Pandemic preparedness from the perspective of Occupational Health professionals.

BACKGROUND: Prior to any infectious disease emergence as a public health concern, early occupational preparedness is crucial for protecting employees from novel pathogens- coronavirus disease 2019 (COVID-19) is no different. AIMS: This study ascertains how occupational safety and health (OSH)/Human Resource (HR) professionals in the Republic of Ireland had managed to prepare their workplaces prior to the advent of COVID-19. METHODS: As part of a larger COVID-19 workplace study, online focus groups were conducted with OSH/HR professionals. Collected data were transcribed verbatim and entered into NVivo for thematic analysis incorporating intercoder reliability testing. RESULTS: Fifteen focus groups were conducted with OSH/HR professionals (n = 60) from various occupational settings. Three levels of organizational preparedness were identified: 'early awareness and preparation'; 'unaware and not ready' and 'aware, but not ready'. Most organizations were aware of the COVID-19 severity, but not fully prepared for the pandemic, especially stand-alone enterprises that may not have sufficient resources to cope with an unanticipated crisis. The experiences shared by OSH professionals illustrate their agility in applying risk management and control skills to unanticipated public/occupational health crises that arise. CONCLUSIONS: General pandemic preparedness such as the availability of work-from-home policies, emergency scenario planning and prior experience in workplace outbreaks of infectious diseases were helpful for workplace-associated COVID-19 prevention. This is the first study conducted with OSH/HR professionals in Ireland regarding COVID-19 preparedness in workplaces, which provides valuable insights into research literature, as well as empirical experience for the preparation of future public health emergencies.

Genome-based epidemiology and antimicrobial resistance of Neisseria gonorrhoeae in Spain: A prospective multicentre study.

BACKGROUND: Whole-genome sequencing (WGS) of Neisseria gonorrhoeae isolates combined with epidemiological and phenotypic data provides better understanding of population dynamics. AIM: The objective of this study was to investigate the molecular epidemiology of N. gonorrhoeae isolates from three centres in Spain and determine associations of antimicrobial resistance. METHODS: Genetic characterization was performed in 170 N. gonorrhoeae isolates. WGS was carried out with the HiSeq platform (Illumina). Genome assemblies were submitted to the PubMLST Neisseria database website to determine NG-MAST, MLST and NG-STAR. Antimicrobial resistance genes and point mutations were identified with PubMLST. Phylogenomic comparison was based on whole-genome single nucleotide polymorphism analysis. RESULTS: Twenty-six MLST, 49 NG-MAST and 41 NG-STAR sequence types were detected, the most prevalent being MLST-ST9363 (27.1%), NG-MAST ST569 (12.4%) and NG-STAR ST193 (14.7%). Phylogenetic analysis identified 13 clusters comprising 69% of the isolates, with two of note: one involved cefixime-resistant isolates from Barcelona presenting a mosaic penA X and belonging to MLST-ST7363 and the other involved azithromycin-resistant isolates from Mallorca that possessed the C2611T mutation in the four 23S rRNA alleles belonging to MLST-ST1901. CONCLUSION: The population of N. gonorrhoeae is quite heterogeneous in Spain. Our results agree with previous data published in Europe, albeit with some differences in distribution between regions. This study describes the circulation of two gonococcal populations with a specific resistance profile and sequence type in a specific geographic area. WGS is an effective tool for epidemiological surveillance of gonococcal infection and detection of resistance genes.

Effects of grazing platform stocking rate on productivity and profitability of pasture-based dairying in a fragmented farm scenario.

