Isometric Resistance Training to Manage Hypertension: Systematic Review and Meta-analysis.

PURPOSE OF REVIEW: Hypertension is the primary risk factor for cardiovascular disease and adequate blood pressure control is often elusive. The objective of this work was to conduct a meta-analysis of trial data of isometric resistance training (IRT) studies in people with hypertension, to establish if IRT produced an anti-hypertensive effect. A database search (PubMed, CINAHL, Cochrane Central Register of Controlled Trials, and MEDLINE) identified randomised controlled and crossover trials of IRT versus a sedentary or sham control group in adults with hypertension. RECENT FINDINGS: We included 12 studies (14 intervention groups) in the meta-analyses, with an aggregate of 415 participants. IRT reduced systolic blood pressure (SBP), mean difference (MD) - 7.47 mmHg (95%CI - 10.10, - 4.84), P < 0.01; diastolic blood pressure (DBP) MD - 3.17 mmHg (95%CI - 5.29, - 1.04), P < 0.01; and mean arterial blood pressure (MAP) MD - 7.19 mmHg (95%CI - 9.06, - 5.32), P < 0.0001. Office pulse pressure and resting heart rate was not significantly reduced, neither were 24-h or day-time ambulatory blood pressures (SBP, DBP). Night-time blood pressures, however, were significantly reduced with SBP MD - 4.28 mmHg (95%CI - 7.88, - 0.67), P = 0.02, and DBP MD - 2.22 mmHg (95%CI - 3.55, - 0.88), P < 0.01. IRT does lower SBP, DBP and MAP office and night-time ambulatory SBP and DBP, but not 24-h mean ambulatory blood pressures in people with hypertension.

Rate adaptive pacing in people with chronic heart failure increases peak heart rate but not peak exercise capacity: a systematic review.

Rate adaptive cardiac pacing (RAP) allows increased heart rate (HR) in response to metabolic demand in people with implantable electronic cardiac devices (IECD). The aim of this work was to conduct a systematic review to determine if RAP increases peak exercise capacity (peak VO2) in line with peak HR in people with chronic heart failure. We conducted a systematic literature search from 1980, when IECD and RAP were first introduced, until 31 July 2021. Databases searched include PubMed, Medline, EMBASE, EBSCO, and the Clinical Trials Register. A comprehensive search of the literature produced a total of 246 possible studies; of these, 14 studies were included. Studies and subsequent analyses were segregated according to comparison, specifically standard RAP (RAPON) vs fixed rate pacing (RAPOFF), and tailored RAP (TLD RAPON) vs standard RAP (RAPON). Pooled analyses were conducted for peak VO2 and peak HR for RAPON vs RAPOFF. Peak HR significantly increased by 15 bpm with RAPON compared to RAPOFF (95%CI, 7.98-21.97, P < 0.0001). There was no significant difference between pacing mode for peak VO2 0.45 ml kg-1 min-1 (95%CI, - 0.55-1.47, P = 0.38). This systematic review revealed RAP increased peak HR in people with CHF; however, there was no concomitant improvement in peak VO2. Rather RAP may provide benefits at submaximal intensities by controlling the rise in HR to optimise cardiac output at lower workloads. HR may be an important outcome of CHF management, reflecting myocardial efficiency.

Effect of aerobic and resistance training on inflammatory markers in heart failure patients: systematic review and meta-analysis.

Elevated levels of pro-inflammatory markers are evident in patients with heart failure and are associated with disease severity and prognosis. Exercise training has been shown to reduce circulating levels of pro-inflammatory cytokines and other pro-inflammatory markers in healthy and clinical populations. The aim of the systematic review and meta-analysis was to investigate the effect of aerobic (AT) and resistance training (RT) interventions on circulating concentrations of inflammatory markers; tumour necrosis factor-alpha (TNF-α), interleukin 6 (IL-6), C-reactive protein (CRP), fibrinogen, soluble intercellular adhesion molecule (sICAM) and soluble vascular adhesion molecule (sVCAM) in heart failure patients. We conducted database searches (PubMed, EMBASE and Cochrane Trials Register to 30 June 2017) for exercise-based trials in heart failure, using the following search terms: exercise training, inflammation, tumour necrosis factor-alpha, interleukin 6, C-reactive protein, fibrinogen, soluble intercellular adhesions molecule-1, soluble vascular adhesion molecule-1. Twenty studies, representing 18 independent trials, were included in the review. Pooled data of six studies indicated a minimally favourable effect of exercise training on circulating TNF-α [SMD 0.42 (95% CI 0.15, 0.68), p = 0.002)]. However, together the pooled and descriptive analyses failed to provide strong evidence for a reduction in other pro-inflammatory markers. However, given the complexity of heart failure and the pathways involved in the immune and inflammatory process, large prospective trials considering aetiology, comorbidities and local skeletal muscle inflammation are required to elucidate on the anti-inflammatory effect of exercise in this population.

