The role of surgical tissue injury and intraoperative sympathetic activation in postoperative immunosuppression after breast-conserving surgery versus mastectomy: a prospective observational study.

BACKGROUND: Breast cancer is the second most common cause of death from cancer in women worldwide. Counterintuitively, large population-based retrospective trials report better survival after breast-conserving surgery (BCS) compared to mastectomy, corrected for tumour- and patient variables. More extensive surgical tissue injury and activation of the sympathetic nervous system by nociceptive stimuli are associated with immune suppression. We hypothesized that mastectomy causes a higher expression of plasma damage associated molecular patterns (DAMPs) and more intraoperative sympathetic activation which induce postoperative immune dysregulation. Immune suppression can lead to postoperative complications and affect tumour-free survival. METHODS: In this prospective observational study, plasma DAMPs (HMGB1, HSP70, S100A8/A9 and S100A12), intraoperative sympathetic activation (Nociception Level (NOL) index from 0 to 100), and postoperative immune function (plasma cytokine concentrations and ex vivo cytokine production capacity) were compared in patients undergoing elective BCS (n = 20) versus mastectomy (n = 20). RESULTS: Ex vivo cytokine production capacity of TNF, IL-6 and IL-1ß was nearly absent in both groups one hour after surgery. Levels appeared recovered on postoperative day 3 (POD3), with significantly higher ex vivo production capacity of IL-1ß after BCS (p = .041) compared to mastectomy. Plasma concentration of IL-6 was higher one hour after mastectomy (p = .045). Concentrations of plasma alarmins S100A8/A9 and S100A12 were significantly higher on POD3 after mastectomy (p = .003 and p = .041, respectively). Regression analysis showed a significantly lower percentage of NOL measurements ≤ 8 (absence of nociception) during mastectomy when corrected for norepinephrine equivalents (36% versus 45% respectively, p = .038). Percentage of NOL measurements ≤ 8 of all patients correlated with ex vivo cytokine production capacity of IL-1ß and TNF on POD3 (r = .408; p = .011 and r = .500; p = .001, respectively). CONCLUSIONS: This pilot study revealed substantial early postoperative immune suppression after BCS and mastectomy that appears to recover in the following days. Differences between BCS and mastectomy in release of DAMPs and intraoperative sympathetic activation could affect postoperative immune homeostasis and thereby contribute to the better survival reported after BCS in previous large population-based retrospective trials. These results endorse further exploration of (1) S100 alarmins as potential therapeutic targets in breast cancer surgery and (2) suppression of intraoperative sympathetic activation to substantiate the observed association with postoperative immune dysregulation.

Recovery and immune function after low pressure pneumoperitoneum during robot-assisted radical prostatectomy: a randomised controlled trial.

OBJECTIVE: To compare the effectiveness of low intra-abdominal pressure (IAP) facilitated by deep neuromuscular block (NMB) to standard practice in improving the quality of recovery, preserving immune function, and enhancing parietal perfusion during robot-assisted radical prostatectomy (RARP). PATIENTS AND METHODS: In this blinded, randomised controlled trial, 96 patients were randomised to the experimental group with low IAP (8 mmHg) facilitated by deep NMB (post-tetanic count 1-2) or the control group with standard IAP (14 mmHg) and moderate NMB (train-of-four 1-2). Recovery was measured using the 40-item Quality of Recovery questionnaire and 36-item Short-Form Health survey. Immune function was evaluated by plasma damage-associated molecular patterns, cytokines, and ex vivo lipopolysaccharide-stimulated cytokine production. Parietal peritoneum perfusion was measured by analysing the recordings of indocyanine-green injection. RESULTS: Quality of recovery was not superior in the experimental group (n = 46) compared to the control group (n = 50). All clinical outcomes, including pain scores, postoperative nausea and vomiting, and hospital stay were similar. There were no significant differences in postoperative plasma concentrations of damage-associated molecular patterns, cytokines, and ex vivo cytokine production capacity. The use of low IAP resulted in better parietal peritoneum perfusion. CONCLUSION: Despite better perfusion of the parietal peritoneum, low IAP facilitated by deep NMB did not improve the quality of recovery or preserve immune function compared to standard practice in patients undergoing RARP.

Deep neuromuscular blockade in adults undergoing an abdominal laparoscopic procedure.