The area adjacent to the milking parlor, accessible for grazing by lactating dairy cows (i.e., the grazing platform [GP]), can be limited on fragmented pasture-based dairy farms. Such farms, with a moderate overall farm stocking rate, typically have a much higher stocking rate of dairy cows on the GP. This study quantified the effects of farm fragmentation on milk and herbage production and profitability in a whole-farm systems-scale study over 3 yr (2017-2019). Four systems, each with an overall farm stocking rate of 2.5 cows/ha but with different grazing platform stocking rates (GPSR), were examined. The proportions of the overall farm area within the GP were 100%, 83%, 71%, and 63% in each of the 4 systems, respectively. Hence, the 4 systems had a GPSR of 2.5, 3.0, 3.5, and 4.0 cows/ha. The GP was used for grazing and silage (ensiled herbage) production, and the non-GP portion of each GPSR system was used solely for silage production. Concentrate supplementation per cow was the same across all GPSR systems; approximately 10% of the annual feed budget. All systems were compact spring-calving with 24 cows per system. We discovered a lower proportion of grazed herbage in the diet with higher GPSR. All silage produced on the non-GP areas was required to support higher GPSR on each of the systems. Annual herbage production and milk production per cow were not different between GPSR systems, resulting in similar milk production per hectare of the overall system area. The economic implications of different GPSR on fragmented farms were modeled in 2 scenarios: (1) quantifying the cost associated with different levels of farm area fragmentation; (2) investigating the optimum GPSR on fragmented pasture-based dairy farms, depending on variable criteria. A greater level of farm fragmentation lowered the profitability of pasture-based dairy production. Costs of production increased with higher GPSR and longer distances between GP and non-GP areas. At a fixed GP area, it was most profitable to increase GPSR up to 4 cows/ha on the GP when milk price was high, land rental price was low, and shorter distance existed between GP and non-GP areas.

Increases in 'deaths of despair' during the COVID-19 pandemic in the United States and the United Kingdom.

OBJECTIVES: The COVID-19 pandemic significantly impacted mental health, health-related behaviours such as drinking and illicit drug use and the accessibility of health and social care services. How these pandemic shocks affected 'despair'-related mortality in different countries is less clear. This study uses public data to compare deaths from alcohol, drugs and suicide in the United States and the United Kingdom to identify similarities or differences in the impact of the pandemic on important non-COVID causes of death across countries and to consider the public health implications of these trends. STUDY DESIGN AND METHODS: Data were taken from publicly available mortality figures for England and Wales, Northern Ireland, Scotland and the United States of America, 2001-2021, and analysed descriptively through age-standardised and age-specific mortality rates from suicide, alcohol and drug use. RESULTS: Alcohol-specific deaths increased in all countries between 2019 and 2021, most notably in the United States and, to a lesser extent, England and Wales. Suicide rates did not increase markedly during the pandemic in any of the included nations. Drug-related mortality rates rose dramatically over the same period in the United States but not in other nations. CONCLUSIONS: Mortality from 'deaths of despair' during the pandemic has displayed divergent trends between causes and countries. Concerns about increases in deaths by suicide appear to have been unfounded, whereas deaths due to alcohol have risen across the United Kingdom and in the United States and across almost all age groups. Scotland and the United States had similarly high levels of drug-related deaths pre-pandemic, but the differing trends during the pandemic highlight the different underlying causes of these drug death epidemics and the importance of tailoring policy responses to these specific contexts.

Determinants of diarrhoeal infections among users of shared sanitation in informal settlements in Durban, South Africa.

Diarrhoeal disease continues to be a major health problem in many parts of the world, especially in developing countries, mainly due to the lack of access to sanitation, water, and hygienic living conditions. Identifying the determinants of diarrhoeal infections continues to be a challenge in developing countries. In this study, we ascertained the factors behind diarrhoea among inhabitants of informal settlements in the city of Durban, South Africa. Prevalence of diarrhoea in the study area varied between 7-year historical clinical records and data collected during the current study (primary data), with the primary data giving the highest monthly prevalence odds ratio (POR) up to 18.1 (±1.6)%. The main factors associated with diarrhoeal infections were open defaecation (POR = 1.8; 95% confidence interval (CI): 0.9-3.12), use of shared sanitation (POR = 1.7; 95%; CI: 1.05-2.26), and exposure to faecal matter around the homes (POR = 1.69; 95% CI: 1.25-3.10). Several other factors were also determined to be associated with diarrhoeal infections, such as hygiene practices in the communities, the non-treatment of water before use, and the presence of solid waste and faecal materials around the households. This study shows that diarrhoeal disease infections in informal settlements could be multifactorial; therefore, a multifactorial approach is needed to reduce these infections. These could include improving education on hygiene practices within the home setting as well as in public places, such as the community ablution blocks.