Exercise therapy and autonomic function in heart failure patients: a systematic review and meta-analysis.

A large body of evidence exists indicating that autonomic imbalance is characteristic of heart failure, with several parameters of autonomic function associated with adverse clinical outcomes. The aim of this systematic review and meta-analysis was to investigate the effects of exercise training on parameters of autonomic function in patients with heart failure and where possible quantify the size of the effect. We conducted database searches (PubMed, EMBASE and Cochrane Trials Register to 31 March 2017) for exercise-based rehabilitation trials in heart failure; using search terms, exercise training, autonomic function, heart rate recovery, heart rate variability and muscle sympathetic nerve activity. Pooled data indicated a statistically significant increase in heart rate recovery at 1 min (HRR1) in exercise compared to control groups, mean difference 5.90 bpm (95%CI 5.12, 6.69; p < 0.00001). Pooled data also indicated that exercise training improved the short-term heart rate variability (HRV) parameters of root mean square of successive differences between normal heart beats (RMSSD (ms)) [mean difference 10.44 (95%CI 0.60, 20.28, p = 0.04)] and high-frequency normalised units (HFnu) [mean difference 7.72 (95%CI 3.32, 12.12, p = 0.0006), which are predominantly reflective of parasympathetic activity. Analyses also indicated a statistically significant decrease in muscle sympathetic nerve activity (MSNA) bursts/minute (mean difference - 11.09 (95%CI - 16.18, - 6.00; p < 0.0001) and MSNA bursts/100 heart beats (mean difference - 15.44 (95%CI - 20.95, -9.92; p < 0.00001) in exercise groups compared to controls. With improvements in HRR, HRV and MSNA, exercise training appears to facilitate an improvement in parasympathetic tone and reduction in sympathetic activity.

Aerobic Training Intensity for Improved Endothelial Function in Heart Failure Patients: A Systematic Review and Meta-Analysis.

Objective. Flow-mediated dilation (FMD) is widely utilised to assess endothelial function and aerobic exercise improves FMD in heart failure patients. The aim of this meta-analysis is to quantify the effect of aerobic training intensity on FMD in patients with heart failure. Background. A large number of studies now exist that examine endothelial function in patients with heart failure. We sought to add to the current literature by quantifying the effect of the aerobic training intensity on endothelial function. Methods. We conducted database searches (PubMed, Embase, ProQuest, and Cochrane Trials Register to June 30, 2016) for exercise based rehabilitation trials in heart failure, using search terms exercise training, endothelial function, and flow-mediated dilation (FMD). Results. The 13 included studies provided a total of 458 participants, 264 in intervention groups, and 194 in nonexercising control groups. Both vigorous and moderate intensity aerobic training significantly improved FMD. Conclusion. Overall both vigorous and moderate aerobic exercise training improved FMD in patients with heart failure.

Effect of exercise on diastolic function in heart failure patients: a systematic review and meta-analysis.

Diastolic dysfunction contributes to the development and progression of heart failure. Conventional echocardiography and tissue Doppler imaging are widely utilised in clinical research providing a number of indices of diastolic function valuable in the diagnosis and prognosis of heart failure patients. The aim of this meta-analysis was to quantify the effect of exercise training on diastolic function in patients with heart failure. Exercise training studies that investigate different indices of diastolic function in patients with heart failure have reported that exercise training improves diastolic function in these patients. We sought to add to the current literature by quantifying, where possible, the effect of exercise training on diastolic function. We conducted database searches (PubMed, EBSCO, EMBASE, and Cochrane Trials Register to 31 July 2016) for exercise based rehabilitation trials in heart failure, using the search terms 'exercise training, diastolic function and diastolic dysfunction'. Data from six studies, with a total of 266 heart failure with reduced ejection fraction (HFrEF) participants, 144 in intervention groups and 122 in control groups, indicated a significant reduction in the ratio of early diastolic transmitral velocity (E) to early diastolic tissue velocity (E') (E/E' ratio) with exercise training, exercise vs. control mean difference (MD) of -2.85 (95% CI -3.66 to -2.04, p < 0.00001). Data from five studies in heart failure with preserved ejection fraction (HFpEF) patients, with a total of 204 participants, 115 in intervention groups and 89 in control groups, also demonstrated a significant improvement in E/E' in exercise vs. control MD of -2.38 (95% CI -3.47 to -1.28, p < 0.0001).

