 19 TKA and 11 THA operations were recorded. During TKA, for the primary surgeon and the assistant, the equivalent continuous sound pressure level (LAeq) was over 80 dB, exceeding the LEAV set out by the Noise at Work Regulations by HSE. During THA, the average LAeq and peak sound pressure levels did not exceed the LEAV. The calculated daily exposure for the primary surgeon in TKA was 82 dB. A Tukey post hoc test revealed that LAeq was statistically significantly lower in the anaesthetist and MPS (p < .001) compared to the primary surgeon and assistant in both TKA and THA. CONCLUSIONS: Operating room staff, particularly the primary surgeon and assistant are exposed to significant levels of noise during Mako robotic-arm assisted TKA and THA. Formal assessments should be performed to further assess the risk of noise induced hearing loss in robotic-arm assisted arthroplasty.


Subject(s)
Arthroplasty, Replacement, Hip , Arthroplasty, Replacement, Knee , Noise, Occupational , Occupational Exposure , Operating Rooms , Robotic Surgical Procedures , Humans , Robotic Surgical Procedures/methods , Arthroplasty, Replacement, Hip/methods , Occupational Exposure/prevention & control , Prospective Studies , Arthroplasty, Replacement, Knee/methods
7.
Biosystems ; 239: 105214, 2024 May.
Article in English | MEDLINE | ID: mdl-38642881

ABSTRACT

The place of living organisms in the natural world is a nearly perennial question in philosophy and the sciences; how can inanimate matter yield animate beings? A dominant answer for several centuries has been to treat organisms as sophisticated machines, studying them with the mechanistic physics and chemistry that have given rise to technology and complex machines. Since the early 20th century, many scholars have sought instead to naturalize biology through thermodynamics, recognizing the precarious far-from-equilibrium state of organisms. Erwin Bauer was an early progenitor of this perspective with ambitions of "general laws for the movement of living matter". In addition to taking a thermodynamic perspective, Bauer recognized that organisms are fundamentally behaving systems, and that explaining the physics of life requires explaining the origins of intentionality, adaptability, and self-regulation. Bauer, like some later scholars, seems to advocate for a "new physics", one that extends beyond mechanics and classical thermodynamic, one that would be inclusive of living systems. In this historical review piece, we explore some of Bauer's ideas and explain how similar concepts have been explored in modern non-equilibrium thermodynamics and dissipative structure theory. Non-living dissipative structures display end-directedness, self-maintenance, and adaptability analogous to organisms. These findings also point to an alternative framework for the life sciences, that treats organisms not as machines but as sophisticated dissipative structures. We evaluate the differences between mechanistic and thermodynamic perspectives on life, and what each theory entails for understanding the behavior of organisms.


Subject(s)
Thermodynamics , Animals , Humans , Models, Biological
8.
ACS Omega ; 9(4): 5014-5023, 2024 Jan 30.
Article in English | MEDLINE | ID: mdl-38313497

ABSTRACT

Transfection, defined as functional delivery of cell-internalized nucleic acids, is dependent on many factors linked to formulation, vector, cell type, and microenvironmental culture conditions. We previously developed a technology termed glycosaminoglycan (GAG)-binding enhanced transduction (GET) to efficiently deliver a variety of cargoes intracellularly, using GAG-binding peptides and cell penetrating peptides (CPPs) in the form of nanoparticles, using conventional cell culture. Herein, we demonstrate that the most simple GET transfection formulation (employing the FLR peptide) is relatively poor at transfecting cells at increasingly lower dosages. However, with an endosomally escaping version (FLR:FLH peptide formulations) we demonstrate more effective transfection of cells with lower quantities of plasmid (p)DNA in vitro. We assessed the ability of single and serial delivery of our formulations to readily transfect cells and determined that temperature, pH, and atmospheric pressure can significantly affect transfected cell number and expression levels. Cytocompatible temperatures that maintain high cell metabolism (20-37 °C) were the optimal for transfection. Interestingly, serial delivery can maintain and enhance expression without viability being compromised, and alkaline pH conditions can aid overall efficiencies. Positive atmospheric pressures can also improve the transgene expression levels generated by GET transfection on a single-cell level. Novel nanotechnologies and gene therapeutics such as GET could be transformative for future regenerative medicine strategies. It will be important to understand how such approaches can be optimized at the formulation and application levels in order to achieve efficacy that will be competitive with viral strategies.

