Antihypertensive drug effects on long-term blood pressure: an individual-level data meta-analysis of randomised clinical trials

Objective Evidence from randomised trials of pharmacological treatments on long-term blood pressure (BP) reduction is limited. We investigated the antihypertensive drug effects on BP over time and across different participant characteristics. Methods We conducted an individual patient-level data meta-analysis of 52 large-scale randomised clinical trials in the Blood Pressure Lowering Treatment Trialists’ Collaboration using mixed models to examine treatment effects on BP over 4 years of mean follow-up. Results There were 363 684 participants (42% women), with baseline mean age=65 years and mean systolic/ diastolic BP=152/87 mm Hg, and among whom 19% were current smokers, 49% had cardiovascular disease, 28% had diabetes and 69% were taking antihypertensive treatment at baseline. Drugs were effective in lowering BP showing maximal effect after 12 months and gradually attenuating towards later years. Based on measures taken ≥12 months postrandomisation, mean systolic/diastolic BP difference (95% CI) between more and less intense BP-lowering treatment was −11.1 (−11.3 to −10.8)/−5.6 (−5.7 to −5.4) mm Hg; between active treatment and placebo was −5.1 (−5.3 to −5.0)/−2.3 (−2.4 to −2.2) mm Hg; and between active and control arms for drug comparison trials was −1.4 (−1.5 to −1.3)/−0.6 (−0.7 to −0.6) mm Hg. BP reductions were observed across different baseline BP values and ages, and by sex, history of cardiovascular disease and diabetes and prior antihypertensive treatment use. Conclusion These findings suggest that BP-lowering pharmacotherapy is effective in lowering BP, up to 4 years on average, in people with different characteristics. Appropriate treatment strategies are needed to sustain substantive long-term BP reductions

Prevalence of facet joint pain in chronic spinal pain of cervical, thoracic, and lumbar regions

BACKGROUND: Facet joints are a clinically important source of chronic cervical, thoracic, and lumbar spine pain. The purpose of this study was to systematically evaluate the prevalence of facet joint pain by spinal region in patients with chronic spine pain referred to an interventional pain management practice. METHODS: Five hundred consecutive patients with chronic, non-specific spine pain were evaluated. The prevalence of facet joint pain was determined using controlled comparative local anesthetic blocks (1% lidocaine or 1% lidocaine followed by 0.25% bupivacaine), in accordance with the criteria established by the International Association for the Study of Pain (IASP). The study was performed in the United States in a non-university based ambulatory interventional pain management setting. RESULTS: The prevalence of facet joint pain in patients with chronic cervical spine pain was 55% 5(95% CI, 49% – 61%), with thoracic spine pain was 42% (95% CI, 30% – 53%), and in with lumbar spine pain was 31% (95% CI, 27% – 36%). The false-positive rate with single blocks with lidocaine was 63% (95% CI, 54% – 72%) in the cervical spine, 55% (95% CI, 39% – 78%) in the thoracic spine, and 27% (95% CI, 22% – 32%) in the lumbar spine. CONCLUSION: This study demonstrated that in an interventional pain management setting, facet joints are clinically important spinal pain generators in a significant proportion of patients with chronic spinal pain. Because these patients typically have failed conservative management, including physical therapy, chiropractic treatment and analgesics, they may benefit from specific interventions designed to manage facet joint pain

Long term time variability of cosmic rays and possible relevance to the development of life on Earth

An analysis is made of the manner in which the cosmic ray intensity at Earth has varied over its existence and its possible relevance to both the origin and the evolution of life. Much of the analysis relates to the 'high energy' cosmic rays ($E>10^{14}eV;=0.1PeV$) and their variability due to the changing proximity of the solar system to supernova remnants which are generally believed to be responsible for most cosmic rays up to PeV energies. It is pointed out that, on a statistical basis, there will have been considerable variations in the likely 100 My between the Earth's biosphere reaching reasonable stability and the onset of very elementary life. Interestingly, there is the increasingly strong possibility that PeV cosmic rays are responsible for the initiation of terrestrial lightning strokes and the possibility arises of considerable increases in the frequency of lightnings and thereby the formation of some of the complex molecules which are the 'building blocks of life'. Attention is also given to the well known generation of the oxides of nitrogen by lightning strokes which are poisonous to animal life but helpful to plant growth; here, too, the violent swings of cosmic ray intensities may have had relevance to evolutionary changes. A particular variant of the cosmic ray acceleration model, put forward by us, predicts an increase in lightning rate in the past and this has been sought in Korean historical records. Finally, the time dependence of the overall cosmic ray intensity, which manifests itself mainly at sub-10 GeV energies, has been examined. The relevance of cosmic rays to the 'global electrical circuit' points to the importance of this concept.Comment: 18 pages, 5 figures, accepted by 'Surveys in Geophysics