Effect of exercise training on endothelial function in heart failure patients: A systematic review meta-analysis.

OBJECTIVE: Endothelial dysfunction contributes to the development and progression of cardiovascular disease and heart failure (HF) and is associated with an increased risk of mortality. Flow-mediated dilation (FMD) is widely utilised to assess endothelial function and is improved with exercise training in heart failure patients. The aim of this meta-analysis is to quantify the effect of exercise training in patients with heart failure. BACKGROUND: A large number of studies now exist that have examined endothelial function in patients with heart failure. We sought to add to the current literature by quantifying the effect of exercise training on endothelial function. METHODS: We conducted database searches (PubMed, EMBASE, PROQUEST and Cochrane Trials Register to June 2016) for exercise based rehabilitation trials in heart failure, using search terms exercise training, endothelial function, flow-mediated dilation (FMD) and endothelial progenitor cells (EPCs). RESULTS: The 16 included studies provided a total of 529 participants, 293 in an intervention and 236 in controls groups. FMD was improved with exercise training in exercise vs. control, SMD of 1.08 (95%CI 0.70 to 1.46, p<0.00001). CONCLUSION: Overall exercise training improved endothelial function, assessed via FMD, and endothelial progenitor cells in heart failure patients.

The hallmarks of osteoarthritis and the potential to develop personalised disease-modifying pharmacological therapeutics.

Osteoarthritis (OA) is an age-related condition and the leading cause of pain, disability and shortening of adult working life in the UK. The incidence of OA increases with age, with 25% of the over 50s population having OA of the knee. Despite promising preclinical data covering various molecule classes, there is regrettably at present no approved disease-modifying OA drugs (DMOADs). With the advent of next generation sequencing technologies, other therapeutic areas, in particular oncology, have experienced a paradigm shift towards defining disease by its molecular composition. This paradigm shift has enabled high resolution patient stratification and supported the emergence of personalised or precision medicines. In this review we evaluate the potential for the development of OA therapeutics to undergo a similar paradigm shift given that OA is increasingly being recognised as a heterogeneous disease affecting multiple joint tissues. We highlight the evidence for the role of these tissues in OA pathology as different "hallmarks" of OA biology and review the opportunities to identify and develop targeted disease-modifying pharmacological therapeutics. Finally, we consider whether it is feasible to expect the emergence of personalised disease-modifying medicines for patients with OA and how this might be achieved.

Comparison of a simple dose-guided intervention technique for prostate radiotherapy with existing anatomical image guidance methods.

OBJECTIVES: A simple dose-guided intervention technique for prostate radiotherapy using an isodose overlay method combined with soft-tissue-based corrective couch shifts has been proposed previously. This planning study assesses the potential clinical impact of such a correction strategy. METHODS: 10 patients, each with 8-11 on-treatment CT studies (n=97), were assessed using this technique and compared with no intervention, bony anatomy intervention and soft-tissue intervention methods. Each assessment technique used a 4-mm action level for intervention. Outcomes were evaluated using measures of sensitivity, specificity and dosimetric effect, and compared across intervention techniques. Dosimetric effect was defined as the change in dosimetric coverage by the 95% isodose from the no intervention case of an evaluation construct called the verification target volume. RESULTS: Bony anatomy, soft tissue and dosimetric overlay-based interventions demonstrated sensitivity of 0.56, 0.73 and 1.00 and specificity of 0.64, 0.20 and 0.66, respectively. A detrimental dosimetric effect was shown in 7% of interventions for each technique, with benefit in 30%, 35% and 55% for bony anatomy, soft tissue and dosimetric overlay techniques, respectively. CONCLUSION: Used in conjunction with soft-tissue-based corrective couch shifts, the dosimetric overlay technique allows effective filtering out of dosimetrically unnecessary interventions, making it more likely that any intervention made will result in improved target volume coverage.

Validity and inter-rater reliability of the Lindop Parkinson's Disease Mobility Assessment: a preliminary study.