9.
J Control Release ; 367: 209-222, 2024 Mar.
Article in English | MEDLINE | ID: mdl-38244841

ABSTRACT

Physical-based gene delivery via biolistic methods (such as the Helios gene gun) involve precipitation of nucleic acids onto microparticles and direct transfection through cell membranes of exposed tissue (e.g. skin) by high velocity acceleration. The glycosaminoglycan (GAG)-binding enhanced transduction (GET) system exploits novel fusion peptides consisting of cell-binding, nucleic acid condensing, and cell-penetrating domains, which enable enhanced transfection across multiple cell types. In this study, we combined chemical (GET) and physical (gene gun) DNA delivery systems, and hypothesized the combination would generate enhanced distribution and effective uptake in cells not initially transfected by biolistic penetration. Physicochemical characterization, optimization of bullet contents and transfection experiments in vitro in cell monolayers and engineered tissue demonstrated these formulations transfected efficiently, including DC2.4 dendritic cells. We incorporated these formulations into a biolistic format for gene gun by forming fireable dry bullets obtained via lyophilization (freeze drying). This system is simple and with enhanced scalability compared to conventional methods to generate bullets. Flushed GET bullet contents retained their ability to mediate transfection (17-fold greater and 13-fold greater reporter gene expression than standard spermidine bullets in the absence and presence of serum, respectively). Fired GET bullets in vitro (in cells and collagen gels) and in vivo (mice) showed increased reporter gene transfection compared to untreated controls, whilst maintaining cell viability in vitro and having no obvious toxicity in vivo. Lastly, a SARS-CoV-2 plasmid DNA vaccine with spike (S) protein-receptor binding domain (S-RBD) was delivered by gene gun using GET bullets. Specific T cell and antibody responses comparable to the conventional system were generated. The non-physical and physical combination of GET­gold-DNA carriers using gene gun shows potential as an alternative DNA delivery method that is scalable for mass deployable vaccination and intradermal gene delivery.


Subject(s)
Cell-Penetrating Peptides , Nucleic Acids , Vaccines, DNA , Mice , Animals , Biolistics/methods , Cell-Penetrating Peptides/chemistry , Transfection , DNA/chemistry
10.
J Chest Surg ; 57(2): 120-125, 2024 Mar 05.
Article in English | MEDLINE | ID: mdl-38225829

ABSTRACT

Background: This study aimed to assess the outcomes of patients with complex rib fractures undergoing operative or nonoperative management at our major trauma center. Methods: A retrospective review of all patients who were considered for surgical stabilization of rib fractures (SSRF) at a single major trauma center from May 2016 to September 2022 was performed. Results: In total, 352 patients with complex rib fractures were identified. Thirty-seven patients (11%) fulfilled the criteria for surgical management and underwent SSRF. The SSRF group had a significantly higher proportion of patients with flail chest (32 [86%] vs. 94 [27%], p<0.001) or Injury Severity Score (ISS) >15 (37 [100%] vs. 129 [41%], p<0.001). No significant differences were seen between groups for 1-year mortality. Patients who underwent SSRF within 72 hours were 6 times less likely to develop pneumonia than those in whom SSRF was delayed for over 72 hours (2 [18%] vs. 15 [58%]; odds ratio, 0.163; 95% confidence interval, 0.029-0.909; p=0.036). Prompt SSRF showed non-significant associations with shorter intensive care unit length of stay (6 days vs. 10 days, p=0.140) and duration of mechanical ventilation (5 days vs. 8 days, p=0.177). SSRF was associated with a longer hospital length of stay compared to nonoperative patients with flail chest and/or ISS >15 (19 days vs. 13 days, p=0.012), whilst SSRF within 72 hours was not. Conclusion: Surgical fixation of complex rib fractures improves outcomes in selected patient groups. Delayed surgical fixation was associated with increased rates of pneumonia and a longer hospital length of stay.