Priming as a strategy to overcome detrimental pH effects on cells for intervertebral disc regeneration.

Disc disease is characterised by degeneration of the nucleus pulposus (NP), the central gelatinous tissue of the intervertebral disc (IVD). As degeneration progresses, the microenvironment of the IVD becomes more hostile (i.e. decrease in oxygen, glucose and pH), providing a significant challenge for regeneration using cell-based therapies. Tissue engineering strategies such as priming cells or micro tissues with growth factors prior to implantation may overcome some of these issues by providing a pre-formed protective niche composed of extracellular matrix. The present study investigated the effect of priming on bone-marrow-derived stem cells (BMSCs) and articular chondrocytes (ACs) using transforming growth factor ß3 (TGF-ß3), cultured at different pH levels (pH 7.1, 6.8 and 6.5) representative of the in vivo disc microenvironment. Low pH was found to have a detrimental effect on both cell viability and matrix accumulation, which could be mitigated by priming cells using TGF-ß3. Investigating the activation of the transmembrane acid-sensing ion channels (ASIC-1 and -3) showed an increased expression of ASIC-1 in BMSCs and ASIC-3 in ACs at lower pH levels post-priming. Metabolic activity in terms of lactic acid production was also found to be affected significantly by priming, whereas oxygen and glucose consumptions did not change considerably. Overall, the study demonstrated that cells could be equipped to sustain the harsh environment of the IVD and promote accumulation of NP-like matrix through priming. Such an approach may open new avenues to engineer tissues capable of sustaining challenging microenvironments such as those found in the IVD.

Routine testing of close contacts of confirmed COVID-19 cases - National COVID-19 Contact Management Programme, Ireland, May to August 2020.

OBJECTIVES: The objective of this study was to inform public health practitioners who are designing, adapting and implementing testing and tracing strategies for Coronavirus disease (COVID-19) control. STUDY DESIGN: The study design is monitoring and evaluation of a national public health protection programme. METHODS: All close contacts of laboratory-confirmed cases of COVID-19 identified between the 19th May and 2nd August were included; secondary attack rates and numbers needed to test were estimated. RESULTS: Four thousand five hundred eighty six of 7272 (63%) close contacts of cases were tested with at least one test. The secondary attack rate in close contacts who were tested was 7% (95% Confidence Interval [CI]: 6.3 - 7.8%). At the 'day 0' test, 14.6% (95% CI: 11.6-17.6%) of symptomatic close contacts tested positive compared with 5.2% (95% CI: 4.4-5.9%) of asymptomatic close contacts. CONCLUSIONS: The application of additional symptom-based criteria for testing in this high-incidence population (close contacts) is of limited utility because of the low negative predictive value of absence of symptoms.

In vitro co-culture and ex vivo organ culture assessment of primed and cryopreserved stromal cell microcapsules for intervertebral disc regeneration.