BACKGROUND: Laparoscopic surgery is the preferred option for many procedures. To properly perform laparoscopic surgery, it is essential that sudden movements and abdominal contractions in patients are prevented, as it limits the surgeon's view. There has been a growing interest in the potential beneficial effect of deep neuromuscular blockade (NMB) in laparoscopic surgery. Deep NMB improves the surgical field by preventing abdominal contractions, and it is thought to decrease postoperative pain. However, it is uncertain if deep NMB improves intraoperative safety and thereby improves clinical outcomes. OBJECTIVES: To evaluate the benefits and harms of deep neuromuscular blockade versus no, shallow, or moderate neuromuscular blockade during laparoscopic intra- or transperitoneal procedures in adults. SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search date was 31 July 2023. SELECTION CRITERIA: We included randomised clinical trials (irrespective of language, blinding, or publication status) in adults undergoing laparoscopic intra- or transperitoneal procedures comparing deep NMB to moderate, shallow, or no NMB. We excluded trials that did not report any of the primary or secondary outcomes of our review. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcomes were 1. all-cause mortality, 2. health-related quality of life, and 3. proportion of participants with serious adverse events. Our secondary outcomes were 4. proportion of participants with non-serious adverse events, 5. readmissions within three months, 6. short-term pain scores, 7. measurements of postoperative recovery, and 8. operating time. We used GRADE to assess the certainty of evidence for each outcome. MAIN RESULTS: We included 42 randomised clinical trials with 3898 participants. Most trials included participants undergoing intraperitoneal oncological resection surgery. We present the Peto fixed-effect model for most dichotomous outcomes as only sparse events were reported. Comparison 1: deep versus moderate NMB Thirty-eight trials compared deep versus moderate NMB. Deep NMB may have no effect on mortality, but the evidence is very uncertain (Peto odds ratio (OR) 7.22, 95% confidence interval (CI) 0.45 to 115.43; 12 trials, 1390 participants; very low-certainty evidence). Deep NMB likely results in little to no difference in health-related quality of life up to four days postoperative (mean difference (MD) 4.53 favouring deep NMB on the Quality of Recovery-40 score, 95% CI 0.96 to 8.09; 5 trials, 440 participants; moderate-certainty evidence; mean difference lower than the mean clinically important difference of 10 points). The evidence is very uncertain about the effect of deep NMB on intraoperatively serious adverse events (deep NMB 38/1150 versus moderate NMB 38/1076; Peto OR 0.95, 95% CI 0.59 to 1.52; 21 trials, 2231 participants; very low-certainty evidence), short-term serious adverse events (up to 60 days) (deep NMB 37/912 versus moderate NMB 42/852; Peto OR 0.90, 95% CI 0.56 to 1.42; 16 trials, 1764 participants; very low-certainty evidence), and short-term non-serious adverse events (Peto OR 0.94, 95% CI 0.65 to 1.35; 11 trials, 1232 participants; very low-certainty evidence). Deep NMB likely does not alter the duration of surgery (MD -0.51 minutes, 95% CI -3.35 to 2.32; 34 trials, 3143 participants; moderate-certainty evidence). The evidence is uncertain if deep NMB alters the length of hospital stay (MD -0.22 days, 95% CI -0.49 to 0.06; 19 trials, 2084 participants; low-certainty evidence) or pain scores one hour after surgery (MD -0.31 points on the numeric rating scale, 95% CI -0.59 to -0.03; 22 trials, 1823 participants; very low-certainty evidence; mean clinically important difference 1 point) and 24 hours after surgery (MD -0.60 points on the numeric rating scale, 95% CI -1.05 to -0.15; 16 trials, 1404 participants; very low-certainty evidence; mean clinically important difference 1 point). Comparison 2: deep versus shallow NMB Three trials compared deep versus shallow NMB. The trials did not report on mortality and health-related quality of life. The evidence is very uncertain about the effect of deep NMB compared to shallow NMB on the proportion of serious adverse events (RR 1.66, 95% CI 0.50 to 5.57; 2 trials, 158 participants; very low-certainty evidence). Comparison 3: deep versus no NMB One trial compared deep versus no NMB. There was no mortality in this trial, and health-related quality of life was not reported. The proportion of serious adverse events was 0/25 in the deep NMB group and 1/25 in the no NMB group. AUTHORS' CONCLUSIONS: There was insufficient evidence to draw conclusions about the effects of deep NMB compared to moderate NMB on all-cause mortality and serious adverse events. Deep NMB likely results in little to no difference in health-related quality of life and duration of surgery compared to moderate NMB, and it may have no effect on the length of hospital stay. Due to the very low-certainty evidence, we do not know what the effect is of deep NMB on non-serious adverse events, pain scores, or readmission rates. Randomised clinical trials with adequate reporting of all adverse events would reduce the current uncertainties. Due to the low number of identified trials and the very low certainty of evidence, we do not know what the effect of deep NMB on serious adverse events is compared to shallow NMB and no NMB. We found no trials evaluating mortality and health-related quality of life.

Sex-based treatment and outcomes for coronary bifurcation stenting: A report from the e-ULTIMASTER registry.