12.
PLoS Biol ; 21(6): e3002121, 2023 Jun.
Article in English | MEDLINE | ID: mdl-37315073

ABSTRACT

Pluripotency defines the unlimited potential of individual cells of vertebrate embryos, from which all adult somatic cells and germ cells are derived. Understanding how the programming of pluripotency evolved has been obscured in part by a lack of data from lower vertebrates; in model systems such as frogs and zebrafish, the function of the pluripotency genes NANOG and POU5F1 have diverged. Here, we investigated how the axolotl ortholog of NANOG programs pluripotency during development. Axolotl NANOG is absolutely required for gastrulation and germ-layer commitment. We show that in axolotl primitive ectoderm (animal caps; ACs) NANOG and NODAL activity, as well as the epigenetic modifying enzyme DPY30, are required for the mass deposition of H3K4me3 in pluripotent chromatin. We also demonstrate that all 3 protein activities are required for ACs to establish the competency to differentiate toward mesoderm. Our results suggest the ancient function of NANOG may be establishing the competence for lineage differentiation in early cells. These observations provide insights into embryonic development in the tetrapod ancestor from which terrestrial vertebrates evolved.


Subject(s)
Homeodomain Proteins , Pluripotent Stem Cells , Animals , Homeodomain Proteins/metabolism , Ambystoma mexicanum/genetics , Ambystoma mexicanum/metabolism , Zebrafish/genetics , Cell Differentiation , Nanog Homeobox Protein/genetics , Nanog Homeobox Protein/metabolism , Gene Expression Regulation, Developmental
13.
J Control Release ; 360: 93-109, 2023 08.
Article in English | MEDLINE | ID: mdl-37315695

ABSTRACT

Insulin regulates blood glucose levels, and is the mainstay for the treatment of type-1 diabetes and type-2 when other drugs provide inadequate control. Therefore, effective oral Insulin delivery would be a significant advance in drug delivery. Herein, we report the use of the modified cell penetrating peptide (CPP) platform, Glycosaminoglycan-(GAG)-binding-enhanced-transduction (GET), as an efficacious transepithelial delivery vector in vitro and to mediate oral Insulin activity in diabetic animals. Insulin can be conjugated with GET via electrostatic interaction to form nanocomplexes (Insulin GET-NCs). These NCs (size and charge; 140 nm, +27.10 mV) greatly enhanced Insulin transport in differentiated in vitro intestinal epithelium models (Caco2 assays; >22-fold increased translocation) with progressive and significant apical and basal release of up-taken Insulin. Delivery resulted in intracellular accumulation of NCs, enabling cells to act as depots for subsequent sustained release without affecting viability and barrier integrity. Importantly Insulin GET-NCs have enhanced proteolytic stability, and retained significant Insulin biological activity (exploiting Insulin-responsive reporter assays). Our study culminates in demonstrating oral delivery of Insulin GET-NCs which can control elevated blood-glucose levels in streptozotocin (STZ)-induced diabetic mice over several days with serial dosing. As GET promotes Insulin absorption, transcytosis and intracellular release, along with in vivo function, our simplistic complexation platform could allow effective bioavailability of other oral peptide therapeutics and help transform the treatment of diabetes.


Subject(s)
Cell-Penetrating Peptides , Diabetes Mellitus, Experimental , Humans , Mice , Animals , Insulin/pharmacology , Diabetes Mellitus, Experimental/drug therapy , Glycemic Control , Caco-2 Cells , Cell-Penetrating Peptides/chemistry , Transcytosis , Administration, Oral , Blood Glucose
14.
JMIR Res Protoc ; 12: e46643, 2023 06 06.
Article in English | MEDLINE | ID: mdl-37279056

ABSTRACT

BACKGROUND: In the Canadian province of Saskatchewan, the global COVID-19 pandemic appeared amidst existing social health challenges in food insecurity, housing precarity and homelessness, poor mental health, and substance misuse. These chronic features intersected with the pandemic, producing a moment in time when the urgency of COVID-19 brought attention to underlying shortcomings in public health services. OBJECTIVE: The objectives of the program of research are (1) to identify and measure relationships between the pandemic and wider health and social impacts, namely, food insecurity, housing precarity and homelessness, and mental health and substance use in Saskatchewan, and (2) to create an oral history of the pandemic in Saskatchewan in an accessible digital public archive. METHODS: We are using a mixed methods approach to identify the impacts of the pandemic on specific equity-seeking groups and areas of social health concern by developing cross-sectional population-based surveys and producing results based on statistical analysis. We augmented the quantitative analysis by conducting qualitative interviews and oral histories to generate more granular details of people's experiences of the pandemic. We are focusing on frontline workers, other service providers, and individuals within equity-seeking groups. We are capturing digital evidence and social media posts; we are collecting and organizing key threads using a free open-source research tool, Zotero, to trace the digital evidence of the pandemic in Saskatchewan. This study is approved by the Research Ethics Board at the University of Saskatchewan (Beh-1945). RESULTS: Funding for this program of research was received in March and April 2022. Survey data were collected between July and November 2022. The collection of oral histories began in June 2022 and concluded in March 2023. In total, 30 oral histories have been collected at the time of this writing. Qualitative interviews began in April 2022 and will continue until March 2024. Survey analysis began in January 2023, and results are expected to be published in mid-2023. All data and stories collected in this work are archived for preservation and freely accessible on the Remember Rebuild Saskatchewan project's website. We will share results in academic journals and conferences, town halls and community gatherings, social and digital media reports, and through collaborative exhibitions with public library systems. CONCLUSIONS: The pandemic's ephemeral nature poses a risk of us "forgetting" this moment and the attendant social inequities. These challenges inspired a novel fusion among health researchers, historians, librarians, and service providers in the creation of the Remember Rebuild Saskatchewan project, which focuses on preserving the legacy of the pandemic and capturing data to support an equitable recovery in Saskatchewan. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/46643.

