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In this contribution, we applied a multi-stage machine learning (ML) framework to map daily values of nitrogen dioxide (NO 2 ) and particulate matter (PM 10 and PM 2.5 ) at a 1 km 2 resolution over Great Britain for the period 2003-2021. The process combined ground monitoring observations, satellite-derived products, climate reanalyses and chemical transport model datasets, and traffic and land-use data. Each feature was harmonized to 1 km resolution and extracted at monitoring sites. Models used single and ensemble-based algorithms featuring random forests (RF), extreme gradient boosting (XGB), light gradient boosting machine (LGBM), as well as lasso and ridge regression. The various stages focused on augmenting PM 2.5 using co-occurring PM 10 values, gap-filling aerosol optical depth and columnar NO 2 data obtained from satellite instruments, and finally the training of an ensemble model and the prediction of daily values across the whole geographical domain (2003-2021). Results show a good ensemble model performance, calculated through a ten-fold monitor-based cross-validation procedure, with an average R 2 of 0.690 (range 0.611-0.792) for NO 2 , 0.704 (0.609-0.786) for PM 10 , and 0.802 (0.746-0.888) for PM 2.5 . Reconstructed pollution levels decreased markedly within the study period, with a stronger reduction in the latter eight years. The pollutants exhibited different spatial patterns, while NO 2 rose in close proximity to high-traffic areas, PM demonstrated variation at a larger scale. The resulting 1 km 2 spatially resolved daily datasets allow for linkage with health data across Great Britain over nearly two decades, thus contributing to extensive, extended, and detailed research on the long-and short-term health effects of air pollution., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Background: Evidence for long-term mortality risks of PM2.5 comes mostly from large administrative studies with incomplete individual information and limited exposure definitions. Here we assess PM2.5-mortality associations in the UK Biobank cohort using detailed information on confounders and exposure., Methods: We reconstructed detailed exposure histories for 498,090 subjects by linking residential data with high-resolution PM2.5 concentrations from spatio-temporal machine learning models. We split the time-to-event data and assigned yearly exposures over a lag window of 8 years. We fitted Cox proportional hazard models with time-varying exposure controlling for contextual and individual-level factors, as well as trends. In secondary analyses, we inspected the lag structure using distributed lag models and compared results with alternative exposure sources and definitions., Results: In fully adjusted models, an increase of 10 μg/m³ in PM2.5 was associated with hazard ratios (HRs) of 1.27 (95%CI: 1.06-1.53) for all-cause, 1.24 (1.03-1.50) for non-accidental, 2.07 (1.04-4.10) for respiratory, and 1.66 (0.86-3.19) for lung cancer mortality. We found no evidence of association with cardiovascular deaths (HR=0.88, 95%CI: 0.59-1.31). We identified strong confounding by both contextual- and individual-level lifestyle factors. The distributed lag analysis suggested differences in relevant exposure windows across mortality causes. Using more informative exposure summaries and sources resulted in higher risk estimates., Conclusions: We found associations of long-term PM2.5 exposure with all-cause, non-accidental, respiratory, and lung cancer mortality, but not with cardiovascular mortality. This study benefits from finely reconstructed time-varying exposures and extensive control for confounding, further supporting a plausible causal link between long-term PM2.5 and mortality., Competing Interests: Competing financial interests: The author declares he has no actual or potential conflict of interest., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: A causal link between air pollution exposure and cardiovascular events has been suggested. However fewer studies have investigated the shape of the associations at low levels of air pollution and identified the most important temporal window of exposure. Here we assessed long-term associations between particulate matter < 2.5 µm (PM 2.5 ) at low concentrations and multiple cardiovascular endpoints using the UK Biobank cohort., Methods: Using data on adults (aged > 40) from the UK Biobank cohort, we investigated the associations between 1-year, 3-year and 5-year time-varying averages of PM 2.5 and incidence of major adverse cardiovascular events (MACE), myocardial infarction (MI), heart failure, atrial fibrillation and flutter and cardiac arrest. We also investigated outcome subtypes for MI and stroke. Events were defined as hospital inpatient admissions. We fitted Cox proportional hazard regression models applying extensive control for confounding at both individual and area level. Finally, we assessed the shape of the exposure-response functions to assess effects at low levels of exposure., Results: We analysed data from 377,736 study participants after exclusion of prevalent subjects. The average follow-up (2006-2021) was 12.9 years. We detected 19,353 cases of MACE, 6,562 of acute MI, 6,278 of heart failure, 1,258 for atrial fibrillation and flutter, and 16,327 for cardiac arrest. Using a 5-year exposure window, we detected positive associations (for 5 μg/m 3 increase in PM 2.5 ) for 5-point MACE of [1.12 (95 %CI: 1.00-1.26)], heart failure [1.22 (1.00-1.50)] and cardiac arrest [1.16 (1.03-1.31)]. We did not find any association with acute MI, while non-ST-elevation MI was associated with the 1-year exposure window [1.52 (1.12-2.07)]. The assessment of the shape of the exposure-response relationships suggested that risk is approximately linear for most of the outcomes., Conclusions: We found positive associations between long-term exposure to PM 2.5 and multiple cardiovascular outcomes for different exposure windows. The cardiovascular risk tends to rise even at exposure concentrations below 12-15 μg/m 3 , indicating high risk below UK national and international thresholds., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Evidence on the association of arterial stiffness and left ventricular (LV) concentric remodelling/ LVH assessed by echocardiography, with abnormal blood pressure (BP) phenotypes, defined by office and ambulatory BP monitoring (ABPM) in the community is scanty. We investigated this issue in the participants to the Pressioni Monitorate E Loro Associazioni (PAMELA) study., Methods: The study included 491 participants who attended the second and third survey of the PAMELA study performed after 10 and 25 years from the initial evaluation. Data collection included medical history, anthropometric parameters, blood examinations, office, ABPM, echocardiographic and Cardio-Ankle Vascular Index (CAVI) measurements., Results: In the whole study sample (age 66 + 10 years, 50% males), the prevalence rates of sustained normotension (NT), white coat hypertension (WCH), masked hypertension (MH), sustained hypertension (SH) and non-dipping (ND) were 31.2, 10.0, 24.2, 34.6, and 35.8% and respectively. The likelihood of having SH, the BP phenotype carrying the greatest CV risk, was four times higher (OR= 4.31, CI:2.39-7.76, p<0.0001) in participants with increased CAVI and LV remodelling/LVH compared to their counterparts without organ damage. This association showed an incremental value in discriminating SH compared to both isolated markers of organ damage (OR=1.92,p=0.03 for increased CAVI and OR= 2.02, p=0.02 for LV remodelling/LVH). The presence of isolated but also combined organ damage was unrelated to ND., Conclusions: Our study provides new evidence of the incremental value of looking for both vascular and cardiac organ damage to optimize the identification and clinical management of SH in the general population., (© The Author(s) 2024. Published by Oxford University Press on behalf of American Journal of Hypertension, Ltd.)