BACKGROUND: Percutaneous coronary intervention (PCI) for bifurcation lesions can be technically challenging and is associated with higher risk. There is little data on sex-based differences in strategy and outcomes in bifurcation PCI. AIMS: We sought to assess whether differences exist between women and men in the treatment and outcomes of bifurcation PCI. METHODS: We collected data on 4006 patients undergoing bifurcation PCI, from the e-ULTIMASTER study, a prospective, multicentre study enrolling patients from 2014 to 2018. We divided the bifurcation cohort according to sex, with 1-year follow-up of outcomes (target lesion failure [TLF], target vessel failure [TVF], and patient-oriented composite endpoint [POCE]). FINDINGS: Women were older (69.2 ± 10.9 years vs. 64.4 ± 11.0 years), with a greater burden of cardiovascular comorbidities. For true and non-true bifurcation lesions, women and men were equally likely to undergo a single stent approach (true: 63.2% vs. 63.6%, p = 0.79, non-true: 95.4% vs. 94.3%, p = 0.32), with similar rates of final kissing balloon (FKB) (37.2% vs. 35.5%, p = 0.36) and proximal optimization (POT) (34.4% vs. 34.2%, p = 0.93) in cases where two stents were used. Lastly, after propensity score matching, there was no difference between women and men in the incidence of the composite endpoints of TLF (5.5% vs. 5.2%, RR 1.05 [95% CI 0.77-1.44], p = 0.75), TVF (6.2% vs. 6.3%, RR 0.99 [95% CI 0.74-1.32], p = 0.96), and POCE (9.9% vs. 9.5%, RR 1.05 [95% CI 0.83-1.31], p = 0.70). CONCLUSION: In this contemporary, real-world study of bifurcation PCI, we report no difference in stent strategy between women and men, with similar outcomes at 1-year.

Pelvic insufficiency fractures and pelvic bone metastases after neoadjuvant (chemo)radiotherapy for rectal cancer.

BACKGROUND: Pelvic insufficiency fractures (PIFs) are a late complication of radiotherapy for pelvic malignancies. We evaluated the incidence, radiologic findings, clinical course, and outcome of PIFs in patients treated with neoadjuvant (chemo)radiotherapy ((C)RT) for rectal cancer. MATERIAL AND METHODS: Data of patients diagnosed with rectal cancer from a large teaching hospital treated from 2002 to 2012 were extracted from the Dutch Cancer Registry. All hospital records were reviewed for the diagnosis of PIFs or pelvic bone metastases. An expert radiologist reassessed all imaging procedures of the lower back, abdomen, and pelvis. RESULTS: A total of 513 rectal cancer patients were identified of whom 300 patients (58.5%) were treated with neoadjuvant (C)RT (long- vs. short-course radiotherapy: 91 patients [17.7%] vs. 209 [40.7%], respectively). Twelve PIFs were diagnosed initially according to hospital records and imaging reports of all 513 patients. These 12 patients were treated with neoadjuvant (C)RT. After reassessment of all pelvic imaging procedures done in this patient group (432 patients (84.2%)), 20 additional PIFs were detected in patients treated with neoadjuvant (C)RT, resulting in a 10.7% PIF rate in irradiated patients. One PIF was detected in the group of patients not treated with neoadjuvant (C)RT for rectal cancer. This patient had palliative radiotherapy for prostate cancer and is left out of the analysis. Median follow-up time of 32 PIF patients was 49 months. Median time between start of neoadjuvant (C)RT and diagnosis of PIF was 17 months (IQR 9-28). Overall median survival for patients with PIF was 63.5 months (IQR 44-120). CONCLUSION: PIFs are a relatively common late complication of neoadjuvant (C)RT for rectal cancer but are often missed or misdiagnosed as pelvic bone metastases. The differentiation of PIFs from pelvic bone metastases is important because of a different treatment and disease outcome.

Urinary peptide biomarker panel associated with an improvement in estimated glomerular filtration rate in chronic kidney disease patients.

Background: An improvement in the glomerular filtration rate (GFR) of chronic kidney disease patients has been an underestimated clinical outcome. Although this may be considered as an unexpected disease course, it may provide some insights into possible mechanisms underlying disease remission and/or regression. Therefore, our aim was to identify urinary peptide biomarkers associated with an improvement in estimated GFR (eGFR) over time and to improve patient stratification. Methods: Capillary electrophoresis coupled with mass spectrometry (CE-MS) was employed to evaluate the urine peptidome of patients with different types of renal diseases. In total, 376 patients with a slope/year between -1.5% and +1.5% were designated as non-progressors or stable, while 177 patients with a > 5% slope/year were designated as patients with an improved eGFR for state-of-art biomarker discovery and validation. Results: We detected 384 significant peptide fragments by comparing the CE-MS data of the stable patients and those with improved renal function in our development cohort. Of these 384, a set of 141 peptides with available amino acid sequence information were used to generate a support vector machine-based classification panel. The biomarker panel was applied to our validation cohort, achieving a moderate area under the curve (AUC) value of 0.85 (81% sensitivity and 81% specificity). The majority of the peptides (78%) from the diagnostic panel arose from different types of collagen. Conclusions: We have developed a panel of urinary peptide markers able to discriminate those patients predisposed to improve their kidney function over time and possibly be treated with more specific or less aggressive therapy.

The risk of nephrolithiasis is causally related to inactive matrix Gla protein, a marker of vitamin K status: a Mendelian randomization study in a Flemish population.

