Erythropoietin (Epo) plays a crucial role in the formation and maturation of erythrocytes and is produced primarily by peritubular cells in the renal cortex. Previous studies suggest that renal sympathetic nerve activity (RSNA) may influence Epo regulation. Catheter-based renal denervation (RDN) has been shown to reduce renal noradrenaline spillover and blood pressure in patients with resistant hypertension. We therefore aimed to investigate whether RDN influences Epo levels. 33 patients with resistant hypertension (age 61 ± 12 y; baseline office blood pressure (BP) 165 ± 16/85 ± 18 mmHg despite treatment with an average of 4.9 ± 1.7 antihypertensive medications) underwent bilateral RDN. Plasma levels of Epo, office blood pressure, 24 h ambulatory blood pressure monitoring (ABPM), muscle sympathetic nerve activity (MSNA), renal function and haemoglobin were measured before the procedure and at 3 months follow-up. Antihypertensive medication was not changed during the first 3 months after RDN. Office blood pressure was reduced by 15 ± 19/5 ± 12 mmHg at 3 months after denervation (p < 0.001 for systolic BP; p = 0.033 for diastolic BP). 24h-mean systolic and diastolic BP were also reduced (from 145 ± 16 to 140 ± 18 mmHg; p = 0.036, and from 80 ± 11 to 77 ± 12 mmHg; p = 0.024), respectively. While haemoglobin levels remained unchanged, a significant increase in plasma Epo levels was observed at 3 months after RDN (7.81 ± 3.68 versus 9.88 ± 5.06 mIU/mL; p = 0.025). Changes in Epo levels correlated with baseline MSNA (r = 0.580, p = 0.004 for burst frequency; r = 0.471, p = 0.023 for burst incidence), such that the increase in Epo was most pronounced in patients with high baseline MSNA. The RDN-induced changes in MSNA tended to correlate inversely with changes in Epo levels (r = −0.402; p = 0.064). Our findings suggest that RDN is associated with increased plasma levels of Epo in the absence of changes in haemoglobin, and that these effects are possibly mediated via a reduction in sympathetic nerve activity.

Renal denervation (RDN) is an adjunct therapy for resistant hypertension, reducing blood pressure (BP) by inhibiting both afferent sensory and efferent sympathetic renal nerve activity. The resulting reduction in central sympathetic outflow including that directed toward the heart may beneficially impact cardiac remodeling, left ventricular hypertrophy (LVH) and atrial fibrillation (AF). RDN has been shown to reduce left ventricular mass and AF burden but long-term data is sparse. Forty patients (72.5% male, 69.2 ± 9.6 years) underwent 12-lead ECG at baseline prior to RDN and at a mean long-term follow-up (LTFU) of 8.3 ± 0.9 years post-intervention. A 24-h ambulatory blood pressure monitor (ABPM) was obtained at both time points. Cornell voltage indices were calculated at baseline and LTFU, then converted to left ventricular mass based on validated formulae accounting for sex. ECGs underwent cardiologist review for determination of AF at both time-points. There was no difference in Cornell voltages or left ventricular mass index (LVMI) between baseline and long-term follow-up in neither males (p = 0.89) nor females (p = 0.91). BP lowering at LTFU was correlated with a more pronounced reduction in LVMI (r = 0.50, p = 0.0011) No change was observed in the incidence of atrial fibrillation between baseline or long-term follow-up (p = 0.99). There was no reduction in mean Cornell voltage or LVMI across the cohort between baseline and long-term follow-up. However, changes in ambulatory systolic BP correlated with reduction in LVMI suggestive of an RDN-induced BP dependent long-term reduction in LVMI out to eight years post-RDN.

Measures obtained from the full blood count have been shown to vary around a set point, are stable over years, and provide an indication of disease risk and mortality. In this study, we examined the association between sympathetic nerve activity and components of the full blood count. We performed a retrospective analysis of data drawn from our clinical database. Subjects were included if available data comprised full blood count and muscle sympathetic nerve activity (MSNA). Data were obtained from 160 individuals, comprising healthy volunteers, subjects who were overweight or with clinical obesity, and patients with high blood pressure. MSNA was correlated to the red cell distribution width (RDW, Spearman's rho 0.49 for MSNA b/min and 0.48 for MSNA b/100hb, p < 0.001 for both), but bore no association with any of the other blood variables. Regression analysis indicated that the RDW could be predicted by a combination of MSNA and BMI and to the number of components and diagnosis of the metabolic syndrome, measures of insulin resistance, and markers of inflammation. Our observations may provide insight into the possible mechanisms linking the RDW with mortality.