In resistant hypertensive patients acute carotid baroreflex stimulation is associated with a blood pressure (BP) reduction, believed to be mediated by a central sympathoinhbition.The evidence for this sympathomodulatory effect is limited, however. This meta-analysis is the first to examine the sympathomodulatory effects of acute carotid baroreflex stimulation in drug-resistant and uncontrolled hypertension, based on the results of microneurographic studies. The analysis included 3 studies assessing muscle sympathetic nerve activity (MSNA) and examining 41 resistant uncontrolled hypertensives. The evaluation included assessment of the relationships between MSNA and clinic heart rate and BP changes associated with the procedure. Carotid baroreflex stimulation induced an acute reduction in clinic systolic and diastolic BP which achieved statistical significance for the former variable only [systolic BP: -19.98 mmHg (90% CI, -30.52, -9.43), P < 0.002], [diastolic BP: -5.49 mmHg (90% CI, -11.38, 0.39), P = NS]. These BP changes were accompanied by a significant MSNA reduction [-4.28 bursts/min (90% CI, -8.62, 0.06), P < 0.07], and by a significant heart rate decrease [-3.65 beats/min (90% CI, -5.49, -1.81), P < 0.001]. No significant relationship was detected beween the MSNA, systolic and diastolic BP changes induced by the procedure, this being the case also for heart rate. Our data show that the acute BP lowering responses to carotid baroreflex stimulation, although associated with a significant MSNA reduction, are not quantitatively related to the sympathomoderating effects of the procedure. This may suggest that these BP effects depend only in part on central sympathoinhibition, at least in the acute phase following the intervention., (© 2024. The Author(s), under exclusive licence to The Japanese Society of Hypertension.)

Recent developments in linkage procedures and exposure modelling offer great prospects for cohort analyses on the health risks of environmental factors. However, assigning individual-level exposures to large population-based cohorts poses methodological and practical problems. In this contribution, we illustrate a linkage framework to reconstruct environmental exposures for individual-level epidemiological analyses, discussing methodological and practical issues such as residential mobility and privacy concerns. The framework outlined here requires the availability of individual residential histories with related time periods, as well as high-resolution spatio-temporal maps of environmental exposures. The linkage process is carried out in three steps: (1) spatial alignment of the exposure maps and residential locations to extract address-specific exposure series; (2) reconstruction of individual-level exposure histories accounting for residential changes during the follow-up; (3) flexible definition of exposure summaries consistent with alternative research questions and epidemiological designs. The procedure is exemplified by the linkage and processing of daily averages of air pollution for the UK Biobank cohort using gridded spatio-temporal maps across Great Britain. This results in the extraction of exposure summaries suitable for epidemiological analyses of both short and long-term risk associations and, in general, for the investigation of temporal dependencies. The linkage framework presented here is generally applicable to multiple environmental stressors and can be extended beyond the reconstruction of residential exposures. IMPACT: This contribution describes a linkage framework to assign individual-level environmental exposures to population-based cohorts using high-resolution spatio-temporal exposure. The framework can be used to address current limitations of exposure assessment for the analysis of health risks associated with environmental stressors. The linkage of detailed exposure information at the individual level offers the opportunity to define flexible exposure summaries tailored to specific study designs and research questions. The application of the framework is exemplified by the linkage of fine particulate matter (PM 2.5 ) exposures to the UK Biobank cohort., (© 2024. Crown.)