Background: Vitamin K (VK)-dependent γ-glutamate carboxylation and serine phosphorylation activate matrix Gla protein (MGP) to a potent locally acting inhibitor of calcification. Nephrolithiasis represents a process of unwanted calcification associated with substantial mortality and high recurrence rates. We hypothesized that the risk of nephrolithiasis increases with VK shortage, as exemplified by higher plasma levels of desphospho-uncarboxylated MGP (dp-ucMGP). Methods: In 1748 randomly recruited Flemish individuals (51.1% women; mean age 46.8 years), we determined dp-ucMGP and the prevalence of nephrolithiasis at baseline (April 1996-February 2015) and its incidence during follow-up until March 2016. We estimated the multivariable-adjusted relative risk associated with the doubling of dp-ucMGP, using logistic or Cox regression. We did a Mendelian randomization analysis using four MGP genotypes as instrumental variables. Results: With adjustments applied for sex, age and 24-h urinary volume and calcium excretion, the odds of having prevalent nephrolithiasis [n = 144 (8.2%)] associated with dp-ucMGP was 1.31 [95% confidence interval (CI) 1.04-1.64; P = 0.022]. dp-ucMGP levels were associated (P ≤ 0.001) with MGP variants rs2098435, rs4236 and rs2430692. In the Mendelian analysis, the causal odds ratio was 3.82 (95% CI 1.15-12.7; P = 0.029). The incidence of nephrolithiasis over 12.0 years (median) was 37 cases (0.2%). With similar adjustments as before, the hazard ratio in relation to dp-ucMGP was 2.48 (95% CI 1.71-3.61; P < 0.001). Additional adjustment for a nephrolithiasis propensity score produced consistent results. Conclusion: Higher levels of inactive dp-ucMGP may be causally associated with the risk of nephrolithiasis. Whether or not VK deficiency plays a role in these observations remains to be firmly established.

Renal function in relation to sodium intake: a quantitative review of the literature.

We undertook a quantitative literature review to search for evidence underpinning current guidelines proposing a reduction of sodium intake to less than 2.4 g/d for the management of chronic kidney disease. We searched PubMed for peer-reviewed articles published from January 1980 through May 2016. Two investigators screened 5072 publications and extracted data from 36, including 11 cross-sectional and 5 longitudinal observational studies and 20 intervention trials. Within-study effect sizes were pooled and standardized to a sodium gradient of 100 mmol/d by using inverse-variance weighted random effects models. Among cross-sectional studies, the pooled odds ratio for albuminuria was 1.23 (95% confidence interval [CI], 0.92-1.64, P = 0.16), and the pooled mean difference in glomerular filtration rate amounted to 8.5 ml/min (CI, -2.3 to 19.2 ml/min; P = 0.12). In the cohort studies, the pooled relative risk of a renal endpoint was 1.08 (CI, 0.92-1.29; P = 0.35). In the intervention trials (median duration, 14 days [range, 4-186 days]), the mean differences in estimated glomerular filtration rate and albuminuria (high vs. low sodium intake) averaged 4.6 ml/min (CI, 3.4-5.8 ml/min; P < 0.0001) and 53% (CI, 21-84; P = 0.001), respectively. Cochran's Q statistic indicated significant heterogeneity among cross-sectional studies for both estimated glomerular filtration rate and albuminuria (P < 0.0001) and among intervention trials for albuminuria (P = 0.04). In conclusion, there is no robust evidence suggesting that long-term reduction of salt intake would prevent chronic kidney disease or delay its progression. However, our current findings, which were mainly obtained in people with slight renal impairment, cannot be extrapolated to patients with moderate or severe chronic kidney disease.

PEAR1 is not a major susceptibility gene for cardiovascular disease in a Flemish population.

BACKGROUND: Platelet Endothelial Aggregation Receptor 1 (PEAR1), a membrane protein highly expressed in platelets and endothelial cells, plays a role in platelet contact-induced activation, sustained platelet aggregation and endothelial function. Previous reports implicate PEAR1 rs12041331 as a variant influencing risk in patients with coronary heart disease. We investigated whether genetic variation in PEAR1 predicts cardiovascular outcome in a white population. METHODS: In 1938 participants enrolled in the Flemish Study on Environment, Genes and Health Outcomes (51.3% women; mean age 43.6 years), we genotyped 9 tagging SNPs in PEAR1, measured baseline cardiovascular risk factors, and recorded Cardiovascular disease incidence. For SNPs, we contrasted cardiovascular disease incidence of minor-allele heterozygotes and homozygotes (variant) vs. major-allele homozygotes (reference) and for haplotypes carriers vs. non-carriers. In adjusted analyses, we accounted for family clusters and baseline covariables, including sex, age, body mass index, mean arterial pressure, the total-to-HDL cholesterol ratio, smoking and drinking, antihypertensive drug treatment, and history of cardiovascular disease and diabetes mellitus. RESULTS: Over a median follow-up of 15.3 years, 238 died and 181 experienced a major cardiovascular endpoint. The multivariable-adjusted hazard ratios of eight PEAR1 SNPs, including rs12566888, ranged from 0.87 to 1.07 (P ≥0.35) and from 0.78 to 1.30 (P ≥0.15), respectively. The hazard ratios of three haplotypes with frequency ≥10% ranged from 0.93 to 1.11 (P ≥0.49) for mortality and from 0.84 to 1.03 (P ≥0.29) for a cardiovascular complications. These results were not influenced by intake of antiplatelet drugs, nonsteroidal anti-inflammatory drugs, or both (P-values for interaction ≥ 0.056). CONCLUSIONS: In a White population, we could not replicate previous reports from experimental studies or obtained in patients suggesting that PEAR1 might be a susceptibility gene for cardiovascular complications.