Priming towards a discogenic phenotype and subsequent cryopreservation of microencapsulated bone marrow stromal cells (BMSCs) may offer an attractive therapeutic approach for disc repair. It potentially obviates the need for in vivo administration of exogenous growth factors, otherwise required to promote matrix synthesis, in addition to providing 'off-the-shelf' availability. Cryopreserved and primed BMSC microcapsules were evaluated in an in vitro surrogate co-culture model system with nucleus pulposus (NP) cells under intervertebral disc (IVD)-like culture conditions and in an ex vivo bovine organ culture disc model. BMSCs were microencapsulated in alginate microcapsules and primed for 14 d with transforming growth factor beta-3 (TGF-ß3) under low oxygen conditions prior to cryopreservation. For the in vitro phase, BMSC microcapsules (unprimed or primed) were cultured for 28 d in a surrogate co-culture model system mimicking that of the IVD. For the ex vivo phase, microcapsules (unprimed or primed) were injected into the NP of bovine discs that underwent nucleotomy. In vitro results revealed that although NP cells produced significantly more matrix components in co-culture with BMSC microcapsules regardless of the differentiation state, unprimed microcapsules were inadequate at synthesising matrix as compared to primed microcapsules. However, this difference was diminished when evaluated in the ex vivo organ culture model,withboth unprimed and primed BMSC microcapsules accumulating large amounts of sulphated glycosaminoglycan (sGAG) and collagen and filling the defect cavity. Both models demonstrated that cryopreservation of BMSC microcapsules may offer a feasible strategy for predesigned delivery through cryobanking for on-demand regeneration of the IVD.

Stroma: the forgotten cells of innate immune memory.

All organisms are exposed constantly to a variety of infectious and injurious stimuli. These induce inflammatory responses tailored to the threat posed. While the innate immune system is the front line of response to each stimulant, it has been considered traditionally to lack memory, acting in a generic fashion until the adaptive immune arm can take over. This outmoded simplification of the roles of innate and acquired arms of the immune system has been challenged by evidence of myeloid cells altering their response to subsequent encounters based on earlier exposure. This concept of 'innate immune memory' has been known for nearly a century, and is accepted among myeloid biologists. In recent years other innate immune cells, such as natural killer cells, have been shown to display memory, suggesting that innate immune memory is a trait common to several cell types. During the last 30 years, evidence has slowly accumulated in favour of not only haematopoietic cells, but also stromal cells, being imbued with memory following inflammatory episodes. A recent publication showing this also to be true in epithelial cells suggests innate immune memory to be widespread, if under-appreciated, in non-haematopoietic cells. In this review, we will examine the evidence supporting the existence of innate immune memory in stromal cells. We will also discuss the ramifications of memory in long-lived tissue-resident cells. Finally, we will pose questions we feel to be important in the understanding of these forgotten cells in the field of innate memory.

11 Beta-hydroxysteroid dehydrogenase type 1 regulates synovitis, joint destruction, and systemic bone loss in chronic polyarthritis.

OBJECTIVE: In rheumatoid arthritis, the enzyme 11 beta-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) is highly expressed at sites of inflammation, where it converts inactive glucocorticoids (GC) to their active counterparts. In conditions of GC excess it has been shown to be a critical regulator of muscle wasting and bone loss. Here we examine the contribution of 11ß-HSD1 to the pathology of persistent chronic inflammatory disease. METHODS: To determine the contribution of 11ß-HSD1 to joint inflammation, destruction and systemic bone loss associated with persistent inflammatory arthritis, we generated mice with global and mesenchymal specific 11ß-HSD1 deletions in the TNF-transgenic (TNF-tg) model of chronic polyarthritis. Disease severity was determined by clinical scoring. Histology was assessed in formalin fixed sections and fluorescence-activated cell sorting (FACS) analysis of synovial tissue was performed. Local and systemic bone loss were measured by micro computed tomography (micro-CT). Measures of inflammation and bone metabolism were assessed in serum and in tibia mRNA. RESULTS: Global deletion of 11ß-HSD1 drove an enhanced inflammatory phenotype, characterised by florid synovitis, joint destruction and systemic bone loss. This was associated with increased pannus invasion into subchondral bone, a marked polarisation towards pro-inflammatory M1 macrophages at sites of inflammation and increased osteoclast numbers. Targeted mesenchymal deletion of 11ß-HSD1 failed to recapitulate this phenotype suggesting that 11ß-HSD1 within leukocytes mediate its protective actions in vivo. CONCLUSIONS: We demonstrate a fundamental role for 11ß-HSD1 in the suppression of synovitis, joint destruction, and systemic bone loss. Whilst a role for 11ß-HSD1 inhibitors has been proposed for metabolic complications in inflammatory diseases, our study suggests that this approach would greatly exacerbate disease severity.