15.
Philos Trans A Math Phys Eng Sci ; 381(2252): 20220278, 2023 Aug 07.
Article in English | MEDLINE | ID: mdl-37334453

ABSTRACT

The physical origin of behaviour in biological organisms is distinct from those of non-living systems in one significant way: organisms exhibit intentionality or goal-directed behaviour. How may we understand and explain this important aspect in physical terms, grounded in laws of physics and chemistry? In this article, we discuss recent experimental and theoretical progress in this area and future prospects of this line of thought. The physical basis for our investigation is thermodynamics, though other branches of physics and chemistry have an important role. This article is part of the theme issue 'Thermodynamics 2.0: Bridging the natural and social sciences (Part 1)'.


Subject(s)
Physics , Social Sciences , Thermodynamics
16.
Clin Nucl Med ; 48(4): 356-358, 2023 Apr 01.
Article in English | MEDLINE | ID: mdl-36727861

ABSTRACT

ABSTRACT: CT pulmonary angiogram and ventilation-perfusion scintigraphy are the 2 primary imaging modalities for evaluating patients with CTEPH (chronic thromboembolic pulmonary hypertension). PET/CT and MRI currently have a limited role in the evaluation of acute or chronic pulmonary embolism. We present incidentally captured dynamic pulmonary perfusion images in a patient with history of CTEPH who underwent 82 Rb myocardial perfusion PET/CT for evaluation of chest pain. Analysis of the PET data revealed delayed perfusion of the affected lobes suggesting collateralization, highlighting a potentially new imaging paradigm for assessment of pulmonary perfusion.


Subject(s)
Hypertension, Pulmonary , Pulmonary Embolism , Humans , Positron Emission Tomography Computed Tomography , Lung , Positron-Emission Tomography , Chronic Disease
17.
Entropy (Basel) ; 24(12)2022 Dec 08.
Article in English | MEDLINE | ID: mdl-36554198

ABSTRACT

All organisms depend on a supply of energetic resources to power behavior and the irreversible entropy-producing processes that sustain them. Dissipative structure theory has often been a source of inspiration for better understanding the thermodynamics of biology, yet real organisms are inordinately more complex than most laboratory systems. Here we report on a simulated chemical dissipative structure that operates as a proto cell. The simulated swimmer moves through a 1D environment collecting resources that drive a nonlinear reaction network interior to the swimmer. The model minimally represents properties of a simple organism including rudimentary foraging and chemotaxis and an analog of a metabolism in the nonlinear reaction network. We evaluated how dynamical stability of the foraging dynamics (i.e., swimming and chemotaxis) relates to the rate of entropy production. Results suggested a relationship between dynamical steady states and entropy production that was tuned by the relative coordination of foraging and metabolic processes. Results include evidence in support of and contradicting one formulation of a maximum entropy production principle. We discuss the status of this principle and its relevance to biology.