A urinary proteome-based classifier for the early detection of decline in glomerular filtration.

BACKGROUND: Chronic kidney disease (CKD) progression is currently assessed by a decline in estimated glomerular filtration rate (eGFR) and/or an increase in urinary albumin excretion (UAE). However, these markers are considered either to be late-stage markers or to have low sensitivity or specificity. In this study, we investigated the performance of the urinary proteome-based classifier CKD273, compared with UAE, in a number of different narrow ranges of CKD severity, with each range separated by an eGFR of 10 mL/min/1.73 m 2 . METHODS: A total of 2672 patients with different CKD stages were included in the study. Of these, 394 individuals displayed a decline in eGFR of >5 mL/min/1.73 m 2 /year (progressors) and the remaining individuals were considered non-progressors. For all samples, UAE values and CKD273 classification scores were obtained. To assess UAE values and CKD273 scores at different disease stages, the cohort was divided according to baseline eGFRs of ≥80, 70-79, 60-69, 50-59, 40-49, 30-39 and <29 mL/min/1.73 m 2 . In addition, areas under the curve for CKD273 and UAE were calculated. RESULTS: In early stage CKD, the urinary proteome-based classifier performed significantly better than UAE in detecting progressors. In contrast, UAE performed better in patients with late-stage CKD. No significant difference in performance was found between CKD273 and UAE in patients with moderately reduced renal function. CONCLUSIONS: These results suggest that urinary peptides, as combined in the CKD273 classifier, allow the detection of progressive CKD at early stages, a point where therapeutic intervention is more likely to be effective. However, late-stage disease, where irreversible damage of the kidney is already present, is better detected by UAE.

Renal artery and parenchymal changes after renal denervation: assessment by magnetic resonance angiography.

OBJECTIVES: Relatively little is known about the incidence of long-term renal damage after renal denervation (RDN), a potential new treatment for hypertension. In this study the incidence of renal artery and parenchymal changes, assessed with contrast-enhanced magnetic resonance angiography (MRA) after RDN, is investigated. METHODS: This study is an initiative of ENCOReD, a collaboration of hypertension expert centres. Patients in whom an MRA was performed before and after RDN were included. Scans were evaluated by two independent, blinded radiologists. Primary outcome was the change in renal artery morphology and parenchyma. RESULTS: MRAs from 96 patients were analysed. Before RDN, 41 renal anomalies were observed, of which 29 mostly mild renal artery stenoses. After a median time of 366 days post RDN, MRA showed a new stenosis (25-49% lumen reduction) in two patients and progression of pre-existing lumen reduction in a single patient. No other renal changes were observed and renal function remained stable. CONCLUSIONS: We observed new or progressed renal artery stenosis in three out of 96 patients, after a median time of 12 months post RDN (3.1%). Procedural angiographies showed that ablations were applied near the observed stenosis in only one of the three patients. KEY POINTS: • The incidence of vascular changes 12 months post RDN was 3.1%. • No renal vascular or parenchymal changes other than stenoses were observed. • Ablations were applied near the stenosis in only one of three patients.

Sham or no sham control: that is the question in trials of renal denervation for resistant hypertension. A systematic meta-analysis.

BACKGROUND: Studies of renal denervation (RDN) in patients with apparent treatment resistant hypertension have been hampered by a number of patient and physician related confounders on blood pressure (BP) including poor drug adherence. It remains uncertain whether RDN lowers BP. We aimed to investigate whether the use of sham control is essential in RDN studies or whether systematic use of 24-hour ambulatory BP provides enough information thereby making an invasive sham control redundant. METHODS: We meta-analyzed randomized controlled trials of the BP response to RDN on top of continued or optimized antihypertensive drugs in patients with resistant hypertension. On top of the randomized trials reviewed earlier, we additionally included three studies, one conducted in Spain (24 patients, RDN vs. spironolactone), one conducted in Denmark (69 patients, sham controlled) and one conducted in Netherlands (139 patients, RDN vs. continued treatment). We analyzed 24-hour ambulatory BP in 3 sham controlled studies vs. 7 no sham controlled studies. RESULTS: The updated meta-analysis of 10 studies showed 3.6 mmHg (p = .45) and 1.0 mmHg (p = .54) reductions in office and in 24-hour systolic BP, respectively. Meta-analysis of 24-hour systolic BP in the 3 sham-controlled studies showed a reduction of 2.18 mmHg (95% confidence intervals (CIs) -4.70 to 0.33 mmHg, n = 396 vs. 230, p = .07). For the 7 no sham controlled studies there was no difference in 24-hour systolic BP (+0.38 mmHg; 95% CIs -5.29 to 6.04 mmHg, n = 215 vs. 245, p = .90). The test for sub-group heterogeneity showed no significant interaction (p = .69). Removing one trial at a time produced confirmatory results. CONCLUSION: The overall meta-analysis of 10 randomized and controlled studies showed no significant effect on BP of RDN in resistant hypertension. Moreover, our analysis does not support the use of sham control but rather suggests extensive use of 24-hour ambulatory BP in studies of RDN in resistant hypertension.