Perspectives on the underlying drivers of urgent and emergency care reconfiguration in Ireland.

BACKGROUND: There is an increasing tendency to reconfigure acute hospital care towards a more centralised and specialised model, particularly for complex care conditions. Although centralisation is presented as "evidence-based", the relevant studies are often challenged by groups which hold perspectives and values beyond those implicit in the literature. This study investigated stakeholder perspectives on the rationale for the reconfiguration of urgent and emergency care in Ireland. Specifically, it considered the hypothesis that individuals from different stakeholder groups would endorse different positions in relation to the motivation for, and goals of, reconfiguration. METHODS: Documentary analysis of policy documents was used to identify official justifications for change. Semi-structured interviews with 175 purposively sampled stakeholders explored their perspectives on the rationale for reconfiguration. RESULTS: While there was some within-group variation, internal and external stakeholders generally vocalised different lines of argument. Clinicians and management in the internal stakeholder group proposed arguments in favour of reconfiguration based on efficiency and safety claims. External stakeholders, including hospital campaigners and local political representatives expressed arguments that focused on access to care. A "voter" argument, focused on the role of local politicians in determining the outcome of reconfiguration planning, was mentioned by both internal and external stakeholders, often in a critical fashion. CONCLUSION: Our study adds to an emerging literature on the interaction between a technocratic approach to health system planning advocated by clinicians and health service managers, and the experiential "non-expert" claims of the public and patients.

Rheological characteristics of faecal sludge from VIP latrines and implications on pit emptying.

This work aims at characterizing the rheological properties of faecal sludge from Ventilated Improved Pit (VIP) latrines and their implication on pit emptying. Faecal sludge was sampled from 3 pit latrines located in the eThekwini Municipality (Durban, South Africa). Samples were taken at different positions within the pit. For each of the samples, measurements in the rheometer in triplicates were performed in order to determine their rheological properties, and their moisture and ash content were measured also in triplicates. Experiments in the rheometer were performed for samples for which its moisture content was modified. In order to better understand the influence of water addition into the pit. During pit emptying, calculations were carried out from the experimental data, based in the criteria set in the Omni-Ingestor initiative, carried out by the Bill & Melinda Gates Foundation. Faecal sludge exhibited a shear thinning behaviour, i.e. a decrease in viscosity with increasing shear rate, and presented a yield stress comprised between 500 to 1000 Pa. This needs to be surpassed in order to overcome the elastic resistance of the sludge to flow. Similar viscosities were found for the samples from the different pits, irrespective of the position within the pit, except for the sample from the bottom of one of the pits for which it was not possible to induce a flow. This sample had a considerably lower moisture content (67% wet basis) compared to the other samples (around 80% wet basis), probably due to a higher biodegradation as it was the most aged sludge in the pit. According to the experimental results and calculations, the pumping requirements during pit emptying will decrease drastically by increasing the moisture content of the sludge. The addition of water into the pit would then facilitate the pit emptying operation by reducing the head and power required for pumping. However, this practice would require employing considerable amounts of water and handling higher volumes of sludge, which would lead to longer pit emptying times and increase the difficulty of the operation. For example, increasing the moisture content of the sludge from 75 to 90% will reduce the head and power of the pump by a factor 100, but will triplicate the amount of water in the sludge and, consequently, the time for pit emptying. Therefore, a compromise has to be made between increasing the pumping feasibility and adding water to the pit.

