Renal artery sympathetic denervation:observations from the UK experience

Background: Renal denervation (RDN) may lower blood pressure (BP); however, it is unclear whether medication changes may be confounding results. Furthermore, limited data exist on pattern of ambulatory blood pressure (ABP) response—particularly in those prescribed aldosterone antagonists at the time of RDN. Methods: We examined all patients treated with RDN for treatment-resistant hypertension in 18 UK centres. Results: Results from 253 patients treated with five technologies are shown. Pre-procedural mean office BP (OBP) was 185/102 mmHg (SD 26/19; n = 253) and mean daytime ABP was 170/98 mmHg (SD 22/16; n = 186). Median number of antihypertensive drugs was 5.0: 96 % ACEi/ARB; 86 % thiazide/loop diuretic and 55 % aldosterone antagonist. OBP, available in 90 % at 11 months follow-up, was 163/93 mmHg (reduction of 22/9 mmHg). ABP, available in 70 % at 8.5 months follow-up, was 158/91 mmHg (fall of 12/7 mmHg). Mean drug changes post RDN were: 0.36 drugs added, 0.91 withdrawn. Dose changes appeared neutral. Quartile analysis by starting ABP showed mean reductions in systolic ABP after RDN of: 0.4; 6.5; 14.5 and 22.1 mmHg, respectively (p < 0.001 for trend). Use of aldosterone antagonist did not predict response (p < 0.2). Conclusion: In 253 patients treated with RDN, office BP fell by 22/9 mmHg. Ambulatory BP fell by 12/7 mmHg, though little response was seen in the lowermost quartile of starting blood pressure. Fall in BP was not explained by medication changes and aldosterone antagonist use did not affect response

Aortic stiffness in aortic stenosis assessed by cardiovascular MRI: a comparison between bicuspid and tricuspid valves

Objectives To compare aortic size and stiffness parameters on MRI between bicuspid aortic valve (BAV) and tricuspid aortic valve (TAV) patients with aortic stenosis (AS). Methods MRI was performed in 174 patients with asymptomatic moderate-severe AS (mean AVAI 0.57 ± 0.14 cm2/m2) and 23 controls on 3T scanners. Valve morphology was available/analysable in 169 patients: 63 BAV (41 type-I, 22 type-II) and 106 TAV. Aortic cross-sectional areas were measured at the level of the pulmonary artery bifurcation. The ascending and descending aorta (AA, DA) distensibility, and pulse wave velocity (PWV) around the aortic arch were calculated. Results The AA and DA areas were lower in the controls, with no difference in DA distensibility or PWV, but slightly lower AA distensibility than in the patient group. With increasing age, there was a decrease in distensibility and an increase in PWV. After correcting for age, the AA maximum cross-sectional area was higher in bicuspid vs. tricuspid patients (12.97 [11.10, 15.59] vs. 10.06 [8.57, 12.04] cm2, p < 0.001), but there were no significant differences in AA distensibility (p = 0.099), DA distensibility (p = 0.498) or PWV (p = 0.235). Patients with BAV type-II valves demonstrated a significantly higher AA distensibility and lower PWV compared to type-I, despite a trend towards higher AA area. Conclusions In patients with significant AS, BAV patients do not have increased aortic stiffness compared to those with TAV despite increased ascending aortic dimensions. Those with type-II BAV have less aortic stiffness despite greater dimensions. These results demonstrate a dissociation between aortic dilatation and stiffness and suggest that altered flow patterns may play a role. Key Points • Both cellular abnormalities secondary to genetic differences and abnormal flow patterns have been implicated in the pathophysiology of aortic dilatation and increased vascular complications associated with bicuspid aortic valves (BAV). • We demonstrate an increased ascending aortic size in patients with BAV and moderate to severe AS compared to TAV and controls, but no difference in aortic stiffness parameters, therefore suggesting a dissociation between dilatation and stiffness. • Sub-group analysis showed greater aortic size but lower stiffness parameters in those with BAV type-II AS compared to BAV type-I

A Genome-Wide Association Study of Diabetic Kidney Disease in Subjects With Type 2 Diabetes

dentification of sequence variants robustly associated with predisposition to diabetic kidney disease (DKD) has the potential to provide insights into the pathophysiological mechanisms responsible. We conducted a genome-wide association study (GWAS) of DKD in type 2 diabetes (T2D) using eight complementary dichotomous and quantitative DKD phenotypes: the principal dichotomous analysis involved 5,717 T2D subjects, 3,345 with DKD. Promising association signals were evaluated in up to 26,827 subjects with T2D (12,710 with DKD). A combined T1D+T2D GWAS was performed using complementary data available for subjects with T1D, which, with replication samples, involved up to 40,340 subjects with diabetes (18,582 with DKD). Analysis of specific DKD phenotypes identified a novel signal near GABRR1 (rs9942471, P = 4.5 x 10(-8)) associated with microalbuminuria in European T2D case subjects. However, no replication of this signal was observed in Asian subjects with T2D or in the equivalent T1D analysis. There was only limited support, in this substantially enlarged analysis, for association at previously reported DKD signals, except for those at UMOD and PRKAG2, both associated with estimated glomerular filtration rate. We conclude that, despite challenges in addressing phenotypic heterogeneity, access to increased sample sizes will continue to provide more robust inference regarding risk variant discovery for DKD.Peer reviewe

