Backward in Coming Forward.

As far back as the ancient Egyptians and Greeks, physicians have observed and interpreted the arterial pulse to help diagnose certain illnesses. However, until William Harvey’s discoveries in the 17th century, some of the basic concepts were misunderstood. Harvey described the circular blood flow in the body and discovered that the arterial pulse is generated by the contraction of the left ventricle. He also came up with the concept that the arterial pulse is a wave, thus paving the way for modern studies in pulse wave analysis. Another pivotal discovery was the introduction of pulse wave velocity (PWV) by Crighton Bramwell in the early 20th century. He recognised that PWV changes in proportion to the arterial wall tension and blood pressure, and thus, is an indirect measure of atrial wall elasticity1. Despite these important historic discoveries, it has only been in the last 20 years, with advances in modern engineering, that the pulse wave analysis has become more widely available, reliable, and reproducible technique to assess arterial pulse waves.Professor Wilkinson is funded by British Heart Foundation (Grant number: FS/12/8/29377)

Inverting the patient involvement paradigm: defining patient led research.

PLAIN ENGLISH SUMMARY: Patients usually understand their disease and lifestyle needs better than many medical professionals. They also have important ideas about what research would be most beneficial to their lives, especially on how to manage symptoms in a way that improves daily quality of life. In the UK, the National Institute for Health Research has recognised the value of patient insight, and now requires researchers with public funding to involve patients and the public throughout the research process. There are many opportunities for involvement, but these generally focus on improving study design to ensure the trial is acceptable to participants. Some programmes work towards setting research priorities as important to patients, public members, and medical experts, but due to the complexity and cost involved in running clinical trials, the majority of research originates with the pharmaceutical industry or academic institutions. There is a clear mismatch between research ideas that patients prioritise (quality of life), and those actually investigated (drug development).The Patient Led Research Hub (PLRH) is a new initiative hosted by the Cambridge Clinical Trials Unit. The PLRH supports research ideas as proposed by patient organisations, providing resources and expertise in research design and delivery. The PLRH aims to co-produce any technically feasible project, regardless of disease or symptom focus. The proposing patient group maintains ownership of the project with an active role in study management. This method of research has proven to produce credible research studies that are of direct relevance to patients. ABSTRACT: Patient and Public Involvement has become an indispensable and expected component of healthcare research in the United Kingdom, largely driven by the National Institute of Health Research and other research funders. Opportunities for patients to become involved in research abound, and many organisations now have dedicated 'public involvement' teams. However, its value is often questioned amidst criticism of tokenism and the recognition that a mismatch persists between patient priorities and funded research. Although patients are frequently consulted, evidence that their involvement influences the research agenda remains limited. We propose a novel model that allows patients and the public not only to propose research questions, but to design, initiate and deliver their own research with all the necessary support from research professionals. We demonstrate the feasibility and utility of this approach in reporting the establishment, experiences and progress of the Patient Led Research Hub. Using this resource, patient organisations are now able to initiate and conduct rigorous clinical research unfettered by the constraints of academic or economic agendas

Two Cases of Severe Hypertension in JAK2 Mutation-Positive Myeloproliferative Neoplasms

Background. Myeloproliferative neoplasms are a heterogeneous group of disorders resulting from the abnormal proliferation of one or more terminal myeloid cells—established complications include thrombosis and haemorrhagic events; however, there is limited evidence to suggest an association with arterial hypertension. Herein, we report two independent cases of severe hypertension in JAK2 mutation-positive myeloproliferative neoplasms. Case Presentations. Case 1: a 39-year-old male was referred to our specialist hypertension unit with high blood pressure (BP) (200/120 mmHg), erythromelalgia, and headaches. We recorded elevated serum creatinine levels (146 μM) and panmyelosis. Bone marrow biopsy confirmed JAK2-mutation-positive polycythaemia vera. Renal imaging revealed renal artery stenosis. Aspirin, long-acting nifedipine, interferon-alpha 2A, and renal artery angioplasty were employed in management. BP reached below target levels to an average of 119/88 mmHg. Renal parameters normalised gradually alongside BP. Case 2: a 45-year-old male presented with high BP (208/131 mmHg), acrocyanosis, (vasculitic) skin rashes, and nonhealing ulcers. Fundoscopy showed optic disc blurring in the left eye and full blood count revealed thrombocytosis. Bone marrow biopsy confirmed JAK2-mutation-positive essential thrombocytosis. No renal artery stenosis was found. Cardiac output was measured at 5 L/min using an inert gas rebreathing method, providing an estimated peripheral vascular resistance of 1840 dynes/s/cm5. BP was well-controlled (reaching 130/70 mmHg) with CCBs. Conclusions. These presentations highlight the utility of full blood count analysis in patients with severe hypertension. Hyperviscosity and constitutive JAK-STAT activation are amongst the proposed pathophysiology linking myeloproliferative neoplasms and hypertension. Further experimental and clinical research is necessary to identify and understand possible interactions between BP and myeloproliferative neoplasms

