Pain scores and functional outcomes of patients with shoulder labral repair using all-suture anchors versus conventional anchors.

HYPOTHESIS/PURPOSE: The purpose of this study was to compare PROMs in patients undergoing anterior glenoid labral repair using all-suture versus conventional anchors. We hypothesized PROMs would be similar between groups. METHODS: We performed a retrospective review of the Arthrex Global Surgical Outcomes System (SOS) database, querying patients who underwent arthroscopic glenoid labral repair between 01/01/2015 and 12/31/2020. Patients aged 18-100, who had isolated glenoid labrum repair with at least 12-month follow-up were included. The visual analog pain scale (VAS), Western Ontario Shoulder Instability Index, Veteran's RAND 12-items health survey, single assessment numeric evaluation and the American Shoulder and Elbow Surgeons score (ASES) were compared preoperatively, 3 months, 6 months, 1 year and 2 years postoperatively in patients who received all-suture anchors versus conventional anchors in the setting of anterior glenoid labrum repair. Our primary aim was comparison of PROMs between patients receiving all-suture versus conventional suture anchors. Secondarily, a sub-analysis was performed comparing outcomes based on anchor utilization for patients with noted anterior instability. RESULTS: We evaluated 566 patients, 54 patients receiving all-suture anchors and 512 patients receiving conventional anchors. At two-year follow-up there was no significant difference between the two groups in PROMs. In a sub-analysis of isolated anterior labrum repair, there was an improvement in ASES (P = 0.034) and VAS (P = 0.039) with the all-suture anchor at two-year follow-up. CONCLUSIONS: All-suture anchors provide similar or superior pain and functional outcome scores up to 2 years postoperatively compared to conventional anchors. CLINICAL RELEVANCE: As all-suture anchors gain popularity among surgeons, this is the largest scale study to date validating their use in the setting of glenoid labrum repair. Institutional Review Board (IRB): IRB202102550.

Single-centre experience with peptide receptor radionuclide therapy for neuroendocrine tumours (NETs): results using a theranostic molecular imaging-guided approach.

AIM: To summarise our centre's experience managing patients with neuroendocrine tumours (NETs) in the first 5 years after the introduction of peptide receptor radionuclide therapy (PRRT) with [177Lu]Lu-DOTA-octreotate (LUTATE). The report emphasises aspects of the patient management related to functional imaging and use of radionuclide therapy. METHODS: We describe the criteria for treatment with LUTATE at our centre, the methodology for patient selection, and the results of an audit of clinical measures, imaging results and patient-reported outcomes. Subjects are treated initially with four cycles of ~ 8 GBq of LUTATE administered as an outpatient every 8 weeks. RESULTS: In the first 5 years offering LUTATE, we treated 143 individuals with a variety of NETs of which approx. 70% were gastroentero-pancreatic in origin (small bowel: 42%, pancreas: 28%). Males and females were equally represented. Mean age at first treatment with LUTATE was 61 ± 13 years with range 28-87 years. The radiation dose to the organs considered most at risk, the kidneys, averaged 10.6 ± 4.0 Gy in total. Median overall survival (OS) from first receiving LUTATE was 72.5 months with a median progression-free survival (PFS) of 32.3 months. No evidence of renal toxicity was seen. The major long-term complication seen was myelodysplastic syndrome (MDS) with a 5% incidence. CONCLUSIONS: LUTATE treatment for NETs is a safe and effective treatment. Our approach relies heavily on functional and morphological imaging informing the multidisciplinary team of NET specialists to guide appropriate therapy, which we suggest has contributed to the favourable outcomes seen.

Fourier transform infrared spectroscopy as a non-destructive method for analysing herbarium specimens.