In patients with end-stage renal disease (ESRD) undergoing haemodialysis, hypertension is of common detection and frequently inadequately controlled. Multiple pathophysiological mechanisms are involved in the development and progression of the ESRD-related high blood pressure state, which has been implicated in the increased cardiovascular risk reported in this hypertensive clinical phenotype. Renal sympathetic efferent and afferent nerves play a relevant role in the development and progression of elevated blood pressure values in patients with ESRD, often leading to resistant hypertension. Catheter-based bilateral renal nerves ablation has been shown to exert blood pressure lowering effects in resistant hypertensive patients with normal kidney function. Promising data on the procedure in ESRD patients with resistant hypertension have been reported in small scale pilot studies. Denervation of the native non-functioning kidney's neural excitatory influences on central sympathetic drive could reduce the elevated cardiovascular morbidity and mortality seen in ESRD patients. The present review article will focus on the promising results obtained with renal denervation in patients with ESRD, its mechanisms of action and future perspectives in these high risk patients., (© 2024. The Author(s).)

Purpose of Review: To examine published and unpublished data documenting the role of sympathetic neural factors in the pathogenesis of different hypertensive phenotypes. These phenotypes relate to attended or unattended blood pressure measurements, to nighttime blood pressure profile alterations, and to resistant, pseudoresistant, and refractory hypertension. Results of original clinical studies as well as of recent meta-analyses based on the behavior of different sympathetic biomarkers in various hypertensive forms will be also discussed., Recent Findings: Studies performed in the past decade have shown that office blood pressure measurements, including in recent years those characterizing unattended or attended blood pressure assessment, are associated with profound changes in the behavior of different sympathetic biomarkers. This is the case for the clinical hypertensive phenotypes characterized by alterations in the nocturnal blood pressure profile and by sleep duration abnormalities. This is also the case for the clinical conditions defined as resistant, refractory, and pseudoresistant hypertension. Data reviewed in the present paper highlight the relevance of sympathetic neural factors in the development and progression of different clinical hypertensive phenotypes. This suggests that a common hallmark of the majority of the essential hypertensive states detectable in current clinical practice is represented by the alteration in the sympathetic blood pressure control., (© 2023. The Author(s).)

Background and Aims: Chronic coffee consuption has been reported to be associated with a modest but significant increase in blood pressure (BP), although some recent studies have shown the opposite. These data, however, largely refer to clinic BP and virtually no study evaluated cross-sectionally the association between chronic coffee consuption, out-of-office BP and BP variability., Methods and Results: In 2045 subjects belonging to the population of the Pressioni Arteriose Monitorate E Loro Associazioni (PAMELA) study, we analyzed cross-sectionally the association between clinic, 24-hour, home BP and BP variability and level of chronic coffee consumption. Results show that when adjusted for confounders (age, gender, body mass index, cigarette smoking, physical activity and alcohol drinking) chronic coffee consumption does not appear to have any major lowering effect on BP values, particulary when they are assessed via 24-hour ambulatory (0 Cup/day: 118.5 ± 0.7/72.8 ± 0.4 mmHg vs 3 cups/day: 120.2 ± 0.4/74.8 ± 0.3 mmHg, PNS) or home BP monitoring (0 cup/day: 124.1 ± 1.2/75.4 ± 0.7 mmHg vs 3 cups/day: 123.3 ± 0.6/76.4 ± 0.36 mmHg, PNS). However, daytime BP was significantly higher in coffee consumers (about 2 mmHg), suggesting some pressor effects of coffee which vanish during nighttime. Both BP and HR 24-hour HR variability were unaffected., Conclusion: Thus chronic coffee consumption does not appear to have any major lowering effect either on absolute BP values, particulary when they are assessed via 24-hour ambulatory or home BP monitoring, or on 24-hour BP variability., (Copyright © 2023 The Italian Diabetes Society, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.)