Using submersible fluorescence sensors to track the removal of organic matter in decentralized wastewater treatment systems (DEWATS) in real time.

Decentralized wastewater treatment systems (DEWATS) using anaerobic treatment are increasingly being considered for wastewater treatment with options for non-potable water reuse at the community scale. One challenge for ensuring performance and reliability of DEWATS is the lack of suitable on-site sensors to monitor failure or contamination events. In this study, the aim was to use in situ fluorescence sensors to track the performance of a DEWATS, consisting of an anaerobic baffled reactor (ABR) coupled to anaerobic filter (AF) and constructed wetland (CW) treatment processes. A submersible in situ fluorometer equipped with tryptophan (TRP) and chromophoric dissolved organic matter (CDOM) sensors was deployed in each chamber of the ABR-AF-CW system, and results showed that TRP fluorescence was preferentially removed over CDOM fluorescence throughout the system. Significant relationships between TRP fluorescence and chemical oxygen demand (COD) also suggested that TRP fluorescence could be used as a surrogate for COD and soluble COD concentrations. Strong agreement between results obtained from the 1D in situ fluorometer and those obtained from a 3D benchtop fluorometer lends further support to the use of in situ fluorescence sensors to track DEWATS performance.

The role of stromal cells in inflammatory bone loss.

Rheumatoid arthritis (RA) is an autoimmune disease characterized by chronic inflammation, local and systemic bone loss and a lack of compensatory bone repair. Fibroblast-like synoviocytes (FLS) are the most abundant cells of the stroma and a key population in autoimmune diseases such as RA. An increasing body of evidence suggests that these cells play not only an important role in chronic inflammation and synovial hyperplasia, but also impact bone remodelling. Under inflammatory conditions FLS release inflammatory cytokines, regulate bone destruction and formation and communicate with immune cells to control bone homeostasis. Other stromal cells, such as osteoblasts and terminally differentiated osteoblasts, termed osteocytes, are also involved in the regulation of bone homeostasis and are dysregulated during inflammation. This review highlights our current understanding of how stromal cells influence the balance between bone formation and bone destruction. Increasing our understanding of these processes is critical to enable the development of novel therapeutic strategies with which to treat bone loss in RA.

Treatment of inflammatory arthritis via targeting of tristetraprolin, a master regulator of pro-inflammatory gene expression.

OBJECTIVES: Tristetraprolin (TTP), a negative regulator of many pro-inflammatory genes, is strongly expressed in rheumatoid synovial cells. The mitogen-activated protein kinase (MAPK) p38 pathway mediates the inactivation of TTP via phosphorylation of two serine residues. We wished to test the hypothesis that these phosphorylations contribute to the development of inflammatory arthritis, and that, conversely, joint inflammation may be inhibited by promoting the dephosphorylation and activation of TTP. METHODS: The expression of TTP and its relationship with MAPK p38 activity were examined in non-inflamed and rheumatoid arthritis (RA) synovial tissue. Experimental arthritis was induced in a genetically modified mouse strain, in which endogenous TTP cannot be phosphorylated and inactivated. In vitro and in vivo experiments were performed to test anti-inflammatory effects of compounds that activate the protein phosphatase 2A (PP2A) and promote dephosphorylation of TTP. RESULTS: TTP expression was significantly higher in RA than non-inflamed synovium, detected in macrophages, vascular endothelial cells and some fibroblasts and co-localised with MAPK p38 activation. Substitution of TTP phosphorylation sites conferred dramatic protection against inflammatory arthritis in mice. Two distinct PP2A agonists also reduced inflammation and prevented bone erosion. In vitro anti-inflammatory effects of PP2A agonism were mediated by TTP activation. CONCLUSIONS: The phosphorylation state of TTP is a critical determinant of inflammatory responses, and a tractable target for novel anti-inflammatory treatments.

Expression of chemokines CXCL4 and CXCL7 by synovial macrophages defines an early stage of rheumatoid arthritis.