Results of a randomized controlled pilot trial of intravascular renal denervation for management of treatment-resistant hypertension.

OBJECTIVE: Previous trials of catheter-based renal-artery denervation (RDN) as treatment modality in resistant hypertension (rHT) generated unconvincing results. In the Investigator-Steered Project on Intravascular Denervation for Management of Treatment-Resistant Hypertension (INSPiRED; NCT01505010), we optimized selection and management of rHT patients. METHODS: With ethical clearance to randomize 18 patients, three Belgian hypertension centers screened 29 rHT patients on treatment with ≥3 drugs, of whom 17 after optimization of treatment (age <70 years; systolic/diastolic office blood pressure (BP) ≥ 140/90 mm Hg; 24-h BP ≥130/80 mm Hg; glomerular filtration rate [eGFR] ≥ 45 mL/min/1.73 m2; body mass index <40kg/m2) were randomized and 15 were analyzed 6 months later, while medical treatment was continued (n = 9) or combined with RDN by the EnligHTN™ multi-electrode system (n = 6). RESULTS: The baseline-adjusted between-group differences amounted to 19.5/10.4 mm Hg (change in control vs. intervention group, +7.6/+2.2 vs. -11.9/-8.2 mm Hg; P = .088) for office BP, 22.4/13.1 mm Hg (+0.7/+0.3 vs. -21.7/-12.8; mm Hg; P ≤ .049) for 24-h BP, the primary efficacy endpoint, and 2.5 mL/min/1.73 m2 (+1.5 vs. -1.1 mL/min/1.73 m2; P = .86) for eGFR, the primary safety endpoint. At 6 month, ECG voltages and the number of prescribed drugs (P ≤ .036) were lower in RDN patients, but quality of life and adherence, captured by questionnaire and urine analysis were similar in both groups. Changes in BP and adherence were unrelated. No major complications occurred. CONCLUSIONS: The INSPiRED pilot suggests that RDN with the EnligHTN™ system is effective and safe and generated insights useful for the design of future RDN trials.

Diffusion-weighted MRI for Early Prediction of Treatment Response on Preoperative Chemoradiotherapy for Patients With Locally Advanced Rectal Cancer: A Feasibility Study.

OBJECTIVE: This study investigates the predictive value of diffusion-weighted magnetic resonance imaging (DW-MRI) for good pathological response at different time points during and after preoperative chemoradiotherapy (CRT) in locally advanced rectal cancer. BACKGROUND: Preoperative CRT followed by total mesorectal excision (TME) is the standard of care for locally advanced rectal cancer. The use of standard radical surgery in good treatment responders after CRT is being questioned. METHODS: Patients with locally advanced rectal adenocarcinoma were treated with preoperative CRT followed by surgery. DW-MRI scans were performed before CRT, during the third week of CRT, 4 weeks post-CRT and presurgery. Tumor apparent diffusion coefficient (ADC) values were acquired from the DW-MRI scans. After surgery the pathological tumor regression grade was assessed according to the classification by Mandard et al [Cancer. 1994;73:2680-2686]. Patients with pathological complete or near-complete response (tumor regression grade 1-2) were classified as good responders (GRs). RESULTS: Twenty-two patients participated of which 9 were GRs (41%). Pre-CRT ADC values were lower in good versus moderate/poor responders (P = 0.04). ADC values during CRT and four weeks post-CRT were higher in GR. ADC values presurgery did not differ between response groups. For all time points the relative ADC increase (ΔADC) compared to the ADC pre-CRT was higher in GR (P < 0.001). The ΔADC during CRT and four weeks post-CRT were the best predictive parameters for pathological good response. CONCLUSIONS: This study shows that DW-MRI is feasible to select good treatment responders during preoperative CRT for locally advanced rectal cancer.

Renal function estimation and Cockroft-Gault formulas for predicting cardiovascular mortality in population-based, cardiovascular risk, heart failure and post-myocardial infarction cohorts: The Heart 'OMics' in AGEing (HOMAGE) and the high-risk myocardial infarction database initiatives.