Background: Left ventricular hypertrophy (LVH) is an independent predictor of cardiovascular events, and evidence has been obtained that an increase of a normal left ventricular mass (LVM) or new-onset LVH over time augments cardiovascular outcomes., Methods: We addressed this issue in a sample of a general population at relatively low cardiovascular risk. We analyzed subjects with normal echocardiographic LVM enrolled in the PAMELA (Pressioni Arteriose Monitorate E Loro Associazioni) study to follow the increase of LVM over time and assess the prognostic impact of this change on the incidence of cardiovascular events (mean follow-up 18.5 years)., Results: In 990 subjects with no LVH at baseline, there was a significant average increase of LVM (21.2%), LVMI BSA (18.9%), and LVMI HT (22.3%) more than 10 years later. About a quarter developed LVH. The LVMI BSA change exhibited an association with the cardiovascular risk mortality during the following 18.5 years, and the association remained significant after adjustment for confounders (hazard ratio, 1.2 [1.0-1.5]). Similar findings were obtained for LVM in absolute values or indexed for height. The association was seen in both genders, but the link with the cardiovascular risk was statistically significant in males only., Conclusions: Thus, although over 10 years, the LVM increase does not reach a LVH status, it is associated with an augmented cardiovascular mortality risk. This suggests that it might be important to consider periodical LVM assessment, even when LVM is within the normal range, to timely detect its increase and cope with the need of cardiovascular risk restratification., Competing Interests: Disclosures None.

Background: Heat and cold are established environmental risk factors for human health. However, mapping the related health burden is a difficult task due to the complexity of the associations and the differences in vulnerability and demographic distributions. In this study, we did a comprehensive mortality impact assessment due to heat and cold in European urban areas, considering geographical differences and age-specific risks., Methods: We included urban areas across Europe between Jan 1, 2000, and Dec 12, 2019, using the Urban Audit dataset of Eurostat and adults aged 20 years and older living in these areas. Data were extracted from Eurostat, the Multi-country Multi-city Collaborative Research Network, Moderate Resolution Imaging Spectroradiometer, and Copernicus. We applied a three-stage method to estimate risks of temperature continuously across the age and space dimensions, identifying patterns of vulnerability on the basis of city-specific characteristics and demographic structures. These risks were used to derive minimum mortality temperatures and related percentiles and raw and standardised excess mortality rates for heat and cold aggregated at various geographical levels., Findings: Across the 854 urban areas in Europe, we estimated an annual excess of 203 620 (empirical 95% CI 180 882-224 613) deaths attributed to cold and 20 173 (17 261-22 934) attributed to heat. These corresponded to age-standardised rates of 129 (empirical 95% CI 114-142) and 13 (11-14) deaths per 100 000 person-years. Results differed across Europe and age groups, with the highest effects in eastern European cities for both cold and heat., Interpretation: Maps of mortality risks and excess deaths indicate geographical differences, such as a north-south gradient and increased vulnerability in eastern Europe, as well as local variations due to urban characteristics. The modelling framework and results are crucial for the design of national and local health and climate policies and for projecting the effects of cold and heat under future climatic and socioeconomic scenarios., Funding: Medical Research Council of UK, the Natural Environment Research Council UK, the EU's Horizon 2020, and the EU's Joint Research Center., Competing Interests: Declaration of interests We declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

We assessed the value of 3 electrocardiographic (EKG) voltage criteria in detecting variations of left ventricular mass (LVM) over time, taking echocardiographic (ECHO) LVM as reference, in the Pressioni Arteriose Monitorate E Loro Associazioni study. In 927 subjects (age 47 ± 13 years on entry, 49.9% men) an ECHO evaluation of LVM and EKG suitable for measurement of EKG-LVH criteria (Sokolow-Lyon voltage, Cornell voltage and R-wave voltage in aVL) were available at baseline and at a 2 nd evaluation performed 10 years later. Δ (delta) LVM, Δ LVMI, and Δ EKG parameters values were calculated from 2 nd evaluation to baseline. The sensitivity of the EKG criteria in the diagnosis of LVH, poor at baseline, becomes even worse after 10 years, reaching very low values. Only the sensitivity of R-wave amplitude exhibited slight increase over time but with unsatisfactory absolute values. Despite the prevalence of ECHO-LVH at the 2 nd evaluation was threefold increased compared to baseline (29.3% and 33.7% for LVM indexed to BSA and height 2.7 , respectively), the prevalence of EKG-LVH was unchanged when evaluated by Sokolow-Lyon criteria, significantly reduced when assessed by Cornell voltage index, while significantly increased using R-wave voltage in aVL criteria. Despite an ECHO-LVM increase over the time, mean EKG changes were of opposite sign, except for R-wave amplitude in aVL. Our study highlights the discrepancy between ECHO and EKG in monitoring LVM changes over the time, especially for Sokolow-Lyon and Cornell voltage. Thus, EKG is an unsuitable method for the longitudinal evaluation of LVM variations., (© 2023 The Authors. The Journal of Clinical Hypertension published by Wiley Periodicals LLC.)

