Distal Fibula Pro-Tibial Screws in Salvage Fixation of Bimalleolar Ankle Fractures in Osteoporotic Bone - A Novel Technique.

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.

Bio-analog dissipative structures and principles of biological behavior.

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.

Study on impact of robotic-assisted orthopaedic industrial noise (SIREN).

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.

Effects of Microenvironment and Dosing on Efficiency of Enhanced Cell Penetrating Peptide Nonviral Gene Delivery.

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.

Combined biolistic and cell penetrating peptide delivery for the development of scalable intradermal DNA vaccines.

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.

Surgical Rib Fracture Fixation: Early Operative Intervention Improves Outcomes.

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.

Thermodynamics, organisms and behaviour.

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)'.

Capturing and Documenting the Wider Health Impacts of the COVID-19 Pandemic Through the Remember Rebuild Saskatchewan Initiative: Protocol for a Mixed Methods Interdisciplinary Project.

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.

NANOG is required to establish the competence for germ-layer differentiation in the basal tetrapod axolotl.

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.

Orally-delivered insulin-peptide nanocomplexes enhance transcytosis from cellular depots and improve diabetic blood glucose control.

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.

Novel Depiction of Collateral Flow in Chronic Thromboembolic Pulmonary Hypertension Using 4D Dynamic 82 Rb PET/CT.

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.

Foraging Dynamics and Entropy Production in a Simulated Proto-Cell.

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.

Direct contact-mediated non-viral gene therapy using thermo-sensitive hydrogel-coated dressings.

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.

SGLT-2 inhibitor associated euglycaemic diabetic ketoacidosis in an orthopaedic trauma patient.

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.

The importance of visual control and biomechanics in the regulation of gesture-speech synchrony for an individual deprived of proprioceptive feedback of body position.

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.

Development of a Gene-Activated Scaffold Incorporating Multifunctional Cell-Penetrating Peptides for pSDF-1α Delivery for Enhanced Angiogenesis in Tissue Engineering Applications.

Non-viral gene delivery has become a popular approach in tissue engineering, as it permits the transient delivery of a therapeutic gene, in order to stimulate tissue repair. However, the efficacy of non-viral delivery vectors remains an issue. Our lab has created gene-activated scaffolds by incorporating various non-viral delivery vectors, including the glycosaminoglycan-binding enhanced transduction (GET) peptide into collagen-based scaffolds with proven osteogenic potential. A modification to the GET peptide (FLR) by substitution of arginine residues with histidine (FLH) has been designed to enhance plasmid DNA (pDNA) delivery. In this study, we complexed pDNA with combinations of FLR and FLH peptides, termed GET* nanoparticles. We sought to enhance our gene-activated scaffold platform by incorporating GET* nanoparticles into collagen-nanohydroxyapatite scaffolds with proven osteogenic capacity. GET* N/P 8 was shown to be the most effective formulation for delivery to MSCs in 2D. Furthermore, GET* N/P 8 nanoparticles incorporated into collagen-nanohydroxyapatite (coll-nHA) scaffolds at a 1:1 ratio of collagen:nanohydroxyapatite was shown to be the optimal gene-activated scaffold. pDNA encoding stromal-derived factor 1α (pSDF-1α), an angiogenic chemokine which plays a role in BMP mediated differentiation of MSCs, was then delivered to MSCs using our optimised gene-activated scaffold platform, with the aim of significantly increasing angiogenesis as an important precursor to bone repair. The GET* N/P 8 coll-nHA scaffolds successfully delivered pSDF-1α to MSCs, resulting in a significant, sustained increase in SDF-1α protein production and an enhanced angiogenic effect, a key precursor in the early stages of bone repair.

Before/after intervention study to determine impact on life-cycle carbon footprint of converting from single-use to reusable sharps containers in 40 UK NHS trusts.

OBJECTIVES: To compare global warming potential (GWP) of hospitals converting from single-use sharps containers to reusable sharps containers (SSC, RSC). Does conversion to RSC result in GWP reduction? DESIGN: Using BS PAS 2050:2011 principles, a retrospective, before/after intervention quantitative model together with a purpose-designed, attributional 'cradle-to-grave' life-cycle tool, were used to determine the annual greenhouse gas (GHG) emissions of the two sharps containment systems. Functional unit was total fill line litres (FLL) of sharps containers needed to dispose of sharps for 1-year period in 40 trusts. Scopes 1, 2 and 3 emissions were included. Results were workload-normalised using National Health Service (NHS) national hospital patient-workload indicators. A sensitivity analysis examined areas of data variability. SETTING: Acute care hospital trusts in UK. PARTICIPANTS: 40 NHS hospital Trusts using RSC. INTERVENTION: Conversion from SSC to RSC. SSC and RSC usage details in 17 base line trusts immediately prior to 2018 were applied to the RSC usage details of the 40 trusts using RSC in 2019. PRIMARY OUTCOME MEASURE: The comparison of GWP calculated in carbon dioxide equivalents (CO2e) generated in the manufacture, transport, service and disposal of 12 months, hospital-wide usage of both containment systems in the 40 trusts. RESULTS: The 40 trusts converting to RSC reduced their combined annual GWP by 3267.4 tonnes CO2e (-83.9%); eliminated incineration of 900.8 tonnes of plastic; eliminated disposal/recycling of 132.5 tonnes of cardboard and reduced container exchanges by 61.1%. GHG as kg CO2e/1000 FLL were 313.0 and 50.7 for SSC and RSC systems, respectively. A sensitivity analysis showed substantial GHG reductions within unit processes could be achieved, however, their impact on relevant final GWP comparison varied <5% from base comparison. CONCLUSIONS: Adopting RSC is an example of a sustainable purchasing decision that can assist trusts meet NHS GHG reduction targets and can reduce GWP permanently with minimal staff behavioural change.

Easier Said Than Done? Task Difficulty's Influence on Temporal Alignment, Semantic Similarity, and Complexity Matching Between Gestures and Speech.

Gestures and speech are clearly synchronized in many ways. However, previous studies have shown that the semantic similarity between gestures and speech breaks down as people approach transitions in understanding. Explanations for these gesture-speech mismatches, which focus on gestures and speech expressing different cognitive strategies, have been criticized for disregarding gestures' and speech's integration and synchronization. In the current study, we applied three different perspectives to investigate gesture-speech synchronization in an easy and a difficult task: temporal alignment, semantic similarity, and complexity matching. Participants engaged in a simple cognitive task and were assigned to either an easy or a difficult condition. We automatically measured pointing gestures, and we coded participant's speech, to determine the temporal alignment and semantic similarity between gestures and speech. Multifractal detrended fluctuation analysis was used to determine the extent of complexity matching between gestures and speech. We found that task difficulty indeed influenced gesture-speech synchronization in all three domains. We thereby extended the phenomenon of gesture-speech mismatches to difficult tasks in general. Furthermore, we investigated how temporal alignment, semantic similarity, and complexity matching were related in each condition, and how they predicted participants' task performance. Our study illustrates how combining multiple perspectives, originating from different research areas (i.e., coordination dynamics, complexity science, cognitive psychology), provides novel understanding about cognitive concepts in general and about gesture-speech synchronization and task difficulty in particular.