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study

Background: The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection. Methods: This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation. Findings: This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 81·7% (219 of 268) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28–2·40], p\textless0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65–3·22], p\textless0·0001), American Society of Anesthesiologists grades 3–5 versus grades 1–2 (2·35 [1·57–3·53], p\textless0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01–2·39], p=0·046), emergency versus elective surgery (1·67 [1·06–2·63], p=0·026), and major versus minor surgery (1·52 [1·01–2·31], p=0·047). Interpretation: Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery. Funding: National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research

A Peer-Reviewed Journal on Nutraceuticals and Nutrition Editor-in-Chief Pilot Study: Orally-Administered Yeast β β1,3-glucan Prophylactically Protects Against Anthrax Infection and Cancer in Mice Yeast β β1,3-glucan and Its Use Against Anthrax Infection a

In this edition of JANA, the paper by Vetvicka et al. makes an important contribution to our scientific understanding of the nutraceutical stimulation of the immune system in the treatment of both infectious disease and cancer. While abundant evidence demonstrates the ability of β1,3-glucans to activate macrophages and neutrophils when given intravenously or intraperitoneally, there has been little information concerning its efficiency when given orally. In their study, Vetvicka et al. used oral β1,3-glucan (Imucell TM WGP Beta Glucan) from a yeast source in mice infected with Bacillus anthracis. With the high incidence of complications associated with anthrax vaccines, an alternative approach is badly needed in this era of bioterrorism threat. Dr. Ken Alibek, a top-ranking scientist at the Russian bioweapons labs, stated that because of the number of possible bioweapon agents available, something other than mass inoculations would be needed. He suggested non-specific immune stimulation. The most effective form of nonspecific immune stimulation is macrophage activation. The anthrax bacillus secretes two toxins, edema toxin and lethal toxin. Edema toxin stimulates an outpouring of fluid, especially into the lungs. Lethal toxin, inhibits neutrophil phagocytosis and triggers destructive intracellular reactions that destroy macrophage cells. Of primary interest is the fact that anthrax lethal toxin inhibits the macrophages from releasing their immune messengers, primarily IL-1, IL-2, IFN-gamma, and TNF-alpha. Of particular importance in combating infection release from the macrophage, apparently overcoming inhibition by anthrax lethal toxin. This would account for the high survival figures in the β1,3-glucan-treated animals. Some previous studies found no increase in TNF-alpha but a significant increase in IL-1β. 1 Other researchers have demonstrated increased TNF-alpha in response to ß-glucan stimulation. 2 My own review of the literature confirms their statement that the most effective source of β1,3-glucan is from Saccharomyces cerevisiae, the one chosen by most researchers. Purity of the product is vital, since protein contaminants, as seen in the earlier-used source Zymosan, can cause untoward immune reactions. β1,3-glucan also stimulates phagocytosis of neutrophils. In one study, the killing efficiency of neutrophils was increased 20-to 50-fold. 3 This is important since the capsular antigen poly-D-glutamic acid from the anthrax organism inhibits neutrophil phagocytosis. It is the two lethal toxins and the capsular antigen that makes the anthrax organism especially deadly. In addition, β1,3-glucan has been shown to increase clearance of bacteria by the reticuloendothelial system. Thus far, no other solutions have solved this problem. As for β1,3-glucan&apos;s effects on tumor growth, several studies have shown a significant effect on tumor growth in animal models. 4,5 Early studies using immune stimulation found occasional tumor growth enhancement. This was later found to be secondary to stimulation of blocking antibody production. A safer and more effective method of immune stimulation is directed at cellular immunity, in particular the stimulation of T-helper cells and NK cells. β1,3-glucan has been shown to increase lymphocyte production, NK cell activation, and activation of macrophages. Several studies have also demonstrated the role played by cytokines in inhibiting tumor growth; again, particular interest is in TNF-alpha release. 6 Of interest also is the role played by IL-1β, which is increased by β1,3-glucan as well. Interleukin 1β has been shown to enhance mobilization of PMLs in the bone marrow and enhance their chemotactic ability. In addition, IL-1β increases the lymphocyte count and increases their activity. 7 The use of β1,3-glucan is of special interest in the cancer patient undergoing chemotherapy and/or radiation treatment, since β-glucans have shown a remarkable ability to accelerate hematopoetic recovery in both sublethally and lethally irradiated mice, even when given after the radiation dose. It can also stimulate recovery of the bone marrow following chemotherapy, something vital to restricting tumor growth and preventing infectious complications during treatment. While data provided in the research by Vetvicka and co-workers is preliminary and needs to be confirmed by a larger controlled trial, this is an important pilot study, in that it demonstrates the effectiveness of oral β1,3-glucan in treating both infectious agents and tumors. ABSTRACT β1,3-glucans from various bacterial, mushroom, yeast, and cereal sources have been established as immunomodulators. In the present paper we demonstrate that orallyadministered yeast β1,3-glucan (WGP Beta Glucan) had significant effects as a prophylactic treatment to reduce the mortality of anthrax infection in mice. In addition, the same type of treatment also inhibited the growth of cancer cells in vivo. The mechanism of action involves the stimulation of three important cytokines: IL-2, IFN-γ, and TNF-α. These results provide preclinical evidence for the beneficial effects of orally-administered yeast β1,3-glucan