Background Pain management of sedated and ventilated patients in intensive care units lacks consistency. Objectives To investigate nurses’ training, governance, practices, knowledge and attitudes relating to pain management in consideration of published guidelines and explore nurses’ perspectives. Methods A survey design, using an online questionnaire with free text responses, was employed. Quantitative and qualitative data from nurses working across different hospitals were collated and saved on Qualtrics platform. Quantitative data were analysed non-parametrically and narrative responses thematically. CROSS and SRQR reporting guidelines were adhered to. Outcome measures Demographics, training, governance, clinical practice, knowledge, and attitudes. Results/findings 108 nurses participated with ninety-two completed surveys analysed. Analgesia was used to complete nursing tasks regardless of comfort needs (n = 49, 53.3 %). Changes in vital signs prompted opioid administration (n = 48, 52.1 %). Choice of analgesia depended on doctor’s preference (n = 63, 68.5 %). Non-opioid therapy was administered before opioids (n = 42, 45.7 %). Sedatives were used to alleviate agitation(n = 50,54.3 %). No statistically significant difference in nurses’ knowledge existed between hospitals. Weak positive relationship: r = [0.081], p = [0.441] between “knowledge scores” and “years of ICU experience” and weak negative relationship r = [-0.119], p = [0.260] between “knowledge scores” and “hours of clinical practice” was detected. Lack of training, resources, policies, high patient acuity and casual employment were acknowledged barriers to pain management. Two overarching themes emerged from narrative responses: “Pain assessment, where is it?” And “Priorities of critical illness.” Conclusion The study uncovered pain management situation and examined nurses’ demographics, training, governance, practices, knowledge and attitudes. Narrative responses highlighted barriers to pain management. Implications for clinical practice Health organisations should provide education, institute governance and develop policies to inform pain management. Nurses’ role encompasses updating knowledge, adhering to interventions and overcoming biases. This subsequently manifests as improvement in patient outcomes.

BackgroundExtractive methods for machine reading comprehension (MRC) tasks have achieved comparable or better accuracy than human performance on benchmark data sets. However, such models are not as successful when adapted to complex domains such as health care. One of the main reasons is that the context that the MRC model needs to process when operating in a complex domain can be much larger compared with an average open-domain context. This causes the MRC model to make less accurate and slower predictions. A potential solution to this problem is to reduce the input context of the MRC model by extracting only the necessary parts from the original context. ObjectiveThis study aims to develop a method for extracting useful contexts from long articles as an additional component to the question answering task, enabling the MRC model to work more efficiently and accurately. MethodsExisting approaches to context extraction in MRC are based on sentence selection strategies, in which the models are trained to find the sentences containing the answer. We found that using only the sentences containing the answer was insufficient for the MRC model to predict correctly. We conducted a series of empirical studies and observed a strong relationship between the usefulness of the context and the confidence score output of the MRC model. Our investigation showed that a precise input context can boost the prediction correctness of the MRC and greatly reduce inference time. We proposed a method to estimate the utility of each sentence in a context in answering the question and then extract a new, shorter context according to these estimations. We generated a data set to train 2 models for estimating sentence utility, based on which we selected more precise contexts that improved the MRC model’s performance. ResultsWe demonstrated our approach on the Question Answering Data Set for COVID-19 and Biomedical Semantic Indexing and Question Answering data sets and showed that the approach benefits the downstream MRC model. First, the method substantially reduced the inference time of the entire question answering system by 6 to 7 times. Second, our approach helped the MRC model predict the answer more correctly compared with using the original context (F1-score increased from 0.724 to 0.744 for the Question Answering Data Set for COVID-19 and from 0.651 to 0.704 for the Biomedical Semantic Indexing and Question Answering). We also found a potential problem where extractive transformer MRC models predict poorly despite being given a more precise context in some cases. ConclusionsThe proposed context extraction method allows the MRC model to achieve improved prediction correctness and a significantly reduced MRC inference time. This approach works technically with any MRC model and has potential in tasks involving processing long texts.

