Bystander cardiopulmonary resuscitation for paediatric out-of-hospital cardiac arrest in England: An observational registry cohort study.

INTRODUCTION: Bystander cardiopulmonary resuscitation (BCPR) is strongly advocated by resuscitation councils for paediatric out-of-hospital cardiac arrests (OHCAs). However, there are limited reports on rates of BCPR in children and its relationship with return of spontaneous circulation (ROSC) or survival outcomes. OBJECTIVE: We describe the rate of BCPR and its association with any ROSC and survival- to- hospital-discharge. METHODS: We conducted retrospective analysis of prospectively collected paediatric (<18 years of age) OHCA cases in England; we included specialist registry patients treated by emergency medical services (EMS) with known BCPR status and outcome between January 2014 and November 2018. Data included patient demographics, aetiology, witness status, initial rhythm, EMS, season, time of day and bystander status. Associations between BCPR, and any ROSC and survival-to-hospital-discharge outcomes were explored using multivariable logistic regression. RESULTS: There were 2363 paediatric OHCAs treated across 11 EMS regions. BCPR was performed in 69.6% (1646/2363) of the cases overall (range 57.7% (206/367) to 83.7% (139/166) across EMS regions). Only 34.9% (550/1572) of BCPR cases were witnessed. Overall, any ROSC was achieved in 22.8% (523/2289) and survival to hospital discharge in 10.8% (225/2066). Adjusted odds ratio (aOR) for any ROSC was significantly improved following BCPR compared to no BCPR (aOR 1.37, 95% CI 1.03-1.81), but adjusted odds ratio for survival-to-hospital-discharge were similar (aOR 1.01, 95% CI 0.66-1.55). CONCLUSIONS: BCPR was associated with improved rates of any ROSC but not survival-to-hospital-discharge. Variations in EMS BCPR rates may indicate opportunities for regional targeted increase in public BCPR education.

Experiences of diagnostic radiographers through the Covid-19 pandemic.

INTRODUCTION: Diagnostic Radiography plays a major role in the diagnosis and management of patients with Covid-19. This has seen an increase in the demand for imaging services, putting pressure on the workforce. Diagnostic radiographers, as with many other healthcare professions, have been on the frontline, dealing with an unprecedented situation. This research aimed to explore the experience of diagnostic radiographers working clinically during the Covid-19 pandemic. METHODS: Influenced by interpretative phenomenology, this study explored the experiences of diagnostic radiographers using virtual focus group interviews as a method of data collection. RESULTS: Data were analysed independently by four researchers and five themes emerged from the data. Adapting to new ways of working, feelings and emotions, support mechanisms, self-protection and resilience, and professional recognition. CONCLUSION: The adaptability of radiographers came across strongly in this study. Anxieties attributed to the provision of personal protective equipment (PPE), fear of contracting the virus and spreading it to family members were evident. The resilience of radiographers working throughout this pandemic came across strongly throughout this study. A significant factor for coping has been peer support from colleagues within the workplace. The study highlighted the lack of understanding of the role of the radiographer and how the profession is perceived by other health care professionals. IMPLICATIONS FOR PRACTICE: This study highlights the importance of interprofessional working and that further work is required in the promotion of the profession.

The SPaCE diagnostic: a pilot study to test the accuracy of a novel point of care sensor for point of care detection of burn wound infection.

BACKGROUND: Wound infection in burn patients is common and has an impact on outcomes. There is no objective method to diagnose infection at point of care (PoC). Early diagnosis prevents progression to sepsis. Diagnostic subjectivity supports over-diagnosis, unnecessary hospitalization, and antibiotic overuse. AIM: This pilot study aimed to investigate the accuracy of a novel PoC wound infection diagnostic in burn patients. METHODS: We produced, and in vitro tested, a PoC diagnostic for early wound infection diagnosis. The prototype SPaCE diagnostic uses a patented lipid vesicle suspension into which a clinical swab is placed. The diagnostic delivers a colour-response to Staphylococcus aureus, Pseudomonas aeruginosa, Candida species and Enterococcus faecalis at toxin release. A pilot clinical diagnostic accuracy study was undertaken. The reference standard was a retrospective decision made by an expert clinical panel using routinely available data. FINDINGS: Data was available from 33 of 34 patients. Of these, 52% were considered to have a wound infection, 42% not, and two (6%) were equivocal. The diagnostic results showed 24% were infected, 42% were not and 33% produced intermediate results. Agreement between clinical judgement and diagnostic result, assessed using a weighted Kappa, was 0.591 suggesting moderate agreement. If the intermediate results were excluded, 22 sets of data with definitive results achieved a Kappa statistic of 0.81 suggesting 'almost perfect' agreement. Sensitivity and specificity were 57% (8/14) and 71% (12/17), respectively. CONCLUSION: This pilot study provided evidence that the SPaCE diagnostic could provide valuable and timely data to support clinical decision-making at PoC for wound infection.