Dried plant specimens stored in herbaria are an untapped treasure chest of information on environmental conditions, plant evolution and change over many hundreds of years. Owing to their delicate nature and irreplaceability, there is limited access for analysis to these sensitive samples, particularly where chemical data are obtained using destructive techniques. Fourier transform infrared (FTIR) spectroscopy is a chemical analysis technique which can be applied non-destructively to understand chemical bonding information and, therefore, functional groups within the sample. This provides the potential for understanding geographical, spatial and species-specific variation in plant biochemistry. Here, we demonstrate the use of mid-FTIR microspectroscopy for the chemical analysis of Drosera rotundifolia herbarium specimens, which were collected 100 years apart from different locations. Principal component and hierarchical clustering analysis enabled differentiation between three main regions on the plant (lamina, tentacle stalk and tentacle head), and between the different specimens. Lipids and protein spectral regions were particularly sensitive differentiators of plant tissues. Differences between the different sets of specimens were smaller. This study demonstrates that relevant information can be extracted from herbarium specimens using FTIR, with little impact on the specimens. FTIR, therefore, has the potential to be a powerful tool to unlock historic information within herbaria.

Acrylamide-based hydrogels with distinct osteogenic and chondrogenic differentiation potential.

Regeneration solutions for the osteochondral interface depth are limited, where multi-material implants have the potential to delaminate affecting the regeneration process and impacting the final integrity of tissue interface. Here we explore regionally mixed hydrogel networks, presenting distinct chemical features to determine their compatibility in supporting osteogenic or chondrogenic cell behaviour and differentiation. Poly(N-isopropylacrylamide) (pNIPAM) and poly(N-tert-butylacrylamide) (pNTBAM) hydrogels were assessed in terms of their chemical differences, mechanical strength, internal architecture, porosity and capacity to support cell viability, migration, and differentiation. pNTBAM polymerized with a Young's modulus of up to 371 ± 31 kPa compared to the more flexible pNIPAM, 16.5 ± 0.6 kPa. Viability testing revealed biocompatibility of both hydrogels with significantly increased cell numbers observed in pNTBAM (500 ± 95 viable cells/mm2) than in pNIPAM (60 ± 3 viable cells/mm2) (P ≤ 0.05). Mineralization determined through alkaline phosphatase (ALP) activity, calcium ion and annexin A2 markers of mineralization) and osteogenic behaviour (collagen I expression) were supported in both hydrogels, but to a greater extent in pNTBAM. pNTBAM supported significantly elevated levels of chondrogenic markers as evidenced by collagen II and glycosaminoglycan expression in comparison to little or no evidence in pNIPAM (P ≤ 0.05). In conclusion, structurally similar, chemically distinct, acrylamide hydrogels display variable capacities in supporting osteochondral cell behaviours. These systems demonstrate spatial control of cell interaction through simple changes in monomer chemistry. Fine control over chemical presentation during the fabrication of biomaterial implants could lead to greater efficacy and targeted regeneration of semi-complex tissues.

Gradient biomimetic platforms for neurogenesis studies.

There is a need for the development of new cellular therapies for the treatment of many diseases, with the central nervous system (CNS) currently an area of specific focus. Due to the complexity and delicacy of its biology, there is currently a limited understanding of neurogenesis and consequently a lack of reliable test platforms, resulting in several CNS based diseases having no cure. The ability to differentiate pluripotent stem cells into specific neuronal sub-types may enable scalable manufacture for clinical therapies, with a focus also on the purity and quality of the cell population. This focus is targeted towards an urgent need for the diseases that currently have no cure, e.g. Parkinson's disease. Differentiation studies carried out using traditional 2D cell culture techniques are designed using biological signals and morphogens known to be important for neurogenesisin vivo.However, such studies are limited by their simplistic nature, including a general poor efficiency and reproducibility, high reagent costs and an inability to scale-up the process to a manufacture-wide design for clinical use. Biomimetic approaches to recapitulate a morein vivo-like environment are progressing rapidly within this field, with application of bio(chemical) gradients presented both as 2D surfaces and within a 3D volume. This review focusses on the development and application of these advanced extracellular environments particularly for the neural niche. We emphasise the progress that has been made specifically in the area of stem cell derived neuronal differentiation. Increasing developments in biomaterial approaches to manufacture stem cells will enable the improvement of differentiation protocols, enhancing the efficiency and repeatability of the process with a move towards up-scaling. Progress in this area brings these techniques closer to enabling the development of therapies for the clinic.