BACKGROUND: Renal impairment is a major risk factor for mortality in various populations. Three formulas are frequently used to assess both glomerular filtration rate (eGFR) or creatinine clearance (CrCl) and mortality prediction: body surface area adjusted-Cockcroft-Gault (CG-BSA), Modification of Diet in Renal Disease Study (MDRD4), and the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation. The CKD-EPI is the most accurate eGFR estimator as compared to a "gold-standard"; however, which of the latter is the best formula to assess prognosis remains to be clarified. This study aimed to compare the prognostic value of these formulas in predicting the risk of cardiovascular mortality (CVM) in population-based, cardiovascular risk, heart failure (HF) and post-myocardial infarction (MI) cohorts. METHODS: Two previously published cohorts of pooled patient data derived from the partners involved in the HOMAGE-consortium and from four clinical trials - CAPRICORN, EPHESUS, OPTIMAAL and VALIANT - the high risk MI initiative, were used. A total of 54,111 patients were included in the present analysis: 2644 from population-based cohorts; 20,895 from cardiovascular risk cohorts; 1801 from heart failure cohorts; and 28,771 from post-myocardial infarction cohorts. Participants were patients enrolled in the respective cohorts and trials. The primary outcome was CVM. RESULTS: All formulas were strongly and independently associated with CVM. Lower eGFR/CrCl was associated with increasing CVM rates for values below 60 mL/min/m2. Categorical renal function stages diverged in a more pronounced manner with the CG-BSA formula in all populations (higher χ2 values), with lower stages showing stronger associations. The discriminative improvement driven by the CG-BSA formula was superior to that of MDRD4 and CKD-EPI, but remained low overall (increase in C-index ranging from 0.5 to 2 %) while not statistically significant in population-based cohorts. The integrated discrimination improvement and net reclassification improvement were higher (P < 0.05) for the CG-BSA formula compared to MDRD4 and CKD-EPI in CV risk, HF and post-MI cohorts, but not in population-based cohorts. The CKD-EPI formula was superior overall to MDRD4. CONCLUSIONS: The CG-BSA formula was slightly more accurate in predicting CVM in CV risk, HF, and post-MI cohorts (but not in population-based cohorts). However, the CG-BSA discriminative improvement was globally low compared to MDRD4 and especially CKD-EPI, the latter offering the best compromise between renal function estimation and CVM prediction.

Incidence of nephrolithiasis in relation to environmental exposure to lead and cadmium in a population study.

Whether environmental exposure to nephrotoxic agents that potentially interfere with calcium homeostasis, such as lead and cadmium, contribute to the incidence of nephrolithiasis needs further clarification. We investigated the relation between nephrolithiasis incidence and environmental lead and cadmium exposure in a general population. In 1302 participants randomly recruited from a Flemish population (50.9% women; mean age, 47.9 years), we obtained baseline measurements (1985-2005) of blood lead (BPb), blood cadmium (BCd), 24-h urinary cadmium (UCd) and covariables. We monitored the incidence of kidney stones until October 6, 2014. We used Cox regression to calculate multivariable-adjusted hazard ratios for nephrolithiasis. At baseline, geometric mean BPb, BCd and UCd was 0.29µmol/L, 9.0nmol/L, and 8.5nmol per 24h, respectively. Over 11.5 years (median), nephrolithiasis occurred in 40 people. Contrasting the low and top tertiles of the distributions, the sex- and age-standardized rates of nephrolithiasis expressed as events per 1000 person-years were 0.68 vs. 3.36 (p=0.0016) for BPb, 1.80 vs. 3.28 (p=0.11) for BCd, and 1.65 vs. 2.95 (p=0.28) for UCd. In continuous analysis, with adjustments applied for sex, age, serum magnesium, and 24-h urinary volume and calcium, the hazard ratios expressing the risk associated with a doubling of the exposure biomarkers were 1.35 (p=0.015) for BPb, 1.13 (p=0.22) for BCd, and 1.23 (p=0.070) for UCd. In conclusion, our results suggest that environmental lead exposure is a risk factor for nephrolithiasis in the general population.

Long-Term Exposure to Particulate Matter Air Pollution Is a Risk Factor for Stroke: Meta-Analytical Evidence.

BACKGROUND AND PURPOSE: Epidemiological studies suggest an association between stroke incidence and stroke mortality and long-term exposure to particulate matter (PM) air pollution. However, the magnitude of the association is still unclear. METHODS: We searched the Pubmed citation database for epidemiological studies and reviews on stroke and PM exposure. Then, we carried out a meta-analysis to quantify the pooled association between stroke incidence and mortality and long-term exposure to PM. Meta-analyses were performed for stroke events and stroke mortality and for PM10 and PM2.5 separately and jointly. RESULTS: We identified 20 studies, including a total of >10 million people, on long-term PM exposure and stroke event or stroke mortality. For exposure to PM10 (including estimated exposure to PM10 from studies using PM2.5), the pooled hazard ratio for each 10-µg/m3 increment in PM10 was 1.061 (95% confidence interval, 1.018-1.105) and 1.080 (0.992-1.177) for overall stroke events and stroke mortality, respectively. A stratified analysis by continent revealed that the association between stroke and long-term PM10 exposure was positive in North America (1.062 [1.015-1.110]) and Europe (1.057 [0.973-1.148]), but studies in Asia (1.010 [0.885-1.153]) showed a high degree of heterogeneity. Considering exposure to PM2.5 (Europe and North America combined), the hazard ratios for a 5-µg/m3 increment were 1.064 (1.021-1.109) and 1.125 (1.007-1.256) for stroke events and mortality, respectively. CONCLUSIONS: The scientific evidence of the past decade identifies long-term exposure to PM, and PM2.5 in particular, as a risk factor for stroke. However, we found some currently unexplained geographical variability in this association.