Abstract Efforts to limit the impact of the coronavirus disease (COVID‐19) pandemic led to the implementation of public health measures and reallocation of health resources. To investigate trends in blood pressure (BP), hypertension and BMI in the Australian population during the COVID‐19 pandemic, data from publicly accessible health stations were analyzed. Average BP and BMI measured by the SiSU Health Station network in Australia in over 1.6 million health screenings were compared between the years 2018 and 2021. Additionally, paired trajectories for BP and BMI development before and during the COVID‐19 pandemic were calculated. Comparisons between pre‐COVID years and post‐COVID years of 2018 versus 2020, 2019 versus 2020, 2018 versus 2021, and 2019 versus 2021 showed increases in average adjusted systolic BP of 2.0, 1.7, 2.6, and 2.3 mmHg, respectively. Paired analysis of longitudinal data showed an overall increase in the trajectory of systolic BP of 3.2 mmHg between pre‐ and post‐COVID years. The prevalence of hypertension in users of the health stations increased by approximately 25% in the years 2020–2021. Similar trends were seen for BMI. Data from public Australian health stations indicated a strong trend toward higher BP during the COVID‐19 pandemic. At the population level, BP increments have been shown to markedly increase cardiovascular disease risk. Anti‐pandemic measures need to be carefully evaluated in terms of secondary public health effects and health support systems extended to effectively target cardiovascular risk.

Background: Renal denervation (RDN) has been consistently shown in recent sham-controlled clinical trials to reduce blood pressure (BP). Salt sensitivity is a critical factor in hypertension pathogenesis, but cumbersome to assess by gold-standard methodology. Twenty-four-hour average heart rate (HR) and mean arterial pressure (MAP) dipping, taken by ambulatory blood pressure monitoring (ABPM), stratifies patients into high, moderate, and low salt sensitivity index (SSI) risk categories. Objectives: We aimed to assess whether ABPM-derived SSI risk could predict the systolic blood pressure reduction at long-term follow-up in a real-world RDN patient cohort. Methods: Sixty participants had repeat ABPM as part of a renal denervation long-term follow-up. Average time since RDN was 8.9 ± 1.2 years. Based on baseline ABPM, participants were stratified into low (HR < 70 bpm and MAP dipping > 10%), moderate (HR ≥70 bpm or MAP dipping ≤ 10%), and high (HR ≥ 70 bpm and MAP dipping ≤ 10%) SSI risk groups, respectively. Results: One-way ANOVA indicated a significant treatment effect ( P = 0.03) between low ( n = 15), moderate ( n = 35), and high ( n = 10) SSI risk with systolic BP reduction of 9.6 ± 3.7 mmHg, 8.4 ± 3.5 mmHg, and 28.2 ± 9.6 mmHg, respectively. Baseline BP was not significantly different between SSI Risk groups ( P = 0.18). High SSI risk independently correlated with systolic BP reduction ( P = 0.02). Conclusions: Our investigation indicates that SSI risk may be a simple and accessible measure for predicting the BP response to RDN. However, the influence of pharmacological therapy on these participants is an important extraneous variable requiring testing in prospective or drug naive RDN cohorts.

Purpose Mental stress is of essential consideration when assessing cardiovascular pathophysiology in all patient populations. Substantial evidence indicates associations among stress, cardiovascular disease and aberrant brain–body communication. However, our understanding of the flow of stress information in humans, is limited, despite the crucial insights this area may offer into future therapeutic targets for clinical intervention. Methods Key terms including mental stress, cardiovascular disease and central control, were searched in PubMed, ScienceDirect and Scopus databases. Articles indicative of heart rate and blood pressure regulation, or central control of cardiovascular disease through direct neural innervation of the cardiac, splanchnic and vascular regions were included. Focus on human neuroimaging research and the flow of stress information is described, before brain–body connectivity, via pre-motor brainstem intermediates is discussed. Lastly, we review current understandings of pathophysiological stress and cardiovascular disease aetiology. Results Structural and functional changes to corticolimbic circuitry encode stress information, integrated by the hypothalamus and amygdala. Pre-autonomic brain–body relays to brainstem and spinal cord nuclei establish dysautonomia and lead to alterations in baroreflex functioning, firing of the sympathetic fibres, cellular reuptake of norepinephrine and withdrawal of the parasympathetic reflex. The combined result is profoundly adrenergic and increases the likelihood of cardiac myopathy, arrhythmogenesis, coronary ischaemia, hypertension and the overall risk of future sudden stress-induced heart failure. Conclusions There is undeniable support that mental stress contributes to the development of cardiovascular disease. The emerging accumulation of large-scale multimodal neuroimaging data analytics to assess this relationship promises exciting novel therapeutic targets for future cardiovascular disease detection and prevention.