Consensus demonstrates four indicators needed to standardize burn wound infection reporting across trials in a single-country study (ICon-B study).

INTRODUCTION: Evidence-based interventions are needed to treat burn wound infection (BWI). Evidence syntheses have been limited by heterogeneity of indicators used to report BWI across trials. Consistent reporting of BWI would be facilitated by an agreed minimum set of indicators. The Infection Consensus in Burns study aimed to achieve expert consensus about a core indicator set (CIS) for BWI. METHODS: The CIS was established through development of a long list of BWI indicators identified from a systematic review and expert input. In a Delphi survey, UK expert participants rated the indicators according to use in everyday practice, importance for diagnosis and frequency of observation in patients with BWI. Indicators were included in the CIS if ≥75% of participants agreed it was important for diagnosis and used in everyday practice, and ≥50% of participants rated it as frequently observed in patients with BWI. RESULTS: One hundred and ninety-five indicators were identified from the systematic review and reduced to 29 survey items through merging of items with the same meaning. Seventy-five UK experts participated in the Delphi survey. Following a single survey round and a consensus meeting with an expert panel, four items were included in the CIS: pyrexia, spreading erythema, change in white cell count, and presence of pathogenic microbes. DISCUSSION AND CONCLUSIONS: To facilitate evidence synthesis, a single-country systematic, expert-informed approach was taken to develop a CIS to be reported consistently across trials reporting BWI as an outcome. Future work requires verification of the CIS with international experts.

Impact of intended and relative dose intensity of R-CHOP in a large, consecutive cohort of elderly diffuse large B-cell lymphoma patients treated with curative intent: no difference in cumulative incidence of relapse comparing patients by age.

BACKGROUND: The increasing incidence of diffuse large B-cell lymphoma (DLBCL) in ageing populations places a significant burden on healthcare systems. Co-morbidity, frailty, and reduced organ and physiological reserve contribute to treatment-related complications. The optimal dose intensity of R-CHOP to optimize outcome across different ages with variable frailty and comorbidity burden is unclear. OBJECTIVES AND METHODS: We examined the influence of intended (IDI) and relative (RDI) dose intensity of the combination of cyclophosphamide and doxorubicin, age and comorbidity on outcomes for DLBCL patients ≥70 years in a representative, consecutive cohort across eight UK centres (2009-2018). We determined predictors of survival using multivariable Cox regression, and predictors of recurrence before death using competing risks regression. RESULTS: Porgression-free survival (PFS) and overall survival (OS) were significantly inferior in patients ≥80 vs. 70-79 years (P < 0.001). In contrast, 2-year cumulative relapse incidence, when accounting for non-relapse mortality as a competing risk, was no different between 70-79 vs. ≥80 years (P = 0.27) or comorbidity status (CIRS-G: 0-6 vs. >6) (P = 0.27). In 70-79 years, patients with an IDI ≥80% had a significantly improved PFS and OS (P < 0.001) compared to IDI < 80%. Conversely, in patients ≥80 years, there was no difference in PFS (P = 0.88) or OS (P = 0.75) according to IDI <80% vs. ≥80%. On multivariable analysis, when comparing by age, there was a significantly higher cumulative relapse rate for patients aged 70-79 years with an IDI <80% (vs. >80%) (P = 0.04) but not for patients ≥80 years comparing IDI (P = 0.32). CONCLUSION: 'R-mini-CHOP' provides adequate lymphoma-specific disease control and represents a reasonable treatment option in elderly patients ≥80 years aiming for cure.