Modification of the surface nanotopography of implant devices: A translational perspective.

There is an increasing need for the development of superior, safe, and more sophisticated implants, especially as our society historically has been moving towards an increasingly aging population. Currently, most research is being focused on the next generation of advanced medical implants, that are not only biocompatible but have modified surfaces that direct specific immunomodulation at cellular level. While there is a plethora of information on cell-surface interaction and how surfaces can be nanofabricated at research level, less is known about how the academic knowledge has been translated into clinical trials and commercial technologies. In this review, we provide a clinical translational perspective on the use of controlled physical surface modification of medical implants, presenting an analysis of data acquired from clinical trials and commercial products. We also evaluate the state-of-the-art of nanofabrication techniques that are being applied for implant surface modification at a clinical level. Finally, we identify some current challenges in the field, including the need of more advanced nanopatterning techniques, the comparatively small number of clinical trials and comment on future avenues to be explored for a successful clinical translation.

Impact of type-1 collagen hydrogel density on integrin-linked morphogenic response of SH-SY5Y neuronal cells.

Cellular metabolism and behaviour is closely linked to cytoskeletal tension and scaffold mechanics. In the developing nervous system functional connectivity is controlled by the interplay between chemical and mechanical cues that initiate programs of cell behaviour. Replication of functional connectivity in neuronal populations in vitro has proven a technical challenge due to the absence of many systems of biomechanical regulation that control directional outgrowth in vivo. Here, a 3D culture system is explored by dilution of a type I collagen hydrogel to produce variation in gel stiffness. Hydrogel scaffold remodelling was found to be linked to gel collagen concentration, with a greater degree of gel contraction occurring at lower concentrations. Gel mechanics were found to evolve over the culture period according to collagen concentration. Less concentrated gels reduced in stiffness, whilst a biphasic pattern of increasing and then decreasing stiffness was observed at higher concentrations. Analysis of these cultures by PCR revealed a program of shifting integrin expression and highly variable activity in key morphogenic signal pathways, such as mitogen-associated protein kinase, indicating genetic impact of biomaterial interactions via mechano-regulation. Gel contraction at lower concentrations was also found to be accompanied by an increase in average collagen fibre diameter. Minor changes in biomaterial mechanics result in significant changes in programmed cell behaviour, resulting in adoption of markedly different cell morphologies and ability to remodel the scaffold. Advanced understanding of cell-biomaterial interactions, over short and long-term culture, is of critical importance in the development of novel tissue engineering strategies for the fabrication of biomimetic 3D neuro-tissue constructs. Simple methods of tailoring the initial mechanical environment presented to SH-SY5Y populations in 3D can lead to significantly different programs of network development over time.

Protein targeting to glycogen is a master regulator of glycogen synthesis in astrocytes.

The storage and use of glycogen, the main energy reserve in the brain, is a metabolic feature of astrocytes. Glycogen synthesis is regulated by Protein Targeting to Glycogen (PTG), a member of specific glycogen-binding subunits of protein phosphatase-1 (PPP1). It positively regulates glycogen synthesis through de-phosphorylation of both glycogen synthase (activation) and glycogen phosphorylase (inactivation). In cultured astrocytes, PTG mRNA levels were previously shown to be enhanced by the neurotransmitter noradrenaline. To achieve further insight into the role of PTG in the regulation of astrocytic glycogen, its levels of expression were manipulated in primary cultures of mouse cortical astrocytes using adenovirus-mediated overexpression of tagged-PTG or siRNA to downregulate its expression. Infection of astrocytes with adenovirus led to a strong increase in PTG expression and was associated with massive glycogen accumulation (>100 fold), demonstrating that increased PTG expression is sufficient to induce glycogen synthesis and accumulation. In contrast, siRNA-mediated downregulation of PTG resulted in a 2-fold decrease in glycogen levels. Interestingly, PTG downregulation strongly impaired long-term astrocytic glycogen synthesis induced by insulin or noradrenaline. Finally, these effects of PTG downregulation on glycogen metabolism could also be observed in cultured astrocytes isolated from PTG-KO mice. Collectively, these observations point to a major role of PTG in the regulation of glycogen synthesis in astrocytes and indicate that conditions leading to changes in PTG expression will directly impact glycogen levels in this cell type.