Blood pressure(BP) management interventions have been shown to be more effective when accompanied by appropriate patient education. As high BP remains poorly controlled, there may be gaps in patient knowledge and education. Therefore, this study aimed to identify specific content and delivery preferences for information to support BP management among Australian adults from the general public. Given that BP management is predominantly undertaken by general practitioners(GPs), information preferences to support BP management were also ascertained from a small sample of Australian GPs. An online survey of adults was conducted to identify areas of concern for BP management to inform content preferences and preferred format for information delivery. A separate online survey was also delivered to GPs to determine preferred information sources to support BP management. Participants were recruited via social media. General public participants (n = 465) were mostly female (68%), >60 years (57%) and 49% were taking BP-lowering medications. The management of BP without medications, and role of lifestyle in BP management were of concern among 30% and 26% of adults respectively. Most adults (73%) preferred to access BP management information from their GP. 57% of GPs (total n = 23) preferred information for supporting BP management to be delivered via one-page summaries. This study identified that Australian adults would prefer more information about the management of BP without medications and via lifestyle delivered by their GP. This could be achieved by providing GPs with one-page summaries on relevant topics to support patient education and ultimately improve BP management.

BACKGROUND:Renal denervation is a recognized adjunct therapy for hypertension with clinically significant blood pressure (BP)-lowering effects. Long-term follow-up data are critical to ascertain durability of the effect and safety. Aside from the 36-month follow-up data available from randomized control trials, recent cohort analyses extended follow-up out to 10 years. We sought to analyze study-level data and quantify the ambulatory BP reduction of renal denervation across contemporary randomized sham-controlled trials and available long-term follow-up data up to 10 years from observational studies. METHODS:A systematic review was performed with data from 4 observational studies with follow-up out to 10 years and 2 randomized controlled trials meeting search and inclusion criteria with follow-up data out to 36 months. Study-level data were extracted and compared statistically. RESULTS:In 2 contemporary randomized controlled trials with 36-month follow-up, an average sham-adjusted ambulatory systolic BP reduction of -12.7±4.5 mm Hg from baseline was observed (P=0.05). Likewise, a -14.8±3.4 mm Hg ambulatory systolic BP reduction was found across observational studies with a mean long-term follow-up of 7.7±2.8 years (range, 3.5-9.4 years; P=0.0051). The observed reduction in estimated glomerular filtration rate across the long-term follow-up was in line with the predicted age-related decline. Antihypertensive drug burden was similar at baseline and follow-up. CONCLUSIONS:Renal denervation is associated with a significant and clinically meaningful reduction in ambulatory systolic BP in both contemporary randomized sham-controlled trials up to 36 months and observational cohort studies up to 10 years without adverse consequences on renal function.