Fluctuation, invisibility, fatigue - the barriers to maintaining employment with systemic lupus erythematosus: results of an online survey.

OBJECTIVES: Systemic lupus erythematosus (SLE) is associated with high levels of workplace disability and unemployment. The objective of this study was to understand the reasons for this and to describe the barriers and facilitators of employment identified by people with SLE to develop appropriate solutions. Unemployment, as well as unsuitable work, has adverse health outcomes. METHODS: Adults with SLE completed a UK-specific online survey, through the LUPUS UK website, designed to find out more about the difficulties and successes that people with SLE have in maintaining employment. The survey was predominantly qualitative, to understand participants' employment experiences to generate possible solutions. RESULTS: Three hundred and ninety-three people gave detailed responses to the survey within eight weeks. Every respondent reported a detrimental effect of SLE on their ability to work: 40.45% had left employment because of it. The themes of concern to respondents were unambiguous: (i) the difficulties of working (and career damage) with SLE, (ii) fear and anxiety overshadowing work/family life, (iii) the greater potential to remain in some employment or stay in full employment when modifications of work pattern and support from management and colleagues were available. SLE-related fatigue, its invisibility and fluctuating nature were felt to be the main barriers to maintaining employment. Numerous respondents could work only part-time and anxiety was high regarding their future ability to continue working. Many had taken substantial pay reductions and refused offered promotions to preserve their health. Distress due to loss of work and the benefits it brings were reported by every respondent who had left work. CONCLUSION: SLE presents specific difficulties for maintaining employment - fatigue, fluctuation and invisibility - not addressed by current anti-discrimination legislation or currently available 'reasonable adjustments'. This study demonstrates that (i) employment is an important area of concern for people with SLE, (ii) SLE has significant detrimental effects on individuals' ability to participate and progress in employment, (iii) legislators and employers need information about SLE as invisibility and fluctuation cause hidden problems, and (iv) more data is needed to inform workplace adjustments if individual distress and societal loss of skills are to be addressed.

Fetal growth restriction shortens cardiac telomere length, but this is attenuated by exercise in early life.

BACKGROUND AND AIMS: Fetal and postnatal growth restriction cause a predisposition to cardiovascular disease (CVD) in adulthood. Telomeres are repetitive DNA-protein structures that protect chromosome ends, and the loss of these repeats (a reduction in telomere length) is associated with CVD. As exercise preserves telomere length and cardiovascular health, the aim of this study was to determine the effects of growth restriction and exercise training on cardiac telomere length and telomeric genes. METHODS AND RESULTS: Pregnant Wistar Kyoto rats underwent bilateral uterine vessel ligation to induce uteroplacental insufficiency and fetal growth restriction ("Restricted"). Sham-operated rats had either intact litters ("Control") or their litters reduced to five pups with slowed postnatal growth ("Reduced"). Control, Restricted, and Reduced male rats were assigned to Sedentary, Early exercise (5-9 wk of age), or Late exercise (20-24 wk of age) groups. Hearts were excised at 24 wk of age for telomere length and gene expression measurements by quantitative PCR. Growth restriction shortened cardiac telomere length ( P < 0.001), but this was rescued by early exercise ( P < 0.001). Early and Late exercise increased cardiac weight index ( P < 0.001), but neither this nor telomere length was associated with expression of the telomeric genes Tert, Terc, Trf2, Pnuts, or Sirt1. DISCUSSION AND CONCLUSIONS: Growth restriction shortens cardiac telomere length, reflecting the cardiac pathologies associated with low birth weight. Exercise in early life may offer long-term protective effects on cardiac telomere length, which could help prevent CVD in later life.

The offset droplet: a new methodology for studying the solid/water interface using x-ray photoelectron spectroscopy.