'It's nice to have something to do': early-onset dementia and maintaining purposeful activity.

As the global focus on dementia care increases due to the demand on health, social, legal and financial services, it is imperative to further understand the experience of those living with a diagnosis of dementia. There is a particular lack of research focused on younger people (under the age of 65 years) with dementia and virtually none focuses on the experience of the family unit. The literature suggests that periods of transition place significant stressors on families living with dementia. One such transition is the transition out of perceived purposeful activity, be this employment or voluntary work. This transition was explored during the course of a qualitative repeated interview study with younger people with dementia and their families. Nine families (20 participants) took part in semi-structured research interviews that were transcribed and analyzed using a Framework approach to qualitative analysis. Meaningful Activity emerged as a major theme through this analysis. Two subthemes also emerged: (1) the traumatic cessation of work; and (2) the need for purposeful activity. These themes have significant clinical implications as maintaining a purposeful role through high-quality, age-specific dementia services may decrease the direct and indirect costs of dementia to global economies.

Surface treatments for microfluidic biocompatibility.

Microfluidic systems allow small volumes of liquids to be manipulated, either by being passed through channels or moved around as liquid droplets. Such systems have been developed to separate, purify, analyze, and deliver molecules to reaction zones. Although volumes are small, reaction rates, catalysis, mixing, and heat transfer can be high, enabling the accurate sensing of tiny quantities of agents and the synthesis of novel products. The incorporation of multiple components, such as pumps, valves, mixers, and heaters, onto a single microfluidic platform has brought about the field of lab-on-a-chip devices or micro total analysis systems (µTAS). Although used in the research laboratory for numerous years, few of these devices have made it into the commercial market, due to their complexity of fabrication and limited choice of material. As the dimensions of these systems become smaller, interfacial interactions begin to dominate in terms of device performance. Appropriate selection of bulk materials, or the application of surface coatings, can allow control over surface properties, such as the adsorption of (bio)molecules. Here we review current microfluidic technology in terms of biocompatibility issues, examining the use of modification strategies to improve device longevity and performance.

Superhydrophobicity for antifouling microfluidic surfaces.

Fouling of surfaces is often problematic in microfluidic devices, particularly when using protein or -enzymatic solutions. Various coating methods have been investigated to reduce the tendency for protein molecules to adsorb, mostly relying on hydrophobic surface chemistry or the antifouling ability of -polyethylene glycol. Here we present the potential use of superhydrophobic surfaces to not only reduce the amount of surface contamination but also to induce self-cleaning under flow conditions. The methodology is presented in order to prepare superhydrophobic surface coatings having micro- and nanoscale feature dimensions, as well as a step-by-step guide to quantify adsorbed protein down to nanogram levels. The fabrication of these surfaces as coatings via silica sol-gel and copper nano-hair growth is presented, which can be applied within microfluidic devices manufactured from various materials.

Biotic interactions in temporal trends (1992-2010) of organochlorine contaminants in the aquatic food web of Lake Laberge, Yukon Territory.