BACKGROUND AND OBJECTIVES: For our understanding of the pathogenesis of rheumatoid arthritis (RA), it is important to elucidate the mechanisms underlying early stages of synovitis. Here, synovial cytokine production was investigated in patients with very early arthritis. METHODS: Synovial biopsies were obtained from patients with at least one clinically swollen joint within 12 weeks of symptom onset. At an 18-month follow-up visit, patients who went on to develop RA, or whose arthritis spontaneously resolved, were identified. Biopsies were also obtained from patients with RA with longer symptom duration (>12 weeks) and individuals with no clinically apparent inflammation. Synovial mRNA expression of 117 cytokines was quantified using PCR techniques and analysed using standard and novel methods of data analysis. Synovial tissue sections were stained for CXCL4, CXCL7, CD41, CD68 and von Willebrand factor. RESULTS: A machine learning approach identified expression of mRNA for CXCL4 and CXCL7 as potentially important in the classification of early RA versus resolving arthritis. mRNA levels for these chemokines were significantly elevated in patients with early RA compared with uninflamed controls. Significantly increased CXCL4 and CXCL7 protein expression was observed in patients with early RA compared with those with resolving arthritis or longer established disease. CXCL4 and CXCL7 co-localised with blood vessels, platelets and CD68(+) macrophages. Extravascular CXCL7 expression was significantly higher in patients with very early RA compared with longer duration RA or resolving arthritis CONCLUSIONS: Taken together, these observations suggest a transient increase in synovial CXCL4 and CXCL7 levels in early RA.

Synovial CD4+ T-cell-derived GM-CSF supports the differentiation of an inflammatory dendritic cell population in rheumatoid arthritis.

OBJECTIVE: A population of synovial inflammatory dendritic cells (infDCs) has recently been identified in rheumatoid arthritis (RA) and is thought to be monocyte-derived. Here, we investigated the role and source of granulocyte macrophage-colony-stimulating factor (GM-CSF) in the differentiation of synovial infDC in RA. METHODS: Production of GM-CSF by peripheral blood (PB) and synovial fluid (SF) CD4+ T cells was assessed by ELISA and flow cytometry. In vitro CD4+ T-cell polarisation experiments were performed with T-cell activating CD2/CD3/CD28-coated beads in the absence or presence of pro-Th1 or pro-Th17 cytokines. CD1c+ DC and CD16+ macrophage subsets were flow-sorted and analysed morphologically and functionally (T-cell stimulatory/polarising capacity). RESULTS: RA-SF CD4+ T cells produced abundant GM-CSF upon stimulation and significantly more than RA-SF mononuclear cells depleted of CD4+ T cells. GM-CSF-producing T cells were significantly increased in RA-SF compared with non-RA inflammatory arthritis SF, active RA PB and healthy donor PB. GM-CSF-producing CD4+ T cells were expanded by Th1-promoting but not Th17-promoting conditions. Following coculture with RA-SF CD4+ T cells, but not healthy donor PB CD4+ T cells, a subpopulation of monocytes differentiated into CD1c+ infDC; a process dependent on GM-CSF. These infDC displayed potent alloproliferative capacity and enhanced GM-CSF, interleukin-17 and interferon-γ production by CD4+ T cells. InfDC with an identical phenotype to in vitro generated cells were significantly enriched in RA-SF compared with non-RA-SF/tissue/PB. CONCLUSIONS: We demonstrate a therapeutically tractable feedback loop of GM-CSF secreted by RA synovial CD4+ T cells promoting the differentiation of infDC with potent capacity to induce GM-CSF-producing CD4+ T cells.

The prevalence of Type 2 diabetes and related complications in a nationally representative sample of adults aged 50 and over in the Republic of Ireland.