Background: Recent sham-controlled randomized clinical trials have confirmed the safety and efficacy of catheter-based renal denervation (RDN). Long-term safety and efficacy data beyond 3 years are scarce. Here, we report on outcomes after RDN in a cohort of patients with resistant hypertension with an average of ≈9-year follow-up (FU). Methods: We recruited patients with resistant hypertension who were previously enrolled in various RDN trials applying radiofrequency energy for blood pressure (BP) lowering. All participants had baseline assessments before RDN and repeat assessment at long-term FU including medical history, automated office and ambulatory BP measurement, and routine blood and urine tests. We analyzed changes between baseline and long-term FU. Results: A total of 66 participants (mean±SD, 70.0±10.3 years; 76.3% men) completed long-term FU investigations with a mean of 8.8±1.2 years post-procedure. Compared with baseline, ambulatory systolic BP was reduced by −12.1±21.6 (from 145.2 to 133.1) mm Hg ( P <0.0001) and diastolic BP by −8.8±12.8 (from 81.2 to 72.7) mm Hg ( P <0.0001). Mean heart rate remained unchanged. At long-term FU, participants were on one less antihypertensive medication compared with baseline ( P =0.0052). Renal function assessed by estimated glomerular filtration rate fell within the expected age-associated rate of decline from 71.1 to 61.2 mL/min per 1.73 m 2 . Time above target was reduced significantly from 75.0±25.9% at baseline to 47.3±30.3% at long-term FU ( P <0.0001). Conclusions: RDN results in a significant and robust reduction in both office and ambulatory systolic and diastolic BP at ≈9-year FU after catheter-based RDN on less medication and without evidence of adverse consequences on renal function.

Cardiovascular and metabolic complications associated with excess adiposity are linked to chronic activation of the sympathetic nervous system, resulting in a high risk of mortality among obese individuals. Obesity-related positive energy balance underlies the progression of hypertension, end-organ damage, and insulin resistance, driven by increased sympathetic tone throughout the body. It is, therefore, important to understand the central network that drives and maintains sustained activation of the sympathetic nervous system in the obese state. Experimental and clinical studies have identified structural changes and altered dynamics in both grey and white matter regions in obesity. Aberrant activation in certain brain regions has been associated with altered reward circuitry and metabolic pathways including leptin and insulin signaling along with adiposity-driven systemic and central inflammation. The impact of these pathways on the brain via overactivity of the sympathetic nervous system has gained interest in the past decade. Primarily, the brainstem, hypothalamus, amygdala, hippocampus, and cortical structures including the insular, orbitofrontal, temporal, cingulate, and prefrontal cortices have been identified in this context. Although the central network involving these structures is much more intricate, this review highlights recent evidence identifying these regions in sympathetic overactivity in obesity.

It was on 6 June, 2007 that catheter-based renal denervation was first used experimentally to treat a patient with hypertension. The introduction of renal denervation into the routine clinical care of hypertension has had a long gestation, but a tipping point has now been reached, justified by the clinical trial evidence. The theoretical basis for this device therapy remains strong, the antihypertensive effect of renal denervation in animal models of hypertension, and the existence of activation of the renal sympathetic outflow in essential hypertension. Notably, renal sympathetic activation is present in obesity-hypertension, despite the cardiac sympathetic outflow being normal. Selecting those patients with hypertension who will benefit most from renal denervation is now the key issue. Choosing primarily patients with neurogenic essential hypertension will not be feasible, as the testing required to do this accurately is too complicated. Most likely the target hypertension population for RDN will be those patients with treated but uncontrolled hypertension. This will be because of the evident clinical need, but also because of something additional and counter-intuitive. Patients with uncontrolled hypertension are commonly nonadherent with their antihypertensive prescription. Testing has shown that many would prefer device over drug therapy for their hypertension. Selectively treating this patient group with RDN thus becomes congruent with patient-centred therapy. Pharmacological treatment of hypertension commonly fails to lower blood pressure to target, for multiple reasons, but importantly due to patient nonadherence to the antihypertensive prescription. Faced with this therapeutic failure, devices which treat hypertension are increasingly being evaluated. Of these, catheter-based renal denervation has the strongest evidence base.

Purpose Stress produces many physiological changes, some of which may contribute to the development of cardiovascular disease (CVD). Individuals with intellectual disability (ID) are exposed to multiple and stressful challenges everyday which may put them at increased cardiovascular risk. This current study aimed to establish whether adults with ID experience higher levels of subjective stress and encounter different stressors (including social isolation) than the general population, and whether there is a relationship between stress and cardiometabolic profile in this population. Methods Adults with ID (n = 35) aged 18-45 years completed the Subjective Stress Survey, and underwent a physiological assessment to measure blood pressure, metabolic profile and subclinical CVD risk factors, and were compared to a control group (n = 29). Multiple regression was used to investigate whether cardiometabolic parameters were predicative of SSS scores. Results Findings showed adults with ID have higher perceived stress levels (total score ID: 21.3 +/- 11.4 vs control: 13.9 +/- 9.0, p = 0.006), which is elicited by unique stressors, when compared to people without ID. Stress was strongly associated with increased social isolation (r = -0.38, p = 0.002) and with obesity in females with mild ID (r = 0.72). Regression showed that arterial stiffness was predictive of total SSS score (p = 0.038). Conclusions Adults with ID aged 18-45 years report higher levels of perceived stress when compared to people without ID.