Declines in 6 organochlorine (OC) contaminant groups; chlordane (CHL), DDT, HCH, toxaphene (CHB), PCB and chlorinated benzenes (CBz) were measured in biota of a sub-Arctic lake (Lake Laberge, YT) following the closure of a commercial fishery in 1991. This study examined morphological (length, weight, age), biochemical (lipid content, δ(13)C, δ(15)N), population and OC data for 9 fishes and zooplankton between 1993 and 2003 (2010 for lake trout) to investigate causes for the OC declines. Growth dilution was a major factor influencing the decrease of OCs in lake trout, round whitefish and possibly zooplankton most notably in the early 2000s. A decline in lipids of most fish species also contributed to OC declines, although no such change was evident for zooplankton. It is suspected that increases in fish populations or climate variations over the 1990s, may have contributed towards a shift in plankton community composition. From 1991 to 1999, CPUE increased for 7 of the fish species and declined for 2 others. Concurrently, the zooplankton community shifted from an abundance of C. scutifer in 1993 to dominance by D. pribilofensis in 2001. Nitrogen and carbon stable isotope data suggested that food web interactions for most fish species have not changed over time. Although concentrations of OCs have declined in many fishes, the "rate" of OC transfer (using slopes of log OC vs. nitrogen isotope ratios) through the food web was greater in 2001 than in 1993. Overall, the declines in OC concentrations in the fish from Lake Laberge occurred concurrently with changes in their growth, lipid, and abundance, suggesting that ecosystem responses to the closure of the fishery were in part responsible for the lower contaminants in these fishes. As a result of this study, the Yukon government rescinded the health advisory for limiting the consumption of fish from Lake Laberge.

Inhibition of Yersinia pestis DNA adenine methyltransferase in vitro by a stibonic acid compound: identification of a potential novel class of antimicrobial agents.

BACKGROUND AND PURPOSE: Multiple antibiotic resistant strains of plague are emerging, driving a need for the development of novel antibiotics effective against Yersinia pestis. DNA adenine methylation regulates numerous fundamental processes in bacteria and alteration of DNA adenine methlytransferase (Dam) expression is attenuating for several pathogens, including Y. pestis. The lack of a functionally similar enzyme in humans makes Dam a suitable target for development of novel therapeutics for plague. EXPERIMENTAL APPROACH: Compounds were evaluated for their ability to inhibit Dam activity in a high-throughput screening assay. DNA was isolated from Yersinia grown in the presence of lead compounds and restricted to determine the effect of inhibitors on DNA methylation. Transcriptional analysis was undertaken to determine the effect of an active inhibitor on virulence-associated phenotypes. KEY RESULTS: We have identified a series of aryl stibonic acids which inhibit Dam in vitro. The most active, 4-stibonobenzenesulfonic acid, exhibited a competitive mode of inhibition with respect to DNA and a K(i) of 6.46 nM. One compound was found to inhibit DNA methylation in cultured Y. pestis. The effects of this inhibition on the physiology of the cell were widespread, and included altered expression of known virulence traits, including iron acquisition and Type III secretion. CONCLUSIONS AND IMPLICATIONS: We have identified a novel class of potent Dam inhibitors. Treatment of bacterial cell cultures with these inhibitors resulted in a decrease in DNA methylation. Expression of virulence factors was affected, suggesting these inhibitors may attenuate bacterial infectivity and function as antibiotics.

Multiplexed suspension array platform for high-throughput protein assays.

A multiplexed suspension array platform, based on SU8 disks patterned with machine-readable binary identification codes is presented. Multiple probe molecules, each attached to individual disks with different unique codes, provide multiplexed detection of targets in a small sample volume. The experimental system consists of a microfluidic chamber for arraying the particles in a manner suitable for high throughput imaging using a simple fluorescent microscope, together with custom software for automated code readout and analysis of assay response. The platform is demonstrated with a multiplexed antibody assay targeting 3 different human inflammatory cytokines. The suitability of the platform for other bio-analytical applications is discussed.

'It's easier just to separate them': practice constructions in the mental health care and support of younger people with dementia and their families.