The routine study of the solid-water interface by XPS is potentially revolutionary as this development opens up whole new areas of study for photoelectron spectroscopy. To date this has been realised by only a few groups worldwide and current techniques have significant restrictions on the type of samples which can be studied. Here we present a novel and uniquely flexible approach to the problem. By introducing a thin capillary into the NAP-XPS, a small droplet can be injected onto the sample surface, offset from the analysis area by several mm. By careful control of the droplet size a water layer of controllable thickness can be established in the analysis area-continuous with the bulk droplet. We present results from the solid-water interface on a vacuum prepared TiO2(110) single crystal and demonstrate that the solid/liquid interface is addressable.

Systemic Treatment with a miR-146a Mimic Suppresses Endotoxin Sensitivity and Partially Protects Mice from the Progression of Acute Graft-versus-Host Disease.

Acute GVHD (aGVHD) is driven by interactions between the allogenic T cell response, inflammation, tissue injury and microbial products that enter the circulation when protective barriers such as the intestinal epithelium become compromised. Mice with aGVHD become hypersensitive to LPS, secreting large quantities of inflammatory mediators that exacerbate tissue injury. We hypothesized that microRNA (miR) modulators could be used in vivo to mitigate LPS hypersensitivity, altering the course of aGVHD. Using the C57BL/6 → (C57BL/6 × DBA/2)F1 -hybrid model of aGVHD, we measured intestinal permeability over time and used a qPCR array to detect concomitant changes in the expression levels of certain microRNAs (miRs) in the intestine. Large increases in permeability were seen on day 15, when endotoxemia becomes detectable and GVHD-associated histopathological lesions develop. Amongst the miRs with altered expression levels were some that regulate sensitivity to endotoxin. We chose to focus on miR-146a and treated recipient mice systemically with a miR-146a mimic early in the GVH reaction. This led to a reduction in the burst of IFNγ that likely plays a priming role in the mechanism underlying heightened sensitivity to endotoxin. LPS-induced TNFα release and GVHD-associated weight loss were also diminished and survival was prolonged. In summary, systemic treatment with a miR-146a mimic dampens the heightened sensitivity to LPS that occurs concomitantly with increased intestinal permeability and provides partial protection from the progression of acute GVHD.

Reproducibility and relative validity of a food frequency questionnaire to estimate intake of dietary phylloquinone and menaquinones.

BACKGROUND/OBJECTIVES: This study aims to investigate the reproducibility and relative validity of the Dutch food frequency questionnaire (FFQ), to estimate intake of dietary phylloquinone and menaquinones compared with 24-h dietary recalls (24HDRs) and plasma markers of vitamin K status. SUBJECTS/METHODS: In a cross-sectional study among 63 men and 58 women, the FFQ was completed three times over a 1-year period and the reproducibility was calculated over these measurements. Twelve-monthly 24HDR were collected to estimate relative validity. In addition, the relative validity of the FFQ, compared with plasma phylloquinone and desphospho-uncarboxylated matrix Gla protein (dpucMGP), was assessed cross-sectionally among 507 postmenopausal women. RESULTS: Intraclass correlations showed a good reproducibility, with correlations ranging from 0.65 to 0.83. The relative validity for phylloquinone intake compared with 24HDR was lower for women (rs=0.28) than men (rs=0.40). The relative validity, compared with 24HDR, for intake of short-chain menaquinones were ranging between 0.30 and 0.34. Long-chain menaquinones showed good relative validity (rs=0.60-0.69). Plasma phylloquinone concentrations were weakly correlated with phylloquinone intake (rs=0.16 (0.07-0.24). Plasma dpucMGP was negatively but weakly correlated with phylloquinone intake (rs=-0.09 (-0.18; -0.01)) and long-chain menaquinones (rs=-0.13 (-0.21; -0.04)), but not with short-chain menaquinones (rs=-0.04 (-0.13; 0.05)). CONCLUSIONS: The FFQ is reproducible to rank subjects for phylloquinone and menaquinone intake.The relative validity of our FFQ, compared with 24HDR, to estimate intake of phylloquinone and short-chain menaquinones was low, but the relative validity for long-chain menaquinones was good. The relative validity of our FFQ, compared with plasma phylloquinone and dpucMGP, was relatively low for both phylloquinone and menaquinone intake.

Cardiac telomere length in heart development, function, and disease.