Handling method alters the hedonic value of reward in laboratory mice

Mice are the most widely used model species for drug discovery and scientific research. Consequently, it is important to refine laboratory procedures and practices to ensure high standards of welfare and scientific data quality. Recent studies have identified that the standard practice of handling laboratory mice by their tails increases behaviours indicative of anxiety, which can be overcome by handling mice using a tunnel. However, despite clear negative effects on mice’s behaviour, tunnel handling has yet to be widely implemented. In this study, we provide the first evidence that tail handling also reduces mice’s responses to reward. Anhedonia is a core symptom of clinical depression, and is measured in rodents by assessing how they consume a sucrose solution: depressed mice consume less sucrose and the size of their licking bouts when drinking (their ‘lick cluster sizes’) also tend to be smaller. We found that tail handled mice showed more anhedonic responses in both measures compared to tunnel handled mice, indicative of a decreased responsiveness to reward and potentially a more depressive-like state. Our findings have significant implications for the welfare of laboratory mice as well as the design and interpretation of scientific studies, particularly those investigating or involving reward

Virtual Patients and Sensitivity Analysis of the Guyton Model of Blood Pressure Regulation: Towards Individualized Models of Whole-Body Physiology

Mathematical models that integrate multi-scale physiological data can offer insight into physiological and pathophysiological function, and may eventually assist in individualized predictive medicine. We present a methodology for performing systematic analyses of multi-parameter interactions in such complex, multi-scale models. Human physiology models are often based on or inspired by Arthur Guyton's whole-body circulatory regulation model. Despite the significance of this model, it has not been the subject of a systematic and comprehensive sensitivity study. Therefore, we use this model as a case study for our methodology. Our analysis of the Guyton model reveals how the multitude of model parameters combine to affect the model dynamics, and how interesting combinations of parameters may be identified. It also includes a “virtual population” from which “virtual individuals” can be chosen, on the basis of exhibiting conditions similar to those of a real-world patient. This lays the groundwork for using the Guyton model for in silico exploration of pathophysiological states and treatment strategies. The results presented here illustrate several potential uses for the entire dataset of sensitivity results and the “virtual individuals” that we have generated, which are included in the supplementary material. More generally, the presented methodology is applicable to modern, more complex multi-scale physiological models

Muscle weakness and lack of reflex gain adaptation predominate during post-stroke posture control of the wrist

Instead of hyper-reflexia as sole paradigm, post-stroke movement disorders are currently considered the result of a complex interplay between neuronal and muscular properties, modified by level of activity. We used a closed loop system identification technique to quantify individual contributors to wrist joint stiffness during an active posture task. Continuous random torque perturbations applied to the wrist joint by a haptic manipulator had to be resisted maximally. Reflex provoking conditions were applied i.e. additional viscous loads and reduced perturbation signal bandwidth. Linear system identification and neuromuscular modeling were used to separate joint stiffness into the intrinsic resistance of the muscles including co-contraction and the reflex mediated contribution. Compared to an age and sex matched control group, patients showed an overall 50% drop in intrinsic elasticity while their reflexive contribution did not respond to provoking conditions. Patients showed an increased mechanical stability compared to control subjects. Post stroke, we found active posture tasking to be dominated by: 1) muscle weakness and 2) lack of reflex adaptation. This adds to existing doubts on reflex blocking therapy as the sole paradigm to improve active task performance and draws attention to muscle strength and power recovery and the role of the inability to modulate reflexes in post stroke movement disorders.Mechanical, Maritime and Materials Engineerin

Unwanted pregnancy, mental health and abortion: untangling the evidence

Abortion policy is still contentious in many parts of the world, and periodically it emerges to dominate health policy debates. This paper examines one such debate in Australia centering on research findings by a New Zealand research group, Fergusson, Horwood & Ridder, published in early 2006. The debate highlighted the difficulty for researchers when their work is released in a heightened political context. We argue that the authors made a logical error in constructing their analysis and interpreting their data, and are therefore not justified in making policy claims for their work. The paper received significant public attention, and may have influenced the public policy position of a major professional body. Deeply held views on all sides of the abortion debate are unlikely to be reconciled, but if policy is to be informed by research, findings must be based on sound science