Poor family functioning mediates the link between childhood adversity and adolescent non-suicidal self-injury

Background: Non-suicidal self-injury (NSSI) is a common harmful behavior during adolescence. Exposure to childhood family adversity (CFA) is associated with subsequent emergence of NSSI during adolescence. However, the pathways through which this early environmental risk may operate are not clear. Aims: We tested four alternative hypotheses to explain the association between CFA and adolescent-onset NSSI. Methods: A community sample of n = 933 fourteen year olds with no history of NSSI were followed for three years. Results: Poor family functioning at age 14 mediated the association between CFA before age 5 and subsequent onset of NSSI between 14-17 years. Conclusion: The findings support the cumulative suboptimal environmental hazards (proximal family relationships as a mediator) hypothesis. Improving the family environment at age 14 may mitigate the effects of CFA on adolescent onset of NSSI.MC was funded by a doctoral scholarship from the Gates Cambridge Trust. ALvH is funded by a Royal Society Dorothy Hodgkin Fellowship (No DH150176). PBJ by the NIHR CLAHRC East of England. The study was funded by the Wellcome Trust (Grant no. 074296)

Endothelin-1 regulates arterial pulse wave velocity in vivo

AbstractObjectivesThe aim of this study was to investigate whether endothelin-1, acting locally, regulates arterial distensibility, assessed by measuring pulse-wave velocity in vivo.BackgroundArterial stiffness is a key determinant of cardiovascular risk. Several lines of evidence support a role for the endothelium in regulating arterial stiffness by release of vasoactive mediators. However, the role of endothelin-1 (ET-1) in the regulation of arterial stiffness has not been investigated.MethodsAll studies were conducted in anesthetized sheep. Pulse wave velocity (PWV) was calculated using the foot-to-foot methodology from two pressure waveforms simultaneously recorded with a high-fidelity, dual pressure-sensing catheter placed in the common iliac artery.ResultsIntra-arterial infusion of ET-1 significantly increased iliac PWV by 12 ± 5% (mean ± STD; p < 0.001), whereas infusion of the endothelin-A (ETA) receptor antagonist BQ-123 significantly reduced PWV by 12 ± 4% (p < 0.001). After BQ-123 infusion, exogenously infused ET-1 did not significantly change PWV compared with infusion of saline (change of −0.08 ± 0.11% vs. −0.01 ± 0.07%; p = 0.53). Importantly, infusion of BQ-123 or ET-1 distal to the common iliac artery did not affect PWV.ConclusionsThese results demonstrate, for the first time, that endogenous ET-1 production directly regulates large artery PWV in vivo. In addition, exogenous ET-1 increases PWV, and this can be blunted by ETAreceptor blockade. These observations explain, in part, why conditions that exhibit up-regulation of ET-1 are also associated with arterial stiffening. Therefore, drugs that block ETAreceptors may be effective in reducing large artery stiffness in humans, and thus cardiovascular risk

Effects of oral lycopene supplementation on vascular function in patients with cardiovascular disease and healthy volunteers: a randomised controlled trial.

AIMS: The mechanisms by which a 'Mediterranean diet' reduces cardiovascular disease (CVD) burden remain poorly understood. Lycopene is a potent antioxidant found in such diets with evidence suggesting beneficial effects. We wished to investigate the effects of lycopene on the vasculature in CVD patients and separately, in healthy volunteers (HV). METHODS AND RESULTS: We randomised 36 statin treated CVD patients and 36 healthy volunteers in a 2∶1 treatment allocation ratio to either 7 mg lycopene or placebo daily for 2 months in a double-blind trial. Forearm responses to intra-arterial infusions of acetylcholine (endothelium-dependent vasodilatation; EDV), sodium nitroprusside (endothelium-independent vasodilatation; EIDV), and NG-monomethyl-L-arginine (basal nitric oxide (NO) synthase activity) were measured using venous plethysmography. A range of vascular and biochemical secondary endpoints were also explored. EDV in CVD patients post-lycopene improved by 53% (95% CI: +9% to +93%, P = 0.03 vs. placebo) without changes to EIDV, or basal NO responses. HVs did not show changes in EDV after lycopene treatment. Blood pressure, arterial stiffness, lipids and hsCRP levels were unchanged for lycopene vs. placebo treatment groups in the CVD arm as well as the HV arm. At baseline, CVD patients had impaired EDV compared with HV (30% lower; 95% CI: -45% to -10%, P = 0.008), despite lower LDL cholesterol (1.2 mmol/L lower, 95% CI: -1.6 to -0.9 mmol/L, P<0.001). Post-therapy EDV responses for lycopene-treated CVD patients were similar to HVs at baseline (2% lower, 95% CI: -30% to +30%, P = 0.85), also suggesting lycopene improved endothelial function. CONCLUSIONS: Lycopene supplementation improves endothelial function in CVD patients on optimal secondary prevention, but not in HVs. TRIAL REGISTRATION: ClinicalTrials.gov NCT01100385

Tetrahydrobiopterin Supplementation Improves Endothelial Function But Does Not Alter Aortic Stiffness in Patients With Rheumatoid Arthritis.