AIM: To investigate the prevalence of diagnosed Type 2 diabetes and its related complications in a nationally representative sample of older adults in the Republic of Ireland. METHODS: Cross-sectional analysis of a population-based sample of adults aged ≥ 50 years from the first wave of The Irish Longitudinal Study on Ageing (TILDA), (2009-2011). Diagnosed Type 2 diabetes prevalence was estimated by self-report or the use of oral hypoglycaemic agents. The prevalence of microvascular and macrovascular complications was determined by self-report. RESULTS: Diagnosed Type 2 diabetes prevalence was 8.4% [95% confidence interval (CI): 7.8-9.0%] and was higher among men [10.3% (95% CI: 9.4-11.2%)] than women [6.6% (95% CI: 5.9-7.5%)]; P ≤ 0.001. Among participants with diagnosed Type 2 diabetes, the overall prevalence of microvascular complications was 26.0% (95% CI: 22.4-30.0%) with no evidence of gender-specific differences (P = 0.7). The overall prevalence of macrovascular complications was 15.1% (95% CI: 12.2-18.4%) and was higher among men [17.8% (95% CI: 14.3-23.1%)] than women [11.4% (95% CI: 7.7-16.4%)]; P ≤ 0.001. CONCLUSIONS: In the absence of a national diabetes register, these findings provide a robust estimate of the national prevalence of diagnosed Type 2 diabetes and level of complications among adults aged 50 years and over in Ireland.

Transverse Compression of Tendons.

A study was made of the deformation of tendons when compressed transverse to the fiber-aligned axis. Bovine digital extensor tendons were compression tested between flat rigid plates. The methods included: in situ image-based measurement of tendon cross-sectional shapes, after preconditioning but immediately prior to testing; multiple constant-load creep/recovery tests applied to each tendon at increasing loads; and measurements of the resulting tendon displacements in both transverse directions. In these tests, friction resisted axial stretch of the tendon during compression, giving approximately plane-strain conditions. This, together with the assumption of a form of anisotropic hyperelastic constitutive model proposed previously for tendon, justified modeling the isochronal response of tendon as that of an isotropic, slightly compressible, neo-Hookean solid. Inverse analysis, using finite-element (FE) simulations of the experiments and 10 s isochronal creep displacement data, gave values for Young's modulus and Poisson's ratio of this solid of 0.31 MPa and 0.49, respectively, for an idealized tendon shape and averaged data for all the tendons and E = 0.14 and 0.10 MPa for two specific tendons using their actual measured geometry. The compression load versus displacement curves, as measured and as simulated, showed varying degrees of stiffening with increasing load. This can be attributed mostly to geometrical changes in tendon cross section under load, varying according to the initial 3D shape of the tendon.

Viscoelasticity of Tendons Under Transverse Compression.

Tendons are highly anisotropic and also viscoelastic. For understanding and modeling their 3D deformation, information is needed on their viscoelastic response under off-axis loading. A study was made, therefore, of creep and recovery of bovine digital extensor tendons when subjected to transverse compressive stress of up to ca. 100 kPa. Preconditioned tendons were compression tested between glass plates at increasing creep loads. The creep response was anomalous: the relative rate of creep reduced with the increasing stress. Over each ca. 100 s creep period, the transverse creep deformation of each tendon obeyed a power law dependence on time, with the power law exponent falling from ca. 0.18 to an asymptote of ca. 0.058 with the increasing stress. A possible explanation is stress-driven dehydration, as suggested previously for the similar anomalous behavior of ligaments. Recovery after removal of each creep load was also anomalous. Relative residual strain reduced with the increasing creep stress, but this is explicable in terms of the reducing relative rate of creep. When allowance was made for some adhesion occurring naturally between tendon and the glass plates, the results for a given load were consistent with creep and recovery being related through the Boltzmann superposition principle (BSP). The tendon tissue acted as a pressure-sensitive adhesive (PSA) in contact with the glass plates: explicable in terms of the low transverse shear modulus of the tendons.