Background: Results of recent clinical trials have shown that in heart failure (HF) heart rate (HR) values > 70 beats/minute are associated with an increased cardiovascular risk. No information is available on whether the sympathetic nervous system is differently activated in HF patients displaying resting HR values above or below this cutoff., Methods: In 103 HF patients aged 62.7 ± 0.9 (mean ± SEM) years and in 62 heathy controls of similar age we evaluated muscle sympathetic nerve traffic (MSNA, microneurography) and venous plasma norepinephrine (NE, HPLC assay), subdividing the subjects in different groups according to their resting clinic and 24-h HR values., Results: In HF progressively greater values of clinic or 24-h HR were associated with a progressive increase in both MSNA and NE. HR cutoff values adopted in large scale clinical trials for determining cardiovascular risk, i.e., 70 beats/minute, were associated with MSNA values significantly greater than the ones detected in patients with lower HR, this being the case also for NE. In HF both MSNA and NE were significantly related to clinic (r = 0.92, P < 0.0001 and r = 0.81, P < 0.0001, respectively) and 24-h (r = 0.91, P < 0.0001 and r = 0.79, P < 0.0001, respectively) HR. The behavior of sympathetic markers described in HF was specific for this clinical condition, being not observed in healthy controls., Conclusions: Both clinic and 24-h HR values greater than 70 beats/minute are associated with an increased sympathetic activation, which parallels for magnitude the HR elevations. These findings support the relevance of using in the therapeutic approach to HF drugs exerting sympathomoderating properties., (© 2022. The Author(s).)

Previous studies focused on the relationships between Serum Uric Acid (SUA) and lipids have found an association mainly with triglycerides. Furthermore, previous studies on adiposity indices have been focused on the evaluation of the Visceral Adiposity Index (VAI). The present study was aimed at providing within the same population a systematic evaluation of lipids and adiposity indices with SUA, employing both the classic cutoff for hyperuricemia and the newly one identified by the Uric Acid Right for Heart Health (URRAH) study. We analyzed data collected in 1892 subjects of the Pressioni Arteriose Monitorate E loro Associazioni (PAMELA) study with available SUA, lipid profile and variables necessary to calculate VAI, Cardio-Metabolic Index (CMI) and Lipid Accumulation Product (LAP). At linear regression model (corrected for confounders) SUA correlated with all the lipids values (with the strongest β for triglycerides) and adiposity indices. When the two different cutoffs were compared, the URRAH one was significantly related to atherogenic lipids profile (OR 1.207 for LDL and 1.33 for non-HDL, P < 0.001) while this was not the case for the classic one. Regarding adiposity indices the classic cutoff displays highest OR as compared to the URRAH one. In conclusions, newly reported URRAH cutoff for hyperuricemia better relate to atherogenic lipoprotein (LDL and non-HDL) when compared to the classic one. The opposite has been found for adiposity indexes where the classic cut-off seems to present highest performance. Among adiposity indexes, LAP present the highest OR for the relationship with hyperuricemia., (© 2022 The Authors. The Journal of Clinical Hypertension published by Wiley Periodicals LLC.)

We evaluated the relationships between Berlin questionnaire (BQ) scores, hypertension and other metabolic variables in 598 subjects (age: 65.8 ± 10 years, mean ± SD) enrolled in the PAMELA (Pressioni Arteriose Monitorate E Loro Associazioni) study representative of the general population, treated or untreated with antihypertensive drugs. Two hundred and eleven subjects (35%) had a positive BQ with two or more positive categories of the inquiry. Compared to those without sleep disorders these subjects showed a greater male prevalence (55.9%), worse serum cholesterol, triglycerides and glucose profile, greater body mass index (BMI) (28.9 ± 4.9 vs. 24.9 ± 3.4 kg/m 2 ), higher office (and to a lesser extent 24-h) BP and HR values, higher serum creatinine values and greater rate of echocardiographic left ventricular (LV) hypertrophy (25% vs. 13%). These differences were not detected when the data analysis was restricted to treated hypertensive patients. Thus, BQ scores allow to identify among subjects belonging to a general population those with elevated BP, organ damage and altered metabolic. When antihypertensive drug treatment is present, however, the approach fails to detect differences between groups with low or high BQ index., (© 2022 The Authors. The Journal of Clinical Hypertension published by Wiley Periodicals LLC.)