Coronary risk in relation to genetic variation in MEOX2 and TCF15 in a Flemish population.

BACKGROUND: In mice MEOX2/TCF15 heterodimers are highly expressed in heart endothelial cells and are involved in the transcriptional regulation of lipid transport. In a general population, we investigated whether genetic variation in these genes predicted coronary heart disease (CHD). RESULTS: In 2027 participants randomly recruited from a Flemish population (51.0 % women; mean age 43.6 years), we genotyped six SNPs in MEOX2 and four in TCF15. Over 15.2 years (median), CHD, myocardial infarction, coronary revascularisation and ischaemic cardiomyopathy occurred in 106, 53, 78 and 22 participants. For SNPs, we contrasted CHD risk in minor-allele heterozygotes and homozygotes (variant) vs. major-allele homozygotes (reference) and for haplotypes carriers (variant) vs. non-carriers. In multivariable-adjusted analyses with correction for multiple testing, CHD risk was associated with MEOX2 SNPs (P ≤ 0.049), but not with TCF15 SNPs (P ≥ 0.29). The MEOX2 GTCCGC haplotype (frequency 16.5 %) was associated with the sex- and age-standardised CHD incidence (5.26 vs. 3.03 events per 1000 person-years; P = 0.036); the multivariable-adjusted hazard ratio [HR] of CHD was 1.78 (95 % confidence interval, 1.25-2.56; P = 0.0054). For myocardial infarction, coronary revascularisation, and ischaemic cardiomyopathy, the corresponding HRs were 1.96 (1.16-3.31), 1.87 (1.20-2.91) and 3.16 (1.41-7.09), respectively. The MEOX2 GTCCGC haplotype significantly improved the prediction of CHD over and beyond traditional risk factors and was associated with similar population-attributable risk as smoking (18.7 % vs. 16.2 %). CONCLUSIONS: Genetic variation in MEOX2, but not TCF15, is a strong predictor of CHD. Further experimental studies should elucidate the underlying molecular mechanisms.

Design and feasibility of "PREMATurity as predictor of children's Cardiovascular-renal Health" (PREMATCH): A pilot study.

The microvasculature and macrovasculature undergo extensive, organ-specific perinatal maturation. Multiple studies show associations between low birth weight and subsequent cardiovascular dysfunction in adulthood, suggesting that extreme preterm birth interferes with this maturation process. Therefore, we designed PREMATCH (PREMATurity as predictor of Cardiovascular-renal Health) to phenotype the microcirculation and macrocirculation during childhood in former preterm infants. A well-characterized cohort of former extreme preterm birth survivors and gender- and age-matched controls (aged 8-13 years) will be investigated for microvascular and macrovascular structure and function. In addition to cognitive performance and anthropometrics, we will investigate (i) the microvascular structure and function by endothelial function (photoplethysmography), sublingual capillary glycocalyx function (sidestream dark field imaging) and retinal structure (diameters of arterioles and venules); and (ii) the macrovascular phenotype by cardiac and renal ultrasound, repeated blood pressure measurements and arterial pulse-wave recordings. The PREMATCH study is unique in its design, and ongoing recruitment demonstrates excellent feasibility. The expectation is that the results of this study will identify risk factors during childhood for subsequent cardiovascular-renal disease in the adult life of former preterm infants, while further analysis on mediators in neonatal life of this cardiovascular-renal outcome may provide new information on perinatal risk factors.

Study for Promotion of Health in Recycling Lead - Rationale and design.

BACKGROUND: The level at which low-level lead exposure produces subclinical adverse health effects in adults remains to be established. METHODS: The Study for Promotion of Health in Recycling Lead (SPHERL) will enroll 500 newly hired workers, whose blood lead during 2 years of follow-up is expected to increase from levels less than 2 µg/dl, as currently observed in the US population, to 20-30 µg/dl. The main outcome variables to be studied are (i) blood pressure (BP) analyzed as a continuous or categorical variable, both cross-sectionally and longitudinally, and using conventional and ambulatory BP measurement; (ii) indexes of glomerular and tubular renal function, (iii) heart rate variability analyzed in the frequency domain as measure of autonomous sympathetic modulation, (iv) peripheral nerve conductivity velocity, (v) neurocognitive performance, and (vi) quality of life. Expected outcomes. Assuming a 10-fold increase in blood lead, SPHERL will have sufficient statistical power to detect over 2 years a steepening of the age-related rise in systolic BP from 1 to 5 mmHg and a doubling of the age-related decline in the estimated glomerular filtration rate from 3.5 to 7.0 ml/min/1.73 m(2). The longitudinal design of our study complies with the temporality principle of the Bradford-Hill criteria for assessing possible causality between outcomes and exposure. SPHERL will attempt to resolve the apparent contradiction between general population studies showing associations between adverse health effects and low lead exposure with blood lead levels below 5 µg/dl and studies conducted in occupational cohorts indicating that adverse effects of lead exposure occur at much higher blood lead levels.