Telomeres are repetitive nucleoprotein structures at chromosome ends, and a decrease in the number of these repeats, known as a reduction in telomere length (TL), triggers cellular senescence and apoptosis. Heart disease, the worldwide leading cause of death, often results from the loss of cardiac cells, which could be explained by decreases in TL. Due to the cell-specific regulation of TL, this review focuses on studies that have measured telomeres in heart cells and critically assesses the relationship between cardiac TL and heart function. There are several lines of evidence that have identified rapid changes in cardiac TL during the onset and progression of heart disease as well as at critical stages of development. There are also many factors, such as the loss of telomeric proteins, oxidative stress, and hypoxia, that decrease cardiac TL and heart function. In contrast, antioxidants, calorie restriction, and exercise can prevent both cardiac telomere attrition and the progression of heart disease. TL in the heart is also indicative of proliferative potential and could facilitate the identification of cells suitable for cardiac rejuvenation. Although these findings highlight the involvement of TL in heart function, there are important questions regarding the validity of animal models, as well as several confounding factors, that need to be considered when interpreting results and planning future research. With these in mind, elucidating the telomeric mechanisms involved in heart development and the transition to disease holds promise to prevent cardiac dysfunction and potentiate regeneration after injury.

The significance of bromide in the Brust-Schiffrin synthesis of thiol protected gold nanoparticles.

The mechanism of the two-phase Brust-Schiffrin synthesis of alkane thiol protected metal nanoparticles is known to be highly sensitive to the precursor species and reactant conditions. In this work X-ray absorption spectroscopy is used in conjunction with liquid/liquid electrochemistry to highlight the significance of Br- in the reaction mechanism. The species [AuBr4]- is shown to be a preferable precursor in the Brust-Schiffrin method as it is more resistant to the formation of Au(i) thiolate species than [AuCl4]-. Previous literature has demonstrated that avoidance of the Au(i) thiolate is critical to achieving a good yield of nanoparticles, as [Au(i)X2]- species are more readily reduced by NaBH4. We propose that the observed behavior of [AuBr4]- species described herein explains the discrepancies in reported behavior present in the literature to date. This new mechanistic understanding should enable nanoparticle synthesis with a higher yield and reduce particle size polydispersity.

Prototype Development of the Intelligent Hydrogel Wound Dressing and Its Efficacy in the Detection of Model Pathogenic Wound Biofilms.

The early detection of wound infection in situ can dramatically improve patient care pathways and clinical outcomes. There is increasing evidence that within an infected wound the main bacterial mode of living is a biofilm: a confluent community of adherent bacteria encased in an extracellular polymeric matrix. Here we have reported the development of a prototype wound dressing, which switches on a fluorescent color when in contact with pathogenic wound biofilms. The dressing is made of a hydrated agarose film in which the fluorescent dye containing vesicles were mixed with agarose and dispersed within the hydrogel matrix. The static and dynamic models of wound biofilms, from clinical strains of Escherichia coli, Pseudomonas aeruginosa, Staphylococcus aureus, and Enterococcus faecalis, were established on nanoporous polycarbonate membrane for 24, 48, and 72 h, and the dressing response to the biofilms on the prototype dressing evaluated. The dressing indicated a clear fluorescent/color response within 4 h, only observed when in contact with biofilms produced by a pathogenic strain. The sensitivity of the dressing to biofilms was dependent on the species and strain types of the bacterial pathogens involved, but a relatively higher response was observed in strains considered good biofilm formers. There was a clear difference in the levels of dressing response, when dressings were tested on bacteria grown in biofilm or in planktonic cultures, suggesting that the level of expression of virulence factors is different depending of the growth mode. Colorimetric detection on wound biofilms of prevalent pathogens (S. aureus, P. aeruginosa, and E. faecalis) is also demonstrated using an ex vivo porcine skin model of burn wound infection.

Association of 25-Hydroxyvitamin D status and genetic variation in the vitamin D metabolic pathway with FEV1 in the Framingham Heart Study.