Aims: We examined whether to what extent resting heart rate (HR) values are capable to reflect in the metabolic syndrome (MS) a different degree of sympathetic activation. We also thought to determine at which HR cutoff values the sympathetic nervous system becomes more activated in the MS., Methods: In 70 MS patients aged 55.5 ± 1.8 (mean ± SEM) years we evaluated muscle sympathetic nerve traffic (MSNA, microneurography) and venous plasma norepinephrine (NE, HPLC assay), subdividing the study population in three different subgroups according to resting clinic and 24-h HR values (< 70, 70-79 and ≥ 80 beats/min)., Results: MS patients with clinic HR values ≥ 80 beats/min displayed MSNA and NE values significantly increased when compared to those found in MS with HR between 70 and 79 beats/min or below 70 beats/min (MSNA: 55.2 ± 0.9 vs 44.6 ± 0.6 and 39.2 ± 0.6 bursts/min, P < 0.01, NE: 403.9 ± 6.9 vs 330.1 ± 4.3 and 258.3 ± 6.8 pg/ml, respectively, P < 0.01). A similar behavior was observed for 24-h HR. In the group as a whole both MSNA and plasma NE showed highly significant direct relationships with clinic HR, the correlation being similar for MSNA and NE (r = 0.89 and r = 0.91, P < 0.01 for both) Similar significant relationships were also found between 24-h HR values and MSNA or NE., Conclusions: In the MS HR values ≥ 80 beats/min are associated with an increased sympathetic activation, both when assessed by direct recording of MSNA and when evaluated as plasma NE. The sympathetic overdrive parallels for magnitude the HR elevations, this being the case for both clinic and 24-h HR., (© 2022. The Author(s).)

Previous studies have shown that white-coat and masked uncontrolled hypertension (WUCH and MUCH, respectively) are clinical conditions with very poor reproducibility over time. This is also the case for the different nighttime blood pressure (BP) patterns (dipping, nondipping, reverse dipping or extreme dipping). Whether and to what extent the phenomenon might depend on the type of antihypertensive treatment is unknown. In the present study, we addressed this issue by analyzing the data collected in the Plaque Hypertension Lipid-Lowering Italian Study (PHYLLIS), in which office and ambulatory BP were measured three times during an almost 3-year treatment period. The results showed that a limited number of WUCH or MUCH patients at an initial office measurement and 24-h systolic (S) BP measurement maintained the same status at a second set of measurements one or more years later. This was also the case for all dipping patterns, and only a minimal number of patients exhibited the same phenotype throughout all on-treatment SBP measurements. The results were similar for treatment with a thiazide diuretic or an ACE inhibitor and are in line with those of the European Lacidipine Study on Atherosclerosis (ELSA) trial, i.e., the only other available trial with multiple on-treatment office and ambulatory BP measurements, in which patients were treated with a calcium channel blocker or a beta-blocker. All the BP patterns identified in hypertensive patients treated by joint office and ambulatory BP measurements display poor reproducibility, and this is unrelated to the type of antihypertensive treatment used., (© 2022. The Author(s), under exclusive licence to The Japanese Society of Hypertension.)

Rationale: Whereas metronidazole-induced hepatotoxicity is quite rare in the general population, in individuals carrying a nucleotide excision repair disorder, namely Cockayne syndrome, there is a high risk of developing this complication., Patient Concerns: We report the case of a 44-year-old man, affected by xeroderma pigmentosum, who was admitted to the hospital presenting aspiration pneumoniae caused by worsening dysphagia and with severe hepatotoxicity during the hospitalization., Diagnoses: Acute hepatitis, which was leading to acute liver failure, occurred during antibiotic treatment with metronidazole and ceftazidime with an elevation of liver enzymes consistent with hepatocellular damage pattern., Interventions: Hydration with glucose 5% solution, pantoprazole and vitamin K were administered, meanwhile other causes of hepatitis were ruled out and the ongoing antibiotic treatment was stopped suspecting a drug-induced liver injury., Outcomes: Liver function nearly completely recovered 1 month later with a first rapid improvement, within few days, of aminotransferases and coagulation studies, and slower of cholestatic enzymes., Lessons: We describe the first case available in the literature of hepatotoxicity associated with metronidazole treatment in a xeroderma pigmentosum patient. Clinicians therefore, based on this report and according to the possible underlying mechanism shared by other genetic diseases characterized by alterations in the pathway of DNA-repair, should consider such adverse event also in patients affected by this rare disease., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: According to some guidelines, white-coat hypertension (WCH) carries little or no increase of cardiovascular risk in the absence of organ damage (OD), but no data are available on this issue., Methods: Using the population data from PAMELA (Pressioni Arteriose Monitorate E Loro Associazioni), we evaluated cardiovascular and total mortality over a median follow-up of 29 years in WCH (elevated office and normal 24-hour or home blood pressure [BP]) and normotensive controls (normal in- and out-of-office blood pressure) with no echocardiographic left ventricular hypertrophy and no reduction of estimated glomerular filtration rate. Patients with sustained hypertension (SH, in- and out-of-office blood pressure elevation) and normotensive, WCH, and SH with cardiac and renal OD served as controls., Results: In the 1423 subjects analyzed, there were 165 cardiovascular and 526 all-cause deaths. After adjustment for confounders, no-OD WCH exhibited a risk of fatal cardiovascular events lower than that of no-OD SH but greater than that of no-ODN (hazard ratio, 2.0 [95% CI, 1.1-3.6], P =0.02), this being the case also for all-cause mortality. Compared with no-OD normotensive, no-OD WCH also exhibited a greater 10-year adjusted risk to develop new SH or OD. Similar findings were obtained in normotensive, WCH, and SH with OD., Conclusions: The present study provides the first evidence that WCH with no OD is accompanied by a noticeable increase in long-term risk of mortality, new hypertension, and new OD, thereby differing from normotension.