There is no standard model of specialist care for younger people with dementia (onset before the age of 65 years) and specialist service provision varies widely throughout the UK. In order to gain a clearer picture about ways in which clinical staff work with younger people with dementia, semi-structured interviews were conducted with dementia care staff working in the north-west of England. Interviews focused on exploring daily working practices and the meaning placed on clinical decision making when involving family/carers in routine practice. Content analysis generated three core themes: (1) Maintaining Separation: how clinical staff conceptualize the meaning of 'family' in the provision of dementia care services; (2) Providing Practical Help: the focus in care provision on assisting families with aspects of daily life such as finances, education and physical care; and (3) Acknowledging the Family Context: how staff understand and interact with family members in an attempt to initiate care, utilizing biographically informed practice. By understanding how staff view their role in providing younger people with dementia with effective, high-quality dementia care, it is anticipated that a more family-centred approach can be integrated into already established patterns of working that more holistically meet the needs of this group.

Penetrating paediatric thoracic injury.

Paediatric penetrating chest trauma is common in conflict, but rarely seen in peacetime. We describe the successful hospital management of a five year old female civilian casualty with life threatening penetrating thoracic trauma caused by a fragment from an explosive device.

The folic acid endophenotype and depression in an elderly population.

OBJECTIVES: Folate status and/or genes have been linked to depression in a number of studies. This may be via a direct action (or actions) on neuronal membranes or indirect effects through the metabolism of methyl groups involved in neurotransmitter synthesis. This study examines folate and related thiol metabolism that might underpin either phenomenon. DESIGN: Cohort study describing the relationship between several genetic and nutritional aspects of folic acid homeostasis and depression assessed by the HADS psychometric index in an elderly cohort. SETTING: New South Wales (Australia) retirement village. PARTICIPANTS: 118 elderly participants (age 65-90 years). RESULTS: Stepwise multiple regression was used to determine the best statistical model to predict depression; C677T-MTHFR (p=0.0103) was found to be positively associated with depression, while the thiol dipeptide Cys-Gly was negatively associated (p=0.0403). The statistical models used accounted for the major folate related indices (genetic and biochemical) that are most often evaluated in the context of health and disease. When only genetic data were examined for interactions, C677T-MTHFR was found to be negatively associated with the HADS Depression Index Score (p=0.0191). CONCLUSION: The potential influence of Cys-Gly on this phenotype is novel, and of considerable interest given that it has been linked to altered spontaneous activity and sedation in an animal model. Cys-Gly is a recognised ligand at the N-methyl-D-aspartatic acid (NMDA) subclass of glutamate receptor, a system associated with depression. In addition, the C677T-MTHFR association adds further support to existing findings underscoring the potential role of folate in depression.

Historical interrelated variations of mercury and aquatic organic matter in lake sediment cores from a subArctic lake in Yukon, Canada: further evidence toward the algal-mercury scavenging hypothesis.

This study investigates the role of climate-driven aquatic productivity increases in conrolling the sedimentary accumulation of mercury (Hg) in Kusawa Lake, Yukon, Canada. Organic geochemistry data reveals a significant link between the increasing trends of Hg and of labile algal-derived organic matter (OM) over the centuries and in particular over recent decades. Sedimentary Hg accumulation rates continue to increase even though atmospheric concentrations of Hg have remained the same or even declined. Together, these findings indicate that the significant rise in Hg content recorded in the sediments since the early 1950s may not be representative of increasing atmospheric Hg levels but are strongly influenced by elevated concentrations of algal-derived OM in the water-column. These likely increase the scavenging rate of "available" Hg from the water column. Therefore, recent increases in algal productivity may result in overestimation of the historical rates of atmospheric Hg deposition recorded in the sediments. This study confirms earlier published findings from two High Arctic lakes, and shows that the Hg-OM scavenging hypothesis may also apply to sub-Arctic lakes.