BACKGROUND: Vitamin D is associated with lung function in cross-sectional studies, and vitamin D inadequacy is hypothesized to play a role in the pathogenesis of chronic obstructive pulmonary disease. Further data are needed to clarify the relation between vitamin D status, genetic variation in vitamin D metabolic genes, and cross-sectional and longitudinal changes in lung function in healthy adults. METHODS: We estimated the association between serum 25-hydroxyvitamin D [25(OH)D] and cross-sectional forced expiratory volume in the first second (FEV1) in Framingham Heart Study (FHS) Offspring and Third Generation participants and the association between serum 25(OH)D and longitudinal change in FEV1 in Third Generation participants using linear mixed-effects models. Using a gene-based approach, we investigated the association between 241 SNPs in 6 select vitamin D metabolic genes in relation to longitudinal change in FEV1 in Offspring participants and pursued replication of these findings in a meta-analyzed set of 4 independent cohorts. RESULTS: We found a positive cross-sectional association between 25(OH)D and FEV1 in FHS Offspring and Third Generation participants (P=0.004). There was little or no association between 25(OH)D and longitudinal change in FEV1 in Third Generation participants (P=0.97). In Offspring participants, the CYP2R1 gene, hypothesized to influence usual serum 25(OH)D status, was associated with longitudinal change in FEV1 (gene-based P<0.05). The most significantly associated SNP from CYP2R1 had a consistent direction of association with FEV1 in the meta-analyzed set of replication cohorts, but the association did not reach statistical significance thresholds (P=0.09). CONCLUSIONS: Serum 25(OH)D status was associated with cross-sectional FEV1, but not longitudinal change in FEV1. The inconsistent associations may be driven by differences in the groups studied. CYP2R1 demonstrated a gene-based association with longitudinal change in FEV1 and is a promising candidate gene for further studies.

The emerging role of non-coding RNA in essential hypertension and blood pressure regulation.

Unravelling the complete genetic predisposition to high blood pressure (BP) has proven to be challenging. This puzzle and the fact that coding regions of the genome account for less than 2% of the entire human DNA support the hypothesis that genetic mechanism besides coding genes are likely to contribute to BP regulation. Non-coding RNAs (ncRNAs) are emerging as key players of transcription regulation in both health and disease states. They control basic functions in virtually all cell types relevant to the cardiovascular system and, thus, a direct involvement with BP regulation is highly probable. Here, we review the literature about ncRNAs associated with human BP and essential hypertension, highlighting investigations, methodology and difficulties arising in the field. The most investigated ncRNAs so far are microRNAs (miRNAs), small ncRNAs that modulate gene expression by posttranscriptional mechanisms. We discuss studies that have examined miRNAs associated with BP in biological fluids, such as blood and urine, and tissues, such as vascular smooth muscle cells and the kidney. Furthermore, we review the interaction between miRNA binding sites and single nucleotide polymorphisms in genes associated with BP. In conclusion, there is a clear need for more human and functional studies to help elucidate the multifaceted roles of ncRNAs, in particular mid- and long ncRNAs in BP regulation.

The association between vitamin K status and knee osteoarthritis features in older adults: the Health, Aging and Body Composition Study.

BACKGROUND: Vitamin K-dependent (VKD) proteins, including the mineralization inhibitor matrix-gla protein (MGP), are found in joint tissues including cartilage and bone. Previous studies suggest low vitamin K status is associated with higher osteoarthritis (OA) prevalence and incidence. OBJECTIVE: To clarify what joint tissues vitamin K is relevant to in OA, we investigated the cross-sectional and longitudinal association between vitamin K status and knee OA structural features measured using magnetic resonance imaging (MRI). METHODS: Plasma phylloquinone (PK, vitamin K1) and dephosphorylated-uncarboxylated MGP ((dp)ucMGP) were measured in 791 older community-dwelling adults who had bilateral knee MRIs (mean ± SD age = 74 ± 3 y; 67% female). The adjusted odds ratios (and 95% confidence intervals) [OR (95%CI)] for presence and progression of knee OA features according to vitamin K status were calculated using marginal models with generalized estimating equations (GEEs), adjusted for age, sex, body mass index (BMI), triglycerides and other pertinent confounders. RESULTS: Longitudinally, participants with very low plasma PK (<0.2 nM) were more likely to have articular cartilage and meniscus damage progression after 3 years [OR (95% CIs): 1.7(1.0-3.0), 2.6(1.3-5.2) respectively] compared to sufficient PK (≥ 1.0 nM). Higher plasma (dp)ucMGP (reflective of lower vitamin K status) was associated with higher odds of meniscus damage, osteophytes, bone marrow lesions, and subarticular cysts cross-sectionally [ORs (95% CIs) comparing highest to lowest quartile: 1.6(1.1-2.3); 1.7(1.1-2.5); 1.9(1.3-2.8); 1.5(1.0-2.1), respectively]. CONCLUSION: Community-dwelling men and women with very low plasma PK were more likely to have progression of articular cartilage and meniscus damage. Plasma (dp)ucMGP was associated with presence of knee OA features but not progression. Future studies are needed to clarify mechanisms underlying vitamin Ks role in OA.