OBJECTIVES: To assess the validity and inter-rater reliability of the Lindop Parkinson's Disease Mobility Assessment (LPA); a scale developed to gather objective information on gait and bed mobility in patients with Parkinson's disease. DESIGN: Two therapists scored a group of patients with Parkinson's disease using the motor examination section of the Unified Parkinson's Disease Rating Scale (UPDRS-ME) and the LPA scale. The association between scores obtained using the two scales was calculated, and the scores obtained by the therapists using each scale were compared. SETTING: A Parkinson's disease clinic in a day hospital in a district general hospital. PARTICIPANTS: Forty-nine subjects with Parkinson's disease were recruited (33 males, 16 females, mean age 75.84+/-7.16 years). RESULTS: There was a significant association between the LPA and UPDRS-ME data for both raters (Rater A, rho -0.67; Rater B, rho -0.63; P<0.001). The limits of agreement showed that the two raters scored within two scale points of each other on 95% of occasions, and that there was no systematic bias between raters. Percentage agreement between raters ranged from 82% to 100% for the LPA. The LPA took significantly less time to complete [mean 7.7 (standard deviation 2.9) minutes] than the UPDRS-ME [mean 10.5 (standard deviation 2.2) minutes; P<0.001]. CONCLUSIONS: The results suggest that the LPA is a valid measure with good inter-rater reliability. It is quick and easy to administer, and provides objective information about the gait and bed mobility of elderly patients with Parkinson's disease.

Inheritance of persistent foramen ovale and atrial septal defects and the relation to familial migraine with aura.

OBJECTIVE: To determine whether smaller atrial shunts (large persistent foramen ovale (PFO) and small atrial septal defect (ASD)) are inherited and whether this has a role in the inheritance of migraine with aura. METHODS: Contrast echocardiography was used to detect atrial shunts in 71 relatives of 20 probands with a significantly sized atrial shunt (large PFO or ASD). Four families with three generations, 14 families with two generations, and two sibships were studied. The contrast echocardiograms were performed blind to history of migraine. A consultant neurologist, who was blinded to cardiac findings, categorised migraine symptoms in subjects. RESULTS: The occurrence of atrial shunts was consistent with autosomal dominant inheritance. Usually shunts were large PFOs, but in some cases they were ASDs. There was also evidence that inheritance of more complex congenital heart disease may be related to the inheritance of PFOs. When the proband had migraine with aura and an atrial shunt, 15 of the 21(71.4%) first degree relatives with a significant right to left shunt also had migraine with aura compared with three of 14 (21.4%) without a significant shunt (p < 0.02). CONCLUSIONS: There is dominant inheritance of atrial shunts. This is linked to inheritance of migraine with aura in some families.

Pleuromutilins. Part 1. The identification of novel mutilin 14-carbamates.

A novel series of mutilin 14-carbamates has been discovered as a result of structure-activity studies on the naturally occurring antibiotic pleuromutilin (1). In particular, the 4-methoxybenzoylcarbamate, SB-222734 (15o) displays potent antibacterial activity against a number of bacterial pathogens which are resistant to currently used agents and shows enhanced metabolic stability when compared to earlier pleuromutilin derivatives. Such derivatives therefore have the potential to provide a new class of antibacterial agents for human therapy which address the threat of bacterial resistance.

Relationship between right-to-left shunts and cutaneous decompression illness.

The presence of a large right-to-left shunt is associated with neurological decompression illness after non-provocative dives, as a result of paradoxical gas embolism. A small number of observations suggest that cutaneous decompression illness is also associated with a right-to-left shunt, although an embolic aetiology of a diffuse rash is more difficult to explain. We performed a retrospective case--control comparison of the prevalence and sizes of right-to-left shunts determined by contrast echocardiography performed blind to history in 60 divers and one caisson worker with a history of cutaneous decompression illness, and 123 historical control divers. We found that 47 (77.0%) of the 61 cases with cutaneous decompression illness had a shunt, compared with 34 (27.6%) of 123 control divers (P<0.001). The size of the shunts in the divers with cutaneous decompression illness was significantly greater than in the controls. Thus 30 (49.2%) of the 61 cases with cutaneous decompression illness had a large shunt at rest, compared with six (4.9%) of the 123 controls (P<0.001). During closure procedures in 17 divers who had cutaneous decompression illness, the mean diameter of the foramen ovale was 10.9 mm. Cutaneous decompression illness occurred after dives that were provocative or deep in subjects without shunts, but after shallower and non-provocative dives in those with shunts. The latter individuals are at increased risk of neurological decompression illness. We conclude that cutaneous decompression illness has two pathophysiological mechanisms. It is usually associated with a large right-to-left shunt, when the mechanism is likely to be paradoxical gas embolism with peripheral amplification when bubble emboli invade tissues supersaturated with nitrogen. Cutaneous decompression illness can also occur in individuals without a shunt. In these subjects, the mechanism might be bubble emboli passing through an 'overloaded' lung filter or autochthonous bubble formation.

Influence of erythrocyte aggregation on leukocyte margination in postcapillary venules of rat mesentery.