18.
Biomater Adv ; 143: 213177, 2022 Dec.
Article in English | MEDLINE | ID: mdl-36371970

ABSTRACT

Nanotechnologies are being increasingly applied as systems for peptide and nucleic acid macromolecule drug delivery. However systemic targeting of these, or efficient topical and localized delivery remains an issue. A controlled release system that can be patterned and locally administered such as topically to accessible tissue (skin, eye, intestine) would therefore be transformative in realizing the potential of such strategies. We previously developed a technology termed GAG-binding enhanced transduction (GET) to efficiently deliver a variety of cargoes intracellularly, using GAG-binding peptides to mediate cell targeting, and cell penetrating peptides (CPPs) to promote uptake. Herein we demonstrate that the GET transfection system can be used with the moisturizing thermo-reversible hydrogel Pluronic-F127 (PF127) and methyl cellulose (MC) to mediate site specific and effective intracellular transduction and gene delivery through GET nanoparticles (NPs). We investigated hydrogel formulation and the temperature dependence of delivery, optimizing the delivery system. GET-NPs retain their activity to enhance gene transfer within our formulations, with uptake transferred to cells in direct contact with the therapy-laden hydrogel. By using Azowipe™ material in a bandage approach, we were able to show for the first-time localized gene transfer in vitro on cell monolayers. The ability to simply control localization of gene delivery on millimetre scales using contact-mediated transfer from moisture-providing thermo-reversible hydrogels will facilitate new drug delivery methods. Importantly our technology to site-specifically deliver the activity of novel nanotechnologies and gene therapeutics could be transformative for future regenerative medicine.


Subject(s)
Cell-Penetrating Peptides , Hydrogels , Hydrogels/chemistry , Poloxamer/chemistry , Bandages , Genetic Therapy
19.
BMJ Case Rep ; 15(9)2022 Sep 16.
Article in English | MEDLINE | ID: mdl-36113958

ABSTRACT

Euglycaemic diabetic ketoacidosis is a serious but rare adverse effect of treatment with sodium-glucose cotransporter-2 (SGLT-2) inhibitors. A man in his 60s with type 2 diabetes mellitus underwent total hip replacement for an intracapsular neck of femur fracture. His SGLT-2 inhibitor was continued perioperatively and blood glucose levels were normal throughout the admission. A diagnosis of severe euglycaemic diabetic ketoacidosis was made in the operating theatre which required treatment in a critical care unit. This resulted in increased morbidity due to decreased postoperative mobilisation and a new requirement for subcutaneous insulin. This case highlights the need for withholding SGLT-2 inhibitors in patients admitted for emergency surgery and a need for regular ketone monitoring in these patients, even in the context of normoglycaemia.


Subject(s)
Diabetes Mellitus, Type 2 , Diabetic Ketoacidosis , Orthopedics , Sodium-Glucose Transporter 2 Inhibitors , Blood Glucose , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/drug therapy , Diabetic Ketoacidosis/chemically induced , Diabetic Ketoacidosis/diagnosis , Humans , Hypoglycemic Agents/adverse effects , Insulin , Ketones/adverse effects , Male , Sodium , Sodium-Glucose Transporter 2 Inhibitors/adverse effects
20.
Sci Rep ; 12(1): 14775, 2022 08 30.
Article in English | MEDLINE | ID: mdl-36042321

ABSTRACT

Do communicative actions such as gestures fundamentally differ in their control mechanisms from other actions? Evidence for such fundamental differences comes from a classic gesture-speech coordination experiment performed with a person (IW) with deafferentation (McNeill, 2005). Although IW has lost both his primary source of information about body position (i.e., proprioception) and discriminative touch from the neck down, his gesture-speech coordination has been reported to be largely unaffected, even if his vision is blocked. This is surprising because, without vision, his object-directed actions almost completely break down. We examine the hypothesis that IW's gesture-speech coordination is supported by the biomechanical effects of gesturing on head posture and speech. We find that when vision is blocked, there are micro-scale increases in gesture-speech timing variability, consistent with IW's reported experience that gesturing is difficult without vision. Supporting the hypothesis that IW exploits biomechanical consequences of the act of gesturing, we find that: (1) gestures with larger physical impulses co-occur with greater head movement, (2) gesture-speech synchrony relates to larger gesture-concurrent head movements (i.e. for bimanual gestures), (3) when vision is blocked, gestures generate more physical impulse, and (4) moments of acoustic prominence couple more with peaks of physical impulse when vision is blocked. It can be concluded that IW's gesturing ability is not based on a specialized language-based feedforward control as originally concluded from previous research, but is still dependent on a varied means of recurrent feedback from the body.


Subject(s)
Gestures , Speech , Biomechanical Phenomena/physiology , Feedback, Sensory , Humans , Posture , Speech/physiology
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