The biological impact of living with chronic breathlessness - a role for the hypothalamic-pituitary-adrenal axis?

Breathlessness is a common and distressing symptom in advanced cardiorespiratory disease, with recognised psychological, functional and social consequences. The biological impact of living with chronic breathlessness has not been explored. As breathlessness is often perceived as a threat to survival, we propose that episodic breathlessness engages the stress-response, as regulated by the hypothalamic-pituitary-adrenal (HPA) axis. Furthermore, we hypothesise that chronic breathlessness causes excessive stimulation of the HPA axis, resulting in dysfunctional regulation of the HPA axis and associated neuropsychological, metabolic and immunological sequelae. A number of observations provide indirect support for this hypothesis. Firstly, breathlessness and the HPA axis are both associated with anxiety. Secondly, similar cortico-limbic system structures govern both breathlessness perception and HPA axis regulation. Thirdly, breathlessness and HPA axis dysfunction are both independent predictors of survival. There is a need for direct observational evidence as well as experimental data to investigate this hypothesis which, if plausible, could lead to the identification of a new biomarker pathway to support breathlessness research.

Associations between vitamin K status and haemostatic and inflammatory biomarkers in community-dwelling adults. The Multi-Ethnic Study of Atherosclerosis.

Vitamin K is integral to haemostatic function, and in vitro and animal experiments suggest that vitamin K can suppress production of inflammatory cytokines. To test the hypothesis that higher vitamin K status is associated with lower haemostatic activation and inflammation in community-dwelling adults, we analysed the cross-sectional association between serum phylloquinone (vitamin K1) with haemostatic and inflammatory biomarkers in 662 participants in the Multi-Ethnic Study of Atherosclerosis (MESA) [mean (SD) age=62 (10) years; 46% female; 37% Caucasian, 25% African-American, 25% Hispanic, 13% Chinese-American]. Following adjustment for demographic and lifestyle characteristics, medication use, triglycerides and body mass index, those in the highest quartile of serum phylloquinone had significantly lower circulating interleukin-6 [adjusted mean (SEM) pmol/l: quartile 4 (Q4)=1.22 (0.07), quartile 1 (Q1)=1.45 (0.07); p-trend<0.01], C-reactive protein [adjusted mean (SEM) mg/dl: Q4=1.57 (0.11), Q1=2.08 (0.18); p-trend=0.02], soluble intercellular adhesion molecule-1 [adjusted mean (SEM) ng/ml: Q4=247 (11), Q1=288 (11); p-trend=0.02], and plasmin-antiplasmin complex [adjusted mean (SEM) nmol/l: Q4=4.02 (0.1), Q1=4.31 (0.1), p-trend=0.04]. We detected an interaction between age and serum phylloquinone with respect to factor VIII and D-dimer (interaction p-values=0.03 and 0.09, respectively). Among participants ≥70 years, serum phylloquinone was inversely associated with factor VIII activity (p-trend=0.06) and positively associated with D-dimer (p-trend=0.01), but was not associated with either marker among participants <70 years (both p≥0.38). In contrast, dietary phylloquinone intake was not associated with any inflammatory or haemostatic biomarker evaluated (all p-trend>0.11). These findings are consistent with laboratory-based studies that suggest a possible anti-inflammatory role for vitamin K. Whether or not these associations predict clinical outcomes linked to elevated inflammation or haemostatic activation remains to be determined.