Purpose of Review: To examine published and unpublished data collected in the context of the Pressioni Arteriose Monitorate E Loro Associazioni (PAMELA) study on the relationships between serum uric acid (SUA), office and out-of-office blood pressure (BP), and organ damage., Recent Findings: SUA values were directly and significantly related to a large number of covariates that participate at cardiovascular risk determination, such as blood glucose, total serum cholesterol, serum triglycerides, body mass index, and serum creatinine. Additional variables included echocardiographically-determined left ventricular mass index and BP values, the latter not just when measured in the office but also when evaluated at home or over the 24-h period. White-coat hypertension and masked hypertension were characterized, as sustained hypertension, by a significant increase in SUA levels, which were also directly related to different indices of 24-h BP variability. No substantial difference in SUA levels was found when data were analyzed according to the dipping or non-dipping nocturnal BP profile. Data collected in the frame of the PAMELA study document the presence of a close relationship between SUA levels and BP values independently on the hypertensive phenotype patterns of BP increase (office, 24 h, or both) and nighttime BP profile. They also document the increase in SUA as a potential factor favoring the occurrence of new hypertension and new left ventricular hypertrophy., (© 2022. The Author(s).)

Background: Scarce and non-homogeneous data are available on the prognostic value of clinic heart rate (HR) in coronavirus disease 2019 (COVID-19)., Methods: The present study evaluated in 389 patients hospitalized for COVID-19 the in-hospital prognostic value of resting HR, assessed over different time periods, i.e., at hospital admission, during initial 3 days and 7 days of hospitalization., Results: Results show that assessment of this hemodynamic variable during hospitalization provides information on the clinical outcome of the patients, greater HR values being associated with a worse inhospital prognosis. The prognostic value of elevated HR during COVID-19: 1) was independent on other confounders such as age, gender, comorbidities and fever, 2) appeared to be strengthened by repeated measurements of HR during the initial 3/7 days of hospitalization, and 3) was detectable in patients in which the therapeutic intervention did not include drugs, such as beta-blockers, calcium antagonists, digoxin, ivabradine and antiarrhythmic compounds known to interfere with HR., Conclusions: Heart rate may represent an important marker of a patient's outcome in COVID-19.

While state sequence analysis (SSA) has been long used in social sciences, its use in pharmacoepidemiology is still in its infancy. Indeed, this technique is relatively easy to use, and its intrinsic visual nature may help investigators to untangle the latent information within prescription data, facilitating the individuation of specific patterns and possible inappropriate use of medications. In this paper, we provide an educational primer of the most important learning concepts and methods of SSA, including measurement of dissimilarities between sequences, the application of clustering methods to identify sequence patterns, the use of complexity measures for sequence patterns, the graphical visualization of sequences, and the use of SSA in predictive models. As a worked example, we present an application of SSA to opioid prescription patterns in patients with non-cancer pain, using real-world data from Italy. We show how SSA allows the identification of patterns in prescriptions in these data that might not be evident using standard statistical approaches and how these patterns are associated with future discontinuation of opioid therapy.

Background: Inconsistent evidence has assessed the impact of air pollution exposure on children's growth trajectories. We investigated the role of 90-day average postnatal fine particulate matter (PM 2.5 ) exposures by estimating the magnitude of effects at different ages, and the change in child weight trajectory by categories of exposure., Methods: We obtained weight values from electronic health records at each hospital visit (males = 1859, females = 1601) from birth to 6 years old children recruited into the Boston-based Children's HealthWatch cohort (2009-2014). We applied mixed models, adjusting for individual and maternal confounders using (1) varying-coefficient models allowing for smooth non-linear interaction between age and PM 2.5 , (2) factor-smooth interaction between age and PM 2.5 quartiles. Additionally, we stratified by sex and low birthweight (LBW) status (≤2500 g)., Results: Using varying-coefficient models, we found that PM 2.5 significantly modified the association between age and weight in males, with a positive association in children younger than 3 years and a negative association afterwards. In boys, for each 10 µg/m 3 increase in PM 2.5 we found a 2.6% increase (95% confidence interval = 0.8, 4.6) in weight at 1 year of age and a -0.6% (95% confidence interval = -3.9, 2.9) at 5 years. We found similar but smaller changes in females, and no differences comparing growth trajectories across quartiles of PM 2.5 . Most of the effects were in LBW children and null for normal birthweight children., Conclusions: This study suggests that medium-term postnatal PM 2.5 may modify weight trajectories nonlinearly in young children, and that LBW babies are more susceptible than normal-weight infants., Competing Interests: The authors declare that they have no conflicts of interest with regard to the content of this report., (Copyright © 2021 The Authors. Published by Wolters Kluwer Health, Inc. on behalf of The Environmental Epidemiology. All rights reserved.)