The role of erythrocyte (red blood cell; RBC) aggregation in affecting leukocyte (white blood cell; WBC) margination in postcapillary venules of the mesentery (rat) was explored by direct intravital microscopy. Optical techniques were refined and applied to relate the light-scattering properties of RBCs to obtain a quantitative index of aggregate size (G), which, under idealized conditions, represents the number of RBCs per aggregate. WBC margination, defined as the radial migration of WBCs to the venular wall and their subsequent rolling along the endothelium, was measured as the percentage of the potentially maximal WBC volumetric flux within the microvessel lumen (F(WBC)(*)). In normal blood, F(WBC)(*) increased exponentially fourfold, and G increased from 1 to 1.15 as wall shear rates () were reduced from a steady-state value of approximately 600 to <100 s(-1) by proximal occlusion with a blunt microprobe. Enhancement of aggregation by infusion (iv) of dextran 500 (428 kDa), to attain a systemic concentration of 3 g/100 ml, resulted in a four- and sevenfold increase in G and F(WBC)(*), respectively, as was reduced below 100 s(-1). Inhibition of RBC aggregation by infusion of dextran 40 (37.5 kDa) caused F(WBC)(*) to fall to one-half of its steady-state level for < 100 s(-1). Thus it appears that the well-known increase of WBC margination with reductions in is strongly dependent on the occurrence of RBC aggregation. Increasing the extent of RBC aggregation during reductions in also increased the firm adhesion of WBCs to the endothelium because of an enhanced probability of contact between leukocytes and the postcapillary venular wall.

The clinical role of clinical biochemists.

Project EVETSIN investigated the training of clinical biochemists and other professional groups in the UK National Health Service. One of the most significant professional changes (with a training implication) identified was the increasing importance of the clinical role of clinical biochemists. The skills involved and the processes by which trainee clinical biochemists learn them had not been described or analysed to a significant extent. Factors that influence this changing role, the nature of the skills, how they are acquired and maintained, and the associated knowledge base are presented and discussed in the context of the training of clinical biochemists in the UK.

Novel C-2 substituted carbapenem derivatives. Part IV. Synthesis and biological activity of five membered heteroaromatic derivatives.

The synthesis, antibacterial activity, and stability to human dehydropeptidase-1 (DHP-1) of a novel series of (5R,6S)-6-[(1R)-1-hydroxyethyl]-2-heterocyclylcarbapen-2-em-3-carb oxylates are described. Of the compounds investigated 1,5-disubstituted pyrazol-3-yl and 3-substituted isoxazol-5-yl derivatives have the best combination of antibacterial activity and stability to DHP-1. They are particularly active against community-acquired respiratory tract pathogens and have stabilities to DHP-1 superior to that of meropenem.

Novel C-2 substituted carbapenem derivatives. Part III. Synthesis and biological activity of 2-(functionalised ethenyl, oxyiminomethyl and alpha-[hydroxy]benzyl)-carbapenems.

The synthesis, antibacterial activity and stability to human dehydropeptidase-1 (DHP-1) of three small series of carbapenems carrying carbon-linked substituents at C-2 are described. C-2 Ethenyl carbapenems showed moderate antibacterial activity but poor stability to DHP-1, C-2 Oxyiminomethyl carbapenems demonstrated variable activity and stability C-2 alpha-(Hydroxy)benzyl carbapenems were the most promising and showed good potency and DHP-1 stability.

Novel C-2 substituted carbapenem derivatives. Part I. Synthesis and biological activity of non-aromatic heterocyclic derivatives.

A new series of carbapenems, having a saturated or partially unsaturated heterocycle at C-2, has been synthesised. The in vitro antibacterial activity of these compounds and their stability to human dehydropeptidase-1 (DHP-1) are described. The stereochemistry of the C-2 side-chain and the presence of a double bond in the heterocycle were shown to have significant effects on the stabilities of the compounds to DHP-1.

Novel C-2 substituted carbapenem derivatives. Part II. Synthesis and structure-activity relationships of isoxazolin-2-yl, isoxazolidin-2-yl and 2-pyrazolin-2-yl carbapenems generated using 1,3-dipolar cycloaddition chemistry.

A series of carbapenems containing novel C-2 semisaturated heterocyclic substituents were synthesised by 1,3 dipolar cycloaddition reactions of nitrile oxides, nitrile imines and a nitrone to 2-vinylcarbapenem. The isoxazoline and isoxazolidine compounds showed potent antibacterial activity but moderate stability to human dehydropeptidase 1 (DHP-1). Stability to DHP-1 was improved by methyl substitution in the isoxazoline ring, but at the expense of antibacterial activity. The pyrazolines exhibited excellent stability to DHP-1, but reduced potency against Gram-negative organisms.