Beta-adrenergic blockade has been associated with improved cancer survival in patients with triple-negative breast cancer (TNBC), but the mechanisms of these effects remain unclear. In clinical epidemiological analyses, we identified a relationship between beta-blocker use and anthracycline chemotherapy in protecting against TNBC progression, disease recurrence, and mortality. We recapitulated the effect of beta-blockade on anthracycline efficacy in xenograft mouse models of TNBC. In metastatic 4T1.2 and MDA-MB-231 mouse models of TNBC, beta-blockade improved the efficacy of the anthracycline doxorubicin by reducing metastatic development. We found that anthracycline chemotherapy alone, in the absence of beta-blockade, increased sympathetic nerve fiber activity and norepinephrine concentration in mammary tumors through the induction of nerve growth factor (NGF) by tumor cells. Moreover, using preclinical models and clinical samples, we found that anthracycline chemotherapy up-regulated β 2 -adrenoceptor expression and amplified receptor signaling in tumor cells. Neurotoxin inhibition of sympathetic neural signaling in mammary tumors using 6-hydroxydopamine or genetic deletion of NGF or β 2 -adrenoceptor in tumor cells enhanced the therapeutic effect of anthracycline chemotherapy by reducing metastasis in xenograft mouse models. These findings reveal a neuromodulatory effect of anthracycline chemotherapy that undermines its potential therapeutic impact, which can be overcome by inhibiting β 2 -adrenergic signaling in the tumor microenvironment. Supplementing anthracycline chemotherapy with adjunctive β 2 -adrenergic antagonists represents a potential therapeutic strategy for enhancing the clinical management of TNBC.

Background: Raised blood pressure (BP) remains the single most important modifiable risk factor contributing to cardiovascular and all-cause mortality in Australia and worldwide. May Measurement Month, a global BP measurement and screening campaign initiated by the International Society of Hypertension and carried out in Australia since its inception in 2017, aimed at obtaining standardized BP measurements from members of the community to increase awareness of high BP and its associated risks. Method: Adults participants (≥18 years) were recruited through opportunistic sampling across Australia during the month of May in 2017, 2018 and 2019. Trained volunteers recorded BP readings in a standardized manner and collected data on demographic, lifestyle factors and comorbidities. Hypertension was defined as SBP of at least 140 mmHg, or DBP of at least 90 mmHg, or taking antihypertensive medication. Data were collated centrally and analysis was carried out using regression models to evaluate the associations between BP and participant characteristics. Results: A total of 10 046 participants were screened, of whom 3097 (31.0%) had hypertension, only 48.5% were aware of their condition and 44.4% were taking antihypertensive medication. Of those taking antihypertensive medication, 53.2% were controlled to less than 140/90 mmHg, whereas the remaining 46.8% of participants had BP of at least 140/90 mmHg suggestive of inadequately treated hypertension. Conclusion: Consecutive data obtained over a 3-year period in Australia demonstrated stagnating awareness, treatment and control rates with the latter two being substantially lower than global rates and those in other high-income countries. Concerted efforts from all stakeholders will be required to help overcome the unacceptably poor rates of BP treatment and control in Australia.

Patients with panic disorder, at rest in the absence of a panic attack, have increased brain serotonin turnover, which seems to be the CNS substrate of the condition. The abnormality parallels midbrain raphe serotonergic activation in anxiety responses in experimental animals. Also at rest in panic disorder, there are demonstrable, potentially deleterious features of sympathetic nervous biology, an impairment of neuronal reuptake of noradrenaline, and a tendency for multiple single sympathetic fibre firing in salvos within a cardiac cycle, not seen in health. With activation of the cardiac sympathetic outflow during a panic attack, these sympathetic nervous features intensify the stimulation of the heart, in a significant minority of patients triggering coronary artery spasm and cardiac arrhythmias.