We examined in 11 young subjects (age 29.7±3.6 years, mean±SEM) whether carotid baroreceptor stimulation via the neck chamber device may affect central venous pressure (CVP), thus potentially involving other reflexogenic areas in the examined responses. Application of progressively greater neck chamber subatmospheric pressures caused a progressive lengthening in RR interval, which reached a peak at the maximal value of negative neck chamber pressure applied. This was accompanied by significant and progressively greater reduction in CVP values when the data were calculated considering the early changes occurring within the first 2 seconds of the stimulus. There was a weak correlation between the early changes in CVP and the RR interval responses when all stimuli were pooled together (r = 0.32, P < .05). The results of the present study suggest that the neck chamber technique employed to assess carotid baroreceptor-heart rate sensitivity can transiently affect via the CVP reduction cardiopulmonary receptors activity, which may participate at the integrated reflex responses., (© 2021 The Authors. The Journal of Clinical Hypertension published by Wiley Periodicals LLC.)

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Purpose: The present paper will review the impact of different therapeutic interventions on the autonomic dysfunction characterizing chronic renal failure., Methods: We reviewed the results of the studies carried out in the last few years examining the effects of standard pharmacologic treatment, hemodialysis, kidney transplantation, renal nerve ablation and carotid baroreceptor stimulation on parasympathetic and sympathetic control of the cardiovascular system in patients with renal failure., Results: Drugs acting on the renin-angiotensin system as well as central sympatholytic agents have been documented to improve autonomic cardiovascular control. This has also been shown for hemodialysis, although with more heterogeneous results related to the type of dialytic procedure adopted. Kidney transplantation, in contrast, particularly when performed together with the surgical removal of the native diseased kidneys, has been shown to cause profound sympathoinhibitory effects. Finally, a small amount of promising data are available on the potential favorable autonomic effects (particularly the sympathetic ones) of renal nerve ablation and carotid baroreceptor stimulation in chronic kidney disease., Conclusions: Further studies are needed to clarify several aspects of the autonomic responses to therapeutic interventions in chronic renal disease. These include (1) the potential to normalize sympathetic activity in uremic patients by the various therapeutic approaches and (2) the definition of the degree of sympathetic deactivation to be achieved during treatment., (© 2021. The Author(s).)

Background: Vitamin B 12 deficiency-induced thrombotic microangiopathy, known as pseudothrombotic microangiopathy, is a rare condition which resembles the clinical features of thrombotic thrombocytopenic purpura but requires a markedly different treatment. Most cases of vitamin B 12 deficiency have only mild hematological findings, but in approximately 10% of patients life-threatening conditions have been reported., Case Presentation: We report a case of a 46-year-old Moroccan man presenting with severe hemolytic anemia, thrombocytopenia, and renal failure in absence of macrocytosis, thus mimicking a genuine thrombotic thrombocytopenic purpura. Rapid improvement of renal function observed with only hydration and transfusions of packed red blood cells and the presence of pancytopenia suggested a bone marrow deficiency associated to a hemolytic component of unclear origin. Detection of low levels of vitamin B 12 and rapid restitutio ad integrum with its replacement supported the diagnosis of pseudothrombotic thrombocytopenic purpura caused by vitamin B 12 deficiency., Conclusions: Diagnosis of pseudothrombotic thrombocytopenic purpura caused by vitamin B 12 deficiency might be difficult. Awareness of clinicians toward this differential diagnosis might spare patients from unnecessary therapeutic plasma exchange that is burdened by morbidity and mortality.

Rationale: Granulomatosis with polyangiitis (GPA) is an antineutrophil cytoplasmatic antibodies (ANCA)-associated vasculitis affecting small- and medium-sized blood vessels, mostly involving lung and kidney., Patient Concerns: We report the case of a 33-year-old man that presented with acute respiratory distress syndrome caused by alveolar hemorrhage., Diagnoses: Aggressive GPA presenting with diffuse alveolar hemorrhage and multiorgan involvement., Inteventions: Immunosuppressive therapy, plasma exchange, extracorporeal membrane oxygenation (ECMO)., Outcomes: Relapse occurred very early, despite immunosuppressive treatment, with a rare involvement of genital system (epididymitis) and rapidly progressive glomerulonephritis difficult to treat., Lessons: GPA is a challenging, multifaceted disease that can require aggressive supportive therapy and is associated with a high rate of relapse that may present with uncommon site of involvement.