BACKGROUND: Rheumatoid arthritis is a systemic inflammatory condition associated with increased cardiovascular risk that may be due to underlying endothelial dysfunction and subsequent aortic stiffening. We hypothesized that supplementation with tetrahydrobiopterin (BH4) would recouple endothelial nitric oxide synthase and thus improve endothelial function and consequently reduce aortic stiffness. METHODS AND RESULTS: We conducted 2 randomized, double-blinded, placebo-controlled crossover studies examining 2 separate regimens: an acute regimen, with a single dose of BH4 400 mg versus placebo (n=18), and a short-term regimen, composed of a 1-week treatment with BH4 400 mg once daily versus placebo (n=15). Flow-mediated dilatation and aortic pulse wave velocity were studied 4 times, before and after each treatment phase. Acute BH4 supplementation led to an improvement of flow-mediated dilatation, whereas placebo had no effect (mean±SD of effect difference 2.56±4.79%; P=0.03). Similarly, 1-week treatment with BH4 improved endothelial function, but there was no change with placebo (mean±SD of effect difference 3.50±5.05%; P=0.02). There was no change in aortic pulse wave velocity following acute or short-term BH4 supplementation or placebo (mean±SD of effect difference: acute 0.09±0.67 m/s, P=0.6; short-term 0.03±1.46 m/s, P=0.9). CONCLUSION: Both acute and short-term supplementation with oral BH4 improved endothelial function but not aortic stiffness. This result suggests that BH4 supplementation may be beneficial for patients with rheumatoid arthritis by improving endothelial dysfunction and potentially reducing risk of cardiovascular disease. There appears to be no causal relationship between endothelial function and aortic stiffness, suggesting that they occur in parallel, although they may share common risk factors such as inflammation.KMMP and IBW were funded by British Heart Foundation. IBW, JC and NS received funding from the Comprehensive Local Research Network and IBW and JC from the National Institute for Health Research: Cambridge Biomedical Research Centre.This is the final version of the article. It first appeared from Wiley Blackwell via http://dx.doi.org/10.1161/JAHA.115.00276

Geological Hydrogen Storage: Geochemical Reactivity of Hydrogen with Sandstone Reservoirs

[Image: see text] The geological storage of hydrogen is necessary to enable the successful transition to a hydrogen economy and achieve net-zero emissions targets. Comprehensive investigations must be undertaken for each storage site to ensure their long-term suitability and functionality. As such, the systematic infrastructure and potential risks of large-scale hydrogen storage must be established. Herein, we conducted over 250 batch reaction experiments with different types of reservoir sandstones under conditions representative of the subsurface, reflecting expected time scales for geological hydrogen storage, to investigate potential reactions involving hydrogen. Each hydrogen experiment was paired with a hydrogen-free control under otherwise identical conditions to ensure that any observed reactions were due to the presence of hydrogen. The results conclusively reveal that there is no risk of hydrogen loss or reservoir integrity degradation due to abiotic geochemical reactions in sandstone reservoirs

Measurement Invariance in Longitudinal Bifactor Models: Review and Application Based on the p Factor.

Bifactor models are increasingly being utilized to study latent constructs such as psychopathology and cognition, which change over the lifespan. Although longitudinal measurement invariance (MI) testing helps ensure valid interpretation of change in a construct over time, this is rarely and inconsistently performed in bifactor models. Our review of MI simulation literature revealed that only one study assessed MI in bifactor models under limited conditions. Recommendations for how to assess MI in bifactor models are suggested based on existing simulation studies of related models. Estimator choice and influence of missing data on MI are also discussed. An empirical example based on a model of the general psychopathology factor (p) elucidates our recommendations, with the present model of p being the first to exhibit residual MI across gender and time. Thus, changes in the ordered-categorical indicators can be attributed to changes in the latent factors. However, further work is needed to clarify MI guidelines for bifactor models, including considering the impact of model complexity and number of indicators. Nonetheless, using the guidelines justified herein to establish MI allows findings from bifactor models to be more confidently interpreted, increasing their comparability and utility